Rhodium(III)-catalyzed cyanation of vinylic C-H bonds: N-cyano-N-phenyl-p-toluenesulfonamide as a cyanation reagent

Article abstract of DOI:10.1039/c4cc09790d

Rh(iii)-catalyzed direct vinylic C-H cyanation reaction has been developed as a practical method for the synthesis of alkenyl nitriles. N-Cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS), a user-friendly cyanation reagent, was used in the transformation.

Full text of DOI:10.1039/c4cc09790d

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Rhodium(III)-Catalyzed Cyanation of Vinylic C-H Bonds: N-Cyano-N-
Phenyl-p-Toluenesulfonamide as Cyanation Reagent
§
§
Wei Su , Tian-Jun Gong , Bin Xiao and Yao Fu*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, China
5
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
Rh(III)-catalyzed directed vinylic C-H cyanation reaction
has been developed as a practical method for the synthesis
compatibility.[10-12] This result led us to attempt the direct
cyanation of vinylic C-H bonds. Here in, we describe a highly
1
0
of
alkenyl
nitriles.
N-cyano-N-phenyl- 45 efficient and selective Rh(III)-catalyzed direct intermolecular
p-methylbenzenesulfonamide (NCTS),
a
user-friendly
C-H cyanation of acrylamides and ketoximes using
cyanation reagent, was used in the transformation. Both
acrylamides and ketoximes can be employed in the new
C-H cyanation process.
N-cyano-N-phenyl-p-toluenesulfonamide.
Initially, we chose N,N-diisopropyl-2-phenylacrylamide (1a)
and N-cyano-N-phenyl-p-toluenesulfonamide (2, NCTS) as
1
2
2
3
3
5
0
5
0
5
Nitriles are versatile building blocks in the synthesis of natural 50 model substrates to screen the reaction conditions. When 1a (0.1
products and pharmaceuticals.[1] Moreover, nitriles can be easily
transformed to a series of functional groups, such as amines,
aldehydes, amidines, tetrazoles, and amides.[2] As a result, the
methods to build the R-CN bonds have been intensively studied
mmol)
RhCp*(CH
and
CN)
2
(SbF
(0.2
mmol)
was
treated
with
o
3
3
6
)
2
(5 mol%) in DCE at 120 C for 24 h, we
were disappointed to find that we failed to obtain any desired
product 3a (entry 1, Table 1). Fortunately, when catalytic amount
in synthetic organic chemistry. The early synthetic efforts for the 55 of base NaOAc (20 mol%) to the reaction, we got desired product
preparation of organonitriles included two traditional methods
3a in 80% yield (entry 3). The acid HOPiv completely suppressed
such as the Sandmeyer reaction and Rosenmund−von Braun
the reaction (entry 4). To further improve the yield, the
[
3]
reaction. Recently, a variety of protocols on the basis of
transition metal-catalyzed cyanation of halides, pseudohalides
and metallic reagents have been developed.[4] In contrast, direct 60 on the cyanation reaction. Reduced yields were gained in other
combination of NaOAc and Ag
2 3
CO improved the yield to 88%
(entry 5). Subsequently, we investigated the effect of the solvent
cyanation through C-H bond functionalization is more attractive
due to the conciseness of the synthetic route without
pre-functionalization (Scheme 1).[5-8] For instance, Yu, Chang and
Jiao respectively reported Cu- or Pd-catalyzed C-H cyanation of
solvents, such as toluene and 1,4-dioxane (entry 6, 7). The
combination of [RhCp*Cl and AgSbF displayed similar
reactivity to catalyze the C-H cyanation reaction (entry 8).
Additionally, we carried out a control experiment (entry 9) that
2
]
2
6
[
7]
arenes. Notwithstanding these pioneering examples involving 65 showed the present reaction does not proceed smoothly when
C-H cyanation of arenes under the assistance of various directing
groups, few examples have been reported to access
alkenyl-nitriles via C-H bond cleavage. The alkenylnitrile is
highly versatile and widely represented in important dyes,
herbicides and natural products.[9]
2 2
[Ru(p-cymene)Cl ] replaced Rh(III) catalyst. No product was
obtained in the absence of Rh catalyst (entry 10).
[
8]
a
Table 1. Optimization of the reaction conditions
f
b
entry
Additive
—
NaHCO
NaOAc
Solvent
DCE
DCE
DCE
DCE
Yield (%)
trace
58
1
2
3
4
5
6
7
3
80
HOPiv
trace
88(82)
67
75
85
NaOAc+AgCO
NaOAc+AgCO
NaOAc+AgCO
NaOAc+AgCO
NaOAc+AgCO
3
3
3
3
3
DCE
Toluene
dioxane
DCE
DCE
DCE
c
Scheme 1. Transition Metal-Catalyzed C-H Cyanation.
8
9
d
15
0
e
Recently we reported a Rh(III)-catalyzed directed arene C-H
10
NaOAc+AgCO3
a
cyanation using N-Cyano-N-phenyl-p-toluenesulfonamide (NCTS) 70
Reaction conditionsc: acrylamide 1a (0.1 mmol), 2 (0.2 mmol),
RhCp*(CH CN) (SbF (10 mol%), additive (20 mol%), solvent (0.5 ml),
20 C, Ar. Determined by GC analysis. The yield in parenthesis is
isolated yield. Using [RhCp*Cl
catalyst. Using [Ru(p-cymene)Cl
as the cyanation source.[10] Rhodium(III)-catalyzed C-H reaction
3
3
6 2
)
4
0
o
b
1
has been proved to be a good complement to other transition
metals in terms of substrate scope and functional group
c
2
]
2
2
(5 mol%) and AgSbF (20 mol%) as
6
(5 mol%) and AgSbF (20 mol%) as
6
d
]
2
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Page 2 of 4
e
f
catalyst. Without RhCp*(CH
3
CN)
3
(SbF
6
)
2
.
Using NaOAc (20 mol%)
and AgCO (20 mol%) when both of them were used.
3
Table 2. Scope of Substituted Vinylamides
35
Scheme 2. Scaled-up C-H cyanation reaction.
To explore the scope of the Rh-catalyzed C-H cyanation
process with regards to other directing groups, we tested
O-methyl oximes and pyridines (Scheme 3). It was found that
both of O-methyl oximes and pyridines can be used in the
reaction to generate the desired cyanated products in good yields.
This finding is synthetically valuable because the O-methyl
oximes are derived from the ketone groups. Furthermore, we
tested the application of the new C-H cyanation reaction to
complex bioactive molecules. When dehydropregnenolone
derivatives was treated with the Rh-catalyzed C-H cyanation
process, we successfully obtained cyanated products in 66%
isolated yield (Scheme 3). Our result indicated that the new C-H
cyanation process may be useful for rapid generation of the
derivatives of bioactive compounds.
4
0
45
a
5
2 2 6 3
Condition :[RhCp*Cl ] (5 mol%), AgSbF (20 mol%), NaHCO (20
o
mol%), DCE, 120 C, Ar, 24 h. Isolated yields.
With the optimized reaction conditions in hand
[RhCp*(CH CN) ](SbF Ag CO NaOAc in DCE at
20 °C for 24 h), a variety of acrylamides were examined to
(
1
3
3
6
)
2
,
2
3
,
1
1
2
2
3
0
5
0
5
0
test the scope of the reaction (Table 2). when
N,N-diethylamide derivative replaced 1a, the reaction gave a
moderate yield. Both electron-donating and withdrawing
groups could be tolerated in this reaction. For
5
0
a
electron-donating groups, 4-OMe and 4,5-OCH
gave isolated yields of 78% (3c) and 71% (3f). Electron
withdrawing groups, such as 4-COOMe, 3-NO , 3-Ac can also
2
O derivatives
Conditions: as conditions in Table 1, entry 5.
a
Scheme 3. Cyanation of ketone oximes and pyridines.
2
proceed in the reaction (3e, 3j, 3k). Moreover, the aryl-Cl
groups were well compatible with the Rh-catalyzed C-H
cyanation processes, which made additional functionalization
possible at this position (3d). Pharmaceutically interesting
fluorinated, trifluoromethylated and trifluoromethoxylated
derivatives were also cyanated effectively under the optimized
conditions (3h, 3i, 3g). To our delight, heterocycles which are
important block in the drug synthesis were also be tolerated in
the cyanation reaction. Furan and dibenzofuran derivatives
were transformed into the corresponding alkenylnitriles in
On the basis of previous reports on rhodium-catalyzed C-H
activation reacted with an unsaturated system, we proposed the
following mechanism[13] for the Rh-catalyzed C-H cyanation
reaction: Firstly, the Rh(III) catalyst reacted with the substrate 1a
through C-H activation step to generate a rhodacycle(III)
intermediate I. Secondly, intermediate I was coordinated with
NCTS followed by insertion of the CN moiety into the
C-Rh(III) bond to produce II. Finally, elimination of a tosyl
aniline-coordinated Rh(III) complex from II took place to
generate the target product 3a. The Rh(III) complex then went
back to the catalytic cycle.
55
60
4
8% and 83% yield (3m, 3n). Importantly, 2-methacrylamide
was also converted effectively with the modificatory condition
3o) and the conformation of product was confirmed by X-ray
(
analysis (Scheme 2). To prove the utility of the new strategy,
we performed the C-H cyanation reaction on a preparative
scale. Under the optimum reaction conditions, we were able to
prepare 3a and 3o in slightly reduced yield (Scheme 2).
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In summary, we have developed a practical Rh-catalyzed C-H
activation with N-cyano-N-phenyl-p-toluenesulfonamide for the
synthesis of alkenyl nitriles. The reaction tolerated a variety of
synthetically important functional groups (e.g. aryl-Cl,
heterocycles). Both acrylamides and ketoximes can be employed
as directing group in the new C-H cyanation process. Further
exploration of the synthetic utilities of this chemistry and
in-depth mechanistic study are currently in progress.
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Author Contributions
§
1
5
W. S and T.-J.G. contributed equally
This work was supported by the 973 Program
(
2
2012CB215306),
1361140372),
NSFC
CAS
(21325208,
(KJCX2-EW-J02),
21172209,
SRFDP
(
20123402130008), Anhui Provincial Natural Science
1
0
2
0
Foundation (1408085QB25) and FRFCU.
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1
3
We conducted deuterium exchange experiments and found C-H
activation process is reversible, see the supporting information.
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