Synthetic equivalents of benzenethiol and benzyl mercaptan having faint smell: Odor reducing effect of trialkylsilyl group

Article abstract of DOI:10.1016/S0040-4039(02)02052-X

Syntheses and odor tests of the trialkylsilylated benzyl mercaptans and benzenethiols have revealed that the trimethylsilyl substituent on the benzene ring has a remarkable effect in reducing the foul smell of the parent benzyl mercaptan and benzenethiol.

Full text of DOI:10.1016/S0040-4039(02)02052-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8569–8573
Synthetic equivalents of benzenethiol and benzyl mercaptan
having faint smell: odor reducing effect of trialkylsilyl group
Kiyoharu Nishide, Tetsuo Miyamoto, Kamal Kumar, Shin-ichi Ohsugi and Manabu Node*
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received 9 August 2002; accepted 13 September 2002
Abstract—Syntheses and odor tests of the trialkylsilylated benzyl mercaptans and benzenethiols have revealed that the
trimethylsilyl substituent on the benzene ring has a remarkable effect in reducing the foul smell of the parent benzyl mercaptan
and benzenethiol. Protodesilylation allowed these silylated thiols to function as odorless synthetic equivalents of benzyl mercaptan
and benzenethiol. This discovery will greatly improve the physical environment of the researcher working with these malodorous
compounds. © 2002 Elsevier Science Ltd. All rights reserved.
Introduction of a sulfur substituent into organic
molecules is one of the basic reactions in organic syn-
thesis. Unfortunately, sulfur-containing reagents gener-
ally have such a strong, foul smell that working with
them can be extremely unpleasant. Recently, we have
been involved in a program aimed at the development
of odorless thiols1 and sulfides2 which can be substi-
tuted for malodorous reagents such as ethanethiol,
benzyl mercaptan and dimethyl sulfide. Odorless substi-
tutes for these foul-smelling molecules are always desir-
able from an environmental standpoint. Among the
purified 1-alkanethiols tested, 1-dodecanethiol (1) was
found to have no odor. An alkyl chain of over 12
carbon atoms in the thiol was crucial in reducing the
offending smell. Consequently, we synthesized 4-
alkylphenylmethanethiols, and discovered that the 4-
heptylphenylmethanethiol (2), which has a 12-carbon
chain, was also odorless. We next demonstrated that
the alkanethiols 1 and 2 could be used as odorless
substitutes for ethanethiol and benzyl mercaptan in
dealkylation and thiol-introducing reactions, as shown
in Eqs. (1) and (2), respectively (Scheme 1).1 However,
the odorless thiol 2 could not be used to introduce a
benzylthio group because removal of the heptyl group
on the benzene ring proved difficult. Therefore, we
developed odorless thiols, which possessed a removable
substituent on the phenyl and the benzyl groups, as
shown in Eq. (3).
During our search for odorless thiols, we found that the
4-tert-butylphenylmethanethiol did not possess the
odor of a thiol but rather that of an alcohol. We
Scheme 1.
Keywords: odorless benzyl mercaptan; odorless benzenethiol; trimethylsilyl group; odor scale; Michael addition; protodesilylation.
* Corresponding author. Tel.: +81-75-595-4639; fax: +81-75-595-4775; e-mail: node@mb.kyoto-phu.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02052-X

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K. Nishide et al. / Tetrahedron Letters 43 (2002) 8569–8573
therefore envisioned introducing a more bulky tri-
alkylsilyl group onto the benzene ring that would
reduce the smell of the parent benzenethiol and benzyl
mercaptan, if indeed the olfactory sense of the human
nose recognizes the odor of a compound by its steric
bulkiness. Although the sterically bulky ortho-
trimethylsilylbenzenethiol3 and 4-tert-butyl-benzene-
thiol4 have been used for enantio- and diastereoselective
Michael additions of a,b-unsaturated carbonyl com-
pounds, there is no mention of their odor. Herein we
report the effect of a trialkylsilyl substituent on the
benzene ring in reducing the smell of the parent thiol,
and their development as odorless synthetic equivalents
of the parent benzyl mercaptan and benz-
enethiol by protodesilylation.
considerably less odor than the parent benzyl mercap-
tan and slightly less than tert-butylphenylmethanethiol.
The presence of a propyl group in the trialkylsilyl unit
seems to cause a stronger thiol odor. Trimethylsilyl and
triethylsilyl substituents were found to have a very faint
odor and in some cases were virtually odorless, regard-
less of their position on the benzene ring.
Since the trimethylsilyl substituent on the benzene ring
has been found to have a remarkable effect in reducing
the smell of the parent benzyl mercaptan, we decided to
prepare the trimethylsilylbenzenethiols6 (from bromo-
phenols as the starting material) and test their
respectiveodors(Table2).ortho-,meta-andpara-Bromo-
phenols were transformed into the trimethylsilylbenz-
enethiols (9) by silylation, N,N-dimethylaminothiocar-
bamoylation, the Newman–Kwart rearrangement,7 and
reduction. The cleavage of the OꢀSi bond of ortho-
trimethylsilylphenyloxy trimethylsilyl ether required
treatment with TBAF (Table 2, entry 3), whereas the
bonds of the corresponding para and meta derivatives
were easily cleaved by treatment with a 1N HCl solu-
tion (Table 2, entries 1 and 2). The Newman–Kwart
rearrangement of O-(trimethylsilyl)phenyl N,N-
dimethylaminothiocarbamates was greatly influenced
by the position of the trimethylsilyl substituent. The
yields of the rearrangement decreased as the silyl sub-
stituent was moved from para to ortho, indicating that
the steric bulkiness of the ortho-trimethylsilyl sub-
stituent interferes with the intramolecular approach of
the thiocarbamoyl group to the aromatic carbon
attached to the trimethylsilyl group. All of the
First, we synthesized the trialkylsilylphenylmethanethi-
ols having a trialkylsilyl group at every position on the
benzene ring. We adopted the reactions without foul-
smell for their syntheses. The results are shown in Table
1. 1-Bromo-2-, 3-, and 4-methylbenzenes were con-
verted to the corresponding trialkylsilylphenyl-
methanethiols (5) in satisfactory yields through
silylation by lithium–halogen exchange, bromination at
the benzylic position with N-bromosuccinimide (NBS),
and thiolation with thiourea. All of the prepared thiols
5 were purified using high performance gel-permeation
chromatography5 after silica gel column chromatogra-
phy. Their odors were scaled by the human nose of two
test subjects in descending order of odor with benzyl
mercaptan being the most foul-smelling (5) and the
odorless thiol (0). The silylated benzyl mercaptans have
Table 1. Syntheses and odor scales of trialkylsilylphenylmethanethiols 5
Entry
Substrate
R3SiCl
R
Yield (%)
Odor scalea of 5
3
4
5
A
B
1
2
3
4
5
6
7
8
9
para
meta
ortho
para
meta
ortho
para
meta
ortho
Me
Me
Me
Et
Et
Et
Pr
Pr
Pr
93
80
67
61
66
100
60
97
75
87
61
78
100
79
90
94
64
71
56
53
98
89
94
97
64
72
0
1
1
1
0
0
1
2
1
5
1
1
0
1
1
1
2
2
1
5
100
1
1
aOdor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B.
bCited from Ref. 1b.

K. Nishide et al. / Tetrahedron Letters 43 (2002) 8569–8573
Table 2. Syntheses and odor scales of trimethylsilylbenzenethiols 9
8571
Entry
Substrate
Yield (%)
Odor scalea of 9
6
7
8
9
A
B
1
2
3
para
meta
ortho
78
100
100
60
82
53
30
71
83
84
1
1
0
5
1
1
1
5
90
89b
2
2
a Odor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B.
b Treatment of TBAF was required for the cleavage of OꢀTMS bond. Overall yield.
trimethylsilylbenzenethiols (9) prepared had a faint
odor or none at all. The trimethylsilyl group on the
substituted benzenethiols had a remarkable effect in
reducing the foul smell of the parent benzenethiol.
butylammonium fluoride (TBAF) in THF10 successfully
catalyzed the Michael addition of para-trimethylsilyl-
ated benzyl mercaptan (odd entries), whereas triethyl-
amine or DBU in petroleum ether11 catalyzed the reac-
tion of para-trimethylsilylated benzenethiol (even
entries). The efficiency of the Michael addition with
a,b-unsaturated carbonyl compounds was dependent
on the nucleophilicity of the thiols. A longer reaction
time was necessary with 4-trimethylsilylbenzenethiol
than with 4-trimethylsilylphenylmethanethiol. The b-
substituents on the a,b-unsaturated carbonyl com-
pounds significantly retarded the reaction of
We substituted the odorless trimethylsilylated benzyl
mercaptan and benzenethiol for the parent compounds
in the Michael addition of a,b-unsaturated carbonyl
compounds and the results are shown in Table 3. The
benzyl mercaptan and benzenethiol silylated at the
para-position8 were selected because of the steric and
electronic nature of the trimethylsilyl group.9 Tetra-
Table 3. Michael addition and protodesilylation
Entry
a,b-Unsat. carb. compd
Thiol
n
Base (amount)
Solv.a
Temp.
Time
Yield (%)
R1
R2
R3
R4
10
11
1
2
3
4
5
6
7
8
9
H
H
H
H
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
Me
Me
H
H
H
Me
Me
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Et
1
0
1
0
1
0
1
0
1
0
TBAF (0.2 equiv.)
Et3N (0.1 equiv.)
TBAF (0.2 equiv.)
DBU (1.2 equiv.)
TBAF (0.2 equiv.)
Et3N (0.1 equiv.)
TBAF (0.2 equiv.)
DBU (1.2 equiv.)
TBAF (0.2 equiv.)
Et3N (1.2 equiv.)
THF
PE
THF
PE
THF
PE
THF
PE
rt
0°C–rt
rt
rt
rt
50°C
rt
rt
rt
0.5 h
2.5 days
0.5 h
0.5 h
0.5 h
2 days
20 h
1 day
0.5 h
6 h
100
100
95
57
98
91
71
n.r.
95
88
100
90
100
100
85
53
–
97
100
THF
PE
10
H
H
Et
rt
100
a THF: tetrahydrofuran, PE: petroleum ether.

8572
K. Nishide et al. / Tetrahedron Letters 43 (2002) 8569–8573
Scheme 2.
4-trimethylsilylphenylmethanethiol (entry 7). Further-
more, the reaction with 4-trimethylsilylbenzenethiol did
not proceed even under prolonged reaction times (entry
8). Protodesilylation3a,9a of the Michael adducts with
trifluoroacetic acid12 permitted the introduction of the
benzylthio and phenylthio groups under odorless reac-
tion conditions.
mental working conditions in which foul-smelling thiols
are used. In addition, other possible functional group
manipulations15d,16 of the trimethylsilyl group on the
benzene ring could conceivably expand the synthetic
value of these odorless silylated thiols.
Acknowledgements
Several applications of 4-trimethylsilylbenzenethiol, not
including the Michael addition, were also tested, as
shown in Scheme 2. The radical addition of 4-
trimethylsilylbenzenethiol to ethyl phenylpropiolate
under neat reaction conditions (100°C, 15 min) fol-
We are grateful for a Grant-in-Aid from the Ministry
of Education, Science, Sports and Culture of Japan, for
partial financial support of this research.
lowed
by
hydrolysis
gave
a-(4-trimethylsilyl-
phenylthio)cinnamic acid, as does benzenethiol itself
according to the literature.13 4-Trimethylsilylbenz-
enethiol can be used in the reduction of nitro groups to
oximes under reductive conditions at room temperature
for 1 h using stannous chloride (1.5 equiv.) and triethyl-
amine (5.0 equiv.).14 The 4-trimethylsilyl group on the
benzene ring can tolerate even the acidic conditions of
p-toluenesulfonic acid in benzene at reflux, 1N HCl–
MeOH at room temperature, and 6N HCl–MeOH at
0°C for 24 h, but it decomposed to benzenethiol under
stronger acidic conditions. Lewis acidic conditions,
such as boron trifluoride etherate, dibutylboron triflate,
and triethylborane were not suitable, whereas
lanthanide(III) triflates (Yb, Sc, Sm, La) did not
decompose 4-trimethylsilylbenzenethiol at room tem-
perature. In addition to protodesilylation, 4-trimethyl-
silylbenzenethiol was useful for the introduction of the
4-bromo- or 4-iodophenylthio group under odorless
conditions by electrophilic bromination or iodination
using bromine–pyridine12 or iodine monochloride,15
respectively.
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