Indoles Vilsmeier formylation

Likewise, Houben-Hoesch aqrlation (cf. p. 112) of indole gives rise to 3-aqfl indoles. ViLSMEiER formylation ofindole occurs efSdently with DMF/POClj and gives rise (via intermediate 7 and its hydrolysis) to indole-3-aldehyde (8) ... 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino s 6-formylindole[2,3-fl]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-fl]carbazole was readily obtained in six steps from indigo (1458). Using Somei s procedure, indigo (1458) was transformed to the cis-chlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydiin 1461 gave 5-hydroxy-indolo[2,3-fl]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-fl]carba-zole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCI) afforded the tiis-MOM-protected compound 1555. Following Hibino s approach, the tris-MOM-protected indolocarbazole 1555... 

Resin-bound indoles can also be acylated at C-3, either with acyl halides (Entry 5, Table 15.7) or under the conditions of the Vilsmeier formylation (Entry 6, Table... 

The combination of tertiary amides, such as dimethylformamide, and phosphoryl chloride generates reactive electrophiles capable of being attacked by electron-rich nucleophiles and is widely used as the Vilsmeier formylation process. The Vilsmeier process has become more general, with the use of more varied amides, and has been particularly successful for the functionalization of pyrroles and indoles. Greater flexibility has been achieved with the replacement of phosphoryl chloride by trifluoromethanesulfonic anhydride. 

The isomeric systems brassilexin and sinalexin 390 can be obtained applying a different method based on Vilsmeier formylation of indole-2-thione 389 (see Section 4.05.9.1.1). 

H- or 4-alkylfuro[3,2-6]indole-2-carboxaldehydes (346-349) have been obtained by Vilsmeier formylation of the corresponding furo[3,2-Z)]indoles (342-345) (Equation (8)) <77JHC975>. 

Indolizine, pA a 3.9, is much more basic than indole (pA a -3-5) and the implied relative stability of the cation makes it less reactive and thus indolizines resistant to acid-catalysed polymerisation cf. Section 17.1.9). Indolizine protonates at C-3, but 3-methylindolizine protonates mainly (79%) at C-1 the delicacy of the balance is further illustrated by 1,2,3-trimethyl- and 3,5-dimethylindolizines, each of which protonate exclusively at C-3. Electrophilic substitutions such as acylation," Vilsmeier formylation, and diazo-coupling all take place at C-3. 

The iminium ion chemistry of activated indoles has been reviewed (47 references). Focusing particularly on the Vilsmeier formylation, this reaction has been generalized over time to include a greater variety of amide types. The traditional Vilsmeier protocol... 

Acylation and metallation studies on monomers, dimers, trimers, and tetramers containing linked thiophen, pyridine, pyrimidine, furan, benzofuran, benzothiophen, and indole moieties have been published/ Deuteriation, halogenation, and diazo-coupling reactions of 2-oxo- and 2-thioxo-l,2-dihy-dropyrimidinium salts have been studied and compared with results for 2,2-dialkyl-1,2-dihydropyrimidinium and 2,3-dihydro-1,4-diazepinium salts in order to demonstrate the effect of an adjacent 0x0- or thioxo-group on the properties of a 1,5-diazopentadienium system/ Vilsmeier formylation of, and tautomerism in, 2-hydroxypyrazolo[5,l-h]quinazolone and l-phenylpyrazolo[5,l-A]-quinazoline-2,9-dione have been studied/ The pyrazolo[3,4-c]pyrazole (71) has been methylated and acetylated, the major products being (72)/ ... 

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... 

UV spectroscopy, 4, 178, 179 vertical resonance energy, 4, 191 Vilsmeier-Haack formylation, 4, 221, 222 3H-Indoles... 

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>... 

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 and various 2-substituted indoles give the 3-formyl derivative in generally excellent yields under Vilsmeier-Haack conditions (79HC(25-3)357, B-70MI30609). 3-Methylindole gives the 2-carbaldehyde, but in rather poor yield (63JPS645). 

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... 

---