Pyrrole Vilsmeier acylation

But this mixture would decompose the pyrrole 101. We use instead the Vilsmeier acylation, replacing the acid chloride by the tertiary amide and AICI3 by POCI3. The amide is very unreactive but combines with POCI3 102 to give a reactive species that does attack the pyrrole 104 in the right position to give, after rearomatisation 105, the iminium salt 106 that is hydrolysed to the ketone 101. You will notice the similarities to electrophilic substitution on benzene. 

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." ... 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

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). 

Thiophene is also readily acylated under both Friedel-Crafts and Vilsmeier-Haack conditions and similarly to pyrrole and furan gives 2-acylated products. An almost quantitative conversion of thiophene into its 2-benzoyl derivative is obtained by reaction with 2-benzoyloxypyridine and trifluoroacetic acid. The attempted preparation of 2-benzoylthiophene under standard Friedel-Crafts conditions, however, failed (80S139). 

Pyrrole, 2-acetyl-1 -(2-hydroxyethyl)-5-nitro-cydization, 4, 74 ipso substitution, 4, 243 Pyrrole, 2-acetyl-1-methyl-dipole moment, 4, 194 photocydization reactions with 2,3-dimethylbut-2-ene, 4, 269 Pyrrole, 3-acetyl-4-methyl-Vilsmeier-Haack formylation, 4, 222 Pyrrole, 2-acetyl-3-nitro-reduction, 4, 297 Pyrrole, acyl-basicity, 4, 207 isomerization, 4, 208 oximes... 

Some reactions can be controlled to give good yields of monosubstituted products. One is the Vilsmeier reaction in which a combination of an N, N- d imet hyla mide and POCI3 is used to make a carbon electrophile in the absence of strong acid or Lewis acid. It is a substitute for the Friede 1-Crafts acylation, and works with aromatic compounds at the more reactive end of the scale (where pyrrole is). 

An early approach to the synthesis of cephalotaxine (Scheme 32) was reported by Dolby et al. (64) in 1972, shortly before Auerbach s and Wein-reb s report (22). The Vilsmeier-Haack condensation of piperonylamide 187 with pyrrole yielded ketone 188, which was successively reduced with sodium borohydride, hydrogenated, and acylated to give the precursory chloro amide 189. The photocyclization of 189 produced lactam 190, which, after reduction of the carbonyl with lithium aluminum hydride and subsequent oxidation with mercuric acetate, yielded the enamine 43. This mate-... 

Reactions of Pyrroles. 1,3-Di-t-butylpyrrole forms the first stable protonated pyrrole, the salt (104). Electrophilic substitution of pyrrole with MeaC or Me FC in the gas phase occurs mainly at the j3-position, as does nitration and Friedel-Crafts acylation of l-phenylsulphonylpyrrole2 Pyrrole-2,5-dialdehyde has been prepared by Vilsmeier-Haack formylation of the ester (105), followed by hydrolysis. A similar method has been used to convert the di-acetal (106) into pyrrole-2,3,5-tricarbaldehyde. AT-Benzoyl-pyrrole reacts with benzene in the presence of palladium(II) acetate to yield a mixture of l-benzoyl-2,5-diphenylpyrrole, the bipyrrolyl (107), and compound (108). Treating lithiated A-methylpyrrole with nickel(II) chloride results in the polypyrrolyls (109 = 0-4). 2-Aryl-1-methylpyrroles are obtained by cross-coupling of l-methylpyrrol-2-ylmagnesium bromide with aryl halides in the presence of palladium(0)-phosphine complexes. ... 

Another acylation procedure uses iminium salts rather than acyl halides. The Vilsmeier-Haack reaction is a well-known process illustrated by reaction of pyrrole with the POCI3 complex of N,N-dimethylacetamide (207, which can decompose to a chloroiminium salt). The acylation reaction gave 208, which was converted to 2-acetylpyrrole by hydrolysis with aqueous sodium acetate.A synthetic example is taken from Lai s synthesis of indole analogs of mycophenolic acid,l in which 209 reacted with POCI3 and DMF to give a 77% yield of the aldehyde 210. 

Alkylation of pyrroles proves to be problematic because the usual Lewis acid catalysts initiate polymerization. The Vilsmeier-Haack formylation, however, leads to the formation of pyrrole-2-carbaldehyde in good yield. The Houben-Hoesch acylation (reaction with nitriles in the presence of hydrogen chloride) provides 2-acylpyrroles ... 

As is the case with pyrroles, C-alkylation of indoles results in mixtures of products. Formylation and acylation, however, occur more readily. The Vilsmeier-Haack reaction furnishes indole-3-carbaldehyde heating with acetic anhydride produces 3-acetylindole. In the Houben-Hoesch acylation, substitution takes place in the 3-position. 

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