Synthesis of new pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidines and their use in the preparation of tetraheterocyclic systems

Article abstract of DOI:10.1080/00397910903020783

8,10-Dimethyl-3-(unsubstituted, methyl, ethyl, n-butyl, phenyl)-4-hydroxypyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidin-2(1H)-ones and 3-(2-hydroxyethyl)-2,8,10-trimethylpyrido[2',3':3,4]pyrazolo[1,5-a] pyrimidin-4-ol were synthesized by cyclocondensation of 3-amine-4,6-dimethyl-1H- pyrazolo[3,4-b]pyridine with ethyl malonates and-acetyl-butyrlolactone. Dichloro-and diazido-derivatives were obtained from the reaction of pyridopyrazlopyrimidine derivatives with POCl3 followed by NaN3. The tetrahetrocyclic systems were formed by cyclization of 4-chloro-3-(2- chloroethyl)-2,8,10-trimethylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine with the appropriate primary amines. The structures of all compounds were established by NMR and mass spectra.

Full text of DOI:10.1080/00397910903020783

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Synthesis of New
Pyrido[2′,3′:3,4]pyrazolo[1,5-
a]pyrimidines and Their Use in the
Preparation of Tetraheterocyclic Systems
Farag A. El-Essawy a
a Department of Chemistry , Faculty of Science, Menoufia
University , Shebin El-Koam, Egypt
Published online: 22 Feb 2010.
To cite this article: Farag A. El-Essawy (2010) Synthesis of New Pyrido[2′,3′:3,4]pyrazolo[1,5-
a]pyrimidines and Their Use in the Preparation of Tetraheterocyclic Systems, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:6, 877-887, DOI: 10.1080/00397910903020783
To link to this article: http://dx.doi.org/10.1080/00397910903020783
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Synthetic Communications1, 40: 877–887, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903020783
SYNTHESIS OF NEW PYRIDO[20,30:3,4]PYRAZOLO-
[1,5-a]PYRIMIDINES AND THEIR USE IN THE
PREPARATION OF TETRAHETEROCYCLIC SYSTEMS
Farag A. El-Essawy
Department of Chemistry, Faculty of Science, Menoufia University,
Shebin El-Koam, Egypt
8,10-Dimethyl-3-(unsubstituted, methyl, ethyl, n-butyl, phenyl)-4-hydroxypyrido[20,30:3,
4]pyrazolo[1,5-a]pyrimidin-2(1H)-ones and 3-(2-hydroxyethyl)-2,8,10-trimethylpyrido
[20,30:3,4]pyrazolo[1,5-a]pyrimidin-4-ol were synthesized by cyclocondensation of
3-amine-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine with ethyl malonates and a-acetyl-c-
butyrlolactone. Dichloro- and diazido- derivatives were obtained from the reaction of
pyridopyrazlopyrimidine derivatives with POCl3 followed by NaN3. The tetrahetrocyclic
systems were formed by cyclization of 4-chloro-3-(2-chloroethyl)-2,8,10-trimethylpyrido
[20,30:3,4]pyrazolo[1,5-a]pyrimidine with the appropriate primary amines. The structures
of all compounds were established by NMR and mass spectra.
Keywords: Cyclocondensation; dichloride; pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-2(1H)-ones; tetrahe-
trocyclic systems
1H-Pyrazolo[3,4-b]pyridines constitute a very interesting class of compounds because
of their significant and versatile biological and pharmacological activities, such as anti-
malarial,[1] antiproliferative,[2] antimicrobial,[3–5] cardiovascular,[6–8] antiviral,[9–11]
and antileishmanial[12] activities and their inhibition of cyclin-dependent kinases.[13]
Moreover, pyridopyrazolopyrimidines revealed antiproliferative activity[14] and are
used as potent kinase inhibitors.[15] In general, the pyrazolopyridines are active
antitubercular agents[16,17] and are active against Gram-positive and Gram-negative
bacteria.[18] The pyrazolopyrimidines[19,20] are selective inhibitors of cyclic
30,50-adenosine monophosphate (cAMP) phosphodiesterases in vitro, and some of
them possess anxiolytic properties comparable to those of benzodiazepines.[21] To
enhance the activity of pyrazolopyridines and pyrazolopyrimidines, several
approaches to construct another ring over those ring systems described in the
literature[22–25] are available on preparation of pyridopyrazolopyrimidines, which left
much scope for further study. In view of these reports, I have synthesized a number of
new pyridopyrazolopyrimidine derivatives and constructed another ring over those
ring systems.
Received April 19, 2009.
Address correspondence to Farag A. El-Essawy, Department of Chemistry, Faculty of Science,
Menoufia University, Shebin El-Koam, Egypt. E-mail: el_essawy2000@yahoo.com
877

878
F. A. EL-ESSAWY
The synthesis of 4-hydroxy-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]
pyrimidin-2(1H)-one derivatives 2a–e was achieved by cyclocondensation of
3-amine-4,6-dimethyl-1H-pyrazolo[3,4-b]pyridine 1[26,27] with ethyl malonates at
220–225 ꢀC using diphenyl ether as a solvent. Structural assignment by infrared
(IR) spectroscopy showed the characteristic absorption bands at 3430–3290 cmꢁ1
due to OH and NH groups. The mass spectrum revealed a molecular ion peak for
each derivative. In the 1H NMR spectra, the signal due to the NH present in all com-
pounds appeared at d 11.06–11.66 ppm, as singlets. The OH proton was observed at
d 13.33–15.43 ppm as a broad band. All the other aromatic and aliphatic protons
were observed at the expected regions. The dichloride derivatives were obtained
by halohydroxylation of the derivatives 2b,c with POCl3 at reflux temperature
to afford 2,4-dichloro-3,8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine 3b
and 2,4-dichloro-3-ethyl-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine 3c.
The structures of the obtained dichorides were elucidated by 1H NMR spectra, which
showed three singlets at d 2.60, 2.63, and 2.78 ppm, corresponding the three methyl
groups for 3b, and a triplet at d 1.26ppm and a quartet at 3.02, the corresponding
ethyl group for 3c. The dichlorides 3b,c were converted readily into 2,4-diazido-3,
8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (4b) and 2,4-diazido-3-ethyl-
8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (4c) after treatment with NaN3,
in dimethylformamide (DMF) at room temperature. Structures 4b,c were proven by the
presence of the two azide absorptions at 2134–2195 cmꢁ1 in the IR spectra (Scheme 1).
Condensation of the 3-aminopyrazolopyridine 1 with a-acetyl-c-butyrolactone
in ethanol in the presence of a catalytic amount of glacial acetic acid gave
Scheme 1. Synthesis of pyridopyrazolopyrimidine derivatives.

NEW HETEROCYCLIC SYSTEMS
879
3-{(2Z,2E)-2-[(4,6-dimethyl-2H-pyrazolo[3,4-b]pyridin-3-yl)imino]propyl}dihydro-
furan-2(3H)-one (5), which was confirmed by its spectral data and the fact that it was
readily cyclized in an aqueous basic solution to give 3-(2-hydroxyethyl)-2,8,10-
trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-4-ol (6). The latter dihydroxy 6
was prepared by boiling 1 with a-acetyl-c-butyrolactone in diphenyl ether. Its struc-
ture was elucidated by the mass spectrum, which showed the molecular ion peak
at m=z 273 and 272 corresponding to (Mþ þ t from here H, 14) and (Mþ, 11). The
chlorination of 6 with POCl3 afforded the 4-chloro-3-(2-chloroethyl)-2,8,10-
trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine (7), which was reacted with
NaN3 in DMF to afford 4-azido-3-(2-azidoethyl)-2,8,10-trimethylpyrido[20,30:3,
4]pyrazolo[1,5-a]pyrimidine (8). This showed, in its IR spectrum, the characteristic
peaks of the two azide groups at 2139 and 2115 cmꢁ1 (Scheme 2).
The dichloride 7 served as intermediate for the preparation of tetraheyrocyclic
systems through its treatment with appropriate primary amines. 1-Phenyl-1,2,3,4-
tetrahydro-5,7,9-trimethylpyridazino[2,3-e]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine
(9) and 2,3-dihydro-4,6,8-trimethylthiopheno[2,3-d]pyrido[20,30:3,4]pyrazolo[1,5-a]
Scheme 2. The reaction of butyrolactone with 3-aminopyrazolopyridine and formation of the diazido
derivative.

880
F. A. EL-ESSAWY
Scheme 3. Formation of the tetraheterocyclic systems.
pyrimidine (10) were obtained on the reaction of 7 with both phenyl hydrazine and
thiourea in ethanol and=or tetrahydrofuran (THF), respectively, in good yield.
The 1H NMR spectrum of 9 showed the increase of aromatic protons due to
presence of phenyl group with H-8 at d 6.85–7.29 ppm and broad singlets at d
10.66 ppm for the NH group of pyridazine. The structure of the obtained 10
was confirmed by the mass spectra, which showed a [Mþ þ 1] peak in agreement
with their molecular formula. N-Alkyl=aralkyl-2,3-dihydro-4,6,8-trimethylpyr-
rolo[3,2-d]pyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidines 11a–d were synthesized by
cyclization of dichloride 7 with methyl amine, 2-ethnolamine, aniline, and ben-
zylamine in absolute ethanol in the presence of an equimolar amount of Na2CO3
1
and=or triethylamine. Structural assignment by H NMR spectra showed a sing-
let at d 3.69 ppm corresponding to N-Me for 11a, four triplets at d 3.18, 3.94,
3.98, and 4.42 ppm corresponding to the CH2CH2-N of pyrrol ring and the side
chain CH2CH2OH group for 11b, a multiple in the aromatic region at d
6.66–7.47 ppm for the phenyl group in 11c, and a singlet at d 5.56 ppm due to
CH2Ph for 11d. Mass spectra peaks corresponded to the molecular formulas
(Scheme 3).
EXPERIMENTAL
Instruments
Melting points were determined using a Kofter block instrument. Thin-layer
chromatography (TLC) was performed on plastic plates with silica gel 60 F254 (E.
Merk, layer thickness 0.2 mm). NMR spectra were recorded on a Bruker AC 250
Fourier transform (FT) NMR spectrometer at 300 MHz for 1H NMR and at
75.5 MHz for 13C NMR with TMS as an internal standard. IR spectra were
recorded on a Nicolet FT-IR spectrophotometer. Mass spectra were measured
on a Kratos 50 TC spectrometers. The microanalyses were performed at
the microanalytical unit, Cairo University, Egypt, and agreed with the calculated
values.

NEW HETEROCYCLIC SYSTEMS
881
8,10-Dimethyl-3-(unsubstituted, methyl, ethyl, n-butyl, phenyl)-
4-hydroxypyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-2(1H)-ones (2a–e)
General procedure. A mixture of 3-aminopyrazolopyridine 1 (1.62 g,
10 mmol) and the appropriate malonic ester (10 mmol) in 10 mL diphenyl ether
was heated in an oil bath for 20–30 min to 220–250 ꢀC using a short air condenser
to remove the liberated ethanol. After cooling, the reaction mixture was digested
with diethyl ether and petroleum ether, and the obtained precipitate was filtered,
washed with diethyl ether, dried, and recystallized from acetic acid, giving 2a–e in
83–96% yields.
4-Hydroxy-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-2(1H)-
one (2a). Yellow powder, 1.90 g (83%), mp 328–330 ꢀC; IR: OH=NH 3422–3267, CO
1
1680 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 2.59, 2.81 (2s, 6H, 2 CH3), 7.31 (s,
1H, H-3), 6.81 (s, 1H, H-9), 11.32 (s, 1H, NH), 14.15 (s, 1H, OH). MS (EI): m=z
231 [14, (M þ H)þ], 230 (Mþ, 100), 189 (21), 162 (77), 133 (20), 107 (27), 69 (50). Anal.
calcd. for C11H10N4O2: C, 57.39; H, 4.38; N, 24.34. Found: C, 57.79; H, 4.08; N, 23.94.
4-Hydroxy-3,8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-2
(1H)-one (2b). Yellow powder, 2.10 g (88%); mp > 360 ꢀC; IR: OH=NH 3445–3252,
CO 1653 cmꢁ1; 1H NMR (300 MHz, DMSO-d6): d ¼ 2.51, 2.79, 2.98 (3s, 9H, 3 CH3),
6.83 (s, 1H, H-9), 11.13 (s, 1H, NH), 13.68 (s, 1H, OH); MS (EI): m=z 245 [27,
(M þ H)þ], 244 (Mþ, 100), 189 (47), 147 (8). Anal. calcd. for C12H12N4O2: C,
59.01; H, 4.95; N, 22.94. Found: C, 59.31; H, 4.35; N, 22.64.
3-Ethyl-4-hydroxy-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidin-
2(1H)-one (2c). Yellow powder, 2.10 g (84%); mp 334–336 ꢀC; IR: OH=NH
3421–3271, CO 1665 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.06 (t, 3H,
J ¼ 7.2 Hz, CH2CH3), 2.47 (q, 2H, J ¼ 14.70 Hz, CH2CH3), 2.58, 2.80 (2s, 6H, 2
CH3), 6.79 (s, 1H, H-9), 11.12 (s, 1H, NH), 13.33 (s, 1H, OH); MS (EI): m=z 259
[6, (M þ H)þ], 258 (Mþ, 35), 243 (100), 189 (14), 175 (8), 97 (6). Anal. calcd. for
C13H14N4O2: C, 60.45; H, 5.46; N, 21.69. Found: C, 60.75; H, 5.75; N, 22.09.
3-Butyl-4-hydroxy-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimi-
din-2(1H)-one (2d). Yellow powder, 2.39 (85%); mp 358–360 ꢀC; IR: OH=NH,
3387–3246, CO 1654 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.02 (t, 3H,
J ¼ 7.2 Hz, CH3 of butyl), 1.29–1.31 (m, 4H, 2 CH2 of butyl group), 2.41 (t, 2H,
J ¼ 7.2 Hz, CH2 of butyl), 2.53, 2.61 (2s, 6H, 2 CH3), 6.87 (s, 1H, H-9), 11.06 (s,
1H, NH), 13.26 (s, 1H, OH); MS (EI): m=z 287 [11, (M þ H)þ], 286 (Mþ, 1), 243
(13), 189 (27), 162 (100), 69 (15), 55 (15). Anal. calcd. for C15H18N4O2: C, 62.92;
H, 6.34; N, 19.57. Found: C, 63.62; H, 6.64; N, 19.17.
4-Hydroxy-8,10-dimethyl-3-phenylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimi-
din-2(1H)-one (2e). Yellow powder, 2.92 g (96%); mp 328–330 ꢀC; IR: OH=NH
3389–3226, CO 1626 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 2.49, 2.86 (2s,
6H, 2 CH3), 6.83 (s, 1H, H-9), 11.66 (s, 1H, NH), 15.43 (s, 1H, OH); MS (EI): m=
z 307 [21, (M þ H)þ], 306 (Mþ, 100), 189 (80), 147 (27), 118 (29), 89 (28), 77 (10).
Anal. calcd. for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.36; H,
4.31; N, 18.59.

882
F. A. EL-ESSAWY
3-Alkyl-2,4-dichloro-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (3b,c)
General procedure. A mixture of 3-alkylpyridpyrazolopyrimidine 2b,c
(8 mmol) and 10 mL of POCl3 was refluxed for 3 h. After cooling, the mixture was
poured into ice water, and a crystalline solid was collected by filtration. The product
was recrystallized from ethanol to give 3b,c in 47–77% yields.
2,4-Dichloro-3,8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine
(3b). Pale yellow powder, 1.70 g (77%); mp 180–183 ꢀC; 1H NMR (300 MHz,
DMSO-d6): d ¼ 2.57, 2.62, 2.76 (3s, 9H, 3 CH3), 7.06 (s, 1H, H-9); 13C NMR
(75.5 MHz, DMSO-d6): d ¼ 17.44, 19.22, 26.34 (3 CH3), 104.85, 110.51, 119.70,
120.91, 138.11, 144.67, 148.67, 160.73, 164.72 (ArC). MS (EI): m=z 281 (Mþ, 100),
280 (25) 189 (16), 162 (30), 133 (13), 107 (60), 69 (40). Anal. calcd. for C12H10Cl2N4:
C, 51.27; H, 3.59; Cl, 25.22; N, 19.93. Found: C, 51.57; H, 3.29; Cl, 25.62; N, 2023.
2,4-Dichloro-3-Ethyl-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyri-
midine (3c). Pale yellow powder, 1.70g (74%); mp 150–153 ꢀC; 1H NMR (300MHz,
DMSO-d6): d ¼ 1.26 (t, 3H, J ¼ 7.5 Hz, CH2CH3), 2.51, 2.77 (2s, 6H, 2 CH3), 3.02 (q,
2H, J ¼ 15.0 Hz, CH2CH3), 7.07 (s, 1H, H-9); MS (EI): m=z 295 (Mþ, 100), 294 (25),
243 (16), 189 (12), 175 (81), 97 (6). Anal. calcd. for C13H12Cl2N4: C, 52.90; H, 4.10;
Cl, 24.02; N, 18.98. Found: C, 52.60; H, 3.80; Cl, 23.62; N, 18.68.
3-Alkyl-2,4-dazido-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-
a]pyrimidine (4b,c)
General procedure. A mixture of dichloride 3b,c (2 mmol) and sodium azide
(0.26 g, 4 mmol) in 10 mL dry DMF was stirred at room temperature for 3 h. The
reaction mixture was diluted with cold water with stirring for 0.5 h to crystallize
the precipitate, which was collected by filtration and recrystallized from ethanol to
afford 4b,c in 66–77% yields.
2,4-Diazido-3,8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimidine
(4b). Pale yellow powder, 0.41 g (77%); mp 160–163 ꢀC; IR: N3 2191, 2134 cmꢁ1; 1H
NMR (300 MHz, DMSO-d6): d ¼ 2.29, 2.51, 2.58 (3s, 9H, 3 CH3), 7.02 (s, 1H, H-9);
MS (EI): m=z 294 (Mþ, 100), 280 (22) 189 (60), 162 (15), 131 (18), 106 (12), 77 (40).
Anal. calcd. for C12H10N10: C, 48.98; H, 3.43; N, 47.60. Found: C, 48.68; H, 3.13; N,
47.90.
2,4-Diazido-3-ethyl-8,10-dimethylpyrido[20,30:3,4]pyrazolo[1,5-a]pyrimi-
din (4c). Pale yellow powder, 0.39 g (66%); mp 170–173 ꢀC; IR: N3 2194, 2135 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 1.21 (t, 3H, J ¼ 7.5 Hz, CH2CH3), 2.61, 2.72
(2s, 6H, 2 CH3), 2.82 (q, 2H, J ¼ 15.0 Hz, CH2CH3), 7.02 (s, 1H, H-9); ms (EI):
m=z 308 (Mþ, 15), 280 (25), 252 (16), 224 (100), 175 (16), 77 (12). Anal. calcd. for
C13H12N10: C, 50.64; H, 3.92; N, 45.43. Found: C, 50.94; H, 3.52; N, 45.13.

NEW HETEROCYCLIC SYSTEMS
883
3-{(2Z,2E)-2-[(4,6-Dimethyl-2H-pyrazolo[3,4-b]pyridin-3-
yl)imino]propyl}dihydrofuran-2(3H)-one (5)
Acetic acid (2 mL) was added to a solution of 1 (1.62 g, 10 mmol) and a-acetyl-
c-butyrolactone (1.92 g, 15 mmol) in 20 mL absolute ethanol. The mixture was
refluxed for 72 h. A pale yellow precipitate was collected and recrystallized from
ethanol to give 5 (2.41 g, 85%), mp 210–212 ꢀC; IR: NH 3291, OCO 1712 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6): d ¼ 2.21, 2.49, 2.59 (3s, 9H, 3 CH3), 2.88 (t, 2H,
J ¼ 8.0 Hz, OCH2CH2), 4.32 (t, 2H, J ¼ 8.0 Hz, OCH2CH2), 6.81 (s, 1H, ArH),
10.35 (s, 1H, NH), 12.88 (s, 1H, NH); MS (EI): m=z 273 [10, (M þ H)þ], 272 (Mþ,
35), 243 (100), 189 (16), 175 (12), 77 (6). Anal. calcd. for C14H16N4O2: C, 61.75;
H, 5.92; N, 20.58. Found: C, 61.45; H, 6.22; N, 20.18.
3-(2-Hydroxyethyl)-2,8,10-trimethylpyrido[20,30:3,4]pyrazolo[1,5-a]
pyrimidin-4-ol (6)
Method A. A mixture of 5 (2.69 g, 9.9 mmol) and 1.0 g of trimethylamine
(9.9 mmol) in 5 mL H2O was allowed to stand at room temperature for 18 h. The
solution was neutralized with AcOH to give a crystalline product. Recrystallization
from AcOH afforded 6 (2.52 g, 93%).
Method B. A mixture of 3-aminopyrazolopyridine 1 (3.24 g, 20 mmol) and the
a-acetyl-c-butyrolactone (2.56 g, 20 mmol) in 20 g of diphenyl ether was heated in an
oil bath for 15 min to 220–225 ꢀC using a short air condenser to remove the liberated
ethanol. After cooling, the reaction mixture was digested with diethyl ether, and the
precipitate was filtered, washed with diethyl ether, and recrystallized from AcOH to
afford the yellow crystal of 6 (2.53 g 98%).
Data. Mp 305–308 ꢀC; IR: OH 3350–3210 cmꢁ1; 1H NMR (300 MHz, DMSO-
d6): d ¼ 2.46, 2.56 (2s, 6H, 2 CH3), 2.77 (t, 2H, J ¼ 7.2 Hz, HOCH2CH2), 2.80 (s, 3H,
CH3) 3.52 (t, 2H, J ¼ 7.2 Hz, HOCH2CH2), 4.61 (bs, 1H, HOCH2CH2), 6.76 (s, 1H,
H-8), 11.66 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): d ¼ 19.08, 21.73, 21.88 (3
CH3), 30.88 (CH2CH2OH), 60.46 (CH2CH2OH), 107.13, 114.31, 121.45, 130.74,
144.13, 147.32, 155.92, 163.13, 172.74 (ArC); MS (EI): m=z 273 [14, (M þ H)þ],
272 (Mþ, 11), 243 (57), 142 (33), 241 (100), 187 (44), 147 (12), 78 (23). Anal. calcd.
for C14H16N4O2: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.24; H, 5.62; N, 20.18.
4-Chloro-3-(2-chloroethyl)-2,8,10-trimethylpyrido[20,30:3,4]pyrazolo
[1,5-a]pyrimidine (7)
A mixture of 6 (8.16 g, 20 mmol) and 20 mL of POCl3 was refluxed for 3 h with
stirring. After cooling, the mixture was poured into ice-water, and a crystalline solid
was collected by filtration. The product was recrystallized from ethanol with
1
charcoal to give colorless 7 (8.15 g, 88%). Mp 179–182 ꢀC; H NMR (300 MHz,
DMSO-d6): d ¼ 2.62, 2.80, 2.83 (3s, 9H, 3 CH3), 3.44 (t, 2H, J ¼ 7.2 Hz, ClCH2CH2),
3.96 (t, 2H, J ¼ 7.2 Hz, ClCH2CH2), 7.03 (s, 1H, H-9); 13C NMR (75.5 MHz,
DMSO-d6): d ¼ 19.65, 25.19, 26.80 (3 CH3), 33.31, 43.81 (CH2CH2), 105.18,
119.62, 121.84, 138.24, 143.44, 145.44, 158.21, 161.43, 164.70 (ArC); MS (EI): m=z

884
F. A. EL-ESSAWY
309 (Mþ, 13), 308 (Mþꢁ1, 72), 259 (100), 141 (11), 105 (35), 77 (72), 67 (16). Anal.
calcd. for C14H14Cl2N4: C, 54.38; H, 4.56; Cl, 22.93; N, 18.12. Found: C, 53.90;
H, 4.26; Cl, 23.33; N, 17.82.
4-Azido-3-(2-azidoethyl)-2,8,10-trimethylpyrido[20,30:3,4]pyrazolo
[1,5-a]pyrimidine (8)
A mixture of dichloride 7 (1.24 g, 4 mmol) and sodium azide (0.52 g, 8 mmol) in
20 mL dry DMF was stirred at room temperature for 4 h. The reaction mixture was
diluted with cold water with stirring for 0.5 h to crystallize the precipitate, which was
collected by filtration and recrystallized from ethanol to afford 8 (1.20 g, 93%). Mp
1
322–323 ꢀC; IR: N3 2139, 2115 cmꢁ1; H NMR (300 MHz, DMSO-d6): d ¼ 1.96 (t,
2H, J ¼ 7.2 Hz, N3CH2CH2), 2.30, 2.49, 2.63 (3s, 9H, 3 CH3), 2.85 (t, 2H, J ¼ 7.2 Hz,
N3CH2CH2), 6.09 (s, 1H, H-9); MS (EI): m=z 323 [21, (M þ H)þ], 322 (Mþ, 1), 288
(15), 252 (37), 251 (100), 240 (53). Anal. calcd. for C14H14N10: C, 52.17; H, 4.38; N,
43.45. Found: C, 51.77; H, 4.08; N, 43.05.
1-Phenyl-1,2,3,4-tetrahydro-5,7,9-trimethylpyridazino[2,3-e]pyrido
[20,30:3,4]pyrazolo[1,5-a]pyrimidine (9)
A mixture of 8 (0.32 g, 1 mmol), phenyl hydrazine (0.22 g, 2 mmol), and
Na2CO3 (0.40 g, 4 mmol) in 20 mL ethanol was refluxed for 6 h and concentrated
in vacuo. The residue was dissolved in H2O, and the crystalline product was col-
lected by filtration and recrystallized from ethanol to give the yellow crystal of 9
1
(0.29 g, 88%). Mp 75–78 ꢀC; H NMR (300 MHz, DMSO-d6): d ¼ 2.46, 2.58 (2s,
6H, 2 CH3), 2.69 (t, 2H, J ¼ 7.2 Hz, NCH2CH2), 2.81 (s, 3H, CH3), 3.89 (t, 2H,
J ¼ 7.2 Hz, NCH2CH2), 6.85 (s, 1H, H-8), 6.88–7.29 (m, 5H, Ph), 10.64 (s, 1H,
NH); MS (EI): m=z 344 (Mþ, 13), 258 (100), 143 (11), 105 (35), 77 (27), 67 (8).
Anal. calcd. for C20H20N6: C, 69.75; H, 5.85; N, 24.40. Found: C, 69.45; H,
5.55; N, 42.10.
2,3-Dihydro-4,6,8-trimethylthieno[2,3-d]pyrido[20,30:3,4]pyrazolo
[1,5-a]pyrimidine (10)
A mixture of 8 (0.32 g, 1 mmol) and thiourea (0.08 g, 1.3 mmol) in 15 mL etha-
nol was refluxed for 2 h and concentrated in vacuo. Ten mL of K2CO3 (3 N) was
added to the residue, and the resulting mixture was extracted with CHCl3. The
extract was evaporated, and the residue was recrystallized from ethanol to give pale
yellow crystals of 9, 0.22 g (85%). Mp 240–243 ꢀC; 1H NMR (300 MHz, DMSO-d6):
d ¼ 2.62, 2.76, 2.94 (3s, 9H, 3 CH3), 3.64 (t, 2H, J ¼ 8.3 Hz, OCH2CH2), 3.65 (t, 2H,
J ¼ 8.3 Hz, OCH2CH2), 7.75 (s, 1H, H-7); 13C NMR (75.5 MHz, DMSO-d6): d 20.08,
21.92, 24.25 (3 CH3), 33.40, 34.69 (OCH2CH2), 108.27, 110.91, 118.05, 128.26,
144.73, 152.44, 153.41, 156.33, 158.02 (ArC); MS (EI): m=z 270 (Mþ, 13), 239
(100), 212 (11), 105 (40), 77 (25), 77 (8). Anal. calcd. for C14H14N4S: C, 62.20; H,
5.22; N, 20.72; S, 11.86. Found: C, 62.50; H, 5.52; N, 21.21; S, 11.46.

NEW HETEROCYCLIC SYSTEMS
885
N-Alkyl/aralkyl-2,3-dihydro-4,6,8-trimethylpyrrolo[3,2-d]pyrido
[20,30:3,4]pyrazolo[1,5-a]pyrimidines (11a–d)
General procedure. A mixture of 8 (3.20 g, 9.95 mmol), appropriate primary
amine (13.7 mmol), and 3 mL of triethylamine (21.5 mmol) in 15 mL ethanol was
refluxed for 2–6 h, cooled, and filtered. The filtrate was concentrated in vacuo to give
a solid, which was recrystallized from ethanol to give 11a–d in 78–91% yields.
2,3-Dihydro-1,4,6,8-tetramethyl-1H-pyrrolo[3,2-d]pyrido[20,30:3,4]pyraz-
1
olo[1,5-a]pyrimidine (11a). Pale yellow powder, 2.20 g (83%); mp 255–257 ꢀC; H
NMR (300 MHz, DMSO-d6): d ¼ 2.28, 2.48, 2.73 (3s, 9H, 3 CH3), 3.19 (t, 2H,
J ¼ 9.0 Hz, CH3NCH2CH2), 3.63 (s, 3H, NCH3), 3.75 (t, 2H, J ¼ 9.0 Hz,
CH3NCH2CH2), 6.68 (s, 1H, H-7); MS (EI): m=z 268 [17, (M þ H)þ], 267 (Mþ,
100), 266 (69), 252 (11), 239 (14), 133 (6). Anal. calcd. for C15H17N5: C, 67.39; H,
6.41; N, 26.20. Found: C, 67.09; H, 6.71; N, 25.90.
2-(2,3-Drihydro-4,6,8-trimethyl-1H-pyrrolo[3,2-d]pyrido[20,30:3,4]pyrazo-
lo[1,5-a]pyrimidin-1-yl)ethanol (11b). Pale yellow crystal, 2.30 g (78%); mp
1
243–245 ꢀC; H NMR (300 MHz, DMSO-d6): d ¼ 2.43, 2.64, 2.84 (3s, 9H, 3 CH3),
3.18 (t, 2H, J ¼ 9.0 Hz, NCH2CH2), 3.93–4.00 (m, 4H, 2 CH2), 4.21 (s, 1H, OH),
4.42 (t, 2H, J ¼ 5.0 Hz, OCH2CH2), 6.67 (s, 1H, H-3); 13C NMR (DMSO-d6): d
18.62, 21.64, 24.83 (3 CH3), 25.24, 49.32, 51.77, 59.67 (4 CH2), 102.60, 107.91,
115.84, 146.04, 146.53, 149.02, 151.90, 160.85, 162.57 (ArC); MS (EI): m=z 298
[12, (M þ H)þ], 297 (Mþ, 100), 268 (33), 251 (44), 239 (12), 133 (6), 77 (8). Anal.
calcd. for C16H19N5O: C, 64.63; H, 6.44; N, 23.55. Found: C, 64.33; H, 6.74; N,
23.85.
2,3-Dihydro-1-phenyl-4,6,8-tetramethyl-1H-pyrrolo[3,2-d]pyrido[20,30:3,4]
pyrazolo[1,5-a]pyrimidine (11c). Yellow crystal, mp 277–280 ꢀC; 1H NMR
(300 MHz, DMSO-d6): d ¼ 2.44, 2.49, 2.66 (3s, 9H, 3 CH3), 3.20 (t, 2H, J ¼ 9.0 Hz,
PhNCH2CH2), 3.82 (t, 2H, J ¼ 9.0 Hz, PhNCH2CH2), 6.90 (s, 1H, H-7), 6.93–7.33
(m, 5H, Ph); MS (EI): m=z 330 [30, (M þ H)þ], 329 (Mþ, 100), 266 (44), 253 (31),
243 (9), 132 (15), 77 (11). Anal. calcd. for C20H19N5: C, 72.43; H, 5.05; N, 21.26.
Found: C, 72.13; H, 5.35; N, 21.96.
1-Benzyl-2,3-dihydro-4,6,8-tetramethyl-1H-pyrrolo[3,2-d]pyrido[20,30:3,4]
pyrazolo[1,5-a]pyrimidine (11d). Pale yellow crystal, 3.10 g (90%); mp
1
229–231 ꢀC; H NMR (300 MHz, DMSO-d6): d ¼ 2.39, 2.49, 2.52 (3s, 9H, 3 CH3),
3.15 (t, 2H, J ¼ 9.0 Hz, NCH2CH2), 3.74 (t, 2H, J ¼ 9.0 Hz, NCH2CH2), 5.56 (s,
2H, PhCH2N), 6.74 (s, 1H, H-7), 7.28–7.36 (m, 5H, Ph); MS (EI): m=z 344 [15,
(M þ H)þ], 343 (Mþ, 100), 266 (30), 253 (50), 242 (12), 133 (19), 77 (8). Anal. calcd.
for C21H21N5: C, 73.44; H, 6.16; N, 20.39. Found: C, 73.74; H, 5.86; N, 19.69.
ACKNOWLEDGMENTS
I express my gratitude to Professor Magdy Kamal, head of my department, for
his encouragement. I am also indebted to Professor Adel Nassar for his assistance in
spectral measurements.

886
F. A. EL-ESSAWY
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