Vilsmeier-Haack reaction formylation

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. ... 

The reaction of electron-rich aromatic compounds with yV,A -dimethylformamide 2 and phosphorus oxychloride to yield an aromatic aldehyde—e.g. 3 from the substituted benzene 1—is called the Vilsmeier reaction or sometimes the Vilsmeier-Haack reaction. It belongs to a class of formylation reactions that are each of limited scope (see also Gattermann reaction). 

The reaction with disubstituted formamides and phosphorus oxychloride, called the Vilsmeier or the Vilsmeier-Haack reaction,is the most common method for the formylation of aromatic rings. However, it is applicable only to active substrates, such as amines and phenols. An intramolecular version is also known.Aromatic hydrocarbons and heterocycles can also be formylated, but only if they are much more active than benzene (e.g., azulenes, ferrocenes). Though A-phenyl-A-methyl-formamide is a common reagent, other arylalkyl amides and dialkyl amides are also used. Phosgene (COCI2) has been used in place of POCI3. The reaction has also been carried out with other amides to give ketones (actually an example of 11-14),... 

Another useful method for introducing formyl and acyl groups is the Vilsmeier-Haack reaction.67 /V.A-dialkylamidcs react with phosphorus oxychloride or oxalyl chloride68 to give a chloroiminium ion, which is the reactive electrophile. 

Scheme 11.5 gives some examples of these acylation reactions. Entry 1 is an example of a chloromethylation reaction. Entry 2 is a formylation using carbon monoxide. Entry 3 is an example of formylation via to-chloromethyl ether. A cautionary note on this procedure is the potent carcinogenicity of this reagent. Entries 4 and 5 are examples of formylation and acetylation, using HCN and acetonitrile, respectively. Entries 6 to 8 are examples of Vilsmeier-Haack reactions, all of which are conducted on strongly activated aromatics. 

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>... 

Benzodipyrrole 1 is selectively formylated at the 3- and 6-positions by a Vilsmeier-Haack reaction to produce 3,6-diformylbenzodipyrrole which is reduced by lithium aluminium hydride to give 3,6-dimethylbenzodipyrrole. This can also undergo subsequent Vilsmeier-Haack formylation to afford the 2,5-dialdehyde (Scheme 2) <2005AGE4053>. 

Under controlled conditions, the acetylaminopyrazole 80 was converted by Vilsmeier-Haack reaction to a mixture of chloro derivatives (81 R2 = H, CHO) in poor and moderate yields, respectively. Cyclization is preceded by C-formylation and formation of the imidoyl chloro group.95... 

In structural and synthetic chemistry, we also find instances of reconsideration 3-(3-methoxyphenoxy)-2-butanone gives by ringclosing dehydration a mixture of 2,3-dimethyl-4-methoxybenzofuran and 2,3-dimethyl-6-methoxybenzofuran,101 not just the 6-derivative.102 2-Ethyl-7-methoxybenzofuran is not formylated in position 3 by the Vilsmeier-Haack reaction, but in position 4.10,103... 

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-... 

While there are several reports concerning electrophilic substitution on to (5,5)-fused heterocycles, very few of these involve a study with the parent system. The ir-excessive systems (50), (51), (52) and (53) were found to be susceptible to attack by electrophilic reagents at the positions indicated, leading to alkylation, formylation (Vilsmeier-Haack reaction), acylation, tritylation, metalation, tricyanoethylation, halogenation, thiocyanation, nitrosation, nitration and diazo coupling (77HC(30)l). 

The standard Vilsmeier-Haack reaction involves combination of POCI3 with DMF or yV-methylformanilide to form a chloromethyleneiminium salt which efficiently formylates a variety of electron-rich aromatic and heteroaromatic... 

New syntheses of ( )-ar-turmerone (79) and ( )-nuciferal (80) have been reported (Schemes 10 and 11 ) whereas Meyers and Smith have used the (+)-oxazoline (81) to good effect in an asymmetrically induced synthesis of (+)-ar-turmerone (82) (Scheme 12). A neat one-pot synthesis of /3-curcumene (83) has been developed which involves only two steps (Scheme 13). In a synthesis of the aromatic analogue, (-)-a-curcumene (84), Kumada et al. have used an asymmetrically induced cross-coupling Grignard reaction in the presence of a nickel complex of (85) to produce (84) in 66% enantiomeric excess (Scheme 14). A Vilsmeier-Haack-Arnold formylation of (-f-)-limonene has been used as... 

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. 

Substituted pyrazoles are formylated (Vilsmeier-Haack reaction) and acetylated (Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in positions 3 and 5 facilitate the reaction (80ACH(105) 127,80CHE1), but the heteroatoms compete with the C-substitution. For instance, when the amino derivative (91 R = =Ph, R = H) was submitted to the Vilsmeier-Haack reaction, the 4-formyl-5-dimethylaminomethylene derivative was isolated. 

N. G. Ramesh and K. K. Balasubramanian, Vilsmeier-Haack reaction of glycals. A short route to C-2 formyl glycals. Tetrahedron Lett. 32 3875 (1991). 

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