Rhodium-catalyzed directed C-H cyanation of arenes with N-cyano-N-phenyl-p-toluenesulfonamide

Article abstract of DOI:10.1021/ja405742y

A Rh-catalyzed directed C-H cyanation reaction was developed for the first time as a practical method for the synthesis of aromatic nitriles. N-Cyano-N-phenyl-p-toluenesulfonamide, a user-friendly cyanation reagent, was used in the transformation. Many different directing groups can be used in this C-H cyanation process, and the reaction tolerates a variety of synthetically important functional groups.

Full text of DOI:10.1021/ja405742y

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Directed C−H Cyanation of Arenes with N-
Cyano‑N‑phenyl‑p‑toluenesulfonamide
Tian-Jun Gong,†,∥ Bin Xiao,†,∥ Wan-Min Cheng,† Wei Su,† Jun Xu,† Zhao-Jing Liu,† Lei Liu,‡,§
and Yao Fu*,†
†Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
‡Department of Chemistry, Tsinghua University, Beijing 100084, China
§State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000 Lanzhou, China
S
* Supporting Information
C−H cyanation with NCTS. Significantly, many different
ABSTRACT: A Rh-catalyzed directed C−H cyanation
reaction was developed for the first time as a practical
method for the synthesis of aromatic nitriles. N-Cyano-N-
phenyl-p-toluenesulfonamide, a user-friendly cyanation
reagent, was used in the transformation. Many different
directing groups can be used in this C−H cyanation
process, and the reaction tolerates a variety of synthetically
important functional groups.
directing groups (e.g., oxime, pyridine, pyrazole) can be
employed in this new C−H cyanation reaction, and the C−H
activation process tolerates a variety of synthetically important
functional groups (e.g., sulfane, unprotected phenol, Ar−I,
epoxide) that would be challenging with other TM catalysts.
We chose the C−H cyanation of acetophenone O-methyl
oxime (1a) with NCTS as a model reaction. When 1a was treated
with [RhCp*Cl2]2, AgSbF6, and NCTS (2) in dioxane at 110 °C
for 24 h, the desired ortho-cyanated product 3a was obtained in
35% yield (Table 1, entry 1). The catalysts [RhCp*(CH3CN)3]-
(SbF6)2 and Cp*Rh(OAc)2 gave higher yields (48 and 37%,
respectively) even in the absence of AgSbF6 (entries 2 and 3).
Changing the additive to Cu(OAc)2, AgOAc, KOAc, or HOAc
diminished the reactivity (entries 4−7), whereas the use of
Ag2CO3 increased the yield to 56% (entry 8). Increasing the
reaction temperature to 120 °C further improved the yield to
he introduction of a CN group onto the aromatic rings of
Tbiologically active compounds or other functional mole-
cules may dramatically modify their properties.1 As a result, the
development of new methods to build aryl−CN bonds has been
intensively studied in synthetic organic chemistry.2 While earlier
studies in this field usually relied on the use of very toxic reagents
such as KCN, Zn(CN)2, and CuCN,3 recent attention has been
turned to more benign and user-friendly cyanation reagents such
as K3Fe(CN)6 and N,N-dimethylformamide (DMF).4 At
present, an interesting challenge is to employ these new
cyanation reagents in catalytic arene C−H functionalization
reactions.5 For instance, Cu-6 and Pd-catalyzed7 C−H cyanation
reactions of 2-arylpyridines with CH3NO2 and DMF/NH3,
respectively, as the CN source and a Pd-catalyzed 3-cyanation
reaction of indoles using DMF as the CN source8 have been
reported. However, further development of user-friendly C−H
cyanation reactions [particularly ones using other transition-
metal (TM) catalysts] is needed to expand the scope and utility
of this category of synthetically valuable transformations.
In this context, we were interested in the use of Rh catalysts for
directed cyanation of aromatic C−H bonds. Our study was
inspired by the recent reports that Rh catalysts can complement
other transition metals for C−H functionalization in terms of
selectivity, substrate scope, and functional group compatibility.9
After several attempts, we found that N-cyano-N-phenyl-p-
toluenesulfonamide (NCTS),10 a less toxic, easily handled, and
bench-stable crystalline salt, is a practical reagent for Rh-
catalyzed C−H cyanation.11 It can be readily synthesized with a
low cost via treatment of phenylurea with p-toluenesulfonyl
chloride.12 Very recently, Beller and co-workers reported
cyanation reactions of arylboronic acids and Grignard reagents
with NCTS.13 Here we describe the first example of Rh-catalyzed
a
Table 1. Optimization of the Reaction Conditions
additive
T
yield
b
entry
[Rh] (5 mol %)
[RhCp*Cl2]2
[RhCp*(CH3CN)3](SbF6)2
Cp*Rh(OAc)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
[RhCp*(CH3CN)3](SbF6)2
−
(20 mol %)
(°C)
(%)
1
2
AgSbF6
−
−
110
110
110
110
110
110
110
110
120
100
120
120
120
35
48
37
0
3
4
Cu(OAc)2
AgOAc
KOAc
HOAc
Ag2CO3
Ag2CO3
Ag2CO3
−
5
42
0
6
7
19
56
86
21
81
0
8
9
10
11
12
13
BF3·OEt2
−
−
0
a
All of the reactions were carried out with 0.2 mmol of 1a and 0.4
mmol of 2 in 1 mL of dioxane. Isolated yields.
b
Received: June 8, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja405742y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
86% (entry 9). Without Ag2CO3, the yield was slightly lower
(81%; entry 11). In view of a recent report that BF3·OEt2 can
catalyze the direct cyanation of indoles and pyrroles,11 we carried
out a control experiment showing that the present reaction does
not proceed through a Lewis acid-promoted electrophilic
aromatic substitution process (entry 12). Furthermore, without
adding Rh catalyst we obtained no product (entry 13).
glycoconjugate (3p). Finally, we were surprised to find that an
epoxide group smoothly survived the cyanation process, as
confirmed by X-ray analysis of the product (3q). This finding is
synthetically interesting because epoxides are useful groups for
additional functionalization and very few TM-catalyzed C−H
activation reactions are compatible with epoxides.
To explore the scope of other directing groups in this Rh-
catalyzed C−H cyanation process, we first tested several different
O-methyl oximes (Table 3). Both acyclic and cyclic O-methyl
With the optimized reaction conditions in hand, we examined
the effect of substrate substitution on the reaction (Table 2).
a
a
Table 2. Scope of Aryl Ketone Oximes
Table 3. Scope of Other Directing Groups
a
The reactions were carried with substrate (0.2 mmol), 2 (0.4 mmol),
[RhCp*(CH3CN)3](SbF6)2 (5 mol %), and Ag2CO3 (20 mol %). See
the Supporting Information (SI) for details.
oximes can be used in the reaction to generate the desired ortho-
cyanated products in modest to good yields (3r−v). This finding
is synthetically valuable because O-methyl oximes are derived
from ketones. More gratifyingly, other N-based directing groups
were also found to be useful in the transformation. For instance,
using pyrazole as the directing group gave the C−H cyanation
product 3w in 84% yield despite the presence of a potentially
reactive Cl in the substrate. In addition, using dihydroimidazole,
dihydrooxazole, or pyridine as the directing group also afforded
the desired products (3x−z). Our data indicate that the present
Rh-catalyzed C−H cyanation process is a rather general reaction
that can be extended to many more directing groups.
Heteroaromatic compounds are highly interesting as building
blocks in drug design. Accordingly, we were interested to see
whether the Rh-catalyzed C−H cyanation reaction could be used
to synthesize cyanated aromatic heterocycles (Table 4). We were
delighted to find that furan (4a, 4e), thiophene (4b−d, 4f),
pyrrole (4g, 4h), and indole (4j) derivatives were successfully
cyanated when a directing group (either an oxime version of the
acyl group or an N-heterocycle) was available. In the case of 4c,
cyanation occurred only at the 2-position and not at the 4-
a
Reactions were carried out at 120 °C for 24 h on a 0.2 mmol scale.
Isolated yields are shown.
First, for the O-methyl oximes of methylated acetophenones, the
4-Me derivative gave a 79% isolated yield of 3b and the 3-Me
derivative afforded the less sterically crowded isomer 3c in 94%
yield. In contrast, the 2-Me derivative gave a much lower yield of
3d (40%), possibly because the 2-Me group interfered with the
formation of the five-membered rhodacycle intermediate.14 As to
the electronic effect of the substituents, both electron-donating
(3e) and -withdrawing (3f) groups could be tolerated. Moreover,
the halogen and OTs substituents were well-compatible with the
Rh-catalyzed process (3g−k), enabling additional functionaliza-
tion at these positions. Thus, the present reaction is
complementary to previous cyanation methods involving TM-
catalyzed cross-coupling.4g,6−8
a
Table 4. Cyanation of Aromatic Heterocycles
Interestingly, when an acetamide group was present in the
substrate, the C−H cyanation reaction occurred only at the
position ortho to the oxime residue (3l). Furthermore, the
reaction tolerated an unprotected phenol group (3m). A recent
study described the Rh-catalyzed cyanation of arylboronic acids
with NCTS.13 Here we found that an N-methyliminodiacetic
acid (MIDA)-protected boronic acid15 easily survived the C−H
cyanation process to afford 3n, a MIDA boronate building block
ready for further transformations. In the case of a substrate
containing an alkyl−Cl moiety, the present cyanation reaction
selectively introduced a CN group without affecting the C−Cl
bond (3o). Such selectivity would be rather difficult to achieve
using the conventional nucleophilic cyanation reagents. We also
found that the C−H cyanation process could be applied to a
a
See the SI for details.
B
dx.doi.org/10.1021/ja405742y | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
position. Furthermore, when no directing group was present, the
C−H cyanation reaction did not take place (4i).
Scheme 4. Measurement of the Kinetic Isotope Effect
To test the application of the new C−H cyanation reaction to
complex bioactive molecules, we converted zaltoprofen (a
nonsteroidal anti-inflammatory drug) to its O-methyl oxime
methyl ester derivative 5. When 5 was subjected to the Rh-
catalyzed C−H cyanation process, we successfully obtained 6 in
74% isolated yield (Scheme 1). Significantly, although thioethers
a
Scheme 1. Cyanation of Zaltoprofen Derivative 5
a
The optimized conditions (see Table 1, entry 9) were used.
Figure 1. Proposed mechanism.
impede many TM-catalyzed reactions, the thioether moiety in 5
was well-tolerated in the Rh-catalyzed C−H cyanation process.
This result indicates that the new C−H cyanation process may be
useful for the rapid generation of derivatives of bioactive
compounds.
In a scaled-up experiment (5 mmol scale, Scheme 2), we found
that the catalyst loading could be lowered to 2 mol % while
generate five-membered rhodacycle intermediate I.18 NCTS
then coordinates to Rh(III) in I, after which insertion of the C
N moiety into the C−Rh(III) bond produces II. Finally,
elimination of a tosylaniline-coordinated Rh(III) complex from
II generates the product (3a), and the Rh(III) complex is
returned to the catalytic cycle.
Scheme 2. A Larger-Scale C−H Cyanation Reaction
To summarize, we have developed an unprecedented Rh-
catalyzed C−H cyanation reaction that uses less toxic and readily
available N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as
the cyanation reagent. This transformation extends the concept
and scope of the recently popularized Rh-catalyzed C−H
functionalization reactions. Many different directing groups
(e.g., oxime, pyridine, pyrazole) can be used in this C−H
cyanation process. The reaction also tolerates a variety of
synthetically important functional groups (e.g., unprotected
phenol, Ar−I, epoxide) that are challenging with other TM
catalysts (e.g., Pd). A number of aromatic and heteroaromatic
nitriles were successfully synthesized using the new method.
Because CN can be readily converted to many other synthetically
useful groups, the present reaction may provide a practical tool
for rapid derivatization of functional molecules.
maintaining a satisfactory yield (82%). The CN group in the
product 3a was converted to the ester and amide groups in 7 and
8 through acid and base treatments, respectively. Moreover,
product 9 obtained by C−H cyanation of 1-phenylpyrazole
(Scheme 3) was readily reduced to benzylamine 10, which was
Scheme 3. Introduction of an Aminomethyl Group
ASSOCIATED CONTENT
* Supporting Information
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
fuyao@ustc.edu.cn
previously used as a key intermediate for the development of
thrombin inhibitors.16 Thus, the Rh-catalyzed C−H cyanation
reaction is synthetically useful because CN can be readily
converted to various functional groups.
To comprehend the mechanism of the reaction, we carried out
a kinetic isotope effect (KIE) experiment.17 When a 1:1 mixture
of 1a and 1a-d5 was subjected to the Rh-catalyzed reaction
conditions, we obtained the cyanation products 3a and 3a-d4 in a
ratio of 3:1 (Scheme 4). This KIE value of 3 is typical of Rh-
catalyzed C−H activation processes.
On the basis of the above KIE experiment, we propose the
mechanism shown in Figure 1. First, the Rh(III) catalyst reacts
with the substrate (1a) through a C−H activation step (mostly
likely via a concerted metalation−deprotonation process) to
■
Author Contributions
∥T.-J.G. and B.X. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China
(2012CB215306, 2013CB932800), the NNSFC (21172209),
CAS (KJCX2-EW-J02), and the China Postdoctoral Science
Foundation (2011M500289, 2012T50078) for support.
C
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Journal of the American Chemical Society
Communication
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