Pyrrole phosphoryl chloride

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). 

Poor stirring during formylation of 2,5-dimethylpyrrole with the preformed complex of dimethylformamide with phosphoryl chloride caused eruption of the flask contents. Reaction of the complex with a local excess of the pyrrole may have been involved. 

The central point of another approach involves an electrophilic attack on a pyrrole system. Under the influence of phosphoryl chloride, pyrrole reacts... 

The combination of tertiary amides, such as dimethylformamide, and phosphoryl chloride generates reactive electrophiles capable of being attacked by electron-rich nucleophiles and is widely used as the Vilsmeier formylation process. The Vilsmeier process has become more general, with the use of more varied amides, and has been particularly successful for the functionalization of pyrroles and indoles. Greater flexibility has been achieved with the replacement of phosphoryl chloride by trifluoromethanesulfonic anhydride. 

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-... 

The reactions of iminium complex 668, generated in the reaction of 4-(dimethylamino)-l,l,l-trifluorobut-3-en-2-one 667 with phosphoryl chloride or trifluoromethanesulfonic anhydride, with pyrroles proceeded stereospecifically to give finally (after hydrolysis of intermediates 669) the ( )-isomers of 2-vinylpyrroles 670 (Scheme 133) <1998T119, 1999RCR437>. The reactions with trifluoroacetyl alkenes depicted in Equation (160) and Schemes 132 and 133 are also applied to indole systems <1999RCR437>. 

Pyrrole reacts with malonamides in phosphoryl chloride giving pyrroli-zines in moderate yields (Scheme 6).15 Benzimidazole-2-propionic acid undergoes cyclization and subsequent formylation under Vilsmeier conditions at room temperature (RT) (Scheme 7).16... 

Vilsmeier acylation of pyrroles, formylation with dimethylformamide/phosphoryl chloride in particnlar, is a generally applicable process. The actual electrophilic species is an Al,Al-diaIkyl-chloromethyleneiminium cation (the chloride is available commercially as a solid). " Here again, the presence of a large pyrrole-A-substituent perturbs the intrinsic a-selectivity, formylation of A-tritylpyrrole favonring the P-position by 2.8 1 and trifluoroacetylation of this pyrrole giving only the 3-ketone " the nse of bulky iV-silyl substituents allows P-acylation with the possibility of subsequent removal of the N-snbstituent." The final intermediate in a Vilsmeier reaction is an iminium salt requiring hydrolysis to prodnce the isolated product aldehyde. When a secondary lactam is used, hydrolysis does not take place and a cyclic imine is obtained." ... 

T reatment of A -(2-acetylaminophenyl)-1 //-pyrrole-1 -amine (50 X = H) with phosphoryl chloride resulted in intramolecular cyclization to give the five-membered ring benzimidazole (51) (80% yield), while the A -methyl compound (50 X = Me) underwent cyclization to form a seven-membered ring such as the pyrrblo[l,2-i]-l,2,5-benzotriazepine (52) (95% yield) (Scheme 8) <838757, 90FES1, 90FES817>. 

In a porphyrin synthesis, 2-cyanopyrrole derivatives were prepared by dehydration of the corresponding pyrrole-2-carbaldoxime with phosphoryl chloride [1092]. 

An interesting substitution which gives a product (13) related to the Mannich bases, by means of a modified Vilsmeier reaction, occurs between pyrrole, pyrrolidone and phosphoryl chloride . Other examples are known27i, 3i3 ... 

To 23] Further examples have been described of the reaction between pyrroles and pyrrolidone in the presence of phosphoryl chloride i. The use of -d -pyrrolin-2-ones in place of pyrrolidone gives bipyrroles, whilst J4-pyrrolin-2-ones lead to dipyrrylpyrrolines . 

To5f Pyrrole magnesium bromide and 2-(l-methylpyrrolyl) lithium give tertiary phosphine oxides with phosphoryl chloride s. 

In the opinion of the authors in [10], one of the first reactions in the synthesis of phosphorylated pyrroles (the reaction of potassiopyrrole with phosphorus trichloride) leads to tris(2-pyrrolyl)phosphine, from which the corresponding thioxide and a complex with copper(I) chloride were obtained. However, the authors of [21] repeated the transformations and on the basis of a study of the 13C NMR spectra came to the conclusion that tris(N-pyrryl)amidophosphite (29) is formed in this reaction ... 

Michael addition has been applied to the formation of cyclopropanic systems. Thus, the addition of phosphonate carbanions generated by LDA in THF, by NaH in THF, by thallium(I) ethoxide in refluxing THF, or by electrochemical technique to oc,P-unsaturated esters provides a preparation of substituted 2-(alkoxycarbonyl)cyclopropylphosphonates in moderate to good yields via a tandem Michael addition-cyclization sequence (Scheme 8.47). The cyclopropanation has also been achieved via oxidation with iodine in the presence of KF-AI2O3. Nitrile ylides prepared from acyl chlorides and diethyl isocyanomethylphosphonate in the presence of Et3N react with methyl acrylates by a 1,3-dipolar cycloaddition to give phosphoryl pyrrolines or pyrroles. ... 

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