Synthesis of highly reactive organosulfur compounds

Article abstract of DOI:10.1002/hc.10068

Application of novel bowl-type and dendrimer-type steric protection groups to the first synthesis of stable aromatic S-nitrosothiols is described. These compounds showed remarkable thermal stability whereas they easily reacted with appropriate reagents. X-ray crystallographic analysis established their structures, where the C-S-N-O linkage adopts only the syn conformation. Synthesis of a stable sulfenic acid by taking advantage of the bowl-type substituent is also delineated.

Full text of DOI:10.1002/hc.10068

Heteroatom Chemistry
Volume 13, Number 5, 2002
Synthesis of Highly Reactive Organosulfur
Compounds
Renji Okazaki1 and Kei Goto2
1Department of Chemical and Biological Sciences, Faculty of Science, Japan Women’s University,
2-8-1 Mejirodai, Bunkyo-ku, Tokyo 112-8681, Japan
2Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received 22 June 2001; revised 30 March 2002
of human physiological processes. As for aliphatic
ABSTRACT: Application of novel bowl-type and
S-nitrosothiols, there have been several compounds
dendrimer-type steric protection groups to the first syn-
isolated and structurally characterized so far [3–6].
thesis of stable aromatic S-nitrosothiols is described.
By contrast, aromatic S-nitrosothiols are much
These compounds showed remarkable thermal sta-
less stable than aliphatic derivatives and there has
bility whereas they easily reacted with appropriate
been no example of the isolation of an aromatic
reagents. X-ray crystallographic analysis established
S-nitrosothiol. Usually, such compounds accumu-
their structures, where the C S N O linkage adopts
late only transiently and rapidly decompose to the
only the syn conformation. Synthesis of a stable
corresponding disulfides and NO [7,8]. We have
sulfenic acid by taking advantage of the bowl-type
been investigating the synthesis of highly reactive
C
substituent is also delineated. 2002 Wiley Periodicals,
species by taking advantage of kinetic stabilization
Inc. Heteroatom Chem 13:414–418, 2002; Published online
afforded by bowl-type substituents [9]. In this paper,
in Wiley Interscience (www.interscience.wiley.com).
we describe the synthesis, structure, and reactivities
DOI 10.1002/hc.10068
of the first stable aromatic S-nitrosothiols bearing
bowl-type and newly designed dendrimer-type sub-
stituents. The stabilization of some related highly re-
active organosulfur compounds is also delineated.
INTRODUCTION
In 1983 Oae et al. wrote a review on S-nitrosothiols
(RSNO) and S-nitrothiols (RSNO2), which are the
sulfur analogs of nitrites and nitrates, and sum-
marized their pioneering work on these sulfur
compounds [1]. Some stable S-nitrosothiols were al-
ready known at that time, but much more atten-
tion has been focused on S-nitrosothiols, since they
have been revealed to be an excellent precursor of
nitric oxide (NO) [2], which has been of current
interest because of its key roles in a wide range
RESULTS AND DISCUSSION
Concept and Molecular Design
For kinetic stabilization of reactive species, var-
ious types of steric protection groups have been
developed so far. Among sulfur-containing reactive
species, there are many compounds to which only
one substituent can be introduced. Steric protection
of such species is a hard task, especially when an
aromatic substituent is employed; in comparison
with an aliphatic substituent extending toward
three directions, it is rather difficult to protect a
reactive functionality from all sides by an aromatic
Correspondence to: Kei Goto; e-mail: goto@chem.s.u-tokyo.ac.jp.
Contract grant sponsor: Ministry of Education, Culture, Sports,
Science and Technology, Japan.
c
2002 Wiley Periodicals, Inc.
414

Synthesis of Highly Reactive Organosulfur Compounds 415
SCHEME 1 Redox reactions of a sulfenic acid.
to disulfides and to sulfinic acids (Scheme 1) [12].
However, the evidence for these processes is entirely
circumstantial due to the instability of sulfenic acids;
they usually undergo very easy self-condensation
to the corresponding thiosulfinates. The reaction
of thiol 2 bearing a Bmt group with iodosoben-
zene, a mild oxidant which usually converts thiols to
disulfides, afforded sulfenic acid 3, which was iso-
lated by silica gel chromatography as stable crystals
(Scheme 2) [9c]. X-ray crystallographic analysis has
established the structure of 3, where two rigid m-
terphenyl units surround the SOH group like a brim
of a bowl (Fig. 2). This represents the first exam-
ple of direct oxidation of a thiol to a stable sulfenic
acid.
The reactions of sulfenic acid 3 with 1-butane-
thiol and thiophenol afforded the corresponding
unsymmetrical disulfides 4a and 4b, respectively
(Scheme 2). Dithiothreitol reduced 3 to thiol 2 via the
intermediary disulfide 4c. Treatment of 3 with ben-
zylamine afforded sulfenamide 5. These reactions
of 3 with nucleophiles demonstrate that a sulfenic
acid exhibits electrophilic reactivity even under basic
conditions. Sulfenic acids can be regarded as sulfur
analogs of hydroperoxides and trivalent phosphorus
reagents have been suggested to reduce a transient
sulfenic acid. The reduction of 3 with triphenylphos-
phine gave thiol 2 in a good yield. Sulfenic acid 3
was oxidized to sulfinic acid 6 by oxaziridine 7. By
FIGURE 1 Concept of bowl-type molecules.
substituent. S-Nitrosothiols are typical examples as
described above and so are sulfenic acids (RSOH).
While several alkanesulfenic acids have been
isolated by kinetic stabilization [10], no stable are-
nesulfenic acid has been obtained, even with bulky
substituents such as a 2,4,6-triisopropylphenyl or a
2,4,6-tri-tert-butylphenyl (denoted as Mes*) group
[11]. For stabilization of such species, we designed
bowl-shaped molecules that are schematically
depicted in Fig. 1. In these molecules, the functional
groups X and Y cannot approach each other because
of the steric repulsion of the brims of the bowls,
whereas they can react with other reagents because
there is relatively large space around them. The
functionalities X and Y can be either of the same
kind or of different kinds. We have designed several
kinds of molecular bowls such as bimacrocyclic cy-
clophanes [9a,e] and bridged calix[6]arenes [9b,d,e],
and recently we have developed a novel substituent
1 (denoted as Bmt hereafter) [9c,e–g] where two
rigid m-terphenyl groups form the brim of the bowl.
The inert, all-carbon framework of the Bmt group is
considered to be favorable for the investigation of
the intrinsic reactivities of the chemical species.
Stabilization of a Sulfenic Acid by a Bowl-Type
Substituent
Sulfenic acids are generally assumed to be tran-
sient intermediates in the oxidation of thiols both
SCHEME 2 Synthesis and reactions of BmtSOH (3).

416 Okazaki and Goto
FIGURE 2 Crystal structure of BmtSOH (3).
FIGURE 3 Crystal structure of BmtSNO (8).
taking advantage of a Bmt group, all the processes
in Scheme 1 have been demonstrated conclusively.
bond lengths are similar to those of the aliphatic
analogs.
S-Nitrosothiol 8 showed high thermal stability.
No reaction took place in benzene-d6 at 50 C for
12 h, but the decomposition was completed in re-
fluxing benzene for 75 h to give the correspond-
ing disulfide 9 (Scheme 4). Considering the reported
fact that the half-life times of ArSNO (Ar = phenyl,
p-methoxyphenyl, p-nitrophenyl, 3,5-di-tert-butyl-4-
hydroxyphenyl) are 7–14 min in dichloromethane at
room temperature [8], the stability of 8 is remark-
able. In order to know the efficiency of the Bmt
group, Mes*SNO was synthesized. The reaction of
Mes*SH with tert-butyl nitrite in the presence of ex-
cess trifluoroacetic acid gave Mes*SNO as reddish-
brown crystals. Mes*SNO was found to be much less
stable than 8 and completely decomposed after 48 h
at room temperature in chloroform, indicating that
the stabilization by the Bmt group is much more ef-
fective than that by Mes*.
In spite of high thermal stability, S-nitrosothiol
8 undergoes some reactions as shown in Scheme 5.
The reaction with ␣-toluenethiol gave unsymmet-
rical disulfide 10, while the reaction of triphenyl-
phosphine and lithium diethylamide afforded thiol
2. Less reactive nitrogen nucleophiles such as
N-methylaniline and diethylamine did not react
with 8. Oxidation of 8 with tert-butyl nitrite gave
S-nitrothiol 11. S-Nitrothiol 11 is quite stable in con-
trast to the reported instability of simple aromatic
nitrothiols such as p-XC6H4SNO2 (X = Cl, Br, CH3),
Stabilization of an Aromatic S-Nitrosothiol
by a Bowl-Type Substituent
Okazaki has recently applied the Bmt group to the
stabilization of an aromatic S-nitrosothiol [13]. Re-
action of thiol 2 with tert-butyl nitrite (1.2 equiv)
in chloroform at room temperature gave the cor-
responding S-nitrosothiol 8 as deep green crystals
(Scheme 3). The structure of 8 was definitively es-
tablished by X-ray crystallography (Fig. 3). The SNO
group is almost perpendicular to the benzene ring
attached to it and adopts the syn conformation with
regards to the S N bond. The conformation of the
S N O group of S-nitrosothiols is one of the cur-
rent topics, and several theoretical and experimental
studies on this subject have recently been reported.
While S-nitrosoacetyl-D,L-penicillamine (SNAP) [3]
and Ph3CSNO [4] adopt anti conformation with re-
gard to the S N bond, TrmSNO (Trm: tris(2,200,6,600-
tetramethyl-m-terphenyl-50-yl)methyl) [6] exists as
a mixture of the anti and syn isomers. The bond
lengths of N O, S N, and C S in the C S N O
˚
group of 8 are 1.208, 1.806, and 1.796 A, re-
spectively. It should be noted that the C S bond
length is considerably shorter than those reported
˚
˚
for SNAP (1.842 A), Ph3CSNO (1.867 A), and
˚
TrmSNO (1.841 A) although the N O and S N
SCHEME 3 Synthesis of BmtSNO (8).
SCHEME 4 Thermal reaction of BmtSNO (8).

Synthesis of Highly Reactive Organosulfur Compounds 417
SCHEME 5 Reactions of BmtSNO (8)
FIGURE 4 Crystal structure of BpqSNO (14). The disorder
ratio of N(1) O(1) to N(2) O(2) is 0.55:0.45.
which decompose rapidly at room temperature [14].
The reaction of 11 with triphenylphosphine gave
S-nitrosothiol 8, providing an alternative synthetic
approach to 8.
in hydrocarbon solvents is usually considered to
involve the bimolecular reaction of an initially
formed thiyl radical with the second molecule of
S-nitrosothiol [2d]. The present results suggest that
the Bpq group effectively suppressed the reaction
of thiyl radical 16 with the second molecule of
S-nitrosothiol 14, which enabled the very slow
conversion to 15 and 13 to take place.
Stabilization of an Aromatic S-Nitrosothiol
by a Dendrimer-Type Substituent
Although the efficiency of the Bmt group was found
to be remarkable, the prolonged heating of S-nitro-
sothiol 8 afforded the corresponding disulfide 9.
Recently, Goto designed a novel m-terphenyl based
dendrimer-type substituent 12 (denoted as Bpq
hereafter) as a more effective steric protection
group and synthesized
a stable S-nitrosothiol
bearing this substituent [15]. Treatment of thiol
13 with an equimolar amount of ethyl nitrite
afforded S-nitrosothiol 14, which was isolated as
brownish-green crystals (Scheme 6). X-ray crys-
tallographic analysis established the structure of
14 (Fig. 4). In the crystalline state, there was a
rotational disorder of the N O moiety around
the C S bond in the ratio of 0.55:0.45. In both
fragments, the C S N O linkage adopts only the
syn conformation, which is similar to the case
of BmtSNO (8). BpqSNO (14) showed a much
higher thermal stability than hitherto known for
S-nitrosothiols, even in comparison with BmtSNO
(8). It was found that, even after heating in C6D6 at
80 C for 60 h, 38% of 14 remained unchanged. The
rest of 14 was converted to the dibenzothiophene
derivative 15 (46%) and thiol 13 (15%), which
are considered to be formed via thiyl radical 16
(Scheme 7). In this reaction, the formation of
the symmetrical disulfide 17 was not detected.
The mechanism of thermolysis of S-nitrosothiols
S-Nitrosothiol 14 also reacted with several
reagents (Scheme 8). The reaction of 14 with 1-
butanethiol or methanol afforded the unsymmetrical
disulfide 18 or methyl sulfenate 19, respectively. Ox-
idation of 14 with an excess amount of tert-butyl ni-
trite or N2O4 afforded the corresponding S-nitrothiol
20 quantitatively, which was isolated as stable crys-
tals. S-Nitrothiol 20 reacted with 1-butanethiol to
give the unsymmetrical disulfide 18 which was sim-
ilar to S-nitrosothiol 14. Reduction of 14 with triph-
enylphosphine afforded 14 quantitatively. These
SCHEME 6 Synthesis of BpqSNO (14).
SCHEME 7 Thermal reaction of BpqSNO (14).

418 Okazaki and Goto
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ACKNOWLEDGMENTS
The authors thank all the coworkers, Profs. Takayuki
Kawashima, Gaku Yamamoto, and Norihiro Tokitoh,
Drs. Michel Holler, Keiko Takenaka, and Nobuhiro
Takeda, Ms. Maiko Ito, Ms. Yoko Hino, and Mr.
Yusuke Takahashi for their invaluable contributions
to this work. We also thank Tosoh Finechem Corpo-
ration for a generous gift of alkyllithiums.
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