Synthesis, structure, and reactivities of a stable primary-alkyl-substituted sulfenic acid

Article abstract of DOI:10.1246/cl.150046

A primary-alkyl-substituted sulfenic acid was synthesized and isolated by taking advantage of a cavity-shaped steric protection group and characterized by X-ray crystallographic analysis. The reactivities of the sulfenic acid toward various reagents were

Full text of DOI:10.1246/cl.150046

Received: January 19, 2015 | Accepted: February 4, 2015 | Web Released: February 14, 2015
CL-150046
Synthesis, Structure, and Reactivities of a Stable Primary-alkyl-substituted Sulfenic Acid
Michihiro Ishihara, Noriaki Abe, Shohei Sase, and Kei Goto*
Department of Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
2-12-1 Ookayama, Meguro-ku, Tokyo 152-8551
(E-mail: goto@chem.titech.ac.jp)
A primary-alkyl-substituted sulfenic acid was synthesized
X
and isolated by taking advantage of a cavity-shaped steric
protection group and characterized by X-ray crystallographic
analysis. The reactivities of the sulfenic acid toward various
reagents were investigated, and it was demonstrated experimen-
tally and theoretically that the addition of a sulfenic acid to
a simple alkene to produce the corresponding sulfoxide is
thermodynamically more favorable than the reverse reaction, i.e.
syn-β-elimination of a sulfoxide.
CH2
BpqCH2–X
Chart 1. Structure of BpqCH2X.
i
ii
iii
BpqCH2Br
BpqCH2S-t-Bu
2 (81%)
BpqCH2S(O)-t-Bu
3 (89%)
BpqCH2SOH
1
4 (99%)
Sulfenic acids (RSOH) have been recognized as important
intermediates not only in organosulfur chemistry but also in
biological systems.1,2 They are the reversibly oxidized form of
cysteine thiols, which play crucial roles as a catalytic center in
enzymes and as a sensor of oxidative stress in enzymes and
transcriptional regulators.2 However, much of our knowledge of
the chemistry of sulfenic acids has been obtained in quite an
indirect and speculative manner because they are notoriously
unstable in artificial systems because of very rapid self-
condensation, leading to the corresponding thiosulfinates
(RSS(O)R) (Scheme 1).1
Scheme 2. Synthesis of sulfenic acid 4. Reagents and
conditions; (i) t-BuSH, NaH, THF, rt; (ii) mCPBA, CH2Cl2,
0 °C; (iii) solid state, 180 °C, in vacuo.
S
O
C
For the synthesis of stable sulfenic acids, kinetic stabiliza-
tion using bulky substituents has been successfully employed,
and isolation of tertiary-alkyl derivatives3 as well as aromatic
derivatives4 has been achieved by taking advantage of appro-
priate steric protection groups. However, there has been no
example of the isolation of a primary-alkyl-substituted sulfenic
acid although it is the most relevant as chemical models of
sulfenic acids derived from cysteine residues in protein.2 As for
thermodynamically stabilized sulfenic acids, some solution-
stable sulfenic acids stabilized by strong electron-withdrawing
effects of perfluoroalkyl (RCF2CF2) groups have been reported
recently although they have not been isolated.5 Here, we report
the synthesis and isolation of a stable primary-alkyl-substituted
sulfenic acid by taking advantage of a cavity-shaped steric
protection group. We also demonstrated that addition reactions
of sulfenic acids to simple alkenes are thermodynamically more
favorable processes than the reverse reactions, i.e. syn-β-
elimination of sulfoxides.
Figure 1. ORTEP drawing of 4 (50% probability). Hydrogen
atoms are omitted for clarity. Selected bond lengths (¡) and
bond angle (degree) for 4: C-S, 1.813(4); S-O, 1.631(4); C-S-
O, 100.96(18).
to undergo facile bimolecular decomposition. It is expected that
the peripheral steric protection effect due to this substituent will
also efficiently suppress the self-condensation of a sulfenic acid.
As the precursor of a sulfenic acid bearing the BpqCH2 group,
t-butyl sulfoxide 3 was prepared according to Scheme 2.
Thermolysis of 3 in the solid state at 180 °C in vacuo afforded
the desired sulfenic acid 4 almost quantitatively, which was
isolated as colorless crystals in 99% yield. This is the first
example of the isolation of a primary-alkyl-substituted sulfenic
acid.
1
The H NMR (C6D6) spectrum of 4 showed the signal of
Recently, we have developed a primary-alkyl steric protec-
tion group, a BpqCH2 group (Chart 1), with a cavity-shaped
framework and applied it to the stabilization of primary-alkyl-
substituted derivatives of a sulfenyl iodide (X = SI)6a and a
selenenic acid (X = SeOH),6b both of which are usually known
SOH at ¤ = 2.02. It is readily exchangeable with D2O. The IR
spectrum (CHCl3) showed a sharp O-H stretching absorption at
3398 cm indicating that 4 has the sulfenyl form (R-S-O-H)
¹1
rather than the sulfoxide form (R-S(O)-H) in solution. The
structure of 4 was finally established by X-ray crystallographic
analysis (Figure 1).7 The CH2-S-O-H moiety is incorporated
within the cavity and effectively protected by the peripheral
moiety of the substituent. The S-O bond length of 4 (1.631(4) ¡)
is comparable to those of the kinetically stabilized sulfenic acids
reported so far.3c,4c Furthermore, the bond length is significantly
longer than those of sulfoxides,8 showing that 4 has the sulfenyl
– H2O
2 R–SOH
R–S–S(O)–R
Scheme 1. Facile self-condensation of a sulfenic acid to form
a thiosulfinate.
Chem. Lett. 2015, 44, 615–617 | doi:10.1246/cl.150046
© 2015 The Chemical Society of Japan | 615

n-BuSH (4 equiv)
Table 1. Reaction of 4 with alkenes
BpqCH2–S–S–n-Bu
5 (93%)
C6D6, 80 °C, 232 h
H
R'
BpqCH2–SOH
PhCH2NH2 (11 equiv)
CDCl3, 60 °C, 310 h
H
H
R'
S
H
S
R'
H
BpqCH2–S–NHCH2Ph
4
H
(4 equiv)
CDCl3
6 (84%)
BpqCH2–SOH
+
CH2Bpq
BpqCH2
4
O
O
Scheme 3. Reactions of sulfenic acid 4 with 1-butanethiol and
benzylamine. All yields were estimated by H NMR by using a
1
7
8
Entry Alkene
Conditions 7 (Yield/%)a 8 (Yield/%)a
(TMS)2CH2 as an internal standard.
1
2
3
R¤ = n-Bu
R¤ = Ph
R¤ = CO2Me rt, <1 h
60 °C, 64 h
60 °C, 21 h
7a, 95
7b, 94
7c, NDb
8a, NDb
8b, NDb
8c, 99
R
R
R
R
R
R
R
R
R'
S
H
+
R'–SOH
aEstimated by 1H NMR using (TMS)2CH2 as an internal standard.
bNot detected.
O
Scheme 4. Syn-β-elimination of sulfoxides and addition of
sulfenic acids to alkenes.
H
S
Me
Me
S
H
Me–SOH
+
form even in the crystalline state. The shortest intermolecular
S£S distance (7.76 ¡) is much longer than the sum of van der
Waals radii of the sulfur atoms, showing that 4 is monomeric in
the crystalline state.
Sulfenic acid 4 showed remarkable thermal stability both in
the solid state and in solution. In the solid state, it decomposed
at high temperature (220.5-222.0 °C). In benzene-d6, no decom-
position of 4 was observed after heating at 80 °C in a sealed
tube for 7 d. This indicates that the peripheral steric protection
provided by the BpqCH2 group is efficient enough to prevent
a sulfenic acid inside the cavity from undergoing self-
condensation.9
The reactions of sulfenic acids with thiols and amines have
been postulated to be important from a biological point of view.2
We previously reported the reactions of stable sulfenic acids
bearing an aromatic substituent with these reagents.4a,4c The
primary-alkyl derivative 4 was also found to react with
1-butanethiol and benzylamine to produce the corresponding
disulfide 5 and sulfenamide 6, respectively, in high yields
(Scheme 3).
Me
or
Me
Me
O
B
O
A
kcalmol−1
30
anti-Markovnikov-addition
Markovnikov-addition
20
10
17.4
TS
3.5 kcal mol-1
MeSOH
+
MeCH=CH2
13.7
0
0.0
–3.4
–3.6
B
A
–7.7
–9.0
–10
–20
–30
17.3 kcal mol–1
20.8 kcal mol–1
Figure 2. Energy profiles of the reaction of MeSOH with
propene to give sulfoxides at B3LYP/6-31G(d) level.
The synthesis of alkenes by syn-β-elimination of sulfox-
ides1,10 has been employed as an important synthetic method,
and the reaction generally proceeds on heating to generate
sulfenic acids concomitantly (Scheme 4).
While β-elimination of sulfenic acids from sulfoxides is
usually carried out under heating, the present results suggest that
the addition of sulfenic acids to alkenes is thermodynamically
more favorable than the elimination. To elucidate the energy
profile and regioselectivity of the addition of a sulfenic acid to a
simple alkene, DFT calculations on the reaction of MeSOH with
propene were performed (Figure 2). The calculation showed that
the addition of MeSOH to propene is more exothermic than the
reverse reaction, i.e. the β-elimination from the sulfoxides. In
terms of the regioselectivity, the formation of the Markovnikov
adduct A was found to be more favorable than the anti-
Markovnikov adduct B. These calculations are consistent with
the experimental results, corroborating that, in the reaction of
sulfenic acid and alkenes, the addition reaction is thermody-
namically more favorable than the reverse elimination process.
It is reasonably explained that, in the usual alkene syntheses
by thermal syn-β-elimination of sulfoxides (Scheme 4, forward
reaction), the resulting sulfenic acids are so labile that they
readily undergo irreversible decomposition to leave the alkenes
as products. By using sulfenic acid 4 with high thermal stability,
which can be subject to prolonged heating conditions (Table 1,
Entries 1 and 2), the reverse process of Scheme 4 was
demonstrated unequivocally.
On the other hand, examples of the reverse reaction, i.e.
addition of sulfenic acids to alkenes, have been rather limited.
While there have been several reports on the reactions of
transiently generated sulfenic acids with a large excess of
alkenes,1,11 addition of isolated sulfenic acids to alkenes has not
been investigated except for the reaction with a strained cyclic
alkene.12 Reactions of 4 with simple alkenes as well as an alkene
conjugated with an activating group were then examined. It was
reported that the transiently generated sulfenic acid was trapped
by simple alkenes to afford the corresponding Markovnikov
adducts.11d Treatment of 4 with 1-hexene (4 equiv) at 60 °C in
CDCl3 afforded sulfoxide 7a, a Markovnikov adduct, in a high
yield of 95% (Table 1, Entry 1). The reaction of 4 with styrene
also produced the Markovnikov adduct 7b in 94% yield
(Entry 2). In the reaction of 4 with methyl acrylate, an activated
alkene, the Michael-type addition proceeded promptly to
produce the corresponding sulfoxide 8c quantitatively (Entry 3),
which is consistent with the previous reports on the reaction of
sulfenic acids generated in situ with an acrylate.11a,11c,11e
616 | Chem. Lett. 2015, 44, 615–617 | doi:10.1246/cl.150046
© 2015 The Chemical Society of Japan

Table 2. Reaction of 4 with alkynes
References and Notes
R1
R2
1
a) D. R. Hogg, in The Chemistry of Sulphenic Acids and Their
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Aversa, P. Bonaccorsi, D. Madec, G. Prestat, G. Poli, in
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genation, and C-X Bond Forming Reactions, ed. by P. G.
Andersson, Wiley-VCH Verlag, Weinheim, 2012, p. 47.
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Okazaki, J. Org. Chem. 1996, 61, 2924. c) K. Goto, M. Holler,
R. Okazaki, J. Am. Chem. Soc. 1997, 119, 1460. d) K. Goto,
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Crystallographic data for 4¢MeCN¢c-C5H11OMe: C67H80OS¢
C2H3N¢C6H12O, fw: 1074.58, crystal size: 0.22 © 0.07 ©
0.07 mm3, T = 123 K, monoclinic, P21/n, a = 19.646(5), b =
9.293(2), c = 36.951(9) ¡, ¢ = 104.358(4)°, V = 6535(3) ¡3,
Z = 4, Dcalcd 1.092 g cm¹3, m = 0.094 mm¹1, No. of indep
reflns (parameters): 9526 (796), GOF = 1.019, R1(I > 2·(I)) =
0.0742, wR2 (all data) = 0.1828.
S-O distances and C-S-O angles of sulfoxides: 1.47-1.53 ¡,
103.5-108.9°; Cambridge Structural database, ConQuest version
1.16, the 2014 release.
R1
(4 equiv)
R2
BpqCH2–SOH
H
S
CH2Bpq
CDCl3
4
O
9
Entry Alkyne
Conditions 9 (Yield/%)a
1
2
3
R1 = H, R2 = n-Bu
rt, 72 h
9a, 77
9b, 93
9c, 96
R1 = CO2Me, R2 = H rt, <1 h
R1, R2 = CO2Me
rt, <5 min
2
3
aEstimated by H NMR using (TMS)2CH2 as an internal standard.
1
We also investigated the reactions of sulfenic acid 4 with
alkynes. It has been reported that sulfenic acids generated in situ
react with alkynes to produce vinyl sulfoxides as adducts with
different regioselectivities. The reactions with activated alkynes
such as methyl propiolate to give the corresponding Michael-
type adducts have often been utilized for trapping of transient
sulfenic acids.1,11a,11c,11e It was reported that the addition follows
Markovnikov’s rule in the reactions with simple alkynes.1,11c,13
When 4 was treated with 1-hexyne, the corresponding vinyl
sulfoxide 9 with the Markovnikov orientation was obtained in
77% yield (Table 2, Entry 1). This reaction proceeded even at
room temperature in contrast with the reaction of 4 with 1-
hexene, which required heating conditions, indicating that the
reactivity of a sulfenic acid toward a simple alkyne is somewhat
higher than that to a simple alkene. The reaction of 4 with
methyl propiolate produced the Michael-type addition product
9b in high yield within an hour (Entry 2). Treatment of 4 with
dimethyl acetylenedicarboxylate also gave the corresponding
vinyl sulfoxide 9c in excellent yield (Entry 3).
In summary, we have succeeded in the synthesis and
isolation of a primary-alkyl-substituted sulfenic acid. Remark-
able thermal stability of the sulfenic acid was achieved by
utilizing a cavity-shaped substituent, which enabled us to study
the reactivities of otherwise labile species toward various
reagents. The addition of sulfenic acids to unsaturated C-C
bonds has been investigated both experimentally and theoret-
ically, and it was shown that the addition of a sulfenic acid to a
simple alkene is intrinsically exothermic, although the reverse
process, i.e. thermolysis of sulfoxides, has been widely utilized in
organic syntheses. Further investigations on the reactivities of the
sulfenic acid toward various reagents are currently in progress.
4
5
6
7
8
9
In the case of the selenium analogue, BpqCH2SeOH, heating at
60 °C in benzene-d6 for 230 h resulted in dehydrative decom-
position. See ref 6b.
10 C. A. Kingsbury, D. J. Cram, J. Am. Chem. Soc. 1960, 82, 1810.
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b) D. H. R. Barton, D. G. T. Greig, G. Lucente, P. G. Sammes,
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This work was partly supported by Grants-in-Aid for The
Global COE Program for Education and Research Center for
Emergence of New Molecular Chemistry and for Scientific
Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
M. I. is grateful to a Grant-in-Aid for JSPS Fellows.
13 a) D. Neville Jones, P. D. Cottam, J. Davies, Tetrahedron Lett.
1979, 20, 4977. b) R. Bell, P. D. Cottam, J. Davies, D. N. Jones,
J. Chem. Soc., Perkin Trans. 1 1981, 2106.
Supporting Information is available electronically on J-STAGE.
Chem. Lett. 2015, 44, 615–617 | doi:10.1246/cl.150046
© 2015 The Chemical Society of Japan | 617