Friedel-Crafts Alkylation of pyrrole via pyrrole-2-carboxaldehyde; pyrroles

Ian Westmoreland ([email protected]),
A contribution from the Arnold Group, UC Berkeley

Chemicals Used
Pyrrole (distilled prior to use), Oxalyl chloride, Aluminium chloride, N,N-dimethylformamide, 2-Chloro-2-methylpropane (tert-butyl chloride), Sodium hydroxide, Methylene chloride (dried over activated alumina)

Procedure
A solution of oxalyl chloride 12.7 g, 100 mmol) in methylene chloride (50 ml) was added to a solution of N,N-dimethylformamide (7.7 ml, 100 mmol) in methylene chloride (100 ml) at 0⁰C over 30 min. After complete addition the cold bath was removed and the mixture stirred for a further 30 min. The solution was then re-cooled to 0⁰C, and to it was rapidly added a solution of pyrrole (6.9 ml, 100 mmol) in methylene chloride (50 ml). The resulting brown solution was stirred for 15 min at room temperature and aluminium chloride (29.3 g, 220 mmol) was then added cautiously via powder funnel, followed by 2-chloro-2-methylpropane (10.9 ml, 100 mmol). The resulting mixture was stirred for either (a) 2 h or (b) 24 h. After this time, the reaction mixture was neutralised with NaOH (30% solution). The organic phase was separated, and the aqueous fraction was exhaustively extracted with methylene chloride. Concentration under reduced pressure of the combined organic phases gave a brown residue. This material was redissolved in pentane, filtered through celite, and recrystallised by cooling to -35⁰C. The product is thus obtained as a white crystalline solid in 65-75 % yield (ca. 10 -12 g)

Author's Comments
The length of time allowed for the electrophilic addition dictates whether (a) the kinetic or (b) thermodynamic product is obtained. Conversion is 100% of isolated material in either case, although intermediate reaction times lead to inseparable mixtures of both isomers. These results are replicated if the Friedel-Crafts alkylation is performed on pyrrole-2-carboxaldehyde. If the synthesis is attempted as described above, prior distillation of pyrrole will give improved yields. Care should also be taken with the addition of aluminium chloride.

Data
(a) 2-formyl-4-tert-butylpyrrole ¹H NMR (293K, CDCl3) 10.63 (1H, bs, NH), 9.30 (1H, s, CHO), 6.61 (1H, s, CH), 6.48 (1H, s, CH), 1.10 (9H, s, tBu) ppm. (b) 2-formyl-5-tert-butylpyrrole ¹H NMR (293K, CDCl3) 9.55 (1H, bs, NH), 9.27 (1H, s, CHO), 6.75 (1H, d, CH), 6.05 (1H, d, CH), 1.20 (9H, s, tBu) ppm.

Lead Reference
H. J. Anderson and C. E. Loader, Synthesis, 1985, 354.

Other References
J. M. Patterson, Synthesis, 1976, 281.

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