5 Aromatic compounds By ALAN P. CHORLTON Zeneca Specialties Hexagon House Blackley Manchester UK M9 8ZS 1 General and theoretical studies Aromaticity is one of the fundamental concepts of organic chemistry. Methods of assessment of aromaticity have been the subject of a great deal of interest. This debate centres round conflicting hypotheses that aromaticity is at least a two dimensional phenomenon the classical view opposed by the concept that aromaticity can be fully described by magnetic criteria. Krygowski and Cyranski have put forward a model that supports the classical view.1 In this model the energetic and geometric components that contribute to aromaticity can be separated. Schleyer et al. however support the magnetic concept of aromaticity and in a recent study have demonstrated how NMRshifts in larger aromatic systems can be correlated with the magnetic susceptibility exaltations to provide an e¶cient aromaticity probe.2 Bird has made a study of diamagnetic susceptibility enhancements for a large number of aromatic systems and has concluded that there is no apparent justification for the separation of classical and magnetic concepts of aromaticity.3 Katritzky et al.have shown that the aromaticity of a system can vary depending on its molecular environment. Aromaticity of a number of systems has been studied experimentally and theoretically and is found to increase with the polarity of the medium.4 Bond fixation and aromaticity have been studied in a number of strained annulated benzenes. The biphenylene fused dihydropyrene 1 has been examined by NMR spectroscopy.Analysis of this data indicates that biphenylene has about 55% of the relative bond fixing ability of benzene and has a Dewar resonance of 1.59 times that of benzene which compares favourably with a calculated Dewar resonance energy 1.55 times that of benzene.5 A comprehensive study of the bond resonance energies of polycyclic benzenoid and non-benzenoid hydrocarbons has been carried out.6 Incorporation of the biphenylene moiety into a cyclic system gives the cyclic [n]phenylenes; theoretical studies of [6]phenylene (antikekulene) 2 have shown it to be planar and to be appreciably destabilized relative to the linear [6]phenylene 3.7 Theoretical studies have been carried out on kekulene 4 to establish whether it exists in a benzenoid resonance form 5 or the annulenoid form 6 consisting of an outer [30]annulene and an inner [18]annulene which would give rise to superaromaticity.This work concludes that the benzenoid representation of kekulene is the most realistic.8 A recent high level ab initio study has concluded that [5]pericyclyne 7 is not homoaromatic based on geometric energetic and magnetic criteria.9 Royal Society of Chemistry–Annual Reports–Book B 119 1 2 3 4 5 6 R R R R R R R R R R 7 R = CH3 Theoretical studies on the valence isomers of benzene have attracted attention. Results of semiempirical MNDOC-CI and ab initio CASSCF calculations have revealed that fulvene 8 is a primary product of the photolysis of benzene. The most probable mechanism for the photochemical isomerization of benzene to fulvene in- 120 Alan P. Chorlton 1 * S0('A19) 245 nm • • • • S1('B24) 9 10 8 Scheme 1 H H H H 11 12 Scheme 2 D D 13 D D H H • 15 D D • • 14 • • Scheme 3 volves the intermediate structures prefulvene 9 and 1,3-cyclopentadienylcarbene 10 (Scheme 1).10 Similar calculations on the electrocyclic ring opening of Dewar benzene predict conrotatory electrocyclic ring opening to give the unknown Mo� bius benzene 11.This is contrary to the assumed disrotatory ring opening of Dewar benzene to give benzene. These calculations also support the existence of another new benzene isomer trans- Dewar benzene 12 (Scheme 2).11 The thermal isomerization of [1,4-D 2 ]-benzene 13 and [1,2-13C 2 ]-benzene 14 have been studied in excess hydrogen at 750–850 °C in a quartz flow system. In both cases the main isomerization products are the corresponding meta isomers.The data suggest a radical intermolecular interchange of benzene carbons by 1,2-carbon shifts. In the deuterium case the rearrangement is thought to proceed via the bicyclo[3.1.0]hexanyl intermediate 15 (Scheme 3).12 Theoretical interest in benzyne has been renewed because of the discovery that p-benzyne derivatives formed by Bergman cyclization are involved in DNA-cleaving activity of antitumour antibiotics. Ab initio calculations of hydrogen abstraction reaction of phenyl radical and p-benzyne suggest that the rate of hydrogen abstraction for p-benzyne diradical at room temperature should be 14 times lower than the phenyl radical.13 In an experimental study the hydrogen abstraction rate of 9,10-dehydroan- 121 Aromatic compounds thracene was found to be 100–200 times lower than the phenyl or 9-anthryl radical.14 The 13C dipolar NMR spectrum of matrix isolated [1,2-13C 2 ]o-benzyne has been reported.The resulting 13C spectrum was analysed to obtain the 13C chemical shift tensor of the two labelled carbons and to determine the length of the triple bond which compares favourably to the triple bond in cycloctyne.15 The isomeric o- m- and p-benzyne negative ions have been formed in gas-phase experiments and their thermochemical properties were investigated. The meta and para isomers were previously unknown.16,17 Theoretical studies gave good agreement between experimental estimates for electron proton and hydrogen atom binding energies. The 1,3,5-trimethylbenzene negative ion 16 has also been characterized.18 CH2 – H2C CH2 •• • • 16 Interactions between aromatic units play a significant role in supramolecular chemistry.These interactions are important in diverse phenomena such as base–base interactions in DNA intercalation of small molecules between nucleotides packing of aromatic molecules in crystals the tertiary structures of proteins and host–guest binding. To gain more information about these interactions a theoretical study has examined benzene and toluene dimers in the gas phase and in aqueous solution. These calculations have revealed that the T-shaped benzene dimer is more stable than its stacked homologue and with toluene the T-shaped structure is also favoured.A conclusion that could be made from these results is that the toluene dimers are a better model for the study of p–p interactions in proteins.19 In a similar study the interactions between toluene and the ammonium cation have been examined.This interaction was calculated to be 3 kcal mol~1 and this type of association is shown to be clearly favoured in non-polar environments. These observations concur with the analysis of Phe–Lys interactions in several protein structures.20 Dougherty and co-workers have performed a series of ab initio computational studies on the binding of the sodium cation to the p face of a range of aromatic structures. An excellent correlation between the binding energy and electrostatic potential of these complexes was obtained.21 The thermochemistry of molecular complexes of halogens with benzene and benzene derivatives has been studied.22 The measurement of proton a¶nities in aromatics is especially important in the context of electrophilic substitution reactions yielding insight into the reaction mechanism and reactivity of substituted benzene derivatives.Experimentally proton a¶nities are very di¶cult to determine. A theoretical study of the additivity of proton a¶nities in aromatics and polysubstituted benzene molecules has proved to give very good agreement with the latest experimental data.23,24 2 Preparation of benzene molecules from non-aromatic precursors The resurgence of interest in the cyclization of enediynes to aromatics via Bergman cyclization and related processes continues. This is in large part due to the inter- 122 Alan P. Chorlton • R • R Rh cat. Rh R Rh• • Scheme 4 1 equiv. RhCl(Pri 3P)2 Et3N C6D6 70 °C 12 h [Rh]• [Rh]• [Rh] • • Scheme 5 mediacy of arene diradicals which are implicated in the DNA-cleaving activity of the eneyne family of antitumour antibiotics.With respect to the preparation of benzenes from non-aromatic precursors a number of recent contributions in this area have synthetic and methodological significance.25,26 A rhodium(I)-catalysed variant of the Myers cycloaromatization has been developed and is summarised in Scheme 4. An example of the utility of this process is shown in Scheme 5.27 An acyclic enediyne possessing an aminomethyl group 17 has been designed and synthesized as a potential substrate for pyridoxal-dependant enzymes. Cycloaromatization of 17 was achieved with pyridoxal or isonicotinaldehyde (Scheme 6).28 Shibuya et al. have developed a methodology in which cis-enediynes are generated via hydrolysis and decarboxylation of malonate ester derivatives (Scheme 7).29 Meyers cycloaromatization has been used in conjunction with an intramolecular Diels–Alder reaction in a cascade sequence (Scheme 8).30 The reaction of Fischer carbene complexes with alkynes continues to be of synthetic importance for the preparation of oxygenated benzene molecules.This methodology has been extended to incorporate the use of conjugated 1,3-diynes. This new procedure provides a new stratagem for the synthesis of biaryls (Scheme 9).31 The intermediates and transition structures of the benzannulation of heteroatomstabilized chromium carbene complexes with ethyne have been subjected to a density functional study. This work reveals a number of interesting observations regarding the mechanism and explains the experimental observation that aminocarbenes require a greater reaction temperature compared with hydroxycarbenes.32 In the above process the aromatic ring-forming reaction can be viewed as 6p-electrocyclisation of dienylketene 18 (Scheme 10).By analogy dienylvinylidenes can be invoked as precursors to a novel 6p-electrocyclization process (Scheme 11). This hypothesis has been tested out 123 Aromatic compounds Scheme 6 Reagents i PL-HCl (1 equiv.) NEt 3 (2 equiv.) dioxane 37 °C 40 min.; ii Ac 2 O Pyr. rt 12 h; iii HCl H 2 O acetone rt 1.5 h R1 R2 R3 CO2R4 MeO CO2R4 R1 R2 R3 CO2H MeO CO2R4 R1 R2 R3 • OMe CO2R4 R1 R3 R2 CO2R4 OMe • • Scheme 7 successfully to provide a novel aromatic ring forming cyclization (Scheme 12).33 Two novel benzannulation methods have been developed which provide ready access to highly substituted arenes (Scheme 13),34 and an easy synthesis of paracyclophanes (Scheme 14).35 The ring expansion of 4-alkenyl (or aryl) cyclobutenones to aromatic systems has led to a number of useful synthetic applications.These include the synthesis of the monoterpene espintanol (Scheme 15)36 and highly substituted annulated furans (Scheme 16).37 If 4-allenylcyclobutenones are thermally ring expanded reactive o-quinomethanes are formed and can be trapped. The reaction has synthetic 124 Alan P. Chorlton • refluxing benzene • • • • • • H H 50% Scheme 8 OR (CO)5Cr OH Ph Ph OR Ph Ph Scheme 9 • O OH 18 Scheme 10 •M M H M = Transition metal Scheme 11 Scheme 12 125 Aromatic compounds Scheme 13 (CH2)10 (CH2)10 Pd(PPh3)4 toluene 65 °C 1 h high dilution 48% Scheme 14 Scheme 15 Bun Bun OMe O Bun Ar i D ii TFA O Bun MeO MeO Bun Bun 74% Scheme 16 potential as a route to highly substituted phenols benzofurans and aryl analogues of hexahydrocannabinol (Scheme 17).38 The Diels–Alder reaction is often used in preference to conventional aromatic substitution to construct highly substituted benzenoid systems to limit regiochemical problems.The synthesis of multisubstituted naphthalenes,39 anilines40 and p-terphenyl41 are recent examples (Scheme 18). 126 Alan P. Chorlton MeO MeO O OH • CH3 CH3 CH3 CH3 H3C CH3 O MeO MeO OH O OH OMe OMe H H C6H6 40–50 °C Scheme 17 Scheme 18 A novel benzannulation sequence based on chromium(0)-promoted [6p]4p] cycloaddition followed by a Ramberg–Ba� cklund rearrangement has been disclosed.A noteworthy feature of this two-operation methodology is the simultaneous production of two rings during the cyclization process (Scheme 19).42 A number of new methods for the regioselective synthesis of naphthalene derivatives have been developed (Scheme 20).43–45 In a new simple route to phenanthrenes aryl pinacols have been 127 Aromatic compounds Scheme 19 Scheme 20 found to react in triflic acid to give substituted phenanthrenes in excellent yield. The regiochemistry of this reaction can be controlled by deactivating substituents (Scheme 21).46 3 Non-aromatic compounds from benzene precursors The biotransformation of benzene and its derivatives to their corresponding cisdihydrodiols has been exploited as a key step in the synthesis of highly oxygenated natural products.The current status and future perspectives of this transformation in organic synthesis have been reviewed.47,48 Recent advances in the this area include the dioxygenase-catalysed oxidation of dihydronaphthalenes49 and the synthesis of deuterated carbohydrates (Scheme 22).50 The muconic acid pathways provide key routes for the microbiological degradation of benzene derivatives (Scheme 23). Kirby and co-workers have shown that (Z,Z)-3- methylmuconic acid 19 undergoes enzymic cyclization by syn addition of carboxy groups to the distal double bond to form the S-4-methylmuconolactone 20 in bacteria 128 Alan P. Chorlton OH HO Cl Cl TfOH 98% Cl Cl Scheme 21 Scheme 22 Reagents i Pseudomonas putida Me OH OH 4 HO2C Me CO2H 19 O Me HO2C O H 3 3 S 21 O O CO2H S Me 20 ii i 4 Scheme 23 Reagents i bacteria; ii fungi 129 Aromatic compounds + O O O O O O 22 Scheme 24 Scheme 25 whereas in fungi syn cyclization of 19 gives the S-muconolactone 21.51 This group have also reported the synthesis and absolute configurations of 3- and 4-methylmuconolactones 21 and 20.52 Chlorinated aromatics are well known recalcitrant pollutants because of their slow biodegradation by micro-organisms.It has been demonstrated that 2,4,6-trichlorophenol can be degraded chemically by the action of hydrogen peroxide catalysed by iron tetrasulfophthalocyanines.53 The oxidation of an aromatic ring with dimethyldioxirane has been the subject of a number of studies;54,55 hexamethylbenzene gave the triepoxide 22 in 51% yield (Scheme 24).55 Addition to functionalized arenes provides a useful procedure for the generation of non-aromatic compounds from aromatic systems this area has been reviewed.56 The conjugate addition of organolithium reagents to arenes is one of the most useful examples of this type of process.Two examples highlighting the power of this methodology are given in Scheme 25.57,58 The irradiation of aromatics in the presence of alkenes provides [2]2] [3]2] and [4]2] cycloadducts. Tethering the alkene to the arene gives a degree of control in this process and allows the synthesis of complex multi-ring compounds from simple precursors. An excellent example of this concept is the total synthesis of (^)-ceratropicanol in seven steps the key step being an intramolecular [3]2] photocycloaddi- 130 Alan P. Chorlton Scheme 26 H H H NC hn 254 nm (PhCO2)2 CH3CN 90–95 °C Scheme 27 N O H H Ar Ar C N O + – Scheme 28 tion (Scheme 26).59 The previous synthesis of ([)-ceratropicanol had involved 19 steps.In a similar process Wender et al. have accessed the complex fenestrane skeleton in three steps (Scheme 27).60 Polycyclic aromatics have been shown to undergo 1,3- dipolar cycloadditions with 3,5-dichloro-2,4,6-trimethyl- and 2,4,6-trimethyl-benzonitrile oxide (Scheme 28).61 4 Substitution in the benzene ring Electrophilic substitution The desire to introduce fluorine into aromatic compounds to influence physical chemical and biological properties has led to a number of new fluorination methodologies. Banks et al. have provided a full account of the conception and laboratory synthesis of the site-selective and easily handled 1-alkyl-4-fluoro-1,4-diazoniabicyclo[ 2.2.2]octane salts.62 It may be argued that the problem of electrophilic fluorination has been solved by the use of such stable electrophilic fluorinating agents.However these agents have initially to be prepared by the direct use of fluorineThe controlled use of elemental fluorine as an electrophile would clearly be beneficial on a large scale. In this respect a direct fluorination method for the synthesis of 4- fluorobenzoic acid in formic acid and sulfuric acid has been developed.63 A mild chlorination of aromatic compounds has been reported with tin(IV) chloride and lead tetraacetate. This methodology is particularly e§ective for selective chlorination of polyalkylbenzenes and also obviates the need for chlorine gas.64 Regioselective introduction of bromine into aromatic substrates has been the focus of a number of investigations.Highly e¶cient para-selective bromination of simple aromatics has 131 Aromatic compounds OMe OMe OMe OMe OAc X PhI(OAc)2 TMSX X = Cl or Br Scheme 29 been achieved by means of bromine and a reusable zeolite.65 The ortho para ratio of bromination of anilines can be controlled to varying degrees depending on the surfactants employed.66 Iodoarenes are key substrates for transition metal coupling reactions; this has fuelled a need for more versatile iodination procedures. N-Iodosuccinimide in acetonitrile has proved to be a mild and regiospecific method for the introduction of iodine into a wide range of methoxy-substituted benzenes and naphthalenes. 67 Deactivated aromatic systems can be iodinated in a system consisting of iodine sulfuric acid and perfluorocarbon solvent through which elemental fluorine is passed.68 A novel method for the haloacetoxylation of 1,4-dimethoxynaphthalenes using hypervalent iodine chemistry has been developed.This transformation represents a formal addition of AcOX to benzyne and thus 1,4-dimethoxynaphthalenes represent benzyne equivalents (Scheme 29).69 Nitrogen dioxide in the presence of ozone acts as a powerful nitrating agent for aromatic substrates (the Kyodai nitration). This process o§ers regiospecific advantages over conventional nitration methodologies. The Kyodai nitration of methyl phenylacetate gave an overall yield of 85% of which 88% was the o-nitro isomer. This is the highest ortho-isomer proportion so far observed in electrophilic aromatic nitration.70 A similar reversal of selectivity has been observed in the Kyodai nitration of naphthalene where the 1-nitro 2-nitro isomer ratios were found to be remarkably high.This enhancement in regioselectivity compared with conventional nitrations has been interpreted in terms of an electron transfer mechanism involving the nitrogen trioxide as the initial electrophile.71 In an attempt to render the Kyodai nitration more user friendly ozone has been replaced by oxygen in the presence of tris(pentane-2,4- dionato)iron(III) use of this procedure has allowed moderately activated arenes to be nitrated in fair to good yields.72 High para-selective nitration of simple aromatic compounds has been achieved by a solvent free process using a stoichiometric quantity of nitric acid and acetic anhydride at 0–20 °C in the presence of b-zeolite as the catalyst.This process represents a clean synthesis of simple nitroaromatics the zeolite being easily recovered and the only byproduct formed is acetic acid.73 Sulfuric acid supported on silica gel has also been used e§ectively as a catalyst for aromatic nitration.74 Heterogeneous catalysis of the Friedel–Crafts (F–C) alkylation has been achieved with copper or zinc chloride doped natural phosphate and tricalcium phosphate. The process gives high levels of monoalkylated products.75 The bond-forming step in F–C alkylation reactions has been investigated through use of a method for introducing essentially free carbocations into an aromatic solvent in the absence of catalyst. This study supports the view that the methanism proceeds through a single transition state.76 Chlorobenzotrifluorides under typical F–C reaction conditions react e¶ciently with aromatic compounds to a§ord dichlorodiphenylmethanes in an excellent yield.The expected difluorodiphenylmethanes are not isolated as a result of halogen exchange (Scheme 30).77 132 Alan P. Chorlton R + X CF3 Cl Cl R R R = H Me X OMe X = 2-Cl X = 4-Cl Yield > 90% AlCl3 (3 moles) EDC 0 °C Scheme 30 Scheme 31 The F–C acylation is generally performed using aluminium chloride as a Lewis acid catalyst. This process can be particularly problematical in an industrial situation where the reaction requires more than a stoichiometric amount of aluminium chloride which cannot be reused because of its instability in aqueous workup.In order to solve these problems several approaches to catalytic F–C acylation have been reported. These include hafnium trifluoromethanesulfonate (triflate),78,79 zirconium tetrachloride 80 metal bis(trifluoromethylsulfonyl)amides,81 lanthanide triflate–lithium perchlorate82 and polymer-supported scandium catalysts.83 Anisole undergoes regiospecific trifluoracetylation in neat trifluoroacetic anhydride in the presence of CoCl 2 as catalyst. However with a 1 1 anisole trifluoroacetic anhydride ratio only the para-dimerized product is obtained (Scheme 31).84 A number of novel Lewis acid mediated electrophilic substitution reactions related to the F–C reaction have been reported (Scheme 32).85–87 The regioselectivity of the Gattermann–Koch formylation of 1-methylnaphthalene using various compositions of HF–SbF 5 has been examined.It was found that 4-methyl-1-naphthaldehyde was formed preferentially when the ratio of SbF 5 1- methylnaphthalene was 1 1. However if the ratio of SbF 5 to 1-methylnaphthaldehyde was increased a mixture of the 4-methyl-1-naphthaldehyde and 1-methyl-2-naphthaldehyde were formed. This regioselective di§erence was rationalised as being derived from the protonation of 1-methylnaphthalene under a solvent-cage-like atmosphere (Scheme 33).88 Deformylation of aromatic aldehydes has been achieved e¶ciently with scandium trifluoromethanesulfonate as a catalyst.89 The first example of a thia-Fries rearrangement has been reported. In this process aryl phenylsulfinates are treated with aluminium chloride at 25 °C to give good yields of (phenylsulfinyl)phenols (Scheme 33).90 The aza-Claisen rearrangement has been promoted by the use of zeolites (Scheme 34).91 Symmetrical binaphthyl derivatives have been formed in a high yielding catalytic process from naphthalene derivatives using NaNO 2 and CF 3 SO 3 H.This reaction is presumed to proceed via a radical cation intermediate (Scheme 34).92 133 Aromatic compounds Scheme 32 Scheme 33 Nucleophilic substitution The generally accepted mechanism for nucleophilic aromatic substitution is an addition –elimination process and involves the formation of a Meisenheimer type of intermediate. Whether the rate limiting step of this mechanism is the formation of the intermediate or expulsion of the leaving group has been found to depend on the 134 Alan P. Chorlton R N R¢ R¢¢ R NH R¢ Zeolite 80 °C Hexane 2 h R¢¢ + R N R¢ R¢¢ CH3 Scheme 34 Scheme 35 character of the nucleophile and the leaving group as well as on the solvent.Matsson and co-workers have studied the solvent dependent leaving group fluorine kinetic isotype (FKIE) e§ect in a nucleophilic aromatic substitution reaction of 2,4-dinitro- fluorobenzene with piperidine. A significant FKIE was observed in THF suggesting that in this solvent departure of the leaving group is the rate-limiting step. However with acetonitrile as the solvent no such FKIE was observed which is consistent with addition of the nucleophile to the aromatic substrate being the rate-limiting step.93 The kinetics and mechanism of the reaction of 2,4-dinitrofluorobenzene with hydroxide ion in ‘water in oil’ microemulsions has been investigated.The results show that the rate of the reaction depends mainly on the nature of the surfactant molecules and the amount of water present in the microemulsion. The reaction rate is enhanced by about 40-fold in cationic microemulsions relative to aqueous solutions and by three orders of magnitude in relation to anionic microemulsions.94 1,3,5-Trinitrobenzene is known to react with aldehydes and ketones containing an a-hydrogen to yield only the carbon-bonded Meisenheimer complexes; the oxygencentred adducts have surprisingly never been detected. Buncel et al. have presented unequivocal evidence for the low temperature existence of an oxygen-bonded enolate Meisenheimer complex. As the temperature is allowed to rise the carbon-bonded Meisenheimer complex becomes the major product.95 The reaction of 3,5-difluoro-4-chloronitrobenzene with thiophenoxide anion leads predominantly to substitution of the chlorine atom through an S N Ar orbital-controlled process.However when the harder methoxide anion is used the substitution of the meta-fluorine atom becomes the dominant pathway. Kinetic measurements and theoretical calculations indicated that the observed meta substitution of fluorine is an S N Ar charge-controlled reaction with a loosely bonded transition state (Scheme 36).96 The regioselective nucleophilic substitution of tri- and di-substituted fluorobenzoates and fluorobenzonitriles has been accomplished by sequential addition of various oxygen and nitrogen nucleophiles. An example is given in Scheme 37.97 135 Aromatic compounds SPh F F NO2 85% Cl F F NO2 Cl F OCH3 NO2 67% PhS– MeO– Scheme 36 NC F F N Boc OK NC F O NBoc + HO2C OMe O NBoc i KOMe ii NaOH Scheme 37 Scheme 38 A convenient synthesis of triarylamines via ester-mediated nucleophilic aromatic substitution has been disclosed.This method complements the traditional Ullmantype condensation of diarylamines with haloarenes (Scheme 38).98 The use of pyridine as a cocatalyst for the synthesis of N-phenylanthranilic acid by the Ullman reaction has been reported.99 A new one-pot procedure for the synthesis of polyfluoroanisoles from poly- fluoroanilines has been developed.100 Aromatic fluorides can be formed e¶ciently via diazotization of aminoarenes followed by in situ fluorodediazoniation of the diazonium ions; this has successfully been accomplished using hydrogen fluoride in combination with base solutions.101 The formation of carbon–carbon bonds via vicarious nucleophilic substitution (VNS) of hydrogen continues to be exploited.Alkylnitrobenzenes,102 p-nitroarylaldehydes103 and a-disubstituted-p-anitrophenylacetic esters104 have been made in this way (Scheme 39). Makosza et al. have developed a VNS methodology which proceeds via heterocyclic ring opening (Scheme 40).105 VNS of hydrogen with amine nucleophiles has been demonstrated. In this process 1,1,1-trimethylhydrazinium iodide was utilized as a VNS reagent for the introduction of amino groups into nitroaromatic substrates (Scheme 41).106 VNS methodology has significant synthetic utility; however the requirement for an auxiliary leaving group has a number of disadvantages including complexity of the nucleophile.Nucleophilic aromatic substitution of hydrogen with oxidation at the intermediate r-complex does not have this limitation but su§ers from others namely the sensitivity of nucleophiles towards oxidation. This problem can be overcome if an 136 Alan P. Chorlton Scheme 39 Scheme 40 NO2 NO2 NO2 NO2 NH2 NH2 2 equiv.(CH3)3N+–NH2 NaOMe DMSO I– Scheme 41 oxidant can be found that oxidizes the r-complex faster than the starting nucleophile. The use of KMnO 4 in liquid ammonia and photochemical oxidation have both been shown to lead to successful examples of oxidative nucleophilic substitution of hydrogen (Scheme 42).107,108 The reaction of 1,3,5-trinitrobenzene with methoxide and hypochlorite gives 3,5- dichloro-2,4,6-trimethoxynitrobenzene as the major product and 1,3,5-trichloro-2,4,6- 137 Aromatic compounds Scheme 42 NO2 O2N NO2 NO2 Cl Cl MeO OMe OMe Cl Cl Cl MeO OMe OMe + MeO– MeOH ClO– H2O Scheme 43 trimethoxybenzene as the minor product.This could formally be regarded as oxidative nucleophilic substitution of hydrogen but it is thought to take place via a three step mechanism involving nucleophilic addition of methoxide ion electrophilic chlorination by attack of hypochlorite ion trans to the methoxy group and base-induced E2 elimination (Scheme 43).109 Substitution via organometallic intermediates The burgeoning interest in transition metal-catalysed cross-coupling reactions continues. This area dominates the literature for new methodologies for the functionalisation of aromatic compounds. The advances in this area include improvements in catalysts extension of methodologies to new substrates solid-phase processes new synthetic applications and processes for the arylation of amines and thiols.The palladium-catalyst reaction of organic halides with alkenes (Heck reaction) has become a well established synthetically important method for forming carbon–carbon bonds. Recent advances include the use of tetraalkylammonium salts which can lead to enhanced reactivity selectivity and which obviate the need for phosphine ligands used molten as solvents and in certain cases allow aqueous processes to be carried out.110,111 Tetraalkylammonium salts have also been used in an e¶cient palladiumcatalysed coupling of terminal alkynes with aryl halides.112 Nanostructured palladium clusters can be stabilized in propylene carbonate; these colloidal solutions can also catalyse the Heck reaction in the absence of phosphine ligands.113,114 One disadvantage of cross-coupling reactions is that they are in general limited to expensive aryl iodide or bromide substrates.Recent developments have addressed this 138 Alan P. Chorlton Scheme 44 Scheme 45 issue. The more economic and synthetically accessible chloroarenes,115,116 arylmesylates117,118 and arenediazonium salts119 have all been successfully used in crosscoupling reactions. The palladium-catalysed cross-coupling of aryl halides and organozinc reagents (Negishi–Kumada reaction) o§ers advantages over the aryltin derivatives (Stille reaction) and boronic esters (Suzuki reaction). This process can tolerate many functionalities and can be e§ected under milder reaction conditions especially using a copper(I) cocatalyst.120 The robustness and high generality of transition metal cross-coupling reactions has led to solid-phase variants being developed for combinatorial synthesis.A solid-phase variant of the Suzuki reaction has been developed.121 Microwaveassisted solid-phase Suzuki coupling gives very fast reaction times.122 A solid-phase version of the Negishi–Kumada reaction has also been developed.123 Libraries of aromatic amines have also been produced by solid-phase transition metal-catalysed coupling reactions between aryl bromides and amines.124,125 In the above solid-phase processes the aryl moiety is generally linked to the polymer backbone via an ester or amide which is subsequently cleaved at the end of the reaction sequence to yield the final product.These processes are limited because the functionalized aromatic always contains an acid amide or ester grouping. Han et al. have developed a solid-phase Suzuki-coupling in which the aryl halide is linked to the polymer via an aryl silane linkage. This arylsilane linker can be cleaved with a variety of electrophiles such as H` I` Br` Cl` Ac`andNO 2 ` to give more diversity in the combinatorial libraries.126 The synthetic utility of the Heck reaction has been extended to give high levels of enantioselectivity (Scheme 44).127 Allylic alcohols have been synthesized via palladium-mediated reactions of stannoxanes with aryl halides (Scheme 45).128 Oligophenylenes are of interest for use in electro- and photo-chemical devices. The Suzuki aryl–aryl coupling when used in an iterative processes has proved successful in 139 Aromatic compounds R Br R Br + B(OH)2 Br R R > 95% (HO)2B R R 40–60% Br R R Br Br 85% toluene Na2CO3(aq) [Pd] 3 d reflux BunLi B(OCH3)3 HCl(aq) 11 toluene Na2CO3(aq) [Pd] 3 d reflux i ii iii Scheme 46 R1 X HN NH R2 N NH R2 R1 + PdCl2[P( o-tol)3]2 NaOBut X = Br I Scheme 47 the synthesis of various oligophenylenes;129–132 an example of this is given in Scheme 46.129 Transition metal-catalysed cross-couplings have primarily focused on aryl–aryl or aryl–alkene/alkane bond formation.Recently a number of groups have turned their attention to the arylation of amines. The groups of Buchwald and Hartwig have independently developed second generation palladium catalysts for the conversion of aryl bromides and iodides to mixed secondary and tertiary aryl amines.133–136 The synthetic utility of this reaction has found application in the synthesis of the arylpiperazines which have provoked recent interest because of their medicinal and electronic properties (Scheme 47).137–139 Solid-phase synthesis of arylamines via palladium-catalysed amination of polymer bound aromatic bromides has also been reported.124,125 The introduction of sulfur into the aromatic ring has also been successfully achieved via palladium-catalysed coupling reactions (Scheme 48).140–142 Palladium-catalysed carbonylation and hydroformylation methodologies continue to be developed two useful contributions are outlined in Scheme 49.143,144 140 Alan P.Chorlton S Ar R R X S R R ArSCN 2SmI2 PdCl2 cat Pd S O NHMe R X = I OTf i NaSTlPS Pd(PPh3)4 ii (Bu)4NF SH Scheme 48 N O O X + NH2 NHCO N O O PdCl2L2 PPh3 DBU–CO–DMAc OTf CHO CO R3SiH Pd(OAc)2 ligand Et3N DMF 70 °C Scheme 49 As the examples above testify palladium and nickel are the dominant catalysts in this area.Allred and Liebeskind have developed a copper-mediated cross-coupling of organostannanes with organic iodides. This protocol is simple and also o§ers the advantage of a rapid reaction rate at low temperatures and although it is stoichiometric in copper it may prove to be a competitor to many palladium-catalysed processes. 145 Copper catalysts have also found use in the direct amination of nitrobenzenes with o-alkylhydroxylamines and in the oxidative electrophilic amination of cyanocuprates with lithium amides (Scheme 50).146,147 Directed ortho-metallation (DOM) continues to be exploited as an e§ective synthetic tool for the construction of regiospecifically substituted aromatic rings.Spangler 141 Aromatic compounds Scheme 50 SO2OPri CONPr2 i SO2OPri CONPr2 i CONPr2 i + + i Bu nLi ii MeI 90% 6% 90% recovered Scheme 51 CF3 Cl CF3 Cl CF3 Cl Li Li CF3 Cl CF3 Cl COOH COOH CO2 CO2 LiCH(CH3)C2H5 LiC4H9 Scheme 52 has demonstrated that alkyl benzenesulfonates are very powerful ortho directors relative to known DOM groups (Scheme 51).148 The DOM capacity of the carboxylic group has been classified as intermediate in reactivity compared with a selection of DOM groups.149 The metallation of fluoroarenes carrying chlorine or bromine as additional substituents always occurs ortho to the fluorine when potassium tert-butoxide activated butyllithium or lithium 2,2,6,6-tetramethylpiperidine is used as the base.150 The control of DOM selectivity can be modulated by the choice of base (Scheme 52).151 142 Alan P.Chorlton FVP 1–2 torr 1200–1300 °C Scheme 53 O O Me3 SiO OSiMe3 LDA ClSiMe3 FVP 1000 °C Scheme 54 5 Condensed polycyclic aromatic compounds Benzenoid aromatics Curved polycyclic aromatic hydrocarbons (PAH) of five- and six-membered rings organised in the same arrangement as those found on the surface of fullerenes have attracted considerable attention since the first isolation of C 60 . Scott et al. have achieved the synthesis of a fullerene fragment which comprises 60% of C 60 . The benefits of this synthesis are that the C 36 H 12 fragment is obtained in just one step by vacuum pyrolysis (FVP) of the commercially available precursor decacylene (Scheme 53).152 In a similar approach towards C 60 fragments the chromium complexes of butyldecacylene and tri-tert-butyl-decacylene have been considered as possible precursors to bowl-shaped PAHs.153 Corannulene is the simplest of the curved PAHs.Lin and Rabideau have reported a new corannulene synthesis via the FVP of silyl vinyl ethers (Scheme 54).154 This procedure may have advantages where the usual precursor the bis(chlorovinyl) derivative is not accessible from the diketone. The addition of an extra five-membered ring to the corannulene carbon framework increases significantly both the curvature and rigidity of the system. The barriers to inversion of corannulenes are in the range *G‡\10–11 kcal mol~1 whereas the cyclopentacorannulene 23 has been determined at *G‡\27.61–27.67 kcal mol~1 over the temperature range 52.1–99.3 °C.Deuteration of cyclopentacorannulene 23 takes place with p-facial stereochemistry to give exclusively the exo-dideuteriocyclopentacorannulene 24.155 Gas phase argon ion fragmentation of hexafluorotribenzotriphenylene generates a key fullerene fragment trifluorohemifullerene (Scheme 54).156 Mass spectral evidence for the formation of trace quantities of C 60 from mellitic trianhydride has been reported (Scheme 56).157 143 Aromatic compounds F F F F F F F F F + other Fragments Scheme 55 O O O O O O O O O Ph2O reflux 24 h C60 trace by MS Scheme 56 FVT 1000 °C Scheme 57 23 H D H 24 D PAHs containing fully unsaturated five-membered rings as integral components of their trigonal carbon networks have also attracted interest due to their photophysical and biological properties.These non-alternant cyclopenta-fused PAHs are thought to arise from alternant PAHs. These transformations have been studied by FVP by a number of groups.158–160 An example of this is the conversion of triphenylene to cyclopent[h,i]acephenanthrylene (Scheme 57).160 The PAH dibenzotetraphenylperiflanthene 25 synthesized via an e¶cient high yielding oxidative coupling was found to emit blue light under conditions of electrogenerated chemiluminescence (Scheme 58).161 A number of previously unknown dicyclopentapyrenes have been synthesized via FVP of bis(chlorovinyl) precursors (Scheme 59).162 The interest in C 60 and 144 Alan P. Chorlton O Fissure-coupling Fjord-coupling Cove-coupling i heat ii H+ CoF3–TFA reflux 25 Scheme 58 Cl Cl Cl Cl Cl Cl Scheme 59 145 Aromatic compounds AlCl3–CuCl2 Scheme 60 fullerene precursors has led to a renaissance of interest in PAHs from a synthetic and materials viewpoint.Molecular electronics research has recently focused on thin film devices. There is therefore a requirement for organic materials that can be vapour deposited to give controlled films without thermal degradation. A number of C 54 PAHs have been synthesized which fulfil these application requirements (Scheme 60).163 27 26 The biphenylene dimer 26 has been synthesized and has been considered as a molecular fragment of a two dimensional carbon-net 27 (Scheme 61).164 A family of graphite ribbons have been synthesized by stilbene-like photocyclizations (Scheme 62).165 The cyclic PAHs coronene 28 and [7]circulene 29 have both been synthesized by new methods (Scheme 63).166,167 The highly hindered PAH decaphenylanthracene 30 has been synthesized.Despite the highly sterically crowded nature of the anthracene moiety it still retains the characteristics of a normal anthracene.168 Non-benzenoid aromatics Benz[a]azulenes 31 are a well-known class of polycyclic non-benzenoid aromatics. The dearth of synthetic methodologies for their preparation has hindered progress in this area. Anovel one-pot tropylium ion-mediated furan ring opening process has been 146 Alan P. Chorlton R R R R hn I2 Scheme 61 Scheme 62 147 Aromatic compounds Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph 30 O R R O Ph3C+BF4 – Scheme 63 31 32 developed that allows the successful synthesis of benz[a]azulene derivatives (Scheme 64).169 Protonation of azuleno[1,2-a]acenaphthylene 32 has been studied in superacids.The resulting monocation is best viewed as an azulenium ion having strong tropylium ion character with limited charge delocalisation into the naphthalene moiety.170 A series of push-pull azulenes have been synthesized and the e§ect of the substituents has been examined by NMR and UV–VIS spectroscopy.171 Ring strain precludes D 10h symmetry for the parent [10]annulene 33. A number of planar all-cis[10]annulene derivatives (34 and 35) have been proposed which takes advantage of strain to overcome the planarity problem in simple all-cis derivatives of 33. Theoretical studies on the aromatization of these derivatives indicates that they are attractive candidates worthy of experimental investigation.172 10p 10p 10p 33 34 35 148 Alan P.Chorlton Scheme 64 The novel thia[13]annulene 36 had been prepared and is notably diatropic and shows about 40% of the ring current of the parent bridged [14]annulene 37.173 Mechanistic studies on the formation of fullerenes suggests that monocyclic species play a key role in formation of carbon cages. Tobe et al. have designed dodecadehydro[18]annulene 38 and hexadecadehydro[24]annulene 39 annulated by [4.3.2]propellatriene units as new viable precursors of cyclo[18]carbon 40 and cyclo[24]carbon 41. The C 18 ~ and C 24 ~ ions were observable when the precursors 38 and 39 were subjected to negative ion LD-TOF mass spectrometry. A photochemical study of 38 was carried out in furan which gave a number of products including the 149 Aromatic compounds Scheme 65 furan adduct 42 which may have resulted from cyclo[18]carbon 40 (Scheme 64).174 6 Cyclophanes Recent advances in cyclophane chemistry have been reviewed by Bodwell.175 The first example of a corannulene cyclophane 43 has been reported.The e§ect of the cyclophane is to lock e§ectively the corannulene into only one bowl form.176 The remarkably distorted 1,8-dioxa[8](2,7)pyrenophane 44 was prepared by the valence isomerization and dehydrogenation of the tethered [2,2]metacyclophanediene 45. In the crystal the overall bend is nearly 90°. The curvature of the aromatic surface approximates that expected for a fragment of the C 6h-symmetric C 84 molecule (Scheme 65).177 Appropriately substituted [2.2]paracyclophanes are molecules that are linearly chiral chemically stable and racemize only at high temperatures.A unique homochiral amino acid derived from [2.2]paracyclophane 46 has been synthesized.This product should have great potential as a chiral auxiliary.178 The long sought after [3. 6 ] (1,2,3,4,5,6)cyclophane 47 has finally been synthesized. The structure of this molecule has resulted in it being referred to as a molecular pinwheel.179 References 1 T.M. Krygowski and M. Cyranski Tetrahedron 1996 52 10 255. 2 P. v.R. Schleyer C. Maerker A. Dransfield H. Jiao and N. J. R. van Eikema Hommes J. Am. Chem. Soc. 150 Alan P. Chorlton 1996 118 6317. 3 C.W. Bird Tetrahedron 1996 52 9945. 4 A.R. Katritzky M. Karelson and A. P. Wells J. Org. Chem. 1996 61 1619. 5 R.H.Mitchell and V. S. Iyer J. Am. Chem. Soc. 1996 118 2903. 6 J.-I. Aihara J. Chem. Soc. Perkin Trans. 2 1996 2185. 7 J.M. Schulman and R. L. Disch J. Am. Chem. Soc. 1996 118 8470. 8 H. Jiao and P. v. R. Scheyer Angew. Chem. Int. Ed. Engl. 1996 352383. 9 H. Jiao N. J. R. van Eikema Hommes P. v. R. Schleyer and A. de Meijere J. Org. Chem. 1996 61 2826. 10 J. Dreyer and M. Klessinger J. Eur. Chem. 1996 2 335. 11 R. P. Johnson and K. J. Daoust J. Am. Chem. Soc. 1996 118 7381. 12 G. Zimmermann M. Nuchter H. Hopf K. Ibrom and L. Ernst Liebigs Ann. 1996 1407. 13 C. F. Logan and P. Chen J. Am. Chem. Soc. 1996 118 2113. 14 M.J. Schottelius and P. Chen J. Am. Chem. Soc. 1996 118 4896. 15 A.M. Orendt J. C. Facelli J. G. Radziszewski W. J. Horton D.M. Grant and J. Michl J. Am. Chem. Soc. 1996 118 846.16 P. G. Wenthold J. Hu and R. R. Squires J. Am. Chem. Soc. 1996 118 11 865. 17 J. J. Nash and R. R. Squires J. Am. Chem. Soc. 1996 118 11 872. 18 J. Hu and R. R. Squires J. Am. Chem. Soc. 1996 118 5816. 19 C. Chipot R. Ja§e B. Maigret D. A. Pearlman and P. A. Kollman J. Am. Chem. Soc. 1996 118 11 217. 20 C. Chipot B. Maigret D. A. Pearlman and P. A. Kollman J. Am. Chem. Soc. 1996 118 2998. 21 S. Mecozzi A. P. West Jr. and D. A. Dougherty J. Am. Chem. Soc. 1996 118 2307. 22 I. Drepaul V. Fagundez F. Guiterrez E. H. Lau and J. A. Joens J. Org. Chem. 1996 61 337. 23 Z. B. Maksic D. Kovacek M. Eckert-Maksic and I. Zrinski J. Org. Chem. 1996 61 6717. 24 M. Eckert-Maksic M. Klessinger and Z. B. Maksic J. Eur. Chem. 1996 2 1251. 25 B. Konig Angew. Chem. Int. Ed. Engl. 1996 35 165.26 P. Chen Angew. Chem. Int. Ed. Engl. 1996 35 1479. 27 K. Ohe M. Kojima K. Yonehara and S. Uemura Angew. Chem. Int. Ed. Engl. 1996 35 1823. 28 M. Wakayama H. Nemoto and M. Shibuya Tetrahedron Lett. 1996 37 5397. 29 M. Shibuya M. Wakayama Y. Naoe T. Kawakami K. Ishigaki H. Nemoto H. Shimizu and Y. Nagao Tetrahedron Lett. 1996 37 865. 30 K. K. Wang Z. Wang A. Tarli and P. Gannett J. Am. Chem. Soc. 1996 118 10 783. 31 J. Bao M. J. Fumo E. B. Grant D. P. Heller M. C. Whitcomb and S. Yeung J. Am. Chem. Soc. 1996 118 2166. 32 M.M. Gleichmann K. H. Dotz and B. A. Hess J. Am. Chem. Soc. 1996 118 10 551. 33 C. A. Merlic and M.E. Pauly J. Am. Chem. Soc. 1996 118 11 319. 34 T. Takahashi R. Hara Y. Nishihara and M. Kotora J. Am. Chem. Soc. 1996 118 5154. 35 S. Saito M. W. Salter V. Gevorgyan N.Tsuboya K. Tando and Y. Yamamoto J. Am. Chem. Soc. 1996 118 3970. 36 C. S. Tomooka H. Liu and H. W. Moore J. Org. Chem. 1996 61 6009. 37 P. Turnbull M. J. Heileman and H. W. Moore J. Org. Chem. 1996 61 2584. 38 M. Taing and H. W. Moore J. Org. Chem. 1996 61 329. 39 N. G. Anderson S. P. Maddaford and B. A. Keay J. Org. Chem. 1996 61 2885. 40 J. E. Cochran T. Wu and A. Padwa Tetrahedron Lett. 1996 37 2903. 41 Y. Yamamoto K. Nunokawa M. Ohno and S. Eguchi Synthesis 1996 949. 42 J. H. Rigby and N. C. Warshakoon J. Org. Chem. 1996 61 7644. 43 Y. Tanabe S. Seko Y. Nishii T. Yoshida N. Utsumi and G. Suzukamo J. Chem. Soc. Perkin Trans. 1 1996 2157. 44 R. Grigg and L.-H. Xu Tetrahedron Lett. 1996 37 4251. 45 K.M. Yadau P. K. Mohanta H. Ila and H. Junjappa Tetrahedron 1996 52 14 049. 46 G.D. Olah D. A. Klumpp and G. N. Q. Wang Synthesis 1996 321. 47 T. Hudlicky and A. J. Thorpe Chem. Commun. 1996 1993. 48 T. Hudlicky K. A. Abboud P. A. Entwistle R. Fan R. Maurya A. J. Thorpe J. Bolonick and B. Meyers Synthesis 1996 897. 49 D. R. Boyd N. D. Sharma N. A. Kerley R. Austin S. McMordie G. N. Sheldrake P. Williams and H. Dalton J. Chem. Soc. Perkin Trans. 1 1996 62. 50 T. Hudlicky K. K. Pitzer M. R. Stabile A. J. Thorpe and G. M. Whited J. Org. Chem. 1996 61 4151. 51 B. Chen G. W. Kirby G. V. Rao and R. B. Cain J. Chem. Soc. Perkin Trans. 1 1996 1153. 52 A. A. Freer G.W. Kirby G. V. Rao and R. B. Cain J. Chem. Soc. Perkin Trans. 1 1996 2111. 53 A. Sorokin D. De Suzzoni-Dezard D. Poullain J. P. Noel and B. Meunier J. Am. Chem. Soc. 1996 118 7410. 54 R.W. Murray M. Singh and N.P. Rath Tetrahedron Lett. 1996 37 8671. 55 R.W. Murray M. Singh and N. P. Rath J. Org. Chem. 1996 61 7660. 56 T. Bach Angew. Chem. Int. Ed. Engl. 1996 35 729. 57 D. Amurrio K. Khan and E. P. Kundig J. Org. Chem. 1996 61 2258. 151 Aromatic compounds 58 M. Shimano and A. I. Meyers J. Org. Chem. 1996 61 5714. 59 C. Baralotto M. Chanon and M. Julliard J. Org. Chem. 1996 61 3576. 60 P. A. Wender T. M. Dore and M.A. Delong Tetrahedron Lett. 1996 37 7687. 61 A. Corsaro V. Librando U. Chiacchio and V. Pistara Tetrahedron 1996 52 13 027. 62 R. E. Banks M. K. Besheesh S. N. Mohialdin-Kha§af and I. Sharif J. Chem. Soc. Perkin Trans. 1 1996 2069. 63 R. D. Chambers C. J. Skinner J. Hutchinson and J. Thomson J. Chem. Soc. Perkin Trans. 1 1996 605. 64 H. A. Muathen Tetrahedron 1996 52 8863.65 K. Smith and D. Bahzad Chem. Commun. 1996 467. 66 G. Cerichelli L. Luchetti and G. Mancini Tetrahedron 1996 52 2465. 67 M. C. Carreno J. L. Garcia Ruano G.-S.M. A. Toledo and A. Urbano Tetrahedron Lett. 1996 37 4081. 68 R. D. Chambers C. J. Skinner M.J. Atherton and J. S. Moilliet J. Chem. Soc. Perkin Trans. 1 1996 1659. 69 P. A. Evans and T. A. Brandt Tetrahedron Lett. 1996 37 6443. 70 H. Suzuki T. Takeuchi and T. Mori J. Org. Chem. 1996 61 5944. 71 H. Suzuki and T. Mori J. Chem. Soc. Perkin Trans. 1 1996 677. 72 H. Suzuki S. Yonezawua N. Nonoyama and T. Mori J. Chem. Soc. Perkin Trans. 1 1996 2385. 73 K. Smith A. Musson and G. A. Deboos Chem. Commun. 1996 469. 74 J. M. Riego Z. Sedin J. M. Zaldivar N. C. Marziano and C. Tortatos Tetrahedron Lett. 1996 37 513. 75 S. Sebti A.Rhilhil and A. Saber Chem. Lett. 1996 721. 76 E. H. White R. W. Darbeau Y. Chen S. Chen and D. Chen J. Org. Chem. 1996 61 7986. 77 R. K. Ramchandani R. D. Wakharkar and A. Sudalai Tetrahedron Lett. 1996 37 4063. 78 S. Kobayashi M. Moriwaki and I. Hachiya Tetrahedron Lett. 1996 37 4183. 79 S. Kobayashi M. Moriwaki and I. Hachiya Tetrahedron Lett. 1996 37 2053. 80 D. C. Harrowven and R. F. Dainty Tetrahedron Lett. 1996 37 7659. 81 K. Mikami O. Kotera Y. Motoyama H. Sakaguchi and M. Maruta Synlett 1996 171. 82 A. Kawada S. Mitamura and S. Kobayashi Chem. Commun. 1996 183. 83 S. Kobayashi and S. Nagayoma J. Org. Chem. 1996 61 2256. 84 J. Ruiz D. Astrue and L. Gilbert Tetrahedron Lett. 1996 37 4511. 85 A. Orlinkov I. Akhrem S. Vitt and M. Vol’pni Tetrahedron Lett. 1996 37 3763. 86 V.G. Nenajdenko I. L. Baraznenok and E. S. Balenkova Tetrahedron 1996 52 12 993. 87 N. Yonezawa Y. Tokita T. Hino H. Nakamura and R. Katakai J. Org. Chem. 1996 61 3551. 88 M. Tanaka M. Fuijiwara H. Ando and Y. Souma Chem. Commun. 1996 159. 89 C. B. Castellani O. Carugo M. Giusti C. Leopizzi A. Perotti A. G. Invernizzi and G. Vidari Tetrahedron 1996 52 11 045. 90 M. E. Jung and T. I. Lazarova Tetrahedron Lett. 1996 37 7. 91 R. Sreekumar and R. Padmakumar Tetrahedron Lett. 1996 37 5281. 92 M. Tanaka H. Nakashima M. Fujiwara H. Ando and Y. Souma J. Org. Chem. 1996 61 788. 93 J. Perrson S. Axelsson and O. Matsson J. Am. Chem. Soc. 1996 118 20. 94 E. N. Durantini and C. D. Borsarelli J. Chem. Soc. Perkin Trans. 2 1996 719. 95 E. Buncel J. M. Dust and R. A. Manderville J. Am. Chem. Soc. 1996 118 6072.96 M. Cervera J. Marquet and X. Martin Tetrahedron 1996 52 2557. 97 K.M. Wells Y.-J. Shi J. E. Lynch G. R. Humphery R. P. Volante and P. J. Reider Tetrahedron Lett. 1996 37 6439. 98 T. Hattori T. Satoh and S. Miyano Synthesis 1996 515. 99 R. F. Pellon T. Mamposo R. Carrasco and L. Rodes Synth. Commun. 1996 26 3877. 100 N. Takechui Y. Fukai K. Oka and R. Huisgen Chem. Lett. 1996 23. 101 N. Yoneda and T. Fukuhara Tetrahedron 1996 52 23. 102 D. J. Bull M.J. Fray M. C. Mackenny and K. A. Malloy Synlett 1996 647. 103 A. R. Katritzky and L. Xie Tetrahedron Lett. 1996 37 347. 104 N. J. Lawrence J. Liddle and D. A. Jackson Synlett 1996 55. 105 M. Makosza M. Sypniewski and T. Glinka Tetrahedron 1996 37 3189. 106 P. F. Pagoria A. R. Mitchell and R. D. Schmidt J. Org. Chem. 1996 61 2934.107 M. Cervera and J. Marquet Tetrahedron Lett. 1996 37 7591. 108 M. Makosza K. Stalinski and c. Klepka Chem. Commun. 1996 837. 109 F. B. Mallory D. S. Amenta C.W. Mallory and J.-J. J. C. Cheung J. Org. Chem. 1996 61 1551. 110 T. Je§ery Tetrahedron 1996 52 10 113. 111 D. E. Kaufmann M. Nouroozian and H. Henze Synlett 1996 1091. 112 J.-F. Nguefack V. Bolitt and D. Sinou Tetrahedron Lett. 1996 37 5527. 113 M. T. Reetz R. Breinbauer and K. Wanniger Tetrahedron Lett. 1986 37 4499. 114 M. T. Reetz and G. Lohmer Chem. Commun. 1996 1921. 115 S. Saito M. Sakai and N. Miyaura Tetrahedron Lett. 1996 37 2993. 116 K.-I. Gouda E. Hagiwara Y. Hatanaka and T. Hiyama J. Org. Chem. 1996 61 7232. 117 Y. Kobayashi and R. Mizojiri Tetrahedron Lett. 1996 37 8531. 118 M. Rottlander N. Palmer and P.Knochel Synlett 1996 573. 152 Alan P. Chorlton 119 S. Darses T. Je§ery J.-P. Genet J.-L. Brayer and J.-P. Demoute Tetrahedron Lett. 1996 37 3857. 120 A. Weichert M. Bauer and P. Wirsig Synlett 1996 473. 121 J. W. Guiles S. G. Johnson and W.V. Nurray J. Org. Chem. 1996 61 5169. 122 M. Larhed G. Lindeberg and A. Hallberg Tetrahedron Lett. 1996 37 8219. 123 S. Marquais and M. Arlt Tetrahedron Lett. 1996 37 5491. 124 Y. D. Ward and V. Farina Tetrahedron Lett. 1996 37 6993. 125 C. A. Willoughy and K. T. Chapman Tetrahedron Lett. 1996 37 7181. 126 Y. Han S. D. Walker and R. N. Young Tetrahedron Lett. 1996 37 2703. 127 O. Loiseleur P. Meier and A. Pfaltz Angew. Chem. Int. Ed. Engl. 1996 35 201. 128 G. A. Kraus and B. M. Watson Tetrahedron Lett. 1996 37 5287. 129 P. Galda and M.Rehahn Synthesis 1996 614. 130 M. A. Keegstra S. De Feyter F. C.De Schryver and K. Mullen Angew. Chem. Int. Ed. Engl. 1996 35 774. 131 S. Chodorowski-Kimmes M. Beley J.-P. Collin and J.-P. Sauvage Tetrahedron Lett. 1996 37 2963. 132 P. Liess V. Hensel and A.-D. Schluter Liebigs Ann. 1996 1037. 133 J. P. Wolfe and S. L. Buchwald J. Org. Chem. 1996 61 1133. 134 J. P. Wolfe S. Wagaw and S. L. Buchwald J. Am. Chem. Soc. 1996 118 7215. 135 M. S. Driver and J. Hartwig J. Am. Chem. Soc. 1996 118 7217. 136 J. F. Hartwig S. Richards D. Baranano and F. Paul J. Am. Chem. Soc. 1996 118 118 3626. 137 S.-H. Zhao A. K. Miller J. Berger and L. A. Flippin Tetrahedron Lett. 1996 37 4469. 138 A. J. Pearson A. M. Gelormini M. A. Fox and D. Watkins J. Org. Chem. 1996 61 1297. 139 S.-K. Kang H.-W. Lee W.-K.Choi R.-K. Hung and J.-S. Kim Synth. Commun. 26 4219. 140 I. W.J. Still and F. D. Toste J. Org. Chem. 1996 61 7677. 141 H. Harayama T. Kozera M. Kimura S. Tanaka and X. Tamaru Chem. Lett. 1996 543. 142 J.-C. Arnould M. Didelot C. Cadilhac and M.J. Pasquet Tetrahedron Lett. 1996 37 4523. 143 R. J. Perry and B. D. Wilson J. Org. Chem. 1996 61 7482. 144 H. Kotsuki P. K. Datta and H. Suenga Synthesis 1996 470. 145 G. D. Allred and L. S. Liebeskind J. Am. Chem. Soc. 1996 118 2748. 146 S. Seko and N. Kawamura J. Org. Chem. 1996 61 442. 147 A. Alberti F. Cane P. Dembech D. Lazzari A. Ricci and G. Seconi J. Org. Chem. 1996 61 1677. 148 L. A. Spangler Tetrahedron Lett. 1996 37 3639. 149 G. Ameline M. Vaultier and J. Mortier Tetrahedron Lett. 1996 33 8175. 150 F. Mongin and M. Schlosser Tetrahedron Lett.1996 37 6551. 151 F. Mongin O. Desponds and M. Schlosser Tetrahedron Lett. 1996 37 2767. 152 L. T. Scott M. S. Bratcher and S. Hagen J. Am. Chem. Soc. 1996 118 8743. 153 K. Zimmermann R. Goddard C. Kruger and M.W. Haenel Tetrahedron Lett. 1996 37 8371. 154 C. Z. Liu and P. W. Rabideau Tetrahedron Lett. 1996 37 3437. 155 A. Sygula A. H. Abdourazak and P. W. Rabideau J. Am. Chem. Soc. 1996 118 339. 156 M. J. Plater M. Praveen B. K. Stein and J. A. Ballantine Tetrahedron Lett. 1996 37 7855. 157 G. Adamson and C. W. Rees J. Chem. Soc. Perkin Trans. 1 1996 1535. 158 R. F. C. Brown K. J. Coulston and F. W. Eastwood Tetrahedron Lett. 1996 37 6819. 159 M. Sarobe L. W. Jenneskens and U. E. Wiersum Tetrahedron Lett. 1996 37 1121. 160 R. H. G. Neilen and U. E. Wiersum Chem. Commun.1996 149. 161 J. D. Debad J. C. Morris V. Lynch P. Magnus and A. J. Bard J. Am. Chem. Soc. 1996 118 2374. 162 L. T. Scott and A. Necula J. Org. Chem. 1996 61 386. 163 M. Muller J. Peterson R. Strohmaier C. Gunther N. Karl and K. Mullen Angew. Chem. Int. Ed. Engl. 1996 35 886. 164 A. Rajca A. Safronov S. Rajca C. R. Ross and J. J. Stezowski J. Am. Chem. Soc. 1996 118 7272. 165 F. B. Mallory K. E. Butler A. C. Evans and C. W. Mallory Tetrahedron Lett. 1996 37 7173. 166 J. T. M. Van Dikj A. Hartwijk A. C. Blecken J. Lugtenburg and J. Cornelisse J. Org. Chem. 1996 61 1136. 167 K. Yamamoto H. Sonobe H. Matsubara M. Sato S. Okamoto and K. Kitaura Angew. Chem. Int. Ed. Engl. 1996 35 69. 168 X. Qiao M. A. Padulas D.M. Ho N. J. Vogelaar C. E. Schutt and R. A. Pascal Jr. J. Am. Chem. Soc.1996 118 741. 169 K. Yamamura T. Yamane M. Hashimoto H. Miyake and S.-I. Nataksuji Tetrahedron Lett. 1996 37 4965. 170 K. K. Laali S. Bolvig S. Kuroda M. Oda M. Mouri I. Shimao T. Kajioka and M. Yasunami J. Chem. Soc. Perkin Trans. 2 1996 1091. 171 J. Zindel S. Maitra and D. A. Lightner Synthesis 1996 1217. 172 P. v. R. Schleyer H. Jiao H. M. Sulzbach and H. F. Schaefer J. Am. Chem. Soc. 1996 118 2093. 173 R. H. Mitchell and V. S. Iyer J. Am. Chem. Soc. 1996 118 722. 174 Y. Tobe T. Fujii H. Matsumoto K. Narmura Y. Achiba and T. Wakabayashi J. Am. Chem. Soc. 1996 118 2758. 175 G. J. Bodwell Angew. Chem. Int. Ed. Engl. 1996 35 2085. 153 Aromatic compounds 176 T. J. Seiders K. K. Baldridge and J. Siegel J. Am. Chem. Soc. 1996 118 2754. 177 G. J. Bodwell J. N. Bridson T. J. Houghton J. W.J. Kennedy and M. R. Mannion Angew. Chem. Int. Ed. Engl. 1996 35 1230. 178 A. Pelter R. A. N. C. Crump and H. Kidwell Tetrahedron Lett. 1996 37 1273. 179 Y. Sakamoto N. Miyoshi and T. Shinmyoza Angew. Chem. Int. Ed. Engl. 1996 35 549. 154 Alan P. Chorlton