A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C

Article abstract of DOI:10.1016/j.tetlet.2005.01.098

An industrially viable cyanation of aryl bromides with Zn(CN)₂ was accomplished in the presence of inexpensive and readily accessible Pd/C, Zn dust, ZnBr₂, and PPh₃ in DMA to provide functionalized aryl nitriles in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2005.01.098

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1849–1853
A practical synthesis of highly functionalized aryl nitriles through
cyanation of aryl bromides employing heterogeneous Pd/C
Masanori Hatsudaa and Masahiko Sekib,*
aProcess Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-ku, Osaka 532-8505, Japan
bExport and Import Group, Purchasing Department, Logistics Division, Tanabe Seiyaku Co., Ltd, 3-2-10, Dosho-Machi,
Chuo-Ku, Osaka 541-8505, Japan
Received 17 December 2004; revised 13 January2005; accepted 20 January2005
Abstract—An industrially viable cyanation of aryl bromides with Zn(CN)2 was accomplished in the presence of inexpensive and
readilyaccessible Pd/C, Zn dust, ZnBr , and PPh3 in DMA to provide functionalized aryl nitriles in moderate to high yields.
2
Ó 2005 Elsevier Ltd. All rights reserved.
Palladium-catalyzed cyanation of aryl halides has
recentlyaroused considerable attention due to the
significance in the preparation of valuable compounds
such as drugs and natural products.1 Because of the
expanding need for the industrial application, much
effort have been devoted to develop a practical cyana-
tion protocol that inexpensivelydelivers products with
prevention of pollution. However, the existing methods2
employing homogeneous Pd catalyst still suffer from at
least either one of the following drawbacks:3 (1) require-
ment of quite expensive and/or hazardous phosphine
ligand or additives, (2) lack of a proper procedure for
recovering and/or removing expensive and toxic Pd
from the reaction mixture, and (3) poor reproducibility
of the reaction. A more efficient and practical cyanation
method that fulfills all the criteria on sustainabilityand
economyis, therefore, still in much demand. In a series
of our synthetic studies of (+)-biotin,4 we have reported
heterogeneous Pd/C-catalyzed Fukuyama reactions,
i.e., transformations of thiol esters to aldehydes4l or
ketones.4a–e,k As an extension of the study, reported
herein is a novel and highlypractical snythesis of
aryl nitriles through cyanation of aryl bromides employ-
ing inexpensive Pd/C, Zn dust, ZnBr2, and PPh3.
(4 mol %), PPh3 (0.16 equiv) and Zn dust (0.4 equiv) in
DMA at 130–150 °C for 20–24 h was found to provide
desired aryl nitrile 2a. However, the reaction often
stopped without completion and the yield varied from
31–72% (Table 1, entry1). The unreliable results may
be ascribed to insufficient activation of the surface of
the Zn dust and/or unexpected formation of inactive
Pd black. Meanwhile, as shown in our previous report4k
on the Fukuyama coupling reaction of zinc reagents
with thiol esters, prior addition of Br2 to Zn dust, which
in situ produces ZnBr2, is veryeffective not onlyfor acti-
vation of Zn dust but also for generation of active alkyl
zinc halide (RZnBr) through a shift of the Schlenk equi-
librium from R2Zn to RZnBr (Scheme 1, R = alkyl). We
envisioned that the Schlenk-type equilibrium might
occur as well on Zn(CN)2 (Scheme 1, R = CN), and much
enhanced activityand solubilitywere expected of
CNZnBr rather than Zn(CN)2 because of higher leaving
group activityof ZnBr
as compared with CNZnBr
2
which was liberated on reaction with palladium com-
plex, ArPdBrL2. The well-documented Pd deactivation2j
bycoordination with cyanide ion maybe suppressed as
well through the gradual formation of soluble CNZnBr
from fairlyinsoluble Zn(CN) . The reaction was thus
2
conducted with initial addition of Br2 (0.2 equiv) to
the mixture of Zn dust in DMA at 25 °C to activate
Zn dust and in situ generate ZnBr2. As expected, with
this pre-treatment, the reaction was completed in 3 h
at much lower temperature (80 °C) to afford 2a in 97%
yield in highly reproducible manner (Table 1, entry
2).6 It should be noted that the addition of Zn dust is
indispensable for the reaction: elimination of Zn dust
In our initial study, cyanation of methyl 4-bromobenzo-
ate 1a was investigated as a typical example. Treatment
of 1a with Zn(CN)2 (0.6 equiv) in the presence of Pd/C5
*
Corresponding author. Fax: +81 662055178; e-mail: m-seki@
tanabe.co.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.01.098

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M. Hatsuda, M. Seki / Tetrahedron Letters 46 (2005) 1849–1853
Table 1. Cyanation of methyl 4-bromobenzoate (1a) with Zn(CN)2 in the presence of Pd/C, Zn dust, PPh3, and various additives
(i) Zn (0.4 equiv), Additive (0.2 equiv), DMA
MeO2C
CN
MeO2C
Br
(ii) Pd/Ca (4 mol%), Zn(CN)2 (0.6 equiv)
PPh3 (0.16 equiv)
2a
Conv.b (%)
1a
b
Assayyield (%)
EntryAdditive
Temp. (
°C)
130–150
Period (h)
1
2
3
4
5
6
None
Br2
20–24
29–100
100
99
31–72
97
92
80
80
80
80
80
3
4
3
4
7
I2
TMSCl
Br(CH2)2Br
Zn(OAc)2
100
100
73
95
90
c
—
aPd/C was purchased from Degussa Japan Co., Ltd.5
b Determined byHPLC.
c Not determined.
+
ZnBr2
2RZnBr
active
R2Zn
As for the phosphine ligand, dppf participated similarly
well in the cyanation (Table 2, entry2). In contrast, elec-
tron-rich bulkyligands such as P( o-tol)3, Cy3P, and t-
Bu3P were almost inactive (Table 2 entries 3–5). In con-
sidering the cost and the effectiveness, PPh3 was chosen
as the ligand for the cyanation.
less active
R = alkyl, CN
+ ArPdBrL2
RZnBr
ZnBr2
The present cyanation tolerates substantial variation in
aryl bromides as the substrates (Table 3). Even aryl bro-
mides carrying electron-donating substituents, which
gave poor yields through the reported procedure,7 fur-
nished the corresponding aryl nitriles in good to
excellent yields at slightly higher reaction temperature
(115–125 °C) (Table 3, entries 3, 4, 6–8). Functional
groups such as acetyl, hydroxyl, amino, and sulfide
groups were all compatible with the reaction conditions
(Table 3, entries 2, 4, and 6–9). To the best of our knowl-
edge, the successful cyanation of sterically congested
electron-rich aryl bromides such as 2-N,N-dimethyl-
aminobromobenzene 1d and 2-hydroxybromobenzene
1g represents the first examples hitherto recorded. More
inexpensive aryl chloride such as 40-chlorobenzoate and
40-chloroacetophenone was not cyanated by the use of
the present conditions.
ArPdRL2
Scheme 1. Equilibrium of zinc reagents and zinc cyanide in the
presence of zinc bromide and their reaction with palladised aryl
bromides.
as an additive resulted in no reaction. The presence of
Zn dust should be significant not onlyto reduce the ini-
tiallyoxidic Pd/C 5 (reduction degree: 0–25%) but also to
prevent the labile Pd(0) species from oxidation. While
the reaction proceeded as well in the presence of other
Zn-activating reagents such as I2, TMSCl or 1,2-di-
bromoethane which, upon treatment with Zn dust, also
generates zinc halides (ZnX2, X = I, Br or Cl), theyfur-
nished somewhat lower yields (Table 1, entries 3–5). Of
particular interest is the inferior result (73% yield) ob-
Comparison of the present protocol with those employ-
ing homogeneous Pd catalyst was then tested (Table 4).
Cyanation of 3-bromo-4-hydroxymorpholinobenzamide
1j in the presence of Pd(OAc)2 (5 mol %) and PPh3
tained bythe addition of Zn(OAc) , a known efficient
2
activator for the cyanation of aryl halides employing
2f
homogeneous Pd catalyst (Table 1, entry6).
Table 2. Screen of the phosphine ligand in the cyanation of methyl 4-bromobenzoate (1a)
(i) Zn dust (0.4 equiv), Br2 (0.2 equiv), DMA
(ii) Pd/Ca (4 mol%), Zn(CN)2 (0.6 equiv)
Phosphine (0.16 equiv), 80oC, 4 h
MeO2C
CN
MeO2C
Br
2a
1a
b
b
Assayyield (%)
EntryPhosphine
Conv
(%)
1
2
3
4
5
PPh3
dppf c
100
100
1
97
88
d
P(o-tol)3
Cy3P
t-Bu3P
—
—
d
0
d
5
—
aPd/C was purchased from Degussa Japan Co., Ltd.5
b Determined byHPLC.
c 0.08 equiv of phosphine was employed.
d Not determined.

M. Hatsuda, M. Seki / Tetrahedron Letters 46 (2005) 1849–1853
Table 3. Cyanation of various aryl bromides 1a–i to aryl nitriles 2a–ia
1851
Pd=Cb;Zn dust;Br2;PPh3
ƒƒƒƒƒƒƒƒƒƒƒ!
DMA
Ar-Br þ ZnðCNÞ
Ar-CN
2
c
Assayyield (%)
EntrySubstrate
1a–i
Product 2a–i
Temp. (°C)
Period (h)
MeO C
2
MeO C
2
1d
80
80
3
97
Br
CN
2a
1a
O
O
2d
5
82
Br
CN
1b
2b
MeO
MeO
3d
4d
5d
6e
7e
8d
9d
115
115
115
125
125
80
8
8
2
4
4
5
8
89
93
92
65
60
75
89
Br
CN
2c
NMe
1c
NMe
2
2
Br
Br
CN
CN
1d
2d
1e
2e
CN
Br
H N
2
H N
2
1f
2f
OH
Br
OH
CN
CN
1g
2g
Br
N
1h
N
2h
S
S
115
Br
NC
2i
1i
a The compounds 2a–i obtained have been fullycharacterized byIR, NMR and Mass spectra.
bPd/C was purchased from Degussa Japan Co., Ltd.5
c Determined byHPLC.
d Pd/C (4 mol %), PPh3 (0.16 equiv), Zn dust (0.4 equiv), Br2 (0.2 equiv), Zn(CN)2 (0.6 equiv).
e Pd/C (8 mol %), PPh3 (0.32 equiv), Zn dust (1.2 equiv), Br2 (0.4 equiv), Zn(CN)2 (0.5 equiv).
(20 mol %) required much higher temperature (150 °C)
and yielded an undesirable result (82% conversion)
accompanied byconsiderable amount of reduction
byproduct 3 [2j/4-hydroxymorpholinobenzamide (3) =
75/25] (Table 4, entry2). Addition of ZnBr 2, which
was in situ generated from Zn dust and Br2, to the sys-
tem involving Pd(OAc)2 and PPh3 considerablyim-
proved the reaction to provide 2j in a higher yield
(87%), though it is poorer than that employing Pd/C
(Table 4, entry3 vs 1). The present process using Pd/C

1852
M. Hatsuda, M. Seki / Tetrahedron Letters 46 (2005) 1849–1853
Table 4. Comparison of the present cyanation employing Pd/C with those catalyzed by homogeneous Pd catalystsa
O
O
O
Zn(CN)2 (0.6 equiv)
Pd Catalyst, Additive
H
CN
OH
Br
N
N
N
+
O
O
O
DMA
OH
OH
1j
2j
3
b
Assayyield (%)
EntryPd Castta(lymol %)
Additive (equiv)
Temp. (
°C)
Period (h)
Conv.b (%)
2j:3b
1
2
3
Pd/Cc (4)
PPh3 (0.16), Zn (0.6), Br2 (0.2)
PPh3 (0.2), Zn (0.56)
PPh3 (0.16), Zn (0.6), Br2 (0.2)
115
150
115
4
2
3
100
82
91
98/2
75/25
98/2
d
Pd(OAc)2 (5)
Pd(OAc)2 (4)
—
87
100
a The compound 2j obtained has been fullycharacterized byIR, NMR, and Mass spectra.
b Determined byHPLC.
c Pd/C was purchased from Degussa Japan Co., Ltd.5
d Not determined.
Harn, N. K.; Pagh, L. M.; Wepsiec, J. P. J. Org. Chem.
1998, 63, 8224–8228; (b) Maligres, P. E.; Waters, M. S.;
Fleitz, F.; Askin, D. Tetrahedron Lett. 1999, 40, 8193–
8195; (c) Jin, F.; Confalone, P. N. Tetrahedron Lett. 2000,
41, 3271–3273; (d) Sundermeier, M.; Zapf, A.; Mutyala,
S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M. Chem.
Eur. J. 2003, 9, 1828–1836; (e) Sundermerier, M.; Zapf, A.;
Beller, M. Angew. Chem., Int. Ed. 2003, 42, 1661–1664; (f)
Chidambaram, R. Tetrahedron Lett. 2004, 45, 1441–1444;
(g) Yang, C.; Williams, J. M. Org. Lett. 2004, 6, 2837–
2840; (h) Marcantonio, K. M.; Frey, L. F.; Liu, Y.; Chen,
Y.; Strine, J.; Phenix, B.; Wallace, D. J.; Chen, C.-Y. Org.
Lett. 2004, 6, 3723–3725; (i) Shareina, T.; Zapf, A.; Beller,
M. Chem. Commun. 2004, 1388–1389; (j) For a review, see:
Sundermerier, M.; Zapf, A.; Beller, M. Eur. J. Inorg.
Chem. 2003, 3513–3526.
in conjunction with the addition of Zn dust, ZnBr2, and
PPh3 thus appears to be superior to the protocols
employing homogeneous Pd catalysts.
Elucidation of the precise mechanism of the present cya-
nation needs further investigation. Nonetheless, the use
of the heterogeneous Pd/C catalyst has an advantage in
that Pd metal is embedded and finelydispersed on the
charcoal matrix at least in the initial stage of the reac-
tion,8 which mayassure the formation of monomeric
or dimeric Pd–phosphine complex without aggregating
to inactive Pd black.9 The recoveryof Pd was conducted
in the reaction of 1a to 2a byinitial oxidation of PPh 3.10
Air bubbling of the reaction mixture at 60 °C followed
bysimple filtration at 25 °C led to virtuallycomplete
recoveryof Pd (99% yield). Although the recovered cat-
alyst was not reused as such, it could be employed in the
subsequent cyanation without any problems after sub-
jecting to usual recoveryprocess involving combustion.
3. The reported cyanation procedures need expensive and/or
hazardous Pd catalyst, ligand and/or additive: Anderson
approach:2a Pd(PPh3)4, CuI; Maligres approach:2b Pd2
(dba)3, dppf; Jin approach:2c Pd2(dba)3, dppf;
Beller approach:2d dpppe, TMEDA; Beller approach:2e
dpppe, TMSCN; Chidambaram approach:2f Pd2(dba)3,
dppf; Yang approach:2g Pd2(dba)3, Bu3SnCl; t-Bu3P;
Marcantonio approach:2h P(o-tol)3; Beller approach:2i
dppf.
4. (a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2000, 41, 5099–
5101; (b) Shimizu, T.; Seki, M. Tetrahedron Lett. 2001, 42,
429–432; (c) Shimizu, T.; Seki, M. Tetrahedron Lett. 2002,
43, 1039–1042; (d) Mori, Y.; Seki, M. Heterocycles 2002,
58, 125–126; (e) Mori, Y.; Seki, M. J. Org. Chem. 2003, 68,
1571–1574; (f) Seki, M.; Hatsuda, M.; Mori, Y.; Yamada,
S. Tetrahedron Lett. 2002, 43, 3269–3272; (g) Seki, M.;
Mori, Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002,
67, 5527–5536; (h) Seki, M.; Shimizu, T.; Inubushi, K.
Synthesis 2002, 361–364; (i) Mori, Y.; Kimura, M.; Seki,
M. Synthesis 2003, 2311–2316; (j) Seki, M.; Kimura, M.;
Hatsuda, M.; Yoshida, S.; Shimizu, T. Tetrahedron Lett.
2003, 44, 8905–8907; (k) Kimura, M.; Seki, M. Tetrahe-
dron Lett. 2004, 45, 1635–1637; (l) Kimura, M.; Seki, M.
Tetrahedron Lett. 2004, 45, 3219–3223; (m) For a review,
see: Seki, M.; Kimura, M. J. Syn. Org. Chem. Jpn. 2004,
62, 882–894.
In conclusion, a practical cyanation of aryl bromides
employing heterogeneous Pd/C was worked out by the
use of inexpensive Zn dust, ZnBr2 (in situ generated
from Zn dust and Br2) and PPh3. The present process
is featured byease of operation, high recoveryof Pd,
use of inexpensive phosphine ligand (PPh3) and addi-
tives (Zn dust and ZnBr2), and high reproducibility,
which would permit a highlysustainable and robust
access to multifunctional aryl nitriles, compounds of
great pharmaceutical significance.
Acknowledgements
The authors wish to thank Degussa Japan Co., Ltd. for
disclosing the chemical properties of the Pd/C catalyst.
References and notes
5. Pd/C catalyst employed in this study was purchased from
Degussa Japan Co., Ltd. and has the following chemical
properties: impregnation depth, 200–500 nm (thick shell);
reduction degree, 0–25%; Pd dispersion, 28%; water
content, less than 3 wt %. The catalyst is commercially
available at Degussa Japan Co., Ltd.
6. General procedure for the Pd-catalyzed cyanation: A
reaction vessel was charged with zinc dust (52 mg,
0.8 mmol) and DMA (5.7 mL). The vessel was then briefly
1. (a) Larock, R. C. In Comprehensive Organic Transforma-
tions, 2nd ed.; John Wiley& Sons: New York, 1999; pp
1707–1708; (b) Kleemann, A.; Engel, J.; Kutscher, B.;
Reichert, D. Pharmaceutical substances syntheses, patents,
applications, 4th ed.; Georg Thieme: Stuttgart, 2001.
2. For recently developed Pd-catalyzed cyanation of aryl
halides, see: (a) Anderson, B. A.; Bell, E. C.; Ginah, F. O.;

M. Hatsuda, M. Seki / Tetrahedron Letters 46 (2005) 1849–1853
1853
evacuated and backfilled with N2 five times. Then, Br2
(20 lL, 0.4 mmol) was dropwise added at 25 °C and
the mixture was stirred at 25 °C for 0.5 h. To the mixture
7. The conversion from 1f to 2f bythe use of Chidambaram
approach [Pd2(dba)3, dppf, 90 °C, 24 h]2f has been
reported to be 20%.
8. The leaching of Pd from Pd/C was measured at the end of
the reaction of 1a to 2a byX-rayfluorescence analysis of
the filtered solution, and 30% of the initiallyadded Pd was
found to dissolve from the charcoal matrix to the solution
phase.
9. For the side reaction (precipitation to Pd black) in the
Suzuki coupling, see: Chem. Eng. News 2004, Sep. 6, 49–58.
10. In contrast, the recoveryof Pd in the Heck reaction
employing Pd/C was conducted by reducing the Pd(II)
species, see: Heidenreich, R. G.; Krauter, J. G. E.; Pietsch,
J.; Ko¨hler, K. J. Mol. Cat. A 2002, 182–183, 499–509.
were successivelyadded Zn(CN)
(141 mg, 1.2 mmol),
2
PPh3 (85 mg, 0.32 mmol), Pd/C5 (Pd: 5 wt %, 170 mg,
0.08 mmol) and aryl bromide (2 mmol) at 25 °C.
The vessel was brieflyevacuated and backfilled with N
2
five times. The mixture was stirred at 80–125 °C for 3–
15 h. After completion of the reaction, the suspension
was cooled down to room temperature, diluted with
AcOEt (15 mL), and filtered. The filtrate was concen-
trated, and the residue was purified bysilica gel column
chromatographyor recrystallization to provide the desired
product.