Copper(I)-Promoted C-N Cross-Coupling of N-Heterocyclic Compounds with 1,2-Di(pyrimidin-2-yl) Disulfides

Article abstract of DOI:10.1055/s-0035-1561946

A CuTC-promoted C-N cross-coupling of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocyclic compounds including indoles, triazole benzotriazole, and benzoimidazole by C-S cleavage of the disulfides is reported.

Full text of DOI:10.1055/s-0035-1561946

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
K.-J. Wei et al.
Letter
Synlett
Copper(I)-Promoted C–N Cross-Coupling of N-Heterocyclic
Compounds with 1,2-Di(pyrimidin-2-yl) Disulfides
Kai-Jie Weia,b
O
Ar
O
Ar
Zheng-Jun Quan*a,b
Zhang Zhanga,b
Yu-Xia Daa,b
CuTC (1 equiv)
Cs2CO3 (3 equiv)
X
EtO
N
EtO
N
Y
+
dioxane, 120 °C
C–N coupling
N
H
Me
N
N
Me
N
S
Xi-Cun Wang*a,b
2
X
Y
indole
triazole
benzoimidazole
benzotriazole
a Key Laboratory of Eco-Environment-Related Polymer
Materials, Ministry of Education, China, Gansu 730070,
P. R. of China
23 examples
up to 89% yield
b Key Laboratory of Polymer Materials, College of
Chemistry and Chemical Engineering, Northwest
Normal University, Gansu 730070, P. R. of China
quanzhengjun@hotmail.com
wangxicun@nwnu.edu.cn
Received: 25.01.2016
Accepted after revision: 06.03.2016
Published online: 01.04.2016
ly, some groups independently developed the C–H thiola-
tion of heterocycles including indole and imidazoheterocy-
cles with disulfides achieving C–S coupling in the presence
DOI: 10.1055/s-0035-1561946; Art ID: st-2016-w0046-l
12c
of oxidants such as I2/(NH)2S2O8,12a I2/FeF3,12b and AgNO3
Abstract A CuTC-promoted C–N cross-coupling of 1,2-di(pyrimidin-2-
yl) disulfides with N-heterocyclic compounds including indoles, triazole
benzotriazole, and benzoimidazole by C–S cleavage of the disulfides is
reported.
(Scheme 1, a).12
a) Reported work: C–S coupling
X
X
SAr
(NH4)2S2O8 or I2
AgNO3, etc.
S
Ar
+
Y
X
Y
Ar
b) This work: C–N coupling
Het
S
Key words N-heterocycles, indoles, disulfides, CuTC, C–N cross-cou-
pling
N
H
N
H
X
Y
CuTC
S
Y
+
Transition-metal-catalyzed C–N cross-coupling reac-
tions are considered one of the most powerful methods for
the construction of nitrogen-containing skeletons.1 Espe-
cially, the N-aryl nitrogen heterocycle motif is present in a
multitude of bioactive natural products2 and pharmaceuti-
cally interesting compounds.3 Ullmann coupling and
Buchwald–Hartwig reactions are typical efficient methods
for us to construct the C–N bond. Generally, such proce-
dures involve the coupling of an activated electrophilic sub-
strate4 with a nucleophile through a transition-metal-me-
diated cross-coupling reaction. However, most of the reac-
tions require stringent conditions, such as the use of noble
or transition metals as catalyst (palladium5 and nickel6),
and aryl halides7 or aryl sulfonates8,6b as electrophiles. Gen-
erally, the synthesis of aryl halides often involves tedious
steps, harsh reaction conditions, and waste production.9
Therefore the focus of attention has been the search for in-
expensive catalysts and alternative electrophiles as sub-
strates instead of organic halides for cross-coupling reac-
tions.10
Het
S
N
Cs2CO3
N
H
Het
X, Y = CH, N
Scheme 1 Cross-coupling of disulfide with N-heterocycles
To our surprise, before 2014, there has been a notable
absence of examples of C–C couplings between a disulfide
and an arylboronic acid or an alkyne. In 2014, we reported
the first metal-catalyzed and copper(I) carboxylate-mediat-
ed C–C cross-coupling reaction of disulfides through C–S
bond cleavage of di(hetero)aryl disulfides with arylboronic
acids or alkynes, which employed a nitrogen-containing di-
heteroaryl disulfide.13a In 2015, our group developed a sim-
ple and efficient method for the cross-coupling of di(hete-
ro)aryl disulfides with Grignard reagents, providing C–S
and C–C products with excellent chemoselectivity.13b How-
ever, to the best of our knowledge, there is no report on the
C–N cross-coupling reaction of disulfides with N-heterocy-
cles. Based on these examples, we believed that it is possi-
ble to achieve the copper-promoted C–N coupling reaction
of 1,2-di(pyrimidin-2-yl) disulfides with N-heterocycles
(Scheme 1, b). Herein, we demonstrate that simple and
readily available 1,2-di(pyrimidin-2-yl) disulfides13 are ex-
cellent substrates for the copper(I)-catalyzed C–N cross-
Organic disulfides are structurally symmetrical. Partic-
ularly, diaryl disulfides are air stable and easy to handle.
They are common intermediates for organic transforma-
tions and are widely used as sulfenyl and sulfinyl reagents
through S–S cleavage with various reagents.11 More recent-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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B
K.-J. Wei et al.
Letter
Synlett
coupling reaction with a series of N-heterocycles, and in
doing so add to the motifs (pyrimidine, indole, triazole,
benzotriazole, and benzoimidazole) available for use in
these valuable C–N coupling processes.
Table 1 Optimization of the Cross-Coupling Reaction of Disulfides 1a
and Indole 2aa
To optimize the reaction conditions, the C–N coupling of
1,2-di(pyrimidin-2-yl) disulfide 1a and indole (2a) in the
presence of Cs2CO3 was used as a model reaction, and the
results are summarized in Table 1. No desired product was
detected in the absence of catalyst, but the starting material
1a was recovered (Table 1, entry 1). Ni(PPh3)Cl2 and
Ni(dppp)Cl2, used in the reaction, facilitated the formation
of product 3a albeit with low yield of 45% and 53%, respec-
tively (Table 1, entries 2 and 3). Subsequent evaluation of
various copper sources was carried out. Among the used
copper sources, CuCl or CuTC rather than CuI, Cu2O, or CuBr
could remarkably increase the yield of 3a, and CuTC provid-
ed the best result (Table 1, entries 4–8). Next, the effects of
bases in this reaction were investigated. Replacement of
Cs2CO3 with either K3PO4, K2CO3, or t-BuONa led to inferior
results (Table 1, entries 9–11). One more time, we experi-
mented with CuTC and Ni(dppp)Cl2 as bimetallic catalyst,
no significant effect on the yield was observed (Table 1, en-
try 12 vs. entry 8). Finally, the reaction gave trace amounts
of 3a under an air atmosphere (Table 1, entry 12). Based on
the above research, the reaction was best conducted with
CuTC as the catalyst, Cs2CO3 as the base, and dioxane as the
solvent at 120 °C for 12 hours. The product 3a was fully
base
catalyst
EtO2C
EtO2C
Me
N
N
+
dioxane,120 °C
12 h, N2
N
Me
N
S
H
N
N
2
1a
2a
3a
Entry
Catalyst (equiv)
Base (3 equiv)
Yield (%)b
1
2
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
N.R.
45
53
43
31
49
75
80
61
37
72
82
Ni(PPh3)Cl2 (0.1)
3
Ni(dppp)Cl2 (0.1)
CuI (1.0)
4
5
Cu2O (1. 0)
CuBr (1. 0)
CuCl (1. 0)
CuTC (1. 0)
CuTC (1. 0)
CuTC (1. 0)
CuTC (1. 0)
6
7
8
9
10
11
12
K2CO3
t-BuONa
Cs2CO3
Ni(dppp)Cl2 (0.1)
CuTC (1. 0)
13c
CuCl (1. 0)
Cs2CO3
<5
1
characterized by H NMR and 13C NMR, HRMS, and X-ray
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), dioxane (3 mL).
b Isolated yield after column chromatography (based on both pyrimidine
groups from one molecule).
crystallographic studies (Figure1).14
c The reaction was carried out at air atmosphere;
Ph3P = triphenylphosphine hydrobromide; dppp = 1,3-bis(diphenylphos-
phino)propane; CuTC = copper(I) thiophene-2-carboxylate.
The reaction conditions were suitable for a variety of disul-
fides and indole to give products (3a–i). Similarly, diverse
disulfides and benzoimidazole delivered the corresponding
products in fairly good yields (3j–n). We could extend the
scope of nitrogenous heterocyclic compounds to 1,2,4-1H-
triazole and benzotriazole which are also competent reac-
tion partners to give corresponding products in good yields
(3o–r). We tried to extend the scope of disulfides to 2,2′-
dithiodipyridine and diphenyl disulfide under optimized
conditions (Table 1, entry 8) or bimetallic catalysts (Table 1,
entry 12). Unfortunately, products 3s and 3t could not ob-
tained. Compared with the tested 1,2-di(pyrimidin-2-yl) di-
sulfides, both nitrogen-containing diheteroaryl disulfides
and aryl disulfides showed much lower reactivity.
Next, we further explored the C–N coupling reaction of
2-methylindole with disulfides under the optimized condi-
tions, but we did not detect the corresponding products,
but achieved an unexpected C–S coupling product.16 Thank-
fully, when we executed the reaction under bimetallic cata-
lyst conditions (Table 1, entry 12), the C–N coupled prod-
Figure 1 X-ray crystal structure of 3a
The above optimized conditions (Table 1, entry 8) were
then applied to the C–N cross-coupling reactions of various
1,2-di(pyrimidin-2-yl) disulfides 1 and a diverse set of N-
heterocyclic compounds 2 (Scheme 2).15 As show in Scheme
2, the process proved to be relatively broad in scope, toler-
ating a variety of steric and electronic changes to both reac-
tion partners to give the products 3a–r with good yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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C
K.-J. Wei et al.
Letter
Synlett
ucts were obtained. The reaction conditions were suitable
for a variety of disulfides and 2-methylindole to give the
corresponding products (4a–e) in good yields (Scheme 3).17
After the tests towards symmetrical diheteroaryl disul-
fides, unsymmetrical disulfides 5a and 5b were examined
in the C–N coupling reaction. Interestingly, the reaction of
disulfide 5a with indole gave the C–N coupling product 3a
in a high yield of 73% with the formation of diaryl disulfide
7 (37%), but compound 6 was not detected. Similarly, using
disulfide 5b as substrate gave the corresponding 3c (78%)
and 7 (46%, Scheme 4).16
O
Ar
O
Ar
N
CuTC (1 equiv)
Cs2CO3 (3 equiv)
R1
N
R1
N
X
+
R2
N
R2
S
dioxane, 120 °C
12 h, N2
N
H
N
2
X
3
1
2
Me
F
O
O
O
EtO
O
Cl
N
EtO
N
EtO
N
N
EtO
N
Me
N
N
Me
N
N
Me
N
N
Me
N
3a, 80%
3b, 78%
3c, 85%
3d, 71%
Cl
Br
NO2
O
O
O
O
EtO
N
EtO
N
N
MeO
N
N
EtO
N
Me
N
N
Me
N
Me
N
Me
N
N
3e, 84%
3f, 87%
3g, 81%
3h, 89%
F
O
O
O
Cl
N
O
EtO
Me
N
N
EtO
Me
N
N
EtO
N
N
EtO
Me
N
N
N
Me
N
N
Me
N
N
N
3i, 73%
3j, 74%
3k, 75%
3l, 72%
Br
Me
NO2
O
O
O
O
EtO
N
N
EtO
Me
N
EtO
Me
N
EtO
N
N
Me
N
N
N
N
N
Me
N
N
N
N
N
N
N
3m, 79%
3n, 79%
3p, 70%
3o, 73%
Cl
O
O
EtO
N
EtO
N
Me
N
N
Me
N
N
N
N
N
N
3q, 71%
3r, 75%
Scheme 2 The coupling reactions of disulfides with N-heterocyclic compounds
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

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K.-J. Wei et al.
Letter
Synlett
References and Notes
O
Ar
N
EtO
N
(1) (a) McCormick, T. M.; Liu, Q.; Wang, S. Org. Lett. 2007, 9, 4087.
(b) Swapna, K.; Vijay Kumar, A.; Prakash Reddy, V.; Rama Rao, K.
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K. Bioorg. Med. Chem. 1997, 5, 437. (b) Wolfe, J. P.; Buchwald, S.
L. Angew. Chem. Int. Ed. 1999, 38, 2413. (c) Schlummer, B.;
Scholz, U. Adv. Synth. Catal. 2004, 346, 1599. (d) Surry, S.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2008, 47, 6338.
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Chem. 2013, 69, 735. (g) Ackermann, L. Org. Process Res. Dev.
2015, 19, 260.
Me
+
N
Me
S
H
2
1
2b
O
Ar
N
CuTC (1 equiv)
Cs2CO3 (3 equiv)
Ni(dppp)Cl2 (0.1 equiv)
EtO
N
Me
N
dioxane 120 °C
12 h, N2
Me
4
R
O
EtO
R = Me, 4b, 75%
R = F, 4c, 87%
R = Cl, 4d, 80%
R = Br, 4e, 85%
O
N
EtO
N
Me
N
N
Me
N
N
Me
4a, 79%
(4) (a) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You, J. J. Org. Chem.
2007, 72, 8535. (b) Jiao, J.; Zhang, X. R.; Chang, N. H.; Wang, J.;
Wei, J. F.; Shi, X. Y.; Chen, Z. G. J. Org. Chem. 2011, 76, 1180.
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Chem. Soc. 2010, 132, 7119. (b) Roche, M.; Frison, G.; Brion, J.-
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Li, H.-X.; Ren, Z.-G.; Du, W.-Y.; Xu, W.-C.; Lang, J.-P. Tetrahedron
2011, 67, 5282.
Me
Scheme 3 The coupling reactions of disulfides with 2-methylindole
In conclusion, we have developed an efficient method
for C–N cross-coupling reaction of 1,2-di(pyrimidin-2-yl)
disulfides with N-heterocycles via CuTC-promoted C–S
bond cleavage of disulfides. The use of a copper salt such as
CuTC or CuCl was necessary for an efficient formation of the
C–N bond in this reaction. The reaction tolerated a wide
substrate scope and achieved good to excellent yields.
Acknowledgment
(8) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Limmert,
M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364.
(c) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552. (d) Vo, G. D.; Hartwig, J. F. J. Am.
Chem. Soc. 2009, 131, 11049.
We are thankful for financial support from the National Natural Sci-
ence Foundation of China (No. 21362032, 21362031 and 21562036),
Gansu Provincial Department of Finance, and Natural Science Foun-
dation of Gansu Province (No. 1308RJZA299).
Supporting Information
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(b) Kondo, T.; Uenoyama, S.-y.; Fujita, K.-i.; Mitsudo, T.-a. J. Am.
Chem. Soc. 1999, 121, 482. (c) Arisawa, M.; Yamaguchi, M. Org.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561946.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
R
N
R
Me
N
H
O
O
6, 0%
+
CuTC (1 equiv)
EtO
Me
N
Me
Cs2CO3 (3 equiv)
RO
Me
N
S
dioxane 120 °C
N2, 12 h
N
S
S
N
N
S
Me
Me
5a, R = H
5b, R = F
3a, R = H, 73%
3c, R = F, 78%
7, 37–46%
Scheme 4 Cross-coupling of unsymmetrical disulfides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E