Copper-mediated selective cyanation of indoles and 2-phenylpyridines with ammonium iodide and DMF

Article abstract of DOI:10.1021/ol301674m

Copper-mediated regioselective cyanation of indoles and 2-phenylpyridines was developed by using ammonium iodide and DMF as the combined source of a cyano unit under Pd-free conditions. Mechanistic studies indicate that the reaction of indoles proceeds through a two-step sequence: electrophilic initial iodination and then cyanation. The cyanation has a broad substrate scope, high functional group tolerance, and excellent regioselectivity.

Full text of DOI:10.1021/ol301674m

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
Copper-Mediated Selective Cyanation
of Indoles and 2-Phenylpyridines with
Ammonium Iodide and DMF
000–000
Jinho Kim, Hyunwoo Kim, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface Research Center, Korea
Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
sbchang@kaist.ac.kr
Received June 19, 2012
ABSTRACT
Copper-mediated regioselective cyanation of indoles and 2-phenylpyridines was developed by using ammonium iodide and DMF as the combined source
of a cyano unit under “Pd-free” conditions. Mechanistic studies indicate that the reaction of indoles proceeds through a two-step sequence: electrophilic
initial iodination and then cyanation. The cyanation has a broad substrate scope, high functional group tolerance, and excellent regioselectivity.
Nitrile is a key building unit in organic synthesis to serve as
a versatile precursor for various functional groups such as
aldehydes, amines, amidines, tetrazoles, amides, or other
cyano sources such as MCN (M = K, Na, or Zn), TMSCN,
or K Fe(CN) was shown to be readily mediated by metal
3
6
6À10
species including palladium, nickel, or copper complexes.
In addition, certain organic precursors such as acetone cyano-
1
carboxy derivatives. In particular, aryl or heteroaromatic
nitriles are widely utilized in synthetic chemistry or in industry
for the manufacture of pharmaceuticals, agrochemicals, or
1
1
12
hydrin (CH ) CH(OH)(CN) or nitromethane CH NO
3 2 3 2
were often employed to provide the cyano unit in metal-
13
catalyzed cyanation reactions.
2
3
dyes. Sandmeyer reaction and RosenmundÀvon Braun’s
4
procedures are conventional methods to prepare these nitrile
compounds using CuCN as the cyanating reagent. In recent
Along this line, we recently discovered that the cyano
unit “CN” could be generated in situ from aqueous am-
monia and N,N-dimethylformamide (DMF) under copper-
5
decades, cyanation of aryl (pseudo)halides with anionic
1
4
mediated oxidative conditions. This novel procedure was
utilized in the palladium-catalyzed direct CÀH cyanation
(
1) (a) The Chemisty of the Cyano Group; Rappoport, Z., Ed.; Interscience:
London, 1970. (b) Larock, R. C. Comprehensive Organic Transformations: A
Guide to Fucntional Group Preparations; VCH: New York, 1989.
(
2) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-
(
2
8) For the transition metal catalyzed cyanations using Zn(CN) , see:
tical Substance: Synthesis, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, 2001.
(a) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B.;
King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887. (b) Maligres,
P. E.; Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40,
8193. (c) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
(d) Chidambaram, R. Tetrahedron Lett. 2004, 45, 1441. (e) Jensen, R. S.;
Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Tetrahedron Lett.
2005, 46, 8645. (f) Buono, F. G.; Chidambaram, R.; Mueller, R. H.;
Waltermire, R. E. Org. Lett. 2008, 10, 5325. (g) Martin, M. T.; Liu, B.;
Cooley, B. E., Jr.; Eaddy, J. F. Tetrahedron Lett. 2007, 48, 2555.
(9) For the transition metal catalyzed cyanations using TMSCN, see:
(a) Chatani, N.; Hanafusa, T. J. Org. Chem. 1986, 51, 4714.
(b) Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller,
M. J. Organomet. Chem. 2003, 684, 50.
(
3) (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.
4) (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 2,
749. (b) Lindley, J. Tetrahedron 1984, 40, 1433.
5) (a) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779.
b) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011, 40, 5049.
(
1
(
(
(
(6) For the transition metal catalyzed cyanations using KCN, see:
a) Sakakibara, Y.; Okuda, F.; Shimobayashi, A.; Kirino, K.; Sakai, M.;
Uchino, N.; Takagi, K. Bull. Chem. Soc. Jpn. 1988, 61, 1985.
b) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh,
L. M.; Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224. (c) Yang, C.;
Williams, J. M. Org. Lett. 2004, 17, 2837. (d) Cristau, H.-J.; Ouali, A.;
Spindler, J.-F.; Taillefer, M. Chem.;Eur. J. 2005, 11, 2483.
(7) For the transition metal catalyzed cyanations using NaCN, see:
a) Okano, T.; Iwahara, M.; Kiji, J. Y.; Sakakibara, F.; Okuda, A.
(
(10) ForthetransitionmetalcatalyzedcyanationsusingK Fe(CN) , see:
3
6
(a) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
(b) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508.
(c) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46, 2585.
(d) Grossman, O.; Gelman, D. Org. Lett. 2006,8, 1189. (e) Schareina, T.; Zapf,
A.; M €a gerlein, W.; M u€ ller, N.; Beller, M. Tetrahedron Lett. 2007, 48, 1087.
(
Synlett 1998, 243. (b) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 2890.
1
0.1021/ol301674m r XXXX American Chemical Society

are widely utilized in organic synthesis, medicinal chemistry,
21
and materials science. Therefore, facile and selective deri-
vatization of indoles is highly important and desirable. In
this regard, we describe herein a new entry of the regioselec-
tive CÀH cyanation of indoles with the use of ammonium
iodide and DMF.
Scheme 1. Cyanation of CÀB and CÀH Bonds with
NH I/DMF
4
a
Table 1. Optimization of Cu-Mediated Cyanation of 1a
1
5
of 2-phenylpyridine and its derivatives. Based on the
labeling experiments, it was concluded that the carbon
and nitrogen atom of the “CN” unit were originated
1
6
from ammonia and the N,N-dimethyl moiety of DMF,
1
7
respectively. With a slight modification by employ-
ing ammonium iodide instead of aqueous ammonia,
we could extend this method for the cyanation of aryl
boronic acids (their esters and borate salts) and electron-
additive
(equiv)
yield
b
entry
[Cu] (equiv)
cocatalyst
(%)
1
2
3
4
5
6
7
8
Cu(NO
Cu(ClO
Cu(OMe)
Cu(CH
Cu(OTf)
3
)
2
3 3H
2
O (2.0)
À
À
À
À
À
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
HOAc (2.0)
TFA (2.0)
0
4
)
2
6H
2
O (2.0)
0
3
1
8
rich benzenes without requiring a palladium catalyst. In
this study, it was proposed that ammonium iodide has a
dual role as a supplier of both an iodine and a nitrogen
atom. Mechanistic studies revealed that substrates are first
iodinated and then iodoarenes intermediates are cyanated
under the copper-mediated conditions (Scheme 1). Since
the position of the initial iodination of benzenes is con-
2
(2.0)
27
38
0
3
COO)
(2.0)
2
(2.0)
2
Cu(CF
Cu(CF
Cu(CF
Cu(CF
3
3
3
3
COO)
COO)
COO)
COO)
2
(2.0)
(2.0)
(2.0)
(2.0)
À
62
54
61
39
90
72
c
2
2
2
2
PdCl
c
2
Pd(OAc)
9
À
À
À
d
1
0
Cu(CF
Cu(CF
3
COO)
2
(1.2)
(1.2)
HOAc (1.2)
HOAc (1.2)
19
d,e
trolled by the electrophilic aromatic substitution pathway,
we envisioned that the developed CÀH cyanation protocol
11
3
COO)
2
a
17a,c,20
could also be applied to the reaction of indoles.
Conditions: 1a (0.3 mmol), NH I (2.0 equiv), additive, and [Cu] in DMF
4
Indoles
b 1
1.5 mL). H NMR yield (internal standard: 1,1,2,2-tetrachloroethane).
(
c
d
4
Palladium species in 10 mol % was used. NH I, copper, and additive were
e
used in 1.2 equiv amounts for 12 h. Under air balloon.
(
11) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
003, 42, 1661. (b) Park, E. J.; Lee, S.; Chang, S. J. Org. Chem. 2010, 75,
760. (c) Schareina, T.; Zapf, A.; Cott ꢀe , A.; Gotta, M.; Beller, M. Adv.
2
2
Synth. Catal. 2011, 353, 777.
12) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
13) For the use of other cyanation sources, see: (a) Luo, F.-H.; Chu,
C.-I.; Cheng, C.-H. Organometallics 1998, 17, 1025. (b) Sato, N.; Yue, Q.
Tetrahedron 2003, 59, 5831. (c) Zhang, Z.; Liebeskind, L. S. Org. Lett.
We initiated the present study with 1-methylindole (1a) asa
model substrate using NH I (2 equiv) in DMF (Table 1). It
(
4
(
was first found that the nature of copper species was critical
for determining the cyanation efficiency. When copper(II)
nitrate (2 equiv) was used, with which the cyanation of
arylboronic acids and benzenes was highly efficient in our
2006, 8, 4331. (b) Anbarasan, P.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2011, 50, 519. (c) Yang, Y.; Zhang, Y.; Wang, J. Org.
Lett. 2011, 13, 5608.
1
8
(14) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
previous study, the reaction was totally ineffective (entry 1).
While the reaction progress was varied depending on the
copper species examined (entries 2À5), copper(II) trifluoro-
acetate showed especially notable reactivity to afford 3-cya-
no-1-methylindole (2a) in 62% NMR yield (entry 6). Other
isomeric compounds (e.g., 2-cyano-1-methylindole) were not
(
15) For the direct CÀH bond functionalizations developed in this
group, see: (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068. (b) Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc.
2008, 130, 9254. (c) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2008, 130, 16158. (d) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew.
Chem., Int. Ed. 2009, 48, 9127. (e) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang,
S. Angew. Chem., Int. Ed. 2010, 49, 9899. (f) Kwak, J.; Kim, M.; Chang, S.
J. Am. Chem. Soc. 2011, 133, 3780. (g) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho,
S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110.
(
16) Our related works on the use of ammonia in synthetic methods:
a) Kim, J.; Chang, S. Chem. Commun. 2008, 3052. (b) Kim, J.; Lee, S. Y.;
Lee, J.; Do, Y.; Chang, S. J. Org. Chem. 2008, 73, 9454.
17) For similar approaches for generating the cyano unit “CN” from
ammonia and DMF (DMSO) under copper-mediated conditions, see:
a) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
(
Scheme 2. Indole Cyanation Using Ammonium Salts and DMF
(
(
6725. (b) Zhang, G.; Ren, X.; Chen, J.; Hu, M.; Cheng, J. Org. Lett.
2011, 13, 5004. (c) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(18) Kim., J.; Choi, J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012,
134, 2528.
(19) (a) Jereb, M.; Zupan, M.; Stavber, S. Chem. Commun. 2004,
2614. (b) Pavlinac, J.; Zupan, M.; Stavber, S. Synthesis 2006, 2603.
(20) (a) Do, H.-Q.; Daugulis, O. Org. Lett. 2010, 12, 2517. (b) Yan,
G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052. (c) Reddy,
B. V. S.; Begum, Z.; Reddy, Y. J.; Yadav, J. S. Tetrahedron Lett. 2010,
5
1, 3334.
(
21) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873.
observed in this reaction. The fact that the presence of
palladium catalysts such as PdCl or Pd(OAc) did not affect
(
(
b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.
c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
2
2
B
Org. Lett., Vol. XX, No. XX, XXXX

the product yield and selectivity (entries 7À8) is especially
significant in that Cheng and Jiao reported that palladium
catalysts were essential in the cyanation of 1-methylindole
the C6- or C4-position were cyanated in lower yields (2k
and 2l, respectively).
With regard to N-substituents, a range of different groups
could be employed. N-Phenyl and N-benzylindole were cyan-
ated exclusively at the 3-position in moderate to good yields
(2m and 2n, respectively). It is noted that cyanation of
unprotected indole took place in an acceptable yield (2o), thus
again demonstrating a high level of flexibility of the present
protocol (2mÀ2o). In addition, cyanation of N-carbonyl
group substituted indoles readily proceeded, but with con-
comitant decarbonylation leading to 3-cyano-1H-indole (2o)
with varied yields. On the other hand, N-tosylindole (1s) did
not undergo the cyanation. When 1,3-dimethylindole was
subjected to the conditions, only decomposition occurred. In
addition, no conversion was observed with benzofuran.
To gain mechanistic insights, a reaction profile was ob-
tained in the cyanation of 1-methylindole (1a) under the
(
1a) under slightly different conditions (Scheme 2). While the
product yield was decreased upon the use of trifluoroacetic
acid instead of acetic acid (entry 9), it was found that the
reaction efficiency could be improved by careful tuning of the
molar ratio of the reactant, reagent, and additive. Indeed, the
highest yield was obtained by using 1.2 equiv (relative to 1a) of
NH I, Cu(CF COO) , and HOAc each (entry 10). We assume
4
3
2
that this result is related to the stability of an in situ generated
intermediate, 3-iodo-1-methylindole (vide infra). Under air, the
efficiency of the cyanation was decreased (entry 11).
a,b
Scheme 3. Copper-Mediated Cyanation of Indoles
2
2
standard conditions (Figure 1). In analogy with our pre-
18
vious results in the cyanation of aryl boronic acids, iodinated
indole (3a) was initially observed to form in over 60% yield
within 1 h. The cyanated product 2a then started to generate
gradually over time upon the decrease of 3a, implying that an
iodinated indole is indeed an intermediate in the present
process. Besides, when an independently prepared iodoindole
3a was subjected to the present copper-mediated oxidative
conditions, 3-cyano-1-methylindole 2a was obtained in 67%
17b
yield in the absence of acetic acid (eq 1). Thus, we have
developed the regioselective cyanation of indoles with ammo-
nium iodide and DMF via sequential iodination and subsequent
cyanation in the absence of a palladium catalyst.
a
Reaction conditions: 1 (0.3 mmol) and NH
4
I (0.36 mmol) in DMF
b
(
1.5 mL) under O
2
at 130 °C for 12 h. Isolated yields.
With encouraging conditions in hands, we next investi-
gated the scope and limitations of our cyanation protocol
Scheme 3). First, it was observed that the reaction effi-
(
ciency and regioselectivity were highly maintained even
with substrates that do not bear a substituent at the
2
-position of indoles (compare 2a and 2b). In contrast, in
Jiao’s system, the cyanation became quite sluggish with
low selectivity when unsubstituted indoles at that position
1
7c
were subjected (Scheme 2). Second, the cyanation was
not much influenced by the electronic nature of substrates
as demonstrated by 2cÀ2i although electron-deficient
substituents slightly lowered the product yields. Third, an
excellent level of functional group tolerance was observed
and a wide range of labile groups were indeed intact under
the present cyanation conditions (2fÀ2i). While the pre-
sence of a substituent at the 7-position did not affect the
reaction efficiency (2j), indoles having the same group at
Figure 1. Reaction profile in the Cu-mediated cyanation of 1a.
Recently, Yu et al. reported the direct cyanation
of 2-phenylpyridines under copper-mediated conditions
12
using TMSCN or nitromethane, and a single electron
transfer pathway was proposed to be responsible for this
(22) See the Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

process. Along this line, we also envisaged that cyanation of
-phenylpyridines would be possible in a sequence of initial
iodination followed by cyanation using the presently devel-
2
Scheme 4. Proposed Pathway of the Present Cyanation
23
oped conditions without requiring palladium catalysts. It
should be mentioned that when aqueous ammonia and DMF
were used in the direct cyanation of 2-phenylpyridines, a
palladium catalyst was essential to achieve the rate-limiting
1
4
CÀH bond activation.
We were pleased to observe that regioselective cyanation of
2
-phenylpyridines was achieved under the current copper-
mediated oxidative conditions in the absence of palladium
catalysts (Table 2). When 2-phenylpyridine was subjected to
the conditions, a mixture of mono- and bis-cyanated products
was obtained with a similar ratio (entry 1). In contrast,
sterically congested substrates were cyanated selectively to
afford only monocyano products in high yields (entries 2À3).
In addition, cyanation of benzoquinoline took place without
difficulty (entry 4). It was observed that the cyanation did not
take place when other ammonium salts (NH Cl or NH OAc)
4
4
14,18
In analogy with the previous proposal,
a copper-mediated
rather than NH I were employed under otherwise identical
4
conditions, implying that the reaction proceeds via two
sequential steps: initial iodination followed by cyanation.
reaction of ammonia and DMF is postulated to provide a
cyanide anion. In addition, it is assumed that ammonium
iodide plays a dual role under the employed conditions: as a
24
source of iodide for the formation of iodine molecule and as
a supplier of a nitrogen atom of the cyano unit. An electro-
philic aromatic substitution is believed to involve the iodina-
tion of indoles to offer a 3-iodoindole intermediate. On the
other hand, 2-phenylpyridine might undergo the iodination
via a radical-cation pathway leading to an intermediate A
a
Table 2. Copper-Mediated Cynation of 2-Phenylpyridines
12,25
based on the chelation assistance.
In both substrates, the
subsequent cyanation step is proposed to operate utilizing a
copper species.
In conclusion, we have developed a copper-mediated
cyanation of indoles and 2-phenylpyridines using ammo-
nium iodide and DMF under “palladium-free” conditions.
The reaction proceeds via two sequential steps: initial
iodination followed by cyanation. The direct CÀH cyana-
tion has a broad substrate scope, high functional group
tolerance, and excellent regioselectivity.
Acknowledgment. This work was supported by the Na-
tionalResearch Foundation (KRF-2008-C00024) and MIRC
(NRF-2011-0001322). We thank Jiho Choi (KAIST) and
Kwangmin Shin (KAIST) for their helpful discussions.
Supporting Information Available. Experimental details,
1
13
and H and C NMR spectra of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
a
Reaction conditions: 4 (0.3 mmol) and NH I (0.36 mmol) in DMF
4
b
(
1.5 mL) under O
2
at 130 °C for 12 h. Isolated yields.
(
24) (a) Lyday, P. A. Ullmann’s Encyclopedia of Industrial Chemistry, 5th
Based on the present experimental studies and our prece-
a plausible pathway is proposed in Scheme 4.
Completely Revised Edition, Vol. A14; VCH: Weinheim, 1991; pp 388À389.
14,18
dent results,
(b) Mohan, K. V. V. K.; Narender, N.; Kulkarni, S. J. Tetrahedron Lett.
2
004, 45, 8015.
(
25) Biphenyl was not reacted under the present conditions.
(23) (a) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11,
716. (b) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem.
4
2009, 74, 9470.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX