Vilsmeier-Haack intermediate

An interesting variation of this procedure relies upon the formation of malondialdehyde precursors in situ. Vinylogs of Vilsmeier-Haack intermediates (60), formed from dimethylaminoacroleins (59) and phosgene, undergo reaction with 2,4,6-triaminopyrimidine to yield 6-alkyl- and 6-aryl-substitutcd 2,4-diaminopyrido[2,3-d]-pyri-midines (61). Dimethylaminoacroleins were found to be unsatisfactory. ... 

Figure 6.12 shows that carboxylic acids can also be converted into acid chlorides without releasing HC1. This is possible when carboxylic acids are treated with the chloroenamine A. First the carboxylic acid adds to the C=C double bond of this reagent electrophilically (see Figures 3.51 and 3.53). Then, the addition product B dissociates completely to give the ion pair C. This constitutes the isopropyl analog of the Vilsmeier-Haack intermediate B of the DMF-catalyzed carboxylic chloride synthesis of Figure 6.11. The new Vilsmeier-Haack intermediate reacts exactly like the old one (cf. previous discussion) The chloride ion undertakes an SN reaction at the carboxyl carbon. This produces the desired acid chloride and isobutyric N, IV-dimethylamide.

Scheme 92 Synthesis of thiophene nitriles via Vilsmeier-Haack intermediates [143]...

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). 

There are several schemes for the synthesis of cellulose formates (slow) reaction of the polymer with formic acid faster reaction in the presence of a mineral acid catalyst, e.g., sulfuric or phosphoric acid. The latter route is usually associated with extensive degradation of the polymer chain. Reaction of SOCI2 with DMF produces the Vilsmeier-Haack adduct (HC(Cl) = N (CH3)2C1 ) [145]. In the presence of base, cellulose reacts with this adduct to form the unstable intermediate (Cell - O - CH = N" (CH3)2C1 ) from which cellulose formate is obtained by hydrolysis. The DS ranges from 1.2 to 2.5 and the order of reactivity is 5 > C2 > C3 [140-143,146]. 

That is, the difference between the mechanisms of action of the two bases lies in the ability of EtsN to add to the Vilsmeier-Haack adduct to form a tetrahedral intermediate, susceptible to Sn2 attack by (at least partially de-protonated) cellulose. This leads to formation of the desired Cell - Tos. 

A type Ilbc approach to pyrroles was employed in the synthesis of pyrrolo[2,l-fc]thiazoles <06S1433>. The key step involved a formylation with the Vilsmeier-Haack reagent followed by a cyclocondensation of the putative iminium intermediate. 

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]. 

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... 

CAi90) 123047). The isolation of 2-chloro-5-formylpyrrole from the Vilsmeier-Haack formylation of 2-bromopyrrole (75JOC3161) can be rationalized in terms of an addition-elimination reaction of the intermediate azafulvenium cation (Scheme 82). Displacement... 

The indolophenanthridine (179) was the unexpected product when 1,4-diphenylcarbazole was treated with a mixture of Ar-methyl-formanilide and phosphoryl chloride.204 Presumably the Vilsmeier-Haack complex attacks at nitrogen, but no explanation was offered to account for the oxidation (of either the Vilsmeier intermediate... 

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... 

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... 

Other cyclizing agents include the Vilsmeier-Haack reagent prepared from DMF and phosphoryl chloride (27CB119) which permits the formylation and cyclization of 4,5-diaminopyrimidines to be carried out at low temperatures (6UCS5048) and is especially valuable for the preparation of chloropurines from chloropyrimidines. A modified Vilsmeier-Haack procedure which involves cyclization of an intermediate azomethine (253) at low temperatures in situ has also been applied to chloropurine synthesis (6UCS5048). 

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