9
cyanating agent. Subsequent attempts to engage aryl chlo-
1
0
rides have included the use of amine cocatalysts, acetone
Table 1. Effect of Pd Source and Ligand on the Cyanation of
-Chloroaniline
1
1
12
cyanohydrin, or potassium hexacyanoferrate as the cya-
nide source, microwaves, or the use of sterically demanding,
electron-rich phosphine ligands. Two common themes
throughout these methods are (i) the use of very high
temperatures, 120-160 °C, and (ii) few successful cyanations
4
13
14
15
of challenging electron-rich aryl chlorides. In addition, the
experimental conditions are often difficult to scale (sealed
tube, microwaves). Most recently, Beller has demonstrated
the successful cyanation of both electron-neutral and electron-
rich aryl chlorides using the ligand di(1-adamantyl)-1-
butylphosphine; however, this system still requires fairly high
thermal activation (140-160 °C).16
Herein, we wish to report two new and highly reactive
palladium-based catalyst systems for the cyanation of aryl
chlorides, including electron-rich aryl chlorides, under
relatively mild and operationally simple conditions with
reasonable reaction times (80-95 °C, N,N-dimethylaceta-
mide, 3-18 h). Together, both of these catalyst systems allow
the cyanation of a wide variety of aryl and heteroaryl
chlorides encompassing varying functionality in good to
excellent yields.
HPLC solution
yield after 3 h
entry
Pd source
ligand
1
2
3
4
5
6
7
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
(binaphthyl)P(t-Bu)2
(binaphthyl)P(t-Bu)2
S-Phos
<1%
99%
3%
12%
<1%
<1%
5%
X-Phos
dppf (4.2% ligand used)
PCy3
Pd[P(t-Bu)3]2 none
(TFA)
2
(TFA ) trifluoroacetate) in combination with the
Buchwald biaryl ligand racemic 2-di-tert-butylphosphino-
,1′-binaphthyl ((binaphthyl)P(t-Bu) ) proved to be by far
2
the best palladium/ligand combination, providing the cyan-
ated product in essentially quantitative yield after 3 h at 95 °C
2
entry 2). Curiously, Pd(OAc) was markedly inferior as the
and other Buchwald biaryl
ligands S-Phos (2-(dicyclohexylphosphino)-2′,6′-dimethoxy-
2
0
1
During the course of a recent project, it became necessary
to develop a robust, practical, and scaleable cyanation of an
electron-rich aryl chloride to provide multikilogram quantities
of a drug candidate. Using 4-chloroaniline as a model
substrate, a variety of palladium sources and commercially
(
2
1-23
palladium source (entry 1),
2
4
1
,1′-biphenyl; entry 3) and X-Phos (2-(dicyclohexylphos-
25
1
7
phino)-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl; entry 4) proved
available ligands were screened using Zn flakes as a
1
8
far less effective. More traditional phosphine ligands such
cocatalyst, Zn(CN)
2
as the cyanating agent, and N,N-
dimethylacetamide (DMAC) as the solvent19 (Table 1). Pd-
as the aforementioned dppf (entry 5) and PCy
proved quite ineffective, as did the relatively air-stable and
crystalline preformed catalyst Pd[P(t-Bu) (entry 7).
Other very electron-rich aryl chlorides can be cyanated
using Pd(TFA) /(binaphthyl)P(t-Bu) such as the ortho-
3
(entry 6) also
3 2
]
(
7) For recent selected articles on palladium-catalyzed cyanation of aryl
bromides, see: (a) Chidambaram, R. Tetrahedron Lett. 2004, 45, 1441-
444. (b) Marcantonio, K. M.; Frey, L. F.; Liu, Y.; Chen, Y.; Strine, J.;
Phenix, B.; Wallace, D. J.; Chen, C.-Y. Org. Lett. 2004, 6, 3723-3725.
c) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508-
1
2
2
(
1
substituted 2-chlorophenol (Table 2, entry 2). To the best of
our knowledge, these are the first examples of successful
palladium-catalyzed cyanations of highly challenging 4-chlo-
roaniline and 2-chlorophenol. Other electron-rich (entry 4)
as well as electron-neutral (entry 5) and electron-deficient
substrates (entry 7) can also be efficiently cyanated using
510. (d) Hatsuda, M.; Seki, M. Tetrahedron 2005, 61, 9908-9917. (e)
Jensen, R. S.; Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F.
Tetrahedron Lett. 2005, 46, 8645-8647. (f) Li, L.-H.; Pan, Z.-L.; Duan,
X.-H.; Liang, Y.-M. Synlett 2006, 2094-2098.
(8) For Ni-mediated cyanation of aryl chlorides, see: Arvela, R.;
Leadbeater, N. E. J. Org. Chem. 2003, 68, 9122-9125 and references
therein.
(
9) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271-3273.
2 2
Pd(TFA) /(binaphthyl)P(t-Bu) .
(10) (a) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J. Tetrahedron
Lett. 2001, 42, 6707-6710. (b) Sundermeier, M.; Zapf, A.; Mutyala, S.;
Baumann, W.; Sans, J.; Weiss, S.; Beller, M. Chem.-Eur. J. 2003, 9, 1828-
Of interest is that an aryl chloride bearing a boronic acid
unit may also be cyanated in good yield (entry 11) thus
1
4
4
4
4
836.
(11) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003,
2, 1661-1664.
(20) Torraca, K. E.; Kuwabe, S.-I.; Buchwald, S. L. J. Am. Chem. Soc.
2000, 122, 12907-12908.
(21) For cyanations of less electron-rich substrates, we have found Pd-
(OAc)2 to be as efficient as Pd(TFA)2.
(22) We speculate that the greater efficacy of Pd(TFA)2 may be due to
a more rapid reduction of the Pd(II) precatalyst to the Pd(0) active species.
Successful cyanations are often characterized by a deep purple color, and
this deep purple color consistently develops at a lower temperature when
using Pd(TFA)2 as the Pd source.
(12) Schareina, T.; Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689,
576-4583.
13) Pitts, M. R.; McCormack, P.; Whittall, J. Tetrahedron 2006, 62,
705-4708.
14) Chobanian, H. R.; Fors, B. P.; Lin, L. S. Tetrahedron Lett. 2006,
7, 3303-3305.
15) For an alternative method to synthesize electron-rich benzonitriles
(
(
(
from electron-rich aryl chlorides using irradiation, see: Dichiarante, V.;
Fagnoni, M.; Albini, A. Chem. Commun. 2005, 3001-3003.
(23) Amatore and Jutand have demonstrated that the rate of formation
of anionic Pd(0) complexes is more rapid for Pd(TFA)2 than Pd(OAc)2
and that [Pd(PPh3)2TFA] is slightly more reactive than [Pd(PPh3)2OAc]
(
16) Schareina, T.; Zapf, A.; Magerlein, W.; Muller, N.; Beller, M.
-
-
Tetrahedron Lett. 2007, 48, 1087-1090.
(17) The type of zinc used (flakes vs dust) was largely irrelevant on
toward oxidative addition with phenyl iodide in DMF at 25 °C: Amatore,
C.; Jutand, A.; Lemaitre, F.; Ricard, J. L.; Kozuch, S.; Shaik, S. J.
Organomet. Chem. 2004, 689, 3728-3734.
small-scale reactions; however, we found it was essential to use fine zinc
particles on larger scales to enable a homogeneous dispersion throughout
the reaction medium under mechanical overhead stirring conditions.
(24) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871-1876.
(
18) Other cyanide sources were found to be inferior: t-BuSi(Me)2CN,
SiMe3CN, acetone cyanohydrin, CuCN, NaCN, K4Fe(CN)6.
19) DMAC was found to be superior to DMF and NMP.
(25) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653-6655.
(
1712
Org. Lett., Vol. 9, No. 9, 2007