Copper-mediated cyanation of aryl halide with the combined cyanide source

Article abstract of DOI:10.1021/ol201713b

A simple copper-mediated cyanation of aryl halide with the combination of ammonium bicarbonate and N,N-dimethylformamide as a cyanide source is achieved, providing nitriles in moderate to good yields. This new approach represents an exceedingly practical and safe method for the synthesis of aryl nitriles.

Full text of DOI:10.1021/ol201713b

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5004–5007
Copper-Mediated Cyanation of Aryl Halide
with the Combined Cyanide Source
Guoying Zhang, Xinyi Ren, Jianbin Chen, Maolin Hu,* and Jiang Cheng*
College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325027,
P. R. China
jiangcheng@wzu.edu.cn; maolin@wzu.edu.cn
Received June 26, 2011
ABSTRACT
A simple copper-mediated cyanation of aryl halide with the combination of ammonium bicarbonate and N,N-dimethylformamide as a cyanide
source is achieved, providing nitriles in moderate to good yields. This new approach represents an exceedingly practical and safe method for the
synthesis of aryl nitriles.
The cyanation reaction plays an important role in organic
synthesis because nitriles are versatile building blocks in the
synthesis of natural products, pharmaceuticals, and agri-
cultural chemicals.1 Moreover, nitriles may be facilely
transformed to a series of functional groups, such as amines,
aldehydes, amidines, tetrazoles, and amides.2 The Sand-
meyer and Rosenmundꢀvon Braun reactions are tradi-
tional methods to access nitriles.3 However, the reactions
suffer from the toxicity of a cyanide source at high tempera-
ture with prolonged times and multiple procedures. The
industrial method involves ammoxidation of toluene deri-
vatives with oxygen, at 300ꢀ550 °C under high pressure.4
The transition-metal-catalyzed direct cyanation of arene
CꢀH bonds represents a graceful method to access
aryl nitriles.5 In 2006, Yu described the Cu-catalyzed
cyanation of 2-arylpyridine CꢀH bonds using TMSCN
and CH3NO2.6 Encouraged by Yu’s works, we reported a
Pd-catalyzed direct cyanation of 2-arylpyridine CꢀH
bonds with CuCN and a cascade bromination/cyanation
reaction of the CꢀH bond using K3Fe(CN)6.7 Subse-
quently, Wang and Reddy reported the Pd-catalyzed
direct cyanation of an indole CꢀH bond, respectively.8
(6) Chen, X.; Hao, X.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
(1) (a) Murahashi, S. I. Synthesis of Nitriles with Retention of the
Cyano Group; Science of Synthesis; Georg Thieme: Stuttgart, 2004; p 345.
(b) Sriram, D.; Yogeeswari, P. Medicinal Chemistry; Pearson Education:
M€unchen, 2007; p 35.
(2) (a) Chemistry of the Cyano Group; Rappoport, Z., Ed.; Wiley:
London, 1970. (b) Larock, R. C. Comprehensive Organic Transformations;
Wiley-VCH: New York, 1989; p 819. (c) Anbarasan, P.; Schareina, T.;
Beller, M. Chem. Soc. Rev. 2011, DOI: 10.1039/c1cs15004a.
(3) (a) Sandmeyer, T. Ber. Chem. Dtsch. Chem. Ges. 1885, 18, 1492.
(b) Rosenmund, K. W.; Struck, E. Ber. Chem. Dtsch. Chem. Ges. 1919, 2,
1749. (c) Ellis, G. P; Romney-Alexander, T. M. Chem. Rev. 1987, 87,
779. (d) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
(4) (a) Denton, W. I.; Bishop, R. B.; Caldwell, H. P.; Chapman, H. D.
(7) (a) Jia, X.; Yang, D.; Zhang, S.; Cheng, J. Org. Lett. 2009, 11,
4716. (b) Jia, X.; Yang, D.; Wang, W.; Luo, F.; Cheng, J. J. Org. Chem.
2009, 74, 9470.
(8) (a) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12,
1052. (b) Reddy, B. V. S.; Begum, J.; Reddy, J.; Yadav, J. S. Tetrahedron
Lett. 2010, 51, 3334.
(9) For selected examples of transition-metal-catalyzed cyanantion
of aryl halides, see: (a) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2003, 125, 2890. (b) Sundermeier, M.; Zapf, A.; Beller, M.
Eur. J. Inorg. Chem. 2003, 3513. (c) Erhardt, S.; Grushin, V. V.;
Kilpatrick, A. H.; Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J.
Am. Chem. Soc. 2008, 130, 4828. (d) Zhou, W.; Xu, J.; Zhang, L.; Jiao,
N. Org. Lett. 2010, 12, 2888. (e) Sawant, D. N.; Wagh, Y. S.; Tambade,
P. J.; Bhatte, K. D.; Bhanage, B. M. Adv. Synth. Catal. 2011, 353, 781.
(f) Yu, H.; Richey, R. N.; Miller, W. D.; Xu, J.; May, S. A. J. Org. Chem.
2010, 76, 665. (g) Ushkov, A. V.; Grushin, V. V. J. Am. Chem. Soc. 2011,
133, 10999. (h) Shevlin, M. Tetrahedron Lett. 2010, 51, 4833.
(10) (a) Zhang, Z.; Liebeskind, L. S. Org. Lett. 2006, 8, 4331.
(b) Liskey, C. W.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc. 2010,
132, 11389. (c) Zhang, G.; Zhang, L.; Hu, M.; Cheng, J. Adv. Synth.
Catal. 2011, 353, 291. (d) Anbarasan, P.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2011, 50, 519.
€
Ind. Eng. Chem. 1950, 42, 796. (b) Martin, A.; Kalevaru, N. V.; Lucke,
B.; Sans, J. Green Chem. 2002, 4, 481.
(5) For examples of direct cyanation through CꢀH bond cleavage,
see: (a) So, Y.-H.; Miller, L. L. J. Am. Chem. Soc. 1980, 102, 7119. (b)
Dohi, T.; Morimoto, K.; Kiyono, Y.; Tohma, H.; Kita, Y. Org. Lett.
2005, 7, 537. (c) Mariampillai, B.; Alberico, D.; Bidau, V.; Lautens, M. J.
Am. Chem. Soc. 2006, 128, 14436. (d) Do, H.-Q.; Daugulis, O. Org. Lett.
2010, 12, 2517. (e) Qin, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 15893.
(f) Lu, Z.; Hu, C.; Guo, J.; Li, J.; Cui, Y.; Jia, Y. Org. Lett. 2010, 12, 480.
r
10.1021/ol201713b
Published on Web 09/07/2011
2011 American Chemical Society

Nevertheless, the requirement of the chelation group would
limit the substrate scope.
Table 1. Selected Results of Screening the Optimal Conditionsa
Recently, the transition-metal-catalyzed cyanation of aryl
halides,9 borons,10 or mesylates11 provides a promising
alternative to the cyanating reactions. Yet, except for
K4[Fe(CN)6] and K3[Fe(CN)6],12 the toxicity of the cya-
nide source of MCN (M = Cu, K, Zn, TMS), acetone
cyanohydrin,13 would greatly decrease the utility of the
aforementioned transformations. Therefore, the develop-
ment of a new and safe cyanide source in the cyanation
reaction witha broadsubstratescoperemainsanextremely
attractive but challenging task for organic chemists.
Recently, Chang reported the Pd-catalyzed chelation-
assisted cyanation of a 2-arylpyridine CꢀH bond using the
combination of ammonia and DMF as a safe cyanide
source.14 Subsequently, we demonstrated the Pd-catalyzed
cyanation of an indole CꢀH bond with the combination of
NH4HCO3 and DMSO.15 Very recently, Jiao described a
direct cyanation of indoles and benzofurans in which
DMF was disclosed for the first time as a source of
ꢀCN.16 However, the requirement of a chelation group
and employment of an expensive palladium catalyst are
required. Hideo described the conversion of aromatic
bromides and aromatics into aromatic nitriles via aryl-
lithiums or Grignard reagents and their DMF adduct in
the presence of equivalents of I2 and ammonia.17 Here-
in, we report a novel and facile strategy to obtain aryl
nitriles starting from commercially available aryl ha-
lides and the combination of DMF and NH4HCO3 as a
safe cyanide source based on the well-developed cop-
per-mediated cyanation.
entry
Cu source
ligand
yield (%)
1
CuBr2
--
12
2
CuBr2
L2
L2
L2
L2
L2
L2
L1
L3
L4
L5
L6
--
46
3
CuCl2
29
4
Cu(OAc)2
Cu(TFA)2
CuSO4
85 (80)b
63
5
6
21
7
--
0c0d0e
51
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
9
29
10
11
12
13
14
15
16
61
62
58
46
L2
L2
L2
46f(0)g
0h
<5i(26) j
a Reaction conditions: 1a (0.2 mmol), NH4HCO3 (1.5 equiv), copper
(1.2 equiv), ligand (20 mol %), under air, dry DMF (1 mL), 150 °C in a
sealed tube for 22 h. b O2. c DDQ. d K2S2O8. e PhI(OAc)2. f NH4I. g (NH4)2-
S2O3. h Dioxane. i DMSO. j CH3NO2.
We initiated our investigation by examining the reaction
of p-iodoanisole with DMF and NH4HCO3 (Table 1).
Fortunately, the cyanation product was obtained in 12%
yield with the combination of 1a, NH4HCO3, and CuBr2
in DMF (entry 1, Table 1). The reaction efficiency was
improved by using L2 as a ligand (entry 2, Table 1).
Gratifyingly, 2a was formed in 85% yield when 1.2 equiv
of Cu(OAc)2 was employed in the presence of L2 (entry 4,
Table 1). Other coppers, such as CuCl2, Cu(TFA)2, and
CuSO4, resulted in low efficiencies (entries 3, 5, 6, Table 1).
In the absence of copper, the employment of an oxidant, such
as DDQ, K2S2O8, and PhI(OAc)2, inhibited the reaction
(entry 7, Table 1). The influence of ligands was also investi-
gated, and the employment of 20 mol % of L2 was found to
be the best, providing the product in excellent yields for all the
above transformations (entries 8ꢀ13, Table 1). Meanwhile,
reaction in dioxane, DMSO, and CH3NO2 or with NH4Iand
(NH4)2S2O3 resulted in low efficiencies or no reaction (entries
14ꢀ16, Table 1).18 Importantly, this transformation is very
practical, as the expensive palladium catalyst or a large excess
of ammonia is not required.
With the optimized reaction conditions in hand, we
applied this new protocol to a range of aryl iodides, as
shown in Figure 1.
(11) Yeung, P. Y.; So, C. M.; Lau, C. P.; Kwong, F. Y. Angew.
Chem., Int. Ed. 2010, 49, 8918.
A series of functional groups, such as methoxy, benzy-
loxy, acetyl, free phenolic hydroxyl, and free acetamido
were compatible with the reaction conditions, and the
cyanation products were isolated in good yields. The
electronic properties of the substituents on the phenyl ring
of aryl iodides had some effect on the reaction. Generally,
the aryl iodides possessing electron-donating groups gave
slightly higher yields than those possessing electron-with-
drawing groups (2aꢀ2h vs 2nꢀ2p, Figure 1). Importantly,
various substitutents at the para, meta, and ortho position
(12) (a) Ren, Y.; Liu, Z.; Zhao, S.; Tian, X.; Wang, J.; Yin, W.; He, S.
Catal. Commun. 2009, 10, 768. (b) Schareina, T.; Zapf, A.; Beller, M.
Chem. Commun. 2004, 1388. (c) Schareina, T.; Zapf, A.; Beller, M. J.
Organomet. Chem. 2004, 689, 4576. (d) Yeung, P.; So, C.; Lau, C.;
Kwong, F. Org. Lett. 2011, 13, 648. (e) DeBlase, C.; Leadbeater, N. E.
Tetrahedron 2010, 66, 1098. (f) Zhao, Z.; Li, Z. Eur. J. Org. Chem. 2010,
5460.
(13) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2003, 42, 1661. (b) Park, E. J.; Lee, S.; Chang, S. J. Org. Chem. 2010, 75,
ꢀ
2760. (c) Schareina, T.; Zapf, A.; Cotte, A.; Gotta, M.; Beller, M. Adv.
Synth. Catal. 2011, 353, 777.
(14) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
(15) Ren, X.; Chen, J.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
6725.
(16) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(17) (a) Ushijima, S.; Moriyama, K.; Togo, H. Tetrahedron 2011, 67,
958. (b) Ishii, G.; Moriyama, K.; Togo, H. Tetrahedron Lett. 2011, 52,
2404. (c) Ushijima, S.; Togo, H. Synlett 2010, 1562.
(18) For the effect of other solvents and ammonium salt, see Sup-
porting Information for details.
(19) Commercially available DMF (carbonyl-13C, 99%) and
15NH4Cl (15N 99%) were employed.
Org. Lett., Vol. 13, No. 19, 2011
5005

respectively. Disappointingly, the alkyl, alkenyl, and
alkynyl iodides did not work under the standard
reaction conditions.
Figure 2. Copper-mediated cyanation of aryl bromides. aReac-
tion conditions: 3aꢀf (0.2 mmol), NH4HCO3 (1.5 equiv), Cu-
(OAc)2 (1.2 equiv), L2 (40 mol %), under air, dry DMF (1 mL),
150 °C, 22 h. bp-Chloroanisole.
To broaden the scope of substrates used, we carried out
reactions of aryl bromides with a combined cyanide source
under the standard conditions as shown in Figure 2. The
corresponding aryl nitriles were also afforded in moderate
yields.
In the absence of any ammonium, only a trace of the
cyanating product (<1%) or no product was detected by
GC-MS in DMF and NMP, respectively (entries 1, 4, and
5, Table 2). Under the standard procedures, replacing
DMF with DMF 13C-labeled on the carbonlyl19 formed
the normal product 2a mostly. Moreover, 2a was obtained
in 12% yield when NMP was employed. These results
Figure 1. Copper-mediated cyanation of aryl iodides. aReaction
conditions: 1aꢀu (0.2 mmol), NH4HCO3 (1.5 equiv), Cu(OAc)2
(1.2 equiv), L2 (20 mol %), under air, dry DMF (1 mL), 150 °C
in a sealed tube for 22 h. bp-Iodophenyl acetate.
Table 2. Study on the “CN” Formationa
wereall cyanatedsmoothlyunder the standardprocedures.
The cyanation of mono-, di-, and trimethoxy phenyl
iodides furnished the corresponding products in excellent
yields, and the order of activity is tri > di in terms of
yields (2bꢀ2f, Figure 1). Meanwhile, the hindrance on
the phenyl ring of aryl iodides had a slight effect on the
efficiency (2h vs 2i and 2s vs 2r, Figure 1). Fortunately, free
phenolic hydroxyl group survived well in the standard
procedure, leading to 2j in excellent yield. Intrigu-
ingly, when p-iodophenyl acetate was subjected to
the procedure, a 68% yield of 2j was isolated. Notably,
the acetamido (2k) and dialkylamino (2l) groups tol-
erated this transformation, and importantly, N-con-
taining substrates, such as 2-(2-iodophenyl)pyridine
and 3-iodo-1-methyl-1H-indole, were also good reaction
partners, providing 2t and 2u in 53% and 43% yield,
entry
ammonium
ligand
solvent
DMF
yield (%)
1
2
3
4
5
6
7
8
ꢀ
L2
L2
L2
L2
L4
L2
L2
L2
<1
<5b
12
0
NaHCO3
NH4HCO3
ꢀ
DMF
NMP
NMP
ꢀ
DMF
<1
62
79c
56
NH4Cl
NH4HCO3
15NH4Cl
DMF
H13CON(CH3)2
DMF
a Reaction conditions: 1a (0.2 mmol), Cu(OAc)2 (1.2 equiv), ammo-
nium (1.5 equiv), ligand (20 mol %), under air, dry solvent (1 mL),
150 °C in a sealed tube for 22 h. b NaHCO3 (1.5 equiv). c DMF (0.25 mL).
5006
Org. Lett., Vol. 13, No. 19, 2011

indicated the C-atom in the “CN” may be derived from the
methyl of DMF or NMP (entries 3, 7, Table 2). Chang also
confirmed the combination of NMP and ammonia
provided the cyanating product. Meanwhile, 1a was
allowed to react with 15NH4Cl to provide 2a00 under the
standard conditions, and almost complete isotopic
incorporation into the cyano moiety was observed,
strongly indicating that ammonia serves as the nitrogen
source of “CN” (entry 8, Table 2).
In the kinetic study, the reaction showed zero-order for
ArI.20 However, Paine confirmed it was first-order for ArI in
the copper-mediated cyanation of ArI with CuCN in DMF.21
The cyanide indicator paper supports the formation of
cyanide.22 Similar to Chang’s procedure, the CNꢀ is
formed, which takes part in the cyanation as the
copper-catalyzed cyanation of ArI.23 However, the
mechanism of the formation of the CNꢀ from the
combination of DMF and NH4HCO3 in detail cur-
rently remains unclear.
In conclusion, we have demonstrated a new copper-
mediated protocol for the generation of a cyano unit from
two readily available precursors. The convenience of the
methodology is promising for application in synthesizing a
broad range of nitriles in bioactive natural products or
other specific organic materials. Further mechanistic in-
vestigations are underway.
Acknowledgment.We thank the National Natural Science
Foundation of China (Nos. 20972115 and 21071111) and the
Natural Science Foundation of Zhejiang Province (No.
R4110294) for financial support.
(20) See Supporting Information for details.
(21) Couture, C.; Paine, A. J. Can. J. Chem. 1985, 63, 111.
(22) The CNꢀ was detected by indicator paper when the combination
of NH4HCO3, DMF, and Cu(OAc)2 was heated at 150 °C for 2 h.
However, heating of NH4HCO3, DMF, and TMEDA or p-iodoanisole
at 150 °C for 2 h did not produce any detectable CNꢀ. These results
indiꢀcated the Cu played an important role in the in situ formation of
CN . See Supporting Information for details.
Supporting Information Available. Experimental pro-
cedures along with copies of spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(23) Cristau, H.-J.; Ouali, A.; Spindler, J.-F.; Taillefer, M. Chem.;
Eur. J. 2005, 11, 2483.
Org. Lett., Vol. 13, No. 19, 2011
5007