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All posts Subject: NaBH4/NiCl2/Boc2O: Nitriles to N-Boc-Amines Please login to post

Rhodium
(Chief Bee)
10-20-03 10:33
No 465743
User Picture NaBH4/NiCl2/Boc2O: Nitriles to N-Boc-Amines
(Rated as: excellent)

A generic approach for the catalytic reduction of nitriles
S.Caddick, D.B. Judd, A.K. Lewis, M.T. Reich and M.R.V. Williams
Tetrahedron 59(29), 5417-5423 (2003) (https://www.rhodium.ws/pdf/nitrile2boc-amine.nabh4-nicl2.pdf)
DOI:10.1016/S0040-4020(03)00858-5

Abstract
The scope of nickel boride mediated reduction of nitriles has been extended further to allow the preparation of Boc protected amines via a mild catalytic process. It is noteworthy that the toxicity of this procedure is greatly reduced due to its catalytic nature in nickel(II)chloride used in combination with excess sodium borohydride. The protocol is marked by its resilience towards air and moisture and hence an easy and general practical protocol.

Typical procedure for the reduction of a nitrile to a Boc amine

N-Boc-benzylamine (2a).
To a stirred solution of benzonitrile 1a (204 L, 2.0 mmol) in dry methanol (15 mL), cooled to 0°C, were added Boc₂O (873 mg, 4.0 mmol) and NiCl₂·6H₂O (48 mg, 0.2 mmol). NaBH₄ (530 mg, 14.0 mmol) was then added in small portions over 30 min. The reaction was exothermic and effervescent. The resulting reaction mixture containing a finely divided black precipitate was allowed to warm to room temperature and left to stir for a further 1 h, at which point diethylenetriamine (216 L, 2.0 mmol) was added. The mixture was allowed to stir for 30 min before solvent evaporation. The purple residue was dissolved in EtOAc (50 mL) and extracted with saturated NaHCO₃ (2Ч50 mL). The organic layer was dried (MgSO₄) and the solvent removed in vacuo to yield 2a as a white solid (330 mg, 80%). mp 54–55°C (lit. mp 52–53°C, mp 55.5–56.5°C).

Catalytic reduction of all nitriles was carried out according to the same procedure as described above, on an identical scale, however, in most cases the reaction time was 15 h.

N-BOC-Phenethylamine from Phenylacetonitrile (2b)
424 mg, 96%; pale yellow solid; mp 58–59°C (lit. mp 59.1°C).

N-BOC-4-Bromophenethylamine from 4-Bromophenylacetonitrile (2h)
402 mg, 67%; pale yellow solid; mp 58–59°C (lit. mp 61–62°C).

N-BOC Tryptamine from Indole-3-acetonitrile (2v)
302 mg, 58%; yellow oil.

Convenient synthesis of protected primary amines from nitriles
S. Caddick, A.K. Haynes, D.B. Judd and M.R.V. Williams
Tetrahedron Letters 41(18), 3513-3516 (2000)
DOI:10.1016/S0040-4039(00)00410-X

Abstract
Investigations into the use of nickel chloride and sodium borohydride for the reduction of nitriles showed the secondary amine dimers to be the major products under normal conditions. The addition of a suitable trapping agent, such as di-tert-butyl dicarbonate, allowed the isolation of the protected primary amines.

Preparation of N-BOC-phenethylamine
NaBH₄ (0.79 g, 21 mmol) was cautiously added to a solution of NiCl₂ (0.71 g, 3 mmol), BOC₂O (1.31 g, 6 mmol) and benzyl cyanide (0.32 ml, 3 mmol) in MeOH (25 ml) at 0°C (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir, at room temperature, for 24 h. Methanol was removed under reduced pressure and the precipitate dissolved in EtOAc and NaHCO₃, filtered and repeatedly washed with EtOAc. The combined organic phases were dried (Na₂SO₄) and concentrated to yield N-BOC-phenethylamine (99%) Mp: 59.1°C.

Preparation of diphenethylamine
NiCl₂ (1 equiv., 1.19 g, 5 mmol), MeOH (50 ml) and benzyl cyanide (1 equiv., 0.53 ml, 5 mmol) were added to a round bottom flask. NaBH₄ (7 equiv., 1.32 g, 35 mmol) was cautiously added to this solution at 0°C, vigorous effervescence was accompanied by the formation of a black solid. The reaction mixture was left to stir at room temperature for 20 h. The methanol was then removed under reduced pressure, leaving a black precipitate. The precipitate was then dissolved in EtOAc and NaHCO₃, filtered and repeatedly washed with EtOAc. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo to yield diphenethylamine (99%, 0.56 g, 2.49 mmol).

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	All posts		Subject: NaBH4/NiCl2/Boc2O: Nitriles to N-Boc-Amines		Please login to post


		Rhodium (Chief Bee) 10-20-03 10:33 No 465743				NaBH4/NiCl2/Boc2O: Nitriles to N-Boc-Amines (Rated as: excellent)
						A generic approach for the catalytic reduction of nitriles S.Caddick, D.B. Judd, A.K. Lewis, M.T. Reich and M.R.V. Williams Tetrahedron 59(29), 5417-5423 (2003) (https://www.rhodium.ws/pdf/nitrile2boc-amine.nabh4-nicl2.pdf) DOI:10.1016/S0040-4020(03)00858-5 Abstract The scope of nickel boride mediated reduction of nitriles has been extended further to allow the preparation of Boc protected amines via a mild catalytic process. It is noteworthy that the toxicity of this procedure is greatly reduced due to its catalytic nature in nickel(II)chloride used in combination with excess sodium borohydride. The protocol is marked by its resilience towards air and moisture and hence an easy and general practical protocol. Typical procedure for the reduction of a nitrile to a Boc amine N-Boc-benzylamine (2a). To a stirred solution of benzonitrile 1a (204 L, 2.0 mmol) in dry methanol (15 mL), cooled to 0°C, were added Boc₂O (873 mg, 4.0 mmol) and NiCl₂·6H₂O (48 mg, 0.2 mmol). NaBH₄ (530 mg, 14.0 mmol) was then added in small portions over 30 min. The reaction was exothermic and effervescent. The resulting reaction mixture containing a finely divided black precipitate was allowed to warm to room temperature and left to stir for a further 1 h, at which point diethylenetriamine (216 L, 2.0 mmol) was added. The mixture was allowed to stir for 30 min before solvent evaporation. The purple residue was dissolved in EtOAc (50 mL) and extracted with saturated NaHCO₃ (2Ч50 mL). The organic layer was dried (MgSO₄) and the solvent removed in vacuo to yield 2a as a white solid (330 mg, 80%). mp 54–55°C (lit. mp 52–53°C, mp 55.5–56.5°C). Catalytic reduction of all nitriles was carried out according to the same procedure as described above, on an identical scale, however, in most cases the reaction time was 15 h. N-BOC-Phenethylamine from Phenylacetonitrile (2b) 424 mg, 96%; pale yellow solid; mp 58–59°C (lit. mp 59.1°C). N-BOC-4-Bromophenethylamine from 4-Bromophenylacetonitrile (2h) 402 mg, 67%; pale yellow solid; mp 58–59°C (lit. mp 61–62°C). N-BOC Tryptamine from Indole-3-acetonitrile (2v) 302 mg, 58%; yellow oil. Convenient synthesis of protected primary amines from nitriles S. Caddick, A.K. Haynes, D.B. Judd and M.R.V. Williams Tetrahedron Letters 41(18), 3513-3516 (2000) DOI:10.1016/S0040-4039(00)00410-X Abstract Investigations into the use of nickel chloride and sodium borohydride for the reduction of nitriles showed the secondary amine dimers to be the major products under normal conditions. The addition of a suitable trapping agent, such as di-tert-butyl dicarbonate, allowed the isolation of the protected primary amines. Preparation of N-BOC-phenethylamine NaBH₄ (0.79 g, 21 mmol) was cautiously added to a solution of NiCl₂ (0.71 g, 3 mmol), BOC₂O (1.31 g, 6 mmol) and benzyl cyanide (0.32 ml, 3 mmol) in MeOH (25 ml) at 0°C (vigorous reaction with the formation of a black precipitate). Once the reaction had subsided the mixture was left to stir, at room temperature, for 24 h. Methanol was removed under reduced pressure and the precipitate dissolved in EtOAc and NaHCO₃, filtered and repeatedly washed with EtOAc. The combined organic phases were dried (Na₂SO₄) and concentrated to yield N-BOC-phenethylamine (99%) Mp: 59.1°C. Preparation of diphenethylamine NiCl₂ (1 equiv., 1.19 g, 5 mmol), MeOH (50 ml) and benzyl cyanide (1 equiv., 0.53 ml, 5 mmol) were added to a round bottom flask. NaBH₄ (7 equiv., 1.32 g, 35 mmol) was cautiously added to this solution at 0°C, vigorous effervescence was accompanied by the formation of a black solid. The reaction mixture was left to stir at room temperature for 20 h. The methanol was then removed under reduced pressure, leaving a black precipitate. The precipitate was then dissolved in EtOAc and NaHCO₃, filtered and repeatedly washed with EtOAc. The combined organic phases were dried (Na₂SO₄) and concentrated in vacuo to yield diphenethylamine (99%, 0.56 g, 2.49 mmol).

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