Synlett 2017; 28(20): 2891-2895
DOI: 10.1055/s-0036-1590882
letter
© Georg Thieme Verlag Stuttgart · New York

Unexpected Rearrangement of 2-Bromoaniline under Biphasic Alkylation Conditions

Scott J. Barraza
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA   Email: sdenmark@illinois.edu
,
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA   Email: sdenmark@illinois.edu
› Author Affiliations
This work is generously supported by Janssen Research and Development LLC, San Diego.
Further Information

Publication History

Received: 21 June 2017

Accepted after revision: 28 July 2017

Publication Date:
21 August 2017 (eFirst)

Dedicated to big brother Vic on the festive occasion of his entry into the ninth decade

Abstract

Alkylation of 2-bromoaniline with benzyl bromide under ostensibly basic N-alkylation conditions resulted in migration of bromine from the 2- to the 4-aryl position. Herein we report our studies to elucidate the mechanism of this rearrangement with the objective of suppressing this unexpected outcome. We find that careful choice of reagents is critical, and that this behavior may be extrapolated to alkylation reactions of electron-rich bromo- and iodoanilines in general.

Supporting Information

 
  • References and Notes

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  • 14 General Procedure for Rearrangement Experiments The relevant aniline (0.5 mmol) was weighed into an oven-dried, threaded dram vial, followed by the sequential addition of anhydrous DMF (1 mL), an additional reagent (if required), and an alkyl halide (if required) last. The vial was tightly capped and placed in a pre-heated aluminum block (80 °C or 120 °C). After 24 h, the vial was removed from the block and allowed to cool to ambient temperature (23 °C), at which point it was cautiously opened (may be pressurized). The most common reaction colors are: colorless, black, amber, green, and blue. The reaction mixture was diluted with 1:1 hexanes/EtOAc (20 mL) and washed with 10% aq NaHCO3 (30 mL), 10% aq LiCl (30 mL), and brine (30 mL), dried over anhydrous Na2SO4 (1 g), decanted, and concentrated on a rotovap (30 °C, 15 mm Hg). The crude product was then dried further under high vacuum (0.1 mm Hg) for 1 h before being diluted with a solution of a known quantity of tetramethylurea (TMU) in CDCl3 (1 mL). The targeted quantity was 0.05 mmol TMU/1 mL CDCl3, prepared as stock solutions in 10 mL volumetric flasks at 23 °C. TMU was measured by mass, and the actual quantity per mL CDCl3 is reported. The solution was then transferred to a 5 mm NMR tube and analyzed by 1H NMR and 13C NMR spectroscopy (600 MHz, 1H).