A practical synthesis of highly functionalized aryl nitriles through cyanation of aryl bromides employing heterogeneous Pd/C: In quest of an industrially viable process

Article abstract of DOI:10.1016/j.tet.2005.06.061

Preparation of aryl nitrile 2a through classical Rosenmund-von Braun reaction of aryl bromide 1a resulted in a poor yield (61%) due to a high reaction temperature (165°C) and a lack of efficient procedure for separating 2a from a large quantity of heavy metal waste (Cu salts). To address these issues, a practical synthesis of multifunctional aryl nitriles through cyanation of aryl bromides has been developed with heterogeneous Pd/C used as the catalyst. Treatment of aryl bromides 1 with Zn(CN)₂ in the presence of Pd/C, Zn, ZnBr₂ and PPh₃ in DMA provided aryl nitriles 2 involving those carrying sterically demanding electron-rich substituent in good yields and in highly reproducible manner. The activity of Pd/C is highly dependent on the properties of the Pd/C. Oxidic thickshell type catalyst Pd/C D5 was found to furnish the highest rate acceleration and yield. The use of heterogeneous Pd/C might anchor and disperse Pd over the solid support of the catalyst, at least in the initial stage of the reaction, to assure the formation of monomeric Pd complex without precipitating to inactive Pd black. The use of a slightly excess of Zn(CN)₂ (0.6 equiv) and air oxidation of phosphine ligand, after end of the reaction, converted Pd species to insoluble phosphine-free Pd cyanides, from which Pd was recovered in high yield through simple filtration followed by usual recovery process involving combustion.

Full text of DOI:10.1016/j.tet.2005.06.061

Tetrahedron 61 (2005) 9908–9917
A practical synthesis of highly functionalized aryl nitriles through
cyanation of aryl bromides employing heterogeneous Pd/C:
in quest of an industrially viable process
a
Masanori Hatsuda and Masahiko Seki
b,
*
a
Process Chemistry Research Laboratories, Tanabe Seiyaku Co., Ltd, 3-16-89, Kashima, Yodogawa-Ku, Osaka 532-8505, Japan
Export & Import Group, Logistics Division, Purchasing Department, Tanabe Seiyaku Co., Ltd, 3-2-10, Dosho-Machi, Chuo-Ku,
Osaka 541-8505, Japan
b
Received 4 February 2005; revised 12 April 2005; accepted 10 June 2005
Available online 15 July 2005
Abstract—Preparation of aryl nitrile 2a through classical Rosenmund-von Braun reaction of aryl bromide 1a resulted in a poor yield (61%)
due to a high reaction temperature (165 8C) and a lack of efficient procedure for separating 2a from a large quantity of heavy metal waste (Cu
salts). To address these issues, a practical synthesis of multifunctional aryl nitriles through cyanation of aryl bromides has been developed
with heterogeneous Pd/C used as the catalyst. Treatment of aryl bromides 1 with Zn(CN) in the presence of Pd/C, Zn, ZnBr and PPh in
2
2
3
DMA provided aryl nitriles 2 involving those carrying sterically demanding electron-rich substituent in good yields and in highly
reproducible manner. The activity of Pd/C is highly dependent on the properties of the Pd/C. Oxidic thickshell type catalyst Pd/C D5 was
found to furnish the highest rate acceleration and yield. The use of heterogeneous Pd/C might anchor and disperse Pd over the solid support of
the catalyst, at least in the initial stage of the reaction, to assure the formation of monomeric Pd complex without precipitating to inactive Pd
2
black. The use of a slightly excess of Zn(CN) (0.6 equiv) and air oxidation of phosphine ligand, after end of the reaction, converted Pd
species to insoluble phosphine-free Pd cyanides, from which Pd was recovered in high yield through simple filtration followed by usual
recovery process involving combustion.
q 2005 Elsevier Ltd. All rights reserved.
1
c
1. Introduction
in the past decade, Pd-catalyzed cyanation is far from
perfect and still needs further investigation for subjecting to
scalable and cost-effective preparations. Intensive efforts to
improve the reaction have currently been undertaken not
only in academia but also in pharmaceutical industries.
However, they still pose many challenges, when aimed at
applying for commercial-scale production. They need
inherently very expensive and/or toxic phosphine ligand or
additive. Cyanation of aryl halides carrying sterically
demanding electron-rich substituent, such as amino and
hydroxyl group, has hardly been accomplished, still posing a
big challenge for the practical use. Reported herein is a course
of our investigations to develop a more versatile and
Development of an industrially viable process for drug
synthesis forces one to consider a number of factors to affect
feasibility of the reaction as well as economy of the overall
sequence. For protection of the ecology, the reaction with
lower environmental impact is required as well. Meanwhile,
Pd-catalyzed cross coupling reaction has recently been
underscored as a synthetic methodology and its application
to large-scale production of chemicals carrying various
functional groups has been extensively investigated with
1
some measure of success. As significance of aryl nitriles in
the drug synthesis increases, so does the demand for the
2
4
truly efficient synthetic method. Synthesis of aryl nitriles
through Pd-catalyzed cyanation of aryl halides represents
industrially viable process for the cyanation of aryl bromides.
3
one of the most direct approaches to this important class of
compounds. In contrast to remarkable leading-edge tech-
nologies, accomplished on the Pd-catalyzed C–C and C–X
2. Results and discussion
(XZN, O and S) bond forming reaction such as Suzuki–
Miyaura coupling, Heck reaction, amination and amidation
2.1. Synthesis of aryl nitrile 2a through Rosenmund-von
Braum reaction of aryl bromide 1a
Keywords: Cyanation; Palladium on charcoal; Cross-coupling reaction;
Aryl bromides; Aryl nitriles; Zinc dust; Bromine; Zinc bromide.
Cyanation of aryl bromide was first investigated applying
classical Rosenmund-von Braum reaction with 3-bromo-4-
hydroxymorpholinobenzamide (1a) used as the typical
5
*
Corresponding author. Tel.: C81 6 6300 5879; fax: C81 6 6300 5880;
e-mail: m-seki@tanabe.co.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.061

M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
9909
Scheme 1. The Rosenmund-von Braun reaction of 1a to 2a and isolation of the product 2a.
6
substrate (Scheme 1). Treatment of 1a with CuCN
1.5 equiv) in DMA at 165 8C for 3.5 h gave desired aryl
CuCl2) and subsequent crystallization, provided much
purified 2a (purity: 99%). However, the yield was moderate
(61%), because of considerable loss of 2a to the mother
liquor.
(
nitrile 2a in 93% yield (98% conversion), accompanied by a
small amount of hydration byproduct, 3-carbamoyl-4-
hydroxymorpholinobenzamide (3) (2a/3Z95:5). Isolation
of the product 2a was initially conducted by direct
crystallization of the residue that was obtained by
evaporation of DMA. Purity of the resulting 2a was,
however, at most 90%, as it was contaminated with a large
2.2. Synthesis of aryl nitrile 2a through cyanation of aryl
bromide 1a with Zn(CN) employing Pd/C, Zn and PPh
2
3
To lower the reaction temperature and to eliminate the
formation of a large amount of hazardous Cu salts, we
investigated Pd-catalyzed cyanation of aryl bromides as an
alternative method. In a series of our synthetic studies of
I
amount of insoluble Cu salts. The use of an alternative
I
workup, involving oxidation of the insoluble Cu salts to
II
soluble and easy-removable Cu analogues (CuClBr and/or
2 3
Table 1. Cyanation of various aryl bromides 1b–g to aryl nitriles 2b–g with Zn(CN) in the presence of Pd/C D5, Zn and PPh
a
Entry
Substrate 1b–g
Substrate 2b–g
Conv. (%)
Assay yield
a
(
%)
b
1
29–100
31–72
93
1
b
2b
2
99
1
c
2c
2d
2e
3
4
5
100
100
6
91
58
1
d
1
e
c
—
1
f
2f
c
6
0
—
1
g
2g
a
Determined by HPLC.
The reaction was conducted at 130–150 8C for 20–24 h.
Not determined.
b
c

9910
M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
2.3. Synthesis of aryl nitriles 2 through cyanation of aryl
bromides 1 with Zn(CN) employing Pd/C, Zn, ZnBr
and PPh3
2
2
7
k
As shown in our previous report on the Fukuyama
coupling reaction of zinc reagents with thiol esters, prior
addition of Br to Zn dust, that in situ produces ZnBr , is
2
2
very effective not only for activation of Zn dust but also for
generation of active alkyl zinc halide (RZnBr) through a
shift of the Schlenk equilibrium from R Zn to RZnBr
2
(
equilibrium might occur as well on Zn(CN) (Scheme 2,
Scheme 2, RZalkyl). We envisioned that the Schlenk type
2
RZCN). Much enhanced activity and solubility would be
expected of CNZnBr than Zn(CN)2 because of higher
leaving group activity of ZnYBr (YZhalogen or car-
boxylate anion etc.) compared with CNZnY, both of which
are assumed to liberate on reaction with palladium complex,
Scheme 2. Equilibrium of zinc reagents and Zn(CN)
2
ZnBr and their reaction with palladised aryl bromides and carboxylates.
2
in the presence of
3
k
ArPdYL . The well-documented Pd-deactivation by
2
7
C)-biotin, we have reported heterogeneous Pd/C-cata-
(
lyzed Fukuyama reactions, that is, transformations of thiol
coordination with cyanide ion might be suppressed as well
through the gradual formation of soluble CNZnBr from
fairly insoluble Zn(CN)2.
7
a–e,k
esters to aldehydes or ketones.
As an extension of the
study, we investigated the synthesis of aryl nitriles through
cyanation of aryl bromides employing readily accessible
and inexpensive Pd/C.
The reaction was thus conducted with initial addition of Br2
(0.2 equiv) to the mixture of Zn dust in DMA at 25 8C to
activate Zn dust and in situ generate ZnBr . As expected,
2
In our initial study, cyanation of methyl 4-bromobenzoate
with this pre-treatment, the reaction was completed in 3 h at
much lower temperature (80 8C) to afford 2b in 97% yield
and in highly reproducible manner (Table 2, entry 2). While
the reaction proceeded as well in the presence of other Zn-
1
b was investigated as a typical example. Treatment of 1b
with Zn(CN) (0.6 equiv) in the presence of Pd/C D5
8
2
(oxidic, uniform type, vide infra) (4 mol%), inexpensive
9
PPh3 (0.16 equiv) and Zn dust (0.4 equiv) in DMA at 130–
activating reagents such as I , TMSCl or 1,2-dibromoethane
2
1
2
50 8C for 20–24 h was found to provide desired aryl nitrile
b. However, the reaction fluctuated widely (31–72%) and
that, on treatment with Zn dust, also generates zinc halides
1
0
(
ZnX , XZI, Br or Cl ), the yield slightly declined
2
overall lacked reproducibility (Table 1, entry 1). The
protocol is problematic in scope and limitation as well.
While, in the case of electron-deficient aryl bromides 1c–e,
a moderate to high yield of the desired products 2c–e were
similarly obtained, the relatively electron-rich aryl bromides
(
Table 2, entries 3–5). An inferior result (73% yield) was
obtained by the addition of Zn(OAc) , a known efficient
2
activator for the cyanation of aryl halides employing
homogeneous Pd catalyst (Table 2, entry 6). The
3
f
K
observation reflects the importance of halide anion (Cl ,
K K 11
Br and I ) of zinc halides in the cyantaion (vide infra).
1
f,g were almost inactive under the same reaction
conditions (Table 1, entries 1–4 vs entries 5 and 6). What
we had to come up with was an alternative reaction protocol,
which is, applicable even with electron-rich aryl bromides
and controls reaction precisely for scale-up.
Dppf participated similarly well in the cyanation (Table 2,
entry 7). In contrast, electron-rich bulky ligands such as P(o-
tol) , Cy P and t-Bu P were almost inactive (Table 2, entries
3
3
3
a
2 3
Table 2. Cyanation of 1b to 2b with Zn(CN) in the presence of Pd/C D5, Zn dust, PPh and various additives
b
b
Entry
Phosphine
Additive
None
Br
Temp (8C)
Period (h)
Conv. (%)
Assay yield (%)
1
2
3
4
5
6
7
8
9
PPh
PPh
PPh
PPh
PPh
PPh
3
3
3
3
3
3
130–150
80
80
80
80
80
80
80
80
20–24
29–100
100
99
100
100
73
100
1
0
31–72
97
92
2
3
4
3
4
7
3
3
3
3
I
2
TMSCl
Br(CH
Zn(OAc)
95
90
2
)
2
Br
c
2
—
88
d
dppf
P(o-tol)
Cy
t-Bu
Br
2
Br
2
Br
2
Br
2
c
3
—
—
c
3
P
c
10
3
P
80
5
—
a
b
c
d
8
Pd/C was purchased from Degussa Japan Co., Ltd.
Determined by HPLC.
Not determined.
Ligand 0.08 equiv was employed.

M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
9911
Comparison of the present protocol with those employing
homogeneous Pd catalyst was then tested (Table 4).
Cyanation of 1a in the presence of Pd(OAc) (5 mol%),
2
PPh (0.2 equiv) and zinc dust (0.56 equiv) required much
3
higher temperature (150 8C) and exhibited an unsatisfying
conversion (82%), accompanied by considerable amount of
reduction byproduct 4 [2a/4Z75/25] (Table 4, entry 2).
Addition of ZnBr , that was in situ generated from Zn dust
and Br , to the system involving Pd(OAc) , PPh and Zn
2
2
2
3
dust considerably improved the reaction to provide 2a in a
higher yield (87%), though it is still poorer than that
employing Pd/C (Table 4, entry 3 vs entries 1 and 2).
Because about 30% of the total Pd was consistently
dissolved from Pd/C into the solution (vide infra), the
reaction was tested by the use of 1.2 mol% (4 mol%!0.3)
8
Figure 1. Screen of Pd/C catalyst in the cyanation of 1b to 2b. The
reaction was conducted by the use of Pd/C (4 mol%), Zn (0.4 equiv), Br
0.2 equiv) and PPh (0.16 equiv) at 80 8C in DMA. Pd/C D1: oxidic,
2
of Pd(OAc) . Through this treatment, were observed not
2
(
3
only incomplete conversion (44%) but also elevation of the
reduction byproduct 4 (2a/4Z74/26) (Table 4, entry 4). In
contrast, conducting the reaction in the presence of the same
amount of Pd/C D5 (1.2 mol%) in place of Pd(OAc)2
provided 2a in a higher selectivity (2a/4Z91/9), while the
conversion (33%) remained almost unchanged (Table 4,
entry 5 vs entry 4). Despite for just one substrate 1a, the
present process using Pd/C appears to be superior to the
protocols employing homogeneous Pd catalysts.
eggshell; Pd/C D2: reduced, eggshell; Pd/C D3: oxidic, uniform; Pd/C D4:
reduced, uniform; Pd/C D5: oxidic, thickshell; Pd/C D6: reduced,
thickshell.
8–10). For explanation of the inferior result obtained by the
addition of t-Bu P, there are not any possibilities that the
3
remaining Br oxidizes the highly basic phosphine t-Bu P in
3
2
preference over less basic PPh and dppf, because Br , upon
3
2
addition to zinc dust, disappears rapidly through reduction
to ZnBr . Although dppf is expensive, PPh is economical in
practice and easy to handle, and, hence, it has finally been
chosen as the ligand for the cyanation.
Clarifying the reaction mechanism of the present cyanation
was the next subject for our investigation. There are
controversies on the mechanism of the cross coupling
2
3
1
3
reaction employing heterogeneous Pd/C. It is often
difficult to identify the actual reaction site and the role of
the solid support of Pd/C. When phosphine ligand is added
to the reaction mixture, Pd might thoroughly dissolve from
the solid support into the solution phase through coordi-
8
The next step is to optimize Pd/C catalyst in the cyanation
of 1b to 2b (Fig. 1). Among the Pd/C catalysts tested, oxidic
thickshell type Pd/C D5, where Pd disperses at 200–500 nm
from the surface and having low reduction degree, exhibited
the highest activity. In contrast, oxidic eggshell type Pd/C
D1, where Pd localizes closer to the surface (50–150 nm),
was almost inactive. Somewhat delayed rate acceleration,
observed in oxidic uniform type Pd/C D3 as compared with
Pd/C D5, might reflect inferior diffusion of the substrate 1b
to the Pd surface in Pd/C D3. The reduced type Pd/C D4, D2
and D6 were much less active than the oxidized counterparts
Pd/C D3 and D5, though Pd/C D1 irregularly behaved.
1
4
nation with phosphine ligand. It implies the reaction might
actually occur not on a solid support but in a homogeneous
system. If it is true, the use of Pd/C involving activated
carbon as the solid support is useless, especially as a device
to promote the reaction. However, dependence of the
present cyanation on the properties of the Pd/C catalysts,
shown in Figure 1, demonstrates that the extent of Pd
dispersion in the charcoal matrix does considerably affect
the rate of the reaction. Finaly dispersed Pd, which is
realized by the use of the thickshell or uniform type
catalysts, is responsible for higher activities in the
The present cyanation tolerates substantial variation in aryl
bromides as the substrates (Table 3). Even aryl bromides 1i,
15
cyanation. The use of heterogeneous Pd catalyst has,
1
k, and 1l carrying electron-donating substituents, that gave
therefore, an advantage in that Pd metal is embedded and
finely dispersed on the charcoal matrix, which assures the
formation of monomeric Pd-phosphine complexes.
1
2
poor yields through the reported procedure, furnished the
corresponding aryl nitriles 2i, 2k, and 2l in good to excellent
yields at slightly higher reaction temperature (115–125 8C)
(
Table 3, entries 4, 6, and 7). Broad range of functional
The hypothesis on the reaction site of the present cyanation
is further supported by the extent of Pd leaching during the
reaction. As shown in Figure 2, the concentration of Pd,
dissolved in the solution phase, remained almost unchanged
all the way from beginning of the reaction [ca. 30% of the
groups such as acetyl, ester, amino, hydroxyl, and sulfide
groups were all compatible with the reaction conditions
(
Table 3, entries 1, 2, 4, and 6–9). To the best of our
knowledge, the successful cyanation of sterically congested
electron-rich aryl bromides, such as 2-N,N-dimethylamino-
bromobenzene 1i and 2-hydroxybromobenzene 1l, rep-
resents the first examples hitherto recorded. However, the
present cyanation is limited in scope. It was effective with
the aryl bromides but not with less reactive and less
expensive aryl chloride such as 4 -chloroacetophenone 1o.
Even prolonged heating the reaction mixture of 1o at 140 8C
provided only 4% conversion (Table 3, entry 10).
1
6
initially added Pd (1.2 mol% relative to 1b)]. The reaction
was not finished in the presence of 1.2 mol% of Pd(OAc) or
2
Pd/C D5 or dissolved ‘Pd’ (1.2 mol%) obtained through
filtration of a mixture of Zn dust (0.6 equiv), Br (0.2 equiv),
2
Pd/C and Ph P (0.16 equiv) (Table 4, entries 4 and 5 and
3
0
Scheme 3). The observations suggest the reaction does not
reach to completion only by initially dissolved Pd
(1.2 mol%). It needs a help of remaining Pd (2.8 mol%)

9
912
M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
2 3
in the presence of Pd/C D5, Zn, ZnBr and PPh
Table 3. Cyanation of various aryl halides 1b, 1c, 1h–n to aryl nitriles 2b, 2c, 2h–n with Zn(CN)
2
Entry
Substrate
Product
Temp (8C)
Period (h)
Assay yield
a
(
%)
b
1
80
3
97
82
1
b
2b
b
2
80
5
1
c
2c
2h
2i
b
3
115
115
8
8
89
93
1
h
b
4
1
i
b
5
115
2
92
1
j
2j
c
6
125
125
80
4
4
5
65
60
75
1
k
2k
2l
c
7
1
l
b
8
1
m
2m
b
9
115
140
8
89
1
n
2n
b
d
4
10
17
1
o
2c
a
b
c
d
Determined by HPLC.
Pd/C D5 (4 mol%), PPh
Pd/C D5 (8 mol%), PPh
Conversion (%).
3
(0.16 equiv), Zn dust (0.4 equiv), Br
(0.32 equiv), Zn dust (1.2 equiv), Br
2
2
(0.2 equiv), Zn(CN)
(0.4 equiv), Zn(CN)
2
(0.6 equiv).
(0.5 equiv).
3
2
present in Pd/C. To account for the consistency of the
concentration of Pd in the solution phase, re-deposition of
Pd to the solid surface of Pd/C should take place during the
reaction, proving that the Pd/C does not just serve as a
reservoir for Pd. The use of heterogeneous Pd/C carrying
suitable charcoal matrix is, therefore, crucial for attaining
satisfactory progression of the cyanation.
functional groups (carboxyl group etc.) present on the
1
8
solid support. Based on the mechanism of Pd-catalyzed
cross coupling reaction, demonstrated by Amatore and
coworkers, the Pd -activated charcoal complex (Pd /C)
1
7
19
II
II
would rapidly coordinate with PPh to form tetrasubstituted
3
II
Pd complex 5. Reduction of 5 with Zn dust in the presence
0
of ZnBr2 gives trisubstituted Pd complex 6. The Pd
0
complex 6, thus obtained, is activated through coordination
of the carbonyl oxygen with Zn Br cation to form reactive
C
A possible reaction pathway of the present cyanation is
described in Scheme 4. In Pd/C, Pd metal is attached to the
charcoal matrix through coordination with various
0
Pd species, which is, closer to coordinatively unsaturated
0
Pd (PPh ) . While, in the Amatore’s system, this type of
19
19
3
2

M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
9913
Table 4. Comparison of the cyanation of 1a to 2a employing Pd/C with those catalyzed by homogeneous catalysts
a
Entry
Pd catalyst
mol%)
Additive (equiv) Temp ( 8C)
Period (h)
Conv. (%)
Assay yield (%)
91
2a:4
(
1
2
3
4
5
Pd/C D5 (4)
PPh
3
(0.16), Zn
0.6), Br (0.2)
115
150
115
115
115
4
2
3
4
4
100
82
98:2
(
PPh
2
b
—
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
(5)
3
(0.2), Zn
75:25
98:2
(
PPh
0.56)
(4)
3
(0.16), Zn
100
44
87
(
PPh
0.6), Br
2
(0.2)
(0.16), Zn
(0.2)
(0.16), Zn
(0.2)
b
—
(1.2)
3
74:26
91:9
(
PPh
0.6), Br
2
b
—
Pd/C D5 (1.2)
3
33
(
0.6), Br
2
a
Determined by HPLC.
Not determined.
b
intermediate has been generated by reduction at electrode,
the present reaction, that employs Zn dust as the reductant,
is much easier to be conducted on a large-scale preparation.
Oxidative addition of aryl bromide 1 to 6 is accelerated as
well by liberating ZnBr of good leaving group activity to
2
II
form cis-tetrasubstituted Pd complex 7. The preference of
ZnBr over ZnI or ZnCl , shown in Table 2, might be a
2
2
2
consequence of higher Lewis acidity of ZnBr (ZnBr O
2
2
2
0
ZnI OZnCl ), that acts as a balance to the modest leaving
2
2
group ability of ZnBr (ZnI OZnBr OZnCl ). Cyanation
2
2
2
2
of 7 with CNZnBr, that might be generated by the reaction
of Zn(CN) with ZnBr , would subsequently take place to
2
2
II
give cis-cyanated Pd complex 9. In this stage, the complex
dissolves into the solution phase, with zinc bromide salt of
9
activated charcoal 8 left in the mixture. After reductive
elimination of aryl nitrile 2 from 9, three pathways (path A,
B and C), shown in Scheme 4, are possible. In path A, the
0
0
reduced Pd complex [Pd (PPh ) ], generated from 9,
3
2
Figure 2. Pd leaching in the cyanation of aryl bromide 1b to aryl nitrile 2b.
The Pd leaching was determined by XRF analysis of the filtered solution.
The conversion was determined by HPLC. The reaction was conducted by
0
coordinates back to 8 to regenerate three coordinated Pd
complex 6. In path B, the reaction with ZnBr affords
2
the use of Pd/C D5 (4 mol%), Zn (0.4 equiv), Br
0.16 equiv) at 80 8C in DMA.
2
(0.2 equiv) and PPh
3
0
trisubstituted Pd complex 10, which is, activated by
(
K C
coordination of Br ligand with Zn Br. Following the
reaction with aryl bromide 1 and subsequently with
2
Scheme 3. Comparison of the cyanation of 1a employing Pd/C D5 with those employing Pd(OAc) or dissolved Pd species from Pd/C D5.

9914
M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
2 2
Scheme 4. A possible reaction pathway for the cyanation of aryl bromides 1 to aryl nitriles 2 employing Zn(CN) in the presence of Pd/C, Zn dust and ZnBr .
II
CNZnBr, the complex 10 is converted to the cyanated Pd
complex 9 that, upon reductive elimination, would provide
aryl nitrile 2 (10/12/9/2). Path C is an undesirable0
pathway, which leads to trisubstituted cyanated Pd
complex 11, that is, unable to participate in the oxidative
The issue of high catalyst loading needs to be addressed,
especially when it comes to a stage of production. Because
the catalyst loading of 4 mol%, employed in the present
protocol, is relatively high, efficient recovery of Pd should
be achieved for attaining the cost-effective process. The
recovery of Pd was carried out in the reaction of 1a to 2a by
3
j
addition with aryl bromide 1. However, through the
reaction of 11 with ZnBr , the active Pd species 10 would be
produced. As a consequence, the crucial roles of ZnBr in
2
2
initial oxidation of PPh that coordinates Pd and dissolves
3
2
1
Pd into the solution. After air bubbling of the reaction
mixture at 60 8C, Pd was recovered in 97% yield through
simple filtration followed by usual recovery process
involving combustion.
the present reaction might be as follows: (1) initial
0
generation of 6 from 5, (2) trap of the fragile Pd species
0
[
through path B), (3) conversion of the inactivated cyanated
Pd (PPh ) ], generated from 9, as a form of 10 (9/10
3
2
0
Pd species 11 to 10 (11/10 through path C), and (4)
possible activation of Zn(CN) to CNZnBr.
2
3. Conclusions
The elevated formation of reduction byproduct 4, from 1a
by employing homogeneous Pd(OAc) in the absence of
ZnBr (Table 4, entry 2), reflects the significance of the use
2
As described above, a practical cyanation of aryl bromides
employing heterogeneous Pd/C was worked out by the use
2
of heterogeneous Pd/C in combine with ZnBr to generate
2
of inexpensive Zn dust, ZnBr
dust and Br ) and PPh . The use of heterogeneous Pd/C not
(in situ generated from Zn
2
0
monomeric Pd species such as 6. The competing reaction,
2
3
that is, reduction of 1a to 4, takes place with Pd on the metal
surface of Pd black. Without ZnBr or the solid support for
only allows the facile recovery of the catalyst but also
contributes to promote and maintain the catalytic cycle. The
present reaction produces a lot of Zn waste. However, Zn
0
2
0
Pd, the Pd species tends to cluster and eventually
0
precipitates to Pd black that effects the reduction of 1a to
22
waste is relatively innocuous by-product, compared with
3
a
3g
4
. Although precise estimation of the contribution of each
heavy metals such as Cu or Sn, found in the previous
cyanation protocols. The feasibility of the present process
was undoubtedly confirmed at pilot-plant scale (60 kg scale)
synthesis of 4-morpholinocarbonyl-2-hydroxybenzonitrile
(2a). The present process is featured by many advantages
such as ease of operation, versatility of the substrates, less
Pd contamination into the product, high recovery of Pd, use
pathway (path A, B and C) is not obtained, some extent of
cyanation may proceed through path A, because not all the
Pd was dissolved into the solution phase (Fig. 2). The role of
the solid support is, as mentioned above, to anchor Pd metal
on the solid support in a highly dispersed manner to allow
the generation of the monomeric Pd phosphine complexes
such as 6 and 7 without agglomerating to Pd black, at least
in the initial stage of the reaction.
of inexpensive phosphine ligand (PPh ), and additives (Zn
3
dust and ZnBr ), and high reproducibility, which would
2

M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
9915
C
[MCH] ; elemental analysis calcd (%) for C H N O ; C,
12 12 2 3
62.06; H, 5.21; N, 12.06; found: C, 61.63; H, 5.2; N, 11.81.
permit to fuel a lot of expansion as one of the efficient
approaches to multifunctional aryl nitriles.
4.2. General procedure for the cyanation of aryl
bromides employing Pd/C
4
. Experimental
4
.1. General methods
A reaction vessel was charged with zinc dust (0.8 mmol,
52 mg) and DMA (5.7 mL). The vessel was then briefly
evacuated and backfilled with N five times. Then, Br
Melting points were measured using B u¨ chi melting point
2
2
1
13
apparatus (B-540) and are uncorrected. H and C NMR
spectra (400 and 100 MHz, respectively) were recorded on a
Bruker Avance 400 spectrometer using tetramethylsilane as
the internal standard. Mass spectra were obtained on a
Hitachi M-2000A double-focusing mass spectrometer and
on a Finnigan MAT LC-Q. Elemental analyses were
measured on a Perkin-Elmer 2400II microanalyzer. Silica
gel column chromatography was performed using Kieselgel
(20 mL, 0.4 mmol) was dropwise added at 25 8C and the
mixture was stirred at 25 8C for 0.5 h. To the mixture were
successively added Zn(CN)2 (114 mg, 1.2 mmol), PPh3
(
85 mg, 0.32 mmol), Pd/C D5 (Pd: 5 wt%, 170 mg,
.08 mmol) and aryl bromide (2 mmol) at 25 8C. The vessel
was briefly evacuated and backfilled with N five times. The
0
2
mixture was stirred at 80–125 8C 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 concentrated, and the residue
was purified by silica gel column chromatography or
recrystallization to provide the desired product. When
recovery of the catalyst was needed, the reaction mixture,
obtained after the reaction, was subjected to air bubbling at
6
0 (E. Merck). Thin-layer chromatography (TLC) was
carried out on E. Merck 0.25 mm precoated glass-backed
plates (60 F254). Development was accomplished using 5%
phosphomolybdic acid in ethanol-heat or they were
visualized by UV light where feasible. Zinc cyanide (purity:
2
3
9
8%, caution: highly toxic ) was purchased from Sigma-
Aldrich Fine Chemicals. Zinc dust was purchased from
Hakusui Tech (Pb content: less than 50 ppm). All solvents
and reagents were used as received. Pd/C D1, D2, D3, D5,
and D6 were purchased from Degussa Japan Co., Ltd. They
have properties listed in Table 5.
6
0–65 8C for 1 h, and then the mixture was cooled to 25 8C.
The mixture was diluted with AcOEt (15 mL) and filtered
through paper filter that was pre-coated with activated
charcoal. The solids obtained were allowed to recovery
process involving combustion to recover Pd in 97% yield
based on the initially added Pd.
4
.1.1. Synthesis of 3-cyano-4-hydroxymorpholinobenz-
amide (2a) through Rosenmund-von Braum reaction of
-bromo-4-hydroxymorpholinobenzamide (1a).
24
.2.1. Methyl 4-cyanobenzoate (2b). The crude material
4
was purified by silica gel column chromatography (AcOEt/
3
A
reaction vessel was charged with 1a (3 g, 11.2 mmol) and
Cu(CN) (1.4 g, 16.8 mmol) and DMA (15 mL). The vessel
was then briefly evacuated and backfilled with N three
2
times. The mixture was stirred under reflux (165 8C) for 4 h.
After the reaction was finished, the suspension was cooled
down to 80 8C, and then added concd HCl (3.5 mL). After
air bubbling of the mixture for 1 h at the same temperature,
the solvent was evaporated. The residue was crystallized by
hexaneZ3:97–15:85) to afford 2b (97%) as colorless
crystals. Mp 68–69 8C, (lit. : 67–68 8C); H NMR
2
24
1
(
2
400 MHz, CDCl ) dZ8.12–8.09 (m, 2H), 8.03–8.00 (m,
3
13
H), 3.91 (s, 3H); C NMR (100 MHz, CDCl ) dZ165.0,
3
1
33.4 (2s), 132.7, 129.7 (2d), 118.0, 115.4 (2s), 52.7 (q); IR
K1
(
ATR) nmaxZ3676, 2988, 2229, 1717 cm ; MS (70 eV,
C
EI) m/z 161 [M] ; elemental analysis calcd (%) for
C H NO ; C, 67.08; H, 4.38; N, 8.69; found: C, 67.02; H,
9
7
2
adding AcOEt (10 mL), c.-HCl (1.7 mL) and H O (18 mL),
2
4.34; N, 8.61.
and the crystals formed were collected by filtration to give
2
1
a (1.59 g, 61%) as colorless crystals. Mp 238–240 8C; H
NMR (400 MHz, DMSO-d ) dZ11.58 (s, 1H), 7.70 (d, JZ
4.2.2. 2-Hydroxy-5-morpholinocarbonylbenzonitrile
(2a). The crude material was crystallized from acetone–
H O to afford 2c (91%) as colorless crystals. The chemical
2
6
2
.0 Hz, 1H), 7.57 (dd, JZ2.0, 8.8 Hz, 1H), 7.07 (d, JZ
1
3
.8 Hz, 1H), 3.59 (br, 4H), 3.48 (br, 4H); C NMR
8
(
1
100 MHz, DMSO-d ): dZ167.3 (s), 161.1 (s), 134.0 (d),
properties of the product were identical with those of 2a
obtained by Rosenmund-von Braum reaction (Section
4.1.1).
6
32.5 (d), 126.6 (s), 116.3 (s), 116.0 (d), 98.6 (s), 65.9 (2t);
K1
IR (ATR) nmaxZ2229, 1578 cm ; MS (APCI) m/z 233
Table 5. Properties of the Pd/C catalysts
a
b
c
c
Catalyst
Pd distribution
Impregnation depth
nm)
Reduction degree (%)
Pd dispersion (%)
Water content (wt%)
(
Pd/C D1
Pd/C D2
Pd/C D3
Pd/C D4
Pd/C D5
Pd/C D6
eggshell
eggshell
uniform
uniform
thickshell
thickshell
50–150
50–150
0–25
25–99
0–25
25–99
0–25
25–99
28
27
36
36
35
26
3.2
4.2
1–1.5
1.8
1–1.5
3.0
d
—
d
—
200–500
200–500
a
8
Purchased from Degussa Japan Co., Ltd Catalysts Division.
b
c
d
Detected by temperature programmed reduction (TPR) measurement.
Pd dispersion is calculated with CO chemisorption.
Not determined.

9916
M. Hatsuda, M. Seki / Tetrahedron 61 (2005) 9908–9917
2
.2.3. 4-Acetylbenzonitrile (2c). The crude material was
4
29
4
purified by silica gel column chromatography (AcOEt/
4.2.9. 4-Aminobenzonitrile (2k). The crude material was
purified by silica gel column chromatography (AcOEt/
hexaneZ20:80–4:55) to afford 2k (65%) as red crystals. Mp
hexaneZ10:90–15:85) to afford 2c (82%) as colorless
crystals. Mp 57–58 8C, (lit. : 57–60 8C); H NMR
2
4
1
29
1
85–86 8C (lit. : 84–85 8C); H NMR (400 MHz, CDCl )
dZ7.40 (ddd, JZ2.4, 4.4, 4.8 Hz, 2H), 6.65 (ddd, JZ2.4,
4.4, 4.8 Hz, 2H), 4.21 (br s, 2H); C NMR (100 MHz,
3
(
2
400 MHz, CDCl ) dZ8.05 (ddd, JZ1.6, 3.2, 4.8 Hz,
3
1
3
13
H), 7.78 (ddd, JZ1.2, 3.2, 4.8 Hz, 2H), 3.03 (s, 3H);
C
NMR (100 MHz, CDCl ) dZ196.5, 139.9 (2s), 132.5, 128.7
CDCl ) dZ150.5 (s), 133.8 (d), 120.2 (s), 114.4 (d), 100.1
3
3
K1
(
2d), 117.9, 116.4 (2s), 26.8 (q); IR (ATR) nmaxZ2229,
(s); IR (ATR) nmaxZ3477, 3369, 2212, 1622, 1600 cm
MS (APCI) m/z 119 [MCH] .
;
K1 C
684 cm ; MS (70 eV, EI) m/z 145 [M] ; elemental
C
1
analysis calcd (%) for C H NO; C, 74.56; H, 4.86; N, 9.65.
Found: C, 74.56; H, 4.69; N, 9.56.
9
7
3
0
4.2.10. 2-Hydroxybenzonitrile (2l). The crude material
was purified by silica gel column chromatography (AcOEt/
hexaneZ2:1) to afford 2l (60%) as colorless crystals. Mp
3
g
4
.2.4. 4-Trifluoromethylbenzonitrile (2d). The crude
material was purified by silica gel column chromatography
hexane/MTBEZ8:1) to afford 2d (91%) as colorless
3
0
1
91–92 8C (lit. : 97–98 8C); H NMR (400 MHz, CDCl )
dZ7.51–7.44 (m, 2H), 7.03–6.95 (m, 2H), 5.92 (s, 1H);
3
1
3
(
C
K1
1
crystals. Mp 35 8C; IR (ATR) nmaxZ2237, 1314 cm ; H
NMR (400 MHz, CDCl ) dZ7.84–7.76 (m, 4H); C NMR
NMR (100 MHz, CDCl ) dZ158.8 (s), 134.8, 132.9, 120.9,
3
1
3
3
116.7 (4d), 116.5, 99.4 (2s); IR (ATR) n Z3232, 2231,
max
1630 cm ; MS (70 eV, EI) m/z 119 [M] .
K1
C
(
(
100 MHz, CDCl ) dZ134.6 (q), 132.8 (d), 126.3 (q), 123.2
3
C
q), 117.5 (s), 116.2 (s); MS (70 eV, EI) m/z 171 [M] .
2
8
.2.11. 3-Cyanopyridine (2m). The crude material was
4
purified by silica gel column chromatography (AcOEt/
2
.2.5. 4-Chlorobenzonitrile (2e). The crude material was
5
4
purified by silica gel column chromatography (AcOEt/
hexaneZ2:1) to afford 2m (75%) as colorless crystals. Mp
2
8
1
hexaneZ5:95–25:75) to afford 2e (58%) as colorless
crystals. Mp 90 8C (lit. : 90.5–91.5 8C); IR (ATR) nmaxZ
5
0–51 8C (lit. : 52 8C); H NMR (400 MHz, CDCl ) dZ
3
2
5
8.91 (d, JZ1.6 Hz, 1H), 8.84 (dd, JZ1.6, 4.8 Hz, 1H), 7.99
K1
1
1
3
2
2
1
226 cm ; H NMR (400 MHz, CDCl ) dZ7.62–7.60 (m,
3
13
(ddd, JZ2.0, 4.0, 6.0 Hz, 1H), 7.48–7.45 (m, 1H); C NMR
H), 7.48–7.45 (m, 2H); C NMR (100 MHz, CDCl ) dZ
39.6 (s), 133.3 (d), 130.0 (d), 118.0 (s), 110.8 (s); MS
70 eV, EI) m/z 137 [M] .
3
(100 MHz, CDCl ) dZ153.0, 152.5, 139.3, 123.7 (4d),
3
1
16.5, 110.2 (2s); IR (ATR) n Z3062, 2230, 1587,
max
K1 C
C
(
1
564 cm ; MS (APCI) m/zZ105 [(MCH) ].
.2.12. Benzo[b]thiophene-3-carbonitrile (2n). The
crude material was purified by silica gel column chroma-
2
.2.6. 4-Methoxybenzonitrile (2h). The crude material
6
3
1
4
was purified by silica gel column chromatography (AcOEt/
4
hexaneZ5:95–20:80) to afford 2h (89%) as colorless
crystals. Mp 59–60 8C, (lit. : 59 8C); H NMR (400 MHz,
tography (AcOEt/hexaneZ2:98–4:96) to afford 2n (89%)
as colorless crystals. Mp 73–74 8C (lit. : 70–71 8C); IR
2
6
1
3
1
K1
1
CDCl ) dZ7.60–7.57 (m, 2H), 6.97–6.94 (m, 2H), 3.86 (s,
3
(ATR) nmaxZ3108, 2222 cm
;
H NMR (400 MHz,
1
3
3
1
2
H); C NMR (100 MHz, CDCl ) dZ162.9 (s), 134.0 (d),
3
CDCl ) dZ8.11 (s, 1H), 7.98 (d, JZ7.7 Hz, 1H), 7.90 (d,
3
1
3
19.2 (s), 114.8 (d), 104.0 (s), 55.6 (q); IR (ATR) nmaxZ
217, 1604 cm ; MS (70 eV, EI) m/z 133 [M] ; elemental
JZ8.2 Hz, 1H), 7.55–7.46 (m, 2H); C NMR (100 MHz,
K1
C
CDCl ) dZ128.5 (s), 137.5 (d), 137.3 (s), 126.2, 126.0,
3
analysis calcd (%) for C H NO; C, 72.17; H, 5.30; N, 10.52;
8
7
122.8, 122.5 (4d), 114.3 (s), 107.1 (s); MS (70 eV, EI) m/z
C
found: C, 72.31; H, 5.25; N, 10.52.
1
6
59 [M] ; elemental analysis calcd (%) for C H NS; C,
9 5
7.9; H, 3.17; N, 8.8. Found: C, 67.73; H, 3.08; N, 8.77.
2
7
4
.2.7. 2-N,N-Dimethylaminobenzonitrile (2i). The crude
material was purified by silica gel column chromatography
hexane to AcOEt/hexaneZ15:85) to afford 2i (93%) as
(
Acknowledgements
1
pale yellow oil; H NMR (400 MHz, CDCl ) dZ7.51–7.49
3
(
(
1
1
m, 1H), 7.43–7.38 (m, 1H), 6.90–6.88 (m, 1H), 6.86–6.82
The authors wish to thank Degussa Japan Co., Ltd for
disclosing the properties of the Pd/C catalysts.
1
3
m, 1H), 3.05 (s, 6H); C NMR (100 MHz, CDCl ) dZ
3
55.3 (s), 135.0, 133.5 (2d), 119.7 (s), 119.1, 116.7 (2d),
K1
01.3 (s), 43.0 (q); IR (ATR) nmaxZ2214, 1597 cm ; MS
70 eV, EI) m/z 145 [M] .
C
(
2
8
4
.2.8. Naphthalene-1-carbonitrile (2j). The crude
material was purified by silica gel column chromatography
hexane to AcOEt/hexaneZ8:92) to afford 2j (92%) as pale
References and notes
(
1. (a) Farina, V. Adv. Synth. Catal. 2004, 346, 1519–1521 and
references cited therein. (b) Miyaura, N. Adv. Synth. Catal.
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A. M. Chem. Eng. News 2004, 82, 49–58 and references cited
therein.
2
8
1
yellow crystals. Mp 36–38 8C (lit. : 37–38 8C); H NMR
(
400 MHz, CDCl ) dZ8.25 (d, JZ8.4 Hz, 1H), 8.09 (d, JZ
3
8
7
.2 Hz, 1H), 7.93 (d, JZ8.2 Hz, 1H), 7.92 (dd, JZ1.0,
.2 Hz, 1H), 7.70 (ddd, JZ1.3, 7.2, 8.2 Hz, 1H), 7.63 (ddd,
JZ1.0, 6.9, 7.2 Hz, 1H), 7.53 (dd, JZ7.2, 8.2 Hz, 1H);
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32.3 (s), 128.6, 128.5, 127.5, 125.1, 124.9 (5d), 117.8,
110.1 (2s); IR (ATR) nmaxZ2219 cm ; MS (70 eV, EI)
m/z 153 [M] ; elemental analysis calcd (%) for C H N; C,
6.25; H, 4.61; N, 9.16. Found: C, 85.98; H, 4.39; N, 9.16.
1
3
C
2. Arvela, R. K.; Leadbeater, N. E.; Sangi, M. S.; Williams, V.
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1
K1
3. For recently developed Pd-catalyzed cyanation of aryl halides,
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f
2
3
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4
. For preliminary report on the present cyanation, see: Hatsuda,
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. (a) Rosenmund, K. W.; Struck, E. Ber. Dtsch. Chem. Ges.
4
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Justus Liebigs Ann Chem. 1931, 488, 111–126.
. While CuBr is known to be scarcely soluble in water and
1
4. Dissolution of Pd form Pd/C to solution phase has been
6
observed in the Suzuki–Miyaura coupling employing Pd/C and
2 2
acetone, CuBr and CuCl are highly soluble in water, acetone
1
3i
PPh
3
.
and alcohol, see: Maryadele, J. O. The Merck Index, 13th ed.;
Merck: Rahway, 2001; pp 460 and 463.
. (a) Shimizu, T.; Seki, M. Tetrahedron Lett. 2000, 41,
1
1
5. The preference of thickshell type Pd/C has been reported as
7
well in the Fukuyama reduction.
l
7
6. In the Heck reaction employing Pd/C, the initial concentration
of Pd in the solution phase is the highest (20% of the total Pd
content) and then inched down to 0.2% when the reaction was
5099–5101. (b) Shimizu, T.; Seki, M. Tetrahedron Lett.
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1
3g
finished.
17. The reaction mechanism involving dissolution and re-
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Y.; Hatsuda, M.; Yamada, S. J. Org. Chem. 2002, 67,
deposition of Pd has been proposed as well in the Heck
1
reaction.
3g
5
2
2
527–5536. (h) Seki, M.; Shimizu, T.; Inubushi, K. Synthesis
002, 361–364. (i) Mori, Y.; Kimura, M.; Seki, M. Synthesis
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Yoshida, S.; Shimizu, T. Tetrahedron Lett. 2003, 44,
8
905–8907. (k) Kimura, M.; Seki, M. Tetrahedron Lett.
004, 45, 1635–1637. (l) Kimura, M.; Seki, M. Tetrahedron
2
21. In contrast, the recovery of Pd in the Heck reaction employing
1
Pd/C was conducted by reducing the Pd(II) species.
3g
Lett. 2004, 45, 3219–3223. (m) For a review, see: Seki, M.;
Kimura, M. J. Synth. Org. Chem. Jpn. 2004, 62, 882–894.
. Pd/C catalyst employed in this study was purchased from
Degussa Japan Co., Ltd. The catalysts are commercially
available. The Pd/C catalysts tested in this study have three
types of Pd distribution: eggshell, thickshell, and uniform. In
the eggshell type catalyst, Pd distributes close to the surface
within 50–150 nm depth. In contrast, Pd disperses homo-
geneously in the uniform type catalyst. The thickshell type
catalyst denotes the one whose Pd distributes until 200–
2
2
2. Lethal dose (i.v.) of ZnCl in rats is 60–90 mg/kg. Zn has been
2
8
used as food additives for skim milk.
3. Cyanide containing wastes can be decontaminated using a
solution of NaOCl in water, see: Lunn, G.; Sansone, E. B.
Destruction of Hazardous Chemicals in the Laboratory, 2nd
ed.; Wiley: New York, 1994; pp 133–138.
2
4. Takagi, K.; Sasaki, K.; Sakakibara, Y. Bull. Chem. Soc. Jpn.
1
991, 64, 1118–1121.
5. Murahashi, S.; Naota, T.; Nakajima, N. J. Org. Chem. 1986,
1, 898–901.
2
5
00 nm from the surface.
5
2
2
6. Liebscher, J. Synthesis 1982, 1084–1086.
7. Gupton, J. T.; Idoux, J. P.; Baker, G.; Colon, C.; Crews, A. D.;
Jurss, C. D.; Rampi, R. C. J. Org. Chem. 1983, 48, 2933–2935.
8. Capdevielle, P.; Lavigne, A.; Maumy, M. Synthesis 1989, 6,
2
2
3
4
51–452.
9. Kijima, M.; Nambu, Y.; Endo, T.; Okawara, M. J. Org. Chem.
984, 49, 1434–1436.
1
0. Molina, P.; Alajarin, M.; Vilaplana, M. J. Synthesis 1982,
9
0. Takai, K.; Kakiuchi, T.; Utimoto, K. J. Org. Chem. 1994, 59,
671–2673.
. The price of PPh
3
is about $30/kg.
1016–1017.
1
31. Yoshida, K.; Miyoshi, K. J. Chem. Soc., Perkin Trans. 1 1992,
2
333–335.