Synthesis of substituted pyridines by the reactions of halopyridines with sulfur, oxygen and carbon nucleophiles under focused microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(02)00424-6

The nucleophilic substitution reactions of halopyridines with sulfur, oxygen and carbon nucleophiles under microwave irradiation was complete within several minutes with yields up to 99%. The method using microwave irradiation is superior to those conducted under conventional heating processes.

Full text of DOI:10.1016/S0040-4020(02)00424-6

TETRAHEDRON
Pergamon
Tetrahedron 58 -2002) 4931±4935
Synthesis of substituted pyridines by the reactions of
halopyridines with sulfur, oxygen and carbon nucleophiles under
focused microwave irradiation
Yie-Jia Cherngp
Department of Medical Technology, Chung-Tai Institute of Health Science and Technology, Taichung 40605, Taiwan
Received 6 February 2002; revised 20 March 2002; accepted 11 April 2002
AbstractÐThe nucleophilic substitution reactions of halopyridines with sulfur, oxygen and carbon nucleophiles under microwave irradia-
tion was complete within several minutes with yields up to 99%. The method using microwave irradiation is superior to those conducted
under conventional heating processes. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
HMPA or NMP -N-methylpyrrolidone) at about 1008C for a
short period -0.5±3 min) afforded a quantitative yield of
2-phenylthiopyridine. Although substitution with benzyl
alcohol was achieved in NMP to provide an 81% of
2-benzloxypyridine, the reaction with PhONa in NMP was
less ef®cient to give only 36% yield of 2-phenoxypyridine.
The yield was improved to 77 and 84% by using DMSO and
HMPA as the solvents.
Extensive efforts have been exerted on developing method-
ology for the synthesis of pyridine derivatives, which are
often found in natural products and pharmaceuticals -such
as phenoxypyridines which are anticholinergic agents).1 For
example, Hunt has reported the synthesis and the pharma-
cological effects of pyridine onium derivatives.2 However,
introduction of substituents to pyridine rings often requires
long reaction times and vigorous conditions to achieve
acceptable yields under conventional heating or photolysis
conditions.3 Along with the application of microwaves in
promoting organic reactions,4 we have found that the
reaction time of nucleophilic aromatic substitution drama-
tically decreases by using microwave heating.5 We report
herein that microwave heating also provides a convenient
and ef®cient way to the synthesis of substituted pyridines.
The nucleophilic displacement reactions of 2-bromopyri-
dine, 2-chloropyridine and 2-¯uoropyridine were similarly
carried out -Table 1, entries 11±40). Of the four halo-
pyridines studied, the relative reactivity of 2-halopyridines
toward sulfur nucleophiles -PhSNa and MeSNa) in HMPA
appeared to decrease in the order of I.Br.Cl.F
-compared entries 1, 11, 24 with 33, and 3, 15, 26 with 34
in Table 1). In the series of four halogens, polarizability
increases steadily from ¯uorine to iodine. As iodide ion is
the best leaving group than other halides, the trend of
2-halogenpyridines toward sulfur nucleophiles is predict-
able. The results suggested that the second step of the
nucleophilic aromatic substitution -SNAr) is rate-determin-
ing because ¯uoride is the poorest leaving group. In
contrast, 2-halopyridines reacted with the oxygen nucleo-
phile -PhCH2OH) in NMP followed the reactivity of
F.Cl.Br.I -compared entries 5, 17, 28 with 36 in
Table 1). The rate-determining steps might vary in the
SNAr mechanism when different nucleophiles are employed.
A charge-controlled reaction might occur with a charge-
localized nucleophile such as PhCH2OH. The ¯uorine
atom with the highest electronegativity would induce a
highly electrophilic center at C-2,3a and thus ¯uorine is
displaced by PhCH2OH considerably faster than Cl, Br
and I. The reactions of the four 2-halopyridines toward the
carbon nucleophile -PhCH2CN) showed no substantial
difference in reactivity -entries 9, 21, 32 and 40 in Table 1).
2. Results and discussion
A detailed study of the reactions of halopyridines with
nucleophiles in various amounts, reaction times, tempera-
tures and solvents was investigated in order to ®nd the opti-
mized conditions for the preparation of pyridine derivatives
-Tables 1±3). When 2-iodopyridine was treated with the
sulfur, oxygen and carbon nucleophiles -PhSNa, MeSNa,
PhCH2OH, PhONa and PhCH2CN) under irradiation in a
monomode microwave reactor, the corresponding 2-substi-
tuted pyridines were obtained in 36±99% yields -Table 1,
entries 1±10). The reaction with PhSNa -2 equiv.) in either
Keywords: microwave irradiation; nucleophilic heteroaromatic substitu-
tion; halopyridines.
Tel.: 1886-4-22391647 ext. 7006; fax: 1886-4-22393305;
e-mail: yjcherng@chtai.ctc.edu.tw
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020-02)00424-6

4932
Y.-J. Cherng / Tetrahedron 58 (2002) 4931±4935
Table 1. Reactions of 2-halopyridine with nucleophiles
Entry
X
Nucleophile
Solvent
Molar
proportions
of
Temp. -8C)
Time -sec)
Product, Rˆ
Yield -%)
nucleophile
1
2
3
4
5
6
7
8
I
I
I
I
I
I
I
I
PhSNa
PhSNa
MeSNa
MeSNa
PhCH2OH
PhONa
PhONa
PhONa
PhCH2CN
PhCH2CN
PhSNa
PhSNa
PhSNa
PhSNa
MeSNa
MeSNa
PhCH2OH
PhONa
PhONa
PhONa
PhCH2CN
PhCH2CN
PhCH2CN
PhSNa
HMPA
NMP
HMPA
NMP
NMP
2.0
2.0
1.5
2.0
2.0
3.0
3.0
4.0
4.0
3.0
2.0
2.0
2.0
2.5
1.5
2.0
2.0
3.0
3.0
4.0
4.0
3.0
3.0
2.0
4.0
1.5
2.0
2.0
3.0
3.0
3.0
4.0
2.0
1.5
2.0
2.0
3.0
2.0
3.0
4.0
100
110
80
30
180
30
40
60
120
120
180
60
60
40
40
40
420
40
45
60
120
120
180
60
60
60
60
600
40
45
60
120
120
300
60
90
60
60
60
210
45
SPh
SPh
SMe
SMe
OCH2Ph
OPh
OPh
99
99
67
74
81
36
84
77
68
59
97
N.R.a
97b
91
60
74
91
43
67
64
73
70
56
91
53
50
54
93
4
90
100
110
110
120
110
110
110
110
110
110
90
NMP
HMPA
DMSO
NMP
HMPA
HMPA
HMPA
HMPA
NMP
OPh
9
I
I
CH-CN)Ph
CH-CN)Ph
SPh
SPh
SPh
SPh
SMe
SMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
HMPA
NMP
NMP
90
100
110
110
120
110
110
110
110
120
90
OCH2Ph
OPh
OPh
NMP
HMPA
DMSO
NMP
HMPA
DMSO
HMPA
NMP
HMPA
NMP
NMP
OPh
CH-CN)Ph
CH-CN)Ph
CH-CN)Ph
SPh
SPh
SMe
PhSNa
MeSNa
MeSNa
PhCH2OH
PhONa
PhONa
PhONa
PhCH2CN
PhSNa
MeSNa
MeSNa
PhCH2OH
PhONa
90
SMe
100
110
110
120
110
110
90
OCH2Ph
OPh
OPh
NMP
HMPA
DMSO
NMP
HMPA
HMPA
NMP
NMP
NMP
HMPA
DMSO
NMP
45
38
68
68
41
72
95
56
74
72
67
OPh
CH-CN)Ph
SPh
SMe
F
F
F
F
F
F
F
90
SMe
100
110
110
110
110
OCH2Ph
OPh
OPh
OPh
CH-CN)Ph
PhONa
PhONa
PhCH2CN
60
60
a
Heating in an oil bath. N.R. represents no reaction.
Benzoquinone -10 mol%) was added to the reaction.
b
In principle, these reactions might proceed with either SNAr
or SRN1 mechanisms. In an attempted inhibition experiment
using 10 mol% of benzoquinone as a radical scavenger, the
yield for the substitution reaction of 2-bromopyridine with
sodium thiophenoxide remained practically unchanged
It is well known that 3-halopyridines are less reactive than
2-halopyridines in nucleophilic reactions.7 High yields -97±
99%) of 3-phenylthiopyridine were still attainable by micro-
wave irradiation of 3-iodopyridine or 3-bromopyridine with
PhSNa in HMPA for 1±2.5 min -entries 1 and 6 in Table 2).
On the other hand, the reaction of 3-¯uoropyridine with
PhCH2OH afforded 3-benzyloxypyridine in the yield up to
88% -entries 16±18, Table 2). The dipolar solvent HMPA
might facilitate the substitution reactions. The yield
-0±58%) decreased dramatically by using 3-iodopyridine,
3-bromopyridine or 3-chloropyridine -entries 4, 8 and 12,
Table 2). The reactivity of 3-halopyridines toward the
nucleophile PhCH2CN also followed F.Cl.Br.I
-compared entries 5, 9, 13 with 19 in Table 2). Upon micro-
wave irradiation, 2-phenyl-2--3-pyridyl)acetonitrile was
prepared in 69% yield from 3-¯uoropyridine and phenyl-
-entry 13, Table 1). The result indicated that the SRN
mechanism did not operate.
1
In order to compare the ef®cacy of microwave irradiation
with conventional heating, a HMPA solution of 2-bromo-
pyridine and PhSNa -2 equiv.) was heated at 1108C in an oil
bath for 40 s. No product of 2-phenylthiopyridine was
found -entry 12, Table 1). Thus, the high yields in
substitution reactions of 2-bromopyridine might be attribut-
able to the microwave effect in addition to heating
ef®ciency.6

Y.-J. Cherng / Tetrahedron 58 (2002) 4931±4935
Table 2. Reactions of 3-halopyridine with nucleophiles
4933
Entry
X
Nucleophile
Solvent
Molar
proportions
of
Temperature -8C)
Time -min)
Product, Rˆ
Yield -%)
nucleophile
1
2
3
4
5
6
7
8
I
I
I
I
PhSNa
PhSNa
MeSNa
PhCH2OH
PhCH2CN
PhSNa
HMPA
NMP
NMP
NMP
NMP
HMPA
NMP
NMP
2.0
4.0
3.0
5.0
5.0
2.0
3.0
5.0
5.0
2.0
3.0
5.0
5.0
2.0
3.0
5.0
4.0
4.0
5.0
5.0
110
120
100
110
110
110
90
110
110
110
100
120
110
110
100
110
100
100
100
100
1
10
2.5
10
10
2.5
2.5
5
10
10
2.5
3
1.5
3.5
2.5
3
2
2
SPh
SPh
SMe
OCH2Ph
CH-CN)Ph
SPh
99
77
55
0
I
0
Br
Br
Br
Br
Cl
Cl
Cl
Cl
F
F
F
F
F
97
70
17
6
MeSNa
SMe
PhCH2OH
PhCH2CN
PhSNa
OCH2Ph
CH-CN)Ph
SPh
9
NMP
10
11
12
13
14
15
16
17
18
19
20
HMPA
NMP
NMP
63
45
58
30
68
70
70
88
65
69
48
MeSNa
SMe
PhCH2OH
PhCH2CN
PhSNa
OCH2Ph
CH-CN)Ph
SPh
NMP
HMPA
NMP
NMP
HMPA
DMSO
NMP
MeSNa
SMe
PhCH2OH
PhCH2OH
PhCH2OH
PhCH2CN
PhCH2CN
OCH2Ph
OCH2Ph
OCH2Ph
CH-CN)Ph
CH-CN)Ph
F
F
2
1.5
HMPA
Table 3. Reactions of 4-iodopyridine with nucleophiles
Entry
Nucleophile
Solvent
Molar
Temperature -8C)
Time -sec)
Product, Rˆ
Yield -%)
proportions
of
nucleophile
1
2
3
4
5
6
7
8
PhSNa
MeSNa
PhCH2OH
PhCH2OH
PhCH2OH
PhONa
NMP
NMP
NMP
HMPA
DMSO
NMP
2.5
2.0
3.0
4.0
2.0
5.0
5.0
5.0
110
100
110
110
110
120
120
120
180
40
SPh
SMe
OCH2Ph
OCH2Ph
OCH2Ph
OPh
99
73
30
32
28
42
60
57
120
120
120
900
360
600
PhONa
PhONa
HMPA
DMSO
OPh
OPh
acetonitrile in NMP -entry 19, Table 2). The substitution
reactions of 3-halopyridines occurred in a regioselective
manner. The reaction is not likely to proceed with pyridyne
intermediates as no 2- or 4-substituted pyridine products
were found.
dine.3-halopyridine. This method is especially important
for the preparation of 3-pyridyl ethers, thioethers and aceto-
nitriles, because these substrates are not readily accessible
by the conventional procedures.8
Under microwave irradiation, 4-iodopyridine also reacted
with PhSNa, MeSNa, PhCH2OH, PhONa and PhCH2CN
to give the corresponding 4-substituted pyridines in varied
yields -28±99%, Table 3). The results indicated that the
chemical behavior of 2- and 4-iodopyridines were similar.
3. Experimental
1H NMR spectra were measured in CDCl3 solutions on a
Varian Mercury 400 spectrometer using Me4Si as the
internal standard. Reactions were monitored by analytical
thin-layer chromatography using silica gel 60 F-254
-0.2 mm layer thickness). Flash chromatography was
carried out by utilizing silica gel 60 -70±230 mesh
ASTM). The Synthewave 402e monomode microwave
reactor was purchased from Prolabo Co.
In conclusion, ef®cient nucleophilic substitution reactions
of 2-, 3- and 4-halopyridines are realized by using micro-
wave irradiation. These reactions probably proceed via an
SNAr mechanism. The relative reactivity of halopyridines in
substitutition reactions follows 2-halopyridine.4-halopyri-

4934
Y.-J. Cherng / Tetrahedron 58 (2002) 4931±4935
3.1. General procedure for reaction of halopyridines
with nucleophile
3.1.12. 4-Phenoxypyridine.7b Colorless crystals, mp 42±
438C -lit. 44±458C); 1H NMR -400 MHz) d 8.46 -d,
Jˆ5.8 Hz, 2H), 7.45±7.09 -m, 5H), 6.84 -d, Jˆ5.8 Hz, 2H).
3.1.13. 4-Benzyloxypyridine.11 Colorless crystals, mp 50±
518C -lit. 55±568C); 1H NMR -400 MHz) d 8.49 -d,
Jˆ4.8 Hz, 2H), 7.41±7.36 -m, 5H), 6.92 -d, Jˆ4.8 Hz,
2H), 5.13 -s, 2H).
In a quartz reaction vessel -12 mL) were placed a nucleo-
phile and a halopyridine -0.3 mmol) in an appropriate
solvent -1 mL). t-BuOK -1.1 equiv. vs nucleophile) could
be added as the base if needed. The reaction vessel was then
placed into the cavity of a focused monomode microwave
reactor -Synthewave 402) and irradiated for the period listed
in the tables. The reaction temperature was maintained by
modulating the power level of the reactor. The crude reac-
tion mixture was then absorbed directly onto silica gel, and
puri®ed by silica gel chromatography eluting with a mixture
of hexane and ethyl acetate.
Acknowledgements
The author thanks the ®nancial support of the Chung-Tai
Institute of Health Science Technology, and the facility
support of the Department of Chemistry, National Chung-
Hsing University.
3.1.1. 2-Phenylthiopyridine.3d Yellow oil, 1H NMR
-400 MHz) d 8.43 -d, Jˆ4.8 Hz, 1H), 7.62±7.59 -m, 2H),
7.48±7.42 -m, 4H), 7.00 -m, 1H), 8.00 -d, Jˆ8.0 Hz, 1H).
3.1.2. 2-Methylthiopyridine.3d Yellow oil, 1H NMR
-400 MHz) d 8.44 -d, Jˆ4.0 Hz, 1H), 8.49 -m, 1H), 7.19
-d, Jˆ8.0 Hz, 1H), 6.98 -m, 1H), 2.58 -s, 3H).
3.1.3. 2-Phenoxypyridine.3a Colorless crystals, mp 40±
418C -lit. 42±448C); 1H NMR -400 MHz) d 8.21 -d,
Jˆ4.8 Hz, 1H), 7.68 -m, 1H), 7.43±7.14 -m, 5H), 6.99
-m, 1H), 7.90 -d, Jˆ8.4 Hz, 1H).
3.1.4. 2-Benzyloxypyridine.3e Yellow oil, 1H NMR
-400 MHz) d 8.17 -dd, Jˆ5.2, 1.4 Hz, 1H), 7.58 -m, 1H),
7.47±7.31 -m, 5H), 6.88 -m, 1H), 6.80 -d, Jˆ8.4 Hz, 1H),
5.37 -s, 2H).
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1
d 8.61 -d, Jˆ4.8 Hz, 1H), 7.71 -m, 1H), 7.46±7.33 -m, 5H),
7.27±7.26 -m, 2H), 5.11 -s, 1H).
3.1.6. 3-Phenylthiopyridine.3c Yellow oil, 1H NMR
-400 MHz) d 8.55 -d, Jˆ1.6 Hz, 1H), 8.46 -dd, Jˆ4.8,
1.6 Hz, 1H) 7.60 -ddd, Jˆ8.0, 1.8, 1.6 Hz, 1H), 7.40±7.31
-m, 5H), 7.22 -dd, Jˆ8.0, 4.8 Hz, 1H).
3.1.7. 3-Methylthiopyridine.3d Yellow oil, 1H NMR
-400 MHz) d 8.51 -d, Jˆ2.4 Hz, 1H), 8.38 -d, Jˆ4.8, 1H),
7.58 -m, 1H), 7.23 -dd, Jˆ8.0, 4.8 Hz, 1H), 2.51 -s, 3H).
3.1.8. 3-Benzyloxypyridine.8a Yellow oil, 1H NMR
-400 MHz) d 8.39 -d, Jˆ2.4 Hz, 1H), 8.23 -dd, Jˆ4.4,
1.6 Hz, 1H), 7.45±7.32 -m, 5H), 7.25 -dd, Jˆ2.4, 1.6 Hz,
1H), 7.23 -d, Jˆ4.4 Hz, 1H), 5.11 -s, 2H).
3.1.9. 2-Phenyl-2-*3-pyridyl)acetonitrile.10 Colorless
1
needles, mp 60±618C -lit. 63±658C); H NMR -400 MHz)
d 8.64 -s, 1H), 8.61 -d, Jˆ4.0 Hz, 1H), 7.48 -d, Jˆ8.4 Hz,
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7.46 -m, 3H), 6.95 -dd, Jˆ4.8, 1.6 Hz, 2H).
3.1.11. 4-Methylthiopyridine.8a Yellow oil, 1H NMR
-400 MHz) d 8.39 -dd, Jˆ4.8, 1.2 Hz, 2H), 7.10 -dd,
Jˆ4.8, 1.2 Hz, 2H), 2.49 -s, 3H).
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4935
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