Copper-catalyzed cyanation of heterocycle carbon-hydrogen bonds

Article abstract of DOI:10.1021/ol100772u

A method for regioselective cyanation of heterocycles has been developed. A number of aromatic heterocycles as well as azulene can be cyanated in reasonable to good yields by using a copper cyanide catalyst and an iodine oxidant.

Full text of DOI:10.1021/ol100772u

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2517-2519
Copper-Catalyzed Cyanation of
Heterocycle Carbon-Hydrogen Bonds
Hien-Quang Do and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
olafs@uh.edu
Received April 2, 2010
ABSTRACT
A method for regioselective cyanation of heterocycles has been developed. A number of aromatic heterocycles as well as azulene can be
cyanated in reasonable to good yields by using a copper cyanide catalyst and an iodine oxidant.
The nitrile functional group is found in many pharmaceuticals
and agrochemicals.1,2 Sandmeyer and Rosenmund-von
Scheme 1. Cyanation Methods
Braun reactions are classic methods for the synthesis of
aromatic nitriles (Scheme 1A).3 However, both procedures
employ a stoichiometric copper(I) cyanide reagent and
prefunctionalized starting materials. Cyanation of aryl halides
by employing catalytic copper or palladium is also well-
known.4 In contrast, direct cyanation through C-H bond
functionalization is more attractive due to the use of readily
available reactants.5 Direct cyanation can be achieved by
employing an appropriate oxidant in combination with a
cyanide source (Scheme 1B).6 Methods for direct cyanation
of pyridines,6b thiophenes,6c,e substituted indoles,6c,e,h
pyrroles,6c,e and 2-phenylpyridines6d,f,g have been reported
in the literature. However, direct transition-metal-catalyzed
(1) (a) Murdoch, D.; Keam, S. J. Drugs 2005, 65, 2379. (b) Njar,
V. C. O.; Brodie, A. M. H. Drugs 1999, 58, 233
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(2) Ozoe, Y.; Ishikawa, S.; Tomiyama, S.; Ozoe, F.; Kozaki, T.; Scott,
J. G. ACS Symp. Ser. 2007, 948, 39
.
(3) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. (b) Galli,
C. Chem. ReV. 1988, 88, 765. (c) Rosenmund, K. W.; Struck, E. Chem.
Ber. 1919, 52, 1749. (d) von Braun, J.; Manz, G. Liebigs Ann. Chem. 1931,
488, 111. (e) Connor, J. A.; Leeming, S. W.; Price, R. J. Chem. Soc., Perkin
Trans. 1 1990, 1127. (f) Ellis, G. P.; Romney-Alexander, T. M. Chem.
ReV. 1987, 87, 779.
(6) (a) So, Y.-H.; Miller, L. L. J. Am. Chem. Soc. 1980, 102, 7119. (b)
Katritzky, A. R.; Scriven, E. F. V.; Majumder, S.; Tu, H.; Vakulenko, A. V.;
Akhmedov, N. G.; Murugan, R. Synthesis 2005, 993. (c) Dohi, T.;
Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y. Org. Lett. 2005, 7, 537.
(d) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (e) Dohi, T.; Morimoto, K.; Takenaga, N.; Goto, A.;
Maruyama, A.; Kiyono, Y.; Tohma, H.; Kita, Y. J. Org. Chem. 2007, 72,
109. (f) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 4716.
(g) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem. 2009,
74, 9470. (h) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
1052. (i) Mariampillai, B.; Alliot, J.; Li, M.; Lautens, M. J. Am. Chem.
Soc. 2007, 129, 15372. (j) 2-Cyanoimidazoles can be prepared by the
reaction of the corresponding imidazole with cyanogen bromide: (k) Whitten,
J. P.; McCarthy, J. R.; Matthews, D. P. Synthesis 1988, 470. Electrochemical
oxidation of caffeine in the presence of cyanide has been shown to afford
8-cyanocaffeine: (l) Sono, M.; Toyoda, N.; Shizuri, Y.; Tori, M. Tetrahedron
Lett. 1994, 35, 9237.
(4) (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 2890. (b) Cristau, H.-J.; Ouali, A.; Spindler, J.-F; Taillefer, M.
Chem.sEur. J. 2005, 11, 2483. (c) Schareina, T.; Zapf, A.; Ma¨gerlein, W.;
Mu¨ller, N.; Beller, M. Chem.sEur. J. 2007, 13, 6249. (d) Sundermeier,
M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003, 3513. (e) Sundermeier,
M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661.
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Acc. Chem. Res. 2008, 41, 1013. (b) Campeau, L.-C.; Fagnou, K. Chem.
Soc. ReV. 2007, 36, 1058. (c) Ackermann, L. Synlett 2007, 507. (d) Chen,
X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009,
48, 5094. (e) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007, 36, 1173.
(f) Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147. (g) Daugulis,
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10.1021/ol100772u  2010 American Chemical Society
Published on Web 05/04/2010

cyanation of acidic heterocycles such as azoles, imidazoles,
and triazoles has not been described yet.6k,l We report here
a method for regioselective, direct cyanation of aromatic
heterocycles as well as azulene by employing copper
catalysis and an iodine oxidant.
gain insight into the reaction pathway. The results indicate
that the cyanation is a stepwise reaction. Benzothiazole is
iodinated to afford 2-iodobenzothiazole followed by copper-
catalyzed cyanation yielding the desired product 2. Conse-
quently, reaction conditions should be optimized with respect
to both iodination and cyanation. Among tested cyanide
sources, sodium cyanide provides the highest reactivity due
to its solubility in dioxane. However, it has been well-
established that high concentration of cyanide will deactivate
copper catalyst due to strong complexation.4 Careful tuning
of the solvent polarity led to significant improvement of
conversion to the product (Table 1).
Several key issues need to be addressed for achieving a
general cyanation procedure. First, high regioselectivity is
required for the procedure to be synthetically relevant. High
regioselectivity observed in direct arylation7 and halogenation
reactions8 (Scheme 2A) is imparted by the initial deprotonation
step. This protocol rules out the use of positive cyanide sources
due to their incompatibility with strong bases. Consequently,
simple cyanide salts such as NaCN or KCN must be employed.
Second, choice of base is important. As described earlier,7,8
tBuOLi allows for functionalization of a wide range of
substrates possessing DMSO pKa’s below 35-37. Third, the
oxidant has to be compatible with all other reagents. It should
not react with the organolithium intermediate producing
byproducts that can not be converted to the desired cyanation
product. Oxygen reactivity with some arylmetals complicates
the catalytic system by requiring the use of zinc or
magnesium amide bases.9 Iodine is compatible with copper
catalysts, and aryl iodides formed in the reaction of ArLi
with I2 can be converted to aryl cyanides.4,8 Consequently,
we decided to employ iodine as the oxidant in conjunction
with tBuOLi base and a copper catalyst (Scheme 2B).
Table 1. Optimization of Cyanation Conditions
entry
1
solvent
MCN
2a
DMF
NaCN, KCN, Zn(CN)2,
or K3[Fe(CN)6]
NaCN
KCN, Zn(CN)2
K3[Fe(CN)6]
NaCN
0%
2
3
dioxane
dioxane
42%
<2%
4
5
6
7
8
9
xylene
0%
54%
72%
90%
78%
59%
dioxane/xylene (9/1)
dioxane/xylene (4/1)
dioxane/xylene (7/3) NaCN
dioxane/xylene (3/2)
dioxane/xylene (1/1)
NaCN
NaCN
Scheme 2. Method Development
NaCN
NaCN
a Conversion by GC reported.
Table 2. Optimization of Copper Catalyst
Benzothiazole was chosen as a model substrate, and
copper(I) cyanide/phenanthroline catalyst was used to screen
for suitable reaction conditions. DMF solvent was chosen
as a starting point for optimization because it has been
successfully used in base-mediated iodination.8 Several
cyanating reagents such as NaCN, KCN, Zn(CN)2, and
K3[Fe(CN)6] were screened. However, none of these reac-
tions afforded any cyanation product. Solvent screening
revealed that 1,4-dioxane yields 42% conversion to the
desired product if NaCN is employed as the cyanating
reagent (Table 1). The reaction mixture was monitored to
entry
catalyst/ligand
CuCN/no ligand
CuCN/phenanthroline (1/1)
CuCN/phenanthroline (1/2)
CuCN/bipyridine (1/2)
2a
3a
1
2
3
4
5
6
<2%
60%
90%
88%
87%
90%
<2%
16%
<2%
<3%
<2%
<2%
CuCl/phenanthroline (1/2)
CuI/phenanthroline (1/2)
(7) (a) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2009, 11,
1511. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c)
Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185. (d) Do, H.-Q.; Daugulis, O. Chem. Commun. 2009, 6433.
(8) Popov, I.; Do, H.-Q.; Daugulis, O. J. Org. Chem. 2009, 74, 8309.
(9) (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009,
131, 5044. (b) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2009, 131, 17052.
(c) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs, A. P.
a Conversion by GC reported. Dioxane/m-xylene solvent (7/3).
Ligand optimization is shown in Table 2. The cyanation
did not proceed in the absence of phenanthroline. In addition,
a considerable amount of benzothiazole dimer byproduct was
observed if less than 20 mol % of phenanthroline was used.
¨
Tetrahedron Lett. 2003, 44, 1691. (d) Demir, A. S.; Reis, O.; Emruallahoglu,
M. J. Org. Chem. 2003, 68, 10130.
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Org. Lett., Vol. 12, No. 11, 2010

sodium cyanide, iodine oxidant, and mixed dioxane/m-xylene
solvent. These conditions were applied to cyanation of a
variety of heterocycles (Table 3).
Table 3. Cyanation Scopea
Heterocycles such as benzoxazole, benzothiazole, benz-
imidazole, caffeine, and triazoles are cyanated in reasonable
to good yields (entries 1-7). Electron-deficient 2-phenylpy-
ridine oxide is also cyanated in good yield (entry 8). Pyridine
derivatives with electron-withdrawing (fluorine) or electron-
donating (methoxy) substituents are reactive under the
general conditions affording products in acceptable yields
(entries 9 and 10). In both cases, the cyano group was
introduced at the 2-position. Similar selectivity has been
reported by Katritzky in the direct cyanation of pyridines
by the addition/elimination approach.6b
Indoles constitute an important motif of aromatic com-
pounds encountered in many natural products and pharma-
ceuticals. Hence, selective functionalization of indoles has
attracted much attention in recent years.10 Wang and co-
workers have recently developed a method for palladium-
catalyzed cyanation of 1- and 2-substituted indoles by
employing 3 equiv of Cu(OAc)2 reoxidant.6h
Minor modifications of our general conditions enabled
regioselective cyanation of N-methylindole and azulene. The
following changes in procedure were required for achieving
high yield of the product. First, pyridine additive prevents
the solidification of the reaction mixture. Second, sodium
phosphate base was found to be more efficient than tBuOLi
in the iodination step. Third, copper catalyst was added to
the reaction mixture after the iodination step was complete.
Consequently, the combination of iodine and sodium
phosphate in dioxane provided effective iodination conditions
that are compatible with the subsequent copper-catalyzed
cyanation. Copper catalyst was added after the iodination
step in entries 11 and 12 to prevent the oxidation of copper(I)
catalyst.7d This procedure selectively afforded 3-cyano-1-
methylindole in excellent yield (entry 11). Azulene was
cyanated in moderate yield (36%) due to low reactivity of
iodoazulene intermediate in the cyanation step.
In conclusion, we have developed a method for copper-
catalyzed cyanation of aromatic heterocycles and azulene.
The use of mild iodine oxidant allows for regioselective
sequential iodination/cyanation of heterocycles with acidic
C-H bonds, methylindole, and azulene.
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571), the NIGMS (Grant No. R01GM077635), A. P.
Sloan Foundation, Norman Hackerman Advanced Research
Program, and Camille and Henry Dreyfus Foundation for
supporting this research.
a Substrate (1 equiv), tBuOLi (2-2.13 equiv), iodine (1.35-1.5 equiv),
NaCN (1.3 equiv), CuCN (0.1 equiv), and phenanthroline (0.2 equiv). Yields
are isolated yields. b Cyanide as the limiting reagent. c Substrate (1.5-2
equiv), pyridine (0.76 equiv), Na3PO4 (2 equiv), iodine (1-1.35 equiv),
and dioxane solvent. Copper(I) catalyst (0.2 equiv), phenanthroline (0.3
equiv), and sodium cyanide (1-1.3 equiv) were added after the iodination
step. See Supporting Information for details.
Supporting Information Available: Experimental details,
data, and spectra for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL100772U
The bipyridine ligand was shown to be almost as efficient
as phenanthroline (entry 4). Copper(I) chloride and copper(I)
iodide can also be employed as catalysts. The optimized
conditions involve CuCN catalyst, phenanthroline ligand,
(10) For recent reviews, see: (a) Humphrey, G. R.; Kuethe, J. T. Chem.
ReV. 2006, 106, 2875. (b) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105,
2873. (c) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (d) Joucla, L.; Djakovitch, L. AdV. Synth. Catal. 2009, 351, 673.
Org. Lett., Vol. 12, No. 11, 2010
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