Michael addition of activated nitriles to 4[(+)-camphor-10′-sulfonylamino]-acetophenone and some of its chalcones

Article abstract of DOI:10.1080/10426500307861

4-[(+)-Camphor-10′-sulfonylamino]acetophenone (2) and some of its chalcones 3 were easily prepared in quantitative yields starting from (+)-camphor-10-sulfonyl chloride. Several new 2-oxo-, 2-thio-, as well as 2-amino-pyridines carrying the camphor sulfonylamino group as a substituent were synthesized easily in one step by Michael addition of several activated nitriles to compounds 2 and 3. The synthesis of some fused pyridines also was investigated.

Full text of DOI:10.1080/10426500307861

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Michael Addition of Activated Nitriles to 4[(+)-
Camphor-10′-Sulfonylamino]acetophenone and Some
of its Chalcones
Ashraf A. El-Shehawy a & Adel M. E. Attia a
a Tanta University , Egypt
Published online: 27 Oct 2010.
To cite this article: Ashraf A. El-Shehawy & Adel M. E. Attia (2003) Michael Addition of Activated Nitriles to 4[(+)-
Camphor-10′-Sulfonylamino]acetophenone and Some of its Chalcones, Phosphorus, Sulfur, and Silicon and the Related
Elements, 178:5, 1129-1142, DOI: 10.1080/10426500307861
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:1129–1142
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Copyright 2003 Taylor & Francis
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DOI: 10.1080/10426500390208965
MICHAEL ADDITION OF ACTIVATED NITRILES
TO 4[(+)-CAMPHOR-100-SULFONYLAMINO]-
ACETOPHENONE AND SOME OF ITS CHALCONES
Ashraf A. El-Shehawy and Adel M. E. Attia
Tanta University, Egypt
(Received July 1, 2002; accepted November 10, 2002)
4-[(+)-Camphor-100-sulfonylamino]acetophenone (2) and some of its
chalcones 3 were easily prepared in quantitative yields starting from
(+)-camphor-10-sulfonyl chloride. Several new 2-oxo-, 2-thio-, as well
as 2-amino-pyridines carrying the camphor sulfonylamino group as a
substituent were synthesized easily in one step by Michael addition of
several activated nitriles to compounds 2 and 3. The synthesis of some
fused pyridines also was investigated.
Keywords: , -unsaturated ketones; activated nitriles; camphor-10-
sulfonyl chloride; deazapyrimidines; pyridinethiones; pyridones
Over the last decade there has been widespread interest to the synthe-
sis of substituted-3-deazapyrimidines because of their potent biological
effects.1–7 Although many homochiral camphor-based derivatives have
been used extensively in asymmetric synthesis as either chiral auxil-
iaries or ligands in enantioselective catalysis,8–13 the use of camphor
as a substituent in heterocyclic compounds has been poorly studied.
As a part of our research directed at the development of new simple
and efficient procedures for the synthesis of several deaza analogs and
other antimetabolites,14–18 we report herein on a convenient one-step
synthesis of different new 2-oxo- and 2-thio-pyridines as well as the
2-aminopyridines, via Michael addition of activated nitriles to 4[(+)-
camphor-100-sulfonylamino]acetophenone and its chalcones by differ-
ent synthetic routes. The present study also aimed to define the scope
Address correspondence to Ashraf A. El-Shehawy, Chemistry Department, Faculty of
Education, Kafr El-Sheikh, Tanta University (Kafr El-Sheikh Branch), Egypt. E-mail:
elshehawy2@hotmail.com
1129

1130
A. A. El-Shehawy and A. M. E. Attia
and limitation of our procedures for the synthesis of some fused pyridine
derivatives.
RESULTS AND DISCUSSION
(+)-Camphor-10-sulfonyl chloride (1) was prepared according to the re-
ported method19. Amidation of 1 with 4-aminoacetophenone smoothly
afforded the corresponding 4-[(+)-camphor-100-sulfonylamino]aceto-
phenone (2) as the sole product. The IR spectrum of the sulfon-
amide 2 revealed the presence of strong absorptions at 1675 and
1
1740 cm assignable for the acetyl and camphor carbonyls, respec-
tively. 13C-NMR spectrum also shows the characteristic signals at
196.93 and 206.02 ppm attributed to the carbonyl groups of acetyl
and camphor moiety, respectively, indicating that the carbonyl of cam-
phor moiety was not involved in such reaction. Chalcones 3a–c have
been prepared by the Claisen-Schmidt condensation of 2 with ary-
laldehydes in refluxing ethanol (Scheme 1). The structure of chal-
cones 3a–c was supported by microanalytical and spectral data (see
Experimental).
As a part of this program directed to the synthesis of some pyridin-
2(1H)thiones, the synthesized acetophenone derivative 2 and its chal-
cones 3a–c were subjected to reactions with cyanothioacetamide and
some of its arylidenes. Thus, it has been found that compound 2 re-
acts with 3-arylidenecyanothioacetamide in boiling ethanol contain-
ing catalytic amounts of piperidine to yield a product for which the
pyridin-2(1H)thione structure 4 was considered (Scheme 1). Struc-
ture 4c, for example, was established based on 1H-NMR which re-
vealed the characteristic singlet signals at 6.95 and 12.24 ppm as-
signed to the pyridine 5-H and NH protons, respectively. Moreover,
13C-NMR spectrum of 4c shows the characteristic signals at 118.15
and 182.59 ppm attributed for the CN and C S groups, respectively, of
pyridine moiety. Formation of the pyridin-2(1H)thiones 4a–c from the
above reaction is assumed to proceed via Michael adduct20 22 by initial
addition of the methyl function in 2 to the activated double bond in
the arylidenecyanothioacetamide followed by spontaneous cyclization,
dehydration, and dehydrogenation to furnish the final isolable pyridin-
2(1H)thione derivatives 4a–c. The reaction is very simple to perform
and the pyridin-2(1H)thiones 4a–c precipitated in good yields from the
reaction mixture. It is worth mentioning that the synthesis of com-
pounds 4a–c also could be achieved by reacting the chalcones 3a–c with
cyanothioacetamide in refluxing ethanol containing catalytic amounts
of piperidine (Scheme 1). Microanalytical and spectral data also

Michael Addition of Activated Nitriles
1131
SCHEME 1
were found to be in agreement with the pyridin-2(1H)thione structures
4a–c.
Compound 4, with its latent functional substituent, was found to be
useful for the synthesis of fused pyridines. Thus, when compounds 4a–c
were subjected to the action of phenacyl bromide as alkylating agent,
the S-alkylated derivatives were not isolated, but cyclization to the cor-
responding thieno[2,3-b]pyridine derivatives 5a–c occurred (Scheme 1).
The IR spectrum of the thienopyridine 5c, for example, revealed the ab-
sence of a cyano band while 1H-NMR revealed the complete absence of
the pyridine NH signal in addition to the appearance of new broad sin-
glet signal at 6.54 ppm assignable to the amino function.
In another approach to the synthesis of some new substituted
2-oxo- and 2-amino-pyridines, compounds 2 and 3 were subjected

1132
A. A. El-Shehawy and A. M. E. Attia
to the reaction with ethylcyanoacetate and some of its arylidenes,
cyanoacetamide, as well as malononitrile. Under appropriate reaction
conditions, the study of such reaction also has been reported to
involve Michael addition followed by spontaneous cyclization, dehy-
dration, and dehydrogenation.21,23,24 Thus, the above-mentioned re-
action was investigated. In a one-step synthesis, reaction of 2 with
3-arylideneethylcyanoacetates in presence of excess ammonium acetate
afforded the desired product which proved by microanalytical and spec-
tral data to be the desirable 4,6-disubstituted-3-cyano-2(1H)pyridones
(6) (Scheme 2).
1H-NMR spectrum of 3-cyanopyridone 6a revealed the characteris-
tic signals at 6.66 and 12.13 ppm assigned to the pyridone 5-H and
N-H protons, respectively. Moreover, 13C-NMR spectrum showed the
signals at 117.52 and 166.37 ppm attributed to the cyano and carbonyl
groups, respectively, of the pyridone moiety. It is noteworthy that, un-
der similar reaction conditions, cyclocondensation of chalcones 3a–c
with ethylcyanoacetate yielded the same 3-cyano-2-pyridones 6a–c in
good yields (Scheme 2). The preparation of the same pyridones 6a–c
also was further achieved in a single step by reacting chalcones 3a–c
with cyanoacetamide in boiling ethanol containing catalytic amounts of
piperidine (Scheme 2). In all cases, microanalytical and spectral data of
the isolated products were found to be identical and in agreement with
the pyridone structure 6.
Reaction of compound 2 with arylidenemalononitriles in absolute
ethanol and in the presence of excess amount of ammonium acetate
also was investigated and smoothly led to the formation of the corre-
1
sponding 2-aminopyridines 7a–c in high yields (Scheme 2). H-NMR
spectrum of 7b showed, in addition to a signal assignable to the pyri-
dine 5-H, a broad singlet signal at 6.49 ppm attributed to an amino
group and its 13C-NMR revealed the characteristic signal at 116.97 ppm
assigned to the cyano group. Under similar reaction conditions, 2-
aminopyridines 7a–c also could be obtained by the reaction of chalcones
3a–c with malononitrile in presence of excess amount of ammonium ac-
etate (Scheme 2).
Finally, the preparation of well crystalline 1,2,4-triazolo[4,3-
a]pyridines 9a–c were achieved by acetylation of compounds 6a–c using
acetic anhydride followed by treatment of the obtained N-acetyl deriva-
tives 8a–c with hydrazine hydrate (Scheme 2). The IR spectra of the
1,2,4-triazolo[4,3-a]pyridines 9a–c revealed, in addition to the complete
absence of the acetyl and pyridone carbonyl bands of compounds 8a–c,
1
a characteristic band at 2220 cm attributed for the cyano group. The
structural assignment of the final products 9a–c also was based on
1H-NMR spectral data (see Experimental).

Michael Addition of Activated Nitriles
1133
SCHEME 2
In conclusion, the synthesized compounds obtained through these
results contain (+)-camphor-10-sulfonylamino group as a substituent
have high potential synthetic value and seem promising for further
chemical transformation as well as for biological evaluation studies.
Further works in this area are in progress.

1134
A. A. El-Shehawy and A. M. E. Attia
EXPERIMENTAL
Melting points are uncorrected. TLC (thin layer chromatography) was
carried out using Merck precoated silica gel plates (Merck 5554, 60F254
)
and the spots were detected with UV model UVGL-58. IR spectra were
recorded on Perkin-Elmer 1430 spectrophotometer using the KBr Wafer
Technique. H- and 13C-NMR spectra were recorded on a Varian EM-
1
400 MHz spectrometer using TMS as an internal reference and chem-
ical shifts are expressed in ppm units. Microanalytical data were
obtained by the microanalytical center at Cairo University. Molecular
rotation data were recorded at 20 C on a Perkin-Elmer 241 Polarimeter
(concentrations are given as g/100 ml of solvent).
Synthesis of 4-[(+)-Camphor-
100-sulfonylamino]acetophenone (2)
To a solution of (+)-camphor-10-sulfonyl chloride (1) (10 mmol) in 50 ml
of dry tetrahydrofuran cooled at 0 C was added triethylamine (1.4 ml,
10 mmol) and 4-aminoacetophenone (10 mmol). The reaction mixture
was stirred for 3 h at room temperature and then quenched with 2N-HCl
(25 ml). After evaporation of THF under vacuum, the resulting aqueous
solution was extracted with ether (3 25 ml). The combined extracts
were dried over MgSO4 and evaporated under reduced pressure to leave
the crude product 2 which was crystallized from EtOH/H2O.
m.p. 118 C; yield (3.35 g, 96%); [ ]D 64.5 (c 0.57, MeOH); (Found:
C, 61.90; H, 6.58; N, 4.07; S, 9.17. Calc. for C18H23NO4S: C, 61.87; H,
6.63; N, 4.01; S, 9.18%); max/cm 1 3165 (NH), 1740 (CO, camphor), 1675
(CO, acetyl);
(CDCl3) 0.94 (s, 3H, 80-CH3), 1.04 (s, 3H, 90-CH3), 1.4–
H
1.6 (m, 1H, CH), 1.95–2.2 (m, 5H, CH + 2CH2), 2.4–2.5 (m, 1H, CH),
2.64 (s, 3H, COCH3), 2.85 (d, 1H, J 16, CH), 3.2 (d, 1H, J = 16 Hz, CH),
7.31 (d, 2H, J = 8.31 Hz, Ar-H), 7.76 (d, 2H, J = 8.31 Hz, Ar-H), 7.85 (s,
1H, NH); C 19.07 (C-90), 19.73 (C-80), 25.35 (CH3CO), 27.56 (C-50), 32.1
(C-60), 35.74 (C-30), 43.09 (C-40), 47.33 (C-70), 48.66 (C-100), 58.87 (C-10),
126.2, 127.97, 129.09, 137.35 (Carom.), 196.93 (CH3CO), 206.1 (C-20).
Synthesis of the Chalcones 3 (General Procedure)
Few drops of 50% aqueous solution of potassium hydroxide were added
to a mixture of 2 (10 mmol) and arylaldehyde (10 mmol) in 50 ml of
ethanol. The reaction mixture was heated under reflux for 10 min. The
resulting yellowish white solid that separated on cooling was filtered
off and recrystallized from ethanol to afford the chalcone 3.

Michael Addition of Activated Nitriles
1135
3a: m.p. 158 C; yield (4.07 g, 93%); [ ]D 95.8 (c 0.45, CH2Cl2);
(Found: C, 68.67; H, 6.20; N, 3.24; S, 7.30. Calc. for C25H27NO4S: C,
68.62; H, 6.22; N, 3.20; S, 7.33%); max/cm 1 3200 (NH), 1735 (CO, cam-
phor), 1640 (Ar-CO); H (CDCl3) 0.89 (s, 3H, 80-CH3), 0.93 (s, 3H, 90-CH3),
1.4–1.55 (m, 1H, CH), 1.94–2.26 (m, 4H, 2CH2), 2.48–2.61 (m, 2H, CH2),
2.81 (br, s, 1H, NH), 2.95 (d, 1H, J = 14 Hz, CH), 3.22 (d, 1H, J = 14 Hz,
CH), 6.59 (d, 1H, J = 10.7 Hz, CH C), 7.02 (d, 1H, J = 10.9 Hz, CH C),
7.04–7.87 (m, 9H, Harom.); C 18.71 (C-90), 19.15 (C-80), 27.69 (C-50), 31.73
(C-60), 36.34 (C-30), 43.51 (C-40), 46.75 (C-70), 49.03 (C-100), 58.68 (C-10),
126.91, 128.16, 129.55, 130.82, 131.20, 133.05, 133.36 (Carom.), 136.94
(ArCH), 137.53 (ArCOCH), 198.19 (ArCO), 205.37 (C-20).
3b: m.p. 187 C; yield (4.29 g, 95%); [ ]D 49.3 (c 1.05, CH2Cl2);
(Found: C, 69.17; H, 6.38; N, 3.12; S, 7.05. Calc. for C26H29NO4S: C,
69.15; H, 6.47; N, 3.10; S, 7.10%); max/cm 1 3180 (NH), 1730 (CO, cam-
phor), 1640 (Ar-CO); H (CDCl3) 0.94 (s, 3H, 80-CH3), 1.03 (s, 3H, 90-CH3),
1.33–2.62 (m, 10H, CH + 3CH2 + Ar-CH3), 2.86 (br, s, 1H, NH), 3.11 (d,
1H, J = 14 Hz, CH), 3.28 (d, 1H, J = 14 Hz, CH), 6.34 (d, 1H, J 10.7,
CH C), 6.91 (d, 1H, J = 10.9 Hz, CH C), 7.09–7.78 (m, 8H, Harom.);
18.09 (C-90), 19.31 (C-80), 21.74 (Ar-CH3), 27.16 (C-50), 31.23 (C-60),
C
35.92 (C-30), 44.19 (C-40), 47.22 (C-70), 48.54 (C-100), 59.16 (C-10), 125.03,
127.22, 129.05, 132.10, 132.23, 133.09 (Carom.), 135.55 (ArCH), 138.92
(ArCOCH), 196.03 (ArCO), 205.91 (C-20).
3c: m.p. 141 C; yield (4.44 g, 95%); [ ]D 58.5 (c 0.59, CH2Cl2);
(Found: C, 66.77; H, 6.28; N, 3.00; S, 6.90. Calc. for C26H29NO5S: C,
66.79; H, 6.25; N, 2.99; S, 6.86%); max/cm 1 3220 (NH), 1730 (CO, cam-
phor), 1645 (Ar-CO);
(CDCl3) 0.88 (s, 3H, 80-CH3), 0.95 (s, 3H, 90-
H
CH3), 1.35–1.85 (m, 5H, CH + 2CH2), 2.11–2.43 (m, 2H, CH2), 2.60
(br, s, 1H, NH), 3.31 (d, 1H, J = 14 Hz, CH), 3.52 (d, 1H, J = 14 Hz,
CH), 3.75 (s, 3H, OCH3), 6.12 (d, 1H, J = 10.7 Hz, CH C), 6.77 (d,
1H, J = 10.9 Hz, CH C), 7.14–8.01 (m, 8H, Harom.),
18.85 (C-90),
C
19.71 (C-80), 27.24 (C-50), 32.54 (C-60), 35.61 (C-30), 42.08 (C-40), 47.64
(C-70), 49.62 (C-100), 55.59 (OCH3), 59.89 (C-10), 124.04, 125.09, 127.32,
128.17, 128.59, 131.15, 133.65, 135.49 (Carom.), 136.63 (ArCH), 137.07
(ArCOCH), 193.78 (ArCO), 204.11 (C-20).
Synthesis of 4,6-Disubstituted-3-cyanopyridin-
2(1H)thiones (4) (General Procedure)
To a mixture of 2 (10 mmol) and 3-arylidenecyanothioacetamide
(10 mmol) in absolute ethanol (50 ml), a few drops of piperidine were
added. The reaction mixture was heated under reflux for 4 h. The precip-
itated solid that separated on cooling was filtered off and recrystallized

1136
A. A. El-Shehawy and A. M. E. Attia
from ethanol to afford the products 4a (4.81 g, 93%), 4b (4.89 g, 92%),
and 4c (4.93 g, 90%), respectively.
The same procedure described above was applied as well to the reac-
tion of cyanothioacetamide (10 mmol) with the appropriate chalcone 3
(10 mmol). After refluxing for 5 h and the usual work-up procedure, the
same products 4a (4.55 g, 88%), 4b (4.84 g, 91%), and 4c (5.04 g, 92%),
respectively, were obtained.
4a: m.p. 192 C; [ ]D 99.3 (c 0.85, CHCl3); (Found: C, 64.99; H, 5.26;
N, 8.13; S, 12.40. Calc. for C28H27N3O3S2: C, 64.96; H, 5.26; N, 8.12; S,
1
12.39%); max/cm 3280 (NH), 2220 (CN), 1720 (CO).
4b: m.p. 139 C; [ ]D 103.9 (c 0.69, CHCl3); (Found: C, 65.57; H,
5.47; N, 7.93; S, 12.10. Calc. for C29H29N3O3S2: C, 65.51; H, 5.50;
1
N, 7.90; S, 12.06%); max/cm 3260 (NH), 2225 (CN), 1720 (CO);
H
(CDCl3) 0.79 (s, 3H, 80-CH3), 0.91 (s, 3H, 90-CH3), 1.13–1.25 (m, 1H,
CH), 1.34–1.95 (m, 5H, CH + 2CH2), 2.14–2.61 (m, 5H, CH + SO2NH
+ ArCH3), 3.08 (d, 1H, J = 13.5 Hz, CH), 3.17 (d, 1H, J = 13.5 Hz,
CH), 6.82 (s, 1H, pyridine 5-H), 7.22–8.18 (m, 8H, Harom.), 13.25 (s, br,
1H, NH); C 18.64 (C-90), 19.53 (C-80), 21.99 (ArCH3), 27.66 (C-50), 31.81
(C-60), 36.9 (C-30), 44.48 (C-40), 46.32 (C-70), 48.71 (C-100), 59.90 (C-10),
105.81 (C-3), 116.39 (CN), 120.45, 122.74, 125.47, 127.62, 130.29, 134.76
(Carom.), 141.32 (C-5), 145.91 (C-4), 154.85 (C-6), 180.39 (C-2), 209.54
(C-20).
4c: m.p. 167 C; [ ]D 39.7 (c 0.95, CHCl3); (Found: C, 63.61; H, 5.28;
N, 7.63; S, 11.70. Calc. for C29H29N3O4S2: C, 63.60; H, 5.34; N, 7.67; S,
1
11.71%); max/cm 3250 (NH), 2220 (CN), 1725 (CO);
(CDCl3) 0.85
H
(s, 3H, 80-CH3), 0.97 (s, 3H, 90-CH3), 1.38–2.48 (m, 7H, CH + 3CH2),
2.85 (br, s, 1H, SO2NH), 3.38 (d, 1H, J = 13.5 Hz, CH), 3.56 (d, 1H, J =
13.5 Hz, CH), 3.85 (s, 3H, OCH3), 6.95 (s, 1H, pyridine 5-H), 7.15–8.11
(m, 8H, Harom.), 12.24 (br, s, 1H, NH); C 18.75 (C-90), 19.83 (C-80), 27.42
(C-50), 31.98 (C-60), 35.90 (C-30), 45.88 (C-40), 46.74 (C-70), 49.04 (C-100),
56.34 (OCH3), 59.83 (C-10), 104.57 (C-3), 118.15 (CN), 126.05, 127.80,
128.83, 129.14, 131.62, 133.16, 134.56 (Carom.), 142.82 (C-5), 147.11 (C-
4), 154.37 (C-6), 182.59 (C-2), 211.35 (C-20).
Synthesis of 2,4-Disubstituted-5-amino-6-benzoyl-
thieno[2,3-b]pyridines (5) (General Procedure)
A mixture of pyridin-2(1H)thione 4 (10 mmol), K2CO3 (0.02 mmol), and
phenacyl bromide (0.01 mmol) in dry DMF (50 ml) was stirred overnight
at room temperature and then diluted with ice-cold water (50 ml). The
resulting solid product was collected by filtration and crystallized from
methanol to afford 5.

Michael Addition of Activated Nitriles
1137
5a: m.p. 178 C; yield (5.79 g, 91%); [ ]D 28.1 (c 0.35, CHCl3);
(Found: C, 68.05; H, 5.22; N, 6.65; S, 10.12. Calc. for C36H33N3O4S2: C,
1
68.01; H, 5.23; N, 6.61; S, 10.09%); max/cm 3320 (NH2), 3150 (NH),
1725 (CO, camphor), 1670 (CO, benzoyl); H (CDCl3) 0.86 (s, 3H, 80-CH3),
0.92 (s, 3H, 90-CH3), 1.03–1.56 (m, 2H, CH2), 1.73–1.99 (m, 3H, CH +
CH2), 2.12–2.57 (m, 3H, CH2 + SO2NH), 3.16 (d, 1H, J = 14 Hz, CH),
3.37 (d, 1H, J = 14 Hz, CH), 6.77 (br, s, 2H, NH2), 7.01 (s, 1H, pyridine
5-H), 7.19–8.13 (m, 14H, Harom.).
5b: m.p. 147 C; yield (5.85 g, 90%); [ ]D 74.3 (c 0.66, CHCl3);
(Found: C, 68.35; H, 5.37; N, 6.45; S, 9.80. Calc. for C37H35N3O4S2:
1
C, 68.39; H, 5.43; N, 6.45; S, 9.87%); max/cm 3350 (NH2), 3150 (NH),
1730 (CO, camphor), 1660 (CO, benzoyl).
5c: m.p. 132 C; yield (6.26 g, 94%); [ ]D 33.4 (c 0.57, CHCl3);
(Found: C, 66.80; H, 5.32; N, 6.28; S, 9.60. Calc. for C37H35N3O5S2:
1
C, 66.74; H, 5.30; N, 6.31; S, 9.63%); max/cm 3330 (NH2), 3130 (NH),
1730 (CO, camphor), 1660 (CO, benzoyl);
(CDCl3) 0.97 (s, 3H, 80-
H
CH3), 1.02 (s, 3H, 90-CH3), 1.16–1.68 (m, 3H, CH + CH2), 2.07–2.66 (m,
5H, SO2NH + 2CH2), 3.41 (d, 1H, J = 14 Hz, CH), 3.53 (d, 1H, J = 14
Hz, CH), 4.03 (s, 3H, OCH3), 6.54 (br, s, 2H, NH2), 6.88 (s, 1H, pyridine
5-H), 7.06–8.21 (m, 13H, Harom.).
Synthesis of 4,6-Disubstituted-3-cyano-
2(1H)pyridones (6)
Method A (General Procedure)
To a mixture of 2 (10 mmol) and ammonium acetate (30 mmol)
in 50 ml of absolute ethanol was added 3-arylideneethylcyanoacetate
(10 mmol). The reaction mixture was heated under reflux for 4 h and
then left to cool. The separated solid was filtered off and dried. After re-
crystallization from ethanol, the pyridones 6a (4.51 g, 90%), 6b (4.85 g,
94%), and 6c (4.94 g, 93%), respectively, were obtained.
The same procedure described above was applied as well to the re-
action of ethylcyanoacetate (10 mmol) with the appropriate chalcone 3
(10 mmol). After refluxing for 6 h and the usual work-up procedure, the
same products 6a (4.46 g, 89%), 6b (4.69 g, 91%), and 6c (4.89 g, 92%),
respectively, were obtained.
Method B (General Procedure)
To the appropriate chalcone 3 (5 mmol) in 25 ml of absolute ethanol,
5 mmol of cyanoacetamide and a few drops of piperidine were added.
The reaction mixture was heated to reflux for 12 h. The pyridone 6 pre-
cipitated on cooling was collected by filtration. A further crop of product
could be obtained by evaporation of the mother liquors. The combined

1138
A. A. El-Shehawy and A. M. E. Attia
crops were crystallized from ethanol to afford the same products 6a
(4.46 g, 89%), 6b (4.85 g, 94%), and 6c (4.78 g, 90%), respectively.
6a: m.p. 191 C; [ ]D 94.7 (c 1.03, CH2Cl2); (Found: C, 67.07; H, 5.41;
N, 8.40; S, 6.35. Calc. for C28H27N3O4S: C, 67.05; H, 5.42; N, 8.38; S,
6.39%); max/cm 1 3200 (NH), 2215 (CN), 1725 (CO, camphor), 1650 (CO,
pyridone);
(DMSO) 0.90 (s, 3H, 80-CH3), 0.95 (s, 3H, 90-CH3), 1.03–
H
1.55 (m, 3H, CH + CH2), 1.73–2.5 (m, 4H, 2CH2), 3.29 (d, 1H, J = 14 Hz,
CH), 3.44 (d, 1H, J = 14 Hz, CH), 4.89 (br, s, 1H, SO2NH), 6.66 (s, 1H,
pyridone 5-H), 7.17–8.02 (m, 9H, Harom.), 12.13 (br, s, 1H, pyridone NH);
C 18.63 (C-90), 19.40 (C-80), 26.81 (C-50), 30.94 (C-60), 34.55 (C-30), 41.97
(C-40), 46.70 (C-70), 48.14 (C-100), 58.20 (C-10), 107.08 (C-3), 113.34 (C-
4), 117.52 (CN), 127.95, 129.33, 130.52, 131.61, 133.21, 134.54, 137.86
(Carom.), 147.16 (C-5), 151.46 (C-6), 166.37 (C-2), 211.40 (C-20).
6b: m.p. 165 C; [ ]D 87.2 (c .83, CH2Cl2); (Found: C, 67.58; H, 5.60;
N, 8.20; S, 6.20. Calc. for C29H29N3O4S: C, 67.55; H, 5.67; N, 8.15; S,
1
6.22%); max/cm 3150 (NH), 2220 (CN), 1725 (CO, camphor), 1645
(CO, pyridone);
(DMSO) 0.92 (s, 3H, 80-CH3), 0.97 (s, 3H, 90-CH3),
H
1.02–1.56 (m, 3H, CH + CH2), 1.70–2.65 (m, 7H, 2CH2 + ArCH3), 3.22
(d, 1H, J = 14 Hz, CH), 3.43 (d, 1H, J = 14 Hz, CH), 5.26 (br, s, 1H,
SO2NH), 6.42 (s, 1H, pyridone 5-H), 7.05–7.99 (m, 8H, Harom.), 12.56 (br,
s, 1H, pyridone NH); C 18.70 (C-90), 19.33 (C-80), 22.65 (Ar-CH3), 26.57
(C-50), 31.61 (C-60), 34.13 (C-30), 42.50 (C-40), 46.63 (C-70), 47.41 (C-100),
57.84 (C-10), 105.57 (C-3), 114.72 (C-4), 118.01 (CN), 125.92, 127.13,
128.15, 130.01, 131.03, 132.99, 133.81 (Carom.), 147.64 (C-5), 152.66 (C-
6), 167.89 (C-2), 212.62 (C-20).
6c: m.p. 142 C; [ ]D 102.8 (c 1.66, CH2Cl2); (Found: C, 65.54; H,
5.49; N, 7.88; S, 6.10. Calc. for C29H29N3O5S: C, 65.52; H, 5.50; N, 7.90;
1
S, 6.03%); max/cm 3200 (NH), 2220 (CN), 1720 (CO, camphor), 1650
(CO, pyridone);
(DMSO) 0.95 (s, 3H, 80-CH3), 1.03 (s, 3H, 90-CH3),
H
1.22–2.49 (m, 7H, CH + 3CH2), 3.03 (d, 1H, J = 14 Hz, CH), 3.28 (d,
1H, J = 14 Hz, CH), 3.72 (s, 3H, OCH3), 5.02 (br, s, 1H, SO2NH), 6.60 (s,
1H, pyridone 5-H), 6.98–7.89 (m, 8H, Harom.), 12.85 (br, s, 1H, pyridone
NH);
18.62 (C-90), 19.13 (C-80), 26.27 (C-50), 30.63 (C-60), 33.71 (C-
C
30), 42.80 (C-40), 47.05 (C-70), 48.96 (C-100), 55.52 (OCH3), 58.20 (C-10),
108.33 (C-3), 113.58 (C-4), 117.62 (CN), 124.03, 127.04, 129.42, 130.08,
130.94, 131.50, 134.08 (Carom.), 150.14 (C-5), 152.31 (C-6), 163.82 (C-2),
213.85 (C-20).
Synthesis of 4,6-Disubstituted-2-amino-3-cyanopyridines
(7) (General Procedure)
A mixture of 2 (10 mmol), arylidenemalononitirile (10 mmol), and am-
monium acetate (20 mmol), absolute ethanol (50 ml) was heated under

Michael Addition of Activated Nitriles
1139
reflux for 4 h. The reaction mixture was concentrated to one half of its
volume. On cooling, the separated solid product was filtered off, dried,
and recrystallized from ethanol to afford 7a (4.61 g, 92%), 7b (4.63 g,
90%), and 7c (4.83 g, 91%), respectively.
The same procedure described above was applied as well to the re-
action of malononitirile (10 mmol) with chalcone 3 (10 mmol). After
refluxing for 6 h and the same work-up procedure, the same products
7a (4.40 g, 88%), 7b (4.68 g, 91%), and 7c (4.93 g, 93%), respectively,
were obtained.
7a: m.p. 231 C; [ ]D–87.3 (c 1.5, CHCl3); (Found: C, 67.20; H, 5.63;
N, 11.16; S, 6.37. Calc. for C28H28N4O3S: C, 67.18; H, 5.64; N, 11.19; S,
1
6.40%); max/cm 3370 (NH2), 3130 (NH), 2220 (CN), 1725 (CO).
7b: m.p. 175 C; [ ]D 108.8 (c 1.75, CHCl3); (Found: C, 67.74; H,
5.92; N, 10.86; S, 6.26. Calc. for C29H30N4O3S: C, 67.68; H, 5.87; N,
1
10.89; S, 6.23%); max/cm 3380 (NH2), 3145 (NH), 2210 (CN), 1730
(CO);
(CDCl3) 0.87 (s, 3H, 80-CH3), 0.92 (s, 3H, 90-CH3), 1.21–2.42
H
(m, 7H, CH + 3CH2), 2.49 (s, 3H, Ar-CH3), 3.64 (d, 1H, J = 14 Hz,
CH), 3.82 (d, 1H, J = 14 Hz, CH), 5.11 (br, s, 1H, NH), 6.49 (br, s, 2H,
NH2), 6.95–8.07 (m, 9H, Harom. + pyridine 5-H);
18.53 (C-90), 19.34
C
(C-80), 21.81 (ArCH3), 26.97 (C-50), 31.19 (C-60), 33.91 (C-30), 43.11 (C-
40), 46.33 (C-70), 48.56 (C-100), 58.12 (C-10), 116.97 (CN), 122.64 (C-4),
125.05, 128.86, 129.14, 131.76, 133.08, 134.56, 135.97 (Carom.), 135.97
(C-5), 146.04 (C-3), 151.07 (C-6), 154.57 (C-2), 209.91 (C-20).
7c: m.p. 202 C; [ ]D 77.3 (c 1.34, CH2Cl2); (Found: C, 65.61; H,
5.69; N, 10.51; S, 6.00. Calc. for C29H30N4O4S: C, 65.64; H, 5.70; N,
1
10.56; S, 6.04%); max/cm 3350 (NH2), 3140 (NH), 2220 (CN), 1725
(CO);
(CDCl3) 0.88 (s, 3H, 80-CH3), 0.94 (s, 3H, 90-CH3), 1.19–1.95
H
(m, 5H, CH + 2CH2), 2.22–2.39 (m, 2H, CH2), 3.59 (d, 1H, J = 14 Hz,
CH), 3.77 (d, 1H, J = 14 Hz, CH), 3.99 (s, 3H, OCH3), 5.27 (br, s, 1H,
NH), 6.36 (br, s, 2H, NH2), 7.00–8.09 (m, 9H, Harom. + pyridine 5-H);
C
17.56 (C-90), 19.03 (C-80), 27.45 (C-50), 31.90 (C-60), 34.22 (C-30), 42.73 (C-
40), 46.57 (C-70), 48.04 (C-100), 56.85 (OCH3), 59.06 (C-10), 117.17 (CN),
122.29 (C-4), 125.55, 127.66, 129.02, 129.18, 132.10, 133.09, 134.12
(Carom.), 132.30 (C-5), 142.87 (C-3), 150.45 (C-6), 155.15 (C-2), 210.15
(C-20).
Synthesis of 4,6-Disubstituted-1-acetyl-3-cyanopyridin-
2-ones (8) (General Procedure)
A mixture of pyridone 6 (10 mmol) and acetic anhydride (30 ml) was
heated under reflux for 3 h. The reaction mixture was allowed to cool to
room temperature and then poured onto ice-cold water. The separated
solid was filtered off, dried, and crystallized from ethanol to afford 8.

1140
A. A. El-Shehawy and A. M. E. Attia
8a: m.p. 161 C; yield (5.16 g, 95%); [ ]D 56 (c 1.25, CH2Cl2); (Found:
C, 66.33; H, 5.37; N, 7.72; S, 5.84. Calc. for C30H29N3O5S: C, 66.28; H,
1
5.38; N, 7.73; S, 5.90%); max/cm 3170 (NH), 2215 (CN), 1735 (CO,
camphor), 1695 (CO, acetyl), 1665 (CO, pyridone).
8b: m.p. 127 C; yield (5.35 g, 96%); [ ]D 63 (c 1.51, CH2Cl2); (Found:
C, 66.84; H, 5.58; N, 7.52; S, 5.77. Calc. for C31H31N3O5S: C, 66.78; H,
1
5.60; N, 7.53; S, 5.75%); max/cm 3150 (NH), 2220 (CN), 1745 (CO,
camphor), 1700 (CO, acetyl), 1660 (CO, pyridone);
(CDCl3) 0.95 (s,
H
3H, 80-CH3), 1.05 (s, 3H, 90-CH3), 1.28–2.54 (m, 10H, CH + 3CH2 +
ArCH3), 2.75 (s, 3H, CH3CO), 3.55 (d, 1H, J = 13.5 Hz, CH), 3.71
(d, 1H, J = 13.5 Hz, CH), 5.33 (br, s, 1H, NH), 6.49 (br, s, 1H, pyri-
done 5-H), 6.99–8.13 (m, 8H, Harom.); 17.89 (C-90), 19.90 (C-80), 22.42
C
(ArCH3), 26.90 (CH3CO), 27.44 (C-50), 32.80 (C-60), 35.19 (C-30), 42.07
(C-40), 46.23 (C-70), 48.07 (C-100), 59.68 (C-10), 104.69 (C-3), 111.54 (C-4),
115.87 (CN), 120.41, 122.08, 125.89, 127.86, 131.19, 132.45, 137.78
(Carom.), 149.70 (C-5), 154.92 (C-6), 166.72 (C-2), 197.55 (COMe), 210.97
(C-20).
8c: m.p. 98 C; yield (5.45 g, 95%); [ ]D 92.6 (c 1.34, CH2Cl2);
(Found: C, 64.93; H, 5.48; N, 7.33; S, 5.60. Calc. for C31H31N3O6S: C,
64.90; H, 5.45; N, 7.32; S, 5.59%); max/cm 1 3150 (NH), 2210 (CN), 1740
(CO, camphor), 1690 (CO, acetyl), 1670 (CO, pyridone); H (CDCl3) 0.93
(s, 3H, 80-CH3), 0.99 (s, 3H, 90-CH3), 1.28–2.58 (m, 7H, CH + 3CH2),
2.65 (s, 3H, CH3CO), 3.32 (d, 1H, J = 13.5 Hz, CH), 3.49 (d, 1H, J =
13.5 Hz, CH), 3.95 (s, 3H, OCH3), 5.15 (br, s, 1H, NH), 6.31 (br, s, 1H,
pyridone 5-H), 7.05–8.04 (m, 8H, Harom.);
18.40 (C-90), 19.71 (C-80),
C
27.30 (C-50), 28.74 (CH3CO), 32.69 (C-60), 36.33 (C-30), 42.59 (C-40), 45.93
(C-70), 47.90 (C-100), 53.43 (OCH3), 59.07 (C-10), 106.75 (C-3), 114.52 (C-
4), 116.87 (CN), 126.84, 127.57, 128.33, 128.55, 128.65, 130.17, 135.05
(Carom.), 152.68 (C-5), 154.70 (C-6), 165.88 (C-2), 195.92 (COMe), 210.08
(C-20).
Synthesis of 5,7-Disubstituted-3-methyl-8-cyano-1,2,4-
triazolo[4,3-a]pyridines (9) (General Procedure)
A mixture of 8 (10 mmol) and 98% hydrazine hydrate (3 ml) in absolute
ethanol (30 ml) was heated under reflux for 6 h. The reaction mixture
was left to cool and the separated solid product was filtered, dried, and
recrystallized from methanol to afford 9.
9a: m.p. 189 C; yield (4.75 g, 88%); [ ]D 81.2 (c 0.92, CH2Cl2);
(Found: C, 66.80; H, 5.42; N, 12.95; S, 5.91. Calc. for C30H29N5O3S:
1
C, 66.77; H, 5.42; N, 12.98; S, 5.94%); max/cm 3130 (NH), 2220 (CN),
1725 (CO);
(DMSO) 0.89 (s, 3H, 80-CH3), 0.95 (s, 3H, 90-CH3), 1.24–
H
2.51 (m, 10H, CH + 3CH2 + NCCH3), 3.34 (d, 1H, J = 14 Hz, CH), 3.46

Michael Addition of Activated Nitriles
1141
(d, 1H, J = 14 Hz, CH), 4.56 (br, s, 1H, NH), 6.89 (s, 1H, pyridine CH),
7.15–8.09 (m, 9H, Harom.).
9b: m.p. 206 C; yield (4.82 g, 87%); [ ]D 102.9 (c 0.1.1, CH2Cl2);
(Found: C, 67.29; H, 5.61; N, 12.64; S, 5.80. Calc. for C31H31N5O3S: C,
1
67.25; H, 5.64; N, 12.65; S, 5.79%); max/cm 3130 (NH), 2220 (CN),
1725 (CO).
9c: m.p. 155 C; yield (5.18 g, 91%); [ ]D 55.8 (c 1.22, CH2Cl2);
(Found: C, 65.39; H, 5.51; N, 12.34; S, 5.60. Calc. for C31H31N5O4S:
1
C, 65.36; H, 5.48; N, 12.29; S, 5.63%); max/cm 3130 (NH), 2220 (CN),
1730 (CO);
(DMSO) 0.91 (s, 3H, 80-CH3), 0.97 (s, 3H, 90-CH3), 1.3–
H
2.64 (m, 10H, CH + 3CH2 + NCCH3), 3.38 (d, 1H, J = 14 Hz, CH),
3.59 (d, 1H, J = 14 Hz, CH), 4.03 (s, 3H, OCH3), 5.15 (br, s, 1H, NH),
7.08–8.00 (m, 9H, Harom. + pyridine CH).
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