Rhodium-Catalyzed Direct C-H Bond Cyanation in Ionic Liquids

Article abstract of DOI:10.1021/acs.orglett.8b01952

A Cp?Rh(III)/IL-based direct C-H bond cyanation system was developed for the first time. The system is a mild, efficient, and recyclable method for the synthesis of aryl nitriles. Many different directing groups can be used in this cyanation, and the reaction tolerates a variety of functional groups.

Full text of DOI:10.1021/acs.orglett.8b01952

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Direct C‑H Bond Cyanation in Ionic Liquids
Songyang Lv, Yaling Li, Tian Yao, Xinling Yu, Chen Zhang, Li Hai,* and Yong Wu*
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, Chengdu 610041, P. R. China
S
* Supporting Information
ABSTRACT: A Cp*Rh(III)/IL-based direct C-H bond
cyanation system was developed for the first time. The system
is a mild, efficient, and recyclable method for the synthesis of
aryl nitriles. Many different directing groups can be used in
this cyanation, and the reaction tolerates a variety of
functional groups.
ryl nitriles are a class of important compounds that are
widely encountered as key structural features in drugs,
agrochemicals, and natural products. For example, Neratinib is
an anticancer drug and Etravirine is an effective anti-HIV drug
(Figure 1).1 In addition, the cyano functional group as a valuable
Scheme 1. Strategies for the Synthesis of Aryl Nitriles
A
Figure 1. Representative important nitrile-containing molecules.
intermediate can be readily derivatized into various important
functional groups such as carboxyl derivatives, aldehydes,
amines, and heterocycles.2 Thus, developing methods for the
synthesis of cyano aromatics is of great interest to chemists.
Traditionally, cyanations are achieved through the Rose-
nmund−von Braun reaction or the Sandmeyer reaction
(Scheme 1a),3 which both require tedious workup and
stoichiometric amounts of CuCN. Cross-coupling cyanations
of aryl (pseudo)halides were developed to solve the problems
mentioned above, but those reactions require preactivated
arenes or produce halogen byproducts (Scheme 1b).4 To
overcome these issues, transition-metal-catalyzed direct C-H
bond cyanation reactions have become an attractive, efficient,
and user-friendly alternative for the synthesis of aromatic
cyanides, and a range of ecofriendly cyanating agents were
successfully developed for these processes (Scheme 1c).5
Although C-H bond cyanations have already made significant
advances, harsh reaction conditions (heating over 100 °C) and
the use of nonrecyclable reaction systems limit their practical
application. Hence, a mild, efficient, and recyclable strategy is
still highly desired to facilitate cyanations in organic synthesis.
In recent years, ionic liquids (ILs) have been widely used as
stable and recyclable reaction media and catalysts in organic
synthesis. Compared with traditional organic agents, ILs have
unique advantages such as low melting points, negligible vapor
pressures, low toxicities, high conductivities, and excellent
chemical and thermal stability, and they are also easy to recycle
and can readily dissolve many organic and inorganic
compounds.6 To date, ILs have been successfully applied in
Suzuki, Heck, Wittig, and Friedel−Crafts reactions, Michael
additions, Diels−Alder cycloadditions, and stereoselective
halogenations.7 However, their application in C-H activation
cyanations has not been reported. Considering recent develop-
ments and our previous work in Rh-catalyzed ortho-cyanations
of 2-aryl-1,2,3-triazole,8 we describe a direct C-H bond
cyanation strategy using a mild, efficient, and recyclable
Cp*Rh(III)/IL system.
Received: July 6, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01952
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
At the start of our investigation, the Rh-catalyzed C-H bond
cyanation of 2-phenylpyridine (1a) with N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS, 2) was studied as a model reaction.
When 1-butyl-3-methylimidazolium bis(trifluoromethane-
sulfonyl)imide ([BMIM]NTf2) was used as the reaction
medium, desired ortho-cyanide product 3a was obtained in
58% yield (Table 1, entry 1). To optimize the yield of 3a, we
Scheme 2. Scope of 2-Phenylpyridines
a
Table 1. Optimization of the Reaction Conditions
b
time
(h)
yield
(%)
entry
cat. (5 mol %)
ILs
1
2
3
4
[Cp*RhCl2]2
Cp*Rh(OAc)2
RhCl3·H2O
[Cp*Rh(Me
-CN)3](SbF6)2
[BMIM]NTf2
[BMIM]NTf2
[BMIM]NTf2
[BMIM]NTf2
24
24
24
24
58
trace
NR
52
5
6
7
8
9
10
11
12
13
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[BMIM]OTf
[BMIM]BF4
24
24
24
24
24
48
72
48
48
54
49
45
trace
trace
66
67
73
78
[BDMIM]BF4
[MTMG]BF4
[BTMG]NTf2
[BMIM]NTf2
[BMIM]NTf2
[BMIM]NTf2
[BMIM]NTf2
c
c,d
a
Reaction conditions: 2-phenylpyridine (1a, 0.10 mmol), NCTS (2
0.15 mmol), cat. 5 mol % AgNTf2 (0.03 mmol), AgOAc (0.05 mmol),
b
and IL 0.3 mL. Isolated yield by chromatography on silica gel.
AgOAc 0.10 mmol. NCTS 0.20 mmol. Cp* = pentamethylcyclo-
pentadienyl; [BMIM] = 1-butyl-3-methylimidazolium; [BDMIM] =
1-butyl-2,3-dimethylimidazolium; [MTMG] = N,N,N′,N′,N′-pentam-
ethyl-quinone; [BTMG] = N,N,N′,N′-tetramethyl-N″-butylhydrazine.
a
c
d
(a) Reaction conditions: 2-phenylpyridine 1 (0.30 mmol), NCTS (2,
0.60 mmol), 5 mol % [Cp*RhCl2]2, AgNTf2 (0.09 mmol), AgOAc
(0.30 mmol), and [BMIM]NTf2 (0.5 mL), 30 °C for 48 h. The
product yields were determined following column chromatography.
(b) NCTS (2, 0.90 mmol). (c) Temp = 50 °C. (d) Temp = 80 °C.
screened several parameters, and the results are shown in Table
1. It was found that [Cp*RhCl2]2 showed better catalytic activity
than other Rh(III) catalysts (entries 1−4). Then, combinations
of anions and cations for the ionic liquids were explored (entries
5−9). Notably, only ILs with imidazolium as the cation were
effective, and [BMIM]NTf2 afforded the best result. Extending
the reaction time to 48 h increased the yield, but further
prolonging the reaction time to 72 h had no effect on the
reaction outcome (entries 10−11). In addition, increasing the
amount of NCTS and silver salt improved the yield to 78%
(entries 12−13). Furthermore, other catalysts and additives
were also screened, but no better results were found (Supporting
Information (SI), Table S1). Accordingly, the reaction
conditions were optimized to the following: 1.0 equiv 2-
phenylpyridine, 2.0 equiv NCTS, 5 mol % [Cp*RhCl2]2, 0.3
equiv AgNTf2, and 1.0 equiv AgOAc in [BMIM]NTf2 at 30 °C
for 48 h.
With the optimized reaction conditions in hand, the C-H
bond cyanation of 2-phenylpyridines was examined. The results
are shown in Scheme 2. Unsubstituted 2-phenylpyridine 1a gave
78% isolated yield of 3a, and the 4′-Me and 5′-Me derivatives
gave slightly increased yields of 3c and 3i, i.e., 81% and 80%,
respectively. In contrast, the 6′-Me derivative only afforded a
70% isolated yield of 3b. This result was probably because the
steric hindrance from the 6′-Me group interferes with the
formation of the product. Both electron-donating and -with-
drawing groups can tolerate this reaction, and it was
demonstrated by the isolation of 82% of 3l and 66−70% of
3e−g. Halogen substituents were well tolerated in this process,
and there was a positive correlation between conjugation and
yield. When the 2-phenyl moiety was replaced with 2-biphenyl,
2-naphthyl, and 2-thienyl groups, the yields of 3m−o were
significantly increased compared to that of 3a. Interestingly,
when the 2-aromatic ring was replaced with a 2-aliphatic ring
such as 2-cyclohexenyl, the cyanation still proceeded and
afforded 3p in 73% yield. This result showed that this reaction
was not limited to direct aromatic functionalizations but can also
be applied to aliphatic alkenes. It is worth noting that changing
the directing group (DG) to other N-heterocycles such as
pyrimidine, pyrazole, and triazole can also successfully afford
cyanide products through this strategy (3q−v). Notably,
pyrimidine-substituted substrates afforded mixtures of the
mono- and biscyanide products, but 1q and 1r remained.
Increasing the equivalents of NCTS (2) afforded exclusively
biscyanide products 3q and 3r. In all cases, this strategy showed
a wide substrate scope with mild conditions and high efficiency
under the optimized conditions.
Encouraged by these initial findings, we sought to further
define the scope of this reaction. The feasibility of using an
oxime, a commonly used DG, was also examined in this
cyanation (Scheme 3). Fortunately, 1-phenyl-O-methyloxime
B
DOI: 10.1021/acs.orglett.8b01952
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Organic Letters
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a
Scheme 3. Scope of Aryl Ketone Oxime Ethers
Figure 2. Recycling study results.
To elucidate the mechanism of this reaction, a series of
experiments were conducted.9,10 The H/D exchange experi-
ment was performed by treating 1a with CD3OD in [BMIM]-
NTf2. The 1H NMR spectrum showed that 40% of the ortho-C-
H bond in 1a was deuterated after 4 h, which suggested that the
C-H activation was reversible (Scheme 5a). The intermolecular
Scheme 5. Mechanistic Studies
a
Reaction conditions: aryl ketone oxime 4 (0.30 mmol), NCTS (2,
0.60 mmol), 5 mol % [Cp*RhCl2]2, AgNTf2 (0.09 mmol), AgOAc
(0.30 mmol), and [BMIM]NTf2 (0.5 mL), 30 °C for 48 h. The
product yields were determined following column chromatography.
led to 80% isolated yield of 5a. Various common functional
groups, including methyl, methoxy, halogens, and even nitro
moieties, were well tolerated and furnished the corresponding
products in good to excellent yields (5b−k). As the amount of
conjugation was increased, the cyanation reaction afforded
higher yields of the products (5l, 5m). The steric hindrance from
the oxime ethers decreased the yields of 5n and 5o, and product
5p was not observed. Our data indicated that O-methyl oxime
ethers served as viable substrates in this reaction (65−88% yield
of 5a−o). Compared with N-heterocycles, oxime ethers are
useful groups for additional functionalization steps and have
more potential applications.5c,10
To investigate the efficiency and further practicality of this
transformation, a 10-fold scale-up of the reaction using 4d and 2
was performed. The desired product 5d was isolated in 87%
yield. Pleasingly, when the amount of the catalyst was decreased
to 2.5 mmol %, 5d was also obtained in 81% yield after stirring
for only 24 h (Scheme 4). On this basis, we further investigated
competition experiment between 1c and 1f highlighted an
obvious preference for electron-rich substrate 1c in the C-H
bond cyanation reaction (Scheme 5b). The kinetic isotope effect
was also measured from experiments conducted under identical
conditions using 1a and d5-1a with NCTS (2) as the coupling
partner. A value of kH/kD = 2.8 was obtained. This indicates that
the C-H bond cleavage occurs during the rate-determining step
(Scheme 5c).
Scheme 4. 10-Fold Scale-up Reaction and the Study of the ILs
Reaction System Reusability
On the basis of the above results and previous related
studies,5c,7g,h,8 a possible mechanism for this C-H cyanation is
given in Scheme 6. First, treatment of the Rh precursor with
AgOAc generates reactive cationic Rh species A. This reacts with
2-phenylpyridine 1a to afford cyclic Rh species B with a vacant
coordination site. B reacts with 2 to form tight transition states
C. C is the key intermediate in this reaction. Subsequently,
transition states C lead to product 3a and rhodium complex D.
Finally, in the presence of protons, active Rh species A is
obtained and participates in the next catalytic cycle.
the reusability of the catalyst and solvent. The yields of product
5d determined following column chromatography are shown in
Figure 2. The reusability of the ionic liquid reaction system
(without adding fresh Rh catalyst) was studied for five cycles,
and only a marginal decrease in the yield of the desired product
was observed. These results strongly suggested that the ILs were
indeed an easily recycled reaction medium.
C
DOI: 10.1021/acs.orglett.8b01952
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Organic Letters
Letter
ORCID
Scheme 6. Proposed Mechanism
Yong Wu: 0000-0003-0719-4963
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
(NSFC) (grants 81573286, 81773577) for financial support.
■
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b01952.
(11) (a) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J.
Chem. Soc. Rev. 2016, 45, 2900. (b) Wencel-Delord, J.; Droge, T.; Liu,
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F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740.
Experimental details and characterization of new
compounds (1H, 13C, 19F NMR spectra) (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*(Y.W.) E-mail: wyong@scu.edu.cn.
*(L.H.) E-mail: smile@scu.edu.cn.
D
DOI: 10.1021/acs.orglett.8b01952
Org. Lett. XXXX, XXX, XXX−XXX