Alkylation Reactions of the Pyrrole Grignard Reagent^1a

Abstract

Pyrrolylmagnesium bromide and chloride react with 4-chlorobutanenitrile to yield a mixture of 2-and 3-(3-cyanopropyl)pyrrole, with the former predominant, and not 2-pyrrol-2-yl-2-pyrroline as reported in the literature. The isomer distribution is similar to that obtained in the reaction of pyrrolylmagnesium chloride with butyl chloride, heptyl chloride, and l-chloro-4-methoxybutane. The constitution of pyrrolylmagnesium chloride in tetrahydrofuran is the same as in ethyl ether. In the alkylation with 4-chlorobutanenitrile initial complexing of the Grignard reagent with an unshared electron pair of the nitrile group occurs.Isomeric 1-, 2-, and 3-alkylpyrroles and those alkyl-substituted derivatives examined can be distinguished by their infrared absorption in the in-plane deformation region.Pursuant to the synthesis of 2,2'-bipyrroles2-6 it was of interest to attempt the synthesis of the parent unsubstituted bipyrrole by the dehydrogenation of the compound reported7 as 2-pyrrol-2-yl-2-pyrroline, which was synthesized from the reaction of pyrrolylmagnesium bromide with 4-chlorobutanenitrile. Since the earlier report describing this synthesis, a number of studies8-15 have established that the isomeric 1pyrroline is actually to be expected. As a consequence of our examination of the pyrrole Grignard reagenthalonitrile product and the variety of observations recorded in the literature14•16-21 for related studies we have been led to initiate an extensive investigation. In this first paper some features of the study of the reaction of the pyrrole Grignard reagent with 4chlorobutanenitrile and associated results are described. Results and DiscussionProduct from Pyrrole Grignard Reagent and 4-Chlorobutanenitrile.-Attempts on our part to dehydrogenate this product (I), which was obtained as an oil, by heating with platinum on charcoal22 were unsuccessful as were those with the formyl derivative (II) obtained from I via the Vilsmeier-Haack reaction.23 Direct comparison of the oil (I) from the Grignard re-(1) (a) Presented in part before the Division of Organic Chemistry, 139th

N‐Functionalization of 4‐amino‐2‐(trifluoromethyl)‐1H‐pyrroles: Synthesis of N‐alkyl derivatives and 1,2,3‐triazol‐4‐yl‐pyrrole scaffolds

“…The literature shows that the most commonly applied methods to perform C ‐alkylation of pyrroles use copper‐ and iron‐based catalysts [23–25], organocatalysts [26,27], and ionic liquids [28]. Although the most reactive position for S E Ar in pyrroles is at the 2‐ and 5‐positions, 3‐alkylation can occur in some special cases, and mixtures of products 3‐ and 5‐dialkylated products are usually obtained [29,30]. Despite this, our NMR data showed only one compound, and the assignment of the obtained product was achieved through 1 H‐ 13 C HMBC experiments (Scheme 3).…”

“…Reaction scope for the synthesis of N-methyl, N-allyl, and N-propargyl pyrroles 2a-i. general reaction conditions: Pyrrole 1a-g (1 mmol), propargyl bromide (2 mmol, 0.238 g), K 2 CO 3 (2 mmol, 0.276 g), acetone (10 mL), reflux, 2 h. a Reaction conditions: Pyrrole 1a (1 mmol, 0.262 g), allyl bromide (1 mmol, 0.121 g) for 2h or methyl iodide (1 mmol, 0.142 g) for 2i, K 2 CO 3 (1 mmol, 0.138 g), acetone (10 mL), 16 h usually obtained [29,30]. Despite this, our NMR data showed only one compound, and the assignment of the obtained product was achieved through 1 H- 13 C HMBC experiments (Scheme 3).…”

Electrophilic Substitution of the Pyrrole Ring

“…* 385 When the methylation of (H39a) is allowed to proceed to only 10% completion, it is found that the initially formed 2-and 3-methylpyrroles are methylated at the same rate, but that the 2,3-dimethylpyrrole is methylated at the 5-position more rapidly than the methylation of 2,5-dimethylpyrrole at the 3-position. (144,145) Contrary to earlier reports (408) that (H39a) reacts with 4-chlorobutyronitrile to give 2-(2-pyrryl)-l-pyrroline (H43a), it has been established that normal alkylation of the pyrrole ring occurs to give 2-and 3-(3-eyanopropyl)pyrrole in a ratio of 4-4 : l. (399) However, it has also been claimed that equimolar amounts of the nitrile and 2,3,4-trimethylpyrrylmagnesium halides give (H43b), whereas when there is an excess of the nitrile the 2//-pyrrole (H44) is formed. The inductive effect of alkyl groups should make the alkylpyrroles less acidic but the anions should be more nucleophilic than pyrrole.…”