Rhodium-catalyzed regioselective C-H chlorination of 7-azaindoles using 1,2-dichloroethane

Article abstract of DOI:10.1021/ol502447w

An unexpected rhodium-catalyzed regioselective C-H chlorination of 7-azaindoles was developed using 1,2-dichloroethane (DCE) as a chlorinating agent and 7-azaindole as the directing group. This protocol provides an efficient access to ortho-chlorinated azaindoles with operational simplicity, good functional group tolerance, and a wide substrate scope. (Chemical Equation Presented).

Full text of DOI:10.1021/ol502447w

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Regioselective C−H Chlorination of 7‑Azaindoles
Using 1,2-Dichloroethane
Guangyin Qian,† Xiaohu Hong,† Bingxin Liu,*,† Hong Mao,† and Bin Xu*,†,‡,§
†Department of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
‡State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
§Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University,
Shanghai 200062, China
S
* Supporting Information
ABSTRACT: An unexpected rhodium-catalyzed regioselective
C−H chlorination of 7-azaindoles was developed using 1,2-
dichloroethane (DCE) as a chlorinating agent and 7-azaindole
as the directing group. This protocol provides an efficient access
to ortho-chlorinated azaindoles with operational simplicity, good
functional group tolerance, and a wide substrate scope.
as the directing group has not been reported yet in all the
aforementioned cases.
he azaindole skeleton is one of the most attractive
Tframeworks as a bioisostere for indoles with a wide range
of biological and pharmacological activities, and has been found
in numerous biologically active natural products and marketed
drugs.1 Due to their ability to act as both hydrogen-bond donor
and acceptor, azaindoles have exhibited a broad spectrum of
biological activities such as antitumor,2 antibacterial,3 and anti-
inflammatory activity.4 The structural feature of electron-rich
azole and electron-deficient azine rings in the 7-azaindoles
makes them a unique structure in many therapeutic agents,
such as marketed anticancer drug Vemurafenib,5 hNK1
receptor,6 and potent antimelanoma agent PLX4720.7 Given
the broad utilities of 7-azaindoles in medicinal chemistry,
efficient functional group modifications at the C2 or C3
position of azaindoles with the aid of transition metals have
been described.8 A site-selective direct arylation of the 7-
azaindole core was also developed by making use of both the N-
oxide activation strategy and the Larrosa arylation protocol to
achieve the 6- and 2-arylation products, respectively.9
In recent decades, transition metal catalyzed direct C−H
bond functionalization has achieved great success in the
formation of C−C, C−N, and C−heteroatom bonds, which
provides efficient protocols to construct many useful
molecules.10 Among them, the ligand-directed C−H activation
approach has emerged as one of the most important processes
in organic synthesis to simplify the preparation of function-
alized building blocks and intermediates.11 In this context, a
range of nitrogen- and oxygen-containing directing groups such
as phenols,12a heterocycles (e.g., benzo[h]quinoline, pyrazole,
pyridine, quinoline),12b imines,12c amides,12d carboxylic
acids,12e esters,12f and ketones12g have been used for C−H
functionalization. However, C−H activation using 7-azaindole
Isocyanides have proven to be uniquely versatile building
blocks in organic synthesis due to their structural and reactive
properties and have been widely applied in the synthesis of
heterocycles.13 As their sustainable contribution, isocyanides
were recognized as an efficient cyanated reagent for the prepa-
ration of (hetero)aryl nitriles.14 For example, Zhu14a and we14b
have reported a palladium-catalyzed oxidative C−H cyanation
reaction independently using easily available tert-butyl iso-
cyanide as the novel cyanide source. As a complementary
method to our previously palladium-catalyzed cyanation
reaction,14b a rhodium-catalyzed regioselective C−H bond
cyanation of arenes was developed to achieve (hetero)aryl and
cycloalkenyl nitriles successfully in the presence of tert-butyl
isocyanide (Scheme 1).14c However, attempting to expand this
rhodium catalysis protocol to N-phenyl-7-azaindole (1a) failed.
To our surprise, an ortho aryl C−H bond chlorination reaction
had taken place instead and afforded the corresponding
chlorinated product 2a in 53% isolated yield (Table 1, entry
1), without observation of any desired cyanated product or
isomeric product 2a′ which was chlorinated at the more favored
electron-rich C3 position of the azole ring.15 To continue our
research interests on the isocyanide chemistry14b,c,16 and
assembling heterocycles through C−H bond functionaliza-
tion,17 herein we report an unexpected rhodium-catalyzed
regioselective C−H chlorination of 7-azaindoles (Scheme 1).
To our knowledge, this approach represents the first example of
Rh-catalyzed intermolecular C−H chlorination using 1,2-
Received: August 18, 2014
Published: September 24, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
conversions even prolonging the reaction time (entries 11−12),
and diminished yields were obtained by decreasing the amount
of Li2CO3 and t-BuNC (entries 13−14). Further investigations
revealed that in the absence of [RhCp*Cl2]2 (entry 15) or t-
BuNC (entry 16), or when reaction was conducted under a
nitrogen atmosphere (entry 17), the reaction became sluggish
and furnished 2a in lower yields. No reaction could be observed
in the absence of Cu(TFA)2, which indicated that the copper
source was crucial for this reaction (entry 18).
Scheme 1. Rh-Catalyzed Regioseletive C−H
Functionalization of Heteroarenes
With the establishment of the optimal conditions, the scope
and limitation of this chlorination reaction were next
investigated, as shown in Scheme 2. Substrates bearing an
electron-donating or electron-withdrawing group reacted
smoothly to afford the desired products in moderate to good
yields, in which the functional groups such as alkyl (2b, 2l),
alkoxyl (2c, 2m), phenyl (2k), halides (F, Cl, Br, I) (2d−2g),
ester (2h), acyl (2i), and nitro (2j) were all tolerated, regardless
of their electronic properties. The substrate with a strong
electron-withdrawing nitro group resulted in a slightly
complicated reaction, and the corresponding product 2j was
isolated in 32% yield. For meta-substituted substrates, the ortho
monochlorinated reaction selectively occurred at the less
sterically hindered position (2l−2m).
Encouraged by the success of a direct C−H chlorination
reaction of azaindoles, to further explore the generality and
scope of this practical approach, a variety of substituted 7-
azaindoles were investigated (Scheme 3). This chlorination
reaction worked well with many functionalized azaindoles
bearing substitutions at the C2−5 positions with different
electronic properties and gave desired products in moderate to
dichloroethane (DCE) as a chlorinating agent18 and 7-
azaindole as the new directing group for C−H activation.
At the outset of this investigation, we commenced our study
by conducting this chlorination reaction in the absence of
AgSbF6, and a comparable yield was obtained after reacting for
18 h at 130 °C (Table 1, entry 2). The use of Cu(OAc)2 or
Cu(acac)2 instead of Cu(TFA)2 gave worse results with a
longer reaction time (entries 3−4), while a C3-chlorinated
product 2a′ was produced predominately in the presence of
Cu(OTf)2 or CuCl2 (entries 5−6). The addition of bases could
improve the reaction, and the use of Li2CO3 turned out to be
the best choice (entries 7−10). Lowering the reaction
temperature simply resulted in decreased yields with poor
a
Table 1. Optimization of Reaction Conditions
b
yield (%)
entry
Cu source
additive
base
temp (°C)
time (h)
2a
53
2a′
1
Cu(TFA)2
Cu(TFA)2
Cu(OAc)2
Cu(acac)2
Cu(OTf)2
CuCl2
t-BuNC/AgSbF6
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
t-BuNC
−
−
−
−
−
−
−
130
130
130
130
130
130
130
130
130
130
120
100
130
130
130
130
130
130
20
18
48
48
48
13
50
35
26
41
47
55
40
37
54
31
55
52
−
−
−
−
32
72
−
−
−
−
−
−
−
−
−
−
−
−
2
58
31
N.R.
−
3
4
5
6
−
7
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
Cu(TFA)2
−
NaHCO3
Na2CO3
Li2CO3
pyridine
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
61
73
76
74
61
30
8
9
10
11
12
13
14
15
16
17
18
c
66
d
55
e
52
45
f
t-BuNC
27
t-BuNC
N.R.
a
Reaction conditions: 1a (0.2 mmol), Rh[Cp*Cl2]2 (2.0 mol %), Cu source (2.0 equiv), additive (2.0 equiv), base (1.0 equiv), 130 °C, air, DCE (1.0
b
c
d
mL). Cu(TFA)2 = Cupric trifluoroacetate. DCE = 1,2-Dichloroethane, N.R. = No Reaction. Isolated yield. Li2CO3 (0.5 equiv) was used. t-BuNC
(1.0 equiv) was used. Without Rh[Cp*Cl2]2. Under N2.
e
f
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Organic Letters
Letter
a
,b
4o) groups were all compatible in the reaction. Furthermore,
azaindoles having a bromo or iodo substitution at the C3 or C5
position (4c−4d and 4o) could also undertake this reaction
smoothly with a halide atom remaining, which provided
potential application for further transformation. The identity
of 4j was determined by spectral analysis and further confirmed
by X-ray crystallographic analysis.19
Scheme 2. Scope of Azaindoles Varying with N-Aryl Ring
The produced ortho-chlorinated N-aryl azaindoles represent a
class of potential antagonists of corticotropin-releasing
hormone-1 receptor (CRH1-R)20 and provide a useful template
for further analogue synthesis (Scheme 4). For example, ortho-
functionalized N-aryl azaindoles 5a−5b could be generated in
high yields from aryl or vinyl boronic acids using a well-
documented Suzuki reaction.
Scheme 4. Application of Chlorinated Product
a
Reaction conditions: 1 (0.3 mmol), Rh[Cp*Cl2]2 (2.0 mol %),
Cu(TFA)2 (2.0 equiv), t-BuNC (2.0 equiv), Li2CO3 (1.0 equiv), DCE
b
(1.5 mL), 130 °C, air, 23−53 h. Isolated yield.
Although a detailed reaction pathway remains to be clarified,
a tentative mechanism for this rhodium-catalyzed C−H
chlorination reaction is depicted in Scheme 5. One experiment
Scheme 3. Scope of Azaindoles Varying with Azaindole
Ring
a
,b
Scheme 5. Proposed Mechanism for Synthesis of 2a
was performed to provide support for the proposed
mechanism, involving the addition of 2,2,6,6-tetramethyl-1-
piperidinoxyl (TEMPO) to effectively quench the reaction.
This reaction may involve the formation of a C−Rh bond in the
first step to afford intermediate A, which presumably reacts
with hydrogen chloride generated in situ from 1,2-dichloro-
ethane18,21 to afford rhodium complex B. The formed
intermediate B followed by reductive elimination to give the
final product 2a, and the rhodium catalyst could be regenerated
by the oxidation of Cu(II) and atmospheric oxygen. For the
case without using a rhodium catalyst (Table 1, entry 15), the
reaction will go through copper complexes C and D followed
a
Reaction conditions: 3 (0.3 mmol), Rh[Cp*Cl2]2 (2.0 mol %),
Cu(TFA)2 (2.0 equiv), t-BuNC (2.0 equiv), Li2CO3 (1.0 equiv), DCE
b
(1.5 mL), 130 °C, air, 22−49 h. Isolated yield.
good yields. 1,2-Diphenyl-7-azaindole with high steric hin-
drance was found to be a suitable substrate and afforded 4a in
good yield. Substituents including alkoxyl (4k), aryl (4i−4j, 4n,
4p−4r), cycloalkyl (4m), acyl (4e−4h), and halide (4b−4d, 4l,
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product 2a.21
In conclusion, we have developed a rhodium-catalyzed
regioselective C−H chlorination reaction using easily available
1,2-dichloroethane (DCE) as a “Cl” source and 7-azaindole as
the directing group. This protocol provides an efficient access
to chlorinated 7-azaindoles with operational simplicity, good
functional group tolerance, and a wide substrate scope. Further
insight into the mechanism, reaction scope, and synthetic
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds, X-ray structure of compound 4j (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xubin@shu.edu.cn.
*E-mail: bxliu@shu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466.
We thank the National Natural Science Foundation of China
(No. 21272149) and Innovation Program of Shanghai
Municipal Education Commission (No. 14ZZ094) for financial
support. The authors thank Prof. Hongmei Deng (Laboratory
for Microstructures, SHU) for NMR spectroscopic measure-
ments.
(e) Stowers, K. J.; Sanford, M. S. Org. Lett. 2009, 11, 4584. (f) Song,
B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth. Catal. 2010, 352, 329.
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