Lewis acid catalyzed direct cyanation of indoles and pyrroles with N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)

Article abstract of DOI:10.1021/ol202335p

BF₃?OEt₂-catalyzed direct cyanation of indoles and pyrroles using a less toxic, bench-stable, and easily handled electrophilic cyanating agent N-cyano-N-phenyl-para-toluenesulfonamide (NCTS) affords 3-cyanoindoles and 2-cyanopyrroles in good yields with excellent regioselectivity. The substrate scope is broad with respect to indoles and pyrroles.

Full text of DOI:10.1021/ol202335p

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5608–5611
Lewis Acid Catalyzed Direct Cyanation
of Indoles and Pyrroles with N-Cyano-N-
phenyl-p-toluenesulfonamide (NCTS)
Yang Yang, Yan Zhang, and Jianbo Wang*
Beijing National Laboratory of Molecular Sciences (BNLMS) and Key Laboratory of
Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of
Chemistry, Peking University, Beijing 100871, China
wangjb@pku.edu.cn
Received August 29, 2011
ABSTRACT
BF3 OEt2-catalyzed direct cyanation of indoles and pyrroles using a less toxic, bench-stable, and easily handled electrophilic cyanating agent
N-cyano-N-phenyl-para-toluenesulfonamide (NCTS) affords 3-cyanoindoles and 2-cyanopyrroles in good yields with excellent regioselectivity.
The substrate scope is broad with respect to indoles and pyrroles.
3
Aryl nitriles are important constituents of pharmaceu-
ticals, agrochemicals, dyes, and natural products.1 In
addition, the nitrile moiety also serves as a key intermedi-
ate for a broad range of functional group transformations
leading to the formation of amines, aldehydes, acids,
ketones, amides, and heterocycles.2 The Rosenmundꢀvon
Braun reaction3 and the Sandmeyer reaction4 represent
two classical methods for the introduction of a cyano group
onto the aromatic ring, where copper(I) cyanide is used
as the cyanating reagent. In recent decades, nucleophilic
transition-metal-catalyzed cyanation of aryl halides using
KCN,5 Zn(CN)2,6 acetone cyanohydrin,7 trimethylsilyl
cyanide,8 and K4[Fe(CN)6]9 as cyanating agents has
emerged as a useful alternative for the preparation of aryl
nitriles. Advancesintransition-metal-catalyzed CꢀH bond
functionalization have also enabled the direct cyanation of
aromatic compounds.10 However, severe drawbacks of cy-
anide sources including the notorious toxicity or the gen-
eration of stoichiometric amounts of metal wastes prevent
their wide application in academic laboratories and the
(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-
tical Substances: Syntheses, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001.
(2) (a) Larock, R. C. Comprehensive Organic Transformations: A
Guide to Functional Group Preparations; VCH: New York, 1989. (b)
Rappoport, Z. Chemistry of the Cyano Group; John Wiley & Sons: London,
1970; pp 121ꢀ312. (c) For a recent example, see: Liskey, C. W.; Liao, X.;
Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 11389.
(3) (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 2,
1749. (b) Mowry, D. T. Chem. Rev. 1948, 48, 189.
(4) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. (b)
Hodgson, H. H. Chem. Rev. 1947, 40, 251. (c) Galli, C. Chem. Rev. 1988,
88, 765.
(5) Selected examples: (a) Takagi, K.; Okamoto, T.; Sakakibara, Y.;
Oka, S. Chem. Lett. 1973, 471. (b) Sundermeier, M.; Zapf, A.; Beller, M.;
Sans, J. Tetrahedron Lett. 2001, 42, 6707. (c) Zhu, Y.-Z.; Cai, C. Eur. J.
Org. Chem. 2007, 2401.
(6) Selected examples: (a) Chidambaram, R. Tetrahedron Lett. 2004,
45, 1441. (b) Jensen, R. S.; Gajare, A. S.; Toyota, K.; Yoshifuji, M.;
Ozawa, F. Tetrahedron Lett. 2005, 46, 8645.
(7) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
ꢀ
M. Adv. Synth. Catal. 2011, 353, 777.
(8) Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller,
2003, 42, 1661. (b) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller,
M. J. Organomet. Chem. 2003, 684, 50.
(9) For the first use of K4[Fe(CN)6] in Pd-catalyzed cyanation of aryl
halides, see: (a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004,
1388. For a recent example, see: (b) DeBlase, C.; Leadbeater, N. E.
Tetrahedron 2010, 66, 1098.
(10) (a) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M.
J. Am. Chem. Soc. 2007, 129, 15372. (c) Jia, X.; Yang, D.; Zhang, S.;
Cheng, J. Org. Lett. 2009, 11, 4716. (d) Jia, X. F.; Yang, D. P.; Wang,
W. H.; Luo, F.; Cheng, J. J. Org. Chem. 2009, 74, 9470. (e) Kim, J.;
Chang, S. J. Am. Chem. Soc. 2010, 132, 10272. (f) Do, H.-Q.; Daugulis,
O. Org. Lett. 2010, 12, 2517. (g) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J.
Org. Lett. 2010, 12, 1052. (h) Reddy, B. V. S.; Begum, Z.; Reddy, Y. J.;
Yadav, J. S. Tetrahedron Lett. 2010, 51, 3334. (i) Ren, X.; Chen, J.; Chen,
F.; Cheng, J. Chem. Commun. 2011, 47, 6725. (j) Ding, S.; Jiao, N. J. Am.
Chem. Soc. 2011, 133, 12374.
r
10.1021/ol202335p
Published on Web 09/14/2011
2011 American Chemical Society

pharmaceutical industry. Moreover, the efficiency of these
transformations is hamperedby the high affinity of cyanide
toward transition-metal-based catalytic systems, which
often results in the rapid formation of stable cyanide
complexes and deactivation of transition-metal catalysts.11
To circumvent this problem, electrophilic cyanation is
among the most promising approaches to access aryl
nitriles. To date, electrophilic cyanation of reactive orga-
nometallic species (i.e., Grignard reagents,12 organolithium
reagents,13 organozinc reagents,14 arylstannanes15) have
been investigated. However, most of the established elec-
trophilic cyanations need highly toxic cyanogen halides,
either used as cyanating sources directly or to prepare
electrophilic cyanating agents.16 Moreover, the presence of
a highly reactive carbonꢀmetal bond somehow under-
mines the functional group tolerance of this type of
method. Therefore, new methodologies enabling the direct
electrophilic cyanation through aromatic CꢀH bond func-
tionalization using environmentally friendly cyanating
reagents under mild conditions would be highly desirable
for the synthetic organic community.
On the other hand, indoles are ubiquitous motifs in
natural products and pharmaceutical agents.19 Currently,
most commonly used methods for the cyanation of indoles
proceed through a stepwise manner where isocyanates are
employed.20 Kita and co-workers reported an intriguing
hypervalent iodine(III)-mediated direct cyanation which is
believed to proceed through a single electron transfer
(SET) process.21 However, due to the highly reactive
nature of the hypervalent iodine(III) reagent, this metho-
dology suffers from inferior yields and poor regioselec-
tivity with regard to indole substrates. Recently, cyanation
through transition-metal-catalyzed CꢀH bond functiona-
lization has attracted great attention.10 For example,
Ding and Jiao reported Pd-catalyzed cyanation of indoles
by using N,N-dimethylformamide as a cyanating agent.10j
As a continuation of our interest in developing an envi-
ronmentallybenign cyanation process,10g and alsoinspired
by the recent development of cyanation with electrophilic
cyanating agents, we decided to explore the possibility
of electrophilic cyanation through direct CꢀH bond
functionalization.
During our search for less toxic and easily handled
electrophilic cyanating agents, we were attracted to NCTS
(1). NCTS is a bench-stable crystalline compound first
synthesized by Kurzer in 1949.17 It is noteworthy that
NCTS is readily synthesized in an environmentally benign
fashion from inexpensive phenylurea by dehydrative tosy-
lation in pyridine without the use of toxic cyanogen
halides. However, to our surprise the potential of this
NꢀCN bond containing compound as an electrophilic
cyanating reagent was not evaluated until very recently.18
In 2011, Beller and co-workers reported a Rh-catalyzed
cyanation of arylboronic acids with NCTS as a cyanating
agent.18a Furthermore, they have developed an electro-
philic cyanation through the reaction of NCTS with aro-
matic Grignard reagents.18b
Initial investigations were aimed at promoting the cya-
nation of N-substituted indoles with NCTS 1. At the
beginning of our research, indole derivatives with various
N-protecting groups (e.g., ꢀBn, ꢀTIPS, ꢀTs, etc.) were
screened, and we were disappointed to find that NCTS was
ineffective in all the cyanation studies. At this stage, we
reasoned that a Lewis acid might serve to activate the
cyanating agent NCTS and render the desired cyanation
reactionasfavorable. Afterconducting anextensive survey
of Lewis acids, to our delight, it was observed that a
catalytic amount of BF3 OEt2 (Table 1, entry 8) uniquely
3
facilitated the desired cyanation. Other conventionally
used Lewis acids such as Zn(OTf)2, FeCl3, AlCl3, and
Sm(OTf)3 (Table 1, entries 1ꢀ4) proved to be poor cata-
lystsfor thisreaction. Withthe useof In(OTf)3 and AgOTf,
only low tomoderateyieldsof the 3-cyanatedproduct were
observed (Table 1, entries 5 and 6, respectively). Interest-
ingly, AuCl3, a superior catalyst for the electrophilic
halogenation of aromatic compounds,22,23 failed to afford
any cyanated product except a trace amount of undesired
3-chlorinated indole (Table 1, entry 7). Finally, no desired
(11) (a) Sundermeier, M.; Zapf, A.; Mutyala, S.; Bauman, W.; Sans,
J.; Weiss, S.; Beller, M. Chem.;Eur. J. 2003, 9, 1828. (b) Cristau, H.-J.;
Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem.;Eur. J. 2005, 11, 2483.
(c) Dobbs, K. D.; Marshall, W. J.; Grushin, V. V. J. Am. Chem. Soc.
2007, 129, 30. (d) Erhardt, S.; Grushin, V. V.; Kilpatrick, A. H.;
Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc.
2008, 130, 4828. (e) For a most recent study, see: Ushkov, A. V.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 10999.
(12) Anbarasan, P.; Neumann, H.; Beller, M. Chem.;Eur. J. 2010,
16, 4725.
(13) (a) Wu, Y.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S.
Org. Lett. 2000, 2, 795. (b) Sato, N.; Yue, Q. Tetrahedron 2003, 59, 5831.
(c) Sato, N. Tetrahedron Lett. 2002, 43, 6403.
(14) Klement, I.; Lennick, K.; Tucker, C. E.; Knochel, P. Tetrahe-
dron Lett. 1993, 34, 4623.
(15) Bartlett, E. H.; Eaborn, C.; Walton, D. R. M. J. Organomet.
Chem. 1972, 46, 267.
(16) For examples, see: (a) Wheland, R. C.; Martin, E. L. J. Org.
Chem. 1975, 40, 3101. (b) Davis, W. A.; Cava, M. P. J. Org. Chem. 1983,
48, 2774. (c) Van Leusen, A. M.; Jagt, J. C. Tetrahedron Lett. 1970, 12,
967. (d) Hughes, T. V.; Hammond, S. D.; Cava, M. P. J. Org. Chem.
1998, 63, 401. (e) Hughes, T. V.; Cava, M. P. J. Org. Chem. 1999, 64, 313.
(f) Wu, Y.-Q.; Limburg, D. C.; Wilkinson, D. E.; Hamilton, G. S. Org.
Lett. 2000, 2, 795.
(19) For a recent review, see: Bandini, M.; Eichhozer, A. Angew.
Chem., Int. Ed. 2009, 48, 9608.
(20) (a) Graf, R. Chem. Ber. 1956, 89, 1071. (b) Mehta, G.; Dhar,
D. N.; Suri, S. C. Synthesis 1978, 374. (c) Lohaus, G. Chem. Ber. 1967,
100, 2719. (d) Mehta, G.; Dhar, D. N.; Suri, S. C. Synthesis 1978, 374. (e)
Kirsanov, A. V. Zh. Obshch. Chem. 1954, 24, 1033. (f) Smaliy, R. V.;
Chaikovskaya, A. A.; Pinchuk, A. M.; Tolmachev, A. A. Synthesis 2002,
2416. For an example of a one-pot procedure using the Vilsmeier
reagent, see: (g) Ushijima, S.; Togo, H. Synlett 2010, 7, 1067. For other
methods, see: (h) Tamura, Y.; Kawasaki, M.; Adachi, M.; Tanio, M.;
Kita, Y. Tetrahedron Lett. 1977, 18, 4417. (i) Tamura, Y.; Adachi, M.;
Kawasaki, T.; Yasuda, H.; Kita, Y. J. Chem. Soc., Perkin Trans. 1 1980,
1132.
(21) (a) Dohi, T.; Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y.
Org. Lett. 2005, 7, 537. (b) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto,
A.; Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007,
72, 109.
(17) (a) Kurzer, F. J. Chem. Soc. 1949, 1034. (b) Kurzer, F. J. Chem.
Soc. 1949, 3029.
(18) (a) Anbarasan, P.; Neumann, H.; Beller, M. Angew. Chem., Int.
Ed. 2011, 50, 519. (b) Anbarasan, P.; Neumann, H.; Beller, M. Chem.;
Eur. J. 2011, 17, 4217.
(22) (a) Mo, F.; Yan, M. J.; Qiu, D.; Li, F.; Zhang, Y.; Wang, J.
Angew. Chem., Int. Ed. 2010, 49, 2028. (b) Qiu, D.; Mo, F.; Zheng, Z.;
Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 5474.
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Boorman, T.; Larrosa, I. Chem. Soc. Rev. 2011, 40, 1910.
Org. Lett., Vol. 13, No. 20, 2011
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product was observed through the use of a catalytic amount
of Brønsted acids (e.g., TFA, entry 9). Under optimal
conditions, treatment of 1-methyl-2-phenyl-1H-indole with
transition-metal catalysis remains intact under this cyana-
tion protocol, allowing for further cross-couplings and
demonstrating the advantage of this methodology. N-
para-Methoxylphenyl and N-allyl indoles (Scheme 1, 3m
and 3n) weresuccessfully transformedinto3-cyanoindoles.
Finally, the cyanation of free indoles proceeded smoothly
as well (Scheme 1, 3o and 3p).
NCTS in the presence of catalytic BF3 OEt2 in DCE at
3
80 °C for 12 h delivered the cyanated product in 93% yield
(Table 1, entry 8).
Table 1. Screening of Lewis Acid Catalystsa
Scheme 1. BF3 OEt2-Catalyzed Cyanation of Indolesa
3
entry
cat. (mol %)
yield (%)b
1
2
3
4
5
6
7
8
9
Zn(OTf)2 (20)
FeCl3 (20)
N.R.c
N.R.
N.R.
N.R.
<20
AlCl3 (10)
Sm(OTf)3 (20)
AgOTf (20)
In(OTf)3 (20)
AuCl3 (8)
47
d
ꢀ
BF3 OEt2 (10)
97(93)e
3
TFA (10)
N.R.
a Unless otherwise noted, the reaction conditions are as follows:
indole (0.24 mmol, 1.2 equiv), NCTS 1 (0.20 mmol, 1.0 equiv), DCE (0.2
mL). b Yield determined based on GC-MS analysis using dodecane as
internal standard. c N.R.: no reaction occurred. d Only trace amount of
undesired 3-chlorinated product was observed. e Isolated yield in
parentheses.
With the optimized reaction conditions in hand, a wide
range of indole substrates were investigated in the BF3
3
OEt2-catalyzed cyanation process with NCTS (Scheme 1).
2-Substituted indoles afforded the corresponding cyanated
products in excellent yields (Scheme 1, 3aꢀc). More satis-
fyingly, we found that, in the absence of a substituent at the
C2 position, the cyanation proceeded regioselectively to
furnish 3-cyanoindoles as the only products (Scheme 1,
3dꢀe). In this regard, this newly established protocol is
superior over the previously reported palladium-catalyzed
cyanation procedure, where indoles without C2 substitu-
ents were troublesome substrates due to the insuppressible
formation of homocoupling byproducts.10g C5- and C6-
substituted indoles were found to be suitable substrates
(Scheme 1, 3f and 3i). Moreover, an electron-donating
methoxy group (Scheme 1, 3g) and an electron-withdrawing
nitro group (Scheme 1, 3h) at the C5 position were well-
tolerated, although in the latter case a stoichiometric
a Unless otherwise noted, the reaction conditions are as follows:
indole (0.48 mmol, 1.2 equiv), NCTS 1 (0.40 mmol, 1.0 equiv), DCE
(0.4 mL). All the yields refer to isolated yield. b40 mol % BF3 OEt2 was
3
used. c100 mol % BF3 OEt2 was used. d20 mol % BF3 OEt2 was used.
3
3
amount of BF3 OEt2 was needed to achieve a satisfactory
3
conversion of the 5-nitro-substituted indole substrate to
product 3h. In addition to this, indoles bearing an electron-
donating para-methoxyphenyl group (Scheme 1, 3k) or
electron-withdrawing para-bromophenyl and para-fluor-
ophenyl groups (Scheme 1, 3j and 3l, respectively) at the
C2 position were also found to be excellent substrates.
Notably, the highly susceptible bromide moiety toward
Encouraged by the success in the direct electrophilic
cyanation of indoles, we next attempted to extend the
substrate scope to pyrroles and arenes (Scheme 2). Grat-
ifyingly, pyrroles were also found to be suitable substrates
for this reaction, although higher amounts of BF3 OEt2
were often needed and the yield was slightly lower than in
the case of cyanation with indoles. While N-benzyl pyrrole
3
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Org. Lett., Vol. 13, No. 20, 2011

of this transformation, we subjected a variety of arenes
to the standard or slightly modified reaction conditions.
It was observed that the reaction became sluggish in
most cases, yet to our gratification, the cyanation of
electron-rich 1,3,5-trimethoxybenzene still afforded a
Scheme 2. BF3 OEt2-Catalyzed Cyanation of Pyrrolesa
3
moderate yield through the use of 1 equiv of BF3 OEt2
(Scheme 2, 3v).
In summary, we have developed a mild BF3 OEt2-
3
3
catalyzed protocol for the direct cyanation of indoles and
pyrroles using a bench-stable, easily handled, and less toxic
electrophilic cyanating agent NCTS. The reaction is broad
in scope with respect to indole and pyrrole substrates. This
methodology does not use transition metal catalysts and
provides an effective and practical means for accessing
3-cyanoindoles and 2-cyanopyrroles. Designing and devel-
oping novel electrophilic cyanating reagents to enable
direct cyanation of other aromatic compounds based on
a catalytic CꢀH bond functionalization strategy are cur-
rently underway in our laboratory.
a The reaction conditions are as follows: pyrrole or arene (0.48 mmol,
1.2 equiv), NCTS 1 (0.40 mmol, 1.0 equiv), DCE (0.4 mL). All the yields
refer to isolated yields. b20 mol % BF3 OEt2 was used. c40 mol %
3
Acknowledgment. The project is supported by the 973
Program (No. 2009CB825300) and NSFC (Grant Nos.
20832002, 20821062, 20902005, 21072009). The authors
acknowledge Xi Wang for providing samples of N-sub-
stituted indoles for reactivity test.
BF3 OEt2 was used. The ratio of 3r and 3r0 was 8:1 based on GC-MS
3
analysis. The yield refers to the isolated product of 3r. d150 mol %
BF3 OEt2 was used. e100 mol % BF3 OEt2 was used.
3
3
afforded a mixture of 2- and 3-cyanated products (Scheme 2,
3r and 3r0, 8:1), the cyanation of N-para-tert-butyl pyrrole
proceeded in a regiospecific manner (Scheme 2, 3q). The
reaction also worked well with pyrroles bearing three
substituents including an electron-withdrawing ester
group (Scheme 2, 3t and 3u). To further probe the scope
Supporting Information Available. Experiment proce-
1
dure, characterization data, H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 20, 2011
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