Rhodium catalyzed cyanation of chelation assisted C-H bonds

Article abstract of DOI:10.1021/ol402201c

A rhodium-catalyzed cyanation of chelation assisted C-H bonds is described employing N-cyano-N-phenyl-p-methylbenzenesulfonamide as an efficient cyanating reagent. The present method allowed the synthesis of various benzonitirle derivatives in good to excellent yield. A number of chelating groups are also effective in the present cyanation of C-H bonds. In addition, the developed methodology was applied in the formal synthesis of the isoquinoline alkaloid, menisporphine.

Full text of DOI:10.1021/ol402201c

ORGANIC
LETTERS
2013
Vol. 15, No. 19
4960–4963
Rhodium Catalyzed Cyanation of
Chelation Assisted CÀH Bonds
Manthena Chaitanya, Dongari Yadagiri, and Pazhamalai Anbarasan*
Department of Chemistry, Indian Institute of Technology Madras, Chennai-600036,
India
anbarasansp@iitm.ac.in
Received August 2, 2013
ABSTRACT
A rhodium-catalyzed cyanation of chelation assisted CÀH bonds is described employing N-cyano-N-phenyl-p-methylbenzenesulfonamide as an
efficient cyanating reagent. The present method allowed the synthesis of various benzonitirle derivatives in good to excellent yield. A number of
chelating groups are also effective in the present cyanation of CÀH bonds. In addition, the developed methodology was applied in the formal
synthesis of the isoquinoline alkaloid, menisporphine.
Benzonitriles (cyanoarenes) are frequently encountered
in both nature and industry, as natural product subunits
and as an integral part of herbicides, agrochemicals,
pharmaceuticals, natural products, and dyes, respectively.1
In organic synthesis, cyano functionality serves as a valu-
able intermediate, which can be readily diversified into
various important functionalized products, such as ben-
zoic acid derivatives, aldehydes, amines, heterocycles, etc.
Traditionally, direct cyanations were achieved through
stoichiometric strategies; this includes the RosenmundÀ
von Braun reaction2 and Sandmeyer reaction.3 In recent
decades these methods have been replaced with the transi-
tion metal catalyzed cyanation of aryl halides or its
equivalents with various nucleophilic cyanating reagents.4
Nonetheless, general problems in these reactions are the
use of expensive aryl halides, highly toxic cyanating re-
agents, high catalyst loading due to the cyanide poisoning
or need for superstoichiometric amounts of additives
(generally metal salts), and harsh reaction conditions
(Scheme 1).
Selective cyanation of highly abundant CÀH bonds
with a suitable reagent is probably the most economic
and benign route to the synthesis of benzonitrile deriva-
tives. Representative examples on the cyanation of CÀH
bonds include palladium catalyzed and copper mediated
cyanation of directing group assisted CÀH cyanation
employing nitromethane,5 DMF/NH3,6 and DMF7 as a
“CN” source (Scheme 1).8 However, these reactions also
suffer from the high catalyst loading and need for excess
oxidant; thus the development of a corresponding catalytic
transformation is highly desirable. Based on the require-
ment of catalytic cyanation of CÀH bonds and inspired by
the recent development in the rhodium catalyzed selective
functionalization of CÀH bonds of various arene deriva-
tives,9 we herein disclose the rhodium-catalyzed cyanation
of chelation assisted CÀH bonds.
(1) (a) Larock, R. C. Comprehensive Organic Transformations; VCH:
Weinheim, 1989; p 819. (b) Grundmann, C. In Houben-Weyl: Methoden
der Organischen Chemie, Vol. E5, 4th ed.; Falbe, J., Ed.; Thieme:
Stuttgart, 1985; p 1313.
(2) (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919,
52, 1749–1756. (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(3) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. (b)
Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii, P. V.
J. Organomet. Chem. 2004, 689, 3810.
(4) For a review on transition metal catalyzed cyanations, see: (a)
Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779. (b)
Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003, 2003,
3513. (c) Schareina, T.; Zapf, A.; Cotte, A.; Muller, N.; Beller, M.
Synthesis 2008, 2008, 3351. (d) Anbarasan, P.; Schareina, T.; Beller, M.
Chem. Soc. Rev. 2011, 40, 5049. (e) Kim, J.; Kim, H. J.; Chang, S. Angew.
Chem., Int. Ed. 2012, 51, 11948.
(5) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
(6) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
(7) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(8) (a) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem.
2009, 74, 9470. (b) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett.
2009, 11, 4716. (c) Xu, H.; Liu, P.-T.; Li, Y.-H.; Han, F.-S. Org. Lett.
2013, 15, 3354.
r
10.1021/ol402201c
Published on Web 09/16/2013
2013 American Chemical Society

not show a similar trend (Table 1, entries 1À5). In all these
reactions, the formation of a precipitate wasobservedfrom
the homogeneous reaction mixture; we anticipated that
might be the cause for the low conversion and yield.
Various attempts to isolate and characterize the solid
formed were unsuccessful. Furthermore, use of a coaddi-
tive such as potassium carbonate also did not improve the
yield of the reaction; instead a decrease in the reaction
conversion was observed (Table 1, entry 6).
Scheme 1. Different Approaches to the Synthesis of Benzonitrile
Derivatives
Table 1. Rhodium Catalyzed Cyanation of 2-Phenylpyridine 1:
Optimizationa
At the start of our investigation, rhodium catalyzed
CÀH cyanation of 2-phenyl pyridine was examined with
various commercially available and readily accessible elec-
trophilic cyanating reagents to afford the 2-(2-pyridyl)b-
enzonitriles. Interestingly, reaction of 2-phenyl pyridine
1 with [Cp*RhCl2]2 (1 mol %), AgSbF6 (40 mol %)
in chloroform at 70 °C utilizing N-cyano-N-phenyl-p-
methylbenzenesulfonamide 2 (NCTS, 3 equiv),10 an envir-
onmentally benign electrophilic cyanating reagent,11 only
provided the expected product in isolable yield. Having
found the target reaction, various other parameters were
screened to find the optimized reaction conditions (Table 1).
No reaction was observed when the reaction was per-
formed without either a rhodium catalyst or silver salt.
This proves that the present reaction was indeed catalyzed
by a rhodium catalyst. Next, increasing the reaction tem-
perature (70 to 120 °C) with 1,2-DCE and toluene as
solvent gave a higher conversion and higher yield of 3;
however, a further increase in temperature with xylene did
temp
conver-
yield ratiod
entry
X
Y
solvent
(°C)
sion (%)b
(%)c
3:4
e
e
1
3
40
40
40
40
40
40
CHCl3
70
À
22
24
32
53
38
30
67
73
68
91
92
0
À
e
e
e
2
3
3
3
3
3
1,2-DCE
toluene
toluene
xylene
90
À
À
À
e
3
100
120
140
120
120
120
120
120
120
120
À
4
99
83
41
96
82
73
99
99
0
4:1
e
5
À
e
6f
7
toluene
toluene
toluene
toluene
toluene
À
1.5 40
1.5 20
1.5 10
12:1
10:1
9:1
12:1
7:1
0
8
9
10
11
12
2
2
2
10
10g toluene
10h toluene
a Reaction conditions: 2-Phenylpyridine (1 equiv), NCTS (X equiv),
[Cp*RhCl2]2 (1 mol %), AgSbF6 (Y mol %), solvent (2 mL), temp,
24À36 h. b Based on the recovered starting material. c Combined isolated
yield of 3 and 4. d Based on the isolated product. e Not determined. f In
presence of 2 equiv of K2CO3. g AgClO4 was used. h NaBF4 was used.
Keeping the optimal reaction temperature as 120 °C and
solvent astoluene, theinfluenceof equivalentsofcyanating
reagents and AgSbF6 were studied. Decreasing the equiva-
lents of cyanating reagents to 1.5 equiv and screening the
mol % of AgSbF6 (40, 20, and 10 mol %) gave only a
marginal change in the selectivity toward the formation of
monocyanated products (∼10:1), while the overall conver-
sion of the reaction was decreased (Table 1, entires 7À9).
Next, a slight increase in the equivalents of the cyanating
reagent from 1.5 to 2 equiv gave the best conversion and
yield (>99% and 91%, respectively), where the turnover
number of the catalyst is ∼50, based on the isolated yield of
the product (Table 1, entry 10). The change of the Ag salt
to AgClO4 also gave a similar result, while NaBF4 com-
pletely ceased the reaction (Table 1, entries 11 and 12). The
optimized reaction conditions included NCTS (2 equiv),
[Cp*RhCl2]2 (1 mol %), AgSbF6 (10 mol %), toluene,
120 °C, and 36 h.
(9) For reviews on rhodium catalyzed CÀH functionalizations, see:
(a) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2009, 110,
624. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Satoh,
T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. (d) Colby, D. A.; Tsai,
A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2011, 45, 814. (e)
Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. For recent
examples on rhodium catalyzed CÀH functionalization of 2-phenyl
pyridine derivatives, see: (f) Yu, S.; Wan, B.; Li, X. Org. Lett. 2013,
15, 3706. (g) Tang, R.-J.; Luo, C.-P.; Yang, L.; Li, C.-J. Adv. Synth.
Catal. 2013, 355, 869. (h) Grohmann, C.; Wang, H.; Glorius, F. Org.
Lett. 2013, 15, 3014. (i) Schroder, N.; Wencel-Delord, J.; Glorius, F.
J. Am. Chem. Soc. 2012, 134, 8298. (j) Li, Y.; Zhang, X.-S.; Zhu, Q.-L.;
Shi, Z.-J. Org. Lett. 2012, 14, 4498. (k) Kwak, J.; Ohk, Y.; Jung, Y.;
Chang, S. J. Am. Chem. Soc. 2012, 134, 17778. (l) Kim, J. Y.; Park, S. H.;
Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134,
9110. (m) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J.
Am. Chem. Soc. 2011, 133, 1248. (n) Mizuno, H.; Takaya, J.; Iwasawa, N.
J. Am. Chem. Soc. 2011, 133, 1251. (o) Kawamorita, S.; Miyazaki, T.;
Ohmiya, H.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2011, 133, 19310.
(10) (a) Kurzer, F. J. Chem. Soc. 1949, 1034. (b) Kurzer, F. J. Chem.
Soc. 1949, 3029.
(11) (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2010, 50, 519. (b) Anbarasan, P.; Neumann, H.; Beller, M. Chem.;
Eur. J. 2011, 17, 4217. (c) Yang, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011,
13, 5608. During the preparation of this manuscript, Fu et al. reported
Rh(III)-catalyzed CÀH cyanation of oxime derivatives using NCTS.
The author also showed CÀH cyanation of 2-phenylpyridine as a
substrate; see: Gong, T.-J.; Xiao, B.; Cheng, W.-M.; Su, W.; Xu, J.;
Liu, Z.-J.; Liu, L.; Fu, Y. J. Am. Chem. Soc. 2013, 135, 10630.
Next, the scope and limitation of aryl groups and chelating
groups were investigated. As can be seen in Scheme 2,
various substitutions are tolerated under the present rhodium
catalyzed cyanation reaction. Alkyl substituted phenyl ring
Org. Lett., Vol. 15, No. 19, 2013
4961

74% and 82% yield, respectively. Furthermore, the change
of pyridine to other heterocyclic system, such as pyrazine
and pyrimidine as chelating groups, also gave the cyanated
product (3u and 3v) in good yield.
Scheme 2. Rhodium(III) Catalyzed Cyanation of 2-Arylpyridine
Derivatives with NCTSa
Scheme 3. Rhodium(III) Catalyzed Cyanation of CÀH Bonds:
Scope and Limitation of Chelating Groupa
a Reaction conditions: 2-Arylpyridine (1 equiv), NCTS (2 equiv),
[Cp*RhCl2]2 (1 mol %), AgSbF6 (10 mol %), toluene (2 mL), 120 °C,
36 h. All are isolated yields. b Isolated yield of dicyano derivative.
a Reaction conditions: Arene (1 equiv), NCTS (2 equiv), [Cp*RhCl2]2
(1 mol %), AgSbF6 (10 mol %), toluene (2 mL), 120 °C, 36 h. b 48 h. c
2 mol % of catalyst.
gave the corresponding cyanated products (3aÀe) in good
to excellent yield, irrespective of its position in the phenyl
ring (ortho, meta, and para). Sterically hindered substrates
(2-methylphenyl and 1-naphthyl substituted pyridine 3d and
3f) also underwent a smooth reaction under the optimized
conditions. meta-Methoxy substituted phenyl substrates, an
electron-donating group containing arenes, gave the corre-
sponding cyanated products 3g in good yield along with the
dicyano derivative. In general, formation of a dicyano deri-
vative was observed for electron-rich arene substituted 2-aryl
pyridine derivatives. Interestingly, an electron-withdrawing
group containing an arene (p-OMe, m-Cl, p-OCF3, and
o-CN) also afforded the expected product (3hÀk) with good
to moderate yield. Substrates (3lÀm) having an additional
coordination site, such as cyanide, pyridine did not undergo
the expected cyanation reaction, and all the starting materials
were recovered.9m
Subsequently, the screening of various nitrogen based
chelating groups was also examined under the optimized
rhodium catalyzed cyanation conditions (Scheme 3). Both
electron-donating and -withdrawing group substitution on
the pyridine ring in 2-phenyl pyridine furnished the corre-
sponding cyanated product (3nÀs) in moderate to excel-
lent yield. Substitution at the third and sixth positions
of the pyridine gave a lower yield of cyanated product
compared to the substitution at the fourth and fifth posi-
tions, presumably due to the steric effect. Instead of simple
2-phenyl pyridine, cyanation of 2-phenylisoquinoline and
7,8-benzoquinoline also afforded the products 3s and 3t in
Scheme 4. Synthetic Utility of Benzonitriles
After the scope of arenes and chelating groups was
revealed, the utility of the nitrile group was demonstrated
by the transformation into various carboxylic acid deriva-
tives and amines. Thereductionof a nitrilegroupin3awith
lithium aluminum hydride (LAH) afforded benzylamine
derivative 5 in excellent yield (Scheme 4). Successively,
benzoic acid derivative 6 was achieved in 76% yield
through the hydrolysis of nitrile under basic conditions.
Furthermore, hydration of nitrile 3a to corresponding
primary amide 7 was achieved on reaction with potassium
hydroxide and tert-butanol at 60 °C in good yield.
In addition to the elegant conversion of the nitrile group
into various functionalities, the key intermediate 12 for
the synthesis of menisporphine 1312 was synthesized to
4962
Org. Lett., Vol. 15, No. 19, 2013

Scheme 5. Application of Rhodium Catalyzed Cyanation in the
Synthesis of Intermediate for Construction of Menisporphine
Scheme 6. Plausible Mechanism for the Rhodium-Catalyzed
Cyanation of CÀH Bonds
demonstrate the potential of the present methodology
(Scheme 5). Menisporphine 13 is a naturally available
alkaloid, isolated from Menispermum dauricum DC
(Menispermaceae)13 and shown to possess cytotoxic
activity.14 Structurally menisporphine possesses a unique
7H-dibenzo[de,h]quinolone skeleton, which can be readily
accessed from the key intermediate 12. Synthesis of appro-
priate precursor 11 for the synthesis of intermediate 12 was
achieved in two steps from 3,4-dimethoxyphenylethylamine
8 and 4-methoxybenzoic acid 9 through amide coupling
and a cyclization sequence with an overall yield of 75%.
Subsequently, the reaction of cyclized product 11 with
NCTS under optimized conditions underwent cyanation
followed by successive oxidation to afford the key inter-
mediate 12 in 71% yield.
On the basis of previous reports on the rhodium(III)-
catalyzed CÀH functionalization of 2-phenylpyridine and
related compounds,15 we postulate the following mechan-
ism for the rhodium(III)-catalyzed cyanation of chelation
assisted CÀH bonds (Scheme 6). Initially, treatment of a
rhodium precursor with AgSbF6 generates the reactive
cationic rhodium(III) species A, which on reaction with 1
affords the cyclic rhodium species B through CÀH func-
tionalization. Coordination of NCTS 2 with B would form
the rhodium speciesC. Theformation ofD couldbereadily
envisioned through transfer of the aryl motif to the nitrile
carbon atom of the cyanating reagent. Rearrangement of
D affords the required cyanated product along with the
reactive rhodium species E. Finally, ligand exchange
will furnish the active rhodium species A to complete the
catalytic cycle. On the other hand, rhodium species E can
also react directly with 1 to form the cyclic rhodium species
B to continue the catalytic cycle.
In conclusion, we have demonstrated the direct rhodium
catalyzed cyanation of chelation assisted CÀH bonds.
The use of readily accessible and environmentally benign
N-cyano-N-phenyl-p-methylbenzenesulfonamide (NCTS,
2) as a cyanating reagent allowed the synthesis of various
aryl nitriles having different functional groups from corre-
sponding arenes in good to excellent yield under mild
conditions. In addition to the normal pyridine derivative,
isoquinoline, benzoquinoline, pyrazine, and pyrimidines
were readily employed as a chelating group in the present
cyanation reactions. The potential of the developed meth-
odology was further demonstrated by synthesizing the
key intermediate for the synthesis of menisporphine 13,
an alkaloid possessing cytotoxic activity.
Acknowledgment. This work was funded by Indian
Institute of Technology Madras through New Faculty
Scheme and Council of Scientific & Industrial Research
(CSIR). M.C. thanks CSIR, and D.Y. thanks IITM for a
fellowship.
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Supporting Information Available. Experimental meth-
ods, characterizations data, and 1H and 13C NMR spectra
of isolated compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 19, 2013
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