Synthesis Vilsmeier-Haack reaction

Benzisothiazole, 3-methyl-bromination, 6, 155 nitration, 6, 154 synthesis, 6, 171, 172 Vilsmeier-Haack reaction, 6, 149, 152... 

The classical Vilsmeier-Haack reaction is one of the most useful general synthetic methods employed for the formylation of various electron rich aromatic, aliphatic and heteroaromatic substrates. However, the scope of the reaction is not restricted to aromatic formylation and the use of the Vilsmeier-Haack reagent provides a facile entry into a large number of heterocyclic systems. In 1978, the group of Meth-Cohn demonstrated a practically simple procedure in which acetanilide 3 (R = H) was efficiently converted into 2-chloro-3-quinolinecarboxaldehyde 4 (R = H) in 68% yield. This type of quinoline synthesis was termed the Vilsmeier Approach by Meth-Cohn. ... 

Acheson and co-workers [78JCS(P1)1117, 80AX(B)3125] reported the synthesis of 3-acetyl-1-methoxyindole (107, 42%) from 1-methoxyindole (71) by applying Vilsmeier-Haack reaction using Ai,V-dimethylacetamide. We repeated the reaction, but in our hands, the yield was lower (around 14%) (Scheme 16). 

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>. 

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... 

Synthesis from quinazoline precursors was achieved by carrying out a Vilsmeier-Haack reaction on 3-amino-2-methyl-4-quinazolone (96) to give the intermediate diformyl derivative 97 that cyclized to 3-formylpyra-zolo[5,l-b]-quinazolin-9-one (98) [73IJC532 84IJC(B)161]. 

O. Meth-Cohn, S. P. Stanforth, The Vilsmeier-Haack Reaction, in Comprehensive Organic Synthesis (B. M. Trost, I. Fleming, Eds.), Vol. 2, 111, Peigamon Press, Oxford, 1991. 

The synthesis (Scheme 7) employed by Crenshaw and co-workers22, 23 may be rationalized as proceeding via a thione intermediate. In a later variation,24 a Vilsmeier-Haack reaction was... 

There are several methods for the direct introduction of an aldehyde group into an aromatic compound. In the Vilsmeier-Haack reaction, activated aromatic systems such as aryl ethers and dialkylanilines are formylated by a mixture of dimethylformamide, HCONMe2, and phosphorus oxychloride, POCL, (Scheme 6.4). The process involves elec-trophilic attack by a chloroiminium ion, Me2N=CHCl, formed by interaction of dimethylformamide and phosphorus oxychloride. Hydrolysis of the dimethyl imine completes the synthesis. 

In a related reaction, the Gattermann aldehyde synthesis, the carbon monoxide of the previous reaction is replaced by hydrogen cyanide (Scheme 6.6). This reaction gives poor yields with benzene itself, but is successful with activated species such as aryl ethers and phenols. The reaction proceeds via an aryl imine and the mechanism is not dissimilar to that of the Vilsmeier-Haack reaction. 

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