Development of an open-air and robust method for large-scale palladium-catalyzed cyanation of aryl halides: The use of i-PrOH to prevent catalyst poisoning by oxygen

Article abstract of DOI:10.1021/op9000725

Palladium-catalyzed cyanation of aryl halides is an often capricious reaction and lacks robustness due to catalyst poisoning by oxygen. In this report, an open-air and robust method for large-scale cyanation was developed and the use of commercially avail

Full text of DOI:10.1021/op9000725

Organic Process Research & Development 2009, 13, 764–768
Development of an Open-Air and Robust Method for Large-Scale
Palladium-Catalyzed Cyanation of Aryl Halides: The Use of i-PrOH to Prevent
Catalyst Poisoning by Oxygen
Yunlai Ren, Zhifei Liu, Shebin He, Shuang Zhao, Jianji Wang,* Ruiqi Niu, and Weiping Yin
School of Chemical Engineering and Pharmaceutics, Henan UniVersity of Science and Technology,
Luoyang, Henan 471003, P.R. China
Abstract:
Palladium-catalyzed cyanation of aryl halides is an often capricious
reaction and lacks robustness due to catalyst poisoning by oxygen.
In this report, an open-air and robust method for large-scale
cyanation was developed and the use of commercially available
i-propanol as an additive was critical for achieving the open-air,
robust and scaleable process. Under the protection by i-propanol,
the catalyst life was significantly prolonged.
Figure 1. Application of Weissman’s ligand-free procedure for
Pd-catalyzed cyanation.
solvent is rigorously degassed and the reaction is run in stringent
inert conditions,15 which restricts the applications of the Pd-
catalyzed aryl cyanation.
During the course of applying Weissman’s ligand-free
procedure to large-scale synthesis of the compound shown in
Figure 1,16 we suffered from unexpected reaction failures, which
resulted possibly from the presence of low-level amounts of
oxygen either from the solvent or introduced during setup and
monitoring. Thus, some inexpensive additives were screened
to protect the reaction from being destroyed by oxygen.
Previous studies of palladium-catalyzed cyanation reactions
revealed that zinc dust and polymethylhydrosiloxane (PMHS)
are able to protect the palladium-catalysts from being poisoned
by oxygen.17 Considering that the use of zinc dust would lead
to heavy metal waste, PMHS was chosen to prevent catalyst
poisoning. Unluckily, the addition of PMHS into the reaction
mixture resulted in the formation of an unacceptable amount
of undesired products. To our knowledge, another air-insensitive
procedure is Gelman’s procedure in which 1,8-bis(diisopropy-
lphosphino)triptycene/Pd(OAc)2 was used as the catalyst,18 but
the use of an expensive ligand compelled us to abandon the
application of Gelman’s procedure.
Introduction
Aryl nitriles play an important role in organic synthesis since
they not only constitute key components of a range of
pharmaceuticals, agrochemicals, dyes, etc.1 but can also easily
be transformed into various classes of compounds such as
nitrogen-containing heterocycles, aldehydes, acids, and acid
derivatives.2 One of the most convenient methods for the
synthesis of aryl nitriles is the transition metal-catalyzed
cyanation of aryl halides such as the palladium-,3-10 nickel-,11
and copper-catalyzed methods.12-14 Of these methods, Pd-
catalyzed aryl cyanation has recently attracted the most con-
siderable attention owing to its versatility. Unluckily, the
palladium catalysts have often been poisoned by trace amounts
of oxygen in the solvent.15 In order to avoid or suppress the
deactivation of the catalysts, it has often been required that the
* Author to whom correspondence may be sent. Fax: 86-379-64210415.
E-mail: Jwang@henannu.edu.cn.
(1) Larock, R. C. ComprehensiVe Organic Transformations; VCH: New
Subsequently, we decided to develop a more economical
and air-insensitive procedure for large-scale Pd-catalyzed aryl
cyanation by improving Weissman’s ligand-free procedure.19
We report our results here.
York, 1989, pp 819-995.
(2) Rappoport, Z. Chemistry of the Cyano Group, 1st ed.; John Wiley &
Sons: London, 1970.
(3) Ellis, G. P.; Romney-Alexander, T. M. Chem. ReV. 1987, 87, 779–
794.
(4) Anderson, B. A.; Bell, E. C.; Ginah, F. O.; Harn, N. K.; Pagh, L. M.;
Wepsiec, J. P. J. Org. Chem. 1998, 63, 8224–8228.
(5) Sundermeier, M.; Mutyala, S.; Zapf, A.; Beller, M. J. Organomet.
Chem. 2003, 684, 50–55.
Results and Discussion
In our initial study, cyanation of iodobenzene was chosen
as a model reaction, and PMHS was used as an additive to
prevent the Pd-catalyst from being deactivated.26 Unluckily, the
addition of PMHS led to the formation of a considerable amount
(6) Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 1388–1489.
(7) Schareina, T.; Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M.
Tetrahedron Lett. 2007, 48, 1087–1090.
(8) Velmathi, S.; Leadbeater, N. E. Tetrahedron Lett. 2008, 49, 4693–
4694.
(9) Ryberg, P. Org. Process Res. DeV. 2008, 12, 540–543.
(10) Erhardt, S.; Grushin, V. V.; Kilpatrick, A. H.; Macgregor, S. A.;
Marshall, W. J.; Roe, D. C. J. Am. Chem. Soc. 2008, 130, 4828–
4845.
(15) All the reactions of palladium-catalyzed aryl cyanation in refs 12-14
were performed in inert ambiance.
(16) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceutical
substances: syntheses, patents, applications, 4th ed.; Georg Thieme
Verlag: Stuttgart, NY, 2001, pp 825-826.
(11) Arvela, R. K.; Leadbeater, N. E. J. Org. Chem. 2003, 68, 9122–9125.
(12) Schareina, T.; Zapf, A.; Beller, M. Tetrahedron Lett. 2005, 46, 2585–
2588.
(17) Martin, M. T.; Liu, B.; Cooley, B. E.; Eaddy, J. J. F. Tetrahedron
Lett. 2007, 48, 2555–2557.
(13) Schareina, T.; Zapf, A.; Ma¨gerlein, W.; Mu¨ller, N.; Beller, M. Chem.-
Eur. J. 2007, 13, 6249–6254.
(18) Grossman, O.; Gelman, D. Org. Lett. 2006, 8, 1189–1191.
(19) Weissman, S. A.; Zewge, D.; Chen, C. J. Org. Chem. 2005, 70, 1508–
1510.
(14) Ren, Y. L.; Liu, Z. F.; Zhao, S.; Tian, X. Z.; Wang, J. J.; Yin, W. P.;
He, S. B. Catal. Commun. 2009, 10, 768–771.
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10.1021/op9000725 CCC: $40.75  2009 American Chemical Society
Published on Web 05/14/2009

a
Table 1. Cyanation of iodobenzene catalyzed by Pd(OAc)2
i-PrOH
entry ambiance (vol %)b time (min) conv. (%)c yield (%)c
1
air
N2
N2
air
air
air
air
air
air
air
air
air
-
40
40
40
40
40
40
40
40
40
40
20
20
45
86
44
81
88
93
42
74
91
89
88
87
69
91
2
-
3
4.6
4.8
-
0.3
1.2
2.4
3.3
6.9
4.7
4.8
>99
>99
44
4
5
Figure 2. Effect of concentration of H2O on the cyanation of
bromobenzene (under the reaction conditions as shown in entry
8, Table 2).
6
85
7
>99
>99
>99
>99
81
8
9
10
11
12d
99
a Reaction conditions are shown in the Experimental Section of this paper (1
mmol iodobenzene was used). b Equal to [Vi-PrOH/(Vi-PrOH
+
VNMP)]
×
100%.
c Determined by GC with n-tetradecane as an internal standard. d 5.2 vol % H2O
was used.
of undesired products, which prompted us to use other additives.
According to the previous report,20 some alcohols can be used
as the reductants for Pd-catalyzed homocoupling of aryl halides,
which implies that oxygen may be eliminated by alcohols in
the presence of Pd catalyst. Thus, a variety of alcohols such as
MeOH, EtOH, i-PrOH, n-BuOH, t-BuOH, and t-AmOH were
screened as the additives to eliminate oxygen, and it was found
that i-propanol had a notable ability to protect the Pd-catalyzed
cyanation from being destroyed by oxygen. As shown in Table
1, when cyanation of iodobenzene was performed completely
open to the air without degassing of the solvent, the addition
of i-propanol increased the yield from 44% to 93% (Table 1,
entries 1, 4). However, when the reaction was performed under
inert conditions the beneficial effect of i-propanol was uncon-
spicuous (Table 1, entries 2, 3), which implied that the solvent
effect of i-propanol was insignificant for the reaction. In
conclusion, only under the condition of exposure to air, was
the reaction significantly affected by i-propanol. This result
revealed that i-propanol was able to protect the Pd-catalyzed
cyanation from being destroyed by oxygen, which was also
supported by the fact that the oxidation product of i-propanol
was detected in our open air reaction. These results were
possibly rationalized by assuming that active Pd(0) catalytic
species were oxidated to inactive Pd(II) by oxygen, and then
i-propanol reduced Pd(II) to active Pd(0).
Then our attention was turned to the optimization of the
concentration of i-propanol. As shown in Table 1 (entries
5-10), all the reactions were performed completely open to
the air without stringent degassing of the solvent. The cyanation
reaction in the absence of i-propanol gave benzonitrile in only
42% yield (Table 1, entry 5). The yield increased from 74% to
91% with the concentration of i-propanol increasing from 0.3
vol % to 1.2 vol %, and then remained almost constant with
further increase of the concentration of i-propanol (Table 1,
entries 6-10). These results revealed that more than 1.2 vol %
i-propanol was preferred for facilitating the open air Pd-
Figure 3. Effect of concentration of i-propanol on the cyanation
of bromobenzene (under the reaction conditions as shown in
entry 8, Table 2).
catalyzed cyanation. Subsequently, 5.2 vol % H2O was added
into the reaction system to further improve our procedure. As
seen from Table 1 (entries 11, 12), the addition of H2O did
accelerate the cyanation reaction, which was possibly attributed
to that H2O played a role of cosolvent to help solubilize
K4[Fe(CN)6].21,22 Then our attentions turned to the optimization
of concentration of H2O, and it was found that 4-6 vol % H2O
was preferred for facilitating the Pd-catalyzed cyanation.
Cyanation reaction with H2O as the solvent was also investi-
gated, but the obtained yield was very low, resulting possibly
from a poor solubility of iodobenzene in H2O.
Optimization experiments for the cyanation of bromobenzene
included the effect of i-propanol, H2O, reaction time, and
temperature. As seen from Figures 2 and 3, about 2-6 vol %
i-propanol and 4-6 vol % H2O were optimal for facilitating
the reaction. 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 Na2CO3 from the reaction, but such
modification resulted in no conversion to product.
In order to demonstrate further the effectiveness of i-propanol
in this process, Gas chromatography was used to monitor the
cyanation of iodobenzene. As seen from Figure 4, the open air
reaction in the presence of i-propanol proceeded at essentially
the same rate as the reaction performed in inert ambiance, while
the same open air reaction in the absence of i-propanol stalled
after only 25 min (up to 47% yield was obtained). These results
revealed that the effectiveness of i-propanol was significant to
protect Pd-catalyzed cyanation from being destroyed by oxygen.
When the aforementioned reactions proceeded for 60 min,
(21) Stazi, F.; Palmisano, G.; Turconib, M.; Santagostino, M. Tetrahedron
Lett. 2005, 46, 1815–1518.
(20) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359–1470.
(22) Buono, F. G.; Chidambaram, R.; Mueller, R. H.; Waltermire, R. E.
Org. Lett. 2008, 10, 5325–5328.
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a
Table 2. Cyanation of various aryl halides catalyzed by Pd(OAc)2
a Reaction conditions are shown in the Experimental Section of this paper (1 mmol aryl halide was used). b Characterized by comparison of 1H NMR and 13C NMR data
with that in the literature. c Determined by GC with n-tetradecane as an internal standard. d Isolated yield.
Figure 5. Reuse of the mixture containing the catalyst for
cyanation of iodobenzene without separation of the product.
Besides the reaction time (60 min), other reaction conditions
are shown in entry 4, Table 1.
Figure 4. Palladium-catalyzed cyanation of iodobenzene (under
the reaction conditions as shown in entry 4, Table 1).
experimental results (Figure 5): without separation of the
product, the mixture containing the catalyst could be reused
five times with no significant loss of activity in the case of both
the presence of i-propanol and exposing the reaction to air, while
the catalyst showed a complete deactivation after being reused
only one time in the case of both the absence of i-propanol and
protecting the reaction with argon.
iodobenzene and K4[Fe(CN)6] were again added into the
reaction system to reuse the catalyst without separation of
the product. As shown in Figure 4, in the case of reusing the
catalyst, the rate of the open air reaction in the presence of
i-propanol far exceeded the rate of the reaction performed in
inert ambiance, which also implied that i-propanol was of ability
to protect the catalyst from inactivation and thus prolong the
catalyst life. This conclusion was supported by the following
To clarify further the roles of i-propanol in this process,
Pd(OAc)2-catalyzed cyanation of iodobenzene was purposefully
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Table 3. Large-scale cyanation of bromobenzenea
in the case of exposing the reaction to air, we performed the
scaleable reaction in a closed vessel without the protection of
inert gas. Several aryl bromides were tested to determine the
scope and limitation of this protocol for the large-scale reaction.
As shown in Table 4, all the tested aryl halides proceeded
efficiently with 0.4 mol % catalyst on a 2.5 mol scale.
entry
1
order of addition of the reagents
yieldb
56
i-PrOH, Na2CO3, Pd(OAc)2, K4[Fe(CN)6]·3H2O,
and bromobenzene were mixed with NMP,
whereafter the mixture was heated to 140 °C
i-PrOH, Na2CO3, Pd(OAc)2, and bromobenzene
were heated to 140 °C in NMP, whereafter
K4[Fe(CN)6]·3H2O were added.
Na2CO3, Pd(OAc)2 and bromobenzene were heated 35
to 140 °C in NMP, whereafter
K4[Fe(CN)6]·3H2O and i-PrOH were added.
2
3
90
Conclusions
In conclusion, an open-air and robust method for the large-
scale palladium-catalyzed cyanation of aryl halides was devel-
oped, and the use of i-propanol as an additive was critical for
achieving the open-air, robust and scaleable process. Under the
protection by i-propanol, the catalyst life was significantly
prolonged. The suggested protocol allowed the cyanation of
aryl halides to be smoothly completed within 0.5-7 h on a 2.5
mol scale.
a Reaction time is 5 h, other reaction conditions are shown in the Experimental
Section of this paper. b Isolated yield.
stalled by exposure to air prior to the addition of i-propanol,
and the result showed that the addition of i-propanol failed to
restart the stalled reaction, revealing that i-propanol could not
reactivate the catalyst that has been deactivated.
A series of aryl iodides were then screened to determine
the scope and limitation of the suggested large-scale protocol.
As shown in Table 2, the cyanation reactions were able to
tolerate a wide range of functional groups such as ketone,
carbonyl, ester, and methoxy groups. The primary amino group
was even well tolerated and did not suffer from N-arylation
(Table 2, entry 5), which possibly resulted from the high affinity
of the cyanide nucleophile toward the palladium catalyst.23 The
electronic effect of the substrate seemed to be unpredictable
under our conditions. Both electron-poor and electron-rich aryl
iodides gave moderate to high yields under similar conditions
(Table 2, entries 2-7). 4-Iodotoluene gave a yield of 98% in
0.4 h, while 2-iodotoluene gave a lower yield of 69% in a longer
reaction time (Table 2, entries 6, 7). These results indicated
that the substituent in ortho-position lowered the reaction rate.
Considering that aryl bromides are less expensive than corre-
sponding aryl iodides, we applied the present open-air protocol
to the cyanation of aryl bromides. Although the cyanation of
aryl bromides was slower, moderate to high yields of the
aromatic nitriles could still be obtained in a longer reaction time
(Table 2, entries 8-14).
Subsequently, the suggested protocol was applied to the
large-scale cyanation of bromobenzene, and a yield of 56% was
obtained (Table 3, entry 1). In an attempt to optimize the
conditions for the large-scale reaction, several experiments were
conducted where different orders of addition of the reagents
were evaluated. As seen from Table 3, the addition of
K4[Fe(CN)6]·3H2O to a preheated mixture of other reactants
was critical for achieving a robust and scaleable process (Table
3, entry 2). The addition of i-PrOH prior to the heating operation
had also positive effect on the scaleable reaction.
Experimental Section
General Details. All chemicals were of reagent grade
quality, obtained from commercial sources, and used without
1
further purification. H NMR and 13C NMR spectra were
recorded on a Bruker 400 MHz spectrometer in CDCl3. GC
analysis was performed on Varian CP-3800 gas chromatograph
with a capillary column (CP-WAX 57CB 25 mm × 0.32 mm).
General Experimental Procedure for Small-Scale Cya-
nation of Aryl Halides. i-PrOH (4.8 vol %), Na2CO3 (159 mg,
1.5 mmol) and Pd(OAc)2 (1.4 mg, 0.006 mmol) were ordinally
added into a 10 mL tube equipped with 2 mL of N-methyl-2-
pyrrolidone (NMP). In order to give a homogeneous solution
as soon as possible, the mixture was stirred at room temperature
for about 5 min. Then aryl halides (1.5 mmol) and NMP (2
mL) were added. After the tube was sealed with a 50 mL
balloon that was fully filled with air, the reaction mixture was
heated to 140 °C. K4[Fe(CN)6] (221 mg, 0.6 mmol) was then
added. The final mixture was stirred for corresponding reaction
times given in Tables 1 and 2 at 140 °C. Filtration was followed
by the GC analysis of the corresponding products. The desired
products were purified by column chromatography and char-
acterized by comparison of 1H NMR and 13C NMR data with
those in the literature.
Typical Experimental Procedure for Large-Scale Cya-
nation of Aryl Halides. i-PrOH (4.8 vol %), Na2CO3 (265 g,
2.5 mol), Pd(OAc)2 (2.3 g, 0.01 mol), and aryl halides (2.5 mol)
were mixed with DMF (2.5 L). After the reaction mixture was
heated to 140 °C, K4[Fe(CN)6]·3H2O (317 g, 0.75 mol) was
added. Then the vessel was sealed, and the final mixture
was stirred for corresponding reaction times given in Tables 3
and 4 at 140 °C. After the product was analyzed by GC with
n-tetradecane as an internal standard, the reaction mixture was
filtered, and the filter cake was washed with DMF (0.1 L).
Fractionation of the filtrate afforded the desired product in high
purity (>95%), and the product was characterized by comparison
of 1H NMR and 13C NMR data with those in the literature.
All compounds are known, and their characterization data
The isolation of the products was difficult in the case of using
NMP as the solvent, prompting us to use DMF having a lower
boiling point than the solvent. Luckily, the reaction also
proceeded smoothly in DMF. After the reaction proceeded to
completeness, the fractionation of the mixture afforded the
desired product in high purity (>95%). Whereafter, we focused
on the safety issues of the scaleable reaction. Considering that
volatilization of the solvent was dangerous to the environment
1
are as follows. Benzonitrile: H NMR (400 MHz, CDCl3): δ
(ppm) ) 7.57-7.61 (m, 2H), 7.55-7.56 (m, 1H), 7.39-7.45
(m, 2H); 13C NMR (400 MHz, CDCl3) δ (ppm) ) 132.8, 132.1,
129.1, 118.8, 112.3. 4-Acetylbenzonitrile: 1H NMR (400 MHz,
(23) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125,
2890–2891.
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767

Table 4. Large-scale cyanation of various aryl halidesa
a Reaction conditions were shown in the Experimental Section of this paper (2.5 mol aryl halide was used).
CDCl3) δ (ppm) ) 8.04-8.07 (m, 2H), 7.78-7.80 (m, 2H),
2.66 (s, 3H); 13C NMR (400 MHz, CDCl3) δ (ppm) ) 196.5,
139.9, 132.5, 128.7, 117.9, 116.4, 26.8. Methyl-4-cyanoben-
zoate: 1H NMR (400 MHz, CDCl3) δ (ppm) ) 8.12-8.14 (m,
2H), 7.73-7.75 (m, 2H), 3.95 (s, 3H); 13C NMR (400 MHz,
CDCl3) δ (ppm) ) 165.4, 133.9, 132.2, 130.1, 117.9, 116.4,
(400 MHz, CDCl3) δ (ppm) ) 141.6, 132.6, 132.3, 130.1, 126.2,
117.9, 112.5, 20.2.
Acknowledgment
We are grateful for financial supports from the National High
Technology Research and Development Program of China (863
Program, Grant No.2007AA05Z454) and the Innovation Sci-
entists and Technicians Troop Construction Projects of Henan
Province (Grant No. 084200510015).
1
52.7. 4-Methoxybenzonitrile: H NMR (400 MHz, CDCl3) δ
(ppm) ) 7.57-7.61 (m, 2H), 6.94-6.97 (m, 2H), 3.86 (s, 3H);
13C NMR (400 MHz, CDCl3) δ (ppm) ) 162.8, 134.0, 119.2,
114.7, 103.9, 55.5. 4-Aminobenzonitrile: 1H NMR (400 MHz,
CDCl3) δ (ppm) ) 7.40-7.43 (m, 2H), 6.64-6.67 (m, 2H),
4.23 (s, 1H); 13C NMR (400 MHz, CDCl3) δ (ppm) ) 150.5,
133.8, 120.2, 114.4, 99.9. 4-Methylbenzonitrile: 1H NMR (400
MHz, CDCl3) δ (ppm) ) 7.52-7.55 (m, 2H), 7.25-7.27 (m,
2H), 2.42 (s, 3H); 13C NMR (400 MHz, CDCl3) δ (ppm) )
143.7, 132.0, 129.8, 119.2, 109.3, 21.8. 2-Methylbenzonitrile:
1H NMR (400 MHz, CDCl3) δ (ppm) ) 7.39-7.44 (m, 1H),
7.35-7.37 (m, 1H), 7.14-7.20 (m, 2H), 2.39 (s, 3H); 13C NMR
Supporting Information Available
Typical experimental procedure, characterization data, and
copies of 1H and 13C NMR spectra for all cyanation products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Received for review March 26, 2009.
OP9000725
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