tert-Butyl N-(tert-butoxycarbonyloxy)carbamate

Chemical Properties

White crystalline powder

Uses

N,O-Di-Boc-hydroxylamine (N,O-Bis(tert-butoxycarbonyl)hydroxylamine) may be used for the synthesis of the following:

• 5-lipoxygenase inhibitor LY280810
• hydroxylamines
• hydroxamic acids,

Synthesis Reference(s)

Journal of the American Chemical Society, 81, p. 955, 1959 DOI: 10.1021/ja01513a049
Tetrahedron Letters, 34, p. 7043, 1993 DOI: 10.1016/S0040-4039(00)61592-7

Synthesis

The general procedure for the synthesis of N,O-di-BOC-hydroxylamine from di-tert-butyl dicarbonate was as follows: first, hydroxylamine hydrochloride (550.0 g, 7.9 mol) was dissolved in a solvent mixture of water (5.5 L) and heptane/MTBE (5:1, 5.5 L), and the mixture was cooled to -5 °C. Subsequently, a solution of di-tert-butyl dicarbonate (3.55 Kg, 16.3 mol) and triethylamine (1.67 Kg, 16.5 mol) in heptane/MTBE (5:1, 1.1 L), which was pre-cooled to -5°C, was slowly added dropwise to the above mixture, and the dropwise process lasted for more than 2 hours. The reaction mixture was continued to be stirred at -5°C for 1 hour, then gradually warmed up to room temperature and stirred overnight. Upon completion of the reaction, the organic layer and the aqueous layer were separated, and the organic layer was washed twice with saturated aqueous ammonium chloride solution (2 L) and saturated aqueous sodium chloride solution (1 L) sequentially, then dried with anhydrous sodium sulfate, filtered and concentrated to obtain an oily product, which was converted to a white solid by crystallization. Finally, the resulting solid was stirred with heptane (1 L) in an ice-water bath and filtered to afford the target product N,O-dibOC-hydroxylamine (1360.2 g, 73% yield). The structure of the product was confirmed by 1H NMR (d6-DMSO) with characteristic peaks located at δ 10.7 (broad single peak, 1H), 1.44 (single peak, 9H), 1.40 (single peak, 9H).

References

[1] Tetrahedron Letters, 1993, vol. 34, # 44, p. 7043 - 7044
[2] Journal of the Chemical Society - Perkin Transactions 1, 1998, # 20, p. 3471 - 3478
[3] Journal of Organic Chemistry, 2009, vol. 74, # 1, p. 254 - 263
[4] Patent: WO2014/66132, 2014, A1. Location in patent: Page/Page column 19
[5] Patent: WO2015/138208, 2015, A1. Location in patent: Page/Page column 7