Reactions of C-metallated Pyrroles

Reactions of the species produced by the lithiation of TV-substituted pyrroles are efficient for the introduction of groups to the 2-position, either by reaction with electrophiles or by coupling processes based on boron or palladium chemistry.  

Some examples where removable AT-blocking groups have been used in the synthesis of 2-substituted pyrroles, via lithiation, are shown below. 

Metal/halogen exchange on 2-bromo-l- -butoxycarbonylpyrrole and on its 2,5-dibromo conterpart proceed normally and the mono- or dilithiated species thus produced react with the usual range of electrophiles, as illustrated below. 

Metal/halogen exchange using 3-bromo-7V-triisopropylsilylpyrrole very usefully allows the introduction of groups to the pyrrole yS-position and can complement direct electrophilic substitution of 7V-triisopropylsilylpyrrole (see sections 13.1.2 and 13.1.4). 

Me2N=CHCI Cl CH2CI2. reflux then aq. NaOH 

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Jury JC, Swamy NK, Yazici A, Willis AC, Pyne SG (2009) Metal-catalyzed cycloisomerization reactions of c -4-hydroxy-5-alkynylpyrrolidinones and cii-5-hydroxy-6-alkynylpi-peridinones synthesis of furo[3,2-i)]pyrroles and furo[3,2-b]pyridines. J Org Chem 74 5523-5527... 

N-Alkylpyrroles may be obtained by the Knorr synthesis or by the reaction of the pyrrolyl metallates, ie, Na, K, and Tl, with alkyl haUdes such as iodomethane, eg, 1-methylpyrrole [96-54-8]. Alkylation of pyrroles at the other ring positions can be carried out under mild conditions with allyhc or hensylic hahdes or under more stringent conditions (100—150°C) with CH I. However, unless most of the other ring positions are blocked, poly alkylation and polymerisation tend to occur. N-Alkylation of pyrroles is favored by polar solvents and weakly coordinating cations (Na", K" ). More strongly coordinating cations (Li", Mg " ) lead to more C-alkylation. 

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

Pyrrole and alkylpyrroles can be acylated by heating with acid anhydrides at temperatures above 100 °C. Pyrrole itself gives a mixture of 2-acetyl- and 2,5-diacetyl-pyrrole on heating with acetic anhydride at 150-200 °C. iV-Acylpyrroles are obtained by reaction of the alkali-metal salts of pyrrole with an acyl halide. AC-Acetylimidazole efficiently acetylates pyrrole on nitrogen (65CI(L)1426). Pyrrole-2-carbaldehyde is acetylated on nitrogen in 80% yield by reaction with acetic anhydride in methylene chloride and in the presence of triethylamine and 4-dimethylaminopyridine (80CB2036). 

In the presence of various metal ions, 2-(fluoroenone)benzothiazoline has been found to rearrange to A-2-mercaptophenylenimine, while a free radical mechanism involving the homolysis of C-S and C-N bonds has been invoked to explain the formation of 3-phenyl-1,2,4-triazole derivatives from the thermal fragmentation and rearrangement of 2-(arylidenehydrazino)-4-(5//)-thiazolone derivatives. The cycloadducts (36) formed from the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxide (34) with nitric oxides or miinchnones (35) have been found to undergo pyrolytic transformation into a, jS-unsaturated nitriles (38) by way of pyrrole-isothiazoline 1,1-dioxide intermediates (37). 

The reaction of ketoximes with vinyl halides at 80-130°C in the presence of alkali metal hydroxides and DMSO leads to pyrroles (80ZOR672) (Scheme 55). Varying the ratio of reactants and the conditions, it is possible to carry out the reaction selectively and obtain either pyrroles (R3 = H) in about 40% yield or their W-vinyl derivatives (yield to 35%). 

Porphobilinogen and Studies of Its Biosynthesis, ft. Neier. Synthesis and Cycloaddition Reactions of Iso-Condensed Heteroaromatic Pyrroles, C. K. Sha. Azacyclopentadienyl Metal Compounds Historical Background and Recent Advances, C. Janiak and N. Kuhn. Recent Developments in the Synthesis of Marine Pyridoacridine Alkaloids, A. M. Echavar-ren. Alkaloid Synthesis Using 1-Acylpyridinium Salts as Intermediates, D. L. Comins and S. P. Joseph. Index. S S... 

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