Synthesis of N-acylsulfenamides through aerobic cross dehydrogenative coupling of thiols and amides by supported copper hydroxide catalyst

Article abstract of DOI:10.1246/cl.151090

In the presence of a supported copper hydroxide catalyst Cu(OH)_x/Al₂O₃, KF (base), and O₂ (terminal oxidant), various structurally diverse N-acylsulfenamides could be synthesized through aerobic cross-dehydrogenative coupling of benzenethiols and cyclic amides.

Full text of DOI:10.1246/cl.151090

Received: November 25, 2015 | Accepted: December 6, 2015 | Web Released: December 11, 2015
CL-151090
Synthesis of N-Acylsulfenamides through Aerobic Cross Dehydrogenative Coupling of Thiols
and Amides by Supported Copper Hydroxide Catalyst
Konomi Sakagami, Xiongjie Jin, Kosuke Suzuki, Kazuya Yamaguchi, and Noritaka Mizuno*
Department of Applied Chemistry, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656
(
E-mail: tmizuno@mail.ecc.u-tokyo.ac.jp)
In the presence of a supported copper hydroxide catalyst
Cu(OH)x/Al2O3, KF (base), and O2 (terminal oxidant), various
structurally diverse N-acylsulfenamides could be synthesized
through aerobic cross-dehydrogenative coupling of benzene-
thiols and cyclic amides.
thiols and amides.16,17 In this paper, we report that a supported
copper hydroxide catalyst (Cu(OH)x/Al2O3) can effectively
promote the CDC of thiols and amides in the presence of KF to
produce the corresponding N-acylsulfenamides using O as the
2
terminal oxidant.
A supported copper hydroxide catalyst (Cu(OH)x/Al2O3)
1
8
was prepared according to the following procedure. An
aqueous solution of CuCl ¢2H O (16.6 mM, 60 mL) containing
Organic molecules that contain X­X or X­X¤ bond(s)
2
2
(
X, X¤ = heteroatom) are of great importance; thus, construction
Al2O3 powder (2.0 g, pre-calcined at 550 °C) was vigorously
stirred at room temperature. After 15 min, the pH of the solution
was quickly adjusted to 12 by addition of an aqueous solution
of NaOH (1.0 M), and the resulting slurry was further stirred
for 24 h. The solid was then filtered off, washed with a large
amount of water, and dried in vacuo to afford 2.0 g of
Cu(OH)x/Al2O3 as a light blue powder. The copper content
in Cu(OH)x/Al2O3 was ca. 2.6 wt %. The UV­vis spectrum of
Cu(OH)x/Al2O3 showed the absorption band around 700 nm
assignable to the d­d transition of the Cu(II) species (Figure S1).
The XRD pattern of Cu(OH)x/Al2O3 was almost the same as that
of the parent Al2O3 support, and no obvious signals due to
copper oxides and hydroxides were detected (Figure S2). Thus,
Cu(II) hydroxide species are highly dispersed on Al2O3. By the
same procedure, a copper hydroxide catalyst supported on
of such linkages is one of the more important transformations
in organic synthesis. Especially, compounds possessing X­X¤
bond(s) (composed of two different heteroatoms) are useful
synthons due to the different reactivities of each heteroatom
unit and ordinarily show unique bioactivities. Amongst them,
sulfenamides, possessing S­N bond(s), have found widespread
application in many fields, for example, vulcanization accel-
erators, prodrugs, antifungal drugs, thiophilic promoters,
acetylcholinesterase inhibitors, and phototherapeutic agents.
Due to the unique reactivities of S­N bonds, sulfenamides have
1
1
2
3
4
5
7
6
8
been utilized as electrophilic sulfenylating reagents, nucleo-
9
philic aminating (or amidating) reagents, and as aminyl (or
amidyl) radical precursors.10 In addition, several unsaturated
11a
11b
bonds, such as carbon monoxide,
alkynes,
and isocya-
11c
nides, can be inserted into the S­N bonds of sulfenamides.
Classically, sulfenamides have frequently been synthesized
through cross-coupling of sulfenyl halides and amines (or
amides) in the presence of strong bases.12 As for synthesis of
N-acylsulfenamides, cross-coupling of thiols and N-halogenated
amides has occasionally been used.12 However, these procedures
require environmentally unfriendly stoichiometric reagents, such
as thionyl chloride, chlorine, and bromine, for pre-activation
of thiols or amides, and (super)stoichiometric amounts of by-
products are inevitably formed during not only the cross-
coupling but also the pre-activation steps. Thus, the develop-
ment of catalytic synthetic procedures for sulfenamides starting
directly from readily available and inexpensive thiols and
amines (or amides) without using such halogen-based stoichio-
metric reagents is an important subject of research.
Recently, cross dehydrogenative coupling (CDC) reactions
through direct activation of C­H and/or X­H bonds under
aerobic conditions using O2 as the terminal oxidant or acceptor-
less dehydrogenation conditions have emerged as synthesis tools
because they are more atom-efficient and environment-friendly
than classical cross-coupling reactions using pre-activated
substrates. Recently, we have also reported several bond-
forming reactions, e.g., C­N, P­N, Si­C, and Si­N bonds, by
catalytic CDC strategies.14 For synthesis of sulfenamides, the
copper-catalyzed aerobic CDC of thiols and amines was first
reported by Taniguchi.15 Inspired by this system, we attempted
to develop an efficient synthetic procedure for N-acylsulfen-
amides through heterogeneously catalyzed aerobic CDC of
manganese oxide-based octahedral molecular sieve (Cu(OH) /
x
1
9
OMS-2) was also prepared (Figure S2). Previously, we have
clarified that the reduction of the Cu(II) species in Cu(OH)x/
Al O readily proceeds and that the electron-transfer from
18
2
3
the copper species to OMS-2 readily takes place in the case of
19
Cu(OH)x/OMS-2.
To begin with, the Cu(OH)x/Al2O3-catalyzed CDC of p-
toluenethiol (1a) and 2-pyrrolidone (2a) to produce N-(p-
tolylthio)-2-pyrrolidone (3aa) in the presence of KF was carried
out in various solvents under O2 atmosphere (1 atm). Amongst
the solvents examined, mesitylene was the most suitable and
gave the desired N-acylsulfenamide 3aa in good yields (Table 1,
Entries 1 and 2). o-Xylene, toluene, N,N-dimethylformamide
(DMF), and N,N-dimethylacetamide (DMA) gave moderate
yields of 3aa (Entries 5­8). On the other hand, the desired
3aa was hardly produced, and the undesired disulfide 4a was
exclusively obtained through oxidative homocoupling of 1a in
1,4-dioxane and dimethyl sulfoxide (DMSO) (Entries 9 and 10).
In this system, air could be utilized, while the reaction in air was
somewhat slower than that in O2 (Entry 3). To attain high yields
of 3aa, excess amounts of 2a (at least four equiv with respect
to 1a) should be required (Entry 4). In the present CDC, bases
played an important role, and 3aa was not obtained at all when
the reaction was carried out without base (Entry 17). Organic
bases, such as N,N-diisopropylethylamine (DIEA), 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU), and 1,5,7-triazabicyclo[4.4.0]-
dec-5-ene (TBD), were ineffective (Entries 14­16). In addition,
when using TBD, the substrates were mostly converted into
1
3
Chem. Lett. 2016, 45, 173–175 | doi:10.1246/cl.151090
© 2016 The Chemical Society of Japan | 173

Table 1. CDC of p-toluenethiol (1a) and 2-pyrrolidone (2a)
under various reaction conditions
were not effective for the CDC, and 3aa was not formed at all
Entries 21 and 22). Although the reaction proceeded to some
a
(
O
O
extent when using copper(I) salts, such as CuCl and CuI, the
efficiencies were quite low compared with Cu(OH) /Al O
3
SH
S
S
x
2
N
+
HN
(
Entries 23 and 24). The catalytic activities of bulk copper
2
1
a
2a
3aa
4a
Yield/%
aa/4a
hydroxide and oxides, such as Cu(OH)2, CuO, and Cu2O, were
much lower than that of Cu(OH) /Al O (Entries 18­20),
x
2
3
Entry Catalyst
Base
Solvent
indicating that the highly dispersed copper hydroxide species are
effective for the CDC of thiols and amides.
3
1
2
3
4
5
6
7
8
9
0
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)x/Al2O3
Cu(OH)2
KF
KF
KF
KF
KF
KF
KF
KF
KF
KF
LiF
K2CO3
Mesitylene
Mesitylene
Mesitylene
Mesitylene
o-Xylene
Toluene
80/12
79/9
Although Cu(OH) /Al O was effective for the CDC,
b
c
d
x
2
3
Cu(OH)x/OMS-2 gave 3aa in only 8% yield under the
conditions described in Table 1 (Entry 25). We have previously
reported that the Cu(II) species in Cu(OH) /Al O is readily
39/35
38/38
64/17
53/24
43/34
25/52
x
2
3
1
8
reduced to the Cu(I) species. Indeed, when the fresh Cu(OH)x/
Al2O3 was treated with a mesitylene solution of 1a at room
temperature even under air, the absorption band around 700 nm
assignable to the d­d transition of Cu(II) species was signifi-
cantly weakened with the concurrent formation of 4a
DMF
DMA
1,4-Dioxane 1/>99
DMSO
Mesitylene
Mesitylene
1
1/51
(
Figure S1). Therefore, the reduction of the Cu(II) species takes
1
1
<1/79
41/41
3/82
<1/>99
17/72
<1/4
<1/54
26/69
20/63
6/75
<1/>99
<1/88
2/91
place through the thiol homocoupling in the case of Cu(OH)x/
Al2O3. In contrast, the reduction of the Cu(II) species in
Cu(OH)x/OMS-2 is intrinsically very difficult because the
electron transfer from the copper species to OMS-2 takes place
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Na2CO3 Mesitylene
DIEA
DBU
TBD
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
1
9
readily. Moreover, OMS-2 showed much higher catalytic
activity toward thiol homocoupling than with copper species,
thus suggesting that electrons from thiols readily transfer to
f
w/o
KF
KF
KF
KF
KF
KF
KF
2
0
OMS-2 (rather than to copper species). Therefore, we consider
that the in situ generated Cu(I) species is likely the active
species for the present CDC of thiols and amides.
CuO
Cu2O
Cu(OAc)2¢H2O
CuCl2¢2H2O
CuCl
The scope of the present Cu(OH) /Al O -catalyzed aerobic
x
2
3
CDC of thiols and amides is summarized in Figure 1. Various
combinations of substrates were investigated, and we found that
benzenethiols and cyclic amides were applicable to the present
system. The reactions of benzenethiol and its derivatives
possessing electron-donating as well as electron-withdrawing
substituents at each position of the phenyl rings efficiently
afforded the corresponding N-acylsulfenamides in moderate-
to-high yields. Substituted 2-pyrrolidones, cyclic urea, and 2-
azetidinone could be utilized as the nitrogen nucleophiles to
react with benzenethiols. On the other hand, aliphatic thiols and
linear amides were unsuccessful likely because of the instability
of the corresponding thiolate species and the steric and/or
electronic effects of amides. After the reaction, Cu(OH) /Al O
CuI
13/82
8/84
Cu(OH)x/OMS-2 KF
e
Al2O3
KF
KF
<1/83
<1/51
f
w/o
aReaction conditions: 1a (0.5 mmol), 2a (2 mmol), catalyst
Cu: 2 mol % with respect to 1a), base (1 mmol), solvent
2 mL), 100 °C, O2 (1 atm), 1 h. Yields (based on 1a) were
(
(
determined by GC using naphthalene as an internal standard.
b
c
d
e
KF (0.5 mmol). Air (1 atm). 2a (1 mmol). Al2O3 (25 mg).
f
w/o: without.
x
2
3
could easily be recovered by simple filtration. We confirmed by
ICP-AES analysis that no copper species was detected in the
filtrate. When the catalyst reuse experiment for the CDC of 1a
and 2a under the conditions described in Figure 1 was carried
out, the yield of 3aa decreased to 48%.
The reaction profile for the CDC of 1a to 2a showed that the
disulfide 4a was initially produced, followed by the formation of
3aa (Figure S3). In a separate experiment, we confirmed that
3aa was produced even when using 4a as the starting material
(instead of 1a) under the standard conditions (Scheme S1).
Thus, the disulfide is the intermediate for the present CDC. And
so, to elucidate the reaction mechanism, we performed the
following several control experiments. Firstly, the reaction of 4a
with 2a was performed under various conditions. As summa-
rized in Scheme S1, Cu(OH)x/Al2O3, KF, and O2 were all
indispensable components, and no production of 3aa was
observed when one of Cu(OH)x/Al2O3 and KF is missing. Only
unidentified by-product(s) (Entry 16). Amongst the bases exam-
ined, KF showed the best performance, and the reaction
proceeded well even in the presence of an equimolar amount
of KF with respect to 1a (Entry 2). K2CO3 gave a significant
amount of the desired 3aa (Entry 12), while other inorganic
bases, such as LiF and Na2CO3, were poor (Entries 11 and 13).
As stated above, the type of base used was a crucial factor.
Although we cannot clearly explain the effect at this time, we
consider that the role of the base (KF) possibly involves the
abstraction of the amide proton.
In the absence of catalysts or the presence of the Al2O3
support alone, 3aa was not formed (Entries 26 and 27). Amongst
the catalysts examined, Cu(OH)x/Al2O3 showed the highest
catalytic activity; the desired 3aa was obtained in 80% yield
under the conditions described in Table 1 (Entry 1). Copper(II)
salts, such as Cu(OAc)2¢H2O (OAc: acetate) and CuCl2¢2H2O,
174 | Chem. Lett. 2016, 45, 173–175 | doi:10.1246/cl.151090
© 2016 The Chemical Society of Japan

Supporting Information is available on http://dx.doi.org/
0.1246/cl.151090.
O
O
1
S
R
SH
+
HN
R' 2
R''
R
N
R''
N
1
R' 3
References and Notes
O
O
O
1
2
E. M. Leitao, T. Jurca, I. Manners, Nat. Chem. 2013, 5, 817.
G. Rong, Y. Chen, L. Wang, J. Li, J. Wang, M. J. Panzer, Y.
Pang, J. Appl. Polym. Sci. 2014, 131, 39699.
S
S
S
N
N
3
4
V. R. Guarino, V. Karunaratne, V. J. Stella, Bioorg. Med. Chem.
Lett. 2007, 17, 4910.
M. O’Driscoll, K. Greenhalgh, A. Young, E. Turos, S. Dickey,
D. V. Lim, Bioorg. Med. Chem. 2008, 16, 7832.
3
aa, 80% (63%)
3ba, 64% (49%)
3ca, 74% (49%)
O
O
O
S
N
S
N
S
N
5
6
S. K. Maity, N. Basu, R. Ghosh, Carbohydr. Res. 2012, 354, 40.
C. Proença, M. L. Serralheiro, M. E. Araújo, T. Pamplona, S.
Santos, M. S. Santos, F. Frazão, J. Heterocycl. Chem. 2011, 48,
1287.
A. S. Karwa, A. R. Poreddy, B. Asmelash, T.-S. Lin, R. B.
Dorshow, R. Rajagopalan, ACS Med. Chem. Lett. 2011, 2, 828.
a) G.-L. Zhao, R. Rios, J. Vesely, L. Eriksson, A. Córdova,
Angew. Chem., Int. Ed. 2008, 47, 8468. b) Y. Cai, J. Li, W.
Chen, M. Xie, X. Liu, L. Lin, X. Feng, Org. Lett. 2012, 14,
2726. c) P. Saravanan, P. Anbarasan, Org. Lett. 2014, 16, 848.
a) M. Mąkosza, M. Białecki, J. Org. Chem. 1998, 63, 4878.
b) G. Li, M. Arisawa, M. Yamaguchi, Asian J. Org. Chem.
2013, 2, 983.
O
Cl
S
3
da, 63% (60%)
3ea, 86% (61%)
3fa, 81% (71%)
O
N
O
S
N
3ab, 39%
29%)
N
(
7
8
3
ac, 60%
O
(
45%)
S
O
S
N
a
3
ae, 32%
3
(
ad, >99%
76%)
O
9
1
O
S
S
N
H
N
3
af, 45%
N
3ag, 4%
(
40%)
0 a) W. R. Bowman, D. N. Clark, R. J. Marmon, Tetrahedron Lett.
1
991, 32, 6441. b) X. Yuan, K. Liu, C. Li, J. Org. Chem. 2008,
Figure 1. Scope of the present Cu(OH)x/Al2O3-catalyzed CDC
of thiols and amides. Reaction conditions: 1 (0.5 mmol), 2
7
3, 6166.
1
1 a) H. Kuniyasu, T. Kato, S. Asano, J.-H. Ye, T. Ohmori, M.
(2 mmol), Cu(OH)x/Al2O3 (Cu: 2 mol % with respect to 1), KF
(1 mmol), mesitylene (2 mL), 100 °C, O2 (1 atm), 1 h. Yields
(based on 1) were determined by GC using naphthalene as an
Morita, H. Hiraike, S. Fujiwara, J. Terao, H. Kurosawa, N.
Kambe, Tetrahedron Lett. 2006, 47, 1141. b) T. Kondo, A.
Baba, Y. Nishi, T. Mitsudo, Tetrahedron Lett. 2004, 45, 1469.
c) D. Shiro, S. Fujiwara, S. Tsuda, T. Iwasaki, H. Kuniyasu, N.
Kambe, Tetrahedron Lett. 2015, 56, 1531.
internal standard. The values in the parentheses indicate the
a
isolated yields. TBD (0.05 mmol) was used instead of KF.
1
2 a) M. Behforouz, J. E. Kerwood, J. Org. Chem. 1969, 34, 51.
b) L. Craine, M. Raban, Chem. Rev. 1989, 89, 689. c) H. M.
Gillis, L. Greene, A. Thompson, Synlett 2009, 112. d) J. Klose,
C. B. Reese, Q. Song, Tetrahedron 1997, 53, 14411.
a stoichiometric amount of 3aa was formed when the reaction
was conducted under Ar atmosphere (Scheme S1). Notably,
when an equimolar mixture of 4a and diphenyl disulfide (4b)
was treated with Cu(OH)x/Al2O3 under the standard conditions,
a ca. 1:1:2 mixture of 4a, 4b, and p-methylphenyl phenyl
disulfide (4ab) was obtained (Scheme S2), implying the
formation of copper thiolate species. Needless to say, such a
recombination of the S­S bonds was not observed in the absence
of Cu(OH)x/Al2O3 (Scheme S2).
Based on the above-mentioned experimental results, we
here tentatively proposed a possible reaction mechanism for the
present Cu(OH)x/Al2O3-catalyzed CDC. Initially, thiol homo-
coupling takes place to produce a disulfide, and the Cu(II)
species in Cu(OH)x/Al2O3 is reduced to the Cu(I) species at this
stage (step 1 in Scheme S3). Then, the reaction of the disulfide
and a deprotonated amide nucleophile (produced through the
abstraction of amide proton by KF) affords the corresponding N-
acylsulfenamide with concurrent formation of the Cu(I) thiolate
species (step 2). In the presence of O2, the disulfide can be
regenerated from the thiolate species (step 3). At this time,
1
3 a) C. J. Scheuermann, Chem.®Asian J. 2010, 5, 436. b) C.-J. Li,
Acc. Chem. Res. 2009, 42, 335. c) Z. Li, D. S. Bohle, C.-J. Li,
Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 8928.
1
4 a) X. Jin, K. Yamaguchi, N. Mizuno, Chem. Commun. 2012, 48,
4
4
974. b) X. Jin, K. Yamaguchi, N. Mizuno, Org. Lett. 2013, 15,
18. c) K. Yamaguchi, Y. Wang, T. Oishi, Y. Kuroda, N.
Mizuno, Angew. Chem., Int. Ed. 2013, 52, 5627. d) K.
Taniguchi, S. Itagaki, K. Yamaguchi, N. Mizuno, Angew.
Chem., Int. Ed. 2013, 52, 8420. e) X. Jin, K. Yamaguchi, N.
Mizuno, Angew. Chem., Int. Ed. 2014, 53, 455.
1
1
5 a) N. Taniguchi, Synlett 2007, 1917. b) N. Taniguchi, Eur. J.
Org. Chem. 2010, 2670.
6 Intramolecular CDC: a) A. Correa, I. Tellitu, E. Domínguez, R.
SanMartin, Org. Lett. 2006, 8, 4811. b) Z. Wang, Y. Kuninobu,
M. Kanai, J. Org. Chem. 2013, 78, 7337.
1
7 During the course of our investigation, Jang and co-workers
quite recently reported the homogeneously catalyzed aerobic
CDC of thiols and amides using CuI and TBD: C. Lee, Y. N.
Lim, H.-Y. Jang, Eur. J. Org. Chem. 2015, 5934.
we cannot exclude the possibility of the formation of copper
amide species and/or high-valent Cu(III) species.1
5­17
Therefore,
1
8 a) T. Katayama, K. Kamata, K. Yamaguchi, N. Mizuno,
ChemSusChem 2009, 2, 59. b) K. Yamaguchi, T. Oishi, T.
Katayama, N. Mizuno, Chem.®Eur. J. 2009, 15, 10464.
9 T. Oishi, K. Yamaguchi, N. Mizuno, ACS Catal. 2011, 1, 1351.
further mechanistic investigations for the present Cu(OH)x/
Al2O3-catalyzed CDC are now in progress.
1
This work was supported in part by JSPS KAKENHI Grant
Number 15H05797.
20 K. Yamaguchi, K. Sakagami, Y. Miyamoto, X. Jin, N. Mizuno,
Org. Biomol. Chem. 2014, 12, 9200.
Chem. Lett. 2016, 45, 173–175 | doi:10.1246/cl.151090
© 2016 The Chemical Society of Japan | 175