Synthesis of Lithium 1-Alkynesulfenates by the Mild Oxidation of Thiolates with a Pinacolone-Derived N-Sulfonyloxaziridine

Abstract

Lithium 1-alkynethiolates, generated by a base-induced ring cleavage of 4-substituted 1,2,3-thiadiazoles, were efficiently converted into the corresponding sulfenate salts by mild oxidation using an N-sulfonyloxaziridine derived from pinacolone. In situ S-alkylation with alkyl halides led to α,β-acetylenic sulfoxides.

oxidation reaction - sulfoxide - sulfenate salt - oxaziridine - heterocycle

References and Notes

1 For a recent review including chemical and biological aspects of sulfenates, see: O’Donnell JS. Schwan AL. J. Sulfur Chem.  2004,  25:  183 

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Examples of alkynyl alkyl sulfoxides are scarce, in contrast to alkynyl aryl derivatives. One reason is probably a relative instability. For example, polymerization upon standing or decomposition with a vigorous evolution of gas has been mentioned:

3a Russel GL. Ochrymowycz LA. J. Org. Chem.  1970,  35:  2106 

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4 The most relevant alternative routes to sulfenates are the oxidative cleavage of 1-alkynyl sulfoxides using a Pd(0) catalyst followed by transmetallation with Et₂Zn, an addition/elimination methodology with β-sulfinylacrylates and a retro-Michael reaction initiated by a base from β-sulfinylesters. See ref. 1 and: Caupène C. Boudou C. Perrio S. Metzner P. J. Org. Chem.  2005,  70:  2812 

5 The analogous sulfur anion with a higher oxidation state(sulfinate) readily decomposes with SO₂ evolution: Carpino LA. Rynbrandt RH. J. Am. Chem. Soc.  1966,  88:  5682 

6 D’hooge B. Smeets S. Toppet S. Dehaen W. Chem. Commun.  1997,  1753 

7a Brandsma L. Zwikker JW. Bilthoven N. Product Subclass 11: Lithium Alkynolates, Alkanethiolates and Alkyneselenolates, In Science of Synthesis   Vol. 8a:  Snieckus V. Georg Thieme Verlag; Stuttgart: 2006.  p.305 

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The hydrazones were fully characterized and the data collected were in agreement with those previously reported:

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13

4-(1,1-Dimethylethyl)-1,2,3-thiadiazole (3a):^27a R¹ = t-Bu; beige powder, (89%); mp 23 °C (Lit.^27a 23 °C); ¹H NMR (250 MHz, CDCl₃): δ = 1.51 (s, 9 H), 8.15 (s, 1 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 30.9, 34.0, 129.3, 173.6; IR (NaCl): 2964, 2870, 1490, 1462, 1244, 964, 890 cm^-1; MS (EI): m/z (%) = 142 (11) [M⁺], 57 (100), 43 (97), 41 (98). 4-Phenyl-1,2,3-thiadiazole (3b):^27b R¹ = Ph; orange solid recrystallized from n-hexane (83%); mp 76-78 °C (Lit.^27b 77-78 °C); ¹H NMR (250 MHz, CDCl₃): δ 7.41-7.55 (m, 3 H), 8.02-8.07 (m, 2 H), 8.65 (s, 1 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 127.8, 129.6, 129.9, 130.4, 131.2, 163.3; IR (NaCl): 3072, 1462, 1442, 1220, 766, 692 cm^-1; MS (EI): m/z (%) = 162 (6) [M⁺], 134 (100), 90 (18).

14

4-Methyl-1,2,3-thiadiazole (3c):^27c R¹ = Me; white solid which melted rapidly at r.t. (43%); ¹H NMR (250 MHz, CDCl₃): δ = 2.81 (s, 3 H), 8.17 (s, 1 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 13.93, 132.6, 160.0; IR (NaCl): 3104, 1494, 1444, 1224 cm^-1; MS (CI): m/z (%) = 101 (100) [M + H⁺], 71 (79).

15

5-Chloro-4-methyl-1,2,3-thiadiazole: Orange oil (8%); ¹H NMR (250 MHz, CDCl₃): δ = 2.7 (s, 3 H); MS (CI): m/z (%) = 135 (100) [M + H⁺] ³⁵Cl, 137 (35) [M + H⁺] ³⁷Cl, 71 (50).

16 Wu P.-L. Peng S.-Y. Magrath J. Synthesis  1996,  249 

17

N -(1,2,2-Trimethylpropylidene)benzenesulfonamide (4). To a mixture of pinacolone (9.1 mL, 73 mmol) and benzenesulfonamide (5.8 g, 36.5 mmol) in toluene (360 mL), Ti(OEt)₄ (25 g, 110 mmol) was added dropwise while stirring. The reaction mixture was slowly heated to reflux (oil bath temperature at 115 °C). After refluxing for 20 h, the yellow mixture was cooled to r.t. and an aq NaOH solution (0.5 M, 350 mL) was added slowly. The white gel of titanium oxides formed was filtered through celite to give a biphasic filtrate. The organic phase was separated and the aq layer extracted with Et₂O (2 × 150 mL). The combined organic extracts were washed with sat. aq NaCl solution (100 mL) and dried over MgSO₄. Filtration and concen-tration under reduced pressure led to imine 4 (6.5 g, 27 mmol, 75%) as a yellowish solid. The product was used without further purification.

18 Imine 4 was also prepared in good yield (70-80%) by a free radical rearrangement of O-sulfinyl oximes (Hudson reaction) prepared by the reaction of pinacolone oxime with benzenesulfinyl chloride in the presence of triethylamine. Purification of the crude material is essential: Brown C. Hudson RF. Record KAF. J. Chem. Soc., Perkin Trans. 2  1977,  822 

19 Camps F. Coll J. Messeguer A. Pujol F. J. Org. Chem.  1982,  47:  5402 

20

trans -3-(1,1-Dimethylethyl)-3-methyl-2-(phenyl-sulfonyl)oxaziridine (1). KF (8.5 g, 146.8 mmol) was dried by heating at 120 °C for 2 h under reduced pressure (1 Torr) and a solution of commercial MCPBA (70%, 18 g, 73.4 mmol) in CH₂Cl₂ (300 mL) previously dried over MgSO₄ was added. A solution of crude imine 4 (11.7 g, 48.9 mmol) was added and the resulting white suspension was stirred at 0 °C for 3 h and then for a further 12 h at r.t. After filtration to remove the insoluble materials and concen-tration, the residue was filtered through SiO₂ with CH₂Cl₂ as eluent to afford oxaziridine 1 (8.77 g, 34.4 mmol, 71%).

Various oxidizing agents were tested using successful experimental conditions reported in the synthesis of other N-sulfonyloxaziridines. However, most of them gave very disappointing results with, for example, no reaction taking place using Oxone^® and formation of hydrolysis products using H₂O₂:

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22

Crystal-structure determination of 1: Single crystals of oxaziridine 1, suitable for X-ray crystallographic analysis, were obtained by slow evaporation of n-hexane. X-ray diffraction experiments for the monocrystal of 1 were performed at 293.2 K with graphite-monochromatized Mo K_α radiation on an Enraf-Nonius CAD-4 diffractometer. Formula C₁₂H₁₇NO₃S, formula weight 255, crystal system triclinic, space group P-1 (n° 2), a = 9.013 (1) Å, b = 9.169 (4) Å, c = 9.528 (3) Å, α = 108.39 (3)°, β = 108.38 (2)°, γ = 70.09 (2)°, V = 683.2 (4) ų, Z = 2, density calcd = 1.24 g/cm³, µ = 2.3 cm^-1, R = 0.034, wR = 0.0515. Selected bond lengths (Å) and angles (°): O1-C1 1.422 (1), O1-N1 1.484 (1), N1-C1 1.450 (2), S1-N1 1.704 (1), S1-O3 1.421 (1), S1-C7 1.750 (1), C7-C12 1.371 (2), C7-C8 1.374 (2), C1-C2 1.500(2), C1-C3 1.527 (2), C3-C6 1.536 (2), N1-O1-C1 59.90 (7), N1-O1-C1 57.84 (7), O1-C1-N1 62.19 (7), S1-N1-C1 120.27 (9), O2-S1-O3 120.03 (7), O2-S1-N1 102.29 (6), O3-S1-N1 114.31 (6), S1-N1-C1 120.27 (9). Data reduction: TEXSAN (Molecular Structure Corporation). Program(s) used to solve structure: SIR92. Program(s) used to refine structure: TEXSAN. Software used to prepare material for publication: TEXSAN. Crystallographic data for compound 1 have been deposited at the Cambridge Crystallographic Data Centre, CCDC No 615446. Copies of this information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK; [phone]; E-mail: [e-mail] or http://www.ccdc.cam.ac.uk.

23a Hogg DR. Robertson A. J. Chem. Soc., Perkin Trans. 1  1979,  1125 

23b Kobayashi M. Toriyabe K. Sulfur Lett.  1985,  3:  117 

24 This sulfoxide was successfully prepared by thioether oxidation: Villar JM. Delgado A. Llebaria A. Moretó JM. Molins E. Miravitlles C. Tetrahedron  1996,  52:  10525 

25

General Procedure for the Synthesis of 1-Alkynyl Sulfoxides 2: A solution of thiadiazole 3 (1.00 mmol) in anhyd THF (5 mL) was cooled to -78 °C and MeLi (0.69 mL of a 1.6 M solution in Et₂O, 1.1 mmol) was added dropwise. After stirring at -78 °C for 1 h, a solution of oxaziridine 1 (267 mg, 1.05 mmol) in anhyd THF (2 mL) was slowly added dropwise (exothermic reaction). The reaction mixture was stirred at this temperature for 30 min and treated with the alkyl halide (1-5 equiv). The reaction mixture was then warmed to -20 °C over 1.5 h and then the cold bath was removed. After stirring for a further 1.5 h at r.t., the reaction mixture was treated with sat. aq NaCl solution and the product was extracted with Et₂O (3 × 20 mL). The combined organic extracts were washed with sat. aq NaCl solution (3 × 10 mL) and dried over MgSO₄. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (PE-EtOAc mixtures) to give the anticipated sulfoxides 2. 1-Benzylsulfinyl-3,3-dimethylbut-1-yne (2a ₁ ): Obtained from thiadiazole 3a (R¹ = t-Bu, 142 mg, 1 mmol) using benzyl bromide (R² = Bn, 130 µL, 1.1 mmol) as the electrophile gave 2a ₁ as a colorless oil (170 mg, 0.77 mmol, 77%); R _f = 0.19 (PE-EtOAc, 4:1); ¹H NMR (250 MHz, CDCl₃): δ = 1.22 (s, 9 H), 4.25 (s, 2 H), 7.35-7.37 (m, 5 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 28.8, 30.3, 63.1, 75.8, 113.9, 129.0, 129.1, 129.6, 130.9; IR (NaCl) 3032, 2972, 2928, 2868, 2160 (C≡C), 1454, 1252, 1060 cm^-1; MS (EI): m/z (%) = 220 (1) [M⁺], 91 (100), 65 (14); Anal. Calcd for C₁₃H₁₆OS: C, 70.87; H, 7.32; S, 14.55. Found: C, 70.75; H, 7.47; S, 14.76.
1-Ethylsulfinyl-3,3-dimethylbut-1-yne (2a ₂ ). Obtained from thiadiazole 3a (R¹ = t-Bu, 142 mg, 1 mmol) using ethyl iodide (R² = Et, 0.4 mL, 5 mmol) as the electrophile gave 2a ₂ as a colorless oil (92 mg, 0,58 mmol, 58%); (R _f = 0.3 (PE-EtOAc, 4:1); ¹H NMR (250 MHz, CDCl₃): δ = 1.29 (s, 9 H), 1.42 (t, J = 7.4 Hz, 3 H), 2.98 and 3.06 (AB part of ABX₃, J _AB = 13 Hz, J _AX = J _BX = 7.4 Hz, 2 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 6.8, 28.8, 30.4, 50.5, 75.7, 112.6; IR (NaCl): 2972, 2932, 2870, 2160 (C≡C), 1456, 1252, 1070 cm^-1; MS (EI): m/z (%) = 158 (47) [M⁺], 142 (33), 130 (68), 115 (100); HRMS m/z calcd for C₈H₁₄OS: 158.0765; found: 158.0769.
3,3-Dimethyl-1-methylsulfinylbut-1-yne (2a ₃ ). Obtained from thiadiazole 3a (R¹ = t-Bu, 142 mg, 1 mmol) using methyl iodide (R² = Me, 186 µL, 3 mmol) as the electrophile gave 2a ₃ as a pale pink oil (123 mg, 0,85 mmol, 85%); R _f = 0.32 (PE-EtOAc, 1:1); ¹H NMR (250 MHz, CDCl₃): δ = 1.29 (s, 9 H), 2.92 (s, 3 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 28.8, 30.4, 44.1, 77.7, 112.1; IR (NaCl): 2972, 2930, 2870, 2158 (C≡C), 1456, 1252, 1070 cm^-1; MS (EI): m/z (%) = 144 (100) [M⁺], 129 (22), 113 (25), 81 (42); HRMS m/z calcd for C₇H₁₂OS: 144.0608; found: 144.0611.
(3,3-Dimethylbut-1-ynylsulfinyl)acetic acid ethyl ester (2a ₄ ). Obtained from thiadiazole 3a (R¹ = t-Bu, 142 mg, 1 mmol) using 2-bromoacetic acid ethyl ester (R² = CH₂CO₂Et, 0.12 mL, 1.1 mmol) as the electrophile gave 2a ₄ as a colorless oil (162 mg, 0.75 mmol, 75%); R _f = 0.21 (PE-EtOAc, 4:1); ¹H NMR (250 MHz, CDCl₃): δ = 1.29 (s, 9 H), 1.32 (t, J = 7.1 Hz, 3 H), 3.92 and 4.08 (ΑΒ, J = 13.6 Hz, 2 H), 4.26 (q, J = 7.1 Hz, 2 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 14.5, 29.0, 30.3, 61.4, 62.6, 75.7, 114.0, 164.6; IR (NaCl): 2974, 2932, 2870, 2160 (C≡C), 1740 (C=O), 1456, 1366, 1252, 1070 cm^-1; MS (EI): m/z (%) = 216 (35) [M⁺], 201 (62), 173 (80), 113 (36), 67 (38), 59 (48), 43 (100); Anal. Calcd for C₁₀H₁₆O₃S: C, 55.53; H, 7.46; S, 14.82. Found: C, 55.63; H, 7.46; S, 14,52.
1-Benzylsulfinyl-2-phenylacetylene (2b ₁ ). Obtained from thiadiazole 3b (R¹ = Ph, 162 mg, 1 mmol) using benzyl bromide (R² = Bn, 0.130 mL, 1.1 mmol) as the electrophile gave 2b ₁ as an orange oil which needed to be purified quickly on SiO₂ and stored in a fridge (120 mg, 0.50 mmol, 50%); R _f = 0.30 (PE-EtOAc, 4:1); ¹H NMR (250 MHz, CDCl₃): δ = 4.39 (pseudo s, 2 H), 7.35-7.46 (m, 10 H); ¹³C NMR (62.9 MHz, CDCl₃): δ = 63.1, 85.4, 103.7, 120.1, 128.7, 129.0, 129.1, 129.2, 129.4, 131.0, 132.6; IR (NaCl): 3060, 3030, 2974, 2922, 2164 (C≡C), 1490, 1452, 1246, 1060 cm^-1; MS (CI): m/z (%) = 241 (100) [M + H⁺], 181 (65), 107 (95), 91 (55); HRMS (CI): m/z calcd for C₁₅H₁₃OS: 241.0687; found: 241.0690; Anal. Calcd for C₁₅H₁₂OS: C, 74.97; H, 5.03; S, 13.34. Found: C, 73.15; H, 4.99; S, 13.25.
1-Ethylsulfinyl-2-phenylacetylene (2b ₂ ). Obtained from thiadiazole 3b (R¹ = Ph, 162 mg, 1 mmol) using ethyl iodide (R² = Et, 0.4 mL, 5 mmol) as the electrophile gave 2b ₂ as an orange oil. The product is highly unstable as previously reported in the literature (31 mg, 0.17 mmol, 17%); R _f = 0.10 (PE-EtOAc, 4:1); ¹H NMR (250 MHz, CDCl₃): δ = 1.51 (t, J = 7.4 Hz, 3 H), 3.07-3.25 (m, 2 H), 7.34-7.92 (m, 5 H).

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