Ethyl cyanoacetate: A new cyanating agent for the palladium-catalyzed cyanation of aryl halides

Article abstract of DOI:10.1021/ol3014914

A new Pd-catalyzed cyanation reaction has been discovered using ethyl cyanoacetate as the cyanating reagent. A variety of electron-rich and electron-deficient aryl halides were efficiently converted into their corresponding nitriles in good to excellent yields.

Full text of DOI:10.1021/ol3014914

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Ethyl Cyanoacetate: A New Cyanating
Agent for the Palladium-Catalyzed
Cyanation of Aryl Halides
Shuyan Zheng,† Chunhui Yu,† and Zhengwu Shen*
School of Pharmacy, Shanghai University of Traditional Chinese Medicine,
Shanghai 201203, P. R. China, and Basilea Pharmaceutica China Ltd., Haimen,
Jiangsu 226100, P. R. China
jeff_shen_1999@yahoo.com
Received May 31, 2012
ABSTRACT
A new Pd-catalyzed cyanation reaction has been discovered using ethyl cyanoacetate as the cyanating reagent. A variety of electron-rich and
electron-deficient aryl halides were efficiently converted into their corresponding nitriles in good to excellent yields.
The nitrile functional group is a versatile functional
group in organic synthesis and can be easily transformed
into a variety of functional groups, such as amines, alde-
hydes, amides, acids, esters, tetrazoles, triazoles, oxazoles,
and thiazoles.1 Aryl nitriles are not only integral parts of
dyes and pigments but are also important building blocks
of certain pharmaceuticals.2 For example, Casodex
(bicalutamide, Zeneca, antineoplastic, anticancer), Aolept
(pericyazine, Bayer, antipsychotic, neuroleptic), and
Femara (letrozole, Novartis Pharma, antineoplastic, aro-
matase inhibitor) all contain an aryl nitrile moiety.1,2
Many methods have been developed to introduce cyano
groups into molecules. The traditional approaches for the
preparation of aryl nitriles1,3involve the Rosenmundꢀvon
Braun reaction from the corresponding halides or the
Sandmeyer reaction from aniline. In an industrial setting,
the ammoxidation reaction is typically used.4 Recently, a
useful alternative for the preparation of aryl nitriles was
developed using transition-metal-catalyzed cyanation of
aryl-X compounds (X = Cl, Br, I, and H). The cyanation
agents used in this approach include MCN (M = Cu, K,
Na, Zn), TMSCN, and K4Fe(CN)6 (Scheme 1, entry a).5
However, there is still great interest in finding safer and
more environmentally friendly cyanation reagents.
Very recently, a few new cyanation reagents were iden-
tified. Nitromethane was used as the ꢀCN source for the
cyanation of 2-phenylpyridine by Yu’s group (Scheme 1,
entry b).6 Chang and co-workers reported a combined
ꢀCN source of DMF and ammonia for the cyanation of a
2-arylpyridine via CꢀH bond activation (Scheme 1, entry
c).7 DMF alone can also be used as a ꢀCN source, as
demonstrated by Jiao’s group (Scheme 1, entry f).8 Cheng
and co-workers reported a reaction using DMF and
NH4HCO3 for the cyanation of aryl halides (Scheme 1,
† These authors contributed equally to this work.
(5) Selected recent reports: (a) Okano, T.; Iwahara, M.; Kiji, J.
Synlett 1998, 243. (b) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun.
2004, 1388. (c) Yang, C. H.; Williams, J. M. Org. Lett. 2004, 6, 2837.
(d) Cristau, H. J.; Ouali, A.; Spindler, J. F.; Taillefer, M. Chem.;Eur. J.
2005, 11, 2483. (e) Ushkov, A. V.; Grushin, V. V. J. Am. Chem. Soc.
2011, 133, 10999.
(1) Anbarasan, P.; Schareina, T.; Beller, M. Chem. Soc. Rev. 2011,40, 5049.
(2) (a) Murahashi, S. I. Science of Synthesis; Georg Thieme: Stuttgart,
2004; Vol. 19, p 345. (b) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert,
D. Pharmaceutical Substances: Syntheses, Patents, Applications, 4th ed.;
Georg Thieme Verlag: Stuttgart, 2001; pp 241ꢀ242.
(6) Chen, X.; Hao, X. S.; Goodhue, C. E.; Yu, Q. J. J. Am. Chem. Soc.
2006, 128, 6790.
(3) (a) Beletskaya, I. P.; Sigeev, A. S.; Peregudov, A. S.; Petrovskii,
P. V. J. Organomet. Chem. 2004, 689, 3810. (b) Lindley, J. Tetrahedron
1984, 40, 1433.
(7) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272.
(8) Ding, S. T.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374.
(9) (a) Zhang, G. Y.; Ren, X. Y.; Chen, J. B.; Hu, M. L.; Cheng, J.
Org. Lett. 2011, 13, 5004. (b) Zanon, J.; Klapars, A.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 2890.
(4) Hagedorn, F.; Gelbke, H. P. In Ullmanns Encyklopa€die der
ꢀ
technischen Chemie, 4th ed.; Bartholome, E., Biekert, E., Hellmann, H.,
Ley, H., Weigert, W. M., Weise, E., Eds.; Verlag Chemie: Weinheim, 1979;
pp 333.
r
10.1021/ol3014914
XXXX American Chemical Society

entry e).9 However, most of these cyanation procedures
involve the use of an aryl iodide or a highly reactive aryl
bromide and the use of specific substrates; thus, the scope
of the applications of these reactions is limited.
Table 1. Reaction Conditions for the Cyanation of 40-Bromo-
acetophenonea
Scheme 1. Sources of ꢀCN in Cyanation Reactions
ratio of
2:3:1b (%)
yield of
2c (%)
entry
ligand
TMEDA
catalyst
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
36:1:63
37:30:33
84:11:5
81:9:10
69:30:1
94:4:2
35
30
75
78
63
90
81
78
25
50
31
74
37
DPPE
3
DPPE þ TMEDA
4d
5
BINAP þ TMEDA Pd(OAc)2
TMEDA
Pd(dppf)Cl2
6e
7e
8
DPPE þ TMEDA Pd(OAc)2
BINAP þ TMEDA Pd(OAc)2
87:5:8
DPPE þ TMEDA
DPPE þ TMEDA
DPPE þ TMEDA
DPPE þ TMEDA
DPPE þ TMEDA
DPPE þ TMEDA
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
83:12:5
36:62:2
63:36:1
35:61:4
82:16:2
48:46:6
9
10f
11g
12h
13e
Pd(OAc)2
Herein, we describe for the first time the direct cyanation
of aryl halides using ethyl cyanoacetate asa source ofꢀCN
(Scheme 1, entry d). Palladium acetate was used as the
catalyst, and the reaction was conducted in the presence of 1,2-
bis(diphenylphosphino)ethane (DPPE), potassium iodide,
and N,N,N0,N0-tetramethylethylenediamine (TMEDA).
Since the ethyl cyanoacetate is an inexpensive, nontoxic
and easily handling organic reagent, this method may
potentially have wide applications.
Pd(OAc)2
Pd(PPh3)2Cl2
a Typical reaction conditions: substrate (1.0 mmol), ethyl cyanoace-
tate (3.0 mmol), palladium catalyst (0.2 mmol), base (3.0 mmol), ligand
(0.3 mmol), TMEDA (1.0 mmol), and DMF (5 mL) stirred at 130 °C
under an Ar atmosphere for 22 h. b The ratio of 2:3:1 was determined by
HPLC; the results are the averages of two identical experiments. c The
yield represents isolated yield. d BINAP (2, 20-bis(diphenylphosphino)-
1,10-binaphthyl). e 1.0 mmol of KI was added. f K3PO4 was used.
g CS2CO3 was used. h NaOtBu was used.
The cyanation of 40-bromoacetophenone was selected as
a model reaction to identify essential additives and to
optimize the reaction conditions. Selected results are pre-
sented in Table 1. Various palladium catalysts, phosphate
ligands, organic bases, and inorganic salts were screened. It
was found that palladium acetate in the presence of
TMEDA, DPPE, sodium carbonate and potassium iodide
gave the best results. Both DPPE and TMEDA were
believed to reduce the deactivation of the palladium cata-
lyst. Either DPPE or TMEDA can be used alone; however,
the combination of these two compounds results in better
reaction yields. In addition, it was found that a greater
amount of palladium catalyst and a higher reaction tem-
perature will increase the yield and reduce the reaction
time. The reaction yield can also be significantly improved
by adding potassium iodide to the reaction mixture. The
mechanism for this improvement may be due to the
exchange between the iodide with bromide or chloride in
the molecule. Both DMF and DMSO can be used as the
reaction solvent withoutdrying. Thereaction isquite clean,
and only small amounts of ethyl 2-(4-acetylphenyl)-2-cya-
noacetate were detected as a byproduct under most of the
reaction conditions.
Different aryl halides with various substituents at the
ortho, meta and para positionswereinvestigated, and most
of the reactions proceeded smoothly under the standard
conditions. In addition, a number of interesting observa-
tions were made. The reactivity of aryl halides decreases as
the bond-dissociation energy of the CꢀX bonds increases
(reactivity: I > Br > Cl) (Table 2, entries 3, 4, 5, 18, 19).1,10
Substituents containing active protons such as phenol
groups or amine groups seem not to inhibit the reaction
(Table 2, entries 2, 9). The presence of two or more strong
electron-withdrawing groups (F, NO2) on the aromatic
ring completely inhibits the cyanation reaction. A nucleo-
philic aromatic substitution proceeds instead (Table 3).
When the reaction is scaled up to the gram scale, the
addition of 1.0 mmol of water is needed,11 and the reac-
tion time must be extended. In certain specific cases, due to
the inertness of the substrate with respect to this cyana-
tion reaction, compound 4 becomes the major reaction
product.
For certain highly electron-deficient aromatic com-
pounds, phenylacetonitrile derivatives were produced
A number of aryl nitriles were synthesized using this new
method (Table 2). In general, the standard conditions
(Table 1, entry 6) gave good to excellent reaction yields.
However, for certain inert species, NaH replaced Na2CO3
when no conversion was observed (Table 2, entries 18, 19,
23, 24, and 29).
€
(10) (a) Martin, A.; Wolf, G. U.; Steinike, U.; Lucke, B. J. Chem.
€
Soc., Faraday Trans. 1998, 94, 2227. (b) Martin, A.; Lucke, B. Catal.
Today 1996, 32, 279.
(11) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett.
2008, 10, 3505.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Pd-Catalyzed Cyanation with Ethyl Cyanoacetatea
a Unless otherwise noted, all substrates used were aryl bromides. Standard reaction conditions: substrate (1.0 mmol), ethyl cyanoacetate (3.0 mmol),
Pd(OAc)2 (0.2 mmol), DPPE (0.3 mmol), TMEDA (1.0 mmol), Na2CO3 (3.0 mmol), KI (1.0 mmol), DMF (5 mL) stirred at 130 °C under Ar for 22 h. The
products were confirmed by 1H NMR, MS, IR and 13C NMR. b KI was not added. c Na2CO3 was replaced by NaH (55ꢀ60%).
instead of aryl nitriles under the standard reaction
conditions (Table 3). Normally, these highly electron-
deficient aromatic compounds were aryl halides bear-
ing two or more strong electron-withdrawing groups
such as NO2 and halides at the ortho and para posi-
tions. Thus, nucleophilic aromatic substitution was
the preferred reaction under the cyanation reaction
conditions. In fact, the aromatic substitution reaction
Org. Lett., Vol. XX, No. XX, XXXX
C

Furthermore, we also found that a small amount of water
will improve the reaction, especially at the gram scale. This
observation hinted that the existence of water may increase
the solubility of inorganic salts. On the basis of all of the
information available, a preliminary mechanism was pro-
posed as shown in Scheme 2.
Table 3. Phenylacetonitrile Produced by Pd-Catalyzed
Cyanation with Ethyl Cyanoacetatea,b
Scheme 2. Proposed Mechanism of the “CN” Transformation
It was assumed that the complex of the enolated ethyl
cyanoacetate and the palladium catalyst plays the key role
in the reaction. This complex can form an intermediate
with the aryl halide and can undergo the cyanation reac-
tion. It can also undergo nucleophilic aromatic substitu-
tion when electron-deficient aryl halides are used. If the
aryl halide is too inert, the complex will react with another
molecule of ethyl cyanoacetate and form a dimer instead.
In summary, we have discovered a new Pd-catalyzed
cyanation reaction using ethyl cyanoacetate as the cyanat-
ing reagent. A variety of electron-rich and electron-
deficient aryl halides were efficiently converted into
their corresponding nitriles in good to excellent yields.
Further optimization to reduce the high loading of
palladium acetate and studies to obtain a deeper under-
standing of the reaction mechanism and to determine
the synthetic applications of this reaction are ongoing
in our laboratory.
a The standard reaction conditions are same as for the preparation of
aryl nitriles. b The yield was obtained by isolation. c The yield was
obtained under the conditions of Na2CO3/DMF/130 °C/22 h.
can proceed smoothly even in the absence of the
palladium catalyst.
Based on the above results, mechanistic studies of the
reactions were performed. First, the control experiment
was performed in the absence of ethyl cyanoacetate. It was
found that the reaction does not proceed at all under these
conditions. Then, DMSO was used as the reaction solvent
instead of DMF, and this reaction yielded the same results.
These results indicated that the “CN” was originated from
ethyl cyanoacetate. An 1H NMR tracking experiment was
also performed. An acetate signal and an ethanol signal
Acknowledgment. This work was supported by Basilea
Pharmaceutica China, Ltd.
Supporting Information Available. Experimental pro-
cedures, characterization, and copies of 1H and 13CNMR
for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
were detected by H NMR after Pd(OAc)2 was reacted
with ethyl cyanoacetate in DMSO-d6 at 100 °C for 2.5 h.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX