Copper-Catalyzed Aerobic Oxidative C-C Bond Cleavage of Unstrained Ketones with Air and Amines

Article abstract of DOI:10.1021/acs.orglett.5b01114

A unique copper-catalyzed aerobic oxidative C-C bond cleavage of simple unstrained ketones with air and amines has been developed. In this chemistry, amides and oxo amides are easily synthesized through the selective C-C bond cleavage of simple ketones or unstrained cycloketones. The broad substrate scopes and use of an inexpensive copper catalyst and green molecular oxygen as an oxidant as well as an O-source make this protocol very attractive for potential synthetic applications. The control experiments reveal that the present copper-catalyzed oxidative C-C bond cleavage of simple ketones proceeds in a novel catalytic pathway rather than through the cleavage of a dioxetane intermediate. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01114

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aerobic Oxidative C−C Bond Cleavage of
Unstrained Ketones with Air and Amines
Wang Zhou,*,† Wenyou Fan,† Qijian Jiang,† Yu-Feng Liang,‡ and Ning Jiao*,‡
†College of Chemical Engineering, Xiangtan University, Xiangtan 411105, China
‡State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road 38,
Beijing 100191, China
S
* Supporting Information
ABSTRACT: A unique copper-catalyzed aerobic oxidative
C−C bond cleavage of simple unstrained ketones with air and
amines has been developed. In this chemistry, amides and oxo
amides are easily synthesized through the selective C−C bond
cleavage of simple ketones or unstrained cycloketones. The
broad substrate scopes and use of an inexpensive copper
catalyst and green molecular oxygen as an oxidant as well as an
O-source make this protocol very attractive for potential
synthetic applications. The control experiments reveal that the present copper-catalyzed oxidative C−C bond cleavage of simple
ketones proceeds in a novel catalytic pathway rather than through the cleavage of a dioxetane intermediate.
ransition-metal-catalyzed unstrained C−C bond cleavage
metal-catalyzed oxidative synthesis of oxo carboxylic acids has
been significantly developed (Scheme 1b).3 Recently, some
advances on Cu-catalyzed aerobic oxidative C−C bond cleavage
of simple ketones have been achieved.7,8 Bi and Liu et al.
reported a chemoselective oxidative C(CO)−C(methyl) bond
cleavage of methyl ketones to aldehydes.7 We disclosed the Cu-
catalyzed highly selective C(CO)−C(alkyl) bond cleavage
strategies for the construction of esters with alcohols,8a α-
ketoesters with alcohols,8b primary amides with azide as a N-
source,8c and acridones through an intramolecular C−H
cyclization process.8d However, the direct transformation of
simple ketones to amides using amines as a N-source has not
been reported to date,9 because (1) electron-rich primary and
secondary amines are not stable under oxidative conditions10
and (2) amines are very good ligands for binding the transition
metal catalysts and inhibiting catalysis.11 Therefore, the C−C
bond cleavage of unstrained ketones with amines still offers a
great challenge. Herein, we disclose for the first time a unique
copper-catalyzed oxidative C−C bond cleavage of simple
unstrained ketones and amines through an oxygenation process
with air (Scheme 1c).
T
enables a straightforward reconstruction strategy of
carbon skeletons that could hardly be achieved by other
means.1−3 Among them, the ring opening reaction of simple
substrates through C−C bond cleavage offers significant
protocols for the construction of compounds containing two
different functional groups. However, despite the significant
ring-opening reactions of three- or four-membered rings,
especially the strained cyclic ketones,4,5 the selective C−C
bond cleavage of an unstrained six- or seven-membered ring is
still limited.
By using redox-neutral Rh-catalysis, Jun and co-workers
pioneeringly disclosed a directing group assisted C−C bond
activation process of unstrained cycloalkanone-imines and their
skeletal rearrangement (Scheme 1a).6 Alternatively, from
simple ketones without a directing group, the transition-
Scheme 1. Novel Route to Synthesize Amide from Ketone 1
Our studies initiated with the reaction of β-tetralone 1a with
aniline 2a. A series of catalysts, ligands, and solvents were
screened (Supporting Information (SI), Tables S1−S3). Under
the optimized conditions [CuCl2·2H2O (10 mol %), 1,10-
phenanthroline monohydrate (20 mol %), mixed solvents
(Vacetonitrile/V1,4‑dioxane = 3/1, 2.0 mL), 40 °C, 24 h, air (1 atm)],
the ring-opening product, 3-(2-formylphenyl)-N-phenyl prop-
anamide 3aa, was obtained in 71% isolated yield (Scheme 2).
Further exploration indicates that both aryl and aliphatic
Received: April 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01114
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab
,
a b
,
Scheme 2. Substrate Scope of Amines
Scheme 3. Substrate Scope of Ketones
a
Reaction conditions: a mixture of 1 (0.50 mmol), 2a (0.25 mmol),
CuCl2·2H2O (10 mol %), 1,10-phenanthroline monohydrate (20 mol
%), and mixed solvents (Vacetonitrile/V1,4‑dioxane = 3/1, 2.0 mL) was
b
c
stirred at 40 °C for 24 h under air (1 atm). Isolated yields. Reflux.
d
GC yield.
transformation (SI, eq S3).13 Interestingly, the reaction of β-
tetralone-1,1,3,3-d4 (1a-d4) with 2a affords 3aa-d3 with 98%
deuterium incorporation in the aldehyde group (eq 1),
a
Reaction conditions: a mixture of 1a (0.50 mmol), 2 (0.25 mmol),
CuCl2·2H2O (10 mol %), 1,10-phenanthroline monohydrate (20 mol
%), and mixed solvents (Vacetonitrile/V1,4‑dioxane = 3/1, 2.0 mL) was
b
c
stirred at 40 °C for 24 h under air (1 atm). Isolated yields. Reflux.
primary amines performed well under the standard conditions,
giving the desired oxo amides in moderate yields (3ab−3as).
The scope of amines could be expanded to secondary amines
(3at−3aw), showing that the compatibility of this trans-
formation is remarkable. Furthermore, this transformation
provided products without any deterioration in the enantio-
purity originated from the starting amines, which makes it
valuable in asymmetric synthesis (3ax-R and 3ax-S).
Encouraged by these preliminary results, the scope of
ketones was explored subsequently (Scheme 3). Under the
standard conditions, seven-membered cycloketone could be
successfully transformed into the product 3ba in 93% yield.
The reaction also showed a good tolerance for β-tetralones with
varying functional groups (3ca−3ia). Notably, α-aryl cyclo-
hexanone could be employed to furnish oxo amide 3ja
smoothly. However, no product was detected when α-tetralone
was used (3ka). In addition, open-chain ketones were also
selectively cleaved, giving the corresponding aldehydes and
amides in good yields.
indicating that the reversible imine−enamine intermediates
were not generated during the transformation, although the
condensation of ketones and amines is very common.
Therefore, the copper-catalyzed oxidative cleavage of enamine
via a dioxetane intermediate8a,14 is an unfavorable pathway (SI,
Scheme S1).
To pursue the reaction mechanism in more detail, 18O
labeling experiments were conducted using ketone 1l and
aniline 2a as substrates. The data listed in Table 1 suggest that
(a) carbonyl oxygen on 4-methoxybenzaldehyde 4l originates
from O2, which can readily exchange with water; (b) carbonyl
oxygen on acetanilide 5la comes mainly from ketone carbonyl
oxygen and partially from water through oxygen exchange
before the reaction; and (c) dioxetane may be not the
intermediate of this reaction (SI, Scheme S1).
During the screening of reaction conditions, some oxo
carboxylic acid 612 and trace amounts of diketone 7 were
detected in the reaction mixture. However, compounds 6 and 7
could not be converted into 3aa under the standard conditions,
indicating that they are not the intermediates for the formation
of oxo amides (SI, eqs S1 and S2). Moreover, benzolactone 8
could not be transformed into 3aa, suggesting that copper-
catalyzed Baeyer−Villiger reaction may be not involved in this
In addition, a set of experimental results imply that this
reaction probably proceeds via a radical pathway (SI, Table S4).
Interestingly, a 58% yield of oxo ester 9 and a trace amount of
3aa were obtained by stoichiometric addition of TEMPO
(Table 2, entry 1). It is noteworthy that aniline 2a was
indispensable for the formation of oxo ester 9 (entry 2). A 10
mol % loading of aniline could facilitate its formation up to 74%
yield (entry 3). Moreover, oxo amide 3aa could not be
B
DOI: 10.1021/acs.orglett.5b01114
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. 18O Labeling Experiments
Scheme 4. Proposed Mechanistic Pathway
a
Reaction conditions: a mixture of substrates, CuCl2 (10 mol %), 1,10-
phen (20 mol %), and anhydrous mixed solvents (Vacetonitrile/V1,4‑dioxane
b
= 3/1, 2.0 mL) was stirred under O2 (1 atm) reflux for 24 h. Isolated
yields. The ratio of 16O to 18O on products was determined by GC-
c
MS. The reaction was carried out under 18O2 (1 atm) instead of O2.
d
The reaction was carried in the presence of H218O (5 equiv).
a
Table 2. Formation of Oxo Ester 9
with amines. In this chemistry, primary and secondary amines
were employed for the selective C−C bond cleavage of simple
ketones or unstrained cycloketones. The broad substrate scopes
and use of an inexpensive copper catalyst and green molecular
oxygen as an oxidant as well as O-source make this protocol
very attractive for potential synthetic applications. The control
experiments reveal that the present copper-catalyzed oxidative
cleavage of simple ketones proceeds in a novel catalytic
pathway rather than through the cleavage of a dioxetane
intermediate. A novel catalytic cycle is proposed based on the
preliminary mechanism studies. Further studies on the
synthetic applications of this method are ongoing in our group.
a
Isolated yields based on 0.25 mmol scale. TEMPO = 2,2,6,6-
ASSOCIATED CONTENT
tetramethyl-1-piperidinyloxy.
■
S
* Supporting Information
Experimental procedures, analytical data for products, NMR
spectra of products. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01114.
converted into oxo ester 9 in the presence of TEMPO under
standard conditions (SI, eq S4).
On the basis of the above investigations and the reported
literature, a plausible mechanism is proposed (Scheme 4). The
catalytic cycle starts with the reaction of copper complex I with
ketone 1 and dioxygen15 to give peroxycopper(III) species II.
Subsequent isomerization affords peroxide III,16 which also
leads to the formation of oxo acid simultaneously.12
Intermediate IV formed through the nucleophilic attack of
amine 2 to species III undergoes homolytic cleavage of O−O
bond, giving copper species V17 and intermediate A. Radical
species B,18 resulting from β-fragmentation of radical A in a
reversible way,19 could be further in turn oxidized by species V
to furnish the desired product 3 and liberate [Cu(II)−OH]
species VI, which delivers the catalyst with the aid of
hydrochloride to initiate a new catalytic cycle. Radical species
B can be trapped by TEMPO,20 followed by the release of
amine 2 to provide oxo ester, which is consistent with the result
carried out under a catalytic loading of aniline 2a (Table 2,
entry 3). This also can reasonably explain the result obtained in
the labeling experiments (Table 1).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: wzhou@xtu.edu.cn.
*E-mail: jiaoning@pku.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from National Science Foundation of China
(Nos. 21102123, 21372188, and 21325206) and Hunan
Provincial Natural Science Foundation (14JJ6012) is greatly
appreciated.
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C
DOI: 10.1021/acs.orglett.5b01114
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Organic Letters
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