Copper-catalyzed Aerobic Oxidative coupling of Aromatic Alcohols and Acetonitrile to β-Ketonitriles

Article abstract of DOI:10.1021/ol403555n

A practical, convenient, and cheap coppercatalyzed aerobic oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles has been developed. The green C-C bond formation involving the loss of two hydrogen atoms from the corresponding two carbons, respectively, unlocks opportunities for markedly different synthetic strategies.

Full text of DOI:10.1021/ol403555n

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aerobic Oxidative Coupling of Aromatic Alcohols
and Acetonitrile to β‑Ketonitriles
Jiaxuan Shen, Dejun Yang, Yuxiao Liu, Shuangshuang Qin, Jingwu Zhang, Jiangkai Sun, Chunhui Liu,
Chaoyang Liu, Xiaomei Zhao, Changhu Chu, and Renhua Liu*
School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai 200237, China
S
* Supporting Information
ABSTRACT: A practical, convenient, and cheap copper-
catalyzed aerobic oxidative coupling of aromatic alcohols and
acetonitrile to β-ketonitriles has been developed. The green
C−C bond formation involving the loss of two hydrogen
atoms from the corresponding two carbons, respectively,
unlocks opportunities for markedly different synthetic strategies.
β-Ketonitriles are very useful compounds for the synthesis of a
wide variety of heterocyclic structures, including amino-
pyrazoles,1 imidazoles,2 furans,3 thiophenes,4 and 2-pyridones.5
Moreover, they have been used as a precursor for the synthesis
of biologically and pharmacologically active compounds,6 e.g.,
anti-HCV drugs6d and inhibitors against NHE-1.6a The
frequently used methods for the preparation of β-ketonitriles
include the coupling of alkylnitriles and esters in the presence
of a strong base7or a cyanide displacement reaction with α-
bromoketones8 (Scheme 1a and b). Recently, several new
CH3ONa, NaNH2 (Scheme 1a), or hypertoxic cyanide, and/or
harsh reaction conditions, as well as a multistep preparation
process.
From a conceptual standpoint, the oxidative cross-coupling
of aldehydes/primary alcohols and unactivated simple alkylni-
triles with molecular oxygen as the oxidant should be one of the
most straightforward and greener approaches to the preparation
of β-ketonitriles, as the catalytic methods avoid the use of
highly toxic cyanide salts, display high atom economy, and
release only innocuous H2O as the byproducts (see Scheme 2).
Scheme 1. Synthetic Methods of β-Ketonitriles
Scheme 2. An Ideal Approach to β-Ketonitriles
Recently, the catalytic C−C coupling of alcohols has received
great attention for both economic and environmental
benefits.12 However, reports on the oxidative C−C cross-
coupling of alcohols and alkylnitriles are scarce. The C−C
cross-coupling faces two major challenges: deprotonation of
unactivated simple alkylnitriles, such as acetonitrile (pKa = 31.3
in DMSO) and the lack of efficient leaving functionalities of the
alcohol partner for traditional C−C cross-coupling reactions.
To solve the problem of deprotonation of acetonitrile for
cyanomethylation of carbonyl substrates, attempts to circum-
vent the deprotonation of acetonitrile by a functionalized
acetonitrile, Me3SiCH2CN, have been reported.13 Another
alternative solution to deprotonation of acetonitrile for
cyanomethylation of carbonyl substrates is transition-metal
catalysis, in which a relatively weak base can be used to
deprotonate acetonitrile. These transition metals mainly include
copper,14 nickel,15 rhodium,16 or ruthenium.17 To obtain the
solution to the lack of efficient leaving functionalities of an
alcohol partner, efforts to activate the C−H bond of aldehydes
methods have been developed. Ganesan reported a method
involving the C-arylation of resin-bound cyanoacetates.9Yoo
and co-worker developed a method that included the indium-
mediated coupling of bromoacetonitriles with cyanides.10 Lee
and co-worker developed a method utilizing the Pd-catalyzed
carbonylation of aryl iodides, trimethylsilylacetonitrile, and
carbonic oxide (or Mo(CO)6) to produce β-ketonitriles11
(Scheme 1c). However, these methods suffer from several
drawbacks such as the need for a strong base, e.g. KOt-Amyl,
Received: October 24, 2013
© XXXX American Chemical Society
A
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Letter
a
with stoichiometric amounts of oxidants for C−C cross-
coupling reactions have been made,18 but the examples with
molecular oxygen as the terminal oxidant under mild conditions
are still scarce. A survey of the literature reveals that no such
oxidative C−C cross-coupling methods for the synthesis of β-
ketonitriles have hitherto been reported. Herein we describe
the discovery and development of a cheap and convenient
copper catalyst system for the oxidative cross-coupling of
aromatic alcohols and acetonitrile to β-ketonitriles with
molecular oxygen as the oxidant under mild conditions
(Scheme 1d).
The investigation began by attempting the aerobic oxidation
of alcohols to the aldehydes using copper as the catalyst. When
a benzyl alcohol was used as the substrate with CuCl2 as the
catalyst, acetonitrile as the solvent, and KOH as a base, we were
surprised to find that CuCl2 could catalytically couple benzyl
alcohol with acetonitrile to afford β-ketonitriles in the presence
of molecular oxygen. To the best of our knowledge, such an
aerobic oxidation has never been reported to date. Thus the
unexpected finding promoted us to further investigate the
reaction.
We chose benzyl alcohol (1a) and acetonitrile (2) as
representative substrates to systematically screen the reaction
conditions. The results were summarized in Table 1. As can be
seen, a base additive is required to achieve the oxidation
conversion. However, it is not the fact that the stronger bases
reach the higher yields of reactions. When strong bases, such as
t-BuOK and NaH, were used, the yields of 3a were 60% and
66%, respectively (Table 1, entries 1 and 3). In fact, potassium
hydroxide, an easily available and inexpensive modest strong
base, resulted in an 86% isolated yield of 3a (Table 1, entry 8)
in the oxidation reactions. The effects of different solvents were
also evaluated. Strong polar aprotic solvents are generally
effective for the oxidative conversion of benzyl alcohol and
acetonitrile to the desired β-ketonitrile. In contrast, weak polar
aprotic solvents, e.g. toluene, are unfavorable to the reaction.
The observations could be rationalized in terms of the KOH
having relatively high solubility in a strong polar aprotic solvent.
A variety of metal salts were screened for their ability to
promote the oxidative cross-coupling reactions. Copper
chloride displayed relatively high catalytic activity in facilitating
the oxidative cross-coupling of benzyl alcohols and acetonitrile
to the corresponding β-ketonitrile with molecular oxygen.
Adversely, FeCl3 and CoCl3·6H2O were totally ineffective
(Table 1, entries 17 and 18). Considering CuCl2 may react with
KOH to generate Cu(OH)2 or CuO in the reaction system, we
directly chose Cu(OH)2 and CuO as the catalysts to perform
the reaction under the standard reaction conditions, and the
results showed no desired products were generated. Thus the
optimal reaction conditions were considered to included benzyl
alcohols (1 equiv), CH3CN (10 equiv), CuCl2 (1 mol %),
KOH (3 equiv), and DMA as the solvent at room temperature
for 12 h.
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
CuCl2
base
solvent
yield (%)
c
1
t-BuOK
CH3ONa
NaH
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMSO
DCM
toluene
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
60
14
66
77
58
c
2
CuCl2
c
3
CuCl2
c
4
CuCl2
KOH
NaOH
Cs2CO3
LiOH
KOH
KOH
KOH
−
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
c
5
CuCl2
c
d
6
CuCl2
n.d.
c
d
7
CuCl2
n.d.
8
CuCl2
CuCl2
95(86)
e
9
85
d
10
11
−
CuCl2
n.d.
d
n.d.
f
d
12
CuCl2
n.d.
13
14
15
16
17
18
19
20
21
22
23
24
25
26
CuCl2
88
10
CuCl2
d
CuCl2
n.d.
d
CuCl2
n.d.
d
FeCl3
n.d.
d
CoCl3·6H2O
CuSO4
CuI
n.d.
g
20
g
19
g
Cu(OTf)2
CuBr2
69
g
60
g
CuBr
69
g
Cu(OAc)2·2H2O
Cu(OH)2
CuO
77
d
n.d.
d
n.d.
a
Conditions: 1a (1 mmol), 2 (10 mmol), catalyst (1 mol %), base (3
b
mmol), solvent (10 mL), O2 balloon, rt, 12 h. GC yield based on 1a
c
used; the number in parentheses shows isolated yield. Base (2 mmol)
d
e
was used. No product was detected by GC. Base (4 mmol) was used.
f
g
Nitrogen balloon. Isolated yield.
oxidative cross-coupling only achieved 45% yields when the
aromatic ring was substituted by two bromide atoms (3k).
However, the compound 3s was not obtained when an iodide
was present on the aromatic ring of benzylic alcohol (3s). The
benzylic alcohols substituted by electron-donating groups are
generally conducive to the oxidation reaction, but substrates
that have strong electron-drawing groups on the aromatic ring
remained unreactive (3r). It is noteworthy that oxygen- and
sulfur-containing compounds, which are usually regarded as
difficult substrates in most aerobic oxidations involving
transition metals due to their strong coordinating ability to
transition metals, were also very smoothly converted into the
corresponding β-ketonitriles with high isolated yields (3l−3p).
Unfortunately, and despite extensive efforts, primary aliphatic
alcohols remained elusive recalcitrant substrates. The use of an
aliphatic aldehyde in place of the corresponding alcohol as the
substrate still remained unreactive. For the nitrile partner,
propionitrile was examined and the results showed they do not
lead to the desired products. Curiously, activated malononitrile,
ethyl cyanoacetate, and benzyl cyanide that are apt to
deprotonate the α-CH protons under basic conditions do not
work.
Having established the optimal conditions for the CuCl2-
based catalysis, we next examined the range of aromatic
alcohols to which this catalytic aerobic oxidation could be
applied, and the results are summarized in Scheme 3. Several
features of this simple inexpensive yet robust system are worth
noting. First, the catalytic system is able to be effectively applied
to a wide range of aromatic alcohols for the synthesis of β-
ketonitriles under mild conditions. The substrates containing a
halogen, such as fluorine, chloride, or bromide, on the aromatic
ring provided very high isolated yields (3e−3j), but the
B
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were not generated. The base-catalyzed aldol condensation of
acetonitrile and benzaldehydes to compound A, a reaction
without dioxygen, did not occur. Moreover, intermediate A was
not detected during all the aerobic oxidations either. Thus route
I should be unreasonable. The negative results toward the aldol
condensation of acetonitrile and benzaldehydes may be
attributed to the alkalinity of KOH being not strong enough
to effectively deprotonate acetonitrile to result in the aldol
condensation reactions. Recognizing that the incorporation of
molecular oxygen into the reaction system has been the
keystone for the aerobic oxidations, we proposed route II as the
mechanism of the oxidative cross-coupling reaction. In route II,
the reactions may proceed via an oxidation of the
benzaldehydes to intermediate B with active oxidant C, and
then the intermediate B was further oxidized by Cu(II)
compound D to generate target β-ketonitrile compounds.
Molecular oxygen was activated by compound D to generate
active oxidant C, and the latter could oxidize benzaldehydes to
B and H2O2. Compound D, derived from CuCl2, KOH, and
CH3CN, fulfilled the oxidation of B to target β-ketonitriles. The
formation of compound D from CuCl2, KOH, and CH3CN is
reasonable as the Lewis acidic copper center would lower the
pKa value of acetonitrile substantially once it is coordinated.
Although no direct evidence was obtained to verify the
oxidation of B with compound D, several reports on copper(II)
salts oxidizing a benzyl free redical have provided useful insights
for understanding the current reaction mechanism.19
Scheme 3. Generalization to Substituted Aromatic Alcohols
with Acetonitrile
a
In conclusion, we have developed an efficient method for the
synthesis of β-ketonitriles from aromatic alcohols and
acetonitrile using easily available CuCl2 as the catalyst and O2
as the oxidant without any ligands under mild reaction
conditions. A plausible overall mechanism described here is
expected to help tailor other catalysts and substrates, so as to
develop more efficient catalytic processes.
a
Conditions: 1 (1 mmol), 2 (10 mmol), catalyst (1 mol %), base (3
b
mmol), DMA (10 mL), O2 balloon, rt, 12 h. Benzaldehyde as
substrate. Yield refers to isolated yields.
In the present case, a detailed mechanism for the overall
catalytic process cannot yet be described, but an outline of a
potential mechanism may be deduced (see Scheme 4) based on
ASSOCIATED CONTENT
■
S
* Supporting Information
Scheme 4. Probable Reaction Mechanism
Experimental procedures, characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liurh@ecust.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (No. 21072055) and the National High
Technology Research and Development Program of China
(863 Program) (No. 2008AA06Z306).
the existing experiment results. At first, the benzyl alcohols
were oxidized to the benzaldehydes by the catalytic system;
indeed, we detected the generation of benzaldehydes during the
reaction. Moreover, when benzaldehydes were used to replace
the corresponding benzyl alcohols to perform the oxidation
reactions, we obtained the same β-ketonitrile products with the
same high yields (Scheme 3, condition b). Thus cyanomethy-
lation of aldehydes with acetonitrile is the key to understanding
the reaction mechanism. Route I was first considered; however,
the experimental results did not support this thinking. We have
carried out the reaction with benzaldehydes and acetonitrile
under standard reaction conditions with the only variance being
the use of N2 in place of O2, and the results showed that both
compound intermediate A and target compound β-ketonitriles
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