Direct C-H heteroarylation of azoles with 1,2-di(pyrimidin-2-yl)disulfides through C-S cleavage of disulfides

Article abstract of DOI:10.1039/c6ra18997k

C-C bond construction via C-H bond functionalization of oxazoles/thiazoles and C-S bond cleavage of di(hetero)aryl disulfides is described. Central to this strategy is the conversion of disulfides into 2-heterocyclic aryl oxazoles or thiazole by palladium

Full text of DOI:10.1039/c6ra18997k

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Direct C-H Heteroarylation of Azoles with 1,2-Di(pyrimidin-2-
yl)disulfides through C-S Cleavage of Disulfides
Kai-Jie Wei,a Zheng-jun Quan,*a Zhang Zhang, Yu-xia Da and Xi-cun Wang *a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The C-C bond constructtion via C-H bond functionalization of
oxazoles/thiazoles and C–S bond cleavage of di(hetero)aryl
disulfides is described. Central to this strategy is the conversion of
disulfides into 2-heterocyclic aryl oxazoles or thiazole by
palladium-catalyzed copper-promoted chemoselectively C–S bond
cleavage and generated the corresponding products in good yields.
Scheme 1. Cross coupling of disulfides with various nucleophiles
a) Reported work: C-S coupling
O
N
CuI/Cs2CO3/O2
O
N
S
Ar
+
SAr
Ar
S
or Pd/Al2O3,CuCl
b) Our previous work: C-N coupling
X
X
Y
CuTC
S
Het
The development of efficient methods to construct a C-C
bond between two heteroarenes has been a topic of high
scientific significance in chemical synthesis.1 Especially, 2-aryl
oxazoles or thiazoles are important structural units found in
natural products, functional materials, agrochemicals, and
pharmaceutically active compounds.2,3 Considering of
environmental and economical problems, direct C−H bond
arylation of oxazoles or thiazoles is a significant alternative to
traditional cross-coupling reactions.4,5 In recent years,
significant progress has been achieved in the development of
the direct C−H bond arylaꢀon of oxazoles and thiazoles
through oxidative coupling or using aryl electrophiles such as
aryl halides and phenol derivatives.6-10 Among the
electrophiles, relatively expensive aryl iodides and triflates
were largely employed because of their high reactivity.
Searching for new aryl electrophiles and improving the
catalytic efficiency of current systems are still active research
topics.
To date, the use of organosulfur compounds such as
sulfoether and diaryl disulfides as electrophiles in transition
metal catalyzed cross coupling reactions has received less
attention. This is presumably due to the poisoning effect on
some reagents and transition metals by sulfur compounds.11
Even so, some successful trials have been carried out. In 2015,
Wang and co-workers developed palladium-catalyzed
arylation of azoles and thiozaoles with aryl thioethers via
Y
+
Het
S
N
N
H
Cs2CO3
Het
X, Y = CH, N
c) This work: C-C coupling
R
R
X
X
N
Pd/dppp
Y
Y
S
Het
Het
Het
S
+
CuTC/Base
N
X, Y =C, O, S
C−H/C−S activation, however, it employed complicatedly
preformed catalysts.12 Further
Yu and co-workers developed
,
the reaction mechanisms by density functional theory
investigation.13 Compared sulfoether, diaryl disulfides
demonstrate more characteristic due to structurally
symmetrical, and easily available. More recently, some groups
independently developed the C-H arylation of heterocycles
including benzoxazole, benzothiazole and 1-methylindole with
diaryl disulfide and achieving C–S coupling products in the
presence of catalyst such as CuI/Cs2CO3/O2,14 Cs2CO3/ionic
16
liquids15 and Pd/Al2O3, CuCl (Scheme 1a). Meanwhile, our
group reported the C-C bond formation through C–S bond
cleavage of di(hetero)aryl disulfides with aryl boronic acids,
terminal alkynes or Grignard reagents, nevertheless, the
nucleophiles always need pre-functionalized.17 In 2016, our
group report C-N coupling reaction of disulfides with anilines,
indoles, triazole, benzotriazole and benzoimidazole through
C–S bond cleavage of di(hetero)aryl disulfides (Scheme 1b).18
Herein, we explored the possibility of applying 1,2-
di(pyrimidin-2-yl) disulfides in the C–C cross-coupling reaction
with oxazoles or thiazoles giving a 2-heterocyclic aryl oxazoles
or thiazoles under Pd catalyzed Cu accelerated conditions
(Scheme 1c). To the best of our knowledge, this is the first
example using disulfides as carbon-electrophile in the
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transition metal catalyzed C-H functionalization of heterocyclic the reaction outcome (entries 11-14). Compared with t-
compounds.
BuONa, t-BuOK, K3PO4, NaOAc, Cs2CO3 performed better in
73% yield. Finally, the controlled experiments without
Pd(OAc)2 or CuTC shown no reaction (entry 15-16) and the
reaction almost could not occur in the air (entry 17). Based on
the above experiments, the reaction was best conducted with
Pd(OAc)2 as the catalyst, CuTC as the copper salt, dppp as the
ligand, the Cs2CO3 as the base, and dioxane as the solvent at
120 oC for 18 h.
Table 1. Optimization of the cross-coupling reaction of disulfides 1a and benzoxazole
2a.a
Scheme 2. The cross-coupling reactions of disulfides with oxazoles and thiazoles.
Ligand
catalyst
[Cu]
Base
Entry
(10
mol%)
dppp
dppp
dppp
/
Yield/%[b]
(5 mol%)
(2 eq.)
(3eq.)
1
2
PdCl2
PdCl2
CuCl
CuBr
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
/
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
Trace
Trace
48
3
PdCl2
4
Pd(acac)2
Pd(dppf)Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
/
43
5
/
56
6
dppp
dppb
X-phos
PPh3
PCy3
dppp
dppp
dppp
dppp
dppp
dppp
dppp
73
7
69
8
48
9
39
10
11
12
13
14
15
16
17c
57
51
NaOAc
tBuONa
tBuOK
35
59
65
Cs2CO3
Cs2CO3
Cs2CO3
N.R.
N.R.
Trace
Pd(OAc)2
Pd(OAc)2
CuTC
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). cThe reaction was carried out at air atmosphere. PPh3
=
Triphenylphosphine hydrobromide. dppb = 1,4-Bis(diphenylphosphino)butane,
dppp 3-Bis(diphenylphosphino)propane. CuTC Copper(I) thiophene-2-
carboxylate.
=
=
To optimize the reaction conditions, 1,2-di(pyrimidin-2-yl)
disulfides 1a with benzoxazole 2a as a C-C coupling reaction
was chosen as a model system. The influence on the model
reaction of various parameters such as catalysts, copper salts,
ligands and bases were examined, and the results are
summarized in Table 1. Initially, we studied the effect of
different copper salts on the C-C coupling reaction of 1a with
2a, using PdCl2 as a catalyst, dppp as a ligand and Cs2CO3 as a
base under nitrogen atmosphere (entries 1-3). When CuTC,
CuCl, and CuBr were tested, CuTC promoted the reaction to
give the desired product 3aa in 48% yield (entries 3), whereas
CuCl, CuBr did not give the desired product with starting
material 1a was recovered (entries 1-2). Next, we screened
various palladium precursors and ligands to increase the yield
of 3aa, and it was found that a catalyst like Pd(OAc)2 and a
ligand like dppp gave 3aa in good yield (entry 6). In contrast,
Pd(acac)2, Pd(dppf)Cl2 and Pd(OAc)2 with kinds ligands, such as
dppb, X-phos, PPh3 and PCy3 provided 3aa in moderate yields
(entries 4-10). Furthermore, the effect of various bases was
studied, and we found that the base plays a significant role on
With these optimized reaction conditions, the general
applicability of the developed protocol was examined for the
C-C coupling reaction of disulfides with oxazoles and thiazole
(Scheme 2). The process proved to be relatively broad in
scope, tolerating a variety of steric and electronic changes to
both reaction partners. In general, moderate to good yields
(65-83%) were obtained under the standard reaction
conditions (3aa-3cf). The reaction conditions were suitable for
a variety of disulfides containing electron-donating group (Me)
on the phenyl ring as well as electron-withdrawing (F, Cl and
NO2) on the phenyl ring (3ba-3fa). The steric effects were
negligible and the 4-(2-chlorophenyl) substituted disulfide or
4-isopropyl substituted disulfide gave the target product 3ea
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in 70% yield or 3ga in 68% yield, respectively. As expected Unfortunately, reaction of 2,2'-dithiodipyridine or diphenyl
disulfides with Me group substituted on the phenyl ring of disulfide with benzoxazole failed to achieve the desired
benzoxazole achieved corresponding products in good yield product, but the starting materials were recovered. Compared
(
3hb-3cc). The reaction conditions were suitable for a variety with the active oxazoles and thiazoles, the 1-methylindole and
of disulfides and 2-phenyl-1,3,4-oxadiazole to give products 1-methylbenzimidazole were relative unactive and failed to
3ad-3de). And also, we attempted to disulfides with thiazole coupling with disulfide to give the corresponding products.
(
deliever corresponding products in modst yields (3af-3cf). To
our surprise, the disulfides 1k with 4-Br substituted on the
phenyl ring coupled with benzoxazole 2a giving the bi(1,3,4-
oxadiazolo)-substituted pyrimidine 3ka (Scheme 3). No matter
Scheme 5. Cross-coupling of unsymmetrical disulfides.
how we decreased the equivalents of 2a
(1k:2a = 1:2) or
raising the equivalents of 1k
3ka was obtained.
(1k:2a = 1:1), the desired product
Scheme 3. The reaction of achieve bi-molecular substituted product.
On the basis of these results and previous literature, [17a, 19]
a possible mechanism pathway for the Pd-catalyzed copper-
promoted C-C coupling of azoles and thiazoles with 1,2-
di(pyrimidin-2-yl) disulfides via C−H/C−S acꢀvaꢀon reagents is
depicted in Scheme 6. Pyrimidine-containing disulfides are
more efficient than aryl disulfides in the reaction, which may
be due to the coordination of a soft basic atom (such as N
atom) to the copper salt promoting C-S activation to give the
C-C cross-coupling products. A formal oxidative addition of
copper into the S-S bond affords Cu(II) dithiolato intermediate
The coupling reaction of disulfides with benzothiazole was
then examined. The previous optimized conditions were
applied to the cross-coupling reaction, but the desired product
was not detected. The choice of ligand was critical to the
success of the reaction, and improved yields were obtained
when PCy3 was screened as ligand using Pd(OAc)2 catalyst, t-
A 20
the formation of the corresponding copper(II) species
oxidative addition of the Pd(0) to the Cu(II) thiolato
intermediate
results in formation of complex C 21
.
Subsequent reductive cleavage of the S-S bond leads to
. Then,
B
B
.
Transmetalation from boron to palladium next occurs, and
then reductive elimination, giving the C-C cross-coupling
product 3.22
o
BuOK as base DMA as a solvent at 140 C, which gave up to
79% and 83% yield of cross-coupling products 5aa and 5ba
,
respectively (Scheme 4). Attempts to apply disulfide 1k with
benzothiazole, the corresponding product 5ka was formed
exclusively.
Scheme 6. Possible mechanism for the C-C coupling reaction of disulfides with
benzoxazole.
Scheme 4. The cross-coupling reactions of disulfides with benzothiazole.
After the tests towards symmetrical diheteroaryl
disulfides, two unsymmetrical disulfides 4a and 4b as reaction
substrates were examined. When the reaction of 4a with 2a
was performed under optimized conditions, the corresponding
3aa was obtained in a high yield of 70% with the formation of
In summary, we developed an efficient method to
construct C-C bond via direct C-H functionalization of oxazoles
or thiazoles with C–S bond cleavage of di(hetero)aryl
disulfides. The use of a copper salt such as CuTC was necessary
for efficient formation of the C-C bond in this C-C coupling
diaryl disulfide
not detected. Similarly, using disulfide 4b gave the
corresponding 3ca (68%) and (28%) (Scheme 5).
6 (41%), but the 2-(p-tolyl)benzoxazole 5 was
6
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Acknowledgements
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21362032,
21362031 and 21562036) and NWNU (NWNU-LKQN-15-1).
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Graphical Abstracts
The C-C Cross-Coupling Reactions of 1,2-Di(pyrimidin-2-yl) disulfides with Azoles and Thiazoles
through C-S Cleavage of Disulfides
Kai-Jie Wei, Zheng-jun Quan, Zhang Zhang, Yu-xia Da and Xi-cun Wang
R
R
X
N
X
N
Y
Pd/dppp
Y
Het
S
S
Het
Het
+
H
CuTC/Base
C-S Cleavage
27 examples
up to 83% yield
X, Y =C, O, S
Key words: benzoxazole, benzothiazole, Disulfides, CuTC, C-C coupling