Rapid, Easy Cyanation of Aryl Bromides and Chlorides Using Nickel Salts in Conjunction with Microwave Promotion

Article abstract of DOI:10.1021/jo0350561

We report here a fast, easy, and efficient method for the preparation of aryl nitriles from aryl bromides and chlorides. The methodology for aryl bromides involves the use of either Ni(CN)₂ or NaCN and NiBr ₂. With aryl chlorides, a mix of NaCN and NiBr₂ is used and the reaction proceeds via the in situ formation of the corresponding aryl bromide. The reaction can be performed in air and is complete within 10 min.

Full text of DOI:10.1021/jo0350561

tions and in many cases improve product yields. It is
possible to obtain high temperatures very easily and, by
using current state-of-the-art scientific laboratory mi-
crowave apparatus, this can be done in a very safe
manner as compared to conventional heating. Alterman
and Hallberg have shown that it is possible to use
microwave irradiation to effect the palladium-mediated
coupling of aryl halides with zinc cyanide, these reactions
being performed in DMF.13 Reaction times of between 2
and 2.5 min are reported with product yields comparable
to longer conventional heating methods being obtained.
We have recently reported two methodologies for the
synthesis of a range of aryl nitriles from halides using
microwave promotion without the need for palladium
catalysts and the anaerobic conditions or expensive
ligands often required. We performed the Rosenmund von
Braun reaction in an ionic liquid, which offers a route
into nitriles from aryl bromides.14,15 However, isolated
yields are low because of problems isolating the nitrile.
We then looked at using water as a solvent for cyanation
reactions.16 Using either CuCN or CuI/NaCN (to generate
CuCN in situ from the cheaper NaCN), it is possible to
convert aryl iodides to nitriles rapidly and in good yields.
This, however, does not work for aryl bromides. In this
paper, we present a methodology for the clean and easy
cyanation of aryl bromides and chlorides using microwave
promotion, again without the need for a palladium
catalyst.
Ra p id , Ea sy Cya n a tion of Ar yl Br om id es
a n d Ch lor id es Usin g Nick el Sa lts in
Con ju n ction w ith Micr ow a ve P r om otion
Riina K. Arvela and Nicholas E. Leadbeater*
Department of Chemistry, King’s College London,
Strand, London WC2R 2LS, United Kingdom
nicholas.leadbeater@kcl.ac.uk
Received J uly 22, 2003
Abstr a ct: We report here a fast, easy, and efficient method
for the preparation of aryl nitriles from aryl bromides and
chlorides. The methodology for aryl bromides involves the
use of either Ni(CN)2 or NaCN and NiBr2. With aryl
chlorides, a mix of NaCN and NiBr2 is used and the reaction
proceeds via the in situ formation of the corresponding aryl
bromide. The reaction can be performed in air and is
complete within 10 min.
Aryl nitriles form integral parts of a range of dyes,
herbicides, natural products, and pharmaceuticals. They
are also useful intermediates in synthesis. As a result,
their preparation has attracted considerable attention.
In particular, a number of routes to aryl nitriles from
aryl halides have been developed.1,2 There are a number
of methodologies for this. One is the direct reaction
between aryl halides and copper cyanide (the Rosenmund
von Braun reaction) which has been known for over 80
years. The reaction is usually carried out for prolonged
times at high temperatures (150-250 °C) using solvents
such as nitrobenzene. More recently, a number of transi-
tion-metal-mediated processes have been developed al-
lowing inexpensive cyanide salts to be used. Many of
these use nickel or palladium complexes as catalysts.3-10
A theme running through many of the methods for
preparation of aryl nitriles from halides is the use of high
temperatures in order to effect the transformation. In our
laboratories, we have an interest in the microwave
promotion of organic reactions. Microwave-promoted
synthesis is an area of increasing research interest as
evidenced by the number of papers and recent reviews
appearing in the literature.11,12 As well as being energy
efficient, microwaves can also enhance the rate of reac-
We have recently reported that it is possible to use
cheap, readily available nickel halide salts as sources of
halide ions for the interconversion of aryl halides.17 The
methodology can be used for conversion of aryl chlorides
to bromides, aryl iodides to bromides and chlorides, and
aryl bromides to chlorides. We believe that the nickel
plays a key role in the reaction. It occurred to us that it
may be possible to effect the cyanation of aryl halides
using nickel cyanide as a source of the cyanide ion, again
with the potential advantage of the use of nickel as a
promoter of the reaction and hence no need for an
additional catalyst or promoter. Although Ni(CN)2 has
been used as a catalyst for a number of transformations,18
we believe that this is the first use of this as a cyanation
reagent. As a starting point for the development of our
methodology we chose to study the reaction of 4-bromo-
(11) For recent reviews on the area, see: (a) Larhed, M.; Moberg,
C.; Hallberg, A. Acc. Chem. Res. 2002, 35, 717. (b) Lew, A.; Krutzik,
P. O.; Hart, M. E.; Chamberlin, A. R. J . Comb. Chem. 2002, 4, 95. (c)
Lindstro¨m, P.; Tierney, J .; Wathey, B.; Westman, J . Tetrahedron 2001,
57, 9225.
(12) For a review on the concepts see: Gabriel, C.; Gabriel, S.; Grant,
E. H.; Halstead, B. S.; Mingos, D. M. P. Chem. Soc. Rev. 1998, 27,
213.
(13) Alterman, M.; Hallberg, A. J . Org. Chem. 2000, 65, 7984.
(14) Leadbeater, N. E.; Torenius, H. M.; Tye, H. Tetrahedron 2003,
59, 2253.
(15) Using conventional heating only aryl iodides have been cyan-
ated (Ren, R. X.; Wu, J . X. Tetrahedron Lett. 2002, 43, 387).
(16) Arvela, R. K.; Leadbeater, N. E.; Torenius, H. M.; Tye, H. Org.
Biomol. Chem. 2003, 1, 1119.
(1) For a review of cyano-dehalogenation, see: Ellis, G. P.; Romney-
Alexander, T. M. Chem. Rev. 1987, 87, 779.
(2) Grushin, V. V.; Alper, H. Chem. Rev. 1994, 94, 1047.
(3) For nickel-catalyzed cyanations, see: (a) Cassar, L. J . Orga-
nomet. Chem. 1973, 54, C57. (b) Sakakibara, Y.; Ido, Y.; Sasaki, K.;
Sakai, M.; Uchino, N. Bull. Chem. Soc. J pn. 1993, 66, 2776. (c) Percec,
V.; Bae, J .-Y.; Hill, D. H. J . Org. Chem. 1995, 60, 6895.
(4) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2003, 42, 1661.
(5) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J .;
Weiss, S.; Beller, M. Chem. Eur. J . 2003, 9, 1828.
(6) Sundermeier, M.; Zapf, A.; Beller, M.; Sans, J . Tetrahedron Lett.
2001, 42, 6707.
(7) J in, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41, 3271.
(8) Kubota, H.; Rice, K. C. Tetrahedron Lett. 1998, 39, 2907.
(9) Maligres, P. E.; Waters, M. S.; Fleitz, F.; Askin, D. Tetrahedron
Lett. 1999, 40, 8193.
(10) Sakamoto, T.; Ohsawa, K. J . Chem. Soc., Perkin Trans. 1 1999,
2323.
(17) Arvela, R. K.; Leadbeater, N. E. Synlett 2003, 1145.
(18) See, for example: (a) McGuire, M. A.; Sorenson, E.; Klein, D.
N.; Baine, N. H. Synth. Commun. 1998, 28, 1611. (b) Zhou, Z. X.; Alper,
H. Organometallics 1996, 15, 3282. (c) RosoLevi, G.; Amer, I. J . Mol.
Catal. A 1996, 106, 51.
10.1021/jo0350561 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/14/2003
9122
J . Org. Chem. 2003, 68, 9122-9125

TABLE 1. Scr een in g of Con d ition s for th e Dir ect
quantity of Ni(CN)2 used in the reaction. We found that
it was possible to reduce this to 0.6 equiv, corresponding
to 1.2 equiv of cyanide ion (Table 1, entry 5). The quantity
of Ni(CN)2 used can be further reduced to 0.5 equiv (ie
to 1.0 equiv of cyanide ion) with only a slight decrease
in product yield (Table 1, entry 6).
a
Cya n a tion of 4-Br om otolu en e w ith Ni(CN)2
yield
(%)
With our optimized reaction conditions in hand, we
screened a representative range of aryl bromides in the
reaction, choosing examples from across the spectrum of
those bearing electron-donating and electron-withdraw-
ing substituents. All the reactions were performed in air
and without degassing the solvent prior to use. The
results are presented in Table 2 and show that the
methodology is applicable to a range of substrates with
good yields being obtained (Table 2, entries 1-9). The
exceptions to this are 1-bromo-4-nitrobenzene and het-
eroaromatic aryl bromides where only a moderate to low
yield of product is obtained and significant decomposition
is observed (Table 2, entries 10-12). This is a problem
that has been reported previously using other methods
for cyanation of heteroaromatic halides.
We were keen to see if it was possible to adapt the
procedure for use of cheaper sodium cyanide rather than
nickel cyanide. We find that if NaCN is used in conjunc-
tion with NiBr2 it is possible to obtain the nitrile product
via an in situ transmetalation (Table 2, entries 13-15).
We find that it is necessary to use a 1:1:2 ratio of aryl
iodide/NiBr2/NaCN in order to obtain good yields of the
nitriles. If catalytic quantities of NiBr2 are used the
product yields drop considerably.
entry
1
reaction conditionsb
2 equiv of Ni(CN)2, 0.5 mL of DMF, T ) 170 °C,
hold time 5 min
0c
27
99
99
99
95
2
3
4
5
6
1 equ iv of Ni(CN)2, 0.5 mL of DMF, 0.25 equ iv
of TBAB, T ) 170 °C, hold time 5 min
1 equ iv of Ni(CN)2, 0.5 mL of DMF, 0.25 equ iv
of TBAB, T ) 200 °C, hold time 5 min
1 equ iv of Ni(CN)2, 1 m L of NMP , T ) 200 °C,
h old tim e 10 m in
0.6 equ iv of Ni(CN)2, 1.0 m L of NMP ,
T ) 200 °C, h old tim e 10 m in
0.5 equ iv of Ni(CN)2, 1.0 m L of NMP ,
T ) 200 °C, h old tim e 10 m in
a
Reactions were run using 1 mmol of aryl halide, a microwave
power of 100 W for reactions using DMF or 120 W for those using
NMP, and a pressure threshold of 200 psi. The temperature was
ramped to that stated and held there for the allotted time.
b
Conditions changed from entry 1 are highlighted in bold. c Only
reaches 150 °C.
toluene with Ni(CN)2, our optimization data being shown
in Table 1.
Using the same reaction conditions as for the halogen
interconversion, namely 1 mmol of aryl halide, 2 mmol
of Ni(CN)2, 0.5 mL of DMF, a microwave power of 100
W, a temperature of 170 °C, and a reaction time of 5 min
we obtained no 4-methylbenzonitrile (Table 1, entry 1),
we believe primarily due to the fact that the reaction
mixture only reaches around 150 °C.19 We thought that
this could be remedied by adding a small quantity of
tetrabutylammonium bromide (TBAB), which we know
allows us to heat mixtures to high temperatures rap-
idly.20,21 Using 0.25 equiv of TBAB, we can heat the
reaction mixture to the desired 170 °C and obtain a 27%
yield of the desired 4-methylbenzonitrile (Table 1, entry
2). We then tried increasing the temperature to 200 °C
and found that this resulted in excellent yields of the
nitrile product (Table 1, entry 3). However, the use of
the TBAB as an additive is not ideal, and its removal at
the end of the reaction is not easy. As a result, we
screened a range of solvents that would allow us to
perform the reaction at higher temperatures and without
the TBAB and found that 1-methyl-2-pyrrolidinone (NMP)
was the best solvent, reaching 200 °C easily.22 Longer
reaction times (10 min instead of 5 min) were required
to take the reaction to completion and a slightly higher
microwave power (120 W instead of 100 W) was optimum;
these modifications gave us a 99% yield of the nitrile
(Table 1, entry 4). We next wanted to decrease the
We then wanted to see if the methodology could be
adapted for conventional heating. Using an oil bath, we
screened the reaction of bromotoluene with NaCN +
NiBr2 to form 4-methylbenzonitrile. We kept the quanti-
ties of reagents exactly the same as in the microwave-
assisted reaction and performed the reaction in a sealed
10 mL microwave tube. We dipped the tube into an oil
bath preheated to 170 °C and held it there for 10 min
before removing it and cooling the reaction mixture.23
A
yield of 4-methylbenzonitrile of 19% was obtained. We
decided to run the reactions at 170 °C rather than the
200 °C used in the microwave-promoted reactions simply
from a safety viewpoint since oil at elevated temperatures
poses a fire risk and also since the vessel is not held
within a safety cavity there is a risk from explosion due
to high pressures generated during the reaction. Extend-
ing the reaction time to 30 min leads to an increased yield
of 33%, but even if this is further extended to 4 h, the
product yield does not improve (Table 2, entries 16 and
17). To make a direct comparison between these results
and those obtained using microwave heating, we per-
formed the reaction in the microwave at 170 °C rather
than 200 °C and obtained a 44% yield of nitrile within
10 min (Table 2, entry 18). Clearly, the microwave
methodology has the advantages of being faster and
easier and leads to significantly higher yields of product.
We should state that we believe that the microwave
simply provides an efficient heating method rather than
there being any specific microwave effect.
(19) CAUTION: All necessary precautions should be taken when
performing such experiments. Vessels designed to withhold elevated
pressures must be used. The microwave apparatus used here incor-
porates a protective metal cage around the microwave vessel in case
of explosion. After completion of an experiment, the vessel must be
allowed to cool to room temperature before removal from the microwave
cavity and opening to the atmosphere.
(20) Deshayes, S.; Liagre, M.; Loupy, A.; Luche, J . L.; Petit, A.
Tetrahedron 1999, 55, 10851.
(21) Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 4, 2973.
(22) Yields for the transformation with other solvents: water, 0%;
DME, 0%; no solvent, 0%.
(23) CAUTION: A blast shield should be in place and vessels
designed to withhold elevated pressures must be used. After completion
of an experiment, the vessel must be allowed to cool before opening to
the atmosphere.
J . Org. Chem, Vol. 68, No. 23, 2003 9123

TABLE 2. Micr ow a ve-P r om oted Cya n a tion of Ar yl Br om id esa
a
Reactions were run using 1 mmol of aryl halide, 0.6 mmol of Ni(CN)2, and 1 mL of NMP. Reactions were run using a microwave
b
power of 120 W and a pressure threshold of 200 psi. The temperature was ramped to 200 °C and held there for 10 min. Significant
decomposition observed. c Using 2 mmol of NaCN and 1 mmol of NiBr2. After 10 min in an oil bath preheated to 170 °C. e After 30 min
d
in an oil bath preheated to 170 °C. f Performed in the microwave but using a temperature threshold of 170 °C.
Having shown that the methodology works well for aryl
bromides, we were keen to extend it for use with aryl
chlorides. The cyanation of aryl chlorides has been the
focus of a number of recent reports.4-7 The most general
procedures involve the use of phosphine-ligated pal-
ladium catalysts, elevated temperatures for prolonged
times, and the use additives such as tetramethylethyl-
enediamine (TMEDA) or some other amine. Even then,
yields can be variable depending on the susbtituents on
the aryl chloride. An obvious extension to our methodol-
ogy was to see whether it could be used with aryl
chlorides. Using 1-chloro-4-methoxybenzene, we at-
tempted to prepare the corresponding nitrile using our
conditions developed for use with the aryl bromides.
However, using nickel cyanide only a 9% yield of product
is observed after 10 min microwave heating at 200 °C.
We then decided to attempt an in-situ halogen exchange/
cyanation reaction. The aim was to use our halogen
exchange methodology to convert the aryl chloride to the
corresponding bromide and then effect a sequential
cyanation reaction. We thought that simply using NiBr2
and NaCN both these steps would be feasible, and indeed,
this is the case. Using a stoichiometric ratio of 4-chloro-
anisole/NiBr2/NaCN of 1:1:2, a 61% yield of the desired
nitrile was prepared in 10 min microwave heating at 200
°C. With these conditions in hand, we screened a repre-
sentative range of aryl chlorides, the results being shown
in Table 3. Good yields of the desired nitriles are formed
in every case except for chlorobenzaldehyde. Interest-
ingly, Buchwald and co-workers have very recently
reported the use of their copper-catalyzed aryl Finkel-
stein reaction in conjunction with a copper-catalyzed
cyanation reaction to take aryl bromides to aryl nitriles
via the intermediate formation of the aryl iodide.24
In summary, we report here a fast, easy, and efficient
method for the preparation of aryl nitriles from aryl
bromides and chlorides. The methodology for aryl bro-
mides involves either the use of Ni(CN)2 or NiCN and
NiBr2, the latter forming Ni(CN)2 in situ. With aryl
chlorides, a mix of NiCN and NiBr2 is used and the
reaction proceeds via the in situ formation of the corre-
sponding aryl bromide. Although the reaction does
involve the use of significant quantities of nickel salts
(24) Zanon, J .; Klapars, A.; Buchwald, S. J . J . Am. Chem. Soc. 2003,
125, 2890.
9124 J . Org. Chem., Vol. 68, No. 23, 2003

TABLE 3. Micr ow a ve-P r om oted Cya n a tion of Ar yl Ch lor id esa
a
Reactions were run using 1 mmol of aryl halide, 2 mmol of NaCN, 1 mmol of NiBr2, and 1 mL of NMP. Reactions were run using a
b
microwave power of 120 W and a pressure threshold of 200 psi. The temperature was ramped to 200 °C and held there for 10 min. After
20 min of heating (reaction had not reached completion within 10 min). c Significant decomposition observed.
(i.e., not catalytic), there are some distinct advantages
of this over other palladium-mediated methodologies. The
reaction can be performed in air, does not require
expensive palladium salts or ligands, and does not suffer
from the problems of catalyst deactivation and reliability
observed in many palladium-mediated examples. Puri-
fication of the product at the end of the reaction is easy
since all the cyanating reagents are water soluble and
the reactions are very clean, giving either product and
unreacted starting material (together with some aryl
bromide in the case of the aryl chlorides).
Ack n ow led gm en t. The Royal Society is thanked for
a University Research Fellowship (N.E.L.). Funding
from King’s College London is acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0350561
J . Org. Chem, Vol. 68, No. 23, 2003 9125