N-Boc-O-Tosyl Hydroxylamine as a Safe and Efficient Nitrogen Source for the N-Amination of Aryl and Alkyl Amines: Electrophylic Amination

Abstract

β-Boc-protected aryl and alkyl hydrazines, useful intermediates for azapeptides and N-substituted pyrazoles, were synthesized by electrophylic amination methodology, using less energetic N-Boc-O-tosyl hydroxylamine as an efficient nitrogen source. Also we have demonstrated a two-step, chromatography-free synthesis of N-Boc-O-tosyl hydroxylamine.

Key words

electrophylic amination - β-Boc-alkylhydrazines - β-Boc-arylhydrazines - N-Boc-O-tosyl hydroxylamine - azapeptides

References

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17

Typical Procedure for 5 To a stirred solution of hydroxylamine (25 mL, 40% w/v, 0.3 mol) in MeOH (100 mL) was added NaHCO₃ (27.7 g, 0.33 mol) and then (Boc)₂O (72.0 g, 0.33 mol) dropwise over a period of 30 min, by maintaining the reaction temperature at 20-25 ˚C. After stirring the reaction mixture at 25 ˚C for 5 h, MeOH was removed under vacuum, and the residue was diluted with H₂O (200 mL) and extracted with EtOAc (2 × 100 mL). The combined organic layer was dried over Na₂SO₄ and concentrated. The crude Boc-hydroxylamine obtained was diluted with CH₂Cl₂ (200 mL), cooled to 0 ˚C and was added NMM (60.6 g, 0.6 mol) and then tosyl chloride (63 g, 0.33 mol) in CH₂Cl₂ (200 mL), dropwise over a period of 1 h. After stirring at r.t. for 3 h, the reaction mixture was diluted with H₂O (500 mL), and the organic layer was separated, washed with H₂O (250 mL), 5% citric acid solution in H₂O (2 × 100 mL), dried over Na₂SO₄ and concentrated. The resulting residue was crystallized from 20% EtOAc in PE to afford the pure product as white solid. ^¹H NMR (300 MHz, CDCl₃): δ = 1.32 (s, 9 H), 2.48 (s, 3 H), 7.38 (d, J = 8.4 Hz, 2 H), 7.61 (s, 1 H), 7.90 (d, J = 8.4 Hz, 2 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.7, 27.7, 83.8, 129.6, 129.7, 130.7, 146.0, 154.3.

19

Even though 5 is less energetic compared to other aminating reagents, keeping safety as priority we carried out all reactions and workup at temperatures below 50 ˚C.

20

Typical Procedure for Aryl Amines (Method A) To a stirred solution of 4-methoxyaniline (1 g, 8.13 mmol) in DMF (10 ml) was added K₂CO₃ (1.46 g, 10.57 mmol), and the reaction mixture was cooled to ca. 10 ˚C. To this was added BocNHOTs (2.8 g, 9.76 mmol) and stirred at r.t. for 2 h. Reaction mixture was diluted with H₂O, and the resulting solid was filtered and dried under suction. The dried solid was crystallized from 3% EtOAc in PE to afford the pure product as brown solid. ^¹H NMR (300 MHz, CDCl₃): δ = 1.34 (s, 9 H), 3.81 (s, 3 H), 6.68 (br s, 1 H), 6.89 (dd, J = 9.0, 2.1 Hz, 2 H), 7.38 (dd, J = 9.0, 2.1 Hz, 2 H), 7.44 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 26.4, 55.5, 81.4, 114.3, 121.8, 130.3, 156.3, 158.5. LC-MS: m/z = 239.3 [M + H⁺].

21

Typical Procedure for Alkyl Amines (Method B) To a stirred solution of morpholine (0.5 g, 5.74 mmol) in CH₂Cl₂ (10 mL) was added NMM (0.75 g, 7.46 mmol), and the reaction mixture was cooled to ca. 10 ˚C and then added BocNHOTs (1.98 g, 6.90 mmol), and the reaction mixture was stirred at r.t. for 18 h. Reaction mixture was diluted with H₂O and extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was dried over Na₂SO₄ and concentrated. The crude obtained was purified by flash column chromatog-raphy to get the pure product as yellow liquid. ^¹H NMR (300 MHz, CDCl₃): δ = 1.27 (s, 9 H), 3.42 (t, J = 4.8 Hz, 4 H), 3.70 (t, J = 4.8 Hz, 4 H), 6.86 (br s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 26.3, 43.9, 66.4, 80.4, 159.9. LC-MS: 203.3
[M + H⁺].