Synthesis of some new spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines

Article abstract of DOI:10.3987/com-99-8797

3-Methylpyrazolin-5-ones (1a,b) were reacted with cycloalkanones (2a-d) in the presence of fused sodium acetate to give the corresponding cycloalkylidene derivatives (3a-h). Reaction of compounds (3a-h) with malononitrile gave the pyrano derivatives (4a-h), which were cyclized to pyranopyrimidines with acetic anhydride/pyridine, formamide and formamide/formic acid.

Full text of DOI:10.3987/com-99-8797

HETEROCYCLES, Vol. 53, No. 3, 2000, pp. 621 - 628, Received, 4th Nobember, 1999
SYNTHESIS OF SOME NEW SPIROPYRAZOLO[4',5' :5,6]-
PYRANO [2,3-d] PYRIMIDINES
Marzoog S. A1-Thebeiti
Department of Chemistry, Faculty of Applied Sciences, Umm Al-Qura University,
Makkah Almukkarramah, P O Box 6876, Saudi Arabia
Abstract - 3-Methylpyrazolin-5-ones (1a,b) were reacted with cycloalkpyranones (2a-d)
in the presence of fused sodium acetate to give the corresponding cycloalkylidene
derivatives (3a-h). Reaction of compounds (3a-h) with malononitrile gave the pyrano
derivatives (4a-h), which were cyclized to pyranopyrimidines with acetic
anhydride/pyridine, formamide and formamide/formic acid.
Nitriles were used as starting materials to prepare a viarity of condensed pyransl-5 for their medicinal
Importance.6,7 Spiro derrvatrves have anticonvulant antibactenal antitubercula and anticancer actrvrtres.8,9
l1,12
Also spiroheterocycles were used as nitric oxide synthesis inhibitors,10 photoisomerization
and potential
topical agents for vaginal infection.13 It is of interest to note that pyrazoles are reported as well
pharmaceuticalsl4-17 and pyrimidines derivatives have been used as adenosine kinase inhibitors.18 From this
point of view and in continuation to our previous work,19-28 we report herein the synthesis of
spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines in the hope that members of them could fmd interesting
biological applications.
3-Methyl-4-cycloalkylidenepyrazolin-5-ones (3a-h) were prepared by the reaction of 3-methylpyrazolin-5-
ones (la,b) with 1 -indanone (2a), 1 -tetralone (2b), fllourenone (2c) and anthrpyranone (2d) in the presence of
fused sodium acetate. The structures of compounds (3a-h) were established from their elemental analyses and
spectroscopic data (Table 1 ). The IR spectrum of 3b showed absorption band at 1710 cm-1 for the carbonyl
1
group of pyrazoline ring. The H-NMR spectrum of 3b (DMSO-d6) showed the following signals: δ2.30 (3H,
s, CH3 group at C3 of the pyrazoline ring), 2.40-2.50 (4H, m, 2 CH2 groups of indan ring) and 7.00-8.15
(9H, m, the aromatic protons of the phenyl group at the nitrogen of the pyrazolinone moiety and the indan
protons). The MS spectrum of 3b showed the molecular ion peak at (m/z, o/o relative intensity) 288 (100) and
the following fragments: 217 (2), 174 (90), 132 (20), 1 15 (30), 91 (70), 77 (95).

It is pertinent to mention here that compounds (3a-d) where formed to be mixture of two geometrica isomers,
Z and E.29 The major E were purified and were reacted with malononitrile. Reaction of 3a-h with
malononitrile in ethanol in the presence of piperidine as a basic catalyst gave the corresponding pyrano[2,3-
c]pyrazole (4a-h) (Scheme l ).
The IR spectrum of 4b showed the following characteristic absorption bands at 2200 cm-1 (CN); 3040,
1
3140 cm-1 (NH2). The H-NMR (CDC13) spectrum showed the following signals: δ2.40-2.60 (4H, m, 2 CH2),
2.25 (3H, s, CH3), 9.80 (2H, s, NH2), 7.00-8.20 (9H, m, arom.).
Reaction of 6-amino-5-cyano-3-methyl- 4 -spiropyrano[2,3-c]pyrazole (4a-h) with acetic anhydrid/ pyridine

mixture, formamide and formamide/formic acid mixture gave the corresponding 3,5-dimethyl-6(H)-5oxo-4-
spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (5a-h), 5-amino-3 -methyl-4-spiropyrazolo [4',5': 5,6]pyrano-
[2,3-d]pyrimidines(6a-h) and 3-methyl-6(H)-5-oxo-4-spiropyrazolo[4',5':5,6]-pyrano[2,3-d]pyrimidines (7a-
1
h) respectively. The H-NMR spectrum showed the following signals: δ2.50-2.80 (6H, m, 3 CH2), 2.30 (3H,
s, CH3), 3.30 (3H, s, CH3), 7.00-8.20 (9H, m, arom) for 5d; 2.40 (3H, s, CH3), 9.80 (2H s NH2), 7 20-8.50
(14H, m, arom) for 6f and 2 35 (3H, s, CH3), 2 90 (2H, s, CH2), 7 20 8 60 (14H, s, arom.) for 7h respectively.
The physical properties and spectral data are given in Table 1 .
Table 1. Physical and Spectral Data of Spiropyrazolinones (3a-h), Spiropyrazolopyrans (4a-h) and
Spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (5a-h; 7a-h)
(Continued)

Table 1. (Continued) Physical and Spectral Data of Spiropyrazolinones (3a-h), Spiropyrazolopyrans (4a-h)
and Spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (5a-h; 7a-h)
(Continued)

Table 1. (Continued) Physical and Spectral Data of Spiropyrazolinones (3a-h), Spiropyrazolopyrans (4a-h)
and Spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (5a-h; 7a-h)

Antimicrobial Activity
The antimicrobial activity of the newly synthesized compounds was tested against Staphylococcus aureus
DSM 346 and Escherichia coli DSM 423 using the agar cup diffusion technique.30 Results of the screened
compounds show no inhibition to the organisms tested at a concentration of 20 µg cm-1 relative to tetracycline,
Only compounds (5f,6h) and (7d,7f) exhibited moderate activity against Staphylococcus aureus DSM 346
and Escherichia coli DSM 423 respectively.
EXPERIMENTAL
The time required for completion ofthe reaction was monitored by TLC. Melting points were determined in
open glass cappillaries and are uncorrected. IR (υ, cm-1) spectra were recorded on a Pye-Unicam SP 200-G
spectrophotometer. NMR (δ, ppm) spectra were measured on EM-360 90-MHz spectrometer using TMS as
internal standard. Elemental analyses were carried out on a Perkin Elmer 240 C microanalyser. MS spectra
were recorded on Jeol JMS 600 instrument.
Synthesis of 3-Methyl-4-cycloalkylidenepyrazolin-5-ones (3a-h)
General Procedure :
A mixture of 3-methylpyrazolin-5-ones (1a,b) (0.01 mol) and the appropriate cyclic ketone (2a-d) (0.012 mol)
was fused in the presence of anhydrous sodium acetate (1.00 g, 0.012 mol) for 30 min, at 200
℃. The reaction
mixture was allowed to cool, poured into water (200 mL) , whereby the products were precipitated, filtered
and crystallized from ethanol (Table 1).
6-Amino-5-cyano-3-methyl-4-spiropyrano[2, 3-c]pyrazole (4a-h)
General Procedure:
A mixture of 3-methyl-4-cycloalkylidenepyrazolin-5-ones (3a-h) (0.01 mol), malononitrile (0.66 g, 0.01 mol)
in absolute ethanol (60 mL) and piperidine (1 mL) was heated under reflux for 10 h, then concentrated to half
of its volume under reduced pressure and allowed to cool to rt. The product was collected by filtration and
recrystallized from dioxane (Table 1).
3 5-Dimethyl-6(H)-5-oxo-4-spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (5a-h)
General Procedure:
A solution of 4a-h (0.01 mol) in acetic anhydride/pyridine mixture (20 mL, 2: I v/v) was heated at 90℃ on
a steam bath for 12 h, then cooled and poured into an ice/water mixture. The solid product thus formed was
filtered off and washed several times with water and recrystallized from ethanol.

5-Amino-3-methyl-4-spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (6a-h )
General Procedure :
A mixture of 4a-h (0.01 mol) and formamide (28.35 g, 0.63 mol) was heated under reflux for 3 h. After
coollng, the precipitated product was filtered off and washed several times with cold water and recrystallized
from dioxane.
3-Methyl-6(H) -5-oxo - 4-spiropyrazolo[4',5':5,6]pyrano[2,3-d]pyrimidines (7a-h )
General Procedure:
A mixture of 4a-h (0.01 mol) and formic acid (6.10 g, 0.13 mol) in formamide (22.68 g, 0.50 mol) was
refluxed for 5 h. After cooling, the reaction mixture was poured into an ice/water mixture and the solid
product thus formed was filtered off and recrystallized from dioxane.
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