β-Sulfinyl acrylate esters as a convenient source of alkane- and arenesulfenate anions

Article abstract of DOI:10.1016/S0040-4039(03)01521-1

Methyl acrylate esters bearing alkane- and arenesulfinyl units on the 2-carbon liberate sulfenate anions upon nucleophilic attack. The sulfenates are readily captured through sulfur alkylation. When a sulfenate derived from R-cysteine is generated, diastereoselective benzylation is observed.

Full text of DOI:10.1016/S0040-4039(03)01521-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6293–6296
b-Sulfinyl acrylate esters as a convenient source of alkane- and
arenesulfenate anions
Jennifer S. O’Donnell and Adrian L. Schwan*
Guelph-Waterloo Centre for Graduate Work in Chemistry, Dept. of Chemistry and Biochemistry, University of Guelph, Guelph,
Ontario, Canada, N1G 2W1
Received 30 May 2003; revised 17 June 2003; accepted 18 June 2003
Abstract—Methyl acrylate esters bearing alkane- and arenesulfinyl units on the 2-carbon liberate sulfenate anions upon
nucleophilic attack. The sulfenates are readily captured through sulfur alkylation. When a sulfenate derived from R-cysteine is
generated, diastereoselective benzylation is observed.
© 2003 Elsevier Ltd. All rights reserved.
Sulfenic acid anions, compounds possessing the general
structure 1,1–3 have well established value in organic
chemistry as precursors to sulfoxides,4–15 sulfena-
mides9,10 and protected16 as well as unprotected thiols.17
Furthermore, these species have been implicated in
important biological mechanisms18–23 particularly as
intermediates in the oxidation of cysteine residues of
proteins18–20 and as a reactive component along the
mechanistic pathway by which thiols activate
leinamycin for DNA alkylation.22,23
Once a sulfenate has been generated in solution, the
common method for establishing its structure is
through alkylation at sulfur1 and characterization of
the resulting sulfoxide. The alkylation can proceed in a
diastereoselective fashion under suitable conditions.24
Furukawa has described particular heteroaromatic
sulfenate anions 3 which can be isolated and character-
ized directly by IR spectroscopy.5 Despite the number
of interesting and useful advances in this area, it would
appear as recently stated,24 that a general procedure to
sulfenic acid anions, one suitable for a large and varied
selection of substituents on sulfur, has yet to be
established.
Modern approaches to selected sulfenate anions involve
sulfur oxidation chemistry,7,24 an addition–elimination
approach,5 ring opening4,6,8,11,13–15 or ring manipulation
protocols,12 a [2,3]-sigmatropic rearrangement17 and a
metal insertion reaction ultimately creating a zinc sulfe-
nate.25 These different methods have produced 1-alke-
nesulfenates,6,8–11,13,14 dienesulfenates,15 (het)arene-
sulfenates5,7,25 and a limited number of alkanesulfe-
nates.5,12,17 In the latter cases, cyclopropanesulfenate (2)
is available through an anionic ring contraction
protocol12 and sulfenates with a homoallyl component
attached to sulfur arise from the aforementioned sigma-
tropic rearrangement.17
While our group was pursuing the Grignard reactions
of optically enriched a,b-unsaturated esters, we noted
that an alkenyl sulfoxide possessing a (E)-2-carbo-
methoxyethenyl unit displayed electrophilic character
toward alkoxide and that chemistry led to a sulfenate
anions.26 For this communication, we have examined
this reaction and demonstrate its general relevance as a
valuable and straightforward method for the generation
of both alkane- and arenesulfenate anions.
The requisite starting materials (4, Table 1) are easily
prepared by treating methyl propiolate with a thiol
under basic conditions.27 This protocol usually affords
both E/Z isomers which are immediately oxidized to a
mixture of isomeric sulfoxides. Experiments show that
the makeup of the isomeric mixture is not critical to the
outcome of the next reaction.
Keywords: sulfenate; sulfoxide; alkylation; sulfinylcysteine.
* Corresponding author. Tel.: (519)-824-4120 X58781; fax: (519)-766-
1499; e-mail: schwan@uoguelph.ca
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01521-1

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J. S. O’Donnell, A. L. Schwan / Tetrahedron Letters 44 (2003) 6293–6296
Table 1. Yields of sulfoxide recovered in the sulfenate generation reactions
Entry
RSO−M+(6)a
Nu−M+ (equiv.)
MeO−Na+ (1.02)
R%X
Yield of 7b
1
2
3
4
5
6
7
8
p-TolSO−Na+
BnBr
BnBr
BnBr
BnBr
MeI
BnBr
MeI
BnBr
BnBr
MeI
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
BnBr
84
50
13–84
77
83
61
63
65
0–27
71
85
88
81
63–80
85
76
75
62
75
p-MeC(O)NHC6H4SO−Na+
BnSO−Na+
n-C6H13SO−Na+
n-C6H13SO−Na+
n-C16H33SO−Na+
n-C16H33SO−Na+
c-C6H11SO−Na+
MeSO−Na+
9
10
11
12
13
14
15
16
17
18
19
20
p-TolSO−Li+
c-C6H11O−Li+ (1.2)
p-TolSO−Li+
cis-p-TolSO−Li+
trans-p-TolSO−Li+
BnSO−Li+
n-C6H13SO−Li+
n-C16H33SO−Li+
MeSO−Li+ (6a)
MeSO−Li+ (6a)
BnSO−Li+ (6b)
CH2(CH2SO−Li+)2 (6c)c
c-C6H11S−Li+ (1.0)
74
21
BnBr
46
a The starting sulfoxide was a mixture of double bond isomers in each case unless otherwise indicated.
b Yield of chromatographically pure sulfoxides recovered from the two step reaction sequence of sulfenate liberation and then alkylation. All new
sulfoxides (7 and 4) gave suitable spectroscopic and analysis data.
c Bissulfenate 6c was liberated with 2 equiv. of c-C6H11S−Li+ and captured with 2 equiv. of PhCH2Br to give two diastereomeric bissulfoxides in
a 3:4 ratio.
d Benzylation of sulfenate 6d gave a mixture of diastereomers, see text.
Three sets of conditions were chosen to effect nucle-
ophile induced liberation of sulfenates from the acrylate
substrates. After base addition, each mixture was
quenched with a reactive alkyl halide and was warmed
slowly to room temperature. The results of several
reactions are outlined in Table 1. Following the lead of
Furukawa,5 sodium methoxide was initially tried. A
commercial source proved convenient, but yields of
isolated sulfoxide rarely reached 80% and the benzyl
and methyl systems routinely gave irreproducible
results. Lithium cyclohexanolate, the nucleophile that
introduced us to this chemistry,26 gave improved yields
and was a reliable source of lithium methanesulfenate
(6a) as judged by dependable sulfoxide yield, yet benzyl
sulfoxide recovery was still somewhat variable. Since
deprotonation a to the sulfinyl was viewed as a possible
competitive reaction, lithium cyclohexanethiolate was
also employed as a more nucleophilic, less basic alter-
native. That reagent successfully liberated benzyl sulfe-
nate 6b and brought about eventual sulfoxide
formation in a reproducible 76% yield. A by-product in
all reaction mixtures was the product of displacement
of the sulfenate unit as indicated in the reaction equa-
tion (Table 1). The alkene so obtained (5) is consistent
with an addition–elimination pathway for this
chemistry.†
† Spectral date for new sulfoxides. Precursor sulfoxide to 6c, one
diastereomer, E,E-configuration. 1H NMR (400 MHz), l: 7.54 (d,
J=15.0 Hz, 2H), 6.57 (d, J=15.0 Hz, 2H), 3.74 (s, 6H), 3.06 (m,
2H), 2.82 (m, 2H), 2.37 (m, 1H), 2.17 (m, 1H); 13C NMR (100.6
MHz), l: 163.9, 148.8, 126.6, 52.3, 50.0, 15.7; IR (CDCl3), cm−1
:
3071, 2954, 1728, 1622, 1437, 1068, 1031, 959; MS (EI), m/z (%):
308 (M+, <1), 191 (5), 175 (100), 102 (8), 89 (11), 59 (8). Anal. calcd
for C11H16O6S2: C, 42.84; H, 5.23. Found: C, 42.67; H, 5.11.
Precursor sulfoxide to 6d, one diastereomer, E-configuration. 1H
NMR (400 MHz), l: 7.63 (d, J=15.0 Hz, 1H), 6.63 (d, J=14.9 Hz,
1H), 5.78 (br m, 1H), 4.58 (br m, 1H), 4.18 (q, J=6.7 Hz, 2H), 3.76
(s, 3H), 3.43 (dd, J=13.3 and 8.6 Hz, 1H), 3.22 (m, 1H), 1.39 (s,
9H), 1.24 (t, J=7.0 Hz, 3H); 13C NMR (100.6 MHz), l: 169.9,
163.9, 155.2, 149.6, 126.0, 80.5, 62.2, 54.3, 52.3, 49.7, 28.1, 14.0; IR
(CDCl3), cm−1: 3428, 3058, 2983, 1746, 1715, 1695, 1061; MS (EI),
m/z (%): no M+ peak, 276 (5), 249 (7), 217 (7), 176 (7), 160 (94), 159
(10), 116 (17), 114 (8), 102 (8), 57 (100). Anal. calcd for
C
14H23NO7S: C, 48.13; H, 6.64; Found: C, 48.13; H, 6.56.
n-Hexadecyl benzyl sulfoxide. 1H NMR (400 MHz), l: 7.32 (m, 5H),
3.97 (ABq, J=12.9 Hz, 2H), 2.55 (t, J=8.0 Hz, 2H), 1.72 (m, 2H),
1.29 (m, 2H), 1.24 (br s, 24H), 0.86 (t, J=6.9 Hz, 3H); 13C NMR
(100.6 MHz), l: 130.1, 130.0, 128.9, 128.3, 58.2, 50.9, 31.9, 29.7,
29.6 (2C), 29.5 (4C), 29.3 (2C), 29.2, 28.8, 22.7, 22.4, 14.1; IR

J. S. O’Donnell, A. L. Schwan / Tetrahedron Letters 44 (2003) 6293–6296
6295
To our knowledge, methanesulfenate (6a) has been
reported once before, and was produced under the very
harsh setting of reducing metal conditions. The reduc-
tion of DMSO affords sodium (or potassium) methane-
sulfenate and a dimsyl anion.28 Clearly a synthetic
manipulation of the sulfenate requires first voiding the
higher reactivity of the dimsyl anion. The formation of
all sulfenates 6 including methanesulfenate in this work
happens under substantially milder conditions and the
trapping chemistry is not affected by the by-product, an
unreactive, comparatively non-polar, push–pull alkene
(5). The addition–elimination sequence of Furukawa5
which is suitable for arenesulfenates was applied to
adamantanesulfenate as the lone alkanesulfenate and
the yield of sulfoxide was only 26%. Overall, the
method reported herein is a general approach for the
formation of alkanesulfenate anions.
tions,34 our system will be the subject of a full investiga-
tion in order to optimize this chemistry and establish
the origin of the stereoinduction.
In summary, we unveil b-alkanesulfinyl acrylates as the
first general source of alkanesulfenates anions. By
demonstrating the broad applicability of this chemistry
we have introduced what appears to be the first bifunc-
tional sulfenate dianion (6c). The discovery that sulfe-
nate 6d shows stereoselection during alkylation opens
the door to a conceptually novel preparative mode for
sulfoxides of S-alkylcysteines.
General experimental: To a solution of a,b-unsaturated
sulfoxide (4, ca. 100 mg, 1 equiv.) in dry THF (1 mL/10
mg) at −78°C was added a solution of c-C6H11S− (or
O−)Li+ in THF (1–2 mL) (or MeO−Na+ as a 25%
solution in MeOH) and stirring proceeded for 20 min.
A −78°C solution of RX (1.2 equiv.) in THF (1–2 mL)
was then added and the reaction mixture stirred
overnight with slow warming to rt. The mixture was
filtered through a bed of Celite,™ and concd crude
sulfoxide (7) was purified by flash chromatography on
SiO2 using EtOAc/hexanes as the eluant.
A number of organometallic sulfenato complexes have
been prepared and characterized29–32 and have shown
utility, for example, as models for nickel containing
enzymes.29 Their preparation can be viewed as being
achieved through complexation of a sulfenate with a
metal although they are commonly arrived at through
sulfur oxidation of thiolato complexes.29–32 Bifunctional
species 6c and 6d or close derivatives of them may
possess the necessary structure to serve as metal chelat-
ing agents and accordingly introduce a new preparative
motif for these important organometallic compounds.
Acknowledgements
The authors thank NSERC of Canada for generously
funding this research. J.S.O. thanks the Ontario Gov-
ernment for a Science and Technology Graduate
Scholarship.
As a final note, amino acid derivative 8 was isolated in
46% yield, in a diastereomeric ratio of 82:18 (Eq. (1)).
Crystallization of that sample gave 73% mass recovery
(ca. 55 mg) of an optically pure (1H NMR) material
([h]2D3=−69.4° (CHCl3)). The absolute configuration of
enantiopure 8 has been tentatively assigned (RS,RC),
based on comparison to a related compound.33 Such
diastereoselective alkylations have been observed by the
Perrio group who noted that sulfenate 9 could be
alkylated with dr’s of ca. 4:1 to 49:1. Those authors
suggest that internal complexation contributes to the
observed selectivity.24 Since S-alkylcysteine sulfoxides
are important substances with a variety of applica-
References
1. Hogg, D. R. Chemistry of sulfenic acids and esters. The
Chemistry of Sulphenic Acids and Their Derivatives;
Wiley-Interscience: Toronto, 1990; p. 361.
2. Hogg, D. R.; Robertson, A. J. Chem. Soc., Perkin Trans.
1 1979, 1125.
3. Hogg, D. R.; Robertson, A. Tetrahedron Lett. 1974, 15,
3783.
4. Blake, A. J.; Cooke, P. A.; Kendall, J. D.; Simpkins, N.
S.; Westaway, S. M. J. Chem. Soc., Perkin Trans. 1 2000,
153.
(CDCl3), cm−1: 2928, 2855, 1029, 791; MS (CI, NH3), m/z (%): 365
((M+H)+, 53), 292 (33), 292 (86), 291 (28), 289 (12), 258 (92), 257
(13), 256 (100), 176 (14), 116 (21), 91 (92). Anal. calcd for
5. Furukawa, N.; Konno, Y.; Tsuruoka, M.; Ogawa, S.
C23H40OS: C, 75.76; H, 11.06; Found: C, 75.59; H, 10.96.
Heteroat. Chem. 1992, 3, 495.
1,3-Bis(benzylsulfinyl)propane, mixture of diastereomers. 1H NMR
(400 MHz), l: 7.35 (m 6H), 7.26 (m, 4H), 3.98 (ABq, J=12.0 Hz,
4H, major isomer), 3.97 (ABq, J=12.9 Hz, 4H, minor isomer), 2.68
(m, 4H), 2.27 (m, 2H); 13C NMR (100.6 MHz), l: 129.9, 129.3,
6. Schwan, A. L.; Lear, Y. Sulfur Lett. 2000, 23, 111.
7. Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997,
62, 8626.
8. Refvik, M. D.; Froese, R. D. J.; Goddard, J. D.; Pham,
H. H.; Pippert, M. F.; Schwan, A. L. J. Am. Chem. Soc.
1995, 117, 184.
129.0, 128.5, 58.3, 58.2, 49.1, 48.9, 16.6, 16.1; IR (CH2Cl2), cm−1
:
3054, 2987, 1422, 1255, 1045, 896. Anal. calcd for C17H20O2S2: C,
63.71; H, 6.24; Found: C, 63.52; H, 6.28.
Sulfoxide 8. [h]2D3: −69.4° (c 1.08, CHCl3); 1H NMR (400 MHz), l:
7.33 (m, 5H), 5.72 (br d, J=7.8 Hz, 1H), 4.65 (br m, 1H), 4.19 (q,
J=7.1 Hz, 2H), 4.04 (ABq, J=13.0 Hz, 2H), 3.09 (ABX pattern,
9. Schwan, A. L.; Refvik, M. D. J. Chem. Soc., Chem.
Commun. 1995, 1949.
10. Refvik, M. D.; Schwan, A. L. Tetrahedron 1996, 52,
8387.
11. Schwan, A. L.; Pippert, M. F.; Pham, H. H.; Roche, M.
R. J. Chem. Soc., Chem. Commun. 1993, 1312.
12. Jones, D. N.; Kogan, T. P.; Newton, R. F.; Smith, S. J.
Chem. Soc., Chem. Commun. 1982, 589.
J
AB=13.0 Hz, JAX=7.8 Hz, JBX=3.4 Hz, 2H) 1.42 (s, 9H), 1.23 (t,
J=7.1 Hz, 3H); 13C NMR (100.6 MHz), l: 170.3, 155.3, 130.1,
129.3, 129.0, 128.6, 80.3, 62.0, 59.0, 52.0, 50.2, 28.2, 14.0; IR
(CDCl3), cm−1: 3432, 3033, 2983, 2934, 1740, 1711, 1503, 1369,
1311, 1254, 1161, 1029, 855, 790. Anal. calcd for C17H25O5NS: C,
57.44; H, 7.03; Found: C, 57.66; H, 7.17.

6296
J. S. O’Donnell, A. L. Schwan / Tetrahedron Letters 44 (2003) 6293–6296
13. Bonini, B. F.; Maccagnani, G.; Mazzanti, G.; Piccinelli,
P. Tetrahedron Lett. 1979, 20, 3987.
25. Maezaki, N.; Yoshigami, R.; Maeda, J.; Tanaka, T. Org.
Lett. 2001, 3, 3627.
14. Bonini, B. F.; Maccagnani, G.; Mazzanti, G.; Zani, P.
26. Strickler, R. R.; Motto, J. M.; Humber, C. C.; Schwan,
A. L. Can. J. Chem. 2003, 81, 423.
27. Schwan, A. L.; Strickler, R. R.; Lear, Y.; Kalin, M. L.;
Rietveld, T. E.; Xiang, T.-J.; Brillon, D. J. Org. Chem.
1998, 63, 7825.
28. O’Connor, D. E.; Lyness, W. I. J. Org. Chem. 1965, 30,
1620.
29. Grapperhaus, C. A.; Darensbourg, M. Y. Acc. Chem.
Res. 1998, 31, 451.
30. Galvez, C.; Ho, D. G.; Azod, A.; Selke, M. J. Am. Chem.
Soc. 2001, 123, 3381.
31. Heinrich, L.; Li, Y.; Vaissermann, J.; Chottard, J.-C. Eur.
J. Inorg. Chem. 2001, 1407.
32. Heinrich, L.; Mary-Verla, A.; Li, Y.; Vaissermann, J.;
Chottard, J.-C. Eur. J. Inorg. Chem. 2001, 2203.
33. Nakamura, S.; Goto, K.; Kondo, M.; Naito, S.; Bando,
M.; Kido, M.; Shishido, K. Bioorg. Med. Chem. Lett.
1996, 6, 937.
34. Holland, H. L.; Brown, F. M.; Johnson, D. V.; Kerridge,
A.; Mayne, B.; Turner, C. D.; van Vliet, A. J. J. Mol
Catal. B-Enzym. 2002, 17, 249.
Gazz. Chim. Ital. 1990, 120, 115.
15. Crumbie, R. L.; Ridley, D. D. Aust. J. Chem. 1981, 34,
1017.
16. Schwan, A. L.; Refvik, M. D. Synlett 1998, 96.
17. Fokin, A. A.; Kushko, A. O.; Kirij, A. V.; Yurchenko, A.
G.; Schleyer, P.v. R. J. Org. Chem. 2000, 65, 2984.
18. Poole, L. B.; Ellis, H. R. Method. Enzymol. 2002, 348,
122.
19. Boschi-Muller, S.; Azza, S.; Sanglier-Cianferani, S.; Tal-
fournier, F.; Van Dorsselear, A.; Branlant, G. J. Biol.
Chem. 2000, 275, 35908.
20. Crane, E. J., III; Parsonage, D.; Claiborne, A. Biochem-
istry 1996, 35, 2380.
21. Ziegler-Skylakakis, K.; Nill, S.; Pan, J. F.; Andrae, U.
Environ. Mol. Mutagen. 1998, 31, 362.
22. Chatterji, T.; Kizil, M.; Keerthi, K.; Chowdhury, G.;
Pospisil, T.; Gates, K. S. J. Am. Chem. Soc. 2003, 125,
4996.
23. Breydo, L.; Gates, K. S. J. Org. Chem. 2002, 67, 9054.
24. Sandrinelli, F.; Perrio, S.; Averbach-Pouchot, M.-T. Org.
Lett. 2002, 4, 3619.