Copper-catalyzed aerobic oxidative C-C bond cleavage for C-N bond formation: From ketones to amides

Article abstract of DOI:10.1002/anie.201403528

A novel copper-catalyzed aerobic oxidative C(CO)-C(alkyl) bond cleavage reaction of aryl alkyl ketones for C-N bond formation is described. A series of acetophenone derivatives as well as more challenging aryl ketones with long-chain alkyl substituents could be selectively cleaved and converted into the corresponding amides, which are frequently found in biologically active compounds and pharmaceuticals.

Full text of DOI:10.1002/anie.201403528

Angewandte
Chemie
DOI: 10.1002/anie.201403528
CÀC Bond Cleavage Hot Paper
À
À
Copper-Catalyzed Aerobic Oxidative C C Bond Cleavage for C N
Bond Formation: From Ketones to Amides**
Conghui Tang and Ning Jiao*
Abstract:
A novel copper-catalyzed aerobic oxidative
C(CO)ÀC(alkyl) bond cleavage reaction of aryl alkyl ketones
for CÀN bond formation is described. A series of acetophe-
none derivatives as well as more challenging aryl ketones with
long-chain alkyl substituents could be selectively cleaved and
converted into the corresponding amides, which are frequently
found in biologically active compounds and pharmaceuticals.
C
arbon–carbon bonds are ubiquitous in organic compounds.
Compared to the highly developed CÀC bond forming
reactions, the chemoselective cleavage of CÀC bonds has
always been on the cutting edge in organic chemistry,
[
1]
biodegradation, and industrial applications. Among them,
Scheme 1. Aerobic oxidative CÀC single-bond cleavage.
the cleavage of CÀC single bonds is the most challenging issue
because of their thermodynamic stability and uncontrollable
[
1]
selectivity.
Chemists have always been pursuing new
carbonyl compounds have been reported. Jiang and co-
[7]
methods to solve these challenges. Employing strained
workers reported a transition-metal-free aerobic oxidative
[
2]
skeletons (three- and four-membered rings) or strategies
CÀC bond cleavage of a-hydroxyketones and subsequent
[
3]
[8]
that make use of chelation assistance are representative
methods to promote CÀC cleavage. To cleave unstrained inert
CÀC bonds, harsh conditions with stoichiometric oxidants,
esterification (Scheme 1a). The group of Bi and Liu
reported a copper-catalyzed C(CO)ÀC(methyl) bond cleav-
age reaction under oxygen atmosphere, which terminates at
the aldehyde stage without overoxidization (Scheme 1b).
Despite significant progress in the area of aerobic oxidative
CÀO and CÀH bond formation through CÀC bond cleavage,
the direct aerobic oxidative CÀN bond formation through
CÀC single-bond cleavage has not been reported to date.
such as peroxides and toxic metal salts, have traditionally
been required. Therefore, there is an urgent need for chemists
to find milder and greener processes. To achieve this goal, two
main approaches have been taken into consideration: 1) The
development of suitable catalytic systems to decrease the
activation energy of CÀC bonds, and 2) the use of air or
Furthermore, aryl ketones with long-chain alkyl groups do not
work in either of the reactions described above, and trans-
formations of such inactive substrates also represent a chal-
lenge.
molecular oxygen as a benign oxidant instead of peroxides
and toxic metal salts.
Molecular oxygen has been considered as an ideal oxidant
for organic synthesis because of its atom-economical and
Herein, we report a novel copper-catalyzed aerobic
oxidative CÀC bond cleavage reaction for CÀN bond
[
4–6]
environmentally benign character.
Recently, a few elegant
[
9,10]
examples of aerobic oxidative CÀC bond cleavage involving
formation,
which enables the direct transformation of
aryl alkyl ketones into benzamides with high efficiency
Scheme 1c). To the best of our knowledge, the aerobic
(
[*] C. Tang, Dr. N. Jiao
oxidative CÀC single-bond cleavage for the formation of CÀN
bonds employing molecular oxygen as the oxidant has not
been disclosed thus far. Environmentally benign molecular
oxygen is employed as the sole oxidant for this simple copper-
State Key Laboratory of Natural and Biomimetic Drugs
School of Pharmaceutical Sciences, Peking University
Xue Yuan Rd. 38, Beijing 100191 (China)
E-mail: jiaoning@bjmu.edu.cn
[
11]
Dr. N. Jiao
catalyzed reaction. Furthermore, this method was used to
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (China)
realize the first aerobic oxidative CÀC single-bond cleavage
of aryl ketones with long-chain alkyl substituents.
Owing to our continuing interest in the construction of
[
**] Financial support from the National Science Foundation of China
[12]
CÀN bonds, we wished to accomplish this goal by using
(
21325206, 21172006), the National Young Top-notch Talent
azide as the nitrogen source. In the beginning, we chose 4’-
phenylacetophenone (1a) as the model substrate. To our
delight, when 1a and sodium azide were treated with
a catalytic system consisting of CuI, TEMPO, and O2 in
DMF at 908C, 4-phenylbenzamide (2a) was obtained in 56%
yield (Table 1, entry 1). 4-Methoxy-TEMPO and 4-oxo-
Support Program, and the Ph.D. Programs Foundation of the
Ministry of Education of China (20120001110013) is greatly
appreciated. We thank Yuchao Zhu in this group for reproducing the
reactions of 2 f and 2l.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403528.
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[
a]
Table 1: Screening of the reaction conditions.
benzamides in moderate yields (2i, 2j). Then,
a series of disubstituted acetophenone derivatives
were tested, which were compatible with the reaction
conditions (2k, 2l). 1-Acetonaphthone and 2-aceto-
naphthone also afforded the desired products in
good yields (2m, 2n). Furthermore, heteroaryl
[
b]
Entry [Cu] (mol%) Additive (mol%)
H O (equiv) T [8C] Yield [%] ketones were also suitable substrates for this trans-
2
formation (2o, 2p).
Moreover, 2-ethoxybenzamide (2q), which is an
37 analgesic and an anti-inflammatory drug named
1
2
3
4
5
6
7
8
9
1
1
1
1
1
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuCl (10)
CuBr (10)
TEMPO (20)
4-MeO-TEMPO (20) H O (20)
H O (20)
90
90
90
56
42
2
2
4-oxo-TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
TEMPO (20)
–
H O (20)
2
H O (30)
90
59
70
79
79
2
Ethenzamide, was obtained in 59% yield [Eq. (1)].
Besides, 3,4-dimethoxybenzamide (2r) and 3,4,5-
trimethoxybenzamide (2s) could be synthesized
from the corresponding ketones using the present
H O (30)
110
110
110
110
110
120
120
120
120
120
2
H O (30)
2
H O (30)
2
CuBr (10)
H O (30)
78
2
2
method; these two products are potential precursors
CuCl (10)
H O (30)
82
84 of the dyspepsia drug Itopride and the antiemetic
2
2
0
1
2
3
4
CuCl (10)
H O (30)
2
2
[
c]
CuCl (10)
H O (30)
0
0
70
47
drug Trimethobenzamide, respectively [Eq. (2) and
(3)].
Having established the broad substrate scope of
this transformation, we investigated more challeng-
ing substrates under the standard conditions
2
2
–
H O (30)
2
CuCl (10)
H O (30)
2
2
CuCl (10)
TEMPO (20)
–
2
[a] Reaction conditions: 1a (0.4 mmol), NaN (1.2 mmol), copper precursor
3
(
0.04 mmol), DMF (2 mL), under O (1 atm) for 16 h. [b] Yields of isolated products.
2
(Scheme 3). To our delight, various aryl alkyl
[c] The reaction was carried out under argon atmosphere. DMF=N,N-dimethyl-
ketones performed well, and the corresponding
benzamides were obtained in moderate yields. Che-
moselective cleavage of the C(CO)ÀC(alkyl) bond
formamide, TEMPO=2,2,6,6-tetramethylpiperidine-1-oxy.
TEMPO were less efficient than
TEMPO (entries 2 and 3). Elevat-
ing the reaction temperature from
9
0 to 1108C led to an increase in
yield to 70% (entry 5). Different
copper catalysts were screened, and
CuCl turned out to be the most
2
effective catalyst (entries 6–9).
When the temperature was further
raised to 1208C, the highest yield
was achieved (84%; entry 10). This
reaction did not proceed in the
absence of molecular oxygen or
copper catalyst (entries 11 and 12).
The yield decreased in the absence
of TEMPO or H O (entries 13 and
2
1
4).
Next, the scope of this copper-
catalyzed CÀC bond cleavage reac-
tion was examined in detail under the optimized reaction
conditions (Scheme 2). Acetophenone (1b) reacted smoothly
to yield benzamide (2b) in 66% yield. Acetophenone
derivatives with alkyl substituents in the para position
performed well, giving the desired products in moderate to
excellent yields (2c–2 f). This transformation could tolerate
aryl ketones with electron-donating as well as electron-
withdrawing substituents on the aryl ring. 4-Methoxy and 4-
fluorobenzamide were obtained in 67% and 58% yield,
respectively (2g and 2h). As previously described, the
coupling of aryl halides with sodium azide can easily afford
was achieved with this method. Halogen substituents such as
a chloride were also tolerated by this catalytic system (2i).
These aryl alkyl ketones were inactive under the conditions of
the aldehyde syntheses described by the group of Bi and
Liu, suggesting that our transformation may proceed
through a different pathway.
To elucidate the mechanism of this reaction, some
potential intermediates were prepared and tested under the
standard conditions. However, benzaldehyde (4), 2-hydroxy-
1-phenylethanone (5), 2-oxo-2-phenylacetaldehyde (6), and
2-oxo-2-phenylacetic acid (7) could not afford benzamide
(2b) under the standard reaction conditions [Eq. (4)–(7)].
These control experiments indicate that the ketone substrate
possibly first reacts with the azide nucleophile and then
[8]
[
13]
aryl azide products,
especially under copper catalysis in
polar solvents. However, it is interesting that halogen
substituents were tolerated in the present CÀC cleavage
process to produce the corresponding halogen-substituted
undergoes oxidation processes catalyzed by the Cu/O system.
2
2
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Scheme 2. Transformation of aryl methyl ketones. Standard reaction
conditions: 1 (0.5 mmol), NaN (1.5 mmol), CuCl (0.05 mmol),
3
2
TEMPO (0.1 mmol), H O (15 mmol), DMF (2 mL) at 1208C under O
2
2
(
1 atm) for 16 h. Yields of isolated products are given.
Scheme 4. Proposed mechanism.
intermediate A in a potentially reversible process. Subse-
quent aerobic oxidation of intermediate A generates a-
hydroxylated intermediate B in the presence of the Cu/O
2
[8,15,16]
oxidative system.
Subsequent rearrangement of inter-
mediate B via its resonance structure C produces intermedi-
ate D through CÀC bond cleavage with release of molecular
Scheme 3. Transformation of aryl alkyl ketones. Standard reaction
conditions: 3 (0.5 mmol), NaN (1.5 mmol), CuCl (0.05 mmol),
[17]
nitrogen and an aldehyde as the byproducts. In some cases,
3
2
the aldehydes undergo a Schmidt reaction to produce the
corresponding nitriles, which could be detected by GC-MS
TEMPO (0.1 mmol), H O (15 mmol), DMF (2 mL), at 1208C under O
2
2
(
1 atm) for 16 h. Yields of isolated products are given.
(see the Supporting Information for details). Finally, tauto-
merization of D affords the desired amide.
Furthermore, N-methylbenzamide (8) did not react under the
standard conditions, implying that a Schmidt reaction of
acetophenone and sodium azide did not occur under the
present conditions [Eq. (8)]. Furthermore, (1-azidovinyl)-
benzene (9) was completely unreactive under the standard
reaction conditions [Eq. (9)].
In conclusion, the aerobic oxidative C(CO)ÀC(alkyl)
cleavage of aryl alkyl ketones for CÀN bond formation
proceeded with high chemoselectivity. An inexpensive copper
catalyst and molecular oxygen as the oxidant are the key
features of this method with promising synthetic applications.
A series of acetophenone derivatives as well as more
challenging aryl ketones with long-chain alkyl substituents
could be efficiently cleaved and converted into the corre-
sponding amides, which are frequently found in biologically
active compounds and pharmaceuticals. Preliminary mecha-
[
14]
Based on the above results, a plausible mechanism of this
copper-catalyzed CÀC bond cleavage of aryl alkyl ketones
leading to amides was proposed (Scheme 4). The substrate is
initially attacked by the azide nucleophile to form unstable
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Angewandte
Communications
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petroleum ether= 1:1) to afford product 2a (66.4 mg; 84%). 2a:
1
yellow solid; H NMR (400 MHz, [D ]DMSO): d = 8.04 (s, 1H), 7.98
6
(
7
d, J = 8.0 Hz, 2H), 7.80–7.70 (m, 4H), 7.48 (t, J = 7.6 Hz, 2H), 7.42–
1
3
.38 ppm (m, 2H); C NMR (100 MHz, [D ]DMSO): d = 167.6,
6
1
42.8, 139.2, 133.1, 129.0, 128.2, 128.0, 126.8, 126.4 ppm; MS (EI)
+
m/z 197.1 (100) [M] .
Received: March 20, 2014
Published online: && &&, &&&&
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Keywords: amides · cleavage reactions · copper · ketones ·
oxygen
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[
[
cleavage reactions of ketones with an alkyl fragment leaving as
a carbonyl moiety, see: H. S. Fung, B. Z. Li, K. S. Chan,
Organometallics 2012, 31, 570.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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These are not the final page numbers!

.
Angewandte
Communications
Communications
CÀC Bond Cleavage
C. Tang, N. Jiao*
&&&& — &&&&
Copper-Catalyzed Aerobic Oxidative CÀC
Bond Cleavage for CÀN Bond Formation:
From Ketones to Amides
A copper-catalyzed aerobic oxidative
C(CO)ÀC(alkyl) bond cleavage of aryl
alkyl ketones for CÀN bond formation
long-chain alkyl groups could be cleaved
efficiently to give the corresponding
amides, which are frequently found in
biologically active compounds and phar-
maceuticals.
proceeds with high chemoselectivity. A
series of acetophenone derivatives as well
as more challenging aryl ketones with
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!