Rh(III)-catalyzed cyclization reaction of azoles with alkynes: Efficient synthesis of azole-fused-pyridines

Article abstract of DOI:10.1039/c5ob01338k

A Rh(III)-catalyzed cyclization of azoles with alkynes has been developed. A variety of azole-fused-pyridines were obtained in good to excellent yields and regioselectivity. Both the C5 and the C4 position of azoles were suitable for the reaction.

Full text of DOI:10.1039/c5ob01338k

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DOI: 10.1039/C5OB01338K
COMMUNICATION
Rh(III)-catalyzed Cyclization Reaction of Azoles with Alkynes:
Efficient Synthesis of Azole-fused-Pyridines
Xuebing Chena, Youzhi Wua, Jinyi Xua, Hequan Yaoa, Aijun Lina and Yue Huanga,b
*
Rh(III)-catalyzed cyclization of azoles with alkynes has been
developed. variety of azole-fused-pyridines were
A
accomplished in good to excellent yields and regioselectivity.
Both the C5 position and the C4 position of azoles were
suitable in the reaction.
In the past few years, chelation-assisted electrophilic
metalation of an ortho sp2 C-H bond directed by the
nitrogenous groups offering an advanced route for the
construction of azacyclic compounds.1 Among of these
nitrogenous directing groups, oximido was frequently reported
in recent years.2 Cheng and Chiba’s groups reported the Rh(I)
or Rh(III)-catalyzed tandem C-C/C-N bond formation reaction
between oximes and alkynes respectively.3 In 2012,
Ackermann and Jeganmohan completed the same reaction
employing Ru(II) as the catalyst.4 These examples provided
concise ways to the synthesis of isoquinolines and their
derivatives (Scheme 1, a).5 However, to our knowledge, the
Scheme 1. Transition metal catalyzed reaction of oximes with
alkynes
Azole-fused-pyridines are common structural skeleton in
bioactive molecules.9 The existing methods to prepare azole-
fused-pyridines mostly start from substituted pyridines to
synthesize the azole rings.10 Recently, our group focused on
the direct functionalization of azoles via C-H activation.11 As
we know, the C-H activation of the C4 position of azoles was
more challenging compared to the C5 position, and few
examples on the C-H functionalization of the C4 position of
azoles with non-preactivated reagents have been reported.12
Continuing our interest in the transition metal catalyzed C-H
functionlization of azoles, in this paper, we will report a Rh(III)-
catalyzed cyclization reaction of thiazoles/oxazoles with
alkynes to construct thiazole/oxazole-fused-pyridines (Scheme
heterocycle-fused-pyridines,
which
possess
extensive
bioactivities, were not studied specifically up to now.6 When
come to heterocycles in directed C-H activation reactions, two
problems maybe meet: (1) Heteroatoms such as nitrogen or
sulphur atoms in substrates often outcompete the directing
groups for catalyst binding, thus making the catalyst poisoned
or preventing the C-H activation progress.7 (2) Some nitrogen-
containing heterocyclic rings such as azoles themselves could
play as directing groups,8 which could make the C-H
functionalization at an undesired position.
1
, b), both the C5 and the C4 position of azoles are suitable in
this reaction.
Initially, we examined the reaction of 1-(2-phenylthiazol-4-
yl)ethanone oxime (1a) with 1,2-diphenylethyne (2a) as the
model reaction to optimize the reaction conditions. When the
two substrates were treated with 2.5 mol % [RhCp*Cl2]2 as a
catalyst, 2 equivalent of NaOAc as an additive in MeOH at 60
oC for 24 h, we were delighted to get the corresponding
product 3a in 91% isolated yield (Table 1, entry 1). Screening
of the base additives revealed that CsOAc was an alternative
base of NaOAc, while K2CO3 decreased the yield to 67% (Table
a.State Key Laboratory of Natural Medicines, China Pharmaceutical University,
Nanjing, 24 Tong Jia Xiang, 210009, P. R. China.
b.Department of Organic Chemistry, China Pharmaceutical University, Nanjing, 24
Tong Jia Xiang, 210009, P. R. China.
E-mail: yhuang@cpu.edu.cn
1
, entries 2-3). Decreasing the equivalent of 2a to 1.2 led to 95%
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Table 2. Scope of thiazoles/oxazoles and alkynes a, b
yield (Table 1, entry 4). The similar yields were achieved when
the equivalent of NaOAc was decreased to 1 or 0.3 (Table 1
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DOI: 10.1039/C5OB01338K
,
entries 5-6). Decreasing the amount of catalyst [RhCp*Cl2]2 to
1 mol % reduced the yield to 76% (Table 1, entry 7). Finally,
when [RuCl2(p-Cymene)]2 was also employed as the catalyst,
no product was observed (Table 1, entry 8).
Table1. Optimization of the reaction conditions a
Entry
Additive (2 equiv.)
Equiv. of 2a
Yield (%)b
1
2
3
4
5
NaOAc
CsOAc
K2CO3
2
2
2
1.2
1.2
1.2
1.2
1.2
91
88
67
95
94
90
76
NR
NaOAc
NaOAc (1 eq.)
NaOAc (0.3 eq.)
NaOAc
6
7c
8d
NaOAc
a
Reaction conditions: 1a (0.2 mmol, 1 equiv.) 2a (0.4
mmol , 2 equiv.), [RhCp*Cl2]2 (2.5 mol %), additive (0.4
o
mmol, 2 equiv.) in 2 mL MeOH at 60 C for 24 h under air
b
c
atmosphere. Isolated yield. 1 mol % [RhCp*Cl2]2 was
used. d 2.5 mol % [RuCl2(p-Cymene)]2 was used.
With the optimal reaction conditions in hand, the scope and
generality were investigated for this Rh(III)-catalyzed
cyclization reaction of azoles with alkynes. The results are
shown in Table 2. We firstly examined the scope of the
thiazoles, electron-donating groups such as methoxy and
methyl as well as halogen groups (F, Cl, Br), and
trifluoromethyl on the para-position of phenyl rings were
tolerated well and afforded the corresponding products in
good to excellent yields (Table 2, 3a-3g). When the thiazole-
substituted benzene carried a methyl at the meta-position, the
corresponding product 3h could also be obtained in 90% yield.
Moreover, the scope of internal alkynes was also examined in
this cyclization reaction. Internal diarylalkynes bearing
methoxy, methyl and halogen groups (Cl, Br) at the para-
position of the phenyl ring offered 3i-3l in 80-91% yields.
Strong electron-withdrawing group trifluoromethyl offered the
desired product 3m in 67% yield. 1,2-di-m-tolylethyne gave 3n
in 84% yield. In addition, the scope of the alkyne could be
extended to dialkyl-substituted alkyne (oct-4-yne) and 3o was
obtained in 84% yield. Unsymmetrical alkynes were also
compatible in our reaction, 3p and 3q could be finished in 77%
and 41% yield respectively. When methyl 3-phenylpropiolate
was tested, the corresponding 3r was only observed in 19%
yield even with increased catalyst loading maybe due to the
electron deficiency property. Finally, we tried the cyclization of
1,2-diphenylethynes with 1-(2-phenyloxazol-4-yl)ethanone
oximes
a
Reaction conditions: 1 (0.2 mmol, 1 equiv.), 2 (0.24 mmol, 1.2
equiv.), [RhCp*Cl2]2 (2.5 mol %), additive (0.4 mmol, 2 equiv.) in 2
mL MeOH at 60 oC for 24 h under an air atmosphere. b Isolated yield.
c 70 oC. d 5 mol % [RhCp*Cl2]2 was used.
Table 3. Scope of thiazoles and alkynes a, b
a
Reaction conditions: 4 (0.3 mmol, 1.5 equiv.), 2 (0.2 mmol, 1
equiv.), [RhCp*Cl2]2 (2.5 mol %), additive (0.4 mmol, 2 equiv.) in 2
mL MeOH at 70 oC for 24 h under an air atmosphere. b Isolated yield.
c 2.0 equiv. of 4 was used.
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and found that oxazoles could also afford the desired products
3s-3v in 65%-94% yields.
In summary, we have developed
a
Rh(III)-catalyzed
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cyclization reaction of azoles with alkyDnOesI: 1v0i.a103s9e/lCe5cOtiBv0e13C38-HK
After the achievement of alkynes coupled with C5 position activation.
A
variety of azole-fused-pyridines were
of thiazoles/oxazoles, we tried the reaction of alkynes with the accomplished in good to excellent yields and regioselectivity.
C4 position of thiazoles, which has lower reactivity compared Furthermore, the reaction of alkynes with C4 position of
to C5 position. In contrast to 4-substituented thiazoles, the 5- thiazoles through C-H activation was achieved for the first time.
substituented thiazole substrate 1-(2-phenylthiazol-5- More direct functionlization of azoles are in progress in our
yl)ethanone oxime (4a) have two Z/E isomers with the ratio of laboratory.
2:3, which are inseparable via slica column chromatography.
Generous financial support from the National Natural
We noticed that the Z-isomer was difficult to activate because Science Foundation of China (NSFC21272276), the Natural
it’s difficult to accomplish the five-membered rhodacycle Science Foundation of Jiangsu Province (BK20140655 and
intermmediate.3 To realize our target, we set the equivalent of BK20130645) and the Foundation of State Key Laboratory of
2a as 1.0 equivalent while increased 4a (Z/E mixtures) to 1.5 Natural Medicines (ZZJQ201306) is gratefully acknowledged.
equivalent at 70 °C in MeOH with [RhCp*Cl2]2 (2.5 mol %) as a
catalyst and NaOAc (2.0 equiv.) as an additive. Fortunately, we
found that the corresponding product 5a was obtained in 85%
Notes and references
isolated yield. Subsequently, the scope of thiazoles and
internal alkynes was investigated. As shown in Table 3, all the
substrates including thiazoles bearing different substituents,
symmetrical or unsymmetrical alkynes could offer the desired
products 5a-5j in 77%-94% yields.
1
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mechanism as illustrated in Scheme 2. The [RhCp*Cl2]2
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A
. Insertion of the alkyne
A
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B.
I
B
a
C.
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