Vilsmeier-Haack salt

Addition of tetrabutylammonium iodide and use of a higher reaction temperature changes fhe product of fhe above Williamson efher synthesis. In the reaction depicted by Scheme 1.T1 the carbonates are obtained directly whereas reaction wifh a secondary halide resulted in the production of a formate (Scheme 2.28) [43]. Formation of fhe formate is explained by formation of fhe Vilsmeier-Haack salt from DMF. 

The electrophile can also he the Vilsmeier-Haack salt (previously formed by the reaction of DMF and POCI3 in 1 1 ratio) to provide the 3-formyl-1-methylindole in 92% yield (eq 10). ... 

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. 

The most useful general method for the C-acylation of pyrroles is the Vilsmeier-Haack procedure in which pyrrole is treated with the phosphoryl chloride complex (55a, b) of an AiA-dialkylamide (54). The intermediate imine salt (56) is hydrolyzed subsequently under mildly alkaline conditions to give the acylated pyrrole (57). On treatment of the imminium salt (56 R =H) with hydroxylamine hydrochloride and one equivalent of pyridine and heating in DMF, 2-cyanopyrrole (58) is formed (80CJC409). 

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. 

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

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... 

Another characteristic of electrophilic reactions of pseudoazulenes is the application of numerous cations as the electrophile, for example, diazonium salts and Vilsmeier- Haack s reagent (see Table VI), tropylium ion,135 triphenylmethyl cation,"4 pyrylium ion,119 and dithiolium ion.166 Very stable cations are formed (e.g., 120) addition of base releases the substituted pseudoazulene (see example in Eq. 10). Generally reactions of this type are thermodynamically favored (see also Section IV,B). The site of substitution... 

Pyridines have been synthesized from an unusual Vilsmeier-Haack reaction where POCl3 dehydrates the appropriate enol to give a diene which in turn reacts with the Vilsmeier reagent leading to an iminium salt which subsequently cyclizes (Scheme 104 Table 7) <2002TL2273>. 

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)... 

Aryl acetones react with the Vilsmeier-Haack reagent to form conjugated iminium salts 726, which spontaneously cyclize upon basic aqueous work-up to afford 3-formyl-pyran-4-ones (Scheme 180) <2004T5069>. (1,3-Diphenylpropane-2,2-diyl)bis(butylsulfane) 727 also reacts with the Vilsmeier-Haack reagent to afford 3,5-diphenyl-4//-pyran-4-one upon basic aqueous workup (Equation 291) <2004T5069>. 

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-... 

C. Reichardt, Vilsmeier-Haack-Arnold Formylations of Aliphatic Substrates with N-Chloromethylene-N,N-dimethylammonium Salts, / Prakt. Chem. 1999, 341, 609-615. 

The salts of methylene derivatives of 2H- and 3//-pyrroles and -indoles are produced in the Ehrlich reaction (Scheme 32, Section 3.05.1.2.8) and they are also intermediates in the Vilsmeier-Haack reaction (Scheme 24, Section 3.05.2.1.6). Although 6-fV,fV-dimethyl-amino-l-azafulvene, i.e. 2-(Ar,Ar-dimethylaminomethylene)-2//-pyrrole, dimerizes spontaneously (see Section 3.05.2.5), the 6-aryl-6-Ar)Ar-dimethylamino-l-azafulvenes (514 R = aryl) can be isolated (71JCS(B)1405) but, curiously, they are more susceptible to reactions with nucleophiles at the 6-position than are the corresponding salts (B-77MI30508). The benzo[6 ]-1 -azafulvenes, obtained from the reaction of 2-formylindoles with dialkylamines, also dimerize spontaneously, but the isomeric benzo[c]-2-azaf ulvenes, derived from 3-formylindoles, are thermally more stable, although they are extremely moisture sensitive... 

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). 

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... 

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