Synthesis and reactions of 3-cyano-4,6-dimethyl-2-pyridone

Article abstract of DOI:10.1002/jhet.545

Rapid synthesis of 3-cyano-4,6-dimethyl-2-pyridone 3, using piprazine as a catalyst was reported. X-ray data of the 4,6-dimethyl-2-oxo-1,2-dihydropyridine- 3-carbonitrile exhibited its oxo form. Synthesis of isoquinolinecarbonitrile and pyridylpyridazine using compound 3 was investigated. Reactivity of the synthesized pyridone toward different organic reagents was also studied.

Full text of DOI:10.1002/jhet.545

272
Synthesis and Reactions of 3-Cyano-4,6-dimethyl-2-pyridone
Vol 48
Abdel-Zaher A. Elassar*
Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, Cairo, Egypt
*E-mail: aelassar@yahoo.com
Received February 1, 2010
DOI 10.1002/jhet.545
Published online 19 November 2010 in Wiley Online Library (wileyonlinelibrary.com).
Rapid synthesis of 3-cyano-4,6-dimethyl-2-pyridone 3, using piprazine as a catalyst was reported. X-
ray data of the 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile exhibited its oxo form. Synthesis
of isoquinolinecarbonitrile and pyridylpyridazine using compound 3 was investigated. Reactivity of the
synthesized pyridone toward different organic reagents was also studied.
J. Heterocyclic Chem., 48, 272 (2011).
INTRODUCTION
in preparing N-substituted pyridones has also been
reported recently [14]. In this article, piprazine, piprazi-
necarboxyaldehyde, and triethylamine were used as a
base catalyst. Piprazine was found to be the most effi-
cient of the three catalysts.
2-Pyridones are biologically interesting molecules,
and their chemistry have received considerable attention
[1–6]. Over the last decade, natural products with this
structure have emerged as potent antitumor and antiviral
agents [7]. Recent studies have shown the usefulness of
2-pyridones as intermolecular connectors between build-
ing blocks in material science. Thus, despite the large
number of methods known for their synthesis, new pro-
cedures are continuously being developed [8]. Many cat-
alysts have been used in the synthesis of 2-pyridone
from 1,3-diketones, such as zeolites [9], lipase enzymes
[10–12], and triethylamine [13]. Microwave irradiation
RESULTS AND DISCUSSION
In this article, treatment of acetylacetone with malo-
nonitrile in presence of triethylamine afforded 3-cyano-
4,6-dimethyl-2-pyridine 3 (Scheme 1), a 45% yield. The
formation of 3 is assumed to proceed via initial conden-
sation of malononitrile and acetylacetone to yield 1
Scheme 1
C
V
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Synthesis and Reactions of 3-Cyano-4,6-dimethyl-2-pyridone
273
may also exist as 5, Nuclear Overhauser Effect (NOE)
difference experiments indicate that the molecule exists
solely as 4. Irradiation of NH at d 12.23 ppm enhanced
methyl group at d 2.54 ppm and vice versa. If the hydra-
zone form 5 exists, enhancement of aryl protons should
have been observed. The formation of 4 provides evi-
dence for the contribution of the charge-separated reso-
nance form (3b) to the structure, and thus 3 behaves as
typical enamines. Compounds 4a–c could also be
obtained when 3-(substituted arylazo)-2,4-pentanedione 6
was treated with malononitrile or cyanoacetamide in a
basic medium as shown in Scheme 2 [21].
Consistent with this finding, compound 3 was bromi-
nated at C-5 to give the 5-bromo-3-cyano-4,6-dimethyl-2-
pyridone 7, through refluxing 3 with N-bromosuccinimide
(Scheme 3). The structure of the product 7 was confirmed
based on its elemental analysis and spectral data.
Figure 1. ORTEP diagram of compound 3.
Typical to alkyl heteroaromatic carbonitriles, com-
pound 3 reacted with arylidenemalononitrile 8 or ben-
zoylacetonitrile 9 in a basic medium to yield 8-amino-3-
methyl-1-oxo-6-aryl-1,2-dihydroisoquinoline-7-carboni-
trile 10 (Scheme 4). Compound 10 is formed most likely
via intermediates 11 and 12 (Scheme 4). Although in
case of benzoylacetonitrile, the reaction is believed to
proceed through the condensation of the carbonyl group
in benzoylacetonitrile with the methyl group to form
nonisolated intermediate 13, followed by the addition of
active methylene to the cyano group, and subsequent cy-
clization to dihydroisoquinolinecarbonitrile derivatives
10a (Scheme 4).
(Scheme 1), which then cyclizes into 2 (Scheme 1). The
latter undergoes a Dimorth-like rearrangement to yield
the final isolable product 3. Higher yield (80%) of 3
was obtained on replacing triethylamine with piprazine.
Although 3 may also exist in the form of structure 3a,
the oxo form 3 is the predominant as evidenced from
X-ray analysis (Deposit number CCDC 668767) [15]. The
crystal structure of compound 3 is shown in Figure 1.
X-ray crystallography. X-ray quality crystals of the
title compound 3 were obtained by slow crystallization
from dimethyl formamide [15]. The data was collected
with the maXus computer programs on a Bruker Nonius
instrument [16–20].
Compound 3 is condensed with chloroacetonitrile to
yield N-alkylated compound 3-cyano-1-(cyanomethyl)-
1,2-dihydro-4,6-dimethyl-2-pyridone 14, rather than
O-alkylated analog 2-(cyanomethoxy)-4,6-dimethylnico-
tinonitrile 15 (Scheme 5). The N-alkylated product 14 is
Interestingly, compound 3 was coupled with aryldiazo-
nium chloride to yield 3-cyano-4,6-dimethyl-5-(aryldia-
zenyl)-2-pyridone 4 or its tautomer 3-cyano-4,6-dimethyl-
5-(arylhydrazono)-2-pyridone 5 (Scheme 2). Although 4
Scheme 2
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A.-Z. A. Elassar
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Scheme 3
Scheme 4
coupled with aromatic diazonium salts to yield 3-cyano-
1-((2-arylhydrazono)cyanomethyl)-4,6-dimethyl-2-pyri-
done 16a–d (Scheme 5). The latter reacted with malo-
nonitrile, in a similar way to that reported for arylhy-
drazononitriles, to yield 5-amino-6-(3-cyano-4,6-di-
methyl-2-oxopyridin-1(2H)-yl)-3-imino-2-aryl-2,3-dihydro-
pyridazine-4-carbonitrile 18a–d via nonisolated intermedi-
ate 17 (Scheme 5).
Similarly, compound 3 is reacted with a-chloroacety-
lacetone to yield the N-alkylation product 3-cyano-1,2-
dihydro-1-(2,4-dioxopentan-3-yl)-4,6-dimethyl-2-pyridone,
19 (Scheme 6). The structure of the latter was established
based on elemental analysis and spectral data. Thus,
IR revealed the disappearance of the NH band, whereas
1H-NMR showed the dihydropyridine-H at d 6.12 ppm.
In contrast to the known behavior of alkylheteroaromatic
carbonitriles condensing 3 with DMFDMA afforded 3-
cyano-4-(2-(dimethylamino)vinyl)-6-methyl-2-pyridone 21
in low yield (Scheme 6), identified from gas chromatog-
raphy-mass spectrometry (GC/MS), which showed m/z
203; rather methylation of 3 took place in good yield. Al-
kylation of pyridones with N,N-dimethylformamide dime-
thylacetal (DMFDMA), has been reported recently [22].
The alkylation product can, thus, be assigned as struc-
tures 3-cyano-1,4,6-trimethyl-2-pyridone 20, or its iso-
meric form 2-methoxy-4,6-dimethylnicotinonitrile 22
(Scheme 6). Again, NOE difference experiments estab-
lished the structure as 20, as irradiating methyl group at
d 2.32 ppm enhanced other methyl group at d 2.41 ppm
indicating that both are especially proximal as would be
the case in 20 (cf. Scheme 6).
Scheme 5
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Synthesis and Reactions of 3-Cyano-4,6-dimethyl-2-pyridone
275
Scheme 6
Treating compound 19 with a nucleophilic reagents,
for example, hydrazine hydrate or phenylhydrazine has
afforded the compound, which may have either 3-cyano-
1,2-dihydro-1-(4,6-dimethyl-1,2-dihydro-2-pyridone-3-car-
bonyl)-4,6-dimethyl-2-pyridone 23 or 3-cyano-1-(3,5-di-
methyl-1H-pyrazol-4-yl)-4,6-dimethyl-1,2-dihydro-2-pyri-
done 24 (Scheme 7). The latter structure (24) was ruled
out based on mass spectrometry (MS) data (m/z 297),
which is in agreement with structure 23 (Scheme 7).
The following Scheme 8 illustrates the pathway for
the formation of product 23, which is believed to be
formed via the addition of nitrogen nucleophile to the
carbon electrophile of the cyano group in the other mol-
ecule to give the imine form, which is then converted to
the keto form under the reaction condition.
hyde or triethylamine. Bromination at C-5 of 3-cyano-
4,6-dimethyl-2-pyridone is investigated. Also, reactivity
of C-5 toward nitrogen electrophiles (aryldiazonium
salt) has been investigated to provide evidence for the
contribution of the charge separated resonance form typ-
ical to enamines. Alkylation of NH in the pyridone ring
with chloroacetylacetone and chloroacetonitrile has also
been studied.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded
1
in KBr with an IR spectrophotometer Shimadzu 408. H-NMR
and 13C-NMR spectra were recorded on Varian EM-390 MHz
spectrometer using tetramethylsilane (TMS) as internal stand-
ard reference, and chemical shifts are expressed as d ppm.
Mass spectra were measured on a Shimadzu GCMS-QP 1000
Ex mass spectrometer. Microanalytical data were obtained
from the Microanalytical Data Unit at Cairo University, Egypt.
3-Cyano-1,2-dihydro-4,6-dimethyl-2-pyridone (3). To a
solution of malononitrile (0.01 mol) in ethanol (50 mL), trie-
thylamine or piprazine or piprazinecarboxyaldehyde (0.01 mol)
CONCLUSIONS
In summary, using piprazine as a catalyst for the syn-
thesis of 3-cyano-4,6-dimethyl-2-pyridone was found to
be more efficient than the use of piprazinecarboxyalde-
Scheme 7
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A.-Z. A. Elassar
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Scheme 8
and acetylacetone (0.01 mol) were added. The solid product,
so formed, after 2, 8, and 12 min (in case of piprazine, pipra-
zine-1-carbaldehyde, and triethylamine, respectively), was left
for 2h at room temperature and then collected by filtration,
washed thoroughly with water, and then dried over sodium sul-
fate anhydrous.
Compound 7 was obtained as yellow crystals 84% from
DMF/EtOH, m.p. 198ꢀC; IR: 3445 (NH), 2224 cmꢁ1 (CN);
1H-NMR: d 10.82 (br, 1H, NH, D2O-exchange), 2.29, 2.21 (s,
6H, 2Me). 13C-NMR: d 179.86 (CO), 116.13 (CN), 161.41,
159.97, 151.35, 107.89 (pyridine carbons), 23.46, 21.51
(methyl carbons). MS: m/z 227, 228, 229 (Mþ, Mþ1, Mþ2);
Anal. Calcd. requires for C8H7BrN2O (227.06): C, 42.32; H,
3.11; N, 12.34. Found: C, 42.63; H, 3.29; N, 12.21.
8-Amino-3-methyl-1-oxo-6-phenyl-1,2-dihydroisoquinoline-
7-carbonitrile (11a) and 8-amino-6-(4-methoxphenyl)-
3-methyl-1-oxo-1,2-dihydroisoquinoline-7-carbonitrile
(11b). Method A. To a solution of 3 (0.01 mol), arylidene-
malononitrile (0.01 mol) in DMF (30 mL), triethylamine (0.5
mL) was added. The reaction mixture was refluxed for 5 h.
The reaction mixture was poured onto ice–cold water. The
resulting precipitated solid was collected by filtration and crys-
tallized from proper solvent.
Compound 3 was obtained as pale yellow crystals (80% in
case of piprazine, 73% in case of piprazinecarboxyaldehyde,
and 45% in case of triethylamine) from ꢁD1 MF/EtOH, m.p.
1
294ꢀC; IR: 3434 (NH), 2218 (CN), 1658 cm (CO); H-NMR:
d 12.32 (br, 1H, NH, D2O-exchange), 6.16 (s, 1H, pyridine-H),
2.30, 2.22 ppm (s, 6H, 2Me). 13C-NMR: d 163.01 (CO), 116.11
(CN), 153.22, 152.13, 117.21, 112.31(pyridine carbons), 22.12,
18.43 (methyl carbons). MS: m/z 148 (Mþ, 100%); Anal. Calcd.
requires for C8H8N2O (148.16): C, 64.85; H, 5.44; N, 18.91.
Found: C, 64.95; H, 5.36; N, 18.99.
3-Cyano-4,6-dimethyl-5-(phenyldiazenyl)-2-pyridone (4a),
3-cyano-5-(4-chlorophenyl-diazenyl)-4,6-dimethyl-2-pyridone
(4b), and 3-cyano-5-(4-nitrophenyldiazenyl)-4,6-dimethyl-2-
pyridone (4c). A mixture of 3 (0.01 mol) in DMF or pyridine
(30 mL), sodium hydroxide (1.0 g), the appropriate arene dia-
zonium chloride (0.01 mol) [prepared by adding sodium nitrite
(0.02 mol) to the appropriate primary aromatic amine (0.01
mol) in concentrated HCl (2 mL) at 0–5ꢀC while stirring] was
added dropwise while cooling at 0 to 5ꢀC and stirring. The
reaction mixture was left in fridge for 3h. The solid product
formed was filtered off and washed many times with water
and then crystallized from proper solvent.
Method B. To a solution of 3 (0.01 mol), benzoylacetoni-
trile (0.01 mol) in DMF (30 mL), triethylamine (0.5 mL) was
added. The reaction mixture was refluxed for 5 h. The reaction
mixture was poured onto cold water. The resulting precipitated
solid was collected by filtration and crystallized from proper
solvent.
Compound 11a was obtained as pale brown crystals 69%
from DMF/EtOH, m.p. 265–266ꢀC; IR: 3345–3223 (NH and
1
NH2), 2218 (CN), 1664 cmꢁ1 (CO); H-NMR: d 12.13, 10.43
(br, 3H, NH and NH2, D2O-exchange), 7.20–7.45 (m, 6H, aro-
matic protons), 6.16 (s, 1H, pyridine-H), 2.29 ppm (s, 3H,
Me). 13C-NMR: d 163.23 (CO), 156.12, 144.51, 142.13,
118.31, 112.02 (pyridine carbons), 148.31, 146.53, 141.64,
140.01, 132.12, 128.12, 112.11, 109.39 (aromatic carbons),
115.64 (CN), 21.14 ppm (Me). MS: m/z 275 (Mþ, 100%);
Anal. Calcd. requires for C17H13N3O (275.30): C, 74.17; H,
4.76; N, 15.26. Found: C, 74.00; H, 4.67; N, 15.36.
All the obtained compounds 4a–c are in agreement with
analysis with the literature data [21,23], melting point of 4a
283 to 284ꢀC lit. M.p. 285ꢀC [21], 4b > 300ꢀC; 4c > 300ꢀC
lit. M.p. > 280ꢀC [21].
Compound 4b was obtained as yellow crystals 7ꢁ81% from
EtOH, m.p. > 300ꢀC; IR: 3423 (NH), 2214 cm
(CN);
1H-NMR: d 12.10 (br, 1H, NH, D2O-exchange), 7.84–7.66
ppm (dd, 4H, C6H4, J ¼ 7.3 Hz), 2.54, 2.45 (s, 6H, 2Me).
MS: m/z 286 (Mþ, 100%); Anal. Calcd. requires for
C14H11ClN4O (286.72): C, 58.65; H, 3.87; N, 19.54. Found: C,
58.62; H, 3.78; N, 19.75.
5-Bromo-3-cyano-4,6-dimethyl-2-pyridone (7). To a solu-
tion of 3 (0.01 mol) in DMF/EtOH mixture (1:1, 50 mL), N-
bromosuccinimide (0.01 mol) was added. The reaction mixture
was refluxed for 3h. Excess solvent was evaporated under vac-
uum. Ice–cold water was then added. The solid product formed
was collected by filtration.
Compound 11b was obtained as brown crystals 71% from
DMF/EtOH, m.p. 216–218ꢀC; IR: 3345–3223 (NH and NH2),
1
2214 (CN), 1661 cmꢁ1 (CO); H-NMR: d 11.43, 10.34 (br, 3H,
NH and NH2, D2O-exchange), 7.20, 6.88 (d, 4H, C6H4, J ¼ 8.8
Hz), 7.32 (s, 1H, isoquinoline-H), 6.14 (s, 1H, pyridine-H), 3.75
(s. 3H, OMe), 2.29 ppm (s, 3H, Me). MS: m/z 305 (Mþ, 100%);
Anal. Calcd. requires for C18H15N3O2 (305.33): C, 70.81; H,
4.95; N, 13.76. Found: C, 70.68; H, 4.61; N, 13.66.
3-Cyano-1-(cyanomethyl)-1,2-dihydro-4,6-dimethyl-2-pyr-
idone (14). A mixture of 3 (0.01 mol) and chloroacetonitrile
(0.01 mol) in DMF (30 mL) containing potassium carbonate
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1
(0.14 g) was refluxed for 3 h. The reaction mixture was left
aside at room temperature overnight then poured onto ice–cold
water. The solid product, so formed, was filtered off, washed
by water (3 ꢂ 10), and dried over anhydrous sodium sulfate.
The solvent was removed in vacuo, and the residue was crys-
tallized from DMF/EtOH
2211 (CN), 1659 cmꢁ1 (CO); H-NMR: d 11.13 (br, 1H, NH,
D2O-exchange), 7.32, 6.33 (dd, 4H, C6H4, J ¼ 8.7 Hz), 6.06
(s, 1H, pyridine-H), 2.32, 2.20 ppm (s, 6H, 2Me). MS: m/z
336 (Mþ, 100%); Anal. Calcd. requires for C16H12N6O3
(336.30): C, 57.14; H, 3.60; N, 24.99. Found: C, 57.22; H,
3.54; N, 25.01.
Compound 14 was obtained as deep yellow crystals 72%,
5-Amino-6-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-
imino-2-phenyl-2,3-dihydropyridazine-4-carbonitrile (18a), 5-
amino-2-(4-chlorophenyl)-6-(3-cyano-4,6-dimethyl-2-oxopyridin-
1(2H)-yl)-3-imino-2,3-dihydropyridazine-4-carbonitrile (18b), 5-
amino-6-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-imino-
2-(4-methoxyphenyl)-2,3-dihydropyridazine-4-carbonitrile (18c),
and 5-amino-6-(3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-3-
imino-2-(4-nitrophenyl)-2,3-dihydropridazine-4-carbonitrile
(18d). To a solution of 16 (0.01 mol) and malononitrile (0.01
mol) in DMF (30 mL), piperidine (5–10 drops) was added.
The reaction mixture was refluxed for 3 h. The solid product,
so formed, was collected by filtration and crystallized from
proper solvent.
1
m.p. 213–217ꢀC; IR: 2210, 2217 (CN), 1656 cmꢁ1 (CO); H-
NMR: d 6.06 (s, 1H, pyridine-H), 4.12 (s, 2H, CH2), 2.34 2.23
ppm (s, 6H, 2Me). 13C NMR: d 157.76 (CO), 154.02, 149.13,
115.35, 111.21 (pyridine carbons), 116.21, 114.90 (CN), 32.23
(CH2), 19.45, 15.04 ppm (2Me). MS: m/z 187 (Mþ, 100%);
Anal. Calcd. requires for C10H9N3O (187.20): C, 64.16; H,
4.85; N, 22.45. Found: C, 64.26; H, 4.75; N, 22.34.
3-Cyano-1-((2-phenylhydrazono)cyanomethyl)-4,6-dimethyl-
2-pyridone (16a), 3-cyano-1-((2-p-chlorophenylhydrazono)cya-
nomethyl)-4,6-dimethyl-2-pyridone (16b), 3-cyano-1-((2-p-
methoxyphenylhydrazono)cyanomethyl)-4,6-dimethyl-2-pyri-
done (16c), and 3-cyano-1-((2-p-nitrophenylhydrazono)cya-
nomethyl)-4,6-dimethyl-2-pyridone (16d). A mixture of 14
(0.01 mol) in DMF (30 mL), sodium acetate (2.0 g), the appro-
priate arene diazonium chloride (0.01 mol) [prepared by add-
ing sodium nitrite (0.02 mol) to the appropriate primary aro-
matic amine (0.01 mol) in concentrated HCl (2 mL) at 0 to
5ꢀC while stirring] was added dropwise while cooling at 0 to
5ꢀC and stirring. The solid product formed was filtered off,
wash many times with water, and the solvent was evaporated
in vacuo, and then the residue was crystallized from proper
solvent.
Compound 18a was obtained as brown crystals 72% from
DMF/EtOH, m.p. char over 250ꢀC; IR: 3345–3221 (NH and
1
NH2), 2220, 2212 (CN), 1657 cmꢁ1 (CO); H-NMR: d 11.13,
10.42 (br, 3H, NH and NH2, D2O-exchange), 7.22- 6.37 (m,
5H, C6H5), 6.14 (s, 1H, pyridine-H), 2.29, 2.21 ppm (s, 6H,
2Me). 13C NMR: d 161.96 (CO), 153.93, 143.77, 115.15,
112.21 (pyridine carbons), 165.32, 155.12, 154.20, 79.38 (py-
ridazine carbon), 145.31, 128.65, 119.98, 116.24 (aromatic car-
bons), 116.09, 115.94 ppm (2CN). MS: m/z 357 (Mþ, 100%);
Anal. Calcd. requires for C19H15N7O (357.37): C, 63.86; H,
4.23; N, 27.44. Found: C, 64.01; H, 4.54; N, 27.64.
Compound 16a was obtained as deep yellow crystals 74%
from acetone/water (1:1), m.p. 242–243ꢀC; IR: 3322 (NH),
Compound 18b was obtained as yellow crystals 69% from
DMF/EtOH, m.p. char over 250ꢀC; IR: 3345–3223 (NH and
1
2216, 2211 (CN), 1656 cmꢁ1 (CO); H-NMR: d 11.12 (br, 1H,
1
NH, D2O-exchange), 7.33–6.14 (m, 5H, C6H5), 6.16 (s, 1H,
pyridine-H), 2.33, 2.21 ppm (s, 6H, 2Me). 13C-NMR: d 162.11
(CO), 154.29 (imine carbon), 118.31, 116.01 (2CN), 154.29,
143.42, 115.34, 109.55 (pyridine carbons), 143.12, 129.51,
118.72, 116.43 (aromatic carbons), 23.45, 21.49 ppm (methyl
carbons). MS: m/z 291 (Mþ, 100%); Anal. Calcd. requires for
C16H13N5O (291.11): C, 65.97; H, 4.50; N, 24.04. Found: C,
65.84; H, 4.55; N, 23.98.
NH2), 2221, 2210 (CN), 1657 cmꢁ1 (CO); H NMR: d 11.15,
10.41 (br, 3H, NH and NH2, D2O-exchange), 7.32, 6.33 (dd,
4H, C6H4, J ¼ 8.6 Hz), 6.16 (s, 1H, pyridine-H), 2.31, 2.22
ppm (s, 6H, 2Me). 13C-NMR: d 162.34 (CO), 154.34, 142.92,
116.41, 109.61, 107.25 (pyridine carbons), 164.93, 153.23,
145.32, 78.98 (pyridazine carbon), 143.45, 130.17, 124.83,
118.37 (aromatic carbons), 116.39, 115.94 (2CN), 14.64, 20.61
ppm (2Me). MS: m/z 391 (Mþ, 100%); Anal. Calcd. requires
for C19H14ClN7O (391.81): C, 58.24; H, 3.60; N, 25.02.
Found: C, 58.34; H, 3.56; N, 25.32.
Compound 18c was obtained as yellow crystals 75% from
EtOH, m.p. char over 250ꢀC; IR: 3345–3223 (NH and NH2),
2221, 2211 (CN), 1657 cmꢁ1 (CO); 1H-NMR: d 11.23, 10.53
(br, 3H, NH and NH2, D2O-exchange), 7.02, 6.35 (dd, 4H,
C6H4, J ¼ 8.9 Hz), 6.14 (s, 1H, pyridine-H), 3.67 (s,3H,
OMe), 2.32, 2.21 ppm (s, 6H, 2Me). 13C-NMR: d 162.32
(CO), 153.61, 143.34, 115.35, 112.02 (pyridine carbons),
164.34, 154.84, 152.92, 79.31 (pyridazine carbon), 151.07,
139.16, 118.13, 115.01 (aromatic carbons), 116.09, 115.79
(2CN), 56.02 (OMe), 14.14, 21.06 ppm (2Me). MS: m/z 387
(Mþ, 100%); Anal. Calcd. requires for C20H17N7O2 (387.39):
C, 62.01; H, 4.42; N, 25.31. Found: C, 62.20; H, 4.37; N,
25.34.
Compound 16b was obtained as yellow crystals 69% from
acetone/water (1:1), m.p. 230–232ꢀC; IR: 3422 (NH), 2216,
1
2212 (CN), 1657 cmꢁ1 (CO); H-NMR: d 11.11 (br, 1H, NH,
D2O-exchange), 7.12, 6.44 (dd, 4H, C6H4, J ¼ 8.6 Hz), 6.14
(s, 1H, pyridine-H), 2.32, 2.20 ppm (s, 6H, 2Me). 13C-NMR: d
162.23(CO), 154.56 (imine carbon), 118.19, 114.93 (2CN),
153.45, 142. 38, 116.54, 111.29 (pyridine carbons), 142.34,
130.37, 123.43, 118.27 (aromatic carbons), 23.42, 21.15 ppm
(methyl carbons). MS: m/z 325 (Mþ, 100%); Anal. Calcd.
requires for C16H12ClN5O (325.75): C, 58.99; H, 3.71; N,
21.50. Found: C, 59.04; H, 3.75; N, 21.56.
Compound 16c was obtained as yellow crystals 75% from
acetone/water (1:1), m.p. 221–223ꢀC; IR: 3422 (NH), 2218,
1
2212 (CN), 1658 cmꢁ1 (CO); H-NMR: d 11.23 (br, 1H, NH,
D2O-exchange), 7.22, 6.23 (dd, 4H, C6H4, J ¼ 8.9 Hz), 6.16
(s, 1H, pyridine-H), 3.63 (s, 3H, MeO), 2.34, 2.23 ppm (s, 6H,
2Me). MS: m/z 321 (Mþ, 100%); Anal. Calcd. requires for
C17H15N5O2 (321.33): C, 63.54; H, 4.71; N, 21.79. Found: C,
63.44; H, 4.75; N, 21.53.
Compound 18d was obtained as brown crystals 68% from
DMF/EtOH, m.p. char over 250ꢀC; IR: 3345–3223 (NH and
1
NH2), 2219, 2211 (CN), 1658 cmꢁ1 (CO); H-NMR: d 11.23,
10.50 (br, 3H, NH and NH2, D2O-exchange), 7.87, 6.72 (dd,
4H, C6H4, J ¼ 8.7 Hz), 6.16 (s, 1H, pyridine-H), 2.40, 2.32
ppm (s, 6H, 2Me). 13C-NMR: d 164.23 (CO), 157.17, 144.21,
Compound 16d was obtained as yellow crystals 75% from
acetone/water (1:1), m.p. > 250ꢀC; IR: 3422 (NH), 2218,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

278
A.-Z. A. Elassar
Vol 48
REFERENCES AND NOTES
115.54, 110.20 (pyridine carbons), 164.66, 155.21, 152.72,
90.21 (pyridazine carbon), 152.11, 140.24, 124.3, 117.7 (aro-
matic carbons), 116.12, 115.36 (2CN), 14.23, 21.06 ppm
(2Me). MS: m/z 402 (Mþ, 100%); Anal. Calcd. requires for
C19H14N8O3 (402.37): C, 56.72; H, 3.51; N, 27.85. Found: C,
56.64; H, 3.50; N, 28.02.
3-Cyano-1,2-dihydro-1-(2,4-dioxopentan-3-yl)-4,6-dimethyl-
2-pyridone (19). A mixture of 3 (0.01 mol) and 3-chloro-2,4-
pentandione (0.01 mol) in DMF (30 mL) containing potassium
carbonate (0.14 g) was refluxed for 3 h. The reaction mixture
was left aside at room temperature overnight then poured into
ice–cold water. The solid product, so formed, was filtered off
and washed with water.
[1] Aberg, V.; Das, P.; Chorell, E.; Hedenstrom, M.; Pinkner,
J. S.; Hultgren, S. J.; Almqvist, F. Bioorg Med Chem Lett 2008, 18,
3536.
[2] Pinkner, J. S.; Remaut, H.; Buelens, F.; Miller, E.; Aberg, V.;
Pemberton, N.; Hedenstrom, M.; Larsson, A.; Seed, P.; Waksman, G.;
Hultgrem, S. J.; Almqvist, F. Proc Natl Acad Sci USA 2006, 103, 17897.
[3] Aberg, V.; Sellstedt, M.; Hedenstrom, M.; Pinkner, J. S.;
Hultgren, S. J.; Almqvist, F. Bioorg Med Chem 2006, 14, 7563.
[4] Aberg, V.; Hedenstrom, M.; Pinkner, J. S.; Hultgren, S. J.;
Almqvist, F. Org Biomol Chem 2005, 3, 3886.
[5] Fujita, Y.; Oguri, H.; Oikawa, H. Tetrahedron Lett 2005,
46, 5885.
Compound 19 was obtained as deep yellow crystals 75ꢁ%1
[6] Verissimo, E.; Berry, N.; Gibbons, P.; Cristiano, M. L. S.;
Rosenthal, P. J.; Gut, J.; Ward, S. A.; O’Neill, P. M. Bioorg Med
Chem Lett 2008, 18, 4210.
from MeOH, m.p. 176ꢀC; IR: 2215 (CN), 1654–1640 cm
1
(CO); H-NMR: d 6.12 ppm (s, 1H, pyridine-H), 5.12 (br, 1H,
CH), 2.44, 2.37, 2.32, 2.24 ppm (s, 12H, 4Me). MS: m/z 246
(Mþ, 100%); Anal. Calcd. requires for C13H14N2O3 (246.26):
C, 63.40; H, 5.73; N, 11.38. Found: C, 63.34; H, 5.43; N,
11.53.
3-Cyano-1,4,6-trimethyl-2-pyridone (20). To a solution of
6 (0.01 mol) in DMF (30 mL), DMF DMA (0.01 mol) was
added. The reaction mixture was refluxed for 5 h. The solvent
was then evaporated in vacuo. The residue was triturated with
ice–cold water; the solid product, so formed, was collected by
filtration.
Compound 20 was obtained as yellow crystals 6ꢁ8%1 from
DMF/EtOH, m.p. 185ꢀC; IR: 2210 (CN), 1655 cm (CO);
1H-NMR: d 6.06 ppm (s, 1H, pyridine-H), 2.41, 2.39, 2.32 (s,
9H, 3Me). 13C-NMR: d 163.01 (CO), 116.11 (CN), 153.20,
152.23, 117.22, 112.33 (pyridine carbons), 24.11, 22.12, 18.43
(methyl carbons). MS: m/z 162 (Mþ, 100%); Anal. Calcd.
requires for C9H10N2O (162.19): C, 66.65; H, 6.21; N, 17.27.
Found: C, 66.32; H, 6.38; N, 17.53.
[7] Barral, K.; Balzarini, J.; Neyts, J.; De Clercq, E.; Hider, R. C.;
Camplo, M. J Med Chem 2006, 49, 43.
[8] Torres, M.; Gil, S.; Parra, M. Curr Org Chem 2005, 9, 1757.
[9] Semichenko, E. S.; Vasilenko, F. N.; Tovbis, M. S.; Yu
Belyae, E. Russ J Org Chem 2005, 41, 313.
[10] Mijin, D. Z.; Milic, B. D.; Misic-Vukovic, M. M.; Indian J
Chem Sec B: Org Chem Incl Med Chem 2006, 45B, 993.
[11] Mijin, D. Z.; Misic-Vukovic, M. M.; Indian J Chem Sec B:
Org Chem Incl Med Chem 1998, 37B, 988.
[12] Mijin, D. Z.; Misic-Vukovic, M. M. J Serb Chem Soc
1994, 59, 959.
[13] Ding, Y.; Hui, Q. Faming Zhuanl. Shenqing Gongkai Shuo-
mingshu 2001, 14.
[14] Mijin, D.; Marinkovic, A. Synth Commun 2006, 36, 193.
[15] CCDC 668767 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[16] Muin, D.; Uscumlic, G.; Perisic-Janjic, N.; Trkulja, I.;
Radetic, M.; Jovancic, P. J Serb Chem Soc 2006, 71, 435.
[17] Mackay, S.; Gilmore, C. J.; Edwards, C.; Stewart, N.;
Shankland, K. maXus Computer Program for the Solution and Refine-
ment of Crystal Structures; Bruker Nonius: Delft, The Netherlands and
MacScience: Japan and The University of Glasgow, 1999.
[18] Johnson, C. K. ORTEP–II. A FORTRAN Thermal–Ellipsoid
Plot Program. Report ORNL-5138; Oak Ridge National Laboratory:
Oak Ridge, Tennessee, 1976.
Compound 21 is agreement in analysis with the literature
data22.
3-Cyano-1,2-dihydro-1-(4,6-dimethyl-1,2-dihydro-2-pyridone-
3-carbonyl)-4,6-dimethyl-2-pyridone. A mixture of 19 (0.01
mol) and hydrazine hydrate or phenylhydrazine (0.01 mol) in a
dry dioxane (30 mL) was refluxed for 3 h.23 The solvent was
evaporated and then dissolved in methanol. Filtration of the
mixture gave mother liquor, which evaporated to give the
product.
Compound 23 was obtained as pale brown crystals 63%
from DMF, m.p. > 250ꢀC; IR: 3422 (NH), 2217 (CN), 1686,
1656 cmꢁ1 (CO); 1H-NMR: d 12.12 (br, 1H, NH, D2O-
exchange), 6.06 (s, 2H, 2pyridine-H), 2.45, 2.35, 2.31, 2.22
ppm (s, 12H, 4Me). 13C-NMR: d 163.01 (CO), 160.22 (CO),
116.23 (CN), 159.54, 149.32, 133601, 135.32, 112.11, 132.33,
131.60, 131.15. (pyridine carbons), 23.46, 22.89, 21.52, 2051
(methyl carbons). MS: m/z 297 (Mþ, 100%); Anal. Calcd.
requires for C16H15N3O3 (297.31): C, 64.64; H, 5.09; N,
14.13. Found: C, 64.54; H, 5.05; N, 14.31.
[19] Otwinowski, Z.; Minor, W. In Methods in Enzymology;
Carter, C. W., Jr.; Sweet, R. M., Eds.; Academic Press: New York,
1997; Vol. 276, p 307.
[20] Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M. C.; Polidori, G.; Camalli, M. J Appl Crystallogr 1994, 27, 435.
[21] Waasmaier, D.; Kirfel, A. Data activities in crystallography,
factor function for free atoms and ions. Acta Crystallogr 1995, A51, 416.
[22] Janin, Y. L.; Huel, C.; Flad, G.; Thirot, S. Eur J Org Chem
2002, 11, 1763.
[23] Elgemeie, G. E. H.; El-Zanate, A. M.; Mansour, A. E. Bull
Chem Soc Jpn 1993, 66, 555.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet