Synthesis, structure, and reactions of a sulfenic acid bearing a novel bowl-type substituent: The first synthesis of a stable sulfenic acid by direct oxidation of a thiol

Full text of DOI:10.1021/ja962994s

1460
J. Am. Chem. Soc. 1997, 119, 1460-1461
Synthesis, Structure, and Reactions of a Sulfenic
Acid Bearing a Novel Bowl-Type Substituent: The
First Synthesis of a Stable Sulfenic Acid by Direct
Oxidation of a Thiol
Kei Goto, Michel Holler, and Renji Okazaki*
Department of Chemistry, Graduate School of Science
The UniVersity of Tokyo
Figure 1. Schematic drawing of a reaction bowl.
7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan
Scheme 1
ReceiVed August 26, 1996
Sulfenic acids are generally assumed to be transient inter-
mediates in the oxidation of thiols to both disulfides and sulfinic
acids (Scheme 1),1 and redox reactions between thiols and
sulfenic acids are of great importance from a biological point
of view.2 It has been suggested that oxidation of cysteinyl side
chains of papain and glyceraldehyde-3-phosphate dehydrogenase
(GPD) yields stable active-site sulfenic acid derivatives, which
can be reduced to the native forms.2a Sulfenic acid derivatives
have also been suggested to play important roles in redox
regulation in some enzymatic reactions.2b,c However, under
nonenzymatic conditions, the evidence for the redox processes
in Scheme 1 is entirely circumstantial due to the instability of
sulfenic acids. Although a trapping experiment of a transient
sulfenic acid in the oxidation of 2-methyl-2-propanethiol was
reported,3 there has been no example of even the observation
of the intermediary sulfenic acid in direct oxidation of a thiol.4,5
As for the redox reactions of sulfenic acids to thiols and to
sulfinic acids, only those of transient species have been reported
so far, where the sulfenic acids were neither actually isolated
nor detected.3,5,7 In this communication, we describe the first
synthesis of a stable sulfenic acid by direct oxidation of a thiol
along with its structure and reactions, which provide the
conclusive demonstration of redox reactions of a sulfenic acid.
We previously reported that the bowl-shaped cyclophane
framework, which we refer to as a “reaction bowl” (Figure 1),
is quite effective for stabilization of the reactive species such
as sulfenic acids.8 Recently, we have developed a novel bowl-
type substituent 1 (denoted as Bmt9 hereafter) with a rigid and
more inert framework and synthesized thiol 2 bearing this
substituent.10 For the investigation on the intrinsic properties
of a sulfenic acid, the all-carbon framework of the Bmt group
is considered to be favorable compared with the compounds
where the properties of the SOH functionality are perturbed by
the effects of the heteroatoms such as the intramolecular
hydrogen bonding effects.1b If iodosobenzene (3), a mild
oxidant which converts thiols to disulfides,11 is used in the
oxidation of 2, it is expected that formation of the symmetrical
disulfide is sterically prevented and the sulfenic acid is obtained
as the final product. Treatment of 2 with 1.1 equiv of 3 in
CHCl3 at room temperature afforded sulfenic acid 4,12 which
was isolated as a crystalline solid in 41% yield by silica gel
chromatography (Scheme 2).13,14 The same compound 4 was
also obtained by pyrolysis of butyl sulfoxide 515 at 225 °C under
no solvent conditions (67%). The reaction of 4 with methyl
propiolate in CH2Cl2 at room temperature afforded an adduct 6
in 58% yield. Sulfenic acid 4 is stable at room temperature in
air for more than several weeks. The 1H NMR (CDCl3)
spectrum showed the signal of the hydroxyl proton at δ ) 1.36
(readily exchangeable with D2O), indicating that it is shielded
by the xylyl rings of the m-terphenyl units similarly to the
(1) For leading references on the chemistry of sulfenic acids, see: (a)
Hogg, D. R. In The Chemistry of Sulfenic Acids and Their DeriVatiVes;
Patai, S., Ed.; John Wiley & Sons: New York, 1990; pp 361-402. (b)
Davis, F. A.; Jenkins, L. A.; Billmers, R. L. J. Org. Chem. 1986, 51, 1033-
1040. (c) Kice, J. L. AdV. Phys. Org. Chem. 1980, 17, 65-181.
(2) For leading references on the biological reactions of sulfenic acids,
see: (a) Allison, W. S. Acc. Chem. Res. 1976, 9, 293-299. (b) Claiborne,
A.; Ross, R. P.; Parsonage, D. Trends Biochem. Sci. 1992, 17, 183-186.
(c) Claiborne, A.; Miller, H.; Parsonage, D.; Ross, R. P. FASEB J. 1993, 7,
1483-1490. The natural formation of sulfenic acids when onion and garlic
are cut has also been reported: (d) Block, E.; Gillies, J. Z.; Gillies, C. W.;
Bazzi, A. A.; Putman, D.; Revelle, L. K.; Wang, D.; Zhang, X. J. Am.
Chem. Soc. 1996, 118, 7492-7501, and references therein.
(3) Davis, F. A.; Billmers, R. L. J. Am. Chem. Soc. 1981, 103, 7016-
7018.
(7) For examples of reduction of a transient sulfenic acid to a thiol, see:
(a) Cooper, R. D. G.; Jose´, F. L. J. Am. Chem. Soc. 1970, 92, 2575-2576.
(b) Hatfield, L. D.; Fisher, J.; Jose´, F. L.; Cooper, R. D. G. Tetrahedron
Lett. 1970, 4897-4900.
(4) For the synthesis of stable sulfenic acids by other methods, see: (a)
Fries, K. Chem. Ber. 1912, 45, 2965-2973. (b) Bruice, T. C.; Markiw, R.
T. J. Am. Chem. Soc. 1957, 79, 3150-3153. (c) Jenny, W. HelV. Chim.
Acta 1958, 41, 326-331. (d) Pal, B. C.; Uziel, M.; Doherty, D. G.; Cohn,
W. E. J. Am. Chem. Soc. 1969, 91, 3634-3638. (e) Kato, K. Acta
Crystallogr., Sect. B. 1972, 28, 55-59. (f) Chou, T. S.; Burgtorf, J. R.;
Ellis, A. L.; Lammert, S. R.; Kukolja, S. P. J. Am. Chem. Soc. 1974, 96,
1609-1610. (g) Bachi, M. D.; Gross, A. J. Org. Chem. 1982, 47, 897-
898. (h) Heckel, A.; Pfleiderer, W. Tetrahedron Lett. 1983, 24, 5047-
5050. (i) Nakamura, N. J. Am. Chem. Soc. 1983, 105, 7172-7173. (j)
Yoshimura, T.; Tsukurimichi, E.; Yamazaki, S.; Soga, S.; Shimasaki, C.;
Hasegawa, K. J. Chem. Soc., Chem. Commun. 1992, 1337-1338. (k) Tripolt,
R.; Belaj, F.; Nachbaur, E. Z. Naturforsch., Sect. B. 1993, 48, 1212-1222.
(l) Machiguchi, T.; Hasegawa, T.; Otani, H. J. Am. Chem. Soc. 1994, 116,
407-408.
(8) (a) Goto, K.; Tokitoh, N.; Okazaki, R. Angew. Chem., Int. Ed. Engl.
1995, 34, 1124-1126. (b) Saiki, T.; Goto, K.; Tokitoh, N.; Okazaki, R. J.
Org. Chem. 1996, 61, 2924-2925.
(9) Bmt denotes 4-tert-butyl-2,6-bis[(2,2′′,6,6′′-tetramethyl-m-terphenyl-
2′-yl)methyl]phenyl.
(10) Goto, K.; Holler, M.; Okazaki, R. Tetrahedron Lett. 1996, 37, 3141-
3144.
(11) Takaya, T.; Enyo, H.; Imoto, E. Bull. Chem. Soc. Jpn. 1968, 41,
1032.
(12) Monitoring of the reaction in CDCl3 by 1H NMR indicated the
formation of 4 at the expense of 2, no intermediate being confirmed.
(13) 4 (4-tert-butyl-2,6-bis[(2,2′′,6,6′′-tetramethyl-m-terphenyl-2′-yl)-
methyl]benzenesulfenic acid): colorless crystals, mp 145-146 °C. 1H NMR
(500 MHz, CDCl3) δ 1.00 (s, 9H, C(CH3)), 1.36 (s, 1H, OH), 1.94 (s, 24H,
CH3), 3.73 (s, 4H, CH2), 6.53 (s, 2H), 6.87 (d, J ) 7.5 Hz, 8H), 6.93 (t, J
) 7.5 Hz, 4H), 7.02 (d, J ) 7.5 Hz, 4H), 7.31 (t, J ) 7.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 21.0 (q), 31.0 (q), 34.0 (t), 34.6 (s), 124.0 (d),
126.4 (d), 126.6 (d), 127.1 (d), 129.0 (d), 136.4 (s), 136.9 (s), 138.3 (s),
141.0 (s), 141.6 (s), 143.3 (s), 150.6 (s); νOH (CH2Cl2) 3460 cm-1; HRMS
(FAB) m/z 778.4239, calcd for C56H58OS 778.4208. Anal. Calcd for
C56H58OS‚H2O: C, 84.38; H, 7.59; S, 4.02. Found: C, 84.55; H, 7.87; S,
3.52.
(5) As for the reactions of silver salts, the oxidation of silver 1,3,6-
trimethyllumazine-7-thiolate to the corresponding silver sulfenate with 1
equiv of hydrogen peroxide and the reduction of the latter to the former
with sodium borohydride have been reported without description of the
conditions and the yield.4h The oxidation of 1,3,6-trimethyllumazine-7-
sulfenic acid to the corresponding sulfinic acid with hydrogen peroxide
has also been reported,4h although this sulfenic acid reportedly shows
behavior atypical of sulfenic acids such as disproportionation to the thiol
and the sulfinic acid under acidic conditions. Recently the synthesis of
thiophenetriptycene-8-sulfenic acid by oxidation of the corresponding
sodium thiolate with mCPBA has been reported.6
(14) Physical and analytical data of 4-6 and 8-10 are described in the
(6) Komiya, K.; Ishii, A.; Nakayama, J. In Abstracts of the 70th Spring
Annual Meeting of the Chemical Society of Japan; the Chemical Society
of Japan, Tokyo, 1996: Vol. 2, p 1244 (3H5 31).
Supporting Information.
(15) Sulfoxide 5 was prepared by oxidation of the corresponding butyl
sulfide10 with mCPBA in 87% yield.
S0002-7863(96)02994-0 CCC: $14.00 © 1997 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 119, No. 6, 1997 1461
sulfenic acid unaffected by heteroatoms. As clearly shown in
Figure 2, 4 has a bowl-shaped structure, where two rigid
m-terphenyl units surround the SOH group like a brim of a bowl.
It has been suggested that a major factor of the stabilization of
sulfenic acids in enzymes is the geometry of their active sites
with a functional group embedded in the cavity and isolated
from other reactive groups.2c Also in compound 4, the sulfenic
acid functionality is incorporated in the molecular cavity, thus
being effectively protected from the self-condensation leading
to the corresponding thiosulfinate. During the oxidation of thiol
2, this bowl-shaped framework is considered to prevent the
initially formed sulfenic acid 4 from reacting with a second
molecule of 2 to yield the symmetrical disulfide. These results
demonstrate that a sulfenic acid can be synthesized by direct
oxidation of a thiol if it is generated in an appropriate
environment.
The reactions of sulfenic acid 4 with a reductant or an oxidant
presented the conclusive demonstration of redox processes from
sulfenic acids to thiols and to sulfinic acids. Trivalent phos-
phorus reagents have been suggested to reduce a transient
sulfenic acid.7,22 Treatment of 4 with triphenylphosphine
afforded thiol 2 in a good yield of 85%. It has been reported
that the oxidation of 2-methyl-2-propanethiol with 2-(benzene-
sulfonyl)-3-phenyloxaziridine (7) rapidly affords the corre-
sponding sulfinic acids and that the intermediary sulfenic acid
can be trapped as an adduct with methyl propiolate.3 Oxidation
of sulfenic acid 4 with an equimolar amount of 7 in CH2Cl2
afforded sulfinic acid 8 in 70% yield (Scheme 2).
Figure 2. ORTEP drawing of BmtSOH (4) with thermal ellipsoid plot
(30% probability). Selected bond lengths (Å), bond angles (deg), and
torsion angle (deg): S(1)-O(1), 1.679(5); S(1)-C(1), 1.770(5); O(1)-
S(1)-C(1), 100.3(3); O(1)-S(1)-C(1)-C(6), 67.1(5).
Scheme 2
It has been reported that the acylphosphatase activity of the
oxidized form of GPD is inactivated by various nucleophiles
such as thiols and amines, which suggests the reaction of the
active-site sulfenic acid with these reagents.2a In the previous
paper, we reported the reaction of a sulfenic acid bearing a
bicyclic cyclophane skeleton with a thiol to afford the corre-
sponding disulfide.8a The reactions of sulfenic acid 4 with an
excess of 1-butanethiol or thiophenol afforded the unsymmetrical
disulfides 9a,b, respectively, in good yields (Scheme 2).
Dithiothreitol (DTT) reduced sulfenic acid 4 to thiol 2 via
disulfide 9c. The reaction of 4 with DTT in CH2Cl2 at room
temperature first gave 9c, which was converted to 2 on silica
gel in a total yield of 90%.23 Treatment of sulfenic acid 4 with
an excess of benzylamine in CH2Cl2 afforded sulfenamide 10
in 75% yield. These reactions of 4 with nucleophiles demon-
strate that a sulfenic acid exhibits the electrophilic reactivity,
even under basic conditions.
In summary, a stable sulfenic acid bearing a novel reaction-
bowl-type substituent was synthesized by direct oxidation of a
thiol, and its structure and unique reactivities were revealed.
By taking advantage of this new type of reaction environment,
all the processes in Scheme 1 have been demonstrated conclu-
sively. Further investigations on the mechanistic aspects of
these reactions as well as applications of the Bmt group to the
stabilization of other reactive species are currently in progress.
mercapto proton of 2 [δ(SH) ) 1.13].10 In the IR spectrum
(CH2Cl2) 4 showed a strong OH stretching absorption at 3460
cm-1, while the bands attributable to the S-H or SdO stretching
vibration were not observed,16 indicating that 4 has the sulfenyl
form (R-S-O-H) rather than the sulfoxide form (R-
S(H)dO).
The molecular structure of 4 was established by X-ray
crystallographic analysis (Figure 2).17 The S-O bond length
[1.679(5) Å] of the SOH group is distinctly longer than that of
sulfoxides,18 indicating that this compound takes the sulfenyl
form also in the crystalline state.19 Although there have been
some examples of the X-ray analysis of sulfenic acids,4e,k,6,8b
all of those compounds have nitrogen, sulfur, or oxygen atoms
in the vicinity of the SOH group20 and their S-O bond lengths
fall between 1.58-1.63 Å. The present one is significantly
longer than any of them and slightly longer than that of
methanesulfenic acid [1.658(2) Å] determined by microwave
spectroscopy,21 showing the structural features of an arene-
Acknowledgment. This work was partly supported by Grants-in-
Aid for Scientific Research (No. 07854035 and 94187) from the
Ministry of Education, Science and Culture, Japan. We also thank
Tosoh Akzo Co., Ltd. for the generous gift of alkyllithiums. M.H. is
grateful to the Japan Society for the Promotion of Science for the
Postdoctoral Fellowship for Foreign Researchers.
(16) Thiol 2 showed the SH absorption at 2542 cm-1. For the IR charts
of 2 and 4, see the Supporting Information.
(17) Crystallographic data for 4‚CH2Cl2: C57H60OSCl2, FW ) 864.07,
triclinic, space group P1h, a ) 12.715(7) Å, b ) 18.47(2) Å, c ) 11.590(8)
Å, R ) 104.47(6)°, â ) 99.84(5)°, γ ) 103.81(6)°, V ) 2481(3) Å3, Z )
2, Dcalcd ) 1.157 g/cm3, µ ) 2.10 cm-1, R (Rw) ) 0.064 (0.077). Full details
of the crystallographic structure analysis are described in the Supporting
Information.
Supporting Information Available: Physical and analytical data
of products 4-6 and 8-10 and the IR spectra of 2 and 4 and
crystallographic data with complete tables of bond lengths, angles, and
thermal and positional parameters for 4 (39 pages). See any current
masthead page for ordering and Internet access instructions.
(18) S-O distance of sulfoxides (103 examples in the Cambridge
Structural Database): 1.444-1.584 Å.
(19) For a discussion about the structure of sulfenic acids, see ref 2d
and the following paper: Lacombe, S.; Loudet, M.; Banchereau, E.; Simon,
M.; Pfister-Guillouzo, G. J. Am. Chem. Soc. 1996, 118, 1131-1138 (and
references therein).
JA962994S
(22) Trialkyl phosphites have often been used as a sulfenic acid trap in
olefin formation by thermolysis of sulfoxides. For example: Trost, B. M.;
Salzmann, T. N.; Hiroi, K. J. Am. Chem. Soc. 1976, 98, 4887-4902.
(23) The intermediary disulfide 9c was isolable by gel permeation liquid
chromatography (81%).
(20) The X-ray structure of 9-triptycenesulfenic acid has been determined,
although not published: Nakamura, N. Private communication.
(21) Penn, R. E.; Block, E.; Revelle, L. K. J. Am. Chem. Soc. 1978,
100, 3622-3623.