Cu(II)-catalyzed coupling of aromatic C-H bonds with malonates

Article abstract of DOI:10.1021/acs.orglett.5b00193

A new Cu(II)-catalyzed oxidative coupling of arenes with malonates has been developed using an amide-oxazoline directing group. The reaction proceeds via C(sp²)-H activation and malonate coupling, followed by intramolecular oxidative N-C bond formation. A variety of arenes bearing different substituents are shown to be compatible with this reaction.

Full text of DOI:10.1021/acs.orglett.5b00193

Letter
pubs.acs.org/OrgLett
Cu(II)-Catalyzed Coupling of Aromatic C−H Bonds with Malonates
Hong-Li Wang,† Ming Shang,† Shang-Zheng Sun,§ Zeng-Le Zhou,† Brian N. Laforteza,‡ Hui-Xiong Dai,*,†
and Jin-Quan Yu*,†,‡
†State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, China
‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
§Department of Chemistry, Innovative Drug Research Center, Shanghai University, 99 Shangda Road, Shanghai 200444, China
S
* Supporting Information
ABSTRACT: A new Cu(II)-catalyzed oxidative coupling of
arenes with malonates has been developed using an amide-
oxazoline directing group. The reaction proceeds via C(sp2)−
H activation and malonate coupling, followed by intra-
molecular oxidative N−C bond formation. A variety of arenes
bearing different substituents are shown to be compatible with this reaction.
Scheme 1. Transition-Metal-Catalyzed Coupling of Aromatic
C−H Bonds with Malonates
ver the past several decades, transition-metal-catalyzed
OC−H functionalization reactions have emerged as
powerful tools for the construction of C−C and C−X bonds
in organic synthesis.1 In this context, the extensively utilized
Heck reaction and Stille, Suzuki, Negishi, and Hiyama
couplings have provided inspiration for the development of
analogous transformations using C−H bonds in lieu of aryl or
alkyl halides as the reaction partners. Most notably, Pd-
catalyzed C−H olefination has undergone substantial progress
in terms of both catalyst development and mechanistic
understanding since 1967.2 On the other hand, the coupling
of C−H bonds with organometallic reagents and other
nucleophiles via Pd(II)/Pd(0) redox catalysis has been far
less developed. The difficulty associated with transfer of a
nucleophilic carbon fragment via transmetalation or direct
displacement to the Pd(II) intermediate, as well as the
subsequent reductive elimination, has historically proven to
be a significant challenge. Despite a series of developments in
Pd-catalyzed C−H coupling with organometallic reagents,3 the
coupling of C−H bonds with a malonate nucleophile remains
challenging. Such a coupling was previously realized in the
context of allylic C−H activation.4 More recently, Pd(II)/
Mn(III)-mediated ortho-C−H coupling of anilide with β-keto
esters via a radical mechanism was accomplished for the first
time, although the substrates were limited to the electron-rich
anilides (Scheme 1, eq 1).5
Cu-catalyzed C−H functionalizations have attracted an
increasing amount of attention in recent years.7−11 Encouraged
by new reports detailing Cu-mediated C−H functionalizations
using an amide−oxazoline directing group,11 we began to
investigate whether this auxiliary could be exploited in the
coupling of C−H bonds with malonate nucleophiles. As such,
we found that oxidative coupling of N-arylbenzamide substrate
1a with 2 equiv of dimethyl malonate 2a proceeded in the
presence of 20 mol % of Cu(OAc)2, 1.5 equiv of Ag2O, and 2.0
equiv of Na2CO3 in DMSO at 80 °C to afford desired product
3a in 38% yield (Table 1, entry 1). To improve this reaction, an
extensive screening of reaction parameters was conducted.
Various bases were investigated, and it was discovered that
Li2CO3 produced the highest yield of 52% (Table 1, entries 2−
8). Furthermore, DMSO and Ag2CO3 also proved to be
optimal choices after evaluation of different solvents (see
During the course of our studies, a Cu(II)-mediated [3 equiv
of Cu(OAc)2] oxidative coupling of benzamide with ethyl
cyanoacetate using 8-aminoquinoline as a directing group was
also discovered (eq 2).6
Herein, we describe a copper-catalyzed, direct oxidative
coupling of aromatic C−H bonds with malonates using an
amide-oxazoline as the directing group. The initially formed
coupling products undergo intramolecular C−N bond for-
mation leading to isoindolinone scaffolds (eq 3).
Received: January 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Substrates
b
entry Cu(OAc)2 (mol %)
[Ag]
base (equiv)
yield (%)
1
20
20
20
20
20
20
20
20
20
20
20
20
30
10
0
Ag2O
Na2CO3 (2.0)
Li2CO3 (2.0)
K2CO3 (2.0)
LiOAc (2.0)
NaHCO3 (2.0)
KHCO3 (2.0)
K2HPO4 (2.0)
KH2PO4 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (2.0)
Li2CO3 (1.0)
Li2CO3 (0)
38
52
9
2
Ag2O
3
Ag2O
4
Ag2O
14
29
27
47
46
57
27
41
79
78
63
n.r.
5
Ag2O
6
Ag2O
7
Ag2O
8
Ag2O
9
Ag2CO3
AgOAc
AgNO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
10
11
12
13
14
15
c
c
c
c
c
d
16
20
20
20
20
79(69)
55
c
17
18
19
ce
,
Li2CO3 (1.0)
Li2CO3 (1.0)
52
cf
,
68
a
Reaction conditions: 1a (0.10 mmol), 2a (0.2 mmol), Cu(OAc)2 (20
mol %), base (0.2 mmol), [Ag] (0.15 mmol), DMSO (1.0 mL), air, 80
b
1
°C, 12 h. Yields were determined by H NMR analysis of crude
reaction mixture using CH2Br2 as an internal standard. DMSO (4.0
mL). Isolated yield. 70 °C. 90 °C.
c
d
e
f
Supporting Information) and oxidants, respectively (Table 1,
entries 9−11). The use of molecular oxygen as the sole oxidant
gave poor yields (<10%). Notably, the yield was increased to
79% when the reaction was run at lower concentrations (Table
1, entry 12). A variety of copper salts are also reactive, albeit
lower yields were obtained when compared to Cu(OAc)2 (see
Supporting Information). Reducing the quantity of Cu(OAc)2
to 10 mol % lowered the yield to 63% (Table 1, entry 14). It
should also be noted that in the absence of copper no reactivity
is observed (Table 1, entry 15). Additionally, altering the
amount of Ag2CO3 and 2a does not seem to have any beneficial
impact on the yield (see Supporting Information). Interestingly,
reducing the amount of Li2CO3 to 1.0 equiv had a negligible
impact on the observed reactivity (Table 1, entry 16). Finally,
increasing the reaction temperature to 90 °C, or reducing the
reaction temperature to 70 °C, did not further increase the
yield (Table 1, entries 18−19).
With these optimized conditions in hand, we proceeded to
examine the substrate scope of this oxidative coupling
cyclization reaction (Scheme 2). In general, both electron-
donating and -withdrawing substituents on the benzene ring of
benzamides were well-tolerated under the current conditions.
Oxidative coupling/cyclization of electron-rich methyl-, tert-
butyl-, and methoxy-substituted arenes proceeded smoothly to
provide the corresponding products in 59−75% yields (3a−
3g). It is noteworthy that when benzamides 1d and 1f, bearing
meta substituents on the benzene ring, were subjected to this
C−H functionalization protocol, the regioselectivity of the
reaction favored the formation of less sterically hindered
products (3d, 3f). Electron-deficient arenes bearing halides,
acetyl, and trifluoromethyl groups also proceeded well,
a
Reaction conditions: 1a−1r (0.10 mmol), 2a−2c (0.2 mmol),
Cu(OAc)2 (20 mol %), Li2CO3 (0.1 mmol), Ag2CO3 (0.15 mmol),
DMSO (4.0 mL), air, 80 °C, 12 h. Isolated yield. Cu(OAc)2 (50 mol
%). 70 °C. 60 °C.
b
c
d
e
affording their corresponding products in moderate yields
(3h−3n, 40−56% yield). Vinyl substrate 1q was also cyclized to
provide 3q in 71% yield. Halogen (3h−3l) and vinyl (3q)
substituents in the products are useful handles for further
synthetic elaborations. As expected, oxidative coupling/
cyclization of substrate 1b with malonates 2b and 2c can also
be converted into desired products of 3s and 3t in 58% and
71% yield, respectively. The structure of 3s was unambiguously
determined by X-ray diffraction analysis (see Supporting
Information).
Interestingly, we found that coupling of benzamide substrate
1a with 3-oxobutanoate 4 afforded methyl 3,6-dimethyl-1-oxo-
1H-isochromene-4-carboxylate 5, derived from enolate O-
acylation following oxidative C−H coupling, in 34% yield
(Scheme 3). No corresponding isoindolinone products were
detected. Apparently, the newly installed enolate assisted the
removal of the amide directing group. The structure of 5 was
B
DOI: 10.1021/acs.orglett.5b00193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Coupling of Benzamides Substrate 1a with 3-
Oxobutanoate
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedure and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
also unambiguously established by X-ray diffraction analysis
(see Supporting Information).
To obtain insights into the mechanism of this cascade
reaction, both intra- and intermolecular kinetic isotope effect
(KIE) experiments were conducted with the deuterium labeled
substrates 1b-d1 and 1b-d5 (Scheme 4). Significant KIEs were
*E-mail: hxdai@sioc.ac.cn.
*E-mail: yu200@scripps.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Scheme 4. Kinetic Isotope Effect Experiments
We gratefully acknowledge Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, the CAS/SAFEA
International Partnership Program for Creative Research
Teams, NSFC-21121062, NSFC-21472211, China Postdoctoral
Science Foundation 2014M551479, and The Recruitment
Program of Global Experts for financial support. We gratefully
acknowledge The Scripps Research Institute, for financial
support. This work was supported by the NSF under the CCI
Center for Selective C−H Functionalization, CHE-1205646.
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