6 Aromatic Compounds By A. P. CHORLTON ZENECA Specialties Hexagon House Blackley Manchester M9 8ZS,UK 1 General and Theoretical Studies The Mills-Nixon effect states that small ring annelation onto benzene would induce significant bond length alternation within the benzene nucleus. The existence of this phenomenon has been the subject of conflicting papers. The effect of fusion of angular strained rings on benzenes (Scheme 1) has been studied by crystallographic and computational techniques.’ The results of these studies show characteristic features of small strained rings such as electron density deformations consistent with ‘bent bonds’. In no case was any appreciable bond alternation observed thus denying the existence of the Mills-Nixon effect. Shepherd has demonstrated that this is also the case with biphenylenoC2,l -a]bi~henylene.~ Scheme 1 The strained benzocyclopropanes required for the above studies are the result of pioneering synthetic work by bill up^.^.^ Siegel has elegantly highlighted the anachron- istic nature of bond alternation in a paper entitled ‘Mills-Nixon Effect Wherefore Art Thou?’.’ From the contrary viewpoint theoretical studies of the Wheland intermediates from benzocycloalkenes have vindicated the Mills-Nixon hypothesis.6 Similar bond alternation has been observed by X-ray crystallography of the arenium cation (l).’ R.Boese D. Blaser W. E. Billups M. M. Haley A. H. Maulitz D. L. Mohler and K. P.C. Vollhardt Angew. Chem. Int. Ed. Engl. 1994 33 313. M. K. Shepherd J.Chem. SOC. Perkin Trans. 1 1994 1055. ’ W. E. Billups and D. J. McCord Angew. Chem. Int. Ed. Engl. 1994 33 1333. W. E. Billups D.J. McCord and B. R. Maughon J. Am. Chem. SOC.,1994 116 8831. ’ J. S. Siegel Angew. Chem. Int. Ed. Engl. 1994 33 1721. M. Eckert-Maksic Z.B. Maksic and M. Klessinger J. Chem. SOC. Perkin Trans. 2 1994 285. ’ R. Rathore S.H. Loyd and J. K. Kochi J. Am. Chem. SOC. 1994 116 8414. 165 A. P. Chorlton Besides having the conventional 6.n electron aromaticity the 3,5-dehydrophenyl cation (2) is stabilized by three-centre two-electron (3c-2e) bonding (3) in the ring plane (in-plane aromaticity). Calculations have shown that the 3,5-dehydrophenyl cation (2) with its double aromaticity is more stable than the phenyl cation.8 Semiempirical calculations (SINDO1 ) of delocalization energies were performed for a large number of mono- and polycyclic hydrocarbons.This information has been used to produce an aromaticity index for polycyclic hydrocarbon^.^ Taylor has shown that three isomers of C,,H, can in principle exist and that they will probably be aromatic." The topological resonance energy (TRE) method has revealed that typical derivatives of c60 are moderately aromatic like the parent C, molecule. For most c60 derivatives polyvalent molecular anions are at least as aromatic as the neutral species whereas polyvalent molecular cations are much less aromatic in nature.' ' The TRE method has also been applied to linear (4) and zigzag (5) isomers of cyclopolyacenes. In general zigzag cyclopolyacenes have been found to be more aromatic than the linear cyclopolyacenes.'2 Interactions between .n systems are fundamental to understanding the nature of such diverse phenomena as base-base interaction in DNA intercalation of drugs in DNA and packing of homogeneous and heterogeneous aromatic molecules in crystals.The benzene-benzene interaction is the prototype of these interactions. To gain more information about these interactions the potential energy surfaces of the benzene dimer have been studied by ab initio methods. These have revealed that the most stable structures were found to be the parallel-displaced structure followed by two T-shaped structures.' P. von R. Schleyer H. Jiao M. N. Glukhovtsev J. Chandrasekhar and E. Kraka J.Am Chem. SOC.,1994 116 10129. S. Behrens A.M. Koster and K. Jug J. Org. Chem. 1994 59 2546. lo R. Taylor J. Chem. SOC.,Perkin Trans. 2 1994 2497. l1 J. Aihara and S. Takata J. Chem. SOC.,Perkin Trans. 2 1994 65. J. Aihara J. Chem. SOC. Perkin Trans. 2 1994 971. l3 P. Hobza H.L. Selzle and E. W. Schlag J. Am. Chem. SOC.,1994 116 3500. Aromatic Compounds 167 The bicyclopropenyls (6k(8) have been synthesized by the vacuum gas phase elimination of p-halocyclopropylsilane precursors over solid fluoride. Of these bicycloprop-2-enyl (6) occupies the most important position in this family since it is one of only four isomers of benzene in which each carbon is bound to only one hydrogen atorn.l4 The a,3-dehydrotoluene biradical and related structures have been recently the subject of considerable interest in relation to the proposed mechanism of DNA cleaving agents (see preparation of benzenes from non-aromatic precursors).This has fuelled interest in the longstanding problem of the heats of formation of biradicals; to this end a number of techniques have been applied. The photoelectronic spectrum of a,3-dehydrotoluene biradical(9) has been measured; the ionization potential obtained from this data has been compared to those of benzyl radical and m-tolyl radical. This suggests that the singlet-triplet splitting of (9) is less than 5 kcal mol-' and that AH,,,, (9) lies just a little below (I kcalmol-') the additivity estimate of 109 kcal mol- '.' The absolute heats of formation for (x,2-( lo) a,3-(9) and a,4- dehydrotoluene (1 1) biradicals have been determined from the measured threshold energies for dissociation of chloride bromide and iodide ion from the corresponding o- m-,and p-halobenzyl anions in the gas phase.The 298 K heats of formation obtained for the iodobenzyl anions resulting from (9) (lo) and (11) are all found to be 103 f3 kcal mol- '. This value compares well with values obtained from MCSCF calculations (105-106 kcal mol- ').16 Picosecond optical grating calorimetry has been used to determine the energy separation between the singlet and triplet states of the diradical of m-naph- thoquinomethane (12); a value of 18.5 kcalmol-' for AE, for (12) was ~btained.'~ Distonic radical ions are reactive intermediates with spatially separated radical and charge sites.FT-ICR mass spectrometry of protonated 4-iodoaniline yields the distonic isomer of ionized aniline (Scheme 2).18 The structure of the benzene cation C6H is discussed in an article entitled 'Molecular Distortions in Reactive Intermediates'. The rotational isomerism of l4 W. E. Billups M. M. Haley R. Boese and D. Blaser Tetrahedron 1994 50 10 693. C.F. Logan J.C. Ma and P. Chen J. Am. Chem. SOC. 1994 116 2137. I6 P.G. Wenthold S.G. Wierschke J. J. Nash and R. R. Squires J. Am. Chem. SOC. 1994 116 7378. " M.I. Khan and J. L. Goodman J. Am. Chem. SOC. 1994 116 10342. L.J. Chyall and H.I. Kenttamaa J. Am. Chem. SOC. 1994 116 3135. l9 T.A. Miller Angew. Chem. Int. Ed. Engl. 1994 33 962. A. P. Chorlton Scheme 2 R3 R3 syn anti Scheme 3 disubstituted benzenes has been studied.If there were restricted rotation then two isomers syn and anti,could exist (Scheme 3). Ortho and meta substituted tolyldi(1-adamanty1)methanolswere synthesized as models to examine this form of isomerism. It was found that the ortho-substituted derivative gives essentially the anti isomer (antilsyn 11.6) the meta-derivative mainly syn (antilsyn 0.77). Thermal equilibration converts the anti ortho isomer also exclusively into syn ortho while the antilsyn ratio is virtually unchanged for the meta derivative.” The relative stability of the conformation equilibria between meta syn and anti isomers has also been examined.’l Conformational studies have revealed that 1,8-diacylnaphthalenes exist solely in the anti (racemic) conformation.22 Hexakis(fluorodimethylsily1) benzene (13) has been studied by NMR and crystallography.At low temperature it was found that the rotation of the silyl groups was frozen but the fluorine atom transfer between vicinal silyl groups is rapid. This ‘merry-go-round process’ corresponds to a cyclic network of consecutive intramolecular S,2 (Si)-type Walden inversions which are very rapid because each silicon atom already forms a quasi-pentacoordinate str~cture.’~ FMqSi SiMqF SiM%F (13) 20 J. S. Lomas and V. Bru-Capdeville J. Chem. SOC.,Perkin Trans. 2 1994 459. 21 J. E. Anderson V. Bru-Capdeville P. A. .Kirsch and J. S. Lomas J. Chem. SOC.,Chem. Commun. 1994 1077. 22 D. Casarini L. Lunazzi E.Foresti and D. Macciantelli J. Org. Chem. 1994 59 4637. 23 K. Ebata T. Inada C. Kabuto and H. Sakurai J. Am. Chem. SOC. 1994 116 3595. Aromatic Compounds 2 Preparation of Benzenes from Non-aromatic Precursors The burgeoning interest in the thermal cyclization of enediynes to aromatics via Bergman cyclization and related processes continues. This is highlighted by a recent issue of Tetrahedron that was devoted to this The activation parameters for the Bergman cyclization of acyclic enediynes (14) and acyclic aromatic enediynes (15) have been determined. It can be concluded from this data that there exists little difference in the activation parameters for acyclic aromatic (1 5) and nonaromatic enediynes and that the acetylene substituent is the primary determining factor in the rate of enediyne cy~lization.~' Magnus has found that azabicyclo[7.3.llenediynes (1 6) undergo cycloaromatiz- ation at dramatically different rates despite the fact that the distance between the bonding acetylenes is practically identical; when the carbamate protecting group is removed to give the secondary amine (17) this cycloaromatizes more rapidly and the entropy of activation changes from a negative to a positive. The origin of this difference has been ascribed to intramolecular hydrogen bonding between the NH and the c=o.26 The rate of singlet-to-triplet intersystem crosslinking in 1,6didehydrobenzene has now been studied. The inability of an applied external magnetic field to affect the rate and product formation and distribution indicates the absence of intersystem crossing in 1,4-didehydro benzene.The Bergman thermal cycloaromatization can also be effected under photochemical conditions.28 Several novel procedures for the synthesis of the enediyne precursors and their subsequent cycloaromatization have been demosntrated. These include [2,3] sigmatropic shifts,29 pinacol rearrangement,30 ceric ammonium nitrate oxidative cy~lization,~' and the use of q2-Co2(Co),complexed acetylene^.^^ A significant effort has been channelled into the synthesis of a model analogous to the anticancer agent neocazinostatin (18);33,34 a typical example of this is shown in Scheme 4.33 24 Tetrahedron 1994,50 131 1. 25 J. W. Grissom T. L. Calkins H. A. McMillen and Y.Jiang J. Org. Chem. 1994 59 5833. 26 P. Magnus and R. A. Fairhurst J. Chem. SOC. Chem. Commun. 1994 1541. 27 W.B. Lott T. J. Evans and C. B. Grissom J. Chem. SOC.,Perkin Trans. 2 1994 2583. 28 N. J. Turro A. Evenzahav and K. C. Nicolaou Tetrahedron Lett. 1994 35 8089. 29 H. Audrain T. Skrydstrup G. Ulibarri C. Riche A. Chiaroni and D. S. Grierson Tetrahedron 1994,50 1469. 30 T. Nishikawa A. Ino and M. Isobe Tetrahedron 1994 50 1449. 31 T. Brandstetter and M. E. Maier Tetrahedron 1994 50 1435. 32 P. Magnus Tetrahedron 1994,50 1397. 33 J. Suffert and R. Bruckner SYNLETT 1994 51. 34 K. Toshima K. Ohta T. Kano T. Nakamura M. Nakata and S. Matsumura J. Chem. SOC. Chem. Commun. 1994 2295. A. P. Chorlton 0 I OMe OMe -(16) R = Ad02C (17) R=H OMe 0 A Meyoyo HOv-NHMe OH Work in this are2 has resulted in the observation of a number of unexpected produ~ts.~’-~~ The majority of these products arise from intramolecular quenching of the a-3-dehydrotoluene biradical by the initiating thiol (Scheme 5).36 Grissom has elaborated on the Bergman cycloaromatization by tethering various 35 H.Sugiyama K. Yamashita T. Fujiwara and I. Saito Tetrahedron 1994 50 1311. 36 H. Sugiyama T. Fujiwara and I. Saito Tetraheduon Lett. 1994 35 8825. 37 P. A. Wender and M. J. Tebbe Tetrahedron 1994 50 1419. 38 K. Toshima K. Yanagawa K. Ohta T. Kano and M. Nakata Tetrahedron Lett. 1994 35 1573. 39 S. Kawata T. Oishi and M. Hirama Tetrahedron Lett. 1994 35 4595.Aromatic Compounds Scheme 4 OH I Scheme 5 Scheme 6 radical acceptors (olefin carbonyl oxime itri rile)^'^^ which participate in tandem enediyne-radical cyclizations to give functionalized tricycles (Scheme 6).41 The diradicals produced by the cyclization of enediynes are thought to be responsible for the cleavage of DNA. Similar diradical species can be produced by thermal ring-opening of cyclobutenones (19)43 and by photoirradiation of dia- zoketones (20).44Both these processes lead to a cleavage of DNA presumably by involvement of the diradical (21). Enediynes have also been employed in a new synthetic route to benzocyclobutenes (Scheme 7).45 The benzannulation of an unsaturated Fischer carbene complex and an alkyne 40 J.W. Grissom T. L. Calkins D. Huang and H. McMillan Tetrahedron 1994 50 4635. 41 J. W. Grissom D. Klingberg S. Meyenburg and B. L. Stallman J. Org. Chem. 1994 59 7877. 42 J. W. Grissom and B. J. Slattery Tetrahedron Lett. 1994 35 5137. 43 R. W. Sullivan V. M. Coghlan S. A. Munk M. W. Reed and H. W. Moore J. Org. Chem. 1994,59,2216. 44 K. Nakatani S. Isoe S. Maekawa and I. Saito Tetrahedron Lett. 1994 35 605. 45 F. Toda K. Tanaka I. Sano and T. Isozaki Angew. Chem. Int. Ed. Engl. 1994 33 1757. 172 A. P. Chorlton / Scheme 7 continues to be of increasing interest. This reaction gives a variety of products depending on the structure and substitution of the carbene the metal and the alkyne employed but typically cyclopentadiene and phenol derivatives are the main products.The commonly accepted mechanism is depicted in Scheme 8. In this proposed mechanism only the cyclohexadienone intermediate (23) has been isolated and characterized. Barluenga et a!. have succeeded in isolating and characterizing complexes that correspond to the intermediates (24) and (25).46 A high degree of regioselectivity is one of the key features of this reaction. The major contributor to the regioselectivity is the steric differential between the two substituents on the alkyne which leads to preferential formation of the phenol (26) where the larger substituent (R,) is incorporated adjacent to the hydroxyl group. Wulff has found that this normal regioselectivity can be reversed by the use of stannyl alkynes (Scheme 9).47 The a-silylated vinyl carbene (27) can also act as a more stable synthon for the unstable parent vinyl carbene; the benzannulated product being desilylated with TFA.48 Reversed regioselectivity has also been observed in the metal-catalysed rearrapge- ment of cyclopropenes; a Fischer benzannulation variant.This process is thought to proceed via the ccmmon intermediate (28).49 The synthetic utility of the Fischer carbene benzannulation methodology is elegantly illustrated by its use in the construction of the tetracyclic ring system of steroids (Scheme 46 J. Barluenga F. Aznar A. Martin S. Garcia-Granda and E. Perez-Carreno J. Am. Chem. Soc.,1994,116 11 191. 41 S. Chamberlin M.L. Waters and W.D. Wulff J. Am. Chem. SOC. 1994 116 3113. 48 S.Chamberlin and W. D. Wulff J. Org. Chem. 1994 59 3047. 49 M. F. Semmelhack S.Ho D. Cohen M. Steigerwald M. C. Lee A. M. Gilbert W. D. Wulff and R.G. Ball J. Am. Chem. SOC. 1994 116 7108. 50 J. Bao W. D. Wulff V. Dragisich S. Wenglowsky and R.G. Ball J. Am. Chem. SOC. 1994 116 7616. Aromatic Compounds X X X [MI = M(CO),; X = NR2 OR RNCOR'. Scheme 8 The Diels-Alder reaction continues to demonstrate its synthetic utility by its iterative use in the construction of linear chains of fused aromatic ring^.^'-'^ A typical example is given in Scheme 1 1 ." The efficient synthesis of anthraquinones has also been of current interest.5L56 Two new dieneophiles have been developed which have allowed the synthesis of benzocyc- lobutenediones (Scheme 12)57 and aromatic amines (Scheme 13).58 A number of anionic [4 + 21 cycloaddition processes equivalents of the Diels-Alder reaction have been established (Schemes 1459 and 1560).In a related process 2,4,6-trianylthiopyridinium salt (29) reacts with arylacetal- 51 M. Loffler and A. D. Schluter SYNLETT 1994 75. 52 R. W. Alder P. R. Allen L. S. Edwards G. I. Fray K. E. Fuller P. M. Gore N. M. Hext M. H. Perry A. R. Thomas and K. S. Turner J. Chem. SOC. Perkin Trans. 1 1994 3071. 53 D. Giuffrida F. H. Kohnke M. Parisi F. M. Raymo and J. F. Stoddart Tetrahedron Lett. 1994,35,4839. 54 G. Majumadar K.V. S.N. Murty and D. Mal Tetrahedron Lett. 1994 35 6139. 55 M. Couturier and P. Brassard Synthesis 1944 703. 56 A.T. Khan B. Blessing R. R. Schmidt Synthesis 1994 255.57 A. H. Schmidt C. Kunz M. Malmbak and J. Zylla Synthesis 1994 422. 58 A. Loffler and G. Himbert Synthesis 1994 383. 59 A. Tyrala and M. Makosza Synthesis 1994 265. 6o G. Majumdar R.Pal K. V.S. N. Murty and D. Mal J. Chem. SOC. Perkin Trans. 1 1994 309. A. P.Chorlton Reagents i HCrCSnBu, THF 50°C; ii TBSOTf NEt Scheme 9 Reagents i Danishefsky's diene CH,CN 25 "C 16h 1 atm CO; ii 1lOT 23 h Scbeme 10 Scheme 11 Scheme 12 Aromatic Compounds 175 R I II m2Me NMe2 C02Me Scheme 13 NH2 Scheme 14 m 00 @-qp OH 0 00 Scheme 15 dehydes (30) in the presence of base uia a 2,5-[C +C,] ring transformation to give 2,4,5-triarylthiobenzophenone(31).61 A novel electrophile-induced benzannulation reaction has been developed indepen- dently (Scheme 16).62963 T.Zimmermann Synthesis 1994 252. M.B. Goldfinger and T.M. Swager J. Am. Chem. SOC. 1994 116 7895. 63 M. A. Ciufolini and T. J. Weiss Tetrahedron Lett. 1994 35 1127. A. P. Chorlton ?/,, -H+ &-J-Scheme 16 Scheme 17 The dehydrative aromatization of cyclohexenone oximes has traditionally been realized by a low yielding Semmler-Wolff reaction. Matsumoto has demonstrated that cyclohexenone oximes can be smoothly dehydrated to the corresponding anilines by the catalysis of palladium on carbon (Scheme 17).64 3 Non-aromatic Compounds from Benzene Precursors Oxidation of phenols to 1,6benzoquinone monoketals continues to be of interest. This transformation is generally achieved by anodic oxidation6' or uia the use of hypervalent iodine reagents such as phenyliodine diacetate or bis(trifluor0-acetoxy)iodo] benzene.66 This methodology has been employed as the key step in the synthesis of the antibiotics bromoxone (32)67 and LL-C10037a (33) (Scheme 18).68 The synthetic utility of this technique has been extended to the preparation of 4-fluorocyclohexane-2,5-dienonesby using pyridinium polyhydrogen fluoride in conjunction with hypervalent iodine (Scheme 19).69 The oxidative cleavage of catechols has been the subject of a number of investigations.This process is a key step in the biodegradation by soil bacteria of naturally occurring aromatic molecules and many aromatic environmental pollutants. Two types of oxidative cleavage are found ortho- or intradiol where cleavage is between the two hydroxy groups; and meta- or extradiol where cleavage is adjacent to the two hydroxy groups.Enzymatic extradiol cleavage of 2,3-dihydroxyphenyl-propionic acid (34) has been demonstrated (Scheme 20).70Intradiol cleavage of catechols has been achieved by a number of workers in a biomimetic fashion with 64 M. Matsumoto J. Tomizuka and M. Suzuki Synth. Commun. 1994 24 1441. 65 E.C.L. Gautier N. J. Lewis A. McKillop and R. J.K. Taylor Synth. Commun. 1994 24 2989. 66 A. McKillop L. McLaren and R.J.K. Taylor J. Chem. SOC. Perkin Trans. 1 1994 2047. E. C. L. Gautier N. J. Lewis A. McKillop and R.J. K. Taylor Tetrahedron Lett. 1994 35 8759. P. Wipf and Y. Kim J. Org. Chem. 1994 59 3518.69 0.Karam J.-C. Jacquesy and M.-P. Jouannetaud Tetrahedron Lett. 1994,35 2541. 'O W. W. Y. Lam and T. D. H. Bugg J. Chem. SOC. Chem. Commun. 1994 1163. Aromatic Compounds Scheme 18 Scheme 19 OH MhpB &IH ___c 0,.Fez+ (34) -0pC OH Scheme 20 iron(1rr)-catalysed ~xidation.~'-~~ This general sequence is illustrated in Scheme 21. Nucleophilic addition of organometallics to arenes provides a useful procedure for the generation of non-aromatic compounds from aromatic systems. The methodology of Meyer~,~~ diastereoselective addition of organometallics to chiral naphthalene oxazoles has been used to prepare dihydronaphthalenes of high enantiomeric purity (Scheme 22). 'v7 Kundig has demonstrated that a non-asymmetric variant of this process can be applied to the benzene ring (Scheme 23).77 71 S.R.Kaschabek and W. Reineke J. Org. Chem. 1994 59,4001. 72 J. E. Baldwin M. R. Spyvee and R. C. Whitehead Tetrahedron Lett. 1994,35 6575. 73 T. Funabiki M. Ishikawa Y. Nagai J. Yorita and S. Yoshida J.Chem.SOC.,Chem. Commun. 1994,1951. 74 A. N. Hulme and A.I. Meyers J. Org. Chem. 1994 59 952. '' M. K. Mokhallalati K. R. Muralidharan and L. N. Pridgen Tetrahedron Lett. 1994 35 4267. 76 X.Bai S.W. Mascarella W.D. Bowen and F.I. Carroll J. Chem. SOC. Chem. Commun. 1994 2401. 77 E.P. Kundig A. Ripa R. Liu and G. Bernardinelli J. Org. Chem. 1994 59 4773. A. P. Chorlton 0 Scheme 21 .. R’ Oy -Wii Reagents i R3Li; ii E+; iii H+ Scheme 22 Reagents i MeLi; ii RX;iii CO Scheme 23 OMe + Meo..& Reagents i BF,; ii DDQ Scheme 24 Complexation of anisole with pantaammineosmium(11) facilitates a non-concerted Diels-Alder reaction with N-methylmaleimide (Scheme 24).78 M.E.Kopach and W. D. Harman J. Org. Chem. 1994 59 6506. Aromatic Compounds Scheme 25 Scheme 26 hv -OY" hv - -A Scheme 27 Chiral naphthalene derivatives undergo [4 +23 cycloaddition with singlet oxygen. The diastereoselectivity of this reaction is dependent on the n-facial selectivity of the substituent (Scheme 25).79 Photocycloaddition of olefins to benzenoids releases the aromaticity of the ring and gives access to complex non-aromatic polycycles. Gilbert has shown that 3-benzylazaprop- 1 -enes undergo intramolecular meta photocycloaddition to give linear azatriquinanes with high selectivity (Scheme 26).80 Wagner has applied the use of chiral auxiliaries to ortho photocycloaddition.This has resulted in diastereoselective cycloaddition and kinetic resolution of the products (Scheme 27).81 l9 W. Adam and M. Prein Tetrahedron Lett. 1994 35 4331. D. C. Blakemore and A. Gilbert Tetrahedron Lett. 1994 35 5267. P. J. Wagner and K. McMahon J. Am. Chem. SOC. 1994 116 10827. 180 A. P. Chorlton The influence of arene substituents on the mode and regiochemistry of the photocycloaddition of furan to the benzene ring has been examined. An interesting observation in this work was isolation of 2-(2'-fury1)benzonitrile (35) from the photoreaction of furan with o-fluorobenzonitrile.This is thought to arise from the ortho cycloadduct (36) via ring opening of the resulting cyclobutene (37).82 (37) 4 Substitution in the Benzene Ring Electrophilic Substitution.-Electrophilic aromatic substitution is generally considered to proceed via the rate-limiting collapse of the electrophile (E) and the aromatic substrate (ArH) to form the o-complex (EArH) or Wheland intermediate. Since many electrophiles are also oxidizing agents an alternative mechanism involving an initial electron transfer to generate the aromatic cation radical (ArH") as the reactive intermediate has been presented. Prior to the formation of the latter are the transient charge-transfer complexes (ArH-E). This process has been studied by examination of the intermediates in aromatic halogenation with iodine monochloride.Kochi has established by spectral studies the formation of the charge transfer complex (ArH-ICI) which suffers electron transfer to afford the reactive triad (ArH' +I*Cl-). This aromatic cation radical is then quenched with chloride or iodine respectively. Iodination versus chlorination thus represents the competition between radical-pair and ion-pair collapse from the reactive triad. The product selectivity can be modulated by solvent polarity non polar solvents giving higher yields of chloro products and polar solvents giving an enhancement of iodo products.83 O'Malley in a similar study demonstrated that iodination predominates in benzonoid arenes whereas chlorination is the sole reaction with polycyclic aromatics.84 Lewis acid catalysed iodination of mesitylene and durene however appears to proceed via a o-complex (IArH).85 Aromatic compounds can be mildly and efficiently iodinated with pyridine-iodine monochloride complex.86 Introduction of iodine into the aromatic nucleus has also been achieved with iodine and a mercury@) salt87 and with iodine monofluoride generated in situ.88 Diaryliodonium salts (Ar,I)+X are an important class of polyvalent iodine compounds.They are generally synthesized indirectly via aryl iodides. However a reagent prepared from a 1:2 molar ratio of (di-acet0xy)iodobenzene and trifluoromethanesulfonic acid facilitates their preparation from aromatic compounds under mild condition^.^' 82 H.Garcia A. Gilbert and 0.Griffiths J. Chem. SOC.,Perkin Trans. 2 1994 247. S.M. Hubig W. Jung and J. K. Kochi J. Org. Chem. 1994 59 6233. 84 D.E. Turner R.F. O'Malley D.J. Sardella L.S. Barinelli and P. Kaul J. Org. Chem. 1994 59 7335. 85 C. Galli and S. Di Gaimmarino J. Chem. SOC.,Perkin Trans. 2. 1994 1261. 86 H.A. Muathen J. Chem. Rex (S) 1994 405. A. Bachki F. Foubelo and M. Yus Tetrahedron 1994 50 5139. 88 0.Thinius K. Dutschka and H. H. Coenen Tetrahedron Lett. 1994,35 9701. 89 T. Kitamura J.-I. Matsuyuki and H. Taniguchi Synthesis 1994 147. Aromatic Compounds Scheme 28 Regioselective bromination has been the subject of a number of papers. The nuclear versus side-chain bromination of methyl substituted anisoles by N-bromosuccinimide has been studied.This investigation led to the conclusion that methyl-substituted anisoles are para brominated rather than side-chain brominated if at least two methyl groups are present at positions 3 and 5 (Scheme 28).90 N,N-disubstituted anilines are preferentially brominated in the ortho position in the presence of surfactant.” Bromination of 2-acetoxymethyl-4-isopropoxy-5,7-dimethoxynaphthalene (38) in buffered solution affords the 8-monobromo compound (39) whereas monobromina- tion in the absence of the buffer yields the isomeric 1-bromonaphthalene (40).This difference in regioselectivity is thought to arise because the 8-bromo compound (39) is the kinetic product whereas the 1-bromo compound (40) is the thermodynamic product.The presence of the buffer traps the HBr thus preventing isomerization to the 8-bromo compound (39).92 OMe opi OMe OPi Me0 OAc Me0 OAc Me0 OAc br (39) a-Cyclodextrin has been shown to catalyse the aqueous bromination of various aromatic ~ubstrates.~~ A new mild chlorination method of aromatics has been developed. In this procedure hydroxy(tosy1oxy)iodobenzene (Koser’s reagent) and lithium or sodium chloride chlorinate polyalkylbenzenes on the ring. This methodol- ogy has been extended to bromination and i~donation.~~ The mechanism of aromatic nitration continues to be the focus of active interest. Gas phase studies without the complicating effects of a solvating environment are directly comparable to those of theoretical methods. Cacace has studied the gas phase aromatic substitution by (CH,ONO,)H+ ions by a combination of FT-ICR mass spectrometry and atmospheric pressure radiolytic techniques.The evidence from these experiments supports a mechanism involving preliminary formation of a Wheland intermediate from the attack of CH,OH-NO; complex on the arene followed by its isomerization 90 G.-J. M. Gruter 0.S. Akkerman and F. M. Bickelhaupt J. Org. Chem. 1994,59 4473. 91 G. Cerichelli and G. Mancini Tetrahedron 1994 50 3797. 92 R.G.F. Giles I. R. Green L.S. Knight V.R. L. Son P. R. K. Mitchell and S.C. Yorke J. Chem. SOC. Perkin Trans. 1 1994 853. 93 O.S. Tee and B.C. Javed J. Chem. SOC.,Perkin Trans. 2 1994 23. 94 P. Bovonsombat E. Djuardi and E. McNelis Tetrahedron Lett. 1994 35 2841. A.P. Chorlton Scheme 29 into the more stable o-protonated nitrobenzene structure uia a proton shift whose rate x is estimated to be ~3.6 107s-' at 315K.95 The thermal and photochemical nitration of aromatic systems has been studied. In this process aromatic hydrocarbons are readily nitrated by nitrogen dioxide in dichloromethane. The initial red colour observed is due to the metastable charge transfer complex (ArH NO+)NO,. Irradiation of this complex gives aromatic nitration even at -78 "C,where the thermal nitration is too slow to compete. In the absence of irradiation the same products are formed at room temperature. The photochemical and thermal processes are thought to proceed through the intermediacy of the radical-cation-containing (ArH + NO ) NO .96 When various alkyl-substituted p-dialkoxybenzenes are subjected to reaction with nitrogen dioxide either nitration or oxidative dealkylation products are formed (Scheme 29).The reason for this is that the aromatic radical intermediate (ArH") undergoes homolytic coupling with NO (which leads to aromatic nitration) and nucleophilic attack by NO; (which results in oxidative dealkylation). This competi- tion between nitration and oxidative dealkylation can be effectively modulated by solvent polarity and added nitrate.97 In a similar study the nitration and oxidation of 4-methoxyphenol by nitrous acid in aqueous acid has been examined.98 Nitrogen dioxide in the presence of ozone acts as a powerful nitrating agent converting non-activated arenes e.g.polychlorobenzenes into their corresponding nitro derivatives in good yields.99 This reaction known as the Kyodai nitration appears to be an electrophilic aromatic process and is characterized by unique features such as high ortho-directing trends of the acyl,"' ester,"' and halogen substitu- ents.'" The neutral conditions of this procedure also allow the nitration of acid-labile aromatic acetals and a~yls.''~ The initial products in the Kyodai nitration have been found to be composed of mainly rneta-nitro derivatives but this isomer distribution is rapidly replaced by the ortho and para isomers as the reaction proceeds. This suggests the operation of an electron-transfer mechanism involving nitrogen dioxide as the initial elec trophile.O4 Olah has reported a convenient and simple method for the nitration of aromatics. In this procedure a mixture of sodium nitrate and chlorotrimethylsilane generates nitryl 95 M. Aschi M. Attina F. Cacace and A. Ricci J. Am. Chem. SOC. 1994 116 9535. 96 E. Bosch and J.K. Kochi J. Org. Chem. 1994 59 3314. 97 R. Rathore E. Bosch and J. K. Kochi Tetrahedron 1994 50 6727. 98 B.D. Beake J. Constantine and R.B. Moodie J. Chem. SOC.,Perkin Trans. 2 1994 335. 99 H. Suzuki T. Mori and K. Maeda Synthesis 1994 841. loo H. Suzuki and T. Murashima J. Chem. SOC.,Perkin Trans. 1 1994 903. lo' H. Suzuki J.-I. Tomaru and T. Murashima J. Chem. SOC.,Perkin Trans. 1 1994 2413. lo' H. Suzuki and T. Mori J. Chem. SOC. Perkin Trans. 2 1994 479. lo3 H. Suzuki S.Yonezawa T. Mori and K. Maeda J. Chem. SOC. Perkin Trans. 1 1994 1367. '04 H. Suzuki T. Murashima and T. Mori J. Chem. SOC. Chem. Commun. 1994 1443. Aromatic Compounds chloride in situ which in the presence of aluminium chloride catalyst nitrates aromatic substrate^."^ The nitration of toluene with n-propyl nitrate has been carried out in the presence of the zeolite H-ZSM-5 as a catalyst. Under optimized conditions the product distribution o :m :p 5 :0 :95 was achieved.'06 Aromatic nitrosation unlike electrophilic aromatic nitration is by and large restricted to only the most electron-rich substrates such as phenols and anilines. Kochi has demonstrated that the less-reactive anisoles and polymethylbenzenes can be nitrosated with the electrophilic nitrosonium salt NO+BF in good yield under mild conditions in which the conventional procedure (based on nitrite neutralization with strong acid) is ineffective.'07 Ryu has shown that 1,3-dicyclohexylcarbodiimide(DCC) in the presence of sulfuric acid or aluminium chloride and an arene substrate give corresponding cyclohexylated arenes in good yield.'08 In this reaction DCC served as a cyclohexyl carbocation source.In an extension of this work a number of cyclohexylamide derivatives have also been used successfully as a source of the cyclohexyl carbocati~n.'~~ The synthesis of C-aryl glycosides has been reviewed this covers Fredel-Crafts (F-C) approaches to their preparation.' 1-Arylalkanes are not usually available via direct F-C alkylation of aromatic substrates on account of the tendency of the primary carbocation intermediates to rearrange.Smith has demonstrated that moderately activated benzenoid compounds undergo alkylation with allylic alcohols in the presence of acidic K10 clay to give almost exclusively 1-arylalk-2-enes by attack at the terminal positions of the intermediate ally1 cation. Catalytic hydrogenation of these derivatives yields the corresponding 1-arylalkanes.' ' ' In a similar manner cation-exchanged Montmoril- lonite-catalysed F-C alkylations have been carried out using methyl vinyl ketone and 4-hydroxybutan-2-one without the many side reactions such as isomerization transalkylation polymerization and polyalkylation that are known to take place when these substrates are used with traditional F-C catalysts."2,' l3 The activation of K1O-montmorillonite-supported zinc chloride (Clayzic) has been investigated as a catalyst in the F-C benzylation of benzene and halobenzenes.It has been found that thermal activation in air can give a rate enhancement greater than 30 compared to unactivated Clayzic in the benzylation of benzene.' ' Montmorillonite can support iron(m) chloride (Clayfec) when this catalyst is used in F-C acylations; chlorostyrene products as well as the expected acylated products are produced (Scheme 30).' ' Thg zeolite H-ZSM-5 has been used to catalyse F-C benzoylations. This catalyst is noted for its remarkable para selectively."6 When H-ZSM-5 is used in the Fries G.A. Olah P. Ramaiah G. Sandford A. Orlinkov and G.K. S. Prakash Synthesis 1994,468. lo6 T. J. Kwok K. Jayasuriya R. Damavarapu and B. W. Brodman J. Org. Chem. 1994 59 4939. lo' E. Bosch and J.K. Kochi J. Org. Chem. 1994 59 5573. J.N. Kim K. H. Chung and E. K. Ryu Tetrahedron Lett. 1994 35,903. I09 K.H.Chung J.N. Kim and E. K. Ryu Tetrahedron Lett. 1994 35,2913. 'Io C. Jaramillo and S. Knapp SYNLETT 1994 1. 'I1 K. Smith and G. M. Pollaud J. Chem. Soc. Perkin Trans. 1 1994 3519. J.-I. Tateiwa H. Horiuchi K. Hashimoto T. Yamauchi and S. Uemura J. Org. Chern. 1994 59 5901. 'I3 J.-I. Tateiwa T. Nishimura H. Horiuchi and S. Uemura J. Chem. Soc. Perkin Trans. 1 1994 3367. S. J. Barlow T.W. Bastock J. H. Clark and S. R. Cullen J. Chem. SOC.,Perkin Trans. 2 1994 41 1. T.W. Bastock J.H. Clark P. Landon and K.Martin J. Chem. Res. (S) 1994 104. 'I6 V. Paul A. Sudalai T. Daniel and K. V. Srinivasan Tetrahedron Lett. 1994 35,2601. A. P. Chorlton Me 0 Me CI MeCOCl &Me + Me Me Me Me Me Me Scheme 30 rearrangement of phenylacetate there is an unexpected tendency for the production of o-hydroxyacetophenone.' ' The regioselectivity in the benzoylation of 2-methoxynaphthalene is strongly influenced by the Lewis acid catalyst used. InCl, FeCl, SnCl, or ZnC1 give predominately the 2-benzoyl-6-methoxynaphthalene (41) whereas AlCI, SbCl, or TiCl give 1-benzoyl-2-methoxynaphthalene(42) as the major product." RCOl moMe moMe 0 (411 Phenols have been found to undergo facile C-benzoylation with a,a,a-tri-chloro- toluene in the presence of phase transfer catalyst to afford hydroxbenzophenone.' l9 Scandium trifluoromethane sulfonate Sc(OTf), was found to be a novel catalyst for F-C acylation.The reaction proceeds smoothly even in the presence of a catalytic amount of Sc(OTf), which can be recovered and reused.'*' The ortho acylation of anilines by nitriles (Sugasawa reaction) in the presence of BCl and a second Lewis acid appears to proceed through an intermediate 'Supercomplex' (43) including all four components (Scheme 31).12' It was found that the chloride affinity of the second Lewis acid governs supercomplex formation. Therefore judicious choice of the Lewis acid leads to yield improvements. This method has been used as the key intermediate in the preparation of a new generation of transcriptase inhibitors.22 A number of interesting Lewis acid mediated electrophilic substitution reactions related to the F-C reactions have been reported (Scheme 32).123*124 Independent groups of workers have developed similar methodologies for the ortho-specific formylation of phenols without the use of HMPA. This is achieved by 117 I. Neves F. Jayat P. Magnoux G. Perot F. R. Ribero M. Gubelrnann and M. Guisnet J. Chem. SOC. Chem. Commun. 1994 717. 118 S. Pivsa-Art K. Okuro,M. Miura S. Murata,and M. Nomura J.Chem.SOC.,Perkin Trans. 1,1994,1703. 119 C. Sarangi and Y.R. Rao J. Chem. Res. (S) 1994 392. 120 A. Kawada S. Mitamura and S. Kobayashi SYNLETT 1994 545. 121 A. W. Douglas N.L. Abrarnson I.N. Houpis S. Karady A. Molina L.C.Xavier and N. Yasuda Tetrahedron Lett. 1994 35 6807. 122 I. N. Houpis A. Molina A. W. Douglas L. Xavier J. Lynch R. P. Volante and P. J. Reider Tetrahedron Lett. 1994 35 6811. 123 G. A. Olah Q. Wang and G. Neyer Synthesis 1994 276. 124 G. Sartori F. Bigi R. Maggi and F. Tornasini Tetrahedron Lett. 1994 35 2393. Aromatic Compounds 2 II Scheme 31 Scheme 32 treating the aryloxymagnesium salts with paraformaldehyde followed by acidic ~ork-up.'~~*'~~ Conventional Vilsmeier formylation [POCl, (Me),NCHO] of naphthalene (44)affords the expected product (45). However if the bulky formamide N-neopentylformamide is used significant quantities of (46) and (47)are formed along with (45)"' In an extension of the Vilsmeier reaction a vinylogous formylation has been achieved with 3-trifloxypropeneiminium triflate (Scheme 33).' 28 A new regioselective tandem amidation reaction of electron-rich arenes has been established (Scheme 34).lz9 Leblanc has extended the utility of his amination reaction of arenes with electron-deficient azodicarboxylates.The procedure can now be used to produce amines from poorly reactive arenes like xylenes and the use of unsymmetrical azodicarboxylates now allows the synthesis of arylhydrazines (Scheme 35).l3O The Bamberger rearrangement is the most convenient and economical method for R. Aldred R. Johnston D. Levin and J. Neilan J. Chem. SOC.,Perkin Trans. 1 1994 1823. '26 R.X. Wang X.Z. You Q.J. Meng E. A. Mintz and X. R. Bu Synth. Commun. 1994 24 1757. "'S.V. Pansare and R. G. Ravi SYNLETT 1994 823. G. Maas R. Rahm M. Scheltz and E.-U. Wurthwein J. Org. Chem. 1994 59 6862. T. Cablewski P.A. Gurr K.D. Raner and C.R. Strauss J. Org. Chem. 1994 59 5814. H. Mitchell and Y. Leblanc J. Org. Chem. 1994 59 682. 186 A. P. Chorlton CHO Formylation <.~ 0 (44) (45) CHO (46) (47) I ii -M \mGe Me\N-CH=CH-CHO OMe H CHO Reagents i (CF,SO,),O; ii H20 Scheme 33 R R R -0 0 OH 2-2, Y OYNH R’ Scheme 34 the synthesis of para-aminophenols directly from nitrobenzenes. Phosphinic acid has been utilized as a hydrogen donor in this rearrangement (Scheme 36).13’ Cerfontain has carried out an in-depth study on the positional reaction order in the sulfonation of phenyl- and naphthyl-substituted naphthalenes with Nucleophilic Substitution.-Aromatic radical nucleophilic substitution or S, 1 has been shown to be an excellent means of effecting the nucleophilic substitution of unactivated aromatic compounds possessing suitable leaving groups.The mechanism of the reaction is a chain process the propagation steps are shown in Scheme 37. Scheme 37 depicts a nucleophile substitution in which radicals and radical anions are intermediates. However this chain process requires an initiation step such as equation 1. In a few systems spontaneous electron transfer (ET) from the nucleophile to the substrate has been observed. When ET does not occur spontaneously it can be induced A. Zoran 0.Khodzhaev and Y.Sasson J. Chem. SOC.,Chem.Commun. 1994 2239. 132 H. Cerfontain Y. Zou and B. H. Bakker Red. Trau. Chim. Pays-Bas 1994 113 517. Aromatic Compounds 0 0 C13Cr'OKN=NKOACCI, +P Reagents i ZnC1,; ii Zn HOAc; iii Bu,NF; iv Ac,O Scheme 35 OH Scheme 36 Initiation Step FU +e'-(Rx)' -1 Propagation Steps (RX)'-R + >t 2 R' + Nu-3 -(RNU)*-+ RX -RNu+(RX)" (RNu)" 4 RX + Nu-5 -RNu+>C Scheme 37 by a number of procedures. Recently Alonso and Lund have respectively used ultra~ound'~~ and electrochemical methods' 34 for this process. The mechanism and reactivity in ET-induced aromatic nucleophilic substitution has been comprehensively reviewed. 35 Aromatic nucleophilic substitution with carbon nucleophiles is an important 133 P. G. Manzo S.M. Palacios and R. A. Alonso Tetrahedron Lett. 1994 35 677. 134 H. Balshev and H. Lund Tetrahedron 1994 50 7889. J.-M. Saveant Tetrahedron 1994 50 10 117. A. P. Chorlton &N=NsBu' CH30COCHfiOCH3 KBU~~DMSO~IIV 0°C,2h + Ph PhN2BF4 -Ph -ArCl + NH3 + &Me POM ;/ e -[ NO2 MeO2C C02Me MeO& C02Me Scheme 38 method for the formation of carbonsarbon bonds. A number of examples are given in Scheme 38.'36-139 Carbon-carbon bonds can also be formed via vicarious nucleophilic substitution (VNS) of hydrogen. The reaction of a-halogenoesters with nitro aromatics has been exploited by a number of workers (Scheme 39).140*141 Makosza has shown that oxidative products can also be formed in preference to the VNS product in the reaction of the carbanion of dithianes with nitroarenes (Scheme 40).14* An elegant example of VNS has been demonstrated by Jung.The key step in this M. Tona F. Sanchez-Baesa and A. Messeguer Tetrahedron 1994,50 8117. T. Sakakura M. Hara and M. Tanka J. Chem. SOC.,Perkin Trans. 1 1994 283. C. Combellas C. Suba and A. Thiebault Tetrahedron Lett. 1994 35 5217. 139 W.-S. Li and J. Thottathil Tetrahedron Lett. 1994 35 6595. I4O G.A. DeBoos and D.J. Milner Synth. Commun. 1994 24 965. 14' 0.Haglund and M. Nilsson Synthesis 1994 242. 142 M. Makosza and M. Sypniewski Tetrahedron 1994 50 4913. Aromatic Compounds Scheme 39 Scheme 40 reaction is the trapping of an a-ketosulfonium salt generated by a Pummerer rearrangement of a 2-(phenylsulfinyl) phenol (Scheme 41).143 A novel nucleophilic aromatic substitution reaction has been described in which the methoxy group of l-methoxy-2-(diphenylphosphinyl)-naphthalene is readily replaced with Grignard reagents alkoxides and amides (Scheme 42). 144 Aromatic nucleophilic substitution by arylselenides has been demonstrated. The arylselenolate ions were produced through reductive cleavage of the Se-Se bond in diaryIselenides.l4' Nucleophilic displacement of 2,4,5-trichloronitrobenzene with potassium fluoride to give 2,4-difluoro-5-chloronitrobenzene is the key step in the cost- effective preparation of 2,4-difluoroaniline and 1,3-difluoroben~ene.'~~ A new example of nucleophilic aromatic substitution of hydrogen has been described.In this process aniline is reacted with azobenzene in the presence of base under aerobic conditions to generate 4-(phenylazo)diphenylamine in high yield (Scheme 43).14' Substitution via Organometallic Intermediates.-Directed ortho-metailation (DoM) continues to be exploited in the synthesis of aromatic compounds. A number of investigations have been carried out into the reactivity and regioselectivity of DoM. In general the DoM group possesses a hetero atom containing an unshared pair of electrons which serve to coordinate the organolithium oligomer as a prelude to the 143 M. E. Jung C. Kim and L. Von dem Bussche J. Org. Chem. 1994 59 3248. 144 T. Hattori J.-I. Sakamoto N. Hayashizaka and S. Miyano Synthesis 1994 199. 14' W. Boa Y.Zhang and S. Chen Synth.Commun. 1994 24 1339. 146 J. Mason and D. J. Milner Synth. Commun. 1994 24 529. 147 M.K. Stern B.K. Cheng F.D. Hileman and J.M. Allman J. Org. Chern. 1994 59 5627. A. P. Chorlton OH OH0 Ph Me OR Scheme 41 Reagents i R,CMgBr; ii RONa; iii R,NLi Scheme 42 ultimate hydrogen metal exchange. For such directing groups the availability of this unshared electron pair is the key to predicting the rate and extent of metallation provided by a particular DoM group in a particular environment. So in the case of anisole resonance of the lone pair on oxygen into the aromatic ring effectively depletes Aromatic Compounds Scheme 43 the coordinating power of the methoxy A decrease in availability of the oxygen lone pair for resonance and an increase in the acidity of the ring protons in anisole should effectively enhance the efficiency of the DoM process.This has been demonstrated a significant rate acceleration being obtained for the DoM of p-fluoroanisole. 149 The rate and regioselectivity of DoM can be dramatically affected by the use of TMEDA. This is thought to be due to the TMEDA reducing the oligomeric structure of alkyl lithiums down to a less sterically demanding dimeric structure . 48 9' O Significant differences in regioselectivity of DoM have been observed with 5-methoxy-2,3-dihydrobenzofuran (49) and -pyran (50).The furan (49) gives preferential lithiation at the CI position whereas with the pyran (50) p lithiation predominate. This is thought to be due to inductive contributions by the ether oxygen being significantly affected by ring size."' The regiochemical metallation of alkyl(alky1thio)benzenes with butyllithium or with the superbasic mixture of butyllithium with potassium t-butoxide has been studied.The reaction pattern depends on the substrate and base used.'52 A reverse of the expected regioselectivity has been observed when ethoxyvinyllithium-HMPA is used as a base (Scheme 44).'53 A number of recent synthetic advances in the use of DoM chemistry have been made. Sequential reaction of prochiral Cr(CO),($-arene) complexes with chiral amine bases and electrophiles yields chiral complexes (Scheme 45).154,'55 The use oflactones as the electrophile in DoM processes provides a mild alternative to Friedel-Crafts acylation (Scheme 46).lS6 The carboxylic group is a recent addition to the synthetic armoury of groups which facilitate D0M.ls7 14' D.W. Slocum R. Moon J. Thompson D. S. Coffey J. D. Li and M. G. Slocurn Tetrahedron Lett. 1994 35 385. 149 D. W. Slocurn D. S. Coffey A. Siegel and P. Grimes Tetrahedron Lett. 1994 35 389. 150 M. Khaldi F. Chretien and Y. Chapleur Tetrahedron Lett. 1994 35 401. ''I L.A. Paquette M.M. Schulze and D.G. Bolin J. Org. Chem. 1994 59 2043. S. Cabiddu C. Fattuoni C. Floris S. Melis and A. Serci Tetrahedron 1994 50 6037. M. Shirnano and A.I. Meyers J. Am. Chem. SOC. 1994 116 10815. 154 D.A. Price N.S. Simpson A.M. Mcleod and A.P. Watt Tetrahedron Lett. 1994 35 6159. 155 E. P. Kundig and A. Quattropani Tetrahedron Lett.1994 35 3497. 156 T. J. Brenstrum M. A. Brimble and R. J. Stevenson Tetrahedron 1994 50 4897. 15' J. Mortier J. Moyroud B. Bennetau and P.A. Cain J. Org. Chem. 1994 59 4042. 192 A. P.Chorlton Scheme 44 OM0 1 OM0 SiM% THF MeiCI. -78 "c Scheme 45 R' 0 R' 0 R2#NPi2 BU'LI -:eNF'+2 + a TMEDA R3 -78 "C oo R' R2,R3 = H OM0 n= 1.2 Scheme 46 N-fluorobenzenesulfonamide and N-fluoro-0-benzenedisulfonimide have been used as fluorine electrophiles in DoM to give access to a variety of monofluorinated aromatics.' 58 Aryllithium reagents prepared by halogen-lithium exchange have also provided a number of synthetic advances. o-Trimethylsilylphenyllithiumcan act as a synthetic equivalent of o-halophenyllithium (Scheme 47).59 Stable 2-lithio-6-nitrophenol derivative have been formed.The stability of these derivatives has been attributed to a chelation effect between the lithium and the nitro group aided by an inductive effect. These species have been trapped by a variety of 15' V. Snieckus F. Beaulieu K. Mohri W. Han C. K. Murphy and F. A. Davis Tetrahedron Lett. 1994,3S 3465. 159 M. Takahashi K. Hatano M. Kimura T. Watanabe T. Oriyama and G. Koga Tetrahedron Lett. 1994 35 579. Aromatic Compounds 193 Scheme 41 ““QBr OE j OH 02N9E P \ Me Me Reagents i PhLi; ii E+ Scheme 48 electrophiles’ 6o and also undergo metallo-Fries rearrangement (Scheme 48).16 Using the method of iodine-lithium exchange 1,3- and 1,4-dilithobenzenes have been generated in solution and isolated in the dry state for the first time.’62 Transition metal-catalysed cross-coupling reactions continue to be widely used for the functionalization of aromatic compounds.Most of these processes involve aryl or vinyl halides (or equivalents) with alkenes or hetero-substituted vinyl compounds or arenes. The Heck and Stille/Suzuki coupling reactions are among the most commonly used. The Heck type process is a palladium-catalysed vinylation of aryl halides. The utility of the reactions has been extended by the development of aqueous processes,163 polymer-bound palladium catalysts,164 and the use of aryl diazonium compounds in place of aryl halogenides. Functionalized olefins such as a-methoxyketenesilyl acetals’66 and [2-(dimethy1amino)ethoxylethenealso increase the synthetic scope of the Heck reaction.’67 The palladium-catalysed coupling between organostannanes 160 I. R. Hardcastle P. Quayle and E. L. Ward Tetrahedron Lett. 1994 35 1747. I. R. Hardcastle and P. Quayle Tetrahedron Lett. 1994 35 1749. 16’ M. Fossatelli R. den Besten H. P. Verkruijsse and L. Bradsma Red. Trau. Chim. Pays-Bas 1994 113 527. T.Jeffery Tetrahedron Lett. 1994 35 3051. P.-W. Wang and M.A. Fox J. Org. Chem. 1994 59 5358. M.Beller H. Fischer and K. Kuhlein Tetrahedron Lett. 1994 35 8773. 16’ T. Sakamoto Y. Kondo K. Masumoto and H. Yamanaka J. Chem. SOC.,Perkin Trans. 1 1994 235. 16’ M.Larhed C. M. Anderson and A. Hallberg Tetrahedron 1994 50 285. A. P. Chorlton Reagents i Pd(PPh,), Na,CO, MeOH/H,O Scheme 49 and unsaturated halides of sulfonates -the Stille coupling -has been the subject of a number of advances which include rate increases with copper(1) salts as cocatalysts,'68 polymer-bound aryl iodides (for combinatorial synthesis),' 69 and n-tributylallenyl stannanes as arylallene precursors.' 70 When the organostannane is replaced by aryl boronic acid the reaction is known as the Suzuki coupling.In this variant particular attention has been paid to the catalyst. Phosphine-free palladium catalysts give a significant rate acceleration and fewer side simple heterogeneous hydrogenation catalysts have also been The Suzuki coupling is carried out in the presence of a base but this is not always compatible with labile functionality present in the reactants.The function of the base in the coupling is thought to be to form a boronate anion that is capable of effecting boron-to-palladium !ransmetallation. Wright has demonstrated that the fluoride anion which has a high affinity for boron can be used to effect the Suzuki coupling under non-basic conditions.' 74 Axially chiral biphenyls have been syn- thesized by the Suzuki cross-coupling of tricarbonyl(arene)chromium complexes with aryl boronic acids (Scheme 49).'753'76 The synthetic utility of cross-coupling has been further exploited with the introduction of a number of new procedures. These include nickel-catalysed reactions of aryl halides in ~yridine,'~~ cross-coupling of arylzinc reagents which have been generated in situ from aryl iodides with a Zn(Agtgraphite couple '78and the use of ar~l'~~ and alkyl halide silanes'" in place of boronic acids and organo stannanes.Similar transition metal methodologies have been used for the introduction of a diverse range of functionalities into the aromatic nucleus. These are illustrated in Scheme 50.' '-I 84 Meyers has reported the chiral oxazoline-mediated Ullmann V. Farina S. Kapadia B. Krishnan C. Wang and L. S. Liebeskind J. Org. Chem. 1994 59 5905. 169 M.S. Deshpande Tetrahedron Lett. 1994 35 5613. 170 D. Badone R. Cardamone and U. Guzzi Tetrahedron Lett. 1994 35 5477. 17' T.I. Wallow and B. M. Novak J. Org. Chem. 1994 59 5034. 17' E. M. Campi W. R. Jackson S. M. Marcuccio and C.G.M. Naeslund J. Chern.SOC. Chem. Comrnun. 1994 2395.173 G. Marck A. Villiger and R. Buchecker Tetrahedron Lett. 1994 35 3277. S. W. Wright D. L. Hageman and L. D. McClure J. Org. Chem. 1994 59 6095. 175 M. Uemura and K. Kamikawa J. Chem. SOC. Chern. Cornmun. 1994 2697. 176 M. Uemura H. Nishimura K. Kamikawa K. Nakayama and Y. Hayashi Tetrahedron Lett. 1994,35 1909. 177 H. Kageyama T. Miyazaki and Y. Kimura SYNLETT 1994 371. 178 A. Furstner R. Singer and P. Knochel Tetrahedron Lett. 1994 35 1047. Y. Hatanaka K.-I. Goda and Y. Okahara Tetrahedron 1994 50 8301. I8O H. Matsuhashi M. Kuroboshi Y. Hatanaka and T. Hiyama Tetrahedron 1994 50 6507. Y. Kubota T.-A. Hanoka K. Takeuchi and Y. Sugi SYNLETT 1994 515. Y. Kubota T.-A. Hanoka K. Takeuchi and Y. Sugi J. Chem. Soc. Chem. Commun. 1994 1553.Aromatic Compounds 195 coupling which affords C,-symmetric biaryls.' 85*186 This methodology was used as the key step in the synthesis of ellagitannin (Scheme 50).ls7 Lipshutz has used intramolecular oxidative coupling of cyanocuprate intermediates to synthesize chiral biaryls.'88 Substitution via Aryl Radicals.-The tandem radical addition-cyclization of sub- stituted diethyl benzyl malonates (51) and alkynes (52) induced by manganese(II1) acetate has been reported. Tetrahydronaphthalenes (53)and spiro[4,5]decatrienes (54) are formed due to competing 6-endo- and 5-em-dig cyclizations.' 89 6-Endo-aryl radical cyclization is also observed in a convergent stereocontrolled synthetic route to linearly hexaannulated condensed hydroaromatic systems (Scheme 51).' 90 Tributyltin hydride-mediated radical cyclizations are useful synthetic transform- ations.A number of alternative procedures for the generation of aryl radicals have been developed and these have been applied to the synthesis of arylated heterocycles (Scheme 52).' 91-194 The reaction of 2,6-dichlorobenzoquinone N-chlorimine with phenol generates the blue anion of indophenol (the Gibbs reaction Scheme 53). This reaction is used as a colorimetric assay for phenols. In an investigation of this reaction the indophenol was found to form via a radical electrophilic aromatic substitution (S,,Ar) on phen01.l~~ The oxidative coupling of phenols is an important synthetic method for the construction of hydroxylated bi- and polyaryls. This reaction usually produces mixtures of compounds from which hydrsxylated biaryls and triaryls have to be separated.Sarturi has found that AlCI in CH,NO promotes a highly selective coupling of phenolic substrates.' 96 Phenolic oxidative coupling can also be achieved rapidly and efficiently under microwave irradiation with FeC13.6H,0 in the solid state.197 5 Condensed Polycyclic Aromatic Compounds Benzenoid Aromatics.-The discovery of the spherical C60 molecule known as a buckminsterfullerene (55) has generated a renewed interest in aromatic hydrocarbons with curved surfaces. Corannulene (56) which represents the polar cap of buckminster- fullerene has been prepared by a new synthetic route.'97 Ab initio calculations predict planar transition states for bowl-to-bowl inversion in corannulene (56) ethenocoran-nulene (57) and semibuckminsterfullerene (58) with energy barriers of 14.4 34.4 and M.Durandetti S. Sibille J.-Y. Nedelec and J. Perichon Synth. Commun. 1994 24 145. A.P. Melissaris and M.H. Litt J. Org. Chem. 1994 59 5818. T.D. Nelson and A.I. Meyers J. Org. Chem. 1994 59 2655. T. D. Nelson and A. I. Meyers Tetrahedron Lett. 1994 35 3259. T. D. Nelson and A.I. Meyers J. Org. Chem. 1994 59 2577. B. H. Lipshutz F. Kayser and Z.-P. Liu Angew. Chem. Int. Ed. Engl. 1994 33 1842. A. Citterio R. Sebastiano A. Maronatti R. Santi and F. Bergamini J.Chem.SOC.,Chem. Commun. 1994 1517. 190 S. P. Jayanta K. Mukhopadhyaya and U.R. Ghatak J. Org. Chem. 1994 59 2687. 19' A. J. Clark D.I. Davies K. Jones and C. Millbanks J. Chem. Soc. Chem. Commun. 1994 41. Y. Liu and J. Schwartz J. Org. Chern. 1994 59 940. 193 M.J. Begley J.A. Murphy and S.J. Roome Tetrahedron Lett. 1994 35 8679. 194 C. Lampard J. A. Murphy F. Rasheed N. Lewis M. B. Hursthouse and D. E. Hibbs Tetrahedron Lett. 1994 35 8675. 195 I. Pallagi A. Toro and 0.Farkas J. Org. Chem. 1994 59 6543. 196 G. Satori R.Maggi F. Bigi and M. Grandi J. Org. Chem. 1994 59 3701. 19' D. Villemin and F. Sauvaget SYNLETT 1994,435. A. P.Chorlton 032 Br + HOG + CO li R' But' 96% 98% Aromatic Compounds several steps I ?Me MeoQ Me0 Me0 Med bMe Reagents i PdCl, dppp base; ii e- Ni DMF; iii HO(Me),CC-CH PdCI,(PPh,), NEt, 40 min; iv KOH (2.5eq) Pr'OH reflux 2.5h; v Cu.py DMF reflux Scheme 50 74 kcal mol- respectively.'98 A large range of bowl-to-bowl inversion barriers have been calculated for heterocorannulenes :pentaazacorannulene has a barrier eight times that of corannulene whilst in pentaborazacorannulene it is less than 1kcal mol-'.'99 Cyclopentacorannulene (59) has been found to be locked into a bowl shape at least on an NMR timescale.200 Considerable synthetic effort has been directed at synthesizing these bowl shaped molecules.This has resulted in the synthesis of a C, hydrocarbon (60) whose carbon framework represents half of the buckminsterfullerene C, (55) surface. These compounds have been referred to as semibuckminsterfullerenes.201Similar C, fragments have also been synthesized uiz.(61)-(63).202-204 lg8 A. Sygula and P. W. Rabideau J. Chem. SOC. Chem. Commun. 1994 1497. 199 R.L. Disch and J.M. Schulman J. Am. Chem. SOC.,1994 116 1533. S. Sygula H. E. Folsom R. Sygula A. H. Abdourazak Z. Marcinow F. R. Fronczek and P. W. Rabideau J. Chem. SOC.,Chem. Commun. 1994 2571. P. W. Rabideau A. H. Abdourazak H. E. Folsom Z. Marcinow A. Sygula and R. Sygula J. Am. Chem. Soc. 1994 116 7891. '02 S. Hagen U. Nuechter M. Nuechter and G. Zimmermann Tetrahedron Lett. 1994.35 7013. '03 F. Sbrogio F. Fabris and 0.De Lucchi SYNLETT 1994 761. '04 M. J. Plater Tetrahedron Lett. 1994 35 6147. A. P. Chorlton t R‘-CZC-H COaEt CO2Et w-p Me b02Me Me i=o&fe Scheme 51 The semibuckminsterfullerene (58)C,,H, has been viewed as a rational precursor to the C, skeleton.AM1 and PM3 SCF-MO calculations suggest that dimerization of (58)to (64)by a mechanism involving six concurrent n2s +n4s additions (Scheme 54) corresponds to a stationary point with six negative force constants; the first stepwise n2s +n4s transition state is found to be highly unsymmetrical with a large barrier to rea~tion.~” Ester and ether derivatives of triphenylene have been widely studied as discotic liquid crystals. This interest has resulted in a number of more practical and economic syntheses of these triphenylene derivatives. 2,3,6,7,10,1l-Hexamethoxytriphenylene has been prepared by oxidative trimerization of 1,2-dimethoxybenzene with iron(rI1) chloride and sulfuric acid in nearly quantitative yield.206 Unsymmetrical derivatives have been prepared independently by similar methods (Scheme 55).207.208 (W (W (n) ’05 M.J. Plater H. S. Rzepa and S. Stossel J. Chem. SOC. Chem. Commun. 1994 1567. ’06 H. Naarmann M. Hanack and R. Mattmer Synthesis 1994 477 ’07 N. Boden R. J. Bushby and A.N. Cammidge J. Chem. SOC.,Chem. Cornrnun. 1994 465. ’08 J. W. Goodby M. Hird K. J. Toyne and T. Watson J. Chem. SOC.,Chem. Commun. 1994 1701. Aromatic Compounds 2RMgBr + CoCI -R2 + Co + 2 MgBrCl 2RMgBr + Co -RzCo+ MgBr + Mg R2Co+ 2 ArBr -R + CoBr + 2k' Fe I R2 Reagents i CoCI, RMgBr; ii Cp,TiCl, NaBH,; iii TTF H,O Me,CO Scheme 52 + "Ct Scheme 53 A. P. Chorlton Scheme 54 OR’ PO OR’ Reagents i FeCl,; ii MeOH Scheme 55 Phenanthrenes have been synthesized by the cyclization of stilbenes by flash vacuum pyrolysis209 and by a palladium-catalysed domino process (Scheme 56).2lo The polycyclic aromatic hydrocarbon (PAH) benzo[a]pyrene is metabolically converted into the highly carcinogenic diol epoxide (65).Meehan has developed an improved economical formal route to this compound.’l’ The next stage in tumorigen- esis is the binding of DNA to this mutagenic metabolite diol epoxide (Scheme 57). To permit further study of this process the derivatives of the amino trans ring opening of these diol epoxides have been synthesi~ed.~~’,~~~ In an advance of these studies the 209 M. J. Plater Tetrahedron Letr. 1994 35 801. 210 G. Dyker and A. Kellner Tetrahedron Lett.1994 35 7633. 211 G. R. .Negrete and T. Meehan Tetrahedron Lett. 1994 35 4727. 212 M. K. Laksham S. Chaturvedi and R. E. Lehr Synth. Commun. 1994 24 2983. 213 V. Y. Shafirovich P. P. Levin V. S. Kuzmin T. E. Thorgeirsson D. S. Kliger and N. E. Geacintov J. Am. Chem. SOC. 1994 116 63. Aromatic Compounds I 1 0 + 0 \ Scheme 56 HO Ho Scheme 57 N6-deoxyadenosine adducts resulting from the cis and trans ring opening of phenanthrene-9,lO-oxide have been prepared.2 l4 Non-benzenoidAromatics.-Ab initio quantum mechanical methods molecular mech- anics and semiempirical theoretical methods have been used to predict the molecular structures and energies of the plausible isomers of [10)annulene. These calculations have revealed a wealth of energetically low-lying structural isomers of the same (CH), connectivity.2l5 2,7-Methanocyclodeca[u]azulene (66) has been synthesized and its properties examined by 'H NMR.These studies have revealed that (66) is composed of a delocalized methano[lO]annulene and localized azulene moieties; there is no '14 M. K. Lakshman X.Xiao J. M. Sayer A.M. Cheh and D. M. Jerina J. Org. Chem. 1994 59 1755. Y. Xie H. F. Schaefer 111 G. Liang and J. P. Bowen J. Am. Chem. SOC.,1994 116 1442. 202 A. P. Chorlton contribution from the peripheral l8.n-electron system.2 l6 In a similar study annulenes fused with azulene were examined. It was found in the 10,12-bisdehydr-3-isopropyl-9,14-dimethyl[ 14]annulene[a]azulene (67) that the fusion of the azulene ring sup- presses the diatropicity of [4n + 21 14.n-electron system to a smaller extent than the benzene ring.21 7,21 A series of tetramethyloctadehydrodihydro[26]- -[28]- -[30]- -[32]- and -[34]- annulenediones (68)-(72) have been synthesized and their properties examined.2 The dications of (68) and (69) were found to be significantly paratropic and diatropic respectively.This is the first confirmation of the alternation of the tropic nature between [4n + 23.n and 4n.n electron systems in monocyclic annulenediones.220 (a) m= n= 1 [a)- (69)[28&m=l,n=2 (70)130). m-n= 2 (71) [32).m= 2 n= 3 (72) [a). m = /I = 3 In an analogous study methano-bridged dichlorodidehydroC 161- -[20]- and -[24]annulendiones were prepared (Scheme 58).22 These annulendiones exhibited 216 K.Ito H. Kawaji and M. Nitta Tetrahedron Lett. 1994 35 2561. 217 H. Higuchi J. Ojirna M. Yasunarni K. Fujirnori and M. Yoshifuji Tetrahedron Lett. 1994 35 1259. 218 H. Higuchi J. Ojirna M. Yasunarni K. Fujirnori M. Ueno M. Yoshifuji and G. Yarnarnoto J. Chem. SOC. Perkin Trans. 1 1994 1167. 219 H. Higuchi S. Kondo Y. Watanabe J. Ojirna and G. Yarnamoto J. Chem. SOC.,Perkin Trans. 1 1994 1957. 220 H. Higuchi S. Kondo Y. Watanabe J. Ojirna and G. Yarnarnoto J. Chem. SOC.,Chem. Commun. 1994 877. 221 H. Higuchi K. Asano J. Ojirna K. Yarnarnoto T. Yoshida J. Adachi and G. Yarnarnoto J. Chem. SOC. Perkin Trans. 1 1994 1453. Aromatic Compounds 0 (75) (24)-m= n=3 (74) m = 1 n = 0 Scheme 58 Reagents i LiOH; ii Br,; iii Bu'OK Scheme 59 strong diatropicity in D,SO due to the dicationic 1471 1871 and 2271-electron species and their diatropicities were shown to increase with increasing ring size.In this investigation the intramolecular Glaser coupling of (73) to give (74) also gave the biproduct (75). The dication of (75) exhibited diatropicity ascribable to the formation of a cationic 1071-electron species.222 Gellman has developed a new synthetic route to the 16-methano[lO]annulene skeleton. The key step in this route is the semibenzylic Favorskii rearrangement of the C4.4.2)propellane (76) to the C4.4.13 propellane. This methodology now provides access to 1,6-methano[ lolannulene derivatives bearing substituents on the bridge carbon (Scheme 59).223 6 Cyclophanes The intramolecular [2 + 21 photocyloaddition of vinyl arenes has been successfully applied to the synthesis of cy~lophanes.~~~ A recent example of this process is the synthesis of metacyclophanes (Scheme 60).225 Conformational studies have been carried out on selectively methylated [2.2] (1,3)( 1,4)cyclophanes.Dynamic 'H NMR spectroscopy was employed to estimate the 222 H. Higuchi C. Sakon K. Asano J. Ojima M. Iyoda K. Inoue and G. Yamarnoto J. Chem. Soc. Perkin Trans. 1 1994 2915. 223 D. G. Barrett G.-B. Liang D.T. McQuade J. M. Despers K. D. Schladetzky and S. H. Gellman J. Am. Chem. SOC.,1994 116 10525. 224 J. Nichimura Y. Okada S. Inokuma Y. Nakamura and S. R. Gao SYNLETT 1994 884. "' Y.Okada F. Ishii Y. Kasai and J. Nishimura Tetrahedron 1994 50 12 159. A. P. Chorlton OMe OMe Me0 OMe Scheme 60 relative conformational barrier in each C2.21 cyclophane. These results show that there is an increase of about 13 kJ mol-going from the parent [2.2](1,3)(1,4)cyclophane (77) to its 12,15-(78) and 12,16-dimethyl (79) derivatives.226 (78) (79) (80) (1,4)Naphthaleno[2.2]-meta-cyclophanes (80) have been synthesized via the sulfox- ide pyrolysis method. These derivatives were found to be conformationally rigid up to 1500C.2278-Methoxy-[2.2]-rneta-cyclophanes form charge transfer complexes with tetracyanoethylene. The effect of substituent has a dramatic effect on the absorption of the charge transfer band. Electron-donating substituents give substantial bathoch- romic shifts whereas no complexes are formed when electron-withdrawing groups are introduced (Scheme 61).228 Cyclophanes have also been employed as effective chiral auxiliaries for asymmetric synthesis (Scheme 62).229 Paracyclophane (83) undergoes ring-opening metathesis polymerization to give poly(pphenyleneviny1ene) (PPV).This polymerization proceeds in a living fashion that provides PPV with a narrow polydispersability and a molecular weight which increases linearly with the amount of monomer reacted (Scheme 63).230 226 Y.-H. Lai A.H.-T. Yap and I. Novak J. Org. Chem. 1994 59 3381. 227 T. Yamato K. Noda K. Tokuhisa and M. Tashiro J. Chem. Res. (S) 1994 210. 228 T. Yamato J.-I. Matsumoto N. Shinoda S. Ide M.Shigekuni and M. Tashiro J. Chem. Res. (S) 1994 178. 229 V. Rozenberg V. Kharitorov 0.Antonov E. Sergeeva A. Aleshkin N. Ikonnikov S. Orlova and Y. Belokun Angew. Chem. Int. Ed. Engl. 1994 33 91. 230 Y.-J. Mia0 and G.C. Bazan J. Am. Chem. SOC. 1994 116 9379. Aromatic Compounds (81) R'=Bu',R~=R~=H,&~~~~ (82) R' = But = OMe R3= H,A,,,,x 640 Scheme 61 OH syn-L Syn-0 Scheme 62 A. P. Chorlton Mez(But)SiO ei Reagents i Mo~(2,6-Pr:Ph)](CHCMe2Ph)[OCMe(CF,),] Scheme 63