Chemoselective oxidative C(CO)-C(methyl) bond cleavage of methyl ketones to aldehydes catalyzed by CuI with molecular oxygen

Article abstract of DOI:10.1002/anie.201305010

Aldehyde Termination: A novel copper-catalyzed transformation from methyl ketones into aldehydes has been accomplished. This method is applicable to a wide range of aromatic and aliphatic methyl ketones and chemoselectively produces aldehydes, accompanied by the release of hydrogen (H₂) and carbon dioxide (CO₂) as by-products. Copyright

Full text of DOI:10.1002/anie.201305010

Angewandte
Chemie
DOI: 10.1002/anie.201305010
À
C C Bond Cleavage
À
Chemoselective Oxidative C(CO) C(methyl) Bond Cleavage of
Methyl Ketones to Aldehydes Catalyzed by CuI with Molecular
Oxygen**
Lin Zhang, Xihe Bi,* Xiaoxue Guan, Xingqi Li, Qun Liu,* Badru-Deen Barry, and Peiqiu Liao
The cleavage of carbon–carbon bonds is a critical issue in both
academic research and industrial applications.[1] The inert
cleavage of ketones that completely terminates at the
aldehyde stage has not been described, this is probably due
to easy overoxidation to the carboxylic acids.[13] As part of our
ongoing efforts to develop transition-metal-catalyzed organic
reactions,[14] we herein report an unprecedented copper-
À
nature of the C C s bond has led to a considerable amount of
research on the exploration of strategies that could assist in
readily breaking these bonds. Although significant progress
À
has been achieved in the development of methods to cleave
catalyzed aerobic C(CO) C(methyl) bond cleavage of
[2]
C C single, double,[3] and triple bonds,[4] the selective
methyl ketones[15] that chemoselectively yields aldehydes as
the sole product, along with the release of hydrogen (H2) and
carbon dioxide (CO2). This reaction constitutes a novel
transformation from methyl ketones into aldehydes.
À
À
oxidative cleavage of C C s bonds still remains one of the
most challenging issues in chemistry and biology. Aldehydes
are an important class of compounds and widely used in all
areas of chemistry; therefore, the development of new
retrosynthetic disconnections of aldehydes is highly desir-
An initial survey of the reaction parameters was per-
formed with a-acetonaphthone (1a) as the model substrate,
and some of the key results obtained are shown in Table 1.
Cupric salts, such as Cu(OAc)2 and CuCl2, proved to be
able.[5] The chemoselective C(CO) C(a) bond cleavage of
À
ketones is a fundamental reaction that has been extensively
studied, and has been used for transformations into acids,[6]
esters,[7] amides,[8] ketones,[9] and acyl-metal complexes[10]
(Figure 1). Very recently, Jiang and co-workers described an
Table 1: Screening of the reaction conditions.[a]
Entry
[Cu]
Solvent
2a[b] [%]
1
2
3
4
Cu(OAc)2
CuCl2
CuI
–
CuI
CuCl
CuOAc
CuI
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
trace
trace
92
n.r.
n.r.
90
5[c]
6
À
Figure 1. The C(CO) C(a) bond cleavage of ketones.
7
8
38
67
À
9
10
CuI
CuI
1,2,3-TCP
CF3Ph
n.r.
n.r.
interesting oxidative cleavage and esterification of the C C
bonds of a-hydroxy ketones under metal-free conditions.[11]
À
Berreau and co-workers reported the regioselective C C
bond cleavage of acireductones to acids by a model system of
[a] Reactions were performed on a 1.0 mmol scale (0.3m with respect to
a-acetonaphthone). [b] Yields of isolated products. [c] Under nitrogen
atmosphere. DMF=N,N-dimethylformamide, DMSO=dimethyl sulf-
oxide, n.r.=no reaction, 1,2,3-TCP=1,2,3-trichloropropane.
iron-containing acireductone dioxygenase.[12] However, to the
best of our knowledge, an oxidative C(CO) C(a) bond
À
[*] L. Zhang, Prof. X. Bi, X. Guan, Prof. X. Li, Prof. Q. Liu, B.-D. Barry,
Dr. P. Liao
ineffective (entries 1 and 2), whereas cuprous salts, such as
CuI, efficiently catalyzed the reaction, thus leading to
a-naphthaldehyde (2a) in 92% yield (entry 3). Both CuI
and O2 are essential for reactivity, as verified by control
experiments (entries 4 and 5). Other cuprous salts, such as
CuCl and CuOAc, afforded significantly different yields of
2a, which is indicative of the strong influence of the counter-
anion on the reaction (entries 6 and 7). The choice of solvent
also appeared to be crucial, because, with the exception of
DMF, the use of other high-boiling solvents, such as 1,2,3-
trichloropropane (1,2,3-TCP) and CF3Ph, led to no conver-
sion. These results are in contrast to the previously docu-
Department of Chemistry, Northeast Normal University
Changchun 130024 (China)
E-mail: bixh507@nenu.edu.cn
liuqun@nenu.edu.cn
Prof. X. Bi
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin 300071 (China)
[**] This work was supported by the NNSFC (21172029, 21202016, and
31101010) and the FRFCU (11CXPY005).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305010.
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À
mented efficacy of these solvents in aerobic C H bond
activation reactions (entries 8–10).[14a,16] The effectiveness of
DMSO may be ascribed to its metal-coordinating properties.
Hence, it may stabilize the catalyst and promote the aerobic
oxidation of its reduced form.[17] As a result, the reaction
conditions described in entry 3 were selected as the standard
conditions for further investigations.
2m), 2) good tolerance of a wide range of functional groups
(2b–2l and 2n–2p), 3) the applicability to electron-rich
heteroaromatic methyl ketones (2q–2s), and 4) clean trans-
formations that afford the aldehyde products in good to
excellent yields. These results demonstrate the broad scope of
(hetero)aryl methyl ketones that are suitable substrates for
À
the copper(I)-catalyzed aerobic C C bond cleavage reaction,
To identify other products that are generated along with
a-naphthaldehyde (2a) in the C C bond cleavage of
a-acetonaphthone (1a), the reaction of 1a was performed in
deuterated dimethyl sulfoxide ([D6]DMSO); the reaction
mixture was analyzed by in situ 13C NMR spectroscopy
[Eq. (1)].[18] Aside from 2a, no other compound was detected.
which hence constitutes a practical method to make aromatic
aldehydes from readily available acetophenones.[5] To date,
a report by Boyer and co-workers that describes the
conversion of acetophenone into benzaldehyde had been
the only known example.[20,21]
À
Efforts were also directed to reactions with aliphatic
methyl ketones. Several methyl ketones, with varying alkyl
chain lengths and substituents, were subjected to the standard
conditions, and the results obtained are summarized in
Scheme 2. To our delight, reactions with methyl ketones 3a–
However, H2 and CO2, the expected by-products of the
decomposition of formic acid (HCOOH), were detected with
a hydrogen analyzer and by the lime-water test, respectively.
In a separate experiment it could be shown that formic acid
alone also generated H2 and CO2 under the standard
conditions.[19] Therefore, the formic acid is probably gener-
ated during the degradation of a-acetonaphthone (1a) and
decomposes to give H2 and CO2.
Next, the scope of the (hetero)aryl methyl ketones was
examined under the standard reaction conditions (Table 1,
entry 3). From the experimental data listed in Scheme 1,
important conclusions include: 1) the significant influence of
the electronic and/or substituent effects on the reaction (2b–
Scheme 2. Carbon–carbon bond cleavage of aliphatic methyl ketones.
3c proceeded smoothly to give the aldehydes 2l and 2t in
good yields. However, in contrast to the reaction of aceto-
phenones 1, much longer reaction times (20–40 h), which
were related to the lengths of the alkyl chain (for example, 3a
vs. 3b), were required for efficient transformation. Notably,
the complete degradation of substrate 3c, which bears two
methyl ketone units, was observed, affording 4-methoxy-
isophthalaldehyde (2t) in 89% yield within 36 h. In addition,
the necessity for benzylic activation was precluded because
n-butyl methyl ketone (hexan-2-one; 3d), which lacks an
aromatic ring at the terminal position of the alkyl chain, also
underwent degradation under the standard conditions to
afford H2 and CO2 (the conversion ratio was determined by
1H NMR analysis of the reaction mixture using toluene as an
internal standard). This result is extremely interesting, as it
represents the first example of a complete degradation of an
aliphatic ketone to H2 and CO2.[22,23] Collectively, the results
listed in Scheme 2 demonstrate the high capability of the
copper(I)-oxygen catalyst system for catalytic degradation.
In order to explore the reaction mechanism, some
representative acetophenone derivatives were selected and
subjected to the standard conditions (Scheme 3). It was found
that a-mono(hydroxy)acetophenone (4a) and a,a-bis-
Scheme 1. Carbon–carbon bond cleavage of (hetero)aryl methyl
ketones.
2
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1
sion (1.9%) of 6a was detected by H NMR analysis of the
reaction mixture [Eq. (3)]. Compared with our previous
observation that propiophenone (4d) was left unchanged
under the standard conditions, we concluded that the
oxidation of a methyl substituent is more favorable than
that of a methylene moiety in the initial step of the
degradation of aliphatic methyl ketones 3. However, the
degradation of aliphatic aldehyde 6b to 2l within a shorter
time (3 h) shows that aliphatic methyl ketones are initially
transformed into the corresponding aldehydes, which then
enter the aldehyde-degradation cycle [Eq. (4)].[25] Also, it
Scheme 3. Reactions of acetophenone derivatives.
(hydroxy)acetophenone (4b) both afforded benzaldehyde
(2l) within a very short period of time; nevertheless, the
reaction was much faster for the latter than for the former (2 h
vs. 4 h). These results suggest a stepwise oxygenation of the
a-methyl group. In addition, the conversion of 4a into 4b was
1
detected by in situ H NMR spectroscopy.[17] The fact that
phenylglyoxylic acid (4c) remained intact under the reaction
conditions implies that no further oxidation of 4b to 4c
occurs; hence, compound 4b must be the precursor for the
À
implies that the cleavage of the C(CO) C(methyl) bond of
methyl ketones should be the rate-limiting step in the
degradation of aliphatic methyl ketones.
À
C C bond cleavage. The tolerance of the aldehyde functional
group to the CuI/O2 catalytic oxidation system was estab-
lished from the fact that compound 2l alone remained
unchanged under the standard conditions. Furthermore, it
was observed that methyl ketones are preferentially oxidized
in the presence of the corresponding aldehydes. For example,
propiophenone (4d), with an ethyl group instead of the
methyl group of acetophenone (1l), was completely unreac-
tive under the standard conditions, whereas the reaction of
a-phenylacetophenone (4e) yielded a mixture consisting of
a-diketone 5a (54% yield) and dimerized product 5b (21%
yield). A low yield (17.8%) of benzaldehyde was obtained by
Sayre et al. from 4e under CuII catalysis;[13a] this might
indicate that a different mechanism is operating in our
copper(I) catalyst system.
On the basis of these results, a reaction mechanism for the
degradation of (hetero)aryl methyl ketones to aldehydes was
proposed (using 1l as a sample substrate; Scheme 4). Firstly,
Furthermore, deuterium-labeling studies revealed a pri-
mary kinetic isotope effect (KIE) (KH/KD = 3.6) in an
intermolecular competition experiment that utilized deuter-
ated substrate [D]-1l [Eq. (2)].[24] This demonstrated that the
Scheme 4. Mechanistic proposal.
acetophenone (1l) undergoes oxidation to give a-mono-
(hydroxy)acetophenone (4a), through the activation of
oxygen by the cuprous salt.[26] Compound 4a is further
oxidized to phenylglyoxal int-a, which quickly converts into
the more-stable hydrated a,a-bis(hydroxy)acetophenone 4b
by picking up one molecule of water.[12] Following a 1,2-
hydride shift in a Cannizzaro type reaction,[27] during which
the methyl hydrogen atom is transferred to the carbonyl
carbon, as supported by the deuterium-labeling experiment,
À
C(methyl) H bond cleavage of acetophenone is the rate-
determining step, and, more importantly, proved that the
aldehydic hydrogen atom originates from the a-methyl group.
When ketone 6a, with a-methylene substituents, was
subjected to the standard conditions, extremely low conver-
À
intermediate int-b is produced [Eq. (2)]. Finally, C C bond
cleavage takes place, leading to product 2l, along with the
release of formic acid. The formic acid subsequently decom-
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Angewandte
Communications
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poses to liberate CO2 and H2, while divalent copper is reduced
to the cuprous ion for the next catalytic cycle.[28]
In summary, the chemoselective oxidative cleavage of the
À
C(CO) C(methyl) bond of methyl ketones that yields
aldehydes has been described for the first time. A wide
range of aromatic and aliphatic methyl ketones can be
subjected to this copper-catalyzed method under an oxygen
atmosphere; the oxidation terminates at the aldehyde stage,
and hydrogen (H2) and carbon dioxide (CO2) are released as
the by-products. This reaction therefore constitutes an
unprecedented dehydrogenation of saturated aliphatics. Pre-
liminary mechanistic studies disclosed an interesting reaction
sequence, involving a-oxygenation/hydration/1,2-hydride
À
shift/C C bond cleavage. These findings could lead to
inspiring insights into copper–oxygen chemistry relevant to
À
C C bond cleavage. Further studies toward the elucidation of
the exact reaction mechanism and the synthetic utility of this
À
novel C C bond cleavage reaction are currently underway.
=
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Typical procedure: A solution of 1-acetonaphthone (1a; 1.0 mmol,
170 mg) and CuI (0.3 mmol, 57 mg) in DMSO (3.0 mL) under oxygen
(balloon) was prepared. The reaction mixture was heated to 1208C
and stirred until the starting material was consumed (monitored by
TLC). Upon cooling to room temperature, the reaction mixture was
diluted with dichloromethane (20 mL), and filtered through a pad of
Celite. The aqueous layer was then extracted with dichloromethane
(2 ꢀ 15 mL). The combined organic layers were reextracted with
water (3 ꢀ 50 mL), collected, dried over MgSO4, and filtered. The
filtrate was concentrated in vacuum, and the residue was purified by
column chromatography on silica gel to afford 2a (143 mg, 92%
yield) as a pale yellow oil.
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Received: June 11, 2013
Revised: August 8, 2013
Published online: && &&, &&&&
Keywords: aldehydes · cleavage reactions · copper · ketones ·
.
oxygen
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d) J. Liu, Z. Fang, Q. Zhang, Q. Liu, X. Bi, Angew. Chem. 2013,
125, 7091 – 7095; Angew. Chem. Int. Ed. 2013, 52, 6953 – 6957.
[15] a) M. C. Kozlowski in Copper-Oxygen Chemistry (Eds.: K. D.
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C. Zhang, C. Tang, N. Jiao, Chem. Soc. Rev. 2012, 41, 3381 – 3430.
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[17] a) S. S. Stahl, Science 2005, 309, 1824 – 1826, and reference
therein; for a disscussion on the effect of DMSO in copper-
mediated radical reactions, see: b) S. Monge, V. Darcos, D. M.
Haddleton, J. Polym. Sci. Part A 2004, 42, 6299 – 6308.
[18] For details, please see the Supporting Information.
[19] For a leading reference on the dehydrogenation of formic acid,
see: A. Boddien, D. Mellmann, F. Gꢂrtner, R. Jackstell, H.
Junge, P. J. Dyson, G. Laurenczy, R. Ludwig, M. Beller, Science
2011, 333, 1733 – 1736.
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[25] In the mid-1960s, Brackman and co-workers investigated the
copper-pyridine-complex-catalyzed oxidative degradation of
aldehydes, see: a) W. Brackman, C. J. Gaasbeek, P. J. Smit,
Recl. Trav. Chim. Pays-Bas 1966, 85, 437 – 445; b) W. Brackman,
H. C. Volger, Recl. Trav. Chim. Pays-Bas 1966, 85, 446 – 454; very
recently, Jiao and co-workers reported a Mn-promoted aerobic
À
oxidative C C bond cleavage of aldehydes, in which the
degradation of aldehydes may be involved; see: c) C. Zhang,
Z. Xu, T. Shen, G. Wu, L. Zhang, N. Jiao, Org. Lett. 2012, 14,
2362 – 2365.
[26] M. Gꢃmez-Gallego, M. A. Sierra, Chem. Rev. 2011, 111, 4857 –
4963.
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[28] For an example of the reduction of a cupric salt by formic acid,
see: B. Wang, X. Wang, Z. Li, Faming Zhuanli Shenqing Gongkai
Shuomingshu 2010, CN 101698497A.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
À
C C Bond Cleavage
L. Zhang, X. Bi,* X. Guan, X. Li, Q. Liu,*
B.-D. Barry, P. Liao
&&&& — &&&&
À
Chemoselective Oxidative C(CO)
C(methyl) Bond Cleavage of Methyl
Ketones to Aldehydes Catalyzed by CuI
with Molecular Oxygen
Aldehyde Termination: A novel copper-
catalyzed transformation from methyl
ketones into aldehydes has been accom-
plished. This method is applicable to
a wide range of aromatic and aliphatic
methyl ketones and chemoselectively
produces aldehydes, accompanied by the
release of hydrogen (H2) and carbon
dioxide (CO2) as by-products.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!