Rhodium-Catalyzed Cyanation of C(sp2)-H Bond of Alkenes

Article abstract of DOI:10.1021/acs.orglett.5b01746

Efficient and selective rhodium-catalyzed cyanation of chelation-assisted C-H bonds of alkenes has been accomplished using environmentally benign N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as a cyanating reagent. The developed methodology tolerates various functional groups and allows the synthesis of diverse substituted acrylonitriles in good to excellent yields. Furthermore, the potential of the methodology was demonstrated through the formal synthesis of chlorpheniramine-based antagonist.

Full text of DOI:10.1021/acs.orglett.5b01746

Letter
pubs.acs.org/OrgLett
Rhodium-Catalyzed Cyanation of C(sp2)−H Bond of Alkenes
Manthena Chaitanya and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai 600036, India
S
* Supporting Information
ABSTRACT: Efficient and selective rhodium-catalyzed cyanation of chelation-assisted C−H bonds of alkenes has been
accomplished using environmentally benign N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS) as a cyanating reagent.
The developed methodology tolerates various functional groups and allows the synthesis of diverse substituted acrylonitriles in
good to excellent yields. Furthermore, the potential of the methodology was demonstrated through the formal synthesis of
chlorpheniramine-based antagonist.
crylonitriles/vinyl nitriles are the most common scaffolds
Typical synthetic routes to acrylonitrile derivatives include the
Wittig/Horner−Wadsworth−Emmons reaction,6 Peterson ole-
fination,7 acrylamide/oxime dehydration,8 carbocyanation of
alkynes,9 cross-metathesis,10 and direct conversion of allylic
carbon to nitrile.11 However, many of them suffer from limited
substrate scope and/or poor stereoselectivity. Alternative and
modern methods are based on the transition-metal-catalyzed
cyanation of alkenyl (pseudo)halides12 and alkenyl metal
reagents,13 which afford acrylonitriles with complete retention
of configuration. Nonetheless, use of expensive alkenyl halides,
hazards related to handling of cyanating reagents, high catalyst
loading due to the cyanide poisoning and/or stoichiometric
amount of additives, and harsh reaction conditions are
unfavorable (Scheme 1).14
A
embedded in various dyes, agrochemicals, herbicides, and
natural products.1 These α,β-unsaturated nitriles also form a core
motif of biologically important pharmaceuticals.2 Representative
examples include entacapone3 and rilpivirine,4 which are used in
the treatment of Parkinson’s disease and HIV infections,
respectively (Figure 1). Besides the potential application in
In this context, the efficient and selective cyanation of highly
abundant C−H bonds with readily accessible cyanating reagent is
the most economically viable and environmentally benign
strategy for the synthesis of acrylonitriles. Although various
directing groups that assisted the cyanation of arene15 C−H
bonds have been extensively studied,16 the direct cyanation of
Scheme 1. Synthesis of Acrylonitriles
Figure 1. Representative examples of biologically important pharma-
ceuticals.
biological systems, they were also employed as versatile
intermediates and building blocks in medicinal/organic chem-
istry, which can be readily converted into various important
functional groups such as acrylic acid derivatives, amines,
aldehydes, nitrogen-based heterocycles, etc. For instance, the
synthesis of chlorpheniramine-based antagonist utilizes the
acrylonitrile derivative as a key intermediate.5
Received: June 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01746
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chelation-assisted alkene C−H bonds is rather limited.17 Due to
the potential of direct cyanation of alkene C−H bonds and our
interest18 in the rhodium-catalyzed cyanation of C−H bonds,19
we herein report the selective rhodium-catalyzed cyanation of a
chelation-assisted C−H bond of alkenes.20
We started our investigation on the cyanation of a C−H bond
employing alkene, 2-(1-phenylvinyl)pyridine (1a), as a model
substrate. Reaction of 1a with NCTS 2 in the presence of 1 mol %
of [Cp*RhCl2]2 and 10 mol % of AgSbF6 in toluene at 120 °C
provided the expected cyanated product 3a in only a detectable
amount (Table 1, entry 1). Increasing the catalyst loading to 3
cyanation of C−H bond of alkene are 2 equiv of 2, [Cp*RhCl2]2
(3 mol %), Cu(OAc)2·H2O (10 mol %), tAmOH, 100 °C, 12 h.
After identifying the best optimized reaction conditions, we
studied the scope and limitation of the present methodology by
changing the substitution on the arene and directing group. As
shown in Scheme 2, simple alkyl- and aryl-substituted arenes
Scheme 2. Rhodium-Catalyzed C−H Cyanation of Alkenes:
Substrate Scope
Table 1. Rhodium-Catalyzed Cyanation of 2-(1-
a
Phenylvinyl)pyridine (1a): Optimization
temp
(°C)
time
(h)
b
entry
additive
solvent
yield (%)
c
1
AgSbF6
AgSbF6
AgSbF6
AgSbF6
toluene
toluene
toluene
xylene
120
120
100
140
100
100
36
36
36
36
36
36
<5
29
34
21
17
38
2
3
4
5
6
d
AgSbF6/NaOAc
toluene
toluene
AgSbF6/ Cu(OAc)2·
d
H2O
e
7
8
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
toluene
100
100
100
36
36
36
38 (11)
1,2-DCE
13
40
1,4-
dioxane
10
Cu(OAc)2·H2O
Cu(OAc)2·H2O
tAmOH
tAmOH
100
100
12
12
65
20
f
11
a
Reaction conditions: 1a (1 equiv), NCTS 2 (2 equiv), [Cp*RhCl2]2
b
(3 mol %), additive (10 mol %), solvent (2 mL), temp, time. Isolated
c
d
yield. 1 mol % of [Cp*RhCl2]2. 20 mol % of coadditive was used.
e
f
Cu(OAc)2·H2O (30 mol %). 1.2 and 2.5 equiv of NCTS.
mol % gave the product 3a in 29% yield after 36 h (Table 1, entry
2). Studying the reaction at 100 and 140 °C afforded the product
3a in 34 and 21% yield, respectively (Table 1, entries 3 and 4).
Next, the effect of coadditives like NaOAc and Cu(OAc)2·H2O
were examined at 100 °C. Although NaOAc did not improve the
yield, addition of Cu(OAc)2·H2O furnished 3a in comparable
yield (Table 1, entries 5 and 6).
Interestingly, with Cu(OAc)2·H2O as the only additive, in the
absence of AgSbF6, formation of cyanated product 3a was
observed in 38% yield (Table 1, entry 7). Next, an increase in the
mol % of copper acetate did not afford any positive influence. It is
important to note that cyanation of 1a was not observed in the
absence of rhodium catalyst and even with the presence of 10 mol
% of Cu(OAc)2·H2O, which suggests the reaction was indeed
catalyzed by rhodium. Consequently, various solvents were
screened, keeping the reaction conditions as [Cp*RhCl2]2 (3
mol %) and Cu(OAc)2·H2O (10 mol %) at 100 °C (Table 1,
entries 8−10). Among them, tAmOH was proven to be the best
solvent and gave the product 3a in improved yield of 65% after 12
h (Table 1, entry 10). Furthermore, no improvement in the
formation of 3a was observed when the number of equivalents of
cyanating reagent was changed to either 1.2 or 2.5 equiv (Table 1,
entry 11). Finally, the best optimized conditions for the
†
1H NMR yield.
containing alkenes gave the corresponding products 3b−d,g,h in
good yield. Electron-donating (−OMe, −SMe) aryls possessing
acrylonitriles 3e and 3f were achieved in 75 and 41% yield,
wherein the formation of 3f was observed in lower yield possibly
due to the sulfur poisoning. Sterically hindered ortho-substituted
aryl groups were tolerated under the present conditions to afford
the corresponding products 3d and 3i in 72 and 76% yield,
respectively. Medicinally important trifluoromethyl- and fluoro-
substituted arenes containing acrylonitriles 3j and 3k were
synthesized in good yield. Readily functionalizable bromo- and
chloro-substituted arenes also underwent smooth reaction to
B
DOI: 10.1021/acs.orglett.5b01746
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Organic Letters
Letter
furnish the corresponding products 3l and 3m in 62 and 72%
yield, respectively. Most interestingly, reactive functional groups
such as acetal, ester, free hydroxy, and carbamates were also well
tolerated under the present conditions to afford the correspond-
ing cyanated products 3n, 3o, 3p, and 3q in good yield. However,
strongly electron-withdrawing and chelating nitro- and acetyl-
substituted aryl-containing alkenes did not furnish the expected
cyanated product (3r and 3s). Next, the substitutions on the
directing group and pyridine ring were also investigated. Most of
the substituted pyridines underwent smooth reaction to give the
cyanated products 3t, 3u, and 3v in good yield. On the other
hand, other directing groups such as quinoline, oxime, and amide
were not successful under the present cyanation conditions.
Gratifyingly, replacement of the aryl moiety in 1 with a methyl
group also afforded the cyanated product 3w in 76% yield.
Having shown the broad scope of 1,1-disubstituted alkenes, we
envisioned the rhodium-catalyzed cyanation of different
trisubstituted alkenes (Scheme 3). Thus, various substituted 2-
Scheme 4. Synthesis of Chlorpheniramine-Based Antagonist 6
the present method in the synthesis of biologically important
intermediates/molecules.
On the basis of previous reports on the rhodium-catalyzed
cyanation of arene C−H bonds,16d,19a we propose the following
mechanism for the rhodium-catalyzed cyanation of the chelation-
assisted C−H bond of alkenes (Scheme 5). Initially, reaction of 1
Scheme 3. Rhodium-Catalyzed C−H Cyanation of
Cycloalkenes
Scheme 5. Plausible Mechanism
†
1H NMR yield.
cycloalkenylpyridines were subjected to the conditions opti-
mized for the rhodium-catalyzed cyanation of C−H bond of
alkenes. Cyanation of 2-cyclohexenylpyridine under the
optimized conditions provided the cyanated product 3aa in
86% yield. Similarly, substituted cyclohexenylpyridines also
underwent smooth reaction to give cyanated products 3ab−ad
in good yield. Changing the ring size of cycloalkene to 5-, 7-, and
8-membered rings also furnished the corresponding products
3ae−ag in 88%, 61%, and 62% yield, respectively. Furthermore,
substitution on the pyridine ring was also well tolerated and
afforded the products 3ah and 3ai in good yields.
Having established the rhodium-catalyzed cyanation of the
alkene C−H bond, we were interested in the demonstration of
application of the developed method through the formal
synthesis of chlorpheniramine21-based antagonist 6. Thus, the
initial reduction of alkene in vinyl nitrile 3m with sodium
borohydride afforded the nitrile 4 in 75% yield (Scheme 4). Next,
amine 5, the potential intermediate for the synthesis of 6,5a was
achieved in good yield from nitrile 4 through reduction with
LiAlH4. This successful transformation revealed the potency of
with reactive Rh(III) species A would afford the cyclic rhodium
species B through C−H bond functionalization. Coordination of
NCTS 2 with B would give the new rhodium species C. Next,
migration of the vinyl motif to the nitrile carbon atom of the
cyanating reagent would readily afford the intermediate D.
Formation of product 3 and the reactive rhodium species E could
be readily envisaged via the rearrangement of rhodium species D.
Ligand exchange in E with XH will regenerate the active rhodium
species A to complete the catalytic cycle. Instead, rhodium
species E could also react directly with 1 to form the cyclic
rhodium species B to complete/continue the catalytic cycle.
In conclusion, we have successfully demonstrated the direct
rhodium-catalyzed cyanation of chelation-assisted C−H bonds
of alkenes employing readily accessible NCTS as cyanating
reagent. The present method tolerates various alkene substrates
with different functional groups, which allows the synthesis of
diverse vinyl nitrile derivatives in good to excellent yields.
Furthermore, the potential of the present methodology was
C
DOI: 10.1021/acs.orglett.5b01746
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Letter
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental methods, characterization data, and H and 13C
1
NMR spectra of isolated compounds. The Supporting
Information is available free of charge on the ACS Publications
website at DOI: 10.1021/acs.orglett.5b01746.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: anbarasansp@iitm.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Indian Institute of Technology Madras New
Faculty Scheme and Board of Research in Nuclear Sciences
(BRNS) through the DAE Young Scientist Award (Project No.
2012/20/37C/14/BRNS) for financial support. M.C. thanks the
Council of Scientific & Industrial Research (CSIR) for a
fellowship.
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D
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