Copper-catalyzed oxidative N-S bond formation for the synthesis of N-sulfenylimines

Article abstract of DOI:10.1021/ol503760b

Despite the remarkable success of the copper-catalyzed oxidative coupling reaction, direct cross-coupling of amines and thiols for the synthesis of N-sulfenylimines has not been previously reported. Using commercially available copper catalysts (CuI) and

Full text of DOI:10.1021/ol503760b

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Oxidative N−S Bond Formation for the Synthesis
of N‑Sulfenylimines
Chan Lee,† Xi Wang,† and Hye-Young Jang*,†,‡
†Department of Energy Systems Research, Ajou University, Suwon 443-749, Korea
‡Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Korea
S
* Supporting Information
ABSTRACT: Despite the remarkable success of the copper-catalyzed oxidative
coupling reaction, direct cross-coupling of amines and thiols for the synthesis of
N-sulfenylimines has not been previously reported. Using commercially available
copper catalysts (CuI) and oxygen as an environmentally benign oxidant,
synthetically useful N-sulfenylimines were prepared from amines and thiols in
good yields without overoxidation of sulfur atoms.
N-Sulfenylimines are sulfur analogs of oximes possessing a
nitrogen−sulfur bond and are also called thio-oximes and
sulfenimines. Despite the utility of sulfenylimines in the
preparation of N-sulfinylimines, N-sulfonylimines, β-lactams,
vinyl formamides, and H2S-releasing reagents, efficient and
catalytic methods to prepare sulfenylimines have not yet been
actively explored.1−4 Based on the pioneering work by Davis,
sulfenylimines were synthesized in a one-step process using
disulfides, aldehydes, ammonia, and silver complexes, although
the use of stoichiometric amounts of silver complexes and
ammonia was required (Scheme 1, eq 1).2d,e,3 S-Aroylthio-
hydroxylamine (SATHA) was also used to prepare sulfenyli-
mines from aldehydes (Scheme 1, eq 2).2g,h The synthesis of
SATHA requires the reaction of acyl chloride with H2S
followed by amination using hydroxylamine sulfonic acid. The
combination of trimethylphosphine and N-(phenylthio)-
phthalimide which is synthesized from thiophenol also
provided sulfenylimines from oximes (Scheme 1, eq 3).4
Although various reaction conditions for the synthesis of
sulfenylimines have been reported, there is no catalytic method
to synthesize sulfenylimines directly from amines.
Copper-catalyzed aerobic oxidative coupling reactions have
been successful for inducing C−C, C−N, C−P, C−S, N−P, P−
S, and N−S bond formation without prefunctionalization of
reactants.5−7 As substrates in the oxidative coupling reaction,
amines are known to be relatively susceptible under oxidation
conditions (e.g., the oxidation of amines to imines and the
oxidative α-functionalized tertiary amines); however, to the best
of our knowledge, direct oxidative coupling of amines with
thiols to afford N-sulfenylimines (N−S bond formation) has
not yet been reported.8,9 The reactions of amines and thiols
often provided sulfonamides under oxidation conditions.6i−k,10
In this study, we present the first copper-catalyzed aerobic
oxidative coupling of amines and thiols to provide various N-
sulfenylimines (Scheme 1, eq 4). Selective oxidation occurred
to form N-sulfenylimines without N-sulfinyl- and N-sulfonyli-
mines.
Scheme 1. Synthesis of N-Sulfenylimines
The optimization results are given in Table 1. Although
disulfides are often used as electrophiles (e.g., sulfenylation of
aromatic compounds), disulfides are formed from thiols under
copper-catalyzed aerobic conditions.11 Therefore, we decided
to use benzenethiol 1b instead of disulfides. For this process, p-
OMe-benzyl amine 1a (2 equiv) and benzenethiol 1b (1 equiv)
were subjected to copper-catalyzed aerobic oxidation con-
ditions. In the presence of CuI (2 mol %), the solution of 1a
and 1b in toluene (0.5 M) was stirred at 100 °C under 1 atm of
oxygen to afford sulfenylimine 1c in 42% yield (entry 1). We
also screened several metal salts; CuBr, CuBr2, FeCl2, and
FeCl3 showed inferior catalytic activity compared to CuI
(entries 2−5). Because the yield of the copper-catalyzed
oxidation of amines is affected by ligand additives, we tested
several ligands. The reactions with 2,2,6,6-tetramethyl-
Received: December 31, 2014
© XXXX American Chemical Society
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DOI: 10.1021/ol503760b
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Table 1. Optimization of the Formation of Sulfenylimine 1c
entry
metal complex
additive
yield
1
CuI (2 mol %)
CuBr (2 mol %)
CuBr2 (2 mol %)
FeCl2 (2 mol %)
FeCl3 (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
CuI (2 mol %)
−
−
−
−
−
42%
9%
6%
−
2
3
4
5
−
6
TEMPO (2 mol %)
PPh3 (2 mol %)
IMes (2 mol %)
29%
30%
31%
7
8
9
1,10-phen (2 mol %) 33%
10
11
12
13
14
15
TBD (1 equiv)
TBD (0.1 equiv)
DBU (1 equiv)
DBU (0.1 equiv)
KOtBu (1 equiv)
33%
a
b
68% (10%, 39% )
53%
58%
--
Figure 1. Examples of sulfenylimines.
from the oxidation of octyl amine followed by hydrolysis were
not observed. The reactions of aliphatic thiol, octyl thiol with
benzyl amine provided trace amounts of N-sulfenyl imines.
To investigate the reaction mechanism, the following
experiments were carried out. As mentioned earlier, disulfide
may be the key intermediate. With diphenyldisulfide 1b′,
sulfenylimine 1c was obtained in 66% yield, a result comparable
to that of the reaction of thiophenol 1b. Next, the role of
copper catalysts was examined. Copper catalysts oxidize thiols
to disulfides, and amines to imines under oxidation conditions.
In addition, copper catalysts might promote nitrogen−sulfur
bond formation in 1a and 1b′. As shown in the second and
third reactions of Scheme 2, in the absence of copper catalysts,
TEMPO (5 mol %) TBD (0.1 equiv)
--
a
b
The reaction was run under nitrogen atmosphere. The reaction was
run in 1 M of toluene.
piperidinyloxy (TEMPO), PPh3, 1,3-bis(2,4,6-trimethyl-
phenyl)imidazol-2-ylidene (IMes), and 1,10-phenanthroline
(1,10-phen) provided 1c in lower yields (entries 6−9). To
improve the deprotonation (α-proton) of the amines, a strong
organic base, 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), was
added. By varying the amount of bases, the yield increased to
68% (entries 10 and 11). In the absence of oxygen, 1c was
formed in low yield (10%, entry 11). To avoid the large amount
of solvents, the reaction was tested in toluene (1 M) to afford
1c in 39% yield (entry 11). Addition of 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU) also improved the yield of 1c to 58%
(entries 12 and 13). Inorganic base KOtBu did not promote
sulfenylimine formation (entry 14). In the absence of metal
complexes, TEMPO was used as an organocatalyst, but 1c was
not formed (entry 15).12
Scheme 2. Reactions of 1a with Disulfide 1b′
To investigate the substrate scope of the reaction, diverse
thiols and amines were subjected to aerobic oxidation
conditions using CuI (2 mol %) and TBD (0.1 equiv) (Figure
1). First, benzyl amine derivatives were exposed to the
optimized reaction conditions. As shown in Figure 1, benzyl
amine was transformed to 2c with a 74% yield. Then, F- and
Cl-substituted benzyl amines were converted to the corre-
sponding sulfenyl imines 3c in 79% yield and 4c in 75% yield.
Electron-rich OMe- and Me-substituted benzyl amines
participated in the reaction to afford the desired products 5c
and 6c in good yields. Piperonyl amine was also incorporated in
the sulfenylimine 7c in 62% yield. Next, we carried out the
reactions of thiophenol derivatives with benzyl amine. Fluoro-
substituted thiophenol reacted with benzyl amine to give 8c in
73% yield. Electron-rich thiophenols participated in the
reaction to afford the corresponding sulfenylimines 9c and
10c in 76% and 75% yield, respectively. Next, amines forming
thio-ketoximes were subjected to the reaction conditions. Thio-
ketoximes possessing phenyl-ethyl 11c, phenyl-methyl 12c,
diphenyl 13c, and OMe-substituted phenyl-methyl group 14c
were synthesized in modest to good yields. As an aliphatic
amine, octyl amine was subjected to the reaction conditions,
but either desired sulfenylimines or octyl aldehydes formed
N−S bond formation did not occur, implying that N−S bonds
were not formed via the simple nucleophilic addition of amines
to disulfides. In other words, the copper catalyst is a
prerequisite for N−S bond formation.
To identify the catalytically active species, CuSPh was
subjected to the optimized conditions as both the catalyst and
substrate (Scheme 3).7d As a catalyst, CuSPh was less efficient
than CuI. The CuSPh-catalyzed reaction afforded 2c in 14%
yield. When CuSPh was used as a reactant in the absence of
CuI, 2c was obtained in only 29% yield. On the other hand,
with 2 mol % of CuI, the reaction of benzyl amine and CuSPh
afforded 2c in 67% yield. These results indicate that CuSPh is
not an active catalyst. Prior to the reaction of copper catalysts
B
DOI: 10.1021/ol503760b
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Letter
Scheme 3. Reactions Using CuSPh as a Catalyst and a
Substrate
ACKNOWLEDGMENTS
■
This study was supported by the Korea Research Foundation
(Nos. 2009-0094046 and 2013008819) and a Korea CCS R&D
Center (KCRC) grant from the Korea Government (Ministry
of Education, Science and Technology; No.
2014M1A8A1049294).
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectra of 1c−14c. This material
is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hyjang2@ajou.ac.kr.
Notes
The authors declare no competing financial interest.
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