Rapid cyanation of aryl iodides in water using microwave promotion

Article abstract of DOI:10.1039/b211612j

We show that using water in conjunction with microwave heating it is possible to prepare aryl nitriles from the corresponding aryl iodides rapidly and in high yield without the need for a palladium catalyst.

Full text of DOI:10.1039/b211612j

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Rapid cyanation of aryl iodides in water using microwave
promotion
a
a
a
b
Riina K. Arvela, Nicholas E. Leadbeater,* Hanna M. Torenius and Heather Tye
a
Department of Chemistry, King’s College London, Strand, London, UK WC2R 2LS.
E-mail: nicholas.leadbeater@kcl.ac.uk; Fax: ϩ44 (20) 7848 2810; Tel: ϩ44 (20) 7848 1147
Evotec OAI, 151 Milton Park, Abingdon, Oxfordshire, UK OX14 4SD
b
Received 26th November 2002, Accepted 30th January 2003
First published as an Advance Article on the web 4th March 2003
We show that using water in conjunction with microwave heating it is possible to prepare aryl nitriles from
the corresponding aryl iodides rapidly and in high yield without the need for a palladium catalyst.
Introduction
We were therefore keen to investigate other solvents for the the
direct cyanation of aryl halides with CuCN using microwave
promotion. In this paper we present our results when using
water as a solvent. We show that it is possible to prepare aryl
nitriles from aryl halides rapidly and in high yield using CuCN.
We also show that it is possible to perform the reaction using
inexpensive NaCN as the cyanide source in the presence of CuI
Microwave-mediated synthesis is a fast growing area of research
interest as evidenced by the increasing numbers of papers and
patents published in the area. This is because it is often
possible to reduce reaction times from many hours to a few
1
,2
3
minutes and also it opens up avenues for new chemistry. With
its high relative permittivity water is a very useful solvent for
microwave-mediated synthesis. Water, being cheap, readily
available, non-toxic and non-flammable has clear advantages as
(
this forming CuCN in situ).
4
,5
a solvent for use in chemistry. There are however problems
such as solubility of substrates but these problems have to some
extent been overcome by the use of phase-transfer catalysts or
using water–organic solvent mixtures. The dipole moments of
these solvents means that they can be heated very rapidly using
microwave irradiation.
Results and discussion
As a starting point for the development of our methodology we
chose to study the reaction of 4-iodotoluene with copper()
cyanide in water (Table 1). Reactions were run in sealed 10 mL
capacity glass tubes using a focused microwave system.
13
CAUTION!
Aryl nitriles form integral parts of a range of dyes, herb-
icides, 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
We find that using a molar ratio of iodide : CuCN of 1 : 2,
one equivalent of tetrabutylammonium bromide (TBAB) as a
phase transfer agent and 0.5 ml water it was possible to obtain
an isolated yield of 80% of 4-methylbenzonitrile after 3 min
microwave irradiation. Using a microwave power of 100 W we
ramped the temperature from rt to 170 ЊC, this taking approx-
imately 30 s, and then held at this temperature for 3 min. The
addition of a phase-transfer catalyst to the reaction mixture
is essential to the success of the cyanation. Without this, the
reaction does not occur. Reduction of the quantity of TBAB
from 1 equiv to 0.5 equiv relative to the 4-iodotoluene has a
significant detrimental effect on the product yield. We find that
with 4-iodotoluene the optimum reaction time is 3 min. If
longer times are used, product decomposition is observed. The
optimum reaction temperature is 170 ЊC. It is necessary to use
6
routes to aryl nitriles from aryl halides have been developed,
many using palladium complexes as catalysts and a range
7–9
of metal cyanides as the source of cyanide. Alterman and
Hallberg have shown that it is possible to use microwave
irradiation to effect that palladium-mediated coupling of aryl
halides with zinc cyanide, these reactions being performed in
DMF. Reaction times of between 2 and 2.5 min are reported
with product yields comparable to longer conventional heating
10
methods being obtained.
One of the most direct ways to prepare aryl nitriles is the
Rosenmund–von Braun reaction (direct reaction between aryl
halides and copper cyanide to give aryl nitriles) which has been
6
2
equiv of CuCN in order to obtain good yields of product
known for over 80 years.
because the addition of cyanide to aryl halides in the reaction
is known to be reversible so a high concentration of cyanide
is key to drive the reaction towards completion. With 1 equiv. a
product yield of only 39% is obtained.
Since the start of the development of microwave-promoted
synthesis, debate into the nature of the microwave heating of
14
reactions has been sparked. The acceleration of reactions
could simply be an effect of the thermal energy generated by the
microwaves interacting with the substrates or could be an
effect specific to microwave heating. In most cases the observed
differences between microwave and conventional heating can be
attributed to simple thermal effects. We wanted to determine
whether our reaction could be equally well performed using
conventional heating. Keeping the quantities of reagents,
TBAB and water exactly the same as in the microwave-
promoted reaction we performed the reaction in an oil bath. We
dipped a sealed 10 mL microwave tube containing the reactants
into oil pre-heated to 170 ЊC and held it there for 3 min before
removing it and cooling. No product was obtained. We attrib-
The reaction is usually carried out at high temperatures (150–
2
50 ЊC) using solvents such as nitrobenzene; however recently
11
there has been a report of the use of ionic liquids as solvents.
When using 1,3-dialkylimidazolium halide-based ionic liquids
it is possible to obtain nitriles from aryl iodides when perform-
ing the reaction using 2 or 3 equivalents of CuCN and heating
at around 90–130 ЊC for 24 h. However isolated yields are low
because of problems isolating the nitrile. We have recently
shown that the reaction can be accelerated by the use of
12
microwave heating. Although this method offers a more rapid
route to aryl nitriles and also opens up the scope of the reaction
to aryl bromides, there is still the problem of product isolation.
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 1 1 9 – 1 1 2 1
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View Online
a
Table 1 Screening of conditions for the cyanation of 4-iodotoluene with CuCN
b
c
Entry
Reaction conditions
Yield (%)
1
2
3
4
5
6
7
2 equiv. CuCN, T = 170 ЊC, hold time 3 min (no solvent)
2 equiv. CuCN, 0.5 mL water, T = 125 ЊC, hold time 3 min
2 equiv. CuCN, 1.0 equiv. TBAB, 0.5 mL water, T = 170 ЊC, hold time 3 min
2 equiv. CuCN, 0.5 equiv. TBAB, 0.5 mL water, T = 170 ЊC, hold time 3 min
2 equiv. CuCN, 1.0 equiv. TBAB, 0.5 mL water, T = 170 ЊC, hold time 5 min
1 equiv. CuCN, 1.0 equiv. TBAB, 0.5 mL water, T = 170 ЊC, hold time 3 min
2 equiv. CuCN, 1.0 equiv. TBAB, 0.5 mL water, T = 170 ЊC, oil bath, hold time 3 min
0
0
80
68
61
39
0
d
a
Reactions were run using 1 mmol aryl halide and 0.5 mL water. Reactions were run using a power of 100 W and a pressure threshold of 200 psi. The
b
c
temperature was ramped to that stated and held there for the allotted time. Conditions changed from entry 1 are highlighted in bold. Isolated
yields. Reaction mixture only reached 125 ЊC.
d
a
Table 2 Microwave-promoted cyanation of aryl halides in water
bc
cd
Entry
1
Aryl halide
Yield (%) using CuCN
Yield (%) using NaCN ϩ CuI
80
81
72
63
2
3
4
5
6
99
81
99
64
e
e
99
90
47
34
a
Reactions were run using 1 mmol aryl halide, 1 mmol TBAB. Reactions were run using a power of 100 W, a temperature threshold of 170 ЊC and
b
a pressure threshold of 200 psi. The temperature was ramped to 170 ЊC and held there for 3 min unless stated otherwise. Using 2 mmol CuCN.
c
d
e
Isolated yield. Using 2 mmol NaCN and 1 mmol CuI. Hold time of 5 min.
ute this difference to the fact that, with microwave promotion,
efficient heating of the sample is possible whereas transfer of
heat through reaction vessel walls is necessary with convention-
ally heated systems, e.g. oil baths. This internal heat transfer
results in minimised wall effects (no thermal boundary layer)
and reaction mixtures can be heated to high temperatures
rapidly.
With our optimized conditions in hand, we screened a range
of aryl iodides bearing electron withdrawing and donating
groups in the microwave-promoted reaction. The results are
shown in Table 2. With the exception of 3-iodopyridine,
excellent yields of product can be obtained showing the
applicability of the methodology. The isolated yields of product
obtained from these reactions is significantly higher than that
when using ionic liquids as solvents, primarily because the
work-up procedure is much easier when using water as the
reaction medium. Unfortunately unlike when using ionic
liquids as solvents, we find that it is not possible to expand the
substrate scope to aryl bromides when using water, no product
being obtained even when using activated bromides.
We were next keen to develop the procedure using the cheaper
sodium cyanide rather than copper cyanide. We found that the
direct reaction of NaCN and aryl iodides in water with TBAB
does not yield any product. This is not unexpected since it is
known that alkali metal cyanides do not react directly with aryl
halides, even activated ones. However if NaCN is used in con-
junction with copper() iodide it is possible to obtain the nitrile
products via an in situ transmetallation (Table 2). We find that it
is necessary to use a 1 : 1 : 2 ratio of aryl iodide : CuI : NaCN in
order to obtain good yields of the nitriles. If catalytic quantities
of copper iodide are used the product yields drop considerably.
Conclusions
We have shown here that is is possible to prepare aryl nitriles
from aryl iodides using either CuCN or NaCN as the cyanide
sources, the latter requiring CuI as an additive. The reactions
are performed in water and tetrabutylammonium bromide is
used as a phase transfer catalyst. The reactions are promoted by
microwave irradiation with reaction times of 3–5 min.
1
120
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Experimental
4-Cyanophenol
1
13
H NMR: δ 7.40 (d, 2H, J 8.7), 7.00 (d, 2H, J 8.7); C NMR:
δ 162, 134, 120, 116, 102.
General experimental
Microwave experiments were conducted using a focused micro-
wave system. The machine consists of a continuous focused
microwave power delivery system with operator selectable
power output from 0–300 W. Reactions were performed in glass
vessels (capacity 10 mL) sealed with a septum. The pressure is
controlled by a load cell connected to the vessel via a 14-gauge
needle which penetrates just below the septum surface. The
temperature of the contents of the vessel was monitored using a
calibrated infrared temperature control mounted under the
reaction vessel. All experiments were performed using a stirring
option whereby the contents of the vessel are stirred by means
of a rotating magnetic plate located below the floor of the
microwave cavity and a Teflon-coated magnetic stir bar in the
vessel. In the reactions presented here, a target temperature was
set together with a maximum microwave power. This maximum
power is then used to heat the reaction mixture to the target
temperature and, once there, the microwave power is varied as
to hold the mixture at this temperature. This is defined as the
3-Cyanopyridine
1
H NMR: δ 9.03 (m, 1H), 9.00 (m, 1H), 8.01 (d, 1H), 7.54
t, 1H); C NMR: δ 154, 153, 140, 125, 117, 111.
13
(
General procedure for the synthesis of aryl nitriles from aryl
iodides using sodium cyanide
Aryl halide (1 mmol) was placed together with TBAB (1 mmol,
0
.322 g), sodium cyanide (2 mmol, 0.098 g) and copper() iodide
(
1 mmol, 0.190 g) into a 10 mL glass tube equipped with
a Teflon coated stirrer bar. Water (0.5 mL) was added and
the tube sealed with a septum. Reactions were run using a
maximum microwave power of 100 W, a temperature threshold
of 170 ЊC and a pressure threshold of 200 psi. Once the temper-
ature threshold was reached, the reaction mixture was held
there for the requisite time. The products were isolated and
characterised in an identical manner to the reactions run using
copper cyanide.
‘hold time’. A maximum pressure of 200 psi is set, this being
a safety precaution since the tubes hold, at a maximum, a
pressure of 250 psi. At the end of a reaction, the tube and
contents are cooled rapidly using a stream of compressed air.
All chemicals used in the reactions were reagent grade and
used as purchased. NMR spectra were recorded at 250 MHz
and 293 K, run in CDCl and referenced to SiMe . Chemical
Acknowledgements
The Royal Society is thanked for a University Research Fellow-
ship (NEL) and King’s College London for a PhD studentship
(
HMT). EvotecOAI are thanked for a CASE award (HMT).
3
4
Financial support from King’s College London and EvotecOAI
is acknowledged.
shifts are expressed in δ (ppm) and coupling constants (J) in
hertz.
References
General procedure for the synthesis of aryl nitriles from aryl
iodides using copper(I) cyanide
1 For reviews on the area see: (a) P. Lindström, J. Tierney, B. Wathey
and J. Westman, Tetrahedron, 2001, 57, 9225; (b) S. Deshayes,
M. Liagre, A. Loupy, J.-L. Luche and A. Petit, Tetrahedron, 1999,
55, 10851; (c) C. R. Strauss, Aust. J. Chem., 1999, 52, 83; (d ) R. S.
Varma, Green Chem., 2001, 3, 98; (e) S. Caddick, Tetrahedron, 1995,
Aryl halide (1 mmol) was placed together with TBAB (1 mmol,
0
.322 g) and copper() cyanide (2 mmol, 0.179 g) into a 10 mL
glass tube equipped with a Teflon coated stirrer bar. Water
0.5 mL) was added and the tube sealed with a septum.
5
1, 10403.
(
2
For reviews on the concepts see: (a) C. Gabriel, S. Gabriel, E. H.
Grant, B. S. Halstead and D. M. P. Mingos, Chem. Soc. Rev., 1998,
Reactions were run using a maximum microwave power of 100
W, a temperature threshold of 170 ЊC and a pressure threshold
of 200 psi. Once the temperature threshold was reached, the
reaction mixture was held there for the requisite time. After the
reaction mixture was cooled, the tube was opened and more
water (2–3 mL) was added. The water layer was removed and
washed with diethyl ether, the ether extract being kept. The
remaining mixture in the microwave tube was dissolved in
acetonitrile, the solution filtered and the filtrate combined with
the ether extract. The combined organics were dried using
2
7, 213; (b) D. M. P. Mingos, Chem. Soc. Rev., 1991, 20, 1.
3 For some recent examples see: (a) J. Westman, Org. Lett., 2001, 3,
3745; (b) N. Kuhnert and T. N. Danks, Green Chem., 2001, 3, 98; (c)
A. Loupy and S. Regnier, Tetrahedron Lett., 1999, 40, 6221.
4
For an introduction to the use of water as a solvent in organic
synthesis see: (a) Organic Synthesis in Water, ed. P. A. Grieco,
Blackie Academic & Professional, London, 1998; (b) C.-J. Li and
T.-H. Chen, Organic Reactions in Aqueous Media, Wiley, New York,
1997.
5 For an introduction to the use of organometallic catalysts in
aqueous-phase catalysis see: Aqueous-Phase Organometallic
Catalysis, Concepts and Applications, ed. B. Cornils and W. A.
Herrmann, Wiley-VCH, Weinheim, 1998.
MgSO . After filtration the solvents were removed in vacuo
4
leaving the product. Reaction products were characterised
1
13
by comparison of H- and C-NMR data with those in the
literature.
6
For a review of cyano-dehalogenation see: G. P. Ellis and T. M.
Romney-Alexander, Chem. Rev., 1987, 87, 779.
(a) M. Sundermeier, A. Zapf, M. Beller and J. Sans, Tetrahedron
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Lett., 2000, 41, 3271; (c) H. Kubota and K. C. Rice, Tetrahedron
Lett., 1998, 39, 2907.
7
4
-Methylbenzonitrile
1
H NMR: δ 7.44 (d, 2H, J 8.1), 7.18 (d, 2H, J 8.1), 2.33 (s, 3H);
C NMR: δ 144, 131, 130, 119, 109, 21.
13
8 P. E. Maligres, M. S. Waters, F. Fleitz and D. Askin, Tetrahedron
Lett., 1999, 40, 8193.
9
T. Sakamoto and K. Ohsawa, J. Chem. Soc., Perkin Trans. 1, 1999,
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10 M. Alterman and A. Hallberg, J. Org. Chem., 2000, 65, 7984.
4
-Nitrobenzonitrile
2
1
13
H NMR: δ 8.20 (d, 2H, J 8.9), 7.82 (d, 2H, J 8.9); C NMR:
δ 150, 133, 124, 118, 117.
1
1
1
1 J. X. Wu, B. Beck and R. X. Ren, Tetrahedron Lett., 2002, 43, 387.
2 N. E. Leadbeater and H. M. Torenius, Tetrahedron, in press.
3 CAUTION: The water is heated well above its boiling point so all
necessary precautions should be taken when performing such
experiments. Vessels designed to withhold elevated pressures must be
used. The microwave apparatus used here incorporates 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 a
temperature below the boiling point before removal from the
microwave cavity and opening to the atmosphere.
4
-Cyanoacetophenone
1
H NMR: δ 7.96 (d, 2H, J 8.2), 7.68 (d, 2H, J 8.2), 2.53 (s, 3H);
C NMR: δ 197, 140, 133, 129, 118, 27.
13
4
-Methoxybenzonitrile
1
H NMR: δ 7.48 (d, 2H, J 7.9), 6.87 (d, 2H, J 7.9), 3.76 (s, 3H);
C NMR: δ 163, 134, 120, 115, 104, 56.
1
4 For a review see: L. Perreux and A. Loupy, Tetrahedron, 2001, 57,
9199.
13
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 1 1 9 – 1 1 2 1
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