Palladium-catalyzed cyanation of aryl halides using K4[Fe(CN)6] as cyanide source, water as solvent, and microwave heating

Article abstract of DOI:10.1016/j.tetlet.2008.05.124

A methodology for the cyanation of aryl iodides and activated aryl bromides is reported using water as the solvent and K₄[Fe(CN)₆] as the cyanide source. Reactions are complete within 20 min.

Full text of DOI:10.1016/j.tetlet.2008.05.124

Tetrahedron Letters 49 (2008) 4693–4694
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed cyanation of aryl halides using K4[Fe(CN)6]
as cyanide source, water as solvent, and microwave heating
Sivan Velmathi a,b, Nicholas E. Leadbeater b,
*
a Department of Chemistry, National Institute of Technology, Tiruchirappalli 620 015, India
b 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 and activated aryl bromides is reported using water as
the solvent and K4[Fe(CN)6] as the cyanide source. Reactions are complete within 20 min.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 May 2008
Revised 22 May 2008
Accepted 28 May 2008
Available online 2 June 2008
Aryl nitriles represent an important class of compounds since
the motif is found in a range of pharmaceuticals, dyes, agrochemi-
cals, and natural products.1,2 They 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 including the direct cyanation
of aryl halides by copper(I) cyanide, known as Rosenmund–von
Braun reaction.3 The classical Rosenmund–von Braun procedure
can require harsh conditions,4 making it incompatible with
sensitive substrates. While modifications to this procedure have
been made5 palladium-, copper-, or nickel-catalyzed aryl cyanation
approaches show more promise.6 A downside with these protocols
was that toxic inorganic or organic cyanide sources such as alkali-
metal cyanides trimethylsilyl cyanide7 or acetone cyanohydrin8
are often required. However, this has been overcome by the dis-
covery that cheap, non-toxic potassium hexacyanoferrate(II),
K4[Fe(CN)6] can be used as a cyanide source.9 Based around this dis-
covery, a number of methodologies have been developed10 includ-
ing some procedures using ligand-free palladium sources.11,12
Research in our laboratory has been focused around the applica-
tion of microwave heating as a tool for preparative chemistry, par-
ticularly in conjunction with the use of water as a solvent.13
Microwave heating has found use as a tool for performing the reac-
tion.14 Sparked by a number of recent reports of cyanation of aryl
halides facilitated using microwave heating,15,16 in addition to
our previous interest in this transformation,17,18 we turned our
attention to developing a methodology based around the use of
water as a solvent in conjunction with microwave heating and
K4[Fe(CN)6] as a cyanide source (Scheme 1). We report our results
here.
hal
CN
MW, [Pd]
+
K Fe(CN)
4 6
base, water
R
R
Scheme 1. Cyanation of aryl halides using water as a solvent in conjunction with
microwave heating, and K4[Fe(CN)6] as a cyanide source.
reaction conditions similar to those we had developed previously
for Suzuki and Heck couplings: water as a solvent, sodium carbon-
ate as base, and tetrabutylammonium bromide (TBAB) as a phase
transfer agent, heating at 150–170 °C. We used 5 mol % palladium
acetate as catalyst and a 1:1 molar equiv of 4-bromoacetophenone
to K4[Fe(CN)6]. Performing the reaction for 20 min at 150 °C led to
a 15% yield of the desired nitrile product. A study of the literature
suggested that sodium carbonate, while efficient as a base for the
reaction in organic solvents, may not be optimal for use in water.
We screened a number of mineral bases and found that sodium
fluoride gave by far the best results. Keeping all other conditions
the same, using NaF (1 equiv) as base gave an 80% yield of 4-acetyl-
benzonitrile. We next turned our attention to reducing the quan-
tity of K4[Fe(CN)6]. One molar equivalent corresponds to a sixfold
excess. We therefore tried reducing the quantity used to a stoichio-
metric equivalent. This was possible but product yield dropped.
Increasing the ratio of K4[Fe(CN)6] to aryl halide very slightly to
0.2:1 allowed us to retain an 80% product yield. We then tried
reducing the reaction time but found that this was not possible
without sacrificing product yield. The same was true when we
tried to reduce the catalyst loading. We tried eliminating the TBAB
from the reaction or replacing it with ethanol as a co-solvent but
both of these modifications resulted in no conversion to product.
We screened a range of palladium complexes as potential catalysts
for the reaction including Pd2(dba)3 and Pd/C but found that
palladium acetate gave the best results. Thus, our optimal reaction
conditions were: aryl halide (1 mmol), K4[Fe(CN)6] (0.22 mmol),
To initiate the work, we decided to screen 4-bromoacetophe-
none as a test substrate on the 1 mmol scale and start by using
* Corresponding author. Tel.: +1 860 486 5076; fax: +1 860 486 2981.
E-mail address: nicholas.leadbeater@uconn.edu (N. E. Leadbeater).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.124

4694
S. Velmathi, N. E. Leadbeater / Tetrahedron Letters 49 (2008) 4693–4694
Table 1
converted to the corresponding nitriles in good yields (Table 1,
entries 1–9). Interestingly however, those substrates bearing an al-
kyl group could not be effectively cyanated (Table 1, entry 7). In the
case of 2-iodophenol, although a high conversion to the desired
nitrile was observed, product purification was difficult and so the
isolated yield was only modest (Table 1, entry 8). Attempts to
use iodopyridines as substrates were not successful, significant
decomposition being observed (Table 1, entries 9 and 10). The
scope of aryl bromides is limited to those bearing electron-with-
drawing groups (Table 1, entries 11 and 12). Using 1-bromo-
4-iodobenzene, we observe a chemoselective cyanation to yield
4-bromobenzonitrile (Table 1, entry 13). Aryl chlorides are unreac-
tive under the conditions used (Table 1, entry 14).
Cyanation of aryl halides using K4[Fe(CN)6] as a cyanide sourcea
hal
CN
MW, Pd(OAc)
2
+ K Fe(CN)
4
6
NaF, TBAB, H O
2
R
R
Entry
1
Aryl halide
Product yield (%)
86
OMe
I
I
COMe
NH2
2
3
4
81
In summary, we have developed a methodology for the cyana-
tion of aryl iodides and activated aryl bromides using water as
the solvent and K4[Fe(CN)6] as the cyanide source. Reactions are
complete within 20 min microwave heating at 150 °C.
94
I
I
86b
Acknowledgments
The Technical Education Quality Improvement Programme (TE-
QIP) of the Government of India is thanked for a scholarship (S.V.).
Equipment support from CEM Corp. is acknowledged.
NH2
5
6
88
I
OMe
References and notes
78
1. Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical Substances:
Syntheses, Patents, Applications, 4th ed.; Georg Thieme: Stuttgart, 2001.
2. Collier, S. J.; Langer, P. Sci. Synth. 2004, 19, 403.
I
7
0
3. (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges. 1919, 2, 1749; (b)
Lindley, J. Tetrahedron 1984, 40, 1433.
I
4. For a review see Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87, 779.
5. Wang, D. P.; Kuang, L. P.; Li, Z. W.; Ding, K. Synlett 2008, 69.
6. For a review see Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.;
Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9, 1828.
7. Sundermeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet.
Chem. 2003, 684, 50.
OH
I
8
(80)c 40
8. Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661.
9. Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388.
10. See for example (a) Cheng, Y. N.; Duan, Z.; Yu, L. J.; Li, Z. X.; Zhu, Y.; Wu, Y. J.
Org. Lett. 2008, 10, 901; (b) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett.
2005, 46, 2585.
11. Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1502.
12. (a) Zhu, Y. Z.; Cai, C. Eur. J. Org. Chem. 2007, 15, 2401; (b) Zhu, Y. Z.; Cai, C. Synth.
Commun. 2007, 37, 3359.
9
0
N
N
I
I
10
11
12
13
0
COMe
OMe
I
13. Leadbeater, N. E. Chem. Commun. 2005, 2881.
14. A number of books on microwave-promoted synthesis have been published
recently. For a recent example see: Microwaves in Organic Synthesis; Loupy, A.,
Ed., 2nd ed.; Wiley-VCH: Weinheim, 2006.
80
40
90d
0
Br
Br
Br
Cl
15. For the first report see: Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984.
16. (a) Srivastava, R. R.; Zych, A. J.; Jenkins, D. M.; Wang, H. J.; Chen, Z. J.; Fairfax, D.
J. Synth. Commun. 2007, 37, 431; (b) Chobanian, H. R.; Fors, B. P.; Lin, L. S.
Tetrahedron Lett. 2006, 47, 3303; (c) Pitts, M. R.; McCormack, P.; Whittall, J.
Tetrahedron 2006, 62, 4705; (d) Cai, L. Z.; Liu, X.; Tao, X. C.; Shen, D. Synth.
Commun. 2004, 34, 1215; (e) Zhang, A.; Neumeyer, J. L. Org. Lett. 2003, 5, 201.
17. Arvela, R. K.; Leadbeater, N. E.; Torenius, H. M.; Tye, H. Org. Biomol. Chem. 2003,
1, 1119.
18. Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2003, 68, 9122.
19. Typical procedure for the cyanation of aryl halides with K4[Fe(CN)6]: In a 10 mL
glass tube was placed 4-iodoanisole (243 mg, 1.0 mmol), potassium hexa-
cyanoferrate(II) (93 mg, 0.22 mmol), sodium fluoride (40 mg, 1.0 mmol),
tetrabutylammonium bromide (323 mg, 1 mmol), and Pd(OAc)2 (10 mg,
5 mol %). After adding water (2 mL), the vessel was sealed with a septum and
placed into the microwave cavity (CEM DiscoverÒ). Initial microwave
irradiation of 150 W was used, the temperature being ramped from rt to the
desired temperature of 150 °C (measured using the built-in IR temperature
device). Once this was reached, the reaction mixture was held at this
temperature until a total time of 20 min had elapsed. During this time, the
power was modulated automatically to hold the reaction mixture at 150 °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 poured into a separating funnel. Water (30 mL) and diethyl ether
(30 mL) were added, and the organic material extracted and removed. After
further extraction of the aqueous layer, combining the organic washings and
drying them over MgSO4, the ethyl acetate was removed in vacuo leaving the
crude product. That product was then isolated and characterized by
comparison of NMR data with that in the literature.
COMe
14
a
Sealed tube, using 1.0 mmol aryl halide, 0.22 mmol K4[Fe(CN)6, 1.0 mmol NaF,
1.0 mmol TBAB, 5 mol % Pd(OAc)2, 2.0 mL water. Initial microwave irradiation of
150 W, temperature ramped from rt to 150 °C where it was then held until a total
time of 20 min had elapsed.
b
Reaction run for 40 min.
Conversion to product.
c
d
4-Bromobenzonitrile.
NaF (1 mmol), TBAB (1 mmol), Pd(OAc)2 (5 mol %), water (2 mL),
heat to 150 °C, and hold until a total time of 20 min had elapsed.
We next screened a range of aryl halides in the reaction, the
results are shown in Table 1.19 A number of aryl iodides can be