N-Bromosuccinimide Promoted Ring Expansion Reactions: Diastereoselective Formation of Functionalized Azaspirocyclic Cyclopentanones

Abstract

N-Bromosuccinimide (NBS) induces ring enlargements of 2-(1-hydroxycyclobutyl)-p-toluenesulfonylenamides such as 1. These high yielding reactions typically occur with good diastereoselectivity. This ring expansion protocol under neutral conditions forms compounds that are potentially versatile intermediates for the construction of spirocycle-containing alkaloids.

bromine - ring expansion - stereoselective - piperidines - spiro compounds

References

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<A NAME="RS05703ST-6">6</A>

All new compounds have been satisfactorily characterized spectroscopically (IR, ¹H NMR, ¹³C NMR, MS).

Examples of the use of NBS and other electrophilic bromine sources to promote migration reactions:

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A representative experimental procedure for the NBS-promoted ring expansion reaction: (5 S ^* ,7 S *,10 S *)-10-Bromo-7-ethoxy-6-[(4-methylphenyl)sulfonyl]-6-azaspiro[4.5]decan-1-one ( 3): To a stirred solution of cyclobutanol 1 (100 mg, 0.285 mmol, 1 equiv) in propylene oxide (2 mL) and i-PrOH (2 mL) at -78 °C was added N-bromosuccinimide (60.8 mg, 0.341 mmol). The mixture was stirred at -78 °C for 2 h. The reaction was warmed to r.t. over 1 h and solvents were removed in vacuo. Column chromatography on silica gel (10% EtOAc-hexanes) gave 117 mg (96%) of a white solid; mp 100-103 °C(dec). IR (KBr): 2938, 1740, 1328, 1137 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.79 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.2 Hz, 2 H), 4.87 (dd, J = 5.2, 1.5 Hz, 1 H), 4.61 (dd, J = 11.6, 4.3 Hz, 1 H), 3.89 (dq, J = 9.8, 7.0 Hz, 1 H), 3.52 (dq, J = 9.8, 7.0 Hz, 1 H), 2.78 (dt, J = 14.0, 9.5 Hz, 1 H), 2.70 (ddd, J = 19.2, 10.4, 8.9 Hz, 1 H), 2.55-2.29 (m, 3 H), 2.42 (s, 3 H), 2.26-2.01 (m, 3 H), 1.86-1.68 (m, 2 H), 1.19 (t, J = 7.0 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 214.2, 143.6, 138.1, 129.4, 127.5, 83.4, 68.2, 63.7, 50.8, 40.3, 37.4, 28.6, 25.3, 21.5, 18.4, 15.2; MS (ESI): m/z 424 [M + 2 - EtOH + K]⁺, 422 [M - EtOH + K]⁺, 408 [M + 2 - EtOH + Na]⁺, 406 [M - EtOH + Na]⁺, 386(47), 384(45).