Benzenes, substituted, cyclizations

From the understanding, provided by the calculations, of the mechanism by which lb cyclizes, what can be predicted about how the rate of this reaction might be affected by substituents on the benzene ring The substiment effects would, in fact, be expected to be small, except for possible steric effects due to substituents in the ortho positions. If both ortho positions are substimted, one would expect to see a decrease in rate, relative to unsubstituted lb. On the other hand, if only one ortho position is substituted, cyclization should be about as fast as in unsubstituted lb but cyclization should preferentially occur at the unsubstituted ortho carbon. Additional (8/8)CASPT2/6-31G calculations by Bill Kamey in our group and subsequent experiments by the Platz group confirmed these qualitative predictions about the effects of ortho substituents. 

Bromo-2-isopropylanisole (191) was prepared from p-bromoanisole (190). It was caused to react with magnesium and ethylene oxide to obtain the alcohol (192). Its bromoderivative on heating with diethylmalonate and sodium ethoxide followed by hydrolysis with alcoholic potassium hydroxide yielded the substituted malonic acid. This on heating furnished acid (193). Its acid chloride in benzene underwenr cyclization with aluminium chloride to yield tetralone (194). It was... 

Dimethyl acetylenedicarboxylate (DMAD) (125) is a very special alkyne and undergoes interesting cyclotrimerization and co-cyclization reactions of its own using the poorly soluble polymeric palladacyclopentadiene complex (TCPC) 75 and its diazadiene stabilized complex 123 as precursors of Pd(0) catalysts, Cyclotrimerization of DMAD is catalyzed by 123[60], In addition to the hexa-substituted benzene 126, the cyclooctatetraene derivative 127 was obtained by the co-cyclization of trimethylsilylpropargyl alcohol with an excess of DMAD (125)[6l], Co-cyclization is possible with various alkenes. The naphthalene-tetracarboxylate 129 was obtained by the reaction of methoxyallene (128) with an excess of DMAD using the catalyst 123[62],... 

Upon treatment with suitable cobalt complexes, methylbutynol cyclizes to a 1,2,4-substituted benzene. Nickel complexes give the 1,3,5-isomer (196), sometimes accompanied by linear polymer (25) or a mixture of tetrasubstituted cyclooctatetraenes (26). 

The aminophenols are chemically reactive, undergoing reactions involving both the aromatic amino group and the phenoHc hydroxyl moiety, as weU as substitution on the benzene ring. Oxidation leads to the formation of highly colored polymeric quinoid stmctures. 2-Aminophenol undergoes a variety of cyclization reactions. 

Electrophilic substitution of thiophene occurs largely at the 2-position and the reactivity of the ring is greater than that of benzene. 3-Substituted derivatives are generally prepared by indirect means or through ring cyclization reactions. 

Reactions of acetylene and iron carbonyls can yield benzene derivatives, quinones, cyclopentadienes, and a variety of heterocycHc compounds. The cyclization reaction is useful for preparing substituted benzenes. The reaction of / fZ-butylacetylene in the presence of Co2(CO)g as the catalyst yields l,2,4-tri-/ f2 butylbenzene (142). The reaction of Fe(CO) and diphenylacetylene yields no less than seven different species. A cyclobutadiene derivative [31811 -56-0] is the most important (143—145). 

Benzisothiazoles are best prepared by oxidative cyclization of o-aminothiobenz-amides (see Section 4.17.9.1.1), reaction of o-toluidines with thionyl chloride (see Section 4.17.9.2.1) or by sulfuration of 2,1-benzisoxazoles (see Section 4.17.10.2). 1,2-Benzisothiazoles can also be prepared from o-disubstituted benzene compounds, cyclodehydration of o-mercaptobenzaldoximes or oxidative cyclization of p-mercaptobenzylamines (see Section 4.17.9.1.1) being the most convenient. Both series of benzo compounds are readily substituted at the 5- and 7-positions by electrophilic reagents. 

Hydrazides of vicinal acetylene-substituted derivatives of benzoic and azole carboxylic acids are important intermediate compounds because they can be used for cyclization via both a- and /3-carbon atoms of a multiple bond involving both amine and amide nitrogen atoms (Scheme 131). Besides, the hydrazides of aromatic and heteroaromatic acids are convenient substrates for testing the proposed easy formation of a five-membered ring condensed with a benzene nucleus and the six-membered one condensed with five-membered azoles. 

The one-pot synthesis of thiazolo[3,4-a]benzimidazoles has been reported using a microwave-assisted condensation-cyclization (see Scheme 17) of a substituted 1,2-diamine, substituted benzaldehyde and mercaptoacetic acid [74]. Heating the mixture at reflux for 12 min using a single-mode microwave reactor for the most part gave the fused benzimidazoles in improved yield and dramatically shorter times, when compared to classical conditions of heating at reflux in benzene for 24-48 h (Scheme 29). 

A radical carboxyarylation approach was introduced as the key step in the total synthesis of several biologically important natural products (Scheme 27). Treatment of thiocarbonate derivatives 112 (R = Me or TBS) with 1.1 equiv of (TMS)3SiH in refluxing benzene and in the presence of AIBN (0.4 equiv added over 6h) as radical initiator, produced compound 113 in 44% yield. This remarkable transformation resulted from a radical cascade, involving (TMSlsSi radical addition to a thiocarbonyl function (112 114), 5-era cyclization (114->115) and intramolecular 1,5-ipso substitution (115 116) with the final ejection of (TMSlsSiS radical. 

The synthetic route represents a classical ladder polymer synthesis a suitably substituted, open-chain precursor polymer is cyclized to a band structure in a polymer-analogous fashion. The first step here, formation of the polymeric, open-chain precursor structure, is AA-type coupling of a 2,5-dibromo-1,4-dibenzoyl-benzene derivative, by a Yamamoto-type aryl-aryl coupling. The reagent employed for dehalogenation, the nickel(0)/l,5-cyclooctadiene complex (Ni(COD)2), was used in stoichiometric amounts with co-reagents (2,2 -bipyridine and 1,5-cyclooctadiene), in dimethylacetamide or dimethylformamide as solvent. 

The thermal, but not the photochemical, decomposition of ferro-cenylsulphonyl azide (14) in benzene gave some intermolecular aromatic substitution product FCSO2NHC6H5 (6.5%) but no intermolecular cyclization product (17). Contrariwise, photolysis of 14 in benzene gave 17 but no anilide 1 ). 

Substituted 3-thiosemicarbazido-2-polyfluorobenzoyl acrylates 168 undergo cyclization in refluxing benzene to afford [ 1,3,4] thiadiazino[6,5,4- ]qu inclines 169. Compounds 168 were prepared by from 167 with thiosemicarbazides (Scheme 22) <1999RJO 698, 2002RJ01790>. 

Reaction of 6-halopurines with Michael acceptors under Heck conditions gives N- -substituted hypoxanthine derivatives <00CCC797>. Reactions of a series of 1-aminobenzimidazoles and l-amino-3-methylbenzimidazolium chlorides with 2,4-pentanediones afford pyridazino[l,6-a]benzimidazoles and 2-pyrazolylanilines, the product ratio depending on conditions and on the electronic character of the substituents at the benzene moiety <00BMC37>. Cyclization reactions of adenine derivative 75 with different amines or hydrazine afford tricyclic polyaza compounds 76 <00CCC1109>. 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

Hill described the Pd(OAc)2-oxidative cyclization of bisindolylmaleimides (e.g., 49) to indolo[2,3-a]pyrrolo[3,4-c]carbazoles (e.g., 50) [69], which is the core ring system in numerous natural products, many of which have potent protein kinase activity [70]. Other workers employed this Pd-induced reaction to prepare additional examples of this ring system [71, 72]. Ohkubo found that PdClj/DMF was necessary to prevent acid-induced decomposition of benzene-ring substituted benzyloxy analogues of 49, and the yields of cyclized products under these conditions are 85-100% [71]. 

The 5-dig-mode of cyclization has been applied in the synthesis of N-heterocycles. For example, treatment of the /i-allenyl dithiosemicarbazide 37 with Bu3SnH and AIBN in hot benzene furnishes the substituted 3H-pyrrole 38 in 41% yield and the isomeric heterocycle 39 in 30% yield (Scheme 11.13) [68], Iminyl radical 40 is formed via Bu3Sn addition to the thiocarbonyl group of the radical precursor 37 and fragmentation of the adduct (not shown). Nitrogen-centered radical 40 adds 5-dig-selectively to provide substituted allyl radical 41. The latter intermediate is trapped by Bu3SnH to furnish preferentially product 38 with an endocydic double bond. 

Dehydrocyclization, 30 35-43, 31 23 see also Cyclization acyclic alkanes, 30 3 7C-adsorbed olefins, 30 35-36, 38-39 of alkylaromatics, see specific compounds alkyl-substituted benzenes, 30 65 carbene-alkyl insertion mechanism, 30 37 carbon complexes, 32 179-182 catalytic, 26 384 C—C bond formation, 30 210 Q mechanism, 29 279-283 comparison of rates, 28 300-306 dehydrogenation, 30 35-36 of hexanes over platintim films, 23 43-46 hydrogenolysis and, 23 103 -hydrogenolysis mechanism, 25 150-158 iridium supported catalyst, 30 42 mechanisms, 30 38-39, 42-43 metal-catalyzed, 28 293-319 n-hexane, 29 284, 286 palladium, 30 36 pathways, 30 40 platinum, 30 40 rate, 30 36-37, 39... 

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