Synthesis of 3-Aryl-3-pyrrolines and 3-Arylpyrroles via Spontaneous Rearrangement of N-Sulfinyl 2-Aryl-2-vinylaziridines

Abstract

Addition of vinylmagnesium bromide across chiral α-chloro N-tert-butanesulfinyl ketimines afforded 3-aryl-1-(tert-butanesulfinyl)-3-pyrrolines in high yield (65-91%) after purification by means of recrystallization from diethyl ether. The synthesis of these 3-aryl-3-pyrrolines is explained by initial formation of 2-aryl-2-vinylaziridines which spontaneously rearrange via carbon-nitrogen bond cleavage to form stabilized 1,3-dipolar intermediates which in turn ring closed to 3-pyrrolines.

Key words

aziridines - rearrangement - heterocycles - imines - pyrrolines

References and Notes

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1

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

32

Synthesis of ( R _S )- N - tert -Butanesulfinyl 3-Phenyl-3-pyrroline (4a) α-Chloro imine 5a (0.91 mmol) was dissolved in dry CH₂Cl₂ (10 mL), and the stirred solution was cooled to -78 ˚C. Two equiv of vinylmagnesium bromide (1 M solution in THF, 1.82 mL, 1.82 mmol) were added to the solution, and the reaction mixture was allowed to stir for 2 h at -78 ˚C before being left at -40 ˚C for 4 h. The reaction mixture was quenched at this temperature by the addition of aq NH₄Cl (5 mL) and immediately extracted with CH₂Cl₂ (2 × 10 mL). The organic layers were dried (MgSO₄, containing little of K₂CO₃), filtered, and concentrated. The mixture was purified by means of recrystallization from Et₂O to afford the pyrroline 4a in 91% yield. Colorless crystals; mp 55.6 ± 0.5 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.50 (9 H, s), 3.39 (1 H, dddd, J = 15.8, 5.5, 4.1, 1.4 Hz), 3.85 (1 H, dddd, J = 15.8, 4.3, 3.3, 3.3 Hz), 4.25 (1 H, dddd, J = 18.4, 3.3, 1.7, 1.7 Hz), 4.40 (1 H, dddd, J = 18.4, 4.4, 4.4, 1.7 Hz), 5.99-6.03 (1 H, m), 7.28-7.37 (5 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 22.1, 36.9, 48.3, 55.4, 112.6, 125.4, 128.1, 128.6, 135.3, 139.1. MS (ES, pos. mode): m/z (%) = 194 (100) [M - t-Bu + 2H]⁺. IR (KBr): ν_max = 1042, 1085, 1364, 1453, 2962 cm^-¹. Anal. Calcd for C₁₄H₁₉NOS: C, 67.43; H, 7.68; N, 5.62. Found: C, 67.17; H, 7.84; N, 5.33. [α]_D -28.3 (c 1.03, CH₂Cl₂).

33

( R _s , S )-1-( tert -Butanesulfinyl)-2-isopropenyl-2-phenylaziridine [( R _s ,S )-6] Yellow crystals; mp 54.2 ± 0.5 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.21 (9 H, s), 1.65 (3 H, s), 2.11 (1 H, s), 3.23 (1 H, s), 4.95 (1 H, s), 5.14 (1 H, s), 7.26-7.47 (5 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 19.8, 22.8, 30.3, 51.1, 57.4, 112.9, 128.3, 128.5, 129.7, 134.9, 145.4. MS (ES, pos. mode): m/z (%) = 264 (100) [M + H]⁺. IR (ATR): ν_max = 696, 1074, 1447, 2961 cm^-¹. Anal. Calcd for C₁₅H₂₁NOS: C, 68.40; H, 8.04; N, 5.32. Found: C, 68.04; H, 8.24; N, 5.12. R _f  = 0.28 (PE-EtOAc = 3:1). [α]_D -394.7 (c 1.03, CH₂Cl₂).

34

( R _S )- N - tert -Butanesulfinyl 2-Methyl-4-phenyl-3-pyrroline (9)
Spectroscopic data of the major diastereomer obtained from the mixture of diastereomers 9 (dr 86:14). Brown oil. ^¹H NMR (300 MHz, CDCl₃): δ = 1.51 (9 H, s), 1.53 (3 H, d, J = 6.6 Hz), 3.88-3.98 (1 H, m), 4.20 (1 H, ddd, J = 18.4, 3.0, 1.4 Hz), 4.39 (1 H, ddd, J = 18.4, 4.1, 1.9 Hz), 5.70-5.72 (1 H, m), 7.27-7.37 (5 H, m). ^¹³C NMR (75 MHz, CDCl₃):
δ = 19.2, 24.5, 42.9, 46.2, 60.9, 122.1, 125.7, 127.9, 128.6, 139.3, 139.8. MS (ES, pos. mode): m/z (%) = 264 (100)
[M + H]⁺. IR (ATR): ν_max = 694, 1050, 1447, 2926 cm^-¹. Anal. Calcd for C₁₅H₂₁NOS: C, 68.40; H, 8.04; N, 5.32. Found: C, 68.69; H, 7.99; N, 5.49.

37

Synthesis of ( R _S )- N -( tert -Butanesulfinyl) 3-(4-Methoxy-phenyl)pyrrole (13e)
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.042 g, 0.18 mmol) was dissolved in 1,4-dioxane (10 mL) and the mixture added dropwise to a solution of (R _S )-N-(tert-butanesulfinyl)-3-(4-methoxyphenyl)-3-pyrroline (4e, 0.057 g, 0.20 mmol) in 1,4-dioxane (10 mL). After stirring for 16 h at r.t., the reaction mixture was quenched by the addition of a 10% solution of NaHSO₃ (5 mL) and immediately extracted with EtOAc (2 × 10 mL). The organic layers were dried (MgSO₄), filtered, and concentrated. The compound was purified by means of column chromatography to afford (R _S )-N-(tert-butanesulfinyl) 3-(4-methoxyphenyl)pyrrole (13e, 0.049 g) in 87% yield; black crystals; mp 133.6 ± 0.5 ˚C. ^¹H NMR (300 MHz, CDCl₃): δ = 1.45 (9 H, s), 3.82 (3 H, s), 5.86 (1 H, dd, J = 9.9, 1.7 Hz), 6.89-6.93 (2 H, m), 7.22-7.26 (2 H, m), 7.53 (1 H, dd, J = 9.9, 2.2 Hz), 7.68-7.70 (1 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 23.2, 55.4, 62.1, 88.8, 113.8, 114.3, 126.6, 131.4, 139.8, 144.9, 158.2. MS (ES, pos. mode): m/z (%) = 278 (100) [M + H]⁺. IR (ATR): ν_max = 1187, 1367, 1591, 2928 cm^-¹. Anal. Calcd for C₁₅H₁₉NO₂S: C, 64.95; H, 6.90; N, 5.05. Found: C, 65.07; H, 6.64; N, 4.89. R _f  = 0.29 (PE-EtOAc = 3:1). [α]_D = 28.7 (c 0.09, CH₂Cl₂).

41

Synthesis of 3,4-Dibromo-3-phenylpyrrolidine (14)
A solution of (R _S )-N-(tert-butanesulfinyl)-3-phenyl-3-pyrroline (4a, 0.1 g, 0.40 mmol) in dry CH₂Cl₂ (10 mL) was cooled to 0 ˚C and Br₂ (1.05 equiv, 0.023 mL, 0.42 mmol) was added dropwise. After stirring for 1 h, Et₃N (1 equiv, 0.06 mL, 0.40 mmol) was added, and the reaction mixture was allowed to stir for another 30 min at r.t. H₂O (10 mL) was added, and the reaction mixture was immediately extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated. The compound was purified by means of column chromatography (R _f  = 0.18; PE-EtOAc = 3:1) to afford 3,4-dibromo-3-phenylpyrrolidine (14, 0.04 g) in 33% yield. Light brown oil. ^¹H NMR (300 MHz, CDCl₃): δ = 3.73 (1 H, dd, J = 14.9, 3.3 Hz), 3.91-3.99 (1 H, m), 4.35 (1 H, dd, J = 15.1, 4.1 Hz), 4.62 (1 H, dd, J = 15.4, 11.6 Hz), 5.11-5.23 (2 H, m), 7.38-7.48 (5 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 49.9, 50.8, 53.0, 66.3, 126.2, 129.1, 129.6, 140.0. IR (ATR): ν_max = 1156, 1337, 2359, 3271 cm^-¹. Anal. Calcd for C₁₀H₁₁Br₂N: C, 39.38; H, 3.64; N, 4.59. Found: C, 39.03; H, 3.88; N, 4.21.