Copper-catalyzed dehydrogenative cross-coupling reaction between allylic C-H bonds and α-C-H bonds of ketones or aldehydes

Article abstract of DOI:10.1002/chem.201402114

A dehydrogenative cross-coupling reaction between allylic C-H bonds and the α-C-H bond of ketones or aldehydes was developed using Cu(OTf) ₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ-unsaturated ketones and aldehydes h

Full text of DOI:10.1002/chem.201402114

DOI: 10.1002/chem.201402114
Communication
&
Synthetic Methods
Copper-Catalyzed Dehydrogenative Cross-Coupling Reaction
between Allylic CÀH Bonds and a-CÀH Bonds of Ketones or
Aldehydes
Xing-Fen Huang,[a] Muhammad Salman,[a] and Zhi-Zhen Huang*[a, b]
Efficient DCC reactions between allylic CÀH bonds and the
Abstract: A dehydrogenative cross-coupling reaction be-
CÀH bonds of a-nitro esters or a-nitro ketones under palladi-
um catalysis were also reported by White et al.[5c–d] In 2008,
tween allylic CÀH bonds and the a-CÀH bond of ketones
or aldehydes was developed using Cu(OTf)2 as a catalyst
and DDQ as an oxidant. This synthetic approach to g,d-un-
saturated ketones and aldehydes has the advantages of
broad scope for both ketones and aldehydes as reactants,
mild reaction conditions, good yields and atom economy.
A plausible mechanism using Cu(OTf)2 as a Lewis acid cat-
alyst was also proposed (DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone; Tf=trifluoromethanesulfonate).
Bao and co-workers developed an allylic alkylation with 1,3-di-
carbonyl compounds promoted by DDQ (DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone).[5e] In 2012, Trost et al. unveiled
that 1,4-diene performed allylic alkylation smoothly with active
methylene compounds as nucleophiles using Pd(OAc)2/Ph3P as
a catalyst and 2,6-DMBQ as an oxidant (DMBQ=dimethoxy-
benzoquinone).[5f] Very recently, Trost’s group also discovered
an enantioselective allylic CÀH alkylation with 1,3-diketones
under palladium catalysis through DCC reaction.[5g]
Despite the elegance of these methods, the nucleophiles are
mainly limited to active methylene compounds, such as 1,3-di-
ketones, b-keto esters, a-nitro esters, a-nitro ketones, and nitro
compounds. To the best of our knowledge, allylic CÀH alkyla-
tion with common ketones or aldehydes remains unknown.
Considering that ketones or aldehydes are less reactive than
active methylene compounds as carbon-nucleophiles, we envi-
sion to use a Lewis acid catalyst to activate ketones or alde-
hydes to promote the allylic CÀH alkylation. Herein we wish to
present our recent results on Lewis acid catalyzed DCC reac-
tion between allylic CÀH bonds and the a-CÀH bond of ke-
tones or aldehydes.
Transitional metal-catalyzed allylic alkylation, especially palladi-
um-,[1] copper-,[2] or molybdenum-catalyzed[3] allylic alkylation,
has become a powerful method for CÀC bond formation in
recent decades. Typically, good leaving groups are required in
the allylic position, such as acetoxy, halo, amino, hydroxy or
carbonate groups.[1–3] To avoid prefunctionalization of the sub-
strates, Tsuji and others performed these reactions through al-
lylic CÀH activation rather than allylic functional group cleav-
age since the 1960s.[4] However, two-step protocols are re-
quired in the allylic CÀH alkylation mediated by stoichiometric
PdII.[4,5b]
Initially, cyclohexanone 1a and 1,3-diphenylpropene 2 were
chosen as model substrates to optimize the DCC reaction. To
our delight, when ZnCl2 and DDQ were employed as a Lewis
acid and an oxidant, respectively, in CH2Cl2 at room tempera-
ture, the desired coupling product, g,d-unsaturated ketone 3a
was obtained, albeit in a low yield (Table 1; entry 1). Other
Lewis acids were then probed in the reaction (see the Support-
ing Information). The acidity of AlCl3 seemed too strong for
this DCC reaction, and no desired coupling product 3a was
observed (Table 1; entry 2). Cu(OTf)2 proved to be the best cat-
alyst with regard to the yield of 3a (Table 1; entry 3). The in-
crease of the load of Cu(OTf) 2 catalyst seemed to be not bene-
ficial to the reaction (Table 1; compare entry 3 with entries 4
and 5). Other oxidants except DDQ, such as tert-butylhydroper-
oxide (TBHP), di-tert-butyl peroxide (DTBP), and meta-chloro-
perbenzoic acid (m-CPBA), were hardly effective in the reaction
(Table 1; entries 6–8). Various solvents were also examined, and
CH3CN resulted in the best yield (Table 1; compare entries 3,
9–11 with 12). In further exploration, when 1.5 equivalents of
H2O was added, the yield of 3a was increased to 75% (Table 1;
entry 13).[7] Raising the reaction temperature from room tem-
perature to 858C led to the reduction of the yield (Table 1;
After nearly half a century, a few methods have been devel-
oped to reduce the above two-step procedure into a single
operation through dehydrogenative cross-coupling (DCC) reac-
tions,[5] which is considered a new generation of CÀC bond for-
mations.[6] In 2006, Li et al. pioneered the allylic CÀH alkylation
with 1,3-diketones or b-keto esters through DCC reactions
using CuBr2 and CoCl2 as catalysts.[5a] In 2008, Shi’s group de-
veloped an intra/intermolecular allylic alkylation of CÀH bonds
with 1,3-diketones as nucleophiles by using a Pd(OAc)2/1,2-bis-
(phenylsulfinyl) ethane/BQ system (BQ=1,4-benzoquinone).[5b]
[a] X.-F. Huang, M. Salman, Prof. Z.-Z. Huang
Department of Chemistry
Zhejiang University
Hangzhou 310028 (P. R. China)
E-mail: huangzhizhen@zju.edu.cn
[b] Prof. Z.-Z. Huang
State Key Laboratory of Elemento-organic Chemistry
Nankai University
Tianjin, 300071 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402114.
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Table 1. Optimization of DCC reaction between cyclohexanone 1a and
1,3-diphenylpropene 2.[a]
Table 2. DCC reaction between ketones 1a–m and 1,3 diphenylpropene
2.[a]
Entry
1
Ketone
Product
Yield [%][b]
86
Entry
Lewis acid [(mol%)] Oxidant [(equiv)] Solvent Yield [%][b]
1
2
3[c]
4[c]
5[c]
6
7
8
9
10
11[c]
12[c]
13[d]
14[d,e]
15[d,g]
ZnCl2(10)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
TBHP(3)
DTBP(3)
m-CPBA(1)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
DDQ(1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
15
NP
38
35
33
NP
NP
NP
30
45
46
55
75
57
86
1a
1b
1c
1d
1e
3a
AlCl3(5)
Cu(OTf)2(5)
Cu(OTf)2(10)
Cu(OTf)2(20)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
Cu(OTf)2(5)
2
3
4
5
3b
3c
3d
3e
87
90
95
84
CHCl3
MeNO2
CH3CN
CH3CN
CH3CN
CH3CN
6
1 f
3 f
65
[a] The mixture of 1a (0.6 mmol), 2 (0.3 mmol), and DDQ (0.3 mmol) in
solvent (1 mL) was stirred at room temperature for 24 h; [b] Isolated
yield; [c] Reaction completed in 2 h; [d] 1.5 equivalents of H2O was
added. Reaction completed in 24 h; [e] 858C; [g] DDQ was added in three
portions at 08C for 1.5 h, and the resulting mixture was stirred for 24 h at
room temperature.
7
1g
1h
1i
3g
3h
3i
77
88
87
82
8
9
10
1j
3j
entry 14). If DDQ was added in three portions at 08C for 1.5 h,
the yield was further increased to 86% after stirring for 24 h at
room temperature (Table 1; entry 15). It was noteworthy that,
in the absence of Cu(OTf)2, no 3a was obtained. Thus, it can
be concluded that the optimized reaction should be per-
formed under the catalysis of 5 mol% Cu(OTf)2 in the presence
of 1.0 equivalent of DDQ and 1.5 equivalents H2O at room tem-
perature in CH3CN.
11
1k
3k
89
12
13
1l
3l
68
62
1m
3m
[a] Reaction conditions: ketone
(5 mol%), DDQ (0.3 mmol), CH3CN (1 mL), room temperature, 24 h; [b] Iso-
1 (0.6 mmol), 2 (0.3 mmol), Cu(OTf)2
With the optimized conditions in hand, the scope of the
DCC reaction was examined. We were pleased to find that vari-
ous substituted cyclohexanones 1b–d underwent the reaction
smoothly to give the desired g,d-unsaturated ketones 3b–d in
excellent yields (Table 2; entries 2–4). Tetrahydropyran-4-one
1e, which bore a strong electron-withdrawing oxygen atom
on the ring, also performed well in the reaction (Table 2;
entry 5). Expanding or compressing the size of cyclic ketone
1a led to significant reductions of yields (Table 2; compare
entry 1 with entries 6 and 7). The straight-chain ketone as
simple as acetone 1h performed the reaction smoothly to give
coupling product 3h in an excellent yield (Table 2; entry 8).
The reaction was highly regioselective for the unsymmetric ke-
tones 1i and j, and the CÀC bonds formed at more substituted
a-carbon of ketones 1i and j to give the corresponding prod-
ucts 2i and j (Table 2; entries 9 and 10). The results are consis-
tent with the formation of a more stable enol under Lewis acid
catalysis. Similarily, although the carbon in 3-position of 3-
methylbutan-2-one 1k is more hindered as compared to that
lated yield, d.r. (anti/syn)ꢀ1:1.
in 1-position, 1k still led to g,d-unsaturated ketone 3k with
forming a quaternary carbon in an excellent yield (Table 2;
entry 11). Besides aliphatic ketones, aromatic ketones also per-
formed the DCC reaction expediently. Both 1-phenylpropanone
1l and 1,2-diphenylethanone 1m resulted in the correspond-
ing g,d-unsaturated ketones 3l and m in satisfactory yields
(Table 2; entries 12 and 13).
Moreover, various aldehydes were also examined in the DCC
reaction under the optimized conditions. It was found that cy-
clohexanal 1n and phenyl acetaldehyde 1o performed the re-
action smoothly to give the corresponding coupling products
3n and o in 90 and 93% yield, respectively (Table 3; entries 1
and 2). Similar to a-alkyl substituted ketone 1k, a-alkyl substi-
tuted aldehyde 1p led to the g,d-unsaturated aldehyde 3p in
a good yield with forming a quaternary carbon (Table 2;
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Communication
Table 3. DCC reaction between aldehydes 1n–w and 1,3-diphenylpro-
pene 2.[a]
Entry
1
Aldehyde
Product
Yield [%][b]
90
1n
3n
2
3
1o
1p
3o
3p
93
88
4
1q
1r
3q
3r
80
75
85
73
80
77
75
5
Scheme 1. Plausible mechanism of the DCC reaction between ketones or al-
dehydes 1 and 1,3-diphenylpropene 2.
6
1s
1t
3s
3t
7
(Table 2; entries 9–11) supports that Cu(OTf)2 as a Lewis acid
activates ketone 1 to form an enol. Afterwards, enol 9 attacks
allylic cation 6 to form coupling product 3, regenerate
Cu(OTf)2, and generate a proton, which is received by DDQH
anion 7 to form DDQH2.
8
1u
1v
1w
3u
3v
3w
9
In conclusion, we have developed a novel dehydrogenative
cross-coupling reaction of common ketones or aldehydes with
1,3-diphenylpropene by using Cu(OTf)2 as a catalyst and DDQ
as an oxidant. It is the first example of DCC reaction between
allylic CÀH bonds and the a-CÀH bond of ketones or alde-
hydes. This synthetic approach to g,d-unsaturated ketones and
aldehydes has the advantages of broad scope for both ketones
and aldehydes as reactants, mild reaction conditions, good
yields and atom economy, which makes it practical in future
applications. A plausible mechanism using Cu(OTf)2 as a Lewis
acid catalyst to activate ketone or aldehyde was also proposed.
The DCC reactions of other allylic compounds with aldehydes
or ketones under Lewis acid catalysis and their mechanisms
are currently under way.
10
[a] Reaction conditions: 1 (0.6 mmol), aldehyde 2 (0.3 mmol), Cu(OTf)2
(5 mol%), DDQ (0.3 mmol), CH3CN (1 mL), room temperature, 24 h;
[b] Isolated yield, d.r. (anti/syn)ꢀ1:1.
entry 3). A series of straight-chain aldehydes 1r–w were suit-
able to the DCC reaction, affording g,d-unsaturated aldehydes
3r–w in good yields (Table 3; entries 5–10).
Our experiment also demonstrated that when tert-butyldi-
methylchlorosilane (TBSCl) was employed instead of Cu(OTf)2,
the DCC reaction of ketone 1a with 1,3-diphenylpropene 2
also occurred in the presence of DDQ.[8] Thus, under the opti-
mized conditions, DDQ rather than Cu(OTf)2 should result in
the formation of positive allylic species.[5e] Similar to TBSCl,
Cu(OTf)2 should function as a Lewis acid to promote the enoli-
zation of ketone 1 in this reaction. A plausible mechanism for
the DCC reaction is depicted in Scheme 1. First, an electron in
the CÀC double bond of 1,3-diphenylpropene 2 is transferred
to DDQ to form a radical cation 4 and a DDQ radical anion 5.
Then, an allylic hydrogen atom is abstracted by the DDQ radi-
cal anion 5 to generate an allylic cation 6 and a DDQH anion
7. At the other hand, ketone 1 coordinates with Cu(OTf)2 to
form complex 8, followed by its keto-enol tautomerization to
form copper-complexed enol 9.[9] The result that the DCC reac-
tion is probably through a more stable enol intermediate
Experimental Section
General Procedure for the DCC Reaction of Ketones or Alde-
hydes 1 with 1,3-Diphenylpropene 2
To a mixture of Cu(OTf)2 (5.4 mg, 0.015 mmol) in CH3CN (1 mL),
were added 1,3-diphenylpropene 2 (58.2 mg, 0.3 mmol), ketone or
aldehyde 1 (0.6 mmol) and H2O (8.1 mg, 0.45 mmol) in sequence.
At 08C, the resulting mixture was stirred to become a solution.
Then, DDQ (68.1 mg, 0.3 mmol) was added in three portions within
1.5 h. After that, the reaction mixture was stirred for 24 h at room
temperature. Then the mixture was filtered and the filtrate was
evaporated under reduced pressure. The residue was purified by
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Communication
Fullerton, T. J. Dietsche, J. Am. Chem. Soc. 1978, 100, 3407; d) B. M. Trost,
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2013, 52, 1523.
Acknowledgements
Financial supports from MOST of China (973 program
2011CB808600) and National Natural Science Foundation of
China (No. 21072091 and 21372195) are gratefully acknowl-
edged.
[6] Reviews on dehydrogenative cross-coupling reactions: a) C. J. Li, Z. Li,
Pure Appl. Chem. 2006, 78, 935; b) C. J. Li, Acc. Chem. Res. 2009, 42, 335;
c) C. Scheuermann, Chem. Asian J. 2010, 5, 436; d) C. S. Yeung, V. M.
Dong, Chem. Rev. 2011, 111, 1215.
Keywords: aldehyde
reactions · ketones
·
allylic
·
CÀH bonds
· coupling
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of 2 with cyclohexanone 1a occurred at room temperature using DDQ
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Received: February 11, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
&
Synthetic Methods
X.-F. Huang, M. Salman, Z.-Z. Huang*
&& – &&
Copper-Catalyzed Dehydrogenative
Cross-Coupling Reaction between
Allylic CÀH Bonds and a-CÀH Bonds
of Ketones or Aldehydes
A lovely couple: The first example of
a dehydrogenative cross-coupling reac-
tion between allylic CÀH bonds and the
a-CÀH bond of ketones or aldehydes
was developed using Cu(OTf)2 as a cata-
lyst and DDQ as an oxidant (see
scheme; DDQ=2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone; Tf=trifluorome-
thanesulfonate).
Chem. Eur. J. 2014, 20, 1 – 5
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These are not the final page numbers! ÞÞ