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. Author manuscript; available in PMC: 2010 Sep 23.
Published in final edited form as: Tetrahedron Lett. 2009 Sep 23;50(38):5424–5427. doi: 10.1016/j.tetlet.2009.07.063

Radical-mediated thiodesulfonylation of the vinyl sulfones: Access to (α-fluoro)vinyl sulfides

Pablo R Sacasa 1, Jessica Zayas 1, Stanislaw F Wnuk 1,*
PMCID: PMC2748331  NIHMSID: NIHMS133263  PMID: 20161068

Abstract

Radical-mediated thiodesulfonylation of the vinyl and (α-fluoro)vinyl sulfones, derived from aldehydes and ketones, with aryl thiols in organic or aqueous medium provided access to vinyl and (α-fluoro)vinyl sulfides. The vinyl sulfides were formed predominantly with E stereochemistry independent of the stereochemistry of the starting vinyl sulfones.

Keywords: Fluoroalkenes, Radical reactions, Vinyl sulfides, α-Fluoro vinyl sulfides, Vinyl sulfones

Vinyl sulfides are valuable tools in organic synthesis and are used as enolate ion equivalents,1 as components of [2+2] cyclo-additions,2 and as substrates in transition metal catalyzed carbon-carbon bond forming reactions.3 Methods for the synthesis of 1-alkenyl sulfides include Wittig reaction,4 ionic and radical additions of thiols to alkynes,5 coupling of 1-alkenyl halides with thiols,6–9 and transition metal catalyzed anti-Markovnikov hydrothiolation9–12 of alkynes with arenethiols and alkanethiols to produce E isomers, including hydrothiolation in water medium.13

Vinyl sulfonium ions, generated via the biological methylation of the corresponding vinyl sulfides act as inhibitors of thioether S-methyltransferase14 and proteolytic enzyme papain.15 They are highly reactive towards nucleophiles and bind covalently to DNA, RNA and proteins in vivo.16 Moreover, vinyl sulfonium salts are more electrophilic than the corresponding vinyl sulfones, which are known for their ability to inhibit cysteine proteases.17,18

The (α-halo)vinyl sulfides can be prepared by Wittig-Horner reactions with diethyl chloro(phenylthio)-methanephosphonate19 or by addition of the hydrogen halides (HI, HBr and HCl) to acetylenic sulfides (chalcogenides).20 The regioselectivity and stereoselectivity of such additions were improved when equivalent quantities of hydrogen halide, generated in situ from trimethylsilyl halides and anhydrous methanol, were utilized21 instead of excess aqueous HX or saturated gaseous HX in benzene. The (α-halo)vinyl sulfides have been employed in Stille,21,22 Negishi22 and Sonogashira23 couplings, Friedel-Crafts vinylation,24 and other transformations.21,25,26

Removal of the sulfonyl group from the vinylic carbon is usually achieved by reductive methods27 or by addition-elimination processes in which the sulfonyl group is replaced, for example, with tributylstannyl substituent.28–30 The latter can be then conveniently removed by protiodestanylation or utilized in other synthetic transformations.29,31 Heating of the vinyl arylsulfones with tris(trimethylsilyl)silane or germane at reflux in benzene or toluene effected substitution of a sulfonyl group with a silyl or germyl group to give vinyl silanes or germanes including α-fluoro substituded analogues.32,33

Herein, we report stereoselective radical-mediated thiodesulfonylations of vinyl and (α-fluoro)vinyl sulfones with aryl thiols to provide access to vinyl and (α-fluoro)vinyl sulfides. Such thiodesulfonylation provides a flexible alternative to the hydrothiolation of alkynes with thiols under radical or metal catalysis conditions. It also offers convenient preparations of (α-fluoro)vinyl sulfides – a class of interesting fluoroalkenes which remain unexplored.34 The thiodesulfonylation can be also viewed as reductive deoxygenation of sulfones to the corresponding sulfides - a transformation which requires harsh conditions incompatible with most functional groups.35

Treatment of the sulfonyl-stabilized enolates generated from diethyl (phenylsulfonyl)methylphoshonate with aliphatic and aromatic aldehydes and ketones 1a–g gave the corresponding E-vinyl sulfones 2a–f and vinyl sulfone 2g (72–95%, Scheme 1).32 Analogous treatment of 1a–h with diethyl fluoro(phenylsulfonyl)methylphoshonate produced (α-fluoro)vinyl sulfones 3a–h.31,32

Scheme 1.

Scheme 1

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Synthesis of E-vinyl and (E/Z)-(α-fluoro)vinyl sulfones

Reaction of the conjugated vinyl sulfone E-2a with benzenethiol (2 equiv.) in the presence of ACCN as a radical initiator at reflux in toluene (12 h) produced the vinyl sulfide 4a (61%; Scheme 2; Table 1, entry 1). The radical thiodesulfonylation was also effective in aqueous36 medium. Thus, treatment of E-2a with benzenethiol/ACCN or AIBN in water (100 °C) produced sulfide 4a in 71% and 65% yields (entry 2). Replacement of water with MeOH or EtOH produced a homogenous reaction mixture and did not affect the yield of the thiodesulfonylation reaction (entry 3). The reaction has a general character since the presence of the alkyl (series b), electron-withdrawing (CF3, series c) or electron-donating (MeO, series d) groups on the phenyl ring attached to the double bond had only modest effect on rate and yield of thiodesulfonylation reactions with benzenethiol (entries 11–15, 18–20).

Scheme 2.

Scheme 2

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Thiodesulfonylation of vinyl sulfones. Synthesis of vinyl sulfides

Table 1.

Synthesis of vinyl sulfides via thiodesulfonylation of vinyl sulfones.

Entry Sulfone Methoda Productb (E/Z)c Yieldd
1 2a (E) A 4a (95:5) 61
2 2a (E) B 4a (95:5) 71e, 65e,f, 10e,g
3 2a (E) C 4a (95:5) 70e
4 2a (E) C 4a (95:5) 20e,h
5 2a (E) B 5a (95:5) 61
6 2a (E) B 6a (98:2) 55
7 2a (E) C 7a (95:5) 85
8 2a (Z) A 4a (95:5) 65e
9 2a (Z) B 4a (95:5) 95e
10 2a (Z) C 4a (95:5) 70, (80e)
11 2b (E) A 4b (85:15) 55e
12 2b (E) B 4b (85:15) 54, (63e)
13 2c (E) A 4c (95:5) 59, (70e), 5e,g
14 2c (E) B 4c (95:5) 85e, 80e,f, 50g
15 2c (E) C 4c (95:5) 94e, 96e,i
16 2c (E) B 5c (95:5) 58
17 2c (E) B 6c (95:5) 40, (55e)
18 2d (E) A 4d (75:25) 55
19 2d (E) B 4d (75:25) 64e
20 2d (E) C 4d (85:15) 70e
21 2e (E) A,B,C 4e n.r.
22 2f (E) A,B,C 4f n.r.
23 2g B 4g 55
24 2g C 4g 76e
25 2g C 5g 62
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a

Method A: thiol/ACCN/toluene/110 °C/12 h; Method B: thiol/ACCN/H2O/100 °C/10 h; Method C: thiol/ACCN/MeOH/65 °C/10 h.

b

Reactions were performed on 0.1–1.0 mmol scale of sulfones (0.05 mM) with 1.25–2.0 equiv. of thiols and 0.1–0.5 equiv. of ACCN or AIBN.

c

Determined by GC-MS and/or 1H NMR.

d

Isolated yield.

e

Based on GC-MS.

f

AIBN instead of ACCN.

g

Without ACCN.

h

Disulfide instead of thiol, 16 h.

i

In EtOH.

Treatment of the vinyl sulfones derived from the aliphatic aldehydes (series e and f) with benezenethiol/AIBN or ACCN under protic and aprotic conditions did not yield the corresponding vinyl sulfides (entries 21–22). However, sulfone 2g, derived from cyclohexanone, underwent thiodesulfonylation reaction affording sulfide 4g (entries 23–24), demonstrating that the thiodesulfonylation can serve as a convenient method for the synthesis of the trisubstituted vinyl sulfides.

Thermal reaction of E-2a with benzenethiol without radical initiators produced 4a but in lower yield (entry 2). Likewise, the replacement of benzenethiol with phenyl disulfide also effected conversion of the sulfone 2a to the sulfide 4a in low yield, although reaction required longer time (entry 4). However, reaction of 2a with phenyl disulfide without radical initiator failed to afford 4a.

Treatment of E-2a with 4-methylbenzenethiol or 4-aminobenzenethiol in H2O/ACCN produced the corresponding vinyl sulfides 5a (61%) and 6a (55%) (entries 5–6). Analogously, E-2c was converted to 5c and 6c (entries 16–17). Thiodesulfonylation of E-2a with 4-mercaptobenzoic acid (R2 = CO2H) in MeOH produced the methyl ester 7a (85%; entry 7). Thus, thiodesulfonylation protocol is compatible with amino and carboxylate functional groups vulnerable to the oxidative and reductive procedures. Attempted thiodesulfonylations of 2a or 2c, as well as 3a, with alkanethiols (2-mercaptoethanol, 1-propanethiol) or thioacetic acid under radical conditions did not produce the corresponding vinyl sulfides.

Radical-mediated thiodesulfonylation of the vinyl sulfones 2 occurred basically with retention of the E stereochemistry although small amounts of the Z isomers were detectable by GC-MS and 1H NMR of the crude reaction mixtures (Table 1). In order to study stereochemical outcome of the thiodesulfonylation reactions Z-vinyl sulfone 2a was prepared by anti-Markovnikov addition of PhSH/NaOH to phenylacetylene followed by the oxidation of the resulting (Z)-2-phenyl-1-phenylthioethene.37 Treatment of Z-2a with PhSH in aqueous or organic medium produced sulfide 4a in very good yields with inversion of stereochemistry (E/Z, 95:5; entries 8–10). Thus, the vinyl sulfides are formed predominantly with E stereochemistry independent of the stereochemistry of the starting vinyl sulfones.

Radical thiodesulfonylation permitted synthesis of the sparsely developed34 (α-fluoro)vinyl sulfides 8–11 in high yields (Scheme 3). Thus, treatment of 3a (E/Z, 96:4) with benzenethiol in organic or protic medium in the presence of ACCN gave E/Z-8a in good to excellent yields with the “overall” retention of stereochemistry (Table 2, entries 1–2). Thiodesulfonylation appears fairly general since sulfones 3b, 3c and 3d with the alkyl (Me), electron-withdrawing (CF3) or electron-donating (MeO) substituents on the phenyl ring attached to the double bond also produced (α-fluoro)vinyl sulfides (entries 4–6, 9–10).38 Thiodesulfonylation of α-fluoro sulfone 3b (E/Z, 84:16; 0.5 equiv.) with PhSH (1.0 equiv.; Method C) in the presence of the parent α-H sulfone E-2b (0.5 equiv.) showed that product 8b [30 min. (70%; E/Z, 93:7; with all Z-3b being consumed); 1 h (88%; E/Z, 93:7); 2h (95%; E/Z, 93:7)] is formed faster than 4b [30 min (35%, E/Z, 90:10), 1 h (45%, E/Z, 88:12); 2 h (48%; E/Z, 88:12)].

Scheme 3.

Scheme 3

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Thiodesulfonylation of (E/Z)-(α-fluoro)vinyl sulfones. Synthesis of (E/Z)-(α-fluoro)vinyl sulfides

Table 2.

Synthesis of (α-fluoro)vinyl sulfides via thiodesulfonylation of (α-fluoro)vinyl sulfones.

Entry Sulfone Methoda Productb (E/Z)c Yieldd
1 3a (96:4) A 8a (92:8) 92
2 3a (96:4) B 8a (94:6) 65e
3 3a (94:4) A 10a (83:17) 50
4 3b (86:14) A 8b (93:7) 82, 62f
5 3b (86:14) B 8b (92:8) 56
6 3b (86:14) C 8b (92:8) 92 f
7 3b (86:14) C 9b (92:8) 90
8 3b (86:14) C 11b (94:6) 69 f
9 3c (90:10) B 8c (93:7) 60f, 72
10 3d (97:3) B 8d (93:7) 73
11 3e (88:12) B 8e (70:30) 10g
12 3f (84:16) C 8f (70:30) 12h
13 3g B 8g 65
14 3h (57:43) B 8h (50:50) 58
15 3h (57:43) C 8h (50:50) 68
16 3h (100:0) C 8h (50:50) 85
17 3h (0:100) C 8h (33:67) 70
18 3h (100:0) C 9h (64:36) 96
19 3h (57:43) B 9h (50:50) 59
20 3h (57:43) C 11h (55:45) 42
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a

Method A: thiol/ACCN/toluene/110 °C/6 h; Method B: thiol/ACCN/H2O/100 °C/6 h; Method C: thiol/ACCN/MeOH/65 °C/5 h.

b

Reactions were performed on 0.1–0.5 mmol scale of sulfones (0.05 mM) with 1.25–2.0 equiv. of thiols and 0.25–0.50 equiv. of ACCN or AIBN.

c

Determined by GC-MS and 1H or 19F NMR.

d

Isolated yield.

e

Reaction with phenyl disulfide gave 8a (55%, Methods B or C).

f

AIBN instead of ACCN.

g

83% based on Z-3e.

h

75% based on Z-3f.

Treatment of the unconjugated sulfone 3e or 3f with benzenethiol produced the vinyl sulfide 8e or 8f in low yields (entries 11–12). Careful analysis of the crude reaction mixture indicated that Z-3e or Z-3f isomers were consumed during reactions to produce primarily E-sulfides while the E-sulfones remained mostly unreacted. These results are in agreement with the lack of reactivity of E-2e and E-2f vinyl sulfones. Sulfone 3g produced tetrasubstituted sulfide 8g (entry 13).

Reaction of 3h (E/Z, 57:43) with benzenethiol also afforded tetrasubstituted (α-fluoro)vinyl sulfide 8h (E/Z, 50:50; entries 14–15). Thiodesulfonylation was not stereospecific since reactions of pure E-3h or Z-3h with benzenethiol also gave 8h as mixture of E/Z-isomers (entries 16–17). Thiodesulfonylation occurred with other aromatic thiols to yield various vinyl sulfides (entries 3,7–8, 18–20). It is noteworthy that hydrothiolation approaches are inapplicable for the synthesis of (α-fluoro)vinyl sulfides since the 1-fluoroalkynes are unstable and virtually unknown.39

Desulfonylation occurred probably via β-elimination of the sulfonyl radical from the radical intermediates formed after addition of PhS• to vinyl sulfones (presumably via a radical addition-elimination mechanism).30,32 Lack of stereochemistry is probably the result of cis-trans isomerization of a radical intermediate leading predominantly to the formation of the more stable E isomers under thermal conditions.5

In summary, we have developed radical-mediated thiodesulfonylations of the vinyl and (α-fluoro)vinyl sulfones with aryl thiols to provide access to vinyl and (α-fluoro)vinyl sulfides. This method offers for the first time a general and bench-friendly procedure for the synthesis of (α-fluoro)vinyl sulfides.

Acknowledgments

This investigation was supported by award SC1CA138176 from NIGMS and NCI. PRS and JZ were sponsored by the MBRS RISE program (NIGMS; R25 GM61347).

Footnotes

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