Vilsmeier-Haack conditions

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]. 

Acylation. Acylation is the most rehable means of introducing a 3-substituent on the indole ring. Because 3-acyl substituents can be easily reduced to 3-aLkyl groups, a two-step acylation—reduction sequence is often an attractive alternative to direct 3-aLkylation. Several kinds of conditions have been employed for acylation. Very reactive acyl haUdes, such as oxalyl chloride, can effect substitution directiy without any catalyst. Normal acid chlorides are usually allowed to react with the magnesium (15) or 2inc (16) salts. The Vilsmeier-Haack conditions involving an amide and phosphoms oxychloride, in which a chloroiminium ion is the active electrophile, frequentiy give excellent yields of 3-acylindoles. 

No significant amounts of diacylated products are obtained under Vilsmeier-Haack conditions an indirect method for preparing pyrrole-2,5-dicarbaldehydes is outlined in Scheme 16 (78S295, 82CJC383). 

Thiophene is also readily acylated under both Friedel-Crafts and Vilsmeier-Haack conditions and similarly to pyrrole and furan gives 2-acylated products. An almost quantitative conversion of thiophene into its 2-benzoyl derivative is obtained by reaction with 2-benzoyloxypyridine and trifluoroacetic acid. The attempted preparation of 2-benzoylthiophene under standard Friedel-Crafts conditions, however, failed (80S139). 

Hydrazones are also useful substrates in the preparation of pyrazoles. Reaction of N-monosubstituted hydrazones with nitroolefins led to a regioselective synthesis of substituted pyrazoles <060L3505>. lf/-3-Ferrocenyl-l-phenylpyrazole-4-carboxaldehyde was achieved by condensation of acetylferrocene with phenylhydrazine followed by intramolecular cyclization of the hydrazone obtained under Vilsmeier-Haack conditions <06SL2581>. A one-pot synthesis of oxime derivatives of l-phenyl-3-arylpyrazole-4-carboxaldehydes has been accomplished by the Vilsmeier-Haack reaction of acetophenone phenylhydrazones <06SC3479>. 

In this route a dihydroisoquinoline (58) is N alkylated with a highly functionalized o -bromoacetophenone (59) to give a quaternary salt (60), which is treated with base and cyclizes to a pyrroloisoquinoline (60). The pyrrole nucleus is then formylated under Vilsmeier-Haack conditions at position 5 and a proximate mesylated phenolic group is deprotected with base to yield a pen-tasubstituted pyrrole (61). Subsequent oxidative cyclization of this formylpyr-role produces the 5-lactone portion of lamellarin G trimethyl ether (36). This sequence allows for rapid and efficient analog synthesis as well as the synthesis of the natural product. 

Under Vilsmeier-Haack conditions 1-substituted 5-hydroxy-l,2,3-triazoles were converted into the chloroaldehydes (75) in 60-90% yields (84JHCI603) (Scheme 27). Phosphorus pentachloride in toluene gave the 5-chloro derivatives from some ethyl 5-hydroxy-1,2,3-triazole-... 

The reduced pyridone 96, (R = Et) under Vilsmeier-Haack conditions gave the formylated product 284.106... 

Hydroxypyridine and formaldehyde give 2-hydroxymethyl-3-hydroxypyridine. Pyrones can be chloromethylated, e.g. (128) — (129). Hydroxymethylation of the 5-position is possible in pyrimidines with at least two electron-releasing substituents. Under Vilsmeier-Haack conditions pyrimidones are converted into 5-formylchloropyrimidines for example (130) gives (131). 

Thermal cyclization of l-(l-methyl-2-pyrrolyl)buta-l,3-diene yields l-methyl-4,5-dihy-droindole (77TL151) and several examples of the cyclization of substituted vinyl derivatives have been reported, e.g. (395) -> (396) <74JCS(Pl)153l), (397) -> (398) <80JCR(S)233>, whilst the 2-(2-indolyl)propenoic ester (399) cyclizes under Vilsmeier-Haack conditions to produce (400) (80T2125). 

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). 

A 4-bond synthesis of pyridines from carbonyl compounds, which were subjected to Vilsmeier-Haack conditions giving the conjugated iminium salts, has been achieved by reaction with ammonium acetate (Scheme 113)... 

Flavan-4-ones react under Vilsmeier-Haack conditions providing 2-aryl-3-formyl-4-chloro-2/7-chromenes in high yield (Equation 42) <2001SC2589>. 

The dibenzo derivatives (103 R2 = H) similarly undergo electrophilic substitution and cycloaddition reactions. Typically, under Vilsmeier-Haack conditions the 7-formyl (103 R2 = CHO) and the 7-acetyl (103 R2 = COMe) derivatives are formed from the unsubstituted compounds (103 R2 = H). With strong acids the dibenzo compounds (103) form salts (73CL175). 

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