Development of Pd/C-catalyzed cyanation of Aryl halides

Article abstract of DOI:10.1021/jo102037y

A practical method for palladium-catalyzed cyanation of aryl halides using Pd/C is described. The new method can be applied to a variety of aryl bromide and active aryl chloride substrates to effect efficient conversions. The process features many advantages over existing cyanation conditions and the practical utility of the process has been demonstrated on scale.

Full text of DOI:10.1021/jo102037y

pubs.acs.org/joc
SCHEME 1. Selected Cyano-Substituted Pharmaceutical Prod-
ucts
Development of Pd/C-Catalyzed Cyanation
of Aryl Halides
,
†
†
Hannah Yu,* Rachel N. Richey, William D. Miller,
†
‡
Jiansheng Xu, and Scott A. May
†
†
Chemical Product Research and Development, Lilly
Research Laboratories, Eli Lilly and Company, Indianapolis,
‡
Indiana 46285, United States , and Shanghai
PharmaExplorer, Shanghai, China, 201203
yu_hannah@lilly.com
Received October 13, 2010
A practical method for palladium-catalyzed cyanation of
aryl halides using Pd/C is described. The new method can
be applied to a variety of aryl bromide and active aryl
chloride substrates to effect efficient conversions. The
process features many advantages over existing cyanation
conditions and the practical utility of the process has been
demonstrated on scale.
palladium will interact with the cyanide ions to form un-
9
reactive complexes. To circumvent this issue, numerous
procedures have been developed to control the level of
cyanide in solution. Reagents with weakly ionizable
7a,c,d,g,k,m,n,q,r,w
M-CN bonds, such as zinc cyanide
and
(7) For representative examples of palladium-catalyzed cyanation of aryl
halides, see: (a) Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.;
Aromatic nitriles constitute a key component of numerous
commercial compounds, including dyes, herbicides, agro-
Pipik, B.; King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887.
(b) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224. (c) Maligres, P. E. Tetrahedron
Lett. 1999, 40, 8193. (d) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000, 41,
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125, 2890. (f) Sundermeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans,
J.; Weiss, S.; Beller, M. Chem.;Eur. J. 2003, 9, 1828. (g) Chidambaram, R.
Tetrahedron Lett. 2004, 45, 1441. (h) Yang, C.; Williams, J. M. Org. Lett.
1
chemicals, and natural products. In particular, the motif is
present in an increasing number of pharmaceutical products
2
Scheme 1). The nitrile group is also an important precursor
(
for various functional groups such as amidines, amides, imidoe-
3
2
004, 6, 2837. (i) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004,
1388. (j) Schareina, T.; Zapf, A.; Beller, M. J. Organomet. Chem. 2004, 689,
576. (k) Stazi, F.; Palmisano, G.; Turconi, M.; Santagostino, M. Tetrahe-
sters, benzamidines, amines, heterocycles, and aldehydes.
4
5
The Sandmeyer and Rosemund-Von Braun reactions
were reported in early examples in converting aryl halides to
4
dron Lett. 2005, 46, 1815. (l) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron
Lett. 2005, 46, 2585. (m) Jensen, R. S.; Gajare, A. S.; Toyota, K.; Yoshifuji,
M.; Ozawa, F. Tetrahedron Lett. 2005, 46, 8645. (n) Hatsuda, M.; Seki, M.
Tetrahedron 2005, 61, 9908. (o) Weissman, S. A.; Zewge, D.; Chen, C. J. Org.
Chem. 2005, 70, 1508. (p) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189.
aryl cyanides. More recently, the transition metal-catalyzed
6
-8
cyanation has attracted widespread interest.
One of the
major challenges for development of robust cyanation con-
ditions lies in the fact that in the presence of cyanide ions,
(
(
q) Pitts, M. R.; McCormack, P.; Whittall, J. Tetrahedron 2006, 62, 4705.
r) Littke, A.; Soumeillant, M.; Kaltenback, R. F., III; Cherney, R. J.; Tarby,
C. M.; Kiau, S. Org. Lett. 2007, 9, 1711. (s) Schareina, T.; Zapf, A.;
Magerlein, W.; Muller, N.; Beller, M. Tetrahedron Lett. 2007, 48, 1087.
(t) Zhu, Y.; Cai, C. Synth. Commun. 2007, 37, 3359. (u) Ryberg, P. Org.
Process Res. Dev. 2008, 12, 540. (v) Ren, Y.; Liu, Z.; He, S.; Zhao, S.; Wang,
J.; Niu, R.; Yin, W. Org. Process Res. Dev. 2009, 13, 764. (w) Shevlin, M.
Tetrahedron Lett. 2010, 51, 4833.
(
1) (a) Larock, R. C. Comprehensive Organic Transformations; VCH:
New York, 1989; pp 819-995. (b) Grundmann, C. In Houben-Weyl:
Methoden der organischen Chemie, 4th ed.; Falbe, J., Ed.; Georg Thieme:
Stuttgart, Germany, 1985; Vol. E5, pp 1313-1527.
(
2) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
Substances: Syntheses, Patents, Applications, 5th ed.; Georg Thieme: Stuttgart,
Germany, 2009.
(8) For representative examples of metal-catalyzed cyanation through
C-H functionalization, see: (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (b) Mariampillai, B.; Alliot, J.; Li,
M.; Lautens, M. J. Am. Chem. Soc. 2007, 129, 15372. (c) Jia, X.; Yang, D.;
Zhang, S.; Cheng, J. Org. Lett. 2009, 11, 4716. (d) Kim, J.; Chang, S. J. Am.
Chem. Soc. 2010, 132, 10272.
(9) (a) Sundermeier, M.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2003,
42, 1661. (b) Sundermeier, M.; Zapf, A.; Beller., M. Angew. Chem., Int. Ed.
2003, 42, 1661. (c) Dobbs, K. D.; Marshall, W. J.; Grushin, V. V. J. Am.
Chem. Soc. 2007, 129, 30. (d) Erhardt, S.; Grushin, V. V.; Kilpatrick, A. H.;
Macgregor, S. A.; Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc. 2008, 130,
4828.
(
3) Rappoport, Z. Chemistry of the Cyano Group; John Wiley & Sons:
London, UK, 1970.
4) (a) Sandmeyer, T. Ber. Dtsch. Chem. Ges. 1884, 17, 1633. (b) Hodgson,
H. H. Chem. Rev. 1947, 40, 251. (c) Galli, C. Chem. Rev. 1988, 88, 765.
5) (a) Mowry, D. T. Chem. Rev. 1948, 42, 189. (b) Ellis, G. P.; Romney-
Alexander, T. M. Chem. Rev. 1987, 87, 779.
6) For reviews, see: (a) Farina, V. In Comprehensive Organometallic
(
(
(
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G., Eds.; Pergamon:
Oxford, UK, 1995; pp 225-226. (b) Sundermeier, M.; Zapf, A.; Beller, M.
Eur. J. Inorg. Chem. 2003, 3513.
DOI: 10.1021/jo102037y
r 2010 American Chemical Society
Published on Web 12/30/2010
J. Org. Chem. 2011, 76, 665–668 665

Yu et al.
JOCNote
a
TABLE 1. Identification of the Pd/C-Catalyzed Cyanation Reaction Conditions
b,c
yield (%)
entry
conditions
(1 equiv), 120 C
Fe(CN) , Na CO
, wet, 120 C
ο
1
2
Pd(OAc)
Pd(OAc)
2
2
3
3
, K
4
Fe(CN)
6
, Na
, dppf (4 mol %), K
2
CO
3
35
65
66
36
5
98 (90)
ο
4
6
2
3
(1 equiv), 120 C
d
3
ο
Pd
Pd
2
(dba)
(dba)
, dppf (4 mol %), Zn(CN)
, dppf (4 mol %), Zn(CN)
2
ο
4
2
2
, Zn (20 mol %), 120 C
e
ο
5
Pd/C, PPh
3
(16 mol %), Zn(CN)
2
, Zn (40 mol %), Br
)
2
(20 mol %), 120 C
O (10 mol %), 110 C
e
6
ο
Pd/C, dppf (4 mol %), Zn(CN)
2
, Zn(CHO
b
2
2
3 2H2
sparging. Yield determined by HPLC potency with 4 as the internal standard. Isolated
a
c
All reactions were run at 1 g scale with 10 min subsurface N
yield is reported in parentheses. DMAC:water = 100:1. 10 wt % Pd/C.
2
d
e
7
i,j,l,o,p,s,v
potassium ferrocyanide(II),
have been found to be
Zn(CN) as the cyanide source. Under the treatment of
2
advantageous over the conventional cyanide sources, such as
KCN and NaCN. Efforts have also been made to control the
cyanide concentration through defined dosing of acetone
Pd(dba) , dppf, and Zn(CN) in DMAC/water (100:1) at
120 C, the reaction stalled when a significant amount of
2
7c
2
ο
starting material 3 still remained (entry 3). Reducing the
catalyst loading to 1 mol % of Pd(dba) and 2 mol % of dppf
9
a
7u,10
cyanohydrin, or through control of addition sequence.
In addition, a variety of additives, such as Bu SnCl,
2
7
h
provided a similar amount of starting material at the end of
the reaction. When the reaction was conducted under the
conditions of Pd(dba) , dppf, Zn(CN) , and zinc dust in
3
7
diamines, Zn dust, Zn/Zn(OAc)2, Zn/ZnBr2, and
f
7d
7g
7n
7
w
Zn/H SO , have been introduced to the system to activate
2
4
2
2
7
d
the catalysts. Despite these improvements, the palladium-
catalyzed cyanation reaction still often suffers from pro-
blems such as a lack of robustness. In addition, many of the
conditions reported are not ideal for multikilogram scale
preparations. For example, expensive catalysts and high
catalyst loadings were often reported. Operating under the
acidic conditions also generates cyanide safety concerns.
Zinc dust was used in many of the conditions, which requires
extra attention to suspend zinc in the reactor and also creates
waste treatment liability.
DMAC (entry 4), an incomplete reaction was still ob-
served. We then carried out the reaction by using Pd/C,
PPh , Zn(CN) , Zn dust, and ZnBr (generated from zinc
3
2
2
ο
7n,11
and Br ) in DMAC at 120 C (entry 5).
2
minimal amount of product 3 was detected.
However, a
1
2
From the industrial application perspective, the use of
heterogeneous palladium catalysts to facilitate cross-coupling
reactions often offers a number of advantages over the
1
3,14
homogeneous catalytic conditions.
We therefore contin-
ued our investigation using Pd/C as the catalyst, aiming to
develop a simplified cyanation condition with reduced Pd
and ligand loading. Under the conditions of Pd/C, dppf, and
During the course of a recent project, we encountered major
issues in our attempts to affect consistent conversion of a
heteroaryl bromide to a heteroaryl nitrile under a variety of
literature conditions. The issues prompted us to look for
additional cyanation conditions. Herein, we wish to report a
practical and scalable cyanation method using heterogeneous
palladium catalyst. This process features many advantages
over the existing conditions. Furthermore, the same process
could be applied to the synthesis of a broad range of aryl nitriles
from aryl bromides and electron-deficient aryl chlorides.
Using 5-bromoindole 3 as a model substrate, we started
our cyanation investigation by using 2 mol % of Pd catalyst
and Zn(CN) or K Fe(CN) as the cyanide source (Table 1).
Zn(CN) in DMAC, no cyanation took place. To our de-
2
light, when 0.1 equiv of zinc formate dihydrate was added to
the reaction mixture, the reaction proceeded smoothly at
ο
105-110 C to give the desired product with 98% HPLC
assay yield (Table 1, entry 6).
The presence of dppf was critical for the success of the
reaction. Without the ligand, the product was not formed.
15
Zinc, a common reducing agent used in the palladium-
catalyzed cyanation, was not needed under our conditions.
Instead, zinc formate dehydrate played a vital role in reacti-
vating the palladium catalyst, presumably via reducing the
2
4
6
9d,16
When 3 was heated with Pd(OAc) , Na CO , and K Fe(CN)
6
products of the catalyst poisoning to active Pd(0).
For-
2
2
3
4
7
o
under a ligandless condition in DMAC, significant
amounts of starting material, along with major impurities,
were observed at the end of the reaction (entry 1). To reduce
mate had been used in the palladium-catalyzed hydroaryla-
tion reactions to convert the corresponding Pd(II) inter-
1
mediate to Pd(0). One of the potential liabilities of using
7
7
j,o
the rate of potential catalyst aggregation, we attempted
the reactions by reducing Pd(OAc) loading. However,
similar results were observed. The reaction was then con-
(11) Hatsuda, M.; Seki, M. Tetrahedron Lett. 2005, 46, 1849.
(12) Reactions attempted with higher catalyst loading or using dppf as the
ligand also gave little conversion.
(13) Seki, M. Synthesis 2006, 2975.
2
ο
7i
ducted in the presence of dppf ligand at 120 C for12 h (entry 2).
An incomplete reaction was again observed. Increasing
temperature or adjusting catalyst loading had no effect on
further conversion. We next turned our attention to using
(
14) Yin, L.; Liebscher, J. Chem. Rev. 2007, 107, 133.
15) We also examined other ligands, such as PPh , P(o-Tol)
P. We found dppf to be superior to other ligands in terms of
reactivity and general scope.
16) The reaction did not work when zinc formate was simply replaced
(
3
3
, BINAP,
and t-Bu
3
(
with zinc, which suggested additional beneficial effects of zinc formate on the
catalyst system. Further investigation is needed to gain additional under-
standing of the mechanistic effects of zinc formate.
(10) Marcantonio, K. M.; Frey, L. F.; Liu, Y.; Chen, Y.; Strine, J.;
Phenix, B.; Wallace, D. J.; Chen, C. Org. Lett. 2004, 6, 3723.
6
66 J. Org. Chem. Vol. 76, No. 2, 2011

Yu et al.
JOCNote
a
a
TABLE 2. Pd/C-Catalyzed Cyanation of Aryl Halides
TABLE 3. Pd/C-Catalyzed Cyanation of Heteroaryl Halides
a
Reaction conditions: aryl halide (100 mol %), Zn(CN)
2
(60 mol %),
Pd/C (2 mol %), dppf (4 mol %), Zn(CHO
(
and dppf loadings can be reduced to 0.1 and 0.2 mol %, respectively
2
)
0.6 M), 12 h. Isolated yield. HPLC solution yield in parentheses. Pd/C
2
2H O (10 mol %), DMAC
2
3
b
c
a
zinc formate in cyanation reactions was the reduction of
Reaction conditions: aryl halide (100 mol %), Zn(CN)
Pd/C (2 mol %), dppf (4 mol %), Zn(CHO 2H O (10 mol %), DMAC
0.6 M), 12 h. Isolated yield. HPLC solution yield in parentheses.
2
(60 mol %),
II 9c
oxidative addition complex (ArLnPd X) before transme-
talation. Under our reaction conditions, the dehalogenation
2
)
2
2
3
b
(
1
impurity (indole) was not detected. This suggested that the
8
II
transmetalation to form the ArLnPd CN intermediate
was a relatively fast step under the reaction conditions.
9c
(entry 4). In addition, the same conditions could be success-
fully applied to the cyanation of 4-chloroacetophenone
(entry 8).
Although the reactions discussed above were carried out
with 2 mol % of Pd/C and 4 mol % of dppf, we also explored
the catalyst loading for the cyanation of 4-bromoacetophe-
none (Table 2, entry 1). The cyanation reaction proceeded
efficiently with as little as 0.1 mol % of Pd/C at 100 C, which
corresponded to a catalyst turnover number (TON) ap-
proaching 1000.
Due to the prevalence of heterocycles in pharmaceutical
products, we are particularly interested in evaluating the
cyanation of heteroaryl halides. Cyanation of nitrogen-
containing heterocycles can often be challenging due to the
This result led to our interest in exploring the scope and
limitations of this strategy. The general utility of the heterogeneous
Pd/C cyanation procedure for the synthesis of a range of aryl
nitriles was explored (Table 2). A variety of aryl bromides
were successfully cyanated to give the desired aryl nitriles
with excellent yields (entries 1-7). The electron density of the
bromide substrates had little effect on the reaction results
and full conversion was achieved with electron-deficient,
neutral, and electron-rich substrates. The reaction also
worked equally well with ortho-substituted aryl bromide
ο
(
17) (a) Burns, B.; Grigg, R.; Ratananukul, P.; Sridharan, V.; Stevenson,
19
ability of nitrogen to potentially deactivate the catalyst.
P.; Worakun, T. Tetrahedron Lett. 1988, 29, 4329. (b) Ruchirawat, S.;
Namsa-aid, A. Tetrahedron Lett. 2001, 42, 1359. (c) Kulagowski, J. J.; Curtis,
N. R.; Swain, C. J.; Williams, B. J. Org. Lett. 2001, 3, 667. (d) Mitchell, D.;
Yu, H. Curr. Opin. Discovery Dev. 2003, 6, 876.
(19) Expensive ligands and higher catalyst loading are often needed for
nitrogen-containing heterocycles, see refs 7k, 7r, and 7u.
(18) A detection limit of 0.1% was applied.
J. Org. Chem. Vol. 76, No. 2, 2011 667

Yu et al.
JOCNote
To our delight, various heteroaryl halides participated effi-
ciently under our cyanation conditions (Table 3). 3-Bromo-
pyridine (entry 2), 3-bromo-4-methylthiophene (entry 3),
Experimental Section
Representative Procedure (Preparation of 4). To a round-
bottomed flask were added 5-bromo-1H-indole (3) (1.0 g,
3
(
-bromoquinoline (entry 5), and 3-bromothianaphthene
entry 6) could all be cyanated with Pd/C and dppf to give
5
highly toxic), 10 wt % Pd/C (108 mg; 0.10 mmol; 2 mol %),
.1 mmol), zinc cyanide (0.36 g; 3.1 mmol; 0.6 equiv) (Caution:
2
0
0
complete conversions. 2-Chloro-6-methylpyridine (entry 4)
also underwent smooth reaction to afford the desired 2-cyano-
1,1 -bis(diphenylphosphino)ferrocene (dppf) (111 mg; 0.20 mmol;
4 mol %), and DMAC (8.5 mL). The resulting slurry
was sparged with subsurface nitrogen for 10 min, and zinc
formate dihydrate (79 mg; 0.51 mmol; 10 mol %) was added
to the reaction mixture. The reaction mixture was again sparged
with subsurface nitrogen for 10 min and was heated under
nitrogen to 110 °C. Reaction conversion was monitored by
HPLC. Upon completion, the reaction mixture was cooled to
rt and diluted with 10 mL of EtOAc. The resulting slurry was
filtered and the cake was rinsed with EtOAc (2 mL). The product
was isolated by washing the filtrate with water (2 ꢀ 10 mL) and
6
-methylpyridine with 96% isolated yield. 4-Chloroqui-
ο
naldine could also be cyanated at 105 C under the same
conditions (entry 7). Inspired by these results, we attempted
our cyanation conditions with less reactive 5-chloroindole.
Unfortunately, the reactivity was not sufficient to drive the
reaction and only starting material was recovered (entry 8).
In summary, we have developed a general condition for
the synthesis of aryl nitriles utilizing easily available Pd/C as
the palladium source. The condition could be applied to a
variety of aryl bromide and active aryl chloride substrates to
effect efficient conversions. More importantly, the process
features many advantages over the existing cyanation con-
ditions, such as avoiding the use of zinc metal, less Pd
contamination in product, and use of easily available and
inexpensive catalyst and ligand. The practical utility of this
process has been consistently demonstrated on the scale-up
of a challenging heteroaryl bromide substrate to afford the
desired nitrile with over 87% yield after crystallization. We
believe the method will find wide use by allowing a practical
access to a variety of aromatic nitriles on scale. Studies are
underway to establish the overall kinetics and to obtain true
mechanistic understanding of the reaction.
5% NH OH (1 ꢀ 10 mL). The organic layer was dried with
4
2 4
Na SO . The volatile was removed in vacuo to give a residue,
which was further purified by silica gel chromatography
EtOAc/heptanes) to provide 4 as a white solid (653 mg;
(
1
4
8
.6 mmol; 90% yield). H NMR (400 MHz, CDCl ) δ ppm
3
.81 (1 H, bs), 8.02 (1 H, s), 7.28-7.51 (3 H, m), 6.65 (1 H, m).
1
3
3
C NMR (400 MHz, CDCl ) δ ppm 137.60, 127.70, 126.63,
1
26.60, 124.84, 120.99, 112.13, 103.40, 102.67. HRMS (ESþ)
9 6 2
exact mass calcd for C H N
141.0047, found, 141.0457.
Acknowledgment. We thank Johnson Matthey for inves-
tigating the effects of different types of Pd/C on a related
substrate.
Supporting Information Available: Experimental details and
spectral data for all entries in Tables 2 and 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
(
20) Reproducible results were obtained with all lots of Pd/C tested. Most
of the reactions were run with 10 wt % Pd/C purchased from Aldrich (wet,
Degussa type E101 NE/W).
6
68 J. Org. Chem. Vol. 76, No. 2, 2011