Novel Synthesis of Chiral Unactivated 2-Aryl-1-benzylaziridines

Abstract

Chiral (R _S ,R)- and (R _S ,S)-N-(tert-butylsulfinyl)-2-aryl-aziridines were transformed into (R)- and (S)-2-aryl-1-benzylaziridines via a short three-step procedure. Deprotection and ring opening of (R _S ,R)- and (R _S ,S)-N-sulfinyl-2-arylaziridines (95-99% de) in acid medium afforded 2-aryl-2-chloroethylamine hydrochlorides in high yield (83-90%). These intermediates were converted into the corresponding chiral N-(benzylidene)-β-aryl-β-chloro-amines in good yield (78-85%). Subsequent reduction of the synthesized ald­imines afforded chiral 2-aryl-1-benzylaziridines in good to excellent yield (74-94%) and enantiomeric excess (83-99% ee). The enantiomeric purity of the chiral aldimines and aziridines was established by NMR spectroscopy using Pirkle alcohol as the chiral solvating agent.

Key words

chiral aziridines - asymmetric synthesis - ring opening - ring closure - haloimines

References and Notes

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1

Postdoctoral Fellow of the Research Foundation-Flanders (FWO).

16

( R _S , R )- N -( tert -Butylsulfinyl)-2-(4-methylphenyl)-aziridine (2d)
Prepared according to a previously described method, see ref. 11a. ^¹H NMR (300 MHz, CDCl₃): δ = 1.29 (s, 9 H), 1.99 (d, J = 3.9 Hz, 1 H), 2.34 (s, 3 H), 2.97 (d, J = 7.2 Hz, 1 H), 3.09 (dd, J = 7.2, 3.9 Hz, 1 H), 7.13-7.20 (m, 4 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.2, 22.8, 28.6, 34.7, 57.4, 126.3, 129.2, 134.6, 137.5. IR (ATR): ν_max = 1063, 1362, 1457, 1681, 2960, 3346 cm^-¹. MS (ES, pos. mode): m/z (%) = 238(100) [M + H⁺]. [α]_D -238.5 (c 1.15, CH₂Cl₂); mp 106.0-107.0 ˚C. Anal. Calcd for C₁₃H₁₉NOS: C, 65.78; H, 8.07; N, 5.90; S, 13.51. Found: C, 65.44; H, 8.35; N, 6.11; S, 13.28.

17

( S )-2-Chloro-2-(4-methylphenyl)ethylamine Hydrochloride (3d)
Prepared according to a previously described method, see ref. 11a,b. ^¹H NMR (300 MHz, D₂O): δ = 2.31 (s, 3 H), 3.19 (dd, J = 12.7, 4.4 Hz, 1 H), 3.26 (dd, J = 12.7, 8.7 Hz, 1 H), 4.93 (dd, J = 8.7, 4.4 Hz, 1 H), 7.26-7.32 (m, 4 H). ^¹³C NMR (75 MHz, D₂O): δ = 20.8, 45.8, 70.0, 126.6, 130.1, 137.1, 139.6. IR (ATR): ν_max = 1146, 1510, 1603, 2361, 2958 cm^-¹. MS (ES, pos. mode): m/z (%) = 152/154(100), 170/172(20) [M + H⁺]. [α]_D +52.6 (c 1.01, MeOH); mp 173.6-174.6 ˚C. Anal. Calcd for C₉H₁₃NCl₂: C, 52.45; H, 6.36; N, 6.80. Found: C, 52.52; H, 6.42; N, 6.57.

18

Preparation of ( S )- N -Benzylidene-[2-chloro-2-(4-methylphenyl)ethyl]amine (4d)
Triethylamine (0.09 g, 0.93 mmol) was added to a solution of (S)-2-chloro-2-(4-methylphenyl)ethylamine hydro-chloride (3d, 0.15 g, 0.88 mmol), MgSO₄ (0.15 g, 1.27 mmol), and benzaldehyde (0.09 g, 0.88 mmol) in CH₂Cl₂ (15 mL). The reaction was stirred for 7 h at 0 ˚C. The suspension was subsequently filtered, and the solvent was evaporated. Diethyl ether (15 mL) was added and the obtained mixture was again filtered and evaporated, yielding 4d which was purified by recrystallization from Et₂O (0.18 g); yield 83%. ^¹H NMR (300 MHz, CDCl₃): δ = 2.35 (s, 3 H), 4.02 (ddd, J = 12.5, 8.5, 1.1 Hz, 1 H), 4.21 (ddd, J = 12.5, 5.0, 1.7 Hz, 1 H), 5.24 (dd, J = 8.5, 5.0 Hz, 1 H), 7.16-7.45 and 7.72-7.76 (m, 9 H), 8.28 (s, 1 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.2, 62.7, 69.0, 127.2, 128.3, 128.6, 129.3, 131.0, 135.8, 137.0, 138.3, 163.7. IR (ATR): ν_max = 1449, 1514, 1645, 2361, 2916 cm^-¹. MS (ES, pos. mode): m/z (%): 258/260(100) [M + H⁺]. [α]_D +55.8 (c 0.70, CH₂Cl₂); mp 79.4-80.4 ˚C. Anal. Calcd for C₁₆H₁₆NCl: C, 74.55; H, 6.26; N, 5.43. Found: C, 74.89; H, 6.37; N, 5.20.

21

Ghorai and co-workers have concluded, based on experimental results, that the Lewis acid mediated nucleophilic ring opening of activated 2-phenylaziridines occurs via an S_N2 pathway, see ref. 14c-e.

23

Preparation of ( R )-1-Benzyl-2-(4-methylphenyl)-aziridine (8d)
To a stirred solution of aldimine 4d (0.12 g, 0.47 mmol) in MeOH (15 mL) was added NaBH₄ (0.02 g, 0.47 mmol), and the reaction mixture was brought to reflux for 3 h. Afterwards, a sat. soln of NaHCO₃ (10 mL) was added, and the organic solvent was evaporated. The resulting mixture was extracted with CH₂Cl₂ (3 × 15 mL), and the combined organic layers were dried (MgSO₄) and filtered to afford
1-benzyl-2-(4-methylphenyl)aziridine (8d, 0.09 g) in pure form after removal of the solvent in vacuo; yield 92%. ^¹H NMR (300 MHz, CDCl₃): δ = 1.82 (d, J = 6.6 Hz, 1 H), 1.97 (d, J = 3.3 Hz, 1 H), 2.32 (s, 3 H), 2.47 (dd, J = 6.6, 3.3 Hz, 1 H), 3.58 (d, J = 13.8 Hz, 1 H), 3.70 (d, J = 13.8 Hz, 1 H), 7.08-7.38 (m, 9 H). ^¹³C NMR (75 MHz, CDCl₃): δ = 21.1, 37.8, 41.4, 64.8, 126.1, 126.9, 127.8, 128.3, 129.0, 136.5, 137.1, 139.2. IR (ATR): ν_max = 1026, 1452, 1517, 2826, 3028 cm^-¹. MS (ES, pos. mode): m/z (%) = 224(100) [M + H⁺]. [α]_D -55.8 (c 1.01, CH₂Cl₂). Anal. Calcd for C₁₆H₁₇N: C, 86.05; H, 7.67; N, 6.27. Found: C, 86.21; H, 7.83; N, 5.96.