The Regiochemistry of Cyclization of Î±-Sulfenyl-, Î±-Sulfinyl-, and Î±

Supporting Information Part One The Regiochemistry of Cyclization of α-Sulfenyl, α-Sulfinyl, and α-Sulfonyl 5-Hexenyl Radicals: Procedures Leading to Regioselective Syntheses of Cyclic Sulfones and Sulfoxides. Ernest W Della* and Sean D Graney Department of Chemistry, Flinders University, Bedford Park, South Australia 5042, Australia [email protected]

Table of Contents 1. Experimental Section Compounds 49 68 Attempted synthesis of 65 Attempted synthesis of 76 92 94

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2. References

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3. Selected Spectra Compounds 68, 70, 71, 72, 75, 74, 79, 80, 81, 73, 85 82, 86, 84, 88, 89, 90, 91, 83, 92, 77, 93, 94, 95, 96, 59, 60 61 (minor diastereomer) 61 (major diastereomer) 97, 98, 33a, 33b, 99, 35a, 34a, 101, 100

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Supporting Information Part ONE

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S7- S20 S22-S32 S32-S44 S46-S48 S48-S50 S51-S66

General Experimental Techniques Proton nuclear magnetic resonance (1H NMR; 300 MHz) and Carbon-13 nuclear magnetic resonance (13C NMR; 75.5 MHz) spectra. Spectra were recorded on samples dissolved in CDCl3. Electron-impact HRMS were recorded at an ionizing voltage of 70 eV and Electrospray HRMS were recorded with a capillary voltage of ~100v. The purity of all compounds, both new and known, was determined by GC analysis, supported by NMR data. General experimental procedures have been described previously. 2

Thiapyran was commercially available material. 2-Methyl-1,4-butanediol,

1

2,2-dimethyl-1,4-

3

butanediol, prepared from the corresponding diesters by standard treatment with LiAlH4, and 24

methylene-1,4-butanediol by treatment with DIBAL, had physical properties consistent with literature 5

data. The diols were converted into the dimesylates under the usual conditions and had physical 6

properties identical with those reported: 2-methyl-1,4-butanediyl dimesylate, 7

butanediyl dimesylate,

8

and 2-methylene-1,4-butanediyl dimesylate.

2,2-dimethyl-1,4-

Treatment of the first two

9

dimesylates with Na2S.2H2O as described afforded the corresponding tetrahydrothiophene which had 9b

physical data in accord with literature values: 13,

and 48.

10

Oxidation of the heterocyclic sulfides 13,

14, 48, and 49 was performed using either NaIO4 or m-chloroperbenzoic acid (MCPBA) to give the corresponding sulfoxides and sulfones, respectively, which had physical properties consistent with 11

literature data: 16,

12

17,

13

19,

20,

14

12,13

51,

15

52,

13

54

9b, 15b,c

and 55.

Methyl thioacetate, synthesised by

treatment of thioacetic acid with NaH followed by iodomethane, had physical properties identical with those published.

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16


9b

4-Methylthiopyran (49). 3-methyl-1,5-pentanediol

was treated with 2 equivs of methanesulfonyl

5

chloride as described to give 3-methyl-1,5-pentanediyl dimesylate: 1H NMR (CDCl3) δ 4.34-4.22 (m, 4H), 3.01 (s, 6H), 1.90-1.77 (m, 3H), 1.67-1.56 (m, 2H), 1.0 (d, J=6.0 Hz, 2H). 13C NMR (CDCl3) δ 60.2 (2 x CH2), 39.3 (2 x CH2), 25.7, 19.8. The dimesylate (6.69 g, 24.4 mmol) in 95% EtOH (90 mL) was 9

treated with a solution of Na2S.2H2O (5.60 g, 49 mmol) in 95% EtOH (20 mL) as described. Work up o

3

o

and distillation of the product (Kugelrohr: 55 C/18mm: lit. 54 C/22mm) yielded 4-methylthiopyran 49 as a clear colorless oil (2.2 g, 78%):

1

H NMR (CDCl3) δ 2.70-2.53 (m, 4H), 1.96-1.88 (m, 2H), 1.40-

1.18(m, 3H), 0.89 (d, J=6.0 Hz, 2H), 1.33 (s, 3H), 1.03 (s, 3H).

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C NMR (CDCl3) δ 35.9 (overlapping

signals 2 x CH2), 32.2, 28.7 (overlapping signals 2 x CH2), 23.0 (lit

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NMR). LRMS m/z (% base), 116

(19), 115 (91), 101 (100), 67 (91), 55 (40).

3-Butenyl thioacetate (68). Thioacetic acid (2.6 mL, 36.0 mmol) in DMF (10 mL) was added dropwise over 20 min to a stirred slurry of sodium hydride (60%, 1.44 g, 36.0 mmol) in DMF (60 mL) under a nitrogen atmosphere at room temperature. After 60 min, 3-butenyl methanesulfonate (5.0 g, 33.3 mmol) in DMF (10 mL) was added over 20 min. After being stirred for 2h, the reaction was quenched by the addition of water (80 mL) and then extracted with pentane (2 x 100 mL). The combined organic extracts were washed with water (3 x 50 mL) and then brine (80 mL) before being dried (Na2SO4). Evaporation of the solvent gave a dark yellow oil, distillation of which (Kugelrohr: 85oC/18mm) afforded the title 1

compound 68 as a colorless oil (3.02 g, 70%): H NMR (CDCl3) δ 5.85-5.71 (m, 1H), 5.11-5.01 (m, 2H), 2.93 (t, J=7.2 Hz, 2H); 2.34-2.27 (m, 2H), 2.34 (s, 3H);

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C NMR (CDCl3) δ 195.5, 136.0, 116.3, 33.3,

30.23, 28.0. HRMS (EI) calcd for C6H10OS: 130.0452, found 130.0451. NMR data were consistent with those reported. S3

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Attempted synthesis of 1-bromo-2-sulfenyl-5-hexene (65). 3-Butenyl thioacetate 68 (1.0 g, 7.6 mmol) was added dropwise over 10 min to a stirred solution of sodium methoxide (0.18 g, 7.6 mmol sodium, 10 mL methanol) at room temperature under nitrogen. After being stirred for 40min, the above solution was added over one hour by cannula to a solution of CH2Br2 (5.4 mL, 10 equivalents) in MeOH (5 mL) and the mixture was stirred for a further 1h at room temperature. Water (40 mL) was added and the extracted with CH2Cl2 (2 x 50 mL). The combined organic extracts were then washed with brine (2 x 40 mL) and then dried (MgSO4). Removal of the solvent under reduced pressure gave a pale brown oil NMR analysis of which showed it to consist of a complex mixture. Distillation (Kugelrohr) afforded two fractions: (i) (bp. 50oC/18mm) identified as 1-methoxy-2-sulfenyl-5-hexene (70): 1H NMR (CDCl3) δ 5.90-5.75 (m, 1H), 5.12-5.02 (m, 2H), 4.64 (s, 2H), 3.35 (s, 3H), 2.66 (t, J=7.5 Hz, 2H), 2.40-2.35 (m, 2H);

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C NMR (CDCl3) δ 137.1, 116.3,55.8, 34.4, 30.4. (ii) (bp.110-120oC/18mm) identified as bis-31

butenylsulfenylmethane (71): H NMR (CDCl3) δ 5.90-5.76 (m, 2H), 5.12-5.01 (m, 4H), 3.69 (s, 2H), 2.70 (t, J=7.3 Hz, 4H), 2.39-2.32 (m, 4H);

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C NMR (CDCl3) δ 136.5, 115.8, 35.1, 33.0, 29.6. LRMS

m/z (% base), 188 (62), 154 (17), 133 (100), 86 (57). HRMS (EI) calcd for C9H16S2: 188.0693, found 188.0696. Attempted oxidation of the stannane 75 to the sulfoxide 76. Sodium metaperiodate 2.13 g, 10.0 mmol) was added portionwise to a to a stirred, cold (0oC) solution of 1-tributylstannyl-2-sulfenyl-5hexene (75) (13.8 g, 9.74 mmol) in 4:1 acetone/water (25 mL) and the mixture allowed to warm to room temperature over 12h. The precipitated sodium iodate was removed by filtration and the filtrate extracted with CH2Cl2 (2 x 40 mL). Removal of solvent under reduced pressure and NMR analysis of the crude product showed 2-sulfinyl-5-hexene (77) to be the major component.

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2-Sulfenyl-5-hexene (92). Methyl thioacetate (2.22 g, 24.6 mmol) was added dropwise over 10 min to a stirred solution of (0.68 g, 29.5 mmol sodium, 22 mL methanol) at room temperature. After stirring for 60 min 3-butenyl methane-sulfonate (3.08 g, 36.0 mmol) was added and the mixture was stirred for a further 2h at room temperature. Water (100ml) was added followed by extraction with pentane (2x100ml). The combined pentane extracts were then washed with brine, dried (MgSO4), and the solvent o

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removed under reduced pressure yielding an oil. Distillation (Kugelrohr: 112-114 C/760mm); lit o

bp 1

121-122 C/724mm) afforded 2-sulfenyl-5-hexene (92) as a pale straw-coloured oil (1.5 g, 71%): H NMR (CDCl3) δ 5.91-5.77 (m, 1H), 5.12-5.00 (m, 2H), 2.56 (t, J=7.2 Hz, 2H); 2.39-2.31 (m, 2H), 2.11 (s, 3H),

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C NMR (CDCl3) δ 136.8, 115.8, 33.4, 33.3, 15.3; lit NMR.

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HRMS (EI) calcd for C5H10S:

102.0503, found 102.0502. 2-Sulfenyl-5-methyl-5-hexene (94). 3-Methyl-3-butenyl thioacetate (85) (4.2 g, 29.16 mmol) was added dropwise over 10min to a solution of sodium methoxide (0.805 g, 35.0 mmol sodium, 30 mL methanol) at room temperature with stirring. After 60 min, methyl iodide (2.24 mL, 36.0 mmol) was added and the mixture was stirred for a further 2h. Water (100 mL) was added and the mixture extracted with pentane (2 x 100 mL). The combined pentane extracts were then washed with brine, and dried (MgSO4), and the solvent removed under reduced pressure to give a pale straw-colored oil (2.76 g, 82%). Distillation (Kugelrohr: 70-75oC/65mm. Lit

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bp 75oC/85mm) yielded 2-sulfenyl-5-methyl-5-hexene (94) 1

as a clear colorless oil (2.5 g, 75%) which had physical properties and H NMR spectral data consistent with those reported:

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:

1

H NMR (CDCl3) δ 4.79-4.76 (m, 1H), 4.75-4.72 (m, 1H), 2.63-2.58 (t, J=7.6

Hz, 2H), 2.33-2.28 (t, J=7.6 Hz, 2H), 2.11 (s, 3H), 1.74 (s, 3H);

13

C NMR (CDCl3) δ 144.1, 111.1, 37.4,

32.4, 22.2, 15.5. LRMS m/z (% base), 115 (38), 101 (5), 69 (8), 68 (17), 67 (17), 61 (100).

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REFERENCES 1. Della, E. W.; Graney, S. D. Organic Letters 2002, 4, 4065. 2. Grisenti, P.; Ferraboschi, P.; Casati, S.; Santaniello, E. Tetrahedron: Asymmetry 1993, 4, 997. 3. Barbarella, G.; Garbesi, A.; Fava, A. J. Am. Chem. Soc. 1975, 97, 5883. 4. Fuchs, J.; Szeimies, G. Chem. Ber. 1992, 125, 2517. 5. Crossland, R. K.; Servis, K. L. J. Org. Chem. 1970, 35, 3195. 6. Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60, 4743. 7. Barbarella, G.; Garbesi, A.; Fava, A. J. Am. Chem. Soc. 1975, 97, 5883. 8. Wade, P. A.; Kondracki, P. A. J. Org. Chem. 1993, 58, 3140. 9. Wolf, D. E.; Folkers, K. Org. React. 1951, 4, 410. (b) Whitehead, E.V.; Dean, R. A.; Fidler, F. A. J. Am. Chem. Soc. 1951, 73, 3632. 10. Barbarella, G.; Dembech, P. Org. Mag. Res. 1980, 13, 282. 11. Oswald, A. A.; Griesbaum, K.; Thaler, W. A.; Hudson, B. E. J. Am. Chem. Soc. 1962, 84, 3897. 12. Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 1999, 64, 2038. 13. Barbarella, G.; Rossini, S.; Bongini, A.; Tugnoli, V. Tetrahedron 1985, 41, 4691. 14. (a) Barbarella, G; Dembech, P; Tugnoli, V. Org. Magn. Reson. 1984, 22, 402. (b) Culshaw, P. N.; Walton, J. C. J. Chem. Soc. Perkin Trans 2 1991, 1201.

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15. (a). Claus, P K.; Rieder, W.; Vierhapper, F. W. Tetrahedron Lett. 1976, 17, 119. (b) Kropp, P. J.; Breton, G. W.; Fields, J. D.; Tung, J. C.; Loomis, B. R. J. Am. Chem. Soc. 2000, 122, 4280. (c) Barbarella, G.; Dembech, P. Org. Magn. Res. 1984, 22, 402. 16. Hall, C. M.; Wemple, J. J. Org. Chem. 1977, 42, 2118. 17. Barbarella, G.; Dembech, P.; Garbesi, A.; Fava, A. Org. Magn. Res. 1976, 8, 469. 18. Minozzi, M.; Nanni, D.; Walton, J. C. Organic Letters 2003, 5, 901. 19. Brown, H. C.; Unni, M. K. J. Am. Chem. Soc. 1968, 84, 2902. 20. Kline, M. L.; Beutow, N.; Kim, J. K.; Caserio, M. C. J. Org. Chem. 1979, 44, 1904. 21. Wilson, S. R.; Carmack, M.; Novotny, M.; Jorgenson, J. W.; Whitten, W. K. J. Org. Chem. 1978, 43, 4675.

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Compound 68

Compound 68

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Compound 70

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Compound 70

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Compound 71

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Compound 71

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Compound 72

Compound 72

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Compound 75

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Compound 75

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Compound 75

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Compound 74

Compound 74

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Compound 79

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Compound 79

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Compound 80

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Compound 80

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Compound 80

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Compound 80

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Compound 81

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Compound 81

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Compound 81

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Compound 81

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Compound 73

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Compound 73

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Compound 85

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Compound 85

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The Regiochemistry of Cyclization of Î±-Sulfenyl-, Î±-Sulfinyl-, and Î±

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