Bynthesis of novel substituted pyridine derivatives from 3,5-diacetyl-2,6-dimethylpyridine

Article abstract of DOI:10.1002/hc.20522

A series of novel (1-acetyl-5-aryl-4,5-dihydro)-1 H-pyrazole substituted pyridine derivatives and poly substituted [2,3'-bipyridine]-5-carbonitrile derivatives were synthesized from 3,5-diacetyl- 2,6-dimethylpyridine. The structures of two typical 3,5-bis

Full text of DOI:10.1002/hc.20522

Heteroatom Chemistry
Volume 20, Number 3, 2009
Synthesis of Novel Substituted Pyridine
Derivatives from 3,5-Diacetyl-2,6-
dimethylpyridine
Jun Zhang,1 Min Zhang,1 Weiguo Cao,1,2 Liping Song,1,2 Qun Qian,1
and Jiwen Tan1
1Department of Chemistry, College of Science, Shanghai University, Shanghai 200444,
People’s Republic of China
2Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, People’s Republic of China
Received 3 December 2008; revised 18 February 2009
and probably to be a novel class of small-molecule
ABSTRACT: A series of novel (1-acetyl-5-aryl-4,5-
necroptosis inhibitors [5–7].
dihydro)-1H-pyrazole substituted pyridine derivatives
Many 3-pyridinecarbonitriles were used as dyes
and poly substituted [2,3ꢀ-bipyridine]-5-carbonitrile
for synthetic fabrics and paper [8,9]. Benzoth-
derivatives were synthesized from 3,5-diacetyl-
iepinopyridine derivatives have been reported the
2,6-dimethylpyridine. The structures of two typ-
importance of valuable pharmacology [10,11]. A
ical 3,5-bis[1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-
cyano group bonded to 3-position of pyridine ring
1H-pyrazol-3-yl]-2,6-dimethylpyridines [3b(1) and
of benzothiepinopyridine derivatives was found to
3b(2)] were confirmed by X-ray diffraction analy-
be an anticancer as well as an anti-HIV active
ꢁ
C
sis.
2009 Wiley Periodicals, Inc. Heteroatom Chem
agent [12]. A methoxy group at the 2-position
of benzothiepinopyridine-3-carbonitrile improved
total observed pharmacological properties [13].
In this study, we utilized 3,5-diacetyl-2,6-
dimethylpyridine 1 as a versatile precursor, which
first reacted with aryl aldehydes to give α,β-
unsaturated ketones by Aldol condensation and then
by cyclization with hydrazine hydrate to gener-
ate a series of 3,5-bis(1-acetyl-5-aryl-4,5-dihydro-
1H-pyrazol-3-yl)-2,6-dimethylpyridines 3a–h. Next,
1 reacted with 2-arylidenemalononitrile through
Michael addition, followed by cyclization of a
nucleophilic attack by methoxy anion to give a se-
ries of 5ꢀ-acetyl-4-aryl-6-methoxy-2ꢀ,6ꢀ-dimethyl[2,3ꢀ-
bipyridine]-5-carbonitrile 4a–h. Synthetic routes are
illustrated as following (Scheme 1).
20:123–130, 2009; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20522
INTRODUCTION
Pyrazolines have been reported showing a wide
spectrum of biological activity [1–4]. 1-Acetyl-4,5-
dihydro-1H-pyrazole derivatives showed to be po-
tent and selective monoamine oxidase-A inhibitors
Correspondence to: Min Zhang; e-mail: mzhang@shu.edu.cn;
Liping Song; e-mail: lpsong@shu.edu.cn.
Contract grant sponsor: The National Natural Science Founda-
tion of China.
Contract grant numbers: 20672072, 20772080.
Contract grant sponsor: The Leading Academic Discipline
Project of Shanghai Municipal Education Commission.
Contract grant sponsor: J50102.
RESULTS AND DISCUSSION
Contract grant sponsor: The Foundation of Education Commis-
sion of Shanghai Municipality.
It is well known that α,β-unsaturated ketones are
versatile precursors for the syntheses of the cor-
responding pyrazoline derivatives. Synthesis of the
123
Contract grant number: 08zz44.
c
ꢀ
2009 Wiley Periodicals, Inc.

124 Zhang et al.
Ar
Ar
N
O
O
O
O
N
N
N
N
N
Ar
Ar
N
NH NH H O
2
2
2
O
O
N
N
AcOH, reflux
80%
+
N
N
Ar
Ar
N
N
O
O
N
(2)
Ar
Ar
N
N
(1)
2a
h
3a
h
O
O
AcOH, H SO
2
4
CN
CN
O
OCH
ArCHO
3
o
ArCH
100 C, 90%
N
CN
MeOH, KOH, rt
50%
N
Ar
N
1
4a
h
Ar: 3a = C6H5, 3b = 4-Cl-C6H4, 3c = 3-Cl-C6H4, 3d = 2-Cl-C6H4, 3e = 2,4-Cl2-C6H3, 3f = 2-F-C6H4,
3g = 4-CH3O-C6H4, 3h = 4-O2N-C6H4.
4a = 4-Cl-C6H4, 4b = C6H5, 4c = 4-(CH3)2N-C6H4, 4d = 4-CH3O-C6H4, 4e = 4-HO-C6H4,
4f = 2-Furyl-, 4g = 3,4-(CH3O)2-C6H3, 4h = 2,4-Cl2-C6H3.
SCHEME 1 Synthetic routes of 3a–h and 4a–h.
α,β-unsaturated ketones 2 by the Aldol condensa-
tuted groups of aryl aldehydes had slight effect on
the product distributions and yields.
The amount of 85% hydrazine hydrate was also
screened. The complete conversion was observed,
and the reaction gave higher yields when 2 equiv
of 85% hydrazine hydrate was employed.
tion from 3,5-diacetyl-2,6-dimethylpyridine was first
reported by Pavel and Antonin in 1992 [14]. How-
ever, the reported method suffered from low yields
(5–68%) [14]. We modified the reaction conditions
by adding the stoichiometric amount of condensed
sulfuric acid in acetic acid as reaction solvent. The
corresponding products 2 were obtained in 80–90%
yields.
In the process of synthesizing of (1-acetyl-4,5-
dihydro-1H-pyrazole)-substituted pyridines 3, the
mixture of 2 and 85% hydrazine hydrate were re-
fluxed in acetic acid to afford the enantiomers 3(1)
and mesomer 3(2) with different Rf value on thin-
layer chromatography (TLC) plate, which could be
separated by column chromatography. The gener-
ality of this reaction was investigated under the
same reaction conditions. When we carried out
the reactions with diverse α,β-unsaturated ketones,
most of reactions proceeded smoothly and the target
products were successfully obtained in moderate to
good yields. The reaction results are summarized in
Table 1. The yield ratio of 3(1) and 3(2) was 1:1
approximately. It was clear that the different substi-
It should be indicated that in acetic acid media,
the reaction directly afforded 1-acylated products
and no pyrazolines were detected. To further study
the possibility of formation of pyrazolines, a variety
of solvents such as EtOH, THF, CH3CN, DMF, PhMe,
and DCM were selected. Unfortunately, the reactions
were unsuccessful and TLC analysis showed that the
reactions were complex.
The structures of two typical 3,5-bis[1-acetyl-5-
(4-chlorophenyl)-4,5-dihydro-1H-pyrazol-3-yl]-2,6-
dimethylpyridine [3b(1) and 3b(2)] were confirmed
by X-ray diffraction analysis (Fig. 1) [15,16]. 3b(1)
were racemic mixtures and 3b(2) was a meso
compound. For the racemic mixtures 3b(1), their
configurations of C-5 of 1-acetyl pyrazole ring
are (R, R) or (S, S); whereas for the pure meso
compound, the corresponding configuration of C-5
of 1-acetyl pyrazole ring is (R, S). It was obvious
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Pyridine Derivatives from 3,5-Diacetyl-2,6-dimethylpyridine 125
TABLE 1 Synthesis of 3,5-Bis(1-acetyl-5-aryl-4,5-dihydro-1H-pyrazol-3-yl)-2,6-dimethylpyridinea
Entry
Ar
Product
Yield (%)b
Product
Yield (%)b
1
2
3
4
5
6
7
8
C H5
3a(1)
3b(1)
3c(1)
3d(1)
3e(1)
3f(1)
38
43
42
39
41
43
41
39
3a(2)
3b(2)
3c(2)
3d(2)
3e(2)
3f(2)
37
40
39
37
39
41
40
35
4-Cl6-C6H4
3-Cl-C6H4
2-Cl-C6H4
2,4-Cl2-C6H3
2-F-C6H4
4-CH3O-C6H4
4-O2N-C6H4
3g(1)
3h(1)
3g(2)
3h(2)
aReaction conditions: α,β-unsaturated ketones (1 mmol), 85% hydrazine hydrate (2 mmol); solvent: acetic acid; refluxed, 8 h.
bIsolated yield.
FIGURE 1 X-ray crystal structures of 3b(1) and 3b(2).
Heteroatom Chemistry DOI 10.1002/hc

126 Zhang et al.
TABLE
dimethyl[2,3ꢀ-bipyridine]-5-carbonitrilea
2
Synthesis of 5ꢀ-Acetyl-4-aryl-6-methoxy-2ꢀ,6ꢀ-
Hz
Hz
Hx
Hx
Ar
Ar
Entry
Ar
Product
Yield of 4 (%)b
O
O
5
5
Hy
Hy
4
4
1
2
3
4
5
6
7
8
4-Cl-C6H4
C6H5
4-(CH3)2N-C6H4
4-CH3O-C6H4
4-HO-C6H4
2-furyl
4a
4b
4c
4d
4e
4f
56
48
51
53
49
47
50
56
N
1
N
1
3
3
N
2
N
2
N
3,4-(CH3O)2-C6H3
2,4-Cl2-C6H3
4g
4h
FIGURE 2 Structure of compound 3, indicating the Hx, Hy
and Hz respectively.
aReaction conditions: 1 (1 mmol), 2-arylidenemalononitrile (1 mmol),
KOH (1 mmol); solvent: MeOH/H2O (v/v= 1:1); rt, 20 h.
bIsolated yield.
that pyridine ring and two 1-acetyl pyrazole rings
adopted the coplanar structure in unit cell.
1
Under the optimal reaction conditions, we
carried out the reactions with diverse 2-arylidene-
malonnitrile, including 2-furylmethylenemalono-
nitrile. The corresponding target products were suc-
cessfully obtained. The reaction results are outlined
in Table 2. Noticeably, the nature of the substituents
had no major effect on the reaction outcome.
The characteristic features of H NMR spectra
of 3(1) were the appearance of three-group doublet–
doublet peaks at δ = 3.16, 3.76, and 5.55 ppm, re-
spectively, with Jxz = 5.0 Hz, Jyz = 12.0 Hz, and
Jxy = 17.5 Hz for the Hx, Hy, and Hz protons (Fig. 2).
The 1H NMR spectra of 3(2) had the similar patterns
compared with that of 3(1). Moreover, the differ-
ent values of chemical shifts were less than 15 ppm
for the corresponding protons of 3b(1) and 3b(2),
respectively.
CONCLUSION
In conclusion, 3,5-diacetyl-2,6-dimethylpyridine,
which was readily available and poorly explored, has
successfully been utilized as starting material for
synthesis of novel (1-acetyl-5-aryl-4,5-dihydro-1H-
pyrazole)-substituted pyridine derivatives and poly-
substituted [2,3ꢀ-bipyridine]-5-carbonitrile deriva-
tives. Our work furnished the compound libraries
of polysubstituted pyridine derivatives, as well as
the methodology for synthesis of heterocycles from
a versatile synthetic precursor.
To expand the utilization of 1 for synthesizing
diverse heterocycles, we investigated that 1 reacted
with 2 equiv of 2-arylidenemalononitrile in the pres-
ence of excess of KOH in MeOH. It was hoped
that 2,2ꢀ-(2,6-dimethyl-3,5-pyridinyl)bisbipyridine-
5-carbonitriles could be obtained. After stirring the
mixture at room temperature for 20 h, a comple-
tion reaction was observed by TLC analysis. To
our surprise, general workup afforded 5ꢀ-acetyl[2,3ꢀ-
bipyridine]-5-carbonitrile derivatives 4 exclusively
in fair to moderate yields, no 2,2ꢀ-(2,6-dimethyl-3,5-
pyridinyl)bisbipyridine-5-carbonitrile was detected.
To further study the structure of products
related to the reaction conditions, we screened var-
ious reaction conditions by varying molar ratio,
base, reaction temperature, and solvents. First, we
examined the amount of 2-arylidenemalononitrile
affecting the formation of products. The reactions
gave the same result, although the amount of
2-arylidenemalononitrile was increased up to
4 equiv. Second, in the presence of excess of
MeOK, a variety of solvents such as THF, CH3CN,
DMF, PhMe, and DCM were also screened. Finally,
the reaction was performed at higher temperature
up to 90◦C. However, all attempts gave the same
reaction results, providing 5ꢀ-acetyl[2,3ꢀ-bipyridine]-
5-carbonitrile derivatives 4 as an exclusive prod-
uct, without the formation of 2,2ꢀ-(2,6-dimethyl-3,5-
pyridinyl)bisbipyridine-5-carbonitrile derivatives.
EXPERIMENTAL
Melting points were measured with digital melt-
ing point apparatus (WRS-1B, Shanghai Precision
& Scientific Instrument Co., Ltd.) and were uncor-
rected. All NMR spectra were obtained in CDCl3
DMSO-d6 on Bruker AM-500 instruments with
Me4Si as the internal standards. FTIR spectra
were obtained with a Nicolet AVATAR-370 spec-
trophotometer. Mass spectrum was determined with
Finnigan GC-MS 4021. Elemental analyses were per-
formed using a Vario ELIII Analyzer. X-ray crystal
structure data were collected on a Bruck SMART
CCD area detector diffractometer using graphite-
˚
monochromatized Mo Kα radiation (λ = 0.71073 A).
Reactions were monitored by thin-layer chromatog-
raphy (TLC) carried out on 0.25-mm silica gel plates
visualized with UV light.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Pyridine Derivatives from 3,5-Diacetyl-2,6-dimethylpyridine 127
M+). Anal. Calcd for C25H19F2NO2: C, 74.43; H, 4.75;
N, 3.47. Found: C, 74.59; H, 4.68; N, 3.39.
General Procedure for the Synthesis of (2E,2ꢀE)-
1,1ꢀ-(2,6-Dimethyl-3,5-pyridinediyl)bis[3-aryl-2-
propen-1-one] Derivatives 2a–h and 3,5-Bis(1-
acetyl-5-ary-4,5-dihydro-1H-pyrazol-3-yl]-2,6-
dimethylpyridines 3a–h
Synthesis of 3,5-Bis(1-acetyl-5-ary-4,5-dihydro-
1H-pyrazol-3-yl)-2,6-dimethylpyridine 3a–h
Synthesis of 2g, h. About 5 mmol of 1 and
10 mmol of aryl aldehyde were dissolved in 5 mL
of MeOH/H2O (v/v = 5:1) and 10 mmol of KOH was
added [14]. The mixture was stirred for 6 h at 0◦C.
The resulting solid was filtered, washed with water,
and recrystallized from 95% ethanol to obtain the
pure product.
About 1 mmol of 2 and 2 mmol of 85% hydrazine hy-
drate solution were dissolved in 5 mL of acetic acid.
The mixture was refluxed for 8 h, allowed to cool at
room temperature, and poured into ice water and
then neutralized with 10% sodium hydroxide solu-
tion. The resulting solid was filtered, washed with
water, dried, and purified by column chromatogra-
phy on silica gel using ethyl acetate/dichloromethane
(v/v = 1/2) as eluent.
Synthesis of 2a–f. About 5 mmol of 1 and
10 mmol of aryl aldehyde were dissolved in 5 mL
of acetic acid and 5 mL condensed sulfuric acid was
added. The mixture was stirred for 6 h at 100◦C,
allowed to cool at room temperature, and poured
into ice water and then neutralized with 10% sodium
hydroxide solution. The resulting solid was filtered,
washed with water, and recrystallized from 95%
ethanol to obtain the pure product.
3,5-Bis(1-acetyl-4,5-dihydro-5-phenyl-1H-pyrazol-
3-yl)-2,6-dimethylpyridine (3a). 3a(1): White solid,
mp: 269–271◦C. IR (KBr, cm−1): 1677, 1594, 1432,
1404, 699. 1H NMR (CDCl3, 500 MHz): 2.42 (s,
6H, CH3), 2.92 (s, 6H, CH3C O), 3.16 (dd, J = 5.0,
17.5Hz, 2H, H-x), 3.76 (dd, 2H, J = 12.0, 17.5 Hz,
H-y), 5.55 (dd, 2H, J = 5.0, 12.0 Hz, H-z), 7.54 (s,
1H, py-H), 7.19–7.35 (m, 10H, Ar-H). ESI-MS m/z
(480.2, M+). Anal. Calcd for C29H29N5O2: C, 72.63;
H, 6.10; N, 14.60. Found: C, 72.27; H, 6.08; N, 14.39.
3a(2): White solid, mp: 264–266◦C. 1H NMR
(CDCl3, 500 MHz): 2.42 (s, 6H, CH3), 2.92 (s, 6H,
CH3C = O), 3.15 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.77
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.56 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 5.55–5.58 (s, 1H, py-H), 7.18–7.33 (m,
10H, Ar-H). EI-MS m/z (100%): 479 (M+, 96), 438
(32), 439 (100), 422 (17), 395 (54), 380 (16). Anal.
Calcd for C29H29N5O2: C, 72.63; H, 6.10; N, 14.60.
Found: C, 72.31; H, 6.05; N, 14.42.
(2E,2ꢀE)-1,1ꢀ -(2,6-Dimethyl-3,5-pyridinediyl)bis-
[3-(2-chlorophenyl)-2-propen-1-one]
(2d). White
solid, mp: 178–180◦C. Yield: 84%. IR (KBr, cm−1):
1
3067, 1659, 1599, 764. H NMR (CDCl3, 500 MHz):
2.75 (s, 6H, CH3), 7.10 (s, 1H, CH CH), 7.11 (s,
1H, CH CH), 7.30–7.71 (m, 8H, Ar-H), 7.95 (s,
1H, CH CH), 7.98 (s, 1H, CH CH), 7.99 (s, 1H,
py-H). ESI-MS m/z (434.4 M+). Anal. Calcd for
C25H19Cl2NO2: C, 68.82; H, 4.39; N, 3.21. Found: C,
68.69; H, 4.18; N, 3.36.
(2E,2ꢀE)-1,1ꢀ -(2,6-Dimethyl-3,5-pyridinediyl)bis-
[3-(2,4-dichloropheny)-2-propen-1-one] (2e). White
solid, mp: 197–199◦C. Yield: 92%. IR (KBr, cm−1):
3,5-Bis[1-acetyl-5-(4-chlorophenyl)-4,5-dihydro-
1H-pyrazol-3-yl]-2,6-dimethylpyridine (3b). 3b(1):
White solid, mp: 261–268◦C. IR (KBr, cm−1): 1652,
1
3057, 1605, 1584, 826, 777. H NMR (CDCl3, 500
MHz): 2.75 (s, 6H, CH3), 7.10 (s, 1H, CH CH), 7.11
(s, 1H, CH CH), 7.30–7.64 (m, 6H, Ar-H), 7.87 (s,
1H, CH CH), 7.90 (s, 1H, CH CH), 7.98 (s, 1H,
py-H). ESI-MS m/z (503.3, M+). Anal. Calcd for
C25H17Cl4NO2: C, 59.43; H, 3.39; N, 2.77. Found: C,
59.61; H, 3.16; N, 2.69.
1
1595, 1492, 1406, 1364, 822. H NMR (CDCl3, 500
MHz): 2.41 (s, 6H, CH3), 2.91 (s, 6H, CH3C O),
3.13 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.77 (dd,
2H, J = 12.0, 17.5 Hz, H-y), 5.52 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.53 (s, 1H, py-H), 7.13–7.31 (m,
10H, Ar-H). ESI-MS m/z (548.2, M+). Anal. Calcd for
C29H27Cl2N5O2: C, 63.51; H, 4.96; N, 12.77. Found:
C, 63.49; H, 4.95; N, 12.65.
(2E,2ꢀE)-1,1ꢀ -(2,6-Dimethyl-3,5-pyridinediyl)bis-
[3-(2-fluorophenyl)-2-propen-1-one]
(2f). White
3b(2): White solid, mp: 274–276◦C. 1H NMR
(CDCl3, 500 MHz): 2.41 (s, 6 H, CH3), 2.93 (s, 6H,
CH3C O), 3.12 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.78
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.53 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.53 (s, 1H, py-H), 7.13–7.30 (m, 10H,
Ar-H). EI-MS m/z (100%): 547 (M+, 79), 507 (69), 505
(100), 463 (58), 448 (21), 324 (17), 140 (18), 125 (24).
solid, mp: 161–163◦C. Yield: 89%. IR (KBr, cm−1):
1
3068, 1651, 1601, 749. H NMR (CDCl3, 500 MHz):
2.74 (s, 6H, CH3), 7.10–7.22 (m, 4H, Ar-H), 7.22
(s, 1H, CH CH), 7.23 (s, 1H, CH CH), 7.39–7.62
(m, 4H, Ar-H), 7.67 (s, 1H, CH CH), 7.70 (s, 1H,
CH CH), 7.97 (s, 1H, py-H). ESI-MS m/z (401.5,
Heteroatom Chemistry DOI 10.1002/hc

128 Zhang et al.
Anal. Calcd for C29H27Cl2N5O2: C, 63.51; H, 4.96; N,
12.77. Found: C, 63.41; H, 4.93; N, 12.69.
Calcd for C29H25Cl4N5O2: C, 56.42; H, 4.08; N, 11.34.
Found: C, 56.22; H, 4.17; N, 11.12.
3e(2): White solid, mp: 308–310◦C. 1H NMR
(DMSO-d6, 500 MHz): 2.33 (s, 6H, CH3), 2.83 (s, 6H,
CH3C O), 3.29 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.94
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.67 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.76 (s, 1H, py-H), 7.10–7.64 (m, 10H,
Ar-H). EI-MS m/z (100%): 617 (M+, 75), 615 (55), 577
(57), 575 (100), 573 (76), 535 (33), 531 (49), 172 (35).
Anal. Calcd for C29H25Cl4N5O2: C, 56.42; H, 4.08; N,
11.34. Found: C, 56.36; H, 4.13; N, 11.28.
3,5-Bis[1-acetyl-5-(3-chlorophenyl)-4,5-dihydro-
1H-pyrazol-3-yl]-2,6-dimethylpyridine (3c). 3c(1):
White solid, mp: 223–225◦C. IR (KBr, cm−1): 1666,
1593, 1438, 1406, 1364, 789. 1H NMR (CDCl3,
500 MHz): 2.42 (s, 6H, CH3), 2.91 (s, 6H, CH3C O),
3.14 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.78 (dd,
2H, J = 12.0, 17.5 Hz, H-y), 5.52 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.53 (s, 1H, py-H), 7.09–7.29 (m,
10H, Ar-H). ESI-MS m/z (548.2, M+). Anal. Calcd for
C29H27Cl2N5O2: C, 63.51; H, 4.96; N, 12.77. Found:
C, 63.54; H, 4.95; N, 12.68.
3,5-Bis[1-acetyl-4,5-dihydro-5-(2-fluorophenyl)-
1H-pyrazol-3-yl]-2,6-dimethylpyridine
(3f). 3f(1):
3c(2): White solid, mp: 239–241◦C. 1H NMR
(CDCl3, 500 MHz): 2.42 (s, 6H, CH3), 2.92 (s, 6H,
CH3C O), 3.14 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.78
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.52 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.52 (s, 1H, py-H), 7.08–7.27 (m, 10H,
Ar-H). EI-MS m/z (100%): 547 (M+, 71), 507 (46), 505
(100), 463 (55), 352 (24), 140 (20), 125 (23), 111 (22).
Anal. Calcd for C29H27Cl2N5O2: C, 63.51; H, 4.96; N,
12.77. Found: C, 63.56; H, 4.92; N, 12.70.
Yellow solid, mp: 217–219◦C. IR (KBr, cm−1): 1661,
1590, 1492, 1404, 1362, 757. 1H NMR (CDCl3,
500 MHz): 2.43 (s, 6H, CH3), 2.90 (s, 6H, CH3C O),
3.16 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.79 (dd,
2H, J = 12.0, 17.5 Hz, H-y), 5.74 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.54 (s, 1H, py-H), 7.04–7.28 (m,
10H, Ar-H). ESI-MS m/z (516.2, M+). Anal. Calcd for
C29H27F2N5O2: C, 67.56; H, 5.28; N, 13.58. Found: C,
67.49; H, 5.19; N, 13.27.
3f(2): Yellow solid, mp: 242–244◦C. 1H NMR
(CDCl3, 500 MHz): 2.45 (s, 6H, CH3), 2.93 (s, 6H,
CH3C O), 3.18 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.83
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.78 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.55 (s, 1H, py-H), 7.05–7.26 (m, 10H,
Ar-H). EI-MS m/z (100%): 515 (M+, 95), 474 (31), 473
(100), 432 (18), 431 (64), 311 (20), 109 (21). Anal.
Calcd for C29H27F2N5O2: C, 67.56; H, 5.28; N, 13.58.
Found: C, 67.53; H, 5.21; N, 13.42.
3,5-Bis[1-acetyl-5-(2-chlorophenyl)-4,5-dihydro-
1H-pyrazol-3-yl]-2,6-dimethylpyridine (3d). 3d(1):
White solid, mp: 268–270◦C. IR (KBr, cm−1): 1656,
1593, 1475, 1406, 363, 756. 1H NMR (CDCl3,
500 MHz): 2.46 (s, 6H, CH3), 2.89 (s, 6H, CH3C O),
3.06 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.85 (dd,
2H, J = 12.0, 17.5 Hz, H-y), 5.86 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.48 (s, 1H, py-H), 7.05–7.47 (m,
10H, Ar-H). ESI-MS m/z (548.2, M+). Anal. Calcd for
C29H27Cl2N5O2: C, 63.51; H, 4.96; N, 12.77. Found:
C, 63.24; H, 4.93; N, 12.58.
19F NMR (CDCl3, 470 MHz): 3f(1) δ: −117.6–
−117.7 (m, F); 3f(2) δ: −117.6—117.7 (m, F).
3d(2): White solid, mp: 265–267◦C. 1H NMR
(CDCl3, 500MHz): 2.46 (s, 6H, CH3), 2.89 (s, 6H,
CH3C O), 3.05 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.86
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.87 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.48 (s, 1H, py-H), 7.04–7.40 (m, 10H,
Ar-H). EI-MS m/z (100%): 547 (M+, 84), 507 (75), 505
(100), 470 (26), 465 (42), 463(74), 327 (27), 146 (25),
140 (25), 125 (36). Anal. Calcd for C29H27Cl2N5O2: C,
63.51; H, 4.96; N, 12.77. Found: C, 63.36; H, 4.91; N,
12.63.
3,5-Bis[1-acetyl-4,5-dihydro-5-(4-methoxyphen-
yl)-1H-pyrazol-3-yl]-2,6-dimethylpyridine
(3g).
3g(1): White solid, mp: 230–232◦C. IR (KBr, cm−1):
1
1660, 1513, 1405, 1366, 870, 829. H NMR (CDCl3,
500 MHz): 2.40 (s, 6H, CH3), 2.91 (s, 6H, CH3C O),
3.15 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.73 (dd, 2H,
J = 12.0, 17.5 Hz, H-y), 3.77 (s, 6H, OCH3), 5.51
(dd, 2H, J = 5.0, 12.0 Hz, H-z), 7.56 (s, 1H, py-H),
6.84–7.15 (m, 10H, Ar-H). ESI-MS m/z (540.2, M+).
Anal. Calcd for C31H33N5O4: C, 69.00; H, 6.16; N,
12.98. Found: C, 68.76; H, 6.55; N, 12.69.
3,5-Bis[1-acetyl-5-(2,4-dichlorophenyl)-4,5-dihy-
dro-1H-pyrazol-3-yl]-2,6-dimethylpyridine
(3e).
3g(2): White solid, mp: 213–215◦C. 1H NMR
(CDCl3, 500 MHz): 2.40 (s, 6H, CH3), 2.91 (s, 6H,
CH3C O), 3.15 (dd, J = 12.0, 17.5 Hz, 2H, H-x), 3.75
(dd, 2H, J = 5.0, 12.0 Hz, H-y), 3.77 (s, 6H, OCH3),
5.51 (dd, 2H, J = 5.0, 12.0 Hz, H-z), 7.55 (s, 1H, py-
H), 6.83–7.13 (m, 10H, Ar-H). EI-MS m/z (100%): 539
(M+, 100), 497 (60), 482 (33), 440 (25), 349 (25), 191
(40), 176 (38), 149 (27), 176 (38). Anal. Calcd for
3e(1): White solid, mp: 279–281◦C. IR (KBr, cm−1):
1654, 1592, 1472, 1405, 1364, 869, 819. 1H NMR
(DMSO-d6, 500 MHz): 2.33 (s, 6H, CH3), 2.82 (s,
6H, CH3C O), 3.27 (dd, J = 5.0, 17.5 Hz, 2H, H-x),
3.96 (dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.67 (dd, 2H,
J = 5.0, 12.0 Hz, H-z), 7.78 (s, 1H, py-H), 7.12–7.67
(m, 10H, Ar-H). ESI-MS m/z (618.0, M+). Anal.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of Pyridine Derivatives from 3,5-Diacetyl-2,6-dimethylpyridine 129
C31H33N5O4: C, 69.00; H, 6.16; N, 12.98. Found: C,
68.82; H, 6.39; N, 12.85.
(m, 5H, Ar-H), 8.12(s, 1H, pyridine-4-H). IR (KBr,
cm−1): 2226, 1688, 1584, 1549, 1459, 1369, 762, 695.
ESI-MS m/z (357.2, M+). Anal. Calcd for C22H19N3O2:
C, 73.93; H, 5.36; N, 11.76. Found: C, 73.73; H, 5.43;
N, 11.66.
3,5-Bis[1-acetyl-4,5-dihydro-5-(4-nitrophenyl)-1H-
pyrazol-3-yl]-2,6-dimethylpyridine (3h). 3h(1): Yel-
low solid, mp: 280–282◦C. IR (KBr, cm−1): 1670,
1
1596, 1518, 1405, 1348, 853. H NMR (DMSO-d6,
5ꢀ -Acetyl-6-methoxy-4-(4-N,N-dimethylphenyl)-
500 MHz): 2.32 (s, 6H, CH3), 2.84 (s, 6H, CH3C O),
3.35 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.93 (dd,
2H, J = 12.0, 17.5 Hz, H-y), 5.63 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.80 (s, 1H, py-H), 7.48–7.50 (d, 4H,
Ar-H), 8.19–8.21 (d, 4H, Ar-H). ESI-MS m/z (570.2,
M+). Anal. Calcd for C29H25N7O6: C, 61.37; H, 4.44;
N, 17.28. Found: C, 60.97; H, 4.78; N, 16.92.
2ꢀ,6ꢀ-dimethyl[2,3ꢀ-bipyridine]-5-carbonitrile
(4c).
Yellow solid, mp: 197–199◦C. 1H NMR (CDCl3,
500 MHz): 2.62 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.80
(s, 3H, CH3), 3.05 [s, 6H, N(CH3)2], 4.11 (s, 3H,
CH3O), 7.17 (s, 1H, pyridine-5-H), 6.79–7.64 (m, 4H,
Ar-H), 8.10 (s, 1H, pyridine-4-H). IR (KBr, cm−1):
2218, 1682, 1580, 1526, 1451, 1365, 828. ESI-MS m/z
(400.2, M+). Anal. Calcd for C24H24N4O2: C, 71.98;
H, 6.04; N, 13.99. Found: C, 71.63; H, 6.12; N, 13.75.
3h(2): Yellow solid, mp: 265–267◦C. 1H NMR
(DMSO-d6, 500 MHz): 2.32 (s, 6H, CH3), 2.85 (s, 6H,
CH3C O), 3.40 (dd, J = 5.0, 17.5 Hz, 2H, H-x), 3.90
(dd, 2H, J = 12.0, 17.5 Hz, H-y), 5.63 (dd, 2H, J = 5.0,
12.0 Hz, H-z), 7.79 (s, 1H, py-H), 7.46–7.48 (d, 4H,
Ar-H), 8.16–8.18 (d, 4H, Ar-H). EI-MS m/z (100%):
569 (M+, 37), 528 (33), 527 (100), 486 (25), 485
(79), 363 (28), 321 (64), 164 (33). Anal. Calcd for
C29H25N7O6: C, 61.37; H, 4.44; N, 17.28. Found: C,
61.19; H, 4.56; N, 16.99
5ꢀ-Acetyl-6-methoxy-4-(4-methoxyphenyl)-2ꢀ,6ꢀ-di-
methyl[2,3ꢀ-bipyridine]-5-carbonitrile (4d). White
1
solid, mp: 199–201◦C. H NMR (CDCl3, 500 MHz):
2.62 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.81 (s, 3H,
CH3), 3.88 (s, 3H, Ar-OCH3), 4.13 (s, 3H, CH3O), 7.18
(s, 1H, pyridine-5-H), 7.05–7.64 (m, 4H, Ar-H), 8.10
(s, 1H, pyridine-4-H). IR (KBr, cm−1): 2226, 1687,
1584, 1144, 1516, 1452, 830. ESI-MS m/z (387.2,
M+). Anal. Calcd for C23H21N3O3: C, 71.30; H, 5.46;
N, 10.85. Found: C, 71.21; H, 5.47; N, 10.62.
General Procedure for the Synthesis of 5ꢀ-Acetyl-
4-aryl-6-methoxy-2ꢀ,6ꢀ-dimethyl[2,3ꢀ-bipyridine]-
5-carbonitriles 4a–h
5ꢀ-Acetyl-4-(4-hydroxylphenyl)-6-methoxy-2ꢀ,6ꢀ-di-
methyl[2,3ꢀ-bipyridine]-5-carbonitrile (4e). Yellow
solid, mp: 260–262◦C. 1H NMR (DMSO-d6,
500 MHz): 2.62 (s, 3H, CH3), 2.65 (s, 3H, CH3),
2.67 (s, 3H, CH3), 4.06 (s, 3H, CH3O), 7.56 (s, 1H,
pyridine-5-H), 6.95–7.65 (m, 4H, Ar-H), 8.39 (s, 1H,
pyridine-4-H), 10.12 (s, 1H, OH). IR (KBr, cm−1):
2220, 1684, 1591, 1551, 1452, 1361, 848. ESI-MS m/z
(373.2, M+). Anal. Calcd for C22H19N3O3: C, 70.76;
H, 5.13; N, 11.25. Found: C, 70.43; H, 5.18; N, 10.90.
About 2 mmol of 1 was dissolved in 5 mL of
MeOH, 2.2 mmol of KOH was dissolved in 1 mL
of water, and taken in a 25 mL round bottom
flask. Then, added 2 mmol 2-arylidenemalononitrile
slowly. The mixture was stirred at room tempera-
ture for 20 h, poured into cold water, and then neu-
tralized with acetic acid. The solid separated was
filtered, washed with water, and recrystallized from
EtOH/THF (v/v = 2/1) to obtain the pure product.
5ꢀ -Acetyl-4-(4-chlorophenyl)-6-methoxy-2ꢀ,6ꢀ -di-
5ꢀ -Acetyl-4-furanyl-6-methoxy-2ꢀ,6ꢀ-dimethyl[2,3ꢀ-
bipyridine]-5-carbonitrile (4f). White solid, mp:
227–229◦C. 1H NMR (CDCl3, 500 MHz): 2.64 (s, 3H,
CH3), 2.73 (s, 3H, CH3), 2.81 (s, 3H, CH3), 4.11 (s,
3H, CH3O), 7.56 (s, 1H, pyridine-5-H), 6.69 (s, 1H,
furan-H), 7.65–7.68 (m, 2H, furan-H), 8.11 (s, 1H,
pyridine-4-H). IR (KBr, cm−1): 2224, 1688, 1592,
1552, 1457, 1359, 767. ESI-MS m/z (347.1, M+).
Anal. Calcd for C20H17N3O3: C, 69.15; H, 4.93; N,
12.10. Found: C, 68.77; H, 4.99; N, 12.10.
methyl[2,3ꢀ-bipyridine]-5-carbonitrile (4a). White
1
solid, mp: 239–241◦C. H NMR (CDCl3, 500 MHz):
2.62 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.81 (s, 3H,
CH3), 4.14 (s, 3H, CH3O), 7.17 (s, 1H, pyridine-5-H),
7.52–7.60 (m, 4H, Ar-H), 8.09 (s, 1H, pyridine-4-H).
IR (KBr, cm−1): 2224, 1690, 1593, 1452, 1365, 1260,
1004, 832. ESI-MS m/z (391.0, M+). Anal. Calcd for
C22H18ClN3O2: C, 67.43; H, 4.63; N, 10.72. Found: C,
67.22; H, 4.77; N 10.35.
5ꢀ -Acetyl-6-methoxy-4-phenyl-2ꢀ,6ꢀ-dimethyl[2,3ꢀ-
5ꢀ-Acetyl-4-(3,4-dimethoxyphenyl)-6-methoxy-2ꢀ,6ꢀ-
dimethyl[2,3ꢀ-bipyridine]-5-carbonitrile (4g). White
solid, mp: 169–171◦C. 1H NMR (DMSO-d6,
500 MHz): 2.63 (s, 3H, CH3), 2.65 (s, 3H, CH3),
2.68 (s, 3H, CH3), 3.84 (s, 3H, Ar-OCH3), 3.85 (s,
bipyridine]-5-carbonitrile (4b). White solid, mp:
1
172–174◦C. H NMR(CDCl3, 500 MHz): 2.62 (s, 3H,
CH3), 2.76 (s, 3H, CH3), 2.82 (s, 3H, CH3), 4.18 (s,
3H, CH3O), 7.21 (s, 1H, pyridine-5-H), 7.54–7.66
Heteroatom Chemistry DOI 10.1002/hc

130 Zhang et al.
[4] Nauduri, D.; Reddy, G. B. Chem Pharm Bull 1998,
46, 1254–1260.
3H, Ar-OCH3), 4.08 (s, 3H, CH3O), 7.16 (s, 1H,
pyridine-5-H), 7.17–7.64 (m, 3H, Ar-H), 8.39 (s, 1H,
pyridine-4-H). IR (KBr, cm−1): 2220, 1685, 1584,
1547, 1517, 1453, 767, 668. ESI-MS m/z (417.2, M+).
Anal. Calcd for C24H23N3O4: C, 69.05; H, 5.55; N,
10.07. Found: C, 68.84; H, 5.62; N, 10.14.
[5] Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.
Bioorg Med Chem Lett 2005, 15, 4632–4635.
[6] Chimenti, F.; Bolasco, A.; Manna, F.; Secci, D.; Chi-
menti, P.; Granese, A.; Befani, O.; Turini, P.; Cirilli,
R.; Torre, F. L.; Alcaro, S.; Ortuso, F.; Langer, T. Curr
Med Chem 2006, 13, 1411–1428.
[7] Jagtap, P. G.; Degterev, A.; Choi, S.; Keys, H.; Yuan,
J. Y.; Cuny, G. D. J Med Chem 2007, 50, 1886–1895.
[8] Basta, A. H.; Girgisb, A. S.; El-Saieda, H. Dyes Pig-
ments 2002, 54, 1–10.
5ꢀ -Acetyl-4-(2,4-dichlorophenyl)-6-methoxy-2ꢀ,6ꢀ-
dimethyl[2,3ꢀ-bipyridine]-5-carbonitrile (4h). White
1
solid, mp: 141–143◦C. H NMR (CDCl3, 500 MHz):
[9] Tyndall, D. V.; Al Nakib, T.; Meegan, M. J. Tetrahe-
dron Lett 1998, 29, 2703–2706.
[10] Wolin, R.; Connolly, M.; Kelly, J.; Weinstein, J.;
Rosenblum, S.; Afonso, A.; James, L.; Kirschmeier,
P.; Bishop, W. R. Bioorg Med Chem Lett 1998, 8,
2521–2526.
[11] Afonso, A.; Kelly, J. M.; Rosenblum, S. B.; Wolin,
R. L.; Weinstein, J. US Patent 6 130 229; Chem Abstr
2000, 133, 281773.
2.62 (s, 3H, CH3), 2.74 (s, 3H, CH3), 2.81 (s, 3H,
CH3), 4.16 (s, 3H, CH3O), 7.15 (s, 1H, pyridine-5-H),
7.35–7.60 (m, 3H, Ar-H), 8.12 (s, 1H, pyridine-4-H).
IR (KBr, cm−1): 2223, 1689, 1589, 1559, 1479, 1366,
998, 829. ESI-MS m/z (425.1, M+). Anal. Calcd for
C22H17Cl2N3O2: C, 61.98; H, 4.02; N, 9.86. Found: C,
62.32; H, 4.28; N, 9.63.
[12] Hammam, A. G.; Abd El-hafez, N. A.; Midura,
W. H.; Mikolojczyk, M. Z Naturforsch B 2000, 55,
417–424.
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Faraga, H. Bioorg Med Chem 2007, 15, 2403–2413.
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Heteroatom Chemistry DOI 10.1002/hc