Cu(OAc)Catalyzed Thiolation of Acyl C-H bonds with thiols using TBHP as an oxidant

Article abstract of DOI:10.1055/s-0032-1318188

Cu(OAc)promoted TBHP oxidative coupling reaction of formamides with thiols successfully proceeded through direct C-H bond activation of formamides. The corresponding S-phenyl dialkyl thiocarbamate compounds were formed with high yield under solvent-free c

Full text of DOI:10.1055/s-0032-1318188

LETTER
▌443
lCettuer (OAc)2-Catalyzed Thiolation of Acyl C–H Bonds with Thiols Using TBHP
as an Oxidant
Cu(OAc)2-Catalyzed Thiolation of Acyl C–H Bonds
Yan-qin Yuan,*a Sheng-rong Guo,a,b Jian-nan Xiang*b
a
Department of Chemistry, Lishui University, 323000 Lishui, P. R. of China
E-mail: guosr9609@lsu.edu.cn
b
College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, P. R. of China
E-mail: jnxiang@hnu.edu.cn
Received: 18.11.2012; Accepted after revision: 17.01.2013
the synthesis of S-aryl thiocarbamates via direct C–H
Abstract: Cu(OAc)2-promoted TBHP oxidative coupling reaction
bond activation of formamides (Scheme 1).
of formamides with thiols successfully proceeded through direct
C–H bond activation of formamides. The corresponding S-phenyl
dialkyl thiocarbamate compounds were formed with high yield un-
der solvent-free conditions.
To determine the optimized reaction conditions, the initial
efforts focused on the direct thiolation of morpholine-4-
carbaldehyde (1a, 1.0 mmol) with 4-chloro thiophenol
(2a, 1.2 mmol) by using TBHP (tert-butylhydroperoxide,
2.0 mmol) as oxidant at 120 °C under N2 atmosphere
Key words: TBHP, Cu(OAc)2, thiolation, thiols, formamide
Transition-metal-catalyzed C–S bond formation has been
a subject of intense study due to the importance of sulfides
and their derivatives in numerous biological and pharma-
ceutically active compounds.1 With the increasing re-
quirements for environmentally benign and atom
economic processes, over the last decades, the activation
of C–H bonds has emerged as an active field in organome-
tallic catalysis, which allows for superior step- and atom-
economic transformations.1a Among these, much effort
has been focused on C–C and C–heteroatom bonds.2
However, few examples of the formation of a C–S bond
through C–H bond cleavage have been reported before. In
2006, Yu and co-workers reported a Cu(OAc)2-catalyzed
thiolation of the 2-phenylpyridine with PhSH and
MeSSMe under oxygen atmosphere.3 Subsequently, in
2009, Fukuzawa and co-workers demonstrated a copper-
catalyzed direct thiolation of a benzoxazole C–H bond
with diaryl disulfides and aryl thiols.4 Recently, Cheng
and co-workers reported Cu-catalyzed thiolation of an
arene C–H bond with diaryl disulfides.5 Very recently, Li
described a free-metal reaction of an sp3 C–H bond with
disulfides.6
Table 1 Screening Optimal Conditions
Cl
O
O
SH
oxidant
Cu
N
S
N
H
+
O
Cl
Entry
Oxidant
Catalyst
Yield (%)a
1
2
TBHP
TBHP
DDQ
–
–
–
–
–
–
–
65
76
0
3
4
K2S2O8
(NH4)2S2O8
CAN
0
5
65
75
0
6
7
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
8
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu2O
87
84
87
83
61
70
72
71
61
65
68
77
9
10
11
12
13
14
15
16
17
18
19
Formamides such as DMF are normally used as solvents;7
a few reports are available on the direct activation of the
formamide C–H bond.8,9 Inspired by the work of Chang8a
and Reddy,9a herein, we report a high yielding protocol for
CuI
O
O
70% aq TBHP
CuBr
N
H
ArSH
+
N
SAr
Cu(OAc)2 120 °C
(1)
FeCl2
1
2
FeCl3
Scheme 1
PdCl2
SYNLETT 2013, 24, 0443–0448
Advanced online publication: 07.02.2013
Pd(OAc)2
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
a Isolated yields.10
DOI: 10.1055/s-0032-1318188; Art ID: ST-2012-W0990-L
© Georg Thieme Verlag Stuttgart · New York

444
Y.-q. Yuan et al.
LETTER
without solvent; the desired product was obtained in 65% of catalyst: Cu2O, CuI, CuBr, FeCl2, FeCl3, PdCl2 and
isolated yield after 24 hours (Table 1, entry 1), and afford- Pd(OAc)2 only gave moderate yields after 12 hours (Table
ed 76% yield with four equivalents of TBHP (Table 1, en- 1, entries 13 and 19), and Cu(OAc)2·H2O was proven to be
try 2). Encouraged by these preliminary results, we further the best catalyst, giving 3a in 87% yield. Thus, we de-
investigated other oxidants with the aim of optimizing the duced that the weak base Cu(OAc)2·H2O may play a role
reaction conditions. Oxidant screening established that to promote the TBHP to form the reaction intermediate.
TBHP was the most efficient oxidant providing the high-
With the optimal reaction conditions in hand, the scope of
est yield of the target product. No reaction was observed
both thiols and formamides was explored (Table 2 and Ta-
using the DDQ as oxidant (Table 1, entry 3), disulfide was
ble 3). Firstly, we investigated the scope of the reaction
using different substituted thiols with 1a. As depicted in
the only product when the K2S2O8 was added (Table 1, en-
try 4), and moderate isolated yields (65–75%) were isolat-
Table 2, the results demonstrated that aryl thiols, bearing
ed under (NH4)2S2O8 or CAN conditions (Table 1, entries
either electron-withdrawing group such as halo atom or
5 and 6). It is noteworthy that no reaction was observed
electron-donating groups on the aromatic ring, were per-
without TBHP (Table 1, entry 7).
fectly tolerated (Table 2, entries 1–8). For example, 4-
To our delight, Cu(OAc)2 improved the reaction greatly: methoxy-substituted thiophene smoothly underwent the
the yield of 3a was enhanced to 87% with the use of 10 reaction with 1a to afford the corresponding product 3c in
mol% of Cu(OAc)2·H2O in the presence of four equiva- 89% yield. The steric hindrance of the ortho-substituted
lents of TBHP at 120 °C after 12 hours (Table 1, entries thiols had a quite limited effect on the yield of the reaction
8), a yield of 84% was obtained when 5 mol% of (Table 2, entries 9–13); the ortho-substituted 2-methoxy-
Cu(OAc)2·H2O were used, and a yield of 87% was ob- thiophene also delivered 81% yield of 3g. Unfortunately,
served with 20 mol% of Cu(OAc)2·H2O (Table 1, entries aryl thiols with very strong electron-withdrawing func-
9 and 10). The reaction temperature also affected the reac- tionalities, such as 4-nitrobenzenethiol, 4-(trifluorometh-
tion: 83% yield at 130 °C and 61% yield at 100 °C were yl)benzenethiol and pyridine-2-thiol, had no reaction with
observed after 12 hours (Table 1, entries 11 and 12). Other 1a (Table 2, entries 14–16). In comparison to aryl thiols,
transition metal catalysts were also employed in the reac- diaryl disulfides performed with moderate yield (61–77%,
tions to compare their catalytic activities, using 10 mol% Table 2, entries 1–6, and 9–12; see footnote c in Table 2).
Table 2 Reactions of 1a with Various Thiolsa
O
O
R
SH
70% aq TBHP
N
S
N
H
R
+
Cu(OAc)2 (10 mol%)
120 °C
O
1a
2
3a–m
Entry
Products
Yield (%)b
Entry
Products
Yield (%)b
O
S
O
S
O
N
O
3a
O
N
N
N
87
81
1
Cl
9
71c
64c
Cl
3i
O
S
O
S
O
N
N
85
83
2
3
4
10
11
12
74c
58c
3b
O
3j
O
S
O
S
O
89
82
OMe
77c
72c
MeO
3c
O
3k
O
O
S
O
N
N
S
84
80
Br
65c
76c
Br
3d
3l
Synlett 2013, 24, 443–448
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cu(OAc)2-Catalyzed Thiolation of Acyl C–H Bonds
445
Table 2 Reactions of 1a with Various Thiolsa (continued)
O
O
R
SH
70% aq TBHP
N
S
N
H
R
+
Cu(OAc)2 (10 mol%)
120 °C
O
1a
2
3a–m
Entry
Products
Yield (%)b
Entry
Products
Yield (%)b
O
S
O
S
O
N
O
N
82
5
13
73
F
61c
EtO
3e
3m
O
S
O
S
O
N
N
O
N
N
N
85
6
7
8
14
15
16
0
0
0
71c
NO2
3f
O
S
O
O
S
O
O
75
CF3
3g
O
S
O
S
O
N
78
S
N
3h
a Reaction conditions:10 1a (1.0 mmol), thiols (1.2 mmol), TBHP (4 mmol), Cu(OAc)2 (10 mol%) at 120 °C for 12 h.
b Isolated yields.
c Isolated yield of disulfides with 1a.
Secondly, we examined the other formamides, such as pi- direct C–S coupling reaction without any target product,
peridine-1-carbaldehyde (1b), and N,N-dimethyl for- supporting the proposed radical pathway.9a
mamide (1c) with different aryl thiols. As depicted in
Table 3, a series of electron-donating groups on the phe-
nyl ring of thiols, such as para-methyl, ortho-methyl,
para-methoxy, ortho-methoxy, ortho-halo and para-halo,
afforded the corresponding products in moderate to good
yields (Table 3, entries 1–13 and 15–27). Disappointingly,
In conclusion, a high yielding, efficient, green methodol-
ogy for the synthesis of S-phenyl dialkyl thiocarbamate
compounds through direct oxidation of acyl C–H was de-
veloped. Moreover, this is a new methodology for the
construction of C–S bonds.
the N-aryl formamide and formamide did not work under
the current condition (Table 3, entries 14 and 28).
O
O
SH
+
R
70% aq TBHP
N
H
On the basis of above results and previous publica-
tions,9,11,12 a plausible catalytic cycle is presented in
Scheme 2. This was attributed to the tendency of thiols to
form intermediate A with Cu(OAc)2; intermediate A de-
composes TBHP to form hydroxyl and tert-butoxy radi-
cals. The hydroxyl can react with intermediate A to form
the trivalent copper salt (intermediate B). The tert-butoxy
radicals can abstract hydrogen from the reacting for-
mamide to generate the corresponding radical, which re-
acts with the copper complex affording the desired
products. Furthermore, the radical scavenger (2,2,6,6-tet-
ramethylpiperidin-1-yl)oxyl (TEMPO) was added to the
above reaction system. The TEMPO prevented the desired
R
N
S
Cu(OAc)2, 120 °C
Cu(OAc)2
(III)
– H2O
S
OAc
Cu
– Cu(OAc)2
AcOH
S
OAc
Cu
B
OH
N
R
t-BuOOH
(II)
A
+
O
+
O
N
H
AcOH
t-BuO
Scheme 2
© Georg Thieme Verlag Stuttgart · New York
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446
Y.-q. Yuan et al.
LETTER
Table 3 Reactions of 1b and 1c with Various Thiolsa
O
O
R
N
H
N
O
S
SH
1b
70% aq TBHP
4a–m
R
+
O
Cu(OAc)2 (10 mol%)
120 °C
2
Me2N
H
R
Me2N
S
1c
5a–m
Entry
1
Products
Yield (%)b
Entry
Products
Yield (%)b
O
S
O
S
Me2N
N
81
15
84
4a
5a
O
S
O
S
N
Me2N
OMe
OMe
2
3
4
5
6
84
83
82
76
81
16
17
18
19
20
85
82
80
79
80
5b
4b
O
S
O
S
Me2N
N
Cl
Br
F
Cl
4c
5c
O
S
O
S
N
Me2N
Br
4d
5d
O
S
O
S
N
Me2N
F
4e
5e
O
S
O
S
N
Me2N
4f
5f
O
S
O
N
Me2N
5g
S
S
7
8
77
72
21
22
75
70
S
4g
O
S
N
O
Me2N
5h
S
S
4h
O
O
S
N
Me2N
9
74
23
77
Me
5i
4i
Synlett 2013, 24, 443–448
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cu(OAc)2-Catalyzed Thiolation of Acyl C–H Bonds
447
Table 3 Reactions of 1b and 1c with Various Thiolsa (continued)
O
O
R
N
H
N
O
S
SH
1b
70% aq TBHP
4a–m
R
+
O
Cu(OAc)2 (10 mol%)
120 °C
2
Me2N
H
R
Me2N
S
1c
5a–m
Entry
10
Products
Yield (%)b
Entry
Products
Yield (%)b
O
O
S
N
N
Me2N
S
S
76
71
74
24
25
26
71
65
68
OMe
OMe
5j
4j
O
O
S
Me2N
11
12
Cl
Cl
5k
4k
O
S
O
N
Me2N
S
Br
Br
5l
4l
O
S
O
N
Me2N
S
13
14
65
0
27
28
70
0
OEt
EtO
5m
4m
O
S
O
N
H2N
H
S
a Reaction conditions:10 1b (or 1c; 1.0 mmol), thiols (1.2 mmol), TBHP (4 mmol), Cu(OAc)2 (10 mol%) at 120 °C for 12 h.
b Isolated yields.
(d) Berger, M. D.; Dutia, M.; Powell, D.; Floyd, B. M.;
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Klaus, H. Chem. Rev. 2010, 110, 1060. (d) Thomas, W. L.;
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Acknowledgment
This work was supported by the Natural Science Foundation of
Zhejiang Province, P. R. of China (Project Y407240), the Key Sci-
ence Foundation of Lishui University (project KY07002), the
Department of Science and Technology Foundation of Hunan Pro-
vince (2010SK2001) and the Hunan Natural Science Foundation
(11JJ5008).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 443–448

448
Y.-q. Yuan et al.
LETTER
10 mL). The organic layers were combined, dried over
anhyd Na2SO4, concentrated under reduced pressure, and
purified over a column of silica gel (EtOAc–hexane as
eluent) to give product 3a in 87% yield. 1H NMR (300 MHz,
CDCl3): δ = 7.34−7.43 (m, 4 H), 3.72 (t, J = 5.1 Hz, 4 H),
3.59 (t, J = 4.8 Hz, 4 H). 13C NMR (75 MHz, CDCl3): δ =
164.6, 135.9, 134.8, 128.2, 125.5, 65.4, 44.3. The identity
and purity of other products were confirmed by1H NMR and
13C NMR spectroscopic analysis.
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(10) Typical Procedure: Under a N2 atmosphere, a reaction
vessel was charged with 1a (or 1b, 1c) (1.0 mmol), ArSH 2
(1.2 mmol), Cu(OAc)2·H2O (10 mol%), and 70% aq TBHP
(4 mmol). The mixture was stirred at 120 °C and monitored
by TLC. Upon completion of the reaction (approximately
12 h), the mixture was cooled to r.t. and mixed with H2O
(15.0 mL). The product was then extracted with CH2Cl2 (3 ×
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Synlett 2013, 24, 443–448
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