Indoles Vilsmeier-Haack reaction

In miscellaneous oxidative processes of indoles, two methods for the preparation of 3-hydroxyindoles have been reported. The first approach involves initial Vilsmeier-Haack reaction of indole-2-carboxylates 176 to afford the corresponding 3-formyl analogs 177. Activation of the aldehyde with p-toluenesulfonic acid (PTSA) and Baeyer-Villiger oxidation with m-chloroperoxybenzoic acid (wi-CPBA) then affords high yields of the 3-hydroxy compounds 178 <00TL8217>... 

A multi-stage synthesis of azocino[4,5,6-cd]indoles has been suggested (03M13519). From 4-bromoindole (84) with the help of successive transformations (among them the Vilsmeier-Haack reaction, Henry nitroaldole condensation, lithium aluminum hydride reduction and insertion of an allyl fragment), indole 85 has been produced in 18% yield. The cyclization of the latter on palladium... 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

The salts of methylene derivatives of 2H- and 3//-pyrroles and -indoles are produced in the Ehrlich reaction (Scheme 32, Section 3.05.1.2.8) and they are also intermediates in the Vilsmeier-Haack reaction (Scheme 24, Section 3.05.2.1.6). Although 6-fV,fV-dimethyl-amino-l-azafulvene, i.e. 2-(Ar,Ar-dimethylaminomethylene)-2//-pyrrole, dimerizes spontaneously (see Section 3.05.2.5), the 6-aryl-6-Ar)Ar-dimethylamino-l-azafulvenes (514 R = aryl) can be isolated (71JCS(B)1405) but, curiously, they are more susceptible to reactions with nucleophiles at the 6-position than are the corresponding salts (B-77MI30508). The benzo[6 ]-1 -azafulvenes, obtained from the reaction of 2-formylindoles with dialkylamines, also dimerize spontaneously, but the isomeric benzo[c]-2-azaf ulvenes, derived from 3-formylindoles, are thermally more stable, although they are extremely moisture sensitive... 

Another acylation procedure uses iminium salts rather than acyl halides. The Vilsmeier-Haack reaction is a well-known process illustrated by reaction of pyrrole with the POCI3 complex of N,N-dimethylacetamide (207, which can decompose to a chloroiminium salt). The acylation reaction gave 208, which was converted to 2-acetylpyrrole by hydrolysis with aqueous sodium acetate.A synthetic example is taken from Lai s synthesis of indole analogs of mycophenolic acid,l in which 209 reacted with POCI3 and DMF to give a 77% yield of the aldehyde 210. 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

At about the same time, Nicolaou and Chen et al. independently reported the synthesis of haplophytine [85]. Retrosynthetically, haplophytine was envisioned by a sequence of Suzuki-Miyaura Coupling, Vilsmeier-Haack reaction, and radical cyclization from indole 205 and vinyl iodide 206. The left-hand domain 205 could arise through the oxidative skeletal rearrangement of enamine 207, which could be obtained from the oxidative coupling of tetrahydro-jS-carboline 208 and diphenol 209 (Scheme 37). 

In the first route (Scheme 4), indoUne (5) is nitrated to 6-nitro-2,3-dUiydroindole (22, 92%). Apphcation of the tungstate method to 22 and subsequent methylation provide l-methoxy-6-nitroindole (9, 77%) via 8a. A Vilsmeier-Haack reaction (94%), followed by nitroaldol reaction (85%), leads 9 to l-methoxy-6-nitro-3-(2-nitrovinyl)indole (23) through 1-methoxy-6-nitroindole-3-carbaldehyde (10b). After selective reduction of the nitro-vinyl part of 23 with NaBH4, the resultant l-methoxy-6-nitro-3-(2-nitro-ethyl)indole (24,84%) is treated with Zn/HCl and then AC2O to give 21 (81%). Reduction of 24 with Zn/AcOH produces 6-amino-l-methoxytryptamine (25, 30%). 

Vilsmeier-Haack conditions have been used most frequently for formylation but are also applicable to longer acyl chains[3]. Reactions with lactams generate 3-(iminyl)indoles which can be hydrolysed to generate co-aminoacyl groups as in equation 11.6 [4]. 

Vilsmeier-Haack formylation, 4, 222 Indole, dimethyl- C NMR, 4, 172 Indole, 1,2-dimethyl-bis-allylation, 4, 357 Indole, 1,3-dimethyl-nitration, 4, 211 reactions... 

Vilsmeier-Haack and Friedel-Crafts reactions, bromination, debromination, debenzylation in indole series and their synthetic application 99YZ35. 

The Vilsmeier-Haack formylation procedure (Scheme 24) provides the most effective synthesis of formylpyrroles and indoles. Reaction of the heterocycles with the immonium cation (72), derived from DMF or (V-methylformanilide with an acid chloride, such as phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, benzoyl chloride or bromotriphenylphosphonium bromide, yields the intermediate heteroarylimmonium salt (73). Under suitable reaction conditions, this salt may be isolated from the reaction involving phosphorus oxychloride as an impure chlorophosphate (78TH30500) or precipitated from the reaction system as the thermally unstable perchlorate by the addition of sodium... 

Indole, 3-(dialkylaminomethyl-) alkylation, 4, 275 Indole, 2,3-dibromo-synthesis, 4, 215 Indole, 2,6-dibromo-3-methyl-synthesis, 4, 215 Indole, 1,3-dichloro-synthesis, 4, 214 Indole, dihydrodehydrogenation, 4, 283, 311 in non-silver photography, 1, 383 Indole, 2,3-dihydro-synthesis, 4, 327, 352 Indole, 2,3-dihydroxy-tautomerism, 4, 37, 199 Indole, 4,6-dimethoxy-Vilsmeier-Haack formylation, 4, 222 Indole, dimethyl-l3C NMR, 4, 172 Indole, 1,2-dimethyl-bis-allylation, 4, 357 Indole, 1,3-dimethyl-nitration, 4, 211 reactions... 

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