Nickel-catalyzed direct thiolation of unactivated C(sp3)-H bonds with disulfides

Article abstract of DOI:10.1039/c5cc01436k

The first nickel-catalyzed thiolation of unactivated C(sp³)-H bonds with disulfides was described. This transformation uses (dppp)NiCl₂ as a catalyst and BINOL as a ligand, which are efficient for the thiolation of β-methyl C(sp

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Nickel-Catalyzed Direct Thiolation of Unactivated C(sp3)–H Bonds with
Disulfides
Sheng-Yi Yan, ‡ Yue-Jin Liu, ‡ Bin Liu, Yan-Hua Liu, Zhuo-Zhuo Zhang, Bing-Feng Shi*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The first nickel-catalyzed thiolation of unactivated C(sp3)-H
bonds with disulfides was described. This transformation uses
(dppp)NiCl2 as catalyst and BINOL as ligand, which is efficient
for the thiolation of β-methyl C(sp3)-H bonds of a broad range
10 of aliphatic carboxamides. The reaction provides an efficient
synthetic pathway to access diverse thioethers.
by chemical synthesis through transition metal-catalyzed/mediated
50 sulfenylation of arylhalides.18 However, these traditional methods
are largely restricted to the use of pre-functionalized precursors. In
our continuous investigations of the functionalization of
unactivated C(sp3)-H bonds,19 we are becoming interested in
developing methods for the thiolation of unactivated C(sp3)-H
55 bonds in consideration of the great challenges associated. Here we
report the first example of nickel-catalyzed thiolation of β-methyl
C(sp3)-H bonds of a broad range of aliphatic carboxamides and
disulfides(Scheme 1B).
In recent years, transition-metal-catalyzed functionalization of
C-H bonds to form C-C and C-heteroatom bond has attracted
significant attention.1 So far, only a few examples of transition-
15 metal-catalyzed thiolation of unactivated C(sp2)−H bonds have
been reported.2 Significant achievements on thiolation of arene
C(sp2)−H bonds mediated by copper have been made by groups of
Yu,3a Qing,3b Cheng3c, Daugulis3d, and Liang3e. The synthesis of
benzoisothiazolones via copper-mediated C-S/N-S formation
20 using elemental sulfur has also been demonstrated by our group.4
The direct thiolation of aryl C-H bonds by using expensive second-
row transition metal catalysts, such as Pd and Rh, has also been
reported recently.5,6 More recently, our group7a and Lu group7b
independently reported a Ni(II)-catalyzed thiolation of aromatic
25 C(sp2)-H bonds with disulfides by using our newly developed 2-
(pyridine-2-yl)isopropylamine (PIP-amine) directing group
(Scheme 1A). In comparison, the direct thiolation of unactivated
C(sp3)-H bonds remains a great challenge, largely on account of
the inherent low reactivity of aliphatic C(sp3)-H bonds8 and the
30 competitive coordination of the sulfur species to interfere with the
C-H functionalization reaction. Therefore, the development of a
general and efficient method for the thiolation of unactivated
C(sp3)–H bonds would be very challenging and extremely
attractive.
Since the seminal work of Daugulis,9 elegant achievements
have been made by using a bidentate directing group in the
transformations of C(sp3)-H bonds.10 However, most of the
transformations of C(sp3)−H bonds reported are catalyzed by
palladium catalysts. Recently, the direct functionalization of
40 C(sp3)-H bonds have been achieved using the bidentate directing
group in conjunction with nickel catalysts,11 which are abundance,
inexpensiveness and relatively low toxicity.12 Despite of elegant
works of the direct C-C, C-N and C-O bond formation via Ni-
catalyzed C-H functionalization,13-16 the more challenging C-S
45 bond formation via C(sp3)-H activation have not been realized.
Owing to their ubiquity in numerous biologically active
compounds and pharmaceuticals,17 tremendous attentions have
been attracted for the construction of sulfur-containing compounds
Scheme 1 Nickel-Catalyzed Unactivated C-H Thiolation
60
Our exploration commenced by studying the reaction between
amide 1a and PhSSPh 2a under the conditions which have been
reported by our group recently.7a To our delight, the desired
product 3a was obtained in 24% yield (Table 1, entry 1). (dppp)
65 NiCl2 was found to be the best after an extensive screening of
nickel catalysts (entry 6). To improve the efficiency of the reaction
further, the influence of the additives was investigated. As shown
in Table 1, the thiolated product 3a was isolated in 53% yield when
Ag2O was employed (entry 14). Unfortunately, a number of bases
70 were screened and found to reduce the yield of the desired product
(entries 15-20). Controlled reaction in the absence of nickel
catalyst revealed that nickel was essential for the success of this
reaction (entry 21).
35
Table 1 Optimization of the Reaction Conditionsa
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Scheme 2 Scope of amidesa
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DOI: 10.1039/C5CC01436K
entry
1
2
3
4
5
6
7
8
[Ni]
NiCl2·6H2O
Ni(acac)2
Ni(OTf)2
NiI2
base
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
KTFA
Na2CO3
NaHCO3
K2CO3
NaOAc
NaTFA
LiTFA
KTFA
additive(equiv)
---
yieldb
24%
19%
20%
24%
23%
27%
trace
N.R
42%
---
---
---
---
NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
(dppp) NiCl2
---
---
Cu(OAc)2(2.0)
CuF2(2.0)
CuO(2.0)
Cu(OH)2 (2.0)
Cu(OH)2CO3(2.0)
Ag2O (2.0)
Ag2CO3
9
10
11
12
13
14
15
16
17
18
19
20
21
40%
45%
37%
20%
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
Ag2O (1.0)
56% (53%c)
39%
23%
20%
17%
44%
35%
N.R
aReaction conditions: 1 (0.1 mmol), 2 (0.2 mmol), [Ni] (10 mol%) BINOL
(20 mol%), base (0.2 mmol) and additive (0.1 mmol) in DMSO (1mL) at
5 140 oC for 12 h. Isolated yield. b1H NMR yield using CH2Br2 as the internal
standard. cIsolated yield.
With the optimized reaction conditions in hand, the scope of
the reaction of aliphatic amides 1 with PhSSPh was investigated as
shown in Scheme 2. In general, aliphatic amides substituted with
10 phenyl group at the ɑ-position reacted exclusively at the methyl
group, and the γ-aromatic C(sp2)-H bonds were not thiolated (3a-
3f). In addition, 2,2-disubstituted propanamides bearing both the
linear and cyclic chains proceeded smoothly to afford the
corresponding thiolated products in medium yield (3h-3o). The
15 methylene C(sp3)-H bonds were unreactive under present reaction
conditions, even with the relatively more reactive benzylic and
cyclopropyl methylene C(sp3)-H bonds (3g, 3h). It is noteworthy
that vinyl functional group was tolerated and produced the desired
product in 31% yield (3f). Notably, no other by-product was
20 observed and the starting materials were recovered in all the case.
The results for thiolation of amide 1a with various disulfides
were shown in Scheme 3. Diaryl disulfides bearing either an
electron-donating or electron-withdrawing group were evaluated
and found to be compatible with the optimized reaction conditions
25 (5a-5d). In addition, 2-methyl-3-furyl disulfide was employed and
afforded the corresponding product 5e in 35% yield. Notably,
dialkyl disulfide 4f also reacted with benzamide 1a, albeit with
reduced yield (5f, 15%).
35 Scheme 3 Scope of disulfidesa
30
In order to gain insights into the mechanism for this
2
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Fundamental Research Funds for the Central Universities, and
transformation, radical trapping experiments were carried out to
40 Zhejiang Provincial NSFC (LZ12B02001) is gratefully
evaluate the possibility that a thiophenyl radical participate in the
present reaction. As shown in Scheme 4, the addition of 1
equivalent of 1,4-dinitrobenzene (electron-transfer scavenger) had
no effect on the reaction. Additionally, when radical inhibitors,
such as TEMPO and 1,4-diphenylethylene was added, the desired
product 3a was obtained in 48% and 54% yield respectively. These
results are in sharp contrast to the finding of the Lu group,7b
indicating that radical intermediates might not be involved in this
View Article Online
DOI: 10.1039/C5CC01436K
acknowledged.
Notes and references
5
Department of Chemistry, Zhejiang University, Hangzhou 310027, China.
E-mail: bfshi@zju.edu.cn
45 † Electronic Supplementary Information (ESI) available: Experimental
details and characterization data for new compounds. See
DOI: 10.1039/b000000x/
10 transformation.
‡ These authors contributed equally to this work.
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Scheme 4 Radical scavenger Experiments
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55
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2
3
When benzenethiol 6 was employed, the desired product 3a
was isolated in 14% yield under the standard conditions, which was
15 consistent with Pd-catalyzed C-H thiolation by Nishihara (Scheme
5).5a-c
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Scheme 5 Thiolation with thiol 6
5644.
10 mol% (dppp)NiCl2
20 mol% BINOL
2.0 equiv KTFA
O
O
5
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Q
Q
N
N
H
H
+
PhSH
(2.0 equiv)
6
Ag2O(1.0 equiv)
DMSO, N2, 140 o
SPh
H
75
C
1a
3a, 14%
6
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thiolation of unactivated C(sp3)-H bonds of aliphatic acid
derivatives with disulfides.22 Besides diaryl disulfides, dialkyl
30 disulfides are also capable of undergoing the thiolation reactions
moderately. This transformation uses (dppp)NiCl2 as catalyst and
BINOL as ligand, which is efficient for the thiolation of β-methyl
C(sp3)-H bonds of a broad range of aliphatic carboxamides and
disulfides. The reaction provides an efficient synthetic pathway to
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45
The first nickel-catalyzed thiolation of unactivated C(sp3)-H bonds with disulfides is described.
50
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