Efficient nucleophilic substitution reactions of pyrimidyl and pyrazyl halides with nucleophiles under focused microwave irradiation

Article abstract of DOI:10.1016/S0040-4020(01)01182-6

Rapid nucleophilic displacement reactions of 2-chloropyrimidine, 2-bromopyrimidine, 5-bromopyrimidine and chloropyrazine with nucleophiles under microwave irradiation was complete within several minutes with yields up to 99%. The method using microwave irradiation is superior to the classical heating processes.

Full text of DOI:10.1016/S0040-4020(01)01182-6

TETRAHEDRON
Pergamon
Tetrahedron 58 ꢀ2002) 887±890
Ef®cient nucleophilic substitution reactions of pyrimidyl
and pyrazyl halides with nucleophiles under focused
microwave irradiation
p
Yie-Jia Cherng
Department of Medical Technology, Chung-Tai Institute of Health Science and Technology, Taichung 40605, Taiwan, ROC
Received 12 October 2001; accepted 26 November 2001
AbstractÐRapid nucleophilic displacement reactions of2-chloropyrimidine, 2-bromopyrimidine, 5-bromopyrimidine and chloropyrazine
with nucleophiles under microwave irradiation was complete within several minutes with yields up to 99%. The method using microwave
irradiation is superior to the classical heating processes. q 2002 Elsevier Science Ltd. All rights reserved.
1
. Introduction
6-methylthiopyrimidine was found in these reactions.
Among various solvents, N-methylpyrrolidone ꢀNMP) was
the solvent ofchoice of r such nucleophilic substitution
reactions. The reactions in NMP tended to give higher yields
than those conducted in HMPA, DMSO or DMF. However,
it is noted in our previous report that the nucleophilic substi-
tution reactions ofquinolyl halides are best per of rmed in
HMPA. As a comparison ꢀentry 2, Table 1), 5-bromo-
pyrimidine was heated with 2 equiv. ofPhSNa at 100 8C in
NMP in an oil bath for 40 s to give only 7% yield of
5-phenylthiopyrimidine, far less than 96% in microwave
irradiation ꢀentry 1, Table 1). As the weaker nucleophile
ofPhONa was used, the reaction required longer time
ꢀ100±600 s) and afforded only low yields ꢀ20±49%) of
the desired product ꢀentries 10±12, Table 1). The reactions
with nitrogen-containing nucleophiles ꢀe.g. benzylamine,
piperidine) failed to give any appreciable quantities of the
desired substitution products.
Pyrimidines and pyrazines are important heterocyclic
compounds. Several derivatives ofthis class ofproducts
are well-known as biologically active compounds:
-ꢀbenzylamino)pyrimidine is an antihistaminic agent,
-ꢀ1H-imidazol-1-yl)pyrimidine and 2-ꢀ1H-pyrazol-1-
yl)pyrimidine have antiucler activity, and some pyrazine
derivatives have been reported to act as analeptics and anti-
pellagric agents. This class ofderivatives are generally
prepared by direct displacement reactions ofpyrimidyl or
pyrazyl halides with nucleophiles via the classical heating
processes, which often require long reaction times and result
in low yields as that found in most of nucleophilic aromatic
substitution reactions. The application ofmicrowaves in
promoting organic reactions has received intense attention
1
2
2
2
3
4
recently. We have previously developed an auxiliary
method with microwave irradiation for acceleration of
5
nucleophilic aromatic substitution reactions. We report
herein an extension ofthis methodology to pyrimidyl and
pyrazyl systems.
One might expect that 2-bromopyrimidine was more
reactive than 5-bromopyrimidine. The results for the
nucleophilic substitution reactions of2-chloropyrimidine
and 2-bromopyrimidine were listed in Table 2. The reaction
of2-chloropyrimidine with PhSNa a off rded 97% yield of
the desired product under microwave irradiation for 30±35 s
in either NMP or HMPA ꢀentries 1 and 2, Table 2). The
reactions with MeSNa, EtONa, and PhONa also proceeded
smoothly under microwave irradiation in NMP, HMPA or
DMSO ꢀentries 39, Table 2). Furthermore, the substitution
reactions of2-chloropyrimidine with nitrogen-containing
nucleophiles were realized by microwave irradiation with-
out using solvent ꢀentries 10, 11 and 13±15, Table 2). The
reactions could be conducted in homogeneous condition
when aniline, benzylamine and piperidine were utilized as
the nucleophiles, or in solid phase when imidazole, pyrazole
and benzotriazole were used as the nucleophiles. The
2
. Results and discussion
We ®rst investigated the nucleophilic reactions of5-bromo-
pyrimidine. When 5-bromopyrimidine was treated with
PhSNa or MeSNa under irradiation in a monomode micro-
wave reactor, high yields of5-phenylthiopyrimidine and
5-methylthiopyrimidine were procured in less than one
minute ꢀTable 1). No isomeric 6-phenylthiopyrimidine or
Keywords: microwave irradiation; nucleophilic substitution; halopyrimi-
dines; chloropyrazine.
p
Tel.: 1886-4-22391647; fax: 1886-4-22393305;
e-mail: yjcherng@chtai.ctc.edu.tw
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020ꢀ01)01182-6

888
Y.-J. Cherng / Tetrahedron 58 *2002) 887±890
Table 1. Reactions of5-bromopyrimidine with nucleophiles
Entry
Nucleophile
Solvent
Molar
proportions
of
Temp ꢀ8C)
Time ꢀs)
Product, Rˆ
Yield ꢀ%)
nucleophile
1
2
3
4
5
6
7
8
9
PhSNa
PhSNa
PhSNa
PhSNa
PhSNa
PhSNa
MeSNa
MeSNa
MeSNa
PhONa
PhONa
PhONa
NMP
NMP
NMP
HMPA
DMSO
DMF
2.0
2.0
2.0
2.0
2.0
2.0
1.8
1.8
1.8
2.5
1.5
1.5
100
100
90
90
90
40
40
40
40
40
40
60
60
SPh
SPh
SPh
SPh
SPh
SPh
SMe
SMe
SMe
OPh
OPh
OPh
96
7
a
86
82
82
76
88
77
70
23
49
20
90
NMP
100
100
100
110
110
110
HMPA
DMSO
NMP
HMPA
DMSO
60
1
1
1
0
1
2
600
150
100
a
Heating in oil bath.
substitution reaction of2-chloropyrimidine with piperidine
occurred readily without using heating or microwave
irradiation.
ꢀEtONa and PhONa) than 2-bromopyrimidine ꢀcompared
entries 5 with 18, and entries 7 with 19 in Table 2).
However, 2-bromopyrimidine was more reactive toward
amine nucleophiles ꢀaniline, benzylamine, piperidine,
imidazole, pyrazole and benzotriazole) than 2-chloro-
pyrimidine ꢀcompared entries 21 with 10, 22 with 11, 24
with 13, 26 with 14, and 27 with 15 in Table 2). To account
for the sharp contrast reactivities of 2-halopyrimidines, the
The nucleophilic substitution reactions of2-bromopyrimi-
dine were similarly carried out ꢀentries 16±27, Table 2). Of
the two 2-halogenopyrimidines studied, 2-chloropyrimidine
was more reactive towards the alkoxide nucleophiles
Table 2. Reactions of2-halopyrimidines with nucleophiles
Entry
X
Nucleophile
Solvent
Molar
proportions
of
Temperature ꢀ8C)
Time ꢀs)
Product, Rˆ
Yield ꢀ%)
nucleophile
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
PhSNa
PhSNa
MeSNa
MeSNa
EtONa
EtONa
PhONa
PhONa
PhONa
NMP
HMPA
NMP
HMPA
NMP
HMPA
NMP
HMPA
2.0
2.0
1.5
1.5
1.8
1.5
1.5
1.5
1.5
3.0
4.0
4.0
3.0
3.0
1.0
2.0
1.7
3.0
2.0
1.5
4.0
4.0
4.0
3.0
3.0
3.0
1.0
85
85
70
70
90
90
100
100
100
120
100
25
120
110
120
85
35
30
35
30
40
35
40
35
40
840
SPh
SPh
SMe
SMe
OEt
97
97
90
73
82
69
73
83
88
40
91
96
62
67
76
95
74
34
54
66
55
97
96
88
39
75
76
OEt
OPh
OPh
OPh
NHPh
NHCH
Piperidyl
Imidazolyl
Pyrazolyl
Benzotriazol-1-yl
SPh
SMe
OEt
OPh
OPh
NHPh
NHCH Ph
2
DMSO
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
NH
NH
2
Ph
a
a
a
a
a
CH Ph
2 2
360
2
Ph
b
Piperidine
Imidazole
Pyrazole
Benzotriazole
PhSNa
MeSNa
EtONa
PhONa
PhONa
1020
1200
870
35
50
60
NMP
NMP
NMP
NMP
95
100
110
110
110
100
25
110
110
110
90
50
60
DMSO
a
PhNH
PhCH
2
180
90
a
a
a
2
NH
2
b
Piperidine
Imidazole
Imidazole
Pyrazole
Piperidyl
900
900
600
120
Imidazolyl
Imidazolyl
Pyrazolyl
NMP
a
a
Benzotriazole
Benzotriazol-1-yl
a
No solvent was used.
The reaction occurred without microwave irradiation.
b

Y.-J. Cherng / Tetrahedron 58 *2002) 887±890
Table 3. Reactions of2-chloropyrazine with nucleophiles
889
Entry
Nucleophile
Solvent
Molar
proportions
of
Temperature ꢀ8C)
Time ꢀs)
Product, Rˆ
Yield ꢀ%)
nucleophiles
1
2
3
4
5
6
7
PhSNa
MeSNa
EtONa
PhONa
PhONa
PhONa
Piperidine
NMP
NMP
NMP
NMP
HMPA
2.0
1.7
1.8
2.0
2.0
2.0
8
80
80
90
100
100
100
110
35
50
45
50
40
50
900
SPh
SMe
OEt
OPh
OPh
OPh
Piperidyl
96
88
68
69
54
62
88
DMSO
a
a
No solvent was used.
rate-determining steps might vary in the S Ar mechanisms
N
the internal standard. Reactions were monitored by analyti-
cal 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.
when different nucelophiles were employed. A charge-
controlled reaction might predominate in the reactions
with charge localized anionic nucelophiles RO. The
chlorine atom with high electronegativity would induce a
6
highly electrophilic center at C-2, and thus facilitate the
substitution reaction with RO. As to aminations with non-
ionic nucleophiles, the bond-breaking process ofCX
appeared to be involved in the rate-determining step. The
substrate with more labile CBr bond would undergo the
substitution reaction with amines more rapidly.
4.1. General procedure for reaction of heteroaromatic
halides with nucleophile
In a quartz reaction vessel ꢀ12 mL) was placed a hetero-
aromatic halide ꢀ0.3 mmol) and a nucleophile in an appro-
priate solvent ꢀ1 mL). The reaction vessel was then placed
into the cavity ofa fo cused monomode microwave reactor
Under microwave irradiation, chloropyrazine also reacted
with the nucleophiles ofPhSNa, MeSNa, EtONa and
PhONa in NMP to afford 69±96% yields of the substituted
pyrazines ꢀTable 3). The reactions could also be conducted
in HMPA or DMSO, albeit in lower yields ꢀentries 5 and 6,
Table 3). Chloropyrazine was less reactive than 2-chloro-
pyrimidine toward nitrogen-containing nucleophiles. Only
the reaction with piperidine gave the desired substitution
product in a good yield of88% ꢀentry 7, Table 3).
ꢀSynthewave 402) and irradiated for the period listed in the
tables. The reaction temperature was kept by modulating the
power level ofthe reactor. The crude reaction mixture was
then absorbed directly onto silica gel, and puri®ed by silica
gel chromatography eluting with a mixture ofhexane and
ethyl acetate.
7
.1.1. 5-Phenylthiopyrimidine. Yellow oil, H NMR
1
4
ꢀ400 MHz) d 9.03 ꢀs, 1H), 8.59 ꢀs, 2H), 7.46±7.37 ꢀm, 5H).
3. Conclusion
8
.1.2. 5-Methylthiopyrimidine. Yellow oil, H NMR
400 MHz) d 9.00 ꢀs, 1H), 8.62 ꢀs, 2H), 2.55 ꢀs, 3H).
1
4
ꢀ
Our present study indicated that chloro- and bromopyrimi-
dines and chloropyrazine are suf®ciently reactive under
microwave irradiation. An ef®cient method for the synthesis
ofethers, thioethers and amines ofpyrimidines and
pyrazines is thus devised. Ofparamount importance, the
nucleophilic substitution reactions with imidazole, pyrazole
and benzotriazole were achieved in solid phase by micro-
wave irradiation. This ®nding is signi®cant as it is an
environmental benign process. From a comparison ofthe
results listed in Tables 1±3, one can deduce the relative
aptitude for the nucleophilic substitution reactions:
1
4
ꢀ
.1.3. 5-Phenoxypyrimidine. Yellow oil,
H NMR
400 MHz) d 8.98 ꢀs, 1H), 8.49 ꢀs, 2H), 7.44±7.06 ꢀm,
13
H); C NMR ꢀ100 MHz) d 155.12, 153.02, 152.34,
5
1
2
46.85, 130.30, 125.02, 119.10; IR ꢀCHCl ): 2956, 2924,
3
2
853, 1498, 1407, 1256 cm ; MS m/e 172 ꢀM ), 77;
1
1
HRMS m/e calcd for C H N O 172.0637, found 172.0631.
8
10
2
7
1
.1.4. 2-Phenylthiopyrimidine. Colorless oil, H NMR
4
ꢀ
7
400 MHz) d 8.49 ꢀd, Jˆ4.8 Hz, 2H), 7.65±7.63 ꢀm, 2H),
2
-halopyrimidine.chloropyrazine,5-bromopyrimidine. In
.46±7.63 ꢀm, 3H), 6.97 ꢀt, Jˆ4.8 Hz, 1H).
9
.1.5. 2-Methylthiopyrimidine. Colorless oil, H NMR
general, microwave irradiation surpasses the conventional
heating process in the nucleophilic aromatic substitution
reactions to enhance the yield and reaction rate.
1
4
ꢀ
400 MHz) d 8.53 ꢀd, Jˆ4.8 Hz, 2H), 6.70 ꢀt, Jˆ4.8 Hz,
1H). 2.57 ꢀs, 3H).
4
. Experimental
1
.1.6. 2-Ethoxypyrimidine. Colorless oil, H NMR
0
1
4
1
H NMR spectra were measured in deuteriochloroform solu-
tions on a Varian Mercury 400 spectrometer using Me Si as
ꢀ400 MHz) d 8.51 ꢀd, Jˆ4.8 Hz, 2H), 6.92 ꢀt, Jˆ4.8 Hz,
1H). 4.43 ꢀq, Jˆ7.2 Hz, 2H), 1.44 ꢀt, Jˆ7.2 Hz, 3H).
4

890
Y.-J. Cherng / Tetrahedron 58 *2002) 887±890
1
.1.7. 2-Phenoxypyrimidine. Colorless needles, mp
8
1
4
Acknowledgements
1
6±888C ꢀlit. mp 89±918C); H NMR ꢀ400 MHz) d 8.57
ꢀ
3
d, Jˆ4.8 Hz, 2H), 7.46±7.42 ꢀm, 2H), 7.46±7.42 ꢀm,
We thank the ®nancial support ofthe Chung-Tai Institute of
Health Science Technology, and the facility support of
the Department ofChemistry, National Chung-Hsing
University.
H), 7.04 ꢀt, Jˆ4.8 Hz, 1H).
1
2
4
1
8
3
.1.8. 2-Anilinopyrimidine.
Colorless needles, mp
1
10±1128C ꢀlit. mp 112.5±1138C); H NMR ꢀ400 MHz) d
.43 ꢀd, Jˆ4.8 Hz, 2H), 7.63±7.61 ꢀm, 2H), 7.37±7.26 ꢀm,
H), 7.08±7.04 ꢀm, 1H), 6.72 ꢀt, Jˆ4.8 Hz, 1H).
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4
7
ꢀ
1
.1.9. 2-,Benzylamino)pyrimidline. White solid, mp
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2
3
4
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1
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4
1
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1
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4
4
1
mp 160±1628C ꢀlit. mp 164±1658C); H NMR ꢀ400 MHz)
d 8.96 ꢀd, Jˆ4.8 Hz, 2H), 8.61 ꢀd, Jˆ8.4 Hz, 1H), 8.18 ꢀd,
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400 MHz) d 8.35 ꢀdd, Jˆ2.8, 1.6 Hz, 1H), 8.24 ꢀd,
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6
4
4
ꢀ
.1.15. Methylthiopyrazine.
1±438C ꢀlit. mp 42±468C); H NMR ꢀ400 MHz) d 8.47
Colorless needles, mp
1
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9
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1
Jˆ2.8 Hz, 1H), 2.57 ꢀs, 3H).
1
3
.1.16. Ethoxypyrazine. Colorless oil,
1
4
H
NMR
1
2. Takeuchi, H.; Watanabe, K. J. Phys. Org. Chem. 1998, 11,
78.
ꢀ
ꢀ
400 MHz) d 8.21 ꢀs, 1H), 8.10 ꢀd, Jˆ2.4 Hz, 1H), 8. 07
4
d, Jˆ2.4 Hz, 1H) 4.39 ꢀq, Jˆ7.2 Hz, 2H), 1.43 ꢀt,
1
1
3. Chapman, N. B.; Rees, C. W. J. Chem. Soc. 1954, 1190.
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Jˆ7.2 Hz, 3H).
1
7
4
5
ꢀ
.1.17. Phenoxypyrazine.
0±518C ꢀlit. mp 50±528C); H NMR ꢀ400 MHz) d 8.43
Colorless needles, mp
1
15. Anne, L.; Alain, T.; Nelly, P.; Guy, Q. Tetrahedron 2000, 56,
709.
3
d, Jˆ1.2 Hz, 1H), 8.27 ꢀd, Jˆ2.8 Hz, 1H), 8.12 ꢀdd,
1
6. Lee, D. H.; Kim, D. H. Xenobiotica 2000, 29, 909.
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74, 3617.
Jˆ2.8, 1.2 Hz, 1H), 7.46±7.16 ꢀm, 5H).
1
1
.1.18. Piperidylpyrazine. Yellow solid, mp 34±358C
8
4
ꢀ
1
lit. mp 36±378C); H NMR ꢀ400 MHz) d 8.13 ꢀd,
1
8. Klein, B.; O'Donnell, E.; Auerbach, J. J. Org. Chem. 1967, 32,
412.
Jˆ1.2 Hz, 1H), 8.04 ꢀdd, Jˆ2.4, 1.2 Hz, 1H), 7.77 ꢀd,
2
Jˆ1.2 Hz, 1H), 3.59±3.57 ꢀm, 4H), 1.70±1.63 ꢀm, 6H).