A facile microwave-assisted palladium-catalyzed cyanation of aryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2006.03.026

We report an efficient method for the preparation of aryl nitriles from aryl chlorides under either microwave assisted or thermal conditions. A catalyst system comprising tris(dibenzylidene acetone)dipalladium (Pd₂(dba)₃) and 2-(2′,6′-dimethoxybiphenyl)dicyclohexylphosphine (S-Phos) is shown to effectively promote cyanation of various aryl chlorides with Zn(CN)₂ as the cyanide source.

Full text of DOI:10.1016/j.tetlet.2006.03.026

Tetrahedron Letters 47 (2006) 3303–3305
A facile microwave-assisted palladium-catalyzed cyanation
of aryl chlorides
Harry R. Chobanian,* Brett P. Fors and Linus S. Lin
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 23 January 2006; accepted 3 March 2006
Available online 22 March 2006
Abstract—We report an efficient method for the preparation of aryl nitriles from aryl chlorides under either microwave assisted or
thermal conditions. A catalyst system comprising tris(dibenzylidene acetone)dipalladium (Pd2(dba)3) and 2-(20,60-dimethoxybiphen-
yl)dicyclohexylphosphine (S-Phos) is shown to effectively promote cyanation of various aryl chlorides with Zn(CN)2 as the cyanide
source.
Ó 2006 Elsevier Ltd. All rights reserved.
Aryl nitriles are of great interest in the pharmaceutical
arena both as par structures of new chemical entities
and as synthetic intermediates. Two examples of mar-
keted drugs that contain the benzonitrile functionality
are Casodex, an antiandrogen and Arensin, a non-ste-
roidal aromatase inhibitor (Fig. 1).2
alone described conditions for a palladium-catalyzed
cyanation reaction of aryl chlorides that utilized
Pd2(dba)3 and DPPF along with a catalytic amount of
Zn with Zn(CN)2 as the cyanide source.6 Subsequently,
Sundermeier and co-workers reported another catalyst
system combining 1,5-bis(diphenylphosphino)pentane
(DPPPE), Pd(OAc)2, and TMEDA.7 Both of these cya-
nation methods of aryl chlorides take 4–16 h to com-
plete, depending on the substrate. In the latter case,
the reaction is performed under thermal conditions in
a sealed tube, rendering these reactions more difficult
to scale.
The utility of aryl nitriles as synthetic intermediates is
exemplified by many transformations including conver-
sion to carboxylic acids, amides, amines, aldehydes,
ketones, amide oximes, and tetrazoles.3 As such, numer-
ous reports have appeared divulging conditions for
cyanation of aryl bromides and iodides3–5 but only a
few accounts to date have extended to aryl chlorides.6,7
Maligres and co-workers reported that the combination
of Pd2(dba)3 and 1,10-bis(diphenylphosphino)ferrocene
(DPPF) in wet DMF with Zn(CN)2 as the cyanide
source is a reliable procedure for the cyanation of vari-
ous aryl bromides.4 Following this report, Jin and Conf-
Recently, we became interested in applying microwave-
assisted conditions to convert aryl chlorides to aryl
cyanides in our drug discovery program. Microwave
irradiation is known to greatly accelerate reactions that
are sluggish under thermal conditions.8 Unfortunately,
the two methods described above for the conversion of
1 to 2 were found to be ineffective in our hands when
modified for microwave-assisted conditions (Table 1, en-
tries 1 and 2). Although the factors underlying these
failed attempts were unclear, a recent publication by
Buchwald and co-workers prompted us to consider
alternative phosphine ligands. In their work, S-Phos
ligand was noted to possess ‘unprecedented activity’ in
the coupling of aryl chlorides with various boronic acids
and esters.9 In addition, these coupling reactions can be
performed with ppm levels of palladium. Indeed, when
the DPPF ligand in entry 3 (Table 1) was replaced with
the S-Phos ligand, cyanation of 1 with Zn(CN)2 in the
presence of 4 mol % Pd2(dba)3, 10 mol % S-Phos in
F
CN
O
O
N
S
N
CF3
O
Me OH
N
NC
Arensin (Ciba-Geigy)
Casodex (Zeneca)
Figure 1. Aryl nitriles of interest in clinical use.
*
Corresponding author. Tel.: +1 732 594 2131; fax: +1 732 594
5350; e-mail: harry_chobanian@merck.com
See Ref. 1.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.026

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H. R. Chobanian et al. / Tetrahedron Letters 47 (2006) 3303–3305
Table 1. Cyanation of 4-chlorobenzanilide
O
O
N
N
H
H
NC
Cl
1
2
Entry
Ligand (mol%)
Palladium source
Solvent
Cyanide source
T (°C)a
t (min)
Yield (%)b
1
2
3
4
5
dppf
dpppe
dppf
NA
S-Phos
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd(PPh3)4
Pd2(dba)3
DMA
Zn(CN)2/cat Zn
KCN
Zn(CN)2
Zn(CN)2
Zn(CN)2
150
150
150
150
150
30
30
30
30
30
0
0
0
08
97
Toluene
wet DMF
DMF
wet DMF
a All microwave reactions were performed on a Biotage Initiator.
b Reactions were performed on 1 mmol scale.
wet DMF led to nearly quantitative conversion to nitrile
2 under microwave-assisted conditions (entry 5).
wide array of electronically and structurally diverse sub-
strates. As can be seen in Table 2, a substrate with an
electron-donating group exhibited somewhat diminished
yield of the product (entry 5), while those with electron
withdrawing groups afforded excellent yield of products,
Delighted with these results, we decided to examine the
scope of these new cyanation conditions by examining a
Table 2. Palladium(0)-S-Phos microwave-assisted cyanation of aryl chlorides
Zn(CN)2, cat Pd2(dba)3, cat S-Phos
99:1 DMF:H2O
Ar-X
Ar-CN
microwave or thermal
Entry
1
Ar-Cl
Producta
Yield (%)b
92
Yield (%)c
94
N
N
Cl
CN
N
N
2
3
76
97
64
65
Cl
CN
O
O
O
N
N
H
H
Cl
NC
O
4
5
90
48
70
48
Cl
Cl
NC
CO2Et
CO2Et
O
O
NC
Cl
Br
CN
6
81
81
94
94
N
N
N
CN
7c
N
a All products gave satisfactory NMR and MS data.
b Isolated microwave yield after column chromatography on silica.
c Isolated thermal yield after column chromatography on silica.

H. R. Chobanian et al. / Tetrahedron Letters 47 (2006) 3303–3305
3305
4. Meligres, P.; Waters, M. S.; Fleitz, F.; Askin, D. Tetra-
hedron Lett. 1999, 40, 8193.
5. Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005,
70, 1508.
6. Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
7. Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J. Tetra-
hedron Lett. 2001, 42, 6707.
8. Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
9. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685.
suggesting that the oxidative insertion step may be rate-
limiting for less reactive chlorides. The cyanation of
3-chloropyridine (entry 2) also worked well under these
conditions (76% isolated yield in 30 min), while a previ-
ously described attempt using KCN, Pd(OAc)2, DPPPE
and TMEDA7 led to 48% isolated yield of 3-cyanopyri-
dine after 16 h of heating. This new catalyst system is
also amenable to thermal conditions, and comparable
yields of products were obtained after 1 h of heating at
120 °C, underlying ‘unprecedented activity’ of this cata-
lyst system previously reported by Buchwald.9 Not sur-
prisingly, these conditions can also be applied to the
conversion of aryl bromides to aryl cyanides (entry 7,
81% yield under microwave-assisted conditions and
94% under thermal conditions).
10. General experimental conditions:
Microwave: 1 (500 mg, 2.2 mmol), (79 mg, 009 mmol), S-
Phos (89 mg, 0.2 mmol), Zn(CN)2 (300 mg, 2.5 mmol)
were dissolved in 10 mL 99:1 v/v DMF/H2O in a 20 mL
microwave vial. The solution was degassed with N2 for
10 min before being capped and heated in the microwave
reactor for 30 min at 150 °C. Once complete, the reaction
was diluted with 1 N NaOH (40 mL) and EtOAc
(100 mL). The EtOAc layer was removed, dried over
MgSO4, filtered, and concentrated giving rise to an oil.
The oil was purified via silica gel chromatography (5–40%
EtOAc/hexanes) and concentrated under reduced pressure
to yield 462 mg (97%) of 2 as a white solid.
Thermal: 1 (500 mg, 2.2 mmol), Pd2(dba)3 (79 mg, 009
mmol), S-Phos (89 mg, 0.2 mmol), Zn(CN)2 (300 mg,
2.5 mmol) were dissolved in 20 mL 99:1 v/v DMF/H2O.
The solution was degassed with N2 for 10 min before being
heated to 120 °C for 1 h. Once complete, the reaction was
purified as described above.
In summary, we have shown that palladium-catalyzed
cyanation of aryl chlorides can be performed readily by
use of the commercially available S-Phos ligand under
either microwave-assisted or thermal conditions.10–12
The reaction is general for a variety of substrates and
can also be applied to aryl bromides.
References and notes
1. Merck Summer Research Intern, University of Montana,
Missoula, MT.
2. (a) Schareina, T.; Zapf, A.; Beller, M. J. Organomet.
Chem. 2004, 689, 4576; (b) Sundermeier, M.; Zapf, A.;
Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M.
Chem. Eur. J. 2003, 9, 1828.
11. S-Phos ligand was purchased from Strem Chemicals Inc.,
7 Mulliken Way, Dexter Industrial Park, Newburyport,
MA 01950.
12. The catalyst loading for the microwave was lowered to
1 mol % Pd2(dba)3 and 2 mol % S-Phos for the conversion
of 1 to 2 without any significant change in yield or reaction
time.
3. Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837.