Novel synthesis of condensed pyridin-2(1H)-one and pyrimidine derivatives

Article abstract of DOI:10.1080/10426500307793

The reaction of N-chloroacetyl derivatives 6-10 with morpholine yielded N-morpholin-1-yl acetyl derivatives 11-15, which were subjected to Thorpe-Zieler cyclization with sodium tert-butoxide to produce the corresponding condensed pyridin-2(1H)-one derivat

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Phosphorus, Sulfur, and Silicon and the Related
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Novel Synthesis of Condensed Pyridin-2(1H)-one and
Pyrimidine Derivatives
A. M. M. Soliman a , A. Khodairy a & E. A. Ahmed a
a Chemistry Department, Faculty of Science, Sohag, Egypt
Available online: 27 Oct 2010
To cite this article: A. M. M. Soliman, A. Khodairy & E. A. Ahmed (2003): Novel Synthesis of Condensed Pyridin-2(1H)-one and
Pyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:4, 649-665
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Phosphorus, Sulfur and Silicon, 2003, Vol. 178:649–665
C
Copyright 2003 Taylor & Francis
1042-6507/03 $12.00 + .00
DOI: 10.1080/10426500390197959
NOVEL SYNTHESIS OF CONDENSED
PYRIDIN-2(1H)-ONE AND PYRIMIDINE DERIVATIVES
A. M. M. Soliman, A. Khodairy, and E. A. Ahmed
Chemistry Department, Faculty of Science, Sohag, Egypt
(Received February 24, 2002; accepted June 9, 2002)
The reaction of N-chloroacetyl derivatives 6–10 with morpholine
yielded N-morpholin-1-yl acetyl derivatives 11–15, which were sub-
jected to Thorpe-Zieler cyclization with sodium tert-butoxide to pro-
duce the corresponding condensed pyridin-2(1H)-one derivatives 16–
20. Treatment of compounds 1, 6–10 with either malononitrile or p-
chlorobenzylidinemalononitrile in presence of triethylamine, afforded
the corresponding pyrimidines 21–25, 27 and pyridine derivative 26
respectively. Moreover compound 1a was treated with ethyl isothio-
cyanoacetate to give the corresponding piprazine derivative 28.
Keywords: Pyridin-2-ones; pyrimidines; Thorpe-Ziegler cyclization
Recently, pyridin-2(1H)-one derivatives were synthesized by new pro-
cedures via the reaction of ylidinenitriles with either active methylene
reagents1 or with halocompounds and hydrazine.2 The importance of
the synthesized pyridine and pyrimidine derivatives as intermediates
for the synthesis of biological active deaza and folic acid ring systems3–6
prompted us to continue our previous work7–11 on the synthesis of
pyridine-2(1H)-one and pyrimidine derivatives.
The intramolecular ring closure reaction by Thorpe-Ziegler cycliza-
tion gives rise to amino substituted heterocycles, which otherwise would
require a multistep synthesis. Electron-withdrawing groups usually ac-
tivate the methylene group for an attack at the nitrile carbon.12 Now, it
was found that even electron donor substituted methylene groups un-
dergo the Thorpe-Ziegler cyclization when a basic catalytic system like
potassium tert-butoxide/dimethyl sulfoxide is employed.12
Address correspondence to A. Khodairy, Department of Chemistry, Faculty of Science,
Sohag, 82524, Egypt. E-mail: khodairy@yahoo.com
649

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A. M. M. Soliman et al.
RESULTS AND DISCUSSION
The starting materials, namely, 3,4-diamino-2,5-dicyano-, 3,4-diamino-
2,5-dicarbethoxy-, 3,4-diamino-2-cyano-5-carbethoxy-, or 3,4-diamino-
13
2,5-dibenzoyl thieno(2,3-b)thiophene 1a–d
,
2-amino-3-cyano-4,5,6,
7-tetrahydrobenzo[b]thiophene 2,14 2-amino-3-cyano-(5H)-4-phenyl-
thiophene 3,14 2,6-diamino-3,5-dicyano-4-phenylthiopyran 4,15 2-
amino-3-cyano-4-phenyl-5,6,7,8-tetrahdro-4H-chromene 5a,16 and
16
2-amino-3-cyano-4-phenyl-1,4,5,6,7,8-hexahydroquinoline 5b
were
treated with chloroacetyl chloride and triethylamine to afford the
corresponding N-chloroacetylated derivatives 6–10 respectively, (c.f.
Scheme 1, Table I), which in turn were allowed to react with morpholine
SCHEME 1

651

652

653

654

655

656

657

658

659

660
A. M. M. Soliman et al.
SCHEME 2

Novel Synthesis of Condensed Pyridin-2(1H)-One and Pyrimidine Derivatives 661
and triethylamine to give the corresponding N-morpholin-1-yl acetyl
derivatives 11–15 respectively.
Compounds 11–15 were subjected to Thorpe-Ziegler11 cyclization
with sodium tert-butoxide in dimethyl sulphoxide as a solvent to yield
pyridin-2(1H)-one derivatives 16–20 respectively. IR spectra of com-
pounds 16–20 showed the presence of absorption bands correspond-
ing to OH, NH2 groups in addition to CO group at 3450 cm 1, 3320,
1
1
3200 cm 1, and 1670 cm respectively. H-NMR spectra showed the
disappearance of the signal corresponding to the methylene group
COCH2-N and the appearance of new peaks at 6.50–6.00 ppm and
5.00 ppm for NH2 and OH groups, respectively (c.f. Scheme 2, Eq. (1),
Table I). The reaction pathway was assumed to involve either a nucle-
ophilic addition of the formed carbanion of the active methylene group
at the CN group or a nucleophilic attack of the methylene group at the
COester or COketone with elimination of ethanol or water molecule (c.f.
Scheme 2, Eq. (1), Table I).
(1)
Treatment of the N-chloroacetylated derivatives 6–10 with malonon-
itrile and triethylamine afforded the corresponding pyrimidine7 deriva-
tives 21–25 (c.f. Scheme 3). The pyridine 26 and pyrimidine 27 deriva-
tives were obtained via the treatment of compound 1b,d or 6b,d with
p-chlorobenzylidinemalononitrile. IR spectra of these compounds 21–
27 showed the absorption bands corresponding of OH, NH, NH2, CN,
1
and CO groups at 3440, 3300, 3219–3100, 2210, and 1690 cm respec-
tively. 1H-NMR spectra are in agreement with the proposed structures
(c.f. Schemes 3 and 4, Table I).
Moreover compound 1a was treated with ethyl isothiocyanoacetate
to give the corresponding piprazine derivative 28 (Eq. (2), Table I).
(2)

662
A. M. M. Soliman et al.
SCHEME 3
EXPERIMENTAL
Synthesis of Compounds 6–10 (General Procedure)
To a solution of compound 1–5 (0.01 mmol) in dioxan (30 ml) and triethy-
lamine (1 ml), was added chloroacetyl chloride (0.01 mmol) dropwise
with stirring. The reaction mixture was refluxed for 5 h, evaporated in
vacuo and the residual solid was washed with water, dried, and crys-
tallized from the appropriate solvent (c.f. Scheme 1, Table I). (In case
of products 6 and 9, we used double ratio of chloroacetyl chloride).

Novel Synthesis of Condensed Pyridin-2(1H)-One and Pyrimidine Derivatives 663
SCHEME 4
Synthesis of Compounds 11–15 (General Procedure)
An equimolar amount (0.02 mmol) of compound 6–10 and morpholine
were dissolved in dioxan (30 ml). The reaction mixture was treated with
triethylamine (1 ml), refluxed for 5 h and concentrated. The precipi-
tated solid was collected by filtration, washed with water, dried, and
crystallized from the appropriate solvent (c.f. Scheme 2, Table I). (In
case of products 11 and 14, the used of morpholine was 0.02 mmol).
Synthesis of Compounds 16–20 (General Procedure)
To a solution of compound 11–15 (0.005 mmol) in dry DMSO (10 ml), was
added sodium tert-butoxide (0.006 mmol of Na in 5 ml of tert-butanol).
The reaction mixture was stirred in an oil bath 100 C for 1 h. On cooling,

664
A. M. M. Soliman et al.
the mixture was poured into ice-water (40 ml) with 3 N HCl (10 ml), the
separated solid was collected by filtration, dried, and crystallized from
the appropriate solvent (c.f. Scheme 2, Table I).
Synthesis of Compounds 21–25 (General Procedure)
To a solution of compound 6–10 (0.01 mol) in dioxan (20 ml), were added
malononitrile (0.01 mmol) and triethylamine (1 ml). The reaction mix-
ture was refluxed for 3 h, evaporated in vacuo, the residual solid was
washed with water, dried, and crystallized from the suitable solvent
(c.f. Scheme 3, Table I). (In case of products 21 and 24, the used of
malononitrile was 0.02 mmol).
Synthesis of Compounds 26 and 27 (General Procedure)
A solution of compound 1b,d or 6b,d (0.02 mmol) in DMF (10 ml), was
treated with p-chlorobenzylidinemalononitrile (0.02 mmol) and triethy-
lamine (1 ml). The reaction mixture was refluxed for 8 h, evaporated in
vacuo, the residual solid was washed with water, dried, and crystallized
from the appropriate solvent (c.f. Scheme 4, Table I).
Synthesis of Compound 28
A
mixture of compound 1a (0.01 mmol), isothiocyanoacetate
(0.01 mmol), and pyridine (20 ml) was refluxed for 3 h. The reaction
mixture was poured into ice water (20 ml) and HCl (5 ml), the precip-
itate was filtered off, dried, and crystallized from ethanol (c.f. Eq. (2),
Table I).
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