Arylhydrazones. cyclization

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

The issue of regioselectivity arises with arylhydrazones of unsymmetrical ketones which can form two different enehydrazine intermediates. Under the conditions used most commonly for Fischer cyclizations, e g. ethanolic HCI, the major product is usually the one arising from the more highly substituted enehydrazine. Thus methyl ketones usually give 2-methy indoles and cycliz-ation occurs in a branched chain in preference to a straight chain. This regioselectivity is attributed to the greater stability of the more substituted enhydrazine and its dominance of the reaction path. 

Another issue of regioselectivity arises with meta-substituted arylhydrazones from which either 4- or 6-substitutcd indoles can be formed. Robinson has tabulated extensive data on this point[9]. A study comparing regioselectivity of cyclization as catalysed by HCl/EtOH and ZnClj was carried out for several m-substituted arylhydrazones of diethyl ketone[10]. The results given in Table 7.1 show some dependence on catalyst but mixtures are obtained under all conditions studied. 

The oxygen analogue of the Fischer cyclization requires the formation of 0-vinyl derivatives of iV-arylhydroxylarnines. These are readily converted to indoles but are less readily accessible than the arylhydrazones used for the Fischer cyclization. 

The reaction of a ,)3-alkynic nitriles (317) with hydroxylamine gave the 5-aminoisoxazoles (318) regiospecifically, whereas in the presence of sodium hydroxide the 3-aminoisoxazoles (319) were obtained exclusively (66CPB1277). Similarly, the course of the cyclization of arylhydrazones (320) was influenced by a change in the base employed (75JOC2604). 

The Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone 1 of an aldehyde or ketone by treatment with acid catalyst or effected thermally to form the indole nucleus 2. ... 

The keto arylhydrazone 22 indolized to give only the 3-H substituted indole 23 upon treatment under the cyclization conditions. Indolization had occurred toward the more substituted carbon atom. ... 

Cyclization of an o-substituted arylhydrazone provides one isomer in many cases. However, the cyclization is more sluggish than the m- or p-substituted analogs. Sometimes the cyclization gives low yields of the desired indole products along with side products. Cyclization of the 2-substituted arylhydrazone can occur either to the unsubstituted side to provide the normal indole product (50), or to the substituted side, where other reactions take place (53 and 56). 

Aniline 77 was converted into its diazonium salt with nitrous acid and this was followed by reduction with stannous chloride to afford the corresponding arylhydrazine 78. Condensation of 78 with 3-cyanopropanal dimethylacetal 79 gave the arylhydrazone 80. Treatment of 80 with PPE resulted in cyclization to indole 81. The nitrile group was then reduced to the primary amine by catalytic hydrogenation. Reaction of the amine with excess formalin and sodium borohydride resulted in Imitrex (82). 

Barbituric acid can be considered as a cyclized malonic acid diamide (malonyl-urea). It is therefore a cyclic diketone that may be classified, in the sense of the compounds discussed in Section 12.6, as a coupling component with a methylene group activated by two carbonyl groups in the a- and a -positions. The reaction with arenediazonium salts was studied by Nesynov and Besprozvannaya (1971). These authors obtained coupling products (in good yield) that they considered to be arylhydrazones. Coupling with 4-(phenylazo)benzenediazonium chloride was studied by Chandra and Thosh (1991). The lH NMR spectra of these compounds are consistent with the arylhydrazone structure 12.68. 

A classical method for synthesizing indoles is by the Fischer indolization, which involves the cyclization of arylhydrazones in the presence of strong acids. Lipinska... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

In the presence of sodium acetate in acetic acid, the arylhydrazones 54 (available from the reaction of tu-halogen-tu-(arylhydrazono)acetophenones with 3-amino[l,2,4]triazole) undergo cyclization to yield 3-aroyl-l-aryl-l//-[l,2,4]-tria-zolo[3,4-c][l,2,4]triazoles 55 (Equation 7) <1987CB965>. 

Examples have been described of cyclization of bis(azostilbene) derivatives by reaction with hydrogen sulfide and hydrochloric acid, by irradiation, and by heat. 2,4,5-Triphenyltriazole is formed in each case. Nonoxidative cyclization of bis arylhydrazones is also reported. A reaction related to these is the oxidation of benzaldehyde... 

Oxidation of arylhydrazones 143 with HTIB in the presence of diisopro-pylethylamine produces pyrazoles 145 in one pot. The intermediate a-tosyloxy compounds 144, which are generated in situ by the oxidation of 143, undergo intramolecular participation of amino group in displacement of the tosyloxy group, thereby yielding cyclized products 145 (91SC1583). 

Mesomalonodialdehyde 1,3-dioxime is treated with arylhydrazines to give the mesoaldehyde 1,3-dioxime-2-arylhydrazones (685), which are O-acetylated with acetic anhydride to afford the mono-and di-acetyl derivatives (Scheme 139). Both intermediates are cyclized to 2-aryl-1,2,3-triazole-4-carbaldehyde oximes (686) and (687) with caesium carbonate. Triazoles (687) are converted to 4-cyanotriazoles by refluxing with acetic anhydride followed by pyrolysis <83JHC1561>. 

A highly efficient one-pot, two-step microwave procedure has been developed for the synthesis of l-aryl-l/7-indazoles. Microwave heating of 2-halobenzaldehydes or 2-haloacetophenones with phenylhydrazines at 160°C for 10 min quantitatively yielded the arylhydrazones, which were further cyclized to give l-aryl-17/-indazoles via Cul/diamine-catalyzed... 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

Folyphosphoric acid trimethylsilyl ester (PPSE)[1] can be used in sulfolane, CH2C12 or nitromethane. It is similar to polyphosphoric acid hut the overall conditions arc milder and the work-up more convenient. PPSE has been used in the cyclization of /fis-arylhydrazones of cyclohexane-1,2-diones to give indolo[2,3-a]carbazole analogues[2],... 

The tricyanovinylpyrazoles 67, isolated from reaction of tetracyanoeth-ylene (TCNE) with 51 (R1 = H,Ph R2 = H, Me), cyclized in refluxing acetic anhydride to 68.76 Analogous products (68 R1 = Ar,R2 = Me) were obtained from thermolysis or photolysis of the charge-transfer complex 69 formed between TCNE and arylhydrazones.77... 

Arylhydrazones (123) are cyclized with SOC1, or PCI, to 2-aryl-2,3,4,5-tetrahydro-l,2-diazepin-3-ones (124) (84CR(B)929>. 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an N-arylhydrazone is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3]sigmatropic rearrangement of an enehydrazone tautomer of the hydrazone. 

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