The First Copper-Directed Regio- and anti-Selective Vicinal Acetoxysulfenylation of Nitroalkenes Generated in situ via the Henry Reaction

Abstract

The first example of a convenient, efficient, and highly regio- and anti-stereoselective multicomponent synthesis of vicinal acetoxysulfenylnitroalkanes along with the preparation of a probe for demonstrating their utility in heterocyclic synthesis is reported. The protocol strategically involves one-pot sequential Henry (nitroaldol) reaction, dehydration, and vicinal functionalization of the olefinic bond of in situ generated nitrostyrenes. The olefinic bond undergoes copper(I)/imidazole-catalyzed vicinal acetoxysulfenyl­ation with an organodisulfide and acetic acid under air followed by reductive cyclization to afford aziridines in good yields (79-84%).

Key words

multicomponent reaction - Henry reaction - nitro­alkanes - stereoselective synthesis - aziridines

References and Notes

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18

General Procedure for the Synthesis of 1,2-Acetoxy-sulfenylnitroalkane 3a
A mixture of trans-β-nitrostyrene 5a (Ar = Ph, 2 mmol), PhSSPh (2, 1 mmol), CuI (0.1 mmol), imidazole (0.1 mmol), and AcOH (0.2 mL) in MeCN (5 mL) was stirred at 70-80 ˚C under air for 5 h. After completion of the reaction (monitored by TLC), H₂O (10 mL) was added, and the product was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic extract was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product thus obtained was purified by SiO₂ column chromatography using EtOAc-n-hexane (2:5) as eluent to afford an analytically pure sample of 3a (Ar = R = Ph). Characterization data of compound 3a is given in ref. 21.

21

General Procedure for the Synthesis of 1,2-Acetoxy-sulfenylnitroalkanes 3 A mixture of an aromatic aldehyde 1 (2 mmol), nitromethane (2 mmol), RSSR 2 (1 mmol), CuI (0.1 mmol), imidazole (0.1 mmol), NH₄OAc (2 mmol), and AcOH (0.2 mL) in MeCN (5 mL) was stirred at 70-80 ˚C under air for the indicated time 6-9 h (Table  [²] ). After completion of the reaction (monitored by TLC), H₂O (10 mL) was added, and the product was extracted with CH₂Cl₂ (3 × 15 mL). The combined organic phase was dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product thus obtained was purified by SiO₂ column chromatography using EtOAc-n-hexane (2:5) as eluent to afford an analytically pure sample of 3.
Characterization Data of Representative Compounds Compound 3a: yellowish solid, yield 92%, mp 167-169 ˚C. IR (KBr): ν_max = 3005, 2988, 2240, 1600, 1582, 1565, 1451, 753, 705 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.07 (s, 3 H, CH₃CO), 5.57 (d, 1 H, J = 7.6 Hz, OCH), 5.85 (d, 1 H, J = 7.6 Hz, SCH), 7.13-7.42 (m, 10 H_arom). ^¹³C NMR (100 MHz, CDCl₃): δ = 21.9, 77.9, 98.4, 124.3, 125.2, 126.9, 127.9, 129.1, 135.2, 142,4, 169.7. MS (EI): m/z = 317 [M⁺]. Anal. Calcd (%) for C₁₆H₁₅NO₄S: C, 60.55; H, 4.76; N, 4.41. Found: C, 60.90; H, 4.47; N, 4.10. Compound 3b: yellowish solid, yield 88%, mp 195-197 ˚C. IR (KBr): ν_max = 3008, 2985, 2241, 1603, 1585, 1563, 1450, 845, 752, 706 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 2.03 (s, 3 H, CH₃CO), 5.52 (d, 1 H, J = 7.7 Hz, OCH), 5.89 (d, 1 H, J = 7.7 Hz, SCH), 7.15-7.45 (m, 9 H_arom). ^¹³C NMR (100 MHz, CDCl₃): δ = 17.9, 78.7, 97.4, 123.6, 126.1, 127.8, 129.0, 132.7, 134.9, 139.4, 171.5. MS (EI): m/z = 351 [M⁺]. Anal. Calcd (%) for C₁₆H₁₄ClNO₄S: C, 54.62; H, 4.01; N, 3.98. Found: C, 54.24; H, 4.23; N, 3.71.
Compound 3h: yellowish solid, yield 90%, mp 171-173 ˚C. IR (KBr): ν_max = 3004, 2989, 2242, 1601, 1583, 1567, 1452, 755, 702 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.89 (t, 3 H, J = 7.2Hz, CH₃), 1.43 (m, 2 H, CH₂), 2.05 (s, 3 H, CH₃CO), 2.47 (t, 2 H, J = 7.2Hz, CH₂), 5.53 (d, 1 H, J = 7.6 Hz, OCH), 5.82 (d, 1 H, J = 7.6 Hz, SCH), 7.25-7.38 (m, 5 H_arom). ^¹³C NMR (100 MHz, CDCl₃) δ = 15.3, 22.1, 23.7, 31.5, 77.9, 95.0, 126.9, 127.8, 130.3, 141.4, 171.2. MS (EI): m/z = 283 [M⁺]. Anal. Calcd (%) for C₁₃H₁₇NO₄S: C, 55.11; H, 6.05; N, 4.94. Found: C, 54.74; H, 6.27; N, 4.63.
Compound 3i: yellowish solid, yield 85%, mp 185-188 ˚C. IR (KBr): ν_max = 3007, 2986, 2239, 1605, 1581, 1566, 1454, 842, 756, 703 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 0.93 (t, 3 H, J = 7.3 Hz, CH₃), 1.45 (m, 2 H, CH₂), 2.07 (s, 3 H, CH₃CO), 2.45 (t, 2 H, J = 7.3 Hz, CH₂), 5.59 (d, 1 H, J = 7.8 Hz, OCH), 5.91 (d, 1 H, J = 7.8 Hz, SCH), 7.27-7.41 (m, 4 H_arom). ^¹³C NMR (100 MHz, CDCl₃): δ = 13.4, 18.3, 24.9, 29.6, 78.3, 94.8, 128.9, 129.4, 132.9, 138.6, 171.2. MS (EI): m/z = 317 [M⁺]. Anal. Calcd (%) for C₁₃H₁₆ClNO₄S: C, 49.13; H, 5.07; N, 4.41. Found: C, 49.34; H, 4.81; N, 4.78.

22

General Procedure for the Synthesis of Aziridines 4 A mixture of 1,2-acetoxysulfenylnitroalkanes 3 (2 mmol) and Fe powder (12 mmol) in AcOH (5 mL) was stirred at 45-50 ˚C for 3-4 h (Table  [³] ), then allowed to cool at r.t. The reaction mixture was neutralized with NaHCO₃ soln, and the product was extracted with EtOAc (3 × 10 mL). The combined organic phase was dried over anhyd Na₂SO₄, the solvent was removed under reduced pressure, and the crude product thus obtained was purified by SiO₂ column chromatography using EtOAc-n-hexane (3:7) as eluent to afford an analytically pure sample of 4.
Characterization Data of Representative Compounds Compound 4a: white needles, yield 82%, mp 63-65 ˚C. IR (KBr): ν_max = 3390, 3009, 2985, 1516, 1452, 1449, 1341, 755, 705, 638 cm^-¹. ^¹H NMR (400 MHz. CDCl₃) δ = 1.70 (1 H, br s, NH, exch. D₂O), 2.97 (d, 1 H, J = 3.9 Hz, 2-H), 3.09 (d, 1 H, J = 3.9 Hz, 3-H), 7.04-7.21 (m, 10 H_arom). ^¹³C NMR (100 MHz, CDCl₃): δ = 43.7, 44.9, 125.3, 126.8, 127.5, 128.9, 129.8, 130.9, 136.7, 138.4. MS (EI): m/z = 241 [M⁺]. Anal. Calcd (%) for C₁₄H₁₃NS: C, 73.97; H, 5.76; N, 6.16. Found: C, 73.70; H, 5.97; N, 6.45.