Synthesis of imidazo[1,2-c]pyrazolo [4,3-e]pyrimidines derived from indole and related heterocycles

Article abstract of DOI:10.1007/s00706-006-0519-8

The syntheses of the title heterocycles were achieved using 5-amino-1-(1-benzyl-1H-indol-3-ylcarbonyl)-1H-pyrazole-4-carbonitrile as starting material. These compounds were converted into the 4-imidazolinyl derivatives which were subjected to cyclization

Full text of DOI:10.1007/s00706-006-0519-8

Monatshefte f€ur Chemie 137, 1195–1202 (2006)
DOI 10.1007/s00706-006-0519-8
Synthesis of Imidazo[1,2-c]pyrazolo
[4,3-e]pyrimidines Derived From Indole
and Related Heterocycles#
ꢀ
Abdel-Rahman Farghaly and Hussein El-Kashef
Chemistry Department, Faculty of Science, Assiut University, Assiut, Egypt
Received December 29, 2005; accepted (revised) February 6, 2006
Published online August 24, 2006 # Springer-Verlag 2006
Summary. The syntheses of the title heterocycles were achieved using 5-amino-1-(1-benzyl-1H-
indol-3-ylcarbonyl)-1H-pyrazole-4-carbonitrile as starting material. These compounds were converted
into the 4-imidazolinyl derivatives which were subjected to cyclization reactions to afford the title
compounds.
Keywords. Indole; Imidazole; Pyrazole; Imidazopyrazolopyrimidine.
Introduction
Several purines are reported to possess anti-tumor activity [1]. Also a few
pyrazolopyrimidines and pyrazolotriazines (purine isosteres) are known for their
therapeutic importance [2, 3]. Moreover, derivatives of pyrazolopyrimidine are
known for their anti-tumor and cytostatic activity [4–8]. Some pyrazolotriazo-
lopyrimidines were reported as new A2A and A3 adenosine receptor antagonists
[9]. On the other hand, it is well known that indole derivatives possess a broad-
spectrum of biological activities, several of these derivatives showed potent
central nervous system (CNS) activity and anti-inflammatory properties [10–14].
Indometacin, an indole derivative, posseses anti-inflammatory and analgesic
activity [15, 16]. Also it has been reported that the substitution at position 1
and 3 of the indole nucleus enhances these activities [17]. Coupling of the
imidazopyrazolopyrimidines with the indole moiety may result in gains of the
pharmacological activity. With this in mind and in continuation to our interest
in the synthesis of new fused polyheterocyclic compounds of potential pharma-
ꢀ
Corresponding author. E-mail: elkashef15@hotmail.com
This work was presented in part at the 10th Blue Danube Symposium on Heterocyclic Chemistry,
#
Vienna=Austria, September 3–6, 2003

1196
A.-R. Farghaly and H. El-Kashef
ceutical importance [8, 18, 19], we report herein the synthesis of the title com-
pounds.
Results and Discussion
In an earlier paper [19], the synthesis of 5-amino-1-(1-benzyl-1H-indol-3-ylcarbo-
nyl-1H-pyrazole-4-carbonitrile (1) has been described. The nitrile function of 1 has
been easily converted into the corresponding imidazolinyl group via the reaction
with ethylenediamine in the presence of a catalytic amount of carbon disulfide
following a reported procedure [20] to yield compound 2. The latter compound
could be ring closed into the tricyclic imidazopyrazolopyrimidine in different
ways. The reaction of 2 with triethyl orthoformate afforded the parent compound
3, and the 5-methyl derivative 4 was obtained by reaction with trimethyl ortho-
acetate. When 2 was allowed to react with benzoyl chloride in boiling pyridine the
corresponding 5-phenyl derivative 5 was formed. Interaction of 2 with benzalde-
hyde in a procedure similar to the one of Ried and Russ [21] afforded the corre-
sponding imidazopyrazolopyrimidine 6 (Scheme 1).
Treatment of 2 with carbon disulfide in boiling pyridine led to the formation of
the corresponding imidazopyrazolopyrimidinethione 7, whereas its reaction with
1,10-carbonyldiimidazole (CDI) in boiling dioxane gave the oxo-derivative 8. The
triazine derivative 9 could be obtained by reacting 2 with nitrous acid at room
temperature (Scheme 2).
Interestingly enough, hydrazinolysis of the thione 7 with hydrazine hydrate did
not afford the expected hydrazino product 11, but led to opening of the pyrimidine
Scheme 1

Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines
1197
Scheme 2
Scheme 3
ring giving back 2. However, 11 could be prepared by treatment of 8 with phos-
phoryl chloride to give the corresponding 5-chloro-derivative 10, which gave the
corresponding 11 upon treatment with hydrazine hydrate (Scheme 3).
On the other hand, when 7 was allowed to react with bioactive alkylating agents,
such as 4-(2-chloroethyl)morpholine hydrochloride or 2-dimethyaminopropyl
chloride hydrochloride in boiling ethanol in the presence of fused sodium acetate,
the S-alkylated products 12 and 13 were obtained.

1198
A.-R. Farghaly and H. El-Kashef
Scheme 4
Scheme 5
The interaction of 1 with 2,5-dimethoxytetrahydrofurane (DMTHF) afforded the
pyrrolyl derivative 14. However, reaction of 1 with formamide gave the aminopyr-
azolopyrimidine 15. An attempt to prepare the pyrazolopyrimidinedithione 16 via
the reaction of 1 with carbon disulfide in boiling pyridine was unsuccessful and 1
was recovered unchanged (Scheme 5).
Finally, acetylation of 1 was accomplished in boiling acetic anhydride to give the
acetyl derivative 17. When 1 was treated with triethyl orthformate in the presence
of acetic anhydride, the product obtained was not the expected ethoxymethylene-
imino derivative 18, but the acetyl derivative 17. On the other hand, when acetyla-
tion was carried out using acetic anhydride in boiling pyridine, the product was the
pyrazolopyrimidine derivative 19 (Scheme 6).

Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines
1199
Scheme 6
Experimental
All melting points were determined on a Kofler melting point apparatus. IR spectra were recorded on a
Pye Unicam SP3-100 spectrophotometer using KBr wafers. 1H NMR spectra were recorded on a Varian
EM 390, 90 MHz spectrometer (TMS as internal reference, ꢀ values in ppm). Mass spectra were obtained
with a Shimadzu QP5050 DI 50 spectrometer. Elemental analyses were carried out using a Perkin-Elmer
240 C Micro analyzer; the results were in satisfactory agreement with the calculated values. Starting
materials were commercially available. Solvents were distilled and dried before use. 5-Amino-1-(1-
benzyl-1H-indol-3-ylcarbonyl)-1H-pyrazole-4-carbonitrile (1) was prepared as described before [19].
3-[5-Amino-4-(4,5-dihydro-1H-imidazol-2-yl)-1H-pyrazol-1-ylcarbonyl]-1-benzyl-1H-indole
(2, C22H20N6O)
A mixture of 3.41g 1 (10 mmol), 5 cm3 ethylenediamine, and 0.9 cm3 CS2 was heated on a water bath
for 8 h. After cooling the reaction mixture was diluted with an ice-H2O mixture. The precipitate formed
was filtered off, washed with H2O, and recrystallized from ethanol to give 5.22 g (95%) 2 as yellow
crystals; mp 104–106ꢁC; IR (KBr): ꢁꢀ¼ 3350, 3250 (NH2), 3100 (NH), 1640 (C¼O), 1610 (C¼N)
1
cmꢂ1; H NMR (CDCl3): ꢀ ¼ 3.45 (m, 4Himidazole), 5.07 (s, 2Hbenzyl), 6.97 (bs, 2H, NH2), 7.13 (m,
H5,6,7indole þ 5Harom), 7.73 (s, H2indole), 8.07 (m, H4indole þ 1Hpyrazole) ppm; MS: m=z (%) ¼ 293
[Mþ – CH2Ph] (2), 289 (4), 264 (12), 250 (22), 173 (3), 91 (62), 65 (6), 51 (2).
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2,3-dihydro-7H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine
(3, C18H16N6O)
A mixture of 384 mg 2 (1mmol) and 5 cm3 triethyl orthformate was heated under reflux for 4 h. After
cooling the solvent was evaporated under reduced pressure and the residue obtained was collected
and recrystallized from ethanol to give 230 mg (58%) 3 as yellow crystals; mp 125–127ꢁC; IR
(KBr): ꢁꢀ¼ 2920 (CHaliph) 1640 (C¼O), 1610 (C¼N) cmꢂ1
;
1H NMR (CDCl3): ꢀ ¼ 3.41 (m,
4Himidazole), 5.07 (s, 2Hbenzyl), 7.13 (m, H5,6,7indole þ 5Harom), 7.43 (s, H4indole), 7.70 (m, H2indole),
8.07 (m, 1Hpyrimidine þ 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-methyl-2,3-dihydro-7H-imidazo[1,2-c]
pyrazolo[4,3-e]pyrimidine (4, C24H20N6O)
A mixture of 384 mg 2 (1mmol) and 8 cm3 trimethyl orthoacetate was heated under reflux for 8 h.
After cooling the solvent was eliminated under reduced pressure and the residue obtained was tritu-

1200
A.-R. Farghaly and H. El-Kashef
rated with ethanol. The product formed was filtered off and recrystallized from ethanol to give 204 mg
(50%) of 4 as yellow crystals; mp 113–115ꢁC; IR (KBr): ꢁꢀ¼ 2920 (CHaliph), 1650 (C¼O), 1620
1
(C¼N) cmꢂ1; H NMR (CDCl3): ꢀ ¼ 2.45 (s, CH3), 3.37 (m, 4Himidazole), 5.07 (s, 2Hbenzyl), 7.13 (m,
H5,6,7indole þ 5Harom), 7.45 (s, H4indole), 7.75 (m, H2indole), 8.15 (s, 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-phenyl-2,3-dihydro-7H-imidazo[1,2-c]
pyrazolo[4,3-e]pyrimidine (5, C29H22N6O)
A mixture of 384 mg 2 (1mmol) and 141 mg benzoyl chloride (1mmol) in 10cm3 pyridine was heated
under reflux for 4 h. After cooling, the solvent was removed in vacuo and the residue obtained was
poured into H2O. The solid precipitate formed was filtered off and recrystallized from ethanol to
give 290 mg (62%) 5 as white crystals; mp 250–252ꢁC; IR (KBr): ꢁꢀ¼ 2900 (CHaliph), 1640 (C¼O),
1620 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 3.41 (m, 4Himidazole), 5.07 (s, 2Hbenzyl), 7.13 (m,
H5,6,7indole þ 10Harom), 7.43 (s, H4indole), 7.70 (m, H2indole), 8.07 (s, 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-phenyl-2,3,5,6-tetrahydro-7H-imidazo[1,2-c]
pyrazolo[4,3-e]pyrimidine (6, C29H24N6O)
A mixture of 384 mg 2 (1mmol), 3 cm3 benzaldehyde (3mmol), and 0.2 cm3 conc. HCl in 10cm3
absolute ethanol was stirred at 50–60ꢁC for 5 h. After cooling the mixture was neutralized with aqu.
Na2CO3. The solid product formed was filtered off and recrystallized from ethanol to give 320 mg
(68%) 6 as yellow crystals; mp 285–287ꢁC; IR (KBr): ꢁꢀ¼ 2930 (CHaliph) 1650 (C¼O), 1610 (C¼N)
1
cmꢂ1 ; H NMR (DMSO-d6): ꢀ ¼ 3.45 (m, 4Himidazole), 5.12 (s, 2Hbenzyl), 7.16 (m, H5,6,7indole
þ
10Harom), 7.42 (s, H4indole), 7.74 (m, H2indole), 8.14 (m, 1Hpyrimidine þ 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2,3,5,6-tetrahydro-7H-imidazo[1,2-c]pyrazolo
[4,3-e]pyrimidin-5-thione (7, C23H18N6OS)
A mixture of 384 mg 2 (1mmol) and 2 cm3 CS2 in 5 cm3 pyridine was heated under reflux on a water
bath for 12h. After cooling the solvent was removed under reduced pressure and the residue was
triturated with H2O. The solid product formed was filtered off and recrystallized from ethanol to afford
303 mg (71%) 7 as yellowish white crystals; mp 122–124ꢁC; IR (KBr): ꢁꢀ¼ 3250 (NH), 1640 (C¼O),
1
1610 (C¼N), 1180 (C¼S) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 4.16 (m, 4Himidazole), 5.50 (s, 2Hbenzyl),
7.30 (m, H5,6,7indole þ 5Harom), 8.23 (s, H4indole þ 1Hpyrazole), 8.40 (m, H2indole), 9.52 (s, NH, ex-
changeable) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2,3,5,6-tetrahydro-7H-imidazo[1,2-c]pyrazolo
[4,3-e]pyrimidin-5-one (8, C23H18N6O2)
A mixture 384 mg 2 (1mmol) and 162 mg 1,10-carbonyldiimidazole (1 mmol) in 10 cm3 dioxane was
heated under reflux for 8 h. After cooling the solvent was removed under reduced pressure and the
residue was triturated with H2O. The solid product formed was filtered off and recrystallized from
ethanol to give 307 mg (75%) 8 as white crystals; mp 175–177ꢁC; IR (KBr): ꢁꢀ¼ 3250 (NH), 1700
1
(C¼O), 1640 (C¼O), 1620 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 3.90 (m, 4Himidazole), 5.43 (s,
2Hbenzyl), 7.31 (m, H5,6,7indole þ 5Harom), 7.97 (s, H4indole þ 1Hpyrazole), 8.23 (m, H2indole), 9.52 (s, NH,
exchangeable) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2,3-dihydro-7H-imidazo[1,2-c]pyrazolo[4,3-e]
triazine (9, C22H17N7O)
To a solution of 384 mg 2 (1mmol) in 10cm3 glacial acetic acid, a cold solution of 3.30 g NaNO2
(10 cm3, 33%, 4.7 mmol) was added dropwise with stirring at rt. After completion stirring was continued
for 1 h. The solid product obtained was filtered off, washed with H2O, dried, and recrystallized from
ethanol to give 230 mg (58%) 9 as buff crystals; mp 138–140ꢁC; IR (KBr): ꢁꢀ¼ 1640 (C¼O), 1610
(C¼N) cmꢂ1; 1H NMR (CDCl3): ꢀ ¼ 4.17 (t, J ¼ 9.00Hz, 2Himidazole), 4.93 (t, J ¼ 9.00 Hz, 2Himidazole),
5.27 (s, 2Hbenzyl), 7.17 (m, H5,6,7indole þ 5Harom), 7.78 (m, H2,4indole), 8.63 (s, 1Hpyrazole) ppm.

Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines
1201
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-chloro-2,3-dihydro-7H-imidazo[1,2-c]
pyrazolo[4,3-e]pyrimidine (10, C23H17ClN6O)
A mixture of 410 mg 8 (0.5mmol) and 10cm3 of POCl3 was heated under reflux for 1 h. After cooling the
solvent was removed under reduced pressure and the residue obtained was poured into an ice-H2O
mixture. The reaction mixture was neutralized with NH4OH and the solid precipitate formed was filtered
off and recrystallized from ethanol to give 368 mg (86%) 10 as buff crystals; mp 128–130ꢁC; IR (KBr):
ꢁꢀ¼ 2950 (CHaliph), 1640 (C¼O), 1600 (C¼N) cmꢂ1; 1H NMR (CDCl3): ꢀ ¼ 3.67 (m, 4Himidazole), 5.20
(s, 2Hbenzyl), 7.13 (m, H5,6,7indole þ 5Harom), 7.50(m, H4indole), 7.80 (s, H2indole), 8.10 (s, 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2,3-dihydro-5-hydrazino-7H-imidazo[1,2-c]
pyrazolo[4,3-e]pyrimidine (11, C23H20N8O)
A mixture of 428 mg 10 (1mmol) and 5 cm3 NH2NH2 ꢃ H2O (100mmol) was heated under reflux for
3 h. After cooling the solvent was removed under reduced pressure and the precipitate obtained was
triturated with 50 cm3 H2O. The solid product formed was filtered off and recrystallized from ethanol
to afford 300 mg (71%) 11 as buff crystals; mp 145–147ꢁC; IR (KBr): ꢁꢀ¼ 3350, 3250, 3150 (NHNH2),
2980 (CHaliph), 1680 (C¼O), 1600 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 4.23 (m, NH2 þ
4Himidazole), 5.50 (s, 2Hbenzyl), 6.47 (sb, NH), 7.37 (m, H5,6,7indole þ 5Harom), 8.17 (m, H2,4indole),
8.28 (s, 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-(2-diethylaminoethylthio)-2,3-dihydro-7H-
imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine (12, C29H31N7OS)
A mixture of 213 mg 7 (0.5mmol), 400 mg fused sodium acetate (5mmol), and 172 mg 2-diethyl-
aminoethyl chloride hydrochloride (1mmol) in 10cm3 ethanol was heated under reflux for 7 h. After
cooling the solvent was eliminated in vacuo and the solid product obtained was washed with H2O,
filtered off, and recrystallized from ethanol to give 210 mg (80%) 12 as yellow crystals; mp
1
100–102ꢁC; IR (KBr): ꢁꢀ¼ 2950 (CHaliph), 1640 (C¼O), 1600 (C¼N) cmꢂ1; H NMR (CDCl3):
ꢀ ¼ 1.23 (s, N(CH2CH3)2), 3.63 (m, 4Himidazole þ S(CH2)2N þ N(CH2CH3)2), 5.23 (s, 2Hbenzyl), 7.17
(m, H5,6,7indole þ 5Harom), 7.53 (s, H4indole), 7.90 (m, H2indole), 8.13 (s, 1Hpyrazole) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-(2-morpholinoethylthio)-2,3-dihydro-7H-
imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine (13, C29H29N7O2S)
A mixture of 213 mg 7 (0.5mmol), 400 mg fused sodium acetate (5mmol), and 188mg 4-(2-chloro-
ethyl)morpholine hydrochloride (1mmol) in 10cm3 ethanol was heated under reflux for 8 h. After
cooling the solvent was eliminated in vacuo and the solid product obtained was washed with H2O,
filtered off, and recrystallized from ethanol to give 220 mg (81%) 13 as yellow crystals; mp 95–97ꢁC;
IR (KBr): ꢁꢀ¼ 2950 (CHaliph), 1640 (C¼O), 1600 (C¼N) cmꢂ1
;
1H NMR (CDCl3): ꢀ ¼ 2.47 (t,
unresolved N(CH2)2), 3.27 (m, SCH2CH2N), 3.63 (m, O(CH2)2 þ SCH2CH2N þ 4Himidazole), 5.20 (s,
2Hbenzyl), 7.17 (m, H5,6,7indole þ 5Harom), 7.83 (m, H2,4indole), 8.13 (s, 1Hpyrazole) ppm.
1-(1-Benzyl-1H-indol-3-ylcarbonyl)-5-(pyrrol-1-yl)-1H-pyrazole-4-carbonitrile (14, C24H17N5O)
A mixture of 341 mg 1 (1mmol) and 145mg DMTHF (1.1mmol) in 10cm3 glacial acetic acid was
heated at 80ꢁC for 1 h. After cooling the reaction mixture was poured into an ice-H2O mixture and
neutralized with Na2CO3. The solid product formed was filtered off and recrystallized from ethanol to
afford 384 mg (98%) 14 as brown crystals; mp 100–102ꢁC; IR (KBr): ꢁꢀ¼ 2920 (CHaliph), 2220 (CꢄN),
1640 (C¼O), 1600 (C¼N) cmꢂ1; 1H NMR (CDCl3): ꢀ ¼ 5.27 (s, 2Hbenzyl), 6.30 (m, H3,4pyrrole), 7.20
(m, H2,5pyrrole, H5,6,7indole, 1Hpyrazole þ 5Harom), 7.83 (s, H2indole), 8.13 (s, H4indole) ppm.
4-Amino -7-(1-benzyl-1H-indol-3-ylcarbonyl)pyrazolo[3,4-d]pyrimidine (15, C21H16N6O)
A mixture of 341 mg 1 (1mmol) and 10cm3 formamide was heated under reflux for 4 h. After cooling
the solvent was removed under reduced pressure and the residue obtained was triturated with H2O. The
solid product formed was filtered off and recrystallized from ethanol to afford 162 mg (44%) 15 as grey

1202
A.-R. Farghaly and H. El-Kashef: Imidazo[1,2-c]pyrazolo[4,3-e]pyrimidines
crystals; mp 166–168ꢁC; IR (KBr): ꢁꢀ¼ 3400, 3200 (NH2), 2900 (CHaliph), 1630 (C¼O), 1600 (C¼N)
1
cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 5.50 (s, 2Hbenzyl), 6.40 (s, NH2), 7.40 (m, H4,5,6,7indole þ 5Harom),
8.27 (s, H2indole), 8.27 (s, H2indole þ 1Hpyrazole), 8.23 (s, 1Hpyrimidine) ppm.
5-Acetylamino-1-(1-benzyl-1H-indol-3-ylcarbonyl)-1H-pyrazole-4-carbonitrile (17, C22H17N5O2)
A mixture of 341 mg 1 (1mmol) and 10cm3 acetic anhydride was heated under reflux for 2 h. After
cooling the solvent was removed under reduced pressure and the residue obtained was poured into an
ice-H2O mixture. The solid product obtained was filtered off and recrystallized from ethanol to afford
349 mg (91%) 19 as brownish red crystals; mp 178–180ꢁC; IR (KBr): ꢁꢀ¼ 3250 (NH), 2950 (CHaliph),
2220 (CꢄN), 1680 and 1640 (C¼O), 1600 (C¼N) cmꢂ1; 1H NMR (DMSO-d6): ꢀ ¼ 2.07 (s, COCH3),
5.47 (s, 2Hbenzyl), 7.23 (m, H5,6,7indole þ 5Harom), 7.93 (s, H4indole), 8.17 (s, H2indole), 8.30 (s,
1Hpyrazole), 10.20 (s, NH) ppm.
7-(1-Benzyl-1H-indol-3-ylcarbonyl)-2-methyl-3,4-dihydropyrazolo[3,4-d]pyrimidin-4-one
(19, C22H17N5O2)
A mixture of 341 mg 1 (1mmol) and 5 cm3 acetic anhydride in 10cm3 pyridine was heated under
reflux for 4 h. After cooling the solvent was removed under reduced pressure and the residue obtained
was poured into an ice-H2O mixture. The solid product obtained was filtered off dried, and recrys-
tallized from ethanol to afford 200 mg (52%) 17 as buff crystals; mp 192–194ꢁC; IR (KBr): ꢁꢀ¼ 3150
1
(NH), 2950 (CHaliph), 1660 and 1630 (C¼O), 1600 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 1.88 (s,
CH3), 5.53 (s, 2Hbenzyl), 7.40 (m, H5,6,7indole þ 5Harom), 8.10 (s, H4indole), 8.30 (s, H2indole), 9.10 (s,
1Hpyrazole), 11.20 (s, NH) ppm.
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