A Lewis Acid-Mediated Protocol for the Protection of Aryl Amines as their Boc-Derivatives

Abstract

A new protocol of protection of poorly reactive aryl amines and functionalized amines with Boc₂O in the presence of Zn(ClO₄)₂·6H₂O as the catalyst is reported. The catalytic action of Zn(ClO₄)₂·6H₂O is specific for the activation of the pyrocarbonates, thus acid sensitive functionalities and stereochemical configurations of the starting materials remain unaltered in the protection ­process.

protection - Lewis acid - zinc perchlorate - aryl amines - Boc-derivatives

References

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12

The reaction was also carried out by changing the Zn(II) counterion of the potentially explosive Zn(ClO₄)₂·6H₂O using Zn(OAc)₂. We obtained worse results, only a 60% conversion after 4.5 h in CH₂Cl₂ at r.t. was detected.

13

Representative Experimental Procedure. Synthesis of tert -Butyl N -Phenylcarbamate ( 2a): To a round-bottom flask were added Zn(ClO₄)₂·6H₂O (28 mg, 0.075 mmol), CH₂Cl₂ (2.25 mL), aniline (0.14 g, 1.50 mmol) and Boc₂O (0.43 g, 1.95 mmol, 1.3 equiv). The reaction mixture was stirred at r.t. for 12 h. After addition of 5 mL of CH₂Cl₂, the solution was washed with H₂O. The organic layer was dried over MgSO₄ and concentrated at reduced pressure. The crude product was purified by column chromatography on silica gel. Compounds 2a, 2b, 2i, 2m, 4a, 4d and 4i are commercial products; 2c, [4] 2d [14] , 2e, [4] 2p [15] , 4c [16] , 4e [17] , 4g [18] and 4h [19] are known compounds. Spectroscopic data for selected examples follow. tert-Butyl N-[4-(Acetylamino)phenyl] Carbamate (2f): ¹H NMR (300 MHz, CDCl₃): δ = 1.51 (s, 9 H, t-Bu), 2.15 (s, 3 H, CH₃), 6.50 (br s, 1 H, NH), 7.20 (br s, 1 H, NH), 7.26-7.35 (m, 2 H, Ph), 7.40-7.45 (m, 2 H, Ph). ¹³C NMR (100 MHz, CDCl₃): δ = 23.7 (CH₃), 26.9 (CH₃), 79.8 (C), 116.3 (CH), 118.8 (CH), 133.3 (C), 134.3 (C), 152.7 (C), 168.4 (C). tert-Butyl N-(3-Sulfanylphenyl) Carbamate (2h): ¹H NMR (300 MHz, CDCl₃): δ = 1.51
(s, 9 H, t-Bu), 3.46 (s, 1 H, SH), 6.60 (br s, 1 H, NH), 6.90-6.95 (m, 1 H, Ph), 7.00-7.05 (m, 1 H, Ph), 7.05-7.10 (m, 1 H, Ph), 7.40 (br s, 1 H, Ph). ¹³C NMR (75 MHz, CDCl₃):
δ = 28.3 (CH₃), 80.7 (C), 115.5 (CH), 118.7 (CH), 123.6 (CH), 129.4 (CH), 131.8 (C), 138.9 (C), 152.5 (C). Diethyl (2S)-2-(4-[(tert-Butoxycarbonyl)amino] Benzoylamino) Pentanedioate (2l): [α] _D = 13 (c 1.05, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.22 (t, 3 H, J _HH = 7.1 Hz, CH₃), 1.30 (t, 3 H, J _HH = 7.2 Hz, CH₃), 1.52 (s, 9 H, t-Bu), 2.05-2.60 (m, 4 H, 2 CH₂), 4.10-4.20 (m, 2 H, CH₂), 4.20-4.30 (m, 2 H, CH₂), 4.75-4.80 (m, 1 H, CH), 6.80 (br s, 1 H, NH), 7.0 (br d, 1 H, J _HH = 7.2 Hz, NH), 7.40-7.45 (m, 2 H, Ph), 7.75-7.80 (m, 2 H, Ph). ¹³C NMR (75 MHz, CDCl₃): δ = 14.0 (CH₃), 14.1 (CH₃), 27.1 (CH₂), 28.2 (CH₃), 30.5 (CH₂), 52.3 (CH), 60.7 (CH₂), 61.6 (CH₂), 80.9 (C), 117.2 (CH), 127.6 (C), 128.2 (CH), 141.8 (C), 152.3 (C), 166.5 (C), 172.0 (C), 173.2 (C).

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