A [4 + 1] Cyclative Capture Access to Indolizines via Cobalt(III)-Catalyzed Csp2-H Bond Functionalization

Article abstract of DOI:10.1021/acs.orglett.6b02421

A Co(III)-catalyzed [4 + 1] cycloaddition of 2-arylpyridines or 2-alkenylpyridines with aldehydes through Csp²-H bond activation has been developed. This protocol provides a facile approach to structurally diverse indolizines including benzoind

Full text of DOI:10.1021/acs.orglett.6b02421

Letter
pubs.acs.org/OrgLett
A [4 + 1] Cyclative Capture Access to Indolizines via Cobalt(III)-
Catalyzed Csp2−H Bond Functionalization
Xun Chen, Xinwei Hu, Yuanfu Deng, Huanfeng Jiang, and Wei Zeng*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510641, China
S
* Supporting Information
ABSTRACT: A Co(III)-catalyzed [4 + 1] cycloaddition of 2-
arylpyridines or 2-alkenylpyridines with aldehydes through
Csp2−H bond activation has been developed. This protocol
provides a facile approach to structurally diverse indolizines
including benzoindolizines with a broad range of functional
group tolerance.
ndolizines and benzoindolizines are pervasive in natural
products, pharmaceuticals, and functional materials (Figure
Scheme 1. Dual Activation Strategy for Transition-Metal-
I
Catalyzed Cascade Csp2−H Functionalization
1).1 In particular, 3-acylindolizines such as Rosabulin (STA-
Figure 1. Selected examples of bioactive indolizines.
5312) exert a potential cytotoxic effect against multiple cancer
cell lines.1c Accordingly, substantial interest has been directed
toward developing concise methods for the synthesis of diverse
3-acylindolizine skeletons.2 Among the various methods,
bromohydrocarbons and silylaryl triflates have been succes-
sively employed to construct indolizine heterocycles via
photocyclization,2d a multicomponent reaction,2e,f and an
aryne annulation process,2i but these methods are only limited
to furnishing benzoindolizines. Therefore, developing efficient
synthetic approaches to 3-substituted indolizines is desirable.3
Recent, chelation-assisted C−H bond functionalizations
provide an innovative strategy for direct Csp2−H addition to
aldehydes.4 The pioneering report by Shi first described that a
Rh(III)-catalyzed aryl C−H addition to aldehydes could
produce diarylmethanols by using pyridine as a directing
group (Scheme 1a).4b More recently, employing the earth-
abundant first-row metals such as manganese5 and cobalt6
catalysts to realize the C−H functionalization has aroused
concerns due to their availability and low cost. In this regard,
Wang took advantage of the directing character of the pyridine
group to enable the manganese-catalyzed Grignard-type
nucleophilic addition of Csp2−H bonds to aldehydes, but the
corresponding alcohols could not undergo a subsequent
intramolecular cyclization (Scheme 1a).4e In contrast, Glorius
found that a pyridine-directed aryl C−H coupling with diazo
compounds could occur in the presence of Co(III) salts, in
which Co(III) salts also played the role of Lewis acid catalyst to
enhance the nucleophilic attack of pyridyl nitrogen on the
carbonyl acceptor and resulted in furnishing polycyclic
hydrocarbons (Scheme 1b).7 These results and our previous
work8 encouraged us to speculate that pyridine-directed Csp2−
H addition to aldehydes could also possibly occur to form
alcohols by employing a Co(III) catalyst, and then a Co(III)
species could activate the resulting hydroxymethylene group,
leading to the formation of 3-substituted indolizines through a
nucleophilic cyclization process (Scheme 1c).
To achieve this transformation, we made the starting material
2-phenylpyridine (1a) and investigated the effect of various
cobalt catalysts (5 mol %) on the aryl C−H addition to ethyl
oxoacetate (2a) in the presence of AgSbF6 (10 mol %) and
NaOAc (20 mol %) using 1,2-dichloroethane (DCE) as solvent
at 80 °C for 12 h (Table 1, entries 1−4), and we soon found
that the [Cp*Co(CO)I2] catalyst provided the desired 3-
Received: August 12, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02421
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Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Parameters
Scheme 2. Substrate Scope
b
entry
catalysts
Co(acac)3
Ag salts
additives
yield (%)
1
AgSbF6
AgSbF6
AgSbF6
−
NaOAc
0
0
2
CoCl3
NaOAc
3
[Cp*Co(CO)I2]
NaOAc
28
21
19
14
25
0
c
4
A
NaOAc
5
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
[Cp*Co(CO)I2]
AgBF4
NaOAc
6
AgOAc
AgNTf2
AgClO4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
NaOAc
7
NaOAc
8
NaOAc
9
CsOAc
24
18
22
16
47
36
18
0
10
11
12
13
14
15
16
17
18
AcOH
PivOH
AgOAc
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
d
e
f
gh
,
71
88
ghi
, ,
a
Unless otherwise noted, all the reactions were carried out using 2-
phenylpyridine (1a) (0.20 mmol) and ethyl glyoxylate (2a) (0.20
mmol) with catalysts (5 mol %) in the presence of silver salts (10 mol
%) and additives (20 mol %) in solvent (2.0 mL) at 80 °C for 12 h
under Ar in a sealed reaction tube. Followed by flash chromatography
b
c
on SiO2. Isolated yield. A refers to [Cp*Co(MeCN)3(SbF6)2].
d
e
f
THF was used as solvent. Toluene was used as solvent. DMF was
g
h
used as solvent. The reaction time is 24 h. The reaction temperature
i
is 110 °C. The ratio of 1a/2a is 1:2.
ethoxycarbonylbenzoindolizine 3a in 28% yield (entry 3). The
[Cp*Co(MeCN)3(SbF6)2] catalyst also gave a 21% yield of 3a
(entry 4). It is worth noting that the further silver salt screening
could not improve the reaction conversion (compare entries
5−8 with entry 3). However, after various additives including
CsOAc, AcOH, PivOH, AgOAc, and Cu(OAc)2 were evaluated
for this transformation, the yield of product 3a was moderately
increased from 28% to 47% using Cu(OAc)2 as an additive
(compare entry 3 with 13). Meanwhile, the solvent screening
also demonstrated that DCE was the optimal solvent (compare
entries 14−16 with 13). Gratifyingly, extending the reaction
time, increasing the reaction temperature, and changing the
ratio of 1a/2a to 1:2 could significantly improve the reaction
yield to 71% and 88%, respectively (entry 17 vs 18).
With the optimized catalytic system in hand, we then turned
our attention toward exploring the scope and limitation of the
cobalt-catalyzed [4 + 1] cycloaddition of various 2-arylpyridines
(1) with ethyl oxoacetate (2a). As shown in Scheme 2, this
reaction protocol could smoothly convert 2-(4-substituted
phenyl)-pyridines to the desired 3-ethoxycarbonyl-
benzoindolizines with good to excellent yields (67−90%),
regardless of whether electron-deficient or -rich substituents
were introduced into the phenyl rings (3a−3i). For example, 2-
(4-methylphenyl)pyridine (1b) and 2-(4-trifluoro-
methylphenyl) pyridine (1i) could afford the desired 3-
acylbenzoindolizines 3b and 3i in 84% and 90% yields,
respectively. Moreover, 3- or 2-substitution on the benzene
ring with an electron-donating group (Me, MeO) or electron-
deficient group (Cl) could also give excellent yields of
a
All the reactions were carried out using 2-substituted pyridine (1)
(0.20 mmol) and aldehyde (2) (0.40 mmol) with [Cp*Co(CO)I2] (5
mol %) in the presence of AgSbF6 (10 mol %) and Cu(OAc)2 (20 mol
%) in DCE (2.0 mL) at 110 °C for 24 h under Ar in a sealed tube.
b
Followed by flash chromatography on SiO2. Isolated yield.
C
Anhydrous MgSO4 (100 mg) was added.
multisubstituted benzoindolizines in excellent yields, in which
no significant effect of steric hindrance was observed in this
transformation (3i−3n, 73% − 87% yields). Note that, 2-(3-
thienyl)pyridine (1o) and 2-(2-thienyl)pyridine (1p) are also
allowed for this transformation to assemble the corresponding
3-substituted thieno[3,2-α]indolizine (3o) and thieno[2,3-
α]indolizine (3p) in good yields. Meanwhile, the reaction
scope with respect to 2-phenyl-3- or 4- or 5-substituted
pyridines was further evaluated, and it was found that these
substrates with eletron-poor and -rich pyridine moieties were
reactive, and could produce the corresponding benzoindolizines
in 61−92% yields (3q−3w). Among them, the structure of 3s
was already unambiguously assigned by single crystal X-ray
analysis [see Supporting Information (SI) for more details].
More importantly, the reactions are not limited to 2-
arylpyridines. 2-Alkenylpyridines could also smoothly undergo
a [4 + 1] cycloaddition with ethyl oxoacetate (2a) to furnish 3-
ethoxycarbonylindolizines, in which 2-pyridyl substituted
B
DOI: 10.1021/acs.orglett.6b02421
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Letter
terminal alkenes and interal akenes are compatible with the
reaction conditions, and produce the corresponding structurally
diverse indolizines (3x−3iz) in moderate to good yields (46−
74%).
Scheme 4. Proposed Mechanism
Finally, the reaction scope with respect to aldehydes was
further investigated. In addition to ethyl oxoacetate, oxo-aryl-
acetaldehyde, and oxo-alkyl-acetaldehyde could give the desired
3-acylindolizines (3jz and 3kz) in accepted yields.9 In contrast,
other aldehydes such as benzaldehyde and acetaldehyde were
not allowed for this transformation, and the starting materials
were recovered completely.
Several control experiments were designed to elucidate the
possible mechanism of this transformation (Scheme 3). When
Scheme 3. Preliminary Mechanistic Studies
coordinate to pyridine “N” of 1a to form a five-membered
cobaltacycle intermediate A via a concerted metalation/
deprotonation (CMD) process.11 Subsequently, an insertion
of α-keto aldehyde 2a to a Co-carbonyl bond of intermediate A
forms the seven-membered Co(III) intermediate B, and then
intermediate B undergoes protonation to give alcohol C in
which the hydroxymethylene group is activated by a Co(III)
Lewis acid. Finally, Co(III)-catalyzed nucleophilic attack of the
pyridine nitrogen on the hydroxymethene carbon leads to the
formation of 3-acylbenzoindolizine (3a) with release of the
Co(III) catalyst.
In conclusion, we have developed a novel cobalt-catalyzed [4
+ 1] cycloaddition of 2-arylpyridines with aldehydes via a
Csp2−H activation process, in which cobalt catalysts play a dual
role as a metal catalyst and Lewis acid. A wide range of 2-
arylpyridines and 2-alkenylpyridines are allowed for this
transformation, and this method provides concise access to 3-
acylindolizines. Excellent functional group tolerance from 2-
substituted pyridines is observed.
the cobalt-catalyzed [4 + 1] cycloaddition of 2-phenylpyridine
(1a) with ethyl oxoacetate (2a) was conducted in the Co(III)/
Cu(OAc)2/AgSbF6 system at 60 °C for 24 h, 3-acylbenzolizine
3a and alcohol 4a were produced in 22% and 13% yields,
respectively (eq 1). Considering that the alcohol 4a was the
possible intermediate for this cycloaddition, alcohol 4a was
then subjected to the AgSbF6/Cu(OAc)2 system in the absence
of a cobalt catalyst at 110 °C for 24 h, and 3a was formed in
31% yield; the starting material 4a could be recovered in 62%
yield (eq 2). However, treating the alcohol 4a with the
Co(III)/Ag(I)/Cu(II) catalytic system at 110 °C for 24 h
afforded a 92% yield of 3a (eq 3). Moreover, deuterium
incorporation at the phenyl C2- and C6-position of 2-
pyridylbenzene (1a) was also observed in the presence of
CD3OD (eq 4). These results implied that alcohol 4a belonged
to the intermediate for this transformation in which Co(III)
salts also played a dual role of transition metal catalyst and
Lewis acid. Subsequently, the parallel kinetic experiments from
1a and d-1a (kH/kD = 1.1) further indicated that aryl C−H
bond-breaking was not involved in the rate-limiting step of this
transformation (eq 5) (see SI for more details).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02421.
Detailed experimental procedures, characterization data,
copies of 1 H NMR and 13 C NMR spectra for all isolated
compounds (PDF)
Crystallographic data for 3s (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zengwei@scut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Based on the preliminary mechanistic investigations, a
plausible mechanism is proposed in Scheme 4. First, [Cp*Co-
The authors thank the NSFC (No. 21372085), National Key
Research Program of China (No. 2016YFA0602900), and
Science and Technology Program of Guangzhou (No.
156300075) for financial support.
(CO)I2] catalysts are activated by additives AgSbF6/Cu(OAc)2
7,10
to form the Co(III) species Cp*Co(OAc)2
which
C
DOI: 10.1021/acs.orglett.6b02421
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Letter
(7) Zhao, D.; Kim, J. H.; Stegemann, L.; Strassert, A.; Glorius, F.
Angew. Chem., Int. Ed. 2015, 54, 4508.
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