7 Aromatic Compounds By R. McCAGUE Drug Development Section Institute of Cancer Research Sutton Surrey SMZ 5NG 1 General and Theoretical Studies Benzene.-The year 1987 has seen the appearance of articles that aim to consolidate the controversial casting aside of molecular orbital theory in favour of valence-bond theory to describe the electronic structure of benzene.’-3 It is using a valence-bond correlation model that Hiberty et al. have emphasized that electron delocalization in benzene occurs in spite of the nelectrons it being a consequence of imposed constraint by the cr-framew~rk.~ Thus the exceptional stability of benzene is because of the unusual property of its 7r-system in allowing the u-framework to achieve bond equality. However Kataska and Nakajuma point out that there is still a place for rr-electron delocalization energy since it correlates well with the experimental resonance en erg^.^ Regarding experimental determinations of the structure of ben- zene Ermer has given a caution; that a D6hstructure for benzene as opposed to a distorted Qhstructure cannot be deduced from an X-ray crystal structure owing to the effects of time and space averaging.6 This should be an important consideration when examining the structure of other delocalized species (e.g.higher annulenes) by X-ray crystallography. Indeed none of the present experimental evidence is considered rigorously to exclude a D3,,structure for benzene.6 In the light of this work new ab initio quantum mechanical calculations show a symmetrical D6, structure is preferred and that there is no minimum energy distorted structure although the amount of energy required for distortion to localized single and double bonds is only 8 kcal m01-l.~ [1,2-I3C2] Benzene prepared from 1,4-dichIorobutane and [13C]cyanide was subjected to high temperature automerization.A benzvalene mechanism has been proposed to explain the redistribution of the isotopic labels (Scheme 1).8 The thermal isomerization of benzocyclobutane to styrene is interesting because a proportion of carbon-13 label from a methylene group becomes incorporated into the aromatic ring. Cleavage to form an aryl radical is only a minor pathway; the principal J. Gerratt Chem. Brit. 1987 327. ’ L,.Pauling Nature (London) 1987 325 396.J. Maddox Nature (London) 1987,327 551. S. S. Shaik P. C. Hiberty J.-M. Lefour and G. Ohanessian J. Am. Chem. SOC.,1987 109 363. M. Kataoka and T. Nakajima J. Org. Chem. 1987 52 2323. 0. Ermer Angew. Chem. Znt. Edn. Engl. 1987 26 782. ’ R. Janoschek Angew. Chem. Znt. Edn. Engl. 1987 26 1298. L. T. Scott N. H. Roelofs and T.-H. Tsang J. Am. Chem. Soc. 1987 109 5456. 157 158 R. McCague * * * I Scheme 2 H H Scheme 3 mechanism has a cyclohepta-l,2,4,6-tetraeneas an intermediate (Scheme 2).9 The cycloheptatetraene can also be formed by thermolysis or photolysis of phenyl- diazomethane." Calculations on the cyclization of a dienyne radical to the phenyl radical (Scheme 3) reveal a high relative stability for the phenyl radical and an activation energy of only 19 kcal mol-'." The ring closure might be important in soot nucleation.A new dimer of benzene (1) has been isolated. It is thermally more stable than its anti-isomer.'2 Hexa-substituted benzenes of interest are hexakis(di-chloromethyl) benzene which is like hexaisopropylbenzene in having gear meshed groups around the ring,13 and tris(ethylenedithio)benzene which together with related compounds give conducting fluoroborate radical cation salts which might be candidates for an organic ferr~magnet.'~ 0. L. Chapman U.-P. E. Tsou and J. W.Johnson J. Am. Chem. SOC.,1987 109 553. 10 R. J. McMahon C. J. Abelt 0. L. Chapman J. W. Johnson C. L. Kreit J.-P. LeRoux A. M. Mooring and P. R. West J. Am. Chern. SOC.,1987 109 2456.I' M. J. S. Dewar W. C. Gardiner Jr. M. Frenklach and I. Oref J. Am. Chem. SOC.,1987 109 4456. l2 N. C. Yang B. J. Hrnjez and M. G. Homer J. Am. Chem. SOC.,1987 109 3158. B. Kahr S. E. Biali W. Schaefer A. B. Buda and K. Mislow J. Org. Chem. 1987 52 3713. 14 R. Lapouyade and J.-P. Morand J. Chem. SOC.,Chem. C'ommun. 1987 223. Aromatic Compounds 159 Homoaromaticity.-An example of three-dimensional homoaromaticity is the 27r 1,3-dehydr0-5,7-adamantanediyldication (2) which has been prepared by superacid- induced fluoride ion abstraction from 1,3-dehydr0-5,7-difluoroadamantane. It has a remarkable carbon-13 n.m.r. spectrum in which the bridged carbon atoms (6 6.6) are at lower frequency than the methylene carbons (6 35.6) despite the positive charges and in which the carbon-proton coupling constants indicate a strong deformation of the framework the bridgehead carbon atoms being drawn in towards the centre of the m~lecule.’~ The dication (3) is a sandwiched bis-homoaromatic system.It has highly shielded shifts in its carbon-13 n.m.r. spectrum.16 On the other hand studies with anionic systems have failed to provide evidence for homo- aromati~ity.’~”~ 2 Construction of the Benzene Ring from Non-aromatic Precursors uia Diels-Alder Cyc1oaddition.-Warrener et al. have advanced the concept of ‘Transfer Technology’.’’ They give as an example the use of quadricycline as an acetylene equivalent in the synthesis of 1 ,Cdisubstituted benzenes bearing electron- withdrawing groups (Scheme 4).C02Me C02Me C02Me I C02Me C02Me C02Me Scheme 4 The Diels-Alder approach is often chosen for the synthesis of highly substituted benzenes. Suitable heterocycles react with acetylenes to give benzenes directly. The most popular are the a-pyrones which yield the benzene ring on elimination of the carbon dioxide from the initial add~ct.~~~~ Since the synthesis of the a-pyrones can start from sodium acetate this methodology allows the preparation of heavily substituted products with specific isotopic labelling of the ring by 2H 3H 13C or 14c.24 An intramolecular Diels- Alder reaction to a 1,2-diazine (elimination of nitrogen) has been used in a synthesis of the components PDEI and PDEII of the c-AMP phosphodiesterase inhibitor CC-1065.The diazines are themselves prepared from an inverse electron demand Diels- Alder reaction of a 1,2,4,5-tetrazine-3,6- dicarboxylate (Scheme 5).24 l5 M. Bremer P. von R. Schleyer K. Schotz M. Kausch and M. Schindler Angew. Chem. Znt. Edn. Engl. 1987 26 761. 16 G. K. S. Prakash M. Farnia S. Keyanian G. A. Olah H. J. Kuhn and K. Schaffner J. Am. Chem. SOC.,1987 109 911. G. Jonsall and P. Ahlberg J. Chem. SOC. Perkin Trans. I 1987 461. l8 G. Trimitsis F.-T. Lin R. Eaton S. Jones M. Trimitsis and S. Lane J. Chem. Soc. Chem. Commun. 1987 1704. 19 R. N. Warrener R. A. Russell R. Solomon 1. G. Pitt and D. N. Butler Tetrahedron Lett. 1987,28,6503. 20 D. L. Boger and M. D. Mullican Org. Synfh. 1987 65 98. 21 S. A. Ahmed E. Bardshiri and T. J. Simpson J.Chem. SOC.,Chem. Commun. 1987 883. 22 A. Ichihara K. Murakami and S. Sakamura Tetrahedron 1987 43 5245. 23 T. Ziegler M. Layh and F. Effenberger Chem. Ber. 1987 120 1347. 24 D. L. Boger and R. S. Coleman J. Am. Chem. SOC.,1987 109 2717. 160 R. McCague Me2Bu'Si0 N-N N?N= -3 Me0,C-f \tCO,Me N=N VN COMe Me0 COMe 230 "C I OSiBu' Me2 \ COMe COMe Me0 COMe Me0 COMe Scheme 5 A particularly interesting synthesis is of a precursor of Fredericamycin A in which the substituted furan was itself prepared by a Diels-Alder cycloaddition and which demonstrates the use of an allene rather than an acetylene as the 2~-component (Scheme 6).25 ' N-o + Ill A -MeCN *Et &Me MeOX OEt 1Bu'OCH,CH=C=CHCO,Me 1.TiCI, u' LiAIH, Et,N. TH F 4 2. O, Me,& CH,CI C02Me EtO Scheme 6 Advances have been made in the use of acyclic dienes. In the reaction of l-acetoxy-3-methyl-(E)-buta-l,3-diene and p-phenylsulphonylacrylate esters the regiochemistry of addition depends on the stereochemistry of the acrylate the 2 and E acrylates give after aromatization of the adducts the meta-and para-toluates respectively.26 A useful diene which had been previously difficult to obtain is 2,3-dicarbomethoxy- 1,3-butadiene. It is conveniently prepared by flash vacuum thernolysis of its anthracene adduct and gives benzene-l,2-dicarboxylatesafter 25 A. V. R. Rao and D. R. Reddy J. Chem. SOC.,Chem. Commun. 1987 574. 26 A. D. Buss G.C. Hirst and P. J. Parsons J.Chem. Soc. Chem. Commun. 1987 1836. Aromatic Compounds Reagents i LiNPr; THF; ii PriSiCI; iii r-CO,Me 150 "C 4 h; iv KF MeOH Scheme 7 reaction with suitable acetylenes followed by ~xidation.~' Alkenyl ketimines have been used in a synthesis of anilines (Scheme 7).28 via Cyc1ocondensation.-Numerous methods have emerged for the synthesis of the benzene ring by cyclocondensation and sulphur substituents that are either lost on aromatization or later removed are particularly useful for activating one of the reacting component^.^^-^' Scheme 8 gives an example. Pyridinium substituents have been similarly employed in a synthesis of chalcone derivative^.^^ SMe ~ R'QSMe Et20 R'WSMe BF,.Et,O MeOH 1 OMe OMe Scheme 8 Frequently used components have extended conjugation such as a,p ;y,S-unsatur-ated aldehydes and An example is an intramolecular Wittig reaction that leads to benzenes bearing perfluoroalkyl groups (R,) (Scheme 9).36 The intramolecular cyclization of large ring dienynyl triflates on solvolysis gives benzo- cycloalkanes (Scheme 27 B.Tarnchompoo C. Thebtaranonth and Y. Thebtaranonth Tetrahedron Lett. 1987 28 6671. 28 E. Differding 0. Vandevelde B. Roekens T. T. Van and L. Ghosez Tetrahedron Lett. 1987 28 397. 29 A. K. Gupta H. Ila and H. Junjappa Tetrahedron Lett. 1987 28 1459. 30 L. W. Singh H. Ila and H. Junjappa Synthesis 1987 873. 31 Y. Ozaki and S.-W. Kim Chem. Lett. 1987 1199. 32 K. Eichinger P. Nussbaumer S. Balkan and G. Schulz Synthesis 1987 1061.33 M. H. Nantz and P. L. Fuchs Synth. Commun. 1987 17 761. 34 M. S. C. Rao and C. S. K. Rao Synthesis 1987 231. 35 D. Stossel and T. H. Chan J. Org. Chem. 1987 52 2105. 36 W. Ding P. Zhang and W. Cao Tetrahedron Lett. 1987 28 81. 37 M. Hanack and R. Rieth Chem. Ber. 1987 120 1659. 162 R. McCague C02Me Ph,P=CH-CH=CH-C0,Me + -ph31f('Jc02Me Rf-C=C-C02Me Rf \ / -Scheme 9 R = Et or CH2CF Scheme 10 Metal Complex Promoted Benzene Ring Formation.-Vollhardt et al. have demon- strated the synthesis of a 5-phenylene by cobalt complex catalysed co-cyclization (Scheme 1 l).38The central ring in the 5-phenylene is highly susceptible to cycloaddi- tion. The failure of an analogous approach to a 6-phenylene would indicate an upper limit to the stability of phenylene~.~~ A simple procedure for cyclotrimerization of alkynes uses a palladium catalyst activated by chlorotrimethylsilane.39 SiPr I Me3Si 51me3 Me3Si Reagents i + (C5H5)Co(CO), DMF; ii Bu4N+F-; iii Me3Si-C%C-SiMe3 (C5cH5)Co(CO)2 ,-THF CuCl-2Hz0 MeOCH,CH,OMe NEt3 Scheme 11 A malecylcobalt complex prepared from dimethyl squarate reacts with alkynes under Lewis acid catalysis to provide q~inones.~' Manganese(111) mediates the radical cyclization of methyl-3-0~0-6-heptenoateto give methyl salicylate in 94% 38 L.Blanco H. E. Helson M. Hirthammer H. Mestdagh S. Spyroudis and K. P. C. Vollhardt Angew. Chem. Int. Edn. Engl. 1987 26 1246. 39 A. K. Jhingan and W. F. Maier J. Org. Chem. 1987 52 1161.40 S. Iyer and L. S. Liebeskind J. Am. Chem. Soc. 1987 109 2759. Aromatic Compounds 0 OH (u" Mn(OAc) Cu(OAc) KOAc CO,Me 94% AcOH. 50 "C Scheme 12 yield (Scheme 12).41 If the terminus of the double bond in the substrate is substituted then a cyclopentenone becomes the preferred product. Other Methods.-A benzene ring annulation utilizing an electrocyclic ring closure has been used to convert tetralone into a 9,lO-dih~drophenanthrene.~~ 2-Bromo-3-methoxycyclohex-2-enone has been shown to be useful as a 3-hydroxyphenyl cation equivalent to arylate lactams in the synthesis of the analgesic drug meptazinol. Aromatization takes place on acid treatment of the add~ct.~~ 3 Substitution in the Benzene Ring Electrophilic Substitution.-Mechanistic Studies.Eberson and Radner have reviewed the matter of whether the a-complex (Wheland intermediate) in aromatic nitration is formed by way of electron transfer (Le. ArH + NO; -* ArH+' + NOz) followed by radical-pair ~ombination.~~ They conclude that in the nitration of naphthalene at least the radical pair does not lie on the pathway to the a-intermediate; an electron transfer mechanism being disfavoured because of the bond reorganization energy required to transform NO; (planar) into NO; (bent). When radical cations do form it is proposed that they do so by homolysis of the a-complex.& Interestingly the rearrangement of nitroanilines in sulphuric acid is suggested to involve migration of nitrogen dioxide rather than the nitronium ion.45 In this reaction it is the migration rate and not the protonation that is rate determining.When nitric oxide is present as a catalyst in nitration Eberson and Radner have noted that radical formation is favoured since bond reorganization is not required for this agent.& Indeed carbon-13 polarization has been demonstrated in the nitrous acid catalysed nitration of giving strong evidence for the intermediacy of the phenoxyl radical. In the reaction of arenes with nitrate radical prepared by photolysis of ammonium nitrate solution electron transfer is favoured because both the nitrate radical and anion are planar.47 However Kochi finds that radical pairs generated by laser flash photolysis of complexes formed between dialkoxybenzenes and tetranitromethane give rise to the same products as in nitration under classical conditions indicating that radical cations may be important for these electron-rich substrate^.^^'^^ 4' J.R. Peterson R.S. Egler D. B. Horsley and T. J. Winter Tetrahedron Lett. 1987 28 6109. 42 T. L. Gilchrist and R. J. Summersell Tetrahedron Lett. 1987 28 1469. 43 R. G. Shepherd and A. C. White 1. Chem. Soc. Perkin Trans. 1 1987 2153. 44 L. Eberson and F. Radner Acc. Chern. Rex 1987 20 53. 45 J. T. Murphy and J. H. Ridd J. Chem. SOC.,Perkin Trans. 1 1987 1767. 46 M. Ah J. H. Ridd J. P. B. Sandall and S. Trevellick 1. Chem. Soc. Chem. Commun. 1987 1168. 47 E. Baciocchi T. D. Giacco S. M. Murgia and G. V. Sebastiani J. Chem. SOC.,Chern. Comrnuri.,1987 1246. 48 S.Sankararaman W. A. Haney and J. K. Kochi J. Am. Chem. Soc. 1987 109 5235. 49 S. Sankararaman W. A. Haney and J. K. Kochi J. Am. Chem. Soc. 1987. 109 7824. 164 R. McCague In a theoretical study of the nitration of benzene the nitro a-intermediate is calculated to have biradicaloid character and to be favoured over the nitrito u-complex only because of s~lvation.~' However in a study of electrophilic aromatic nitration in the gas phase by protonated methyl nitrate this system is concluded to act as a well behaved electrophilic substitution in good analogy with the liquid phase reaction.51 Yet in the gas phase it has been observed that nitration of anisole is slow relative to that of toluene and this is explained by the formation of an early ion-molecule complex.52 In the gas phase alkylation of dihalogenobenzenes by free isopropyl cations peculiarities in the orientation of electrophilic attack are attributed to interactions between cations and radical^.'^ When mercuration is promoted by photolysis arene radical cations are formed as evidenced by mercury- 199 hyperfine coupling in the e.s.r.spectrum.54 Electron transfer has been discounted for elec- trophilic attack by Br+ C1+ CH3CO+ and HgR+ under solution conditions since the reaction rates depend on the stability of the o-c~mplexes.~~ Effenberger et al. have studied the structure and reactivity of some aromatic o-complexes that are particularly stable such as that obtained by bromination of 1,3,S-tripyrrolidinobenzene.The cyclohexadienylium ring in these complexes can be either planar or bent depending on the substituents and since when the ring is bent only the axial ligand can dissociate these complexes can have high stability owing to the high energy barrier to the proton taking up an axial position where it can leave.56 Tricarbonylchromium complexation of an arene has been shown to deactivate the ring only to a small extent towards Friedel-Crafts a~etylation.~'A tri-fluoromethoxy substituent is ortho-para directing by the resonance effect but electron withdrawing by the inductive effect resulting in a strong predominance for para-substitution since the inductive effect diminishes with distance.58 Synthetic Procedures.Regioselective 4-chlorination of anisole ( p/ o > 30) has been achieved with copper(r1) chloride on a neutral alumina support.59 With N-chlorodialkylamines where R,NH+Cl are the active electrophiles even more impress- ive regioselectivity (p/ o up to 500) has been accomplished.60 Halogenation of phenols and their ethers can be simply carried out with the potassium halide and meta-chloroperoxybenzoicacid in the presence of 18-Crown-6.Iodination is success- ful only if there is more than one substituent activating the ring.61 A potentially useful brominating agent for deactivated arenes is bromine monofluoride which is '' J. T. Gleghorn and G. Torossian J. Chem. SOC.,Perkin Trans. 2 1987 1303. 51 M. Attina F. Cacace and M. Yanez J. Am. Chem. SOC.,1987 109 5092. 52 M. Attina F. Cacace and G. de Petris Angew.Chem. Znt. Edn. Engl. 1987 26 1177. 53 B. Aliprandi F. Cacace and S. Fornarini Tetrahedron 1987 43 2831. 54 J. L. Courtneidge A. G. Davies P. S. Gregory D. C. McGuchan and S. N. Yazdi J. Chem. SOC.,Chem. Commun. 1987 1192. 55 E. Baciocchi and L. Mandolini Tetrahedron 1987 43 4035. 56 F. Effenberger F. Reisinger K. H. Schonwalder P. Bauerle J. J. Stezowski K. H. Jogun K. Schollkopf and W.-D. Stohrer J. Am. Chem. SOC.,1987 109 882. 57 J. L. von Rosenberg and A. R. Pinder J. Chem. SOC.,Perkin Tars. I 1987 747. 58 G. A. Olah T. Yamoto T. Hashimoto J. G. Shih N. Trivedi B. P. Singh M. Piteau and J. A. Olah J. Am. Chem. SOC.,1987 109 3708. 59 M. Kodomari S. Takahashi and S. Yoshitomi Chem. Lett. 1987 1901. 60 J. R. L. Smith L. C. McKeer and J.M. Taylor J. Chem. SOC.,Perkin Trans. 2 1987 1533. 61 M. Srebnik R. Mechoulam and I. Yona J. Chem. SOC.,Perkin Trans. 1 1987 1423. Aromatic Compounds 165 prepared from the elements. Ethyl benzoate is rneta-brominated in 95% yield at -45 "C; a Lewis acid not being required.62 Fluorination can be accomplished with N-fluoroperfluoroalkylsulphonimides[e.g. (CF3S02)*NF] but electron-deficient arenes do not react.63 Good para-preference in the nitration of halogenobenzenes is obtained with copper(I1) nitrate on K10 montmorillonite in the presence of acetic anhydride. The improved regioselectivity correlates with a lowering of dielectric constant of the medium.64 Useful agents for the nitration of highly activated substrates are nitrocyc- lohexadienes prepared by ipso-nitration of 2,4,6-trisubstituted phenols.These reagents give much less oxidation than nitric acid in the nitration of l-na~hthol.~~ Electrophilic amination is possible by photolysis with 1 -amino-2-methyl-4,6- diphenylpyridinium tetrafluoroborate. The reaction proceeds uia nitrene or nitrenium ion singlets causing poor positional selectivity owing to the high reactivity of these species.66 For the ethylation of benzene by ethylene trifluoromethanesul- phonic acid is better than aluminium chloride fluorosulphonic acid or sulphuric acid.67 Allylation can be carried out with the cationic iron complex (T~-allyl)Fe(CO)zBF as the electrophile. The method has been used to attach an isoprenyl side chain.68 A useful procedure for introducing a carboxylic acid function is to treat the arene with chloral in the presence of aluminium chloride and then to cleave the two-carbon chain with basic hydrogen peroxide.69 The normal tendency of Friedel-Crafts ring-closure to be directed para to an activating alkoxy substituent can be redirected ortho by incorporation of a trimethyl- silyl group into the position where ring closure is desired.70 The t-butyl group is useful for the blocking of sites on the aromatic ring to prepare 1,2,3-trisubstituted benzenes.An example is in a preparation of [2.2]meta~yclophanes.~~ The resin- supported superacid Nafion H is an alternative to Lewis acids for removal of the t-butyl group.72 Nucleophilic Substitution.-Mechanistic Studies. An encounter complex of the charge-transfer type has been invoked to explain the second-order dependence of rate on nucleophile concentration in substitution reactions of 1,2,3,5-tetranitroben-zene 2,4,6-trinitrofl~orobenzene,~~ 1,2-dinitroben~ene.~~ and When nucleophilic substitution is photoinduced the mechanism can be either classical nucleophilic substitution (S,Ar) on the activated arene or can involve initial electron-transfer from the nucleophile.Which mechanism occurs is dependent on the nucleophile. With 1 -methoxy-4-nitronaphthalene primary amines displace the nitro group by an S,Ar mechanism and the more electron-rich secondary amines displace the methoxy 62 S. Rozen and M. Brand J. Chem. SOC.,Chem. Commun. 1987 752. 63 S. Singh D. D. Desmarteau S. S.Zuberi M. Witz and H.-N. Huang J. Am. Chem. Soc. 1987,109,7194. 64 P. Laszlo and P. Pennetreau J. Org. Chem. 1987 52 2407. 65 M. Lamaire A. Guy J. Roussel and J.-P. Guette Tetrahedron 1987 43 835. 66 H. Takeuchi J. Chem. SOC.,Chem. Commun. 1987 961. 67 B. L. Booth M. Al-Kinany and K. Laali J. Chem. SOC.,Perkin Trans. 1 1987 2049. h8 J. W. Dieter Z. Li and K. M. Nicholas Tetrahedron Lett. 1987 28 5415. 69 P. Menegheli M. C. Rezende and C. Zucco Synth. Commun. 1987 17 457. '' M. P. Suhi K. Shankaran B. I. Alo W. R. Hahn and V. Snieckus Tetrahedron Lett. 1987 28 2933. 71 T. Yamato T. Arimura and M. Tashiro J. Chem. SOC.,Perkin Trans. 1 1957 1. 72 G. A. Olah G. K. S. Prakash P. S. Iyer M. Tashiro and T. Yamato J. Org. Chem. 1987 52 1881. 73 J.4.Hayami S. Otani F. Yamaguchi and Y. Nishikawa Chem. Left. 1987 739. 74 R. I. Cattana J. 0.Singh J. D. Anunziata. and J. J. Silber J. Chem. SOC.,Perkin Trans. 2 1987 79. 166 R. McCague OMe ,"':"" via 3"""' S,Ar* NO2 NMe2 NO2 \ via (CH,),NH electron transfer hv I NO2 Scheme 13 group uia electron tran~fer.~' 4-Nitroveratrole similarly undergoes displacement of either one of the methoxy groups depending on the nucleophile (Scheme 13).76 In the reaction of p-dinitrobenzene with basic hydrogen peroxide the hydroper- oxynitrobenzene is formed as an intermediate eighteen times faster than its conver- sion into p-nitr~phenol.~~ Polychloroarenes have been found to react readily with superoxide. It has been proposed that a similar action may take place in uiuo and account for the high toxicity of polychlorobiphenyl~.~~ Synthetic Procedures.Perhaps the most valuable recent developments in nucleophilic aromatic substitution are where overall it is a proton that is replaced allowing an increase in the number of ring substituents. A review has appeared on the vicarious nucleophilic substitution (VNS) reaction in which the chloromethylsulphone anion is a typical nucleophile which ultimately loses its chlorine atom. It is the elimination of hydrogen chloride that is the rate determining step -the initial addition is fast and rever~ible.'~ Manipulation of the products leads to a synthesis of nitroarylethyl- ene derivatives (Scheme 14).80 When trichloromethyl anion is the nucleophile i Et0,CC H Br -Scheme 14 75 N.J. Bunce S. R. Cater J. C. Scaiano and L. J. Johnston J. Org. Chem. 1987 52 4214. 76 A. Cantos J. Marquet and M. Moreno-Manas Tetrahedron Lett. 1987 28 4191. 77 R. A. Heller and R. Weiler Can. J. Chem. 1987 65 251. 78 H. Sugimoto S. Matsumoto and D. T. Sawyer J. Am. Chem. Soc. 1987 109 8081. 79 M. Makosza and J. Winiarski Arc. Chem. Rex 1987 20 282. 80 M. Makosza and A. Tyrala Synthesis 1987 1142. Aromatic Compounds 167 hydrolysis of the resulting dichloromethyl compound gives the aldehyde.81 The VNS reaction is successful only if the anionic a-complex is sufficiently stabilized. In 1 -cyanonaphthalene stabilization is insufficient and a bis-cyclopropane annelated product results.82 Tele-substitution para to the chlorine leaving group is observed with the tricar- bonylchromium complex of 2-chloro- m-xylene.After decomplexation the product is a 1,3,5-trisubstituted benzene.83 Direct displacement of halogen in 4-chloro- 4-bromo- and 4-iodo-benzene by amines takes place if a pressure of 7.2 kbar is applied.84 For the preparation of diphenyl ethers 1,4-dinitrobenzene has been shown to be better than 4-fluoronitrobenzene in its reaction with the phenoxide anion.85 An electron-transfer mechanism is likely since radical scavengers reduce the yield. Oxazoles as well as oxazolines are good at activating ortho leaving groups in nucleophilic aromatic substitution towards displacement by Grignard reagents.86 Substitution uia Aryl a-Radicals.-Abeywickrema and Beckwith have made a thorough study of the iododediazoniation reaction.Strong evidence for an SRNl mechanism is the observation of intramolecular ring-closure to a double bond revealing the intermediacy of an aryl radical (Scheme 15). The diiodine radical cation (11) is a key chain-transfer reagent in this pro~ess.~’ It has also been demonstrated that aryl radicals generated by tributyltin radical abstraction of bromine can intramolecularly abstract a cyano or acyl group if this group leaves a stabilized radical.88 I NaI -acetone Scheme 15 The approach can be used to synthesize benzonitriles from diazosulphides as an alternative to the Sandmeyer reaction. The radical is generated either by photochemical or electrochemical ind~ction.~~.~’ Electrocatalysis takes place on the cathode and examples are the electrochemical hydrogen-transfer oxidation by aryl halides whereby an alcohol is oxidized to a ketone 91 and in a synthesis of unsymmetrical biaryls by coupling between an aryl halide and phenolate anion.92 ” M.Makosza and 2.Owczarczyk Tetrahedron Lett. 1987 28 3021. a2 M. Makosza T. Glinka S. Ostrowski and A. Rykowski Chem. Lett. 1987 61. 83 F. Rose-Munch E. Rose and A. Semra J. Chem. SOC.,Chem. Cornmun. 1987 942. 84 T. Ibata Y. Isogami and J. Toyoda Chem. Lerf. 1987 1187. 85 P. G. Sammes D. Thetford and M. Voyle J. Chem. SOC.,Chem. Commun. 1987 1373. 86 D. J. Cram J. A. Bryant and K. M. Doxsee Chem. Lett. 1987 19. 87 A. N. Abeywickrema and A.L. J. Beckwith J. Org. Chem. 1987 52 2568. 88 A. L. J. Beckwith D. M. O’Shea S. Gerba and S. W. Westwood J. Chem. SOC.,Chem. Commun. 1987 666. 89 M. Novi G. Petrillo and C. Dell’Erba Tetrahedron Left. 1987 28 1345. 90 G. Petrillo M. Novi G. Garbarino and C. Dell’Erba Tetrahedron 1987 43 4625. 91 C. P. Andrieux J. Badoz-Lambling C. Combellas D. Lacombe J.-M. Saveant A. Thiebault and D. Zann J. Am. Chem. SOC., 1987 109 1518. 92 N. Alam C. Amatore C. Combellas A. Thiebault and J. N. Verpeaux Tetrahedron Lett. 1987,28,6171. 168 R. McCague Substitution tiu Aryl-Metal o-Complexes.-Direct Functionalization ofBenzene. The use of transition metal complex catalysis can enable substituted benzenes not obtain- able by electrophilic substitution to be synthesized.Direct hydroxylation of benzene is possible with palladium(1r) acetate and 1,lO-phenanthroline under 15 atmospheres pressure of oxygen.93 Highly efficient carbonylation of benzene takes place on irradiation with carbon monoxide.94 Curiously monosubstituted benzenes give mainly meta carbonylation irrespective of whether the substituent is electron donat- ing or electron ~ithdrawing.'~ Insertion of isonitriles into benzene to give aldimines takes place on irradiation with the complex Fe(PMe3)2(:CNR)3 obtained from the isonitrile and tetrakis(triphenylphosphine)iron(01.~~ Aryl-MetaZ a-Complex as the Nucleophile. A simplified classification is adopted here that divides aryl-metal a-complexes as behaving as essentially either electrophiles or nucleophiles.Thus in the coupling of an arylboronic acid -preparable from the aryl-lithium by lithium-boron exchange with an aryl palladium bromide generated from the aryl br~mide~~?~~ -the arylboronate is considered to be the nucleophile and the aryl palladium is the electrophile. For the introduction of radiolabelled halogen it has been suggested that aryltrimethylgermanes are preferred to the corresponding stannanes since the former are less sensitive to hydrolysis but more susceptible to electrophilic sub~titution.~~ Fluorine can be introduced by elemental fluorine or acetyl hypofluorite.'OO Arylhydrazines can be prepared by addition of aryllithiums or aryl Grignard reagents to di-t-butyl azodicarboxylate and subsequent acid treatment."' A simple procedure for specific hydroxylation of aromatics is via directed lithiation by s-butyllithium and then introduction of oxygen."* Functionalization adjacent to an aryl-ketone function can be achieved by forma- tion of the aryltetracarbonylmanganese complex which adds to the double bond of olefins that bear electron withdrawing groups (Scheme 16).'03 @CO,Me Scheme 16 Buchwald's zirconocene-benzyne complex (4) can be treated as a benzene-1,2- dianion.After addition of acetonitrile and iodine 2-iodoacetophenone is 93 T. Jintoku H. Taniguchi and Y. Fujiwara Chem. Lett.. 1987 1865. 94 T. Sakahura and M. Tanaka Chem. Lett. 1987 249. 95 T. Sakahura and M. Tanaka Chem. Lett. 1987 1113. 96 W. D. Jones G. P. Foster and J.M. Putinas J. Am. Chem. Soc. 1987 109 5047. 97 M. J. Sharp W. Cheng and V. Snieckus Tetrahedron Lett. 1987 28 5093. 98 W. Cheng and V. Snieckus Tetrahedron Lett. 1987 28 5097. 99 S. M. Moerlein J. Org. Chem. 1987 52 664. 1DO H. H. Coenen and S. M. Moerlein J. Nuorine Chern. 1987 36 63. 101 J. P. Demers and D. H. Klaubert Tetrahedron Lett. 1987 28 4933. 102 K. A. Parker and K. A. Koziski J. Org. Chem. 1987 52 674. I03 L. H. P. Gommans L. Main and B. K. Nicholson J. Chem. SOC.,Chem. Commun. 1987 761. Aromatic Compounds 169 obtair~ed.'~~.'~~ The zirconozene-benzadiyne complex (5) has also been prepared. It behaves as a tetraanion bromine yielding 2,3,5,6-tetrabromo-l,4-dimethoxyben-zene and it can be used for the preparation of a bis-cyclobutane-fused benzene.'06 A clever method for ring closure is shown in Scheme 17.'07 An aryldiethyl- aluminium complex is presumably an intermediate.Scheme 17 Aryl- Metal a-Complex as the Electrophile. Classical nucleophilic aromatic substitu- tion is largely limited to highly activated substrates -transition metal complexes are now playing an important role in overcoming this deficiency. The cyanation of aromatic halides under copper salt catalysis (Rosenmund von Braun reaction) has been reviewed. The mechanism remains uncertain.'08 Copper salts also catalyse the replacement of bromine by methoxy groups. This was used in the synthesis of the highly oxygen-substituted nucleus of ubiq~inone'~'and in the intramolecular dis- placement of bromine by an amine in the synthesis of azetidinones."' Cobalt complexes formed from aryl halides are equivalents of aryl radicals and can add intramolecularly to a nearby double bond.'" Barton et al.have published a series of papers on the use of bismuth (111) and (IV) and related lead(Iv) iodine( III) and antimony(v) for phenylation of alcohols phenols and amines.''2-'*6 Phenyl radicals are not thought to be intermediates in these reaction^."^ Pinhey has demonstrated the use of an aryl-lead triacetate to arylate a vinylogous P-ketoester in the synthesis of (*)-Iyc~ramine."~ 104 S. L. Buchwald B. T. Watson R. T. Lum and W. A. Nugent J. Am. Chem. SOC.,1987 109 7137. 105 S. L. Buchwald A. Sayers €3. T. Watson and J. C. Dewan Tetrahedron Lett.1987 28 3245. 106 S. L. Buchwald E. A. Lucas and J. C. Dewan J. Am. Chem. SOC.,1987 109 4396. 107 B. M. Trost and R. Walchli J. Am Chem. SOC.,1987 109 3487. I08 G. P. Ellis and T. M. Romney-Alexander Chem. Ret.. 1987 87 779. I09 E. Keinan and D. Eren J. Org. Chem. 1987 52 3872. 110 R. Joyeau L. D. S. Yadav and M. Wakselman J. Chem. SOC.,Perkin Trans. 1. 1987 1899. 111 V. F. Patel and G. Pattenden J. Chem. SOC.,Chem. Commun. 1987 871. D. H. R. Barton N. Yadav-Bhatnager J.-P. Finet J. Khamsi W. B. Motherwell and S. P. Stanforth Tetrahedron 1987 43 323. D. H. R. Barton J.-P. Finet C. Giannotti and F. Halley J. Chem. SOC.,Perkin Trans. 1 1987 247. 114 D. H. R.Barton J.-P. Finet W. B. Motherwell and C. Pichon J. Chem. SOC.,Perkin Trans.1 1987 251. I15 D. H. R. Barton J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 887. 116 D. H. R. Barton N. Yadav-Bhatnagar J.-P. Finet and J. Khamsi Tetrahedron Lett. 1987 28 3111. 117 D. J. Ackland and J. T. Pinhey J. Chem. Soc. Perkin Trans. 1. 1987 2695. 170 R. McCague Aryl trifluoromethanesulphonates readily preparable from phenols are proving increasingly valuable. Examples of procedures illustrating their utility that have appeared in 1987 are illustrated in Scheme 18. ArOS02CF3 Scheme 18 In the reaction that forms esters the use of 1,3-bis(diphenylphosphino)propane gave reaction rates 500 times those obtained using triphenylphosphine ligands.’” Coupling between aryl halides and diphenylphosphino-silanes or stannanes allows the introduction of the diphenylphosphino group.123 Vinyl stannanes can be coupled with aryl bromide^"^ as well as with the triflates. Aryldiazonium tetrafluoroborates can be coupled with vinyltrimethyl~ilanes~~~ and coupling is also successful between a tricarbonylchromium-complexed aryl chloride and a trialkylstannane to form the aryl-alkyl bond.’26 Miscellaneous Methods.-In substitutions via benzyne intermediates fing methoxy groups bring about regioselectivity by repelling nucleophiles ortho and para. Thus l-bromo-2,4-dimethoxybenzeneundergoes cine-halogen replacement to give a 1,3,5-trisubstituted An alternative route to 1,3,5-trisubstituted benzenes used in the synthesis of olivetol is by reductive removal of the 2-methoxy group in a 1,2,3-trimethoxy-5-substituted benzene by potassium in dimethylformamide.’28 Schultz et al.have elegantly demonstrated the synthesis of substituted phenols from benzoate esters via temporary removal of the aromatic conjugation (Scheme 19) Protected L-DOPA derivatives have been accessed by the benzylic hydroperoxide rearrangement [ArCH(OOH)CH3 -+ ArOH].’30 A method for hydroxylation a-to 118 A. M. Echavarren and J. K. Stille J. Am. Chem. Soc. 1987 109 5478. 119 G. A. Peterson F.-A. Kunng J. S. McCallum and W. D. Wuiff Tetrahedron Lert. 1987 28 1381. I20 R. E. Dolle S. J. Schmidt and L. I. Kruse J. Chem. SOC.,Chem. Commun. 1987 904. 12’ K. S. Petrakis and T. L. Nagabhushan J. Am. Chem. SOC.,1987 109 2831. 122 X. Lu and J. Zhu Synthesis 1987 726.123 S. E. Tunney and J. K. Stille J. Org. Chem. 1987 52 748. 124 D. R. McKean G. Parrinello A. F. Renaldo and J. K. Stille J. Org. Chem. 1987 52. 422. 12’ K. Ikenaga K. Kikukawa and T. Matsuda J. Org. Chem. 1987 52 1276. ‘26 W. J. Scott J. Chem. SOC.,Chem. Comrnun. 1987 1755. 127 A. Ruzzuk and E. R. Biehl J. Org. Chem. 1987 52 2619. 128 U. Azzana T. Denurra G. Melloni and G. Rassu 1. Chem. SOC.,Chem. Commun. 1987 1549. 129 A. G. Schultz R. E. Harrington M. Macielag P. G. Mehta and A. G. Taveras J. Org. Chem. 1987 52 5482. 130 D. L. Boger and D. Yohannes J. Org. Chem. 1987 52 5283 171 Aromatic Compounds R' + R C02Me R' Scheme 19 a ketone is by reaction of the tin enolate with benzoquinone in the presence of chlorotrimethylsilane.' 31 4 Benzene Derivatives for the Synthesis of Non-aromatic Compounds Reductions.-Birch reduction of m-anisic acid can lead to any one of four 3-oxocyclohexenecarboxylic acids by varying the treatment of the initial reduced product.'32 A trimethylsilyl substituent will override the regiochemical preference favoured by an alkyl group; in a substituted naphthalene the ring containing the trimethylsilyl group is preferentially reduced.'33 A protocol for electrochemical Birch reduction has been developed as an alternative to the use of alkali The photoreduction of aryl nitriles and halides by borohydride proceeds by an electron- transfer pathway but gives different 1,4-dihydro compounds than does the Birch reduction since protonation occurs in the radical anion rather than in the diani011.l~~ Photochemical Processes.-A thorough review of photocycloadditions of aromatic compounds has been pub1i~hed.I~~ Further evidence has appeared for ortho-and meta-cycloaddition proceeding via an initial photoinduced charge-transfer to the arene to give an exiplex ~witterion.'~~-'~' After intramolecular ortho-cycloaddition of olefins and acetylenes to the benzene ring thermal 6rr ring-expansion gives cyclo~ctatrienes'~~ respectively.A benzene derivative heavily sub- and tetraene~'~~ stituted with t-butyl groups undergoes photochemical isomerism not only to the I?l T. Mukaiyama N. Iwasawa T. Yura and R. S. J. Clark Tetrahedron 1987 43 5003. I32 F. X. Webster and R. M. Silverstein Synthesis 1987 922.133 P. W. Rabideau and G. L. Karrick Tetrahedron Lett. 1987 2481. 134 J. Chaussard C. Combellas and A. Thiebault Tetrahedron Lett. 1987 28 1173. 135 M. Kropp and G. R. Schuster Tetrahedron Lett. 1987 28 5295. 136 J. J. McCullough Chem. Rev. 1987 87 811. 13 7 J. Mattay J. Runsink J. A. Piccirilli A. W. H. Jam and J. Cornelisse J. Chem. SOC.,Perkin Trans. 1 1987 15. 138 J. Mattay Angew. Chem. Int. Edn. Engl. 1987 26 825. 139 G. Weber J. Runsink and J. Mattay J. Chem. Soc. Perkin Trans. 1 1987 2333. 140 J. Matray J. Runsink R. Heckendorn and T. Winkler Tetrahedron 1987 43 5781. 141 K. B.Cosstick M. G. B. Drew and A. Gilbert J. Chem. SOC.,Chem. Commun. 1987 1867. 142 M. C. Pirrung J. Org. Chem. 1987 52 1635.172 R. McCague Dewar benzene but further to the prismane. The prismane can revert thermally to a benzene derivative having a new substitution pattern.'43 4-Chlorobiphenyl under- goes photochemical conversion in water partly into the 3-chloro derivative; it has been suggested that the benzvalene (6) could be an intermediate in this process and that the chlorine transposition might have important environmental consequences.144 Thermal Cyc1oadditions.-Bis(trifluoromethyl)tetrazine the most reactive inverse electron-demand diene so far observed reacts thermally with benzene. The arene acts as the 2~-component and the product is a substituted phtha1a~ine.l~~ Phenol gives the 1 :1 cycloadduct (7) with N-(2,6-dimethylphenyl)maleimide in 63% yield.'46 Oxidations.-The oxidation of benzene by the bacteria Pseudornonas putida gives cyclohexa-3,5-diene- 1,2-cis-diol.The functionality thus introduced is ideal for the preparation of a range of natural products an example is the synthesis of (+)-pinit01 (Scheme 20).'47 Mutant strains of Pseudornonas putida can tolerate a wide range of functionality in the benzene nucleus whereupon the products obtained are optically a~tive.'~*-'~~ OH OH Scheme 20 The 2-hydroxyethoxy substituent promotes anodic oxidation of the aromatic nucleus in the presence of methanol to give a ketal of cy~lohexa-2,5-dienone.'~~ A curious anodic oxidation is in a synthesis of (*)-8,14-cedranoxine (Scheme 2l).'" The overall reaction is remarkably similar to the rneta-photocycloaddition reaction.143 H. Wingert H. Irngartinger D. Kallfass and M. Regitz Chem. Eer. 1987 120 825. 144 T. Moore and R. M. Pagni J. Org. Chem. 1987 52 770. 145 G. Seitz R. Hoferichter and R. Mohr Angew. Chem. Int. Edn. Engl. 1987 26 332. 146 D. Bryce-Smith. A. Gilbert I. S. McColl M. G. B. Drew and P.Yianni J. Chem. Soc. Perkin Trans. I 1987 1147. 147 S. V. Ley F. Sternfeld and S. Taylor Tetrahedron Lett. 1987 28 225. 148 J. T. Rossiter S. R. Williams A. E. G. Cass and D. W. Ribbons Tetrahedron Lett. 1987 28 5173. 149 S. J. C. Taylor D. W. Ribbons A. M. 2.Slawin D. A. Widdowson and D. J. Williams Tetrahedron Lett. 1987 28 6391. 1so M. P. Capparelli R. S. DeSchepper and J. S. Swenton J. Chem. SOC.,Chem. Commun. 1987 610.151 Y. Shizuri Y. Okuno H. Shigemori and S. Yamamura Tetrahedron Lett. 1987 28 6661. Aromatic Compounds 173 OMe anode _____. Me0 BU,N+BF,-'OAc Scheme 21 5 Condensed Polycyclic Aromatic Compounds Theoretical Studies.-Developments in computing power have naturally led to theo- retical methods being applied to large molecules. A molecular orbital based molecular mechanics (MOMM) approach is claimed to give greater accuracy than any previous method.'52 Stein and Brown have applied the HMO theory to large hexagonal condensed benzenoid systems of up to 2300 carbon atoms. At the edge of such molecules the properties are predicted to be similar to those in small polynuclear hydrocarbons whereas at the centre the carbon atoms have similar properties to those in graphite.Interestingly there was a calculated minimum resonance energy per electron at about 240 carbon atoms.'53 By Graphical Unitary Group methods the valence bond model has been applied to systems of up to 24 T-centres and gives good agreement with the HMO method.'54 An index of benzenoid character of polycyclic conjugated hydrocarbons has been proposed which entails partitioning the resonance energy into 4n + 2 (aromatic) and 4n (antiaromatic) circuits.'55 Elser and Haddon have predicted that icosahedral c60 (Footballene Buckminsterfullerine) will have a vanishingly small ring-current magnetic suscepti- bility; it may even be weakly paramagnetic. It would however have a very high electron affinity giving a strongly diamagnetic hexaanion which can be visualized as containing cyclopentadienyl anion units.Thus this spherical hydrocarbon is far removed from graphite.'56 Examination of carbon-13 shielding tensors can be used to evaluate bond orders and hence give a measure of ~-delocalization.*~~ This method has been applied to ~yrene.'~~ By high temperature vacuum thermolysis an equilibrium has been set up between aceanthrylene acephenanthrylene and fluoranthene (Scheme 22). The greater amount of aceanthrylene than acephenanthrylene was unexpected in view of the greater resonance energy of phenanthrene over anthracene. The proposed mechanism is a 1,2-carbon shift and then 1,2-hydrogen shift in the resulting ~arbene.'~~ Whereas in these compounds the double bond represents only a small perturbation in the 152 J.Kao J. Am. Chem. SOC.,1987 109 3817. 153 S. E. Stein and R. L. Brown J. Am. Chem. Soc. 1987 109 3721. 154 S. A. Alexander and T. G. Schmalz J. Am. Chem. SOC.,1987 109 6933. 155 M. Randic S. Nikolic and N. Trinajstic Gazz. Chim. Ztal. 1987 117 69. 156 V. Elser and R. C. Haddon Nature (London) 1987,325,792. See also R.B. Mallion Nature (London) 1987 325 760. 157 J. C. Facelli D. M. Grant and J. Michl Acc. Chem. Res. 1987 20 152. 158 C. M. Carter D. W. Alderman J. C. Facelli and D. M. Grant J. Am. Chem. Soc. 1987 109 2639. 159 L. T. Scott and N. H. Roelofs J. Am. Chem. Soc. 1987 109 5461. 174 R. McCugue \/ aceanthrylene acephenanthrylene fluoranthene 17 9 74 Scheme 22 dianions the pathway of electron delocalization is changed and the bridges become important.16' Synthesis of Condensed Aromatic Compounds.-By Diels- Alder Reactions.Reviews have appeared on the use of Diels-Alder strategy in the synthesis of natural products such as the anthracycline antibiotics,'61 and on orthoquinodimethanes which are useful 4.rr-cornponents in the construction of polycyclic systems.162 Regioselectivity in alkoxyisobenzofuran-aryne cycloaddition is at best only 4 :1 and this is attributed to the high reactivity of the partners.163 However some good regioselectivities have been obtained in the reaction of benzynes with 3-cyano-l(3H)isobenzofurans in what is probably a stepwise addition.'64 Useful 27~ components are the arene endoxides such as (8) which is prepared from furan and 1,2,4,5-tetrabromoben- zene.'6s Cycloaddition between anthracene-1,4-endoxide and 2-xylylene leads to a new synthesis of pentacene'66 and similar strategy leads to extended triptycene~.'~' The bicyclo(3.2.2)nonane (9) has been developed as a synthon in tandem Diels- Alder reactions to prepare linearly condensed ring systems.I6' A tandem Claisen rearrange- ment-intramolecular Diels-Alder cycloaddition strategy has been employed in a total synthesis of 1 1 -deoxydaunornycin~ne.'~~ 8 \ "ds c1' (9) Other Methods of Ring Construction.The traditional method for the synthesis of polycyclic ring systems -cycloalkylation of aldehydes and ketone -has been reviewed."' The ring opening of arylcyclobutenone to ketadienes which can undergo 160 Y.Cohen N. H.Roelofs G. Reinhardt L,. T. Scott and M. Rabinovitz J. Org. Chem. 1987 52 4207. 161 A. Ichihara Synthesis 1987 207. 162 J. L. Charlton and M. M. Alauddin Tetrahedron 1987 43 2873. 163 D. J. Pollart and B. Rickborn J. Org. Chem. 1987 62 792. 164 S. P. Khanapure R. T. Reddy and E. R. Biehl J. Org. Chem. 1987 52 5685. 165 H. Hart C.-Y. Lai G. C. Nwokogu and S. Shamouilian Tetrahedron 1987,43 5203. I66 J. Luo and H. Hart J. Org. Chem. 1987 52 4833. 167 W. C. Christopfel and L. L. Miller Tetrahedron 1987 43 3681. 168 B. Demarchi and P. Vogel Tetrahedron Lett. 1987 28. 2239. 169 G. A. Kraus and S. H. Woo J. Org. Chem. 1987 52 4841. 170 G. K. Bradsher Chem.Rev. 1987 87 1283. Aromatic Compounds electrocyclic ring closure is a useful route to highly substituted naphthalene^'^'-'^^ such as the 5-lipoxygenase inhibitor lonapalene (Scheme 23) and to various cyclopen- tene fused polycyclic systems such as a~eanthry1ene.l~~ p-xylene 138°C L Meono-Me0 0 Me0 HO I \ I THF -78 "C OAc OAc OH Scheme 23 A comparable process is the opening of arylcyclopropenones by metal carbonyls to form intermediate chelated carbenes. The additional carbon required for six- membered ring formation derives by carbon monoxide insertion. This method has been used to synthesize naphthols'74 and ring C of anthra~yclinone.'~~ Naphthols have also been prepared by palladium( ir )-catalysed cyclocarbonylation of cinnamyl alcohol acetates.'76 Preparation of Specifically Substituted Products.The weak interaction of the nitro group in 2-nitropyrene with the ring system leads to electrophilic attack at the adjacent 1 -position taking second preference after attack at the distant 6-positiqn. Thus 38% 1,2-dinitropyrene can be 0btair1ed.l~' Pyrenes with substituents at the 2- and 7-positions can be accessed via intramolecular cyclization and oxidation of 8-methoxy-[2.2]metacyclophanes.'7s Carcinogenicity of Polycyclic Aromatic Hydrocarbons (PAH).-Studies into the mechanism by which PAH exert their mutagenic/carcinogenic activity have now progressed to examination of PAH diol epoxide-DNA adducts. The sites of covalent attachment have been identified for benzo[ c]phenanthrene-3,4-diol-1,2-epoxides by n.m.r.Polydeoxyguanosine is particularly good at catalysing the 17' S. T. Perri and H. W. Moore Tetrahedron Lett. 1987 28 4507. I72 K. Chow and H. W. Moore Tetrahedron Lett. 1987 28 5013. 173 Y.3. Chung;H. Kruk 0. M. Barizo M. Katz and E. Lee-Ruff J. Org. Chem. 1987 52 1284. 174 M. F. Semmelhack S. Ho M. Steigerwald and h.C. Lee J. Am. Chem. SOC.,1987 109 4397. I75 K. H. Dotz and M. Popall Angew. Chern. Int. Edn. Engl 1987 26 1158. 176 Y. Koyasu H. Matsuzaka Y. Hiroe Y. Uchida and M. Hidai J. Chem. SOC.,Chem. Commun. 1987,575. 177 A. M. van den Braken-van Leersum J. Cornelisse and J. Lugtenburg J. Chem. Soc. Chern. Commun. 1987 1156. 17R M. Tashiro T. Yamato K. Kobayashi and T. Arimuro J.Org. Chem. 1987 52 3196. 179 S. K. Agarwal J. M. Sayer H. J. C. Yeh L. K. Pannell B. D. HiLon M. A. Pigott A. Dipple H. Yagi and D. M. Jerina J. Am. Chem. SOC.,1987 109 2497. 176 R. McCague hydrolysis of the epoxides'" and the monohydrogenphosphate group is responsible for the catalysis.'" Reduced tumourigenicity in 6-fluorobenz[ a]pyrene-7,8-diol-9,10- epoxide is explained by the fluorine atom causing the diol to adopt a pseudoaxial conformation whereas a diequatorial conformation is required for activity.lg2 Incor- poration of an isopropyl group into benz[ alpyrene distant from the metabolizable ring does not inhibit metabolism but renders the resulting diol epoxide only weakly active presumably because the isopropyl group sterically impedes intercalation.lg3 PAH epoxides such as triphenylene-l,2-oxide have some interesting properties. They undergo rapid racemization via the oxepin valence ta~tomer''~ and undergo an oxygen-walk rearrangement either an oxepin or epoxide tautomer being preferred in the product to retain the phenanthrene delocalization (Scheme 24). '85,186 Oxygen-walk does not take place in naphthalene-1,2-oxide because the energy barrier is too high,lg5 but a nitrogen-walk in the aziridine derived by methoxycarbonylnitrene attack on naphthalene has been rep~rted.'~' Scheme 24 Syntheses of various polyaromatic compounds possessing a fused indeno ring which are widespread environment mutagens using cyclohexane epoxide to add the indeno fragment have been reported.'88 Twisted Condensed Aromatic Hydrocarbons.-Polycyclic aromatic hydrocarbons twisted longitudinally by almost 70" have been Skeletal deformation in 4,5-disubstituted phenanthrenes results from steric overlap of the ~ubstituents'~' and helical twists of up to nearly 30" have been observed.In 3,4,5,6-tetramethyl- phenanthrene the 3-and 6-methyl groups exert a buttressing effect and raise the energy barrier for enantiomer interconversion from 16.1 to 23.1 kcal mol-'. Individual enantiomers are separable at low temperat~re.'~~ The effect of ring 180 N. B. Islam D. L. Whalen H. Yagi and D. M. Jerina J. Am. Chem. SOC.,1987 109 2108. 181 S. C. Gupta N. B. Islam. D. L. Whalen H. Yagi. and D. M. Jerina. J. Org. Chem.. 1987 52 3812. 182 H. Yagi J. M.Sayer D. T. Thakker W. Levin and D. M. Jerina J. Am. Chem. SOC.,1987 109 838. 183 J. Pataki and R. G. Harvey J. Org. Chem. 1987 52 2226. 184 D. R. Boyd D. A. Kennedy J. F. Malone G. A. O'Kane D. T. Thakker H. Yagi and D. M. Jerina J. Chem. SOC.,Perkin Trans. I 1987 369. '*' D. R. Boyd S. K. Agarwal S. K. Balani R. Dunlop G. S. Gadaginamath G. A. O'Kane N. D. Sharma W. B. Jennings H. Yagi and D. M. Jerina J. Chem. Soc. Chem. Commun. 1987 1633. D. R. Boyd and G. A. O'Kane Tetrahedron Lett. 1987 6395. 187 K. Satake H. Mizushima M. Kimura and S. Morosawa J. Chem. Soc. Chem. Commun. 1987 197. 188 B. P. Cho and R. G. Harvey J. Org. Chem. 1987 52 5668. 189 R. A. Pascal Jr. W. D. McMillan D. Van Engen and R. G. Eason J. Am. Chem. SOC.,1987 109,4660. 190 R.A. Pascal Jr. and D. Van Engen Tetrahedron Lett. 1987 28 293. 191 R. Cosmo T. W. Hambley and S. Sternhell J. Org. Chem. 1987 52 3119. 192 R. N. Armstrong H. L. Ammon and J. N. Darnow J. Am. Chem. SOC.,1987 109 2077. Aromatic Compounds distortions in such compounds increases their reactivity to electrophilic substitu- ti~n.'~~ Compound (10) is interesting because apart from having a high barrier (23 kcal mol-') for interconversion between the enantiomeric syn-forms the anti-isomer is considered to be a high energy intermediate of the con~ersion'~~ and therefore there must be some transmission of torsion through the anthracene system. (10) 6 Cyclophanes Distortion of the Benzene Ring.-Z-[6]Paracycloph-3-ene (11 )prepared by thermal valence isomerization of the corresponding Dewar benzene is more strained than [6]paracyclophane.The former undergoes 1,6methanol addition catalysed by tri- fluoroacetic acid whereas the latter is inert. Bending angles derived from X-ray crystal structures of dimethoxycarbonyl derivatives and defined according to Figure 1 are 4 =19.4" and a =20.2" for the [6]para~yclophanes,'~~ and 20.5 and 24.1" for the [6]para~ycloph-3-ene.'~~ Ab initio molecular orbital calculations on [51para-cyclophane give a value of about 23" for the distortion angle 4. The strain causes the molecule to be 78 kcal mol-' less stable than benzene but little variation in bond lengths around the benzene ring is ca1c~lated.l~' /-_ . Figure 1 Definition of bending angles in [n]paracycZophanes (11) (12) (13) (14) 193 A.P. Laws A. P. Neary and R. Taylor J. Chem. Soc. Perkin Trans. 2 1987 1033. 194 I. Agranat M. R. Suissa S. Cohen R. Isakasson J. Sandstrom J. Dale and D. Grace J. Chem. SOC. Chem. Commun. 1987 381. 195 Y. Tobe A. Nakayama K. Kaiuchi Y. Odaira Y. Kai and N. Kasai J. Org. Chem. 1987 52 2639. I 96 Y. Tobe K.4. Ueda T. Kaneda K. Kakiuchi Y. Odaira Y. Kai and N. Kasai J. Am. Chem. SOC. 1987 109 1136. 197 J. E. Rice T. J. Lee R. B. Remington W. D. Allen D. A. Clabo Jr. and H. F. Schaefer 111 J. Am. Chem. SOC.,1987 109 2902. 178 R. McCugue A range of substituted [S]paracyclophanes prepared by photochemical ring open- ing of Dewar benzenes decompose slowly at room temperature.19' Both Dutch and Japanese workers have intercepted [4]paracyclophane (12) pre- pared photochemically from 1,Ctetramethylene Dewar ben~ene.'~~-~'' It is stable at 77 K2O0and has a temporary existence at -20 0C.199It gives 1,4-adducts with trifluoracetic acid and with methanol. Unlike higher cyclophanes the protonated [4]cyclophane does not rearrange to the rnetu-cyclophane because increased bending reduces charge density ortho to the protonation site.'w Attempts to prepare the even more strained cyclophane (13) from a Dewar benzene were unsuccessful indicating that [4]paracyclophane may represent the limit of the synthetic methodology.200 [4]Metacyclophane (14) has been generated thermally but is not isolated; products arise from Diels- Alder dimerization.201 Attempted photochemical generation from the Dewar benzene gave only a prismane.Ring Interactions.-The in-[34~'0][7]metacyclophane (15) has been prepared by themolytic ring contraction of a trithio[9]cyclophane sulphone. In its n.m.r. spec- trum the bridgehead proton resonates at 6 -4.03.202In the [2.2]paracyclophane (16) non-bonded interactions between the rings result in the phenylene ring becoming deactivated to electrophilic substitution and acid-catalysed rearrangement and the tetracyanoethylene complex has lowered stability.203 Paracyclophanes bearing several cyano and dimethylamino groups have been studied as electron acceptors FF and donors respectively.2-206 [2.21Paracyclophanes bearing phenylmethylenyl car- bene substituents have been used as models for high-spin organic molecules that could lead to organic ferr~magnets.~" In the dianion of the paracyclophane (17) the protons shown resonate at S 8.62 and S 10.31; their deshielding results from the anisotropy of the 4n anion.208 Hence the benzene ring in paracyclophanes can be used to probe the electronic structure of its partner.198 G. B. M. Kostermans W. H. deWolf and F. Bickelhaupt Tetrahedron 1987,43 2955. 199 G. B. M. Kostermans M. Bobeldijk W. H. deWolf and F. Bickelhaupt J. Am. Chem SOC.,1987 109 247 1. 2oo T. Tsuji and S. Nishida J. Chem SOC Chem. Commun. 1987 1189. 20 1 G. B. M. Kostermans P. van Dansik W. H. deWolf and F. Bickelhaupt J. Am. Chem SOC.,1987 109 7887. 202 R. A. Pascal Jr. R. B. Grossman and D.Van Engen J. Am Chem. SOC.,1987 109 6878. 203 R. Filler G. L. Cantrell E. W. Choe 1. Org. Chem. 1987 52 511. 204 H. A. Staab G. Gabel and C. Krieger Chem. Ber. 1987 120 269. 205 H. A. Staab P. Wahl and K.-Y. Kay Chem. Eer. 1987 120 541. 206 H. A. Staab C. Krieger P. Wahl and K.-Y.Kay Chem. Ber. 1987 120 551. 207 A. Izuoka S. Murata T. Sugawara and H. Iwamura J. Am. Chm SOC.,1987 109 2631. *08 R. Frim M. Rabinovitz H. Hopf and J. Hucker Angew. Chem. Znt. Edn. Engl. 1987 109 232. Aromatic Compounds 179 Apart from the [2.2]paracyclophanes suitable [3.3]metacyclophanes have facing benzene rings which can interact and show characteristic spectral propertie~.~’’-~~~ Compound (18) which has rings 3.04 8 apart undergoes reversible 27r + 27r cyclo-addition between the rings.209 Even in systems where the benzene rings are not constrained to lie face to face favourable interaction between a neutral phenyl ring and a benzyl cation can influence the product f~rmation.~~~-~~~ 7 Non-benzenoid Aromatic Systems Non-alternant Ring Systems.-A heavy atom-microwave structure of cyclopropenone shows that it has closer bond lengths in the 3-membered ring than methylene- cyclopropene supporting a 27r-aromatic structure yet the molecule is stabilized by electron-pair donation from the oxygen to the unoccupied ring orbital.214 Evidence has been presented that despite its positive charge the tropylium ion can provide anchimeric assistance in the solvolysis of a nearby bromine atom.*” The oxidation of isopyrene (19) with bidentate oxidants takes place at the central bond to leave a [14]annulene perimeter in accord with electron density calcula- tiom216 Cyclohepta[a]phenylene (20) has been prepared and found to be a highly electron donating hydrocarbon (1st oxidation potential 0.39 V).*17 A study of the 209 W.-D.Fessner G. Sedelmeier P. R. Spurr G. Rihs and H. Prinzbach J. Am. Chem. SOC.,1987,109,4626. 210 S. Mataka K. Takahashi T. Mimura T. Hirota K. Takuma H. Kobayashi M. Tashiro K. Imada and M.Kuniyoshi J. Org. Chem. 1987 52 2653. 211 W.-D. Fessner G. Sedelmeier L. Knothe H. Prinzbach G. Rihs 2.-z. Yang B. Kovac and E. Heilbronner Helu. Chim. Acla 1987 70 1816. 212 J. Nishimura A. Ohbayashi Y. Horiuchi Y. Okada S.-i. Yamanaka and A.Oku J. Org. Chem. 1987 52 1409. 213 R. McCague J. Chem. SOC.,Perkin Trans. 1 1987 1011. 214 S. W. Staley T. D. Norden W. H. Taylor and M. D. Harmony J. Am. Chem. SOC.,1987 109 7641. 215 J. W. Wilt C. George and M. Peeran J. Org. Chern. 1987 52 3739. 216 E. Vogel L. Schamlstieg H.-J. Weyer and R. Gleiter Chem. LrL 1987 33. 217 Y. Sugihara H. Yamamoto K. Mizoue and I. Murata Angew. Chem. Znt. Edn. Engl. 1987 26 1247. 180 R. McCugue azulene-azulene rearrangement with carbon-13 labelled azulenes shows that all the atoms in the five-membered ring are rotated consistent with a mechanism proceeding via a sigmatropic rearrangement of the norcaradiene valence tautomer.218 Annu1enes.-Haddon has developed a combined .rr-orbital-axis vector (POAV) analysis-3 D Huckel molecular orbital theory to provide a generalized treatment for non-planar r-systems.The method is particularly applicable to bridged annulene~.~~~ A Pariser-Parr-Pople welectron model taking into account 7r-electron correlation predicts that calculated ring currents are higher in charged than in neutral systems in accord with experiment so that whereas large ring neutral 4n-systems (4n 3 16) become weakly aromatic the charged 4n species are antiaromatic irrespective of ring size.220 N.m.r. studies of the dianions of annulenes show that their properties are markedly dependent on the configuration of the periphery unlike the neutral species.221-222 Although compound (21) may be termed a homoanthracene position 7 has a hundred-fold lower electrophilic reactivity than position 2 unlike.in anthracene where the 9-position is the most reactive. The low reactivity of position 7 in (21) is attributed to the charge not being stabilized in the bis(n0rcaradiene) structure.223 By means of Wittig condensations and intramolecular oxidative alkyne coupling Ojima and co-workers have been able to prepare a substantial range of annulenes (22) having up to a 38-membered ring in order to establish the limiting ring size for dia- and para-tr~picity.~~~~~’ By comparisons of n.m.r. spectra with those of the precursor having uncoupled alkynes the [28]annulene (4n) and [34]annulene (4n + 2) were shown to sustain a paramagnetic and diamagnetic ring current respectively whereas the [32] and [38] annulenes were atropic.218 A. Wetzel and K.-P. Zeller 2. Naturforsch. Teil B 1987 42 903. 219 R. C. Haddon J. Am. Chem. Soc. 1987 109 1676. 220 S. Kuwajima and Z. G. Soos J. Am. Chem. SOC.,1987 109 107. 221 K.-U. Klabunde K. Miillen and H. Vogler Tetrahedron 1987 43 1183. 222 K. Mullen T. Meul P. Schade H. Schmickler and E. Vogel J. Am. Chem. SOC.,1987 109 4992. 223 A. P. Laws and R. Taylor J. Chem. SOC.,Perkin Trans. 2 1987 1691. 224 J. Ojima E. Ejiri T. Kato M. Nakamura S. Kuroda S. Hirooka and M. Shibutani J. Chem. SOC. Perkin Trans. 1 1987 831. 22s J. Ojima S. Fujita M. Masumoto E. Ejiri T. Kato S. Kuroda Y. Nozawa and H. Tatemitsu J. Chem. SOC.,Chem. Commun. 1987 534.