Development of a novel benzyl mercaptan as a recyclable odorless substitute of hydrogen sulfide

Article abstract of DOI:10.1055/s-2007-984524

2,4,6-Trimethoxybenzyl mercaptan (4) was developed as an odorless substitute of hydrogen sulfide to afford β-mercapto carbonyl compounds in a Michael addition and to convert alkyl bromides into alkanethiols. Detrimethoxybenzylation of the Michael adducts prepared from 4 and α,β-unsaturated esters or ketones was facilely carried out by treatment with a solvent mixture of trifluoroacetic acid and toluene to give β-mercapto carbonyl compounds. Successive alkaline hydrolysis of 2,4,6-trimethoxybenzyl isothiouronium salt, which was obtained as a side product, regenerated 4 accompanying disulfide 8 in good yield. The disulfide 8 was also converted into 4 by reduction with LiAlH₄. A similar protocol was applicable to the synthesis of alkanethiols using the S _N2 reaction of alkyl bromides. Our method could be complementary to the classical method of using malodorous benzyl mercaptan as a nucleophile and Birch reduction for debenzylation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984524

1930
LETTER
Development of a Novel Benzyl Mercaptan as a Recyclable Odorless Substitute
of Hydrogen Sulfide
N
ovel Benzyl Mercapt
a
an as
R
ecyc
n
lable
O
dorle
a
ss Substitu
b
te of
H
ydrog
u
e
n
Sulfide Matoba, Tetsuya Kajimoto, Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University,
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412, Japan
E-mail: node@mb.kyoto-phu.ac.jp
Received 20 April 2007
benzyl groups should be cleaved by Birch reduction re-
Abstract: 2,4,6-Trimethoxybenzyl mercaptan (4) was developed as
quiring the tedious task of handling liquid ammonia.
Therefore, we next embarked on the development of a
novel benzyl mercaptan that could be regenerated by
an odorless substitute of hydrogen sulfide to afford b-mercapto
carbonyl compounds in a Michael addition and to convert alkyl
bromides into alkanethiols. Detrimethoxybenzylation of the
Michael adducts prepared from 4 and a,b-unsaturated esters or facile treatment of Michael adducts or SN2 substitutes to
ketones was facilely carried out by treatment with a solvent mixture
of trifluoroacetic acid and toluene to give b-mercapto carbonyl
compounds. Successive alkaline hydrolysis of 2,4,6-trimethoxy-
afford b-mercapto carbonyl compounds and alkanethiols.
Benzyl mercaptans are often employed as nucleophiles in
a Michael addition to afford b-mercapto carbonyl com-
pounds, formal Michael adducts of hydrogen sulfide, by
successive debenzylation reactions. Birch reduction has
been the first choice for the debenzylation; however, the
benzyl moieties cleaved by this method were not easily
recycled to the original benzyl mercaptans. In order to
regenerate an odorless benzyl mercaptan (A) from the
Michael adducts (B), we designed a recycle pathway
treating the Michael adducts with an odorless sulfur
source, e.g., thiourea, under acidic condition followed by
alkaline hydrolysis of isothiouronium salts (C),4 which
would be obtained as a product accompanying the desired
b-mercapto carbonyl compounds (D) in the previous reac-
tion (Scheme 1). The stability of the benzyl cation (E)
generated as an intermediate in the SN1 reaction should be
significant enough to run the recycle pathway smoothly.
We found the introduction of a few methoxy groups into
the phenyl ring to be effective in making benzyl mercap-
tans odorless and stabilizing the benzyl cation. Thus,
Michael addition of ethyl p-bromocinnamate with three
methoxybenzyl mercaptans 2–45 was attempted (Table 1).
Interestingly, while the Michael addition3 resulted in ex-
cellent yields (94–99%), debenzylation of the Michael ad-
ducts 5a and 5b with thiourea and trifluoroacetic acid in
acetonitrile did not give the b-mercapto ester 6a at all
(Table 1, entries 1 and 2).6 Only the debenzylation of 5c7
under the same conditions yielded the desired product 6a8
in a good yield (Table 1, entry 3). This result could be at-
tributed to the presence of more ortho- and para-methoxy
groups that can stabilize the benzyl cation intermediate
derived from 5c, as compared with the case of 5a and 5b.
benzyl isothiouronium salt, which was obtained as a side product,
regenerated 4 accompanying disulfide 8 in good yield. The disulfide
8 was also converted into 4 by reduction with LiAlH4. A similar
protocol was applicable to the synthesis of alkanethiols using the
SN2 reaction of alkyl bromides. Our method could be complemen-
tary to the classical method of using malodorous benzyl mercaptan
as a nucleophile and Birch reduction for debenzylation.
Key words: odorless thiol, Michael addition, b-mercapto carbonyl
compound, alkanethiol, organosulfur reagent
We have developed three types of odorless benzyl
mercaptans, namely p-heptylphenylmethanethiol (1a),
p-octyloxyphenylmethanethiol (1b), and p-trimethylsil-
ylphenylmethanethiol (1c), useful as a source of the mer-
capto group, as a reagent for the synthesis of thiosugars,
and as a synthetic equivalent of the benzylthio group,
respectively (Figure 1).1–3
SH
SH
SH
n-C7H15
Me3Si
n-C8H17
O
1a
1b
1c
for the introduction
of a mercapto group
for the synthesis
of a thiosugar
for the introduction
of a benzylthio group
Figure 1 Reported odorless benzyl mercaptans 1a–c
The reagents 1a–c showed high nucleophilicity in the
Michael addition as well as in the SN2 reaction, and were
found to be useful for carrying out sulfur-involving reac-
tions under completely odorless conditions. However, a
high molecular weight, essential in making a reagent
odorless by suppressing volatility, reduced their value in
terms of atom economy. Actually, by employing the thiols
1a–c as a substitute of hydrogen sulfide, p-substituted
Next, the conditions for the detrimethoxybenzylation of
5c were optimized by changing the solvent and the
amount of trifluoroacetic acid (Table 2). Toluene gave the
best result among the employed solvents (Table 2, entries
1–3) and the suitable amount of trifluoroacetic acid was
one-fifth of the solvent in volume (Table 2, entries 4 and
6). Moreover, the amount of thiourea could be reduced to
two equivalents in the debenzylation reaction of 5c
(Table 2, entry 6).
SYNLETT 2007, No. 12, pp 1930–1934
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Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984524; Art ID: U03807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Novel Benzyl Mercaptan as Recyclable Odorless Substitute of Hydrogen Sulfide
1931
SH
O
(MeO)n
OEt
O
H2N
H2N
R
S
H
D
R
OEt
S
O
+
base
H+
NH2
R
OEt
H
B
S
NH2
SH
(MeO)n
(MeO)n
CF3CO2
A
C
aq NaOH
recycle
Proposed mechanism
SH
O
R
OEt
H
NH2
S NH2
H2N
H2N
H
S
S
SN1
O
(MeO)n
R
OEt
+
(MeO)n
CH2
(MeO)n
E
Scheme 1 Strategy for designing a new odorless benzyl mercaptan
Table 1 Comparison of Utility of New Odorless Benzyl Mercaptans 2–4 as Substitute of H2S in Michael Addition
ArCH2SH
(1.2 equiv)
thiourea
(10 equiv)
SH
O
Ar
S
5
O
O
TBAF (0.2 equiv)
OEt
OEt
OEt
TFA–MeCN
(1:1)
THF, r.t., 4 h
H
H
Br
Br
Br
r.t, 5 h
6a
Entry
ArCH2SH
Michael adduct
Yield of 5 (%)
Yield of 6 (%)
OMe
1
2
5a
99
0
0
SH
OMe
2
MeO
SH
5b
5c
94
99
MeO
OMe
3
OMe
SH
OMe
3
75
MeO
4
Other a,b-unsaturated esters as well as ketones were entries 2–5) and ketones (Table 3, entries 6 and 7), respec-
applied to the Michael addition where 4 was used as the tively, the reaction provided an excellent yield.
nucleophile (Table 3). When a catalytic amount of n-tet-
rabutylammonium fluoride and sodium hydroxide was
added to the reaction of a,b-unsaturated esters (Table 3,
Herein, the practicability of regenerating an odorless ben-
zyl mercaptan 4 from Michael adducts 5 was scrutinized
(Table 4).
Synlett 2007, No. 12, 1930–1934 © Thieme Stuttgart · New York

1932
M. Matoba et al.
LETTER
Table 2 Optimization of Condition in Debenzylation of 5c with Thiourea
OMe
TFA, solvent
SH
O
S
thiourea
O
OEt
MeO
OMe
r.t.
OEt
Br
5c
6a
Br
Entry
Solvent
MeCN
Ratio TFA–Solvent
SC(NH2)2 (equiv)
Time (h)
Yield of 6 (%)
1
2
3
4
5
6
7
1:1
1:1
1:1
1:5
1:10
1:5
1:5
10
10
10
10
10
2
5
5
75
75
95
95
86
95
72
THF
Toluene
Toluene
Toluene
Toluene
Toluene
4
4
12
4
1
12
yield (95%). Successive reduction of 10a with sodium
borohydride followed by debenzylation with sodium
metal in liquid ammonia afforded the b-mercapto alcohol
11 in 61% overall yield. Meanwhile, the nucleophilic at-
tack of 4 on 9 gave the Michael adduct 10b in good yield
(84%), and the successive reduction with sodium boro-
hydride and the debenzylation developed in the present
paper yielded 11 in 84% overall yield. Although the total
yield from 9 to 11 in the latter reaction route (70%) was as
high as that in the former route (61%), the latter route
evaded the dangerous and perplexing task of handling
sodium metal and liquid ammonia, which was required for
debenzylation in the former reaction. In addition, 4 was
applicable as a source of the mercapto group in the synthe-
sis of alkanethiols 12 by using the SN2 reaction of alkyl
bromides 13 and successive treatment of the substitutes 14
with thiourea under acidic conditions (Table 5).
Table 3 Michael Addition of a,b-Unsaturated Carbonyl Com-
pounds with 4
OMe
S
O
4, base
O
MeO
OMe
R
R
R'
THF, r.t., 4 h
R'
H
5
Entry
R
R¢
(equiv) Basea
Yield (%)
1
2
3
4
5
6
7
4-BrC6H4
4-BrC6H4
4-BrC6H4
Ph
OEt
OEt
OBn
OBn
OBn
Ph
1.2
1.2
1.2
1.2
1.2
1.3
1.3
none
0
99
TBAF
TBAF
TBAF
TBAF
NaOH
NaOH
97
91
4-MeOC6H4
Ph
100
90
In conclusion, we have succeeded in the development of a
novel odorless benzyl mercaptan 4, which is an excellent
nucleophile not only in the Michael addition but also in
the SN2 reaction, and behaves as a useful odorless substi-
tute of hydrogen sulfide by treating the products 5 and 14
with thiourea under acidic condition.12 Furthermore, after
the treatment, 4 could be facilely regenerated by alkaline
hydrolysis of the isothiouronium salt 7 generated along
with the desired b-mercapto carbonyl compounds 6,
namely the formal Michael adducts of hydrogen sulfide,
or alkanethiols 12. The disulfide 8 generated as a by-prod-
uct in the alkaline hydrolysis was also converted into 4 by
reduction with LiAlH4.
Ph
Me
99
a TBAF (0.2 equiv) or NaOH (0.1 equiv) was added.
As mentioned above, the Michael adducts 5 were treated
with thiourea in a solvent mixture comprised of trifluoro-
acetic acid and toluene to afford b-mercapto carbonyl
compounds 6 and isothiouronium salt 7,9 which was next
hydrolyzed in an alkaline solution. In general, 2,4,6-tri-
methoxybenzyl mercaptan (4) could be regenerated ac-
companying the disulfide 8 in satisfactory yields (Table 4,
entries 1–5) by this protocol. The disulfide 8 was facilely
reduced to 4 with lithium aluminum hydride. Finally, the
usefulness of 4 and of 1a were compared in the formal
reductive Michael addition of hydrogen sulfide where
(+)-pregone (9) was chosen as an acceptor substrate
(Scheme 2).10,11 In the reaction using 1a as an odorless
thiol, the Michael adduct 10a was obtained in excellent
Our method is complementary to the classical Michael
addition of benzyl mercaptans, either odorless or odorous,
followed by debenzylation using Birch reduction that re-
quires a tedious procedure involving treatment with liquid
ammonia.
Synlett 2007, No. 12, 1930–1934 © Thieme Stuttgart · New York

LETTER
Novel Benzyl Mercaptan as Recyclable Odorless Substitute of Hydrogen Sulfide
1933
Table 4 Regeneration Efficiency of a New Odorless Benzyl Mercaptan 4
OMe
OMe
NH2
NH2
SC(NH2)2
(2 equiv)
S
SH
O
O
+
S
OMe
7
MeO
OMe
R
TFA–PhMe
(1:5)
R
R'
MeO
R'
r.t.
5
6
OMe
3 M NaOH
r.t., 3 h
S
7
4
+
MeO
OMe
2
8
Entry
R
R¢
Time (h)
Yield (%) of 6
Yield (%) of 4 + 8
1
2
3
4
5
4-BrC6H4
4-BrC6H4
Ph
OEt
OBn
OBn
OBn
Ph
4
5
5
8
4
95
92
94
94
96
72 (1.0:1.0)
70 (2.2:1.0)
78 (3.3:1.0)
77 (1.0:1.8)
72 (1.0:1.2)
4-MeOC6H4
Ph
NaBH4
1a (1.3 equiv)
(3.0 equiv)
SH
OH
Na, liq. NH3
O
NaOH (0.1 equiv)
SCH2Ar
–78 °C, 2 h
66%
THF, MeOH
r.t., 30 min
97%
r.t., 24 h
95 %
11 α:β = 1 : 4
overall yield 61%
n-C7H15
10a: Ar =
O
4 (1.3 equiv)
TFA–PhMe (1:5)
NaBH4
(3.0 equiv)
9
NaOH (0.1 equiv)
SC(NH2)2 (2.0 equiv)
O
α:β = 1 : 7
overall yield 70%
11
SCH2Ar'
THF, reflux
16 h, 84%
THF, MeOH
r.t., 30 min
96%
r.t., 4 h
87%
MeO
MeO
OMe
10b: Ar' =
Scheme 2 Comparison of formal reductive Michael addition of H2S to 9 in classical and new methods
Acknowledgment
Table 5 Application of 4 in the Synthesis of Alkanethiols 12
This research was financially supported in part by the Frontier Re-
search Program and the 21st Century Center of Excellence Program
‘Development of Drug Discovery Frontier Integrated from Tradi-
tion to Proteome’ of the Ministry of Education, Culture, Sport and
Technology, Japan. We also thank the Japan Society for the Promo-
tion of Science for their support.
SC(NH2)2
(2.0 equiv)
OMe
4 (1.2 equiv)
base
R–SH
SR
OMe
R–Br
TFA–PhMe
(1:5)
r.t., 7–9 h
TBAI (0.1 equiv)
THF
MeO
13
12
14
Entry RBr
Base
(equiv) (°C)
Temp. Time Yield (%)
References and Notes
(h)
(2 steps)
(1) Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.; Miyamoto, T.
Tetrahedron Lett. 2001, 42, 9207.
(2) Hasegawa, J.; Hamada, M.; Miyamoto, T.; Nishide, K.;
Kajimoto, T.; Uenishi, J.; Node, M. Carbohydr. Res. 2005,
2360.
(3) Nishide, K.; Miyamoto, T.; Kumar, K.; Ohsugi, S.; Node, M.
Tetrahedron Lett. 2002, 43, 8569.
(4) Cossar, B. C.; Fournier, J. O.; Fields, D. L.; Reynolds, D. D.
J. Org. Chem. 1962, 27, 93.
1
2
3
C12H25Br
60
12
93
Br
r.t.
60
2
3
90
91
MeO2C
AcO(CH2)12Br
Synlett 2007, No. 12, 1930–1934 © Thieme Stuttgart · New York

1934
M. Matoba et al.
LETTER
(5) Each benzyl mercaptan was prepared starting with the
reduction of the appropriate methoxybenzaldehyde with
sodium borohydride to afford the corresponding benzyl
alcohol, which was treated with thiourea under acidic
conditions (for 2,6-dimethoxybenzyl alcohol: thiourea, HCl
in aqueous acetone, for 3,4,5-trimethoxybenzyl alcohol:
SOCl2 in Et2O and then thiourea in acetonitrile, for 2,4,6-
trimethoxybenzyl alcohol: thiourea, p-TsOH in acetonitrile).
Hydrolysis of the obtained isothiouronium salts with aq
NaOH gave 2–4 in 51–76% yields.
(9) 7: amorphous powder. 1H NMR (200 MHz, DMSO-d6): d =
3.79 (s, 3 H), 3.81 (s, 6 H), 4.28 (s, 2 H), 6.29 (s, 2 H), 8.98
(br s, 4 H). 13C NMR (50 MHz, DMSO-d6): d = 24.9, 55.7,
56.3 (2 × C), 91.2 (2 × C), 101.1, 158.9 (2 × C), 161.7, 171.1.
MS (FAB+): m/z = 257 [M+ – CF3COO–], 181, 154, 136.
HRMS: m/z [M+ – CF3COO–] calcd for C11H17N2O3S:
257.0960; found: 257.0968.
(10) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106,
29843.
(11) Eliel, E. L.; Lynch, J. E. Tetrahedron Lett. 1981, 22, 2855.
(12) Typical Procedure: 2,4,6-Trimethoxybenzyl mercaptan (4,
606 mg, 2.83 mmol) was added to a solution of ethyl p-
bromocinnamate (601 mg, 2.36 mmol) in THF (5.0 mL) in
the presence of TBAF (0.54 mmol), and the mixture was
stirred for 4 h at r.t. After the reaction was complete, the
reaction mixture was poured into 1 M HCl acid and extracted
with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and the solvent was evaporated. The residue
was purified by silica gel column chromatography (hexane–
EtOAc = 4:1) to afford 5c (1.10 g, 99%).
(6) Lin, C.-E.; Richardson, S. K.; Garvey, D. S. Tetrahedron
Lett. 2002, 43, 4531.
(7) 5c: colorless oil. 1H NMR (200 MHz, CDCl3): d = 1.12 (t,
J = 7.1 Hz, 3 H), 2.77 (dd, A part of AB, JAB = 15.6 Hz, J =
10.0 Hz, 1 H), 2.96 (dd, B part of AB, JAB = 15.6 Hz, J = 5.6
Hz, 1 H), 3.63 (s, 2 H), 3.77 (s, 6 H), 3.80 (s, 3 H), 4.00 (q,
J = 7.1 Hz, 2 H), 4.30 (dd, J = 5.6, 10.0 Hz, 1 H), 6.08 (s, 2
H), 7.24 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.8 Hz, 2 H). 13
NMR (50 MHz, CDCl3): d = 14.1, 23.8, 41.7, 45.0, 55.3,
C
55.7 (2 × C), 60.5, 90.4 (2 × C), 107.4, 120.7, 129.6 (2 × C),
131.1 (2 × C), 140.9, 158.5 (2 × C), 160.2, 170.5. IR
Next, trifluoroacetic acid (0.2 mL) was added to a
suspension of 5c (274 mg, 0.584 mmol) and thiourea (89 mg,
1.17 mmol) in toluene (1 mL), and the mixture was stirred
for 4 h at r.t. After the reaction was finished, the solvents
were removed in vacuo and the residue was washed with
hexane at 60 °C. A soluble part with hexane was evaporated
and purified by silica gel column chromatography (hexane–
EtOAc, 4:1) to afford 6a (160 mg, 95%). Meanwhile, an
insoluble part of the residue was treated with 3 M aq NaOH
at r.t. for 3 h. After the reaction was complete, the mixture
was poured into 1 M HCl acid and extracted with EtOAc.
The organic layer was washed with brine, dried over
Na2SO4, and the solvent was evaporated. The residue was
purified by silica gel column chromatography (hexane–
EtOAc, 4:1 → 2:1) to afford 4 (36.3 mg, 36%) and the
disulfide 8 (36.5 mg, 36%), which could be converted into 4
by reduction with LiAlH4.
(CHCl3): 2941, 2839, 1728, 1609, 1597, 1466, 1437, 1420,
1371 cm–1. MS (20 eV): m/z = 470 [M+ + 2], 468 [M+], 348,
256, 254, 228, 226, 211, 209, 181, 168. HRMS: m/z [M+]
calcd for C21H2579BrO5S: 468.0605; found: 468.0612.
(8) 6a: colorless oil. 1H NMR (200 MHz, CDCl3): d = 1.22 (t,
J = 7.2 Hz, 3 H), 2.23 (d, J = 6.0 Hz, 1 H), 2.94 (d, J = 7.6
Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 4.45 (dt, J = 6.0, 7.6 Hz,
1 H), 7.23 (d, J = 8.5 Hz, 2 H), 7.46 (d, J = 8.5 Hz, 2 H). 13
C
NMR (50 MHz, CDCl3): d = 14.2, 39.0, 44.4, 60.9, 121.3,
128.5 (2 × C), 131.8 (2 × C), 141.8, 170.2. IR (CHCl3): 2985,
1730, 1489, 1406, 1373 cm–1. MS (70 eV): m/z = 290 [M+ +
2], 288 [M+], 257, 255, 215, 213, 203, 201, 187, 185, 132,
104. HRMS: m/z [M+] calcd for C11H1379BrO2S: 287.9819;
found: 287.9826.
Synlett 2007, No. 12, 1930–1934 © Thieme Stuttgart · New York

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