Copper-mediated C-H(sp2)/C-H(sp3) coupling of benzoic acid derivatives with ethyl cyanoacetate: An expedient route to an isoquinolinone scaffold

Article abstract of DOI:10.1039/c4cc03837a

A facile, copper-mediated, direct C-H(sp²)/C-H(sp³) bond coupling of benzoic acid derivatives with ethyl cyanoacetate by the deployment of an 8-aminoquinoline moiety as a bidentate directing group is disclosed. Such a unique transfor

Full text of DOI:10.1039/c4cc03837a

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Copper-mediated C–H(sp2)/C–H(sp3) coupling of
benzoic acid derivatives with ethyl cyanoacetate:
an expedient route to an isoquinolinone scaffold†
Cite this: Chem. Commun., 2014,
50, 10634
Received 20th May 2014,
Accepted 22nd July 2014
Wei Zhu, Dengyou Zhang, Nan Yang and Hong Liu*
DOI: 10.1039/c4cc03837a
www.rsc.org/chemcomm
A facile, copper-mediated, direct C–H(sp2)/C–H(sp3) bond coupling of
benzoic acid derivatives with ethyl cyanoacetate by the deployment of
an 8-aminoquinoline moiety as a bidentate directing group is disclosed.
Such a unique transformation provides a new strategy for the construc-
tion of an isoquinolinone scaffold as one of the privileged cores.
In the past decade, the metal-mediated functionalization of carbon–
hydrogen bonds has emerged as a powerful and promising method
for the formation of carbon–carbon and carbon–heteroatom bonds
in a single synthetic operation.1 In general, a wide range of noble
metals including Pd,2 Au,3 Rh,4 and Ru5 are highly active catalysts
for C–H functionalization. From the viewpoint of practicality and
applicability in academic and industrial communities, however,
huge challenges still remain in the development of economical
and efficient transformation systems for the inert C–H bond.
Among the various deployed metals, copper has attracted
Scheme 1 Copper-mediated C–H/C–H coupling with 8-amino-
quilonines as directing groups.
increasing attention because it is low-cost, environmentally- 3-oxobutanoate11a,12 and 2-cyanoacetate13 for the formation of C–C
benign and abundant.6 More recently, combination of copper salts bonds. In light of these studies, we desired to test such transforma-
with bidentate directing groups, involving N,N0-dual coordinated tions via C–H cleavage, which might be facilitated by the employ-
sites, has emerged as an innovative strategy for the construction of ment of copper salts with bidentate directing groups. Herein, we
carbon–heteroatom or carbon–carbon bonds through C–H cleavage.7 revealed the copper-mediated, direct C–C bond construction of ortho
Daugulis and Stahl successfully demonstrated that arene C–H bonds C–H bonds in an aromatic amide with ethyl cyanoacetate, along with
could be transformed into C–X bonds (X = S, O, N, F) with simultaneous C–N bond formation. Such a unique transformation
8-aminoquilonines as directing groups.8 By the employment of a allows for the smooth construction of an isoquinolinone scaffold,
similar approach, Miura disclosed an efficient copper-mediated standing as one of the privileged moieties, which were ubiquitous in
C–H/C–H coupling of benzoic acid derivatives with 1,3-azoles natural products and pharmaceuticals.14
bearing active sp2 C–H bonds (Scheme 1).9
We initiated our investigations by screening the reported
Despite the significant progress, to our knowledge, copper- bidentate directing groups (A, B, C, D) as they play a significant
mediated C–H(sp2)/C–H(sp3) coupling remains a great challenge role in metal coordination (Table 1, entries 1–4). After extensive
for synthetic chemists. Previous studies have demonstrated the attempts, it was interesting to find that the 8-aminoquinoline-
copper-mediated coupling of prefunctionalized aromatic derivatives containing secondary amide (A) combined with copper salts
with substrates bearing active methylenes10 such as malonate,11 enabled the direct C–H(sp2)/C–H(sp3) coupling with ethyl cyano-
acetate, along with the sequential formation of the C–N bond,
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica,
resulting in the construction of the isoquinolinone scaffold
(entry 1). However, no reaction occurred when 8-aminoquinoline (A)
was replaced with naphthalene (entry 5), indicating that coordination
in an N,N0-fashion is a key step in the reaction. Other substrates with
Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China.
E-mail: hliu@mail.shcnc.ac.cn
† Electronic supplementary information (ESI) available: Experimental proce-
dures, compound characterization, and 1H and 13C NMR spectra. See DOI:
10.1039/c4cc03837a
active methylenes, such as malonate and 2-phenylacetonitrile,
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Table 1 Optimization of the reaction conditionsa
Table 2 Copper-mediated reaction of ethyl cyanoacetate with carboxylic
acid derivativesa,b
Entry
DG
Copper salts
Bases
Solvents
Yieldb (%)
1
2
3
4
5
6
7
8
A
B
C
D
E
A
A
A
A
A
A
A
A
A
A
A
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2H2O
Cu(OTf)2
CuF2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Li2CO3
Na2CO3
Cs2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
iPrOH
DCE
80
N.R.
N.R.
N.R.
N.R.
77
14
35
74
82
71
88
9
10
11
12c
13c
14c
15c
16c,d
64
25
43
74
DMF
DMSO
a
Reaction conditions: 1 (0.4 mmol), ethyl cyanoacetate (1.2 mmol),
b
c
copper salts (1.2 mmol), 110 1C, 12 h, Ar. Isolated yield. 4 h, 90 1C.
d
0.4 mmol TEMPO (1 eq.) was added.
were also explored without the corresponding products observed.
Further optimization of reaction conditions with respect to copper(II)
salts, bases and solvents is summarized in Table 1. Using K2CO3 as
the base and DMSO as the solvent at 110 1C, we found that the
counter ions of copper(II) salts (entries 1 and 6–8) have a remarkable
impact on the reaction yield; and Cu(OAc)2 gave the best yield.
Subsequently, the evaluation of bases revealed that Na2CO3 was
superior to the other alkali carbonates (entries 1 and 9–11). The yield
was further improved by lowering the temperature from 110 1C to
90 1C and reducing the reaction time to 4 h (entry 11). The effects of
various solvents on the reaction were investigated. The use of aprotic
solvent iPrOH (entry 13) and nonpolar solvent DCE (entry 14) was
ineffective, while DMF (entry 15) was apparently inferior to DMSO.
The yield slightly decreased with the presence of TEMPO (entry 16).
With the optimized conditions identified, we next explored a series
a
Reaction conditions: 1 (0.4 mmol), ethyl cyanoacetate (1.2 mmol),
b
c
copper salts (1.2 mmol), 90 1C, 4–6 h, Ar. Isolated yield. a-Isomer
yield: 11%.
of 8-aminoquinoline benzamides to examine the scope and limita- the C–H functionalization of 2-naphthamide occurred predominantly
tions of this process. As shown in Table 2, the desired products 3b–3r at the less sterically-hindered b-sites (3o, 3p). Benzamides bearing
were obtained in moderate to good yields (49–86%) by the treatment substituted quinoline rings also afforded good yields.
of various benzamides (1b–1r) with ethyl cyanoacetate 2a. The
Next, we investigated a variety of cyano-substrates as coupling
introduction of electron-donating groups (–Me, –OMe) at the para- partners (Table 3). Variation of the ester group has little effect on
position of the benzamides resulted in a slight reduction in yields this transformation; isoquinolinone products were obtained in
of target compounds (3b, 3c), while substrates bearing electron- good yield (3s–3u), while the benzyl derivative gave moderate
withdrawing substituents (–CF3, –COOMe) afforded higher yields yield (3v). Apart from cyano substituted esters, we also tested
(3d, 3e). Notably, halides such as fluorine (3f), chloride (3g, 3l) and cyano substituted amides, phosphonates and methylsulfonyls.
bromide (3h) were tolerated under the standard reaction conditions, Gratifyingly, the corresponding isoquinolinone products were
guaranteeing further transformation. The cleavage of C–H bonds in obtained in good yields (3w–3y).
meta-substituted benzamides occurred predominantly at sterically less
To get some insights into the mechanism of this cascade
congested sites, irrespective of the electronic nature of the substitu- reaction, a series of controlled experiments were conducted.
ents (3i–3l). ortho-Substituted benzamides were also compatible, and A stoichiometric amount of TEMPO, frequently used as a radical
gave good yields (3m, 3n). Naphthalene derivatives worked well, and scavenger in transition-metal-mediated reactions, has a slight
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of M4 and intramolecular annulation of 4 provide 3a.8e This
tentative pathway also explains the necessity of excess Cu(OAc)2
and Na2CO3 to realize a good conversion.
Table 3 Copper-mediated reaction of N-(quinolin-8-yl)benzamide with
cyano-substratesa
In conclusion, we have developed copper-mediated C–H/C–H
coupling of benzoic acid derivatives and ethyl cyanoacetate, along
with simultaneous C–N bond formation, with the aid of the
8-aminoquinoline-based double N,N0-coordination strategy. The trans-
formation exhibits wide generality, functional tolerance and high
steric selectivity. It also provides a straightforward approach for the
construction of an isoquinolinone scaffold, which is a privileged
moiety and ubiquitous in natural products and pharmaceuticals.
Further elucidation of the detailed mechanism and application of
this transformation are under investigation in our laboratory.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grants 21021063, 91229204,
and 81025017), and National S&T Major Projects (2012ZX09103101-
072, 2013ZX09507-001, and 2014ZX0950 7002-001), Sponsored by the
Program of Shanghai Subject Chief Scientist (Grant 12XD1407100).
a
Reaction conditions: 1 (0.4 mmol), cyano-substrates (1.2 mmol),
copper salts (1.2 mmol), 90 1C, 4–6 h, Ar.
Notes and references
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cupration of the active menthene of ethyl cyanoacetate under
base conditions provided intermediate M1, which undergoes ligand
exchange with 1a to afford N,N-chelated copper(II) complex M2,
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ring generates the key intermediate M4,15 which is speculated to be
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3.65 (Scheme S2 in the ESI†). The subsequent reductive elimination
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Scheme 2 Plausible reaction mechanism.
10636 | Chem. Commun., 2014, 50, 10634--10636
This journal is ©The Royal Society of Chemistry 2014