Copper-catalyzed oxidative coupling of alkenes with aldehydes: Direct access to α,β-unsaturated ketones

Article abstract of DOI:10.1002/anie.201208920

Let's get radical: The first copper-catalyzed oxidative coupling of alkenes and aldehydes was developed. Various aldehydes were utilized as substrates to construct α,β-unsaturated ketones. A preliminary mechanistic study indicated that this reaction is likely to proceed through a single-electron transfer. Copyright

Full text of DOI:10.1002/anie.201208920

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DOI: 10.1002/anie.201208920
Oxidative Coupling
Copper-Catalyzed Oxidative Coupling of Alkenes with Aldehydes:
Direct Access to a,b-Unsaturated Ketones**
Jing Wang, Chao Liu, Jiwen Yuan, and Aiwen Lei*
Transition-metal-catalyzed cross-coupling reactions, mainly
involving R1X as an electrophile and R2M as a nucleophile,
have been well-developed for many applications in synthesis.
Scheme 1. Direct synthesis of a,b-unsaturated ketones.
Very recently, remarkable efforts to realize cross-coupling in
a green, atom-economic, and sustainable manner have been
made. Oxidative coupling of R1H with R2H,[1] which avoids
the use of halides (or halide equivalents) and organometallic
reagents, possesses practical advantages and has attracted
much attention. Although some progress has been made in
this emerging field, the development of a highly efficient and
highly selective oxidative cross-coupling reaction utilizing two
different hydrocarbons as the reagents is still a great chal-
lenge. One typical example is the oxidative coupling of an
prefunctionalized. Moreover, a wide variety of naturally
occurring and manmade compounds that exhibit extraordi-
nary biological and pharmaceutical properties (e.g. anti-
cancer, antiinflammatory, antioxidant, antimicrobial) possess
a,b-unsaturated ketone core structures (Scheme 2).[7] This
À
À
aldehyde C H bond with other C H bonds. In recent years,
2
À
H
significant progress has been achieved, whereby the Csp
bonds of arenes have been activated for the oxidative
coupling with an aldehyde C H bond to afford ketones.
[2]
À
Also, alkenes have been widely used in oxidative trans-
formations.[3] However, to the best of our knowledge, up to
now, there has been only one example, which involved the
direct oxidative coupling between salicylaldehydes and
alkenes facilitated by a Rh catalyst.[4] In most cases, the
Scheme 2. Examples of important a,b-unsaturated ketone-containing
compounds.
À
direct addition of aldehyde C H bonds to alkenes for the
construction of saturated ketones[5] or b-peroxy ketones[6] was
achieved.
class of compounds is also extremely fascinating owing to
their versatility for further synthetic transformations, thus
enabling the synthesis of compounds such as 1-indanone
compounds, 1,4-dihydropyrazole and pyranocoumarin, which
are important heterocycles that widely occur in natural
products and pharmaceutically molecules.[8] Because of the
important biological and pharmaceutical applications of a,b-
unsaturated ketones, various methods for their synthesis have
been reported.[2c,9] However, the development of an efficient
and general synthetic route with high atom economy is highly
desirable (Scheme 1). Herein, we document a novel approach
for a,b-unsaturated ketones synthesis by the Cu-catalyzed
direct oxidative coupling between alkenes and aldehydes.
Recently, we have demonstrated a Heck-type alkenyla-
tion of secondary and tertiary a-carbonyl alkyl bromides with
alkenes in the presence of a Ni catalyst.[10] Mechanistically, the
reaction was believed to proceed through the a-carbonyl alkyl
radical addition to alkenes followed by radical oxidation to
generate the desired products. Aldehydes could be easily
converted into the corresponding acyl radicals in the presence
of peroxides.[2a,d,e,11] Consequently, we decided to convert
aldehydes into afford acyl radicals and use these instead of a-
carbonyl alkyl radicals to react with alkenes for the direct
synthesis of a,b-unsaturated ketones from aldehydes and
alkenes. Hence, peroxides in combination with transition-
metal catalysts were applied to the oxidative coupling of
aldehydes and alkenes to form a,b-unsaturated ketones.
Alkenes and aldehydes are widely used simple chemical
feedstock. The oxidative coupling of aldehydes with alkenes
would result in the direct construction of a,b-unsaturated
ketones (Scheme 1), and represents a highly attractive and
sustainable strategy for the synthesis of these types of
compounds, as neither the aldehydes nor alkenes need to be
[*] J. Wang,[+] Dr. C. Liu,[+] J. Yuan, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072, Hubei (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Homepage: http://www.chem.whu.edu.cn/GCI_WebSite/
Prof. A. Lei
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery
(Wuhan University), Ministry of Education, and
Wuhan University School of Pharmaceutical Sciences
Wuhan, 430071 (P. R. China)
[+] These authors contributed equally to this work.
[**] This work was supported by the 973 Program (2012CB725302), the
National Natural Science Foundation of China (21025206 and
21272180), and the China Postdoctoral Science Foundation funded
project (2012M521458). We are also grateful for the support from
the Program for Changjiang Scholars and Innovative Research Team
in University (IRT1030).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208920.
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Initially we utilized styrene and 4-methylbenzaldehyde as
a model reaction to investigate different reaction conditions.
Selected data are listed in Table 1. Firstly, various Ni
precursors were screened for the reaction in benzene at
the absence of solvent (Table 1, entry 13). A lower loading
(10 mol%) of CuCl2 resulted in a slower reaction, affording 3j
in 46% yield (Table 1, entry 14). The desired product 3j was
1
obtained in 66% yield, as determined by H NMR spectros-
copy, when the amount of CuCl2 was increased to 100 mol%
(Table 1, entry 15); this result is similar to that obtained when
20 mol% of CuCl2 was used. Only when the ratio of 4-
methylbenzaldehyde and TBHP was 2:1 and the amount of
each component was at least 2.5 equivalents of the styrene,
the product could be obtained in a satisfactory yield (see the
Supporting Information, Table S1). Therefore, the optimized
reaction conditions are: CuCl2 (20 mol%), TBHP (2.5 equiv),
808C, 12 h (Table 1, entry 16).
Table 1: Impact of reaction parameters on Cu-catalyzed oxidative
coupling of aldehydes with alkenes.[a]
Entry
[M]
Solvent
Yield (3j) [%][b]
With the optimized reaction conditions established, we
studied other substrates in this Cu-catalyzed oxidative
coupling of alkenes with aldehydes. Firstly, the scope of the
aldehyde substrate was investigated (Table 2). The reaction of
1
2
3
4
5
6
7
8
[Ni(PPh3)4]
NiCl2
[Ni(acac)2]
CoCl2
CuCl
FeCl2
CuBr2
CuCl2
CuCl2
CuCl2
CuCl2
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
CH3CN
dioxane
DCE
benzene
–
–
–
–
–
–
–
–
–
–
trace
28
–
Table 2: Synthesis of a,b-unsaturated ketones from various aldehydes
with alkenes.[a]
9
10
11
12
13
14
15
16
–
trace
38[d]
57
46[e]
66[f]
76[c]
CuCl2
CuCl2
CuCl2
CuCl2
Entry
1
Product
3
Yield [%][b]
80
CuCl2
3a
[a] Reaction conditions: styrene (0.5 mmol), 4-methylbenzaldehyde
(1.5 mmol), TBHP (1.0 mmol, 70% aqueous solution), [M] (0.1 mmol),
benzene (2.0 mL), 808C, N2, 12 h. [b] Determined by NMR spectroscopy
with CH2Br2 as the internal standard. [c] styrene 0.5 mmol, 4-methyl-
benzaldehyde (2.5 mmol), TBHP (1.25 mmol), CuCl2 (0.1 mmol), 808C,
N2, 12 h. [d] benzene (1.0 mL). [e] CuCl2 (0.05 mmol). [f] CuCl2
2
3
3b
3c
63
63
(0.5 mmol). DCE=1,2-dichloroethane, TBHP=tert-butyl hydroperoxide.
4
3d
3e
3 f
65
69
50
808C in the presence of TBHP. Unfortunately, with the use of
Ni precursors such as [Ni(PPh3)4], NiCl2, or [Ni(acac)2], no
desired product was detected. Conversely, saturated ketones
were the major product, thus indicating that the acyl radical
could be generated and can react with olefin double bonds
under these reaction conditions. However, the benzyl radical,
generated by the addition of the acyl radical to styrene, could
not be oxidized to result in the desired product 3j which a Ni
catalyst was used (Table 1, entries 1, 2, 3). Therefore, other
transition metal catalysts were tested (Table 1, entries 4–8).
To our delight, the desired product 3j was obtained in a 28%
yield, as determined by 1H NMR spectroscopy (Table 1,
entry 8), when CuCl2 was used. When CoCl2, CuCl, FeCl2,
or CuBr2 were used, none or only a trace amount of the
desired product was detected (Table 1, entries 4–7). The
influence of the solvent was also studied. When other
solvents, such as CH3CN, dioxane, and DCE, were applied
instead of benzene, a trace or none of the desired product was
observed (Table 1, entries 9–11). Decreasing the amount of
benzene to 1 mL led to an increased yield (Table 1, entry 12).
This promising result encouraged us to do further optimiza-
tion with regard to the volume of solvent, indeed, the yield of
3j was improved to 57% when the reaction was carried out in
5
6[c]
7
3g
61
8
9
3h
3i
64
34
[a] Reaction conditions: 1 (2.50 mmol), 2 (0.50 mmol), CuCl2
(20 mol%), TBHP (1.25 mmol), 808C, N2, 12 h. [b] Yield of the isolated
product. [c] 1 (3.00 mmol), 2 (0.50 mmol), CuCl2 (20 mol%), TBHP
(1.50 mmol), 908C, N2, 12 h.
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Table 3: Synthesis of a,b-unsaturated ketones from different alkenes
2-naphthaldehyde afforded the desired product in 80% yield
(Table 2, entry 1). The reaction of benzaldehyde also pro-
ceeded well, giving the coupling product in a 63% yield
(Table 2, entry 2). meta-Methyl substituted benzaldehyde was
similarly found to be suitable substrate for this transformation
and gave the corresponding a,b-unsaturated ketones in good
yield (Table 2, entry 3). To our delight, the use of a benzalde-
hyde with a para-SMe substituent, which can be easy oxidized,
afforded the desired product in 65% yield (Table 2, entry 4).
Moreover, the reaction of benzaldehyde bearing an electron-
with aldehydes.[a]
Entry
1
Product
3
Yield [%][b]
73
3j
À
donating group also proceeded well (Table 2, entry 5). A C
Cl bond, which provides the possibility for further function-
alization, was well tolerated by this transformation (Table 2,
entry 6). When thiophene-2-carbaldehyde was used (Table 2,
entry 8), the desired product was obtained in a 64% yield,
upon isolation. A 34% yield was obtained when ortho-
methylbenzaldehyde was used; this poor yield may be due to
steric hindrance (Table 2, entry 9).
2
3
4
3k
3l
57
60
65
Encouraged by these promising results, we further applied
the optimized reaction conditions to examine the substrate
scope of alkenes. Styrenes having alkyl substituents, such as
methyl and tert-butyl, afforded the desired products in good
yields (Table 3, entries 2–4). para-Fluorostyrene reacted with
4-methylbenzaldehyde under the standard reaction condi-
tions to afford the coupling product in a 75% yield (Table 3,
entry 5). Notably, a chloro substituent on the phenyl ring of
styrenes could also be well tolerated (Table 3, entry 6). The
desired product was obtained in 30% yield, upon isolation,
when 4-vinylphenyl acetate was used (Table 3, entry 7). The
acetyl group is a particularly desirable group owing to the
possible use of the deprotected product for further function-
alization. 1,1-Diaryl alkenes were shown to couple with 4-
methylbenzaldehyde in good yields (Table 3, entries 8 and 9).
When investigating the reaction mechanism of Cu-cata-
lyzed oxidative coupling of alkenes and aldehydes, single-
electron transfer (SET) is an obvious consideration. There-
fore, a radical-trapping experiment was carried out. BHT
(2,6-di-tert-butyl-4-methylphenol) was employed under the
standard reaction conditions. The desired reaction did not
occur (Scheme 3), thus indicating that this transformation is
likely to involve a radical intermediate.
3m
5
3n
3o
3p
75
54
30
6[c]
7
8
3q
3r
64
70
9[d]
[a] Reaction conditions: 1 (2.50 mmol), 2 (0.50 mmol), CuCl2
(20 mol%), TBHP (1.25 mmol), 808C, N2, 12 h. [b] Yield of the isolated
product. [c] 1 (3.00 mmol), 2 (0.50 mmol), CuCl2 (20 mol%), TBHP
(1.50 mmol), 908C, N2, 12 h. [d] E/Z=1.6:1.4.
Scheme 3. Investigation into the reaction mechanism.
Furthermore, we postulated that the b-peroxy ketone 6,
which had been reported by the group of Li, maybe an
intermediate in the oxidative coupling.[6] To explore the
validity of our initial hypothesis, the reaction of b-peroxy
ketone 6 under the standard conditions was investigated.
Although the desired product 3b was detected, the isolated
yield was only 15% [Eq. (1)], which is much lower than that
of the reaction under the optimized reaction conditions
(63%; Table 2, entry 2). This result indicates that b-peroxy
ketone 6 might be involved in this process, but it is probably
not an intermediate in the main pathway of this oxidative
coupling.
Based on previous reports[2a,b,d,e,5,6,11] and the above
results,
a proposed reaction pathway is depicted in
Scheme 4. First, the low valent copper species A donates an
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Scheme 4. Proposed mechanism.
electron to TBHP to generate copper species B and the
alkyloxy radical, which then abstracts a hydrogen atom from
aldehyde 1 to generate the acyl radical 1I. The radical
addition of 1I to alkene 2 gives the benzylic radical 3I, which
is believed to undergo the direct oxidation by B and
deprotonation to release the final product 3. Meanwhile, the
low valent copper species A was regenerated to continue the
catalytic cycle.
In conclusion, we have developed the first Cu-catalyzed
oxidative coupling of alkenes with aldehydes. A variety of
functional groups were tolerated on both the aldehyde and
alkene. This work provides a novel approach for the
construction of a,b-unsaturated ketones. Tentative mechanis-
tic studies suggest that this reaction is likely to proceed by
a single-electron transfer. Further exploration of the substrate
scope and mechanistic studies are currently underway and
will be reported in due course.
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Experimental Section
General procedure for the synthesis of 3b: CuCl2 (13.4 mg, 0.1 mmol)
was added to a Schlenk tube equipped with a magnetic stir bar, in an
argon-filled glove box. 1b (265.3 mg, 2.5 mmol), 2a (52.1 mg,
0.5 mmol), and TBHP (112.6 mg, 1.25 mmol) were consecutively
injected into the reaction tube. The reaction was then heated to 808C
and stirred for 12 h. Upon completion, the reaction was quenched
with water and extracted with ethyl ether (3 ꢀ 10 mL). The organic
layers were then combined. The pure product was obtained by flash
column chromatography on silica gel (petroleum/ethyl acetate =
200:1). The yield of the isolated product was 63%.
Received: November 7, 2012
Published online: January 25, 2013
Keywords: aldehydes · alkenes · copper · oxidative coupling ·
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a,b-unsaturated ketones
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