Development of Odorless Thiols and Sulfides and Their Applications to Organic Synthesis

Article abstract of DOI:10.1007/s00706-003-0122-1

Development of new odorless thiols (dodecanethiol, 4-n- heptylphenylmethanethiol, 4-trimethylsilylphenylmethanethiol, 4-trimethylsilylbenzenethiol) and an odorless sulfide (1-methylsulfanyldodecane) and their applications to dealkylation, Michael addition, Swern oxidation, and Corey-Kim oxidation are described.

Full text of DOI:10.1007/s00706-003-0122-1

Monatshefte f€ur Chemie 135, 189–200 (2004)
DOI 10.1007/s00706-003-0122-1
Development of Odorless Thiols and Sulfides
and Their Applications to Organic Synthesis
Kiyoharu Nishide, Shin-ichi Ohsugi, Tetsuo Miyamoto,
ꢀ
Kamal Kumar, and Manabu Node
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
Received September 8, 2003; accepted (revised) September 15, 2003
Published online January 27, 2004 # Springer-Verlag 2004
Summary. Development of new odorless thiols (dodecanethiol, 4-n-heptylphenylmethanethiol, 4-tri-
methylsilylphenylmethanethiol, 4-trimethylsilylbenzenethiol) and an odorless sulfide (1-methyl-
sulfanyldodecane) and their applications to dealkylation, Michael addition, Swern oxidation, and
Corey-Kim oxidation are described.
Keywords. Dealkylation; Michael addition; Alcohols; Swern oxidation; Corey-Kim oxidation.
Introduction
Thiols and sulfides are fundamental and important functional groups in organic
chemistry, and the literature contains ample reports on the organic and bioorganic
chemistry of this group [1]. Among them, benzenethiol is a main component for
the syntheses of heterocycles containing a sulfur atom. Commonly used thiols and
sulfides like ethanethiol, benzyl mercaptan, benzenethiol, and dimethyl sulfide
have malodor making their use difficult and unpleasant. The problem becomes
even worse in industry where these malodorous reagents are used on a large scale.
In an application of green chemistry, odorless substitutes are therefore always
required for the prevention of environmental pollution and stress of the researchers
working with them. In order to improve this drawback, an odorless bulky thiol [2]
and an odorless sodium dithiocarboxylate [3] were reported for demethylations of
phenyl methyl ethers and methyl phosphates. Based on our knowledge of a chiral
1,3-mercapto alcohol used in a novel tandem Michael addition – Meerwein-
Ponndorf-Verley reduction [4], we developed a chiral odorless synthetic equivalent
of hydrogen sulfide for the Michael addition [5]. Recently, odorless versions of the
Corey-Kim oxidation [6] and the Swern oxidation [7, 8] have been published using
odorless substitutes for dimethyl sulfide. We report herein the development of new
odorless thiols and sulfides to replace the usual foul-smelling ones, and their
ꢀ
Corresponding author. E-mail: node@mb.kyoto-phu.ac.jp

190
K. Nishide et al.
applications in organic synthesis, i.e., dealkylation, Michael addition, Swern oxi-
dation, and Corey-Kim oxidation.
Results and Discussions
The Exploitation of Odorless Dod-SH (1)
and 4-n-Heptylphenylmethanethiol (2) [9]
Because the monoterpene mercapto alcohol, 10-mercaptoisoborneol, has not a foul
smell, we planned to test the odor of a number of alkanethiols. The relative odor
index of these thiols compared to the foul-smelling ethanethiol as perceived by the
human nose of two test subjects is listed in Table 1.
The odor of a thiol depends virtually entirely on its purity, i.e., 1-hexa-
decanethiolpurifiedbyHPLConaGPCcolumnwasfoundtobealmostodorless,while
the commercial 1-hexadecanethiol had essentially the same odor as indicated in a
chemical catalog. Therefore, purification of all these thiols was done on HPLC
using a GPC column before analyzing their respective odors. Among the
alkanethiols, 1-dodecanethiol (Dod-SH, 1) was found to be odorless, while lower
carbon-chain thiols were found to be malodorous. These facts suggest that the foul
smell of thiol toward the human olfactory cell is related to the length of its carbon-
chain.
We next examined the odor of benzyl mercaptans having an alkyl chain at their
para-position. Results of the odor testing of various thiols are shown in Table 2.
Table 1. Odor scale for alkanethiols
Entry
Thiols
Carbon atoms
in chain
Bp=ꢁCa
Odor scaleb
A
B
1
2
CH3CH2SH
2
3
35
5
5
5
4
3
4
2
2
1
1
0
0
0
0
5
5
4
3
3
3
1
1
1
0
0
1
0
0
CH3(CH2)2SH
CH3(CH2)3SH
CH3(CH2)4SH
CH3(CH2)5SH
CH3(CH2)6SH
CH3(CH2)7SH
CH3(CH2)8SH
CH3(CH2)9SH
CH3(CH2)10SH
CH3(CH2)11SH (1)
CH3(CH2)13SH
CH3(CH2)14SH
CH3(CH2)15SH
67–68
3
4
98
4
5
126
5
6
150–154
6
7
173–176
7
8
197–200
8
9
220
9
10
11
12
14
15
16
114=13 mm Hg
103–104=3 mm Hgc
266–283
298–320 (mp 7)c
125–128=0.1 mm Hgd
184–191=7 mm Hg
(mp 18–20)
10
11
12
13
14
a
Cited from the Aldrich chemical catalog unless otherwise noted; b odor scale: foul-smelling 5 to odorless 0 by
the human nose of two test subjects A and B; c cited from ‘‘Dictionary of Organic Compounds’’ 2nd Ed., 1989,
d
Koudansya, Tokyo; experimental data

Development of Odorless Thiols and Sulfides
191
Table 2. Odor scale for benzylic mercaptans
Entry
Thiols
Odor scalea
A
B
1
2
3
4
5
6
7
8
PhCH2SH
5
1
2
2
0
0
1
1
5
1
1
1
1
0
0
1
4-t-BuPhCH2SH
4-n-BuPhCH2SH
4-n-PentPhCH2SH
4-n-HexPhCH2SH
4-n-HeptPhCH2SH (2)
4-n-OctPhCH2SH
4-n-NonPhCH2SH
a
Odor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B
Fig. 1. Synthetic applications of odorless thiols 1 and 2
4-n-Heptylphenylmethanethiol (2) was chosen as the odorless substitute for benzyl
mercaptan.
Some applications using odorless 1 and 4-n-heptylphenylmethanethiol (2) are
shown in Fig. 1. Previously, we developed useful reagent systems (hard Lewis
acid–thiol) for the demethylation of aliphatic and aromatic methyl ethers [10].
The yields of the parent alcohols and phenols from methyl, benzyl, and MOM
ethers using aluminum chloride and 1 were very high, similar to those using the
previous reagent system. The selective demethylation of a phenolic methyl ether in
the presence of methyl ester was observed using the new reagent system. We have
also demonstrated that the odorless 2 can be used instead of the parent benzyl
mercaptan in the Michael addition of a thiol to an ꢀ,ꢁ-unsaturated ketone. Reduc-
tive cleavage of the benzylic carbon–sulfur bond with sodium metal in liquid
ammonia gave the 1,3-mercapto alcohols in good yields.

192
K. Nishide et al.
The Exploitation of Odorless TMSBM and TMSBT [11]
The odorless benzyl mercaptan 2 could not be used to introduce a benzylthio group
because removal of the heptyl group on the benzene ring proved to be difficult.
Therefore, we developed new odorless thiols, which possessed a removable sub-
stituent on the phenyl and the benzyl groups. 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 (Table 2, Entry 2). We therefore envisioned introduc-
ing a more bulky trialkylsilyl 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.
Protodesilylation [12] would permit the introduction of a phenylthio or benzylthio
group into the substrates under the odorless reaction conditions.
The syntheses and odor scales of trialkylsilylphenylmethanethiols 5 are shown
in Table 3. The silylated benzyl mercaptans have considerably less odor than the
parent benzyl mercaptan 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 substituted products were found to have a very
faint odor and in some cases were virtually odorless, regardless of the position of
Scheme 1
Table 3. Odor scales of trialkylsilylphenylmethanethiols 5
Substrate
R3SiCl
Yield=%
Odor scalea
R
3
4
5
A
B
a
b
c
para
meta
ortho
Me
Me
Me
93
80
67
75
87
61
71
56
53
0
1
1
1
1
0
d
e
f
para
meta
ortho
Et
Et
Et
61
66
78
98
89
94
1
0
0
1
1
1
100
79
100
g
h
i
para
meta
ortho
Pr
Pr
Pr
60
97
90
94
64
97
64
72
1
2
1
2
2
1
100
PhCH2SHb
4-t-BuPhCH2SHb
5
1
5
1
a
Odor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B; b cited
from Table 2

Development of Odorless Thiols and Sulfides
193
Scheme 2
Table 4. Odor scales of trimethylsilylbenzenethiols 9
Entry
Substrate
Yield=%
Odor scalea
6
7
8
9
A
B
a
b
c
para
meta
ortho
78
100
100
60
82
53
30
71
83
84
1
1
0
1
1
1
90
89b
cf. PhSH
5
2
5
2
4-t-BuPhSH
a
Odor scale: foul-smelling 5 to odorless 0 by the human nose of two test subjects A and B;
b
treatment with TBAF was required for the cleavage of O-TMS bond, overall yield
Scheme 3
Table 5. Michael additions of 5a and 9a and protodesilylation
Entry
ꢀ,ꢁ-Unsat. carb. compd.
Thiol
Base
(amount)
Solv.a
Temp.
Time
Yield=%
R1
R2
R3
R4
n
10
11
1
2
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 eq)
Et3N (0.1 eq)
TBAF (0.2 eq)
DBU (1.2 eq)
TBAF (0.2 eq)
Et3N (0.1 eq)
TBAF (0.2 eq)
DBU (1.2 eq)
TBAF (0.2 eq)
Et3N (1.2 eq)
THF
PE
rt
0.5 h
2.5 d
0.5 h
0.5 h
0.5 h
2 d
100
100
95
88
H
H
H
0ꢁC-rt
100
90
3
H
H
Me
Me
H
THF
PE
rt
4
H
H
rt
57
100
100
85
5
Me
Me
Me
Me
Me
Me
H
THF
PE
rt
50ꢁC
98
6
H
H
91
7
Me
Me
H
H
THF
PE
rt
20 h
1 d
71
53
8
H
rt
n.r.
95
–
9
H
THF
PE
rt
0.5 h
6 h
97
10
H
H
Et
rt
100
100
a
THF: tetrahydrofuran, PE: petroleum ether

194
K. Nishide et al.
the substituent on the benzene ring. 4-Trimethylsilylphenylmethanethiol (TMSBM,
5a) [18] was chosen as a representative for silylated benzyl mercaptans.
Next we applied this knowledge of the odor reducing effect of the TMS group
to benzenethiols. The syntheses and odor scales of trimethylsilylbenzenethiols
9 are summarized in Table 4. Ortho-, meta-, and para-bromophenols were trans-
formed into the trimethylsilylbenzenethiols 9 by silylation, N,N-dimethylami-
nothiocarbamoylation, the Newman-Kwart rearrangement [13], and reduction.
All of the trimethylsilylbenzenethiols 9 prepared had a faint odor or none at all.
We chose 4-trimethylsilylbenzenethiol (TMSBT, 9a) [19] as a representative
for trimethylsilylbenzenethiols. The trimethylsilyl group on the substituted
benzenethiols had a remarkable effect in reducing the foul smell of the parent
benzenethiol.
In order to test the ability of 5a and 9a as odorless substitutes for the parent
thiols, we demonstrated the Michael addition of ꢀ,ꢁ-unsaturated carbonyl com-
pounds and protodesilylation of the Michael adducts. The results are shown in
Table 5. Tetrabutylammonium fluoride (TBAF) in THF successfully catalyzed
the Michael addition of 5a (odd entries), whereas triethylamine or DBU in petro-
leum ether catalyzed the reaction of 9a (even entries). The efficiency of the
Michael addition with ꢀ,ꢁ-unsaturated carbonyl compounds was dependent on
the nucleophilicity of the thiols. A longer reaction time was necessary with 9a
than with 5a. The ꢁ-substituents on the ꢀ,ꢁ-unsaturated carbonyl compounds sig-
nificantly retarded the reaction of 5a (Entry 7). Furthermore, the reaction with 9a
did not proceed even under prolonged reaction time (Entry 8). Protodesilylation of
the Michael adducts with trifluoroacetic acid [12b] permitted the introduction of
the benzylthio and phenylthio groups under odorless reaction conditions.
New Odorless Swern and Corey-Kim Oxidations
Utilizing Dod-S-Me [14]
The Swern oxidation (DMSO-oxalyl chloride) [15] is the most commonly used for
oxidation of primary or secondary alcohols to aldehydes or ketones. Among its
many advantages are mild conditions, stability of acid sensitive functional groups,
no epimerization of the ꢀ-carbon of the carbonyl group, easy work-up, gaseous
byproducts (carbon dioxide and carbon monoxide), and rapid reaction rate [16].
Fig. 2. A new odorless Swern oxidation

Development of Odorless Thiols and Sulfides
195
Nevertheless, one important drawback is the foul odor of the volatile dimethyl
sulfide produced, which is regulated by the offensive odor control law. From an
environmental standpoint, the need for odorless substitutes for foul-smelling mole-
cules like dimethyl sulfide is therefore great.
1-Methylsulfanyldodecane (Dod-S-Me, 12) synthesized from odorless Dod-SH
was found to be odorless, whereas the low alkyl methyl sulfides were malodorous.
We developed a new odorless Swern oxidation using the corresponding sulfoxide
(Dod-S(O)-Me, 13), as shown in Fig. 2.
The optimized reaction conditions for the new odorless Swern oxidation using
12 afforded high yields of the products (Table 6).
Table 6. Odorless Swern oxidation of alcohols using 13
Substrate
Conditions (temp. and
Yield=%a
time after Et3N addition)
Aldehyde or
ketone (lit.)b
Recovery
of 12
benzhydrol
ꢂ60ꢁC ꢃ ꢂ40ꢁC (3.33 h)
ꢂ40ꢁC ꢃ rt (1 h)
95 (98)
91 (95)
95
100
94
95
93
89
99
91
95
benzoin
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
ꢂ60ꢁC ꢃ ꢂ40ꢁC (5 h)
ꢂ40ꢁC ꢃ rt (1 h)
2-bromophenylmethanol
cinnamyl alcohol
geraniol
93 (98)
93 (95)
93 (99)
91 (95)
81 (98)
1-adamantanemethanol
(1S,2R,4S)-borneol
2-octanol
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
ꢂ60ꢁC ꢃ ꢂ40ꢁC (2 h)
ꢂ40ꢁC ꢃ rt (40 min)
a
b
Isolated yield; See Ref. [16c]
Table 7. Odorless Corey-Kim oxidation of alcohols using 12
Yield=%a
NCS ð3 equiv:Þ
12 ð3 equiv:Þ
Alcohols ꢂꢂꢂꢂꢂꢂꢂ! Aldehyes or ketones
Et N ð5 equiv:Þ
3
ꢁ
ꢂ40 C ð14 hÞ
in CH2Cl2
in toluene
benzhydrol
benzoin
95
99
91
99
98
b
–
cinnamyl alcohol
3,5-bis(benzyloxy)-
4-methoxyphenylmethanol
testosterone
90
95
91
97
a
b
Isolated yields; the starting material was insoluble

196
K. Nishide et al.
The other oxidation of alcohols using dimethyl sulfide and N-chlorosuc-
cinimide is known as the Corey-Kim oxidation [17]. Instead of using dimethyl sulfide,
we applied 12 to this oxidation. The results of the new odorless Corey-Kim oxida-
tion are compiled in Table 7. The yields of the products were excellent.
Conclusion
We were able to provide new odorless thiols 1, 2, 5a, 9a, and an odorless sulfide
12, which were applied successfully to dealkylation, Michael addition, Swern oxi-
dation, and Corey-Kim oxidation. These new odorless methods should replace
the classical reactions. We believe that the odorless feature of these new methods
is important for green chemistry as well as for synthetic organic chemistry in
general.
Experimental
Melting points were taken on a micro hot-stage apparatus (Yanagimoto) and were uncorrected. Infrared
(IR) spectra were recorded on a JASCO IR-810 or a Shimadzu FTIR-8300 diffraction grating infrared
1
spectrophotometer and H NMR spectra were obtained on a JEOL JNM-AL300 or a Varian Unity
INOVA-400 spectrometer with tetramethylsilane as an internal standard. Mass spectra (MS) were
determined on a JEOL JMS-SX 102A QQ or a JEOL JMS-GC-mate mass spectrometer. Combustion
analysis was done on a Perkin Elmer Series II CHNS=O Analyzer 2400. Their results agreed favour-
ably with calculated values. Wakogel C-200 (silica gel) (100–200 mesh, Wako) was used for open
column chromatography. Flash column chromatography was performed with Silica Gel 60N (Kanto
Chemical Co., Inc.). Kieselgel 60 F-254 plates (Merck) were used for thin layer chromatography
(TLC). When necessary, compounds were further purified by a recycle HPLC (JAI LC-908) on
GPC column (JAIGEL 1H and 2H) after purification on silica gel or distillation.
1-Dodecanethiol (1) is available from Sigma-Aldrich Fine Chemicals Co. Ltd., or Wako Pure
Chemical Industries, Ltd., but distillation is required for getting pure odorless compound for use.
Dodecyl methyl sulfide (12) is also available from Pfaltz and Bauer Chemicals Co. Ltd. or Lancaster
Co. Ltd. Dodecyl methyl sulfoxide (13) is now available from Wako Pure Chemical Industries, Ltd.
Tetrahydrofuran (THF) and ether were distilled from sodium benzophenone ketyl, and CH2Cl2 was
distilled from CaH2 after ten washings with H2O to remove methanol contaminants. N,N-Dimethyl-
formamide (DMF) was also distilled from CaH2 before use.
Preparation of 4-n-Heptylphenylmethanethiol (2)
To an ether (100 cm3) suspension of 234 mg of CuBrꢄ Me2S (1.14 mmol, 0.6 equiv) and 500mg of
ꢀ,ꢀ0-dibromo-p-xylene (1.89 mmol) a THF solution (3cm3) of n-hexylmagnesium bromide (prepared
from n-hexyl bromide (2.84 mmol, 1.5 equiv) and Mg metal by the standard method) was added
dropwise over 10 min under nitrogen atmosphere at 0ꢁC, and the reaction mixture was stirred for
6 h at the same temperature. The reaction mixture was poured into 20cm3 of cool 1 N HCl, and was
extracted with ether (2 ꢅ 40 cm3). The organic layer was washed with brine, dried (MgSO4), and the
solvent was evaporated under reduced pressure. Purification of the crude product by silica gel column
1
chromatography using hexane as eluent gave 213 mg of 4-n-heptylphenylmethyl bromide (41%). H
NMR (CDCl3, 400 MHz): ꢂ ¼ 0.87 (t, J ¼ 6.80Hz, CH3), 1.23–1.34 [m, (CH2)4], 1.56–1.65 (m, CH2),
2.58 (t, J ¼ 7.60Hz, ArCH2), 4.49 (s, CH2Br), 7.14 (d, 2H, J ¼ 8.05Hz, ArH); MS (70 eV): m=z ¼ 270
(Mþþ2, 2.7), 268 (Mþ, 2.5), 190 (16), 189 (100); HRMS: calcd. for C14H21Br (Mþ): 268.0826, found:
268.0822.

Development of Odorless Thiols and Sulfides
197
A mixture of 212 mg of 4-n-heptylphenylmethyl bromide (0.79 mmol) and 60mg of thiourea
(0.79 mmol) in 2 cm3 of ethanol was refluxed for 14h. The reaction mixture was cooled and diluted
with 5 cm3 of ether to precipitate the thiouronium salt. The 221 mg of thiouronium salt (81%) were
filtered off. White solid; mp 164.5–165.0ꢁC; MS (70 eV): m=z ¼ 265 [(Mþþ1)ꢂ80, 2.6], 264
(Mþꢂ80, 27), 231 (12), 190 (16), 189 (100), 105 (50); HRMS: calcd. for C15H24N2S (Mþ):
264.1660, found: 264.1663.
A mixture of 221 mg of thiouronium salt, 6 cm3 of a 6% NaOH solution, and 2 cm3 of ethanol was
refluxed with stirring for 3 h. The reaction mixture was cooled and acidified with 1 N HCl. The reaction
mixture was extracted with ether (2ꢅ 20cm3). The combined ethereal layer was washed with brine,
dried (MgSO4), filtered, and the solvent was evaporated under reduced pressure to give 124mg of 2
1
(87%) as a colorless oil. H NMR (CDCl3, 400MHz): ꢂ ¼ 0.88 (t, J ¼ 6.95 Hz, CH3), 1.24–1.35
[m, (CH2)4], 1.57–1.64 (m, CH2), 1.74 (t, J ¼ 7.50 Hz, SH), 2.58 (t, J ¼ 7.58 Hz, ArCH2), 3.72
(d, J ¼ 7.50Hz, CH2S), 7.13 (d, 2H, J ¼ 8.05 Hz, ArH), 7.23 (d, 2H, J ¼ 8.05Hz, ArH); IR (CHCl3):
ꢃꢀ¼ 3009, 2928, 2858.3, 2581 (SH), 1612, 1512, 1466, 1377, 1258, 1115, 1022, 895, 826 cmꢂ1; MS
(70 eV): m=z ¼ 224 (Mþþ2, 1.2), 223 (Mþþ1, 3.6), 222 (Mþ, 20), 190 (18), 189 (100); HRMS: calcd.
for C14H22S (Mþ): 222.1442, found: 222.1443.
Preparation of 4-Trimethylsilylphenylmethanethiol (5a) [18]
To a THF solution (100cm3) of 10 g of 4-bromotoluene (58 mmol) n-BuLi (2.7 M n-hexane solution,
48cm3, 128 mmol) was added slowly at ꢂ78ꢁC, and the resulting mixture was stirred for 40min, then
trimethylsilyl chloride (18 cm3, 145 mmol) was added. The reaction was monitored by TLC to con-
sume 4-bromotoluene. The reaction mixture was quenched with saturated-NH4Cl solution, and
extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4), filtered,
and concentrated in vacuo. Purification of the residue by silica gel column chromatography (n-hexane)
1
gave 8.9 g of p-tolyltrimethylsilane (93%). H NMR (CDCl3, 300MHz): ꢂ ¼ 0.29 [s, Si(CH3)3], 2.34
(s, ArCH3), 7.19 (d, 2H, J ¼ 7.43 Hz, ArH), 7.41 (d, 2H, J ¼ 7.98 Hz, ArH); MS (70 eV): m=z ¼ 165
(Mþþ1, 2.2), 164 (Mþ, 13), 150 (15), 149 (100), 121 (12); HRMS: calcd. for C10H16Si (Mþ):
164.1021, found: 164.1027.
A mixture of 400 mg of p-tolyltrimethylsilane (2.4mmol), 434 mg of N-bromosuccinimide
(2.4mmol), and 3 mg of benzoyl peroxide (cat.) in 6 cm3 of CCl4 was refluxed for 2 h. The solvent
was evaporated under reduced pressure. Purification of the residue by silica gel column chromatogra-
1
phy (n-hexane) gave 440 mg of 4-trimethylsilylphenylmethyl bromide (75%). H NMR (300 MHz,
CDCl3): ꢂ ¼ 7.51 (d, J ¼ 8.2 Hz, 2H), 7.37 (d, J ¼ 8.2 Hz, 2H), 4.50 (s, 2H), 0.27 (s, 9H); IR (CHCl3):
ꢃꢀ¼ 2959, 2361, 1917, 1601, 1250 cmꢂ1; MS (70 eV): m=z ¼ 244 (Mþþ2, 3), 242 (Mþ, 3), 229 (27),
227 (26), 163 (100), 148 (46), 148 (46), 135 (17), 110 (7), 105 (31), 91 (11); HRMS: calcd. for
C10H15BrSi: 242.0126, found: 242.0128.
A mixture of 150 mg of 4-trimethylsilylphenylmethyl bromide (0.62 mmol) and 180mg of thiourea
(0.62 mmol) in 3 cm3 of ethanol was refluxed for 14h. After bubbling the reaction mixture with N2 gas,
2 cm3 of a 10% NaOH solution were added and the reaction mixture was refluxed for additional 3 h.
The reaction mixture was neutralized with 1 N HCl, and extracted with ether. The ethereal layer was
washed with H2O, dried (MgSO4), filtered, and concentrated in vacuo. Purification of the residue by
silica gel column chromatography (n-hexane) gave 81mg of 5a (71%) [18]. 1H NMR (CDCl3,
300 MHz): ꢂ ¼ 0.27 [s, Si(CH3)3], 1.76 (t, J ¼ 7.61Hz, SH), 3.74 (d, J ¼ 7.61Hz, CH2S), 7.31 (d,
2H, J ¼ 7.98 Hz, ArH), 7.49 (d, 2H, J ¼ 7.70Hz, ArH); MS (70 eV): m=z ¼ 196 (Mþ, 3), 165 (5), 164
(17), 163 (100), 149 (6), 148 (11), 135 (17).
Preparation of 4-Trimethylsilylbenzenethiol (9a) [19]
To a THF solution (2 cm3) of 100 mg of 4-bromophenol (0.58 mmol) n-BuLi (2.7 M n-hexane solution,
478 mm3, 1.3mmol) was added slowly at ꢂ78ꢁC, and the resulting mixture was stirred for 40 min, then

198
K. Nishide et al.
trimethylsilyl chloride (158mm3, 1.5 mmol) was added. The reaction was monitored by TLC to
consume 4-bromophenol (4h). The reaction mixture was quenched with 1 N HCl, and extracted with
EtOAc. The combined organic layer was washed with brine, dried (MgSO4), filtered, and concentrated
in vacuo. Purification of the residue by silica gel column chromatography (n-hexane=EtOAc¼ 10=1)
1
gave 75 mg of 4-trimethylsilylphenol (78%). H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.43 (d, J ¼ 8.1 Hz,
2H), 6.86 (d, J ¼ 8.1Hz, 2H), 4.76 (s, 1H), 0.27 (s, 9H); IR (CHCl3): ꢃꢀ¼ 3595, 1597, 1504, 1246,
1107, 849 cmꢂ1; MS (20 eV): m=z ¼ 166 (Mþ, 9), 151 (25); HRMS: calcd. for C9H14OSi: 166.0814,
found: 166.0800.
To a DMF solution (2 cm3) of 75 mg of 4-trimethylsilylphenol (0.45 mmol) 22mg of NaH (60%,
0.54mmol) and 67 mg of dimethylthiocarbamoyl chloride (0.54mmol) were added slowly at 0ꢁC, and
the resulting mixture was heated at 85ꢁC for 6 h. The reaction mixture was neutralized with saturated-
NH4Cl solution and extracted with EtOAc. The combined organic layer was washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the residue by silica gel column chro-
matography (n-hexane=EtOAc¼ 10=1) gave 114 mg of O-(4-trimethylsilylphenyl) dimethylthiocarba-
mate (100%). 1H NMR (CDCl3, 300 MHz): ꢂ ¼ 7.54 (d, J ¼ 9.3 Hz, 2H), 7.06 (d, J ¼ 9.3Hz, 2H), 3.47
(s, 3H), 3.35 (s, 3H), 0.27 (s, 9H); IR (CHCl3): ꢃꢀ¼ 3020, 1897, 1589, 1497, 1259, 1107, 1057cmꢂ1
;
MS (70 eV): m=z ¼ 253 (Mþ, 7), 238 (3), 88 (57), 73 (9), 72 (100); HRMS: calcd. for C12H19NOSiS:
253.0957, found: 253.0955.
O-(4-Trimethylsilylphenyl) dimethylthiocarbamate (872mg, 3.4 mmol) was heated at 240ꢁC
for 4 h in a glass oven. The crude product was purified by silica gel column chromatography (n-
1
hexane=EtOAc¼ 5=1) gave 718 mg of S-(4-trimethylsilylphenyl) dimethylthiocarbamate (82%). H
NMR (CDCl3, 300 MHz): ꢂ ¼ 7.53 (d, J ¼ 8.7 Hz, 2H), 7.46 (d, J ¼ 8.7 Hz, 2H), 3.07 (s, 6H), 0.26
(s, 9H); IR (CHCl3): ꢃꢀ¼ 3020, 1659, 1366, 1250, 1099 cmꢂ1; MS (70 eV): m=z ¼ 253 (Mþ, 8), 238
(4), 181 (2), 88 (4), 73 (5), 72 (100); HRMS: calcd. for C12H19NOSiS: 253.0957, found: 253.0966.
To a THF solution (30 cm3) of 670 mg of S-(4-trimethylsilylphenyl) dimethylthiocarbamate
(2.6mmol) 310 mg of LiAlH4 (7.9mmol) were added portionwise at 0ꢁC, and the resulting mixture
was refluxed for 12 h. The reaction mixture was quenched with saturated-MgSO4 solution and acidified
with 1 N HCl, then extracted with EtOAc. The combined organic layer was washed with brine, dried
(MgSO4), filtered, and concentrated in vacuo. Purification of the residue by silica gel column chro-
matography (n-hexane=EtOAc¼ 25=1) gave 343 mg of 9a (71%) [19]. Bp¼ 67–69ꢁC; 1H NMR
(CDCl3, 300 MHz): ꢂ ¼ 7.44 (d, J ¼ 6.0 Hz, 2H), 7.25 (d, J ¼ 8.1Hz, 2H), 2.50 (s, 1H), 0.27 (s,
9H); IR (CHCl3): ꢃꢀ¼ 3059, 1717, 1250, 1115 cmꢂ1; MS (70 eV): m=z ¼ 182 (Mþ, 27), 167 (100),
91 (8), 58 (43); HRMS: calcd. for C9H14SiS: 182.0586, found: 182.0575.
Preparation of Dodecyl Methyl Sulfide (12)
To a suspension of 751 mg of K2CO3 (5.43 mmol) in 3 cm3 of DMF a DMF solution (2cm3) of 1 g of
1-dodecanethiol (1, 4.94 mmol) and 736 mg of MeI (5.19 mmol) was added at 0ꢁC, and the resulting
mixture was stirred at room temperature for 1 h. After the filtration of the reaction mixture, the filtrate
was neutralized with 1 N HCl and concentrated in vacuo. The residue was added to H2O, then extracted
with EtOAc. The organic layer was washed with sodium thiosulfate solution, dried (MgSO4), filtered,
and concentrated in vacuo. Purification of the residue by silica gel column chromatography gave
1
922 mg of 12 (86%). Colorless oil; bp ¼ 110ꢁC (0.2mmHg); H NMR (300MHz, CDCl3): ꢂ ¼ 2.49
(t, J ¼ 7.4Hz, 2H), 2.10 (s, 3H), 1.59 (sextet, J ¼ 7.4 Hz, 2H), 1.43–1.19 (m, 15H), 0.88 (t, J ¼ 6.9 Hz,
3H).
Typical Procedure for the New Odorless Swern Oxidation
Using Dodecyl Methyl Sulfoxide (13)
To a suspension of 95mg of 13 (0.41 mmol) in 4 cm3 of CH2Cl2 oxalyl chloride (1.0 M CH2Cl2
solution, 0.41cm3, 0.41 mmol) was added dropwise at ꢂ60ꢁC, and the resulting mixture was stirred for

Development of Odorless Thiols and Sulfides
199
15min. A CH2Cl2 solution (1 cm3) of 50mg of benzhydrol (0.27 mmol) was added dropwise at ꢂ60ꢁC.
The mixture was stirred for 30 min, 189 mm3 triethylamine (1.36 mmol) were added dropwise, and the
resulting mixture was gradually warmed to ꢂ40ꢁC within 200 min. The reaction mixture was then
warmed to room temperature by removing the cooling bath and stirred for 1 h. The mixture was
quenched with 10 cm3 of H2O, and neutralized with 0.5 cm3 of 1 N HCl, then extracted with
3 ꢅ 40cm3 of CHCl3. The combined organic layer was washed with brine, dried (Na2SO4), filtered,
and concentrated in vacuo. Purification of the residue by silica gel column chromatography
(n-hexane=EtOAc ¼ 40=1) gave 47mg of benzophenone (95%) and 60mg of 12 (100%).
A 10-times scale-up experiment under the above conditions using 500 mg of benzhydrol
(2.7mmol) gave 460 mg of benzophenone (93%), accompanied by 540 mg of 12 (92%).
Typical Procedure for the New Odorless Corey-Kim Oxidation
Using Dodecyl Methyl Sulfide (12)
To 10 cm3 of a CH2Cl2 or toluene solution of 108 mg of N-chlorosuccinimide (0.81 mmol) 2 cm3 of a
CH2Cl2 or toluene solution of 176 mg of 12 (0.81 mmol) were added dropwise at ꢂ40ꢁC, and the
resulting mixture was stirred for 30min. A CH2Cl2 or toluene solution (2cm3) of 50 mg of benzhydrol
(0.27 mmol) was added dropwise at ꢂ40ꢁC. After the mixture was stirred for 2 h, 189 mm3 of
triethylamine (1.36 mmol) were added dropwise at ꢂ40ꢁC. After stirring for 14h, 20 cm3 of H2O
were added to the reaction mixture. The mixture was neutralised with 0.5 cm3 of 1 N HCl, followed by
extraction of the aqueous layer with 3 ꢅ 40cm3 of CHCl3 or 3 ꢅ 40cm3 of EtOAc. The combined
organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Silica gel
chromatography of the residue (n-hexane=EtOAc¼ 40=1) gave 47mg of benzophenone (95% in
CH2Cl2) or 49 mg (98% in toluene).
A 20-times scale-up experiment under the above conditions using 1.0 g of benzhydrol (5.43 mmol)
gave 953 mg of benzophenone (96%).
Acknowledgments
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.
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