Palladium-catalyzed cyanation reactions of aryl chlorides

Article abstract of DOI:10.1016/S0040-4039(00)00384-1

We have discovered an efficient cyanation of aryl chlorides which employs Pd₂(dba)₃, dppf and Zn as the catalyst and Zn(CN)₂ as the cyanide source. Both electron-deficient and electron-rich aryl chlorides are effectively cyanated under these conditions. This discovery represents the first successful palladium-catalyzed cyanation of both electron-deficient and electron-rich aryl chlorides. (C) 2000 DuPont Pharmaceuticals Company.

Full text of DOI:10.1016/S0040-4039(00)00384-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3271–3273
Palladium-catalyzed cyanation reactions of aryl chlorides
Fuqiang Jin ∗ and Pat N. Confalone
Chemical Process R & D, The DuPont Pharmaceuticals Company, DuPont Experimental Station, Wilmington,
DE 19880-0336, USA
Received 16 February 2000; accepted 2 March 2000
Abstract
We have discovered an efficient cyanation of aryl chlorides which employs Pd2(dba)3, dppf and Zn as the
catalyst and Zn(CN)2 as the cyanide source. Both electron-deficient and electron-rich aryl chlorides are effectively
cyanated under these conditions. This discovery represents the first successful palladium-catalyzed cyanation of
both electron-deficient and electron-rich aryl chlorides. © 2000 DuPont Pharmaceuticals Company. Published by
Elsevier Science Ltd. All rights reserved.
Keywords: aryl chlorides; cyanation; palladium.
Cyanation of aryl halides is a common and useful transformation in organic synthesis.1,2 Unfortunately,
the use of aryl chlorides, which are the cheapest and most readily available aryl halides, is generally
avoided in this reaction due to their low reactivity.1,2 For example, much higher temperatures and longer
reaction times are required in the classic cyanation reaction, the Rosenmund–von Braun reaction,1 when
a chloride is involved, rendering this methodology impractical. While nickel catalysts have been reported
to promote cyanation of aryl chlorides under very mild conditions,3,4 the application of this process is
rather limited. Palladium complexes have long been considered not to catalyze displacement of Cl− in
ArCl by CN−, unless the carbon–chlorine bond is strongly activated.5 Recently, we desired a conversion
of the chloride 1 into the corresponding aryl nitrile derivative 2. Attempts to cyanate 1 by either the
Rosenmund–von Braun reaction or the nickel(0)-mediated cyanation were all unsuccessful. Ultimately,
we discovered that the conversion of 1 into 2 can be effectively carried out by a palladium-catalyzed
Scheme 1. Conditions: Zn(CN)2 (0.6 equiv.), Pd2(dba)3 (2 mol%), dppf (4 mol%), Zn (12 mol%), DMA, 120°C, 4 h
∗
Corresponding author. Tel: (302) 695-8666; fax: (302) 695-4632; e-mail: fuqiang.jin@dupontpharma.com (F. Jin)
0040-4039/00/$ - see front matter © 2000 DuPont Pharmaceuticals Company. Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00384-1
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cyanation. Further study indicated that this palladium-catalyzed cyanation can be widely expanded
to a variety of aryl chlorides, not only electron-deficient but also electron-rich aryl chlorides. In this
communication, we report our preliminary results.
Table 1
Palladium(0)-catalyzed cyanation of aryl chloridesa
As expected, under the commonly applied palladium-catalyzed cyanation conditions for aryl iodides
and aryl bromides,6,7 e.g. using Pd(PPh3)4 as catalyst and an alkaline metal cyanide such as KCN
as cyanide source in a suitable solvent such as CH3CN or DMF at 60–80°C, cyanation of 1 did not
proceed, even at a higher temperature. When the catalyst was replaced with Pd2(dba)3 and dppf [1,10-
bis(diphenylphosphino)ferrocene], which is commonly used as a ligand to enhance the reactivity of a
palladium complex,8 we noticed a modest conversion (40%) at 120°C in N,N-dimethylacetamide (DMA),
suggesting the occurrence of an oxidative addition of the palladium complex to the carbon–chlorine bond

3273
in 1. Realizing the incomplete conversion was probably caused by CN−-induced catalyst deactivation,
we improved the conversion to 100% by use of Zn(CN)29 as the cyanide source and addition of a catalytic
amount of Zn powder.10 Thus, when treated with Zn(CN)2 in the presence of Pd2(dba)3 (2 mol%), dppf
(4 mol%) and Zn (12 mol%) in DMA at 120°C, 1 was transformed to 2 completely within 4 h in a yield
of 95% (Scheme 1).
As the successful example of palladium-catalyzed cyanation of non-activated aryl chlorides, we were
extremely interested in the generality of this cyanation reaction. In the cases of 3a (Table 1), which does
not have a fluorine substitute ortho to the chlorine atom and 3b, which lacks the pyrazole ring, under
related conditions (150°C), both 3a and 3b demonstrate a reasonable reactivity towards cyanation. Thus,
3a was transformed to the corresponding nitrile (4a) in a yield of 91% on treatment with Zn(CN)2 and
catalytic amounts of of Pd2(dba)3, dppf and Zn in DMA at 150°C after 10 h, while 4b was generated in
a yield of 85% after 12 h from 3b.
As can be seen from Table 1, both electron-deficient and electron-rich aryl chlorides are cyanated
in high yields.11 As a general trend, electron-deficient aryl chlorides are more reactive than electron-
rich chlorides. For example, a complete conversion is reached within 2 h at 120°C for methyl 2-
chlorobenzoate (3c). However, 4-chloroanisole (3d) requires a higher temperature (150°C), higher
catalyst load, and longer reaction time.
In conclusion, we have discovered a palladium-catalysed cyanation which is suitable for both electron-
deficient and electron-rich aryl chlorides. This cyanation offers practical improvement to the Rosen-
mund–von Braun reaction. Further study on the scope and limitation of this cyanation reaction of aryl
chlorides is underway and will be reported in due course.
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11. Typical experimental procedure: 1 (1.0 g, 3.0 mmol), Pd2(dba)3 (55 mg, 2 mol%), dppf (66 mg, 4 mol%), Zn powder
(23 mg, 12 mol%) and Zn(CN)2 (210 mg, 1.8 mmol) were placed in a flask which was flushed with N2. DMA (6 ml)
was added via syringe. The resulting mixture was heated at 120°C under N2 with vigorous agitation until TLC showed
the disappearance of 1 (∼4 h). The mixture was cooled to room temperature, diluted with ethyl acetate (50 ml), and then
washed with 2 N NH4OH solution and brine. After drying over Na2SO4, the ethyl acetate solution was concentrated by
rotary evaporation. The residue was chromatographed on silica gel using a mixed solvent of ethyl acetate and hexane (1:2)
to afford 1-(30-cyano-40-fluorophenyl)-3-trifluoromethyl-5-(20-furanyl)pyrazole (2) as a white solid (920 mg, 95% yield):
1
mp 111–113°C (hexane); H NMR δ 7.70 (m, 2H), 7.44 (m, 1H), 7.31 (t, J=8.2 Hz, 1H), 6.89 (s, 1H), 6.46 (m, 1H),
6.32 (d, J=3.6 Hz, 1H); 19F NMR δ −60.0 (s, 3F), −105.3 (m, 1F); MS (NH3–CI) m/z 322 (100, M++1). Anal. calcd for
C15H7F4N3O: C, 56.09; H, 2.206; N, 13.08. Found: C, 55.96; H, 2.49; N, 12.90.