The palladium-catalyzed C-N cross-coupling reaction of diheteroaryl disulfides with heterocyclic amines

Article abstract of DOI:10.1002/aoc.4020

The Pd-catalyzed cross-coupling reaction of 1, 2-di(pyrimidin-2-yl) disulfides with heterocyclic amines including 2-amino pyrimidines and 1,3,4-thiadiazol-2-amines to deliver symmetrical C-N coupling products in moderate to good yields is reported. This method provides an opportunity for synthesis of bioactive molecules and pharmaceutically interesting compounds containing heterocycle motifs. The reported protocol shows good functional group compatibility, and provides a new strategy for preparation of C2-amination pyrimidine derivatives from heterocyclic disulfides.

Full text of DOI:10.1002/aoc.4020

Received: 12 May 2017
DOI: 10.1002/aoc.4020
Revised: 6 July 2017
Accepted: 6 July 2017
C O M M U N I C A T I O N
The palladium‐catalyzed C‐N cross‐coupling reaction of
diheteroaryl disulfides with heterocyclic amines
1
,2
1,2
1,2
1,2
Ming‐Xia Liu | Zhang Zhang | Zheng‐Jun Quan | Xi‐Cun Wang
1
Key Laboratory of Eco‐Environment‐
The Pd‐catalyzed cross‐coupling reaction of 1, 2‐di(pyrimidin‐2‐yl) disulfides
with heterocyclic amines including 2‐amino pyrimidines and 1,3,4‐thiadiazol‐
Related Polymer Materials, Ministry of
Education of China, Gansu 730070,
People's Republic of China
2
‐amines to deliver symmetrical C‐N coupling products in moderate to good
2
Gansu Key Laboratory of Polymer
yields is reported. This method provides an opportunity for synthesis of bioac-
tive molecules and pharmaceutically interesting compounds containing hetero-
cycle motifs. The reported protocol shows good functional group compatibility,
and provides a new strategy for preparation of C2‐amination pyrimidine deriv-
atives from heterocyclic disulfides.
Materials, College of Chemistry and
Chemical Engineering, Northwest Normal
University, Anning East Road 967#,
Lanzhou, Gansu 730070, People's Republic
of China
Correspondence
Xi‐Cun Wang, Key Laboratory of Eco‐
Environment‐Related Polymer Materials,
Ministry of Education of China, Gansu
KEYWORDS
C‐N cross‐coupling, diheteroaryl disulfides, heterocyclic amines, Pd catalyst, tetra‐substituted
pyrimidine derivatives
730070, People's Republic of China and
Gansu Key Laboratory of Polymer
Materials, College of Chemistry and
Chemical Engineering, Northwest Normal
University, Anning East Road 967#,
Lanzhou, Gansu 730070, People's Republic
of China.
Email: wangxicun@nwnu.edu.cn
Funding information
Scientific and Technological Innovation
Engineering program of Northwest Nor-
mal University, Grant/Award Number:
NWNU‐LKQN‐15‐1; National Natural Sci-
ence Foundation of China, Grant/Award
Number: Nos. 21362032, 21362031 and
21562036
1
| INTRODUCTION
derivatives have exhibited potent coordination and have
[
11–13]
found some applications in optoelectronics.
Driven by the need for an efficient synthetic route to
Transition‐metal‐catalyzed reaction is always the main
force in cross‐coupling reactions, which plays an
important role in the formation of C‐N bonds and
[
14–16]
these privileged motifs,
several research groups
have aimed at preparation of these privileged structures
[1–7]
C‐heteroatom bonds.
Especially, the N‐aryl nitrogen
via metal‐catalyzed coupling reactions. In the area of
[
17–21]
heterocycle motif is present in a multitude of bioactive
natural products and pharmaceutically interesting
compounds, such as the Gleevec and Osimertinb potent
anticancer drug (Figure 1).
symmetrical or unsymmetrical bis(hetero) arylpyrimidine
Pd‐catalyzed amination of aryl halides,
the
Buchwald–Hartwig amination remains outstanding
owing to its mild reaction conditions, wide substrate
scope, high functional group compatibility, and further
[8–10]
Furthermore, some
[
22–25]
applications.
Our group has successfully
Appl Organometal Chem. 2017;e4020.
wileyonlinelibrary.com/journal/aoc
Copyright © 2017 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.4020

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of 7
LIU ET AL.
[
30]
electrophiles.
Generally, the synthesis of aryl halides
often involves tedious steps, harsh reaction conditions
[
31,32]
and waste production.
Therefore, our focus has been
the search for alternative electrophiles as substrates
instead of organic halides for cross‐coupling reactions.
Bearing in mind that di(hetero)aryl disulfides that are
structurally symmetrical are air stable and easy to han-
[
33,34]
dle,
and they are widely used as electrophiles
reagents for the construction of C‐heteroatom bonds
[
35]
through S‐S or C‐S bond cleavage.
In 2014, we devel-
oped a special method to construct C‐C bonds through
C‐S bond cleavage of di(hetero)aryl disulfides with aryl
FIGURE 1 Examples of drug molecules containing the 2‐amino‐
‐aryl‐pyrimidine structural motif
[
36–39]
4
boronic acids or alkynes.
In 2015, our group devel-
oped a simple efficient method for the cross‐coupling of
accomplished conventional approaches for the synthesis
di(hetero)aryl disulfides with Grignard reagents, provid-
of tetra‐substituted pyrimidines via the Buchwald reac-
ing C‐S and C‐C products with excellent
[
26–29]
[40,41]
tions
by using aryl halides or aryl sulfonates as
chemoselectivity.
Consequently, we reported a
a
TABLE 1 Optimization of the cross‐coupling reaction of disulfides 1a and 2‐aminopyrimidine 2a
b
Entry
Catalyst (3 mol%)
Additive (2.5 equiv.)
Ligand (10 mol%)
Base(3.0 equiv.)
Yield (%)
Trace
Trace
Trace
52.
c
1
PdCl
PdCl
PdCl
2
2
2
Cu(OAc)
CuCl
2
Dppp
Dppp
Dppp
Dppp
–
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
3
3
3
3
3
2
3
4
5
6
7
8
CuBr
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
–
PdCl2
Pd(dppf)Cl
2
33
Pd(PPh
3
)
4
–
Trace
68
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
–
2
Dppp
Dppe
x‐phos
2
2
2
2
2
2
2
54
c
9
51
c
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
PCy
Bpy
3
43
c
32
Dppp
Dppp
Dppp
Dppp
Dppp
Dppp
K
3
PO
t‐BuOK
CO
4
42
36
K
2
3
64
Cs
Cs
Cs
2
2
2
CO
CO
CO
3
3
3
Trace
Trace
Trace
Pd(OAc)
Pd(OAc)
2
2
d
CuTC
a
Reaction conditions: disulfides 1a (1.0 mmol), 2‐aminopyrimidine 2a (2.5 mmol), catalyst (3 mol%), ligand (10 mol%), base (3.0 equiv.) and solvent dioxane (3
ml) under nitrogen atmosphere, 12 h.
b
Isolated yield after column chromatography.
c
dppp, 1,3‐bis(diphenylphosphino)propane; dppe, 1,2‐bis(diphenylphosphino)ethane; CuTC, copper (I) thiophene‐2‐carboxylate; X‐phos, 2‐
(
dicyclohexylphosphino)‐2′,4′,6′‐triisopropylbiphenyl; bpy, 2,2‐bipyridine.
d
The reaction was carried out at air atmosphere.

LIU ET AL.
3 of 7
simple catalytic system to construct C‐N bonds, in which
2 | RESULTS AND DISCUSSION
disulfides serve as an electrophilic partner in reaction
[
42,43]
with aniline and morpholine.
Comparing with morpholine and aniline, the nucleophilic
Considering that the pyrimidine‐containing structure
has a pharmacological activity, we propose the following.
The symmetrical pyrimidine‐substituted secondary amine
is synthesized using 1,2‐di(pyrimidin‐2‐yl) disulfides with
activity of the NH ‐group of aminopyrimidine is lower
2
than those of morpholine and aniline. So there is a need
to pre‐activate aminopyrimidine. Using a Pd‐catalyst is an
alternative to achieve this aim. With this in mind, we firstly
optimized the reaction conditions by chosing the reaction
of 1,2‐di(pyrimidin‐2‐yl) disulfides 1a with 2‐amino‐4‐
aryl(hetero)‐pyrimidine 2a as model substrates in the
2‐amino pyrimidines, making a chain of of new C2‐
amination bimolecule pyrimidine‐substituted secondary
amines derivatives.
Pd(OAc) ( 3 mol% )
2
dppp ( 10 mol% )
R1
R3
N
R1
R3
CuTC ( 2.5 eq. )
2
CO R4
2
CO2R4 Cs CO ( 3 eq. )
R O C
R O C
2
2
2
2
3
N
N
N
+
N
0
Me
N
N
H
3
Me
Me
N
1
S
H2N
N
Me
Me
dioxane, 110 C
2
2
OMe
Cl
N
O
O
O
O
O
O
O
O
EtO
N
N
OEtEtO
N
N
OEt EtO
N
N
OEt EtO
N
N
OEt
Me
Me
N
N
N
Me
Me
N
N
N
Me
Me
N
N
N
Me
Me
N
N
H
H
H
H
3
aa 68%
3ab 70%
3ac 72%
3ad 60%
Br
NO2
Me
Me
Me OMe
O
O
O
O
O
O
O
O
EtO
Me
N
N
OEt EtO
N
N
OEt EtO
N
N
OEt EtO
N
N
OEt
Me
N
N
N
Me
Me
N
N
N
Me
Me
N
N
N
Me
Me
N
N
N
H
H
H
H
3
ae 56%
3af 58%
3bb 74%
3bc 72%
Me
Cl
N
Me
Br
Me NO2
F
Me
O
O
O
O
O
O
O
O
EtO
N
N
OEt EtO
N
N
OEt EtO
N
N
OEt EtO
N
N
OEt
Me
Me
N
N
Me
Me
N
N
N
Me
Me
N
N
N
Me
Me
N
N
N
H
H
H
H
3bd 70%
3be 69%
3bf 62%
3cb 65%
Br
Cl
Br
NO2
OMe
Cl
O
O
O
O
O
O
Me O
O
O
EtO
N
N
OEt EtO
N
N
OEt MeO
Me
N
N
OEtMe
Me
N
N
OEt
Me
Me
N
N
N
Me
Me
N
N
N
Me
N
N
N
Me
N
N
N
H
H
H
H
3
dd 56%
3df 54%
3ec 63%
3fa 67%
Me
NO2
O
O
O
Cl
O
O
O
N
OEt
Me
N
OEt
Me
EtO
Me
N
N
OEt EtO
N
N
OEt
Me
N
N
N
N
N
N
N
N
Me
Me
N
N
N
H
H
H
H
3
gb 67%
3ha 57%
3ia 0%
3ga 0%
SCHEME 1 Cross‐coupling of disulfides and 2‐amino pyrimidine

4
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LIU ET AL.
2
Pd(OAc) (5 mol%)
dppp (10mol% )
CuTC ( 2.5 eq.)
O
O
EtO
Me
N
+
EtO
Me
N
Cs
2
CO
3
( 3 eq.)
N
0
2
S
xylene, 110
C
N
1
a
4
5
O
O
EtO
Me
N
EtO
Me
N
N
N
4
4
4
a R = H 5aa = 60%
b R= OMe 5ab =72%
5ad 68%
c R= Cl
5ac = 65%
SCHEME 2 The cross‐coupling reactions of disulfides with aminothiazole
presnce of Pd‐catalyst, and the results are summarized in
With the optimal conditions in hand, a variety of
Table 1. Initially, we studied the effect of different copper
salts on the C‐N coupling reaction of 1a with 2a, using
PdCl2 as a catalyst, 1,3‐bis(diphenylphosphino)propane
di(pyrimidin‐2‐yl) disulfides smoothly reacted with
different heterocyclic amine nucleophiles (Scheme 1). The
di(pyrimidin‐2‐yl) disulfides derivatives and heterocyclic
aromatic amines bearing electron‐donating substituents
in the para position on the aromatic ring afforded the
desired products in excellent yields. A slightly lower yield
was produced when the substrate had an electron‐with-
drawing group in the para position, as for 3dd and 3df.
Moreover, when the substrate had a symmetrical structure,
such as 3aa and 3bb, with an electron‐donating group,
good to excellent yields were produced. The steric effects
were unimportant when the substituted group in the ortho
and meta positions gave the target product 3gb in 67% yield
and 3ha in 57% yield. Unfortunately, the cross‐coupling
reaction of 2,2′‐dithiodipyridine or diphenyl disulfide with
2‐amino‐4 aryl(hetero)‐pyrimidine failed to give the
desired product 3ia or 3ga using optimal conditions.
Next, we further explored the C‐N coupling reaction of
disulfides with inactive aminothiazole using previous
optimized conditions (Table 1, entry 7), but no desired
product was detected. The solubility of aminothiazole
was critical to the success of the reaction. We found
xylene to be a suitable solvent for the transformation.
Also, an increase in the catalyst loading to 5 mol%
(
dppp) as a ligand and Cs CO as base (entries 1–4). When
2
3
Cu(OAc) , CuCl, CuBr and CuTC were tested, CuTC per-
2
formed better in 52% yield (entry 4). Then, various Pd pre-
cursors were screened (entries 5–7), and it was found that
Pd(OAc) gave 3aa in 68% yield compared with PdCl ,
2
2
Pd(dppf)Cl , Pd(PPh ) (entry 7). Next, a series of ligands were
2
3 4
studied, such as 1,2‐bis(diphenylphosphino)ethane (dppe), 2‐
dicyclohexylphosphino)‐2′,4′,6′‐triisopropylbiphenyl (x‐phos),
(
PCy , 2,2‐bipyridine (bpy), and dppp gave a higher 68%
3
yield delivering 3aa (entries 8–11). Furthermore, the effects
of bases on this reaction were also investigated. Replace-
ment of Cs CO with either K PO , t‐BuOK or K CO led
2
3
3
4
2
3
to inferior results (entries 12–14). Obviously, no 3aa was
detected under catalyst‐free and ligand‐free conditions,
but the starting material 1a was recovered (entries 15 and
1
6). Finally, no reaction was observed in the air atmo-
sphere (entry 17). Based on the above experiments, the
reaction was best conducted with Pd(OAc) as the catalyst,
2
CuTC as the additive, dppp as the ligand, Cs CO as the
2
3
base, and dioxane as the solvent at 110 °C for 12 h under
nitrogen atmosphere.
R
R
Pd(OAc)2 (3 mol%)
dppp (10 mol% )
CuTC ( 2.5 eq. )
Cs2CO3 ( 3 eq. )
Me
O
8
, 0%
S
O
+
EtO
Me
N
+
Me
EtO
Me
N
S
dioxane, 110 o
C
N
S
N
S
Me
6
6
a R = H
b R = F
2a
7aa R = H, 62%
7ba R = F, 68%
Me
9
, 12-15%
SCHEME 3 Cross‐coupling of unsymmetrical disulfides

LIU ET AL.
5 of 7
T
O
CuII
O
Ph
Ph
EtO
O
N
S
N
N
O
II
Pd NH
L
OEt
N L
Base
Me
Me
C
2
a
TC
TC
Cu
S
Pd
O
Ph
N
Ph
Ph
II
Ph
O
N
L
L
N
N
O
EtO
O
N
EtO
Me
N
II
H
EtO
N
OEt
N
S
N L
L
2
Me
Me
Me
1
a
D
B
CuTC
Ph
Me
O
O
II
N
Cu
N
3aa
EtO
OEt
0
Pd Ln (L= dppp)
S
S
SCHEME 4 Possible mechanism for the
C‐N coupling reaction of disulfides with
aminopyrimidines
N
N
Me
Ph
A
Pd(OAc)2 + dppp
allowed us to obtain the coupling product 5aa in 60%
isolated yield (Scheme 2). Meta‐ (4d) and para‐substitu-
tion (4b, 4c) of aminothiazole on the phenyl ring were
well tolerated giving the corresponding products 5ab,
complex C. Following with transmetalation and reduc-
tive elimination gave the C–N cross‐coupling product
3aa (Scheme 4).
5
ac and 5ad in 60–72% yields.
3
| CONCLUSIONS
After the tests towards symmetrical diheteroaryl
disulfides, unsymmetrical disulfides 6a and 6b were
examined as reaction substrates (Scheme 3). When the
reaction of 6a with 2a was performed under optimized
conditions, the corresponding 7aa was obtained in a
moderate yield of 62% with the formation of diaryl
disulfide 9 (12%), but the diaryl amine 8 was not
detected. Similarly, we used disulfide 6b and 2a as a sub-
strate that gave the corresponding 7ba in a yield of 68%
and diaryl disulfide 9 (15%). The experiment further
showed that pyrimidine motif disulfides are more effec-
tive than aryl disulfides in the C‐N cross‐coupling
reaction.
In summary, we have successfully prepared symmetrical
C2‐amination pyrimidine derivatives via the cross‐cou-
pling of disulfides with heterocyclic primary amines
under Pd‐catalyzed conditions. Here we describe an effi-
cient synthetic method for construction of the C‐N bond
between heterocycles. Also, the reported protocol shows
good functional group compatibility, including halides,
nitro and ester motifs. Overall, this transformation pro-
vides a new strategy for preparation of C2‐amination
pyrimidine derivatives from heterocyclic disulfides, and
also supplies an opportunity for the synthesis of bioactive
molecules and pharmaceutically interesting compounds
containing heterocycle motifs.
On the basis of these results and the previous litera-
[
44]
ture,
we speculated that the C‐N bond coupling of
1
,2‐di(pyrimidin‐2‐yl) disulfides with aminopyrimidines
occurred through Pd‐catalyzed Cu‐promoted C‐S bond
cleavage. Pyrimidinyl‐containing disulfide has higher
activity than the aryl groups in the reaction, which was
perhaps due to the coordination of a basic atom (such
as N atom) to the copper salt promoting C–S activation
to give the C–N cross‐coupling products. A formal oxida-
tive addition of copper into the S–S bond affords Cu(II)
intermediate A. Subsequent reductive cleavage of the
S–S bond leads to the formation of the corresponding
copper (II) species B. Then, oxidative addition of the
Pd(0) to the Cu(II) intermediate results in formation of
4
| EXPERIMENTAL SECTION
.1 | General procedure: C‐N cross‐
4
coupling reaction of diheteroaryl disulfides
with heterocyclic amines (3aa‐7ba)
Under an atmosphere of nitrogen, disulfide 1a (1 mmol,
0.546 g), aminopyrimidine 2a (2.5 mmol, 0.643 g),
Pd(OAc)2 (0.03 mmol, 0.006 g), CuTC (2.5 equiv.,
0.476 g), ligand (0.1 mmol, 0.039 g) and base (3.0 equiv.,
0.977 g) were added to an oven‐dried schlenk tube. The

6
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LIU ET AL.
tube was stoppered and degassed with nitrogen three
times. Water‐free dioxane (3 ml) was added by syringe
and the mixture was stirred for 12 h at 110 °C and the reac-
tion monitored by thin‐layer chromatography analysis.
Then, 2 ml diluted hydrochloric acid was added to the
mixture to quench the reaction, and was extracted with
ethyl acetate (3 × 100 ml). The combined organic layers
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8
were washed with aqueous NaHCO and brine, dried over
3
MgSO , filtered, and the volatiles were removed in vacuo.
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Biomol. Chem. 2016, 14, 2352.
4
The residue was purified by column chromatography on
silica gel (ethyl acetate/petroleum ether 1:30) to give the
corresponding products.
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The authors are thankful for the financial support from
the National Natural Science Foundation of China (Nos.
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How to cite this article: Liu M‐X, Zhang Z, Quan
Z‐J, Wang X‐C. The palladium‐catalyzed C‐N cross‐
coupling reaction of diheteroaryl disulfides with
heterocyclic amines. Appl Organometal Chem.
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