Haack Reaction

The Vilsmeier-Haack reagent, chloroiminium salt, is a weak electrophile, therefore, the Vilsmeier-Haack reaction works better with electron-rich carbocycles and heterocycles. 

Marson, C. M. Giles, P. R. Synthesis Using Vilsmeier Reagents CRC Press, 1994. (Review). 

Tasneem, Synlett 2003, 138. (Review of Vilsmeier-Haack reagent). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 279, Springer International Publishing Switzerland 2014 

Example 4, Reaction outcomes differ as temperature differs  

Vilsmeier, A. Haack, A. Ber. 1927, 60, 119-122. German chemists Anton Vilsmeier and Albrecht Haack discovered this recation in 1927. 

Lancelot, J.-C. Laduree, D. Robba, M. Chem. Pharm. Bull. 1985,33,3122-3128. 

Transformation of a carboxylic acid to the corresponding acid chloride using oxa-lyl chloride and catalytic amount of dimethyl formamide (DMF). It is a lot faster than without DMF, which generally needs reflux. 

DMF recovered, therefore only catalytic amount is required 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 260, Springer-Verlag Berlin Heidelberg 2009 

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Acylthiophenes. Manufacturing methods introducing the carboxaldehyde group into the 2- or 5-positions of thiophene and alkylthiophenes utilise the Vilsmeier-Haack reaction. To synthesize 2-thiophenecarboxaldehyde (Table 5), a controlled addition of phosphoms oxychloride to thiophene in /V, /V- dim ethyl form am i de is carried out, causing the temperature to rise. Completion of the reaction is followed by an aqueous quench, neutralization, and solvent extraction to isolate the product. 

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). 

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. 

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 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 reaction of 2,6-dimethylimidazo[2,T. ][l,3,4]thiadiazole 169 gives aldehyde 170, which after reduction with sodium borohydride affords 2,6-dimethyl-5-hydroxymethylimidazo[2,TA [l,3,4]thiadiazole 171 (Scheme 2) <2000AF550, 2006BMC3069, 2006TL2811>. 

YZ1367). On treatment of 6-/ -chlorophenyl-3-methyl-5-nitroso-imi-dazo[2,l-6]thiazole with dilute hydrochloric acid in dioxane at rt a ring transformation occurs [92JCS(CC)1394], Vilsmeyer-Haack reaction of 3-methy -6-phenylimidazo[2,l-6]thiazole (70, R = = H, R = Me, R" =... 

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... 

When (190) was subjected to a Friedel-Crafts reaction with benzoyl chloride, the result was an analog of coralyne with a phenyl rather than a methyl group at position 8. Kametani et al. (74YZ478) have carried out a parallel study using the Vilsmeier-Haack reaction to produce norcoralyne. 

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>. 

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