Nickel N-heterocyclic carbene catalyzed C-C bond formation: A new route to aryl ketones

Article abstract of DOI:10.1002/chem.201500560

A novel nickel N-heterocyclic carbene catalyzed cross-coupling reaction of aryl aldehydes with boronic esters for the synthesis of aryl ketones was developed. This reaction provides a mild, practical method toward aryl ketones, which are versatile intermediates and building blocks in organic synthesis.

Full text of DOI:10.1002/chem.201500560

DOI: 10.1002/chem.201500560
Communication
&
Cross-Coupling |Hot Paper|
Nickel N-Heterocyclic Carbene Catalyzed CÀC Bond Formation: A
New Route to Aryl Ketones
[a, c]
[b]
[a]
Li-Jun Gu,*
Cheng Jin, and Hong-Tao Zhang
using CO gas must be operated with special care. The carbonÀ
carbon bond is the most widespread and fundamental bond
that exists in organic compounds. Very recently, the prepara-
tion of aryl ketones by activation of CÀC bonds has received
Abstract: A novel nickel N-heterocyclic carbene catalyzed
cross-coupling reaction of aryl aldehydes with boronic
esters for the synthesis of aryl ketones was developed.
This reaction provides a mild, practical method toward
aryl ketones, which are versatile intermediates and build-
ing blocks in organic synthesis.
[1b,6]
[7]
much attention.
Despite these advances, versatile and ef-
ficient methods for the direct construction of aryl ketones that
are compatible with various functional groups and use readily
available starting materials remain highly desirable.
Transition-metal-catalyzed cross-coupling reactions are
highly versatile methods for the construction of complex mole-
Aryl ketones are common structural motifs in natural products
and versatile building blocks for the synthesis of more complex
natural products, pharmaceuticals, agricultural chemicals, dyes,
[8]
cules from simple building blocks. Efficient catalytic systems
for a wide range of substrates are utilized in both research lab-
oratories and industry. The most efficient and commonly em-
ployed cross-coupling catalysts feature second- and third-row
transition metals, most notably palladium, to achieve high
[
1]
and other commercially important materials. Consequently,
the development of synthetic methods for the preparation of
aryl ketones has received considerable attention. One general
approach is the Friedel–Crafts acylation of substituted aromatic
[9]
turnover numbers. Despite the maturity of this synthetic
method, cross-coupling catalysis continues to attract signifi-
cant interest, especially with respect to the development of
more sustainable catalysts based on abundant first-row transi-
[2]
rings. Under the acidic conditions of Friedel–Crafts reactions,
the formation of ortho and para isomers with untunable regio-
selectivity results in separation problems and makes aryl ke-
tones with meta substituents difficult to access. Other signifi-
cant approaches include the addition of an organometallic re-
agent to a partner with a higher oxidation state partner and
the addition of an organometallic reagent to an aldehyde and
[10]
tion metals.
metals have been reported and those based on nickel are par-
Various cross-coupling catalysts with first-row
[11]
ticularly promising. So far, nickel-catalyzed cross-coupling re-
actions of aryl aldehydes with boronic esters have not been re-
ported. Herein, we describe a new strategy to construct aryl
ketones that relies on a nickel N-heterocyclic carbene catalyzed
cross-coupling reaction of aryl aldehydes with boronic esters
(Scheme 1). This protocol provides a practical, neutral, and
mild synthetic approach to aryl ketones.
[
3]
reoxidation of the intermediate alcohol. Both of these ap-
proaches suffer from a poor financial, time, step, and redox
economy, as well as the requirement for moisture-sensitive or-
ganometallic reagents. An alternative approach is the reaction
of diazo compounds with aldehydes, but the use of structurally
diverse diazo compounds is hampered by their preparation
[
4]
and safety issues. In recent years, significant progress has
been achieved in carbonylative Suzuki–Miyaura cross-coupling
reactions; various substituted aryl ketones have been success-
[
5]
fully synthesized. However, due to the high toxicity and odor-
less and flammable character of CO gas, transformations by
[a] Prof. Dr. L.-J. Gu, H.-T. Zhang
Scheme 1. New strategy to construct aryl ketones.
Key Laboratory of Chemistry in Ethnic Medicinal Resources
State Ethnic Affairs Commission & Ministry of Education
Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China)
Our investigation began with the reaction of benzaldehyde
[
b] C. Jin
(
1a) with phenylboronic acid pinacol ester (2a) to optimize
New United Group Company Limited
Changzhou, Jiangsu, 213166 (P. R. China)
the reaction conditions (Table S1 in the Supporting Informa-
tion). To our delight, when 1a and 2a were treated with a cata-
lytic system consisting of a,a,a-trifluoroacetophenone (hydro-
gen acceptor, 1.5 equiv), Ni(cod)2 (5 mol %), and 1,3-bis(2,6-
[
c] Prof. Dr. L.-J. Gu
Key Laboratory of Comprehensive Utilization of Mineral Resources
in Ethnic Regions, Yunnan Minzu University
Yunnan Minzu University, Kunming, Yunnan, 650500 (P. R. China)
E-mail: gulijun2005@126.com
bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene
(IPr,
ligand, 6 mol %) in THF at 408C, the desired benzophenone
3aa was formed in 43% yield (Table S1, entry 1). The benzyl
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500560.
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Communication
benzoate by-product (4a) was obtained in 31% yield (Table S1,
entry 1). After considerable effort, we found that hexafluoro-
acetone showed a remarkable enhancement in rate and selec-
tivity for the formation of 3aa (Table S1, entries 1–5). Different
fected the yield (Table 1, entry 3), further extending the scope
of this methodology. Aromatic aldehyde 1j with a naphthyl
group also participated in this Ni-catalyzed cross-coupling re-
action, affording the product in 75% yield (Table 1, entry 4).
Unfortunately, an aliphatic aldehyde did not deliver the corre-
sponding ketone under the same reaction conditions (Table 1,
entry 5).
Ni catalysts were screened and Ni(cod) (cod=1,5-cycloocta-
2
diene) turned out to be the most effective catalyst (Table S1,
entries 4 and 6–9). Other ligands, including phosphorus tricy-
clohexyl (PCy ), 1,3-di-tert-butylimidazol-2-ylidene (ItBu), and
The cross-coupling method was also successfully applied to
a variety of boronic esters 2. As shown in Table 2, a broad
range of boronic esters 2 reacted smoothly with 1a to give
the corresponding aryl ketones in good yields. For example, ar-
3
1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (SIPr), were
tested and found to be less effective than IPr (Table S1, en-
tries 10–12). Of the solvents tested, THF proved particularly
suitable (Table S1, entries 13–15). However, the reaction did
not take place in the absence of a Ni catalyst (Table S1,
entry 16).
[a]
Table 2. Scope of boronic esters.
Next, we used the optimal reaction conditions to extend the
substrate scope by using a series of alternative aryl aldehydes
1
. As summarized in Table 1, the standard reaction conditions
Entry
1
Boronic ester 2
Ketone 3
Yield
[
a]
Table 1. Scope of aromatic aldehydes.
[b]
[%]
2
2
2b: R =p-Me
3ba: R =p-Me
62
69
57
65
70
78
2
2
2
2
2
2
c: R =p-OMe
3ca: R =p-OMe
1
2
d: R =p-F
3da: R =p-F
2
2
e: R =p-Ph
3ea: R =p-Ph
2
2
f: R =p-Me
3 fa: R =p-Me
2
2
Entry
1
Aromatic aldehyde 1
1b: R=p-Me
Ketone 3
Yield
2g: R =m-Me
3ga: R =m-Me
[b]
[
%]
3ab: R=p-Me
3ac: R=p-OMe
3ad: R=p-F
76
71
74
63
55
60
66
2
3
4
66
73
79
1
1
1
1
1
1
c: R=p-OMe
d: R=p-F
e: R=p-Cl
3ae: R=p-Cl
f: R=p-CO
g: R=o-Me
h: R=m-Me
2
Me
3af: R=p-CO
3ag: R=o-Me
3ah: R=m-Me
2
Me
2
3
70
54
[
(
a] Reaction conditions: 1a (0.3 mmol), 2 (0.3 mmol), hexafluoroacetone
1.5 equiv), Ni(cod) (5 mol %), IPr (6 mol %), THF (2 mL), 408C, in Ar at-
2
mosphere for 10 h. [b] Isolated yield.
4
5
75
0
ylboronic esters bearing electron-rich (methoxy, methyl) and
electron-deficient (halogen, phenyl) substituents on the aryl
ring underwent this reaction to give the corresponding prod-
ucts in generally moderate to good yields (57–79%). Substitu-
ents at the ortho-, meta-, or para-positions had no distinct in-
fluence on the reaction. For example, substrates 2b, 2 f, and
[a] Reaction conditions: 1 (0.3 mmol), 2a (0.3 mmol), hexafluoroacetone
(1.5 equiv), Ni(cod) (5 mol %), IPr (6 mol %), THF (2 mL), 408C, in Ar at-
2
2
g with a Me group were transformed into products 3ba, 3 fa,
mosphere for 10 h. [b] Isolated yield.
and 3ga, respectively, with similar yields. Notably, the introduc-
tion of heterocycles into this system made this methodology
more useful for the preparation of pharmaceuticals and materi-
als (Table 2, entry 2). Efforts were made to apply this methodol-
ogy to the synthesis of aryl alkyl ketones; it was found that re-
actions with 2i–2j proceeded smoothly to give the aryl alkyl
ketones 3ia–3ja in good yields (Table 2, entries 3 and 4).
To gain an insight into the course of the reaction, we con-
ducted a series of control experiments. In the absence of a bor-
onic ester, we observed decarbonylation of benzaldehyde 1a
were found to be compatible with a wide range of aryl alde-
hydes 1. These results showed that the cross-coupling reaction
can be realized in good yields irrespective of the nature and
the position of the aryl substituents of substrate 1. Interesting-
ly, the polysubstituted aromatic aldehyde 1i gave the desired
product 3ai in a good yield (Table 1, entry 2). Notably, the re-
placement of the benzyl moiety by a 2-furanyl group hardly af-
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Communication
and materials applications. This method offers
marked improvements in terms of operational sim-
plicity, reaction conditions, general applicability, and
good isolated yields of products.
Experimental Section
General procedure
An oven-dried Schlenk tube (10 mL) was charged with
aryl aldehyde 1 (0.3 mmol), boronic ester 2 (0.3 mmol),
hexafluoroacetone (0.45 mmol), Ni(cod)2 (5 mol %), IPr
(6 mol %), and THF (2 mL). Then, the tube was charged
with argon and stirred at 408C for about 10 h. After the
reaction was complete, the reaction mixture was diluted
with EtOAc (5 mL). The solution was filtered through a celite pad
and washed with EtOAc (15–20 mL). The organic portion was
washed with a saturated solution of brine (3”8 mL), dried
Scheme 2. Experiments for mechanistic studies.
to produce benzene and reduction of hexafluoroacetone
[
12]
(Scheme 2a).
This result supports the intermediacy of an
acyl nickel hydride species, which can undergo decarbonyla-
tion in the absence of a boronic ester. When a 1:1 mixture of
(
Na SO ), and concentrated in vacuum. The resulting residue was
2 4
purified by silica gel column chromatography (hexane/ethyl ace-
tate) to provide the desired product 3.
1
a and [D ]-1a was subjected to the Ni-catalyzed cross-cou-
6
pling reaction conditions, we obtained the cross-coupling
[
13]
products 3aa and [D ]-3aa in a ratio of 5.7:1. The result sug-
5
gests that CÀH bond activation is rate-determining Acknowledgements
Scheme 2b). Computational studies by Fu and co-workers
support the concept of electron-deficient p-ligands on nickel
(
We are grateful for financial support from the Program for In-
novative Research Team (in Science and Technology) in Univer-
sity of Yunnan Province (IRTSTYN 2014-11) and the State Ethnic
Affairs Commission (12YNZ05).
[
14]
promoting oxidative addition into aldehyde CÀH bonds.
On the basis of these preliminary results, and those of previ-
ous studies, we propose the mechanism shown in Scheme 3.
Hexafluoroacetone binds to nickel to form complex A, which
Keywords: aryl ketones · CÀC bond formation · N-heterocyclic
carbenes · nickel
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Received: February 10, 2015
Published online on April 29, 2015
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