Highly regioselective aminobromination of α,β-unsaturated nitro compounds with benzyl carbamate/N-bromosuccinimide as nitrogen/bromine source

Abstract

Aminobromination of α,β-unsaturated nitro compounds with benzyl carbamate and N-bromosuccinimide as nitrogen/bromine sources was reported. This new catalytic system tolerates a wide range of aromatic substrates, as well as heterocyclic and aliphatic substrates, resulting in good chemical yields. The reaction also proceeds smoothly with water as a medium in high efficiency. This practical aminobromination method was also proved to be suitable for large-scale preparation. Furthermore, the N-carbobenzoxy protecting group could be easily cleaved to afford the free vicinal haloamines.

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Introduction

The vicinal haloamine compounds are important and useful building blocks in organic synthesis and medicinal chemistry.¹ These haloamines can also be easily converted into other valuable intermediates, such as β-substituted α-amino acid, aziridines and vicinal diamines.² Aminohalogenation is a useful tool for the synthesis of these vicinal haloamines, by constructing carbon–nitrogen and carbon–halogen bonds in tandem.^3–6 In the past years, we and other groups have reported many regio- and stereoselective aminohalogenation systems with readily available functionalized alkenes as starting materials, including α,β-unsaturated carboxylic esters,⁷ α,β-unsaturated nitriles,⁸ α,β-unsaturated ketones,⁹ methylenecyclopropanes¹⁰ and β-nitrostyrenes.¹¹ Although great progress has been achieved on the alkene substrates, these aminohalogenation processes suffer from the limitation of the nitrogen sources, which are usually limited to sulfonamides.^7–12 In addition, N,N-dichlorocarbamates have been used as nitrogen source for aminohalogenation in 1960s.¹³ However, these pioneering reactions show many of the characteristics of a free-radical addition reaction, which resulted in moderate regio- and stereoselectivities.

Recently, several amides and carbamates have been reported as nitrogen sources for the aminohalogenation of β-nitrostyrenes, which included, succinimide/NCS,¹⁴N-bromoacetamide,¹⁵ benzamides/NCS,¹⁶tert-butyl N,N-dichlorocarbamate¹⁷ and N,N-dibromourethane.¹⁸ Although these contributions expand the scope of nitrogen sources, most of them have the shortcomings of long reaction times, high loading amounts of catalyst and low chemical yields. Furthermore, the N-protecting groups are difficult to remove from the resulting haloamine product, which greatly limits the development and applications of such aminohalogenation reactions. In our ongoing research on this reaction,¹⁹ we found that benzyl carbamate/NBS was an efficient nitrogen/halogen source for the aminohalogenation of α,β-unsaturated nitro compounds. The advantage of such an exploration is that the N-carbobenzoxy protecting group from the resulting products can be easily cleaved to give free vicinal haloamines, as well as a lower amount of catalyst and shorter reaction time.^14–19 Herein, we reported a facile and efficient aminobromination of α,β-unsaturated nitro compounds with benzyl carbamate/NBS as a new nitrogen/bromine source by using 5 mol% K₃PO₄ as the catalyst, giving dibrominated products with up to 97% chemical yields, which was deprotected to give free haloamine (Scheme 1). This new system could complete within 3 h, which greatly shortened the reaction time compared to the previous process.¹⁹

Scheme 1 Aminobromination with CbzNH₂/NBS.

Results and discussion

Initially, β-nitrostyrene 1a, benzyl carbamate 2 and NBS were mixed in acetonitrile and stirred at room temperature without the use of any catalyst. No haloamine product was obtained and most of the starting materials remained even after the reaction time was prolonged to 12 h (entry 1, Table 1). After many tries, we found that the reaction proceeded smoothly catalyzed by 20 mol% K₂CO₃, giving product in 80% yield in 5 h (entry 2). Then, Na₂CO₃, NaHCO₃, KOH and NaOH were tested in the reaction, however, no improvements were obtained at all (entries 3–6). The chemical yield was further increased to 88% when 20 mol% K₃PO₄ was used as catalyst (entry 7). The results showed that only 5 mol% catalyst was enough for the current system, and had almost no effect on the chemical yield (entries 8–9).

Table 1 Aminobromination of β-nitrostyrene with various catalysts^a

Entry	Catalyst	Amount (mol%)	Time (h)	Yield (%)^b
a Conditions: substrate 1a (0.5 mmol), NBS (1.5 mmol), CbzNH2 (1.5 mmol), CH3CN (3 mL), at room temperature. b Isolated yields. c NR: No reaction was observed.
1	No	0	12	NR^c
2	K2CO3	20	5	80
3	Na2CO3	20	5	55
4	NaHCO3	20	12	Trace
5	KOH	20	12	NR^c
6	NaOH	20	12	NR^c
7	K3PO4	20	5	88
8	K3PO4	10	5	90
9	K3PO4	5	5	93

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Then, a scan of common organic solvents was carried out (Table 2). The reaction could also proceed smoothly in dichloromethane, THF, acetone and methanol, giving the desired haloamines with good chemical yields (entries 1, 2, 4 and 7). No reaction was detected with DMSO and cyclohexane, and almost all the starting materials remained (entries 3 and 6). Acetonitrile was the most suitable solvent for this reaction. Only 3 h was needed to consume all the β-nitrostyrene and resulted in an excellent yield (92%, entry 5). The reaction time also showed effects on the chemical yields. A dramatic lower chemical yield was obtained when the reaction was stopped at 2 h (76% yield, entry 10).

Table 2 Optimization of reaction conditions^a

Entry	Solvent	Time (h)	Yield (%)^b
a Conditions: substrate 1a (0.5 mmol), NBS (1.5 mmol), CbzNH2 (1.5 mmol), K3PO4 (5 mol%), solvent (3 mL), at room temperature. b Isolated yields. c NR: No reaction was observed.
1	DCM	5	80
2	THF	5	82
3	DMSO	5	NR^c
4	Acetone	5	83
5	MeCN	3	92
6	Cyclohexane	5	Trace
7	MeOH	5	81
8	Toluene	5	43
9	MeCN	1	65
10	MeCN	2	76
11	MeCN	4	91

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Very recently, we developed a green aminohalogenation of β-nitrostyrenes with t-butyl N,N-dichlorocarbamate as nitrogen/halogen source.^17b We then tried to investigate the potential of using water as the medium for this aminobromination system based on benzyl carbamate. We were surprised to find that the reaction could proceed smoothly with acetonitrile/water (ratio = 1 : 3) as solvent and complete within 8 h, resulting in 83% yield (Scheme 2). This could serve as another example for green aminohalogenation reaction.

Scheme 2 Aminobromination with water as medium.

Then, several α,β-unsaturated nitro compounds were subjected to this reaction to examine the scope and limitation of the current aminobromination reaction (Table 3). As shown in Table 3, a wide range of α,β-unsaturated nitro compounds worked well in the reaction, and completed within 5 h, giving 55–95% chemical yields. The electronegativity of the substituents on the aromatic rings showed almost no effects on the chemical yields. Both electron-rich (entries 7, 8 and 10–12) and electron-deficient substrates (entries 2–6, 13 and 18) could participate well in the reaction, even for methoxy (entries 10–11) and trifluoromethyl (entry 13) groups. On the contrary, the reactivity depended on the position of substituents on the aromatic ring. Especially, the substrates with the ortho-substituted aromatic ring needed longer to consume all the starting material and gave a lower yield (55%, entry 2) probably due to the steric hindrance. Notably, substrates with heterocyclic groups 1n and 1o were also well tolerated in this reaction along with good chemical yields (entries 14 and 15). Furthermore, an aliphatic substrate 1p, (E)-1-nitronon-1-ene was used in the reaction, and only 3 h reaction time was needed with 82% chemical yield (entry 16). This is really the first example that aliphatic substrates can work well in an aminohalogenation system based on α,β-unsaturated nitro compounds until now.^11,15–19 Finally, the stereochemistry of these haloamino nitro compounds has been confirmed by the X-ray diffraction analysis of 3a (Fig. 1).

Fig. 1 ORTEP diagram showing of compound 3a.

Table 3 Scope of the aminobromination^a

Entry	R	Product	time	Yield (%)^b
a Conditions: substrate 1 (0.5 mmol), NBS (1.5 mmol), CbzNH2 (1.5 mmol), K3PO4 (5 mol%), acetonitrile (3 mL), at room temperature. b Isolated yields.
1	C6H5	3a	3	93
2	2-ClC6H4	3b	5	55
3	3-ClC6H4	3c	3	88
4	4-BrC6H4	3d	3	91
5	3-FC6H4	3e	3	86
6	4-FC6H4	3f	3	85
7	3-MeC6H4	3g	3	97
8	4-MeC6H4	3h	3	62
9	1-naphthyl	3i	3	89
10	3-MeOC6H4	3j	3	83
11	4-MeOC6H4	3k	3	95
12	4-BnOC6H4	3l	3	78
13	4-CF3C6H4	3m	3	83
14	1-furyl	3n	3	68
15	1-thienyl	3o	3	72
16	n-heptyl	3p	3	82
17	3-Br-4-MeOC6H3	3q	3	87
18	4-CNC6H4	3r	3	81

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The current system was found to have a broad scope of substrates, excellent regioselectivities and high chemical yields. Furthermore, it was proven to be efficient for large scale preparation (ten gram-scale or greater). Good yield (81%) and excellent regioselectivity were obtained, even the amount of β-nitrostyrene 1a was increased from 0.15 g to 10.0 g in this reaction (Scheme 3). To our delight, the reaction could complete within 18 h, and only a slight decrease in the yield was detected comparing to the 0.15 g scale reaction. This result allows the large scale preparation of vicinal haloamino nitro compounds, useful organic intermediates.²⁰

Scheme 3 Large-scale aminobromination.

According to the regiochemistry of the reaction, an Michael addition pathway involving predominant formation of Michael addition intermediate was proposed in Scheme 4 for this aminobromination reaction.^17b In the initial step, benzyl carbamate reacts with NBS forming the intermediate A, which is activated by K₃PO₄ and results in intermediate B. B undergoes Michael addition to β-nitrostyrene 1a giving intermediate C, followed by the trapping of Br⁺ from NBS to from intermediate D, a normal monobrominated product. Then, the Br⁺ ion migrates from the N–Br of the amide to the α-position of nitro group, resulting in the final dibrominated product 3a.

Scheme 4 Proposed mechanism.

Although various nitrogen sources, including sulfonamides, acid amides and carbamates, have been reported for aminohalogenation,^12–19 almost no reports described the deprotection of the resulted aminohalogenation products. The carbobenzoxy usually serves as a conventional amine protecting group, which can be easily removed under hydrogen atmosphere in the presence of Pd/C²¹ or direct treating with HBr.²² When the aminobromination product 3a was stirred with Pd/C as catalyst under hydrogen atmosphere, ¹H NMR disclosed that a mixture was obtained after 1 h, which could not be isolated and purified. After many trials, the free haloamine 4 was obtained with high isolated yield 85% with 2 h, when 3a was stirred with 33% HBr/HOAc at room temperature (Scheme 5). This study could be looked as the first successful deprotection of aminohalogenation product under simple and mild condition.

Scheme 5 Removal of N-carbobenzoxy protecting group.

Experimental section

General information

Unless otherwise stated, all reagents were purchased from commercial sources and used without further purification. Reaction progress was monitored by TLC using silica gel 60F-254 with detection by UV. Flash chromatography was performed using silica gel 60 (200–300 mesh). Thin layer chromatography was carried out on silica gel 60 F-254 TLC plates of 20 cm × 20 cm. Melting points are uncorrected. IR spectra were collected on Bruker Vector 22 in KBr pellets. ¹H and ¹³C NMR (TMS used as internal standard) spectra were recorded with a Bruker ARX300 spectrometer. High resolution mass spectra for all the new compounds were done by Micro mass Q-Tof instrument (ESI). The crystal structure was recorded on a X-ray diffraction spectrometer.

Typical procedure for aminohalogenation of α,β-unsaturated nitro compounds with CbzNH₂/NBS

Into a vial were added substrates 1 (0.5 mmol), NBS (1.5 mmol), CbzNH₂ (1.5 mmol), K₃PO₄ (5 mol%). Then, 3 mL of acetonitrile was added to the vial. The solution was stirred at room temperature without the protection of inert gas and monitored by TLC. When the reaction was completed, the mixture was directly purified by TLC plate (Petroleum ether/EtOAc, 4 : 1).

Benzyl 2,2-dibromo-2-nitro-1-phenylethylcarbamate (3a). White solid (93% yield). mp 86–87 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.35–7.45 (m, 10H), 6.42 (d, J = 10.2 Hz, 1H), 5.84 (d, J = 10.2 Hz, 1H), 5.08–5.17 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.92, 135.58, 133.38, 129.8, 129.1, 128.67, 128.63, 128.52, 128.41, 93.83, 67.99, 65.15. IR (KBr): ν = 3280, 3064, 2965, 1690, 1573, 1531, 1251 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₆H₁₄N₂O₄Br₂Na: 480.9186; found: 480.9193.

Benzyl 2,2-dibromo-1-(2-chlorophenyl)-2-nitroethylcarbamate (3b). White solid (55% yield). mp 98–99 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.29–7.43 (m, 9H), 6.03 (d, J = 10.3 Hz, 1H), 5.79 (d, J = 10.1 Hz, 1H), 5.02–5.21 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.74, 135.99, 135.40, 131.90, 130.42, 128.9, 128.85, 128.71, 128.68, 128.61, 128.41, 93.10, 68.10, 64.52. IR (KBr): ν = 3339, 3035, 2949, 1693, 1567, 1536, 1352, 1286, 1260, 1028 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₆H₁₃N₂O₄Br₂ClNa: 514.8798; found 514.8802.

Benzyl 2,2-dibromo-1-(3-chlorophenyl)-2-nitroethylcarbamate (3c). White solid (88% yield). mp 87–89 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.47–7.57 (m, 2H), 7.28–7.43 (m, 7H), 6.03 (d, J = 10.0 Hz, 1H), 5.94 (d, J = 10.0 Hz, 1H), 5.05–5.19 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.75, 135.38, 132.45, 131.85, 130.69, 128.69, 128.62, 128.41, 128.13, 124.26, 92.99, 68.10, 64.59. IR (KBr): ν = 3257, 3059, 2967, 1704, 1683, 1574, 1540, 1494, 1258 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₆H₁₃N₂O₄Br₂ClNa: 514.8797; found 514.8802.

Benzyl 2,2-dibromo-1-(4-bromophenyl)-2-nitroethylcarbamate (3d). Colorless oil (91% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.47–7.57 (m, 2H), 7.28–7.42 (m, 7H), 6.03 (d, J = 9.89 Hz, 1H), 5.94 (d, J = 9.8 Hz, 1H), 5.03–5.19 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.73, 135.38, 132.45, 131.85, 130.69, 128.69, 128.62, 128.41, 124.26, 92.99, 68.10, 64.59. IR (KBr): ν = 3409, 3310, 3034, 2958, 1708, 1577, 1490, 1323, 1232 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₆H₁₃N₂O₄Br₃Na: 558.8284; found 558.8298.

Benzyl 2,2-dibromo-1-(3-fluorophenyl)-2-nitroethylcarbamate (3e). White solid (86% yield). mp 102–104 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.29–7.42 (m, 6H), 7.07–7.25 (m, 3H), 6.04 (d, J = 10.3 Hz, 1H), 5.81 (d, J = 10.1 Hz, 1H), 5.06–5.2 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 162.43 (d, ¹J_CF = 248.09 Hz), 154.82, 135.73(d, ³J_CF = 6.43 Hz), 135.42, 130.23 (d, ³J_CF = 7.81 Hz), 128.68, 128.6, 128.39, 125.06, 116.87 (d, ²J_CF = 21.13 Hz), 116.2 (d, ²J_CF = 23.12 Hz), 92.91, 68.12, 64.60. IR (KBr): ν = 3278, 3063, 2968, 1689, 1575, 1533, 1251, 1236 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₆H₁₃N₂O₄Br₂FNa: 498.9105; found 498.9099.

Benzyl 2,2-dibromo-1-(4-fluorophenyl)-2-nitroethylcarbamate (3f). White solid (85% yield). mp 91–93 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.39–749 (m, 2H), 7.28–7.38 (m, 5H), 7.02–7.13 (m, 2H), 6.03 (d, J = 10.1 Hz, 1H), 5.83 (d, J = 10.2 Hz, 1H), 5.05–5.19 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 163.35 (d, ¹J_CF = 250.46 Hz), 154.81, 135.46, 131.02 (d, ³J_CF = 8.37 Hz), 129.32, 128.68, 128.59, 128.37, 115.74 (d, ²J_CF = 22.04 Hz), 93.55, 68.06, 64.52. IR (KBr): ν = 3264, 3062, 3038, 1701, 1686, 1579, 1511, 1326, 1257, 1232 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₆H₁₃N₂O₄Br₂FNa: 498.9104; found 498.9099.

Benzyl 2,2-dibromo-2-nitro-1-m-tolylethylcarbamate (3g). White solid (97% yield). mp 109–111 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.13–7.46 (m, 9H), 6.01 (d, J = 10.3 Hz, 1H), 5.87 (d, J = 10.4 Hz, 1H), 5.01–5.24 (m, 2H), 2.35 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 154.84, 138.44, 135.53, 133.25, 130.53, 129.77, 128.65, 128.57, 128.52, 128.43, 125.98, 93.79, 67.95, 65.11, 21.48. IR (KBr): ν = 3275, 3060, 3038, 1705, 1688, 1574, 1533, 1251, 1054 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₇H₁₆N₂O₄Br₂Na 494.9336; found 494.935.

Benzyl 2,2-dibromo-2-nitro-1-p-tolylethylcarbamate (3h). White solid (62% yield). mp 93–95 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.27–7.43 (m, 7H), 7.14–7.22 (m, 2H), 6.01 (d, J = 10.2 Hz, 1H), 5.83 (d, J = 10.2 Hz, 1H), 5.05–5.19 (m, 2H), 2.36 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 154.89, 139.88, 135.57, 130.32, 129.34, 128.89, 128.65, 128.52, 128.40, 94.06, 67.93, 64.95, 21.23. IR (KBr): ν = 3411, 3312, 3033, 2957, 1712, 1575, 1513, 1324, 1233, 1049 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₁₇H₁₆N₂O₄Br₂Na: 494.9340; found 494.9350.

Benzyl 2,2-dibromo-1-(naphthalen-1-yl)-2-nitroethylcarbamate (3i). Yellow solid (89% yield). mp 103–105 °C. ¹H NMR (300 MHz, CDCl₃): δ 8.44 (d, J = 8.12 Hz, 1H), 7.45–7.98 (m, 6H), 7.27–7.43 (m, 5H), 7.1 (d, J = 10.2 Hz, 1H), 5.94 (d, J = 10.1 Hz, 1H), 5.01–5.18 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 155.01, 135.44, 133.74, 132.01, 131.16, 130.56, 129.03, 128.64, 128.52, 128.39, 127.32, 126.41, 125.24, 124.92, 123.44, 93.76, 68.02, 58.63. IR (KBr): ν = 3412, 3311, 3065, 3035, 1713, 1577, 1322, 1058, 910 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₂₀H₁₆N₂O₄Br₂Na: 530.9350; found 530.9350.

Benzyl 2,2-dibromo-1-(3-methoxyphenyl)-2-nitroethylcarbamate (3j). White solid (83% yield). mp 97–99 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.28–7.45 (m, 6H), 6.89–7.05 (m, 3H), 6.01 (d, J = 10.3 Hz, 1H), 5.81 (d, J = 10.3 Hz, 1H), 5.05–5.19 (m, 2H), 3.81 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 159.52, 154.82, 135.50, 134.74, 129.67, 128.64, 128.52, 128.4, 121.17, 115.16, 114.92, 93.53, 67.98, 65.06, 55.38. IR (KBr): ν = 3286, 3062, 2960, 2886, 1691, 1574, 1531, 1251, 1230, 1056 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₇H₁₆N₂O₅Br₂Na: 510.9304; found 510.9299.

Benzyl 2,2-dibromo-1-(4-methoxyphenyl)-2-nitroethylcarbamate (3k). Yellow oil (95% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.29–7.44 (m, 7H), 6.84–6.93 (m, 2H), 5.99 (d, J = 10.4 Hz, 1H), 5.79 (d, J = 10.2 Hz, 1H), 5.05–5.21 (m, 2H), 3.81 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 160.54, 154.85, 135.57, 130.28, 128.64, 128.51, 128.38, 125.17, 113.99, 94.28, 67.92, 64.73, 55.33. IR (KBr): ν = 3411, 3317, 2959, 2839, 1713, 1574, 1513, 1250, 1030 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₇H₁₆N₂O₅Br₂Na: 510.9299; found 510.9299.

Benzyl 1-(4-(benzyloxy)phenyl)-2,2-dibromo-2-nitroethylcarbamate (3l). Colorless oil (78% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.27–7.58 (m, 12H), 6.94–7.08 (m, 2H), 6.53 (d, J = 10.3 Hz, 1H), 6.44 (d, J = 10.2 Hz, 1H), 5.03–5.21 (m, 4H). ¹³C NMR (75 MHz, CDCl₃): δ 156.79, 155.06, 136.15, 135.79, 131.01, 130.62, 128.80, 128.59, 128.37, 128.24, 127.35, 121.05, 112.91, 94.01, 70.69, 67.68, 62.11. IR (KBr): ν = 3412, 3316, 3033, 2955, 2882, 1716, 1575, 1497, 1227, 1043 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd. For C₂₃H₂₀N₂O₅Br₂Na: 586.9605; found 586.9612.

Benzyl 2,2-dibromo-2-nitro-1-(4-(trifluoromethyl)phenyl)ethylcarbamate (3m). Colorless oil (83% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.66 (d, J = 8.52 Hz, 2H), 7.59 (d, J = 8.52 Hz, 2H), 7.29–7.43 (m, 5H), 6.12 (d, J = 10.4 Hz, 1H), 5.85 (d, J = 10.2 Hz, 1H), 5.05–5.19 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.69, 137.36, 135.32, 131.85 (q, ²J_CF = 32.91 Hz), 129.64, 128.68, 128.4, 125.59 (q, ³J_CF = 3.27 Hz), 123.65 (q, ¹J_CF = 273.29 Hz), 92.46, 68.18, 64.64. IR (KBr): ν = 3415, 3311, 3035, 2959, 1712, 1578, 1326, 1131, 1071, 1018 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₇H₁₃N₂O₄Br₂F₃Na: 548.9075; found 548.9067.

Benzyl 2,2-dibromo-1-(furan-2-yl)-2-nitroethylcarbamate (3n). Brown oil (68% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.42 (dd, J = 0.75, 1.78 Hz, 1H), 7.31–7.41 (m, 5H), 6.44 (d, J = 3.32 Hz, 1H), 6.38 (dd, J = 1.9, 3.35 Hz, 1H), 6.24 (d, J = 10.44 Hz, 1H), 5.84 (d, J = 10.23 Hz, 1H), 5.11–5.26 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 155.07, 146.03, 143.74, 135.49, 128.68, 128.58, 128.39, 111.54, 110.95, 91.18, 68.11, 60.45. IR (KBr): ν = 3254, 3034, 2956, 1694, 1572, 1538, 1323, 1257, 1016 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₄H₁₂N₂O₅Br₂Na: 470.8971; found 470.8986.

Benzyl 2,2-dibromo-2-nitro-1-(thiophen-2-yl)ethylcarbamate (3o). Yellow solid (72% yield). mp 98–100 °C. ¹H NMR (300 MHz, CDCl₃): δ 7.29–7.42 (m, 6H), 7.18 (d, J = 3.72 Hz, 1H), 7.01 (dd, J = 3.62, 5.13 Hz, 1H), 6.38 (d, J = 10.44 Hz, 1H), 5.7 (d, J = 10.39 Hz, 1H), 5.07–5.24 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.72, 135.42, 129.58, 128.66, 128.57, 128.38, 127.37, 126.9, 126.83, 92.62, 68.11, 62.18. IR (KBr): ν = 3269, 3033, 2955, 1693, 1577, 1522, 1323, 1249 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₄H₁₂N₂O₄Br₂SNa: 486.8753; found 486.8757.

Benzyl 1,1-dibromo-1-nitrononan-2-ylcarbamate (3p). Colorless oil (82% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.31–7.42 (m, 5H), 5.08–5.25 (m, 2H), 4.98 (d, J = 10.47 Hz, 1H), 4.65–4.88 (m, 1H), 1.76–1.97 (m, 1H), 1.07–1.55 (m, 11H), 0.88 (t, J = 6.97 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 155.57, 135.83, 128.62, 128.44, 128.21, 93.84, 67.66, 62.43, 32.27, 31.65, 29.00, 28.92, 25.81, 22.60, 14.09. IR (KBr): ν = 3404, 3309, 2955, 2928, 2857, 1709, 1575, 1326, 1247, 1052 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₇H₂₄N₂O₄Br₂Na: 502.9978; found 502.9976.

Benzyl 2,2-dibromo-1-(3-bromo-4-methoxyphenyl)-2-nitroethylcarbamate (3q). Colorless oil (87% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.65 (d, J = 2.36 Hz, 1H), 7.28–7.42 (m, 6H), 6.86 (d, J = 8.57 Hz, 1H), 5.99 (d, J = 10.42 Hz, 1H), 5.84 (d, J = 10.26 Hz, 1H), 5.04–5.18 (m, 2H), 3.9 (s, 3H). ¹³C NMR (75 MHz, CDCl₃): δ 156.88, 154.67, 135.4, 133.62, 129.65, 128.67, 128.57, 128.39, 126.69, 111.79, 111.48, 93.51, 68.07, 64.12, 56.34. IR (KBr): ν = 3409, 3309, 2209, 2958, 2841, 1712, 1576, 1498, 1294, 1056 cm⁻¹. HRMS (ESI/[M+Na]⁺) Calcd For C₁₇H₁₅N₂O₅Br₃Na: 588.8406; found 588.8404.

Benzyl 2,2-dibromo-1-(4-cyanophenyl)-2-nitroethylcarbamate (3r). Colorless oil (81% yield). ¹H NMR (300 MHz, CDCl₃): δ 7.68 (d, J = 8.35 Hz, 2H), 7.59 (d, J = 8.35 Hz, 2H), 7.28–7.41 (m, 5H), 6.11 (d, J = 10.51 Hz, 1H), 5.92 (d, J = 10.41 Hz, 1H), 5.06–5.18 (m, 2H). ¹³C NMR (75 MHz, CDCl₃): δ 154.59, 138.48, 135.19, 132.30, 129.95, 128.69, 128.41, 117.89, 113.83, 91.88, 68.27, 64.62. IR (KBr): ν = 3312, 2957, 2232, 1731, 1715, 1576, 1506, 1232, 1050 cm⁻¹. HRMS (ESI/M+Na]⁺) Calcd. For C₁₇H₁₃N₃O₄Br₂Na: 505.9150; found 505.9146.

Removal of carbobenzoxy protecting group

To a flask containing 3a (2 mmol), a solution of HBr in AcOH (5mL, 33% w/w) was added. The mixture was stirred at room temperature for 2 h. When evolution of bubbles stopped, excess HBr and HOAc were filtered, giving white powder 4 with 85% yield.

2,2-dibromo-2-nitro-1-phenylethanaminium bromide (4). White solid (85% yield). ¹H NMR (300 MHz, D₂O): δ 7.48–7.53 (m, 5H), 5.33 (s, 1H). ¹³C NMR (75 MHz, D₂O): δ 131.66, 130.6, 129.7, 128.42, 127.67, 59.26. IR (KBr): ν = 3264, 3013, 2908, 1959, 1630, 1573, 1499, 1399, 997cm⁻¹.

Conclusions

In summary, we have developed a new aminobromination reaction with benzyl carbamate/NBS as nitrogen/bromine source. This facile and efficient system tolerated a broad range of substrates (aromatic, aliphatic and heterocyclic), giving good to excellent yields, even on the large scale preparation. Furthermore, free bromoamine product could be easily obtained by removing the N-protecting group under convenient and mild conditions. Further study on aminobromination of this nitrogen source is under progress.

Acknowledgements

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21102071) and the Fundamental Research Funds for the Central Universities (No. 1107020522 and No. 1082020502). The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, full spectroscopic data for new compounds, single-crystal X-ray diffraction analysis of 3a and copies of ¹H NMR and ¹³C NMR spectra. CCDC reference number 859296. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra20490h

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