4 Reaction Mechanisms Part (i) Pericyclic Reactions By N.G. RAMSDEN Glaxo Research and Deveiupment Limited Greenford Road Gmenfurd Middtesex UB6 OHE,LJK 1 Cydoadditioas The similarity index proposed recently as a quantitative measure of the extent of electron reorganization during chemical reactions allows discrimination between allowedand forbidden concerted processes. This is due to the difference in the extent of electron correlation between them It also allows a simple evaluation of the relative energies of concerted and non-concerted reaction paths. Several pericyclic reactions have been investigated for the variation in electron correlation during their course. The role of electron correlation is found to be most critical for high energy species along the reaction coordinate.2 The similarity approach to chemicaI reactivity has also been used to study substituent effects in pericyclic p hem is try.^ The use of transition state modelling with empirical force fields for reactions including the Diels-Alder reaction and Cope and Claisen rearrangements has hen re~iewed.~ Transition states for the concerted and stepwise Diels-Alder reaction and 12 + 21 dirnerizationof buta-1,3-diene have been located.On the basis of these the diradical transition state for the DieIs-Alder reaction of ethylene and butadiene appears to lie some 5 kcal mol- above the concerted synchronous transition state.5 Ab initio MO calculations have been used to study the reaction of cyclopentadiene with a variety of dienophiles.Endu cis transition states are favoured and the lack of selectivity with acrylonitrile has been explained. Good agreement is found between enthalpies of activation and reactivities derived both experimentally and at the MB3 leveL6 Kinetic measurements on the Diels-Alder reaction of (1) show that a good correlation between -log k and (EHOMOEL,,,)-exists.’ The Diels-Alder reactions of (2) with phenylacetylenes have been studied by MO calculations. At the HF/6-31G* level head-to-tail cycloadditions are favoured over head-to-head cycloadditions. This finding is in agreement with experimental data and provides the first evidence for R. Ponec J Chem. InJ Comput. Sci. 1993,33 505. ’R.Pons and M.Strad Collect. Czech. Chem. Convniin. 1993,58,1751. R. Ponec Coflect.Czech.Chem. Comun. 1993,58 11. A J.E. Eksterowicz and K.N.Houk Chem. Rev. 1993,93 2439. Y.Li and K.N.Houk J. Am. Chem. Soc. 1993 IIS 7478. ‘W.L. Jorgensen D. Lim and J.K. Blake J. Am. Chem. Soc. 1993,115 2936. ’ R. Sustmann and I. Siangouri-Feulner Chem. Ber. 1993,126. 1241. 71 N.G.Ramsden 11) (21 regioselectivity being controlled by Van de Waal's forces.8 Frontier orbitals along the intrinsic reaction co-ordinate of [4 + 21 and [8 + 21 cycloadditions for ethylene and thiabutadiene have been studied by MO calculations. Even if the orbital phase of the reactant does not give favourable FMO interaction it may be converted into the correct phase on route.g The thermal transannular Diels-Alder reaction of (3) has been studied. Experimental results are in agreement with those predicted by theory.'* In the aminium salt catalysed reaction a diene cation-radical reacts with a neutral ketene in a [4 + 21 cycloaddition (Scheme l)." The influence of phenyl n electrons Scheme 1 during cycloaddition reactions of endo-3,3-diphenyltricyclo[3.2.1.02*4Joct-6-enehas been investigated.Diels-Alder reactions that are accelerated by increasing the electrophilic nature of the medium are accelerated by metal perchlorates in order of charge :radius ratio is. Mg2 > Ba2+ > Li > Na' .This is presumably due to the effect of the cation on the electrophilic nature of the rnedium.13 J. Cioslowski J. Sauer J. Hertzenegger,T. Karcher,and T. Hierstetter,J. Am.Chem. Soc. 1993,115,1353. S.Yamabe S.Kawajiri T.Minato and T. Machiguchi J. Org. Chem. 1993,58 1122. lo A. Ndibwami S. Lamothe P. Souay S. Goldstein and P. Deslongchamps Can. J. Chem. 1993,71,714. R. M.Giuliano A. D. Jordan A. Gaufhier and K. Haogsteen J. Org. Chem. I993,58,4979. M. Peeran J.W. Wilt R. Subrarnanian and D.S. Crumrine J. Org. Chem. I993,58 202. l3 A.Cassoschi C.Desimoni G. Faita A.G. Invernizzi S. Lanati and P.Righetti J. Am. Chem.Soc. 1993 115,8002. Reaction Mechanisms -Part (i) Pericyclic Reactions (4) X=CH20r0 (5)X=CH,orO A dienophile will add to the face opposite the methoxy group in both (4)and (5)due to both the diene conformation and secondary orbital interactions in the transition state.14A procedure for the conversion of endo (6)to exo (7)adductsin the Diels-Alder reaction has been determined (Scheme 2).The high em selectivity was investigated by Scheme 2 AM 1 transition state calculations.' A mechanistically interesting and useful reversal in the facial selectivityof the Diels-Alder reaction has been achieved (Scheme 3).16 The Scheme 3 #?-sulfinyl dienophile (8) has been shown to react with cyclopentadiene with a very high degree of diastereoselectivity.' The LUMO diene controlled [4+ 2) cycloaddition of azaazulenes with tetrazines has been described.I8 Fischer carbenes (9) undergo Diels-Alder reactions with comparable stereoselectivity to the Lewis acid catalysed reaction of the corresponding methyl ester. This makes them useful synthons in cases where the diene is intolerant of Lewis acids.N-arylcycIohepta-2,4,6-triene-1-imines react with benzonitrile oxirnes I4 M. Schrnittel and H. Van Seggern J. Am. Chem. SOC. 1993,115 2165. P.P. M. DoI A. J. H. Klunder and B. Zwannenberg Tetrahedron Lett. 1993 34 3181. H. J. Liu and Y. Hai Tetrahedron Lett. 1993 34,423. l7 T.K. Yang S. M.Hung C.Z. Chen Y. Jiang and A. Q. Mi Youjji Huaxue 1993 13 183. '* G. Frenzen W. Maisa U. Reirnes and G. Seitz Chem. Ber. 1993 125 441. l9 W.D. Wukff and T. S. Powers J. Org. Chem. 1993,58 2381. N.G. Ramsden via [4 + 21 cycloadditions.A Hammett p-value of 0.99 suggests nucleophilic attack of the imines to the nitrile oxides.20 (q6-Cyclohepta-I ,3,5-triene)tricarbonylchromium(o)undergoes a thermal [6 + 41 cycloaddition with both electron-rich and electron-poor butadienes to give the endo product.The reaction between the chirally enriched allene (10) and the perhaloalkene (11)has been studied both experimentally and by molecular modelling. Results suggest that (12)is formed by one continuous minimum energy pathway whilst (13)is formed from two competing pathways. The two stereoisomers of (13) have opposite absolute configurations and thus no chirality transfer is seen from (10) to (13).’* The reaction of fluorine and ethylene has been studied at the MP2/5-31*GleveLZ3 Fluorine approaches the ethylene doubIe bond vertically to form a perpendicular complex as the intermediate. This then rearranges to a rhombic-type complex as a transition state to give the finaf syn product. Cycloadditions between ketenes and cyclopentadiene have been studied by a semiempirical AM1 method.Ketene and methyl ketene react via a concerted but nun-synchronous twisted transition state with a small degree of charge transfer from the cyclopentadiene to the ketene. Chlorornethyl ketene however reacts in a stepwise manner.24 Acetylenic links can act as antarafacial components in [2 + 21 processes.25 N-Methylhex-3-yn-1-aminewill react in a nominal [2 + 2 + 2 + 2J Mobius process. Evidence for the concertedness of this reaction has been discussed. Silenes undergo L2 + 41 and [2 + 21 cycloadditions with imines.26 The [2 + 41 ’* K Ito K. Saito and K. Takahashi Heterocycles 1993 36 21. 21 J.H. Rigby H. S. Ateeq N. R,Charles S. V. Cuisiat M.D. Ferguson J.A. Henshilwood A.C.Krueger C.O. Ogbu K. M. Short and M. J. J. Heeg J. Am. Chem. Soc. 1993,115 I382. ” D.J. Pasto and J. Brophy J. Phys. Org. Chem. 1993,6 95. 23 T. Iwaoka C. Kaneko A. Shigiwara and H. Ichikawa J. Phys. Org. Chem. 1993,6 195. 24 J. Jiang D. Fang and X. Fu Gaodeng Xuexiao Huuxue Xuebuo 1993,14 696. Is A. Viola J. J. Collins N. FiIipp and J. S. Locke J. Org. Chem. 1993 58,5067. 26 A.G. Brook W. J. Chatterton and R. Kimarathasan Organometallics 1993 12 3666. Reaction Mechanisms -Part (i) Pericyclic Reactions adducts generally rearrange to [2 + 23 cycloadducts and these silazetidines decompose by a variety of mechanisms. Computations suggest a multistep diradical mechanism for the head-to-tail cycloaddition of two ~ilaethylenes.~’ Polarization of the double bond in silenes does not Iead to a concerted mechanism.The energy surface is similar to that of the ethylenexthylene reaction but both the activation energy and the energy of the diradical are much lower. The cycloaddition of tetrafluoroethylene and dicyclopen- tadiene is first order in dicyclopentadiene and second order in tetrafluoroethylene.28 The activation energy is 118.56kcal mol- Oxazolium-5-oxide(14)cycloadds to I ,2-dicyanocyclobutene(15) to give the imino acid (16) and the dihydroazepine (17).29 AM1 calculations have been used to rationalize the observed product stereochemistry and evaluate possible reaction mechanisms. The effect of solvent and substituents on the 12 + 21 cycloaddition of t-butyI- cyanoketene and styrene has been studied using a CAS-MCSCF method.The reaction proceeds uia a diradical in which steric interactions are minimized. However this minimization leads to a product with cis stere~chernistry.~’ New models for the [2 + 21 Staudinger reaction have been discussed.31 Simple feed-forward three layer neural networks have been used to classify and predict the regioselectivity of 1,s-dipolar cycIoadditions.32 A quantitative analysis of the transition states and energy barriers of the syn and anti cycloadditionsof norbornene and cis-3,4-dichlorocyclobu tene with formonitrile oxime has investigated the role of many factors involved in facial ~electivity.~~ Further studies have allowed the development of a conceptual framework involving repulsion delocalization and def~rrnation.~~ This has provided a detailed account of the geometry and energy differences between the syn and anti transition states.The cyclization of imine oxides has been studied. In the reaction of (19) with the furanone (18)the major product is derived from an em transition state.35 Exo adducts are also the major products from reactions of (20).36With furanones the stereochemistry ofthe products is cis due to an interaction between the nitrogen lone pair and the carbonyl group. When this interaction is not present for example in the dihydrofurans trans products begin to predominate. ’’ F. ktnardi A. Bottoni M. Olivucci M. A. Robb and A. Venturni J. Am. Chem. Soc. 1993 115 3322. ’’ N.B. Christova S.D. Pavlova and G. K. Kostov Kinet.Cutal. Lett. 1993 49 393. ’’ C.A. Matyanoff and I. J. Turchi Heterocycles 1993 35 649. ’’ M. Reguero R.R. Pappalarda M.A. Robb and H.S. Rzepa f. Chem. SOC.,Perkin Trans. 2 1993 1499. 31 F.P. Cossio 8. ha C. Cuevas A. Mieglo and C. Palomo An. Quim. 1993 89 119. 32 S. Sklenak V. Kvasnicka and J. Pospical Actu Gem. Hung. 1993,130 103. ’’ A. Rastelli M. Bagatti A. Ori R. Gandolfi and M. Burdisso 3. Chem. Soc. Farday Trans. 1993,89,29. ” A. Rastelli M. Bagatti and R. Gandolfi J. Chem. Soc. Faradey Truns. 1993 89 3913. ’’ D. Aionso-Peramau P. de March M.Figuerdo J. Font and A. Seria Tetrahedron,1993 49 4267. 36 P. Cid P.de March M.Figuerdo J. Font,S. Milan A. Soria and A. VirgiIi Tetrahedron 1993,454 3857. N. G.Ramsden I Q dj5O H 0- (19) DiastereoseIectivity in nitrile oxide additions to OppoIzer’s chiral suItarns cannot be explained solely by bulky groups shidding faces of the alkene.37 Transition states were investigated by PM3 methods and the origin ofthe selectivity appears to be a repulsion between the dipolar oxygen and the sultam oxygens.This is supported by the fact that selectivity is lost in the corresponding isothiazolidines. The work supports Hehre’s claim that electrostatic effects are a general determinant of facial selectivity. 2-Ethoxy and 2-ethylthio-l-azetidines(21 undergo 1,3-dipolar cycloadditions with nitrile oxides and nitrile ylids to give stable products. With nitribmines 1,2,4-triazoles (22) are unexpectedly produced.38 Benzonitrile oxides undergo 1,3-~ycloaddition reactions to give 1,2,4-oxadiazoles as the major products.IsoxazoIesand 4,5-dihydroxazoles are also produced. The kinetics of all these reactions have been determined and substituent and solvent effects on product distribution are discussed.39 The regioselectivity of the intramolecular reaction of N-4-methylpent-4-enyl nitrones has been investigated by AM1 MO methods and transition state theory. The difference in selectivity between the E and 2 isomers is enhanced by the effect on the relative activation entropies caused by introduction of the methyl group.40 The reaction of mesoionic 1,3-dithioliurn-4-oate (23) with phenyl isocyanate is not a 37 K. S. Kim,B. H. Kim W. M. Park S.J. Cho and B. J.’Mihn J. Am. Chem. SOC. 1993 115,7472. 38 K.Hemming A. B. N.Luheshi A.D. Redhouse R.K. Smalley,J. R.Thompson P.D. KenneweIl and R. Westwood Tetrahedron. 1993 49 4383. 39 P. Beltrane E. Cadoni C. Floris and G. Gelli Tetrahedron. 1993,49 7001. *O S. Ma and X. Fu Hauxue Xuebao. 1993,51,496. Reaction Mechanisms -Part (i) Pericyclic Reactions 1,3-dipolar cycloaddition as the product is an azetidinone. The phenyl isocyanate reacts with the open ketene isomer (24)of the mesoionic compound.41 The existence of Ar a free-resonant unstabilized azomethine ylid in a 1,3-dipolar cycloaddition has been demonstrated by 3C labelling.42 The cycloaddition of phenylsulfonyl allenes with diazomethane has been studied.43 The product pyrazolines undergo a variety of rnechanisticalIy interesting transformations. 2 Sigmatropic Rearrangements Chiral Lewis acids derived from binaphthol and diisoprupyltitaniurn dichloride catalyse the ene reaction of glyoxylate esters with silyl enol ethers rather than a Mukaiyama aldol reaction.44 Syn diastereoselectivity is very high with either isomer of the silyl enol ether and this can be explained by consideration of transition state geometries.A mechanistic pathway to explain the observed asymmetric induction during the Lewis acid catalysed ene reaction of (25)has been presented.45 The reaction XP A CN A CN (225) of enarnines with ethyf propiolate has been explained as an ene-addition reaction (Scheme 4).46Alloxan (26) and 1,3-dimethyIalloxan (27) undergo ready ene reactions at the centraI CU.47The stereoseiectivity of both reactions is determined by steric factors.The transition states for the ene reaction between propene and formaldehyde imine have been located by ab inibio MO calculation^.^^ The endo transition state is lower in energy when C-C bond formation occurs and the exo transition state is lower in energy when C-N bond formation occurs. This is due to interactions between the nitrogen lone pair and the central carbon atom of the ene. M. Bssaibis A. Robert and A. SouiU J. Chem. Soc. Chem. Comrnun. 1993 998. 42 J.M. Bentley D.M. Smith H.J. Wadsworth and C.L. Willis J. Chem. Res. (S) 1993 240. 43 A. Padwa M.A. Filipkowski D. N. Kline S.S. Murphree and P. E. Yeske,J. Org. Chem. 1993,58,2061. 44 K. Mikami and S. Matsukawa J. Am. Chem. Soc. 1993 115 7039. 4s K.Hiroi and M. Umemura Tetrahedron.,1993,49 1831 46 Z. Huang and M.Wang 3. Chem. Soc. Perkin Trans. 1 1993 1085. 4’ G. B. Gill and M. S. Hidris Tetrahedron. 1993 49 219. ‘* B. E. Thomas TV and K.N. Houk J. Am. Chem. SOC. 1993 115 790. N.G. Ramsden XOPh ““a XOPh U U U 0 (26) R=H (27) R= Me Scheme 4 Terminal fluorine atoms exert a significant inhibitory steric effect on both disrotatory eIectrocyclic closures of hexa- 1,3,5-trienes and Cope rearrangement^.^' Cope rearrangements of perfluorodienes proceed via a 1,4-cydohexyl diradical in contrast to the concerted rearrangement of non-fluorinated dienes.” Mass spectra of 2,s-diphenylhexa- 1,Sdienes have provided evidence for a cation-radical Cope rear-rangement in the gas phase.The reaction directionality is different to that for the thermal process.’ Activation entropies and energies have been calculated for the competing C-C cleavage and Cope rearrangement of (28).52 The stereoselectivity of the thio-Claisen rearrangement of S-crotyl-a-hydroxy ketene dithioacetals (29) is determined by the classical internal control obtained with a [3,3] sigmatropic shift.53 External control also exists based on the stereochemistry of the S-crotyi doubIe bond. The sohent effect on the retro-Claisen reaction has been studied and the rate constants found to be a linear function of Reichardt’s E,f30) solvent polarity This suggests that like the forward reaction the retro-Claisen is concerted with partial charge separation in the transiton state.An investigation of the migratory tendencies of several groups when undergoing a [I ,5] sigmatropic shift suggests that both good conjugative electron-withdrawing ability and the availability of a low-energy vacant orbital lead to good migratory ability.” However steric conformational and secondary orbital interaction effects can mask these. Further evidence is provided for the concerted nature of the reaction. Activation for a [l,5] hydride transfer and cycloaddition have been determined.56 A diradical with little ionic character is generated on themolysis of bicycloC2.1 .O]pen- ‘’W. R. Dolbier Jr and K. W. Palmer J. Am. Chem. Soc. 1993 115,9349. 50 N. Jing and D. M. Lemaf J. Am. Chem. SOC. 1993 115 8481. s1 H. Ikeda T.Takasaki Y. Takahashi and T.Miyashi J.Chem. SOC.,Chem. Commun. 1993,367. ’’ C. Herberg H. D. Beckhaus T.Koertvelyesi and C.Ruechardt Chem. Ber. 1993 126 117. ’’ P. Baslim and S. Perrio Tetrahedron 1993 49 3131. 54 G. Desimoni G. Faita S. Gratti Comini P. P. Righetti and G. Tacconi Tetrahedron 1993,49 2093. 55 D. W.Jones and R. J. Morrnan J. Chem. SOC.,ferkin Trans. I 1993,681. 56 T. H. Petersen and 8.K,Carpenter J. Am Chem. Soc. 1993 115 5466. Reaction Mechanisms -Part (i) Pericyclic Reactions tane derivatives. The energetics of [I ,5] sigmatropic hydrogen shifts in cyclopen- tadiene pyrrole and phosphole and have been determined from ab initio calcuIa-ti on^.'^ Activation enthaIpies have been used to explain the reactions of these heterocycles. The kinetic isotope effect for the [131 sigmatropic rearrangement of cis-penta-l,3-dienes has been studied by a direct dynamics method.” The contribution to the shifts by and the nature of tunnelling effects have been discussed.Kinetic studies on the rearrangement of tetraphenylcyclopentadienes(30)suggest that they occur by [1,3] and [1,5] sigmatropic shifts.” Ab initiu MO calculations show that the Ph Ph Ph Ph6,. Ph (30) suprafacial[1,3] hydrogen shift of H,CHC=PH to H,C=CHPH and the degenerate H,PCH=PH to HP=CHPH shift exist and compete favourably with the an- tarafacial process.60 A [5,5] sigmatropic shift has been observed in the thermal rearrangement of (3 A new route to 3-aminodeoxystatine derivatives employing a [3,3] sigmatropic shift under paIladiurn catalysis has been demonstrated.62 The mechanism and selectivity of the electrocyclization of (32) have been inves- tigated.63 The electrocyclic ring opening of (33) has been discussed.The calculated Gibb’s Free Energies are in agreement with the equilibrium determined experimen- tally.64 The electrocyclic reactions of syn and anti bishornoaromatic heterocycles (34) ’’ S. Bachrach J. Org. Chem. 1993,58 5414. Y.P.Liu C.C. Lyngh T. N. Truong D. H. Liu D.G. Truhlar and B.C. Garrett J. Am. Chem.Soc. 1993 115 2408. s9 P. Sebek,P. Sedmera S. Bohm and J. Kuthan Collect. Czech. Chem. Commun. 1993.58 882. M.T. Nguyen L.Landuyt and L.G. Vanquickenborne. Chem. Phys. Lett. 1993,212 543. 61 K. Hafner H.J.Linder W. Luo K. P. Meinhard! and T. Zink Pure Appf. Chem.1993,65 17. A.M. Doherty B.E. Kornberg and M.D. Rielly J. Org. Chern. 1993,58 795. 63 M. Leclaire S. Bathnagar and J.Y.Lallemand Bull. SOC. Chirn. Fr. 1993 130 310. I. J. Turchi J. B. Press J. J-McNally M. P. Bonner and K.L. Sorgi J. Org. Chem. 1993,58,4529. N. G. Ramsden (34) x =o,s have been studied e~perimentalIy.~~ The electrocyclic ring opening of singlet oxirane has been studied and it is suggested that the stereochemistry of oxirane cycloadditions is due to competition between a conrotatory asynchronous process and a single methylene rotation process.66 AM1 MO calculations of the reaction path for ring expansion of the cycIobutylideny1 carbene suggest that the process produces a lumomer of cyclopentyne rather than cyclopentyne Products obtained from subsequent cydoadditions are consistent with this.Further calculations on the reaction path of these [2 + 21 and [4 + 23 cycloadditions of the lumomer show concertedness for the former process and stepwise for the latter. Results are consistent with Dewar's theory of orbital isomerization.68 3 Other Reactions A [2,3] Wittig rearrangement via a concerted five-ring transition state has been accomplished overcoming a severe six-ring deformation barrier.69 Interactions of buta-1,3-diene with oxygen on a silver surface have been studied by extended Hiickei tight binding calculation^.^^ Interaction of a terminal carbon of the diene with surface oxygen gives an intemediate which undergoes preferential 1,4 ring closure to a tetrahydrofuran.Phenylchlorocarbene reacts with [I. l.l]propellane to give (35). There is nu evidence for a diradical intermediate as is found for the corresponding reaction of diphenyl~arbene.~' " T.Gob,S. Hammes and F.G. Klaerner Chem. Ber. 1993 126 485. 66 Y.Yamaguchi H. F. Schaefer 111 and I.L. Alberts J. Am. Chem. SOC. 1993,115 5790. 67 J.C. Gilbert and S.Kirschner Tetrahedron Lett. 1993 34,599. '* 3. C. Gilbert and S.Kirscbner TetrahedronLett. 1993 34,603. 69 Z. You and M. Koreeda Tetrahedron Lett. 1993 34>2597. 70 B. Schioett and K. A. Jorgensen J. Phys. Chem. 1993,W 10738. '' J.C. Scaiano and P. F. McGarry Tetrahedron Lett. 1993 34 1243.