The Room-Temperature Palladium-Catalyzed Cyanation of Aryl Bromides and Iodides with Tri-t-butylphosphine as Ligand

Article abstract of DOI:10.1055/s-2003-42069

The palladium-catalyzed cyanation of aryl bromides and iodides to the corresponding nitriles occurs at room temperature when tri-t-butylphosphine is used as ligand, Zn(CN)₂ as the cyanide source and Zn dust as a co-catalyst in DMF as solvent. A variety of aromatic halides, including electron-withdrawing and electron-donating, can be efficiently cyanated under these conditions. The reactions are completed in less than 1 hour and products are produced in good to excellent yield.

Full text of DOI:10.1055/s-2003-42069

LETTER
2237
The Room-Temperature Palladium-Catalyzed Cyanation of Aryl Bromides
and Iodides with Tri-t-butylphosphine as Ligand
C
J
yanation
a
of
A
ryl
H
a
i
lides
w
l
ith Tri-
a
t
-butylphos
l
phine
l
a
s
Ligand Ramnauth, Namrta Bhardwaj, Paul Renton, Suman Rakhit, Shawn P. Maddaford*
MCR Research Inc., York University, 4700 Keele Street, Toronto, Ontario M3J 1P3, Canada
E-mail: shawnm@mcr.chem.yorku.ca
Received 15 July 2003
lower catalyst loading greatly affected the yield. When
.25 mol% Pd (dba) , and 2.5 mol% tri-t-butylphosphine
were used, an isolated yield of 60% was obtained after one
Abstract: The palladium-catalyzed cyanation of aryl bromides and
iodides to the corresponding nitriles occurs at room temperature
1
2
3
when tri-t-butylphosphine is used as ligand, Zn(CN) as the cyanide
2
source and Zn dust as a co-catalyst in DMF as solvent. A variety of hour (Table 1, entry 2). Increasing the reaction time to two
aromatic halides, including electron-withdrawing and electron- hours gave an improved yield of 75%. However when
donating, can be efficiently cyanated under these conditions. The
reactions are completed in less than 1 hour and products are pro-
duced in good to excellent yield.
0
.62 mol% Pd (dba) and 1.25 mol% tri-t-butylphosphine
2 3
were used no product was obtained (Table 1, entry 3).
Key words: palladium-catalyzed, cyanation, aryl iodide, aryl bro-
mide, tri-t-butylphosphine.
Br
CN
Pd2(dba)3, P(t-bu)3
Zn(CN)2, Zn, DMF
r.t., 1 h, 86%
Aryl nitriles are important synthetic intermediates in the
pharmaceutical industry because they serve as building
O
O
blocks for a number of different functionalities with inter- Scheme 1
1
esting biological properties. The most direct method for
the synthesis of aryl nitriles is the transition metal-cata-
lyzed cyanation of aryl halides. Although a number of el-
The reaction was also highly dependent on the ligand.
A number of ligands which have been reported to be
effective at higher temperatures for palladium-catalyzed
cyanation reactions, were used in place of tri-t-butylphos-
phine. Replacement of tri-t-butylphosphine with PPh3,
Dppf, Xantphos, or 2¢-dicyclohexylphosphinobiphenyl in
the general procedure yielded no product after 1 hour at
room temperature (Table 1, entries 4–7). This demonstrat-
ed that tri-t-butylphosphine is a superior ligand for this
transformation.
2
egant methods have been developed, the general
procedure calls for elevated temperatures and in many
cases long reaction times. In the course of our work, we
needed a mild method for the preparation of aryl cyanide
from an aryl bromide and thus explored other reaction
conditions. We focused on the possibility of using a palla-
dium(0) catalyzed process since palladium catalysts can
be fine-tuned to perform a number of reactions at lower
temperature. For example, during the past few years, the
use of tri-t-butylphosphine as ligand in a variety of palla- Table 1 Pd-Catalyzed Cyanation of 4¢-Bromoacetophenone
3
4
dium-catalyzed processes, including Suzuki, Heck,
5
6
7
Entry
Pd
Ligand (mol%)
Isolated Yield
%)
Negishi, Sonogashira, amination of aryl halides and
Stille couplings have been reported to occur under very
(
8
mild conditions. Encouraged by these reports, we ex-
plored conditions for the cyanation of aryl halides using a
1
2
3
4
5
6
7
5%
P(t-Bu) (5)
86
60
0
3
2.5%
1.25%
5%
P(t-Bu) (2.5)
3
Pd–P(t-Bu) catalyst system.
3
P(t-Bu) (1.25)
The use of Zn(CN) as the cyanide source in the palladi-
3
2
um-catalyzed cyanation of aryl halides in DMF has been
shown to be general and reliable, albeit at elevated tem-
PPh3
0
2
a,2c–e
Dppfa
peratures.
Using this protocol, with 4¢-bromoace-
5%
0
tophenone as a model substrate, we explored a number of
room temperature reaction conditions (Table 1). To our
delight, with 2.5 mol% Pd (dba) , 5 mol% tri-t-butylphos-
5%
Xantphosb
DCPBc
0
5%
0
2
3
phine and zinc as a co-catalyst, the reaction was complete
in 1 hour and we obtained an excellent isolated yield of
General conditions: Substrate (1.0 equiv), Zn(CN) ( 1.8 equiv), Zn
2
(
0.12 equiv), 1 h at r.t.
4
¢-cyanoacetophenone (Scheme 1) (Table 1, entry 1). A
a
1
,1¢-Bis(diphenylphosphino)ferrocene.
b
c
9
,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene.
2
¢-Dicyclohexylphosphinobiphenyl.
SYNLETT 2003, No. 14, pp 2237–2239
0
6
.1
1
.2
0
0
3
Advanced online publication: 07.10.2003
DOI: 10.1055/s-2003-42069; Art ID: S07903ST
©
Georg Thieme Verlag Stuttgart · New York

2
238
J. Ramnauth et al.
LETTER
The effect of the stoichiometry of the tri-t-butylphophine Table 2 Room Temperature Cyanation Reactions of Aryl Bromides
ligand was also examined in the palladium-catalyzed cya-
and Iodides Catalyzed by Pd(0)–P(t-Bu)3a
nation of 4¢-bromoacetophenone. With 5 mol% of palladi-
Entry Aryl Halide
Product
Yield (%)
86
um, we found that the reaction was not as efficient when
the ratio of Pd–ligand was 1:4 as compared to a 1:1 Pd–
ligand ratio. In fact, the reaction was only about 50% com-
plete after 1 hour and did not proceed further after longer
reaction times. This phenomenon has been observed in
other transition metal-catalyzed reactions involving tri-t-
1
Br
NC
O
O
2
Br
CN
71
7
,9
butylphosphine.
When the cyanide source was changed from Zn(CN) to
O
O
2
KCN no reaction was observed. A similar result has been
reported for the cyanation of aryl chlorides at elevated
temperature and is rationalized on the basis of cyanide
3
4
Br
Br
NC
80
58
2
c
poisoning of the catalyst. We also found that the use of
zinc dust as a co-catalyst facilitates the reaction with com-
O
O
1
0
H
O
H
O
plete conversion after 1 hour. Without zinc, the reaction
was sluggish and went to about 70% completion with an
isolated yield of 66% for the nitrile.
NC
In addition to this, it appears that the polarity of the sol-
vent also plays a key role. The reaction proceeded rapidly
in DMF as solvent, however no product was obtained
when toluene or dioxane were used as solvents.
5
61
Br
Br
I
NC
NC
NC
Having optimized the conditions for the cyanation of 4¢-
OH
OH
OH
bromoacetophenone, we were interested in the scope of
11
6
7
83
84
this methodology. The results are presented in Table 2.
As can be seen, both electron-withdrawing and electron-
donating aryl bromides and iodides are cyanated in good
to excellent yields. The yields are modest for sterically
congested aryl bromides (Table 2, entries 4 and 5). It
should be noted that phenols (Table 2, entries 5, 6 and 9)
and in one case an aniline (Table 2, entry 10) can be cyan-
ated under these conditions in good yields. This shows
that the cyanation is very fast under these conditions and
side reactions do not occur at a significant rate.
OH
O
O
8
I
NC
93
NO2
NO2
9
0
I
I
NC
NC
84
81
In summary, although a number of methods exist for the
synthesis of aryl nitriles via transition metal catalyzed cy-
anation of aryl halides, they require elevated temperatures
and long reaction times. In contrast, we have reported a
practical, efficient and mild, room temperature method for
the palladium-catalyzed cyanation of aryl bromides and
iodides to the corresponding nitriles using tri-t-butylphos-
phine. We are currently exploring conditions to extend
this methodology to aryl chlorides.
OH
OH
1
NH2
NH2
a
General conditions: Substrate (1 equiv), Pd (dba) (0.025 equiv),
Zn(CN) (1.8 equiv), P(t-Bu) (0.05 equiv), Zn (0.12 equiv), 1 h at r.t.
2
3
2
3
Acknowledgment
Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
d) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65,
984. (e) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D.
Tetrahedron Lett. 1999, 40, 8193. (f) Anderson, B. A.; Bell,
E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.; Wepseic, J. P.
J. Org. Chem. 1998, 63, 8224. (g) Kubota, H.; Rice, K. C.
Tetrahedron Lett. 1998, 39, 2907. (h) Sakaikibara, Y.; Ido,
Y.; Sasaki, K.; Sakai, M.; Uchino, N. Bull. Chem. Soc. Jpn.
(
7
We wish to thank the Natural Sciences and Engineering Counsel of
Canada for providing a fellowship to N.B.
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Synlett 2003, No. 14, 2237–2239 © Thieme Stuttgart · New York

LETTER
Cyanation of Aryl Halides with Tri-t-butylphosphine as Ligand
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6
bottom flask was charged with the aryl halide (0.5 mmol),
Zn(CN) (0.9 mmol), Pd (dba) (0.013 mmol), and Zn dust
(
(
2
2
3
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(
(
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Synlett 2003, No. 14, 2237–2239 © Thieme Stuttgart · New York