Convenient synthesis of 3,5-biscarbamoyl-pyridine derivatives

Article abstract of DOI:10.1002/cjoc.201180367

An efficient and convenient method for synthesis of 3,5-bis-carbamoyl-2,6- dimethylpyridine derivatives was achieved in good to excellent yields by reaction of anilines with 3,5-bis(3',5'-dimethyl-1'-pyrazolyl-carbonyl)-2,6- dimethylpyridine, in which pyr

Full text of DOI:10.1002/cjoc.201180367

FULL PAPER
Convenient Synthesis of 3,5-Biscarbamoyl-pyridine Derivatives
Wang, Xiayuna(汪霞云)
Lu, Donglianga(陆东亮)
Zhu, Yiwena(朱逸雯)
Qian, Quna(钱群)
Zhang, Min*,a(张敏)
Chen, Yalia(陈雅丽)
Cao, Weiguoa,b(曹卫国)
Song, Liping*,a,b(宋力平)
Deng, Hongmeic(邓红梅)
a Department of Chemistry, College of Science, Shanghai University, Shanghai 200444, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
c Instrumental Analysis and Research Center, Shanghai University, Shanghai 200444, China
An efficient and convenient method for synthesis of 3,5-bis-carbamoyl-2,6-dimethylpyridine derivatives was
achieved in good to excellent yields by reaction of anilines with 3,5-bis(3',5'-dimethyl-1'-pyrazolyl-carbonyl)-2,6-
dimethylpyridine, in which pyrazoles served as leaving groups. The structures of products were confirmed by
spectra data and microanalysis.
Keywords heterocycles, amide, aromatic amine, synthesis
Introduction
reaction of 3,5-dialkoxylcarbonyl simultaneously. Con-
sidering the importance of several pyridines bearing
carboxamide fragment in medical chemistry, we are
interested in developing synthetic methods for targeted
compounds. In this work, we report a simple and con-
venient synthesis of these compounds involving the re-
action of anilines with 1-acylated pyrazoles, in which
the pyrazoles acted as leaving groups.
Since the discovery of nifedipine, which is a clinically
important antihypertensive and antiangina drug, much
attention has been paid to the transformations and modi-
fications of substituted 1,4-dihydropyridines.1 However,
to the best of our knowledge, published data on the trans-
formations and modifications of Hantzsch pyridines are
lacking due to the difficulty of modification of 3,5-
dialkoxycarbonyl groups simultaneously.2 Furthermore,
the compounds bearing carboxamide moieties have at-
tracted the attention of organic chemists for quite a long
time. For example, nicotinamide,3 Linomide,4 etc., all of
them contain the carboxamide fragment. In terms of for-
mation of carboxamides promoted by organometallic,
recent elegant work by Buchwald5 and Shakespeare6 has
demonstrated the palladium catalyzed N-arylation of
amides with aryl halides, meanwhile, Hartwig7 has also
reported an analogous N-arylation of carbamates. How-
ever, there has been few report on the preparation of 3,5-
bis[(arylamino)-carbonyl]-2,6-dimethylpyridine. Gener-
ally, the common access to the product consists of two
methods. One involves oxidation of the corresponding
1,4-dihydropyridine derivatives, obtained form one-pot
cyclization reaction of the corresponding acetoacetic
acid amides with hexamethylenetetramine in the pres-
ence of ammonium acetate,8 however, the present
method poses the first problem due to the moderate
yields of the prerequisite intermediates. The alternative
way involves the modifications of alkoxycarbonyl
groups at 3,5-position of pyridine,2 however, no present
work has been reported concerning the modification
Results and discussion
To begin with our studies, we firstly investigated the
direct methods for preparation of target products. For
example, we have carried out the reaction of 2,6-
dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester (1)
with an excess of aniline9 in ethanol under refluxing
conditions by aminolysis, however, the expected prod-
uct was not formed. Alternatively, the reaction of aniline
with 2,6-dimethyl-pyridine-3,5-dicarbonyl dichloride,
obtained form the reaction of 2,6-dimethyl-pyri-
dine-3,5-dicarboxylic acid with SOCl2,10 was also
investigated, unfortunately, the reaction afforded the
desired product in lower yields.
It has been reported previously that 1-acylated pyra-
zoles were sensitive to nucleophilic reagent. Reaction of
1-acylated pyrazole derivatives with anilines gave the
corresponding amide products in good to excellent
yields, in which pyrazole rings acted as leaving
groups.11,12
Inspired by the above-mentioned work, we shifted
our attention to the reaction of aniline with 1-acylated
*
E-mail: mzhag@shu.edu.cn (M. Zhang); lpsong@shu.edu.cn (L. Song)
Received March 30, 2011; revised June 24, 2011; accepted July 12, 2011.
Project supported by the National Natural Science Foundation of China (Nos. 20872086, 21072128), the Leading Academic Discipline Project of
Shanghai Municipal Education Commission (No. J50102), the Foundation of Education Commission of Shanghai Municipality (No. 08zz44), and the
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry.
Chin. J. Chem. 2011, 29, 2119— 2123
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
2119

Wang et al.
FULL PAPER
Investigation of the reaction scope revealed that
various amines, both aliphatic and aromatic amines
(bearing electron-withdrawing and electron-donating
groups), can be utilized in this protocol. The reaction re-
sults were listed in Table 1. It has been observed that bet-
ter yields were obtained with substrates having electron-
donating groups. In the cases of ortho-substituted anilines
the yields were slightly lower than para-substituted ones
probably due to steric hindrance (Entries 3—5, 6—8,
Table 1).
pyrazole derivatives. Thus, the compounds 3 were de-
signed and synthesized in good to excellent yields by
treatment of 1 with 85% hydrazine hydrate under the
solvent-free conditions, followed by cyclization reaction
of 2 with acetyl acetone in the presence of a catalytic
amount of p-TsOH. Consequently, treatment of com-
pounds 3 with anilines in refluxing toluene in the pres-
ence of a catalytic amount of acetic acid afforded the
expected products 4 in good to excellent yields (Scheme
1).
It was found that the catalyst played an important
role in the reaction of 3 with the corresponding anilines.
For example, in the absence of the catalyst, the comple-
tion of reaction needed 24 h in refluxing toluene as sol-
vent. While using the catalyst such as p-TsOH or acetic
acid, the reaction completed within 1 h under the same
reaction conditions and afforded the corresponding
products 4 in excellent yields. It was also observed that
use of 10 mol% of HOAc was sufficient to push the re-
action forward and 5 mol% of HOAc was not enough.
Higher amounts of the catalyst did not further improve
the yield of 4 significantly. Note that when the strong
nucleophilic anilines such as 4-methoxyl-phenylamine
was used as the substrates, the reaction proceeded
smoothly and gave the corresponding product 4 within 1
h even though the reaction was carried out in the ab-
sence of catalyst. The similar results were observed
Scheme 1
Table 1 Reaction results of preparation of 4a
Entry
1
Ar
Reaction time/h
Product
4a
4b
4c
Yieldb/%
90
C6H5
1.5
1
2
2-NH2C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
2-ClC6H4
93
3
1
89
4
1
4d
4e
92
5
1
92
6
1
4f
85
7
3-ClC6H4
1
4g
4h
4i
91
8
4-ClC6H4
1
90
9
2-BrC6H4
3-BrC6H4
4-BrC6H4
4-FC6H4
1
85
10
11
12
13
14
15
16
17
18
19
20
21
1
4j
91
1
4k
4l
92
1
89
2,4-(F)2C6H3
2-CH3OC6H4
4-CH3OC6H4
2-C2H5OC6H4
2,4-(CH3)2C6H3
1-Naphthyl
Benzyl
1
4m
4n
4o
4p
4q
4r
85
0.5
0.5
0.5
1
86
89
92
91
2
89
0.5
3
4s
95
3-NO2C6H4
n-C4H9
4t
59
0.5
4u
98
a Reaction conditions: 3 (1.0 mmol), amine (2.0 mmol), acetic acid (Cat. 0.1 mmol) in refluxing toluene (5.0 mL). b Isolated yields.
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Chin. J. Chem. 2011, 29, 2119— 2123

Convenient Synthesis of 3,5-Biscarbamoyl-pyridine Derivatives
when the catalyst was shifted to p-TsOH. Meanwhile,
the effect of solvent on the reaction efficiency and prod-
ucts was also screened. We observed that when the
anilines with electron-donating groups were employed
as the reaction substrates, the reaction could be carried
out in refluxing ethanol instead of toluene as solvent. On
the contrary, when the anilines with electron-
withdrawing groups were used as substrates, the reac-
tion must be carried out in refluxing toluene, otherwise,
the major product obtained was the ethanolysis product
along with a minor expected product 4. This was attrib-
uted to the competition reaction between the ethanol and
the aniline with weak nucleophilicity.
mmol) and a catalytic amount of TsOH (1.0 mmol) in
CHCl3 (12.0 mL) was refluxed for 2 h, the resultant so-
lution was concentrated under reduced pressure, and the
precipitate that formed was recrystallized from ethanol
as a colorless solid in 90% yield.
Typical procedure for synthesis of 3,5-bis[N-aryl-
carbamoyl]-2,6-dimethylpyridine (4)
To a mixture of 3 (1.0 mmol) and corresponding ani-
line (2.0 mmol) in 5.0 mL of toluene was added a cata-
lytic amount of acetic acid (0.10 mmol). The resulting
mixture was refluxed for 1 h, then left to cool. The solid
obtained was filtered off, washed with ethanol and re-
crystallized from ethanol to afford pure products 4.
3,5-Bis[N-(phenyl)-carbamoyl]-2,6-dimethylpyri-
dine (4a) m.p. 290.5—290.8 ℃; 1H NMR (DMSO-d6,
500 MHz) δ: 2.61 (s, 6H), 7.13 (t, J＝8 Hz, 2H), 7.36 (t,
J＝8 Hz, 4H), 7.72 (d, J＝8 Hz, 4H), 8.03 (s, 1H), 10.45
(s, 2H); IR (KBr) ν: 3283, 2966, 1654, 1545, 1497, 1321,
Conclusions
In conclusion, we have developed an efficient and
convenient method for synthesis of 3,5-bis-carbamoyl-
pyridine derivatives in excellent yields. The key step in
our synthetic sequence is the reaction of aniline with
1-acylated pyrazoles, in which pyrazoles served as the
leaving groups. The shorter reaction time, easy work-up
and high yields make this process attractive over the
other available methods.
＋
－1
754, 690 cm ; MS (70 eV) m/z (%): 345 (M , 18), 253
(100), 160 (46), 92 (54). Anal. calcd for C21H19N3O2: C
73.03, H 5.54, N 12.17; found C 73.09, H 5.50, N 12.17.
3,5-Bis[N-(2-aminophenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4b) m.p. ＞330 ℃; H NMR (DMSO-d6,
500 MHz) δ: 2.62 (s, 6H), 4.99 (s, 4H), 6.52 (t, J＝8 Hz,
2H), 6.77 (d, J＝8 Hz, 2H ), 6.97 (t, J＝8 Hz, 2H), 7.26
(d, J＝8 Hz, 2H), 8.20 (s, 1H), 9.66 (s, 2H); IR (KBr) ν:
3435, 3245, 2968, 1643, 1603, 1497, 1456, 1306, 744
Experimental
Melting points were uncorrected. IR spectra were
recorded on AVATA 370 spectrometer (KBr). 1H NMR
spectra were measured on a Bruker DM (500 MHz)
spectrometer using TMS as internal standard. Mass
spectra were determined on HP 5975-A instrument
using the electron impact ionization technique (70 eV).
Element analyses were measure on a Heraeus (CHNO,
rapid) analyzer. 2,6-dimethyl-1,4-dihydropyridine-3,5-
dicarboxylic acid diethylester was synthesized according
to the literature method.13
－1
＋
cm ; MS (70 eV) m/z (%): 375 (M , 20), 239 (30), 160
(100), 107 (97). Anal. calcd for C21H21N5O2: C 67.18, H
5.64, N 18.65; found C 66.69, H 5.60, N 18.32.
3,5-Bis[N-(2-methylphenyl)-carbamoyl-]2,6-dime-
1
thylpyridine (4c) m.p. 179.8—179.9 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.29 (s, 6H), 2.64 (s, 6H),
7.15—7.29 (m, 6H), 7.43 (d, J＝7.5 Hz, 2H), 8.08 (s,
1H), 9.96 (s, 2H); IR (KBr) ν: 3242, 3035, 1684, 164＋0,
－1
1554, 1309, 742 cm ; MS (70 eV) m/z (%): 373 (M ,
32), 267 (100), 160 (12), 106 (25). Anal. calcd for
C23H23N3O2: C 73.97, H 6.21, N 11.25; found C 73.92,
H 6.43, N 11.59.
Synthesis of 3.5-diethoxycarbonyl-2.6-dimethyl pyri-
dine (1)
2,6-Dimethyl-1,4-dihydropyridine-3,5-dicarboxylic
acid diethylester (0.01 mol) and sodium nitrite (0.02 mol)
were dissolved in 35 mL of ethanol/water (5/2, V/V). To
this solution was added dropwise acetic acid (0.02 mol).
The reaction mixture was refluxed for 1 h. After removal
of most of the ethanol solvent in vacuo, the precipitated
solid material was filtered off, and washed with water for
several times to give white solid 1 in 95% yield.
3,5-Bis[N-(3-methylphenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4d) m.p. 252.7—253.2 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.30 (s, 6H), 2.59 (s ,6H), 6.92
(d, J＝8 Hz, 4H), 7.23 (t, J＝8 Hz, 2H), 7.51 (d, J＝8
Hz, 2H), 7.99 (s, 1H), 10.36 (s, 2H); IR (KBr) ν: 3249,
－1
2920, 1645, 1564, 1322, 782, 689 cm ; MS (70 eV)
m/z (%): 373 (M＋, 50), 267 (100), 106 (25), 91 (18).
Anal. calcd for C23H23N3O2: C 73.97, H 6.21, N 11.25;
found C 74.24, H 6.16, N 11.34.
Synthesis of 3,5-bis(hydrazino-carbonyl)-2,6-di-
methylpyridine (2)
3,5-Bis[N-(4-methylphenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4e) m.p. 278.7—278.9 ℃; H NMR
A mixture of 1 (0.01 mol) and hydrazine hydrate (0.04
mol) was refluxed for 6 h, then left to cool. The solid
obtained was filtered off, dried and recrystallized from
80% ethanol to give 2 as white crystals in 85% yield.
(DMSO-d6, 500 MHz) δ: 2.28 (s, 6H), 2.60 (s, 6H), 7.15
(d, J＝8 Hz, 4H), 7.60 (d, J＝8 Hz, 4H), 7.99 (s, 1H),
10.35 (s, 2H);－IR (KBr) ν: 3232, 2921, 1643, 1＋600, 1515,
1
1325, 815 cm ; MS (70 eV) m/z (%): 373 (M , 15), 267
Synthesis of 3,5-bis(3',5'-dimethyl-1'-pyrazolyl-car-
bonyl)-2,6-dimethylpyridine (3)
(36), 149 (32), 105 (100). Anal. calcd for C23H23N3O2:
C 73.97, H 6.21, N 11.25; found C 74.04, H 6.10, N
11.33.
A mixture of 2 (10.0 mmol), acetyl acetone (20.0
Chin. J. Chem. 2011, 29, 2119— 2123
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Wang et al.
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＋
－1
3,5-Bis[N-(2-chlorophenyl)-carbamoyl]-2,6-dime-
515 cm ; MS (70 eV) m/z (%): 381 (M , 37), 271
(100), 106 (28). Anal. calcd for C21H17F2N3O2: C 66.14,
H 4.49, N 11.02; found C 66.10, H 4.46, N 10.98.
1
thylpyridine (4f) m.p. 243.1—243.6 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.66 (s, 6H), 7.29 (t, J＝8 Hz,
2H), 7.41 (t, J＝8 Hz, 2H), 7.57 (d, J＝8 Hz, 2H), 7.66
(d, J＝8 Hz, 2H), 8.09 (s, 1H), 10.24 (s, 2H);－IR (KBr) ν:
3,5-Bis[N-(3,4-diflourophenyl)-carbamoyl]-2,6-di-
methylpyridine (4m) m.p. 274.2 — 274.8 ℃ ; 1H
NMR (DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 7.43—7.46
(m, 4H), 7.88—7.93 (m, 2H,), 8.07 (s, 1H), 10.68 (s,
2H); IR－(KBr) ν: 3260, 1652, 1518, 1415, 1288, 856,
1
3293, 1649, 1588, 1528, 1305, 764, 632 cm ; MS (70
eV) m/z (%): 413 (M＋, 18), 378 (21), 287 (100), 91 (38).
Anal. calcd for C21H17Cl2N3O2: C 60.88, H 4.14, N
10.14; found C 61.08, H 4.10, N 10.10.
＋
1
757 cm ; EI-MS m/z: 417 (M , 26), 289 (100), 106
(28). Anal. calcd for C21H15F4N3O2: C 60.43, H 3.62, N
10.07; found C 60.60, H 3.59, N 9.92.
3,5-Bis[N-(3-chlorophenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4g) m.p. 268.7—269.5 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 7.17—7.20 (m,
2H), 7.41 (t, J＝8 Hz, 2H), 7.61 (d, J＝8 Hz, 2H), 7.94
(t, J＝8 Hz, 2H), 8.08 (s, 1H,), 10.63 (s, 2H);－IR (KBr) ν:
3,5-Bis[N-(2-methoxyphenyl)-carbamoyl]-2,6-di-
methylpyridine (4n) m.p. 314.7—315.0 ℃; 1H NMR
(DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 3.82 (s, 6H), 6.96
—6.99 (m, 2H), 7.10 (d, J＝8 Hz, 2H), 7.17—7.20 (m,
2H) 7.84 (d, J＝8 Hz, 2H), 7.98 (s, 1H), 9.63 (s, 2H); IR
(KBr) ν: 3248, 2932, 1640, 1531, 1494, 1035, 741 cm−1;
MS (70 eV) m/z (%): 405 (M＋, 51), 283 (100), 160 (26).
Anal. calcd for C23H23N3O4: C 68.13, H 5.72, N 10.36;
found C 67.72, H 5.65, N 10.20.
1
3263, 1647, 1593, 14＋78, 1318, 783, 681 cm ; MS (70
eV) m/z (%): 413 (M , 28), 287 (100), 106 (28). Anal.
calcd for C21H17Cl2N3O2: C 60.88, H 4.14, N 10.14;
found C 61.22, H 4.12, N 10.17.
3,5-Bis[N-(4-chlorophenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4h) m.p. 286.1—287.9 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 7.43 (d, J＝8 Hz,
4H), 7.77 (d, J＝8 Hz, 4H), 8.07 (s, 1H), 10.58 (s, 2H);
IR (KB－r) ν: 3231, 3041, 1644, 1596, 1551, 1319, 1090,
3,5-Bis[N-(4-methoxyphenyl)-carbamoyl]-2,6-di-
methylpyridine (4o) m.p. 265.2—265.6 ℃; 1H NMR
(DMSO-d6, 500 MHz) δ: 2.58 (s, 6H), 3.73 (s, 6H), 6.92
(dd, J＝7, 2 Hz, 4H), 7.63 (dd, J＝7, 2 Hz, 4H), 7.79 (s,
1H), 10.29 (s, 2H); IR (KBr) ν: 3219, 2963, 1638, 1551,
＋
1
823 cm ; MS (70 eV) m/z (%): 413 (M , 20), 378 (22),
287 (100), 91 (37). Anal. calcd for C21H17Cl2N3O2: C
60.88, H 4.14, N 10.14; found C 60.75, H 4.09, N 10.09.
3,5-Bis[N-(2-bromophenyl)-carbamoyl]-2,6-dime-
－1
1445, 1245, 1034, 829 cm ; MS (70 eV) m/z (%): 405
(M＋, 49), 283 (100), 160 (21), 83 (33). Anal. calcd for
C23H23N3O4: C 68.13, H 5.72, N 10.36; found C 68.08,
H 5.66, N 10.44.
1
thylpyridine (4i) m.p. 257.9—258.4 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 7.32—7.33 (m,
4H), 7.65 (d, J＝7 Hz, 2H), 8.08 (d, J＝7 Hz, 2H), 8.10
(s, 1H), 10.62 (s, 2H); IR (KBr) ν: 3266, 1677, 1650,
3,5-Bis[N-(4-ethoxyphenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4p) m.p. 248.8—249.5 ℃; H NMR
－1
1579, 1＋520, 1299, 744, 635 cm ; MS (70 eV) m/z (%):
(DMSO-d6, 500 MHz) δ: 1.33 (t, J＝7 Hz, 6H), 2.60 (s,
6H), 4.01 (q, J＝7 Hz, 4H), 6.91 (d, J＝8 Hz, 4H), 7.62
(d, J＝8 Hz, 4H), 7.99 (s, 1H), 10.29 (s, 2H); IR (KBr) ν:
3220, 2928, 1638, 1596, 1512, 1477, 1243, 1115, 835
503 (M , 8), 422 (32), 331 (100), 106 (59). Anal. calcd
for C21H17Br2N3O2: C 50.13, H 3.41, N 8.35; found C
50.02, H 3.59, N 8.64.
＋
－1
3,5-Bis[N-(3-bromophenyl)-carbamoyl]-2,6-dime-
cm ; MS (70 eV) m/z (%): 433 (M , 63), 297 (100),
160 (16). Anal. calcd for C25H27N3O4: C 69.27, H 6.28,
N 9.69; found C 68.94, H 6.31, N 9.65.
1
thylpyridine (4j) m.p. 302.0—302.1 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.61 (s, 6H), 7.30—7.35 (m,
4H), 7.65—7.66 (m, 2H), 8.08 (s, 2H), 8.09 (s, 1H),
10.62 (s, 2H); IR (KBr) ν: 3231, 3074, 1647, 1589, ＋1674,
3,5-Bis[N-(2,4-dimethylphenyl)-carbamoyl]-2,6-
dimethylpyridine (4q) m.p. 301.6—301.8 ℃; 1H
NMR (DMSO-d6, 500 MHz) δ: 2.23 (s, 6H), 2.29 (s,
6H), 2.64 (s, 6H), 6.98 (d, J＝7.5 Hz, 2H), 7.14 (d, J＝
7.5 Hz, 2H), 7.26 (s, 2H), 8.04 (s, 1H) , 9.90 (s, 2H);－IR
－1
1317, 782, 681 cm ; MS (70 eV) m/z (%): 503 (M , 8),
331 (100), 160 (23), 106 (45). Anal. calcd for
C21H17Br2N3O2: C 50.13, H 3.41, N 8.35; found C 50.35,
H 3.39, N 8.37.
1
(KBr) ν: 3254, 1642, 1593, 1473, 1315, 786, 681 cm ;
3,5-Bis[N-(4-bromophenyl)-carbamoyl]-2,6-dime-
MS (70 eV) m/z (%): 401 (M＋, 46), 281 (100), 160 (17),
120 (36). Anal. calcd for C25H27N3O2: C 74.49, H 6.78,
N 10.47; found C 74.45, H 6.68, N 10.25.
1
thylpyridine (4k) m.p. 302.0—302.1 ℃; H NMR
(DMSO-d6, 500 MHz) δ: 2.60 (s, 6H), 7.55 (d, J＝9 Hz,
4H), 7.71 (d, J＝9 Hz, 4H), 8.06 (s, 1H), 10.58 (s, 2H);
IR (KBr) ν: －3227, 1645, 1598, 1529, 1487, 1＋312, 1071,
3,5-Bis[N-(1-naphthyl)-carbamoyl]-2,6-dimethyl-
1
pyridine (4r) m.p. ＞330 ℃; H NMR (DMSO-d6,
1
821, 502 cm ; MS (70 eV) m/z (%): 503 (M , 30), 331
500 MHz) δ: 2.73 (s, 6H), 7.75—7.60 (m, 6H), 7.77 (d,
J＝7 Hz, 2H), 7.87 (d, J＝8 Hz, 2H), 7.98—8.00 (m,
2H), 8.16 (d, J＝8 Hz, 2H), 8.39 (s, 1H), 10.57 (s, 2H);
IR (KB－r) ν: 3278, 2966, 1650, 1542, 1＋495, 1325, 758,
(100), 160 (25), 106 (39). Anal. calcd for
C21H17Br2N3O2: C 50.35, H 3.41, N 8.35; found C 50.38,
H 3.35, N 8.46.
1
3,5-Bis[N-(4-fluorophenyl)-carbamoyl]-2,6-dime-
690 cm ; MS (70 eV) m/z (%): 445 (M , 37), 303 (57),
1
thylpyridine (4l) m.p. 308.1—309.1 ℃; H NMR
142 (28). Anal. calcd for C29H23N3O2: C 78.78, H 5.20,
N 9.43; found C 78.26, H 5.10, N 9.36.
(DMSO-d6, 500 MHz) δ: 2.62 (s, 6H), 7.21 (t, J＝9 Hz,
4H), 7.74—7.77 (m, 4H), 8.05 (s, 1H), 10.51 (s, 2H); IR
(KBr) ν: 3248, 3061, 1649, 1556, 1508, 1406, 1220, 833,
3,5-Bis[N-(benzoy)l-carbamoyl]-2,6-dimethylpy-
ridine (4s)
m.p. 195.0 — 195.3 ℃ ; 1H NMR
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© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 2119— 2123

Convenient Synthesis of 3,5-Biscarbamoyl-pyridine Derivatives
(DMSO-d6, 500 MHz) δ: 2.39 (s, 6H), 4.41 (d, J＝5.5
Hz, 4H), 7.23—7.33 (m, 12H), 7.38 (s, 1H); IR (KBr) ν:
3259, 2872, 1635, 1565, 1449, 1287, 1159, 724, 696
References
1
2
3
4
Sabitha, G.; Kiran Kumar Reddy, G. S.; Reddy, C. S.;
＋
－1
Yadav, J. S. Tetrahedron Lett. 2003, 44, 4129.
Nomura, M.; Nakata, S.; Hamada, F. Nippon Kagaku Kaishi
2002, 141.
cm ; MS (70 eV) m/z (%): 373 (M , 82), 267 (32), 240
(41), 91(100). Anal. calcd for C23H23N3O2: C 73.97, H
6.21, N 11.25; found C 73.84, H 6.19, N 10.97.
Takacs, A.; Jakab, B.; Petz, A.; Kollar, L. Tetrahedron 2007,
63, 10372.
3,5-Bis[N-(3-nitrophenyl)-carbamoyl]-2,6-dime-
1
thylpyridine (4t) m.p. 284.5—284.6 ℃; H NMR
Shi, J. D.; Xiao, Z. L.; Ihnat, M. A.; Kamat, C.; Pandit, B.;
Hua, Z. G.; Li, P. K. Bioorg. Med. Chem. Lett. 2003, 13,
1187.
(DMSO-d6, 500 MHz) δ: 2.64 (s, 6H), 7.67 (t, J＝8 Hz,
2H), 7.98 (dd, J＝8, 1 Hz, 2H), 8.07 (dd, J＝8, 1 Hz,
2H), 8.19 (s, 1H), 8.78 (s, 2H), 10.95 (s, 2H); IR (KBr)
－1
ν: 3283, 2966, 1654, 1545, 1＋497, 1321, 754, 690 cm ;
5
6
7
8
Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
Shakespeare, W. C. Tetrahedron Lett. 1999, 40, 2035.
Hartwig, J. F.; Kawatsura, M. J. Org. Chem. 1999, 40, 2035.
Georges, G.; Jian, L.; Nathalie, R. J. Org. Chem. 1992, 57,
1789.
MS (70 eV) m/z (%): 435 (M , 26), 298 (100), 137 (29),
122 (56). Anal. calcd for C21H17N5O6: C 57.93, H 3.94,
N 16.09; found C 58.06, H 3.98, N 15.84.
3,5-Bis[N-(n-butyl)-carbamoyl]-2,6-dimethylpy-
1
ridine (4u) m.p. 182.6—183.6 ℃; H NMR (CDCl3,
9
Labelle, M.; Gravel, D. J. Chem. Soc., Chem. Commun.
1985, 105.
500 MHz) δ: 0.96 (t, J＝7.5 Hz, 6H), 1.37—1.45 (m,
4H), 1.56—1.62 (m, 4H), 2.56 (s, 6H), 3.40 (t, J＝7.0
Hz, 4H), 6.44 (s, 2H), 7.5 (s, 1H); IR (KBr) ν: 3268,
10 Wang, Z. Q. Chin. J. Pharm. 2002, 33, 469 (in Chinese).
11 Gorobets, N. Y.; Yousefi, B. H.; Belaj, F.; Kappe, C. O.
Tetrahedron 2004, 60, 8633.
－1
2961, 1634, 1569, 1440, 12＋96, 1164, 746, 646 cm ;
MS (70 eV) m/z (%): 305 (M , 35), 248 (17), 233 (100),
106 (30). Anal. calcd for C17H27N3O2: C 66.85, H 8.91,
N 13.76; found C 67.39, H 8.92, N 13.59.
12 Kim, K. C.; Kim, H. S. J. Korean Chem. Soc. 2002, 46, 585.
13 Zehani, S.; Gelbard, G. Bull. Soc. Chim. Fr. 1989, 104.
(E1103302 Cheng, F.; Zheng, G.)
Chin. J. Chem. 2011, 29, 2119— 2123
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
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