Ligand-free CuI-catalyzed cyanation of aryl halides using K4[Fe(CN)6] as cyanide source and water as solvent

Article abstract of DOI:10.1016/j.tet.2009.11.016

A methodology for the cyanation of aryl iodides is reported using copper iodide as the catalyst, K₄[Fe(CN)₆] as the cyanide source, and small quantities of water and tetraethylene glycol as the solvent. Reactions are complete within 30 min of microwave heating at 175 °C. A simple work-up procedure has also been devised.

Full text of DOI:10.1016/j.tet.2009.11.016

Tetrahedron 66 (2010) 1098–1101
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Ligand-free CuI-catalyzed cyanation of aryl halides using K [Fe(CN) ]
4
6
as cyanide source and water as solvent
Catherine DeBlase, Nicholas E. Leadbeater *
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, CT 06269-3060, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A methodology for the cyanation of aryl iodides is reported using copper iodide as the catalyst,
Received 26 August 2009
Accepted 22 September 2009
Available online 6 November 2009
K
4
[Fe(CN)
6
] as the cyanide source, and small quantities of water and tetraethylene glycol as the solvent.
ꢀ
Reactions are complete within 30 min of microwave heating at 175 C. A simple work-up procedure has
also been devised.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
cheaper alternatives. Historically, copper complexes have been
used with success for cyanation reactions. The classical route to aryl
Cyanation of aryl halides to form nitriles represents an impor-
tant synthetic transformation since the nitrile motif is found in
a range of pharmaceuticals, dyes, agrochemicals, and natural
products.1 Nitriles are also valuable intermediates in organic
synthesis and can be easily transformed to a range of heterocycles.
A number of synthetic methods for the preparation of aryl nitriles
have been developed. The majority require the use of toxic in-
organic or organic cyanide sources, such as alkali-metal cyanides,
nitriles is the Rosenmund–von Braun reaction involving use of
10
stoichiometric quantities of copper(I) cyanide. However, this
procedure can require harsh conditions, making it incompatible
,2
11
with sensitive substrates. More recently, copper complexes have
been used as catalysts for the reaction in conjunction with organic
12,13
or inorganic cyanide sources,
using K Fe(CN) .
4 6
including a few recent reports
These procedures tend to require the use of
ligands or additives and also require prolonged reaction times.
14
3
4,5
trimethylsilyl cyanide, or acetone cyanohydrin. In 2004, Beller
and co-workers reported the use of potassium hexacyanoferrate
6
,7
hal
CN
(
II), K
4
Fe(CN)
6
, as a cyanide source.
This has greatly reduced
[cat]
+
K Fe(CN)
4 6
toxicity as compared to alkali-metal cyanides such as KCN. It is used
industrially for metal extractions and making a range of advanced
materials. It is also used in low doses in some food preparation,
serving as an anti-caking agent and removing copper from red
wine. It therefore offers a much greener alternative to other cyanide
sources for use in synthetic chemistry. In addition, all six of the CN
R
R
4 6
Scheme 1. Cyanation of aryl halides using K [Fe(CN) ] as a cyanide source.
Research in our laboratory has been focused around the appli-
cation of microwave heating as a tool for preparative chemistry,
15,16
4 6
moieties of K Fe(CN) can be used for cyanation of aryl halides,
particularly in conjunction with the use of water as a solvent.
harnessing the full potential of the reagent. Given these benefits, it
is not surprising that a review of the recent literature shows that
Microwave heating often reduces reaction times dramatically, and
in the case of metal-catalyzed processes, reduces catalyst loadings.
A number of recent reports describe the cyanation of aryl halides
the application of K
4 6
Fe(CN) as a cyanide source is growing
17,18
(
Scheme 1). Most procedures involve the use of palladium com-
facilitated using microwave heating.
previous interest in this transformation,
Furthermore, we have had
8
1
9,20
plexes as catalysts for the reaction. An issue often encountered
with palladium catalysis for this transformation is that over time
the catalysts are deactivated due to the presence of excess cyanide
in solution.9 As a result, higher catalyst loadings can be required
and, when using palladium salts ligated with phosphine ligands it is
costly. As a result, there has been growing interest in developing
and recently turned
our attention to developing a palladium-catalyzed methodology
based around the use of water as a solvent in conjunction with
microwave heating and K
are complete within 20 min microwave heating at 150 C and use
4
[Fe(CN)
6
] as a cyanide source. Reactions
ꢀ
5
2
mol % Pd(OAc) as catalyst. Building on this work, we have be-
come interested in developing a copper-catalyzed variant with the
objective of developing a clean, cheap, and efficient methodology.
We report the results from our first phase of work here.
*
Corresponding author. Tel.: þ1 860 486 5076; fax: þ1 860 486 2981.
E-mail address: nicholas.leadbeater@uconn.edu (N.E. Leadbeater).
0
040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.016

C. DeBlase, N.E. Leadbeater / Tetrahedron 66 (2010) 1098–1101
1099
2
. Results and discussion
the procedure was the amount of waste the post-reaction work-up
generated. In order to purify the product and ensure complete re-
moval of the TBAB it was necessary to perform numerous aqueous-
organic extractions, this involving the use of significant quantities
of water and organic solvent. Knowing that the use of water as
solvent in the absence of TBAB was not successful, we screened
a number of co-solvents. Use of tetraethylene glycol (TEG) proved
to be optimal; polyethylene glycol (PEG) or water–PEG mixtures
also finding application in other copper-catalyzed reactions. In
the cyanation of 4-iodoanisole we obtained an 81% conversion and
the work-up was greatly simplified (Table 1, entry 10). It now re-
quired addition of small volumes of organic solvent (4ꢁ3 mL) fol-
lowed by water (2ꢁ3 mL) to the reaction vessel, emptying the
contents into a separatory funnel and performing one single wash
with brine. In an attempt to drive the reaction to completion, we
extended the time from 20 min to 30 min and this resulted in a 96%
conversion to the desired nitrile product (Table 1, entry 11). Thus
our optimal conditions for the reaction were: aryl halide,
Our objective was to develop a procedure for cyanation of aryl
halides that used a simple copper salt as catalyst (no added li-
gands), K [Fe(CN) ] as the cyanide source, and water as the sol-
4
6
vent. Our starting point was to use similar reaction conditions to
those from our previously reported palladium-catalyzed pro-
cedure but using copper salts in the place of palladium acetate
and without base. With 4-iodoanisole as a test substrate and
copper(II) acetate (10 mol %) as a catalyst candidate, we per-
formed the reaction using 2 mL water as solvent and 0.3 equiv
2
3
K
4
[Fe(CN)
6
]
and tetrabutylammonium bromide (TBAB) as
ꢀ
a phase-transfer agent. After heating the reaction to 150 C and
holding at this temperature for 20 min, no product was observed
ꢀ
(
Table 1, entry 1). Increasing the temperature to 175 C had no
effect (Table 1, entry 2). We have found in our other protocols
that reactions performed using water as solvent can be highly
concentration dependent. Therefore, we re-screened the same
reaction conditions but using just 0.25 mL water. This small
modification led to a 71% conversion to the desired nitrile
product (Table 1, entry 3). We next wanted to determine if the
use of TBAB was essential and found that indeed it was, per-
forming the reaction in its absence not resulting in product for-
mation (Table 1, entry 4). Given the recent upsurge in procedures
K
4
[Fe(CN)
6
] (0.3 equiv), CuI (15 mol %), water (0.25 mL), tetra-
ꢀ
ethylene glycol (0.25 mL); heat to 175 C and hold at this temper-
ature for 30 min.
Before proceeding, we wanted to determine if the reaction was
indeed copper catalyzed. Previous work in our laboratory, as well as
examples from other groups, has shown that the outcome of re-
actions may in some cases be significantly affected by trace levels of
metal contaminants. In one example, Suzuki-type couplings, ini-
21,22
published using iron catalysts,
whether K [Fe(CN) ] could serve as both cyanide source and also
we wanted to determine
4
6
2
4
catalyst, although unlikely. No product was observed in the ab-
sence of the copper salt (Table 1, entry 5). We next screened
a range of other copper salts as well as copper metal. We found
copper(I) iodide to be the most catalytically active, giving a 74%
conversion in the cyanation of 4-iodoanisole (Table 1, entry 6).
Choosing this as our catalyst candidate for further study, we next
sought to optimize the catalyst loading. When using less than
tially thought to be catalyst-free, were found to be affected by ppb
levels of palladium contaminants found in sodium carbonate
2
5
base. In a very recent case, cross-couplings performed using FeCl
as the catalyst were re-investigated, the results suggesting that
3
2
6,27
copper contaminants played an important role in the reactions.
Knowing the reaction was not iron catalyzed (Table 1, entry 5), we
decided to probe whether trace palladium impurities could be
catalytically active. To achieve this we first attempted to perform
the cyanation chemistry using palladium catalysis. Using our op-
timal conditions (Table 1, entry 11) we performed the reaction
using a number of palladium salts in place of copper iodide. In each
case no product was observed. We next decided to screen our
copper iodide source as a potential catalyst for Suzuki couplings
1
0 mol % CuI, we found conversion dropped significantly. When
using greater than 10 mol % CuI, we observed a plateau at
5 mol % (79% conversion; Table 1, entry 7), above which the
1
conversion did not increase. Interested in determining if ligation
of the copper salt would increase the effectiveness of the catalyst
system, we screened two diamine-based candidates, both of
which had shown applicability in other procedures. However
use of trans-cyclohexane-1,2-diamine or N,N -dimethylenedi-
amine had a deleterious effect (Table 1, entries 8 and 9).
At this point, we wanted to assess our procedure from a green
4 6
chemistry standpoint. We were using K [Fe(CN) ] as our cyanide
source, a small volume of water as solvent, and a non-toxic, readily
available copper salt as catalyst. These were all positive factors, as
was the short reaction time. However, one major disadvantage of
1
3
24,25
using our previously reported conditions for this reaction.
0
When using 4-bromoanisole as a substrate we knew this protocol
was sensitive to levels of palladium down to 5 ppm. Using pre-
viously certified palladium-free sodium carbonate as base, no
product was observed in the Suzuki coupling with phenylboronic
acid when using our copper iodide source as the catalyst candidate.
These two tests supported the assertion that the cyanation reaction
was indeed copper catalyzed.
Table 1
Optimization of reaction conditions for the copper-catalyzed cyanation of 4-iodoanisole using K
4
[Fe(CN)
6
] as a cyanide sourcea
I
CN
MW
K
4
6
Fe(CN) , [Cu]
MeO
MeO
Entry
Conditions
Conversion (%)
ꢀ
ꢀ
1
2
3
4
5
6
7
8
9
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
(10 mol %), water (2 mL), TBAB as additive, 150 C for 20 min
0
0
71
0
(10 mol %), water (2 mL), TBAB as additive, 175 C for 20 min
ꢀ
ꢀ
(10 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
(10 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
ꢀ
No copper catalyst, water (0.25 mL), TBAB as additive, 175 C for 20 min
CuI (10 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
CuI (15 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
CuI (15 mol %), trans-cyclohexane-1,2-diamine (15 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
CuI (15 mol %), N,N -dimethylenediamine (15 mol %), water (0.25 mL), TBAB as additive, 175 C for 20 min
CuI (15 mol %), water (0.25 mL), TEG (0.25 mL), 175 C for 20 min
CuI (15 mol %), water (0.25 mL), TEG (0.25 mL), 175 C for 30 min
0
ꢀ
ꢀ
74
79
56
46
81
95
ꢀ
0
ꢀ
ꢀ
ꢀ
10
1
1
a
4 6
Reactions were performed in a sealed tube, using 1 mmol 4-iodoanisole and 0.3 mmol K Fe(CN) .

1100
C. DeBlase, N.E. Leadbeater / Tetrahedron 66 (2010) 1098–1101
Table 2
cyanation methodology requires a high concentration of re-
agents, this could be incompatible with a preceding halogen-
exchange step.
Substrate screening for the CuI-catalyzed cyanation of aryl halides using K
as a cyanide sourcea
4 6
[Fe(CN) ]
I
CN
MW
During the time we were completing our studies, a report
appeared in the literature presenting cyanation and tandem halo-
gen-exchange/cyanation protocols catalyzed by copper(II) ace-
K
4
6
Fe(CN) , CuI
R
R
2
9
tate. This sparked our interest to compare with our methodology.
The work was performed using a domestic microwave oven, the
reaction vessel being sealed, and placed into a glycerol bath. There
was no stirring or in-situ temperature measurement during the
course of the reaction. Attempts to reproduce the procedure using
our scientific microwave apparatus were unsuccessful, even after
modification to take into account that the reaction mixture may be
significantly hotter than reported in the procedure. We tried re-
peating the procedure using 4-iodoanisole, 4-iodotoluene, and
Entry
1
Aryl halide
Conversion (%)
Yield (%)
72
OMe
94
I
COMe
2
3
4
87
79
89
70
66
79
I
4-iodoacetophenone as aryl halide substrates.
I
3. Summary
I
We have developed a methodology for the cyanation of aryl
4 6
iodides using copper iodide as the catalyst, K [Fe(CN) ] as the cy-
I
anide source, and small quantities of water and tetraethylene glycol
as the solvent. Reactions are complete within 30 min microwave
heating at 175 C. A simple work-up procedure has also been de-
vised. Work is now underway to expand the substrate scope of the
protocol to include aryl bromides. In addition, similar approaches to
C–C, C–N, and C–O bond-forming reactions are being developed.
5
6
85
93
63
73
ꢀ
OMe
I
7
8
79
93
66
40
4
4
. Experimental
I
.1. General experimental
N
I
All materials were obtained from commercial suppliers and
OMe
used without further purification. All reactions were carried out in
air. NMR spectra were recorded at 293 K on a 300 or 400 MHz
spectrometer. All products are known and were characterized by
comparison of NMR data with that in the literature. A commercially
available monomode microwave unit (CEM Discover) was used. The
machine consists of a continuous focused microwave power de-
livery system with operator selectable power output from 0 to
9
0
0
9
Br
COMe
10
12
Br
Sealed tube, using 1.0 mmol aryl halide, 0.3 mmol K
.25 mL water, 0.25 mL tetraethylene glycol. Initial microwave irradiation of 150 W,
a
4
6
[Fe(CN) , 15 mol % CuI,
0
3
00 W. Reactions were performed in 10 mL capacity vessels sealed
ꢀ
temperature ramped from rt to 175 C, held for 30 min.
with a septum. The pressure was controlled by a load cell connected
directly to the vessel and the temperature of the contents of the
vessel was monitored using a calibrated IR sensor located outside
the reaction vessel. The contents of the vessel were 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. Temperature, pressure, and power profiles were monitored
using commercially available software provided by the microwave
manufacturer.
We moved to undertake a substrate screen using our optimal
reaction conditions, the results being shown in Table 2. A number of
aryl iodides could be converted to the corresponding nitriles in
good yields (Table 2, entries 1–7). In the case of 2-iodopyridine,
although a high conversion to the desired nitrile was observed,
product purification was difficult and so the isolated yield was
modest (Table 1, entry 8).
Cyanation of aryl bromides under the optimal reaction con-
ditions was not successful (Table 1, entries 9 and 10). This rep-
resents a limitation of the methodology in its current form.
Buchwald and co-workers reported a methodology for tandem
halogen exchange/cyanation of aryl halides using CuI as the
4.2. Representative procedure for the cyanation of aryl
iodides: cyanation of 4-iodoanisole
In a 10 mL glass tube were placed 4-iodoanisole (243 mg,
1.0 mmol), potassium hexacyanoferrate(II) (126 mg, 0.3 mmol), and
CuI (28 mg, 15 mol %). After adding water (0.25 mL) and tetra-
ethylene glycol (0.25 mL), the vessel was sealed with a septum and
placed into the microwave cavity. Initial microwave irradiation of
150 W was used, the temperature being ramped from rt to the
13
catalyst in the presence of nitrogen-based ligands. Using this,
they could cyanate a range of aryl bromides, first converting
them to the corresponding aryl iodide in an aromatic Finkelstein-
2
8
type reaction using KI as a source of iodide. We wanted to
explore the possibility of incorporating such a halogen-exchange
step into our procedure, thus opening avenues for our use of aryl
bromides as substrates. However, we were unsuccessful. This
could be attributed, at least in part, to the observation made by
Klapars and Buchwald that a high concentration of halide salts in
solution inhibits the desired halogen-exchange reaction via for-
mation of poorly reactive halocuprate complexes. Since our
ꢀ
desired temperature of 175 C where it was held for 30 min. During
this time, the power was modulated automatically to hold the re-
ꢀ
action mixture at 175 C. The mixture was stirred continuously
during the reaction. After allowing the mixture to cool to room
temperature, the reaction vessel was opened and the contents
transferred to a separatory funnel using 2ꢁ3 mL of acetonitrile,

C. DeBlase, N.E. Leadbeater / Tetrahedron 66 (2010) 1098–1101
1101
2
ꢁ3 mL of diethyl ether, and 2ꢁ3 mL of distilled water. Additional
12. (a) Wang, D. P.; Kuang, L. P.; Li, Z. W.; Ding, K. Synlett 2008, 69; (b) Cristau, H. J.;
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added to the separatory funnel and the organic material extracted
and removed. The organic layer was rinsed one time with brine
13. Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890.
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(
4
10 mL), dried over MgSO , and the solvent removed in vacuo
leaving the crude product. The product was then isolated and
1
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2007, 555.
literature.30 Yield and conversion data were obtained by in-
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1
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1
tegration of signals in the H NMR and comparison with an internal
(
standard.
(
1
1
Acknowledgements
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This work was supported by the University of Connecticut De-
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University of Connecticut College of Liberal Arts and Sciences.
Equipment support from CEM Corporation is acknowledged.
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1. For a review see: Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779.
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