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

Article abstract of DOI:10.1021/jo0497306

A study of the cyclization of α-sulfenyl-, α-sulfinyl-, and α-sulfonyl-5-hexenyl and 5-methyl-5-hexenyl radicals reveals a unique contrast in the mode of ring closure of the radicals. In the case of the 5-hexenyl radicals, the sulfinyl-substituted species displays unexpected regioselectivity relative to its analogues. Thus, while the α-S- and α-SO₂-5-hexenyl radicals give measurable and increasing quantities of 6-endo product, the α-sulfinyl species cyclizes with high selectivity (95.5:4.5) via a 5-exo mode. By contrast, ring closure of the 5-methyl-5-hexenyl radicals is found to give substantially the 6-endo product in all cases. It is the α-sulfonyl-5-methyl-5-hexenyl radical that now exhibits high regioselectivity (97.5:2.5) for 6-endo closure: an illustration of the synthetic value of this observation is the independent synthesis of the model cyclohexyl sulfone 61 in high yield. It is found that ring closure under the conditions employed occurs irreversibly in all cases.

Full text of DOI:10.1021/jo0497306

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
Ern.Della@flinders.edu.au
Table of Contents
1. Experimental Section
S2
Compounds
49
68
S2
S3
S3
S4
S5
S5
Attempted synthesis of 65
Attempted synthesis of 76
92
94
2. References
S5
S7
3. Selected Spectra
Compounds
68, 70, 71, 72, 75, 74, 79, 80, 81, 73, 85
S7- S20
S22-S32
S32-S44
S46-S48
S48-S50
S51-S66
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
Supporting Information Part ONE
S1

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.1
Thiapyran was commercially available material. 2-Methyl-1,4-butanediol,2 2,2-dimethyl-1,4-
butanediol,3 prepared from the corresponding diesters by standard treatment with LiAlH4, and 2-
methylene-1,4-butanediol4 by treatment with DIBAL, had physical properties consistent with literature
data. The diols were converted into the dimesylates under the usual conditions5 and had physical
properties identical with those reported: 2-methyl-1,4-butanediyl dimesylate,6 2,2-dimethyl-1,4-
butanediyl dimesylate,7 and 2-methylene-1,4-butanediyl dimesylate.8 Treatment of the first two
dimesylates with Na2S.2H2O as described9 afforded the corresponding tetrahydrothiophene which had
physical data in accord with literature values: 13,9b 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
literature data: 16,11 17,12 19,13 20,14 51,12,13 52,15 5413 and 55.9b, 15b,c Methyl thioacetate, synthesised by
treatment of thioacetic acid with NaH followed by iodomethane, had physical properties identical with
those published.16
Supporting Information Part ONE
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4-Methylthiopyran (49). 3-methyl-1,5-pentanediol9b was treated with 2 equivs of methanesulfonyl
5
1
chloride as described to give 3-methyl-1,5-pentanediyl dimesylate: H 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
treated with a solution of Na2S.2H2O (5.60 g, 49 mmol) in 95% EtOH (20 mL) as described.9 Work up
and distillation of the product (Kugelrohr: 55oC/18mm: lit.3 54oC/22mm) yielded 4-methylthiopyran 49
as a clear colorless oil (2.2 g, 78%): 1H 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). 13C NMR (CDCl3) δ 35.9 (overlapping
signals 2 x CH2), 32.2, 28.7 (overlapping signals 2 x CH2), 23.0 (lit17 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
compound 68 as a colorless oil (3.02 g, 70%): 1H 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); 13C 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. 18
Supporting Information Part ONE
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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
1
fractions: (i) (bp. 50oC/18mm) identified as 1-methoxy-2-sulfenyl-5-hexene (70): H 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); 13C NMR (CDCl3) δ 137.1, 116.3,55.8, 34.4, 30.4. (ii) (bp.110-120oC/18mm) identified as bis-3-
1
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); 13C 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-5-
hexene (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.
Supporting Information Part ONE
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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
removed under reduced pressure yielding an oil. Distillation (Kugelrohr: 112-114oC/760mm); lit19 bp
o
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), 13C NMR (CDCl3) δ 136.8, 115.8, 33.4, 33.3, 15.3; lit NMR.20 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. Lit21 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:21
:
1H 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); 13C 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).
Supporting Information Part ONE
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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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