A mild and efficient palladium-catalyzed cyanation of aryl chlorides with K4[Fe(CN)6]

Article abstract of DOI:10.1021/ol1028892

An efficient palladium-catalyzed cyanation of aryl chlorides is established. In the presence of a highly effective Pd/CM-phos catalyst, cyanation of aryl chlorides proceeds at 70 °C in general, which is the mildest reaction temperature achieved so far for this process. Common functional groups such as keto, aldehyde, ester, nitrile and-NH₂, and heterocyclic coupling partners including N-H indoles are well tolerated. Moreover, a sterically hindered nonactivated ortho,ortho-disubstituted electrophile is shown to be a feasible coupling partner in cyanation.

Full text of DOI:10.1021/ol1028892

ORGANIC
LETTERS
2011
Vol. 13, No. 4
648–651
A Mild and Efficient Palladium-Catalyzed
Cyanation of Aryl Chlorides with
K4[Fe(CN)6]
Pui Yee Yeung, Chau Ming So, Chak Po Lau, and Fuk Yee Kwong*
State Key Laboratory of Chirosciences and Department of Applied Biology and
Chemical Technology, The Hong Kong Polytechnic University, Hung Hom,
Kowloon, Hong Kong
bcfyk@inet.polyu.edu.hk
Received November 30, 2010
ABSTRACT
An efficient palladium-catalyzed cyanation of aryl chlorides is established. In the presence of a highly effective Pd/CM-phos catalyst, cyanation of
aryl chlorides proceeds at 70 °C in general, which is the mildest reaction temperature achieved so far for this process. Common functional groups
such as keto, aldehyde, ester, nitrile and -NH2, and heterocyclic coupling partners including N-H indoles are well tolerated. Moreover, a
sterically hindered nonactivated ortho,ortho-disubstituted electrophile is shown to be a feasible coupling partner in cyanation.
Aromatic nitriles are important structural motifs in
pharmaceuticals,1 agrochemicals, dyes, herbicides, and
insecticides. In organic synthesis, they are highly valuable
because of possible nitrile transformations to benzoic
acids/esters, amines, amides, imidoesters, benzamidines,
aldehydes, and nitrogen-containing heterocycles.2 Tradi-
tional synthetic methods for the formation of aryl
nitriles are the Rosenmund-von Braun3 and Sandmeyer4
reactions and the industrially applied ammoxidation.5
The Rosenmund-von Braun and Sandmeyer reactions
convert aryl iodides/bromides and aryl diazonium, respec-
tively, to corresponding nitriles using stoichiometric
CuCN at high temperature (e.g., 150-250 °C). Ammox-
idation affords aryl nitriles from toluene derivatives in the
presence of oxygen and ammonia under harsh reaction
conditions (e.g., 220-550 °C, under high pressure) with
heterogeneous catalysts.
The relatively limited substrate scope of these reactions
drives chemists to explore alternative transition-metal-
catalyzed cyanations for the preparation of more diversely
substituted aromatic nitriles.6 Nickel,7 copper,8 and palla-
dium complexes are known to be effective catalysts for this
(1) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-
tical Substances: Syntheses, Patents, Applications, 4th ed.; Georg Thieme:
Stuttgart, Germany, 2001; pp 241-242, 488-489, 553, 825-826, 1154,
1598-1599.
(2) (a) Rappoport, Z. Chemistry of the Cyano Group; John Wiley &
Sons: London, U.K., 1970. (b) Larcok, R. C. Comprehensive Organic
Transformations; VCH: New York, U.S.A, 1989; Vol. 819.
(3) (a) Rosenmund, K. W.; Struck, E. Chem. Ber. 1919, 52, 1749.
(b) von Braun, J.; Manz, G. Liebigs Ann. Chem. 1931, 488, 111. For reviews,
see:(c) Moury, D. T. Chem. Rev. 1948, 42, 207. (d) Ellis, G.; Romney-
Alexander, T. Chem. Rev. 1987, 87, 79.
(4) (a) Sandmeyer, T. Chem. Ber. 1884, 17, 2650. (b) Sandmeyer, T.
Chem. Ber. 1885, 18, 1492.
(5) (a) Stevenson, A. C. Ind. Eng. Chem. 1949, 41, 1846. (b) Denton,
W. I.; Bishop, R. B.; Caldwell, H. P.; Chapman, H. D. Ind. Eng. Chem. 1950,
42, 796.
(6) For reviews, see: (a) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J.
Org. Chem. 2003, 3513. (b) Takagi, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley & Sons:
Hoboken, NJ, 2002; Vol. 1, pp 657.
(7) For selected references on nickel-catalyzed cyanation of aryl
halides, see: (a) van Soolingen, J.; Brandsma, L.; Kruse, C. G. EP Patent
613,719, 1993. For microwave-assisted cyanation at 200 °C, see: (b) Arvela,
R. K.; Leadbeater, N. E. J. Org. Chem. 2003, 68, 9122.
r
10.1021/ol1028892
Published on Web 01/05/2011
2011 American Chemical Society

aryl iodides and bromides. They were converted to aryl
nitriles with the aid of various cyanating agents, for
instance, KCN, NaCN,11 CuCN,12 Zn(CN)2,13 TMSCN,14
and acetone cyanohydrins.15 In fact, aryl chlorides are
superior substrates since they are relatively inexpensive
and usually have a wider spectrum of availability when
compared to bromoarenes and iodoarenes.16 In 2000, Jin
and Confalone reported the first palladium-catalyzed cya-
nation of aryl chlorides.17 This procedure utilized Zn(CN)2
as the cyanating sources and required a high reaction
temperature. In 2007, Littke et al. reported mild cyanation
conditions (95 °C in general) for aryl chlorides using the
Buchwald-type ligand, rac-2-di-tert-butylphosphino-1,10-
binapththyl.18 This cyanation used a Zn(CN)2 source
which is considerably toxic to humans and the environ-
ment.19 Thus efforts in seeking a more environmental-
friendly CN source have emerged. In 2004, Beller and co-
workers introduced the Pd-catalyzed cyanation of aryl
bromides mediated by K4[Fe(CN)6].20,21 The reaction
temperature ranged from 140 to 160 °C. To the best of
our knowledge, there has been limited literature report
regarding cyanation of aryl chlorides mediated by K4[Fe-
(CN)6] under mild reaction conditions.22 Herein, we report
a general palladium-catalyzed cyanation of aryl chlorides.
The reaction temperature of 70 °C is the mildest ever
reported in cyanation reactions.
Figure 1. Selected examples of Pd-catalyzed cyanation of aryl
halides in pharmaceutical applications.
reaction. However, substoichiometric to stoichiometric
nickel complexes are required to drive the reaction.7b
Copper-catalyzed protocols are currently not applicable
for cyanation of aryl chlorides. In 1973, Takagi reported
the first palladium-catalyzed cyanation of aryl halides.9
Since then palladium-based cyanation procedures have
attracted a number of applications in pharmaceutical
syntheses (Figure 1),10 because of their favorable features
in better functional group tolerance, higher catalyst stabil-
ity under air/moisture, and superior catalytic activity.
Recent methodology developments in palladium-
catalyzed cyanation were focused on relatively reactive
We initially investigated the palladium-catalyzed cy-
anation using electronically neutral 4-chlorotoluene as
the benchmark aryl chloride. A series of commercially
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King, A. O.; Fortin, M. C.; Pipik, B.; King, S.; Verhoeven, T. R. Synth.
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Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet. Chem. 2003, 41,
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(17) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
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R. J.; Tarby, C. M.; Kiau, S. Org. Lett. 2007, 9, 1711.
(19) Zn(CN)2 [LD50 (oral, rat) = 54 mg/kg]; KCN [LD50 (oral, rat) =
5 mg/kg]. Toxicity data taken from corresponding Material Safety Data
Sheet (MSDS) from Acros Organics, http://www.acros.com. KCN
[LD50 (oral, human) = 2.86 mg/kg]; the LD50 of K4[Fe(CN)6] is even
lower than that for NaCl. Toxicity data taken from corresponding
MSDS from Merck KGA, http://www.merck-chemicals.de.
(20) For initial development by the Beller group, see: (a) Schareina,
T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 12, 1388. (b) Schareina, T.;
Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689, 4576.
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X. Z.; Wang, J. J.; Yin, W. P.; He, S. B. Catal. Commun. 2009, 10, 768.
€
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Hayama, H. Bull. Chem. Soc. Jpn. 1975, 48, 3298.
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Chem. 2006, 71, 4021. (b) Challenger, S.; Dessi, Y.; Fox, D. E.; Hesmondhalgh,
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Lett. 1999, 40, 8193. (d) Beaudin, J.; Bourassa, D. E.; Bowles, P.; Castaldi,
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Okuda, F.; Hokimoto, A.; Ueda, T.; Sakai, M.; Takai, K. Bull. Chem.
Soc. Jpn. 2004, 77, 1013. (b) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J.
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ꢀ
ꢀ
ꢀ
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Org. Lett., Vol. 13, No. 4, 2011
649

Table 1. Effect of Base and Solvent on the Cyantaion of
4-Chlorotoluenea
Scheme 1. Ligand Screening in Palladium-Catalyzed Cyanation
of Aryl Chloridea
entry
base (mmol)
solvent (ratio)
yield (%)b
1
Na2CO3 (0.25)
K2CO3 (0.25)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
MeCN/H2O (1:1)
tBuOH/H2O (1:1)
dioxane/H2O (1:1)
MeCN
91
81
80
69
57
65
96
92
22
50
0
2
3
Na3PO4 (0.25)
K3PO4 (0.25)
4
5
Na2CO3 (1.0)
6
Na2CO3 (0.5)
7
Na2CO3 (0.125)
Na2CO3 (0.063)
Na2CO3 (0.125)
Na2CO3 (0.125)
Na2CO3 (0.125)
Na2CO3 (0.125)
8
9
10
11
12c
MeCN/H2O (1:1)
66
a Reaction conditions: 4-Chlorotoluene (1.0 mmol), K4[Fe(CN)6]•
3H2O (0.5 mmol), Pd(OAc)2 (0.02 mmol), Pd/CM-phos (1:2, precom-
plexation/preactivation of the catalyst was achieved by stirring Pd/CM-
phos with Et3N in CH2Cl2; see Supporting Information for details), base
(as indicated), solvent (2 mL total) at 70 °C for 18 h. b Calibrated GC
yields were reported using dodecane as the internal standard. c Pd2dba3
(0.01 mmol) was used instead of Pd(OAc)2 (0.02 mmol).
a Reaction conditions: 4-Chlorotoluene (1.0 mmol), K4[Fe(CN)6]•
3H2O (0.5 mmol), Pd(OAc)2 (0.02 mmol), Pd/Ligand (1:2), Na2CO3
(0.125 mmol) in MeCN/water (1:1, 2 mL total) at 70 °C for 18 h.
Calibrated GC yields were reported using dodecane as the internal
standard.
available ligands were tested for their efficacy in this
reaction (Scheme 1).
CM-phos23 gave the best conversion (93% yield) of aryl
chloride when compared to XPhos,24 SPhos,25 and
BrettPhos26 (Scheme 1). The CataCXium27 ligand series
did not promote the cyanation reaction. Further experi-
ments were conducted for optimization of the cyanation
process (Table 1). Inorganic bases were found to be
important to promote this cyanation (entries 1-4). Na2CO3
afforded the best result (entry 1). The stoichiometry
of Na2CO3 used also affected the substrate conversion
(entries 1, 5-8). Acetonitrile/water mixtures were the best
solvent medium of choice for this reaction (entry 7 vs 9-10).
It should be noted that a no substrate conversion was
observed when acetonitrile solvent was used alone (entry
11). We were intrigued that this inferior result may be due to
the poor solubility of K4[Fe(CN)6]•3H2O in acetonitrile.
Therefore, we attempted to add water in the reaction system
in order to enhance the solubility of hydrated K4[Fe(CN)6].
The effect of water added to the cyanation reaction is
Figure 2. Effect of cosolvent (water) added to the benchmark
conditions. Reaction conditions: 4-Chlorotoluene (1.0 mmol),
K4[Fe(CN)6]•3H2O (0.5 mmol), Pd(OAc)2 (0.02 mmol), Pd/
CM-phos (1:2), Na2CO3 (0.125 mmol), mixed solvent (2 mL
total) at 70 °C for 18 h. Calibrated GC yields were reported using
dodecane as the internal standard.
summerizedinFigure2. Neitherwater nor acetonitrile alone
provided substrate conversion. The best solvent mixtures
ranged from 30 to 50% water in acetonitrile.
(23) For our initial developments of CM-phos, see: (a) So, C. M.;
Zhou, Z.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008, 47,
6402. (b) So, C. M.; Lau, C. P.; Kwong, F. Y. Angew. Chem., Int. Ed. 2008,
47, 8059. (c) So, C. M.; Lau, C. P.; Chan, A. S. C.; Kwong, F. Y. J. Org.
Chem. 2008, 73, 7731.
(24) For Buchwald’s X-Phos in C-C coupling reactions, see:
Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11818.
(25) For SPhos, see: Barder, T. E.; Walker, S. D.; Marinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
(26) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(27) For CataCXium A, see: (a) Zapf, A.; Ehrentraut, A.; Beller, M.
Angew. Chem., Int. Ed. 2000, 39, 4153. For CataCXium PCy, see:(b) Zapf,
A.; Beller, M. Chem Commun. 2005, 431. For CataCXium PInCy, see:
(c) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees,
A.; Dingerdissen, U.; Beller, M. Chem.;Eur. J. 2004, 10, 2983.
With the optimized reaction conditions in hand, we next
tested the scope of this cyanation (Table 2). Common
functional groups, such as aldehydo, keto, ester, nitrile,
and free amino groups were well tolerated under these
reaction conditions (entries 3, 5-9, 15). A deactivated aryl
chloridealsoaffordedagoodyield (entry 2). Thecyanation
of benzothiazolyl and quinolyl chlorides furnished the
corresponding products in satisfactory yields (entries
11-13). Notably, the cyanation of an unprotected indole
gave the nitrile product in 91% yield (entry 14). The
cyanation proceeded smoothly for sterically congested aryl
chloride (entry 16).
650
Org. Lett., Vol. 13, No. 4, 2011

Table 2. Palladium-Catalyzed Cyanation of Aryl Chloridesa
Scheme 2. One-Pot Sequential Cyanation-Amination
Reactiona
a Reaction conditions: (Cyanation) same as that in Table 2, entry 3;
(Amination) 4-chlorotoluene (0.6 mmol), Cs2CO3 (3.0 mmol), toluene (2
mL, additional) were added and stirred at 110 °C for 24 h (see Support-
ing Information for detailed procedures).
common functional groups are well tolerated. Thus, it is
possible to perform sequential coupling reactions to access
multifunctional molecules. To demonstrate the feasibility
of this approach, a one-pot sequential synthesis was at-
tempted (Scheme 2). 3-Chloroaniline was cyanated to give
3-aminobenzonitrile. Without further addition of catalyst,
the N-aryl aminobenzonitrile was obtained in good yield
after the addition of 4-chlorotoluene (Scheme 2).
In summary, we have reported a general and efficient
palladium-catalyzed cyanation of aryl chlorides. The reac-
tion temperature of 70 °C is the mildest condition reported
so far for such reactions. Particularly noteworthy is that
water is found necessary as cosolvent to facilitate the
cyanation. This key finding may be useful for future
cyanation investigations using K4[Fe(CN)6]•3H2O as the
cyanide source. The mild palladium system described here
exhibits excellent functional group compatibility. Nitrile,
ester, keto, aldehyde, free amine, and heterocyclic groups
remain intact during the course of the reaction. The one-
pot cyanation-amination sequence shows the potential of
this catalyst system for further functional group manip-
ulation of a synthetic devise, yet without isolation of the
intermediate or addition of extra catalyst.
Acknowledgment. Dedicated to Professor Albert S. C.
Chan on the occasion of his 60th birthday. We thank the
Research Grants Council of Hong Kong (PolyU 5008/
08P), PolyU Internal Competitive Research Grant (A-
PG13), and the University Grants Committee Areas of
Excellence Scheme (AoE/P-10/01) for financial support.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data, and copies of 1H and
13C NMR spectra of aryl nitriles. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reaction conditions: ArCl (1.0 mmol), K4[Fe(CN)6]•3H2O
(0.5 mmol), Pd(OAc)2 (0.02 mmol, 2 mol %), Pd/CM-phos (1:2),
K2CO3 (0.125 mmol), MeCN/water (1:1, total 2 mL), 70 °C, 18 h
(reaction time was not optimized for each substrate). b Isolated yields.
c 3 mol % Pd(OAc)2. d 4 mol % Pd(OAc)2. e 5 mol % Pd(OAc)2.
(28) For reviews concerning the application of cross-coupling se-
quences for the preparation of pharmaceutically useful intermediates,
see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442. (b) King, A. O.; Yasuda, N. In Organometallics in Process
Chemistry; Larsen, R. D., Ed.; Springer: Berlin, Germany, 2004; pp
205-246.
A facile assembly of modular organic molecules using
cross-coupling protocols is highly attractive.28 To our
delight, under our reaction conditions for cyanation,
Org. Lett., Vol. 13, No. 4, 2011
651