A convenient procedure for palladium catalyzed cyanation using a unique bidentate phosphorus ligand

Article abstract of DOI:10.1016/j.tetlet.2005.10.052

A palladium complex bearing 1,2-diphenyl-3,4-diphosphinidenecyclobutene ligand (DPCB) has been used to facilitate the catalytic cyanation of aryl bromides. A series of substituted benzonitriles was prepared in good to high yields by the treatment of the corresponding aryl bromides with Zn(CN) ₂ in N-methyl-2-pyrrolidone in the presence of 2-4 mol % catalyst at 100°C for 16 h.

Full text of DOI:10.1016/j.tetlet.2005.10.052

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8645–8647
A convenient procedure for palladium catalyzed cyanation
using a unique bidentate phosphorus ligand
a,b
a
a
Rader S. Jensen, Anil S. Gajare, Kozo Toyota,
a,
b
*
Masaaki Yoshifuji and Fumiyuki Ozawa
a
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai 980-8578, Japan
Research Center for Elements Science, Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0011, Japan
b
Received 11 September 2005; revised 13 October 2005; accepted 17 October 2005
Abstract—A palladiumcomplex bearing 1,2-diphenyl-3,4-diphosphinidenecyclobutene ligand (DPCB) has been used to facilitate the
catalytic cyanation of aryl bromides. A series of substituted benzonitriles was prepared in good to high yields by the treatment of the
corresponding aryl bromides with Zn(CN) in N-methyl-2-pyrrolidone in the presence of 2–4 mol % catalyst at 100 °C for 16 h.
2
Ó 2005 Elsevier Ltd. All rights reserved.
Benzonitriles are frequently encountered in organic
chemistry, appearing in a variety of dyes, pharmaceuti-
cals, and agricultural chemicals, among other things.
Additionally, the cyano group provides a useful syn-
thetic intermediate, being easily transformed into other
functionalities. Indeed, the preparation of benzonitriles
has been extensively studied. In addition to traditional
methods of preparing substituted benzenes, transition
metal-catalyzed cyanation of aryl halides and halide
the poisoning of palladiumcatalysts by cyanide. Conse-
quently, methods which have been demonstrated to be
useful for a broad range of aryl halides typically require
relatively high catalyst loads, although phase transfer
7
conditions as well as the dosed addition of a cyanide
source has allowed the use of catalyst loads of less than
8
,9
1 mol %. These reactions however also suffer disad-
vantages; poor reactivity of bromides in the case of the
former, and lack of simplicity in the latter. Beller et al.
have reported a systemthat proceeds in high yields in
the presence of 0.1 mol % catalyst, however tempera-
1
–3
equivalents has been reported.
The palladium-cata-
lyzed reaction has received particular attention owing
4
–9
10
to its versatility.
tures over 120 °C are necessary.
Several points can be made concerning the work
reported to date. Relatively high temperatures are
typically required for bromides and chlorides, although
some reactions have been shown to proceed at under
It has been pointed out that deactivation occurs through
oxidation of palladium(0) and formation of a dicyano-
palladium(II) species, which is not easily reduced to a
4
a
catalytically active palladium(0) complex. The use of
zinc dust has been found to significantly improve cata-
lyst turnover, presumably by maintaining the palladium
1
00 °C and in some cases, as low as room temperature.
These catalytic systems however, often require highly
air- or moisture-sensitive reagents or ligands, or have
not yet been demonstrated to be general.4
Furthermore, the reaction of ortho substituted as well
as nitro substituted aryl halides tends to proceed in
low yields or requires more rigorous conditions than less
hindered substrates. A frequently reported problemis
4
in a reduced state. It has also been documented that
a,5a,b,6
Zn(CN) gives better yields than KCN or NaCN as a
2
result of lower concentration of cyanide ion in the
5
catalytic solution.
In these laboratories, considerable effort has been
devoted to the chemistry of low-coordinated phospho-
2
rus compounds with sp -hybridized phosphorus
Keywords: Catalytic cyanation; Aryl bromide; Zinc cyanide; Palladium
catalyst; Low-coordinated phosphorus ligand.
1
1
atoms. Particular interest has been focused on the
application of 1,2-diphenyl-3,4-bis(2,4,6-tri-tert-butyl-
phenylphosphinidene)cyclobutene (DPCB, Eq. 1) to
*
Corresponding author at present address: Department of Chemistry,
The University of Alabama, Tuscaloosa, AL 35487-0336, USA. Fax:
1
2
+1 205 348 9104; e-mail: myoshifuji@bama.ua.edu
catalysis. This class of compounds bears extremely
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.052

8646
R. S. Jensen et al. / Tetrahedron Letters 46 (2005) 8645–8647
low-lying p* orbitals mainly located around the phos-
Table 1. Palladium-catalyzed cyanation of aryl halides with Zn(CN)
using DPCB ligand
2
a
phorus and has a marked tendency to engage in metal-
1
3
b
to-phosphorus p-back bonding. This feature could be
expected to stabilize low-valent metal species with high
electron density and hence to facilitate reduction of
transition metal complexes. Therefore, we examined in
this study the palladium-catalyzed cyanation of aryl ha-
lides using DPCB ligand. It was considered that the un-
ique electronic properties of DPCB would provide a
complex more resistant to cyanide poisoning, giving rise
to high catalytic performance.
Entry
Substrate
Product
Yield (%)
41
1
2
85 (90)
94
3
4
5
76 (94)
74 (96)
6
7
8
68 (94)
88 (90)
92 (98)
ð1Þ
9
76
Preliminary examinations showed that a palladium cat-
alyst generated in situ fromPd (dba) ÆCHCl and DPCB
2
3
3
in DMF successfully converted 4-bromoanisole to 4-
methoxybenzonitrile. Accordingly, several solvents and
reaction conditions were evaluated in the presence of
DPCB (2 mol %), Pd (dba) ÆCHCl (1 mol %), zinc dust
1
1
0
1
61
2
3
3
83 (90)
(
10 mol %), and Zn(CN) (1.1 equiv) at 100 °C, using 4-
2
bromoanisole and 4-bromotoluene as substrates. It was
observed that at least 2 mol % of catalyst was required
for high conversion (>80%), and the addition of zinc
metal was necessary to maintain catalytic activity. As
for the solvents, DMF and NMP (N-methyl-2-pyrroli-
done) gave satisfactory results, however, only when the
Pd/DPCB catalyst was generated in a minimum volume
of solvent, prior to the addition of substrates.
1
1
2
3
50 (65)
60
14
15
68 (80)
A typical procedure is as follows. A 5 mL screw-cap vial
with a magnetic stirring bar was charged with DPCB
64 (68)
14
(
15 mg, 0.02 mmol), Pd (dba) ÆCHCl (10 mg, 0.01 mmol),
2 3 3
zinc dust (7 mg, 0.1 mmol), and 0.1 mL of NMP. The
reaction vial was then briefly flushed with a gentle stream
of argon, capped, and stirred for 10 min. 4-Bromoanisole
1
6
c
(
187 mg, 1 mmol) was added, and the purple mixture was
17
85
stirred for another 10 min. Finally, Zn(CN) (62 mg,
2
0
.55 mmol) was added, and the vial was heated on an
1
8
80 (85)
15
oil bath at 100 °C. After 16 h, the mixture was allowed
to cool, diluted with about 30 mL of Et O, washed with
water followed by brine, dried over Na SO , and con-
2
19
2
4
centrated under reduced pressure. Conversion of the
1
bromide was 90% as confirmed by H NMR. 4-Meth-
2
0
35
oxybenzonitrile as the product was isolated by flash
chromatography on silica gel using hexane/EtOAc as
mobile phase (113 mg, 85%) (see Table 1, entry 2).
a
All reactions were run at 100 °C for 16 h on a 1 mmol scale using a
Pd/DPCB catalyst, prepared in situ fromPd (dba) ÆCHCl
0.01 mmol) and DPCB (0.02 mmol) in NMP (0.1 mL) at room
temperature.
2
3
3
(
The present catalyst exhibited a wide functional-group
tolerance (Table 1). Phenyl bromides having a variety
b
c
The numbers given in parentheses are conversion of aryl halides
1
confirmed by H NMR analysis.
of p- and m-substituents, except for the NMe group
2
The reaction was performed using 4 mol % of Pd/DPCB catalyst.
(
entry 1), were converted to the corresponding benzo-

R. S. Jensen et al. / Tetrahedron Letters 46 (2005) 8645–8647
8647
nitriles in good to high yields (entries 2–10). The high
reactivity of sterically congested 2,4,6-trimethylphenyl
bromide was of particular interest, giving the cyanation
product in 83% yield (entry 11). Similarly, o-substituted
phenyl bromides were converted to the corresponding
nitriles in good yields (entries 12–14). The excellent con-
version of 1-bromo-4-nitrobenzene was particularly
gratifying (entry 8). In comparison, identical reaction
2. (a) Chambers, M. R. I.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans. 1 1989, 1265; (b) Cassar, L.; Foa, M. J.
Organomet. Chem. 1979, 173, 335; (c) Cassar, L. J.
Organomet. Chem. 1973, 54, C57.
3
. Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
003, 125, 2890.
. (a) Chidambaram, R. Tetrahedron Lett. 2004, 45, 1441;
b) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41,
271; (c) Okano, T.; Iwahara, M.; Kiji, J. Synlett 1998,
243.
2
4
(
3
conditions employing PPh or dppf as ligand as opposed
3
to DPCB provided 45% and 46% conversion of the
nitro-arene, respectively. 2-Bromonaphthalene was
sufficiently reactive (entry 15), but the reactivity of 2-
bromothiophene was poor (entry 16). 1,4-Dibromoben-
zene was converted to 1,4-dicyanobenzene in 85% yield
5. (a) Okano, M.; Amano, M.; Takagi, K. Tetrahedron Lett.
1998, 39, 3001; (b) Ramnauth, J.; Bhardwaj, N.; Renton,
P.; Rhakit, S.; Maddaford, S. Synlett 2003, 2237; (c)
Tschaen, D. M.; Desmond, R.; King, A. O.; Forin, M. C.;
Pipik, B.; King, S.; Verhoeven, T. R. Synth. Commun.
1
994, 24, 887; (d) Marcantonio, K. M.; Frey, L. F.; Liu,
(
entry 17). The reaction of phenyl iodide with a formyl
Y.; Chen, Y.; Strine, J.; Phenix, B.; Wallace, D. J.; Chen,
C.-Y. Org. Lett. 2004, 6, 3723; (e) Maligres, P. E.; Waters,
M. S.; Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40,
group was also successful (entry 18). On the other hand,
aryl chlorides were unreactive under these conditions,
except for 1-chloro-4-nitrobenzene, which was con-
verted to the corresponding nitrile in 15% yield (entry
8
193.
6. Jiang, B.; Kan, Y.; Zhang, A. Tetrahedron 2001, 57,
1581.
1
9). Consequently, 1-bromo-4-chlorobenzene reacted
only at the bromide position to give 4-chlorobenzonitrile
in 35% yield (entry 20). An attempt to convert 4-fluoro-
toluene to the corresponding nitrile was unsuccessful,
giving a complex mixture containing neither the starting
material nor the desired product.
7. (a) Okano, T.; Kiji, J.; Toyooka, Y. Chem. Lett. 1998, 425;
(
3
b) Cassar, L.; Foa, M. J. Organomet. Chem. 1979, 173,
35.
8
9
. Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int.
Ed. 2003, 42, 1661.
. Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.;
Beller, M. J. Organomet. Chem. 2003, 684, 50.
In summary, DPCB proved to be an effective ligand for
palladium-catalyzed cyanation of aryl bromides. The
ligand is stable toward air and moisture, and is conve-
niently stored and handled under ambient conditions.
Furthermore, the catalytic reaction does not require
the rigorous exclusion of oxygen or water, and all
reagents and solvents can be used as commercially
supplied. Although there are some limitations, it does
provide a convenient and general access to benzonitriles
fromaryl bromides.
1
0. Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004,
388.
1
11. (a) Yoshifuji, M.; Shima, I.; Inamoto, N.; Hirotsu, K.;
Higuchi, T. J. Am. Chem. Soc. 1981, 103, 4587; (b)
Yoshifuji, M.; Shibayama, K.; Inamoto, N.; Matsushita,
T.; Nishimoto, K. J. Am. Chem. Soc. 1983, 105, 2495; (c)
Yoshifuji, M. J. Organomet. Chem. 2000, 611, 210.
1
2. (a) Ozawa, F.; Yoshifuji, M. C. R. Chimie 2004, 7, 747; (b)
Toyota, K.; Masaki, K.; Abe, T.; Yoshifuji, M. Chem.
Lett. 1995, 221; (c) Ikeda, S.; Ohhata, F.; Miyoshi, M.;
Tanaka, R.; Minami, T.; Ozawa, F.; Yoshifuji, M. Angew.
Chem., Int. Ed. 2000, 39, 4512; (d) Ozawa, F.; Yamamoto,
S.; Kawagishi, S.; Hiraoka, M.; Ikeda, S.; Minami, T.; Ito,
S.; Yoshifuji, M. Chem. Lett. 2001, 972; (e) Minami, T.;
Okamoto, H.; Ikeda, S.; Tanaka, R.; Ozawa, F.;
Yoshifuji, M. Angew. Chem., Int. Ed. 2001, 40, 4501; (f)
Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124,
Acknowledgements
This work was supported in part by Grants-in-Aid for
Scientific Research fromthe Ministry of Education, Cul-
ture, Sports, Science and Technology, Japan (13304049,
1
0968; (g) Gajare, A. S.; Toyota, K.; Yoshifuji, M.;
1
5036206, 16033207). A.S.G. is grateful to the Japan
Ozawa, F. Chem. Commun. 2004, 1994; (h) Gajare, A. S.;
Toyota, K.; Yoshifuji, M.; Ozawa, F. J. Org. Chem. 2004,
Society for the Promotion of Science for a Postdoctoral
Fellowship for Foreign Researchers.
6
9, 6504; (i) Gajare, A. S.; Jensen, R. S.; Toyota, K.;
Yoshifuji, M.; Ozawa, F. Synlett 2005, 144.
3. (a) Mathey, F. Angew. Chem., Int. Ed. 2003, 42, 1578; (b)
Mathey, F. J. Organomet. Chem. 2002, 646, 15; (c)
Yoshifuji, M. Phosphorus, Sulfur, Silicon Relat. Elem.
2002, 177, 1827; (d) Weber, L. Angew. Chem., Int. Ed.
2002, 41, 563.
1
References and notes
1
. Takagi, K.; Okamoto, T.; Sakakibara, Y.; Oka, S. Chem.
Lett. 1973, 471.