Nickel N-heterocyclic carbene-catalyzed cross-coupling reaction of aryl aldehydes with organozinc reagents to produce aryl ketones

Article abstract of DOI:10.1039/c5cy00876j

The transformation of aromatic aldehydes into aryl ketones by nickel-catalyzed cross-coupling has been developed. This transformation represents an efficient and attractive synthetic utilization of organozinc reagents. The reaction provides a mild, practical method toward the synthesis of aryl ketones which are versatile intermediates and building blocks in organic synthesis.

Full text of DOI:10.1039/c5cy00876j

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Nickel N-heterocyclic carbene-catalyzed cross-
coupling reaction of aryl aldehydes with
Cite this: DOI: 10.1039/c5cy00876j
organozinc reagents to produce aryl ketones†
Received 15th June 2015,
Accepted 7th July 2015
a
bc
c
*
*
and Minglong Yuan
Cheng Jin, Lijun Gu
DOI: 10.1039/c5cy00876j
www.rsc.org/catalysis
The transformation of aromatic aldehydes into aryl ketones by
nickel-catalyzed cross-coupling has been developed. This trans-
formation represents an efficient and attractive synthetic utiliza-
tion of organozinc reagents. The reaction provides a mild, practical
method toward the synthesis of aryl ketones which are versatile
intermediates and building blocks in organic synthesis.
recently, metal-catalyzed C–H arylation of aldehydes has pro-
vided new pathways for the construction of these molecules.5
Related to this strategy, aryl ketone formation from aldehydes
has been realized using NHC catalysis through reactions with
aromatic electrophiles or benzynes.6 The carbon–carbon bond
is the most widespread and fundamental bond existing in
organic compounds. Very recently, the preparation of aryl
ketones by activation of C–C bonds has received much atten-
tion.7 Despite these advances,8 versatile and efficient methods
for the direct construction of aryl ketones that are compatible
with various functional groups and use readily available
starting materials remain highly desirable.
Aryl ketones are multifaceted compounds that function as
components
of
pharmacophores,
photolabels
and
photosensitizers, organic electronics, and polymers.1
Furthermore, manipulation of the carbonyl group provides a
generic
entry
into
molecules
containing
benzylic
functionality. As
a
consequence, their preparation has
Organozinc reagents have been known for more than 150
years. These reagents are known as unique nucleophiles com-
pared to other common organometallic reagents because the
softer nucleophilicity of organozinc reagents shows higher
functional group tolerance.9 They have been increasingly
applied in bond construction reactions such as Negishi cou-
pling,10 Fukuyama coupling,11 oxidative cross-coupling,12
aldol reaction, etc.9 Notably, the formation of alcohols from
aldehydes and organozinc reagents has been particularly suc-
cessful, whereas the synthesis of ketones from the above two
substrates has still rarely been reported. As part of our ongo-
ing efforts to develop transition-metal-catalyzed organic reac-
tions,13 we herein report an unprecedented nickel
N-heterocyclic carbene (NHC)-catalyzed cross-coupling reac-
tion of aryl aldehydes with organozinc reagents that
received considerable attention in organic chemistry.
Classical methods for the formation of these important
structural motifs include the addition of aryl-metal species to
carbonyl compounds and Friedel–Crafts acylation reactions.2
However, the presence of aromatic heterocycles can limit
these strategies, as organometallic reagents can be incompati-
ble with heteroaromatic nuclei and Friedel–Crafts acylations
usually work best with π-rich arenes and sometimes result in
isomeric mixtures. An alternative approach is the reaction of
diazo compounds with aldehydes,3 but the use of structurally
diverse diazo compounds is hampered by preparation and
safety issues. In recent years, significant progress has been
achieved in carbonylative Suzuki–Miyaura cross-coupling reac-
tion. Various substituted aryl ketones have been successfully
synthesized.4 However, because of the high toxicity, and odor-
less and flammable character of CO gas, transformations
using CO gas must be operated with special care. More
a New United Group Company Limited, Changzhou, Jiangsu, 213166, China
b Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs
Commission & Ministry of Education, Kunming, China
c Engineering Research Center of Biopolymer Functional Materials of Yunnan,
Yunnan Minzu University, Kunming, Yunnan, 650500, China.
E-mail: gulijun2005@126.com, yml@vip.163.com
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5cy00876j
Scheme 1 Reaction of aryl aldehydes and organozinc reagents.
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chemoselectively yields aryl ketones as the desired prod-
uct.14,15 This reaction constitutes a novel transformation
from organozinc reagents into aryl ketones. The method
advantageously enriches and complements the existing tool-
box used by synthetic chemists, and allows a straightforward
access to a wide range of functionalized products (Scheme 1).
Inspired by the pioneering works from the groups of
Molander,16 Cheng,17 Matsubara18 and Dong,15f we initially
chose benzaldehyde 1a and PhZnBr 2a as standard substrates
to test the feasibility of cross-coupling reaction to form
ketones. To our delight, when 1a and 2a were treated with a
catalytic system consisting of 5a (hydrogen acceptor, 1.5
equiv.), MgCl2 (1.0 equiv), NiIJcod)2 (8 mol%), and IPr (ligand,
10 mol%) in THF at 30 °C, the desired benzophenone 3aa
was formed in 31% yield (Table S1,† entry 1). Tishchenko
homodimer 4a was obtained in 38% yield (Table S1,† entry
1). Further explorations showed that hydrogen acceptor 5d
ij2,2,2-trifluoro-1-IJ4-methoxy- phenyl)ethanone] gave good
results.19 Next, different solvents were screened to enhance
the efficiency of this reaction. It was found that a cosolvent
system of 1,4-dioxane and THF was appropriate. Different
nickel catalysts were screened, and NiIJcod)2 turned out to be
the most effective catalyst (entries 6–9). Other ligands, includ-
ing ItBu, PCy3, and SIPr, were tested and found to be less
effective than IPr (Table S1,† entries 10–12). However, the
absence of nickel catalyst resulted in no detectable amounts
of 3aa (Table S1,† entry 16). Without MgCl2, the reaction gave
the cross-coupling product in 46% yield after 10 h (Table S1,†
entry 17). These results indicate that the structures of
organozinc reagents are possibly not as simple as RZnX.9b
The coordination of THF and MgCl2 to RZnX may signifi-
cantly affect the transmetalation step.
Table 1 Scope of aldehydes 1a
Entry
1
Aldehydes 1
Aryl ketones 3
Yieldb (%)
74
2
3
74
56
4
54
5
6
7
61
67
69
8
9
58
52
10
0
a
Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), 5d (1.5 equiv.), MgCl2 (1.0 equiv.), NiIJcod)2 (8 mol%), IPr (10 mol%), THF/1,4-dioxane (3
b
mL, 1 : 1), 30 °C, in Ar atmosphere for 8 h. Isolated yield.
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With a set of optimized conditions in hand, we then inves-
tigated a series of aldehydes to extend the substrate scope. As
summarized in Table 1, the standard reaction conditions
were found to be compatible with a wide range of aldehydes
1. As summarized in Table 1, both electron-donating and -
withdrawing aryl aldehydes could be successfully converted
to the corresponding aryl ketones in moderate to good yields.
Several aromatic substituents, including Me, MeO, F and CF3,
were well-tolerated under standard conditions (Table 1,
entries 1–6); substituents at the ortho-, meta-, or para- posi-
tions had no distinct influence on the reaction (Table 1,
entries 1, 3 and 4). It is noteworthy that trifluoromethyl-
substituted aromatic aldehydes were tolerated well (Table 1,
entry 6), thus leading to a trifluoromethyl-substituted product
which has better membrane permeability and increased
bioavailability.20 The reaction of substrate 1h with the
polysubstituted aromatic aldehyde delivered the desired
product 3ah in good yield (Table 1, entry 7). An aromatic
aldehyde with a naphthyl group also participated in this
Ni-catalyzed cross-coupling reaction, affording the cross-
coupling product in 58% yield (Table 1, entry 8). We also
considered the reaction of 2a with 1j bearing a furanyl
moiety and obtained heteroaryl ketone 3aj in 52% yield
(Table 1, entry 9), further extending the scope of this meth-
odology. Application of an aliphatic aldehyde did not
deliver the corresponding ketone under the same reaction
conditions (Table 1, entry 10).21
To further highlight the synthetic usefulness of our strat-
egy, we turned our attention to the scope of organozinc
reagents (Table 2). Aryl zinc reagents bearing electron-
donating groups at the para position of the phenyl ring, such
as methyl, proceeded smoothly in the reaction to give the cor-
responding aryl ketone 3ab in good yield (Table 2, entry 1).
Substrates substituted with electron-withdrawing groups,
such as Ph and ester, also worked well and afforded the
desired products 3ca–3da in 49% and 73% yields, respectively
(Table 2, entries 2–3). These results indicate that the
electronic nature of the aryl-zinc reagents has little influence
on the cross-coupling process. Heteroaryl-substituted sub-
strates could also be converted into the desired products. For
example, substrates 2e and 2f were transformed into prod-
ucts 3ea and 3fa in 70% and 47% yields, respectively (Table 2,
entries 4–5). Efforts were made to apply this methodology for
the synthesis of aryl alkyl ketones. It was found that reactions
with 2g–2i proceeded smoothly to give the aryl alkyl ketones
in good yields (Table 2, entries 6–8).
Table 2 Scope of organozinc reagents 2a
Entry
1
Organozinc reagents 2
Aryl ketone 3
Yieldb (%)
69
2
3
49
73
4
5
70
47
6
7
62
66
8
77
a
Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), 5d (1.5 equiv.), MgCl2 (1.0 equiv.), NiIJcod)2 (8 mol%), IPr (10 mol%), THF/1,4-dioxane (3
b
mL, 1 : 1), 30 °C, in Ar atmosphere for 8 h. Isolated yield.
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ketones. The process operates under mild conditions,
involves simple experimental protocols, and uses a commer-
cially available N-heterocyclic carbene catalyst. Further inves-
tigations of the mechanism of the reaction and its applica-
tion are ongoing in our laboratory.
Acknowledgements
We are grateful for the financial support from The Educa-
tional Bureau of Yunnan Province (2010Y431) and the State
Ethnic Affairs Commission (12YNZ05).
Scheme 2 Control experiment.
Notes and references
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of ketone 5d may occur prior to or immediately after reduc-
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the undesired product 4a by disrupting the formation of a
cycloisomerization intermediate between two aryl aldehydes.
In summary, we have described a nickel N-heterocyclic
carbene-catalyzed cross-coupling reaction of aryl aldehydes
and organozinc reagents for the formation of complex aryl
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