Unexpected Rearrangement of 2-Bromoaniline under Biphasic Alkylation Conditions

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.

Key words

bromoaniline - alkylation - rearrangement - bromine

• References and Notes

• 1 Excepting reactions (e.g., certain Smiles rearrangements) in which the defining structure of aniline is lost.
• 2a Bamberger E. Ber. Dtsch. Chem. Ges. 1894; 27: 1347
• 2b Bamberger E. Ber. Dtsch. Chem. Ges. 1894; 27: 1548
• 2c Bamberger E. Justus Liebigs Ann. Chem. 1912; 390: 131
• 2d Bamberger E. Justus Liebigs Ann. Chem. 1921; 424: 233
• 3a Fries K. Oehmke G. Justus Liebigs Ann. Chem. 1928; 462: 1
• 3b Fries K. Boeker R. Wallbaum F. Justus Liebigs Ann. Chem. 1934; 509: 73
• 3c Miller B. Tetrahedron Lett. 1962; 2: 55
• 3d Boduszek B. Shine HJ. J. Am. Chem. Soc. 1988; 110: 3247
• 4a Hofmann AW. Martius CA. Ber. Dtsch. Chem. Ges. 1871; 4: 742
• 4b Hofmann AW. Ber. Dtsch. Chem. Ges. 1872; 5: 720
• 5a Reilly J. Hickenbottom WJ. J. Chem. Soc. 1920; 117: 103
• 5b Rhee ES. Shine HJ. J. Am. Chem. Soc. 1986; 108: 1000
• 5c Wright GE. J. Org. Chem. 1980; 45: 3128
• 6a Fischer O. Hepp E. Ber. Dtsch. Chem. Ges. 1886; 19: 2991
• 6b Glazer J. Hughes ED. Ingold CK. James AT. Jones GT. Roberts E. J. Chem. Soc. 1950; 2657
• 6c Neber PW. Rauscher H. Justus Liebigs Ann. Chem. 1942; 550: 182
• 7a Bender G. Ber. Dtsch. Chem. Ges. 1886; 19: 2272
• 7b Armstrong HE. J. Chem. Soc. Trans. 1900; 77: 1047
• 7c Chattaway FD. Orton KJ. P. J. Chem. Soc. 1899; 75: 1046
• 8 Mellor M. Osbourn SE. Tetrahedron 1991; 47: 2255
• 9 Chromatographic methods could not adequately separate the products, as their properties were too similar.
• 10 Cella JA. Bacon SW. J. Org. Chem. 1984; 49: 1122
• 11a McMillen DF. Golden DM. Ann. Rev. Phys. Chem. 1982; 33: 493
• 11b Blanksby SJ. Ellison GB. Acc. Chem. Res. 2003; 36: 255
• 12a O’Bara EJ. Balsley RB. Starer I. J. Org. Chem. 1970; 35: 16
• 12b Effenberger F. Menzel P. Angew. Chem., Int. Ed. Engl. 1970; 10: 493
• 12c Effenberger F. Menzel P. Chem. Ber. 1977; 110: 1342
• 12d Effenberger F. Angew. Chem. Int. Ed. 2002; 41: 1699
• 13 Winemiller MD. Kopach ME. Harman WD. J. Am. Chem. Soc. 1997; 119: 2096
• 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).