The First aza-Wittig Reaction Involving a non-Cumulated Sulfoxy Group

Abstract

3-(Aryliminophosphoranyl)-5-phenyl-4-arylsulfoxy-isoxazoles undergo ring closure via an intramolecular aza-Wittig type reaction of an iminophosphorane onto a non-cumulated sulfoxide. The products obtained are isoxazolo[4,3-c]-2,1-benzothiazines, a hitherto unreported heterocyclic system. This is the first example of the construction of the sulfimide linkage (S=N) via a Wittig type process involving non-cumulated sulfoxides. The requisite iminophosphoranes were synthesised using the Staudinger reaction of an azide with triphenylphosphine. Other key steps include the regio­selective addition of a carbanion to a nitrile oxide in the presence of an azide, and the synthesis and use of the little reported o-azidobenzonitrile oxide.

aza-Wittig reaction - sulfoxides - 1,3-dipolar cycloadditions - sulfimide - 2,1-benzothiazine

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20

Synthesis of 3-( o -Azidophenyl)-4-( p -tolylsulfoxy)-5-phenylisoxazole ( 10a): To a solution of phenacyl p-tolyl sulfoxide (1.3140 g, 5.09 mmol, 1 equiv) and freshly distilled Et₃N (1.42 mL, d = 0.726, 10.17 mmol, 2 equiv) in anhyd EtOH (15 mL) was added, dropwise over 4 h, a solution of o-azido benzohydroximoyl chloride (1.0000 g, 5.09 mmol, 1 equiv) in anhyd EtOH (15 mL), under an atmosphere of dry nitrogen. The mixture was concentrated in vacuo and the crude residue was purified by flash silica column chromatography (eluent: petroleum ether-EtOAc, 3:1) to give 3-(o-azidophenyl)-4-(p-tolylsulfoxy)-5-phenylisoxazole as a yellow solid (0.9470 g, 46% yield), mp 148-149 °C. ¹H NMR ( 400 MHz, CDCl₃): δ = 2.17 (s, 3 H, Me), 7.04 (t, 1 H, J = 7.5 Hz, 1 × ArH), 7.07 (d, 2 H, J = 8.2 Hz, 2 × ArH), 7.12 (d, 2 H, J = 8.2 Hz, 2 × ArH), 7.19 (dt, 1 H, J = 7.5, 0.7 Hz, 1 × ArH), 7.45 (m, 2 H, 2 × ArH), 7.57 (m, 3 H, 3 × ArH), 8.08, (dd, 2 H, J = 8.1, 1.7 Hz, 2 × ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.1 (CH₃), 118.0 (CH), 118.7 (quat.), 119.1 (quat.), 124.3 (CH), 124.4 (CH), 125.6 (quat.), 128.8 (quat.), 128.9 (CH), 129.0 (CH), 131.3 (CH), 131.9 (CH), 132.6 (CH), 137.7 (quat.), 138.8 (quat.), 140.5 (quat.), 160.1 (quat.), 172.5 (quat.). IR: 2925 (m), 2128 (s), 1604 (w), 1581 (w), 1556 (m), 1448 (m), 1300 (s), 1084 (m), 1054 (m) cm^-1. MS (EI): m/z (%) = 372 (100) [M - 28], 237 (80), 189 (70), 119 (30), 91 (40), 77 (98). HRMS (ES+): found MH⁺ 401.1066, C₂₂H₁₆N₄O₂S requires MH 401.1072.

21

Synthesis 3-[ o - N -(Triphenylphosphoranylidene)phenyl]-4-( p -tolylsulfoxy)-5-phenylisoxazole ( 11a): To a solution of 3-(o-azidophenyl)-4-(p-tolyl-sulfoxy)-5-phenyl-isoxazole (10a) (0.2000 g, 0.50 mmol, 1 equiv) in anhyd toluene (10 mL) was added at r.t., under an atmosphere of dry nitrogen, a solution of triphenylphosphine (0.1311 g, 0.50 mmol, 1 equiv) in anhyd toluene (5 mL). The reaction mixture was stirred for a total of 5 h whilst being monitored by TLC. After completion of the reaction, the solvent was removed in vacuo and the crude product was purified by flash silica column chromatography (eluent: petroleum ether-EtOAc, 2:1) to give 3-[o-N-(triphenylphosphoranyl-idene)phenyl]-4-(p-tolylsulfoxy)-5-phenylisoxazole as a bright yellow solid (0.2890 g, 91% yield), mp 102-104 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.16 (s, 3 H, Me), 6.54 (d, 1 H, J = 8.25 Hz, 1 × ArH), 6.74 (t, 1 H, J = 7.5 Hz, 1 × ArH), 6.81 (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.03 (td, 1 H, J = 7.7, 1.7 Hz, 1 × ArH), 7.14 (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.27-7.46 (m, 10 H, 10 × PhH), 7.50 (m, 3 H, 3 × ArH), 7.73-7.85 (m, 6 H, 6 × ArH), 8.13 (dd, 2 H, J = 7.7, 1.9 Hz, 2 × ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.1 (CH₃), 116.7 (CH), 121.1 (CH), 121.3 (CH), 124.4 (CH), 126.8 (quat.), 126.9 (quat.), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.3 (CH), 130.0 (quat.), 130.3 (CH), 130.4 (CH), 130.5 (CH), 130.9 (CH), 131.0 (CH), 131.6 (CH), 132.0 (quat.), 132.1 (quat.), 132.7 (CH), 132.8 (CH), 139.7 (quat.), 140.4 (quat.), 150.7 (quat.), 164.8 (quat.), 171.1 (quat.). IR: 3018 (m), 1677 (m), 1606 (m), 1560 (m), 1438 (m), 1345 (m), 1181 (s), 1119 (m), 694 (m), 666 (m) cm^-1. HRMS (ES+): found MH⁺ 635.1928, C₄₀H₃₁N₂O₂PS requires MH⁺ 635.1922.

22

Synthesis of 3-Phenyl-2-( p -tolyl)-isoxazolo[4,3- c ][2,1]benzothiazine ( 12a): A solution of 3-[o-N-(triphenylphosphoranylidene)phenyl]-4-(p-tolylsulfoxy)-5-phenylisoxazole (11a) (0.2500 g, 0.3939 mmol, 1 equiv) in freshly distilled anhyd toluene (10 mL) was heated at reflux under a dry nitrogen atmosphere for a total of 8 h, whilst being monitored by TLC. After completion of the reaction, the solvent was removed in vacuo and the crude product was purified by flash silica column chromatography (eluent: petroleum ether-EtOAc, 5:1) to give 3-phenyl-2-(p-tolyl)-isoxazolo[4,3-c][2,1]benzothiazine as a bright green oil (0.0700 g, 50% yield), a sample of which solidified on standing. CHN: found (%) C, 74.4; H, 4.4; N, 7.6; S, 9.5. C₂₂H₁₆N₂OS requires (%): C, 74.1; H, 4.5; N, 7.9; S, 9.0. ¹H NMR (400 MHz, CDCl₃): δ = 2.17 (s, 3 H, Me), 6.53 (d, 2 H, J = 8.1 Hz, 2 × ArH), 6.71, (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.11 (t, 1 H, J = 7.5 Hz, 1 × ArH), 7.33 (t, 1 H, J = 7.4 Hz,
1 × ArH), 7.40 (m, 3 H, 3 × ArH), 7.52 (t, 1 H, J = 7.3 Hz,
1 × ArH), 7.83 (d, 1 H, J = 7.9 Hz, 1 × ArH), 8.20 (d, 2 H, J = 7.4 Hz, 2 × ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.0 (CH₃), 110.8 (CH), 121.0 (CH), 122.3 (CH), 123.7 (quat.), 127.5 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 129.6 (CH), 133.1 (CH), 133.3 (quat.), 135.9 (quat.), 137.6 (quat.), 144.7 (quat.), 145.7 (quat.), 168.2 (quat.). IR: 3019 (m), 2925 (m), 1681 (m), 1596 (m), 1478 (m) 1449 (m), 908 (s), 805 (m), 668 (m) cm^-1. MS (ES+): m/z (%) = 379 (100) [M + 23]. HRMS (ES+): found MH⁺ 357.1058, C₂₂H₁₆N₂OS requires MH⁺ 357.1056.

23

Synthesis of 3-( o -aminophenyl)-5-(phenyl)-4-( p -tolylsulfoxy)-isoxazole ( 13a): To a solution of the 3-phenyl-2-(p-tolyl)-isoxazolo[4,3-c][2,1]benzothiazine (12a) (0.0500 g, 0.14 mmol) in THF (5 mL) was added, at r.t., H₂O (1 mL). The reaction mixture was stirred for a total of 20 h whilst being monitored by TLC. After completion of the reaction, the solvent was removed in vacuo and the crude product was purified by flash column chromatography (eluent: petroleum ether-EtOAc, 5:3) to give 3-(o-aminophenyl)-5-(phenyl)-4-(p-tolylsulfoxy)-isoxazole as a pale yellow oil (0.0452 g, 86% yield). ¹H NMR (400 MHz, CDCl₃): δ = 2.27 (s, 3 H, Me), 4.43 (broad s, 2 H, NH₂), 6.59 (d, 1 H, J = 8.0 Hz, 1 × ArH), 6.65 (t, 1 H, J = 7.5 Hz, 1 × ArH), 7.10 (t, 1 H, J = 7.3 Hz, 1 × ArH), 7.20 (m, 3 H, 3 × ArH), 7.26 (m, 3 H, 3 × ArH), 7.36 (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.94 (d, 2 H, J = 8.2 Hz, 2 × ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 21.6 (CH₃), 111.8 (quat.), 116.0 (CH), 117.5 (quat.), 117.6 (CH), 122.8 (quat.), 124.3 (CH), 128.3 (CH), 128.8 (CH), 129.7 (CH), 130.0 (CH), 130.8 (CH), 132.0 (CH), 140.6 (quat.), 142.6 (quat.), 145.3 (quat.), 161.5 (quat.), 173.8 (quat.). IR: 3476 (m, broad), 3381 (m, broad), 3062 (m), 2925 (w), 1671 (s), 1580 (m), 1557 (m), 1499 (s), 1475 (m), 1444 (m), 1374 (m), 1083 (m), 1038 (s), 668 (m)cm^-1. MS (ES+): m/z (%) = 375 (100) [M + H], 397 (55) [M + Na]. HRMS (ES+): found MH⁺ 375.1172, C₂₂H₁₈N₂O₂S requires MH 375.1167.

24 Luheshi A.-BN. Salem SM. Smalley RK. Kennewell PD. Westwood R. Tetrahedron Lett.  1990,  31:  6561