ISSN:0069-3030    

DOI:10.1039/OC99188FX001

出版商:RSC    

年代:1991

数据来源: RSC

ISSN:0069-3030    

DOI:10.1039/OC99188BX003

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

2 Physical Methods and Techniques Part (ii) Organic Mass Spectrometry By J. R. TRAINOR and P. J. DERRICK Institute of Mass Spectrometry and Department of Chemistry University of Warwick Coventry CV4 7AL 1 Introduction To review progress in organic mass spectrometry during the last two years in the space available we have found it necessary to be highly selective and we have been obliged to omit many first-rate papers. We report in three sections the first of which covers technical developments in organic mass spectrometry. The second section covers applications of mass spectrometry and the third reviews fundamental aspects of organic mass spectrometry. As with the previous report,' a strong biological flavour inevitably emerges because so many significant developments over the past five years have concerned large organic molecules of biological importance.2 Technical Developments Ionization Methods.-The mechanisms of the ionization techniques such as fast atom bombardment (FAB) and electrospray' (see below) involving gas-liquid interfaces continued to attract attention. In FAB the effects of acidifying basic mixtures of glycerol-analyte were investigated by Shiea and Sunner3 with the aim of determining the role of preformed ions in the desorption process. Molecule-ion intensities should be enhanced as the concentration of preformed ions in the solution is increased. The study produced mixed results. The authors concluded that acidification of the sample may induce several phase and boundary-layer effects such as changes in the solubility or surface activity of the analyte.The study demonstrates that the desorption process in FAB is controlled by both the chemistry and physics of the solution. The use of benzene as a chemical ionization (CI) reagent for quantitative analysis (quantitation) of hydrocarbon mixtures was investigated by Allgood et aL4 The benzene radical-cation (C,H+Q) produced clean selective ionization of olefinic and benzylic hydrocarbons but did not ionize saturated alkanes. For olefins and alkylben- zenes consistent relative molar sensitivities were achieved for a range of molecular masses. The authors suggested that the reagent has application in quantitation of ' M. A. Baldwin Annu. Rep. Prog. Chem. Sect. B. 1990 86 18-32. M.Sakairi A. L. Yergy K. W. M. Siu J. C. Y. Le Blanc R. Guevremont and S. S. Berman Anal. Chem. 1991 63(14) 1488-90. J. Shiea and J. Sunner Org. Mass Spectrom. 1991 26(1) 38-44. C. Allgood Y. C. Ma and B. Munson Anal. Chem. 1991 63(7) 721-5. 25 26 J. R. Trainor and I? J. Derrick petroleum mixtures where the concentrations of unsaturated aromatics could be determined from a single measurement. Plasma desorption mass spectrometry (PDMS) has been reviewed from the physic- ists' perspective.' For the quantitation of thick layers of polymers PDMS has been shown to offer significant advantages over secondary ion mass spectrometry (SIMS).6 There was a 1-2 order of magnitude increase in the sensitivity of PDMS compared with SIMS and PDMS gave better quantitation of minor components although the major components were detected using both methods.Craig and Bennich' high- lighted the importance of sample preparation in PDMS observing that either bovine serum albumin or lysozyme suppressed the intensities of both melittin and insulin. This was attributed to competition for charge. The sensitivity of plasma desorption ionization was considerably enhanced by using resonance-enhanced multiphoton ionization (REMPI) in a study of adsorbed pyrene. A 100 fold increase in the ions detected following REMPI was observed compared with ions formed by PD alone. Using this method of post-ionization to enhance ion formation in PD the improved sensitivity to pyrene adsorbate deter- mined was sub-femtomole.8 Zubarev et al.have reported a new 'soft' ionization technique exploiting the avalanche of secondary electrons formed in an electron multiplier.' The authors claimed success in desorption/ionization of thermally labile biological molecules of modest molecular masses (up to 1250 Da). Abdel-Baky and Giese" reported high zeptomole ( mole) detection thresholds for electron capture negative ion mass spectrometry which is surely a record for the highest claimed sensitivity. Speir et a/." have used laser desorption to produce neutral peptide molecules in the gas phase and have ionized these molecules by chemical ionization. They were able to correlate the extent of subsequent fragmentation with proton affinity of the reagent species. The photochemistry of small molecules ions has received increasing attention as part of a general increase in the application of laser-based mass spectrometry.In favourable circumstances the injection of energy in quanta of light can be used to distinguish between isomers or influence a reaction path taken when more than one is available.12 Using a C02 laser Wight and Bea~champ'~ distinguished isomers of C4H8 by electron detatchment from C4HI ions trapped for several seconds in an ICR spectrometer. The uses of ICR and FT mass spectrometry are likely to grow as the reactions of trapped ions are studied more dee~1y.l~ Electrospray Ionization (ESI).-Electrospray ionization (ESI) is a recently intro- duced ionization technique which has come of age in a remarkably short time. The potential and limitations of electrospray for the ionization and analysis of biological B.U. R. Sundqvist Anal. Chim. Acta 1991 274(2) 265-75. 'H. Feld A. Leute R. Zurmuehlen and A. Benninghoven Anal. Chem. 1991 63(9) 903-10. ' A. G. Craig and H. Bennich Anal. Chem. 1991 63(4) 352-6. ' D. M. Hrubowchak M. H. Ervin and N. Winograd Anal. Chem. 1991 63(3) 225-32. R. A. Zubarev P. V. Bondarenko A. N. Knush and B. V. Rozynov Rapid Commun. Mass Spectrom. 1991 5( l) 32-4. 10 S. Abdel-Baky and R. W. Giese Anal. Chem. 1991 63(24) 2986-9. J. P. Speir G. S. Gorman D. S. Cornett and I. J. Amster Anal. Chem 1991 63(1) 65-9. l2 M. Bensimon T. Gaeumann and G. Zhao Znt. J. Mass Spectrom. Ion Processes 1990 100 595-609. l3 C. A. Wight and J. L. Beauchamp Int. J. Mass Spectrom.Zon Processes 1990 100 445-55. l4 J. A. Zimmerman C. H. Watson and J. R. Eyler Anal. Chem. 1991,63(4) 361-5. Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 27 molecules have been reviewed ~ritically.'~ The range of mass analysers to which EN sources have been connected has diversified enormously.'6 ESI interfaced with a quadrupole mass analyser has threatened to eclipse the magnetic-sector mass spectrometer as the instrument for modestly high-mass studies. The new-found power of the otherwise 'low mass' quadrupole mass analyser is available at relatively low cost. Coupling ESI to magnetic sector instruments provides greater resolution but there are questions about sensitivity and reliability which are still being addressed.ESI has been successfully interfaced with Fourier transform/ion cyclotron resonance (IT-ICR) mass spectrometers and quadrupole ion trap (IT) instrument^.'^ FT-ICR has the capability to provide the highest resolution of all mass analysers. ESI produces a very large set of related data which is extremely advantageous for advanced statistical analyses,'* offering exciting potential in differentiating components of complex mixtures. Chowdhury and Chait's analysis of three forms (a-, p-and +-) of bovine trypsin in a native mixture" has illustrated this point. These different trypsin isoforms could be distinguished despite their similar masses (23 293,23 311 and 23 329 Da) owing to differentiation in the principal charge-states adopted by each component.The different charge-states are assumed to reflect the higher-order structure of the isoforms and in particular the number of basic groups available as sites for protonation. Unlike other charged droplet techniques it is significant that electrospray can be successfully performed with solutions having an appreciable ionic strength. A study of the dependence of sensitivity upon the conductivity of the electrosprayed solution was made.20 In this work the increase in ion current obtained was small but more importantly perhaps did not decrease with ionic strength. Acidified aqueous sol- utions have proved difficult to study owing to the high surface tension associated with water; requiring high electric fields to cause desorption of ions. These conditions cause corona discharge terminating ion formation.Organic co-solvents are com- monly used which reduce the surface tension; however because the solution chemistry may be altered by the co-solvent this precludes in vivo and native aqueous studies of biomolecules and their reactions. Chowdhury et aL2' found that they could electrospray pure aqueous solutions by using a sharpened needle-tip. This increases the electric field gradient at the tip sufficiently to maintain the electrospray while reducing the risk of corona discharge. Henry et alZ2described experiments in which an electrospray ion source is interfaced to an FT-ICR. They reported mass accuracy of 0.003% and resolving power better than 60 000 from femtogram quantities of material by utilizing pulsed techniques and extremely long trapping times (in the order of 1000s).They were able to assign unambiguously the charge state of the analyte and by internal calibration obtained mass assignments for overlapping isotopic peaks to an accuracy M. Mann Org. Mass Spectrom. 1990 25( 1 l) 575-87. 16 R. T. Gallagher J. R. Chapman and M. Mann Rapid Commun. Mass Spectrom. 1990 4(10) 369-72. 17 K. D. Henry and F. W. McLafferty Org. Mass Spectrom. 1990 25(9) 490-2; G. J. Vanberkel G. L. Glish and S. A. McLuckey Anal. Chem. 1990,62(13) 1284-95; G. J. Vanberkel S. A. McLuckey and G. L. Glish AnaL Chem. 1991 63(11) 1098-1109. A. G. Femge M. J. Seddon and S. Jarvis Rapid Commun. Mass Spectrom. 1991 5(8) 374-7. 19 S. K. Chowdhury and B. T. Chait Biochem Biophys.Res. Commun. 1990 173(3) 927-31. 20 L. Tang and P. Kebarle Anal. Chem. 1991,63(23) 2709-15. 21 S. K. Chowdhury and B. T. Chait Anal. Chem. 1991 63(15) 1660-4. 22 K. D. Henry J. P. Quinn and F. W. McLafferty J. Am. Chem. Soc. 1991 113(14) 5447-9. 28 J. R. Trainor and P. J. Derrick better than 0.001 YO.Difficulty was experienced in determining the average molecular mass to a consistent agreement with the calculated distribution. It may prove necessary in FT-ICR to determine isotopically averaged molecular masses using much shorter trapping times and lower resolutions. Space charge and any kinetic isotopes effects which may accentuate poor reproducibility are likely to be amplified at long trapping times. Laser Techniques.-Matrix-assisted laser desorption/ionization (MALDI) has become the primary area of interest in laser-based organic mass spe~trometry.~~ MALDI is interfaced mostly with time-of-flight (TOF) mass analysers although success with other combinations have been reported.24 The other important areas of application of lasers concerns the injection of energy into a vaporized ion or molecule in order to induce dissociation or ionization.The mechanism of ion formation in MALDI is actively discussed. Measured velocity distributions have been used to support a jet expansion model for the desorption process in high mass polymers .25 Much effort has been devoted to the development of new matrices26 for MALDI. It is generally accepted that one role of the matrix is as a chromophore.A feature of MALDI spectra is often a dominant matrix peak. By controlling the molar ratio of particular matrices and analytes (e.g nicotinic acid and insulin) the matrix peak has be& demonstrated to be reversibly s~ppressed.~~ Radiation of different wavelengths can be used for MALDI however each different wavelength is likely to have its own set of useful matrices. DNA has been ionized from a frozen aqueous matrix containing metal atoms (copper or sodium). The laser photon energy was tuned to resonant electronic transitions in the metal atoms and efficient production of positive ions was observed?8 The introduction of a liquid matrix (3-nitrobenzyl alcohol) is potentially a very significant development in MALDI.29,30 Using a fibrous substrate for the liquid matrix proteins were detected up to 100 000 Da with 0.1-0.2% mass accuracy.Chan et aZ.,31further reported the detection of a molecular mass in excess of 0.5 MDa. The species was a positive singly charged octamer of bovine albumin. The analyte had been dissolved in O.OIo/~trifhoroacetic acid deposited on a drop of 3-nitrobenzyl alcohol and dehydrated in a warm air flow. Lustig and L~bman~~ described a method of analysis based on post ionization for which they claim three orders of magnitude of linear quantitation in the nanogram-sample range. The sample was introduced via a continuous-flow liquid probe vaporized by a laser and seeded into a supersonic jet. Resonance enhanced multi-photon ionization (REMPI) was performed using a second laser and the ions produced were analysed by time-of-flight (TOF).23 F. Hillenkamp M. Karas R. C. Beavis and B. T. Chait Anal. Chem. 1991,63(24) 1193A-1203A. 24 J. A. Hill R. S. Annan and K. Biemann Rapid Commun. Mass Spectrom 1991 5(9) 395-9. 25 R. C. Beavis and B. T. Chait Chem. Phys. Lett. 1991 181(5) 479-84. 26 S. Zhao K. V. Somayajula A. G. Sharkey D. M. Hercules F. Hillenkamp M. Karas and A. Ingendoh Anal. Chem. 1991 63(5) 450-3. 27 T. W. D. Chan A. W. Colburn and P. J. Derrick Org. Mass Spectrom. 1991 26(4) 342-4. 28 R. W. Nelson R. M. Thomas and P. Williams Rapid Commun Mass Spectrom. 1990 4(9) 348-51. 29 S. Zhao K. V. Somayajula A. G. Sharkey D. M. Hercules and J. Fresenius Anal. Chem. 1990,338(5) 588-92. 30 S. Zhao and Zhongshan Daxue Xuebao Ziran Kexueban 1990 29(3) 96-9.31 T-W. D. Chan A. W. C. Colburn and P. J. Derrick 0%.Mass Spectrom. 1992 27(1) 53-56. 32 D. A. Lustig and D. M. Lubman Rev. Sci. Instrum. 1991 62(4) 957-62. Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 29 Boernsen et aZ.33*34compared MALDI with reverse-phase high-performance liquid chromatography (HPLC) for the analysis of a range of macromolecules. Using MALDI the TOF spectra of positive and negative ions of sulfonic acids oligonucleotides polysaccharides and peptides were obtained over a mass range up to 200 kDA from as little as 100 femtograms of material with a mass accuracy of 0.2%. Vacuum ultra-violet (VUV) laser photoionization was applied to a series of C6 to C8organic molecules to compare 10.5 eV photoionization with low-energy (12 eV) electron impact i~nization.~~ The results showed VUV photoionization at these energies to be far ‘softer’ giving more abundant molecular ions less fragmentation and enhanced fragment ions formed via low-energy rearrangements.MALDI has been shown able to differentiate between covalent and non-covalent adducts to biomolecules providing a clear advantage over traditional methods of analysis (i. e. liquid chromatography and UV/visible ~pectrometry).~~ Whilst the analytical use of MALDI appears to be predominantly for the determination of relative molecular masses,37 other applications are being found such as quality control e.g. detecting impurities in protein ~ynthesis.~~ It is predicted that the use and versatility of MALDI will increase and develop sharply.Tandem Mass Spectrometry.-Nowadays tandem mass spectrometry can be perfor- med with varying degrees of success on a range of instruments four-sector tandem mass spectrometers double-focusing mass spectrometers with quadrupoles (hybrids),38 trapping devices (FT-ICR and IT) even tandem TOF.39,40 FT-ICR and IT hybrids and triple quadrupoles typically facilitate exploration of low-energy collision regimes. The higher centre-of-mass (CM) collision energies available for collision-induced dissociation studies have made four-sector tandem mass spec- trometers the method of choice for investigating large molecules (molecular masses >1000 Da). This is made all the more efficient when a point-detector (e.g.an electron multiplier) is replaced by an array-detector (e.g.a multi-channel array).41 Low-energy CID of multiply charged biopolymers formed by ESI have been studied42 using a triple quadrupole mass spectrometer. Dissociation could be accom- plished in the nozzle/skimmer interface by adjusting the magnitude of the applied nozzle bias potential. Specific dissociations could be induced in the RF-only collision cell to obtain partial sequence information. The suggestion was made that biopoly- mers can be fingerprinted from the characteristic dissociations of a series of charge states under known conditions as was exemplified by analyses of dissociation of nine charge states of cytochrome C. 33 K. 0. Boernsen M.Schaer and H. M. Widner Chimiu 1990,44(12) 412-16. 34 K.0.Boernsen M. Schaer E. Gassmann and V. Steiner BioL Mass Spectrom 1991,20(8) 471-8. 35 S. E. Van Bramer and M. V. Johnston J. Am. SOC.Muss Spectrorn 1990 1(6) 419-26. 36 M. M. Siegel I. J. Hollander P. R. Hamann J. P. James L. Hinman B. J. Smith A. P. H. Farnsworth A. Phipps D. J. King M. Karas A. Ingendoh and F. Hillenkamp Anal. Chem. 1991,63(21) 2470-81. 37 B. Stahl M. Steup M. Karas and F. Hillenkamp Anal. Chem. 1991 63(14) 1463-6. 38 R.A.Yost and R. K. Boyd Methods Enzymol. 1990 193 154-200. 39 C. Weickhardt R. Weinkauf K. Walter and U. Boesl Znst. Phys. Con$ Ser. 1991 114 169-72. 40 P.J. Demck D. R. Jardine and D. S. Alderdice Org. Muss Spectrom. 1991,26 915-916. 41 F.C. Walls M. A. Baldwin A. M. Falick B. W. Gibson S. Kaur D. A. Maltby B. L. Gillece-Castro K. F. Medzihradszky S. Evans and A. L. Burlingame Biol. Muss Spectrom. Roc. Znt. Symp. Muss Spectrom. Health Life Sci.,2nd 1989 (Pub. 1990) 197-216. 42 R. D.Smith J. A. Loo C. J. Barinaga C. G. Edmonds and H. R. Udseth J. Am. SOC.Muss Spectrom. 1990 1(1) 53-65. 30 J. R. Trainor and P. J. Derrick Tandem mass spectrometry for electrosprayed ions can be favoured by an in- creased efficiency of collision-induced dissociation. Loo et al.43reported an enhance- ment factor of 20 in sequence information obtained by studying a variety of human and animal serum albumin proteins because of the high collision energies accessible. They suggested on the basis of their results that earlier sequences may be in error.FAB MS-MS is increasing its application as a tool to study geometric isomers (e.g. the linkage position in isomeric disaccharide sugarsa). Falick et aZ!5 exposed artefacts in the four-sector tandem mass spectrometry of protonated peptides using FAB as the ionization technique. Artefacts arise from the large background chemical noise and from metastable decompositions in the third field-free region. Likewise has discussed factors concerning precision and accuracy in relation to collision induced dissociation (CID) measurements using hybrid and triple quad- rupole tandem mass spectrometers. A separate investigation to compare hybrid and 4-sector MS-MS using peptides showed full sequence information only when using the latter te~hnology.~~ The combination of tandem mass spectrometry (MS-MS) and liquid chromatogra- phy (LC) has permitted the detection of nucleoside isomers in RNA,48by virtue of the rapid screening capability of LC and the nanogram sensitivity and selectivity of MS-MS.Tandem mass spectrometry has also been used as a method for chiral recognition4’ on carefully prepared samples. Mass Ana1ysers.-Time-ofRight (TOF). There has been a renaissance in the use of time-of-flight (TOF) as a method of mass analysis. Much of the new interest is driven by the developments in laser-based mass spectrometry however TOF has also been used to determine simultaneously the mass and energy of combustion products in rocket fuel using position-sensitive TOF dete~tion.~’ Development of techniques and apparatus to give time-focusing and ion bunching have been given high priority.Brunelle et aims1 described the design and operation of a high-resolution ion mirror constructed from two grids for which they claim second-order time-focusing properties. Improvements in space and time focusing have been described in other ion mirror designs.52i53 Cerezo and Miller54 described the spatial and temporal focusing properties of two Einzel lens designs used in tandem with a toroidal electrostatic sector. A similar study of the optical properties of a reflectron and Einzel lens has been made by 43 J. A. Loo C. G. Edmonds and R. D. Smith Anal. Chem. 1991 63(21) 2488-99. 44 G. E. Hofmeister Z.Zhou and J. A. Leary J. Am. Chem. SOC., 1991 113(16) 5964-70. 4s A. M. Falick K. F. Medzihradszky and F. C. Walls Rapid Commun. Mass Spectrom. 1990,4(9) 318-22. 46 R. I. Martinez J. Am. SOC.Mass Spectrom. 1990 1(3) 272-3. 47 M. F. Bean S. A. Carr G. C. Thorne M. H. Reilly and S. J. Gaskell Anal. Chem. 1991,63(14) 1473-81. 48 T. Hashizume C. C. Nelson S. C. Pomerantz and J. A. McCloskey Nucleosides Nucleotides 1990 9(3) 355-9. 49 G. Hofmeister and J. A. Leary Org. Mass Spectrom. 1991 26(9) 811-12. 50 J. E. Pollard D. A. Lichtin S. W. Janson and R. B. Cohen Rev. Sci. Instrum. 1990,61(10 Pt.2) 3134-6. ” A. Brunelle S. Della-Negra J. Depauw H. Joret and Y. Le Beyec Rapid Commun. Mass Spectrom. 1991,5(1) 40-3. 52 A. N. Kudryavtsev N. V. Nikonenkov B.M.Dubenskii and D. V. Shmikk Rib. Tekh. Eksp. 1990 (2) 140-3. 53 R. Kutscher R. Grix G. Li and H. Wollnik Znt. J. Mass Spectrom. Zon Processes 1991,103(2-31,117-28. 54 A. Cerezo and M. K. Miller Sud Sci. 1991 246(1-3) 450-6. Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 31 Camus and Melmed.” Several designs for TOF mass analysers have been discussed and compared with the performance of dispersive mass ana1yse1-s.~~~~~ Ion Trap (IT). The quadrupole ion trap (IT) has been developed significantly over the past two particularly in its capabilities for high-mass measurements and for MS-MS. Resolution of 40000-100 000 full-width at half-maximum (FWHM) has been demonstrated using protonated molecule-ions of substance P by modifying the experimental configuration to produce a much slower scan rate.60 Methods for extending mass range have likewise been discussed:61 a calibration using (CsI) Cs+ clusters has been obtained up to (CSI)~~~CS+ (45 000 Da).Despite these exciting developments some problems need attention if there is to be widespread adoption of quadrupole ion traps in mainstream mass spectrometry. Guidugli et al.62described phenomenological ‘black holes’ in their CID spectra produced in an ion trap. At certain values on the Matthieu plot ions were absent or severely reduced in CID spectra. Applications of the IT in chemical studies are growing. Evans et have demonstrated the use of ion-trap mass spectrometry to distinguish isomers of hydroxyindole whose EI spectra are virtually superimposable.Nourse et al.64used the ion trap as ‘reaction vessel’ and analyser to study the methylation of isomeric dihydroxy benzenes. Similarly the identification of the functional double bond location in selected linear alkanes has been made using IT.65 Interfacing Chromatography with Mass Spectrometry.-Much effort has been directed towards coupling of chromatographs with electrospray sources. Covey et al.66have interfaced microbore HPLC directly and full bore HPLC via 20 :1 splitter with an electrospray source fitted to a quadrupole mass spectrometer. They obtained full-scan and MS-MS mass spectra from tryptic digests of peptides of biomedical interest. The suitability of capillary zone electrophoresis as a separator for ESI has been the subject of ~peculation.’~ Verheij et demonstrated the use of FAB with a pseudo-electrochromatography system featuring a larger sample introduction capa- bility than CZE.55 P. P. Camus and A. J. Melmed Surf Sci. 1991 246(1-3) 415-19. 56 T. Bergmann H. Goehlich T. P. Martin H. Schaber and G. Malegiannakis Rev. Sci. Instrum. 1990 61(10 Pt. l) 2585-91; T. Bergmann T. P. Martin and H. Schaber Rev. Sci. Instrum. 1990 61(10 Pt. 11 2592-600; D. C. Hamilton G. Gloeckler F. M. Ipavich R. A. Lundgren R. B. Sheldon and D. Hovestadr Reu. Sci. Insfrum. 1990 61(10 Pt.2) 3104-6. 57 H. Wollnik Nucl. Instrum. Methods Phys. Res. Sect. A 1990 A298(1-3) 156-60. 58 J. F. J. Todd Muss Spectrom. Rev. 1991 10(1) 3-52. 59 R. E. March Org.Mass Spectrom. 1991 26(7) 627-32. 6o J. D. Williams C. A. Cox R. G. Cooks and R. E. Kaiser Rapid Commun.Mass Spectrom. 1991 5(7) 327-9. 61 R. E. Kaiser Jr R. G. Cooks G. C. Stafford Jr J. E. P. Syka and P. H. Hemberger Int. J. Mass Spectrom. Ion Processes 1991 106 79-115. 62 F. Guidugli and P. Traldi Rapid Commun. Mass Spectrom. 1991 5(8) 343-8. 63 C. Evans S. Catinella P. Traldi U. Vettori and G. Allegri Rapid Commun.Muss Spectrom. 1990,4(9) 33 5-40. 64 B. D. Nourse J. S. Brodbelt and R. G. Cooks Org. Muss Spectrom. 1991 26(6) 575-82. 65 J. Einhorn H. I. Kenttamaa and R. G. Cooks J. Am. SOC. Mass Spectrom. 1991 2(4) 305-13. 66 T. E. Covey E. C. Huang and J. D. Henion Anal. Chem. 1991 63(13) 1193-200. 67 E. R. Verheij U. R. Tjaden W.M. A. Niessen and J. Van der Greef J. Chrornutogr. 1991 554(1-2) 339-49. J. R. Trainor and €? J. Derrick 3 Applications Ful1erenes.-The novel species C,' often referred to as 'Buckyballs' (collectively) and higher stable clusters of carbon have been subjected to intensive studies. Ajie et al.68 obtained an improved yield (14%) of carbon clusters from evaporation of graphite by resistive heating which they attributed to the purity of the precursor sample. They estimated the nascent proportion of C,o:C70 to be 85 15 * 3% and discussed formation of mono- and di-cations using electron impact (EI) FAB and LD techniques. A study of the direct laser vaporization of graphite revealed the production of negative-ion clusters comprising up to 13 carbon at0ms.6~ In the low-energy collision-induced dissociation (CID) and ion-molecule reactions of these clusters studied by FT-ICR it was concluded that linear C clusters are formed.Furthermore it was proposed that these species do not exhibit isomeric variation and that the structures are polyethyne for even n and linear cumulene for the odd n clusters. There have been other reports of success in forming and characterizing synthetic carbon clusters derived from coals7' and in plasma di~charge.~' The clusters CL0 and Cf (n = 60,70 and 84) seem to be highly resilient structures resisting dissociation at collision energies as high as 200 eV,72 despite the highly inelastic recoil observed from the target surface. At keV energies in a 4-sector tandem mass spectrometer multiply charged all-carbon clusters show evidence for C2n loss in collisions with helium targets.Accompanying peaks observed in the spectrum have been interpreted as evidence for the incorporation of a helium atom.73 Malhotra and Ross74investigated the natural formation of Buckyballs in various carbonaceous deposits. They reported a general absence of fullerenes (c60and C70) from the mass spectra except in a sample of soot from the low-pressure vaporization of graphite in helium. The results imply that the planar layers of sp2 carbon contained in graphite are important precursors to the formation of fullerenes. Clustered singly and doubly charged carbanions were prepared by laser desorption in an FT-ICR.75 Clusters (c60 C70 and C3') were produced in selected charge states.Ci; ions were distinguished from both CT0 and Cz0 (double harmonic) using isotopic abundance and selective ejection techniques. Organic and Biomolecu1es.-The use of mass spectrometry as a tool in pharmacology for metabolic profiling continues to expand.76 It has been suggested that CID in 68 H. Ajie M. M. Alvarez S. J. Anz R. D. Beck F. Diederich K. Fostiropoulos D. R. Huffman W. Kraetschmer Y. Rubin K. E. Schriver D. Sensharma and R. L. Whetten J. Phys. Chem. 1990,94(24) 8630-3. 69 S. W. McElvany Int. J. Mass Spectrom. Ion Processes 1990 102 81-98. 70 P. F. Greenwood I. G. Dance K. J. Fisher G. D. Willet and L. S. K. Pang Org. Mass Spectrom. 1991 26( lo) 920-2. 71 D. H. Parker P. Wurz K. Chatterjee K.R. Lykke J. E. Hunt M. J. Pellin J. C. Hemminger D. M. Gruen and L. M. Stock J. Am. Chem. SOC. 1991 113(20) 7499-503. 72 R. D. Beck P. St. John M. M. Alvarez F. Diedrich and R. L. Whetten J. Phys. Chem. 1991,95(21) 840-9. 73 T. Weiske D. K. Boehme and H. Schwarz J. Phys. Chem. 1991,95(22) 8451-2. 74 R. Malhotra and D. S. Ross J. Phys. Chem. 1991 95(12) 4599-601. 75 P. A. Limbach L. Schweikhard K. A. Cowen M. T. McDermott A. G. Marshall and J. V. Coe J. Am. Chem. SOC.,1991 113(18) 6795-8. 76 F. P. Abramson Methods Biochem. Anal. 1990 34 (Biomed. Appl. Mass Spectrom.) 289-347; L. M. Harrison and P. V. Fennessey J. Steroid Biochem. 1990 36(5) 407-14; A. Bateman S. Solomon and H. P. J. Bennett J. Biol. Chem. 1990 265(36) 22130-6; J. Claereboudt E.L. Esmans E. G. Van den Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 33 the high pressure region of ESI sources provides the basis for a low-cost biopolymer sequence in~trument.~~ ESI has changed rapidly into a tool for problem solving with a promising role in elucidating mechanistic steps in enzyme Rules for sequencing peptides from mass spectra are now quite well established. Van Setten et aLgOdiscussed the validity of these rules for a series of isomeric tripeptides. The intensity of immonium ions provided information concerning the positions of certain amino acid residues in the peptide skeleton. Sometimes the analysis of biomolecules can be improved significantly if the analyte is derivatized even trivially." For example the analysis of amino polyaro- matic hydrocarbon-deoxynucleoside adducts by FAB was enhanced by trimethylsila- tion of ether derivatives82 (ie.derivatizing a labile proton with a chemically equivalent massive (CH,),Si-group sometimes called a 'slow proton' and also reducing the ability to form hydrogen bonds). The derivatization was claimed to increase sensitivity and the ability to differentiate isomers of amino-phenan- threneguanine. Thermospray mass spectrometry following HPLC has been shown to be useful for the analysis and characterization of spin adducts complimenting nuclear mag- netic resonance and electron spin resonance techniq~es.'~ Radical additions of 'C(CH3)CN from the thermolysis of azobis(isobutyronitri1e)to molecules containing .~~ a nitrone functional group were detected.Zha et ~ 1 examined the FAB mass spectra of nitrogen heterocycles formed from a glycerol matrix in order to ascertain which molecule ions were formed. A predominance of quasimolecular ions (M-H)+ had been reported in earlier work. They found the protonated molecule (M + H)+ to be predominant however they noted the presence of significant (M + nH)+ (n = 2,3). Horeau and No~aille~~ have used mass spectrometry for the determination of optical activity in alcohols. Treatment of an alcohol with enantiomers with the R R enantiomer being isotopically modified produced labelled diastereomers with different nominal masses. The ratios of the resolved peaks provided the information from which the configuration of the optically active carbon in the alcohol could be deduced.Pruesse and SchwarzS6 reported that Fe+ complexes exhibit sequential metastable loss of olefin followed by molecular hydrogen. From a study of the R,N=CHR2 Eeckhout and M. Claeys Nucleosides Nucleotides 1990,9(3) 333-44; V. Katta and B. T. Chait J. Am. Chem. Soc. 1991,113(22) 8534-5; J. E. Alexander D. F. Hunt M. K. Lee J. Shabanowitz H. Michel S. C. Berlin T. L. MacDonald R. J. Sundberg L. I. Rebhun I. Lionel and A. Frankfurter Roc. Natl. Acud. Sci. U.S.A. 1991 88(11) 4685-9; A. J. Alexander P. Thibault R. K. Boyd J. M. Curtis and K. L. Rinehart Znt. J. Muss Spectrom. Ion Processes 1990,98(2) 107-34; A. M. Bridges P. F. Leadlay W. P. Revill and J. Staunton J. Chem. Soc. Chem. Commun. 1991 (ll) 776-9 (two papers).77 V. Katta S. K. Chowdhury and B. T. Chait Anal. Chem. 1991 63(2) 174-8. 78 B. Ganem Y. T. Li and J. D. Henion J. Am. Chem. Soc. 1991 113(20) 7818-19. 79 A. Shneier C. Kleanthous R. Deka J. R. Coggins and C. Abell J. Am. Chem. SOC. 1991 113(24). 8o D. Van Setten W. Kulik and W. Heerma Biomed. Enuiron. Mass Spectrom. 1990 19(8) 475-80. 81 M. A. Baldwin N. Stahl L. G. Reinders B. W. Gibson S. B. Prusiner and A. L. Burlingame Anal. Biochem. 1990 191( l) 174-82. 82 R. S. Annan R. W. Giese and P. Vouros Anal. Biochem. 1990 191(1) 86-95. 83 E. G. Janzen P. H. Krygsman D. A. Lindsay and D. L. Haire J. Am. Chem. SOC.,1990,112(23) 8279-84. 84 Q. Zha and M. J. Bertrand Org. Muss Spectrom. 1990 25(8) 435-7. 85 A. Horeau and A.Nouaille Tetrahedron Lett. 1990 31(19) 2207-10. 86 T. Pruesse and H. Schwarz Helu. Chim. Acta 1990 73(5) 1163-6. 34 J. R. Trainor and Z? J. Derrick complexes there was evidence for metallacyclic intermediates with some energetic preference for particular ring-size intermediates. Clusters.-The study of novel species exhibiting transitional behaviour between the bulk and molecular properties is part of the attraction of the chemistry of clusters. The study of cluster ions is a very active area of mass spectrometry. Kinetic and thermodynamic properties of metal dication clusters with water have been studied by ele~trospray.'~ Resonance-enhanced multiphoton ionization (REMPI) has been widely used in cluster studies. Gord et ~1.'~used one-colour two-photon REMPI to probe the bonding in heteromolecular clusters of benzene with small polar H-containing molecules capable of forming hydrogen bonds of varying strengths.They correlated this ability to form strong .rr-hydrogen bonds with the fragmentation efficiency in post-ionization of the clusters. Examination of benzene clusters formed in the seeded helium-expansion of C6H6 H20 and CH30H has shown that water has a higher binding energy than methanol. The binding of the CH30H is significantly enhanced when a water molecule has been adsorbed.89 Work on metal carbonyls in the gas phase sheds light on traditional areas of wet chemistry and catalysis. The (C0)5M~+ cation has been shown to bind CH4 with a bond energy of less than 30 kJ m~l-',~'the species formed being chemically distinct from (CO)5Mo+(CH3)H.The latter expelled CO following collisional activation whilst (CO)5Mo+/CH4 expelled CH4. In another study Cr(C0)6 changed its photo- physics when solvated with n methanol molecule^.^^ The photochemistry was highly sensitive to wavelength and sufficiently energetic ionization of the solvated molecule (CH,OH),Cr(CO), revealed a number of competitive channels for reaction dissoci- ation and energy transfer. Multiphoton dissociation of clustered alkyl acrylates led to ionization and dissoci- ation consistent with the charge being localized on a central molecular unit of the alkyl a~rylate.~~ The dissociation observed was loss of alkoxy radical which occurred from an uncharged clustered alkyl acrylate molecule.The number of alkoxy radicals expelled depended on the number of photons absorbed. 4 Fundamental Studies Charge-Remote Fragmentations (CRF).-Charge-remote fragmentations (CRF) refers to fragmentation of an ion particularly following collisional activation in which the charge appears to play no direct role. CRF may yield important structural information as was demonstrated by Crockett et aL93in determining the position of double bonds in a series of fatty acids containing 1,4-diene functional groups. A. T. Blades P. Jayaweera M. G. Ikonomou and P. Kebarle Znt. J. Mass Spectrom. Zon Processes 1990,102,251-67. J. R.Gord A. W. Garrett R. E. Bandy and T. S. Zwier Chem. Phys. Lett. 1990,171(5-6) 443-50. 89 K. 0. Boernsen H. L.Selzle and E. W. Schlag 2. Naturforsch. A 1990,45(9-lo) 1217-18. 90 C. E. C. A. Hop and T. B. McMahon J. Am. Chem. SOC.,1991 113(1) 355-7. 91 W. R. Peifer and J. F. Gamey J. Phys. Chem. 1991,95(3) 1177-83. 92 H. Morita J. E. Freitas and M. A. El-Sayad J. Phys. Chern 1991 %(4) 1664-7. J. S. Crockett M. L. Gross W. W. Christie and R. T. Holman J. Am. SOC. Mass Spectrom. 1990 1(2) 93 183-91. Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 35 .~~ Contado et ~ 1 discussed mechanisms of allylic cleavage reactions in the light of the CRF concept. Proton Transfer Reactions.-A study of the protonation of ben~onitrile'~ revealed the initial site of proton attachment to be at the nitrile functional group.Interchange of the adduct proton with ring-bound hydrogen was observed with the rates of transfer decreasing in the order ortho > meta > para. The proton affinities of DNA residues have been determined from the dissociations of proton-bound heterocomplexes with amines of known proton affinitie~.~~ Proton affinity scales have been examined in a study of the gas-phase thermochemistry of small organic molecules.97 There was agreement in the lower part of the proton affinity scale for hydrocarbons such as C3H6 and i-C& however in the upper end of the scale proton affinities found for alkyl amines differed significantly from their accepted values. Finding independent confirmation of their upper limit measure- ments it was suggested that the accepted values for proton affinities were in error.Distonic Ions and Ion-Molecule Complexes.-Distonic ions have been recognized in recent years as being important stable ion structures and important reaction inter- mediates. A distonic ion is distinctive as it represents the radical form of a zwitterion or put another way a radical ion with the centres of charge and spin separated. Loss of methyl radical in the low energy reactions of CH,CH=CHCH(CH,)OCH? and CH,=C(CH,)CH(CH,)OCH'; has been shown to involve rearrangement via distonic ion intermediate^^^ where the reaction was driven by the formation of a more stable oxonium ion. The involvement of 1,2-hydrogen shifts in the elimination reactions of distonic ions has been discussed.99 It is clear that more study of distonic ions is required if the products of their reactions are to be predicted confidently.The oxonium CH3CH20+=CHCH2CH3 has been shown by deuterium labelling to eliminate ethene specifically from the ethoxy group via a mechanism involving an ion-molecule complex.'" An investigation was made into the effect of the size of the ion and neutral partners in ion-molecule complex mediated alkane elimination reactions."' Larger ionic partners discriminated against alkane loss in comparison with alkyl loss. Whilst the larger ion decreases the attraction between neutral and the centre of charge a larger neutral increases the attraction lowering the threshold for alkane elimination. The interaction of remote functional groups has been observed in steroid molecules formed by electron impact ionization.'" It has been proposed that functional groups attached to opposite ends of the ion interact in an ion-molecule complex following the detachment of one of the functional groups.Proton transfer occurs within the ion-molecule complex followed by fragmentation. 94 M. J. Contado J. Adam N. J. Jensen and M. L. Gross J. Am. SOC.Mass Spectrom 1991,2(2) 180-3. 95 H. Wincel R. H. Fokkens and N. M. M. Nibbering J. Am. SOC.Mass Spectrom 1990 1(3) 225-32. 96 F. Greco A. Liguori G. Sindona and N. Uccella J. Am. Chem SOC.,1990 112(25) 9092-6. 97 M. Meot-Ner and L. W. Sieck J. Am.Chem. SOC.,1991 113(12) 4448-60. 98 R. D. Bowen and A. W. Wright J. Chem Soc. Chem. Commun.,1991 (15) 1055-7. 99 R. D. Bowen and A.W. Wright J. Chem SOC. Chem. Commun.,1992 (2) 96-8. 100 R. D. Bowen and P. J. Derrick J. Chem. SOC.,Chem Commun.,1990 (21) 1539-41. 101 D. J. McAdoo C. E. Hudson J. C. Traeger A. Grose and L. L. Griffin J. Am. SOC.Mass Spectrom. 1991 2(4) 261-9. 102 P. Longevialle G. Bouchoux and Y. Hoppilliard Org. Mass Spectrom. 1990 25(10) 527-36. 36 J. R. Trainor and P. J. Derrick Chemical Kinetics and Reaction Dynamics.-Brauman Zare and Levine suggested a test for molecular flu~ionality''~ in the reaction coordinate of molecular dissoci- ation. They described an algorithm for the calculation of the statistical distribution of isotopes amongst fragments formed from a precursor molecule prepared with non-statistical atomic labels. Collision-Induced Dissociation (CID).- The theory and use of collision-induced dissociation (CID) has been revie~ed,'~~*'~~ although curiously the pioneering detailed work of Futrell and co-workerslo6 was not covered in either review.A model based on impulsive energy transfer has reproduced the broad features of those collisions between macromolecular ions and inert gases,lo7 which lead to fragmentation and detection of fragment ions. This treatment predicts that the average energy transferred to an ion in a collision should be proportional to the average energy loss suffered by the ion. The implication that large energies are taken up by macromolecular ions in single collisions with inert gases has been supported by measurements of the dependence of energy losses upon pressure of inert gas.'" Charles and Marbury"' discussed optimizing conditions for the collisional dissoci- ation of halogenated dioxins for the purpose of MS-MS.It was claimed that the optimum collision energy is a function of pressure for argon nitrogen and xenon targets but no such dependence was detected when helium was the target gas. At similar pressures the optimum collision energy was higher for argon and nitrogen than for helium and xenon. An upper-limit for the satisfactory dissociation of singly-charged large molecules appears at about 2500 Da.lo7 Above this mass it has been difficult to deposit sufficient energy to dissociate ions and methods have been sought to extend the range. The use of coherent radiation and the formation of multiply charged ions to increase the internal energy deposited was briefly discussed earlier in this article.The use of a solid in replacement for gaseous targets has produced some success11o with spectra having similar salient features to 193 nm photodissociation spectra. Field dissociation is another technique which merits study for the controlled dissociation of large molecules. Charge Reversal.-The charge reversal phenomenon goes one step further than charge neutralization by producing ions of the opposite charge to the precursor on interaction with a buffer gas. Analysis of isomers has been an area of interest where perhaps the most challenging part of the work lies in obtaining consistent results. Charge reversal mass spectrometry"' was applied to the analysis of ten isomeric heptanones and heptanal with mixed results.Collisional activation of enolate ions formed by the OH- abstraction of the acidic P-proton in these substances produced 103 J. I. Brauman R. N. Zare and R. D. Levine Chem. Phys. Lett. 1990 172(3-4) 231-4. 104 J. Bordas-Nagy and K. R. Jennings Int. J. Muss Spectrom. Ion Processes 1990 100 105-31. 105 R. N. Hayes and M. L. Gross Methods Enzymol. 1990 193 237-63. 106 K. Qian A. K. Shukla and J. H. Futrell J. Am. Chem. SOC.1991 113(19) 7121-9. 107 E. Uggerud and P. J. Derrick J. Phys. Chem. 1991 95(3) 1430-6. 108 C. D. Bradley and P. J. Derrick Org. Mass Spectrom. 1991 26 395-401. 109 M. J. Charles and G. D. Marbury Anal. Chem. 1991 63(7) 713-21. 110 E.R. Williams K. D. Henry F. W. Mclafferty J. Shabanowitz and D. F. Hunt J. Am. SOC.Muss Spectrom. 1990 1(5) 413-16. Ill T. Suerig and H. F. Gruetzmacher Org. Muss Spectrom. 1990 25(9) 446-52. Physical Methods and Techniques -Part (ii) Organic Mass Spectrometry 37 characteristic mass spectra for the open-chain isomers. No success was achieved in differentiating between the isomeric cyclic and bicyclic heptanones. Neutralization/Reionization.-Neutralization/ reionization is an important technique which has been used to probe the qualitative structures of gaseous ions and transient neutrals such as hypervalent radicals.l12 Lorquet et al.li3 have suggested that for neutralization/reionization Franck-Condon factors determined for the separated 'free' species are not applicable in accurately modelling experimental observables.They argued that the potential surfaces where reaction occurs in the region of the vertical transition are distorted. They have treated the distortion as coupling of the separated species in terms of induced dipole interactions. Neutralization of the homologous n-alkane radical cations (ethane to hexane) with atomic alkaline earths was studied by Los et al.l14 Dissociations into radicals occurred favouring rupture of the central bond where possible. This behaviour was interpreted as mode selectivity in the cases of n-butane and n-pentane. It was inferred from the kinetic energy releases that the cleavage proceeds on a repulsive state. Interestingly bond selectivity was not observed in n-hexane where each C-C bond could be cleaved.Turecek et a1.1153116 have used neutralization/reionization to investigate the mechanisms of rearrangements in C,H,O+'. Cyclopropanone radical cation was found to be unstable as a transition state for the degenerate isomerization of 'CH2CH2CO+ whilst the CH2=CH:' --OC ion-molecule complex and the dis- tonic ion CH,=C+OCH; were observed to be stable ions. Quite different chemistry was induced by neutralizing 'CH2CH2CO+ the unstable biradical produced dissoci- ated violently leading to the conclusion that neutralization/reionization is much better able to differentiate the isomers of C3H40'' than CID. Ion-Molecule Reactions.-The chemistry of ions trapped for long periods of time (ams) can be significantly different to that of shorter time-scales (aps).Ions which have long lifetimes may dissipate internal energy supplied upon ionization through a variety of physical processes before reaction can occur.The existence of competitive mechanisms for energy dissipation is indicated where excess energy must be supplied to drive a reaction to completion. This may be manifest as collisional cooling where collisions occur or by other competitive relaxation phenomena which are probable on the same time-scale. The threshold for dissociation of C7H71+' to expel I' is some 0.2-0.3 eV in excess of the threshold calculated."' This excess energy was ascribed partly to a straightforward kinetic shift and partly to an intrinsic competitive shift arising from radiative relaxation.This reaction proceeds on the millisecond time- scale where radiative relaxation processes compete for the activation energy. Some of the energy acquired in activation is dissipated by emitting infra-red photons"' before dissociation becomes probable. Thus for an ion to dissociate under these 112 M. George and J. L. Holmes Org. Muss Spectrom. 1990 25(11) 605-8. 113 J. C. Lorquet B. Leyh-Nibant and F. W. McLafferty Inr. J. Mass Spectrom. Zon Processes,1990 100 465-75. 114 J. Los S. Kornig P. G. Kistemaker and J. H. M. Beigersbergen J. Phys. Chem. 1991 95(6) 2143-5. 115 F. Turecek D. E. Drinkwater and F. W. McLafferty J. Am. Chem. Soc. 1991 113(16) 5950-8. 116 F. Turecek D. E. Drinkwater and F. W. McLafferty J. Am. Chem. Soc.1991 113(16) 5958-64. 11' C. Lifshitz 1. Levin S. Kababia and R. C. Dunbar J. Phys. Chem. 1991 95(4) 1667-71. J. R. Trainor and P. J. Derrick competitive conditions it must acquire in activation a minimum excess of energy above that required to cause dissociation due to leakage. Deprotonation of alkyl vinyl ethers with NH has been shown to yield two product carbanions of the general forms CH,=C-OR (i) and -CH=CHOR (ii). Eichinger and Bowie118 used a trisilyl methylated precursor to prepare (i) exclusively. Under CID generic molecules of type (i) exhibited competitive reaction channels leading to elimination of an alkene or a Wittig rearrangement to yield CH2=CRO- from CH2=C-OR. The same group have reported on the reactions of ally1 vinyl ether in which the first step in a complex reaction series is a Claisen rearrangement.In contrast to the alkyl vinyl ethers the Wittig rearrangement is only a minor ~hanne1.l'~ 5 Conclusion Mass spectrometry overall has grown during the years 1990 and 1991 with excep- tional growth in certain areas. The tremendous growth of ESI has induced expansion in the use of single and triple quadrupoles. The development of MALDI is one step behind that of ESI perhaps only because the necessary TOF technology was not commercially available initially. Interest in TOF is now accelerating. Both ESI and MALDI are ionization techniques whose development is stimulated by interest in biomolecules. FT-ICR still holds much potential similarly IT appears to promise great things and has the virtues of cost and simplicity.Quietly tandem mass spectrometry has become an established technique as more attention has focused on ionization techniques. Improvements in MS-MS must be made particularly regarding increased sensitivity and less obviously interpretation of fragmentations. Lasers have steadily become more common place in mass spec- trometry laboratories although a convincing demonstration that laser-induced photodissociation holds the key to better and more controlled fragmentation of ions is still awaited. 118 P. C. H. Eichinger and J. H. Bowie J. Chern. Soc. Perkin Trans. 2,1990 (ll) 1763-8. 119 P.C.H.Eichinger and J. H. Bowie Aust. J. Chem. 1990,43(9) 1479-85.

ISSN:0069-3030    

DOI:10.1039/OC9918800025

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

3 Theoretical Organic Chemistry By J. J. W. McDOUALL Department of Chemistry University of Manchester Manchester M13 9PL 1 Introduction In preparing this review the very wide diversity of models for studying organic structure and reactivity has emerged quite clearly and what follows is of necessity a personal perspective. In ab initio semiempirical and molecular mechanical schemes the centre stage is still occupied by those methods which have had a long history of application for example in ab initio theory the Hartree-Fock (HF) approach is still unchallenged as the standard starting point for a discussion of electronic structure. Yet in what appears to be some of the most ‘informative’ modelling (in the opinion of this reviewer) there seems to be a push away from standard schemes towards methods which yield in addition to a molecular energy some further insight into the nature of the molecular architecture under investigation.The most useful and transferable insights do not necessarily emerge from the use of the most refined/state-of-the-art wavefunctions but rather from an approach’ that looks beyond the confines of a particular method (or in practice a particular computational package). It is becoming increasingly easier for everyone to use standard computational packages and while this leads to an ever larger database of computational chemistry,2 the rationalization of this ‘data’ through the use and development of qualitative ideas (which are central to theoretical organic chemistry) appears to lag behind.2 Methods A collection of useful reviews has appeared3 covering a wide range of methodology. As Professor E. R. Davidson says in his introduction to the volume ‘There are now a vast array of numerical results and a few new ideas which could not have been foreseen 20 years ago. Unfortunately the growth in thisJield has also led to repeated bifurcations into microjields so that it is now nearly impossible for one person to comprehend the whole jield. It is hoped that the present review will put a few of these microjields into perspective’. There are a number of articles in this volume which are of particular relevance to organic chemistry. These include the discussion of density D. M. Prosperio R.Hoffmann and R.D. Levin J. Am. Chem. Soc. 1991 113 3217.I ’Quantum chemistry literature database. Supplement 10. Bibliography of a6 initio calculations for 1989 ed. K. Ohno K. Morokuma and H. Hosoya THEOCHEM 1991 84 1. E. R. Davidson (Ed.) Chem. Reu. 1991 91(5). 39 J. J. W. McDouall functional theory by Ziegler? Following an overview of the general theory and computational considerations the approximate density functional theory is assessed through its application to bond energy calculations conformational analysis reac- tion paths and transition state structures. The examples are mainly taken from organometallic reactions where the more demanding HF calculations would be difficult. Gerratt and co-workers also provide a complete review of the applications of the spin-coupled valence bond meth~d.~ Again the basic theory is outlined but the emphasis is on the applications and the unique insights offered by this compact and elegant approach.Finally the review of Veillard6 should be mentioned which discusses ab initio calculations of the structure and molecular properties of organometallic systems. In dealing with open-shell systems the two standard approaches in ab initio theory are the unrestricted and restricted open-shell Hartree-Fock methods UHF and ROHF respectively. The UHF method suffers from the problem of spin contamina- tion which leads to poor convergence of the perturbation series for estimating the correlation energy. ROHF on the other hand does not suffer from the spin contami- nation problem but formulation of perturbation theory for it is more difficult.Knowles et aL7 have put forward a transparent formalism for computing the correla- tion energy from a Mdler-Plesset type perturbation series for an ROHF reference function. The method employs semi-canonical orbitals and while Q and p type spin orbitals do possess spatially different forms the spin contamination problem is avoided. Application to NH2 and CN shows this approach leads to a faster conver- gence of the perturbation series than the corresponding UHF based theory. A number of other interesting methodological developments have been reported amongst which should be mentioned the evaluation of analytical gradients in pseudospectral HF theory.8" The pseudospectral schemes provide numerical solu- tions to the HF equations*b-d and eliminate the need to evaluate the vast number of two-electron integrals making them suitable for application to larger molecular problems.At present pseudospectral calculations on a range of molecules (using up to 100 basis functions) show deviations in computed bond lengths of *0.003 A and *lo in bond angles when compared with conventional HF methods. The molecular electrostatic potential (MEP) of molecules is frequently used as a guide to regions of chemical attack/reactivity in a molecule. The MEP is usually evaluated from HF wavefunctions. An interesting study on the effect of electron correlation on the distribution of MEP shows that in HF N2 CO HCN H20 and formaldehyde electron correlation has a significant effect on the MEP near the nuclei.However the MEP determined from SCF wavefunctions remains largely unaffected in regions located outside the van der Waals sphere. T. Ziegler Chem. Rev. 1991 91 651. ' D. L. Cooper J. Gerratt and M. Raimondi Chem. Rev. 1991 91 929. A. Veillard Chern. Rev. 1991 91 743. ' P. J. Knowles J. S. Andrews R. D. Amos N.C. Handy and J. A. Pople Chem. Phys. Lett. 1991 186 130. (a) Y. Won J,-G. Lee M. N.Ringnalda and R. A. Friesner J. Chem. Phys. 1991,94 8152; (b) R. A. Friesner Chem. Phys. Lett. 1985,116,39; J. Chem. Phys. 1986,85 1462; J. Chem. Phys. 1987,86,3522; J. Phys. Chem. 1988,92 3091; (c) M. N.Ringnalda Y. Won and R. A. Friesner J. Chem. Phys. 1990 92 1163; (d) J.-M. Langlois R. P. Muller T. R. Coley W. A. Goddard 111 M. N. Ringnalda Y. Won and R.A. Friesner J. Chem. Phys. 1990 92 7488. F. J. Luque M. Orozco F. Illas and J. Rubio J. Am. Chem. SOC.,1991 113 5203. Theoretical Organic Chemistry 41 A new force field has been developed for studying transition metal complexes." The scheme is called SHAPES and uses a new treatment of angular distortion (three-body) terms based on angular overlap considerations. Angular potential energies are expressed as periodic Fourier terms in spherical internal coordinates. This formulation provides a generalized description of many idealized geometries. For example good accuracy is obtained for a variety of square-planar rhodium complexes (RMS deviation for bond lengths is +0.02 8 and *3' for angles). Finally the electron localization function (ELF) of Becke and Edgecombe"" has been applied to a wide range of small molecules using a new program called GRAPA" which provides high quality graphical output.The ELF maps the electron pair probability distribution and generates interesting pictures of atomic shells core binding and lone pair regions in molecules. The ELF has the important property of being invariant under certain unitary transformations. 3 Bonding and Molecular Structure The interesting series of papers by Messmer on the generalized valence bond (GVB) description of hypervalent molecules continues." The classical interpretation of hypervalency in terms of resonance structures is replaced by a single configuration description which arises when orthogonality constraints are removed from the orbitals.The ONF3 and OPF systems have been studied12" and the N-0 bond in the former is found to be composed of a single bond and three back-bonds while the 0-P bond is a genuine triple bond. The GVB lone pairs in ONF3 are significantly polarized toward N indicating back-bonding. A study of the stabilities of C3Hf and C3H2F; cations' shows that fluorine migration which converts CH2=C+CF3 to the allylic cation CH,=CFCF'; is exother- mic by 31.5 kcalt mol-' with a barrier involving a bridged fluoronium ion of only 6.1 kcal mol-'. Rearrangement of CH,=CfCF3 to CHF=CHCF; is exothermic by 44.9 kcal mol-' and occurs via a multistep process including 1,3 fluorine migration with no barrier higher than 0.3 kcal mol-'. On the basis of this study the authors suggest that CH2=C+CF3 is a good candidate for experimental work on fluorine migration'in carbocations.In substituted ethylene dications of the form C2X2Yi+ it is found14 that C2Fi+ C,(OH);+ C2H2(NH2):+ and C2(OH),(NH2):+ are planar while C2HZ+ C2(NH2);+ and C,(SH)i+ have a twisted structure. The substituents X with lone pair orbitals strongly donate charge into the formally empty carbon T orbitals of C2X;+ yielding partial C-X double bonds. If X is a first row atom conjugation of the resulting double bonds causes the minimum energy conformation to be planar provided that steric repulsion of the vicinal groups is absent. 10 V.S. Allured C. M. Kelly and C. R. Landis J. Am. Chem. Soc. 1991 113 1. " (a) A. D. Becke and K. E. Edgecombe J. Chem.Phys. 1990 92 5397; (b) J. Flad F.-X. Fraschio and B. Miehlich Angew. Chem. Int. Ed. EngZ. 1991,30,409; (c) GRAPA program Institute fir Theoretische Chemie der Universitat Stuttgart 1989. 12 (a) R. P. Messmer J. Am. Chem. SOC.,1991 113 433; (b) P. A. Schultz and R. P. Messmer J. Am. Chem. SOC.,1988 110 8258; (c) C. H. Patterson and R. P. Messmer J. Am. Chem. SOC.,1989 111,8059; (d) C. H. Patterson and R.P. Messmer J. Am. Chem. SOC.,1990 112 4138. l3 M. McAllister T. T. Tidwell M. R. Peterson and I. G. Csizmadia J. Org. Chern. 1991 56 575. l4 G. Frenking J. Am. Chem. SOC.,1991 113 2476. t 1 cal = 4.1845 J. J. W McDouall A twisted double bond in methylenephosphonium ions (R,N),P+=C(SiR;) has also been rep~rted.'~ The twisting of the P+=C double bond is caused by steric hindrance of bulky R and R' groups and facilitated by the electronic structure of the parent compound (R,N),P+=C(SiR;) ,which differs from the genuine double bond structure of H2P+=CH2.For R = R = H there is a rotational barrier of 20 kcal mol-'. A detailed conformational analysis of cyanoguanidine including its tautomer and their respective radical anions,16 shows that when the anion is formed a sizeable fraction of the resonance stabilization of the guanidine moiety is lost and as a consequence there is a greater tendency for the amino groups to rotate out of plane and pyramidalize. Two structures have been located for the 4-protioadamantyl cation (ClOH~,)," one of C symmetry (l) and the other of C1 symmetry (2).Structure (1) lies 8 kJ mol-' higher in energy than (2). It is suggested that (1) is the primary intermedi- ate in the solvolysis of 4-endo-protioadamantyl derivatives while (2) is the primary intermediate in the solvolysis of 4-exo-protioadamantyl derivatives. The benzene dication exists in both a singlet and triplet state. The singlet structure is found to possess a chair-like CZh symmetry while the triplet structure is planar with D6hsymmetry." The strength of T bonds in acetylene and ethylene and their effect on the relative energies of 7r bond addition reactions have been analyzed using CISD/6-3 1G** cal~ulations.'~ Isodesmic reaction schemes were used to obtain bond strengths ionization potentials and electron affinities. Very good agreement with experiment is obtained from the isodesmic approach.The T bond in acetylene is found to require 12 kcal mol-' more energy for dissociation than the T bond in ethylene. The bonding of transition metal ions to acetylene has been investigated at a correlated level of theory." The ions on the left hand side of the first and second transition rows (Sc+-V+ and Y+-Mo+ respectively) insert into the 7r bond to form a three-membered ring but on the right hand side of the rows the bonding is mainly electrostatic. The increased stretching frequency (=C= N-) observed on protonation of Schiffs bases in retinoids and other related systems may be attributed to an increased bond energy for both the single and double bond.21 The lowest unoccupied molecular M. Ehrig H.Horn C. Kolmel and R. Ahlrichs J. Am. Chem. Soc. 1991 113 3701. 16 R. D. Bach J. J. W. McDouall A. L. Owensby H. B. Schlegel J. W. Holubka and J. C. Ball J. Phys. Org. Chem. 1991 4 125. R. Dutter A. Rauk S. M. Whitworth and T. S. Sorensen J. Am. Chem. Soc. 1991 113 411. l8 K. Krogh-Jespersen J. Am. Chem. Soc. 1991 ll? 417. 19 A. Nicolaides and W. T. Borden J. Am. Chem. Soc. 1991 113 6750. 20 M. Sodupe and C. W. Bauschlicher Jr. J. Phys. Chem. 1991 95 8640. 21 D. Bond J. Am. Chem. Soc. 1991 113 385. Theoretical Organic Chemistry orbitals (LUMOs) corresponding to both bonds have negative energies giving enhanced reactivity toward nucleophilic addition of Schiffs bases. Two symmetric (3 (c2h) 4 (c2h)) and two asymmetric (5 (anti),6 (syn))formic acid -formate anion dimers exhibiting strong hydrogen bonds have been deter- mined.22 The existence of all these experimentally and the small calculated differen- ces in energy point to the sensitivity of conformation to molecular environment.Hydrogen bonded complexes between hydrogen fluoride and hydroxylamine have been ~alculated~~" confirming the novel ring structures suggested in reference 23(b). 0 H 0 H H-C / \c-0 H-C / \c-0 \o...H. / \O-H*.. 0/ 0 (5) (6) The 1 :1 complex (7) is predicted to be a loosely bound ring with a strong N-HF bond and a weak HF-NO bond with an association enthalpy of between -6 and -9 kcal mol-'. For the 2 1 complex (8) the second H-F is inserted between the first H-F moiety and OH group and possesses three strong hydrogen bonds with an association enthalpy between -17 and -19 kcal mol-'.Finally two interesting conformational studies should be mentioned. The first concerns the conformational potential energy surface of glycine obtained with a variety of computational which is then used to generate Boltzmann equilibrium distributions and the kinetics of conformational interconversion at various temperatures. The second is concerned with the conformational properties of N-formylglycine dithio acid.25 Three conformations were found and a description emerges of the N-.S nonbonded interaction which has implications for the structure and reactivity of enzyme-substrate complexes which incorporate a similar contact. 22 H. Basch and W. J.Stevens J. Am. Chem. SOC.,1991 113 95. 23 (a) R. E. Brown Q. Zhang and R. J. Bartlett J. Am. Chem. SOC.,1991 113 5248; (6) R. Lascola and L. Andrews J. Am. Chem. SOC.,1987 109 4765. 24 J. H. Jensen and M. S. Gordon J. Am. Chem. SOC.,1991 113 7917. 25 R. Fausto J. J. C. Teixeira-Dias and P. R. Carey J. Am. Chem. SOC.,1991 113 2471 J. J. W McDouall 4 Beyond the Gas Phase Recently there has been much effort directed at the development of models which allow the inclusion of solvent effects into quantum mechanical descriptions of solute molecules. Activity in this important field is growing and it seems appropriate to give a guide to the current literature. What follows is a mixture of methodology and applications including the use of molecular dynamics (MD) simulations and free energy perturbation (FEP) methods as well as continuum models of the solvent.The most simple models (from a computational point of view) appear to be those based on a continuum representation of the solvent. In these models the solute is represented by a quantum mechanical wavefunction and ensconced in a cavity which is surrounded by a medium of continuous dielectric constant representing the solvent. The effect of the solvent medium on the solute is usually incorporated by adding appropriate terms to the one-electron Fock operator and recalculating the molecular orbitals self consistently. This process gives what is termed the self consistent reaction field (SCRF). Tomasi and coworkers26 have provided a concise overview of the theoretical methods based on a continuous distribution of solvent molecules (the continuum dielectric model being the most important).The optimiz- ation of solutes in the presence of a SCRF is important in assessing the effect of solvent on the geometric structure of the solute.27 The use of correlated wavefunctions in reaction field (RF) methods has been developed to include the MP2 and quadratic configuration interaction (QCI) methods with geometry optimization.28 For semi- empirical wavefunctions similar methods have been developed but a study shows that significant errors in the calculated energies of some polar molecules can result if geometry optimization is carried out using approximate gradients which assume a first-order invariance of the density matrix with respect to geometry.29 The AM1 method has been used to investigate RF effects on the tautomeric equilibria of nucleic acid pyrimidine and purine bases and their 1-methyl analogues in water solvent.30 In most cases the same tautomer is predicted to be most stable in the gas phase and solution but the relative stabilities show significant differences which have a substantial effect on nucleic acid base pairing/mis-pairing probability esti- mates.Another application of the AM1-SCRF method to the calculation of radical formation energies for the process R”R’RCH $ R”R’RC’ + H’ in the gas phase and solution,31 indicates that the homolytic dissociation energies of C-H bonds in polar solvents are satisfactorily reproduced but the dissociation paths are not.The comparison of reactions in solution using discrete and continuum representa- tions of the solvent can shed light on the performance of continuum models. A study of neutral and zwitterionic forms of the amino acids glycine alanine and pr01ine~~ suggests that a combined approach in which some solvent molecules are included in the solute cavity and the bulk treated by SCRF methods may be the 26 J. J. Tomasi R. Bonaccorsi R. Cammi and F. J. Olivares de Valle J. Mol. Struct. (THEOCHEM) 1991 234 401. 27 R. Bonaccorsi R. Cammi and J. Tomasi J. Comput. Chem. 1991 12 301. 28 M. W. Wong M. J. Frisch and K. B. Wiberg J. Am. Chem. SOC.,1991 113 4776. 29 H. S. Rzepa M. Yi M. M. Karelson and M. C. Zerner J. Chem. SOC.,Perkin Trans.2 1991 635. 30 A. R. Katritzky and M. Karelson J. Am. Chem. SOC.,1991 113 1561. 31 M. Karelson A. R. Katritzky and M. C. Zerner J. Org. Chem. 1991 56 134. 32 H. S. Rzepa and M. Yi J. Chem. SOC.,Perkin Trans. 2 1991 531. Theoretical Organic Chemistry 45 most reliable approach. A detailed analysis using discrete and continuum representa- tions of the effect of solvent on the Menshutkin reaction as modelled by the process NH3 + CH3Br -+ N+H3CH3+ shows the effects to be similar to other SN2 reactions but includes the following differences a decrease in the energy of activation is observed with an increase in solvent polarity and the transition state is found earlier along the reaction path showing the participation of solvent parameters in the reaction coordinate.The polarization of the solute by the RF created by solvent polarity increases the weight of charge transfer configurations with respect to the gas phase. Truhlar has developed a general parameterized SCF model for calculating free energies of solvation in aqueous sol~tion.~~,~~ Solvation terms are added to the AM1 Fock operator including reaction field polarization cavitation dispersion and hydrophobic effects through an empirical function of solvent accessible surface area. This has been termed the Solvation Model 1 and incorporated into the AMPAC package to produce AMSOL which is distributed through the quantum chemistry program exchange.36 Work on the theory of solvent effects on electronic spectra has been re~iewed.~’ An application to the spectra of conjugated molecules of an all atom solvent representation and a dipole shows the latter to be fast and reliable.The remaining examples in this section involve the use of MD Monte-Carlo (MC) and Brownian dynamics methods.39 A wide diversity of systems have been studied and the following list is by no means exhaustive free energy simulation analysis of the solvent effect on the anomeric equilibrium in D-glUCOSe;40 MD and FEP study of the protomeric equilibrium of 6-chloro-2-hydroxypyridine in the gas phase and solution;41 MC simulations of complex formation in imides and lac tarn^;^^ FEP study of the binding of pepstatin and its derivatives to rhizopus pepsin;43 Brownian dynamics simulation of base pair opening in DNA;44 role of solvent reorganization energies in the catalytic activity of enzymes;45 effects of salt on the structure and dynamics of the bis(penicil1amine) enkephalin ~witterion;~~ proton transfer in the formamidine and water system;47 FEP study of solvation in hydrazine and carbon tetra~hloride;~~ solvation of N-methylacetamide c~nformers.~~ 33 M.SolP A. Lledbs M. Duran J. Bertran and J. L. Abboud J. Am. Chem. SOC.,1991 113 2873. 34 C. J. Cramer and D. G. Truhlar J. Am. Chem. Soc. 1991 113 8305. 35 (a) C. J. Cramer and D. G. Truhlar J. Am. Chem. SOC.,1991 113 8552; (b) C. J. Cramer and D. G. Truhlar J. Am. Chem. Soc. 1991 113 9901. 36 AMSOL version 1 program 606 QCPE Indiana University Bloomington IN. 37 H. Ajgren and K.V. Mikkelsen J. MoL Struct. (THEOCHEM) 1991 234 425. 38 V. Luzhkow and A. Warshel J. Am. Chem. SOC.,1991 113 4491. 39 M. P. Allen and D. J. Tildesley Computer Simulation of Liquids Clarendon Oxford 1987. 40 S. Ha J. Gao B. Tidor J. W. Brady and M. Karplus J. Am. Chem. SOC.,1991 113 1553. 41 0. G. Parchment I. H. Hillier and D. V. S. Green J. Chem. SOC.,Perkin Trans. 2 1991 799. W. L. Jorgensen and D. L. Severance J. Am. Chem. Soc. 1991 113 209. B. G. Rao and U. C. Singh J. Am. Chem. SOC.,1991 113 6735. 42 43 44 F. Briki J. Ramstein R. Lavery and D. Genest J. Am. Chem. Soc. 1991 113 2490. 45 A. Yadov R. M. Jackson J. J. Holbrook and A. Warshel J. Am. Chem. SOC.,1991 113 4800. 46 P. E. Smith and B. M. Pettitt J.Am. Chem. SOC.,1991 113 6029. 47 M. Nagaoka Y. Okuno and T. Yamabe J. Am. Chem. SOC.,1991 113 769. 48 B. G. Rao and U. C. Singh J. Am. Chem. Soc. 1991 113 4381. 49 H.-A. Yu B. M. Pettitt and M. Karplus J. Am. Chem. SOC.,1991 113 2425. J. J. W. McDouall 5 Reactivity Pericyclic Reactions.-A study of a series of dissymmetric cyclohex-1,3-dienes react- ing with maleic anhydride and benzoquinone show a strong preference for addition to the carbonyl face of the dien~phile.~' In dimethyl acetylenedicarboxylate (DMAD) attack from this face decreases with successive methylidine substitution the opposite is true for N-phenyl-l,2,4-triazolinedione. In accounting for this in DMAD the unfavourable orbital interaction of closed shells of carbonyls and methylidines syn to the incoming T orbital of DMAD is thought to be important.Tetrafluoroethylene (TFE) does not undergo a Diels- Alder reaction. An explana- tion for this comes from calculations showing that the presence of fluorines does not have a strong influence on the Diels-Alder transition structure but does show a strong stabilization on diradical f~rrnation.~~ The 1,6diradical formed from TFE is 25 kcal mol-' more stable than that formed from ethylene. Hence TFE reacts with 1,3-butadiene to give 1,1,2,2,-tetrafluoro-3-vinyl-cyclobutane (9) via a diradical path. H FF-F Other interesting studies on Diels- Alder processes include a study of electron rich and electron deficient dienes in Diels- Alder cycloadditions with cyclic dienophile~,~~ and an investigation of the mechanism and site selectivity in the reaction between protoanemonin (5-methyl-2( 5H)-furanone) and b~tadiene.~~ The site specificity is rationalized through a highly asynchronous or two-step mechanism.The Cope rearrangement54 has been investigated using high level ab initio methods.55 Both a symmetrical aromatic transition state and a non-concerted path through an unsymmetrical transition state leading to a diradical intermediate have been located. From the energetics the authors conclude that reaction via both paths appears possible. Another high level treatment studies the formation of 1,3-cyclo- butanedione versus the 2s + 2A dimerization of ketene to diketene. Both products form through unsymmetrical transition states suggesting the reaction is non-synchronous but ~oncerted.~~ The barriers for the two processes differ by only 2 kcalmol-' with the formation of diketene being less favoured.Robb and co- worker~~~ have produced a CASSCF + MP2 study of the chemiluminescent decomposition of 1,2-dioxetanes including a valence bond analysis of the components of the wavefunction. so J. M. Coxon R. G. A. R. Maclagan D. Q. McDonald and P. J. Steel J. Org. Chem. 1991 56 2542. 51 S. J. Getty and W. T. Borden J. Am. Chem. SOC.,1991 113 4334. '* V. Branchadell M. Sodupe R. M. Ortufio A. Oliva D. Gomez-Pardo A. Guingant and J. d'Angelo J. Org. Chern. 1991 56 4135. 53 J. Orti R. M. Ortufio A. Oliva J. Font J. Bertran and J. J. Dannenberg J. Org. Chem.1991 56 2190. 54 W. T. Borden R. J. Loncharich and K. N. Houk Ann. Rev. Phys. Chem. 1988 39 213. 55 M. Dupuis C. Murray and E. R. Davidson J. Am. Chem. SOC.,1991 113 9756. 56 E. T. Seidl and H. F. Schaefer 111 J. Am. Chem. SOC.,1991 113 5195. 57 M. Ruguero F. Bernardi A. Bottoni M. Olivucci and M. A. Robb J. Am. Chem. Soc. 1991 113 1566. Theoretical Organic Chemistry Unsaturated Systems.-A detailed study at the AM1 level of theory of the reactions of ozone with ethylene and cis- and tr~ns-butadiene~~ finds support for the Criegee mechanism. This involves three distinct steps in which ozone and the olefin combine to give a cyclic adduct which then dissociates to a mixture of a carbonyl and a carbonyl oxide which recombine to form the ozonide.It is suggested that this process prevails in solution as well as in vacuo. The transition state geometries for radical additions to alkenesS9 show elec- trophilic nucleophilic and ambiphilic radicals to have a near constancy of the angle of attack (104°-1080) regardless of the nature of the radical. The relative stabiliz- ation of a carbon-carbon double bond by C1 and Br atoms is found to be greater for C1 by 1.3 kcal mol-1.60 This has consequences for the use of kBr/kcl ratios as mechanistic probes in vinylic substitution reactions. Comparison of biradical formation between enediyne (10) -P (1 1) and enyne- allene (12) + (13)61shows the latter to have a smaller activation barrier and a higher exothermicity. H H Singlet O2and triazolinedione (TAD) react with unsymmetrical cis-alkenes with regioselective double bond formation at the larger group.62 Results show that the rotational barriers do not control the selectivity of the ene reaction of singlet 0 and TAD with alkenes but that the regioselective ene product distribution depends on the free energies of activation of the isomeric transition states.SN2Reactions.-A systematic analysis of charge distribution at the transition state for the SN2 reactions63 (Scheme 1) for X = H NH, OH F CCH CN NC SH Nucl-+ CH,X + NuclCH + X-Scheme 1 58 M. J. S. Dewar J. C. Hwang and D. R. Kuhn J. Am. Chem. SOC.,1991 113 735. 59 H. Zipse J. He K. N. Houk and B. Giese J. Am. Chem. SOC.,1991 113 4324. 60 S. Hoz H. Basch J. L. Wolk Z. Rappaport and M.Goldberg J. Org. Chem. 1991 56 5424. 61 N. Koga and K. Morokuma J. Am. Chem. SOC.,1991 113 1907. 62 M. Stratakis Y. Elemes and F. Jensen J. Am. Chem. SOC.,1991 113 3180. 63 Z. Shi and R. J. Boyd J. Am. Chem. Soc. 1991 113 1072. 48 J. J. U? McDouall C1; Nucl = H and X = H NH2 OH F CN SH C1; Nucl = F shows that for some but not all reactions the charges on the nucleophile and the leaving group are the same. In such cases the assumption that the transition state occurs in the vicinity of the crossing of product-like and reactant-like diabatic surfaces holds. However in general the contributions of reactant and product wavefunctions are not equal in the transition state. With an electronegative nucleophile or leaving group charge development at the transition state is small.Intrinsic barriers have also been obtained64 and are found to be classifiable according to the hybridization of the leaving group and the electronic structure of the transition state. A detailed study of the classical SN2 reaction between chloride ion and methyl chloride including the effects of solvent,65 shows that the change in the internal energy of the reactants during the barrier climbing process involves three distinct regimes (i) vibrational activation of methyl chloride in the initial ion-dipole complex (ii) gradual increase in the kinetic and potential energies of the reactants (iii) fast dumping of reactant kinetic energy into the reactant potential energy resulting in reactants reaching the top of the potential energy barrier.The energy gained by the reactants comes primarily from solvent water. Many water molecules are involved in the process and almost as much energy is removed from the reactants as is deposited over the course of the barrier climb. The critical change in charge distribution occurs over a very short time and the total energy of the solvent molecules is almost constant. Oxygen Transfer.-In a study of the relative oxygen donor potential of dioxirane and its isomeric form carbonyl oxide it has been shown66 that reliable transition structures may only be located by geometry optimization at a correlated level of theory (MP2 being the lowest reliable method). To obtain accurate energies for these species higher order correlation effects must be considered including the contribution of triple substitutions.In the gas phase carbonyl oxide shows greater reactivity than dioxirane. Experimental work on substituted dioxiranes in solution shows the opposite trend. An investigation of the nature of the transition state for oxygen atom transfer from a hydroperoxide suggests that the accepted mechanism involving a direct displacement in concert with a 1,2 hydrogen shift must be modified to include the energetics of the 1,2-~hift.~~ The high barrier for the 1,2-shift can be dramatically lowered by the explicit inclusion of 1-2 molecules of solvent water. This yields a decrease of 20 kcal mol-' (relative to isolated reactants) or 10 kcal mol-' (relative to solvated reactants) per solvent molecule.This comes about by forming a cyclic transition structure allowing a 1,4-shift via a proton relay which bypasses the energetically demanding 1,2-shift. A high level ab initio study of the transition structure for the epoxidation of alkenes with peroxyacids6*" has provided a theoretical corroboration of the generally 64 Z. Shi and R. J. Boyd J. Am. Chem. SOC.,1991 113 2434. 65 B. J. Gertner R. M. Whitnell K. R. Wilson and J. T. Hynes J. Am. Chem. SOC.,1991 113 74. 66 R. D. Bach A. L. Owensby J. L. Andrks and H. B. Schlegel J. Am. Chem. SOC.,1991 113 7031. 67 R. D. Bach A. L. Owensby C. Gonzalez H. B. Schlegel and J. J. W. McDouall J. Am. Chem. SOC. 1991 113 6001. (a) R. D. Bach A. L. Owensby C. Gonzalez H. B. Schlegel and J.J. W. McDouall J. Am. Chem. SOC. 1991 113 2338; (b) P. D. Bartlett Rec. Chem. Bog. 1950 11 47. Theoretica1 Organic Chemistry accepted 'butterfly' mechanism proposed in 1950.6gb The electrophilicity of the peracid is attributed to the relatively weak 0-0 bond that is able to provide an empty (electrophilic) cr* orbital early along the reaction coordinate enabling mixing with the nucleophilic T bond of the alkene. General.-AMl MNDO and PM3 calculations of SN1dissociation pathways for N-benzylpyridinium cations69 (Scheme 2) predict that the unimolecular dissociation leads initially to ion-molecule complexes which in some cases are significantly lower in energy than the fully dissociated products. The calculations support an earlier suggestion of the existence of such intermediates made on the basis of experimentally determined activation volumes and of the behaviour of some of the cations toward nucleophilic reagents.R' ,>ffl' Tran Scheme 2 A study of the intrinsic reaction coordinate for the Grignard reaction Mg + C2H3X+ C,H3MgX (X = F C1) finds the activation barriers for C1 and F to be 29.7 kcal mol-' and 22.8 kcal mol-' respectively.'' Both reactions are exothermic by 54 kcal mol-'. The products have a linear C-Mg-X arrangement of Cs symmetry but arrive there via an unsymmetric path (Scheme 3). A similar study has been carried out for Mg insertion into the C-X bond of CH3Cl and CH3F.71 Scheme 3 In the activation of the C-H and C-C bonds by the transition metals iron cobalt nickel rhodium and palladium72 it is found that the barrier for C-C insertion is 14-20kcalmol-' higher than for C-H insertion.The size of the activation barrier is similar among metals in the same transition row but considerably lower for the second row. Other interesting studies include the protonation of 3-acetyltriazine and its rele- vance to the acid catalyzed decomposition of a~yltriazines;~~ the concerted or 69 A. R. Katritzky N. Malhorta G. P. Ford E. Anders and J. G. Tropsch J. Org. Chem. 1991 56 5039. 70 L. Liu and S. R. Davis J. Phys. Chem. 1991 95 8619. S. R. Davis J. Am. Chem. SOC., 71 1991 113 4145. 72 M. R. A. Blomberg P. E. M. Siegbahn U. Nagashima and J. Wennerberg J. Am. Chem. SOC.,1991 113 424. 73 J. L. Ozment A. M.Schiedekamp L. A. Schultz-Merkel R. H. Smith Jr. and C. J. Micheda J. Am. Chem. SOC.,1991 113 397. J. J. W. McDouall stepwise nature of nucleophilic addition to nitrile oxide^;'^ estimation of activation enthalpies for intramo!ecular hydrogen transfer as a function of the size of the cyclic transition state and CHC angle in reactions of a primary radical site with primary secondary and tertiary C-H bonds;75 the effect of hydration and dimerization of the formamidine rearrangement and modelling of proton transfer in nucleic acid bases;76 modes of ring opening in bicycle[ l.l.Olbut-2-yl radical and the relevance of orbital symmetry consideration^.^^ 74 M. T. Nguyen S. Malone A. F. Hegarty and I. H. Williams J. Org. Chem. 1991 56 3683. 75 X.L. Huang and J. J. Dannenberg J. Org. Chem. 1991,56 5421. 76 K. A. Nguyen M. S. Gordon and D. G. Truhlar J. Am. Chem. Soc. 1991 113 1596. 77 S. Olivella and A. SolC J. Am. Chem. SOC.,1991 113 83.

ISSN:0069-3030    

DOI:10.1039/OC9918800039

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (i) Pericyclic Reactions By N. G. RAMSDEN Glaxo Group Research Green ford Middlesex UB6 OHE 1 Cycloaddition Reactions During the past year further experimental and theoretical data has been presented for the concertedness of cycloaddition reactions. The activation energy of the retro-Diels-Alder reaction of 1,2,3,6-tetrahydropyridineover a range of temperatures shows a slight increase in marked contrast with the drop usually seen in simple bond fission. This may reflect a change from a concerted to a biradical mechanism at high temperatures.’ The observed site selectivity of the reaction of butadiene with protoanemonin has been explained on the basis of a highly asynchronous or biradical mechanism with the crucial factor being the formation of a cyclic aromatic radical when attack is at the exocyclic double bond.* Cyclopropabenzene reacts with diphenylisobenzofuran to give the [47r + 27r] adducts.’ In addition the [47r + 2a] adduct is formed presumably via a biradical rearrangement (Scheme 1).High pressure FTIR spectroscopy of the reaction between isoprene and maleic anhydride suggests a two step mechani~m.~ N-Vinylcarbazole and (NC),C=C( CO,Me) react via a zwitterionic intermediate with kinetic evidence being found for both uni- molecular decomposition of the electron donor-acceptor complex and bimolecular reaction with N-vinyl ~arbazole.~ The use of More O’Ferrall diagrams has been modified by the incorporation of the topological theory of chemical reactivity to allow the classification of pericyclic reactions in terms of their degree of concertednes6 Hartree-Fock calculations have been performed to explain why tetrafluoroethylene undergoes [2 + 21 rather than [4 + 21 cycloadditions with b~tadiene.~ They show that whilst fluorine substituents have little effect on the energy of the Diels-Alder transition state they have a profound stabilizing effect on the energy of the 1,4 allylic biradical in the [2 + 21 cycloaddition.The relative energies of biradical versus synchronous pathways for S. S. Sidhu J. H. Kiefer A. Lifshitz C. Tamburu J. A. Walker and W. Tsang Int. J. Chem. Kinet. 1991 23,215. ’V.Branchadell J. Orti R. M. Ortuno A. Oliva J. Font J. Bertran and J. J. Dannenberg J. Org. Chem. 1991 56 2190. U. H.Brinker and H. Wuster Tetrahedron Let?. 1991 32,593. Y.Ikushima N. Saito and M. Arai Bull. Chem. SOC.Jpn. 1991 64 282. ’ T. Gotoh A. B. Padias and H. K. Hall jun. J. Am. Chem. SOC. 1991 113 1308. R. Ponec and M. Stmad J. Math. Chem. 1991,8 103. S. J. Getty and W. T. Borden J. Am. Chem. SOC.,1991 113,4334. 51 N. G. Ramsden Ph Ph Ph Ph Ph Scheme 1 the cycloaddition between the NO; ion and ethyne have been compared by semi- empirical and ab initio calculatiom8 The minimum estimate for the bias to the stepwise route is 11 kcal/mol. MNDO calculations indicate that the reaction of nitroethene and aromatic nitrile oxides is under charge transfer control.' Two regiostereomeric pathways exist. Both are concerted with early transition states.'o911 The dimerization of ketene to cyclobutanedione and diketene has been studied by ab initio SCF calculations.Both products are formed via an unsymmetrical transition state indicating that neither is formed via a 2s + 2a cycloaddition.'' The reaction of l-oxa-2,3-cyclohexadiene in both [4 + 21 and [2+ 21 cycloaddi-tions occurs with remarkable regio- and stereo-specificity. The authors suggest that this indicates a concerted non radical reaction me~hanism.'~ The importance of molecules being in a reactive conformation before undergoing the Diels- Alder reaction has been demonstrated. The reactivity of silyl pyrimidines (1)has been shown experimentally to decrease in the order X = CO >> 0 > CH2 >> NH. Conformational studies on the corresponding desilyl compounds show that this order reflects the probability of the molecule being in a reactive c~nformation.'~ The dicyano pyrimidines (2) are much more reactive in the Diels-Alder reaction than their methylene ana10gues.I~ A comparison of their crystal structures reveals H.S. Rzepa and W. A. Wylie J. Chem. SOC. Perkin Trans. 2 1991 939. A. Baranski and G. Banki Collect. Czech. Chem. Commun. 1991 56 425. 10 A. Baranski and J. Cioslowski Collect. Czech. Chem. Commun. 1991 56 1167. A. Baranski and E. Cholewka Pol. J. Chem. 1991 65 319. 12 E. T. Seidl and H. F. Schaefer 111 J. Am Chem. SOC. 1991 113 5195. 13 R. Ruzziconi Y. Naruse and M. Schlosser Tetrahedron 1991 47 4603. 14 W. A. W. Stolle A. T. M. Marcelis and H. C. Van der Plas ibid.1991 47 1753. 15 W. A. W. Stolle A. E. Frissen A. T. M. Marcelis H. C. Van der Plas Y. Wang L. Haming and C. H. Stam J. Org. Chem. 1991 56 2411. Reaction Mechanisms -Part (i) Pericyclic Reactions that the former have a conformation with the reacting centres much closer and MNDO calculations show that the dicyano compounds possess lower transition state energies. An extensive investigation of the rate of cyclization of 2-furfuryl methyl fumarates (3) has shown that the gem dialkyl effect is due primarily to the reactive rotamer effect and not angle compression.’6 The cyclobutane compound RR’ = (CH2)3 should have a similar reactive rotamer effect to the dimethyl com- pound and thus cyclize relatively rapidly if this effect was dominant.However its larger internal angle should lead to a slower cyclization than the dihydro compound. In fact it cyclizes some 200 times faster than the dihydro compound. (1) R = Me,Si (2) R = H (3) R=H R = CN The effect of solvents and co-solutes on cycloaddition reactions has been studied. A Diels-Alder reaction in the liquid phase has been modelled as a pair of coordinates one associated with chemical reaction motion and the other describing the contrac- tion of the medium cavity surrounding the reaction.” The corresponding kinetics show both equilibrium and non equilibrium behaviour. Cycloaddition of methyl acrylate to 2,6-bis(t-butyldimethylsilyloxy)-3,4-dihydropyridinedisplays 92 :8 exo selectivity in benzene. PM3 MO calculations suggest that this is due to solvent effects in the medium.” The use of the parameters Spand to account for the influence of the medium on the rate and selectivity of the Diels-Alder reaction is complicated by the fact that the effect of dipolar solute-solvent interactions may be included in both terns.” Monte Carlo statistical methods show that the free energy of solvation of the transition state of the reaction between methyl vinyl ketone and cyclo- pentadiene is of the order of 4kcal/mol lower in water than in propane.20 The rate enhancement arises from a hydrophobic effect and enhanced hydrogen bonding to the carbonyl in the more polar transition state.A variety of other cycloadditions are also accelerated in water due to a hydrophobic effect.21*22 Alkali metal salts increase the rate whilst agents capable of forming lipophillic micelles decrease it.The kinetics of the reaction of imine quinone (4)with dienes when plotted against the parameter Dpof solvent nucleophilicity show a very poor quality linear correla- tion with a negative slope.23 The intramolecular reaction of furfurylamides (5) in 16 M. E. Jung and J. Gervay J. Am. Chem. Soc. 1991 113 224. 17 M. V. Basilevski V. M. Ryaboi and N. N. Weinberg J. Phys. Chem. 1991 95 5533. 18 R. Sustman W. Sicking H. Lamy-Schelkens and L. Ghosez Tetrahedron Lett. 1991 32 1401. 19 c. Cativiela J. I. Garcia J. A. Mayoral A. Avenoza J. M. Peregrina and M. A. Roy J. fhys. Org. Chem. 1991 4 48. 20 J. F. Blake and W. L. Jorgensen J. Am. Chem. SOC.,1991 113 7430.21 I. Hunt and C. D. Johnson J. Chem. Soc. Perkin Trans. 2 1991 1051. 22 W. Blokziji M. J. Blandamer and J. B. F. N. Engberts J. Am. Chem. Soc. 1991 113 4241. 23 G. Desimoni G. Faita and P. P. Righetti Tetrahedron 1991 47 5857. N. G.Ramsden q i”CONH DNpco2H CO2H (5) the presence of various supramolecular catalysts has been studied.24 MM calculations suggest that the para compound (6) stabilizes starting material whilst the ortho compound (7) stabilizes the transition state. The effect of lithium ions on cycloaddition reactions continues to be a subject of investigation. No reaction was observed on treatment of 1,8,10-undecatrien-3-one with lithium perchlorate whereas lithium tetrafluoroborate gave the product in quantitative yield.This has been ascribed to the slow release of catalytic boron trifluoride rather than catalysis by the lithium cati01-1.’~ Lithium chloride accelerates the Diels- Alder reaction of N-ethylmaleimide to anthracene-9-carbinol but lithium perchlorate slows the rare. This can be accounted for by a modification of the hydrophobic effect and rules out the lithium cation as the catalyst.26 The Diels-Alder reaction of various substrates in lithium perchlorate/diethyl ether shows significant rate enhan~ement.~~ The catalytic activity of this system has been reviewed during the year.’* Further theoretical and experimental support has been given to the theory that transition state hyperconjugation is responsible for facial selectivity in cycloaddition reactions.A variety of cycloadditions involving 5-substituted adamantane derivatives (8) have shown clear but modest preference for attack at the Zu face.29 Hexa- chlorocyclopentadiene and its dimethoxy analogue react with 1,5-~yclooctadiene to produce a 1:4 syn/anti mixture of diadducts (Scheme 2).30,31 The initial mono- adducts have been shown to be fluxional by 13CNMR and MM calculations show no preferences for the face of attack. The facial selectivity must result from conforma- tionally dependant transition of T-u-T interactions. Hexacyclopentadecadiene 24 S. C. Hirst and A. D. Hamilton J. Am. Chem. SOC.,1991 113 382. 25 D. A. Smith and K. N. Houk Tetrahedron Lett. 1991,32 1549. 26 R. Breslow and C. J. Rizzo J. Am. Chem. SOC.,1991 113 4340.27 M. A. Forman and W. P. Dailey ibid. 1991 113 2761. 28 H. Waldmann Angew. Chem. 1991 103 1335. 29 H. Li J. E. Silver W. H. Watson R. P. Kashyap and W. J. Le Noble J. 0%.Chem 1991 56 5932. 30 J. G. Garcia F. R. Fronzek and M. L. McLaughlin Tetrahedron Lett. 1991 32 3289. 31 J. G. Garcia and M. L. McLaughlin ibid. 1991 32 3293. Reaction Mechanisms -Part (i) Pericyclic Reactions xx xx / C Ycl Anti SYn Scheme 2 derivatives (9) show a strong preference for addition to the carbonyl face.32 Orbital tilting and transition state steric and torsional effects cannot alone account for this and unfavourable orbital interactions between the closed shell of the carbonyl and the methylenes syn to the incoming orthogonal 7r orbital of the alkene may be important.Cycloadditions of N-sulfonyl-5-aza-l,3-butadienes give a single product derived from a >20 1 endo transition state.33 The endo selectivity may be partially due to secondary orbital stabilization but the exceptional selectivity suggests that the transition state with the lone pair on nitrogen and the carbon oxygen bond of the dienophile lying transperiplanar benefits from a n- 7r* stabilization. The addition of alkenes to [4,3,2]-propella-2,4,8,10-tetraen-7-one(10) syn to the five membered (8) X = F Ph (9) X = O,CH (10) X = 0,H ring has been rationalized in terms of the difference in dihedral angle between the cyclohexadiene ring and the two flanking rings.34 The 7r facial selectivity of reaction of spiro-(bicyclo[2,2,1]heptane-2,1’-[ 2,4]cyclopentadiene) has been surmized to be due to steric interactions in the transition state.35 The intramolecular Diels- Alder 32 J.M. Coxon R. G. A. R. Maclagan D. Q. Mcdonald and P. J. Steel J. Org. Chern 1991 56 2542. 33 D. L. Boger W. L. Corbett T. T. Curran and A. M. Kasper J. Am. Chem. SOC,1991 113 1713. 34 T. Tsuji M. Ohkita and S. Nishida J. Org. Chem 1991 56 997. 35 D. J. Burnell and Z. Valenta Can. J. Chem. 1991 69 179. N. G. Ramsden reaction of a series of 7-alkoxy-undecatrienes gives trans fused cycloadducts together with significant amounts of the cis fused ad duct^.^^ These must arise via a boatlike transition state and it would appear that the 7-alkoxy substituent electronically destabilizes the chairlike transition state.The enantioselectivity of p-lactam produc- tion by [2+ 21 cycloaddition of imines and chiral ketenes derived from oxazolidines and oxazolidinones is determined by the chiral a~xiliary.~' The relative stereochemistry is primarily determined by the structure of the imine and the free or bound nature of the ketene. In the non concerted [2 + 21 cycloaddition of chiral ketenes with the 2-imine component of diazepines the stereochemistry is determined by minimum steric interactions in the transition state leading to zwitterionic inter- mediates followed by a conrotatory ring closure to products.38 However reaction of diazepines with N-a-diphenylnitrone gives endo and exo products in the same ratio presumably due to an absence of secondary orbital interactions in the transition state.39 A series of enantiometrically pure vinyl ketene acetals which function as diastereoselective dienes in Diels- Alder reactions have been ~ynthesized.~' The relative order of the transition state energies was determined to be Re exo < Re endo < Si endo < Si exo rationalized by molecular mechanics and T charge distribution calculations.The cyclization reactions of allenes have been studied in some detail. The structures and product distribution of the cycloadducts from the reaction between 1,3-dimethylallene and alkenes indicate a two step reaction via a diradical ir~termediate.~~ The reaction can occur via an anti anti- or anti syn-diradical and product distribution appears to depend upon the degree of develop-ment of the diradical intermediate.Use of chirally enriched allenes gave all four possible cycloadducts with varying degrees of racemization. Molecular modelling calculations on the conformational energy surface for approach to give the activated complex and diradicals suggest that three minimum energy channels exist for the reaction and they differ in the extent of the facial selectivity of attack.42 p-Tolyl vinyl sulfoxide has been activated as a Diels-Alder dienophile and gives very good diastereomeric excess at -20 "C. Endo attack occurs from the Si face with the S-cis conformer of the sulfoxide being preferred.43 A bisoxazolidine/Fe"' couple (1 1) catalyses the chiral Diels- Alder reaction of 3-acryloxyl-l,3-oxazolidine-2-one with Me Me 36 W.R. Roush M. Kageyama R. Riva B. B. Brown J. S. Warmus and K. J. Moriarty J. Org. Chem. 1991 56 1192. 37 L.S. Hegedus J. Montgomery Y. Narukawa and D. C. Snustad J. Am. Chem. Soc. 1991 113 5784. 38 M. Muller D. Bur T. Tschamber and J. Streith Helu. Chim. Acta. 1991 74 767. 39 K. Saito A. Yoshino and K. Takahashi Heterocycles 1991 32 1. 40 M. A. Boehler and J. P. Konopelski Tetrahedron 1991 47 4519. 41 D. J. Pasto K. D. Sugi and J. L. Malandra J. Org. Chem. 1991 56 3781. 42 D. J. Pasto and K. D. Sugi ibid. 1991 56 6216. 43 B. Ronan and H. B. Kagan Tetrahedron; Asymmetry 1991 2 75. Reaction Mechanisms -Part (i) Pericyclic Reactions H cyclohexadiene.4 It is proposed that the major reaction pathway involves a stereoisomeric octahedral complex with the dienophile complexing via an axial and equatorial bond relative to the plane of the ligand.Oxazaborolidine catalysts have been devised which generate chiral adducts with >95 :5 enantioselectivity in the reaction of dienophiles with cyclopentadiene via the proposed adduct (12).45 N-acylnitroso dienophiles derived from C2 symmetric pyrrolidines react with cyclo- hexadiene to give adducts in excellent diastereomeric excess (Scheme 3).46 Use of pyrrolidines of opposite helicity gives products of the opposite configurations. n Scheme 3 Analysis of the microwave spectra of ozone/ethene mixtures shows that they are consistent only with a Van de Waals complex of C3 symmetry with ethene and ozone having near parallel planes:’ It is argued that this complex lies in a shallow minimum prior to the transition state.2 Sigmatropic Reactions The preference for chair-like transition states in the ester enolate Claisen rearrange- ment has been investigated using a variety of straight chain carbocyclic and heterocyclic propanoates. A novel stereoelectronic effect in pyranoid and furanoid 44 E. J. Corey N. Imai and H. Y. Zhang J. Am. Chem. SOC.,1991 113 728. 45 E. J. Corey and T. P. Leh ibid. 1991 113 8966. 46 A. Defoin A. Brouillard-Poichet and J. Streith Helv. Chim. Acta 1991 74 103. 47 C. W. Gillies J. Z. Gillies R. D. Suenram F. J. Lovas E. Kraka and D. Cremer J. Am. Chem. SOC. 1991 113 2412. N. G. Ramsden glycals appears to stabilize the boat-like transition state whilst the preferred transi- tion state in carbocycles is dependent upon steric factors?8 The products from the reaction of methyl hydroxydithioalkanoates with LDA and allylic bromides undergo a thio-Claisen rea1~angement.4~ Both E and 2 isomers give predominantly syn products and a rationalization in terms of transition state structure has been given (Scheme 4).Macrolides synthesized from p-amino acids undergo the Claisen rearrangement to give chiral pyrrolidines via a boatlike transition state (Scheme 5).50 The tri-s-butyl aluminium catalysed Claisen rearrangement of bicyclic allyl Scheme 4 I I CO2Et CO2Et Scheme 5 vinyl ethers gives rise to ring expanded products with exocyclic vinyl ethers reacting uia a chairlike transition state and endocyclic ethers reacting via a boatlike transition ~tate.~' The asymmetric Claisen rearrangement of allyl vinyl ethers has been effected with a chiral organoaluminium species (13).52Conformational analysis of the two chairlike transition states reveals that the aluminium species must differentiate between them on the basis of the orientation of the methylene group of the substrates.A method has been described for the enantioselective Ireland-Claisen rearrangement of achiral allylic esters with high asymmetric induction using a chiral br~moborane.~~ Thus reaction of E-crotyl propionoate and the bromoborane (14) gave either the threo or erythro product depending upon base and solvent. The absolute and relative 48 R.E. Ireland P. Wipf and J. N. Xiang J. Org. Chem. 1991 56 3572. 49 P. Beslin and S. Perrio Tetrahedron 1991 47 6275. 50 J. Cooper D. W. Knight and P. T. Gallagher J. Chem SOC.,Perkin 1 1991 705. 51 L.A. Paquetta D. Fredrich and R. D. Rogers J. Org. Chem. 1991 56 3841. 52 K.Maruoka H. Banno and H. Yamamoto Tetrahedron; Asymmetry 1991 2 647. 53 E. J. Corey and D. H. Lee J. Am. Chem. Soc. 1991 113,4026. Reaction Mechanisms -Part (i) Pericyclic Reactions stereochemistry of the products can be rationalized in terms of the steric bias of the chiral auxiliary. The para-Claisen rearrangement of hydroxypropenyloxy benzaldehydes (15) has been studied.54 Three products are obtained the expected dihydroxypropenyl benzaldehydes (16) dihydroxypropenyl benzene (17) and dihydroxypropenyl ben- zaldehyde (18).The formation of the benzene is rationalized as occurring via a [ 1,2] shift of a formyl group in the ortho-cyclohexadiene intermediate. The formation of the latter benzaldehyde is proposed to occur via a [2,3] sigmatropic shift of the allyl group in the para-cyclohexadiene intermediate. The free phenol group is essential for the formation of these abnormal products. OH OH 3 OH The rearrangement of allyl vinyl ethers in lithium perchlorate in ether occurs via a [ 1,3] sigmatropic rearrangement rather than the normal [3,3] sigmatropic rearrangement .55 The oxy-Cope rearrangement of 1,5-heptadiene-3-ols has been studied.56 The reaction proceeds via chairlike rather than boat-like transition states and the difference in energy levels between them appears to be determined by an equatorially orientated oxido group.Secondary deuterium kinetic isotope effects indicate a highly dissociative transition state with substantial bond breaking of the C-3-C-4 bond 54 S. N. Kilenyi J. M. Mahaux and E. Van Durme .I.Org. Chem. 1991 56 2591. 55 P. A. Grieco J. D. Clark and C. T. Jagoe J. Am. Chem. SOC.,1991 113 5488. 56 L. A. Paquette and G. D. Maynard Angew. Chem. 1991 103 1392. 60 N. G. Ramsden and little bond making between the allylic termini.” The E/Z stereoselection in the reaction of the analogous 4-01s has been determined allowing a reasonable transition state to be p~stulated.’~ The [3,3] sigmatropic shift of the oxy-Cope rearrangement of norbornane derivatives proceeds with 100% stereoselectivity uia an endo chairlike transition state.59 The E and syn stereochemistry of the product enolates is established during chirality transfer at this stage and the oxygen up conformation stems from structural features present in the starting material.The E syn up enolates are thermodynamically unstable with respect to the E syn down atropisomers and the products may arise from reaction of these with electrophiles. Modelling of the Cope rearrangement using a CASSCF wavefunction and a 6-31G* basis set shows both a symmetrical aromatic transition state and a dissymmetric transition state followed by a symmetrical biradical intermediate.60 The ene reactions between chiral aP unsaturated oxazolidines and alkenes do not proceed with high diastereoselectivity as the reaction can occur uia endo or exo transition states and both syn and anti hydrogens can be abstracted.61 The reverse ene reaction of the cyclobutane (19) occurs via a concerted mechanism and the stereochemical outcome is consistent with a transition state with the alkenyl moiety endo with respect to the ring and the breaking C-H bond aligned with the breaking C-C bond.62 A kinetic study of the ene reaction between methyl acrylate and P-pinene under aluminium trichloride catalysis in a variety of solvents suggests that the transition state has pronounced zwitterionic ~haracter.~~ The circumambulatory migration of acyloxy groups or bromine around a cyclopentadiene ring has been elucidated.64y65 Optically active reactant can be recovered unchanged after the thermal rearrangement of the dicyclopropane (20).66However the product (21) is HH 4 Mew H OMe Et 50% racemized.This rules out reaction passing exclusively through a symmetrical biradical intermediate and formally the reaction data can be explained as two competing allowed a2s + a2a reactions passing over diastereomeric transition states to enantiomeric products. 1-t-Butyl-3-methylallene undergoes a thermal [1,3] sig-matropic rearrangement to 1-t-b~tyl-l,3-butadiene.~~ The mechanism is proposed 57 J. J. Gajewski and K. R. Gee J. Am. Chem SOC.,1991 113,967. 58 K. Tomooka S. Y. Wei and T. Nakai Chem. Lett. 1991 43. 59 L. A. Paquette K. D. Combrink S.W. Elmore and R. D. Rogers J. Am. Chern. SOC.,1991 113 1335. 60 M. Dupuis C. Murray and E. R. Davidson ibid. 1991 113 9756. 61 B. B. Snider and Q. Zhang J. Org. Chem. 1991 56 4908. 62 S. J. Getty and J. A. Berson J. Am. Chem. SOC.,1991 113 4607. 63 P. Laszlo and M. Teston-Henry J. Phys. Org. Chem. 1991,4 605. 64 I. E. Mikhailov G. A. Dushenko I. A. Kamenetskaya 0.E. Kompan Y. T. Struchkov and V. I. Minkin Mendeleev Commun. 1991 83. 6s V. I. Minkin I. E. Mikhailov G. A. Dushenko I. A. Yudilevich R. M. Minyaev A. Zschunke and K. Muegge J. Phys. Org. Chem. 1991 4 31. 66 M. D. Wendt and J. A. Berson J. Am. Chem. SOC.,1991 113 4675. 67 D. J. Pasto and J. E. Brophy J. Org. Chem. 1991 56 4554. Reaction Mechanisms -Part (i) Pericyclic Reactions to be concerted with migration of hydrogen to the 2p antibonding orbital on the central carbon atom of the allene and concomitant 90" rotations at the termini of the 1,3-butadiene system.Early transition state structures of the [2,3] Wittig rear- rangements of allylsulfonium methylides have been located with the E3-21(G)* and 6-31 + G" basis sets.68 They have envelope conformations with the slightly formed C-C bond nearly eclipsed with the partially broken C-S bond. The rearrangement of vinyl cyclopropanes to cyclopentenes has been studied. The use of chiral deuterium labelled trans-1-ethenyl-2-methylcyclopropanesin thermal rearrangements has shown that four stereochemically distinct pathways exist.69 There is no significant energetic preference for concert in evidence and orbital symmetry control of the stereochemical outcome does not seem to be a plausible explanation.To avoid steric influences of alkyl substituents on the cyclopro- pane ring deuterium labelled substrates (22) were used.70 The reaction was >85% stereospecific consistent with a disrotatory ring opening followed by a rapid ring closure of the diradical. High stereospecificity at each of the three stereogenic sites is obtained during the rearrangement of cis-2- (2-propy1)- 1 (E) propenyl cyclopro- pane (23).'* This result is predicted if the reaction is controlled by optimal overlap of C-H and 7r bonding orbitals with the C3 syn component of the degenerate 3E' HOMO of the cyclopropane ring. D Dehydrofluorinative aromatization of (24) occurs via a two step rnechani~rn.~~ The first step is a rate determining homolytic hydrogen shift.The [1,3] hydrogen shifts in propene have been studied by MO calculations for both the neutral molecule and the radical cation. The migratory process occurs antarafacially via a C3transition state. The barrier height is reduced from 358 kJ/mol to 139 kJ/mol in the radical cation due to a weakened C-H bond and a more favourable orbital interaction in the transition state. The distribution of localized orbital centroids suggests that proton transfer occurs in propene whilst hydride transfer occurs in the radical 68 Y. D. Wu and K. N. Houk ibid. 1991 56 5657. 69 J. E. Baldwin and N. D. Ghatlia J. Am. Chem SOC.,1991 113 6273.70 J. J. Gajewski and L. P. Olson ibid. 1991 113 7432. 7' P. A. Parziale and J. A. Berson ibid. 1991 113 4595. 72 W. R. Dolbier J. J. Kaeffaber C. R. Burkholder S. F. Sellers H. Koroniak and J. Pradhan Tetrahedron Lett 1991 32 3933. 73 M.T. Nguyen L. Landuyt and L. G. Vanquickenborne Chem. Phys. Lett. 1991 182 225.

ISSN:0069-3030    

DOI:10.1039/OC9918800051

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (ii) Polar Reactions By J. M. PERCY Department of Chemistry Keele University Keele Staffordshire ST5 5BG 1 Introduction The 1991 literature contained an interesting spread of review articles covering many aspects of physical organic chemistry. One of the subject's cornerstones the Hammett equation forms the subject of two articles with different emphases. One' contains an appraisal of the various substituent constants including field and resonance parameters and a large compilation of data including 530 0-constants and 223 values for up+and up-while the second article2 concentrates on applications. Aspects of carbocation chemistry covered include electronegatively-substituted(or electron deficient) carbocations3 and recent theoretical NMR isotope effect and rearrange- ment st~dies.~ Kochi' has reviewed his work on charge transfer interactions and their importance in organic reactions with emphasis on aromatic nitrations while Ridd6 has summarized the evidence for free radical pathways in aromatic nitrations in nitric acid.Alkynyl carboxylate phosphate and sulfonate esters undergo hydrolysis to pro- duce mechanistically-interesting species some with enzyme inhibitory properties; Stang' has reviewed his groups work in this area. Medium effects were covered by a number of authors; the transfer of organic reactions to water produces some most interesting results; Breslow* examined the scope of hydrophobic effects on the Diels- Alder reaction and benzoin condensation. Micellar effects on reaction rates were reviewed' as were theoretical approaches to understanding solvent effects." The effect of high pressure on polar reactions has provided much mechanistic insight and forms the subject of an account by Isaacs." On a more general note Epiotis12 has questioned the theoretical justification for 'arrow-pushing' particularly it's description of hyperconjugation and found it C.Hansch A. Leo and R. W. Taft Chem Rev. 1991 91 165. * J. Shorter Stud. Org. Chem. (Amsterdam) 1991 42 77. X. Creary Chem. Rev. 1991,91 1625. M. Saunders and H. A. Jiminez-Hugo Chem. Rev. 1991 91 375. J. K. Kochi Pure Appl. Chem. 1991 63 255. J. H. Ridd Chem SOC.Rev. 1991 20 149. P. J. Stang Acc. Chem. Res. 1991 24 304. R. Breslow Acc. Chem Res.1991 24 159. C. A. Bunton SurSactant Sci. Ser. 1991 38 13. 0. Tapia Theor. Models Chem. Bonding 1991 4 435 N. S. Isaacs Tetrahedron 1991 47 8463. N. D. Epiotis THEOCHEM 1991 75 205. 63 J. M. Percy lacking. However this author suspects that it may be some time before a technique computational or otherwise is developed which can rival our familiar toxophilic approach for user-friendliness speed or predictive power. 2 Solvolysis and Carbocations Very stable carbocations have been described;13tris( 1-azuleny1)methanes [1(a)-(c)] have pKR+ values of 11.3 11.4 and 10.3 respectively in 50% aqueous acetonitrile the highest values for simple hydrocarbon-derived cations. l(a) R = H; (b) R = Me; (c) R = C02Me. Heats of reaction have been determined for five highly-stabilized carbocations with amines in sulfolane using a calorimetric te~hnique.'~ A good correlation between the heat of reaction and pKR+ was reported but pKBH+ (aqueous) was a poor model for amine nucleophili5ty and the measured heat of reaction proved less sensitive than anticipated to steric hindrance in the nucleophile.The flash photolysis technique has afforded rate constants for the reaction of azide anion and 28 stabilized carbo~ations,'~ validating the 'azide clock' method much used as a probe of solvolytic reactions. Mayr's group have used flash photolytic16 and condu~timetric'~ methods to study the reactions of allylsilanes enol ethers and silyl enol ethers with diaryl carbenium ions. The allyl metals can be regarded simply as donor-substituted alkenes which undergo rate-determining addition to diaryl carbenium ions to form &stabilized carbenium ions (Scheme 1).A nucleophilicity scale for carbon nucleophiles covering seven orders of magnitude is included in the second paper. Scheme 1 Gassman and co-workers have describedI8 a series of experiments designed to probe the nature of allyl cations; cycloaddition trapping reactions show that proton- ation of (2a) and deuteriation of (2b) at -78°C produces distinct cations (3a) and (3b) and not the common species (4). At temperatures below -23 "C diene or cation interconversion fails to compete with cycloaddition though this depends on the l3 S. Ito N. Morita and T. Asao Tetrahedron Lett. 1991 32 773.E. M. Arnett and S. Venimadhavan J. Org. Chem. 1991 56 2742. " R. A. McClelland V. M. Kanagasabapathy N. S. Banait and S. Steenken 1. Am. Chem. Soc. 1991 113 1009. 16 J. Bartl S. Steenken and H. Mayr J. Am. Chem. Soc. 1991 113 7710. 17 G. Hagen and H. Mayr J. Am. Chem. Soc. 1991 113 4954. l8 P. G. Gassman D. A. Singleton and H. Kagechika J. Am. Chem. SOC.,1991 113 6271. Reaction Mechanisms -Part (ii) Polar Reactions acid used. Acids with large counter-ions cause cations (3a) and (3b) to interconvert; it is proposed that the allylic cations exist as tight ion pairs in which the counter-ion controls the reactivity. The biologically-important cyclization of squalene to steroid hormones is believed to involve extended .rr-participation; secondary isotope effects on the solvolysis of (5) in highly polar media are produced" as evidence for concerted tricyclization.In superacid media menthol (6) and neomenthyl chloride (7) were expected to form the simple menthyl cation (8); Dean and Whittake8' have shown that they form distinct cations neither via (8) but both involving group migrations in concert with leaving group departure. It was anticipated that the a-hydroxyketone (9) would afford a destabilized a-ketocation (10) on treatment with trifluoromethane sulfonic acid (Scheme 2). However Olah and Wu2' detected the products of a concerted elimination of benzaldehyde instead. If additional groups capable of stabilizing positive charge were present at the a-position products formed from a-keto cations were observed.19 0. Kronja M. Orlovic K. Humski and S. Borcic J. Am. Chem. SOC.,1991 113 2306. 20 C. Dean and D. Whittaker J. Chem. Soc.,Serkin Trans 2. 1991 1541. 21 G. A. Olah and A. Wu J. Org. Chem. 1991 56 2531. J. M. Percy &To +PhCHO / 0 Scheme 2 Amyes and Richard22 have investigated a-azido benzyl cations (1 l) potential intermediates in the Schmidt reaction by which benzaldehydes are converted to benzonitriles by the action of hydrazoic acid. These cations are more stable than (12) their a-methoxy analogues by factors of 16 (lla) and 60 (llb). No Schmidt products were observed in 50% aqueous trifluoroethanol but as the authors point OMe N3 I XJy+ Xd+ ll(a) X =MeO; (b) X =H. 12(a) X =MeO; (b) X =H.out the rate-determining step may be different in the strongly acidic medium used for the preparative reaction with elimination of nitrogen becoming faster than cation hydrolysis. In less stabilized systems the effect of an additional electron withdrawing substituent can be dramatic. R (13) uia C ionization OH 0-7 R Scheme 3 22 T. L. Amyes and J. P.Richard J. Am. Chem. SOC.,1991 113 1867. Reaction Mechanisms -Part (ii) Polar Reactions 67 Diol(l3) and its C1 antipode (14) undergo stereospecific spirocyclization (Scheme 3) via displacement of the primary hydroxyl group when R is meth~xy.~~ Less electron withdrawing substituents at C-2 allow the more usual C-1 ionization mechanism to compete. Nitrous acid deamination of primary amines has been studied using careful stereochemical experiments; the reaction is almost completely stereospecific compelling evidence against primary carbenium ion formation.24 3 Other Nucleophilic Substitutions Of note this year is a rise in the number of publications dealing with reactions at phosphorus presumably reflecting the increasing importance of nucleotide and oligonucleotide chemistry.Lonnberg's group2' have published a number of papers in this area studying compounds that model dinucleotides. Monomethyl- and monoisopropyl esters of adenosine-3'-monophosphate[15(a) and (b)] undergo three parallel reactions in aqueous solution (Scheme 4); group transfer to the 2'-ester (path a),hydrolysis to a mixture of 2'-and 3'-monophosphates (path b) and cleavage of the glycosidic bond (path c) have all been detected.+ HO 0 / P=O P=O 0 OH HO' I HO/I0-""TiAd 0- \ P=O RO/),-15(a) R Me; (b) R = Pr'. HO 0 \ ,P= RO I 0- 0 OH \ P=O HO /),-Scheme 4 For 15(a) all three pathways operate at comparable rates in acid while under neutral conditions (pH 4-9) path a operates independent of pH. Above pH 9 path b becomes dominant. With 15(b) path c becomes faster than path b. Details of the mechanisms at phosphorus are discussed. Similar studies for a range of dinucleotide 23 L. A. Paquette and J. T. Negri J. Am. Chem. SOC.,1991 113 5072. 24 D. Brosch and W. Kirmse J. Org. Chem. 1991 56,907. 25 M. Oivanen R.Schnell W. Ptleiderer and H.Lonnberg J. Org. Chem. 1991 56 3623 J. M. Percy monophosphates (UpU UpA ApU and ApA) expose reactivity differences centred on the acidities of the 2’- and 3’-hydroxyl groups.26 Dinucleotides with a 5’-uridine are more readily hydrolysed at the diester linkage than those with an adenine in this position but the depurination rate is insensitive to the nature of the heterocyclic base. Menger2’ has published a critical discussion of Breslow and Hwang’s study of the hydrolysis of ApA and UpU in which negative rate constants were reported. Phosphonoformate esters ( 16) are potential pro-drugs for the phosphonoformate trianion (17) an antiviral compound for use in AIDS therapy but of extremely low membrane permeability. Hydrolysis studies on triesters reveal a competitive situation between P-C and C-0 cleavage raising a problem in pro-drug design.28 Initial cleavage of the R-0 bond in (16) exposes a carboxylate anion which drives decar- boxylation to the hydrogen phosphonate diester.When the conjugate base of ROH is a good leaving group which it must be for antiviral activity this situation prevails. Only by making the conjugate base of R’OH a better leaving group than the conjugate base of ROH can the pro-drug be successfully channelled through to (17). 0 0 Scheme 5 A mechanism has been proposed for the hydrolysis of phosphonopyruvate (18) which involves pre-equilibrium proton transfer to the carboxyl oxygen followed by P-C bond cleavage and tautomerization (Scheme 5).29 Forbes and Maskill examined the solvolyses of arenesulfonyl chlorides in aqueous triflu~roethanol.~’ A shift in mechanism from an associative to a dissociative pathway as the arene became strongly electron-donating was reported by earlier authors; this was not confirmed by the present study.Halogen-exchange reactions of 5-bromo- and 5-iodocyclopentadiene are faster than in the corresponding cyclopentyl compounds3’ but the data so far obtained do not allow SN2 and sN2’ pathways to be distinguished nor do they rule out SET processes. Banait and Jenck~~~ have shown that cY-D-glUCOpyranOSyl fluoride under- 26 P. Jarvinen M. Oivanen and H. Lonnberg J. Org. Chem. 1991 56 5396. 27 F. M. Menger J. Org. Chem. 1991 56 6251. 28 E. S. Krol J. M. Davis and G. R.J. Thatcher J. Chem. SOC.,Chem. Commun. 1991 118. 29 S. Freeman W. J. Irwin and C. H. Schwalbe J. Chem. SOC.,Perkin Trans 2 1991 263. 30 R. M. Forbes and H. Maskill J. Chem. SOC.,Chem. Commun. 1991 854. 31 R. Breslow and J. W. Canary J. Am. Chem. SOC.,1991 113,3950. 32 N. S. Banait and W. P. Jencks J. Am. Chem. SOC.,1991 113,7951. Reaction Mechanisms -Part (ii) Polar Reactions goes concerted nucleophilic (ANDN) displacement with anionic nucleophiles a reaction pertinent to the mechanism of action of glycosidase enzymes. 4 Elimination Reactions Hall and co-~orkers~~ examined the formation of methacrylamide (19) from (20) in strong acid (90-102% sulfuric acid) using NMR methods. The E2 elimination described by (21) is the rate-determining step.Labelling the oxygen ("0) of the scissile C-0 bond shows retention of the label ruling out pre-equilibrium exchange of oxygen via an El loss of hydrogen sulfate. Deuterium isotope effects identified a rate-limiting proton transfer and considerations of pK support the E 2 mechanism. Amyes and Richard34 uncovered an interesting pericyclic elimination in the course of their studies of changes between mechanistic pathways. Cumyl derivatives (22) undergo solvolysis the mechanism being determined by substituent X; when X is more electron-withdrawing than a meta-fluorine (ax+> 0.34) unexpectedly large (up to 30%) amounts of a-methylstyrene are detected. These products are formed by pericyclic Ei or (cyclo-D,D,AN) eliminations and are enforced by the instability of intermediates on the stepwise solvolysis pathway.m Eliminations across C-S bonds to form sulfines occur when (23) is treated with methoxide in methanol via a mechanism at the (E lcB)J( E lcB)irrevb~rderline.~' The elimination is facile and possibly facilitated by repulsion between the dipoles of the sulfoxy and sulfonyl groups. 33 C. D. Hall C. J. Leeding S. Jones S. Case-Green I. Sanderson and M. van Hoorn J. Chem. SOC. Perkin Trans. 2 1991 417. 34 T. L. Amyes and J. P. Richard J. Am. Chem. SOC.,1981 113 8960. 35 J. L. Kice and L. Kupczyk-Subotkowska J. Org. Chem. 1991 56 1424. J. M. Percy Sulfene intermediates are involved36 in the reactions of methoxide with aryl mesylates (24); pyrrolidine imine (25) was used to trap these sulfonyl analogues of ketene as sulfone (26).This pathway only predominates when the aryl group is 4-nitrophenyl; less electron-withdrawing groups favour reaction at sulfur. Reactions forming imines3’ from (27) were described; eliminations are regio- specific leading to benzylidenes (28). Base-promoted and solvolytic pathways were identified the former occurring via an E2 mechanism while the latter involves initial leaving-group departure to form a nitrenium contact ion pair from which rate-limiting proton transfer occurs. ~ R PhCN~ + ArO-Scheme 6 The Korean group has also probed the reactions of (E)-0-arylbenzaldoximes (29) with secondary amine~;~~ E2 and S,Ar (Scheme 6) mechanisms compete when the aromatic moiety is highly activated.Highly concentrated or ’strong bases and the picryl leaving-group favour the latter pathway. 5 Addition Reactions The trifluoroacetylation of aryl vinyl sulfides (30) has been in~estigated;~~ second-order rate constants for five para-substituted compounds can be fitted to the Hammett equation with p = -3.0. Deuterium isotope effects at the P-carbon (kH/ kD = 2.5) were consistent with a stepwise trifluoroacetylation via a carbenium ion but at variance with the result of a stereochemical experiment. The introduction of 36 M. J. Pregel and E. Buncel .I.Chem. SOC.,Perkin Trans 2 1991 307. 37 B. R. Cho and S. Y. Pyun J. Am. Chem. SOC.,1991 113 3920. 38 B. R. Cho B. K. Min C. W. Lee and J. T. Je J. Org. Chem. 1991,56 5513. 39 M.Hojo R. Masuda Y. Kamitori and E. Okada 1Org. Chem. 1991,56 1975. Reaction Mechanisms -Part (ii) Polar Reactions 71 deuterium at the P-carbon in a defined stereochemical relationship to the arylthio- group led to the recovery of trifluoroacetylated product in which the stereochemistry was completely retained. The authors propose a mechanism in which addition of the electrophile and proton-loss are concerted. Kresge and Yin4’ have investigated the hydrolysis of 1-methoxycyclooctene (31); by analogy with 1-methylcyclooctene it was anticipated that protonation would be reversible. This has been attributed to some unusual conformational feature of the eight-membered ring but it was shown that the hydrolysis follows the well-established general acid catalysis mechanism.A key piece of evidence is the authors’ failure to recover deuterated starting material after incubation in perdeuterophosphate buffer at pH 8 after the reaction had proceeded to 50% completion. Idtramolecular catalysis of vinyl ether hydrolysis has been identified41 with an effective molarity of 290 M. The carboxyl group of (32) is the most efficient intramolecular catalyst of a reaction involving proton transfer to carbon though the origin of this catalytic effect is unclear. The epoxidation of alkenes is an important synthetic reaction to which Beak and Woods have applied the endocyclic restriction test.42 By making the epoxidation intramolecular either transition state (33) or (34) (Scheme 7) can be preferred by adjusting the tether length.With the short tether (n = l) labelling studies showed that an intermolecular reaction occurred but when the longer tether was present the reaction was exclusively intramolecular supporting Bartlett’s ‘butterfly’ mechan- ism (34). 0 \ clh-+ 02*H -C1YYC02*H II I II I n=lor9 Scheme 7 OH Adamantylidene adamantane bromonium ion (35) has been isolated43 and used to prepare the perdeutero- trans-2-bromo-1-cyclohexyltriflate (36) in unusually high yield. Degenerate bromine transfer from (35) to adamantylidene adamantane occurs with a calculated second-order rate constant of 2 x lo7 M-’ s-’ suggesting to these authors that intermolecular Br+ transfer from bromonium ions to alkenes could be a kinetically-significant process during alkene bromination.The Paris groupa have 40 A. J. Kresge and Y. Yin Can. J. Chem. 1991,69,84. 41 A. J. Kirby and N. H. Williams J. Chem. Soc. Chem. Commun. 1991 1643. 42 K. W. Woods and P. Beak J. Am. Chem. Soc. 1991,113 6281. 43 A. J. Bennet R. S. Brown R. E. D. McClung M. Klobukowski G. M. Aarts B. D. Santarsiero G. Bulluci and R. Bianchini J. Am. Chern. Soc. 1991,113 8523. 44 M.-F. Ruasse S. Motallebi and B. Galland J. Am. Chem. Soc. 1991,113 3440. J. M. Percy examined the role of solvents in alkene bromination using solvent isotope effects and Grunwald- Winstein parameters. In protic media solvent assistance to cleavage of the inter-bromine bond is provided whereas in halogenated solvent this role is fulfilled by a second molecule of bromine which aids progress from charge transfer complex to bromonium and tribromide ions in a reversible process.Bromonium ions can be trapped by solvent when bromination reactions are performed in damp acetonitrile leading to a range of products; this year saw the publication of a kinetic and product distribution ~tudy.4~ 6 Aromatic Addition and Substitution A number of interesting results have been described in the area of electrophilic aromatic substitution. Second-order rate constants have been measured for nitration reactions in concentrated aqueous triflic acid allowing medium effects to be assessed.46 The NO2+ rates show minimal dependence on the acidity or nature of the medium (though these factors do affect the active concentration of the nitrating species).The nitration of methylphenyl sulfone shows biphasic behaviour passing through a maximum at 92% (w/v) triflic acid. The decreasing activity of water as the percentage of triflic acid rises results in increasingly strong interactions between ionic species. This begins to lower the concentration of NO2+ and depress the rate. Nitrations in dinitrogen pentoxide and using nitronium salts have been examined using "N CIDNP NMR. In the former medium SET processes are clearly visible,47 particularly in the nitrodecarboxylation of 3-nitrobenzoic acid and are implicated in its nitration to 3,5-dinitrobenzoic acid. The nitrosation of phenol by isopentyl nitrite (IPN) and S-nitroso-aminopenicillic (SNAP) acid has been st~died.~' The two electrophiles react by different mechanisms; the former electrophile (IPN) undergoes prior hydrolysis to nitrous acid which nitrosates via a polar mechanism whereas SNAP homolyses and nitrosates via a free radical pathway.Friedel-Crafts acetylation of naphthalene affords mixtures of 1-and 2-acetonaph- th~ne;~~ different rate laws were obtained for formation of the two products the a-adduct being formed via a third-order reaction with a second-order process affording the P-isomer. Steric effects at the cr-complex level are responsible for the difference in pathways; the effects exert themselves in the transition state for proton 45 G. Belluci R. Bianchini and C. Chiappe J. Org. Chem. 1991 56 3067. 46 N. C. Marziano C. Tortato and M. Sampoli J.Chem. SOC.,Perkin Trans. 2 1991 645. 47 R. B. Moodie A. J. Sanderson and R. Willmer J. Chern. Soc. Perkin Trans 2 1991 645. 48 S. M. N. Y. F. Oh and D. L. H. Williams J. Chem. SOC.,Perkin Trans. 2 1991. 685. 49 D. Dowdy P. H. Gore and D. N. Waters J. Chem. SOC.,Perkin Trans. 2 1991 1149. Reaction Mechanisms -Part (ii) Polar Reactions 73 loss and rearomatization the more hindered a-species requiring a second molecule of aluminium trichloride to prepare the Wheland intermediate for proton loss. Galli has compared four methods for aromatic iodination5' by competition experi- ments between durene and mesitylene. Within 2 or 3% the mesitylene/durene rate ratio of 50 1 remains constant for the four methods which differ considerably in reactivity.Galli concludes that the reactive species in all four methods is the iodonium ion I+. The basicity of alkali metal alkoxides in methanol forms the subject of a number of papers two of which deal with the reversal of the normal order of basicity as the alkali metal counter-ion is varied. Highly activated anisole derivatives which can form 1:2 and 1 :3 adducts with methoxide in methanol are more reactive with sodium methoxide than with potassium. These higher adducts involve highly local- ized charge which is more effectively solvated by the smaller sodium cation.51 The excess basicity method (X function) has been used to study the reactions of eleven less-activated arene~;'~ m* depends on the degree of solvation in the transition states leading to the Mesenheimer complexes and explain the higher reactivity of ortho- chloronitrobenzene than the para-isomer in concentrated (>3M) methoxide sol- utions.The reactions of the former substrate exhibit a higher slope parameter consistent with a lower degree of external solvation. Transition state (37) is proposed CliTY";[I ' 0- / to explain this difference. With carbon nucleophiles Crampton and Stevens have shown strong parallels between structure and reactivity in the a-adduct forming reactions of carbon nucleophiles with activated anisoles and in their protonation behaviour suggesting that the timing of electronic and solvent reorganization events is similar in both processes.53 The addition of vinyl Grignard reagents to nitroarenes forms the subject of a rigorous product distribution studys4 and a general procedure for fluorodenitration of aromatic compounds was also published including some reactivity data.s5 7 Proton Transfer and Carbanions Aspects of this area studied this year range from the most fundamental proton transfer processes to carbanionic rearrangements of synthetic utility.Berg and JencksS6 have used NMR methods to study the dissociation of ammonium-ion-water complexes. Rate constants for hydrogen bond breaking 50 C. Galli J. Org. Chem. 1991 56 3238. 51 P. C. M. F. Castilho M. R. Crampton and J. Yarwood J. Chem. SOC.,Perkin Trans. 2 1991 639. 52 A. Bagno G. Scorrano and F. Terrier J. Chem. SOC.,Perkin Trans. 2 1991 651. 53 M. R. Crampton and J. A. Stevens J. Chem.SOC.,Perkin Trans. 2 1991 1715. 54 M. Bosco R.Dalpozzo G. Bartoli G. Palmieri and M. Petrin J. Chem. SOC.,Perkin Trans. 2 1991 657. 55 M. Maggini M. Passudetti G. Gonzales-Trueba M. Prato U. Quintilly and G. Scorrano J. Org. Chem. 1991 56 6407. 56 U. Berg and W. P. Jencks J. Am. Chem. SOC.,1991 113 6997. J. M. Percy between 3-substituted quinuclidines and water show a dependence on base strength with /3 = -0.25. Various contributions to the free energy of hydrogen bond breaking were analysed including dispersion forces between donor and acceptor and the energy required to create a cavity for the unbound water molecule to diffuse into. The results suggest that an earlier analysis of negative PN values for phosphoryl transfer reactions based on nucleophile desolvation was correctly made.The enoliz- ation of carbonyl compounds is of fundamental importance and is much studied though usually in the reverse (ketonization) dire~tion.’~ A direct study of aldehyde enolization in concentrated acetate buffer solutions revealed concerted catalysis of the enolization reaction by both acetate and acetic acid components of the buffer. The concerted process is most significant when both acid and base catalysis is effective and appears to be more important for aldehydes than ketones. This difference in behaviour is attributed to the lower basicity higher enol content and higher C-H acidity of the aldehydes compared with the ketones. The high rates of proton abstraction achieved by enzymes from carbon acids such as carbonyl deriva- tives forms the subject of a recent This probes the role of electrophilic catalysis and argues that it’s effect is to lower the pKa of the a-protons to values comparable with those of the active site bases facilitating the rapid proton transfers required.The effect of carbonyl protonation on a-proton acidity is used to model the electrophilic effect. The kinetic acidity of cubane has been determined” using a 3H NMR method; the cage hydrocarbon is shown to be 6.6 x times less acidic than benzene approximately five times more acidic than expected from ‘H-13C coupling constants. Cubane is less acidic than cyclopropane consistent with the lower s-character of its C-H bonds. Equilibrium acidities measured in DMSO have been used to estimate aromatic stabilization energies in heterocyclic anions.60 A typical procedure involves the comparison of a cyclic species {(38) pKa = 13.5) with an acyclic model {(39) pKa = 18.7); the difference is converted to an aromatic stabilization energy and attributed to the formation of a (4n + 2) electron anion.The electroreduction of a-bromoamides in DMF has been used6* to establish a pKa scale in DMF covering 10 orders of magnitude for weak acids and related to the DMSO acidity scale; this allows the calculation of pKas in DMF given values in the other solvent. An extended caesium ion pair acidity scale in THF has been reported62 and used to study the acidity of oxime (40),an interesting class of enolate equivalents The oxime 57 A.F. Hegarty and J. Dowling J. Chem. Soc Chem. Commun. 1991 996. 58 J. A. Gerlt J. W. Kozarich G. L. Kenyon and P. G. Gassman J. Am Chem. Soc. 1991 113 9667. 59 R. E. Dixon A. Streitweiser P. G. Williams and P. E. Eaton J. Am. Chem. Soc. 1991 113 357. 60 F. G. Bordwell and H. E. Fried J. Org. Chem. 1991,56 4218. 61 F. Maran D. Celadon M. G. Severin and E. Vianello J. Am Chem. Soc. 1991 113 9320. 62 A. Streitweiser J. C. Ciula J. A. Kron and G. Thiele J. Org. Chem. 1991 56 1074. 63 J. C. Ciula and A. Streitweiser J. Org. Chem. 1991 56 1989. Reaction Mechanisms -Part (ii) Polar Reactions ethers are around 10" times less acidic than the corresponding ketones due to the lower anion stabilizing ability of the nitrogen atom in the former species.Arnett and Mae@ have investigated the thermochemical properties of a range of syntheti- cally important organolithium bases including the 'superbases' formed by the addition of a metal t-butoxide to the organolithium species. The superbase lithium hexamethyldisilazide/potassium t-butoxide (LiHMDS/ Bu'OK) is intermediate in reactivity between LiHMDS and KHMDS but identical with KHMDS/Bu'OLi when heats of deprotonation of iso-propyl alcohol are measured suggesting that the same active species is present. Reactions involving carbanions include an interesting intramolecular addition to an unactivated C=C bond (Scheme 8);65the reaction is totally regiospecific and more stereospecific than comparable radical mediated processes. Calculations at the 3-21G level support a chair transition state for this process.A related process involves intramolecular attack on an enol ether C=C bond leading to homoallylic alcohols in preference to metallation at the a-position.66 c-,-LLi -dLi Scheme 8 Bowden's group at Essex6' have studied the E-to 2-isomerization in substituted chalcones as models for biologically active compounds. Isomerization occurs uia rate determining attack by amines or methoxide at the P-carbon; Hammett and H,-correlations are reported. 8 Carbonyl Derivatives Enols continue to attract attention with the publication of a homogeneous catalytic method for their generation from allylic alcohols6* and a study of structural effects on the stability of enols derived from cyclic benzyl ketones (41).69Ketone (pKaK) and enol (pKaE) acidity both decrease with increasing ring size; the effect of the phenyl group is to increase the enol content by a factor of 103-104over non-benzylic ketones.A naturally-occurring dienol (42) involved in bacterial catechol metabol- 41(a) n = 1; (b) n = 2; (c) n = 3. 64 E. M. Arnett and K. D. Moe J. Am. Chem. Soc. 1991 113 7068. 65 W. F. Bailey A. D. Kharolkar K. Gavaskar T. V. Ovska K. Rossi Y. Thiel and K. B. Wiberg J. Am. Chem. Soc. 1991 113 5720. 66 W. F. Bailey and L. M. J. Zarcone Tetrahedron Lett. 1991 32 4425. 67 K. Bowden C. K. Duah and R. J. Ranson J. Chem. Soc. Perkin Trans. 2. 1991 109. S. H. Bergens and B. Bosnich J. Am. Chem. Soc. 1991 113,958. 69 S. Eldin R. M. Pollack and D. L. Whalen J.Am. Chem. Soc. 1991 113 1344. J. M. Percy co; co; co; I I I ism has been shown to exhibit high ~tability.~’ Ketonization occurs via rapid conversion to (43) followed by a slower isomerization to (44). Cyclic hemiacetals exist in equilibrium with open-chain forms (Scheme 9).71 Electron-donating substituents R favour the open-chain form; general base catalysis of hemiacetal breakdown (/3 = 0.60)was detected but acid catalysis is inhibited by the presence of the positively-charged nitrogen. Ring-opening was subject to weak hydronium ion catalysis but general acid catalysis could not be detected. Coleman Scheme 9 and Murray72 have described a detailed analysis of acetaldehyde hemiacetal break- down which is subject to general base catalysis.Consideration of a number of kinetic parameters leads to the conclusion that proton transfer and heavy atom reorganiz- ation are coupled. A number of other models for proton transfer catalysis are discussed and the mechanistic criteria used to support and assign these mechanisms is appraised. Orthoester hydrolysis provided the subject of a number of classic early physical organic investigations; Capon and Lee73 have revisited the area with the relatively unexplored orthoesters of D-glucose and D-mannose. They present some evidence for hemiorthoester intermediates in the hydrolyses of these complex species.. A synthetic catalyst for hemiacetal breakdown has been reported74 which achieves modest rate accelerations for the mutarotation of tetramethylglucopyranose and the dissociation of glycolaldehyde dimer.G~thrie’~ has applied Marcus theory to the question of concertedness in acyl transfer reactions which was raised in last year’s Report. He concludes that ‘in essentially all the reactions of aryl acetates the reactions have no intermediates of significant lifetimes because of the very small intrinsic barriers for making or breaking a bond to an aryloxide anion.’ He predicts 70 C. P. Whitman B. A. Aird W. R. Gillespie and W. J. Stolowich J. Am. Chem. SOC.,1991 113 3154. 71 P. E. Sdrensen R. A. McClelland and R. D. Gandour Acta Chem. Scand. 1991,45 558. 72 C. A. Coleman and C. J. Murray J. Am. Chem. SOC. 1991 113 1677. 73 9. Capon and Y. Lee J. Org. Chem. 1991 56,4428. 74 C. Gennari F.Molinari M. Bartoletti U. Piarulli and D. Potenza J. Org. Chem. 1991 56 3201. 75 J. P. Guthrie J. Am. Chem. Soc. 1991 113 3941. 77 Reaction Mechanisms -Part (ii) Polar Reactions concerted reactions for alkoxyl leaving groups/nucleophiles with pK I10 and a transition to a stepwise mechanism for leaving groups in the pK range 11-12. The intrinsic barrier for hydroxyl attack at the carbonyl group is high due to significant solvation changes that occur around this special nucleophile during the addition. Nucleophilic attack at the neutral carboxyl is not generally considered to be an important pathway in the reaction of carboxylic acids with organometallic reagents. It has been claimed76that this direct nucleophilic attack occurs in competition with deprotonation when benzoic acid is treated with butyllithium.The argument rests on the formation of significant amounts of tertiary alcohol (46) in the early stages of the reaction; the alcohol must be formed by organometallic attack on ketone (45) present in the reaction mixture. However as (46) cannot be formed from the dianionic intermediate by loss of lithium oxide it is argued that the ketone results from the less stable intermediate (47) formed by direct organometallic attack on the neutral carboxyl. SET mechanisms have not been ruled out for any of these processes. Ph Bu Bu Ph Bu OLi phKBu Y Y Br(CH,),,CO,-+NBu, 0 OH OH One reagent of choice for macrolactonization of a,w-bromoacids is caesium carbonate; claims have been made that the caesium ion acts to preorganize the nucleophilic and electrophilic centres in a cyclic precursor thus promoting macro-cyclization ( kin,,,) and supressing polymerization ( kint,,).This hypothesis is dis-missed77and shown to be an artefact; the effect of added salts on the formation of ll-undecanolide from (48) was studied and shown to affect the yield of lactone considerably. However the low yield for added lithium salts results because both kinterand kin,, were reduced by tight ion-pairing between the carboxylate nucleophile and the lithium counter-ion. Extending the reaction time with the lithium salts allowed comparable (to the caesium case) yields of lactone to be isolated. Lactone hydrolysis by the unusual A,,2 mechanism was reported by Moore and S~hwab~~ during attempts to selectively cleave the amido-function of (49).Epimerization occurred at C4 only while a '80-labelling experiment showed oxygen exchange at both positions in the lactone. Exchange of the carbonyl oxygen is explicable by the AA,2 mechanism but only the unusual A,,2 pathway via (50) explains exchange into the ring position and the epimerization at C4.Lactone reduction and hydrolysis COH2 PhCONH 0 OH+ Hf$: JY PhCONH Ga 76 C. Einhorn J. Einhorn and J.-L. Luche Tetrahedron Lett. 1991 32 2771. 77 C. Galli and L. Mandolini J. Org. Chem. 1991 56 3045. 78 J. A. Moore and J. M. Schwab Tetrahedron Lett. 1991 32 2331. J. M. Percy has been studied using thermochemical and theoretical methods,79 affording a data set which allows evaluation of the MM3 program when applied to these important cyclic species.Two interesting papers deal with aspects of ketene chemistry; an alkynyl phosphate triester (51) is converted to ketene (52) by the action of a bacterial phos-photriesterase" which is rapidly inhibited by this reactive intermediate. Trimethyl- silyl ketene (53) undergoes neutral hydrolysis (kH20) in aqueous acetonitrile unusually slowly;81 (52) is 390-times more reactive than (53). This is attributed to a ground state stabilizing effect exerted by the silicon; however the TMS group accelerates the acid and base-catalysed hydrolyses by stabilizing negative charge at the a-position in (54) in the base-catalysed pathway and positive charge at the P-position in (55) the intermediate in the acid-catalysed reaction.The hydrolysis /=c=o Bu-OP(O)(OEt)2 R (52) R = Bu; (53) R = Me,% (54) (55) of aryl isocyanides in aqueous DMSO has been characterized8* using a basicity function and Hammett correlations. Stepwise (at high basicity) and concerted (at lower basicity) mechanisms have been proposed while support is provided for the dipolar representation (56) of the isocyanide group rather than the carbene form (57) in polar media. 9 Other Reactions Kre~ge~~ has revisited the hydrolysis of nitramide (58) which affords water and nitrous oxide. A stepwise decomposition reaction was proposed based on general base catalysis of the hydrolysis with Eigen curvature and on isotope effects. A second studys4 reveals that the monoanions of gem-diols (59) are unusually effective catalysts for the decomposition and a proposal is made that these compounds act as bifunctional catalysts uia transition state (60).This mode of catalysis avoids 79 K. B. Wiberg and R. F. Waldron J. Am. Chem. Soc. 1991 113 7697. 80 J. N. Blankenship H. Abu-Soud W. A. Francisco F. M. Raushel D. R,Fischer and P. J. Stang J. Am. Chem. Soc. 1991 113 8560. 81 A. D. Allen and T. T. Tidwell Tetrahedron Lett. 1991 32 7697. 82 I. D. Cunningham G. J. Buist and S. R. Arkle J. Chem. SOC.,Perkin Trans. 2 1991 589. 83 C. H. Arrowsmith A. Awwal B. A. Euser A. J. Kresge P. P. T. Lau D. P. Onwood Y. C. Tang and E. C. Young J. Am. Chem. SOC.,1991 113 172. 84 C. H. Arrowsmith A.J. Kresge and Y. C. Tang J. Am. Chem. Soc. 1991 113 179. Reaction Mechanisms -Part (ii) Polar Reactions NH,NO 0-(58) (59) expulsion of the highly unstable oxide anion (02-). Hegarty's group studied a related which involves the hydrolysis of nitrolic acids to nitrile oxides (Scheme 10). The rate of reaction depends on the stereoelectronic relationship between the nitro-leaving group and the lone pair on the oximato-nitrogen. The 2-isomers which contain an antiperiplanar relationship are more reactive by an unspecified factor. '\i'""" -R-ZF&-O-+ HNOz O2N Scheme 10 Guthrie has applied Marcus theory to the aldol condensations6 using the large set of pK data for enols and enolates currently available. Intrinsic barriers were calculated for both addition and elimination steps; this should allow the calculation of rate constants for novel aldol reactions.Solvent counter-ion and isotope effects have been used to probe the transition state of the important and highly useful oxy-Cope rearrangement (Scheme 1l).87 Scheme 11 11 Isotope effects reveal a minimal degree of bond-making between the C1 and C6 allylic termini while dissociation of the C,-C bond is extensive. The reaction is much faster in DMSO and the possible role of aggregation is discussed. The Nef reaction involves a highly-useful conversion of a nitroalkane to the corresponding ketone and shows an interesting y-silicon effect. Hwu and Gilbert" have shown that a suitably-positioned y-trimethylsilyl group facilitates this reaction.Whereas (61a) readily undergoes Nef degradation to (62) upon treatment with 61(a) R = Me&; (b) R = CH,OMe (62) 85 C. Egan M. Clery A. F. Hegarty and A. J. Welch 1. Chem. SOC.,Perkin Trans. 2 1991 249. 86 J. P. Guthrie J. Am. Chem. Soc. 1991 113 7249. 87 J. J. Gajewski and K. R. Gee J. Am. Chem. SOC.,1991 113 967. 88 J. R. Hwu and B. A. Gilbert J. Am. Chem. Soc. 1991 113 5917. J. M. Percy KH/THF followed by dilute acid (61b) resists this treatment. The manifestation of this effect is attributed to the presence of a carbocation on the reaction pathway. 10 Probes of Polar Reactions Isotope leaving group and solvent effects were all well represented in the 1991 literature. Solvent nucleophilicity (Y)scales were used89 to support a competing- pathway view of the sulfonyl chloride (63).A correlation of the solvolysis rate with Y, is curved or broken and the product selectivity varies with solvent composition. The findings are thought to be inconsistent with a variable transition state model for the reaction. A new improved solvent nucleophilicity scale NT has been proposed,” based on solvolysis of (64). The model compound is easy to prepare and reacts with the more nucleophilic solvents at convenient rates at ambient temperature. Me CF3SOS RZ R R’ Me0 (65) (66) R = isoprenoid Specific solvent interactions form the subject of a number of publications. In the hydrolysis of acyl triazoles (65) the steric effects exerted by R’ and R2are solvent dependent.” This result indicates that steric substituent constants for alkyl and other hydrophobic groups contain a substantial solvation-related contribution.Headley9* examined the solvent dependent variation in order of basicity in the series ammonia to trimethylamine. Using potentiometric titration and multiple parameter regression methods a series of solvent attenuation factors (SAF‘s) were calculated which allow the transfer of gas phase basicities to solution. Specific solvation differences between alkyl and aryl groups were identified;93 incorporating these differences in Grunwald- Winstein treatments leads to improved correlations via a reduction in dispersion (the tendency of different binary mixtures to form separate correlations). The kBr/kcl element effect is often used to distinguish between mechanisms in substitution reactions at aryl vinyl and acyl carbon with kBr/kcl > 1indicating rate-determining cleavage of the carbon-halogen bond.A theoretical study casts doubt on this simple inter~retation~~ which fails to take account of factors such as differential ground 89 I. S. Koo T. W. Bentley D. H. Kang and I. Lee J. Chem. Soc. Perkin Trans. 2 1991 175. 90 D. N. Kevill and S. W. Anderson J. Org. Chem. 1991 56 1845. 91 W. Blokzijl M. J. Blandamer and J. B. F. N. Engberts J. Org. Chem. 1991 56 1832. 92 A. D. Headley J. Org. Chem. 1991 56 3688. 93 T. W. Bentley I. S. Koo and S. J. Norman J. Org. Gem 1991 56 1604. 94 S. Hoz,H. Basch J. L. Wolk Z. Rappoport and M. Goldberg J. Org. Chem.1991 56 5424. Reaction Mechanisms -Part (ii) Polar Reactions state stabilization. Other leaving group ratios (mesylatelpara-nitrobenzoate and tosylatelpara-nitrobenzoate) were shown to be relatively insensitive to the effects of temperature and structure for a reasonable range of corn pound^.^^ These ratios offer potentially useful links to be made between various sets of published data. Isotope effects have been used to characterize the transition states for phos- phodiester hydrolysisy6 quaternization reaction^:^ and nucleophilic displacements In by thi~phenoxide.~~ a study of aniline acylation a ''N effect was used to distinguish between stepwise and concerted acyl transfer pathways.99 Xie and Saundersloo have examined the temperature variation in primary kH/kD effects for enolate formation from labelled 2-pentanone by lithium amide bases.Some unusually large primary isotope effects and an isotope effect on enolate geometry suggest a complex mechanism for deprotonation with more than one active basic species. Poulter and Mantz"' suggest that the phosphorothioate leaving group in (66) may prove a useful probe of reactions where ion-pair return is implicated particularly in reactions at enzyme active sites. This leaving group contains a highly nucleophilic sulfur atom and an added incentive to carbon-sulfur bond formation in the strong phosphorus-oxygen double bond. 95 T. W. Bentley M. Christl and S. J. Norman J. Org. Chem. 1991 56 6238. 96 A. C. Hengge and W. W. Cleland J. Am.Chem. Soc. 1991 113 5835. 97 P. Paneth and M. H. O'Leary J. Am. Chem. Soc. 1991 113 1691. 98 Y-R. Fang and K. C. Westaway Can. J. Chem. 1991. 69 1017. 99 Z. J. Kaminski P. Paneth and M. H. O'Leary J. Org. Chem. 1991 56 5716. 100 L. Xie and W. H. Saunders Jr. J. Am. Chem. Soc. 1991 113 3123. 101 C. D. Poulter and D. S. Mantz J. Am. Chem. Soc. 1991 113 4895.

ISSN:0069-3030    

DOI:10.1039/OC9918800063

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

4 Reaction Mechanisms Part (iii) Free-radical Reactions By R. J. FLETCHER and J. A. MURPHY Department of Chemistry University of Nottingham Nottingham NG7 2RD This field has continued a very rapid expansion. Each year the principal themes vary markedly. This year’s highlights focus on the following areas (1) radicals centred on hydrogen nitrogen and oxygen; (2) metals and their roles in radical reactions; (3) stereochemistry of radicals and of their reactions; (4) cyclizations and fragmentations; (5) radical chemistry of molecules of biological interest; (6) three electron bonds. 1 Radicals Centred on Hydrogen Nitrogen and Oxygen Hydrogen.-A suitable place to start a review of this year’s contributions is with the simplest of radicals the hydrogen atom.Crabtree reports that hydrogen atoms’ are generated by mercury photosensitization of hydrogen gas in an unexceptional apparatus that makes them available for chemistry on a preparatively useful scale at 1 atmosphere of pressure and temperatures from 0-150°C. For example the reaction with diallyl ether (1) is reported to produce 40% of the dimeric product (2). This promises to lead to same very interesting investigations in the near future H 2 ,f \c ,f _. He-Dirncrization 0 0 0 0 0 (1) (2) as the hydrogen atoms react with excess energy due to their method of production; accordingly the radicals produced on reaction with hydrogen atoms are ‘hot’ radicals and their chemistry does not always parallel that of radicals produced in conventional ways.Thus besides the expected products (4) and (6) products of alkyl group migration (5) and (7) formed in the reaction of 3,3-dimethyl-l-butene (3) are ascribed to the intermediacy of ‘high energy radicals’ which promote 1,2-alkyl group migrations. Nitrogen.-The reactions of nitrogen-centred radicals are reported by Newcomb and others. In last year’s report his work with secondary aminyl radical cations C. A. Muedas R. R. Ferguson S. H. Brown and R. H. Crabtree J. Am. Chem. SOC.,1991 113 2233. 83 R. J. Fletcher and J. A. Murphy was discussed. He has carried these studies further noting the comparative effects of a range of Lewis acids on the cyclizations of aminyl radicals2 (8). As an alternative source of nitrogen-centred radicals the imidates (9) have been introduced.The delocalized amidyl radicals ( 10) created on irradiation of thiohydroxamates (9) could in principle react as nitrogen- or oxygen-centred radicals. However only the former reactivity is ~bserved.~ The amidyl radicals are masked forms of primary aminyl radicals. fd* MU+ MI+ X M *+ !d !d BuK* M"+_ BUN. BUG BUN + ._* (8) X=H SePh S-( 2-pyridyl) A very useful synthesis of aminyl radicals has been published by B~wman;~ the initial paper describes solely secondary amines. Here sulfenamides (13) are formed from reaction of the amine (11) with N-benzenesulfenyl phthalimide (12). Treatment of (13) with tributyltin radicals leads to formation of the aminyl radical (14). If ' M. Newcomb and C.Ha Tetrahedron Lett. 1991,32 6493. M. Newcomb and J. L. Esker Tetrahedron Lett. 1991,32 1035. W.R. Bowman D. N. Clark and R. J. Marmon Tetrahedron Lett. 1991,32 6441. Reaction Mechanisms -Part (iii) Free-radical Reactions 0 0 R' -R' R' \/N-H PhS-Nm H N D \/N-SPh \,N= + R2 R2 R2 adjacent to a cyclopropane or a cyclobutane ring opening results in the manner predicted for such radicals. The authors note the more ready cleavage of the PhS group from nitrogen than from carbon. This method of forming aminyl radicals is similar to Zard's method' of forming iminyl radicals from S-phenyl sulfenylimines. His studies have been extended6 to ring-opening of cyclobutane rings by cyclo- butyliminyl radicals. Evidence has been presented for a free radical azido-phenyl~elenenylation~ of alkenes.This reaction occurs when alkenes are treated with (diacetoxyiodo)benzene sodium azide and diphenyl diselenide in dichloromethane at room temperature. The proposed scheme features addition to the alkene triggered by azidyl radicals (15). The addition occurs not only to terminal alkenes but also to (E)-4-octene cyclohexene the electron-rich dihydropyran and the electron-poor methyl crotonate. Moreover more complicated reactions can also be achieved as seen in the formation of the cyclopentane (17) from diene (16). Oxygen.-Beckwith Zard and Newcomb' have investigated the intramolecular reactions of alkoxycarbonyloxy radicals (18a) onto appropriately placed alkenes to form 5-and 6-membered cyclic carbonates.These radicals have previously been shown to be reluctant to decarboxylate in contrast to the behaviour of their nitrogen- containing analogues (18b). Some interesting facts emerge for example exclusive 0 (18) (a) X = OR (b) X = NR J. Boivin E. Fouquet and S. Z. Zard Tetrahedron Lett. 1990 31,85 and 3545. J. Boivin E. Fouquet and S. 2. Zard J. Am.Chem. SOC.,1991 113,1055. ' M. Tingoli M. Tiecco D. Chianelli R. Balducci and A. Temperini J. Org. Chem. 1991 56 6809. M.Newcomb M. Udaya Kumar J. Boivin E. Crepon and S. 2. Zard Tetrahedron Lett. 1991 32,45. A.L.J. Beckwith and I. G. E. Davidson Tetrahedron Lett. 1991 32 49. R. J. Fletcher and J. A. Murphy 5-exo addition occurs onto the hindered alkene in (19) in contrast to the correspond- ing hexenyl radical (i.e.the carbon analogue) for which 6-endo reaction plays a significant role. The 5-membered ring formation can only be used for derivatives of primary allylic alcohols. 6-Membered ring formation occurs for derivatives of many homoallylic alcohols. An example is the conversion of (20) to (21). Note that no intramolecular hydrogen atom abstraction reactions are reported for these oxygen- centred radicals. The balance between ring closures and openings of carbon-centred and oxygen- centred radicals are highlighted in a full report by Fraser-Reid" on the reversibility of cyclizations of radicals (22). The initially bizarre result that cyclizations of carbon-centred radicals (22b) onto aldehydes to give six-membered rings work efficiently but that cyclization is not so facile for the corresponding cyclization of (22a) to give cyclopentanols is well explained by bringing together the relevant kinetic data and understanding that the successful formation of the cyclic alcohols is crucially dependent on the more rapid trapping of the oxygen-centred radicals (k = 3.7 x 10' M-' s-') than carbon-centred radicals (k = 3.2 x lo5 M-' s-l) by tributyltin hydride.kc yclizat ion(set-kS-scission(SeC-l) (a) n = 1 8.7 x lo5 (a) n = 1 4.7 x lo8 (b) n = 2 1.0 x lo6 (b) n = 2 1.1 x lo7 2 Metals and their Roles in Radical Reactions Snider reports the formation of 7- and 8-membered rings by Mn"'-induced radical cyclizations of P-keto esters." The success of particular substrates depends on the kinetics of competing reactions.This paper gives an insight into these parameters R.Walton and B. Fraser-Reid J. Am. Chem. Soc. 1991 113 5791; A. L. J. Beckwith and B. P. Hay J. Am. Chem. SOC,1991 111 230 and 2674. I' B. B. Snider and J. E. Memtt Tetrahedron 1991 47 8663. Reaction Mechanisms -Part ( iii) Free-radical Reactions 87 so that predictions about the synthetic viability of future schemes can be made. The cyclizations are sometimes surprisingly successful. For example oxidation of (23a) affords (24a) in 68% yield while (23b) affords (24b) in 70%yield! Further investiga- tions have shown that the radicals produced in the manganese method'* behave effectively as free radicals i.e. they do not behave in anomalous ways which might happen if a manganese-complexed radical rather than a free radical were involved.P-Ketotulf~xides'~ can be used instead of P-ketoesters in these oxidative radical reactions. The stereochemistry of the sulfoxide very usefully controls the stereochemistry of new centres created during cyclization reactions of these radicals. The scope of the reaction in solvents other than acetic acid has also been pr~bed,'~ and ethanol has been found to be a suitable solvent but to lead to certain differences compared with acetic acid. These principally result from a more efficient quenching of cyclic radicals by hydrogen atom donation from ethanol. The extension of this type of reaction to solvents other than acetic acid is very desirable. C02Me C02Me C02Me d ( :i (Q \ (23) (a) n = 1 (b) n = 2 Pattenden has extended the initial studies on 4-exo-trig cyclization of carbamoyl cobalt reagents to give p-lactams reported here in the 1989 review to a formal total synthesis of thienamy~in.'~ Thus the cobalt salophen reagent (25) was heated in toluene to give the vinyl p-lactam (26) which was converted easily into (27) an established synthetic intermediate on the path to thienamycin.Still on the subject of p-lactams a cobalt-mediated insertion-expansion-P-eliminationof iodomethyl- (25) (26) [Co] = cobalt(II1) salophen 3 =Gokph 0 (27) 12 D. P. Curran T. M. Morgan C. E. Schwartz B. B. Snider and M. A. Dombroski J. Am. Chem. SOC. 1991 113 6607. l3 B. B. Snider B. Y.-F. Wan B. 0. Buckman and B.M. Foxman J. Org. Chem. 1991 56 328. l4 B. B. Snider J. E. Merritt M. A. Dombroski and B. 0.Buckman J. Org. Chem 1991 56 5844. 15 G. Pattenden and S. J. Reynolds Tetruhedron Lett. 1991 32 259. 88 R. J. Fletcher and J. A. Murphy penams (28) has been shown16 to yield the commercially important 3-exomethylene cephalosporin. The particular benefit of using cobalt is evident in the final step of this reaction where a dehydrocobaltation occurs producing the alkene in the product. The ratio of exocyclic alkene (29) endocyclic alkene (30) in the product is dependent on the nature of the ligands around the colbalt. A 95 :5 ratio is achieved when vitamin B,, is used. H H H RN 0 0 0 -"pJ+ RNE& I I I I I C02Me C02Me C02Me (28) (29) (30) Harrowven and Pattenden17 have utilized the nucleophilic properties of cobalt(1) to give the P-hydroxycobaloximes (31).These molecules can be directed along two different pathways depending on whether thermal or photochemical activation is employed. Dehydrocobaltation occurs on heating the hydroxycobaloximes giving the enol of the final product (32) whereas cobalt-carbon bond homolysis occurs on irradiation. Cyclization of the resulting carbon radical trapping with Co" and dehydrocobaltation affords the diol (33). -% [co]' + A -OH -OH -OH (31) lhU An investigation of the mechanism of oxidation of dicarbonyl 7'-cyclopentadienyl iron derivatives of carboxylic acids (Fp-acyl complexes)'8 with ceric ammonium nitrate (CAN) suggests that the initial oxidation product a 17-electron radical cation (34) undergoes a fast homolytic dissociation leading to acyl radicals which (34) I co R-products l6 J.E. Baldwin R. M. Adlington and T. W. Kang Tetrahedron Lett. 1991 32,7093. " D.C. Harrowven and G. Pattenden Tetrahedron Lett. 1991 32,243. C. Amiens G. Balavoine and F. Guibe J. Chem SOC.,Chem. Commun. 1991 1458. Reaction Mechanisms -Part ( iii) Free-radical Reactions 89 have been trapped or following decarbonylation to alkyl radicals which have also been trapped. In an exciting development Merlic" has performed the first radical additions to Fischer carbene complexes. Reasoning that the carbenes are quite electrophilic and that alkyl radicals are nucleophilic he reacted the complexes (35) and (36) with radicals formed from epoxide opening by the Cp,TiCl method of Rajanbabu and Nugent.20 The carbon radicals formed added exclusively to the &carbon of the alkene rather than directly to the carbene carbon reminiscent of the reaction of radicals with Michael acceptors.(,,,sw< ClCH,CH,CI H Q (CO15W(pH (co)swr" [CP,TiC~I Ph \ Ph Ph (35) 43% 12% Ph ,Ph (36) 50% 33% Perhaps the most notable development of this year has been the spread in popularity of samarium diiodide. Inanaga et al. have performed reductive dimeriz- ations of derivatives of conjugated acids. The conditions are quite mild reactions frequently requiring less than one minute at room temperature but some interesting reactions emerge.Thus reductive reaction of the skipped diene (37) produces a cyclopropane (38) in 80% yield. The disadvantage of this and of many reactions featuring this reagent is that they greatly benefit from the addition of toxic HMPA. SmI THF HMPA ROH 80% Me02C-x.=.Jco2Me Meo2CTco2Me (37) (38) In some reactions it is possible to replace HMPA with DMPU. For example Motherwel121 has used a mixture of THF and DMPU in the samarium iodide radical ring openings of cyclopropyl ketones. He has demonstrated that the products (which are a carbon radical and a samarium enolate) can both be trapped as in the conversion of (39) to (40). One of the interesting features of samarium iodide chemistry is that the initial reduction can occur at a number of functional groups.Thus Shibuya et al. have reduced22 the allylic formates (41) to ally1 radicals which are trapped with a second equivalent of samarium iodide. The organosamarium adduct then adds to a hornoallylic formate group to give the hemiacetal (42). l9 C. A. Merlic and D. Xu J. Am. Chem. Soc. 1991 113,9855. 20 T. V. Rajanbabu and W. A. Nugent J. Am. Chem SOC.,1988 110,8561. 21 R.A.Batey and W. B. Motherwell Tetrahedron Lett. 1991 32,6211. 22 K. Shibuya H. Nagaoka and Y. Yamada J. Chem. SOC Chem. Commun. 1991 1545. R J. Fletcher and J. A. Murphy 0 OAc H M01ander~~ has reported the cyclization of P-ketoesters. Thus,the ester (43),on treatment with SmI in the presence of a variety of aldehydes or ketones undergoes an initial radical cyclization.Coupling of the product radical with a further equivalent of SmI gives an organosamarium( 111) intermediate which was trapped by aldehydes or ketones giving (44). One of the attractive features of this type of reaction is the control of relative setereochemistry observed. An interesting full report has also appeared on stereochemical control of intramolecular Reformatsky reactions24 pro- moted by samarium iodide. Although the initial step in these reactions involves electron transfer to an a-halocarbonyl group to produce an enolyl radical trapping of this species by a second equivalent of samarium iodide generates the samarium enolate which actually mediates the reaction. The duality of radical and polar chemistry associated with this reagent is finally illustrated by Curran's discovery25 Sm12 / 23 G.A. Molander and C. Kenny J. Org. Chem 1991,56 1439. 24 G. A. Molander J. B. Etter L. S. Harring and P.-J. Thorel J. Am. Chem Soc. 1991 113 8036. 25 D. P. Curran and R. L. Wolin SYNLEm. 1991 318. Reaction Mechanisms -Part (iii) Free-radical Reactions of a vinylogous Barbier reaction on substrate (45). Although the initial radical cyclization chemistry is uncomplicated the product samarium enolate was shown to give an aldol product with some aldehydes as shown here but to give a Tishchenko reaction with others. 3 Stereochemistry of Radicals and of their Reactions Control of stereochemistry in radical reactions has come strongly to the fore in recent publications.Curran and Rebek26 have employed Kemp’s triacid as the basis for their auxiliary. Radical addition to the maleate (46)occurs with high regioselec- tivity to the carbon p to the auxiliary and with interesting stereoselectivity. Based on the observed products the addition of the radical is suggested to occur preferen- tially to the maleate having the geometry shown -exposing only one face of the alkene to the incoming radical. Further experiments are in hand to understand the surprising regioselectivity of the radical addition. OEt (46) 97:3 Giese and Curran report a ‘Cram’s Rule’ for free radical reactions.” Here a comparison is made between the ratios of isomers formed by (i) hydrogen atom abstraction reactions of the radical (49) giving (48a) and (48b) after work-up and (ii) the addition of lithium aluminium hydride to (47).As seen a remarkable similarity in product ratios exists suggesting similarities in the geometries of the transition states for these reactions. Other examples also support the principle. 26 J. G. Stack D. P.Curran J. Rebek,Jr. and P. Ballester J. Am. Gem. Sor 1991 113 5918. 27 B. Giese W. Damm J. Dickhaut F. Wetterich S.Sun and D. P. Curran Tetrahedron Lett. 1991,32,6097. R. J. netcher and J. A. Murphy R (484 (48b) Me 2.9 1 Pr' 13.3 1 But 8.3 1 (47) (Me,Si),H Bu'ONNOBut I OH OH OH R (484 (48b) Me 2.9 1 Pr' 12.6 1 But 5.3 1 In a separate study on the cause of diastereoselection in radical additions Giese has investigated28 the original suggestion by Porter that allylic strain29 may cause diastereoselection in appropriate test molecules.The cases presented look very convincing. In molecules where hydrogen on Cyand a trigonal carbon at C" are present the preferred conformation of the molecule shows an eclipsed interaction for these substituents. On the other hand if C" is part of a linear group e.g. a nitrile then no such preferred conformation exists. Thus for example the ester (SO) undergoes selective hydrogen-atom abstraction giving a 20 :1 ratio of erythro :threo products whereas the nitrile (51) gives a complete lack of selectivity (1:1). erythro threo ButMe2Si0 \,Y fl-..CH2But H+-&, M'e *N 51 Guindon3' has examined the effect of chelation control on radical reductions of alkyl iodides.The acyclic iodide (52) is reduced by tributyltin hydride and AIBN 28 M. Bulliard H.-G. Zeitz and B. Giese SYNLEn 1991 423 425. 29 R. W. Hoffmann Chem. Reu. 1989 89 1841. 30 Y. Guidon J.-F. Lavallee M. Llinas-Brunet G. Homer and J. Rancourt J. Am. Chem. SOC.,1991 113 9701. Reaction Mechanisms -Part (iii) Free-radical Reactions Ph to (53) [erythro threo ratio 1:>25]. In the presence of MgIz MgBr,.Et,O or AlC13 however the ratio is switched to 25 1 i.e. exactly reversed and this is attributed to the chelation shown. Interestingly the Lewis acid-mediated reactions require no initiation and are proposed to be initiated by electron transfer from tributyltin hydride to the complex or to the Lewis acid.(53) threo As far as synthetic applications of stereoselective radical reactions are concerned Shibasaki has published3' intriguing syntheses of trans-hydrindanes synthetic pre- cursors of molecules of biological interest. Thus the vinyl radicals generated from the vinyl bromides (54) were allowed to react in the presence of low concentrations of tributyltin hydride allowing the intermediate cyclized radicals to equilibrate to the more stable products of 6-endo addition (55). The stereoselectivities for the trans-fused products were excellent. OSiMezBu' OSiMezBut &-OH -3OoC,1hr -OH Et,B,O,,Bu,SnH b Me02C Br Me02C 'H (54) (55) 97% yield 100%trans It is known that the geometry of attack of electrophiles on trigonal carbons (e.g.in alkenes) is very different from the geometry of attack of nucleophiles on trigonal carbons (e.g. in carbonyl groups) so Giese and Ho~k~~ have investigated whether a large difference exists between the transition state geometries for attack of electro-31 S. Satoh M. Sodeoka H. Sasai and M. Shibasaki J. Org. Chem. 1991 56 2278. 32 H. Zipse J. He K. N. Houk,and B. Giese J. Am. Chem. SOC.,1991 113 4324. 94 R. J. Fletcher and J. A. Murphy philic and nucleophilic radicals on trigonal carbons. They calculate that the attack of nucleophilic methyl radical (56a) and of electrophilic malononitrile radical (56b) on ethene show similar transition state geometries. .N ~109.1°173.4"~ 't108.9' 172.5"~ 154.7" 149.9" The nature of the transition state used in 5-hexenyl cyclizations has been examined over many years by many authors but notably by Beckwith.His guidelines based on a pseudo-chair transition state have allowed the prediction of stereochemistry of disubstituted cyclopentanes for many cyclizations. Houk has previously suggested that boatlike transition states may be involved in some such cyclizations; Be~kwith~~ has now investigated a case (57) -+ (58) where the boatlike transition state would betray its presence by the stereoselectivity of the reaction. Thus if only the chair forms of the transition states (59) and (60) were to be used there would be a large difference in energy between that which had the t-butyl group axial and that which had it equatorial so large that the ratio of cis :trans products would be ca.500 1. The observed ratio of 4.5 1 is much closer to that predicted if the trans isomer forms through a boat-like transition state (61). The calculated rate constant for the formation of the cis isomer is 1.6 x lo8sec-' at 80 "C and is the highest rate constant yet recorded for cyclization of a monosubstituted hexenyl radical. But (59) I I I cis (58) trans (58) trans (58) Formation of six-membered rings by radical cyclization is normally slower than formation of five-membered rings but an exceptionally fast 6-membered ring cycliz- ation has appeared (62) + (63) which is super fast with a suggested rate constant for formation of the predominant cis product of 1.1 x 10'" sec-' at 80 "C. The high 33 A.L. J. Beckwith and J. Zimmermann .IOrg. Chern. 1991 56 5791. Reaction Mechanisms -Part (iii) Free-radical Reactions rate34 is suggested to arise since transannular cyclization of (62),in which the radical centre and the double bond are already rotationally constrained imposes a relatively small loss of rotational freedom. There is as yet no satisfactory explanation for the stereoselectivity of the reaction. Bordwell and Gallaghe?' have examined the stability of radicals (64) derived from a-dialkylaminoketones and conclude that an electrostatic stabilization can arise in a particular conformation in such radicals; the reason for the effect is seen if the radicals are drawn in their zwitterionic form. Here the Z-geometry (65)shows the electrostatic stabilization and where the 2-form cannot exist e.g.(66) the radicals have considerably less stabilization. T 4 Cyclizations and Fragmentations A number of full papers describing the formation and fragmentation of large and medium sized rings giving details of work previously described in Communication fOrm36,37 appear this year. Thus full details of Suginome's work on photofragmenta-tion of hypoiodites leading uia alkoxyl radicals to phthalide~~',~~ shows the rather complicated pathway leading to phthalides from benzocyclobutanols. It is still not certain whether the formation of the five-membered ring occurs by a radical or ionic mechanism. Alkoxyl radicals also feature in Pattenden's syntheses4' of hydrazulenones. Fragmentation of the alkoxyl radicals (67) followed by cyclization 34 A.L. J. Beckwith V. W. Bowry and C. H. Schiesser Tetrahedron 1991 47 121. 35 F. G. Bordwell T. Gallagher and X. Zhang J. Am. Chem. SOC.,1991 113 3495. 36 J. E. Baldwin R. M. Adlington M. B. Mitchell and J. Robertson Tetrahedron 1991 47 5901. 37 P. Dowd and S.-C. Choi Tetrahedron 1991 47 4847. 38 K. Kobayashi A. Sasaki Y. Kano and H. Suginome Tetrahedron 1991,47 7245. 39 K. Kobayashi M. Itoh A. Sasaki and H. Suginome Tetrahedron 1991 47 5437. 40 C. Ellwood and G. Pattenden Tetrahedron Lett. 1991 32 1591. R. J. Fletcher and J. A. Murphy leads to the radicals (68) which in the presence of iodosylbenzene diacetate and the hypoiodite form the quenched products (69). Ring expansion is possible with these products on treatment with tributyltin hydride as shown.I Bu,SnH e-- A number of products resulting from bizarre and interesting rearrangements are presented by Bald~in.~' Thus for example it was proposed to synthesize the macrocyclic ketone (71) from the iodoketone (70) by a cyclization fragmentation and elimination sequence. The actual pathways followed did indeed produce some of this product; however the cyclopentenones (72) and (73) were also produced. Proposed pathways are shown. The crucial point is that steric crowding of the ketone carbonyl slows addition to such an extent that alternative processes here -hydrogen atom abstraction -are observed. 0 fl**.vvl -cat. Bu,SnH AIBN -SnBu3 (70) (71) 33% 01 (72) E-isomer 26% (73) Z-isomer 23% :*--(72)+ (73) yJ--)-a*-* SnBu3 SnBu3 SnBu3 41 J.E. Baldwin R. M. Adlington and J. Robertson Tetrahedron 1991,47 6795. Reaction Mechanisms -Part (iii) Free-radical Reactions Ryu Sonoda and co-workers have produced three report^^^-^ featuring the radical chemistry of CO. Formation of an acyl radical by carbonylation of an alkyl radical is followed by trapping with an activated alkene an allylstannane or [intramolecularly] with an unactivated alkene giving products (74)-(76).The relative rates of the reactions and the relative concentration of carbon monoxide to the Bu SnH -RCO. co @C N RI 3 Re AIBN 80 atm Bu,SnH R R = nC,H, (74) 74% 0 CO 10 atm. AIBN other trapping agent are of crucial importance in obtaining high yields.In a related study C~rran~~ has probed the ability of aryl isonitriles (77) to trap pentynyl radicals (78). Here the isolated products are cyclopenta-fused quinolines. Two isomers are produced one the product of ortho attack (79) the other the product of ips0 attack (79) I R R R (80) 42 I. Ryu K. Kusano H. Yamazaki and N. Sonoda J. Org. Chem. 1991 56 5003. 43 I. Ryu H. Yamazaki K. Kusano A. Ogawa and N. Sonoda J. Am. Chem. SOC.,1991 113 8558. 44 I. Ryu K. Kusano M. Hasegawa N. Kambe and N. Sonoda J. Chem. SOC.,Chem. Commun. 1991,1018. 45 D. P. Curran and H. Liu J. Am. Chem. SOC.,1991 113 2127. R. J. Fletcher and J. A. Murphy 5 Radical Chemistry of Molecules of Biological Interest The cleavage of nucleic acids by radical chemistry is again a subject of much research.In a studyM on the cleavage chemistry of the anti-tumour antibiotic neocarzinostatin it has been discovered that the rate-determining step for the cleavage can involve hydrogen atom abstraction from C-4’ or C-5’ of a thymidine residue. The interesting fact is that this does not hold for all thymidines but appears to occur for all thymidines in a GT sequence. It had been that some of the synthetic ‘mimics’ of the enediyne antibiotics may effect their action on DNA by polar routes ie. routes which do not involve the formation of an arene diradical. Tats~ta~~ has examined the cyclization of the simple enediyne (81) (a) in the presence of KOH/DMSO/MeOH and (b) in carbon tetrachloride/DBU either under argon or in air.The product of the first reaction (82) suggests a non-radical cyclization. The second reaction however gives the compounds (83)-(85) in argon and the additional ketone (86) in air. The DBU pathway is proposed to involve free radical intermediates. This re-emphasizes the subtlety and diversity of the chemistry of the enediynes. c1 c1 c1 Interest in methods of producing the hydroxyl radical artificially for the purpose of DNA cleavage is widespread the Saito4’ has found an efficient new photochemi- cally activated source the bis-hydroperoxynaphthaldiimide(87) [activated with UV radiation at 366 nm]. 46 B. L. Frank L. Worth Jr. D. F. Christner J. W. Kozarich J. Stubbe L. S.Kappen and 1.H. Goldberg J. Am. Chem. Soc. 1991 113 2271. 41 K. C. Nicolaou G. Skokotas S. Furuya H. Suemune and D. C. Nicolaou Angew. Chem. Engl. Int. Ed. 1990 29 106/4. 48 K. Toshima K. Ohta T. Oktake and K. Tatsuta Tetrahedron Lett. 1991 32 391. 49 H. Sugiyama T. Sera Y. Dannoue R. Marumoto and I. Saito J. Am. Chem. Soc. 1991 113 2290. Reaction Mechanisms -Part ( iii) Free-radical Reactions 0 OMe (87) To probe the mechanism of action of the anti-tumour antibiotic bleomycin Saito and colleagues” synthesized an oligonucleotide d( GGAriAGG)-d( CCTTCC) where Ari is 2’-deoxyaristeromycin (88). The products derived from interaction of peplomy- cin a derivative of bleomycin with this DNA featured two modifications of the aristeromycin the dehydro product (89) and the alcohol (90).The alcohol (90) was formed with complete stereoselectivity but the source of the oxygen of the alcohol group remains to be established. The formation of these products is consistent with the formation of an intermediate radical at the 4‘position which is subsequently oxidized to a cation. Parallels are frequently drawn between the chemistry of cytochromes P-450and bleomycin since both are thought to involve high valence iron-oxo species. Saito points out that the formal dehydrogenation seen in the formation of the alkene (89) has not been observed before for either bleomycin or P-450. S. Matsugo S. Kawanishi K. Yamamoto H. Sugiyama T. Matsuura and I. Saito Angew. Chem. Znt. Ed. EngL 1991,30 1351. R.J. Fletcher and J. A. Murphy The chemistry of high-valent iron also features in studies on penicillin and cephalosporin biosynthesis. In Baldwin's proposal,*' the high-valent iron oxene in (91) inserts stereospecifically into the methine carbon-hydrogen bond to form an iron-carbon bond. Homolysis of this bond is followed by displacement at sulfur to Enz H H I H Enz RN,S-Fe=o CO2H t COZH CO2H (92) give the penicillin (92). Among the new s-ibstrates examined have been (93) and (94). No methine hydrogen is present for reaction in these substrates. Instead the methyl group undergoes reaction via the modified intermediate (97). The two dideuteriocyclopropanes were found to be regiospecifically converted into the prod- ucts (95) and (96).This implies that the cyclopropane is opened by homolysis with Enz H _. H H I ,OH RN .NuSH Me 0UXy2 CXZ C02H zC02H HO2C (93) X = H Y = DZ = D (95) X = HY =DZ=D (94) X = D Y = H Z = H (96) X = D Y = H Z = H (97) complete stereoselectivity and that the subsequent trapping of the radical by sulfur is faster than the equilibration process shown for (98). If this equilibration process were allowed to occur for a free radical one would expect a lack of regioselectivity in the labelling of the product. (98) 5 \\ J. E. Baldwin R. M. Adlington D. A. Marquess A. R. Pitt and A. T. Russell J. Chem SOC. Chem. Commun. 1991 856. 101 Reaction Mechanisms -Part (iii) Free-radical Reactions Soluble methane monooxygenase converts methane to methanol.In addition it catalyses a broad range of other oxidations. Studies by Daltons2 in Warwick and colleagues from Leicester have probed the mechanism of these enzymatic conver- sions. Specifically it had been previously suggested that the initial step in the oxidation would feature a hydrogen atom abstraction with a mechanism similar to that used by cytochromes P-450. The question arose of whether the hydrogen atom abstracting species was a free hydroxyl radical or a metal-bound oxyl (i.e.a ferryl species). This study found that the CH3' HOCH,' NCCH2' radicals produced in the oxidations of methane methanol and acetonitrile were easily trapped either by 5,5-dimethylpyrroline-l-oxide (DMPO) or by cu-(4-pyridyl-l-oxide)-N-t-butyl-nitrone (POBN).The authors also found that hydroxyl radicals could easily be trapped by their spin-traps also but detected none. They therefore suggest that it is an iron-bound oxyl which abstracts the hydrogen and that no hydroxyl radical is produced during the rection. This in turn implies that heterolysis of an intermediate iron hydroperoxide leads to the ferryl species. 0-11 OCH2Bu' \ Et-P/ OCH2Bu' - OCH~BU' ICHpBu'+I c -Et-P/ THF Bu.N+-OH (Bu'CH,O),P=O I Ft 26% (99) (Bu'CH,O),P=O 73% C2H6 4% C2H4 4% C,H,o 0.3% (Oy OOH 0 n-n .O. *OEt . Et (100) (101) (Bu'CH,O),P=O The degradation of organophosphonates by micro-organisms has been shown to involve cleavage of the C-P bond. All inorganic phosphate needed by the microbe is derived from the phosphonate phosphorus.In a continuation of his pioneering work on organophosphonate degradation Frosts3 has examined the effect of homolytic hydrolysis of organophosphonates. The conditions exposed (99) a model for an enzymatically protonated phosphonate to tetra-n-butylammonium hydroxide THF and either (a) t-butylhydroperoxide and ferrous ions or (b) 2-hydroperoxy- tetrahydrofuran without metal ions. In these cases the isolation of trineopentyl phosphate and alkanes established the homolytic pathway. A curious reaction was observed during this study in which the peroxide (100) was converted into ethoxytetrahydrofuran (101); the mechanism of formation of this compound is currently under investigation. 52 N. Deighton I.D. Podmore M. C. R. Symons P. C. Wilkins and H. Dalton J. Chem. Soc. Chem. Commun. 1991 1086. 53 L. Z. Avila P. A. Bishop and J. W. Frost J. Am. Chem. SOC.,1991,113,2242. R. J. Fletcher and J. A. Murphy 6 Three Electron Bonds The chemistry of radical cations centred or partly centred on sulfur has been the subject of a number of investigations. Asmus has fostered the development of much of this area and has now produced evidence for the first three electron bond54 featuring a phosphorus and a sulfur atom (102). Pulse radiolysis (1 ps pulse) of a solution of (103) saturated with nitrous oxide gave the transient species (102) which absorbed at 385 nm. The lifetime was pH dependent with half-lives of 150 ps and 70 ps at pH 4 and 8.6 respectively.(102) (103) Three electron S-S bonds have been described before but Bushby” has observed an unexpected example. Whereas the arene (104) is oxidized to the wdelocalized radical cation (105) the triphenylene derivative (106) is oxidized to the radical cation (107). This is demonstrated by examination of the ESR spectra of (107a) and its deuteriated analogue (107b). SR SR R .’+ / SR (107) (a) R = (CH2)JH3 (b) R = CHD(CH2),CH 54 H. Hungerbuehler S. N. Guha and K. D. Asmus J. Chem SOC Chem Commun. 1991,999. 55 N.Boden R.Borner R. J. Bushby and J. Clements Tetrahedron Lett. 1991 32 6195.

ISSN:0069-3030    

DOI:10.1039/OC9918800083

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

5 Aliphatic and Alicyclic Chemistry By P. QUAYLE Department of Chemistry The Victoria University of Manchester Manchester M 139PL 1 Introduction Reports concerning the chemistry of molecules of 'theoretical interest' have featured heavily this year. Pride of place must surely go to the generation and spectroscopic characterization of cyclobutadiene encapsulated in the cavity of a hemicarcerand.' The ability to prepare2" in relatively high yield (up to 44%) pure samples of C60 (Buckminsterfullerene) has enabled many groups to study the chemical reactivity of this unusual caged compound.2b Similarly the chemistry of enediynes has continued to attract much attention since the isolation and potential therapeutic properties of the neocarzinostatins and calicheamicins were dis~overed.~ A timely personal account of rational synthetic design chronicles advances over the last two decades? Other areas of intense activity have also been extensively reviewed including an overview of enantiocontrolled cycloaddition processes,' catalytic asymmetric synthesis,6 the use of radical reactions in organic synthesis,' organocopper reagents in organic synthesis,* enzymes in organic synthesis,' syn-thetic applications of carbonyl ylides and related systems," enantioselective alkyla- tion reactions," and the use of non-racemic starting materials such as amino acids'* D.J. Cram M. E. Turner and R. Thomas Angew. Chem. Int. Engl. 1991 30 1024. (a) D. H. Parker P. Wurz W. J. Pellin J. C. Hemminger D. M. Gruen and L. M. Stock J. Am.Chem. SOC.,1991,113,7492; (b)F. Diederich and R. L. Wheller Angew. Chem. Znt. Edn. Engl. 1991,30,678; J. W. Bausch G. K. Prakash G. A. Olah D. S. Tse D. C. Lorents Y. K. Bae and R. Malhortra J. Am. Chem. Soc. 1991 113 3205; G. A. Olah I. Bum C. Lambed R. Aniszfeld N. J. Trivedi D. K. Sensharman and G. K. Prakash J. Am. Chem. SOC.,1991 113,9385; A. Penicaud J. Hsu C. A. Reed A. Koch K. C. Khemani P-M. Allemand and F. Wudl. J. Am. Chem. SOC.,1991 113 6698; H.W. Kroto A. W. Allaf and S. P. Balm Chem. Rev. 1991 91 1213. K. C. Nicolaou and W. M. Dai Angew. Chem. Znt. Edn. Engl. 1991 30 1387; I. H. Goldberg ACC. Chem Res. 1991,24; 191; M. D. Lee G. A. Ellstad and D. B. Borden Acc. Chem. Rex 1991,24,235. E. J. Corey Angew. Chem Zrit. Edn. Engl. 1991 30 435. L.M. Haewood Tetrahedron Asmmmetry 1991,2 1173. K. Narasaka Synthesis 1991 1; K. Burgess and M. J. Ohmeyer Chem. Rev. 1991 91 1179; J. M. Brown Tetrahedron Asyymetry 1991 2 487; P. J. Cox and N. S. Simpkins Tetrahedron Asymmetry 1991 2 1; C. Bolm Angew. Chem. Int. Edn. Engl. 1991 30 542. 'T. V. Rajan Babu Acc. Chem. Res. 1991 24 139; D. P. Curran SYNLEm 1991 63; C. P. Jaspere D. P. Curran and T. L. Fevig Chem. Rev. 1991 91 1231. E. Nakamura SYNLEm 1991 53. R. Csuk and B. I. Glanzer Chem. Rev. 1991 91 49; Z-F. Xie Tetrahedron Asymmetry 1991 2 733; W. Boland C. Frossl and M. Lorenz Synthesis 1991 1049. lo A. Padwa Acc. Chem Res. 1991 24 22; A. Padwa and S. F. Horbuckle Chem. Rev. 1991 91 263. R. Noyori and M. Kitamura Angew. Chem Int. Edn. Engl. 1991,30 49.M. T. Reetz Angew. Chem Int. Edn Engl. 1991 30,1531. 103 104 P. Quayle and epoxy alcohol^'^ in organic synthesis. Recent developments in natural product synthesis have also been re~iewed.’~ 2 Aliphatic Chemistry -Functional Group Chemistry Recent advances in the Peterson olefination reacti~n’~ and palladium catalysed cross-coupling reactions16 have been reviewed. Stang has reviewed the chemistry of ynol esters and related Synthetic applications of di-anion chemistry and rhodium-mediated transformations have also been extensively discussed.18 Most transition metal catalysed coupling reactions between sp3-hybridized alkyl halides and ‘organometallic’ reagents have limited scope due to unwanted p-elimina- tion reactions. However Suzuki” has shown that 9-alkyl-9-BBN derivatives undergo efficient carbonylation reactions with a variety of alkyl halides using Pd(PPh,) as catalyst.The reaction is also promoted by irradiation (Scheme 1). Scheme 1 The synthesis of dienes via a palladium catalysed cross-coupling reaction between a vinyl organometallic reagent and vinyl halide is now a routine operation. In a critical survey Negishi has shown that2’ optimal coupling (in terms of yield and stereospecificity) is obtained when the vinyl zinc reagent is employed as the nucleophilic partner. Using vitamin A (3) as an example (Scheme 2) the crucial I (2) Reagents i Pd’ (2); ii THF TBAF Scheme 2 13 R. M. Hanson Chem. Reu. 1991,91,437. 14 A. Hassner Isr. J. Chem. 1991 31 p.3.15 A. G. M. Barrett J. M. Hill E. M. Wallace and J. A. Flygate SYNLETT; 1991 764. 16 Y. Hatanaka and T. Hiyama SYNLETT 1991 845. 17 P. J. Stang Acc. Chem. Rex 1991 24 304. 18 J. Adams and D. M. Spero. Tetrahedron,1991,47,1765; C. M. Thompson and D. L. C Green Tetrahedron 1991,47 4223. 19 T. Ishiyama N. Miyausa and A. Suzuki Tetrahedron Lett. 1991 32 6923. 2o E.4. Negishi and Z. Owczarczyk Tetrahedron Lett. 1991 32 6683. Aliphatic and Alicyclic Chemistry coupling reaction between the zinc reagent (1)and the iodide (2) proceeded in high yield (87%) with >98% stereospecificity. These coupling reactions2' can be carried out in the presence of unprotected hydroxyl functionality and of electrophilic functional groups (e.g. esters) as illustrated in Scheme 3.OH 92%(E 2). Reagents i 2Bu'Li; ii ZnBr2; iii Me02C.(CH2)3 OH Scheme 3 / =\]/OH R Ar-I 2-Pd(0Ac) /NaHCO, B~:N&I/DMF 1 Pd(0Ac)J PPh,(cat)/ AgOAc/ DMF Ar Scheme 4 The synthesis of allylic alcohols can be achieved in high yields using the Heck reaction in the presence of silver acetate or silver carbonate22 (Scheme 4). Brown23 has published an alternative diene synthesis from vinyl boronic acid derivatives (Scheme 5). Kn~chel~~ has also published a novel diene synthesis from acetylenic R Br i,ii \ 0 R' Reagents i ;ii H+-70% Li Scheme 5 21 J.-M. Duffault J. Einhorn and A. Alexakis Tetrahedron Lett. 1991 32,3701. 22 T. Jeffrey Tetrahedron Lett. 1991 32 2121. 23 H.C. Brown N. G. Bhat and R. R. Iyer Tetrahedron Lett. 1991 32,3655. 24 P.Knochel and M. J. Rzeman Tetrahedron Lett. 1991 32 1855. 106 P. Quayle . .. 1,11 Cu(CN)Li Qo* I\ OH Reagents i ICH2ZnI (excess); ii Scheme 6 copper reagents (Scheme 6). Alternati~ely,~~ palladium catalysed coupling of a vinyl triflate and an allene in the presence of a P-diketone leads to the isolation of functionalized dienes in high yields (Scheme 7). Lipshutz26 has developed a general method for the preparation of buta-l,3-dienes starting from the bis-stannane (4) (Scheme 8). 76% Scheme 7 0 64% Reagents i Me2Cu(CN)Li2; ii / ,-78 "C b Scheme 8 25 V.Gauthier B. Cazes and J. Gore Tetrahedron Lett. 1991 32 915. 26 B. H. Lipshutz and J.I. Lee Tetrahedron Lett. 1991 32 7211. Aliphatic and Alicyclic Chemistry The chemistry of high oxidation state iodine compounds has been the subject of much recent interest. For example Stang2' has developed a novel route to difunc- tionalized acetylenes from the iodonium salt (9,Scheme 9. Alternatively:' the salt (6) can be readily transformed into the tri-substituted olefips (7) in near quantitative yields Scheme 10. The synthesis and coupling reactions of vinyl cup rate^^^ prepared in situ from acetylenes has been the subject of a number of reports. [ Ph-1-= H62 Nu--I-Ph]*+*2 x TfO-NU-? -NU (5) Scheme 9 [R-EE-1-Ph]' BFL i,ii b R)=\ (6) PhSO1 X (7) X = C1 Br I 83-100% Reagents i PhSO,H/MeOH; ii Bu,NX Scheme 10 3 Acyclic Stereoselection A major advance has been the development of an in situ method30a for the prepar- ation of [BINAP.RuC12],-Et3N for use in asymmetric reductions.Hence reaction of (RuCl,.COD), with triethylamine generates a very active catalyst which in the presence of BINAP reduces P-keto esters to the P-hydroxy esters with excellent enantioselectivities (~97% ee). Of particular significance is the observation that this catalyst systems enables reduction to occur at relatively low pressures of hydrogen (50 psig) compared to the high pressurz; (ca. 1500 psig) usually associated with this reduction procedure. A second group have shown that related catalyst systems ( RuC12[ SbPh3I3/BINAP) has a similar reactivity profile reducing P-keto esters to the respective P-hydroxy esters with marginally improved enantioselectivities (>98% ee) (4-5 atmospheres of hydrogen).Sharple~s~~ has reported 'a catalyst system (OsO modified by a dihydroquinidine auxiliary) which enables the dihydroxylation of a variety of olefins to occur in high chemical (75-905'40) and optical yields (up to 99% ee). Corey's oxazaborolidine methodology for the enationselective reduction of has been employed on numerous occasions this year and has been the subject of theoretical in~estigations.~~ 27 P.J. Stang and V. V. Zhdankia J. Am. Chem. SOC.,1991 113 4571. 28 M. Ochai K. Oshima and Y. Masaki Tetrahedron Lett. 1991 32 7711. 29 B. H. Lipshutz and K. Kato Tetrahedron Lett. 1991 32 5647. 30 (a) D. F.Taber and L. J. Silverberg Tetrahedron Lett. 1991,32 4227; (b)M. Kitamura M. Tokunaga T. Ohkuma and R. Noyori Tetrahedron Lett. 1991,32 4163. 31 Y. Ogino H. Chen E. Manoury T. Shibata M. Beller D. Lubben and K. B. Sharpless Tetrahedron Lett. 1991 32 5761. 32 E. J. Corey X.-M. Cheng K. A. Cimprich and S. Sarshar Tetrahedron Lett. 1991 32 6835 C.-P. Chen K. Prasad and 0.Repic Tetrahedron Lett. 1991,32,7175 E. J. Corey and H. Kigoshi Tetrahedron Lett. 1991 32 5025. 33 V.Nevalainen Tetrahedron Assym. 1991 2 827. 108 P.Quayle (9) anti syn = 1:8.6 Scheme 11 M~therwell~~ has described a new method for the generation of enolates. For example reaction of the alkoxide (8) with benzaldehyde in the presence of suitable catalyst afforded the aldol product (9) in 84% isolated yield (anti:syn = 1:8.6) Scheme 11.Japanese workers3' have shown that the potassium enolate generated from the ketone (10) undergoes alkylation to afford an optically active product -hence the intermediate enolate possesses 'memory of chirality' Scheme 12. Gener-ati~n~~ of the enolate from the N-acyl aziridine (1 1) and reaction with benzaldehyde *'"' -aoEt KH 18-C-6 \ ' 'OEt Me1 / OEt 93%ee 66%ee (10) Scheme 12 BnO/''\<OBn i LHMDS; -78 "C ii F'hCHO Ph":"I;OBn 73% OBn afforded the syn-aldol product (12) in 73% yield as the sole product. A number of workers37 have shown that titanium enolates afford syn-selective aldol products (ds > 90 10). Curiously,38 reaction of the prolinal derivative (13) with the amide (14) in the presence of a slight excess of Bu;BOTf afforded the contra-Evans 34 G.L. Edwards W. B. Motherwell D. M. Powell and D. A. Sandheum 1. Chem. SOC.,Chem. Commun. 1991 1399. 35 T. Kawabata K. Yahiro and K. Fuji J. Am. Chem. Soc. 1991 113 9694. 36 D. Tanner and C. Birgeson Tetrahedron Lett. 1991 32 2533. 37 M. D. Bonner and E. R. Thornton J. Am. Chem. SOC,1991,113,1299; D. A. Evans D. L. Eieger M. T. Bioldean and F. Urpi J. Am. Chem. SOC 1991 113 1047. 38 K. Hayashi Y. Hamada and T. Shiori Tetrahedron Lett. 1991 32 7287. Aliphatic and Alicyclic Chemistry Et,N; Bu,"BOTf H b w CH2C120"C Ph Boc OH Ph OCHO I Boc anti (15) Et3N:Bu;BOTf (2 1.8) Syn:anti (1OO:O); Et,N:Bu;BOTf (1.08 1.15) Syn:anti (0 100) Scheme 13 anti-aldol product (15) (100 :1 anti :syn) presumably via an 'open' transition state Scheme 13.Opp0lzer~~ has developed a general strategy for the synthesis of anti-aldol products using chiral sultam methodology.The thianone (16) undergoes kinetic aldol reactions with high anti-selectivities (-96 :4) and serves as a useful surrogate for pentan-3-one in such reactionN (Scheme 14). a-Epoxy aldehydes undergo kinetic aldol reaction41 to afford the anti-aldol products (Felkin- Anh transition state). I-'" .. +Ph 0 OH OH (16) Reagents i LDA -78 "C; ii PhCHO; iii NaBH4/EtOH; iv Raney Ni Scheme 14 F3C -98% ee (17) Reagents i Et3N -78 "C(17); ii RCHO -18 "C Scheme 15 39 W.Oppolzer C. Starkemann I. Rodriguez and G. Bernadinelli Tetrahedron Lett. 1991 32,61. 40 T.Hayashi Tetrahedron Lett. 1991 32,5369. 41 R. C. Peller G. Jimarauel D. G. Powers and C.-T. Chang Tetrahedron Lett. 1991 32 449; J. M. Escudier M. Baltas and L. Gorrichon Tetrahedron Lett. 1991 32,5345. 110 P. Quayle Corey4’ has described the first highly enantioselective ‘Darzens’ reaction Scheme 15. Reet~~~ has described a stereocomplementary approach to the preparation of 1,2-diamines. Conjugate addition to 8-functionalized a$-unsaturated carbonyl and nitro-groups has been the subject of a number of investigations.& The use of binaphthol as a chiral auxiliary in a number of alkylation reactions has been also been reported?’ A number of workers& have remarked upon the stereoselective alkylation reactions of carbon-centred radicals as exemplified by Scheme 16.This area of chemistry promises to be highly fruitful. gH& AIBN/A Hexane 73 :1 (erythro :threo) 67% Scbeme 16 Hydroxy-enones such as (18) undergo highly stereoselective epoxidation reactions using the Sharpless protoc01:~ Scheme 17. OH 0 OH 0 OH 0 @p=(y$+@y CH,CI (18) -15°C >99:1 82% Scbeme 17 4 Alicyclic Chemistry The use of aromatic compounds as synthons in natural product synthesis has been reviewed.48 Experimental validation of the Cieplak model governing the facial 42 E. J. Corey and S. Choi Tetrahedron Lett. 1991 32 2857. 43 M. T. Reetz R. Jaeger R. Drewlies and M.Hubel Angew. Chem. Znt. Edn. Engl 1991 30,103. 44 M. T. Reetz F. Wang and K. Harms J. Chem. SOC.,Chem. Commun. 1991 1309; S. Hanessian and K. Sumi Synthesis 1991 1083;A. G. M. Barrett P. D. Weipert D. Dhanak R.K. Husa and S. A! Lebold J. Am. Chem. SOC.,1991 113 9820. 45 K. Fuji K. Tanaka M. Mizuchi and S. Hosoi Tetrahedron Lett. 1991 32 7277; Y. Tami S. Koike A. Ogura and S. Miyano J. Chem. SOC.,Chem. Commun. 1991 799. 46 N. A. Porter B. Giese and D. P. Curran Acc. Chem. Rex 1991 24 296; P. Renaud Helv. Chim. Acta 1991 74 1305; D. P. G. Hamon P. Razzino and R. Massy-Westropp 1.Chem. SOC.,Chem. Commun. 1991 332; A. L. J. Beckwith R. Hersperger and J. M. White J. Chem Soc. Chem. Commun. 1991 1151; B. Giese W. Damn J. Dickhaut F. Wetterich S. Sun and D.P. Curran Tetrahedron Lett. 1991 32 6097; B. Giese M. Bulli and H.-G. Zeitz SYNLETT 1991 425; N. A. Porter W.-X.Wu and T. McPhail Tetrahedron Lett. 1991 32 707; N. A. Porter R. Breyer E. Swann J. Nally J. Prahan T. Allen and A. T. McPhail J. Am. Chem. SOC. 1991 113 7002; J. G. Stack D. P. Curran J. Rebeck and P. Ballester J. Am. Chem. SOC.,1991 113 5918; W. Smadja M. Zahouily M. Journet and M. Malacria Tetrahedron Lett. 1991 32 3683; Y. Guindon J. F. Lavallee M. L. Brunet G. Homer and J. Rancourt J. Am. Chem. SOC.,1991 113,9701. 47 M. Bailey I. E. Marko and W. D. Ollis Tetrahedron Lett. 1991 32 2687. 48 L. N. Mander SYNLEm 1991 134. Aliphatic and Alicyclic Chemistry 111 selectivity of olefin functionalization has appeared.49 The factors governing the stereoselectivity in nucleophilic addition to cyclic ketones is still the cause for some debate.50 5 Cyclopropanes The use of chiral catalyst systems in olefin cyclopropanation reactions has been the subject of a number of reports.Evanss1 and Ma~arnune~~ have described the use of copper catalysts containing C,-symmetric ligands for effecting highly enantioselec- tive cyclopropanation of olefins. Typically enantioselectivities for these reactions fall into the range of 94-99’/0 ee (Scheme 18). A Rhodium (III)-porphyrin catalyst Ph CO2R COZR N2J CuOTf ; R02CAN C02R Ph-’ ph-p -ph-P 0.1 mol% OH 99% ee (Ref. 51) ‘R2 5 (Ref. 53) Scheme 18 system53 has been reported to be syn-selective in the cyclopronation of styrene with ethyl diazoacetate; unfortunately the reaction proceeded with only modest asym- metric induction (ca.10% ee). Doyle54 has developed a highly effective rhodium- based system for the corresponding intramolecular cyclopropanation reactions (Scheme 18). Reaction” of the homochiral diazoester (19) with styrene in the 49 G. Metha and F. A. Khan J. Chem. SOC.,Chem. Commun. 1991 18. 50 Y. D. Wu A. Tucker and K. N. Houk J. Am. Chem. SOC.,1991 113 5018; G. Frenking K. F. Kohler and M. T. Reetz Angew. Chem. Zntl. Edn. Engl. 1991 30,1146. 51 D. A. Evans K. A. Woerpel M. M. Hinman and M. M. Faul J. Am. Chem. Soc. 1991 113 726. 52 R. E. Lowenthal and S. Masarnune Tetrahedron Lett. 1991 32 7273. 53 S. O’Malley and T. Kodakek Tetrahedron Lett.1991 32 2445. 54 M. P. Doyle R. J. Pieter S. F. Martin R. E. Austin C. J. Oalmann and P. Muller J. Am. Chem. SOC. 1991 113 1423. 55 H. M. Davies and W. R. Cantrell Terrahedron Lett. 1991 32 6509. 112 P. Quayle presence of Rh,(octanoate) afforded the cyclopropane (20) in 67% yield (>98% d.e.) Scheme 19. Alternati~ely,'~ Simmonds-Smith cyclopropanation of the glucose- derivative (21) and removal of the auxiliary afforded the alcohol (22) in a near optically pure state. 1 . B BnO 0 OH6 O-Ph (22) (21) Reagents i Et2Zn/Cu212 Toluene -35 "C +0 "C; ii Tf20; iii H20/Py/DMF Scheme 19 CyclopropanationS7of the allylic alcohol (23) afforded the product (24) in 90% d.e. alternatively direct cyclopropanation of the homochiral cyclopentenol (25) afforded (26) as the sole product in 77% isolated yield (Scheme 20).Harvey5* has shown that unactivated buta-l,3-dienes undergo cyclopropanation rections with the OH .OH 90%ee (24) Scheme 20 56 A. B. Charelle B. Cote and J. F. Maroux J. Am. Chem. Soc. 1991 113,8166. 57 M. Kabat J. Kiegel N. Cohen K. Toth P.M. Wovkulich and M. R. Uskovic Tetrahedron Lett. 1991 32,2343. 58 D.F. Harvey and K. P. Lund J. Am. Chem. SOC.,1991 113,8916. Aliphatic and Alicyclic Chemistry (Ref.58) Me0 71% ?Yo"' (ref. 59a) 0 52% (Ref. 596) Scheme 21 labile molybdenum carbene complex (27) Scheme 21. Intramolecular variantd9" of this process have also been realised (Scheme 21). An intramolecular cyclopropana- tion sequence was utilized in a synthesis of (1)-thaspane (Scheme 22)59b.An efficient6' OH Scheme 22 Thaspane -Me3Si7 0 S i B u ' Ph2 S02Ph OSozMe LDA -78 "C 89% PhS02 SiMe3 a -x TBAF ''.pOH 9& ".fiOSiBu' Ph2 (27) Scheme 23 (a) D. F. Harvey K. P. Lund and D. A. Neil Tetrahedron Lett. 1991,32,6311; (b)A. Snikuishna and K. Rrishnan J. Chem. Soc. Chem. Commun. 1991 1693. 6o M. M. Kabat and J. Wicha Tetrahedron Lett. 1991 32 531. 114 P. Quayle synthesis of the cyclopropene (27) has been reported in which the crucial olefination step involved a fluoride mediated desilylation sequence Scheme 23. A similar6' elimination sequence was employed in the synthesis of the spiropentadiene (28). 6 Cyclobutanes Vollhardt6* employed a [2 + 2 + 21 cycloaddition strategy in the synthesis of illudol (30).The key reaction in this sequence secured the 5-6-4 ring system (29) in 92% yield Scheme 24. Reaction of dichloroketene with the glucal (31) afforded,63 after dehalogenation the optically pure cyclobutanone (32). The cyclobutane (32) was further transformed into the lactone (33) by standard methodology. OTBDMS OTBDMS (29) (92%) I Reagents i CpCo(CO), PhCH3 llO"C hv 6 h. Scheme 24 OMe (33) 61 A. Srikrishna and K. Krishnan J. Chem. SOC.,Chem. Commun. 1991 1693. 62 E. P. Johnson and K. P. C. Vollhardt J. Am. Chem. SOC.,1991 113 381. 63 J. Pan I. Hanna and J.-Y. Lallemand Tetrahedron Lett. 1991 32 7543. Aliphatic and Alicyclic Chemistry 115 Photbcy~loaddition~~ of cyclopentenone with the olefin (34) afforded the adduct (35) in 63% isolated yield.Ketone (35) proved to be a useful intermediate in the synthesis of the spatane ditertepenes. Phot~lysis~~ of the carbene complexes (36) in the presence of the enamide (37) afforded the adducts (38) in moderate yields (50-60% 94-97% de). OTMS 0 RIO-Ph g3, Ph 0 (37) (38) 7 Cyclopentanes Organometallic Approaches.-The Smit modification of the Pauson-Khand reaction has been used with good effect in the synthesis of a variety of cyclopentanone~~~*~~ (Scheme 25). silica 0 85 "C/ 12 hr 53% (Ref. 66) (Ref. 67) Reagents i TsNH-; ii BF,.OEt, -18 "C; iii Me,NO 02 CH2C12 Scheme 25 64 R.G. Salomon N. D. Sachinauala S. Roy B. Basu S. R. Raychaudhuri D. B. Miller and R. R. Sharma J. Am. Chern. Soc. 1991 113 3085. 65 L. S. Hegedus R. W. Bates and B. Soderberg J. Am. Chem. Soc. 1991 113 923. 66 A. L. Veretnov W. A. Srnit L. G. Voronstova M. G. Kurella R. Caple and A. S. Gibin Tetruhderon Lett. 1991 32 2109. 67 N. Jeong S. E. Yoo S. J. Lee and Y. K. Chung Tetrahedron Lett. 1991 32 2137. 116 P. Quayle =aft6* has demonstrated that the intermolecular Pauson-Khand reaction pro- ceeds with enhanced regiocontrol when the reacting partners possess pendent co-ordinating groups (Scheme 26). A remarkable69 rate enhancement in these cycliz- ation processes was observed when the reactions were carried out on the analogous acetylenic carbene complexes (Scheme 27).Pearson7' has developed a carbonylation rection of di-ynes and ene-ynes affording the cy+opentanone derivatives in good yields upon thermolysis with iron pentacarbonyl in toluene. CO,(CO), ~ + Ph-G -Me2NwPh c"" + 72% 4 51 Ph Me2N Scheme 26 Scheme 27 Intramolecular hydroacylation of the alkene (38) afforded the bicyclic system (39) in good yield (60%) (Scheme 28).78 In a rather interesting development Lieb~kind~~ has shown that the readily available molybdenum complex (40)under-went nucleophilic addition at Ca -a reversal of the normal polarity of enones. Hence reaction of (40) with acetophenone enolate and subsequent elaboration and removal of the metal afforded the bicyclic system (41) in excellent overall yield (75%) Scheme 29.Kn~chel~~ has developed an intramolecular carbocupration sequence whereby formation of the organocuprate (42) led upon warming to room temperature and quenching with a suitable electrophile to the isolation of the cyclopentanes (43)in moderate to good yields (55-70%). 68 M. E. Kraft C. A. Juliano I. L. Scott C. Wright and M. D. McEachin J. Am. Chem. SOC.,1991 113 1693. 69 F. Cumps J. M. Moreto S. Ricart and J. M. Vinas Angew. Chem. Inti. Edn. Engl. 1991 30,1470. 70 A. J. Pearson and R. A. Dubbert J. Chem. Soc, Chem. Commun. 1991 202. 71 K. P. Gable and G. A. Benz Tetrahedron Lett. 1991 32 3473. 72 L S. Liebskind and A. Bombrun J. Am. Chem. SOC.,1991 113 8736. 73 S. A. Rao and P. Knochel J. Am.Chem. SOC.,1991 113 5745. Aliphatic and Alicyclic Chemistry [(Ph,P),RhCI], & CP4 "0 ''* CDC1,/6 60% BnO 'o+ (38) (39) Scheme 28 ,,co .. I-IV b-=y Mo d Ph 1 co PF; "0 CP via (40) Reagents i PhCOCH,Li; ii I iii NH:CF,CO,; iv FeCl, Scheme 29 In a related sequence N~rmant'~ has shown that the organozinc reagents (44) readily undergo cyclization to afford the cis-substituted cyclopentanes (45) upon quenching with a suitable electrophile. R' Cu(CN)LiZnMe i 25 "C;2-15 hrs ii E+ c* R R (42) (43) i -70 "C.+ 20 "C c; ii E+ X-Zn OMe Ill I SiMe3 (45) Negishi7' has employed his bi-cyclization-carbonylationmethodology to the syn- thesis of pentalenic acid Scheme 30. 74 G.Courtemanche and J. F. Normant Tetrahedron Lett. 1991 32 5317. 75 G. Agnel and E.4. Negishi J. Am. Chem. SOC.,1991 113 7424. 118 P. Quayle SiMe (84%) \ HO Reagents i ‘Cp,Zr’; ii CO (1 atm) Scheme 30 A number of Pdo-mediated cyclization reactions have appeared a selection of which are presented in Scheme 31. 72% 73% OMe Pd,(dba) XHCl Ph ib 40-35 “C HOAc _____ + phso22 PhSOz (Ref. 78) r SOzPh 86% 76 G. J. Engelbrecht and C. W. Holsapfel Tetrahedron Lett. 1991 32 216). 77 B. M. Trost M. Lautens C. Chan D. J. Jebaratnam and T. Mueller J. Am. Chem. SOC.,1991,113,636. 78 B. M. Trost and Y. Shi J. Am Chem. Soc. 1991 113 701. 119 Aliphatic and Alicyclic Chemistry 0 ? -‘I,,, 61% ‘“1 1 (Ref.80) - Pdo (Ref. 81) 62% 0°c02cH3 S02Ph SO2R Scheme 31 Radical Cyc1ization.-Radical approaches to cyclopentanes are legion a representa- tive selection of the procedures recently discussed are presented in Scheme 32. 0 0 SmI ___ (Ref. 82) TH F DMPU TMS 79% 79 B. M. Trost A. S. Tasker and A.Brande J. Am. Chem. SOC.,1991 113,670. 8o D. Bouyssi G. Balme and J. Gore Tetrahedron. Lett. 1991 32 6541. 81 B. M.Trost T. A. Gresse and D. M. T. Chan J. Am. Chem. SOC.,1991 113 7350. 82 R.A. Batey and W. B. Motherwell Tetrahedron Lett. 1991 32 6649. 120 I? Quayle Qe ZxSMI ____ (Ref. 83) Bu3SnH AIBN A 0 Et0,C-75% Bu,SnH WPh (Ref. 84) AIBN/PhH A -Ph H -C02Me Bu3SnH C02Me (Ref.86) 0,.Toluene 0 "C \ 68% I (Ref. 87) 'SnBu3 86% I 85% Scheme 32 83 S. E. Booth and P. R. Jenkins and C. J. S. Swain J. Chem. SOC.,Chem. Commun. 1991 248. 84 S. Kim S. Lee and J. S. Koh J. Am. Chem. SOC.,1991 113 5106. 85 Y. M. Tsai and C.-D. Cherng Tetrahedron Lett. 1991 32 3515. 86 E. Nakamura T. Innubushi S. Aoki and D. Machi J. Am. Chem. SOC.,1991 113 8982. S. Kim I. S. Kee and S. Lee J. Am. Chem. SOC.,1991 113 9882. G. A. Molander and C. C. Kenny J. Org. Chem. 1991 56 1439. Aliphatic and Alicyclic Chemistry 121 Miscellaneous.-Reaction of the optically pure ep~xide~~ (46) with potassium hydride afforded the trans-functionalized cyclopentane (47) a key intermediate in the synthesis of brefeldin A Scheme 33.?H OBn KH MEMO-___* MEMO-THF 65% 0 0 (44) (47) 1 1 Scheme 33 Me0 Me0 OMe OMe (48) (p :a =29:33) \ OMe (49) Scheme 34 89 D. F. Taber L. J. Siverberg and E. D. Robinson J. Am. Chem. SOC.,1991 113 6639. 122 P. Quayle Taylo?’ has utilized a samarium iodide promoted pinnacol-type coupling reaction in a synthesis of rocaglamide. Hence in the key reaction treatment of the di-carbonyl compound (48) with samarium iodide afforded a 1:l mixture of the diols (49) Scheme 34. Hoye has developed a rhodium catalysed carbene addition-rearrangement sequence for the preparation of fused cyclopentan~nes.~~ Hence reactions of the diazoketone (50) with rhodium acetate in the presence of 2-butyne ultimately afforded the bicyclic system (51) in 51% overall yield.A more ‘traditional’ rhodium catalysed process involved the metal promoted insertion reaction of the ‘carbenoid’ generated from the diazo ketone (52) into a proximal C-H bond to afford the ketone (53) in excellent yield9* (85%). RhJOAc), A Me-=-Me N2 0 25°C 51% 0 Finally treatment of the vinyl iodonium salt (54) with triethylamine in benzene afforded the cyclopentene (59 pesumably oia the intermediates of the alkylidene carbene (56)?3 H (54) (55) 8 Cyclohexanes Diels-Alder Reactions.-As always many synthetic schemes leading to functional- ized six membered rings rely upon Diels-Alder methodology to control regio- and stereochemistry. During the past year a number of catalysts have been developed in order to promote asymmetric Diels- Alder reactions.Of the examples selected for this review the Corey catalyst (57) appears to achieve the highest enantiomeric excess in the Diels-Alder adduct (Table 1). 90 A. E. Davey M. J. Schaeffer and R. J. Taylor J. Chem. Soc. Chem. Commtm. 1991 1137. 91 T. R. Hoye and C. J. Dinsmore Tetrahedron Lett. 1991 32 3755. 92 H. R. Sonawane H. S. Bellier J. R. Ahuja and D. J. Kulkami J. Org. Chem 1991 56 1434. 93 M. Ochai M. Kubiushima S. Tani and Y. Nagao J. Am. Chem. Soc. 1991 113 3135. Aliphatic and Alicyclic Chemistry phh#ph I. CF,SOZN NSOICF3 A< I 48% (Ref. 96) MeS02N ,O Me B (57) I R 95% ee (Ref. 95) 99% ee (Ref.94) 94% ee (Ref. 97) 86% ee (Ref. 98) Table 1 Kea~~~ has reported that furans undergoes a high yielding intramolecular Diels- Alder reaction in the presence of MeAlCl (0.1 eq.) at low temperatures (-65 "C) with high endo :exo ratios. It is suggested that this catalyst regime is complementary to high pressure techniques otherwise used for such reactions (Scheme 35). A 0 .Q7 HO endo :exo =91 :9 Reagents O.leq MeAlCl, CH2C12 -65 "C 2h 91% Scheme 35 Scheme 36 94 E. J. Corey and T.-P. Loh J. Am. Chem. Soc. 1991 113 8966. 95 E. J. Corey N. Imai and S. Pikul Tetrahedron. Lett. 1991 32 7517. 96 P. N. Devine and T. Oh Tetrahedron I+. 1991 32 883. 97 E. J. Corey and Y. Matsumura Tetrahedron Lett. 1991 32 6289. 98 E. J. Corey N.Imai and H.-Y. Zhang J. Am. Chem. Soc. 1991 113 728. 99 C. Rogers and B. A. Keay Tetrahedron Lett. 1991 32 6477. 124 P. Quayle X 0W-com (Ref. 100) C02Me (Ref. 102) (Ref. 101) 0 \ (Ref. 105) (Ref. 103) (Ref. 104) 0&OMe I (Ref. 106) (Ref. 107) (Ref. 108) I Ph (Ref. 109) (Ref. 110) (Ref. 111) 100 T. Hudlicky and H. F. Olivo Tetrahedron Lett. 1991 32 6077. 101 H. C.Kolb and S. V. Ley Tetrahedron Lett. 1991 32 6187. 102 S. F. Martin T. Rein and Y. Liao Tetrahedron Lett. 1991 32 6481. K. Ando N. Akadegawa and H. Takagawa J. Chem. SOC.,Chem. Commun. 1991 1765. 104 E. P. Kundig G. Bernadelli and J. Leresche J. Chem. SOC.,Chem. Commun. 1991 1713. 10s X. Wang J. Chem. SOC.,Chem. Commun.1991 1515. 106 M. Ohkita T. Tsuji and S. Nishida J. Chem SOC. Chem. Commun. 1991 37. lo' S. Hatakeydima K. Sugawara and S. Takano 1 Chem. SOC.,Chem. Commun. 1991 1533. 108 H.-J.Kang C. S. Ra and L. A. Paquette J. Am. Chem. Soc. 1991 113,9384. N.Kitagiri M. Yamoto T. Iwaoka and C. Kaneko J. Chem. SOC.,Chem. Commun. 1991 1429. 'lo D. A. Singleton and J. R. Martinez Tetrahedron Lett. 1991 32 7365. 111 G. H. Posner T. D. Nelson C. M. Kinter and K. Afarinkia Tetrahedron Lett. 1991 32 5295. Aliphatic and Alicyclic Chemistry OMe SiMe, I (Ref. 112) (Ref. 113) (Ref. 114) Table 2 representative list of dienes/dienophiles is tabulated in Table 2. Of interest is the development introduced by Shea' l5 which has been termed 'Pericyclic Umpolung'.In this work a disposable tether was introduced in a link between the diene and dienophile in order to control the regioselectivity of the Diels-Alder process (Scheme 36). Other Methods of Construction.-Radical reactions'16 have been utilized for the synthesis of heavily oxygenated and polycyclic cyclohexane derivatives. Double Michae1117 reactions have been employed in the construction of fused systems e.g. Scheme 37. Wulffl'* has developed a particularly rapid entry into steroidal system based upon carbene cycloaddition chemistry Scheme 38. OTBDMS I Hi COzMe 63% Scheme 37 OTBS Reagents i hOMe, CH,CN CO; ii 120 "C Scheme 38 112 N. K. Bhamare T. Granger C. R.John and P. Yates Tetrahedron Lett. 991 32 4 39.113 J. J. Pegram and C. B. Anderso Tetrahedron Lett. 1991 32 2197. 114 A. Barco S. Benetti G. P. Pollini G. Spalluto and V. Zanirato Tetrahedron Lett. 1991 32 2517. K. J. Shea A. J. Staab and K. S. Zandi Tetrahedron Lett. 1991 32 2715. 116 J. Marco-Contelles L. Martinez A. Martinez-Grau C. Pozuelo and M.L. Jimeno Tetrahedron Lett. 1991,32 6437. I17 N. Ihara S. Suzuki N. Taniguchi F. Fukumoto and C. Kabuto J. Chem. Soc. Chem. Commun. 1991 1168. 118 J. Bao V. Dragisich S. Wenglowsky and W. D. Wulff J. Am. Chem. Soc. 1991 113 9873. 126 P. Quayle A particularly expedient"' approach to shikimic acid relies upon an intramolecular Wittig reaction Scheme 39. 00 Scheme 39 Functionalization.-Davis12' has reported that the enolate generated from the p -keto ester (58) can be oxidized using the oxaziridine (60) to afford the alcohol (59) a pivotal intermediate for the synthesis of anthracyclinones in 70% yield with an optical purity in excess of 95% ee.V M\ wOMe M\ eHOMe Me0 Me0 0 Magnus'*' has developed a concise synthesis of the benzo-morphanone skeleton (62) from the tri-isopropysilyl ether (61). 9 Cycloheptanes Decomposition'22 of the diazo compound (63) in the presence of rhodium acetate dimer and the diene (64) affords the fused cycloheptadiene (65) in 94% yield. Alternati~ely,'~~ ring expansion of the cyclobutanone (66) to the cycloheptanone (67) was accomplished in good yield (68%) upon reaction with Bu3SnH/AIBN. 119 S. Mirza and J. Harvey Tetrahedron Lett.1991 32 4111. 120 F. A. Davis A. Kumar and B. C. Chen Tetrahedron Lett. 1991 32 867. 121 P. Magnus and I. Coldham J. Am. Chem. SOC.,1991 113,672. 122 W. R. Cantrell and H. M. L. Davies J. Org. Chem. 1991 56 723. 123 P. M. Dowd and W. Zhang J. Am. Chem. SOC,1991 113 9875. Aliphatic and Alicyclic Chemistry C02Me rOTBDMS 0 Me (64) (65) H H Clavukerin A'24 (68) has been prepared from the cyclobutanone (69) by way of a Grob-type fragmentation (Scheme 40). Har~ood'~~ has published a modified route to phorbol esters utilizing IMDA reactions of functionalized furans. Banwe11'26 has developed a concise approach' to functionalized tropolones from i ,2-dihydroxy-cyclo hexa-3,Sdienes. n . .. 4 -"'8 -Q 0 0 (49) n a; ii MsCI EQN Reagents i BrMg Scheme 40 10 Cyclooctanes Paq~ette'~~ has developed a double Tebbe-Claisen sequence for the synthesis of functionalized cyclooctanones Scheme 41.Synthetic approaches to the taxanes have been extensively reviewed.12* An intramolecular Diels- Alder- Wittig rearrangement sequence has been developed for the construction of the taxane skeletone Scheme 42.'29 124 S. K. Kim and C.S. Pak J. Org. Chem 1991 56 6829. 125 L. M. Harwood T. Ishikawa H. Phillips and D. Watkin J. Chem. Soc. Chem. Commun. 1991 527. 126 M. G. Banwell and M. P. Collis J. Chem. Soc. Chem. Commun. 1991 1343. 127 C. M. G. Phillipo N. H. Vo and L. A. Paquette J. Am. Chem SOC.,1991 113,2762; C. M. G. Phillipo N. H. Vo and L. A. Paquette J.Am. Chem. Soc. 1991 113 2762. 128 C. S. Swindell Org. Prep. Proc. Int. 1991 23 465. 129 J. S. Yadav and R. Ravishankar Tetrahedron Lett. 1991 32 2629. 128 P. Quayle A 36% < OQ -_ Scheme 41 H OR V " 0 Reagents i. NaBH,; ii BuLi THF -78 "C to r.t. Scheme 42 11 Medium-Large Rings Synthetic approaches to ene-diyne systems related to calicheamycin have been extensively re~iewed.~ Further efforts in this area have recently been reported by MagnusI3' and Nic~laou.'~' Tius has 132 developed a strategy for the synthesis of cembranes utilizing an intramolecular alkylation sequence Scheme 43. Diastereo-LiN(TMS) - THF 55 "C (74%) Scheme 43 130 P. Magnus and M. Davies J. Chem. SOC.,Chem.Commun. 1991 1522. See also M. E. Maier and T. Brandstetter Tetrahedron Lett. 1991 32 3679; M. Hirarna T. Gomibuchi K. Fujiwara Y. Sugiura and M. Vesugi J. Am. Chem. SOC.,1991 113 9851; A. G. Myers P. M. Harrington and E. Y. Kuo J. Am. Chem. Soc. 1991 113 694. 131 K. C. Nicolaou Y.-P. Hong Y. Toisawa S.-C. Tsay and W.-M. Dai J. Am. Chem. SOC.,1991 113 9878; K. C. Nicolaou A. C. Smith S. V. Wenderborn and C.-K. Hwang J. Am. Chem. SOC.,1991,113 3106. 132 M. A. Tius and N. K. Reddy Tetrahedron Lett. 1991 32 3605. Aliphatic and Alicyclic Chemistry cuprate addition to the macrocyle (70) and subsequent Dieckman con- densation and decarboxylation afforded (R)-muscone in -50% overall yield (85% ee) Scheme 44. --+-50% 85% ee H Me2CuLi (70) Scheme 44 12 Total Synthesis IMDA approaches to cytochalasin synthesis have been reviewed.134 Synthetic high- lights this year include approaches to the ginkg~lides,'~~ the total synthesis of (+)-eremantholide A,136calichaernicin~ne,~~~ and onamide A.138 133 T.Ogawa C.-L. Fang H. Suemune and K. Sakai J. Chem. SOC.,Chem. Commun. 1991 1438. 134 E. J. Thomas Acc. Chem. Res. 1991 24 229. 135 E. J. Corey and K. S. Rao Tetrahedron Lett. 1991 32 4623. 136 R. K. Boeckman S. K. Yoon and D. K. Heckendom J. Am. Chem. Soc. 1991 113 9682. 137 J. N. Haselline M. P. Cabal N. B. Mantlo N. Iwasawa D. S. Yamashita R. S. Coleman S. J. Danishefsky and G. K. Schulle J. Am. Gem. Soc. 1991 113 3850. '38 C. Y. Hong and Y. Kishi J. Am.Chem. SOC.,1991 113 9694.

ISSN:0069-3030    

DOI:10.1039/OC9918800103

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

6 Aromatic Compounds By I. G. C. COUlTS Department of Chemistry and Physics Nottingham Polytechnic Nottingham NGl 1 8NS 1 General and Theoretical Studies The ready formation of a trimethylenemethane dianion from isobutene has hitherto been attributed to a conjugative stabilization ('Y-aromaticity') involving all four carbon atoms but recent calculations suggest that the anion is non planar and that the stabilization is caused by maximally distant localization of the T electrons rather than by delocalization.' However the comparative stability of dications formed in SbF5/SO2C1F by rigid tetramethylenes such as pagodane has been explained in terms of nonclassical 'aromatic' structures.2 From a re-examination of the Mills-Nixon effect it was concluded3 that when strain is imposed on a benzene the system localizes its bonds in the Mills-Nixon manner but on annulation of benzene with small rings the effect diminishes due to the formation of 'banana bonds'.The aromaticity of benzenes in which a methine has been replaced by a transition metal and associated ligands (the metallobenzenes) has been reviewed4 and the thermochemical equivalence of substituted benzenes and ethylenes has been used in a study of the aromaticity of heterocycles.' Supersonic jet mass resolved excitation spectroscopy has been employed to determine minimum energy conformations of ethoxybenzenes6 Steric hindrance in crowded benzenehexacarboxylates induces an unusual dual fluore~cence,~ and the ring distortion in triaminotrinitrobenzenes' and in potassium salts of trinitrophloro- glucinol' have been determined by X-ray crystal analysis.Surprisingly the crystal structure of the benzene-picric acid complex has only now been reported." Triaryl- boranes (1) containing ethano bridges can be resolved at room temperature." In a comprehensive investigationt2 the MNDO-calculated hydride affinities of substituted aromatic cations and the proton affinities of substituted benzenes have ' A. Gobbi P. J. MacDougall and G. Frenking Angew. Chem. Znt. Ed. Engl. 1991 30,1001. R. Herges P.v. R. Schleyer M. Schindler and W.-D. Fessner J. Am. Chem. Soc. 1991 113 3649. A. Stanger J. Am. Chem. Soc. 1991 113 8277. J. R. Bleeke Acc. Chem. Rex 1991 24 271. R. S. Hosmane and J. F. Liebman Tetrahedron Lett. 1991 32 3949.'E. R. Bernstein H.4. Im M. A. Young H. V. Secor R. L. Bassfield and J. I. Seeman J. Org. Chem. 1991 56 6059. ' N. Yamasaki Y. Inoue T. Yokoyama A. Tai A. Ishida and S. Takamuku J. Am. Chem. Soc. 1991 113 1933. J. J. Wolff S. F. Nelsen P. A. Petillo and D. R. Powell Chem. Ber. 1991 124 1719. J. J. Wolff S. F. Nelsen D. R. Powell and J. M. Desper Chem. Ber. 1991 124 1727. 10 H. Takayanagi Y. Toubai M. Goto S.-I. Yamaguchi and H. Ogura Chem. Pharm. Bull. 1991,39,2491. K. Okada H. Inokawa and M. Oda Tetrahedron Lett. 1991 32 6363. 12 R. Karaman J.-T. L. Huang and J. L. Fry J. Org. Chern 1991 56 188. 131 I. G. C. Courts Y Y / w \ (1) a X = Me Y = H b X Y = -HC=CH-CH=CH-SiMe3 -2-SiMe3 [Li(THF)I2+ Me3Si LMe3siQ SiMe3 SiMe3 -l3 K.Krogh-Jespersen J. Am. Chem. SOC.,1991 113 417. A. Sekiguchi K. Ebata C. Kabuto and H. Sakurai J. Am. Chem. SOC.,1991 113 1464; 7081. l5 T. Lund and H. Lund Acta Chem. Scad. 1991,45 655. Aromatic Compounds A theoretical study16 indicates that cyclopentadienylidenecarbene may be a stable isomer of o-benzyne; the heat of formation of the latter is calculated” to be 105 kcal/mole. Arynes may be generated from phenol triflates using lithium diisopropy1amidel8 or by halogen-lithium exchange of o-haloaryl triflates.” Methoxydehydrobenzenes react regioselectively with methoxyfurans.20-22 2 Preparation of Benzenes from Non-aromatic Precursors The chemistry and biology of the enediyne anticancer antibiotics have been the subject of a comprehensive review.23 Terminal acetylenes and enynes undergo palladium-catalysed tandem bond formation leading to aromatic rings24 (Scheme 1).Lithiation2’ of 2,3-dibromobicyclo-[2,2,2]octanegave a trimer which by a SET Scheme 1 process yielded the benzene (4). Trisannelated benzenes are also obtained by the cyclodehydration of cycloalkanones catalysed by zirconium26 halides or by tetra- chl~rosilane.~~ Phenols are produced by the Nio-promoted reaction of cyclo-butenones with alkynes,28 and by PdC12( PPh,),-catalysed cyclocarbonylation of penta-2,4-dienyl acetates2’ Thermal conversion of bicycle (5) to fluorobenzene proceeds via 1,l-difluorocyclohexa-2,5-dieneformed by a rate determining homolytic H-~hift.~’ 9dF (4) (5) 16 N.A. Burton G. E. Quelch M. M. Gallo and H. F. Schaefer 111 J. Am. Chem. Soc. 1991 113 764. 17 Y. Guo and J. J. Grabowski J. Am. Chem. Soc. 1991 113 5923. 18 P. P. Wickham K. H. Hazen H. Guo G. Jones K. H. Reuter and W. J. Scott J. Org. Chem. 1991 56 2045. 19 T. Matsumoto T. Hosoya M. Katsuki and K. Suzuki Tetrahedron Lett. 1991 32 6735. 20 R. G. F. Giles M. V. Sargent and H. Sianipar J. Chem. Soc. Perkin Trans. 1 1991 1571. R. G. F. Giles A. B. Hughes and M. V. Sargent J. Chem. Soc. Perkin Trans. 1 1991 1581. 22 R. W. Baker T. M. Baker A. A. Birkbeck R. G. F. Giles M. V. Sargent B. W. Skelton and A. H. White J. Chem. Soc. Perkin Trans. 1 1991 1589. 23 K. C. Nicolaou and W.-M. Dai Angew. Chem. Znt. Ed. Engl. 1991 30,1387. 24 S. Torii H.Okumoto and A. Nishimura Tetrahedron Lett. 1991 32 4167. 25 K. Komatsu S. Aonuma Y. Jinbu R. Tsuji C. Hirosawa and K. Takeuchi J. Org. Chem. 1991,56,195. 26 H.Shirai N. Amano Y. Hashimoto E. Fukui Y. Ishii and M. Ogawa J. Org. Chem. 1991 56 2253. 27 S. S. Elmorsy A. Pelter and K. Smith Tetrahedron Lett. 1991 32 4175. 28 M. A. Huffman and L. S. Liebeskind J. Am. Chem. Soc. 1991 113 2771. 29 Y. Ishii C. Gao M. Iwasaki and M. Hidai J. Chem. Soc. Chem. Commun. 1991 695. 30 W. R. Dolbier Jr J. J. Keaffaber C. R. Burkholder S. F. Sellers H. Koroniak and J. Pradhan Tetrahedron Lett. 1991 32 3933. 134 I. G. C. Coutts In the dehydrogenation of cyclohexane to benzene on platinum a stable surface intermediate C6H9 has been identified.31 1,3-Cyclohexanediones are transformed to dimethyl resorcinols with 12/CH30H,32 while aryl alkyl ethers are obtained from the treatment of a,P -unsaturated cyclohexenones with 12/ROH/ceric ammon- ium nitrate33 or VO( OEt)Cl,/AgOTf/ EtOH.34 Various steroids react with [(C,M~,)RUOM~)~]CF,SO,H to give selective aromatization of the A ring by demethylation,, and Bu,SnH promotes C(9)-C( 10) bond cleavage in representatives of the 3-0x0- 1,4-diene series of steroids to afford36 A-ring aromatic 9,lO-secosteroids.Acid-catalysed dienone-phenol rearrangement of 4-methyl-4-cyanocyc-lohexadienone occurs very ~lowly,~' the dienone being stable for months in CF3C02H. A synthesis of C-aryl glycosides is based on the reductive aromatization of quinone ketal~.~* 3 Substitution in the Benzene Ring Electrophilic Substitution.-Catalysis by cyclodextrins of the coupling of phenol to diazonium cations may be due to the electron-rich character of the cyclodextrin interior stabilizing the a-c~mplex.~~ Interesting new insights continue to be gained into the venerable Friedel-Crafts alkylation of benzenes.Clay-supported metal chlorides are effective catalysts for the alkylation of alkylbenzenes.'"' Laszlo and co-workers have reported41 unusual reactivities in alkylations catalysed by ZnC12- montmorillonite. Toluene is more reactive towards benzyl chloride than mesitylene when the substrates are reacted separately but in one-pot reactions mesitylene is favoured and in both cases benzyl alcohol is a more effective alkylating agent than benzyl chloride.Combinations of alcohols and protonic acids useful for the alkylation of nitroben- zene will also effect substitution of aromatic aldehydes ketones and esters.42 Further examples have appeared of the use of perfluorinated resinsulfonic acid as Friedel- Craft Mixtures of CC13F and AlCl replace H by CF3 in polychloroben- ~enes.~~ Reaction of 1,3,5-triisopropylbenzenewith TaC15/CH2C12 gives the stable complex (6) resulting from an intermolecular isopropyl group migration.46 Ally1 31 C. L. Pettiette-Hall D. P. Land R. T. McIver Jr and J. C. Hemminger J. Am. Chem. SOC.,1991 113 2755. 32 A. S. Kotnis Tetrahedron Lett. 1991 32,3441. 33 C. A. Horiuchi H. Fukunishi M. Kajita A. Yamaguchi H. Kiyomiya and S. Kiji Chem.Lett. 1991 1921. 34 T. Hirao M. Mori and Y. Ohshiro Chem. Lett. 1991 783. 35 F. Urbanos J. Fernandez-Baeza and B. Chaudret J. Chem. SOC.,Chem. Cornmun. 1991 1739. 36 H. Kiinzer G. Sauer and R. Wiechert Tetrahedron Lett. 1991 32,7247. 37 J. N. Marx J. Zuerker and Y.-S. P. Hahn Tetrahedron Lett. 1991 32 1921. 38 K. A. Parker and C. A. Coburn J. Am. Chem. SOC., 1991 113 8516. 39 H. Ye D. Rong and V. T. D'Souza Tetrahedron Lett. 1991 32,5231. 40 S. J. Barlow J. H. Clark M. R. Darby A. P. Kybett P. Landon and K. Martin J. Chem. Res. (S) 1991 74. 41 A. Cornelis C. Dony P. Laszlo and K. M. Nsunda Tetrahedron Lett. 1991 32,2901; 2903. 42 Y.-S. Shen H.-X. Liu M. Wu W.-Q. Du Y.-Q. Chen and N.-P. Li J. Org Chem. 1991 56 7160. 43 T.Yamato C. Hideshima G. K. S. Prakash and G. A. Olah J. Org. Chem. 1991 56 2089; 3955. 44 T. Yamato N. Sakaue T. Furusawa M. Tashiro G. K. S. Prakash and G. A. Olah J. Chem. Res. (S) 1991 242. 45 J. Castaner J. Riera J. Carilla A. Robert E. Molins and C. Miravitlles J. Org. Chem. 1991 56 103. 46 E. Solari C. Floriani A. Chiesi-Villa and C. Rizzoli J. Chem. SOC.,Chem. Cornmun. 1991 841. Aromatic Compounds arenes are obtained from the SnC1,-promoted reaction of allylstannanes with arene~,”~ and vinyl cations stabilized by the sulfur of thiophenyl substituents can take part in the alkylation of benzenes.48 A similar stabilizing effect with selenium is in the reaction of aromatic hydrocarbons with PhSeCH( Br)COzEt/TiC14 yielding PhSeCH(Ar)CO,Et.Stable carbocations such as that formed on the protonation of acetophenone do not alkylate unreactive benzenes but cinnamaldehyde its oxime and imine form dications in CF3S03H with sufficient reactivity to do so,” and in CF3S03H/SbF5 nitriles diprotonate to give RC+=N+Hz capable of Houben-Hoesch and Gatter- mann reactions with ben~ene.~’ It is proposed5’ that the t-butylation of benzo- phenones and benzaldehyde with t-BuLi/ SOClz proceeds by a single electron transfer mechanism (Scheme 2) as does the CoC1,-catalysed acylation of anisoles with acid chlorides.53 0 Scheme 2 Contrary to earlier reports diethyl ether is an effective solvent for the two-phase nitration of ani~ole.’~ By suitable choice of catalyst ozone-mediated reactions of nitrogen oxides can lead to ortho-nitration of acetanilides” and to or 41 J.4.Yamaguchi Y. Takagi A. Nakayama T. Fujiwara and T. Takeda Chem. Lett. 1991 133. 48 T. Takeda F. Kanamori H. Matsusita and T. Fujiwara Tetrahedron Lett. 1991 32 6563. 49 C. C. Silveira E. J. Lenardao J. V. Comasseto and M. J. Dabdoub Tetrahedron Lett. 1991 32 5741. 50 T. Ohwada N. Yamagata and K. Shudo J. Am. Chem. Soc. 1991 113 1364. s1 M. Yato T. Ohwada and K. Shudo 1.Am. Chem. Soc. 1991 113 691. 52 G. A. Olah A.-h. Wu and 0.Farooq Synthesis 1991 1179. 53 J. Iqbal M. A. Khan and N. K. Nayyar Tetrahedron Lett. 1991 32 5179. s4 M. J. Thompson and P. J. Zeegers Tetrahedron 1991 47 8787. 55 H. Suzuki T. Ishibashi T. Murashima and K. Tsukamoto Tetrahedron Lett.1991 32 6591. 56 H. Suzuki T. Murashima K. Shimizu and K. Tsukamoto Chem. Lett. 1991 817. I. G. C. Coutts p~ly-nitration~~ of benzenes. A novel family of stable solid electrophilic fluorinating agents the bisammonium salts (7) has been prepared,58 and the influence of Lewis acids on the directed fluorination of aromatic substrates has been ~tudied.~’ Silver-assisted decomposition of aryldiazosulfides ArN=NSPh in the presence of sub-stoichiometric quantities of fluoride may be a useful route to ‘8F-labelled aromatic compounds.60 Results of the competitive iodination of durene and mesitylene under a variety of conditions support the intermediacy of an I+ species?l The regioselective monoiodination of resorcinol and phloroglucinol has been described?2 R In trifluoromethanesulfonic acid arenes undergo electrophilic hydroxylation with NaBO ,63 phenol triflates are formed by the thermal or photolytic decomposition of diazonium fl~oroborates~~ and hydrazoic acid reacts with aromatic compounds to give primary arylamines by a concerted process involving nucleophilic attack of the arene on the conjugate acid of the azide and elimination of nitrogen.65 The chlorosulfonation of aromatic systems has been reviewed.66 Substitution uia Organometallic Intermediates.-1,2-Bis(bromomagnesio)benzene crystallizes from THF as a tetramer the first to be reported for a diorganylmag- ne~ium.~~ Phenyl Grignard reagents react with 2-methoxybenzoic esters derived from 2,6-dialkylphenols to give l,l’-biphenyl-2-~arboxylates,6~ and undergo nickel-cata- lysed cross-coupling with neopentyl iodides?’ Benzaldehydes can be induced to undergo ortho-substitution by Grignard reagents7’ as shown in Scheme 3 and phenols may be ortho-alkylated by condensation with 1-hydroxymethylbenzotriazole and subsequent nucleophilic displacement of the benzotriazole by Grignard reagents .71 57 H.Suzuki T. Murashima K. Shimizu and K. Tsukamoto J. Chem. Sac. Chem. Cammun. 1991 1049. 58 R. E. Banks S. N. Mohialdin-Khaffat G. S. Lal I. Sharif and R. G. Syvret J. Chem. Sac. Chem. Carnmun. 1992 595. 59 S. T. Purrington and D. L. Woodward J. Org. Chem. 1991 56 142. 60 S. A. Haroutounian J. P. DiZio and J. A. Katzenellenbogen J. Org. Chem. 1991 56 4993. 61 C.Galli J. Org. Chem. 1991 56 3238. 62 I. Thomsen and K. B. G. Torssell Acta Chem. Scand. 1991 45 539. 63 G. K. S. Prakash N. Krass Q. Wang and G. A. Olah SYNLEn 1991 39. 64 N. Yoneda T. Fukuhara T. Mizokami and A. Suzuki Chem. Lett. 1991 459. 65 H. Takeuchi T. Adachi and H. Nishiguchi J. Chem. Sac. Chem. Cammun. 1991 1524. 66 J. P. Bassin R. J. Cremlyn and E. J. Swinbourne Phosphorus Sulfur Silicon 1991 56 245. 67 M. A. G. M. Tinga 0. S. Akkerman F. Bickelhaupt E. Horn and A. L. Spek J. Am. Chem. Sac. 1991 113 3604. 68 T. Hattori T. Suzuki and S. Miyano J. Chem. Sac. Chem. Cornmun. 1991 1375. 69 K. Yuan and W. J. Scott Tetrahedron Lett. 1991 32 189. 70 H. Jendralla Liebigs Ann. Chem. 1991 295. 71 A. R. Katritzky X. Lan and J.N. Lam Chem. Ber. 1991 124 1809. Aromatic Compounds CHO CH=NPh CHO i P~(OAC)~ AcOH ii Ph3P R3MgBr iii HCl H20 Scheme 3 A remarkable synthesis of poly-( p-phenylene) in aqueous media employs72 the Pd-mediated reaction of diboronate (8) and bromodiphenic acid (9) Bisflavonoids have been obtained73 from flavoneboronic acids and iodoflavones and arylboronic acids couple with a variety of 7r-deficient heteroaryl chlorides in the presence of palladium bearing a bidentate phosphorus ligand.74 COzH [ O > W B [ ) Br*Br HOzC 0 (8) (9) In a one-pot preparation of ibuprofen from p-xylene three consecutive selective metalations with BuLi-t-BuOK alternate with three electrophilic substitution^.^^ Selective metal-halogen exchange in 2,4,6-tribromoani~ole,~~ the generation of C,O,O-trilithiated derivatives of dihydric phenols,77 and the p~lylithiation~~ of trimethoxybenzenes have been reported.The tetrazole moiety is a useful directing group for the lithiation of 5-aryl sub~tituents,~~ and Meyers has described" naphthyl- oxazolines which are potent chiral auxiliaries in ortho-lithiation. N,N'-dimethyl- ethylenediamine adducts of salicylaldehydes metalate ortho to the modified alde- hyde group.81 Substituted saccharins may be readily obtained via ortho-lithiative sulfonamidation of N,N-diethylbenzamides.g2Metalation of N-pivaloyl 2-(3-methoxyphenyl) ethylamine with butyllithium occurs between the substituents giving a route to inaccessible 8-methoxyisoquinolinesg3 while dilithiation of N-t- BOC-2-methylbenzylamines affords 3-hydroxytetrahydroisoquinolines.84 A variation of the Friedlander quinoline synthesisg5 starts from ortho-lithiated N-t-BOC-72 T.I. Wallow and B. M. Novak J. Am. Chem. SOC.,1991 113,7411. 73 D.Muller and J.-P. Fleury Tetrahedron Lett. 1991 32,2229. 74 M. B. Mitchell and P. J. Wallbank Tetrahedron Lett. 1991 32,2273. 75 F. Faigl and M. Schlosser Tetrahedron Lett. 1991 32,3369. 76 K. Green J. Org. Chem. 1991 56 4325. 77 J. M. Saa J. Morey G. Suner A. Frontera and A. Costa Tetrahedron Lett. 1991 32,7313. 78 S. Cabbidu L. Contini C. Fattuoni C. Floris and G. Gelli Tetrahedron 1991 47 9279. 79 L. A. Flippin Tetrahedron Lett. 1991 32,6857. 80 D. J. Rawson and A. I. Meyers J. Org. Chem.1991 56 2292. 81 M. Gray and P. J. Parsons SYNLET 1991 729. 82 D. J. Hlasta J. J. Court and R.C. Desai Tetrahedron Lett. 1991 32,7179. 83 M. Schlosser and G. Simig Tetrahedron Lett. 1991 32,1965. 84 R.D.Clark and Jahangir Heterocycles 1991 32,1699. 85 I.-S. Cho L. Gong and J. M. Muchowski J. Org. Chem. 1991 56 7288. I. G. C. Coutts or N-pivaloylanilines. The combined use of metallation and Suzuki cross-coupling has been applied to syntheses of the phenanthrene gymnopusin,86 the azafluoran- thene imel~teine,~~ and dibenzo [b,d] pyran-6-ones related to ellagic acid.88 Aryltin reagents undergo Pdo-catalysed cross coupling with aryl fl~orosulfonates,8~ and with vinyl triflates in polar aprotic solvents.90 A Pd0(R3Sn) catalyst system effects intramolecular coupling of aryl or benzylic halides and has been applied9* to the synthesis of (10) (Scheme 4).(i) Pd(OAc),/PPh,/ (Me3Sn) Scheme 4 (Trifluoromethyl) copper species produced from CF3SiR3/F-/Cu(I) in DMF substitute CF3 for iodine in a variety of aryl iodides,92 and arylcopper intermediates react with trifluoroacetic anhydride to give aryl trifluoromethyl ketones.93 In the oxidative coupling of R'R2CuLi and R'R2Cu(CN)Li2 high yields of unsymmetric biaryls R' R2 can be obtained by temperature control.94 Template-directed intra- molecular Ullmann coupling has been used in the synthesis of unsymmetrical diphenic acids,95 and the preparation of unsymmetric and symmetric biaryls from cis-diarylgold(111) complexes has been reported.96 Upon q2-coordination with osmium phenols and anilines show enhanced reactivity towards electrophiles e.g.in the formation of (12) from (11) and maleic anhydride;97 the reactions of 0 86 X. Wang and V. Snieckus Tetrahedron Lett. 1991 32 4879. 87 B. Zhao and V. Snieckus Tetrahedron Lett. 1991 32 5277. 88 B. I. No A. Kandil P. A. Patil M. J. Sharp M. A. Siddiqui V. Snieckus and P. D. Josephy J. Org. Chem. 1991 56 3763. 89 G. P. Roth and C. E. Fuller J. Org. Chem. 1991 56 3493. 90 V. Farina and G. P. Roth Tetrahedron Left. 1991 32 4243. 91 R. Grigg A. Teasdale and V. Sridharan Tetrahedron Lett. 1991 32 3859. 92 H. Urata and T. Fuchikami Tetrahedron Lett. 1991 32 91. 93 F. A. J. Kerdesky and A. Basha Tetrahedron Lett.1991 32 2003. 94 B. H. Lipshutz K. Siegmann and E. Garcia J. Am. Chem. SOC.,1991 113 8161. 95 M. Takahashi T. Kuroda T. Ogiku H. Ohmizu K. Kondo and T. Iwasaki Tetrahedron Lett. 1991 32 6919. 96 J. Vicente M. D. Bermudez and J. Escribano Organometallics 1991 10 3380. 97 M. E. Kopach J. Gonzalez and W. D. Harman J. Am. Chem. SOC.,1991 113 8972. Aromatic Compounds nucleophiles with chloroarene -Mn( CO) and fluoroarene -Cr( CO) complexes have been exploited in syntheses of diary1 ethers98 and thi~ethers~~ respectively. Dimethyldioxirane liberates arenes quantitatively from Cr(C0)3 complexes."' The chemistry of aryllead(IV) tricarboxylates has been reviewed."' These reagents effect mono-N-arylation of aromatic amines under mild conditions.lo2 Radical Reactions.-Oxidation potentials of phenoxide ions combined with pKHA values provide good estimates of the homolytic bond dissociation energies for 0-H bonds in phenol^."^ Fluorinated biaryl derivatives 4-RC6H4hOH (R = F CF, OCF,) are obtained by coupling 4-RC6H4Br with phenol anions via a photostimu- lated SRNl reaction.lW Liquid ammonia is a suitable solvent for a study of the reaction of aryl radicals with pyrrole anions,'05 and for the electrosynthesis by SRNl processes of 4'-hydroxybiphenyl- 1 -~ulfones,~~~ but in the addition of aryl radicals to alkenes the presence of a proton donor is necessary for reasonable yields.'" Consideration of the product ratio of bitolyls obtained by the sonochemical coupling of bromotoluenes over lithium suggests a radical mechanism for the reaction.lo8 Cyclizations of aryl halides generated by the reaction of bromobenzenes with Bu3SnH have been used in syntheses of quinolines and ben~azepinones,"~ of the oxindole portion of gelsernine,"O and of aporphines."' In an approach112 to the alkaloid ungeremine the benzoyl dihydroindole ( 13) on treatment with DMSO/K2C03 gave a radical which cyclized to (14).0 0 (33) (14) The nucleophilicity of acyl radicals has been used to explore the mechanism of acylation of ferrocene and production of 1,l'-diacylferrocenes points to initial chemistry occurring at the iron centre rather than at the ring carbon^."^ Dediazoniz-ation of an aryldiazonium salt by PI1compounds probably proceeds by a radical 98 A.J. Pearson and P. R. Bruhn J. Org. Chem. 1991 56 7092. 99 M. J. Dickems J. P. Gilday T. J. Mowlern and D. A. Widdowson Tetrahedron 1991 47 8621. 100 A.-M. Lluch F. Sanchez-Bacza F. Camps and A. Messeguer Tetrahedron Lett. 1991 32,5629. 101 J. T.Pinhey Aust. J. Chem. 1991 44 1353. 102 D. H. R. Barton D. M. X. Donnelly J.-P. Finet and P. J. Guiry J. Chem. Soc. Perkin Trans. I 1991 2095. 103 F. G. Bordwell and J.-P. Cheng 1Am. Chem. Soc. 1991 113,1736. 104 R. Beugelmans and J. Chastanet Tetrahedron Lett. 1991 32,3487. 105 M. Chahma C. Combellas H. Marzouk and A. Thibbault Tetrahedron Lett. 1991 32 6121. 106 P. Boy C. Combellas S. Fielding and A. Thiibault Tetrahedron Lett. 1991 32,6705. Z. Chami M. Gareil J. Pinson J.-M.SavCant and A. ThiCbault J. Org. Chem. 1991 56 586. G. J. Price and A. A. Clifton Tetrahedron Lett. 1991 32,7133. A. J. Clark K. Jones C. McCarthy and J. M. D. Storey Tetrahedron Lett. 1991 32,2829. 107 108 109 110 D.J. Hart and S. C. Wu Tetrahedron Lett. 1991 32,4099. 111 J. C. Estevez M. Carmen Villaverde R.-J. Estevez and L. Castedo Tetrahedron Lett. 1991 32,529. 112 U. Lauk D. Diirst and W. Fischer Tetrahedron Lett. 1991 32,65. C. Lampard J. A. Murphy and N. Lewis Tetrahedron Lett. 1991 32,4993. 113 I. G. C. Coutts chain me~hanism."~ by reaction Heck arylation of camphene is smoothly effe~ted"~ with ArN2BF4/ P~(OAC)~. Acetophenones protonated by solution in oleum undergo specific para-substitution by alkyl radicals albeit in poor yield,"6 while electron rich aromatics are trifluoromethylated by radicals obtained' l7 from the oxidation of CF3S02Na.Nucleophilic Substitution.-From a review of the literature and new experimental data an alternative mechanism involving a bimolecular displacement process has been proposed for the reaction of nucleophiles with aromatic radical anions contain- ing leaving groups.' l8 Several workers have reported on the nucleophilic displace- ment of nitro groups from nitroarenes. Fluorodenitration occurs in sulfolane at 180 "C side reactions being suppressed by trapping the liberated nitrile anion with phthaloyl dichloride' l9 or difluoride.12' Conversion of nitrobenzenes or naph- thalenes to the corresponding phenols can be effected by reaction with benzyl alcohol in tetramethylurea followed by debenzylation.'21 A recent monograph'22 discusses the influence of the nitro group in nucleophilic aromatic substitutions.In N-methyl-2-pyrrolidone chlorobenzenes react with sodium alkanethiolates to give thi~phenols,'~~ and potassium thiophenolate displaces chloride from chloroanilines and acetanilides to afford the corresponding thiophenyl corn pound^.'^^ Under phase- transfer conditions hydroxide is sufficient nucleophilic to displace one fluoride from polyfluorobenzenes with Bu4NHS04 being the preferred cata1y~t.l~~ Formation of dinitrophenoxides from hydroxide attack on chlorodinitrobenzenes is claimed to be another reaction proceeding by collapse of a radical anion to a Meisenheimer complex.'26 Anilines are converted directly to fluorobenzenes by treatment'27 with NaNO,/pyridine.HF.Deprotonation of aziridine (15) with butyllithum gives (16) the product of intramolecular nucleophilic aromatic addition.'28 114 S. Yasui M. Fujii C. Kawano Y. Nishimura and A. Ohno Tetrahedron Lett. 1991 32 5601. 115 W. Yong P. Yi Z. Zhuangyu and H. Hongwen Synthesis 1991 967. 116 L. B. Din 0.Meth-Cohn and N. D. A. Walshe J. Chem. SOC Perkin Trans. 1 1991 781. 117 B. R. Langlois E. Laurent and N. Roidot Tetrahedron Lett. 1991 32 7525. 118 D. B. Denney and D. Z. Denney Tetrahedron 1991,47 6577. 119 F. Effenberger and W. Streicher Chem. Ber. 1991 124 157. 120 M. Maggini M. Passudetti G. Gonzalez-Trueba M.Prato U. Quintily and G. Scorrano J. Org. Chem. 1991 32 6406. 121 F. Effenberger M. Koch and W. Streicher Chem. Ber. 1991 124 163. 122 F. Terrier 'Nucleophilic Aromatic Displacement the Influence of the Nitro Group' VCH Publishers New York 1991. 123 J. E. Shaw J. Org. Chem 1991 56 3728. 124 A. J. Caruso A. M. Colley and G. L. Bryant J. Org. Chem. 1991 56 862. D. Feldman D. Segal-Lew and M. Rabinovitz J. Org. Chem. 1991,56 7350. 126 R. Bacaloglu A. Blasko C. Bunton E. Dorwin F. Ortega and C. Zucco J. Am. Chem. Soc. 1992 113 238. 127 T. Fukuhara N. Yoneda K. Tamamura and A. Suzuki J. Fluorine Chem. 1991,51,299. 128 H.-J. Breternitz E. Schaumann and G. Adiwidjaja Tetrahedron Lett. 1991 32 1299. Aromutic Compounds Oxidized Benzenes.-Mixed anodic trimerization of 1,2-dialkoxybenzenes and ben- zocrown ethers leads to the formation of triphenylenes possessing one or two complexing sites.'29 A key step in the synthesis of neoisostegane (17) is a biaryl oxidative coupling induced13' by RuO,/TFA and synthetic appro ache^'^' to the cytotoxic alkaloid discorhabdin C use oxidation by hypervalent iodine of (18) to (19).OH Anodic oxidation gives reasonable yields of verangiaquinol~~~~ from 2,6-dihalo-4- hydroxy phenylacetamides and directly of mixed quinone monoketals from ally1 or propargyl ethers of 4-methoxyphen01.l~~ 1-4-t-Butylperoxy-2,5-cyclohexadiene- ones are obtained by treatment of 2,4,6-trialkylphenols with t-BuOOH in the presence of 12-molybdophosphoric The indium-mediated Reformatsky reaction of quinones gives good yields of p-quinols including jacaranone.135 Benzoquinone bis(dimethy1 ketals) couple to the ortho position of titanium or bromomagnesium phenolates to produce unsymmetrical hydroxylated biphenyl^,'^^ and treatment of arenes with 1,4-dimethyl- 1,4-dimethoxycyclohexadienein the presence of ZnC12 yields arylated p-xylene~.'~' and Reports have appeared of transformations of fl~oro-'~~ halogen^'^^ cis-cyclohexa-3,5-diene-l 2-diols available from the Pseudomonus putidu oxidation of 129 J.-M. Chapuzet N. Simonet-Gueguen I. Taillepied and J. Simonet Tetrahedron Lett. 1991 32 7405. 130 Y. Landais J.-P. Robin and A. Leburn Tetrahedron 1991 47 3787. 131 Y. Kita H. Tohma M. Inagaki K.Hatanaka K. Kikuchi and T. Yakura Tetrahedron Lett. 1991 32 2035. 132 N. Bicchierini M. Cavazza L. Nucci F. Pergola and F. Pietra Tetrahedron Lett. 1991 32 4039. 133 S. Dhanalekshmi K. K. Balasubramanian and C. S. Venkatachalam Tetrahedron Lett. 1991,32 7591. 134 M. Shimizu H. Orita T. Hayakawa Y. Watanabe and K. Takehira Bull. Chem. SOC.Jpn. 1991,64,2583. 135 S. Araki N. Katsumura K. Kawasaki and Y. Butsugan J. Chem. Soc. Perkin Trans. I 1991 499. 136 G. Sartori R. Maggi F. Bigi and G. Casnati J. Chem. SOC.,Perkin Trans. I 1991 3059. 137 F. Alonso and M. Yus Tetrahedron 1991 47 313. 138 H. A. J. Carless and 0.Z. Oak J. Chem. Soc. Chem. Commun. 1991 61. 139 D. R. Boyd M. V. Hand N. D. Sharma J. Chima H. Dalton and G. N. Sheldrake J.Chem. SOC. Chem. Commun. 1991 1630. I. G.C.Coutts benzenes and of cycloaddition reactions of isopropylidene derivatives of related cyclohexadienediols.14' The dimeric product (20) has been isolated from the bacterial degradation of 2,6-~ylenol.'~~ Electron-rich methoxyarenes are effectively oxidized to p-benzoquinones by magnesium monoperoxyphthalate with a water-soluble iron porphyrin as and the Ag' cation induces coupling of 4,4'-dihydroxystil- benes followed by further oxidation to yield phenanthrene-2,7-q~inones.'~~ Phenols are oxidized by dimethyldioxirane to o-quinones'u and catechol is cleaved to 2,Z-muconic acid.'45 The mechanism of the catalytic hydroxylation of aromatic hydrocarbons by hydrogen peroxide has been reviewed.'46 Phenols are converted to catechols by reaction with dioxygen in the presence of a tetrahydroborato Cu' complex,'47 and 4-methoxyphenols are oxidized'48 to the corresponding o-acetoxyphenols by Cu( OAc),/ HOAc.A binuclear three-coordinate Cu' complex containing a polybenz- imidazole ligand exhibits tyrosinase-like activity towards Fluorine reacts with wet acetonitrile to produce an oxidizing agent which converts aromatic amines to the corresponding nitroarenes."' 4 Condensed Polycyclic Aromatic Compounds Naphthalenes.-Useful new approaches to substituted naphthalenes continue to be developed. Nitrile thioethers R-CBr=C( SEt)CN react like a-alkynenitriles with ambiphilic derivatives to yield naphthylamine~.'~' Irradiation of a-diazoketones (21) gives 2-naphthols (22) via arylketen intermediate^,'^^ and phenylbutadienes (23) in which the 2-cis moiety is incorporated into a cyclic structure undergo oxidative photocyclization to na~htha1enes.l~~ Two synthetic approaches to the 140 M.F. Mahon K. Molloy C. A. Pittol R. J. Pryce S. M. Roberts G. Ryback V. Sik J. 0. Williams and J. A. Winders J. Chem. SOC.,Perkin Trans. 1 1991 1255. 141 H. Kneifel C. Poszich-Buscher S. Rittich and E. Breitmaier Angew. Chem. Int. Ed. EngL 1991,30,202. 142 I. Artaud K. B. Aziza C. Chopard and D. Mansuy J. Chem. Soc. Chem. Commun. 1991 31. 143 F. R. Hewgill R. Slamet and J. M. Stewart J. Chem. SOC.,Perkin Trans. 1 1991 3033. 144 J. K. Crandall M. Zucco R. S. Kirsch and D. M. Coppert Tetrahedron Lett. 1991 32 5441.145 A. Altamura C. Fusco L. D'Accolti R. Mello T. Prencipe and R. Curci Tetrahedron Lett. 1991 32 5445. 146 E. A. Kharakhanov S Y. Narin and A. G. Dedov App. Organomet. Chem. 1991 5 445. 147 F. Chioccara P. Di Gennaro G. La Monica R. Sebastiano and B. Rindone Tetrahedron 1991,47,4429. 148 Y. Takizawa A. Tateishi J. Sugiyama H. Yoshida and N. Yoshihara J. Chem. SOC.,Chem. Commun. 1991 104. 149 L. Casella M. Gullotti R. Radaelli and P. Di Gennaro J. Chem. SOC.,Chem. Commun. 1991 1611. M. Kol and S. Rozen J. Chem. SOC.,Chem. Commun. 1991 567. 151 D. Reux and F. Pochat J. Chem. SOC.,Chem. Commun. 1991 1419. 152 A. Padwa D. J. Austin U. Chiacchio J. M. Kassir A. Rescifina and S. L. Xu,Tetrahedron Lett. 1991 32 5923. 153 R.S. Olsen J. C. Minniear W. M. Overton and J. M. Sherrick J. Org. Chem. 1991 56 989. Aromatic Compounds protein kinase C inhibitors the calphostins are based on de novo formation of highly functionalized naphthalenes. In one route 1,1,3-trioxygenated butadienes form Diels-Alder adducts with o-quinol acetate~’’~; the other relies”’ on the anion from (24) reacting with (S)-6-methyl-5,6-dihydropyran-2-one to yield (25) which MOMO MOMO OH 0 C02Et Me0 Me0 can be aromatized with DDQ. Lactones resulting from reaction of a succinyl chloride with benzenes undergo an intramolecular Friedel-Crafts acylation on addition of BBr3 to afford 4-phenylnaphthalen-l-ols, intermediates in the preparation of gossy- ~01.”~ Homophthalic anhydride on treatment with MeOH/ MeI/ K2C03 is conver- directly to 12-methoxybenzo[d]-naphtho[2,3-b]pyran-5-one.’” With an excess of sodium cyclohexanethiolate perfluorodecalin yields octakis(cyc1o-hexylthio) 11aphtha1ene.l’~ 2,2’-Dimethoxy-l,l’-binaphthaleneundergoes spon-taneous resolution on crystallization from ani~ole.’’~ Regioselective alkylation of naphthalene with propan-2-01 or propene over a mordenite catalyst affords 2,6- diisopropylnaphthalene.160 From a kinetic study’61 on the acetylation of naphthalene with CH3COC1/CH2Cl2/AlCl3 it is proposed that the mechanism for P-naphthyl acetylation involves a two-stage process with the second loss of a proton being rate-limiting while a-substitution proceeds through two a-complexes and the decomposition of the second is partly rate-determining.Acylnaphthalenes are also obtained from the products of the reaction of nitriles with zirconocene complexes of substituted naphthalynes.’62 Radical cations are intermediates in the HN02- ~atalysed’~~ and charge-transfer’@ nitration of naphthalenes. 154 R. S. Coleman and E. B. Grant J. Org. Chem. 1991 56 1357. C. A. Broka Tetrahedron Lett. 1991 32 859. 156 J.-T. Huang T.-L. Su and K. A. Watanabe J. Org. Chem. 1991 56 4811. 157 W. V. Murray and S. K. Hadden J. Chem. Res. (S) 1991 279. 158 D. D. MacNicol W. M. McGregor P. R. Mallinson and C. D. Robertson J. Chem. SOC.,Perkin Trans. 1 1991 3380. 159 G. Gottarelli and G. P. Spada J. Org. Chem. 1991 56 2096. 160 A. Katayama M. Toba G. Takeuchi F.Mizukami S. Niwa and S. Mitamura J. Chem. Soc. Chem. Commun. 1991 39. 161 D. D. Dowdy P. H. Gore and D. N. Waters J. Chem. SOC.,Perkin Trans. 2 1991 1149. 162 S. L. Buchwald and S. M. King J. Am. Chem SOC.,1991 113 258. 163 P. J. Gross and J. H. Ridd J. Chem. SOC.,Perkin Trans. 2 1991 1773. 164 S. Sankararaman and J. K. Kochi J. Chem. SOC.,Perkin Trans 2 1991 165. 144 I. G. C. Coutts 1,5-Diodonaphthalene undergoes halogen-metal exchange with t-BuLi to give mono- or di1ithioderi~atives.l~~ Diethyl 1-naphthyl phosphate on treatment with LDA rearranges to diethyl 1-hydroxy-2-naphthyl phosphonate.'66 Reaction of the carbene (CH30C0)& with naphthalene gives a mixture of products originating from addition of the carbene to the 2,3-b0nd,'~~ and cheletropic addition of dichlorocarbene to 1-H-cyclopropa[ blnaphthalene yields 1 l-dichloronaphtho- [b]cy~lobutene.'~~ Tri-and Polycyclic Compounds.-The reaction of arynes with anions of ethyl cyanoacetates constitutes a brief synthesis of anthraquin~nes.'~~ Phenanthrenes are obtained by heating the dilithium salts of the bistosylhydrazones of biphenyl-2,2'- dicarboxaldehydes'70 and from treatment of 2,2'-dialkoxystilbenes with low valent titanium.171 Dicyclopropanthracenes or phenanthrenes may be ~ynthesized'~~ from tetramethylenecyclohexanes as illustrated in Scheme (5).Alkylation of enamines by Cl(Br) Br c1 2Lw c1 Br(C1) CI(Br) DDQ Br:; -benzene c1 Br(C1) \\ Scheme 5 benzylic or (p-haloethy1)aryl halides followed by cyclodehydration and dehydroge- nation provides an efficient route to a wide range of polycyclic corn pound^.'^^ Corannulene is formed directly by flash vacuum pyrolysis of 7,lO-diethynylfluoran- ther~e,'~~ The and an efficient synthesis of circumanthracene has been re~0rted.l~~ previously inaccessible compound (26) containing a dienophilic central double 165 W.Wang S. V. D'Andrea J. P. Freeman and J. Szmuszkovicz J. Org. Chem. 1991 56 2914. 166 B. Dhawan and D. Redmore J. Org. Chem. 1991 56 833. 167 M. Pomerantz and M. Levanon Tetrahedron Lett. 1991 32 995. 168 I. Durucasu N. Saracoglu and M. Balci Tetrahedron Lett. 1991 32 7097. 169 B. M. Bhawal S. P. Khanapure H. Zhang and E. R. Biehl J Org. Chem. 1991,56 2846. I7O M.E.Jung and A.Hagiwara Tetrahedron Lett. 1991 32 3025. 171 A. Banerji and S. K. Nayak J. Chem. SOC.,Chem. Commun. 1991 1432. 17' W.E.Billups M. M. Haley R. C. Claussen and W. A. Rodin J. Am. Chem. SOC.,1991 113 4331. 173 R. G. Harvey J. Pataki C. Cortez P. Di Raddo and C. X.Yang J. Org. Chem. 1991 56 1210. 174 L. T. Scott M. M. Hashemi D. T. Meyer and H. B. Warren J. Am. Chem SOC.,1991 113 7082. 175 R. D. Broen and F. Diedrich Tetrahedron Lett. 1991 32 5227. Aromatic Compounds bond is easily obtained by Heck coupling of 1,8-diiodonaphthalene with acenaph- tha1er1e.l~~ Triptycenes can be prepared’77 in good yield by sequential reaction of quinone-anthracene adducts with LiAlH4 and tosyl ch10ride.l~~Fusing 9,lO- anthradiyl moieties to the benzenoid bonds of triptycene gives rise to a family of iptycenes; the ultimate structure with six fused residues ‘supertriptycene’ (27) has been obtained from a 10-step synthetic sequen~e.’’~ (27) From ab initio calculations it is concluded that kekulene gains extra stability (‘superaromaticity’) from the presence of the circular formation of benzenoid rings.’79A study’” of the dinaphtho[ a,j]anthracene (28) in which rotational motion of the internal methoxy group is restricted suggests that the barrier to linear oxygen inversion is >70 kJ mol-’.OH Thermal reactions of polycyclic aromatic hydrocarbons usually involving radical intermediates has been reviewed.181 The radical cation generated on dissolving bis(pentamethylpheny1)methanein CFJCOzHis that of 1,2,3,4,5,6,7,8-octamethylan-thracene,lS2 and diatropic cations such as (29) are produced on protonation of 176 G.Dyker Tetrahedron Lett. 1991 32 7241. 177 H. K. Patney Synthesis 1991 694. 178 K. Shahlai and H. Hart J. Org. Chem. 1991 56 6905. 179 J. Cioslowski P. B. O’Connor and E. D. Fleischmann J. Am. Chem. SOC.,1991 113 1086. R. B. Gupta M. K. Kaloustian R. W. Franck and J. F. Blount J. Am Chem. SOC.,1991 113 359. 181 S. E. Stein Acc. Chem Res. 1991 24 350. 182 L. Eberson and F. Radner J. Chem. SOC.,Chem. Commun. 1991 1233. 146 I. G. C. Coutts cyclopenta[ ~]phenalenediones.'~~ Formation of 9,lO-anthraquinone on N204nitra-tion of anthracene probably proceeds by a 1,4-addition mechanism rather than via a radical cation.'84 The radical anion obtained on irradiation of 9,lO-dicyanoan- thracene is stable for weeks in the presence of unreactive counter-i~ns.'~~ Reduction of the helicene 5-isopropyl-l,4,8-trimethylphenanthreneyields a 4nr conjugated dianion which preserves its helicity despite the decreased barriers to racemization.'86 Ful1erenes.-This year has seen an explosive increase in papers dealing with the chemical and physical properties of the fullerenes the family of closed carbon cages containing 12 pentagons and two or more hexagons in an sp2 network.Kroto and co-worker~'~~ have given an authoritative account of the pioneering studies on fullerene-60 and more recent work has been reviewed.'88 There has been debate about the aromaticity of the fullerenes.The vanishingly small welectron ring current magnetic susceptibility of c60 has been attributed to cancellation of diamagnetic and paramagnetic contributions leading to 'ambiguous' aromatic character. Using a valence-bond approach it has been s~ggested"~ that c60 is particularly stable as the only fullerene in which it is possible to isolate all the bonds in six-membered rings and none in five-membered rings. C,o is electron-deficient being easily reduced and reacts with nucle~philes.'~' It undergoes stepwise flu~rination'~~ to yield eventually CmF60 and C60(H' C6H5),,with benzene/AlCl,. The availability of fullerenes has been increased by development of a simple bench-top reactor,'94 and of improved separations based on solient extraction^."^ 5 Non-benzenoid Aromatics Some newer methods for the synthesis of tropenoid compounds have been reviewed.Ig6 Tropones may be obtained by reaction of Rh"-stabilized vinylcarbenoids with l-methoxy-l-[trimethylsilyloxy]buta-1,3-diene,'97 and a-homo-o-benzoquin- ones rearrange on treatment with BF,.Et,O to give boron difluoride derivatives of 183 S.Kuroda Y. Kanbata Y. Fukuyama S. Hirooka H. Takeda T. Tsuchida Y. Furuki T. Sumi 0. Hanida M. Yamada and I. Shimao Bull. Chem. SOC., Jpn. 1991 64 971. F. Radner Acta Chem. Scand. 1991 45 49. 185 M. A. Kellett D. G. Whitten 1. R. Gould and W. R. Bergmark J. Am. Chem. SOC.,1991 113 358. R. Frim G. Zilber and M. Rabinovitz J. Chem. SOC.,Chem. Cornmun. 1991 1202. 187 H. W. Kroto A. W. Allaf and S.P. Balm Chem. Rev. 1991,91 1213. F. Diederich and R. L. Whetten Angew. Chem. Int. Ed. EngL 1991 30,678. 189 R. C. Haddon L. F. Schneemeyer J. V. Waszczak S. H. Glahm R. Tycho G. Dabbagh A. R. Kortan A. J. Muller A. M. Mujsce M. J. Rosseinsky S. M. Zahurak A. V. Makhija F. A. Thiel K. Raghavachari E. Cockayne and V. Eiser Nature 1991,350,46. I9O R.Taylor Tetrahedron Lett. 1991 30,3731. 191 J. W. Bausch G. K. S. Prakash G. A. Olah D. S. Tse D. C. Lorents Y. K. Bae and R. Malhotra J. Am. Chem SOC.,1991 113 3205. 19* J. H.Holloway E. G. Hope R. Taylor G. J. Langley A. G. Avent T. J. Dennis J. P. Hare H. W. Kroto and D. R. M. Walton J. Chem. SOC.,Chem. Cornmun. 1991 966 '93 G. A. Olah I. Bucsi C. Lambert R. Aniszfeld N. J. Trivedi D. K. Sensharma and G.K. S. Prakash J. Am. Chem. Soc. 1991 113 9387. 194 A. S. Koch K. C. Khemani and F. Wudl J. Org Chem. 1991 56 4543. 195 D. H. Parker P. Wurz K. Chatterjee K. R. Lykke J. E. Hunt M. J. Pellin J. C. Hemminger D. M. Gruen and L. M. Stock J. Am. Chem. SOC.,1991 113 7499. 196 M. G. Banwell Aust. J. Chem. 1991 44 1. 197 H. M. L. Davies T. J. Clark and G. F. Kimmer J. Org. Chem. 1991 56 6440. Aromatic Compounds 147 a-tropolone~.’~~ Alkoxyazulenes are formed by the reaction of 2H-cyclohepta[ b] -furan-2-ones with or tho ester^.'^^ A synthesis of a new [14lannulene-dione acepleiadylene- 1,2-dione has been reported.200 Oxidation of isopyrene with rn-chloroperbenzoic acid yields quinone (30) to which canonical structures such as (31) make a significant contribution.’” A variety of bridged [14]annulenes are available by LUMO-controlled nucleophilic addition of organometallic reagents to dicyclopenta[ ef,kZ]heptalene and subsequent quenching of the resulting anions.’02 The aromaticity of cyclopentadienide has been probed by examination of the annelation effects of fusion of the anion to a [14]annulene dimethyldihydropyrene; it is concluded that C5H5- has about 50% of the effective aromaticity of ben~ene.”~ Successive replacement of phenyl groups in the tritryl cation by 1-azulenyl residues leads to increased stability with the Pk,+ value of 11.3 for the tri( 1-azuleny1)methyl cation being the highest so far reportedzo4 for methyl cations substituted with hydrocarbon groups.Cremer and co-workers have published results of ab initio calculations of I3C NMR shifts as probes of the structure and homoaromaticity of the tropylium and bis-’06 homocations.The hydrocarbons (32) and (33) valence isomers of homoannulenes undergo interconversion on flow-vacuum pyroly- S~S.’~’ Complexation of the diatropic bridged annulene (34) with Fez(C0)9 occurs in the 14~ annulene system rather than the benzene ring giving a formally 19* M. G. Banwell and M. P. Collis J. Chem. SOC.,Chem. Commun. 1991 1343. 199 T. Nozoe H. Wakabayashi K. Shindo S. Ishikawa C.-P. Wu and P.-W. Yang Heterocycles 1991,32 213. 200 S. Suzuki,S. Tanaka J. Tsunetsugu M. Higashi and H. Yamaguchi J. Chem. Res. (S) 1991 168. 201 E. Vogel L. Schmalstieg P. Henk 0. Wilmes J. Lex R.Gleiter and M. Langer Angew. Chem. Int. Ed. Engl. 1991 30,681. ’02 J. Alexander M. Baumgarten K.-U. Klabunde and K. Mullen Tetrahedron Leu. 1991 32 735. 203 R. H. Mitchell N. A. Khalifa and T. W. Dingle J. Am. Chem. Soc. 1991 113 6696. ’04 S. Ito N. Morita and T. Asao Tetrahedron Lett. 1991 32 773. ’05 D. Cremer F. Reichel and E. Kraka J. Am. Chem. Soc. 1991 113 9459. ’06 P. Svensson F. Reichel P. Ahlberg and D. Cremer J. Chem. Soc. Perkin Trans. 2 1991 1463. 207 M. D. Banciu M. D. Stanescu C. Florea A. Petride C. Draghici and E. Cioranescu Bull. SOC.Chem. Fr. 1991 128 919. 148 I. G. C.Coutts anti-aromatic product.208 An acetoxyl group is introduced into dialkylaminotropones or azulenes by treatment with Pd(OAc) ,209 and palladium mediates the cross-coup- ling of bromotropolones with organostannanes,210 and the Heck vinylation of haloazulenes.211 6 Cyclophanes Cyclophanes have been the subject of a recent comprehensive monograph.212 Reac- tion of readily available difurano-annelated [2,2] paracyclophanes with arynes yields a variety of compounds such as (35) containing alternatingly orthogonal arene units.213 The syn conformer of (36) is more stable than the anti suggesting that Hex -Hex Me0 go ’\ -0Me (37) (38) through-space interactions between 0-and p-benzoquinones are attractive.,14 1,lo-0-Benzo[2,2]orthocyclophane-o-quinones215 and the metacyclophane216 (37) have also been used in studies of intramolecular change-transfer interactions.The interesting diphenoquinonophane (38) has been ~repared,~” and found to be unexpectedly stab1e.Reaction of tetracyanoethylene with [6]( 1,4)anthracenophane occurs at the strained bridge ring to give the first reported [2 + 2]cycloadduct of anthracene.218 Studies of binding between naproxen and chiral mono- and bis( 1,l’-binaphthyl) cyclophanes highlight the difficulty of predicting the conformational preferences of large flexible macro cycle^.^^^ 208 R. H. Mitchell and P. Zhou Angew. Chem. Int. Ed. Engl. 1991,30,1013. ‘09 K. Saito M. Kozaki K. Uenishi N. Abe and K. Takahashi Chem. Pharm. Bull 1991 39 1843. 210 M. G.Banwell J. M. Cameron M. P. Collis G. T. Crisp R. W. Gable E. Hamel J. N. Lambert M. F. Mackay M. E. Reum and J. A. Scoble Aust. J. Chem. 1991,44,705.211 H. Horino T. Asao and N. Inoue Bull. Chem. SOC.Jpn. 1991,64,183. 212 F. Diederich ‘Cyclophanes’ Royal Society of Chemistry Monographs in Supramolecular Chemistry 1991,Cambridge. 213 B. Konig J. Heinze K. Meerholz and A. de Meijere Angew. Chem. Int. Ed. Engl. 1991,30 1361. 214 Y.Fukazawa T. Nakamura and S. Usui Tetrahedron Lett. 1991 32 3183. 21s Y.Fukazawa T.Nakamura T. Haino and S. Usui Chem. Lett. 1991 957. 216 H. A. Staab A. Dohling and C. Krieger Tetrahedron Lett. 1991 32 2215. 217 K. Tani J. Takano T. Tohda M. Ariga H. Higuchi and S. Misumi Chern. Lett. 1991 1461. 218 Y.Tobe T. Takahashi K. Kobiro and K. Kakiuchi Tetrahedron Lett. 1991 32 359. 219 P. P.Castro and F. Diederich Tetrahedron Lett. 1991 32 6277.

ISSN:0069-3030    

DOI:10.1039/OC9918800131

出版商:RSC    

年代:1991

数据来源: RSC

摘要:

7 Heterocyclic Compounds By D. E. AMES Department of Chemistry Queen Mary and Westfield College London El 4NS 1 Introduction Reviews of aromaticity’ and prototropic tautomerism2 of heteroaromatic compounds have been published. Other reviews have covered heterocycles in bio-organic chemistry3 and the use of isothiocyanates in synthesis of heterocycle^.^ 2 Three-membered Rings Highly enantioselective epoxidation catalysts derived from trans-1,2-diaminocyclo-hexane have been introduced.’ For example an 84% yield of oxirane with 92% ee is obtained from (2)-1-phenylprop-1-ene when catalyst (1) is used with sodium hypochlorite as oxidant. Lithiation of phenylsulfonyloxiranes (2; R = H) with butyl lithium at low tem- peratures occurs a to the sulfonyl group.The unstable anions (2; R = Li) react with electrophiles to form functionalized phenylsulfonyloxiranes e.g. acetone gives (2; R = C(OH)Me,) in 67% yield.6 2-Substituted oxiranemethanols (3) have been resolved by enzymatic trans-acetyla- tion using Pseudornonas fluorescens lipase as biocatalyst with vinyl acetate as an acyl donor.’ For example (R,S)-(3) yielded alcohol (4) and acetate (5) in 35-38% yields and 96% ee (Scheme 1). * A. R. Katritzky M. Karelson and N. Malhotra Heterocycles 1991 32 127. A. R. Katritzky M. Karelson and P. A. Hams Heterocycles 1991 32,329. ‘Heterocycles in Bio-organic Chemistry’ ed. J. Bergman Royal Society Chemistry 1991. A. K. Mukerjee and R. Ashare Chem. Reu. 1991,91 1. E. N. Jacobsen W. Zhang A. R. Muci J.R. Ecker and L. Deng J. Am. Chern. Soc. 1991 113,7063. M.Ashwell W. Clegg and R. F. W. Jackson J. Chem. Soc. Perkin Trans. 1 1991 897. ’ P. Ferraboschi D. Brembilla P. Grisenti and E. Santaniello J. Org. Chem. 1991 56 5478. 149 150 D. E. Arnes OH AcO (3) (4) (5) R = n-CgHI9 Reagents i Lipase vinyl acetate Scheme 1 2,3-Dimethylbenzo[ blfuran (6) has been oxidized with dimethyldioxirane to form 2,3-epoxy-2,3-dihydro-2,3-dimethylfuran (7).*This is the proposed ultimate car- cinogen of the benzofuran dioxetane (8) which has also been reduced to oxirane (7) (Scheme 2). 07Me +iQ-Jo c-ii Q3y \ ' 'Me \ \ 0 0 Me Me -Scheme 2 N-Ethoxycarbonylaziridines (9) undergo a smooth thermal transformation into 1,3-oxazolidin-2-ones (10) on flash pyrolysis.' The tandem reaction sequence is equivalent to direct insertion of carbon dioxide into the parent 1H-aziridine (Scheme 3).n N-0,C,NH I II (9) 0 (10) Reagents i Flash pyrolysis Scheme 3 A photochemical reaction of the l-pyridinium alkenylborane (1 1; R = 1-C5H5N+) forms the air-sensitive trans-boratirane (12; R = 1-C5H5N+).'* Similarly (1 1; R = Ph) as the tetramethylammonium salt gives the analogous ion (12; R = Ph)." R Ph \-/ Ph B-C H =CHPh I R Ph (11) W. Adam L. Hadjiarapoglou T. Mosandl C. R. Saha-Moller and D. Wild Angew. Chem. Znr. Ed. Engl. 1991 30,200. M. R. Banks J. I. G. Cadogan I. Gosney P. K. G. Hodgson and D. E. Thomson J. Chem. SOC.,Perkin Trans. 1 1991 961. S.E. Denmark K. Nishide and A.-M. Faucher J. Am. Chem. SOC.,1991 113 6675. M. A. Kropp M. Baillargeon K. M. Park K. Bhamidapaty and G. B. Schuster J. Am. Chem. SOC. 1991 113 2155. Heterocyclic Compounds The halogen-substituted carbenes generated by thermolysis of diazirines (13) add onto phosphaalkynes to form adducts (14) which rearrange to 1-halogeno-1H-phosphirenes (15) (Scheme 4).12 r R2 1 (14) Reagents i A R’CGP Scheme 4 (16) Ar = 2,4,6-tri(t-butyl)phenyl 1 (18) @Ph2 -ArP’I ‘C %C12 (17) Reagents i CC14 BuLi Scheme 5 Reaction of dichlorocarbene with phosphabutatriene (16) gives the dialkyl- idenephosphirane (17) via ethenylidenephosphirane (18) (Scheme 5).13 A diphosphirenium salt (19) has been prepared by cyclization of (20).14 X-Ray evidence indicates that the ion is planar at C-1 and N-2 showing substantial participation of resonance structure (21) in the ion (Scheme 6).A (20) R = Pr’ (19) Reagents i BF3-Et,N Scheme 6 3 Four-membered Rings Photolytic reaction of benzophenone with alkenyl methyl sulfides gives 3-methyl- thiooxetanes regio- and stereo-selectively (Scheme 7).15 12 0. Wagner M. Ehle M. Birkel J. Hoffmann and M. Regitz Chem. Ber. 1991 124 1207. 13 K. Toyota H. Yoshimura T. Uesugi and M.Yoshifuji Tetrahedron Lett. 1991 32 6879. 14 F. Castan A. Baceiredo J. Fischer A. De Cian G. Commenges and G. Bertrand J. Am. Chem. Soc. 1991 113 8160. Is N. Khan T. H. Moms E. H. Smith and R. Walsh J. Chem. Soc. Perkin Trans. 1 1991 865.152 D. E. Ames i Ph2C-0 MeS H MeS H Reagents i Ph2C0 hv Scheme 7 Whereas 2,2-dialkyloxetanes (22) are cleaved by lithium 4,4’-di-t-butylbiphenylide (LDBB) to form primary organolithium-tertiary oxyanions (23) in the presence of triethylaluminium 3-lithio-3,3-disubstitutedpropoxides (24) are produced exclus- ively.I6 Trapping with carbonyl compounds generates diols e.g. (25) and (26) respectively (Scheme 8). OH (25) OH CHMe2 iii bd?6 OH Reagents i LDBB; ii Et,AI; iii Me,CHCHO Scheme 8 Treatment of 3-(chloromethyl)azetidin-2-ones (27) with sodium ethoxide-dimethylformamide effects rearrangement to the azetidine-3-carboxylic acid esters (28) in high yields.” Highly selective reduction of P-lactams (29; X = 0) to azetidines (29; X = H2)has been achieved in high yields using dichloroalane (AIHC~~).~~ R2 R2 EtO2CQ H20wp NR’ XC-NCHZPh An efficient synthesis of l-acetyl-2-azetidine (30)19 utilizes (3 1) which is obtained from epichlorhydrin and benzhydrylamine.Mesylation hydrogenolysis and acetyla- tion give amide (32). Elimination of mesylate forms azetine (30). This on pyrolysis undergoes electrocyclic ring opening to generate l-acetyl-1 -azabutadiene (33) (Scheme 9). 16 B. Mudryk and T. Cohen J. Org. Chem. 1991,56 5760. 17 D. Bartholomew and M. J. Stocks Tetrahedron Lett. 1991 32 4795. 18 I. Ojima M. Zhao T. Yamato and K. Nakahashi J. Org. Chem. 1991 56 5263. 19 M. E. Jung and Y. M. Choi J. Org. Chem. 1991 56 6729. Heterocyclic Compounds MsO ..I-LV -* "OD (32) (30) NCHPh2 79% 'NCOMe 'NCOMe N (31) I COMe (33) Reagents i MsCl Et3N; ii HCl; iii H2-Pd; iv MeCOCl Et3N; v KOBU'; vi flash vacuum pyrolysis Scheme 9 Tetraphenylporphine-sensitized photooxygenation of benzofurans (34) gives dioxetanes (35) (Scheme 10) which are strongly mutagenic.20 Similarly singlet oxygen in a dye-sensitized photooxygenation of 4,5-dimethyl-2,3-dihydrothiophene (36)gives dioxetane (37)which is stable at low temperatures but forms keto-thioester (38) on warming (Scheme 11).21 (34) (35) (Yield 53% when R' = R2 = Me) Reagents i 02,TPP hv Scheme 10 Me 10 ii I\COMe Reagents i O,-hv; ii A Scheme 11 Silicon-functionalized silacyclobutenes (39) have been prepared from tri-chloro(viny1)silane (0) by action of t-butyl lithium to generate the unstable inter- mediate (41)(Scheme 12).22Cycloaddition to alkyne forms the silacyclobutene (39; X = C1) and then by reduction with lithium aluminium hydride (39;X = H).C1,SiCH = CH -!+ [C12Si=CH-CH2But] -!!+ (40) (41) (39) Reagents i Bu'Li; ii PhC-CSiMe Scheme 12 2o W.,Adarn 0.Albrecht E. Feineis I. Reuther C. R. Saha-Moller P. Seufert-Baumbach and D. Wild Liebigs Ann. Chem. 1991 33. 21 K. Gollnick and K. Knutzen-Mies J. Org. Chem. 1991 56 4027. 22 N. Auner C. Seidenschwarz and E. Herdtweck Angew. Chem. Int. Ed. Engl. 1991 30,1151. 154 D. E. Ames p-Lactams.-Rhodium diacetate-induced intramolecular insertion reactions of diazomalonic acid methyl ester and diethylamide (42) gives P-lactones (43) and P-lactams (44) respectively (Scheme 13).23 Me02C po-Me02C c’,N2 X = OMe I X = NEt -Me02C-* i,40% NEt 0 Reagents i Rh2(OAc) Scheme 13 Conversion of /3 -halogenopropanamides into monocyclic p -1actams has been effected under phase-transfer conditions using crown ethers tris(po1yoxa-alky1)amines or quaternary phosphonium halides as catalysts.24 The vinylaziridine (45) prepared efficiently by cyclization of the allylic mesylate (46) undergoes highly stereoselective conversion into azetidinone (47) by a palladium(0)-catalysed carbonylation process (Scheme 14).25 @CH2Ph -i MsO-CHzPh N HNCO,CH,Ph 700h COzCHzPh OCH2Ph 1 0&NCO2CH2Ph Reagents i NaH; ii Pd2(dba), Ph3P CO (47) Scheme 14 Treatment of 2-pyridylthioesters (48) with triethylamine and titanium( IV) chloride affords titanium enolates which add to imines to give p-lactams with moderate stereoselectivity (Scheme 15).26 (48) Reagents i TiC14 Et3N; ii PhCH=NCH,Ph Scheme 15 23 V.G. S. Box N. Marinovic and G. P. Yiannikouros Heterocycles 1991 32 245. 24 M. J. Meegan B. G. Fleming and 0. M. Walsh 3. Chem Rex (S) 1991 156. 25 G. W. Spears K. Nakanishi and Y. Ohfune SYNLET 1991,91. 26 M. Cinquini F. Coui P. G. Cozzi and E. Consolandi Tetrahedron 1991 47 8767. Heterocyclic Compounds 155 P-Lactams with an exocyclic double bond have been prepared from a-methylene P-aminoacid hydrochlorides according to Scheme 16.27 Palladium-catalysed carbonylation of 4-amino-2-alkynyl carbonates (49) pro- ceeds via allenic intermediates to form the alkynyl-substituted azeridinone (50) (Scheme 17).28 Reagents i MsCI Bu,N+HSO; KHCO, CHCI, H20 Scheme 16 R R 66% )--E-CMe2 2 I Me02C0 NHTs (49) R = n-C,HI5 MeOPd L Reagents i Pd(OAc), CO K2C03 PqO ''Y;A J 0 Scheme 17 4-Acetoxy-2-azetidinone has been obtained from the 4-carboxylic acid by elec- trolysis in the presence of sodium acetate and acetic acid.29 3-Amino-2-azetidinones have been reviewed3' and the compounds have been prepared by reaction of imines with amino-esters as the zinc enolates3' and the aluminium enolate~.~~ Turning to fused-ring p-lactams the keto-ester (51; X = H) has been converted into the diazo-compound (51;X = N) which undergoes a rhodium-catalysed cycliz- ation to form the 1-carba-1-dethiapenam (52) with elimination of the N-benzyloxy- group (Scheme 1 8).33 30% (51) C02Me (52) Reagents i Rhz(OAc2), A Scheme 18 27 R.Buchholz and H. M. R. Hoffmann Helv. Chim Acta 1991 74 1213. T. Mandai K. Ryoden M. Kawada and J. Tsuji Tetrahedron Lett. 1991 32 7683. 29 M. Mori K. Kagechika H. Sasai and M. Shibasaki Tetrahedron 1991,47 531. 30 F. H. van der Steen and G. van Koten Tetrahedron 1991 47 7503. 31 F. H. van der Steen H. Kleijn J. T. B. H. Jastrzebski and G. van Koten J. Org. Chem. 1991 56 5147. 32 F. H. van der Steen G. P. M. van Mier A. L. Spek J. Kroon and G. van Koten J. Am. Chem. SOC. 1991 113 5742. 33 M. A. Williams C.-N.Hsiao and M. J. Miller J. Org. Chem. 1991 56 2688. 156 D. E. Ames An enantio-controlled synthesis of the antifungal P-lactam (2K5S) -2- (hydroxy- methy1)clavam (53) has been achieved.34 The acetoxy-lactam (54) was condensed with chiral alcohol (55) to form ether (56). Removal of the phthaloyl and silyl protecting groups and diazotization generated chloro-compound (57) which was protected and reduced to give (58). Conversion of tosylate into iodide followed by treatment with potassium carbonate effected ring closure to form the clavam skeleton and removal of the silyl group completed the synthesis of the target structure (53) (Scheme 19). XNyoAc + H& ,,', X y N y 0 NH OTs 0 OTs OR (54) X = phthaloyl (55) R = SiMe,Bu' (56) Reagents i Zn(OAc), A; ii NH,NH,; iii HCI H20 KNO,; iv K2C03 H,O; v CISiMe,Bu'; vi Bu3SnH azobisisobutyronitrile (AIBN) A; vii NaI; viii K2CO3 ;ix Bu4N+F- HOAc Scheme 19 -..p-; 55% 0 0 0 (59) Scheme 20 Photolysis of N-(methacryloyl) thioamide (59) generates an n7r* triplet excited state (60) which collapses to the thietane-fused p-lactam (61) (Scheme 20).35 A synthesis of 3-oxacepham 1,l-dioxide derivatives (62) is based on the prepar- ation of diazo-compound (63; R = SiMe,Bu') from sulfide (64).Removal of the silyl group yielded (63; R = H) but in only 11% yield; another rhodium-cata- lysed cyclization via a carbene then gave a 2 1 mixture of stereoisomers (62) (Scheme 21).36 34 T. Konosu and S. Oida Chem. Pharm. Bull. 1991 39 2212.3s M. Sakamoto T. Yanase T. Fujita S. Watanabe H. Aoyama and Y. Omote J. Chem. SOC. Perkin Trans. 1 1'991 403. 36 P. H. Crackett P. Sayer R. J. Stoodley and C. W. Greengrass J. Chem. Soc. Perkin Trans. 1 1991,1235. Heterocyclic Compounds C02Me i 0flSCH2C02Me S02-CN2 iii iv --4d 6% NkosiMe2But 30% O \yORI C02Bu' C02Bu' CO~BU' (64) (63) Reagents i KMnO,; ii TsN3; iii HF H,O; iv Rh,(OAc), A Scheme 21 4 Five-membered Rings Terpenoid tetrahydrofurans such as (65) have been synthesized by palladium-catalysed cyclization of 4,6-dienols (Scheme 22h3' A silicon-directed asymmetric synthesis of substituted tetrahydrofurans is based on diastereoselective addition of chiral (E)-crotylsilanes (66) to a-alkoxy-and p -alkoxyaldehydes (Scheme 23).38For example condensation of (66) with 3-benzyl-oxypropanal gave (67; R = SiMe2Ph) in 96% diastereoisomeric excess.Oxidative desilylation with peracetic acid and mercury(11) acetate then gave the hydroxyfuran derivative (67; R = OH; 55%). (65) Reagents i Pd(OAc) ,benzoquinone; ii Pd(dba), Bui3N 1,2-bis-(diphenylphosphino)ethane Scheme 22 Me Me. I H4$RH,C02Me Reagents i PhCH,O(CH,),CHO BF3.Et20 Scheme 23 An interesting preparation of the dihydroxyfuran intermediate (68) is a key step in a synthesis of penicillium metabolite (*)-~itreoviral.~' Acid-catalysed intramolecular reaction of epoxide and hydroxyl groups of compound (69) produces (68) (Scheme 24). 37 P. G. Andersson and J.-E. Backvall J. Org.Chem. 1991 56 5349. 38 J. S. Panek and M. Yang J. Am. Chem. SOC., 1991 113 9868. 39 M. C. Bowden P. Patel and G. Pattenden J. Chem. SOC.,Perkin Trans. 1 1991 1947. 158 D. E. Ames OH OH H Reagents i 4-MeC6H,S03H H20 Scheme 24 Dihydrofuran (70) is formed in 91% ee by a silver-catalysed rearrangement and cyclization of the acetylenic alcohol (71)(Scheme 25).40 The rearrangement of allylic acetals (72)promoted by tin(1v) chloride provides a stereocontrolled route to tetrahydrofurans (73)(Scheme 26).41 OCOCMe3 Phf-' qze H &Ph"HdTk OCOCMe3 Me (71) (70) Reagents i AgBF, A Scheme 25 (72) (73) Yields 76%(R = Et) 64% (R = Ph) Reagents i SnCI,; ii H,O Scheme 26 Addition of the enolate anion of ethyl 2-bromo-4-trialkylsilyloxycrotonate (74) to aldehydes yields the silyl enol-ether terminated oxiranes (75) which undergo a low temperature rearrangement in the presence of trimethylsilyl iodide to form functionalized dihydrofurans (76) (Scheme 27) .42 OR' ... iii R'OCH,CH=CBrCO,Et 3 + (74) H COzEt R' = SiMe,Bu' (75) Reagents i LiNPr;; ii RCHO; iii Me3SiI Scheme 27 40 Y. Shigemasa M. Yasui S.4. Ohrai M. Sasaki H. Sashiwa and H. Saimoto J. Org. Chem. 1991 56 910. 41 M. H. Hopkins L. E. Ovennan and G. M. Rishton J. Am. Chem. SOC.,1991 113 5354. 42 T. Hudlicky and G. Barbieri J. Org. Chem 1991 56 4598. Heterocyclic Compounds Alkynyloxiranes (77) rearrange in the presence of potassium t-butoxide to produce furans (78) probably via the cumulene alkoxide ion (79).The process is of particular interest in that it uses basic conditions whereas most furan syntheses employ acids (Scheme 28).43 R2 R'CH2CZC r==.=*-I.. R' -0 (77) (79) Reagents i KOBU' Scheme 28 Oxidative ring opening of furan with dimethyl dioxirane gives maleic dialdehyde efficiently.44 Substituted maleic anhydrides e.g. (80),and sodium dimethyl phosphite react in refluxing benzene to form furan-2( 5H)-one 5-phosphonates (81). These condense with carbonyl compounds to provide a neat synthesis of 5-alkylidenefuran-2-ones (82; 2-and E-isomers) (Scheme 29).45 Me0)qPh oc ,co0 1+ 41% 11+ 45% Me0 Ar (80) (82) Ar = 2-MeOC6H Reagents i (MeO),POH NaH A; ii ArCOCOzMe Scheme 29 Nafion-H a perfluorinated sulfonic acid resin catalyses ring closure of 2,2'- dihydroxybiphenyls to dibenzofurans under relatively mild condition^.^^ Similarly 2,2'-diaminobiphenyls cyclize on heating with the resin to give carba~oles.~~ Treatment of aromatic acyloxycarbonyl- or acylamidocarbonyl-compounds with titanium on graphite affords benzofurans and indoles respectively (Scheme 30)?* XCOR' R' X = OorNH Reagents i Ti/graphite A Scheme 30 43 J.A. Marshall and W. J. Du Bay J. Org. Chem. 1991 56 1685. 44 B. M. Adger C. Barrett J. Brennan M. A. McKervey and R. W. Murray J. Chem. SOC.,Chem. Commun. 1991 1553. 45 G. Pattenden M. W. Turvill and A. P. Chorlton J. Chem. SOC.,Perkin Trans. 1 1991 2357. 46 T. Yamato C. Hideshima G. K. S. Prakash and G.A. Olah J. Org. Chem. 1991 56 3192. 47 T. Yamato C. Hideshima K. Suehiro M. Tashiro G. K. S. Prakash and G. A. Olah J. Org. Chem. 1991 56 6248. 48 A. Furstner D. N. Jumbam and H. Weidmann Tetrahedron Lett.. 1991 32 6695. 160 D. E. Ames An interesting study has been made of 2,3-dibenzylidene-2,3-dihydrothiophene (83).49 This was generated from (84) by elimination of methanol. Dimerization forms (85) the structure of which was established by X-ray study. On trapping the monomer by reaction with norbornene adduct (86) is produced (Scheme 31). Ph 1H Ph c-7 IH Ph (86) Reagents i LiNPr',; ii norbornene Scheme 31 Heating 3,5-dibroma-2-methylthiophene1,l-dioxide (87) in t-butanol leads to the formation of dimer (88) .50 Hydrogen bromide elimination gives benzo[ blthiophene 1,l-dioxides (89) (Scheme 32).A new route to 1,3-disubstituted benzo[ clthiophenes (90) has been developed (Scheme 33).51 Thioanhydride (91) reacts with phosphorus pentachloride to give Me H BI (88) Reagents i Bu'OH A Scheme 32 1 -@: 83% \ c1 (92) Reagents i PC15 POCI,; ii NaI DMF Scheme 33 49 J. Skramstad and 0. Eriksen Acta Chem. Scand. 1991 45 919. 50 S. Gronowitz G. Nikitidis and A. Hallberg Acta Chem. Scand. 1991 45 632. 51 Y. Okuda M. V. Lakshrnikantham and M. P. Cava J. Org. Chem. 1991 56 6024. Heterocyclic Compounds 161 tetrachloro-derivative (92). Treatment with sodium iodide effects dechlorination to form 1,3-dichlorobenzo[ clthiophene (90; X = Cl).Reaction with butyl lithium produces mono-lithium compound (90; X = Li) which with electrophiles gives functionalized derivatives. For example use of dimethylformamide yields (90; X = CHO; 87%) and methoxycarbonyl chloride affords ester (90; X = C02Me; 75%). Alkylation of l-substituted-lH-pyrro1-3(2H)-ones, e.g. (93) with a soft alkylating agent such as methyl iodide favours C-alkylation but hard alkylating agents give 0-alkylation. Thus (93) can be converted into 3-methoxy-1-phenylpyrrole (94) using methyl tosylate (Scheme 34) .52 LJ0&qoMe Ph Ph (93) (94) Reagents i NaH MeOTs Scheme 34 The enol-ester (99 obtained from cyclohexane-1,3-dione and pyrrole-2-carbonyl chloride rearranges in the presence of triethylamine to form enamino-acid (96).Esterification and aromatization of the carbocyclic ring then leads to the phenolic pyrrole-ester (97) (Scheme 35).53 Reagents i Et3N A; ii CH,N,; iii Hg(OAc)* Scheme 35 3-Nitropyrroles (98) are formed in high yields from nitromethane and l-isocyano- 1-tosylalkenes (99) in the presence of potassium t-butoxide (Scheme 36).54 1,3-Dipolar addition of munchnone (100) (a 1,3-oxazolium Solate) to p-chloro-p- (trifluoromethy1)vinyl phenyl ketone gives the trifluoromethylpyrrole ketone (101) (Scheme 37).55 (98) Yields 94% (R= Ph) 91% (R= But) Reagents i MeNO? KOBU' Scheme 36 52 G. A. Hunter H. McNab L. C. Monahan and A. J. Blake J. Chem. Soc. Perkin Trans. 1 1991 3245. s3 J. E. Oliver W. R. Lusby and R. M. Waters J. Heterocycl. Chem.1991 28 1565. 54 D. van Leusen E. Flentge and A. M. van Leusen Tetrahedron 1991 47 4639. 55 T. Okano T. Uekawa N. Morishima and S. Eguchi J. Org. Chem. 1991 56 5259. 162 D. E. Ames 0' Ph -co -HCI -ODMe ObMe 56% N N N CF3cxPh oc Ph ClO Ph Ph COPh 1 Scheme 37 Cyclopentadiene complexes of cobalt carbonyl catalyse reaction of alkynes with trimethylsilyl cyanide to form 5-amino-1 H-pyrrole-2-carbonitrile derivatives (102).56 Reaction of 1-phenyl-1 H-pyrrol-3(2H)-one (103; X = H) with benzene diazonium chloride under acidic conditions gives 2-coupled products in hydrazono-form (103; X = NNHPh).57 Autoxidation of 3-methoxy-1-methyl-2-phenylpyrrole in acetone solution produces the 5-hydroxypyrrol-2-one (104).58 Similar products have been obtained by oxidative decarboxylation of pyrrole-2-carboxylic acids by a photo- chemical process involving singlet oxygen (Scheme 38).59 N Me Me Reagents i 02,hv Scheme 38 Pyrrole reacts with methylsulfenyl chloride to form 2,3,4,5-tetra(methylthio)pyr-role which can be oxidized to the corresponding sulfoxides and sulfones.60 Phenylselenomethylpyrroles (105) react rapidly under mild conditions with a-free pyrroles (106) in the presence of copper(1) triflate to form dipyrrylmethanes (107) (Scheme 39).61 The process has also been used to prepare tripyrranes from a dipyrrylmethane having one free a-position.Electrochemical oxidation of 3-acetyl-2,5-diphenylpyrrole(108) under anhydrous conditions gives (109) but when water is present the coupling product (110) is obtained.Reduction then leads to the 3,3'-dipyrrole (1 11) (Scheme 40).6* 56 N. Chatani and T. Hanafusa J. Org. Chern. 1991 56 2166. 57 A. J. Blake H. McNab and L. C. Monahan J. Chern. Soc. Perkin Trans. 1 1991 701. 58 A. J. Blake G. A. Hunter and H. McNab J. Chem. Res. (S) 1991 316. 59 D. L. Boger and C. M. Baldino J. Org. Chem. 1991 56 6942. 60 H. M. Gilow C. S. Brown J. N. Copeland and K. E. Kelly J. Heterocycl. Chem 1991 28 1025. 61 C. J. Hawker A. Philippides and A. R. Battersby J. Chern. Soc Perkin Trans. 1 1991 1833. 62 S. Petruso S. Caronna S. Gambino G. Filardo and G. Silvestri J. Heterocycl. Chern. 1991 28 793. Heterocyclic Compounds (106) R = CH,Ph R' = CH2C02Me R2 = (CH,)2C02Me Reagents i CU(I) triflate CaCO Scheme 39 MeCO ~1 Ph i ii 70% I MeCO epph - iii iv Me:-) ::Me Ph I I Ph HO Ph I I Ph Ph N N N H H H (1 10) (111) Reagents i Bu4N+C10h 0.6V; ii H20; iii Zn HOAc; NH3 HzO Scheme 40 The preparations and reactions of ninhydrin and its analogues have been re~iewed.6~ Another useful review covers work on marine natural products containing the indole ring system.64 N-Tosylindole can be prepared efficiently by an acid-catalysed cyclization of the substituted-alkyl N-tosyl anilides (Scheme 41).65 A new general synthesis of indoles is based on a palladium-catalysed heteroannula- tion of internal alkynes (Scheme 42)66by reaction with o-iodoarylamines.SPr' QpoR-aT NHTs Ts Reagents i H,SO, Bu'OH Yields 63% (R = Ac) 67% (R = Me) Scheme 41 63 M.M. JoulliC T. R. Thompson and N. H. Nemerof Tetrahedron 1991 47 8791. 64 M. Alvarez M. Salas and J. A. Joule Heterocycles 1991 32 1391. 65 Y. Murai G.Masuda S. Inone and K. Sato Heterocycles 1991 32 1377. 66 R. C. Larock and E. K.Yum J. Am. Chem. SOC. 1991 113 6689. 164 D. E. Ames 0:""' i_ R' Reagents i R2CrCR3 Pd(OAc), PPh3 Bu4NCC1- Na2C03 Yield e.g. 98% when R' = H R' = SiMe3 R3 = Me Scheme 42 Lithiation of 1 -methoxyindole occurs regioselectively at the 2-po~ition.~~ Reaction with electrophiles then leads to 1 -methoxy-2-substituted indoles. For example dimethylformamide gives 2-formyl-1-methoxyindolewhich can be hydrogenolysed catalytically to produce 2-formylindole.A synthesis of 3,4-disubstituted indoles is based on the reaction of an N-allyl-2- halogenoaniline (1 12) with a zirconocene complex to form the benzyne complex (113) and thence (114). Iodine displaces the metal giving di-iodide (115). Elimination of hydrogen iodide gives the unstable exomethylene compound (116) which reacts with diethyl ethynedicarboxylate to produce the 1,3,4-trisubstituted indole (117) (Scheme 43).68 H I by bgcH2 ii CHpI iii iv a-jOzEtI + __* _.+ 70% \ 53% \ C02Et \N N CH2Ph CH2Ph CHzPh (115) (116) (117) Reagents i Bu'Li Cp,Zr(Me)CI; ii I,; iii DBU A; iv EtO,CC=CCO,Et Scheme 43 New syntheses of lycorine alkaloids involve an interesting new route to 7-substituted hexahydroindole~.~~ A stereo-controlled palladium-catalysed intra- molecular 1,4-chloroamidation of diene (1 18) generates allylic chloride (119).An anti-stereoselective copper( 11)-catalysed reaction with Grignard reagent is then used to elaborate the 7-substituted hydroindole (120) (Scheme 44). The amide (121) derived from 2-iodo-N-methylaniline and ethyl fumarate can be cyclized using butyl lithium at low temperature in the presence of excess of trimethylsilyl chloride to form the 3-substituted oxindole (122) (Scheme 45)." 67 T. Kawasaki A. Kodama T. Nishida K. Shimizu and M. Somei Heterocycles 1991 32 221. 68 J. H. Tidwell D. R. Senn and S. L. Buchwald J. Am. Chem. Soc. 1991 113 4685. 69 J.-E. Backvall P. G. Anderson G. B. Stone and A. Gogoll J. Org. Chem.1991 56 2988. 70 S. Horne N. Taylor S. Collins and R. Rodrigo J. Chem. SOC.,Perkin Trans. 1 1991 3047. Heterocyclic Compounds COzR &O2R (118) R = CH2Ph (119) (120) Ar = 3,4-CH202C,H Reagents i Pd(OAc)z LiCl benzoquinone HOAc; ii ArMgBr Li2CuCl4 Scheme44 CO2Et I Reagents i BuLi Me,SiCl Scheme45 N-Phenylphthalimide has been obtained by a palladium-catalysed carbonylation and coupling of o-di-iodobenzene with aniline.71 Oxidation of benzothiazine dioxides (123) in the presence of base provides substituted isoindole (124) (Scheme 46).72 NMe -H,O I-\ so2 69% so2 -so, 02"' -E NO -NO2 OH (123) Reagents i KZCO, Bu,N+Br- air Scheme46 The final steps of an enantiocontrolled synthesis of (-)-physovenine (125; R = MeNHCO) are summarized in Scheme 47.73 The cyclopentene unit of (126) is used to generate trio1 (127) and by periodate oxidation the Q -hydroxyethylaldehyde (128).Acidic hydrolysis of the amide group then leads to ring closure to form (125; R = Me). Demethylation with boron tribromide to give phenol (125; R = H) followed by reaction with sodium hydride and methyl isocyanate yielded the urethane (125; R = MeNHCO). Pyrazolediazonium salts e.g. (129; X = NfC1-) undergo an efficient sulfur dioxide-catalysed chlorodediazoniation process to form chloropyrazoles (129; X = Cl). Catalysis with copper or its salts was less effective.74 When the acid azide (130) is heated with water Curtius degradation to isocyanate is accompanied by hydrolysis of the trifluoroacetyl group and cyclization to form 4-arylimidazolin-2-one ( 13 l).75 71 R.J. Perry and S. R. Turner X Org. Chem. 1991 56 6573. 72 K. Wojciechowski Liebigs Ann. Chem. 1991 831. 73 S. Takano M. Moriya and K. Ogasawara J. Org. Chem. 1991 56 5982. 74 S. Yamamoto K. Morimoto and T. Sato J. Heterocycl. Chem. 1991 28 1545. 75 S. Rault 0. N. Tembo P. Dallemagne and M. Robba Heterocycles 1991 32 1301. 166 D. E. Ames Reagents i 0,; ii NaBH,; iii HCl-H,O; iv NaIO,; v HCl-H,O Scheme47 I,J;2Me ArCHCH,CON HNKNH NLN I Me NHCOCF 0 It has been that N-alkylation of benzotriazole and 1,2,Ctriazole with alkyl halides proceeds efficiently in the presence of sodium hydroxide in dimethylfor- mamide.76 Treatment of 0-tributylstannyl aldoximes (132) with t-butyl hypochlorite gener- ates nitrile oxides which react with alkenes and alkynes to form isoxazolines (133) and isoxazoles (134) by [3 + 21 dipolar cycloaddition (Scheme 48).77 H i\ phFJ/ C=NOSnBu3 -(j:% phyph Ph 82% NxO Ph NxO (133) (132) (134) Reagents i Bu'OCl PhCH=CH2; ii Bu'OCl PhC=CH Scheme 48 1,2,3-Benzoxathiazole 2,2-dioxides have been prepared for the first time by the processes shown in Scheme 49.78 The N-tosyl group could be removed by fluoride-ion catalysed hydrolysis.Reaction of alkylaminodithiocarbamate salts with gem-dicyanoepoxides (135) involves 5-exo-tet ring opening then nucleophilic attack on a nitrile group. The process provides a synthesis of 2-imino-4-amino-5-cyano-1,3-dithioles (136) (Scheme 76 A.R. Katritzky W. Kuzmierkiewicz and J. V. Greenhill Rec. trau. Chim. Pays-Bus 1991 110 369. 77 0. Moriya H. Takenaka Y. Urata and T. Endo J. Chem. Soc. Chem. Commun. 1991 1671. 78 K. K. Andersen D. D. Bray S. Chumpradit M. E. Clarke G. J. Habgood C. D. Hubbard and K. M. Young J. Org. Chem. 1991 56 6508. 79 M. Guillemet M. Baudy-Floc'h and A. Robert J. Chem Soc. Chem. Commun. 1991 907. Heterocyclic Compounds ii \ NHTs Ts Ts Reagents i 3-chloroperbenzoic acid; ii S02C12 Et,N Scheme 49 R CN RCH+C=N CN n Ho ' y WCN-0-S G Reagents i R'NHCS;K+ A Scheme 50 i_ oc$ QC02H +ii \ SeMe \ /Se \ /Se NO2 NO2 NO2 (139) (137) (138) Reagents i Br2 C5H5N; ii SOClz DMF Scheme 51 2,1-Benzoxaselenol-3-one (137) and 2,1-benzothiaselenol-3-one(138) have been prepared from the methylselenobenzoic acid (139) according to Scheme 51.80 3,5-Disubstituted 1,2,4-~elenadiazoles (140) are obtained by reaction of primary selenoamides with N-bromosuccinimide at low temperatures.81 Pyridoazaphospholes (141) have been prepared82 from 2-alkylpyridines by quater- nization with phenacyl halides followed by condensation of the salt (142) with phosphorus trichloride in the presence of triethylamine.5 Six-membered Rings Treatment of the silver salt of a 4-or 5-terminal alkynoic acid (143) with bromine effects a highly stereoselective cis-addition of carboxylate and bromine across the acetylenic bond to form the 2-bromo-enol lactone (144). Conversely the action of N-bromosuccinimide on the potassium salt gives E-isomer (145) (Scheme 52).83 80 C.Lambert and L. Christiaens Tetrahedron 1991 47 9053. 81 K.Shimada Y. Matsuda S. Hikage Y. Takeishi and Y. Takikawa Bull. Chem. SOC.Japan 1991,64,1037. 82 R. K. Bansal K. Karaghiosoff N. Gupta A. Schmidpeter and C. Spindler Chem. Ber. 1991 124,475. 83 W.Dai and J. A. Katzenellenbogen J. Org. Chem 1991,56 6893. 168 D. E. Ames Br (144) (143) (145) Reagents i NaOH H,O; ii AgNO,; iii Br, H,O; iv K,CO, H,O Nibromosuccinimide Scheme 52 Yields 50%(Ar = Ph R = H),24% (Ar = Ph R = Me) Reagents i piperidine Scheme 53 The enolate ion of 3-oxobutanolactone (146) adds to 1,l-dicyanoalkenes to give enol-lactone (147) and thence the pyran-lactone system (148) (Scheme 53).84 Epoxidation of flavones has been achieved using dimethyl dioxirane in acetone solution at subambient temperature^.^^ On warming to room temperature the epoxide (149) rearranges to 3-hydroxyflavone (150) but with methanol it gives 3-hydroxy-2-methoxyflavanone(1 5 1) (Scheme 54).Mercury( 11)-catalysed cyclization of prop-2-ynyloxyacetic acid (152) yields 6- methylene-l,4-dioxan-2-one(153) (Scheme 55).86 Lineatin (154) is a pheromone of the ambrosia beetle a pest in coniferous forests. It has been synthesized neatly from the substituted cyclobutane acetal (155) by 0 0 (1 50) (149) Reagents i A to r.t.; ii MeOH Scheme 54 /0\1 -69% ("7 Reagents i HgO Scheme 55 84 N. Martin J. L. Segura C. Seoane J.L. Soto M. Morales and M. Suarez Liebigs Ann. Chem. 1991 827. 85 W. Adam D. Golsch and L. Hadjiarapoglou J. Org. Chern. 1991 56 7292. 86 M. Yamamoto T. Dewa H. Munakata S. Kohmoto and K. Yamada J. Chem Res. (S),1991 165. Heterocyclic Compounds action of methylmagnesium iodide to form diol (156) followed by acid-cata- lysed conversion of the dimethyl acetal unit into the bicyclic acetal system of (154) (Scheme 56).87 CH(OMe)2 CH(OMe), I I . .. 1 II -d’ I, ,. AcO’ ‘COMe H0‘ CMe2 OH (155) Reagents i MeMgBr; ii H+ H20 Scheme 56 3,3,6,6-Tetramethyl-1,2,4-trioxan-5-one (1 57)has been prepared by condensation of acetone with trimethylsilyl a-[(trimethylsilyl)peroxy]alkanoates (158) in the presence of trimethylsilyl trifluoromethanesulfonate as catalyst (Scheme 57).88 Reagents i Me2C0 Me,SiOTf; ii pyridine Scheme 57 Hemiperacetals (159) obtained from aldehydes and 2,3-dimethylbut-l -en-3-yl hydroperoxide undergo an intramolecular oxymercuriation on treatment with mer- cury(I1) acetate to form after ion exchange the mercury compounds (160) (Scheme 58).89 These can be reduced to the 1,2,4-trioxanes (161).(159) (160) Reagents i Hg(OAc)* HClO, H20; ii KBr H20; iii NaBH, NaOH H20 Scheme 58 Intramolecular cycloaddition of a carbonyl ylide to an acetylenic group provides a short route to the furobenzopyran system (162) (Scheme 59).90 87 P. Baeckstrom L. Li I. Polec R. Unelius and W. R. Wimalasiri J. Org. Chem. 1991 56 3358. 88 C. W. Jefford J. Currie G.D. Richardson and J.-C. Rosier Helu. Chim. Acta 1991 74 1239. 89 A. J. Bloodworth and A. Shah J. Chem. SOC.,Chem. Commun. 1991 941. C. Bernaus J. Font and P. de March Tetrahedron 1991 47 7713. 170 D. E. Ames 16% Reagents i A Scheme 59 -(11 $ ,;yy(oH)Me ’. (163) + Et (46%) (163) (164) (50%) (165) Reagents i TsOH A; ii TsCI pyridine 2-dimethylaminopyridine Scheme 60 The 2,3-dihydro-174-dithiin (163) is obtained when 2-( l-hydroxyalkyl)-1,3-dithiolan (164) is heated with 4-toluenesulfonic acid (Scheme 60).91 In the example given treatment of (164) with 4-toluenesulfonyl chloride and base gives the 2- alkylidene-174-dithiane (165) as well as (163). Benzo-l,2,4-trithiins (166) have been prepared by reaction of benzopentathiepin (167) with a phosphorus ylide (Scheme 61).92 Ar PPh3 as-;--34% s-s-s-s -Ar = 4-MeOC6H4 Reagents i ArCH,$Ph,Cl- NaH Scheme 61 The anion from (168) has been condensed with aldehyde (169) to give (170) as a mixture of (2)-and (E)-isomers in a 1:2 ratio.The mixture was treated with titanium (IV) chloride to effect ring closure forming (171; R = Me). Demethyla- tion with boron tribromide at low temperature gave the phenol (171; R = H) which was cyclized under basic conditions to produce the Sthiorotenoid core (172) (Scheme 62).93 Optically active pipecolic acid derivatives (173) have been prepared enantio- and diastereo-selectively by an aza-Diels-Alder reaction of dienes with an imine obtained from ethyl glyoxylate and chiral 1-phenylethylamine (Scheme 63)?4 91 C.A. M. Afonso M. T. Barros L. S. Godinho and C. D. Maycock Synthesis 1991 575. 92 R. Sat0 and K. Chino Tetrahedron Lett. 1991 32 6345. 93 L. Crornbie J. L. Josephs J. Larkin and J. B. Weston J. Chem. SOC.,Chem Commun. 1991 973. 94 P. D. Bailey R. D. Wilson and G. R. Brown J. Chem. SOC.,Perkin Trans. 1 1991 1337. Heterocyclic Compounds OMe I OMe E t 0)21;^0 .'. 1 II QCHO + -0 50% I CH,CH(OE t)2 (170) 111 IV I52% "' ' Reagents i LiNPr',; ii A; iii TiCI,; iv MeOH; v NaOEt A Scheme 62 The strongly electrophilic fluorine of acetyl hypofluorite reacts with pyridine to form an N-fluoropyridinium salt in which the ring is activated for nucleophilic attack. Elimination of hydrogen fluoride then gives overall nucleophilic substitution in the 2-po~ition.'~For example pyridine with acetyl hypofluorite in methanol yields 2-methoxy-pyridine (70%).An efficient [5 + 11 heterocyclization route to 4(1H)-pyridones (174) has been developed?6 2-Aza-l,3-dienes (175) react with 1,l'-carbonyl-diimidazoleto form the pyridones (Scheme 64) and they also react with thiophosgene to produce the corresponding 4-chloropyridine. Substituted 4-hydroxy-2-pyridones have been prepared from ethyl a-methyl-acetoacetate and benzylamine (Scheme 65).97 Conversion into the P-aminoacrylate (176) followed by N-acylation gave (177) which was cyclized to pyridone (178) by heating with sodium ethoxide. Palladium-catalysed hydrogenolysis then removed the N-benzyl group quantitatively.95 D. Hebel and S. Rozen J. Org. Chem. 1991 56,6298. 96 J. Barluenga F. J. Gonziilez and R. P. Carlon J. Org. Chem. 1991 56 6751. 97 K. H. Chung K. Y. Cho Y. Asami N. Takahashi and S. Yoshida Heterocycles 1991 32 99. 172 D. E. Ames r 1 L N Reagents i 1,l '-carbonyldiimidazole BF3.Et20 Scheme64 OH Me NH I I N I CH2Ph CH2Ph CH2Ph (176) (177) (178) Reagents i R20CH2COCI; ii NaOEt EtOH A Scheme65 1,l-Di(methylthio)-2,2-dicyanoethenereacts with cyanothioacetamide with elimi- nation of methanethiol to form intermediate (179) which rearranges uia (180) into the 2-( 1H)-pyridinethione (181) (Scheme 66).98 The structures biological activities and syntheses of marine natural products containing quinoline and/or isoquinoline nuclei have been reviewed.99 A photochemical reaction generates the cyclopenta[ blquinoline (182) from ben- zoisonitrile and 1-iodohex-4-yne (183) (Scheme 67)'" by a novel [4 + llradical annulation.98 D. Briel S. Dumke G. Wagner and B. Olk J. Chem. Res (S) 1991 178. 99 M. Alvarez M. Salas and J. A. Joule Heterocycles 1991 32 759. loo D. P. Curran and H. Liu J. Am. Chem. Soc. 1991 113 2127. Heterocyclic Compounds (183) Reagents i PhNC (Me,Sn), A hv Scheme 67 The dihydronaphthalene derivative (184) forms a chromium carbonyl complex (185). After hydrolysis of the N-acyl group this undergoes a photochemical reac- tion to close a piperidine ring which generates the benzomorphan skeleton (186) (Scheme 68)."' - Me0 \ NMe Me0 NMe I \ I MeOQ,Me Reagents i Cr(CO),; ii K2C03H20 ultrasound; iii 02,hv Scheme 68 A modified Bischler-Naperalski process for the preparation of 3-aryl-3,4-dihy- droisoquinolines is based on treatment of amide (187) with oxalyl chloride to form (188).Elimination of chloride ion by reaction with iron(Ir1) chloride gives ion (189) which cyclizes to give (190) the oxalyl derivative of a 1-hydroxytetrahydroisoquino-line. Acid hydrolysis then yields the dihydroisoquinoline (191) (Scheme 69).'02 The interesting functionalized hydroisoquinolinone (192) has been obtained by a thermal or Lewis-acid mediated Diels- Alder cyclo-addition to the unsaturated piperidone-ester (193) (Scheme 70).'03 4,5-Dimethyl- and 4,5,6-trimethylpyridines are brominated at the 5-methyl-group by N-bromosuccinimide but at the 4- or 6-methyl group by bromine in acetic acid to give bromomethyl derivatives in good yields (Scheme 71).'04 A 2-methylthio- substituent is not oxidized under these conditions.101 M. Sainsbury M. F. Mahon C. S. Williams A. Naylor and D. I. C. Scopes Tetrahedron 1991,47,4195. 102 R. D. Larsen R. A. Reamer E. G. Corley P. Davis E. J. J. Grabowski P. J. Reider and I. Shinkai J. Org. Chem. 1991 56 6034. 103 D. 0. Imbroisi and N. S. Simpkins J. Chem. Soc. Perkin Trans. 1 1991 1815. 104 L. Strekowski R. L. Wydra L. Janda and D. B. Harden J. Org. Chem. 1991 56 5610. 174 D. E. Ames I-NH PPh I COR q:co R 0-co/ R (191) Yields 72% (R = H) 88%(R = Me) Reagents i (COCI);; ii FeCI,; iii H,SO, MeOH Scheme 69 i ii MeJSiOp -+ MeOzC QNC02Me 100% '*NCO2Me MeOzC OMe 0 (193) Reagents i; A; ii camphorsulfonic acid Scheme 70 CH2Br Me f)Me 2nMe 2 R R R Yields; 77% (R = H); 68% (R = SMe) Yields; 75% (R = H); 81% (R = SMe) Reagents i N-bromosuccinimide; ii Br, HOAc Scheme 71 In a regioselective synthesis of alkylpyra~ines"~ an (Y -0ximinoketone (194) is condensed with allylamine to form imine (195) which is isomerized by heating with potassium t-butoxide to form the conjugated system (196; R = H).The O-methoxy- carbonyl derivative (196; R = C02Me) undergoes thermal cyclization to form the pyrazine (197) in good yield (Scheme 72).'05 3H-4,1,2-Benzothiadiazines(198; X = S) and the corresponding S,S-dioxides have been obtained by diazotization and cyclization of aminoamides (199; X = S or SO2) (Scheme 73).'06 A useful synthesis of 1,4-thiazines has been based on the addition of reactive alkenes to 2-(dialkylhydrazono)thioacetophenones(200).'07 Elimination of dialkyl- amine from adduct (201) produced 1,4-thiazine (202) (Scheme 74).105 G. Buchi and J. Galindo J. Org. Chem. 1991 56 2605. 106 A.Balbi M. Mazzei and E. Sottofattori J. HeterocycL Chem. 1991,28,1633. 107 A.Reliquet R. Besbes F. Reliquet and J. C. Meslin Synthesis 1991 543. Heterocyclic Compounds NOH NOH / R1 (194) (195) (196) (197) Reagents i CH2=CHCH2NH2 A; ii KOBu‘; iii A Scheme 72 (199) (198) Yields 57%(X = S,R = Et) 19%(X = SO2 R = Et) Reagents i NaNO, HOAc Scheme 73 N COR N Reagents i CH,=CHCOR hydroquinone; ii A Scheme 74 Enamines such as (203) can be prepared from heterocycles having a methyl group at the a-position to the ring nitrogen atom by reaction with N,N-dimethylfor- mamide dimethyl acetal.These enamines react with 2-phenyl-5-(4H) -0xazo1one to form intermediates (204) which cyclize to give azinopyridone (205) (Scheme 75).’08 Reagents i 2-phenyl-5(4H) -oxazolone Ac20 Scheme 75 lo* A. Copar B. Stanovnik and M. TiSler Bull. SOC.Chim. Belg. 1991 100 533. 176 D. E. Ames Cystodytins are antineoplastic alkaloids isolated from an Okinawan tunicate. The first total synthesis reported”’ involves eleven steps (8% overall yield) and is summarized in Scheme 76.In the final steps photolysis of the azide (206) generated a triplet nitrene which formed the pyridine (c)ring by hydrogen abstraction and radical pair recombination. Dehydrogenation then gave cystodytin A (207). CMe2 CMe2 II CH . .. co co 1 I1 -I I 31% 0 Ar = 2-Reagents i hv A; ii DDQ Scheme 76 The dione mono-N,N-dimethylhydrazone(208) obtained by trifluoroacetylation of aldehyde hydrazone (209) reacts with sodium periodate in an unusual oxidative cyclization reaction to form the 1,3,4-oxadiazine (210) (Scheme 77).’1° Reagents i (CF,C0)20; ii NaIO Scheme 77 X-Ray studies have shown”’ that peracid oxidation of 4,5,6-triaryl-1,2,3-triazines gives the 2-oxide (211). 1,2,3,4-Benzotetrazine- 1,3-dioxide (212) is a stable structure prepared by action of dinitrogen pentoxide on the amino-azoxy-compound (2 13).‘ l2 Reaction of ethyl diazoacetate with l-(methylthio)-3,4-dimethylphosphole1-sulfide (214) in refluxing xylene leads to diene-carbene [2 + 13 cycloadduct (215).109 M. A. Ciufolini and N. E. Byrne J. Am. Chem. Soc. 1991 113 8016. 110 Y. Kamitori M. Hojo R. Masuda T. Fujitani and K. Sukegawa Heterocycles 1991 32 1693. 111 A. Ohsawa T. Itoh K. Yamaguchi and C. Kawabata Chem. Pharm. Bull. 1991 39 2117. 112 A. M. Churakov S. L. Ioffe and V. A. Tartakowski Mendeleeu Commun. 1991 101. Heterocyclic Compounds This reacts with triphenyl phosphite to give the phosphinine (216). NMR evidence shows that rearrangement occurred so that the ethoxycarbonyl group is in the 2-position (Scheme 78).Il3 Me Me Me~~CO,Br ii ,Me0 75% PH 75% CO,Et 8'sMe P (214) (215) Reagents i N2CHCO2Et A; ii P(OPh), A Scheme 78 The first 1,3,5-diazaphosphinines (217) have been obtained from 3,Sdiazapyry- lium tetrafluoroborates (21 8) by phosphorus exchange using tris(trimethylsily1)phos-phane.'14 These products react with alkynes in a cascade process in which 1,4-addition gives the heterobarrelene (219).Loss of aryl cyanide and a further addition- elimination sequence leads to the phosphinine (220) (Scheme 79).'14 Reagents i P(SiMe,)3 A; ii R'C=CR2 Scheme 79 6 Seven-membered Rings Photolysis of p-[o-(aryloxy)phenyl]vinyl bromide (221) in the presence of a base gives dibenz[ 6 floxepin (222) quantitatively (Scheme (221) Reagents i hv pyridine I I3 S.Hoiand L. Ricard and F. Mathey J. Org. Chem. 1991 56 4031. 114 G. Mark1 and C. Dorges Angew. Chem. Znt. Ed. Engl 1991 30,106. 115 T. Kitamura S. Kobayashi H. Taniguchi and K. Hori J. Am. Chem. Soc. 1991 113 6240. 178 D. E. Ames The ylide generated from pyridinium salt (223) undergoes 8 .rr-electrocyclization to form the heterocyclic allene (224). In the presence of hydrogen peroxide and water this is transformed into a pyrido[ 1,2-a]azepinone (225) (Scheme 81).'16 Br-3irJMe 5;yo,m \N/ \N Me - - Me (224) 0 (223) (225) Reagents i Et,NH A; ii H,O, H,O Scheme 81 5-Azaazulenes (226) can be obtained from 2-formyl-6-dimethylaminofulvene(227) and (viny1imino)phosphoranes (228) by an aza- Wittig reaction and electrocyclization (Scheme 82)."' CHR 1 -II 24% + Ph,P=N-CPh aCHNMe2 CHO (227) (228) (226) Reagents i A Scheme 82 Bicyclic diazepines are the subject of an important monograph."' A benzodiazepine (229) which inhibits replication of viruses has been synthesized (Scheme 83) .l19 Base-catalysed dimethylallylation of diamine (230) and cyclization gave the heterocycle (231) then reduction of nitro-group to amine and reaction with carbon disulfide yielded imidazolethione (229).\ -W 03 Me (230) (231) (229) Reagents i K,CO, A Me,C=CHCH,Br; ii H, Pd/C; iii CS2 Scheme 83 W. Maier and W. Eberbach Helv. Chim. Acta 1991 74 1095. M.Nitta Y. Ino and S.Mori Tetrahedron Lett. 1991 32 6727. 118 'The Chemistry of Heterocyclic Compounds' Vol. 50 Bicyclic Diazepines ed. R. I. Fryer Wiley- Interscience New York 1991. 119 K. A. Parker and C. A. Coburn J. Org. Chem. 1991 56 4600. Heterocyclic Compounds 2-ha- 1,3-diene (232) and trimethylsilylisothiocyanate react to form the pyrimidine-4( 3H)-thione (233) which can be converted via aziridine (234) into .3,6-dimethyl-2,5-diphenyl-l H-1,4-diazepine-7(6H) -thione (235) (Scheme 84).I2' Action of sulfur dichloride on the di(alkeny1)-P-lactam (236) gives a mixture of the fused-ring thiazepines (237) and (238) (Scheme 85).12' d MeMph phNLcrMe Me I Me (232) (233) (235) Reagents i Me,SiN=C=S A; ii NaH Scheme84 Ph / PhCHCl + V 0' -c1 (237) Reagents i SClz A Scheme 85 Tetrazepinones (239) have been prepared by the sequence shown in Scheme 86."* Reduction of the quinoline (240) to the tetrahydro-derivative and reaction with methyl isocyanate gave (241).Acid-catalysed hydrolysis of the N-t-butoxycarbonyl group and diazotization then yielded the fused-ring tetrazepin-Cone (239). Varacin (242) an antifungal metabolite of the ascidian Lissoclinum uareau is the first natural ben~0pentathiepin.I~~ ... 1,II I iii-v -02- 100% I NH 23% I I AQ Bu'O~C But02C HFm 'N-NMe Me (240) (2411 (239) Reagents i H2 Pd/C; ii MeNCO; iii CF,C02H H20; iv NaHC03 H20; v NaN02 HCI Hz0 Scheme 86 120 J. Barluenga R. P. Carlh F. J. Gonzhlez and F.L. Ortiz J. Chem. Soc. Chem. Commun. 1991 1704. 121 M. Komatsu M. Mohri S. Kume and Y. Ohshiro Heterocycles 1991 32 659. 122 B. J. Jean-Claude and G. Just J. Chem. Soc. Perkin Trans. 1 1991 2525. 123 B. S. Davidson T. F. Molinski L. R. Barrows and C. M. Ireland J. Am. Chem. Soc. 1991 113 4709. 180 D. E. Ames Benzotellurepin (243) has been prepared by reaction of 1,2-di( ethyny1)benzene with sodium telluride and hydrazine in the presence of a phase transfer ~ata1yst.l~~ It is rather unstable and decomposes to naphthalene and tellurium in a few days at room temperature. The 1-benzophosphepine (244) has been obtained as shown in (Scheme 87).’25 Photochemical addition of methyl acrylate to benzophosphole oxide (245) formed a cyclobutane ring as in (246).Hydrolysis and oxidative decarboxylation gave the cyclobutene system (247). Flash vacuum pyrolysis effected ring cleavage to produce (248) which was reduced with trichlorosilane to 1-phenyl-1 -benzophosphepine. 07 6:yo a ~ ii,iii ~ 55% 0’ ‘Ph 0’ ‘Ph (245) (246) O-&+f?JJ+f7JJ P P P 0” ‘Ph 0” ‘Ph I Ph (247) (248) (244) Reagents i hv CH,=CHCO,Me; ii NaOH H,O; iii Pb(OAc), Cu(OAc), pyridine A; iv flash vacuum pyrolysis; v SiHCI3 A; vi NaOH H,O Scheme 87 7 Larger Rings Useful reviews have covered seven eight and nine-membered nitrogen heterocycles’26 and recent literature on the anthelmintic macrolides the avermectins and milbemy~ins.’~~ After successive reactions of diallylamine with n-butyl lithium and t-butyl lithium addition of ethyl lithium generates the lithium complex (249).On treatment with dichlorodimethylsilane followed by hydrolysis this yields the azasilocine (250) (Scheme 88).12* I24 H. Sashida H. Kurahashi and T. Tsuchiya J. Chem. SOC.,Chem. Commun. 1991 802. 125 J. Kurita S. Shiratori S. Vasnike and T. Tsuchiya J. Chem. SOC.,Chem. Commun. 1991 1227. 126 P. A. Evans and A. B. Holmes Tetrahedron 1991 47 9131. 127 H. G. Davies and R. H. Green Chem. SOC.Rev. 1991 20 211 271. 128 J. Barluenga F. Foubelo R. GonzalCz J. Fafianhs and M. Yus J. Chem. SOC.,Chem. Commun. 1991 1001. 181 Heterocyclic Compounds Et n . .. I I1 - 69% Reagents i Cl2SiMe2;ii H20 Scheme 88 Imides (251) react with 3-dialkylamino-2 H-azirines (252) to form adducts (253) which rearrange producing the eight-membered ring systems (254) (Scheme 89).129 An acid-catalysed rearrangement of tetrahydropyrimido[ 1,2-u]indole carbin- 01s (255) leads to the bridged-ring derivative of a 1,5-benzodiazocine (256) (Scheme H OC-N R3 R1f$H + R2 so2 (251) (252) (253) (254) Scheme 89 Reagents i 4-MeC6H,SO3H A Scheme 90 Action of hypervalent iodine compounds on the tetrahydroisoquinolinl amide (257) generates an N-methoxy- N-acyl nitrenium ion which effects a ring expansion to form the nine membered ring of (258) (Scheme 91).13' COBu' Me0 => ::ZWNCO13uf 62% \ N CH2CONHOMe 1 OMe (257) (258) Reagents i PhI(OCOCF,) ,A Scheme 91 129 A.Rahm A.Linden B. R. Vincent and H. Heimgartner Helu. Chim. Acta 1991 74 1002. 130 I. A. Cliffe K. Heatherington and A. C. White J. Chem. Soc. Perkin Trans. 1 1991 1975. 13' Y. Kikugawa and M. Kawase J. Chem. SOC.,Chem. Commun. 1991 1354. 182 D. E. Ames The 3-aza[9]metacyclophane (259) has been obtained from the tetracyclic tetrahy- droisoquinoline (260) by ring cleavage steps. First cyanogen bromide gave the unsaturated tricycle (261) then ozonolysis yielded the twelve-membered ring struc- ture (259) (Scheme 92).’32 (260) (261) (259) Reagents i BrCN K2C0,; ii 0,; iii Me,S Scheme 92 A synthesis of P-resorcyc1i.c macrolides including (S)-zearalenone (262) is based on a palladium-catalysed intramolecular coupling of aryl iodide with vinyl stannane (Scheme 93).’33 R = MeOCH Reagents i Pd(PPh,) on polystyrene support A; ii HCl HZO Scheme 93 An intramolecular Ullmann reaction has been used to prepare diary1 ethers with 14- and 15-membered meta- and para-units in a cyclophane system.First cyclization of (263) yielded the ether-lactone (264; R = Me) which was demethylated by the action of boron triiodide to give (264; R = H) the cytotoxic antibiotic combretastatin D-2 (Scheme 94).134 OMe 1 I ___,3 7% Y-30 0 (263) (264) Reagents i CuMe pyridine A Scheme 94 J. B. Bremner and W. Jaturonrusmee Aust. J. Chem. 1991 44,135. 133 A. Kalivretenos J. K. Stille and L. S. Hegedus J. Org. Chem. 1991 56 2883. 134 D. L. Boger S. M. Sakya and D. Yohannes J. Org. Chem. 1991 56 4204.Heterocyclic Compounds Second a similar process was used to construct a 14-membered amide-ether cyclophane ~tructure.'~~ Third the method was applied to the preparation of the amide-ether heterocyclic moiety of bouvardin a bicyclic hexapeptide antibiotic as part of a synthesis of deoxyb~uvardin.'~~ Heating aromatic aldehydes with pyrrole in propanoic acid and nitrobenzene gives porphyrins dire~tly,'~~ e.g. 4-methoxybenzaldehyde gives 5,10,15,20-tetra(4- methoxypheny1)porphyrin (265; X =H; Ar =4-MeOC,&) in 45% yield. Electrophilic bromination occurs regiospecifically at the antipodal pyrrolenic rings of free-base porphyrins bearing substituents which fix the aromatic delocalization pathway.'38 Thus (265; X =H; Ar =3,5-But2C6H4) gives the corresponding tetra- bromide (X =Br) which reacts with benzene-1,2-dithiol to form (266).The Wittig reaction fails with xanthoporphyrinogens (267; X =0)but methyl- lithium does react to give tetra-mesomethyleneporphyrinogen(267; X =CH2; 13% when R =H 63% when R =Me).'39 Y x=c/\c=x (267) 135 D. L. Boger and D. Yohannes J. Org. Chem. 1991 56 1763. 136 D. L. Boger and D. Yohannes J. Am. Chem. Soc. 1991 113 1427. 137 A. M. d'A. R. Gonsalves J. M. T. B. Varejio and M. M. Pereira J. Heterocycl. Chem. 1991 28 635. 138 M. J. Crossley P. L. Burn S. S. Chew F. B. Cuttance and I. A. Newsom J. Chem. Soc. Chem. Commun. 1991 1564. 139 C. Otto and E. Breitmaier Liebigs Ann. Chem. 1991 1347. 184 D. E. Ames Finally a hexapyrrolic expanded porphyrin (268) has been synthesized (Scheme 95).140 Condensation of the acetoxymethylpyrrole ester (269) with dipyrrolyl (270) gave the linear tetrapyrrole diester (271; R = CH,Ph).Hydrogenolysis to the diacid (271; R = H) and condensation with diformyl-dipyrrole (272) under acidic condi- tions produced the cyclic hexapyrrole salt (268). Salts of this 26-~-electron annulene system were stable but isolation of the free base was not achieved. Et Me Me Et EcN,'j4e Fjt N H H I ___) (270) NH HN 66% + COzR COZR COzCHzPh (271) AcO (269) Et Me Me Et (271; R = H) + H H Et . .. 1 II 40% Me Et Me Me Et (272) Reagents i 4-MeC,H,S03H A; ii O2 Scheme 95 J. L. Sessler T. Morishima and V.Lynch Angew. Chem. Int. Ed. Engl. 1991 30 977.

ISSN:0069-3030    

DOI:10.1039/OC9918800149

出版商:RSC    

年代:1991

数据来源: RSC