4 Reaction Mechanisms Part (i) Pericyclic Reactions By N. G. RAMSDEN Glaxo Group Research Berkeley Avenue Green ford Middlesex UB6 OHE UK 1 Cycloadditions The topological approach to chemical reactivity in terms of second order similarity indices has been applied to a detailed analysis of correlation effects in pericyclic reactions.' A theoretical study of the intramolecular Diels-Alder reaction suggests that reactions leading to 6,s systems have considerable skew strain in the transition state. This is not seen in 6,6-forming reactions2 MM2 force field calculations have shown that transition state flexibility and conformational effects are the most important factors in determining the stereochemical outcome of these reaction^.^ y-N,N-Dibenzylamino-cr,p-didehydroaminoacid esters undergo cycloaddition reactions with diastereoselectivity opposite to that predicted by the principle of 1,3-allylic strain with addition to the most hindered face being refer red.^ Diastereofacial selectivity in Diels-Alder reactions of z,P-unsaturated esters with stereogenic functions containing oxygen occurs in an anti-Felkin-Ahn sense due to a combination of steric and electronic fact01-s.~ Methylene-lactones (1) undergo highly em selective Diels-Alder reactions with cyclopentadiene to give products with >99% enantiomeric excess; the exo selectivity may result from dipolar interactions.6 The Diels-Alder reaction of phthalimide (2)with enol ethers shows a very large increase in stereoselectivity towards the cis adduct as the pressure is increased.' The rate constant for the cis reaction appears to be under a far greater influence from substituents.The electronic effect of the trifluoromethyl group in (3) on the stereochemical outcome of the reaction is important as replacement with other substituents alters the stereochemistry of the product.* The Diels-Alder reaction of 2H-1,4-0xazin-2-ones with substituted olefins occurs with endo selectivity due to both secondary orbital interactions and repulsion ' R. Ponec and M. Strnad Int. J. Quantum Chem.. 1992 42 501. ' F. K. Brown U. C. Singh P. A. Kollman L. Raimondi K. N. Houk and C. W. Bock J. Org. Chern. 1992 57 4862. L. Raimondi F. K. Brown J. Gonzalez and K.N. Houk J. Am. Chem. SOC. 1992 114 4796. M.T. Reetz F. Kayser and K.Harms Tetrahedron Lett. 1992 33 3453. R. Casas T. Parella V. Branchadell A. Oliva R. M. Ortuno and A. Guingant Tetrahedron 1992,48,2659. ' W. R. Roush and B. B. Brown J. Org. Chem. 1992 57 3380. ' L. F. Tietze T. Huebsch J. Oelze C. Ott W. Tost G. Woerner and M. Buback Chem. Ber. 1992 125 2249. M. Suzuki T. Okada T. Taguchi Y. Hanzawa and Y. Iitaka J. Fluorine Chem. 1992 57 239. 45 N. G. Ramsden between the lactone and olefin substituents in the exo transition state.' The transannular Diels-Alder reaction of (4) occurs with high diastereoselectivity that can be rationalized by MM2 modelling of the transition state." A study of the reaction of (5) with cyclopentadienes both experimentally and theoretically indicates that steric factors alone cannot account for the stereoselectivity in asymmetric thermal Diels-Alder reactions.'' Electronic factors in the transition state must be important. Reactions of acroleins with cyclopentadiene catalysed by the chiral oxazaborolide (6) have been studied by NMR spectroscopy.'2 The structure of the complex of the catalyst with 2-methylacrolein shows that both indole and tosyl rings are crucial to enantioselectivity. The Diels-Alder reaction of (7) catalysed by (8) occurs via a 1 1 complex of aluminium and acryloyl oxygen.13 The C symmetric chiral enamine (9) undergoes cycloadditions with very high enantioselectivity. The intramolecular Diels-Alder reaction of silyl tethered reagents such as (10) is highly stereoselective and the geometry of the transition state appears to be constrained by the dienophile stereocentre.' [(Trimethylsilyl)ethynyl]-9-BBNreacts with acyclic dienes to give cyclohexadienes such as (1 1) with a meta relationship of diene- and boron-substituents.'6 Ab initio 0 +H RH Bu C. Fannes L. Meerpoel S. Toppet and G. Hoornaert Synthesis 1992 705. lo T. Takahashi Y. Sakamoto and T. Doi Tetrahedron Lett. 1992 33 3519. I' B. Stammen U. Berlage R. Kindermann W.S. Sheldrick P. Welzel W.R. Roth M. Kaiser and B. Guenther J. Org. Chem. 1992 57 6566. E. J. Corey,T. P. Loh T. D. Roper M. D. Azimioara and M. C.Noe J. Am. Chem. SOC.,1992,114,8290. l3 E.J. Corey S. Sarshar and J. Bordner J. Am. Chem. SOC. 1992 114 7938. l4 J. E. Backvall C. Lofstrom M. Maffei and V.Langer Tetrahedron Lett. 1992 33 2417. D. Craig and J.C. Reader Tetrahedron Lett. 1992 33 6165. l6 D. A. Singleton and S.W. Leung J. Ory.Chem. 1992 57 4796. Reaction Mechanisms -Part (i) Pericyclic Reactions Ph I CF$OzN NS02CF3 Al‘ I (9) calculations suggest that a [4 + 31 transition state with advanced bonding of boron to C-1 of the butadiene is involved. A further study on the reaction of butadiene with vinyl boranes suggests that the reaction proceeds via an endo transition state with very little charge separation or diradical character. ’’Furthermore calculations do not support the presence of Woodward-Hoffman type secondary orbital interactions. Ynamine esters and a$-unsaturated- 1,3-dicarbonyl compounds give funtionalized pyrans in a formal Diels-Alder reaction.’ Chemoselectivity is governed by steric factors.The heterocyclic Diels-Alder reaction between 1 -0xabutadienes and enol ethers gives dihydropyrans.” The reaction of ethylene with aza-and phos-phabutadienes has been examined with the aid of ab initio calculations.” The reactions of phosphabutadienes are characterized by lower activation energies and higher exothermicity. The difference between activation energy of (E)-and (2)-azabutadienes is greater than that for phosphabutadienes possibly due to the less diffuse phosphorus lone pair leading to less repulsion in the transition state. The transition state for the reaction of l-aza-l,3-butadiene with ethene has been compared with that for butadiene and ethene.21 The transition state for the reaction of 2-aza-1,3-butadiene has also been calculated and the effect of the aza group shown to be negligible.22 The rate and stereoselectivity of the reaction of cyclopentadiene and (-)-menthylacrylate has been measured in a variety of solvent~,~~ The empirical parameter a accounts for rate and diastereoselectivity changes but TC*and 6 need to be included to account for changes in the endolexo ratio.Solvent effects in the retro-Diels-Alder reaction suggest that the solvent acts as an electrophile lowering the activation energy of the reaction.24 The effect is similar to that in the Diels-Alder reaction suggesting D.A. Singleton J. Am. Chem. Soc.. 1992 114 6563. C. P. Dell Tetrahedron Lett. 1992 33 699. A. Celli M.Scotton and A. Sega Tetrahedron 1992 48 5883. lo S.M. Bachrach and M. Liu J. Org. Chem. 1992 57 6736. M. E. Tran Huu Dau J. P. Flamant J. M. Lefour C. Riche and D. S. Grierson Tetrahedron Lett. 1992,33 2343. *’ J. Gonzalez and K. N. Houk J. Org. Chem. 1992 57 3031. 23 C. Cativiela J. I. Garcia J. A. Mayoral A. J. Royo L. Salvatella X. Assfeld and M. F. Ruiz-Lopez J. Phys. Orq. Chem. 1992 5 230. 24 G. Desirnoni G. Faita D. Pasini and P. P. Righetti Tetrahedron 1992 48 1667. 48 N. G. Ramsden that the retro-Diels-Alder reaction has a late transition state and solvent effects derive from specific interactions. The Gibbs Free Energy profile of initial state and transition state for the reaction between cyclopentadiene and methyl vinyl ketone has provided an explanation for the enhancement of the rates of Diels-Alder reactions in the presence of water.25 The initial state appears to be destabilized as the transition state is relatively insensitive to changes in the solvent.The rate of Diels-Alder reactions in sodium and guanidinium salt solutions decreases as anion size increases approximat- ing to a Hofmeister series.26 It is surmised that contact between the organic solute and the electrolyte may be involved. The K-10 catalysed Diels-Alder reaction in the presence of polar water miscible solvents would appear to occur in the bulk solvent as the endolexo selectivity is However excellent selectivity is observed with non-polar solvents. Catalytic activity is very dependent upon the Lewis acidity of the cation exchanged onto the clay.The regioselectivity of the reaction between surfactant dienes and surfactant dienophiles appears to be controlled by alignment of reactants at a micelle-water interface.28 Semi-empirical and ab initio calculations for the reaction of indole radical-cations with cyclohexa-l,3-dienes suggest that attack occurs at the 3-position of the indole and have allowed the rationalization of experimentally observed regiosele~tivities.~~ The path of the Diels-Alder reaction between 173-butadiene cation-radical and ethene appears to be concerted non-synchronous and without activation in the gas phase.30 AM 1 and PM3 SCF-MO transition states for reactions involving carbodiimides reveal that the specificity of the reactions is due to substituent stereoelectronic,entropic and steric factor^.^' Ab initio calculations suggest that the reaction between isoxazole and ethene has an activation energy some 13 kcalt mol -greater than that for oxazole possibly explaining the lack of reactivity of isoxazoles in cycloadditions.32 An axiomatic model of the intramolecular Diels-Alder reaction of furans has been created based on the energetics of implicit transition states deduced from explicit conformations of products and reactants.33 The behaviour of pentadienoic acids in cycloaddition reactions together with the effect of cross conjugation has been in~estigated.~~ The mechanism of the Staudinger reaction continues to be a subject of debate. The reaction of ketene and methylenimine has been studied by RHF/3-21G and IRC and results point to a non-synchronous concerted reaction via a twisted transition state.35 Four n-orbitals are involved in a 2 x [I1 + 11 type cycloaddition and rotation is of the methylene rather than the oxygen of the ketene.However other studies suggest that the reaction is not concerted and proceeds via a zwitterionic intermediate formed by nucleophilic addition of the imine to the ketene.36 The cycloaddition of ketene and 1kcal = 4.184kJ. 25 W. Blokzijl and J. B. F.N. Engberts J. Am. Chem. Soc. 1992 114 5440. 26 C. J. Rizzo J. Org. Chem. 1992 57 6382. 27 C. Cativiela J. M. Fraile J. I. Garcia J. A. Mayoral F. Figueras L. C. De Menorval and P. J. Alonso J. Catal. 1992 137 394. D.A. Jaeger and J. Wang Tetrahedron Lett.1992 33 6415. 29 0.Wiest E. Steckhan and F. Grein J. Org. Chem. 1992 57,4034. 30 N.L. Bauld J. Am. Chem. Soc. 1992 114 5800. 31 H. S. Rzepa P. Molina M. Alajarin and A. Vidal Tetrahedron 1992 48 7425. 32 J. Gonzalez E.C. Taylor and K.N. Houk J. Org. Chem. 1992 57 3753. 33 D. P. Dolata and L. M. Harwood J. Am. Chem. Soc. 1992 114 10738. 34 V. Branchadell A. Oliva R. M. Ortuna S. Rafel and M. Ventura Tetrahedron 1992 48 9001. 35 D. Fang and X. Fu Int. J. Quantum Chem. 1992 43 669. 36 J.A. Sordo J. Gonzalez and T. L. Sordo J. Am. Chem. SOC. 1992 114 6249. Reaction Mechanisms -Part (i) Pericyclic Reactions formaldehyde to give 2-oxetanone proceeds by a non-synchronous but concerted mechanism involving a four-membered transition state.37 The reaction of allenes with tert-butylthioacrylonitrile (BTA) suggests that a diradical intermediate is formed by an allene-HOMO-BTA-LUMO intera~tion.~~ Formation of the diradical intermediate is irreversible but closure is not as product distribution appears to be under thermodynamic control.The cycloaddition of methyl propiolate with enantioenriched 1,3-dimethylallene results in 40% of the enantiomeric excess being transferred to the cycloadd~cts.~~ This has been explained by initial formation of the anti syn diradical intermediate (12) which then preferentially closes to the syn-methyl-substituted end of the ally1 radical. The most reasonable interpretation for the results of the reaction between 1,3-dimethylallene and 1,l-dichloro-2,2-difluoroethene involves reaction uia one major continuous low energy pathway uia a similar intermediate.40 Reaction of 1,l-diphenylethene with 1,3-dimethylallene does not lead to cycloadducts but racemization of the allene occurs suggesting that radical formation is reversible.The trapping of zwitterionic intermediates in [2 + 21 cycloadditions has been reported. Phenylselenide (13) reacts with activated alkenes under Lewis acid catalysis to give the cyclobutanes (14) with selenium and acyl substituents cis.41 However in the presence of water Me,SiCO(CH,),COR is formed. The cycloaddition of (15) with HC-CCO,Me occurs via a 1,4-dipole that has been trapped with both methyl propiolate and tert-b~tanol.~’ 37 D.C. Fang and X. Y. Fu Chin. Chem. Lett.1992 3 367. D.J. Pasto and W. Kong J. Phys. Org. Chem. 1992 5 160. 39 D. J. Pasto K. D. Sugi and D. E. Alonso J. Org. Chem. 1992 57.1146. 40 D. J. Pasto and K. D. Sugi J. Org. Chem. 1992 57 12. 41 S. Yamazaki H. Fujitsuka S. Yamabe and H. Tamura J. Ory. Chem. 1992 57 5610. 42 M. L. Graziano M. R.Iesce F. Cermola and G. Cimminiello J. Chem. SOC.,Perkin Trans. I 1992 1269. N. G. Ramsden Molecular fluorine adds to ethylenes in a cis fashion and a mechanism based on HOMO-LUMO interactions of the weak fluorine bond has been proposed.43 (Me,CCO),C=C=O usually dimerizes to give a [2 + 41 dimer. However in the presence of DMSO Bu3P0 or pyridine dimerization occurs across the C=O of the ketene.44 Carbocation-activated olefins add to unactivated olefins in a [2 + 21 cycloaddition to give cycl~butanes.~’ These reactions support the formation of the second C-C bond in the stepwise cycloaddition of allyl cations to 1,3-dienes in a formal Diels-Alder sense.The synchronicity regioselectivity and transition states for the reaction of CH,=N+H-O-with alkenes have been obtained by MO calculation^.^^ Force field models for nitrile oxide cycloadditions account for the observed diastereoselectivity in reactions controlled by steric factors.47 MM2 parameters based on ab initio transition states for intramolecular addition of nitrile oxides to allyl ethers have been developed.48 The regiospecificity of the intramolecular cyclization of N-3 butenyl nitrones is determined by the contribution of activation enthalpy and entropy to two similar parallel reaction pathway^.^' The regiochemical course of cycloadditions of C,N-diary1 nitrones to a,B-unsaturated esters and lactones has been explained.’’ A transition state for the reaction of non-stabilized azomethine ylids with olefins has been pr~posed.~’ It is suggested that chelation to lithium forms a rigid transition state with the largest substituent anti to the approaching olefin.Reactions of substituted 1,2,3-triazolin-1 -imides with dipolarophiles are dipole-HOMO controlled concerted cycl~additions.~~ Benzyl cations react with styrenes in a formal [3 + 21 cy~loaddition.’~ This occurs uia a transition state (16) which minimizes non-bonded interactions and allows some degree of n-n interaction. Methylene cyclopropene (17) reacts in a [3 + 21 cycloaddi- tion with electron deficient 01efins.’~ The stereochemical outcome suggests that the reaction occurs via an endo transition state.The loss of stereoselectivity in polar 43 T. Iwaoka H. Ichikawa and C. Kaneko Chem. Pharm. Bull. 1992,40 1969. 44 C.O. Kappe G. Faerber C. Wentrup and G. Kollenz J. Org. Chem. 1992 57 7078. 45 P. G. Gassman and A. C. Lottes Tetrahedron Lett. 1992 33 157. 46 Y. L. Pascal J. Chanet-Ray R. Vessiere and A. Zeroual Tetrahedron 1992 48 7197. 47 F.K. Brown L. Rairnondi Y. D. Wu and K.N. Houk Tetrahedron Lett. 1992 33,4405. 48 L. Raimondi Y. D. Wu F. K. Brown and K.N. Houk Tetrahedron Lett. 1992 33 4409. 49 S. Ma and X. Fu Huaxue Xuebao 1992,50 811. A. Banerji and S. Basu Tetrahedron 1992 48 3335.G. Negron G. Roussi and J. Zhang Heterocycles 1992 34 293. 52 R.N. Butler F. A. Lysaght and L. A. Burke J. Chem. Soc. Perkin Trans. 2 1992 1103. 53 S.R.Angle and D. 0.Arnaiz J. Org. Chem. 1992 57 5937. 54 S. Ejiri S. Yamago and E. Nakamura J. Am. Chem. Soc. 1992 114 8707. Reaction Mechanisms -Part (i) Pericyclic Reactions solvents suggests that this transition state is polar. 2-Substituted oxazoles react with ethenetetracarbonitrile in a formal [3 + 21 cycloaddition.’’ The reaction is suggested to proceed uia oxazole opening and a zwitterionic intermediate. 2 Sigmatropic Reactions The pericyclic module of CAMEO has been expanded to include both ene and retro-ene reactions 56 whilst the MM2 force field has been modified to rationalize and predict the stereochemical outcome of intramolecular ene reactions.57 Predictions are good for all except activated enophiles. The effect of pressure on the rate constants of ene reactions can be described by a linear free-energy type relationship.’* This points to the reaction being non-concerted. Ene reactions of substrates such as RO,CCOOCOCO,R with olefins give the expected products whose stereochemistry suggests a stepwise ionic me~hanism.’~ This view is supported by a study of intermolecular primary and secondary isotope effects in the ene reaction of tiglic acid derivatives with N-phenyl-l,2,4-triazoline-3,5-dione or singlet oxygen.60 Product ratios in the rearrangement of (18) and (19) to (20) and (21) vary significantly indicative of a substantial isotope effect in this ene reaction.61 MeCH=C(SMe)CH,OTBDMS reacts with aldehydes under Lewis acid catalysis to give syn or anti adducts with high stereoselectivity.62 It is proposed that the reaction proceeds uia a 6-membered chair-like transition state.55 T.Ibata ‘. Isogami H. Nakawa H. Tamura H. Suga X. Shi and H. Fujieda Bull. Chem.SOC.Jpn. 195 65. 1771. 56 G.’D. Paderes and W. L. Jorgensen J. Org. Chem. 1992 57 1904. ” B. E. Thomas IV R. J. Loncharich and K. N. Houk J. Org. Chem. 1992,57 1354. ’’ B. El’yanov E. M. Gonikberg and G. Jenner J. Chem. SOC.,Perkin Trans. 2 1992 137. 59 P. Bleak Z. Song and J.E. Resek J. Org. Chem. 1992 57 944. “ Y. Elemes and C. S. Foote J. Am. Chem. SOC. 1992 114 6044. 61 J.A. Marshall and M.W.Andersen J. Org. Chem. 1992,57 5851. T. Nakamura K. Tanino and I. Kuwajima Chem. Lett. 1992 1425. N. G. Ramsden Two theoretical studies on the rate acceleration of the Claisen rearrangement of allyl vinyl ethers in aqueous solvents have been reported. The free-energy-of-hydration profile obtained by Monte Carlo methods suggests that the transition state is some 3.85 kcal mol- better hydrated than reactant due to the presence ofan extra hydrogen bond.63 This does not reflect charge transfer to an enolate/allyl cation pair but rather increased exposure of the oxygen to the solvent. An SCF solvation method has also been used.64 Similar findings were made and the reaction energetics appear to be very sensitive to substituent effects. The organoaluminium promoted Claisen rearrange- ment of allyl vinyl ethers has also been studied e~perimentally.~~ The observed (E)and (2) stereoselectivity is best explained by two chair-like transition states with substituents axial or equatorial.Both (22)66 and 1,2,6,7-cyclodecatetraene6'have been investigated as substrates in the Cope rearrangement. In each case the d,l-isomer must react via a chair-like transition state whilst the meso isomer is constrained to react via a boat-like transition state. For (22) kd,,/k,,, = 7 x lo6 and it appears that secondary orbital interactions are of little importance in determining this ratio. The d,l-isomers may react via competing non-concerted and concerted processes. Compound (23) reacts on treat- ment with base via a p-dienone intermediate.68 Geometrically pure 1,5-heptadiene- 3-01s undergo anionic oxy-Cope rearrangement^.^' The stereochemistry is under exclusive control of oxyanion orientation with -60% preference for equatorial oxygen due to disfavoured 1,3-diaxiaI interactions.The phospha-Cope reaction of (24) appears to be preceded by a pre-equilibrium between tetra- and pentacoordinate phosph~rus.~' OH 0 I R 63 D. L. Severance and W. L. Jorgensen J. Am. Chem. SOC. 1992 114 10966. 64 C.J. Cramer and D.G. Truhlar J. Am. Chem. Soc. 1992 114 8794. 65 K. Nonoshita K. Maruoka and H. Yamamoto Bull. Chem. SOC. Jpn. 1992 65 541. 66 K. J. Shea G. J. Stoddard W. P. England and C.D. Haffner J. Am. Chem. SOC. 1992 114 2635. 67 W.R. Roth T. Schaffers and M. Heiber Chem.Ber. 1992 125 739. 68 S. Raghavan and G.S. R. Subba Rao Tetrahedron Lett. 1992 33 119. 69 L.A. Paquette and G. D. Maynard J. Am. Chem. SOC.,1992 114 5018. 'O T. Kawashima D. J. Park S. Murata R. Okazaki and N. Inamoto Chem. Lett. 1992 1607. Reaction Mechanisms -Part (i) PericycIic Reactions Electrocyclic openings of cyclobutenes have been studied by both theoretical and experimental techniques. Opening of benzocyclobutene to o-xylyene has been examined by ab initio MO techniques and torqueselectivity theories appear to be applicable.’ Torqueselectivity results in cyclobutene (25) opening in a formyl-in ester-out mode.72 Cyclobutene (26) opens to give the expected product (27)together with the hexahydronapthalene (28).73This product does not arise by a concerted 1,3-shift.1,5-Sigmatropic rearrangements of CH,=CHCH=CHCH,X investigated by MO theory suggest that when X does not possess a lone pair the shift is suprafacial but when X does possess a lone pair the antarafacial pathway is electronically favoured.74 Upon heating benzylidene cyclobutanols undergo electrocyclic ring opening to allenes. Subsequent reactions are dependant upon starting material structure.75 71 C. W. Jefford G. Bernardinelli. Y. Wang D. C. Spellmeyer A. Buda and K. N. Houk J. Am. Chem. Soc. 1992 114 1157. ’’ S. Niwayama and K. N. Houk Tetrahedron Lett.. 1992 33 883. 73 G.C. Paul and J. J. Gajewski J. Org. Chem. 1992 57. 1970. l4 I. Lee B.S. Lee N. D. Kim and C. K. Kim Bull. Koreun Chem. Soc,.. 1992 13 565. ’’ J.E. Ezcurra C. Pham and H.W. Moore J. Org. Chem. 1992 57 4787.