The use of 2-chloro-4H-4-oxo-pyrido[1,2-a]pyrimidine as a building block in the synthesis of some new heterocyclic compounds

Article abstract of DOI:10.1002/jhet.1036

New approaches for the synthesis of some heterocyclic compounds, such as the pyridopyrimidodiazepine derivative 3, pyrazolopyrido[1,2-a]pyrimidine derivative 4, tetrazolo[1.5-a][1,8]naphthyridine derivative 9, pyrazolylpyrido[1,2-a]pyrimidine derivatives 10a,10b,12, pyrrolopyrido[1,2-a] pyrimidine derivatives 14a, 14b, 14c, 14d, and 16a,16b, starting from 2-chloro-4H-4-oxo-pyrido[1,2-a]pyrimidine (1), are described.

Full text of DOI:10.1002/jhet.1036

Month 2013
The Use of 2‐Chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine
as a Building Block in the Synthesis of Some
New Heterocyclic Compounds
*
Doria S. Badawy, Noha M. Awad, and Ebrahim Abdel‐Galil
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt
*
E-mail: dr_doriah@hotmail.com
DOI 10.1002/jhet.1036
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
New approaches for the synthesis of some heterocyclic compounds, such as the pyridopyrimidodiazepine
derivative 3, pyrazolopyrido[1,2‐a]pyrimidine derivative 4, tetrazolo[1.5‐a][1,8]naphthyridine derivative 9,
pyrazolylpyrido[1,2‐a]pyrimidine derivatives 10a,b,12, pyrrolopyrido[1,2‐a]pyrimidine derivatives 14a‐d,
and16a,b, starting from 2‐chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine (1), are described.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
procedure [12]. It is well known that this type of
α‐haloheterocyclic compounds are susceptible to syntheti-
cally important nucleophilic substitution [13–16]. Thus,
treatment of compound 1 with hydrazine hydrate in
hot ethanol afforded 2‐hydrazinyl‐4H‐pyrido[1,2‐a]
pyrimdin‐4‐one (2) [17,18] as shown in Scheme 1.
Treatment of 2 with excess of benzalmalononitrile,
prepared by Knoevenagel condensation [19], in dry
dimethylformamid at 125–130°C for 2 h gives access to the
pyridopyrimidodiazepine derivative 3, or pyrazoloprido
[1,2‐a]pyrimidine derivative 4 [20] (Scheme 2).
The pyridopyrimidines are the most important and investi-
gated compounds among the family of the pyridodiazines.
These compounds have found many applications due to their
medicinal properties such as antibacterial [1], antiallergic [2],
inhibitor of enzyme adenosine kinase [3], or dihydrofolate
reductase [4], and irreversible inhibitor of epidermal growth
factor receptor [5]. In addition, many hetero‐fused pyrimi-
dines exhibit attractive cancer chemotherapy properties as
antitumor agents [6]. Risperidone, SSR6907, and ramastine
are derivatives of pyrido[1,2‐a]pyrimidin‐4‐one, which show
antipsychotic activity [7–9]. Dominguez et al. [10] reported
that some hetero‐fused tricyclic systems exhibited significant
antimalarial activity. It was cited that the biological reactivity
of this category of these compounds is essentially due to
presence of the pyrido[1,2‐a]pyrimidinone moiety in their
molecular structure [11]. Prompted with these investigations,
our strategy aimed at developing new approaches for the
synthesis of some new heterocyclic compounds of possible
biological activity using 2‐chloro‐4H‐4‐oxo‐ pyrido[1,2‐a]
pyrimidine (1) as a building block.
The elemental analysis and spectral data of the isolated
product are in consistent with the pyridopyrimido-
diazepene structure 3. Its IR spectrum showed absorption
bands at 3430, 3382, 3168 cm−1 for (NH2, NH) groups,
1
and 2217 cm−1 for (CN) group. The H‐NMR revealed
signals at δ = 2.45, 3.25 ppm integrated for C4‐H, C5‐H,
a singlet at 6.27 ppm attributed to NH2, a multiplet at
7.08–8.13 ppm assigned to (Ar‐H, NH), and a doublet at
9.11 ppm attributed to C‐6 proton The mass spectrum
showed a molecular ion peak [M+] at m/z = 330 which
was in agreement with its molecular weight. However, on
heating the pyridopyrimidodiazepine derivative 3 with 1N
HCl above 90°C for about 6 h, 3‐phenylpyrazolo[3,4‐d]
pyrido[1,2‐a]pyrimidin‐4(1H)‐one (4) was formed in low
yield (30%). The IR spectrum showed absorption bands
at 3257 for (NH) group, 1652 due to (C O) group, and
RESULTS AND DISCUSSION
The starting 2‐chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine
(1) was prepared following the corresponding literature
© 2013 HeteroCorporation

D. S. Badawy, N. M. Awad, and E. Abdel‐Galil
Vol 000
Scheme 1
via carbonyl ketene intermediates 7,8 [23]. The IR spectrum
of the product displayed an intense absorption band at 3122
cm−1 for (NH) group and mass spectrum of the reaction
product revealed a molecular ion peak [M+] at m/z = 187
which was in consistent with the molecular weight of both
6 and 9. However, the 1H‐NMR spectrum which revealed
a singlet at δ = 5.98 ppm assigned to olifenic proton at
C‐4 and 13C‐NMR spectrum which showed a signal at
δ = 90.98 ppm assigned to (C‐4), and a signal at δ =
159.63 ppm attributed to (C‐5) attached to enolic OH
of the naphthyridine derivative, supported structure 9,
and the other possible structure 6 was ruled out.
N
N
NH2.NH2.H2O
N
N
O
NH-NH2
O
Cl
1
2
1627 cm−1 for (C N) group. The 1H‐NMR revealed signals
at δ = 7.27–7.99 ppm assigned to (Ar‐H, NH) and a
doublet at 9.11 ppm attributed to C‐6 proton. The mass
spectrum showed a molecular ion peak [M+] at m/z = 262
which was in agreement with its molecular weight.
Then, we aimed to incorporate a fused pyrido[1,2‐a]
pyrimidine moiety into the 1‐position of the pyrazole
ring system to obtain new compounds which could be
expected to possess notable biological activity. This could
be readily achieved by the reaction of 2 with various 1,3‐
dicarbonyl compounds. Thus, compound 2 was reacted with
acetylacetone in ethanol under reflux for 2 h to give 2‐(3,5‐
dimethyl‐1H‐pyrazo‐1‐yl)‐4H‐pyrido[1,2‐a]pyrimidin‐4‐
one (10a) (Scheme 4).
Interaction of 2 with sodium nitrite in acetic acid under
cooling (0–5°C) afforded a single product (thin layer
chromatography; TLC analysis) for which two possible
structures has been assumed as shown in Scheme 3,
wherein the initially formed intermediate 5 can undergo
intramolecular cyclization via electrophilic attack either at
C‐3 to give the triazolopyrido[1,2‐a]pyrimidine derivative
6 or at N‐1 [21] followed by pyrimidine ring cleavage [22],
which leads to the tetrazolo[1,8]naphthyridine derivative 9
Scheme 2
N
N
N
N
N
N
O
NH
N
O
C6H5
C6H5
C6H5
N
N
NH2
NC
N
NH2
NC
3
DMF
heat
+
NH -NH2
O
NC CN
H+
N
O
NH
N
C6H5
4
Scheme 3
N
N
N
N
N
N
O
N
O
NH
HO
N
NH
N
+
N
N
N
HONO
N2
6
5
N
N
N
N
O
NH-NH2
+
-
+
- H
H
N
N
N
N
N
+
+
HONO
N2
N
H
N
..
O
N
O
+
N
N
O
H
8
5
7
- H
8
5
9
7
6
N
N
N
1
N
N
N
2
N
N
HO
N
O
N
H
4
3
9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Some New Heterocyclic Compounds
Using 2‐Chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine
Scheme 4
Scheme 5
R
N
N
N
N
N
N
11
N
R
EtOH
O
O
+
O
NH -NH2
O
N
N
O
NH
N
CH3 EtOH
OC2H5
R
OC2H5
O
O
N
N
O
R
CH3
+
O
NH- NH2
10a,b
AcOH
10a, R = CH3
10b, R = ph
AcOH
N
O
N
N
O
N
N
OH
O
N
The structure of 10a was supported by elemental analy-
sis and spectral data. The IR spectrum exhibited absorption
bands at 3072 cm−1 for aromatic (CH), 2923 cm−1 for
aliphatic (CH3), 1676 cm−1 for (C O) group, and 1631 cm−1
for (C N) group. The 1H‐NMR spectrum revealed two signals
at δ = 2.3 and 2.7 ppm integrated for the two methyl protons,
two singlets at 6.01 and 6.98 ppm assigned to C3‐H of the
pyrido[1,2‐a]pyrimidine moiety, C4‐H of the pyrazole
ring, other signals at 7.12–7.75 ppm attributed to three
aromatic protons and a doublet at 9.04 ppm assigned to
C6‐H. The mass spectrum gave a molecular ion peak
[M+ + 1] at m/z = 241.
O
N
O
N
N
HN
N
CH3
CH3
CH3
12
2926, 2857 cm−1 for (CH2, H3) groups, and 1685 cm−1 for
(C O) group. The H‐NMR revealed a singlet at δ = 2.26
1
ppm integrated for the methyl protons, a broad singlet at
δ = 5.98 ppm assigned to the C‐3 proton of the
pyridopyrimidine moiety, a multiplet at 6.85–7.89 ppm
integrated for (aromatic protons, NH), and a broad signal
at δ = 9.12 ppm assigned to the C‐6 proton. The mass
spectrum showed a molecular ion peak [M+] at m/z = 243.
In continuation of our investigation on the preparation of
new pyrido[1,2‐a]pyrimidines of potential biological inter-
est, it was thought to be interesting to synthesize com-
pounds containing the features namely, having pyrido
[1,2‐a]pyrimidine moiety fused with the pyrrole rings.
Attempts to prepare pyrido[1,2‐a] pyrrolopyrimidines by
analogy to the Fisher indole synthesis [24] were explored
by treating the hydrazones of 2, prepared by condensation
of 2 with various ketones, with acids such as polyphosphoric
acid or acetic acid.
To obtain polyheterocyclic compounds, our investigation
started from alicyclic ketones as precursors for the prepara-
tion of hydrazones. So, 2 was reacted with cyclohexanone,
4‐methylcyclohexanone, 4‐tert‐butylcyclohexanone, or 4‐
cyclohexylcyclohexanone in refluxing ethanol to afford the
corresponding hydrazones 13a–d. The formed hydrazones
13a–d were then treated with acetic acid at reflux for 4 h to
provide the pyrido[1,2‐a] pyrrolopyrimidine derivatives
14a–d (Scheme 6). Their structures were assigned on the
basis of elemental and spectral data. As an example, the IR
spectrum showed absorption bands at 3217 (NH), 2933,
2857 (CH2, aliphatic), 1658 (C O), and 1630 cm−1 (C N)
groups, and the mass spectrum gave a molecular ion peak
[M+] at ms: m/z 256 (M+) for compound 13a, and absorption
bands at 3217 cm−1 (NH) group, 2931, 2857 cm−1 for (CH2)
group, 1655 cm−1 due to (C O) group. 1H‐NMR revealed the
disappearance of the signal assigned to C3‐H of the
pyridopyrimidine moiety, and the mass spectrum gave a
molecular ion peak [M+1] at m/z = 243 for compound 14a.
Similarly, 2 was reacted with 1,3‐diphenylpropane‐1,3‐
dione in ethanol to give 2‐(3,5‐diphenyl‐1H‐pyrazo‐1‐yl)‐
4H‐pyrido[1,2‐a]pyrimidin‐4‐one (10b). The IR spectrum
of compound 10b showed absorption bands at 1683 cm−1
characteristic for (C O) group and 1631 cm−1 characteristic
1
for (C N) group. The H‐NMR spectrum revealed signals
at δ = 6.19 (s, 1H, C3‐H), 7.07–7.97 (m, 14 Ar‐H), 8.94
ppm (d, 1H, J = 6 Hz, C6‐H). The mass spectrum gave a
molecular ion peak [M+] at m/z = 364 which was in agree-
ment with its molecular weight.
In the case of ethylacetoacetate, when the reaction was
carried out in ethanol, ethyl 3‐(2‐(4‐oxo‐4H‐pyrido[1,2a]
pyrimidin‐2‐yl)hydrazonobutonoate (11) was obtained.
The structure of 11 was established based on the elemental
analysis and spectral data. The IR spectrum displayed
absorption bands at 3119 cm−1 for (NH) group, 1711 cm−1
due to (C O ester) group, 1691 cm−1 for (C O) group. The
1H‐NMR revealed a triplet and a singlet at δ = 1.30 and
2.02 ppm assigned to the two methyl protons, a quartet at
δ = 4.20 ppm integrated for the CH2 protons, and a singlet
at δ = 6.27 ppm attributed to the C‐3 proton, and a broad
doublet at δ = 8.20 ppm assigned to the NH proton. The
mass spectrum gave a molecular ion peak [M+ + 1] at
m/z = 289.
On the other hand, when the reaction was performed in
acetic acid, 2‐(3‐methyl‐5‐oxo‐2,5‐dihydro‐1H‐pyrazol‐1‐
yl)‐4H‐pyrido[1,2‐a]pyrimidin‐4‐one (12) was produced.
Compound 12 was also obtained on treatment of com-
pound 11 with acetic acid as shown in Scheme 5.
The structure of 12 was fully characterized by spectral
and elemental analyses. The IR spectrum exhibited absorp-
tion bands at 3434, 3122 cm−1 for (NH, enolic OH) groups,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. S. Badawy, N. M. Awad, and E. Abdel‐Galil
Vol 000
Scheme 6
[1,2‐a]pyrimidin‐4‐one (1) and hydrazine hydrate (99%, 1.5
mL) in ethanol (20 mL) was refluxed for 1 h, then the reaction
mixture was filtered while hot to give the title compound (2) as
yellow needles, yield 1.14 g (65%), mp, 238–240°C.
IR (potassium bromide): 3244, 3146 (NH, NH2), 3055 (Ar‐
CH),1686 (C O), 1636 (C N) cm−1; 1H‐NMR (deuteriochloroform):
δ 4.30 (brs, 2H, NH2), 5.57 (s, 1H, C3‐H), 6.94 (m, 1H), 7.16 (d,
1H, J = 3 Hz), 7.69 (m, 1H), 8.13 (s, 1H, NH), 8.67 ppm (d, 1H,
J = 6 Hz); ms: m/z 176 (M+), Anal. Calcd. for C8H8N4O: C,
54.54; H, 4.58; N, 31.80. Found: C, 54.52; H, 4.59; N, 31.81.
Synthesis of (E)‐3‐amino‐6‐oxo‐5‐phenyl‐1,4,5,6‐tetrahydro‐
pyrido[1′,2′:1,2]pyrimido[4,5‐c][1,2]diazepine‐4‐carbonitrile
(3). A solution of 1.76 g (10 mmol) of 2‐hydrazinyl‐4H‐pyrido
8
O
7
9
R
10
6
N
N
N
12
1
N
N
N
11
AcOH
EtOH
+
5
O
NH
N
O
NH
O
NH - NH2
R
4
R
2
3
14a-d
!3a-d
13a
13b R = 4- CH3
13c
13d
R = H
R = t-butyl
R = 4-cyclohexyl
[1,2‐a]pyrimidin‐4‐one (2) and 3.08
g
(20 mmol) of
benzalmalononitrile in 50 mL of dry DMF was heated at 125 –
130°C for 2 h. The solvent was removed from the reaction
mixture in vacuo, treated with water (75 mL), filtered off, and
recrystallized from ethanol to give the title compound as brown
powder, yield 1.52 g (87%), mp 144–146°C.
In a similar manner, cyclopentanone or 3‐methyl‐3‐
cyclopentenone reacted with 2 in ethanol under reflux to
give the corresponding hydrazone derivatives 15a,b,
followed by treatment with acetic acid to give the pyrido
[1,2‐a] pyrrolo pyrimidine products 16a,b (Scheme 7).
The structures of the isolated products were fully character-
ized through their elemental analysis and spectral data.
IR (potassium bromide): 3430, 3382 (NH2), 3168 (NH), 3058
(Ar‐H), 2217 (CN), 1658 (C O), 1633 (C N) cm−1 1H‐NMR
;
(deuteriochloroform): δ 2.45 (s, 1H, C4‐H), 3.25 (s, 1H, C5‐H),
6,27 (s, 2H, NH2), 7.98–8.13 (m, 9H, Ar‐H, NH), 8.82 (d, 1H,
J = 6.0 Hz); ms: m/z = 330 (M+). Anal. Calcd. for C18H14N6O:
C, 65.44; H, 4.27; N, 25.44. Found: C, 65.32; H, 4.22; N, 25.54.
EXPERIMENTAL
Synthesis of 3‐phenylpyrazolo[3,4 ‐d]pyrido[1,2‐a]pyrimidin‐
4(1H)‐one (4). A mixture of 3.30 g (0.01 mol) of compound 3 and
1N HCl (4 mL) in 20 mL ethanol was refluxed for 6 h. The reaction
mixture was poured into crushed ice, and the formed solid was then
filtered off, dried, and recrystallized from ethanol and benzene (1:1)
to obtain compound 4 as yellow powder, yield 0.79 g (30%,); mp
220–223°C.
IR: (potassium bromide): 3257 (NH), 3059 (Ar‐H), 1652
(C O), 1627 cm−1 (C N); 1H‐NMR (deuteriochloroform): δ
7.25–7.29 (m, 3H, Ar‐H), 7.42 (br s, 2H, Ar‐H), 7.71 (br d, 3H,
Ar‐H), 7.99 (s, 1H, NH), 9.11 (d, 1H, J = 4.2 Hz, C6‐H); ms:
m/z = 262 (M+). Anal. Calcd. for C15H10N4O: C 68.69; H, 3.84;
N, 21.36; found: C, 68.64; H, 3.80, N, 21.31.
Infrared (IR) spectra were recorded on MATSON 5000 FTIR
spectrometer with only selected absorption being recorded,
absorption maxima were recorded in cm−1. Nuclear magnetic
resonance (1H‐NMR) spectra were run at 1H‐NMR FX90Q
Varian‐Gemini 200 MHz spectrometer. Spectra were taken using
CDC13 or DMSO‐d6 as solvent with chemical shift quoted in part
per million (ppm) using TMS as internal standard. The mass
spectra (ms) were recorded using Joel TMS‐DX 303 (EL.
GC245) mass spectrometer. The melting points were measured
in an open capillary glass with Graffin melting apparatus and
were uncorrected. The purity of the synthesized compounds
was tested by TLC. Microanalyses were carried out by the
Microanalytical Unit, National Research Center, Dokki, Giza,
Cairo, Egypt, and Spectral Analysis Unit, Chemistry Depart-
ment, Mansoura University, Mansoura, Egypt.
Synthesis of tetrazolo[1,5‐a][1,8]naphthyridin‐5(3H)‐one
(9).
An aqueous solution of sodium nitrite (20%, 4.2 mL)
was slowly added in portions to a stirred mixture of 1.76 g
(0.01 mol) of 2‐hydrazinyl‐4H‐pyrido[1,2‐a]pyrimidin‐4‐one (2)
in acetic acid (40 mL) at 0–5°C. The reaction mixture was then
Synthesis of 2‐hydrazinyl‐4H‐pyrido[1,2‐a]pyrimidin‐4‐
one (2). A mixture of 1.82 g (0.01 mol) of 2‐chloro‐4H‐pyrido
Scheme 7
N
N
N
N
O
O
NH
N
O
8
NH
AcOH
EtOH
EtOH
N
N
16a
!5a
O
NH - NH2
7
O
6
CH3
9
N
N
5
N
N
AcOH
10
4
O
NH
O
NH
11
N
3
H3C
H3C
1
2
16b
15b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Synthesis of Some New Heterocyclic Compounds
Using 2‐Chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine
further stirred for 2 h at the same temperature, then it was diluted
with cold water, and the solid obtained was filtered off, washed
with water, dried, and recrystallized from ethanol to give
compound (4) as white powder, yield 1.25 g (67%), mp 156–158°C.
and recrystallized from ethanol to give compound (12) as dark
brown powder, yield 1.50 g (62%), mp 222–224°C; IR
(potassium bromide): 3434, 3122 (NH, enolic OH) 3034
(Ar‐H), 2926, 2857 (CH2, CH3),1685 (C O), 1622 (C N)
cm−1 1H‐NMR (deuteriochloroform): δ 1.61 (s, 2H, CH3),
;
IR (potassium bromide): 3122 (NH, or enolic OH), 2237,
2159, 2059, 1698 (C O), 1627 (C N), 1565, 1114, 1139 cm−1
;
2.20 (s, 3H, CH3), 5.45 (s, 1H, C3‐H), 6.85–7.89 (m, 5H,
Ar‐H, NH), 9.12 ppm (br d, 1H, C6‐H); ms: m/z 243 (M+).
Anal. Calcd. for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13.
Found: C, 59.7 8; H, 4.2 5; N, 23.27.
General procedure for the synthesis of Hydrazinyl‐4H‐pyrido
[1,2‐a]pyrimidin‐4‐one(13a–d), (15a,b). A mixture of 1.76 g
(0.01 mol) of 2‐hydrazinyl‐4H‐pyrido[1,2‐a]pyrimidin‐4‐one (2)
and ketone (0.01 mol) in 50 mL ethanol was refluxed for 4 h.
The reaction mixture was poured into crushed ice, and the
formed solid was then filtered off, dried, and recrystallized from
the suitable solvent to obtain pure products, (13a–d) and (15a–b).
1H‐NMR (deuteriochloroform): δ 5.92 (s, 1H, C4‐H), 7.15 (m,
1H), 7.56 (d, 1H, J = 9 Hz), 7.82 (br, 1H, enolic OH), 9.03
ppm (d, 1H, J = 6,9 Hz); 13C‐NMR (dimethyl sulfoxided6) δ
90.98 (C‐4), 116.23, 125, 128.17, 139.80, 151.12, 157.95,
159.63 ppm, ms: m/z 187 (M+). Anal. Calcd. for C8H5N5O: C,
51.34; H, 2.69; N, 37.42. Found: C, 51.50; H, 2.79; N, 37.22.
General procedure for the synthesis of 1H‐pyrazo‐1‐yl‐4H‐
pyrido[1,2‐a]pyrimidine‐4‐one (10a,b).
A mixture of 2‐
hydrazinyl‐4H‐pyrido[1,2‐a] pyrimidin‐4‐one (2) (0.01mol) and
1,3‐dicarbonyl compounds (0.01 mol) in 30‐mL absolute
ethanol was refluxed for 2 h. The reaction mixture was poured
into crushed ice, and the formed solid was then filtered off,
dried, and recrystallized from a suitable solvent to give pure
compound.
2‐(2‐Cyclohexylidenehydrazinyl)‐4H‐pyrido[1,2‐a]pyrimidin‐
4‐one(13a). Recrystallized from ethanol as white yellow powder,
yield 1.89 g (74%), mp 178–180°C; IR (potassium bromide): 3217
(NH), 2933, 2857 (CH2, aliphatic), 1658 (C O), 1630 (C N) cm−1;
1H‐NMR (deuteriochloroform): δ 1.68–1.85 (m, 6H, alicyclic‐H),
2.32–2.37 (m, 4H, alicyclic‐H), 6.24 (s, 1H, C3‐H), 6.89
(d, 1H, J = 4.2), 7.24 (d, 1H, J = 4.8 Hz), 7.59 (m, 1H), 7.89
(s, 1H, NH), 8.94 ppm (d, 1H, J = 4.2 Hz, C6‐H); ms: m/z
=256 (M+). Anal. Calcd. for C14H16N4O: C, 65.61; H, 6.29; N,
21.86. Found: C, 65.55; H, 6.26; N, 21.79.
2‐(3,5‐Dimethyl‐1H‐pyrazol‐1‐yl)‐4H‐pyrido[1,2‐a]pyrimidin‐
4‐one (10a). Recrystallized from ethanol as white crystals, yield
1.60 g (67%). mp, 202–204°C. IR (potassium bromide): 3072
(Ar‐H),2923 (CH3), 1676 (C O), 1631 (C N) cm−1 1H‐NMR
;
(deuteriochloroform): δ 2.29 (s, 3H, CH3), 2.71 (s, 3H, CH3),
6.01 (s, 1H, C3‐H, pyrido[1,2‐a]pyrimidine moiety), 6.98
(s, 1H, C4‐H, pyrazole ring), 7.12 (m, 1H), 7.55 (d, 1H, J = 8.8
Hz), 7.75 (m, 1H), 9.04 ppm (d, 1H, J = 7.4 Hz, C6‐H). ms:
m/z 241 (M+ + 1). Anal. Calcd. for C13H12N4O: C, 64.99; H,
5.03; N, 23.32. Found: C, 64.94; H, 5.10; N, 23.20
2‐(2‐(4‐Methylcyclohexylidene)hydrazinyl)‐4H‐pyrido[1,2‐
a]pyrimidin‐4‐one(13b). Recrystallized from ethanol as yel-
low powder, yield 1.86 g (69%), mp 192–194°C; IR (potassium
bromide): 3216 (NH), 2947, 2920, 2857 (CH3, CH2 aliphatic),
1
1657 (C O), 1633 (C N) cm−1; H‐NMR (deuteriochloroform): δ
Synthesis of 2‐(3,5 ‐diphenyl‐1H‐pyrazol‐1‐yl)‐4H‐pyrido
0.95 (s, 3H, CH3), 1.65–2.74 (m, 9H, alicyclic‐H), 6.22 (s, 1H,
C3‐H), 6.89 (m, 1H),7.25 (m, 1H), 7.59 (d, 1H, J = 9 Hz), 7.88
(s, 1H, NH), 8.94 ppm (d, 1H, J = 4.2 Hz, C10‐H); ms: m/z 270
(M+). Anal. Calcd. for C15H18N4O: C, 66.64; H, 6.71; N, 20.73.
Found: C, 66.55; H, 6.97; N, 20.70.
[1,2‐a]pyrimidin‐4‐one (10b).
Recrystallized from ethanol
as dark yellow needles, yield 2.80 g (77%), mp 136–138°C. IR
(potassium bromide): 3099, 3052 (Ar‐CH), 1683 (C O), 1631
(C N) cm−1; 1H‐NMR (deuteriochloroform): δ 6.19 (s, 1H, C3‐
H), 7.07–7.97 (m, 14 Ar‐H), 8.94 ppm (d, 1H, J = 6 Hz, C6‐H);
ms: m/z 364 (M+). Anal. Calcd. for C23H16N4O: C, 75.81; H,
4.43; N, 15.38. Found C, 75.79, H, 4.40; N, 15.31.
Ethyl 3‐(2‐(4‐oxo‐4H‐pyrido[1,2‐a]pyrimidin‐2‐yl)hydrazono]
butanoate (11). A mixture of 1.76 g (0.01 mol) of 2‐hydrazinyl‐
4H‐pyrido[1,2‐a]pyrimidin‐4‐one (2) and ethylacetoacetate
(0.01 mol) in 50 mL ethanol was refluxed for 5 h. The reaction
mixture was poured into crushed ice, and the formed solid
was then filtered off, dried, and recrystallized from ethanol to
give compound (12) as brown powder, yield 2.22 g (77%), mp
130–132°C.
IR (potassium bromide): 3375 (NH), 3072 (Ar‐H), 2919, 2850
(CH2, CH3), 1711 (C O, ester), 1691 (C O), 1628 (C N) cm−1; 1H‐
NMR (deuteriochloroform): δ 1.30 (s, 3H, CH3), 2.02 (s, 3H,
CH3), 3.40 (s, 2H, CH2), 4.20 (q, 2H, OCH2CH3), 6.27 (s, 1H,
C3‐H), 6.95 (br s, 1H),7.30 (d, 1H, J = 8 Hz), 7.65 (br s, 1H),
7.88 (s, 1H, NH), 8.99 ppm (br s, 1H, C6‐H); ms: m/z 289 (M+
+ 1). Anal. Calcd. for C14H16N4O3: C, 58.32; H, 5.59; N,
19.43. Found C, 58.33; H, 5.55; N, 19.40.
2‐(2‐(4‐tert‐Butylcyclohexylidene)hydrazinyl)‐4H‐pyrido
[1,2‐a]pyrimidin‐4‐one (13c).
Recrystallized from etha-
nol as yellow powder, yield 1.68 g (54%), mp 188–190°C;
IR (potassium bromide): 3239 (NH), 2949, 2863 (CH3, CH2‐
aliphatic), 1655 (C O), 1623 (C N) cm−1
;
1H‐NMR
(deuteriochloroform):
δ 0.86 (s, 9H, (CH3)3), 1.24–2.83
(m, 9H, alicyclic‐H) 6.25 (s, 1H, C3‐H), 6.90 (m, 1H), 7.25
(d, 1H, J = 3.6 Hz), 7.60 (m, 1H), 7.88 (s, 1H, NH), 8.95
ppm (d, 1H, J = 4.2, C6‐H); ms: m/z 312 (M+). Anal. Calcd.
for C18H24N4O: C, 69.20; H, 7.74; N, 17.93. Found: C, 69.00;
H, 7.64; N, 17.91.
2‐(2‐(Bi(cyclohexane)‐2‐ylidene)hydrazinyl)‐4H‐pyrido
[1,2‐a]pyrimidin‐4‐one(13d). Recrystallized from ethanol
as yellow powder, yield 2.83 g (84%), mp 118–120°C; IR
(potassium bromide): 3190 (NH), 2925, 2852 (CH2‐aliphatic),
1
1670 (C O), 1634 (C N) cm−1; H‐NMR (deuteriochloroform):
δ 1.14–2.32 (m, 20H, alicyclic‐H), 6.26 (s, 1H, C3‐H), 6.91 (br
s, 1H), 7.25 (br s, 1H) 7.50 (br s, 1H), 7.89 (s, 1H, NH), 8.95
ppm (br, s, 1H, C6‐H); ms: m/z 338 (M+). Anal. Calcd. for
C20H26N4O: C, 70.98; H, 7.74; N, 16.55. Found: 70.88; H,
7.61; N, 16.50.
2‐(3‐Methyl‐5‐oxo‐2,5‐dihydro‐1H‐pyrazol‐1‐yl)‐4H‐pyrido
[1,2‐a]pyrimidin‐4‐one (12). A mixture of 1.76 g (0.01 mol) of
2‐hydrazinyl‐4H‐pyrido[1,2‐a]pyrimidin‐4‐one
ethylacetoacetate (0.01 mol) or ethyl‐3‐[(4‐oxo‐4H‐pyrido[1,2‐a]
pyrimidin‐2‐yl)hydrazono]butanoate (11) in 20 mL acetic acid
was refluxed for 5 h. The reaction mixture was poured into
crushed ice, and the formed solid was then filtered off, dried,
(2)
and
2‐(2‐Cyclopentylidenehydrazinyl)‐4H‐pyrido[1,2‐a]pyrimidin‐
4‐one (15a). Recrystallized from ethanol as yellow powder, yield
2 g (83%), mp 250–252°C; IR (potassium bromide): 3246 (NH),
1
2958, 2924 (CH2 aliphatic), 1688 (C O), 1636 (C N) cm−1; H‐
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. S. Badawy, N. M. Awad, and E. Abdel‐Galil
Vol 000
NMR (deuteriochloroform): δ 1.24–2.50 (m, 8H, alicyclic‐H), 6.22
(s, 1H, C3‐H), 6.91 (br s, 1H), 7.25 (br s, 1H), 7.51 (br s, 1H), 7.75
(s, 1H, NH), 8.95 ppm (br s, 1H, C6‐H); ms: m/z 242 (M+). Anal.
Calcd. for C13H14N4O: C, 64.45; H, 5.82; N, 23.13. Found: C,
64.40; H, 5.80; N, 23.11.
(m, 4H, Ar‐H, NH), 8.89 (d, 1H); ms: m/z 225 (M+). Anal. Calcd.
for C14H11N3O: C, 69.32; H, 4.92; N, 18.66. Found: C, 69.34; H,
4.90; N, 18.66.
1‐Methyl‐3,4‐dihydro‐11H‐[1]cyclopentapyrrolo[2′,3′,4,5]
pyrido[1,2‐a]pyrimidin‐11‐one (16b). Recrystallized from
ethanol as brown powder, yield 1.35 g (57%) mp 266–268°C; IR
(potassium bromide): 3200 (NH), 2902 (CH3), 1650 (C O) cm−1;
1H‐NMR (deuteriochloroform): δ 2.01 (s, 3H, CH3), 3.25 (s, 2H,
CH2), 6.74–7.94 (m, 5H, Ar‐H, NH), 8.91 (d, 1H); ms: m/z 237
(M+). Anal. Calcd. for C14H11N3O: C, 70.87; H, 4.67; N, 17.71.
Found: C 70.85; H, 4.61; N, 17.66.
2‐(2‐(3‐Methylcyclopent‐2‐enylidene)hydrazinyl)‐4H‐pyrido
[1,2‐a]pyrimidin‐4‐one (15b). Recrystallized from ethanol as
yellow powder, yield 1.88 g (74%), mp 232–234°C; IR (potassium
bromide): 3202 (NH), 2968, 2902 (CH3, CH2 aliphatic), 1656
1
(C O), 1629 (C N) cm−1; H‐NMR (deuteriochloroform): δ 1.25–
2.00 (m, 4H, 2CH2), 2.59 (s, 3H, CH3), 6.07 (s, 1H, CH C), 6.21
(s, 1H, C3‐H), 6.91–7.61 (m, 4H, Ar‐H, NH), 8.96 ppm (brs, 1H,
C‐6H); ms: m/z 254 (M+), Anal. Calcd. for C14H14N4O: C, 66.13;
H, 5.55; N, 22.03. Found: C, 66.11; H, 5.53; N, 22.00.
REFERENCES AND NOTES
General procedure for the synthesis of pyrido[1,2‐a]
pyrrolopyrimidines. A mixture of (0.01 mol) of hydrazinylpyrido
[1.2‐a]pyrimidine derivative 13a–d and 15a,b, and aliphatic
ketone (0.01 mol) in 20 mL acetic acid was refluxed for 4 h. The
reaction mixture was poured into crushed ice, and the formed
solid was then filtered off, dried, and recrystallized from the
suitable solvent to obtain pure products, (14a–d) and (16a,b).
[1] Hiber, B. S.; Valenti, B. F. J Med Chem 1968, 11, 708.
[2] (a) Althins, T. H.; Moore, P. E.; Hess, H. J. J Med Chem 1979,
22, 44; (b) Althins, T. H.; Kadin, S. B.; Czuba, I. J.; Moore, P. F.; Hess, H.
J Med Chem 1980, 23, 262.
[3] (a) Cowart, M.; Lee, C. ‐H.; Gfesser, G. A.; Baybutt, E. K.;
Bhagwat, S. S.; Stewart, A. O.; Yu, H.; Kohlhass, K. L.; McGaraughty,
S.; Wismer, C. T.; MIkusa, J.; Zhu, C.; Alexander, K. M.; Jarvis, M. F.;
Kowaluk, E. A. Bioorg Med Chem Lett 2001, 11, 83; (b) Glesser, G.
A.; Baybutt, E. K.; Cowart, M.; DiDomenico, S.; Gomtsyan, A.; Lee, C.
‐H.; Stewart, A. O.; Jarvis, M. F.; Kowaluk, E. A.; Bhagwat, S. S. Eur J
Med Chem 2003, 38, 245.
[4] Smaill, J. B.; Palmer, B. D.; Rewcastle, G. W.; Denny, W. A.;
McNamar Dobrusin, E. M.; Bridges, A. J.; Zhou, H.; Showalter, H. D. H.;
Winters, R. T.; Leapold, W. P.; Fry, D. W.; Nelson, J. M.; Slintak, V.; Elliot,
W. L.; Roberts, B. J.; Vincent, P. W.; Patmore, S. J Med Chem 1999, 42, 1803.
[5] Wang, S.; Folkes, A.; Chuckowree, I.; Cockcroft, X.; Sohal,
S.; Miller, W.; Milton, J.; Wren, S. P.; Vicker, N.; Depledge, P.; Scott,
J.; Smith, L.; Jones, H.; Mistry, P.; Faint, R.; Thompson, D.; Cocks, S.
J Med Chem 2004, 47, 1329.
[6] Bruno, O.; Brullo, C.; Schenone, S.; Bondavalli, F.; Ranise,
A.; Tognolini, M.; Impicciatore, M.; Ballabeni, V.; Barocelli, E. Bioorg
Med Chem 2006, 14, 121.
[7] (a) Josephine, K. L. E.; Aloysius, P. S. M.; Paul, B. F. PCT Int
Appl WO2000020422 A120000413, 2000; (b) Josephine, K. L. E.;
Aloysius, P. S. M.; Paul, B. F. Chem Abstr 265 188t.
[8] (a) Josephine, K. L. E.; Keybus, V. D.; Alfons, F. M.; Carolus,
M. J. PCT Int Appl WO2000020421 A2 20000413, 2000; (b) Josephine,
K. L. E.; Keybus, V. D.; Alfons, F. M.; Carolus, M. J. Chem Abstr 265187c.
[9] Dominguez, J.; Charris, J.; Iarrusso, L.; Lopez, S.; Lobo, G.;
Riggione F. Farmaco 1996, 51, 781.
1,2,3,4‐Tetrahydro‐ pyrido[1′,2′: 1,2]pyrimido[4,5‐b]indol‐
12(5H)‐one(14a). Recrystallized, from ethanol as dark brown
powder, yield 1.29 g (53%), mp 270–272°C; IR (potassium
bromide): 3217 (NH), 1638 (C O) cm−1; 1H‐NMR
(deuteriochloroform): δ 1.68–2.35 (m, 8H), 6.94–7.65 (m, 4H, Ar‐
H, NH), 8.89 (d, 1H); ms: m/z 243 (M+). Anal. Calcd. for
C14H13N3O: C, 70.28; H, 5.48; N, 17.56. Found: C, 69.75; H,
5.20; N, 17.71.
2‐Methyl‐1,2,3,4‐tetrahydro‐pyrido[1′,2′: 1,2]pyrimido[4,5‐
b]indol‐12(5H)‐one (14b). Recrystallized from ethanol as
yellow powder. yield 1.87 g (74%), mp 242–244°C, IR
(potassium bromide):3220 (NH), 2925 (CH3), 1660 (C O)
cm−1 1H‐NMR (deuteriochloroform): δ 0.95 (s, 3H, CH3),
;
1.64–2.68 (m, 7H, alicyclic‐H), 6.93 (m, 1H),7.23 (m, 1H),
7.55 (brd, 1H), 7.83 (s, 1H, NH), 8.91 ppm (d, 1H); ms: m/z
253 (M+). Anal. Calcd. for C15H15N3O: C, 71.13; H, 5.97; N,
16.59. Found: C, 70.93; H, 5.87; N, 16.66%.
2‐tert‐Butyl‐1,2,3,4‐tetrahydro‐pyrido[1′,2′:1,2]pyrimido
[4,5‐b]indol‐12(5H)‐one (14c). Recrystallized from etha-
nol as a yellow powder, yield 1.53 g (52%), mp 252–254°C; IR
(potassium bromide): 3336 (NH), 2955 (CH3), 1660 (C O)
[10] Katritzky, A. R.; Rogers, J. W.; Witek, R. M.; Nair S. K.
ARKIVOC 2004, 8, 52.
[11] Snyder, H. R.; Robison, M. M. J Am Chem Soc 1952, 74, 4910.
[12] Katritzky, A. R.; Waring, A. J. J Chem Soc 1962, 1544.
[13] di Braccio, M.; Roma, G.; Mazzei, M.; Balbi, A.; Schiantarelli,
P.; Cadel, S.; Bongrani, S. Farmaco 1988, 43, 705.
cm−1 1H‐NMR (deuteriochloroform): δ 0.91 (s, 9H, (CH3)3),
;
1.44–2.85 (m, 7H, alicyclic‐H), 7.25 (m, 1H), 7.42 (d, 1H),
7.60 (m, 1H), 7.88 (s, 1H, NH), 8.95 ppm (brd, 1H);ms: m/z
295 (M+). Anal. Calcd. for C18H21N3O: C, 73.19; H, 7.17; N,
14.23. Found: C, 73.22; H, 7.14; N, 14.13.
[14] Plug, C.; Frank, W.; Wentrup, C. J Chem Soc Perkin Trans
1999, 2, 1087.
[15] Snyder, H. R.; Robison, M. M. J Am Soc 1952, 74, 4910.
[16] Oakes, V.; Rydon, H. N. J Chem Soc 1958, 209.
[17] Ingalls, E. A.; Popp, F. D. J Heteocyclic Chem 1967, 4, 523.
[18] (a) Emerson, W. S.; Patric. T. M. J Org Chem 1949, 14, 795;
(b) Popp, F. D.; Catala, A. J Org Chem 1961, 26, 2738.
[19] Dipak, P.; Partha, P. B.; Balkuntha, J. G.; Jaglir, S. S. Beilstein
J Org Chem 2006, 2, 5.
[20] Chaitanya, G. D.; Rina, D. S. Molecules 2002, 7, 554.
[21] Snyder, H. R.; Robison, M. M. J Am Soc 1952, 74, 5945.
[22] Fiksdahl, A.; Plug, C.; Wentrup, C. J Chem Soc Perkin Trans
2002, 2000, 1841.
2‐Cyclohexyl‐1,2,3,4‐tetrahydro‐pyrido[1′,2′: 1,2]pyrimido
[4,5‐b]indol‐12(5H)‐one (14d). Recrystallized from ethanol
as yellow powder, yield 1.96 g (61%) mp 222–224°C; IR
(potassium bromide): 3197 (NH), 1638 (C O) cm−1; 1H‐NMR
(deuteriochloroform): δ 1.24–2.62 (m, 18H, alicyclic‐H), 6.98
(brs, 1H), 7.25 (brs, 1H) 7.54 (brs, 1H), 7.89 (s, 1H, NH), 8.97
ppm (brs, 1H); ms: m/z 321 (M+). Anal. Calcd. for C20H23N3O:
C, 74.74; H, 7.21; N, 13.07. Found: C, 74.24; H, 7.11; N, 13.46.
1,2,3,4‐Tetrahydro‐11H‐[1]cyclopentapyrrolo[2′,3′:4,5]
pyrido[1,2‐a]pyrimidin‐11‐one
(16a).
Recrystallized
from ethanol as yellow powder, yield 1.73 g (77%), mp 220–
222°C; IR (potassium bromide): 3218 (NH), 1661 (C O) cm−1
1H‐NMR (deuteriochloroform): δ 0.84–1.83 (m, 6H), 6.94–7.65
[23] Robinson, B. The Fisher Indole Synthesis; Wiley: Chichester, 1982.
[24] (a) Rosowsky, A.; Chen, H.; Fu, H. J Org Chem 2001, 66,
7522; (b) Rosowsky, A.; Chen, H.; Fu, H.; Queener, S. F. Bioorg Med
Chem 2003, 11, 59.
;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet