Copper-catalyzed site-selective intramolecular amidation of unactivated C(sp3)-H bonds

Article abstract of DOI:10.1002/anie.201311263

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper-catalyzed sp³ C-H bond functionalization process. The reaction favors predominantly the C-H bonds of β-methyl groups over the unactivated methylene C-H bonds. Moreover, a preference for activating sp³ C-H bonds of β-methyl groups, via a five-membered ring intermediate, over the aromatic sp² C-H bonds was also observed in the cyclometalation step. Additionally, sp³ C-H bonds of unactivated secondary sp³ C-H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms. Getting ahead on tams: The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper-catalyzed sp ³ C-H bond functionalization process to deliver β-lactams. The reaction favors the C-H bonds of β-methyl groups over the unactivated methylene C-H bonds, as well as aromatic C(sp²)-H bonds and unactivated secondary C(sp³)-H bonds of rings.

Full text of DOI:10.1002/anie.201311263

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Angewandte
Communications
DOI: 10.1002/anie.201311263
Homogeneous Catalysis
Copper-Catalyzed Site-Selective Intramolecular Amidation of
3
À
Unactivated C(sp ) H Bonds**
Xuesong Wu, Yan Zhao, Guangwu Zhang, and Haibo Ge*
Abstract: The intramolecular dehydrogenative amidation of
aliphatic amides, directed by a bidentate ligand, was developed
catalyzed aminoquinoline-directed intramolecular amidation
3
À
of unactivated C(sp ) H bonds, we report herein the copper-
using a copper-catalyzed sp3 C H bond functionalization
catalyzed bidentate-ligand-directed intramolecular amidation
of sp3-carbon atoms.[4h,i,p,8] This novel method provides
a complementary approach to access mono-, spiro-, and
bicyclic b-lactam derivatives, which are important structural
units in biologically active natural products and medicines.[9]
It should also be mentioned that although copper-catalyzed
À
À
process. The reaction favors predominantly the C H bonds of
À
b-methyl groups over the unactivated methylene C H bonds.
Moreover, a preference for activating sp C H bonds of b-
3
À
methyl groups, via a five-membered ring intermediate, over the
aromatic sp2 C H bonds was also observed in the cyclo-
À
3
metalation step. Additionally, sp C H bonds of unactivated
coupling reactions through an sp2 or sp3 C H activation
À
À
3
secondary sp C H bonds could be functionalized by favoring
the ring carbon atoms over the linear carbon atoms.
process have been extensively studied,[10] there are only few
examples involving direct functionalization of unactivated
sp3-carbon atoms.[11]
À
À
D
espite being a challenging process, direct C H bond
Our investigation began with the oxidative cyclization of
N-(quinolin-8-yl)pivalamide (1a) using catalytic Cu(OAc)2 in
the presence of 1.5 equivalents of KHCO3 as the base and
1.2 equivalents of benzoquinone (BQ) as the oxidant at
1608C (Table 1). After an extensive solvent screening, o-
functionalization of unactivated sp3-carbon atoms by transi-
tion-metal catalysis has received a great deal of attention in
the last couple of decades.[1] Notably, this process does not
require the prefunctionalization of unactivated sp3 C H
À
bonds and the use of stoichiometric amounts of organome-
tallic reagents, and thus is economically and ecologically
favorable compared with the traditional approaches. Within
this reaction class, the bidentate-ligand-directed process is of
current research interest, and significant progress has been
achieved in recent years.[2] In 2002, Sames and co-workers
reported the oxidative Heck coupling of sp3-carbon atoms by
palladium catalysis.[3] Subsequently, the group of Daugulis
developed a series of bidentate ligands, and a variety of
coupling reactions, including acetoxylation, alkoxylation,
alkylation, amination, amidation, arylation, and ethynylation,
Table 1: Optimization of reaction conditions.[a]
Entry
Cu source
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuBr2
CuCl2
CuOAc
CuI
CuBr
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
NaHCO3
K2CO3
1,2-dichlorobenzene
toluene
15
<5
25
24
22
29
<5
24
16
20
<5
<5
35
33
<5
22
<5
32
54
have been discovered since then.[4] Recently, ruthenium-
mesitylene
m-xylene
p-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
3
À
catalyzed carbonylation of unactivated C(sp ) H bonds was
developed in the group of Chatani.[5] Furthermore, iron-
catalyzed direct arylation and alkylation reaction of sp3-
carbon atoms was also demonstrated by Nakamura and co-
workers.[6] Very recently, nickel-catalyzed site-selective alky-
9
3
10
11
12
13
14
15
16
17
18
19
20
21[c]
À
lation of unactivated sp C H bonds was established in our
laboratory.[7] Inspired by recent reports on the palladium-
[*] Dr. X.-S. Wu, Y. Zhao, Dr. G.-W. Zhang, Prof. Dr. H.-B. Ge
Department of Chemistry and Chemical Biology
Indiana University Purdue University Indianapolis
Indianapolis, IN 46202 (USA)
Na2CO3
K3PO4
K2HPO4
PhCO2K
PhCO2Na
PhCO2Na
E-mail: geh@iupui.edu
Prof. Dr. H.-B. Ge
81
Institute of Chemistry and BioMedical Sciences and School of
Chemistry and Chemical Engineering, Nanjing University
Nanjing 210093 (P.R. China)
90(87)[d]
[a] Reaction conditions: 1a (0.3 mmol), Cu source (20 mol%), benzo-
quinone (1.2 equiv), base (1.5 equiv), air, 2.0 mL of solvent, 1608C, 24 h.
[b] Yields and conversions are based on 1a and determined by 1H NMR
spectroscopy using dibromomethane as the internal standard. [c] Dur-
oquinone (1.2 equiv) instead of benzoquinone. [d] Yields of isolated
products. Tf=trifluoromethanesulfonyl.
[**] We gratefully acknowledge Indiana University Purdue University
Indianapolis for financial support. The Bruker 500 MHz NMR was
purchased using funds from an NSF-MRI award (CHE-0619254).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201311263.
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xylene proved to be optimal, albeit with a low yield (entry 6).
Next, the investigation of the effect of different copper
catalysts towards the reaction was carried out, and it showed
that this reaction could be catalyzed by either a copper(II) or
copper(I) source, and CuCl was identified as the optimal
catalyst (entry 13). Following the above investigation, an
extensive screening of bases was carried out, and it turned out
that although low yields were typically observed with the
common organic and inorganic bases, the reaction was
significantly improved by the use of PhCO2Na as the base
(entry 20). Additionally, the reaction yield was improved by
replacing benzoquinone with duroquinone as the oxidant
(entry 21).
With the optimized reaction conditions in hand, we
carried out the substrate scope study of this reaction
(Scheme 1). As expected, all kinds of linear aliphatic amide
derivatives provided the corresponding desired products in
high yields (2a–f). It was also observed that this reaction
showed excellent site selectivity of the b-methyl groups over
À
the methylene groups. Furthermore, the amidation of the C
H bonds of the g- or d-methyl group on the ethyl or propyl
group, respectively, was not observed, thus indicating that the
formation of a five-membered ring intermediate in the
cyclometalation step is predominantly favored over the six-
or seven-membered ring intermediate. Interestingly, with a-
cyclic substrates 1-methyl-N-(quinolin-8-yl)cyclopentane-1-
carboxamide and 1-methyl-N-(quinolin-8-yl)cycloheptane-1-
carboxamide, the selectivity of the b-methyl groups over the
b’-methylene groups was slightly decreased, and small
amounts of bicyclic compounds (2g’ and 2i’) were isolated
along with the major spiroproducts (2g and 2i). However, this
phenomenon was not observed with 1-methyl-N-(quinolin-8-
yl)cyclohexane-1-carboxamide, and the spiro-b-lactam 2h
was obtained as the predominant product. Surprisingly, with
the 2-phenyl-substituted substrates, the reaction showed
3
À
a preference for the sp C H bonds of the b-methyl group
À
over the aromatic C H bonds of the phenyl group (2j and
2m), and indicates that the formation of a five-membered ring
aliphatic copper intermediate should be favored over a six-
membered ring aromatic copper intermediate in the metal-
ation step. Furthermore, with 3,3-dimethyl-N-(quinolin-8-
yl)butanamide as the substrate, the g-lactam 2l was not
produced, thus indicating that the formation of the six-
membered ring cyclometalation intermediate is not feasible
in the process under the current catalytic system. It is also
worthy of mention that the introduction of a methoxy group
at C5 of the quinoline moiety had no apparent effect on the
reaction (2t).
Scheme 1. Direct amidation on sp3-carbon atoms. Reaction conditions:
1 (0.3 mmol), CuCl (20 mol%), duroquinone (1.2 equiv), PhCO2Na
(1.5 equiv), 2.0 mL o-xylene, 1608C, 12-24 h. [a] Yields of isolated
products. [b] 1708C. [c] Unseparable mixture. Q=quinolin-8-yl.
Next, we focused our study on the direct functionalization
of secondary b-sp3-carbon atoms. It was quickly noticed that
secondary benzylic b-carbon atoms are more reactive than the
b’-methyl groups and other unactivated b’-methylene carbon
atoms (2m–p; Scheme 1. As expected, the predominant
selectivity was also observed for the formation of the bicyclic
b-lactam compound 2s.
À
preference for C H bonds of unactivated secondary b-
Furthermore, it was found that a tertiary a-carbon atom is
necessary for this reaction since the amides 3–6 failed to
provide the desired products. In addition, subjection of the
cyclobutanecaroxamide 7 to the reaction conditions provided
no desired product. As suggested by Nakamura and co-
carbon atoms over g-methyl groups was observed because
the formation of a six-membered ring intermediate is not
feasible, as discussed above (2q). Furthermore, functionali-
zation of ring b-carbon atoms was favored over acyclic b’-
carbon atoms (2r and 2s). Interestingly, high syn diastereo-
=
workers, the CH3-C-C( O) bond angle of this substrate is
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Communications
elimination of C produces the b-lactam derivative 2 and
another copper(I) species. The generated copper(I) species is
then oxidized to the copper(II) species by duroquinone, and
the reduced anionic species is quenched by benzoic acid
through an acid/base reaction. It should be mentioned that
a sequential chlorination amidation process could not be
ruled out.[14]
To further broaden the synthetic application of this
methodology, removal of the 5-methoxyquinolyl group of 1-
(5-methoxyquinolin-8-yl)-3,3-dimethylazetidin-2-one
(2t)
was carried out based on the report from the group of
Chen, and the desired b-lactam product 8 was obtained in
63% yield (Scheme 4).[4p]
Scheme 2. Deuterium-labeling experiments.
much wider than its cyclopentyl or cyclohexyl derivative,[6]
and thus the cyclometalation of 7 is less feasible.
Scheme 4. Oxidative cleavage of the 5-methoxyquinolyl group. CAN=
ceric ammonium nitrate.
To further explore the reaction mechanism, we carried out
the deuterium-labeling experiments of 2-ethyl-2-methyl-N-
(quinolin-8-yl)butanamide (1b; Scheme 2). It was noticed
that there was no apparent H–D exchange in this process
In summary, a site-selective intramolecular amidation of
(Scheme 2a). Furthermore, a secondary kinetic isotope effect
N-(quinolin-8-yl)pivalamide derivatives with an 8-aminoqui-
nolinyl group as the bidentate ligand was developed by
3
À
was observed, thus suggesting that the sp C H bond cleavage
3
À
of the amide 1 should not be the rate-limiting step in this
a copper-catalyzed sp C H bond functionalization process.
catalytic process (Scheme 2b).[12]
This reaction proceeds with a preference for sp C H bonds of
b-methyl groups over the unactivated methylene C H bonds.
Unexpectedly, this reaction favors sp C H bonds of b-methyl
groups, which form a five-membered ring intermediate in the
cyclometalation step; the aromatic sp C H bonds are less
reactive as the reaction proceeds via a six-membered ring
3
À
À
On the basis of the above observation and the previous
reports,[8,13] a plausible catalytic cycle of this transformation is
proposed (Scheme 3). Coordination of 1 to a copper(II)
3
À
2
À
À
intermediate. Furthermore, regioselective C H functionali-
zation of secondary b-sp3-carbon atoms was also observed
among methylene groups with the reactivity order of ben-
zylic > ring > linear carbon atoms. Additionally, the forma-
tion of the bicyclic b-lactam derivative 2s by functionalization
of the ring b-carbon atom was performed in a highly
diastereoselective manner by favoring the syn products.
À
Moreover, direct C H functionalization of secondary ben-
zylic b-carbon atoms is preferred over the b’-methyl groups,
and gives the overall reactivity order of this process as b-
benzylic > b-methyl > b-ring > b-linear carbon atoms. With
this method, a,a-disubstituted mono-, spiro-, and bicyclic b-
lactam derivatives could be prepared. The detailed mecha-
nistic studies of this transformation are currently ongoing in
our laboratory.
Scheme 3. Plausible reaction mechanism.
Experimental Section
species and subsequent ligand exchange in the presence of
sodium benzoate generates the copper complex A, which
forms the alkyl/CuII species B by a cyclocupration process.
Oxidation of B with another copper(II) species gives rise to
the alkyl/CuIII complex C and a copper(I) species. Reductive
A 50 mL Schlenk tube was charged with the a,a,a-trisubstituted N-
(quinolin-8-yl)acetamides 1 (0.3 mmol), CuCl (5.9 mg, 0.06 mmol),
duroquinone (59 mg, 0.36 mmol), PhCO2Na (65 mg, 0.45 mmol), and
2.0 mL of o-xylene. Then the vial was sealed, and stirred rigorously at
1608C for 12–24 h. After removal of the solvent, the residue was
3708
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EtOAc in hexanes, v/v) to give the desired product.
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Received: December 29, 2013
Published online: March 3, 2014
À
Keywords: C H activation · copper · heterocycles ·
homogeneous catalysis · synthetic methods
.
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observed as the product. This result indicates that a sequential
chlorination amidation process is also possible.
[14] While
3-chloro-2,2-dimethyl-N-(quinolin-8-yl)propanamide
(1u) was subjected to the standard reaction conditions, 2a was
3710
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