Copper-mediated decarboxylative coupling of benzamides with potassium malonate monoesters via directed CH cleavage

Article abstract of DOI:10.1246/cl.171212

A copper-mediated decarboxylative coupling of benzamides with potassium malonate monoesters via 8-aminoquinoline-directed CH cleavage has been developed. This reaction proceeds only by a copper salt to produce the corresponding alkylation products in good

Full text of DOI:10.1246/cl.171212

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Copper-mediated Decarboxylative Coupling of Benzamides with Potassium Malonate
Monoesters via Directed C-H Cleavage
Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura*
Advance Publication on the web January 23, 2018
doi:10.1246/cl.171212
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1
Copper-mediated Decarboxylative Coupling of Benzamides with Potassium Malonate
Monoesters via Directed C-H Cleavage
Kazutaka Takamatsu, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-0871
E-mail: miura@chem.eng.osaka-u.ac.jp
(Scheme 1a).10e
expanded the substrate scope in the decarboxylative C-H
arylation. During our continuous interest in this chemistry,
we next focused on the copper-mediated decarboxylative C-H
The copper-based system successfully
A
copper-mediated decarboxylative coupling of
benzamides with potassium malonate monoesters via 8-
aminoquinoline-directed C-H cleavage has been developed.
This reaction proceeds only by a copper salt to produce the
corresponding alkylation products in good yields.
alkylation.
Herein, we report
a
copper-mediated
decarboxylative coupling of benzamides with potassium
malonate monoesters13 via directed C-H cleavage (Scheme
1b).
Keywords:
Decarboxylation
Copper
salts,
C-H
cleavage,
We began optimization studies with 2-methyl-N-
(quinolin-8-yl)benzamide (1a) and monomethyl potassium
malonate (2a) as model substrates. After extensive screening
of various reaction parameters,14 we found that the reaction
proceeded in the presence of Cu(OTf)2 and KOAc in heated
DMSO to form the desired 3aa in 42% yield (Scheme 2). The
alkyl group of malonate monoesters 2 somewhat affected the
reaction efficiency, and bulkier ethyl, isopropyl, and tert-butyl
esters improved the yield to 59, 54, and 56% yields,
respectively (3ab, 3ac, and 3ad).15 In this reaction, the 8-
aminoquinoline moiety in 1a was critical. Both the N-H bond
in the amide and the nitrogen atom in the quinoline ring were
essential (1A and 1B) and other bidentate directing groups did
not work under the reaction conditions (1C and 1D).
Moreover, the potassium carboxylate moiety was also
indispensable;16 diethyl malonate (2A)17 and ethyl acetate
(2B) did not react at all. On the other hand, other activated
carboxylic acids including cyanoacetic acid (2C), beta-keto
acids (2D and 2E), and malonamic acid (2F) were ineffective.
Attempts to apply catalytic conditions using O2, MnO2,
peroxides, or silver salts remained unsuccessful.
Over the last decade, much attention has been paid to
developing metal-mediated C-H functionalization reactions
because they are more atom- and step-economical than
traditional synthetic methods with organic halides and/or
organometallic reagents.
In particular, directing-group-
enabled regioselective C-H transformation has attracted great
interest and thus been widely explored by many synthetic
chemists.1
Decarboxylative coupling reactions are also convenient
and powerful strategies to construct C-C and C-heteroatom
bonds because inexpensive, stable, and abundant carboxylic
acids can be used as carbon nucleophiles.2 In these reactions,
carboxylic acids are coupled with not only carbon
electrophiles such as halides3 and sulfonates,4 but also carbon
nucleophiles such as organometallic reagents5 and arene C-Hs
under oxidative conditions.6 However, transition-metal-
mediated decarboxylative coupling via directed C-H cleavage
is still limited in scope; only few arylation7 and alkylation
reactions8 were reported, although there are many successful
examples of directed C-H acylation.9 Moreover, noble
transition metal catalysts such as palladium are essential in
most cases.
On the other hand, copper salts have recently attracted
great attention as inexpensive, less toxic, and abundant
alternatives to noble metals, and our group10 and others11
developed copper-mediated unique C-H functionalization
reactions. Previously, we reported the copper-mediated
decarboxylative C-H arylation of benzamides with ortho-nitro
benzoic acids via 8-aminoquinoline directed12 C-H cleavage
Scheme 2. Copper-mediated decarboxylative C-H alkylation of ortho-
methylbenzamide 1a with potassium malonate monoesters 2. Reaction
Conditions: Cu(OTf)2 (0.50 mmol), KOAc (0.25 mmol), 1a (0.25 mmol),
2 (0.75 mmol), 100 ºC, 6 h, N2. aAt 80 ºC. bSodium malonate monoester
was used instead of potassium malonate monoester.
trifluoromethanesulfonyl, DMSO = dimethylsulfoxide.
Tf =
Scheme 1. Copper-mediated decarboxylative coupling of benzamides

2
electron-donating and -withdrawing substituents at the para-
position were also tolerated (3mb-3ob). Unfortunately, the
sterically hindered 2,5-disubstituted benzamide gave the
product in only 11% yield (3pb). It should be noted that a
more easily removable 5-methoxyquinolinyl group (vide
infra) could also be employed as the directing group (3qb).
Notably, this reaction could be conducted on a tenfold larger
scale, thus indicating the good reproducibility and practicality
of this process (3ab).
To gain insight into the mechanism, we carried out
deuterium-labeling experiments.
At an early stage of
reactions, D/H exchange of [D7]1a was not observed [Eq. (1)].
This result suggests that the C-H bond cleavage step is
irreversible. Additionally, KIE value of the parallel reactions
with 1a and [D7]1a was determined to be 3.4 [Eq. (2)]. Thus,
the C-H cleavage appears to be involved in the rate-determing
step. Moreover, we performed the reaction of 2b without 1a
and Cu(OTf)2 under otherwise identical conditions, and
malonic ester 2b-Me was not observed after methylation [Eq.
(3)]. The finding indicates that the simple and nonproductive
thermal decarboxylation of potassium malonate monoesters
competitively occurred; this can be one of reasons for the
moderate reaction efficiency of the C-H alkylation.
On the basis of the above results and literature
information, we propose the reaction mechanism of 1a with
2b as shown in Scheme 4. First, a copper salt deprotonates
relatively acidic NH in 1a to generate N,N-bidentately
chelated complex 5. Subsequent rate-determing C-H bond
cleavage forms the five-membered metallacycle intermediate
Scheme 3. Copper-mediated decarboxylative C-H alkylation of various
benzamides with potassium malonate monoesters 2. Reaction
1
Conditions: Cu(OTf)2 (0.50 mmol), KOAc (0.25 mmol), 1 (0.25 mmol), 2
1
(0.75 mmol), 100 ºC, 6 h, N2. Value in parentheses indicates H NMR
yield. aAt 80 ºC. bOn a 2.5 mmol scale. cSodium malonate monoester
was used instead of potassium malonate monoester. Q = 8-quinolinyl.
With conditions in Scheme 2, we investigated the
substrate scope of benzamides (Scheme 3). We found that the
ortho-methyl group was necessary for acceptable conversion;
the reaction of meta-methyl (3bb) and non-substituted (3cb)
benzamides formed the corresponding products 3bb and 3cb
in lower yields (41% and 19%, respectively).
Other
substituents at the ortho position were also examined, but
methyl group gave a much better yield (3db-3gb). However,
ortho-methyl benzamides that bear methyl (3hb), methoxy
(3ib), acetoxy (3jb), fluoro (3kb), and chloro (3lb) groups at
the meta-position could be coupled with 2b to form the
desired products in synthetically useful yields. Moreover,
Scheme 4. Plausible reaction mechanism. R = Ac or COCH2CO2Et.
Scheme 5. Derivatization of the alkylated products.
THF =
tetrahydrofuran.

3
Chem. 2017, 82, 3917. See the Supporting Information for a
complete list of references.
6. This step is promoted by the N,N-chelation of the
aminoquinoline moiety to the copper center. The copper(III)
intermediate 718 is then formed by disproportionation with
4
5
6
For recent selected examples of decarboxylative coupling with
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another copper(II) species.
The decarboxylation then
proceeds to form copper(III) alkyl species 8, and the
corresponding product 3ab is finally produced by reductive
elimination. Although the origin of unique positive effects of
ortho-methyl group observed in Scheme 3 is unclear at
present, it might accelerate otherwise challenging reductive
elimination from 8.19, 20
Finally, we performed the derivatization of alkylation
products (Scheme 5). The directing group of 3qb could be
easily removed with cerium ammonium nitrate (CAN) in
MeCN/H2O at room temperature to produce the primary
amide 9 in 57% yield.21 In addition, tert-butyl ester 3ad was
readily cyclized with trifluoroacetic acid in CH2Cl2 to form
the cyclic imide 10 in a good yield. Moreover, isoquinolone
11 was synthesized from alkylation product 3ab with
morpholine and diisobutylaluminum hydride (DIBAL-H) in
THF.22 In contrast, the reaction of 3ab with only DIBAL-H
afforded the simply reduced alcohol 12 in 83% yield.
In conclusion, we have developed an 8-aminoquinoline-
directed, copper-mediated decarboxylative C-H alkylation of
benzamides with potassium malonate monoesters. This
reaction proceeds smoothly by using a copper salt alone to
produce the alkylation products with the ester functionality,
which can be a useful and versatile synthetic handle for
further transformations.
mechanism and development of related C-H activation
reactions with copper catalysts are ongoing in our laboratory.
Elucidation of the detailed
7
8
9
This work was supported by JSPS KAKENHI Grant Nos.
JP 17J00349 (Grant-in-Aid for JSPS Research Fellow) to K.T.,
JP 15H05485 (Grant-in-Aid for Young Scientists (A)) to K.H.,
and JP 17H06092 (Grant-in-Aid for Specially Promoted
Research) to M.M.
Supporting
Information
is
available
on
http://dx.doi.xxxxxxxxx.
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4
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14
15
16
17
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20
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