Efficient synthesis of pyridylacrylonitriles via the Heck reaction

Article abstract of DOI:10.1080/00397910600781356

A new synthetic pathway to pyridylacrylonitriles has been developed based on a palladium-catalyzed Heck reaction. The optimized process and the preparation of related functionalized pyridylacrylonitriles are discussed. Copyright Taylor & Francis Group, LLC.

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Efficient Synthesis of Pyridylacrylonitriles via
the Heck Reaction
Kui Mei a , Junbo Wang b & Xianming Hu a
a College of Pharmacy , Wuhan University , Wuhan, China
b Sundia Meditech Company Ltd. , Shanghai, China
Published online: 27 Oct 2006.
To cite this article: Kui Mei , Junbo Wang & Xianming Hu (2006) Efficient Synthesis of Pyridylacrylonitriles via
the Heck Reaction, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 36:17, 2525-2532, DOI: 10.1080/00397910600781356
To link to this article: http://dx.doi.org/10.1080/00397910600781356
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Synthetic Communicationsw, 36: 2525–2532, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600781356
Efficient Synthesis of Pyridylacrylonitriles
via the Heck Reaction
Kui Mei
College of Pharmacy, Wuhan University, Wuhan, China
Junbo Wang
Sundia Meditech Company Ltd., Shanghai, China
Xianming Hu
College of Pharmacy, Wuhan University, Wuhan, China
Abstract: A new synthetic pathway to pyridylacrylonitriles has been developed based
on a palladium-catalyzed Heck reaction. The optimized process and the preparation of
related functionalized pyridylacrylonitriles are discussed.
Keywords: Heck reaction, palladium acetate, pyridylacrylonitrile
INTRODUCTION
Substituted pyridines, especially functionalized pyridines, exhibit a diverse
range of effects when introduced into biological systems. Among them, pyri-
dylacrylontriles (2) have attracted significant attention because of their
potential as building blocks in medicinal chemistry.[1] Thus, the preparation
of pyridylacrylontriles is of increasing interest.
There are several approaches for the synthesis of pyridylacrylonitriles,
including the Knoevenagel condensation,[2] the Wittig reaction,[3] and the
Peterson reaction.[4] However, these previously reported methods have
Received in Japan August 2, 2005
Address correspondence to Xianming Hu, College of Pharmacy, Wuhan University,
Wuhan, 430072, China. E-mail: xmhu@whu.edu.cn
2525

2526
K. Mei, J. Wang, and X. Hu
certain disadvantages such as limited availability of starting materials, which
limit their applications to some extent.
Recently Hutchinson et al.[5] and Berthiol et al.[6] described an efficient
Heck coupling of 3-bromopyridine with acrylates. We herein report an
improved synthesis of pyridylacrylonitriles via the Heck reaction between
bromopyridines (1) and acrylonitrile (Scheme 1). Generally, a Heck
coupling reaction system involves palladium acetate, ligand, base, solvent,
and other additives. We investigated the effects of these factors and
developed a practical synthesis of pyridylacrylonitriles.
RESULTS AND DISCUSSION
We selected 3-bromopyridine (1a) as the substrate in a model reaction and
performed a comparative study of this coupling reaction under various
conditions. The results are shown in Table 1.
From Table 1, it can be observed that temperature is important for this
reaction. Different solvents worked well for this reaction, as long as they
could sustain the reaction temperature; thus N-methyl-2-pyrrolidinone
(NMP), toluene, and N,N-dimethylformamide (DMF) were good, but
dioxane and acetonitrile gave low yields.
Generally, the ligands play important roles in Heck reaction. We screened
four electron-rich phosphorous-based ligands including triphenylphosphine,
tri-(o-tolyl)phosphine, tri-(2-furyl)phosphine, and tri-(2-thienyl)phosphine
and found that tri-(o-tolyl)phosphine worked best (Entries 4 to 7).
The investigation of various bases was also performed. NaHCO3 (66%)
and triethylamine (TEA) (62%) gave much better results than Na2CO3,
K3PO4, and NaOAc.
A number of reports have indicated that phase-transfer conditions are
superior to Pd-catalyzed Heck reactions, and many reactions under Jeffery’s
conditions did give good yields.[7] Accordingly, we designed two reactions
using tetra-n-butylammonium chloride as phase-transfer agent. We found
that under these conditions the reactions completed faster and no ligand was
necessary (Entries 9 and 10). Interestingly, the reaction worked well with
TEA as base or in toluene (Entries 11 and 12). This fact suggests that tetra-
n-butylammonium chloride in the reaction is not only the phase-transfer
Scheme 1.

Pyridylacrylonitriles Synthesis via Heck Reaction
2527
Table 1. Heck reactions between 3-bromopyridine and acrylonitrilea
Temp.
(8C)b
Time Yieldc
Entry
Ligand
Solvent
Base
TEA
Additive
(h)
(%)
1
2
90
110
140
110
110
110
110
110
110
110
110
110
110
(o-tol)3P
(o-tol)3P
(o-tol)3P
(o-tol)3P
PPh3
DMA
DMA
DMA
DMF
DMF
—
—
—
—
—
—
—
—
24
24
24
24
24
24
24
24
4
18
54
46
62d
45
21
17
66d
85
94
85
90
74
TEA
TEA
3
4
TEA
TEA
5
6
(2-thienyl)3P DMF
TEA
TEA
7
(2-furyl)3P
(o-tol)3P
(o-tol)3P
—
DMF
DMF
DMF
DMF
DMF
8
NaHCO3
9
NaHCO3 n-Bu4NCl
NaHCO3 n-Bu4NCl
10
11
12
13
4
—
—
TEA
n-Bu4NCl
16
16
16
Toluene NaHCO3 n-Bu4NCl
Toluene TEA n-Bu4NCl
—
aUnless otherwise noted, all reactions were performed with 2.0 mmol of 3-bromo-
pyridine, 6.0 mmol of acrylonitrile, 0.04 mmol of Pd(OAc)2.
bOil bath temp.
cIsolated yield.
dWhen this reaction was run for 48 h, yield was not improved.
agent but also presumably the stabilizer of intermediate Pd0 species, as
reported previously.[8]
Overall, we found the following conditions were efficient for the Heck
reaction of 3-bromopyridine with acrylonitrile: (a) Pd(OAc)2, n-Bu4NCl,
DMF, NaHCO3, 110 8C, 4 h; (b) Pd(OAc)2, n-Bu4NCl, toluene, NaHCO3,
110 8C, 16 h; and (c) Pd(OAc)2, n-Bu4NCl, DMF, TEA, 110 8C, 16 h.
Under these optimized conditions, other substituted pyridyl bromides
could be converted into the corresponding functionalized pyridylacrylonitriles
(Table 2).
The Heck reaction of 4-bromopyridine in the presence of n-Bu4NCl with
TEA as the base (Entry 1b) was much better than the one with NaHCO3. As
expected, the Heck reaction of 3,5-dibromopyridine (Entry 1c) gave a
1
mixture of three isomeric products determined by H NMR. The reaction of
4-methyl-3-bromopyridine and 5-bromo-2-methoxypyridine (Entries 1d and
1e) required more catalyst Pd(OAc)2 (6%) to achieve the acceptable yields.
However, we did not obtain coupling products when 2-bromopyridine
was used as substrate, even with higher loading of catalyst or with tetrakis(tri-
phenylphosphine)palladium. Probably the oxidative addition intermediate of
Pd0 dimerizes to form a stable complex,[9] which renders the palladium
catalyst unavailable for further reaction.
In conclusion, we disclosed the Heck reaction between pyridyl bromides
and acryonitrile for the synthesis of a variety of pyridylacryonitriles.

2528
K. Mei, J. Wang, and X. Hu
Table 2. Reaction of various bromopyridines with acrylonitrilea
Timeb Yieldc
Entry
Substrate 1
Product 2
(h)
(%)
E/Zd
5/1
1b
12
94e
1c
1d
4
91
3/3/1f
2.5/1
12
85g
1e
12
71g
4/1
1f
4
4
84
75
2/1
2/1
1 g
aUnless otherwise noted, all reactions were performed with 2.0 mmol of bromopyr-
idine, 6.0 mmol of acrylonitrile, 0.04 mmol of Pd(OAc)2, 2.0 mmol n-Bu4NCl, and
6.0 mmol NaHCO3 in DMF at 1108C.
bMonitored by TLC until the bromopyridine reacted completely.
cIsolated yield.
dDetermined by 1H NMR.
e4-Bromopyridine hydrochloride salt was used, and the base was TEA (8.0 mmol).
fE-E/Z-E/Z-Z.
gPd(OAc)2 (6%) was used.
EXPERIMENTAL
General
All melting points were determined on a ShenGuang WRR apparatus and
1
are uncorrected. H NMR spectra was recorded on Mercury-300 (300 MHz)
using TMS as internal reference in CDCl3 or in CD3OD. The liquid

Pyridylacrylonitriles Synthesis via Heck Reaction
2529
chromatography-mass spectrometry (LC/MS) was equipped with a Symmetry
C
18 (0.46 mm ꢀ 50 mm) column. Mass spectra were recorded by atmospheric
pressure chemical ionization (APCI). The CHN elemental analyses were
performed at Shanghai Institute of Materia Medica, Chinese Academy of
Sciences.
General Procedure for a Heck Coupling between Bromopyridine
and Acrylonitrile
A mixture of bromopyridine (2 mmol), acrylonitrile (6 mmol), Pd(OAc)2
(0.04 mmol), ligand (0.08 mmol, if necessary), n-Bu4NCl (2 mmol, when
present), and base (6 mmol) in 5 ml of solvent was stirred under nitrogen
(for reaction time and temperature, see Tables 1 and 2). After removing the
solvent in a vacuum, the residue was extracted with methylene chloride
(10 ml ꢀ 3) and washed with water (10 ml ꢀ 3). The organic phase was
dried over anhydrous Na2SO4, filtered, and concentrated. The crude product
was purified by flash column chromatography (silica, petroleum ether/ethyl
acetate) to afford the pure desired compound.
Data
3-(3-Pyridyl)acrylonitrile (2a). White solid [E/Z ca. 5/1 (1H NMR)]: mp 82–
1
848C. H NMR (CD3OD): d 6.4 (d, J ¼ 16.8Hz, 1H), 7.5 (m, 1 H), 7.6
(d, J ¼ 16.8Hz, 1H), 8.1 (m, 1H), 8.5 (m, 1H), 8.7 (m, 1H), 5.8
(d, J ¼ 12.3Hz, 0.2H), 7.3 (d, J ¼ 12.3Hz, 0.2H), 7.5 (m, 0.2H), 8.3
(m, 0.2H), 8.6 (m, 0.2H), 8.8 (m, 0.2H). Elemental analysis calcd. (%) for
C8H6N2: C, 73.83; H, 4.65; N, 21.52; found: C, 73.63; H, 4.67; N, 20.99. MS
(APCI): m/e ¼ 131.1 [M þ H]þ. Recrystallized with petroleum ether gave
1
pure E-isomer: mp 105–107 8C (lit.[10] 106–107 8C). H NMR (CD3OD): d
6.4 (d, J ¼ 16.8Hz, 1H), 7.5 (dd, J ¼ 4.8, 8.2 Hz, 1H), 7.6 (d, J ¼ 16.8Hz,
1H), 8.1 (m, 1H), 8.5 (dd, J ¼ 2.1, 4.8 Hz, 1H), 8.7 (d, J ¼ 2.1 Hz, 1H).
3-(4-Pyridyl)acrylonitrile (2b). White solid [E/Z ca. 5/1 (1H NMR)]: mp
1
48–51 8C. H NMR (CD3OD): d 6.5 (d, J ¼ 16.8 Hz, 1H), 7.5–7.6 (m, 3H),
8.5 (m, 2H); 5.9 (d, J ¼ 12.3 Hz, 0.2H), 7.3 (d, J ¼ 12.3 Hz, 0.2H), 7.7 (dd,
J ¼ 1.8, 4.5 Hz, 0.4H), 8.6 (dd, J ¼ 1.8, 4.5 Hz, 0.4H). Elemental analysis
calcd. (%) for C8H6N2: C, 73.83; H, 4.65; N, 21.52; found: C, 73.70; H,
4.58; N, 21.15. MS (APCI): m/e ¼ 131.3 [M þ H]þ. Recrystallized with
petroleum ether gave pure E-isomer: mp 71–72 8C (lit.[10] mp 70–71 8C).
1H NMR (CD3OD): d 6.5 (d, J ¼ 16.8 Hz, 1H), 7.5 (m, 2H), 7.6
(d, J ¼ 16.8 Hz, 1H), 8.5 (m, 2H).
3-[5-(2-Cyanovinyl)(3-pyridyl)]acrylonitrile (2c). White solid [E-E/Z-E/Z-
Z ca. 3/3/1 (1H NMR)]: mp 181–1848 C. 1H NMR (CD3OD): d 6.5

2530
K. Mei, J. Wang, and X. Hu
(d, J ¼ 16.8 Hz, 2H), 7.6 (d, J ¼ 16.8 Hz, 2H), 8.3 (t, J ¼ 2.1, 2.1 Hz, 1H), 8.7
(d, J ¼ 1.8 Hz, 2H); 5.9 (d, J ¼ 12.6 Hz, 1H), 6.4 (d, J ¼ 16.8 Hz, 1H), 7.4
(d, J ¼ 12.6 Hz, 1H), 7.7 (d, J ¼ 16.8 Hz, 1H), 8.5 (t, J ¼ 2.1 Hz, 1.8 Hz,
1H), 8.8 (d, J ¼ 2.1 Hz, 1H), 8.9 (d, J ¼ 2.1 Hz, 1H), 6.0 (d, J ¼ 12.3 Hz,
0.6H), 7.4 (d, J ¼ 12.3 Hz, 0.6H), 8.6 (t, J ¼ 1.8 Hz, 2.4 Hz, 0.3H), 8.9
(d, J ¼ 2.4 Hz, 0.6H). Elemental analysis calcd. (%) for C11H7N3: C, 72.85;
H, 3.86; N, 23.18; found: C, 72.82; H, 3.85; N, 22.87. MS (APCI):
m/e ¼ 182.0 [M þ H]þ.
3-(4-Methyl(3-pyridyl))acrylonitrile (2d). White solid [E/Z ca. 2.5/1 (1H
NMR)]: mp 70–72 8C. 1H NMR (CD3OD):
d 2.4 (s, 3H), 6.32
(d, J ¼ 16.8Hz, 1H), 7.3 (d, J ¼ 4.2 Hz, 1H), 7.8 (d, J ¼ 16.8Hz, 1H), 8.4
(d, J ¼ 5.4 Hz, 1H), 8.7 (s, 1H), 2.3 (s, 1.2H), 5.9 (d, J ¼ 12.0Hz, 0.4H), 7.4
(d, J ¼ 5.4 Hz, 0.4H), 7.6 (d, J ¼ 12.0Hz, 0.4H), 8.4 (d, J ¼ 5.4 Hz, 0.4H),
8.8 (s, 0.4H). Elemental analysis calcd. (%) for C9H8N2: C, 74.95; H, 5.55;
N, 19.43; found: C, 74.60; H, 5.32; N, 19.44. MS: m/e ¼ 145.2 [M þ H]þ.
1
Recrystallized with petroleum ether gave pure E-isomer: mp 102–1048C. H
NMR (CD3OD): d 2.4 (s, 3H), 6.3 (d, J ¼ 16.8Hz, 1H), 7.3 (d, J ¼ 4.2 Hz,
1H), 7.8 (d, J ¼ 16.8Hz, 1H), 8.4 (d, J ¼ 5.4 Hz, 1H), 8.7 (s, 1H).
3-(6-Methoxy(3-pyridyl))acrylonitrile (2e). White solid [E/Z ca. 4/1 (1H
NMR)]: mp 78–80 8C. 1H NMR (CDCl3):
d 3.9 (s, 3 H), 5.7
(d, J ¼ 16.6 Hz, 1H), 6.7 (d, J ¼ 9.0 Hz, 1H), 7.3 (d, J ¼ 16.6 Hz, 1H), 7.7
(dd, J ¼ 9.0, 2.4 Hz, 1H), 8.2 (d, 2.4 Hz, 1H); 4.0 (s, 0.75H), 5.4
(d, J ¼ 12.3 Hz, 0.25H), 6.8 (d, J ¼ 8.7 Hz, 0.25H), 7.0 (d, J ¼ 12.3 Hz,
0.25H), 7.2 (m, 0.25H), 8.3 (m, 0.25H). Elemental analysis calcd. (%) for
C9H8N2O: C, 67.49; H, 5.03; N, 17.49; found: C, 67.14; H, 4.95; N, 17.07.
MS (APCI): m/e ¼ 161.1 [M þ H]þ. Recrystallized with petroleum ether
1
gave pure E-isomer: mp 106–108 8C. H NMR (CDCl3): d 3.9 (s, 3H), 5.7
(d, J ¼ 16.6 Hz, 1H), 6.7 (d, J ¼ 9.0 Hz, 1H), 7.3 (d, J ¼ 16.6 Hz, 1H), 7.7
(dd, J ¼ 9.0, 2.4 Hz, 1H), 8.2 (d, 2.4 Hz, 1H).
5-(2-Cyanovinyl)pyridine-2-carbonitrile (2f). Pale yellow solid [E/Z ca. 2/1
(1H NMR)]: mp 145–147 8C. 1H NMR (CD3OD): d 6.5 (d, J ¼ 16.8Hz, 1H),
7.6 (d, J ¼ 16.8Hz, 1H), 7.8 (d, J ¼ 8.4 Hz, 1H), 8.2 (dd, J ¼ 8.4, 2.1 Hz,
1H), 8.7 (d, J ¼ 2.1 Hz, 1H); 6.0 (d, J ¼ 12.3Hz, 0.5H), 7.4 (d, J ¼ 12.3Hz,
0.5H), 7.9 (d, J ¼ 8.4 Hz, 0.5H), 8.4 (dd, J ¼ 8.4, 2.4 Hz, 0.5H), 8.9
(d, J ¼ 2.1 Hz, 0.5H). Elemental analysis calcd. (%) for C9H5N3: C, 69.67;
H, 3.25; N, 27.08; found: C, 69.58; H, 3.35; N, 26.79.
Methyl 5-(2-cyanovinyl)pyridine-3-carboxylate (2 g). White solid [E/Z ca.
1
2/1 (1H NMR)]: mp 130–133 8C. H NMR (CDCl3): d 3.9 (s, 3H), 6.5 (d,
J ¼ 16.5 Hz, 1H), 7.6 (d, J ¼ 16.5 Hz, 1H), 8.6 (m, 1H), 8.9 (d, J ¼ 2.1 Hz,
1H), 9.1 (d, J ¼ 2.1 Hz, 1H), 4.0 (s, 1.5H), 5.9 (d, J ¼ 12.3 Hz, 0.5H), 7.4
(d, J ¼ 12.3 Hz, 0.5H), 8.8 (m, 0.5H), 9.0 (d, J ¼ 2.1 Hz, 0.5H), 9.1
(d, J ¼ 1.5 Hz, 0.5H). Elemental analysis calcd. (%) for C10H8N2O2: C,

Pyridylacrylonitriles Synthesis via Heck Reaction
2531
63.80; H, 4.25; N, 14.88; found: C, 63.98; H, 4.35; N, 14.70. MS (APCI): m/
e ¼ 189.1 [M þ H]þ.
ACKNOWLEDGMENT
We are grateful for the financial support from Sundia Meditech Company Ltd.,
Shanghai, China, and technical advice from its scientific staff.
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