Pyrazoles and pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines, I. Synthesis and antimicrobial activity

Article abstract of DOI:10.1007/s00706-004-0234-2

The synthesis of the title compounds was achieved using 1-phenyl-5-(pyrrol-1-yl)-1H-pyrazole-3-carboxylic acid azide as starting material. The latter compound was allowed to react with alcohols and amines to afford the corresponding carbamates and urea de

Full text of DOI:10.1007/s00706-004-0234-2

Monatshefte f€ur Chemie 136, 217–227 (2005)
DOI 10.1007/s00706-004-0234-2
Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-
a]pyrazines, I. Synthesis and Antimicrobial
Activity
ꢀ
Abdel-Rahman Farghaly and Hussein El-Kashef
Chemistry Department, Faculty of Science, Assiut University, 71516 Assiut, Egypt
Received May 18, 2004; accepted (revised) June 16, 2004
Published online October 8, 2004 # Springer-Verlag 2004
Summary. The synthesis of the title compounds was achieved using 1-phenyl-5-(pyrrol-1-yl)-1H-
pyrazole-3-carboxylic acid azide as starting material. The latter compound was allowed to react with
alcohols and amines to afford the corresponding carbamates and urea derivatives. Alkaline hydrolysis
of the carbamates gave the corresponding amine, which was acylated and=or aroylated to give amide
derivatives. These and the urea derivatives were subjected to cyclodehydration to give the title com-
pounds. Antibacterial and antifungal activities were observed for several derivatives.
Keywords. Pyrazoles; Pyrrolylpyrazoles; Pyrazolopyrazines; Pyrazolopyrrolopyrazines.
Introduction
1-Phenyl-1H-pyrazolo[3,4-b]pyrazines have been reported to possess antiviral,
antineoplastic, antifungal, and antiparasitic activities [1–4]. Also other compounds
of related structure have been prepared for pharmacological evaluation [5]. Fur-
thermore, some tricyclic systems containing the pyrazole moiety with a bridge-
head nitrogen atom have been extensively studied owing to their interesting
biological and pharmacological activities [6, 7]. In view of these findings and in
continuation of our program directed towards the synthesis of new pyrazolopyr-
azines [3, 4] and other fused pyrazines [8–12] we report herein the synthesis and
antimicrobial activities of some new pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines and
related heterocycles.
Results and Discussion
The synthesis of the acid azide 2 has been reported earlier [2, 13]. We have pre-
pared the same azide by treating the carbohydrazide 1 with nitrous acid. Heating
ꢀ
Corresponding author. E-mail: elkashef15@hotmail.com

218
A.-R. Farghaly and H. El-Kashef
Scheme 1
this azide in boiling benzene in the presence of aliphatic or aromatic amines gave
the corresponding urea derivatives 3b–3i. When hydrazine hydrate was used in the
former reaction the semicarbazide derivative 3a was obtained. However, when 2
was allowed to decompose in refluxing alcohols the corresponding carbamates
4a–4d resulted. The product of its decomposition in boiling water was identified
as the symmetrical urea 5 (Scheme 1). It is obvious that the formation of the above-
mentioned compounds 3–5 occurred via the isocyanate key intermediate 6, which
was formed in situ by Curtius rearrangement of the acid azide 2. Several semi-
carbazones 7a–7c were obtained from the reaction of the semicarbazide 3a with
aromatic aldehydes. On the other hand, the alkaline hydrolysis of the carbamates,
e.g. 4a and 4d, led to the amine 8, which gave the corresponding anils 9a–9e
through its interaction with aromatic aldehydes (Scheme 2).
The formamido derivative 11a was obtained by reaction of 2 with formic acid
(Scheme 3). It is worthy to note that when 2 was heated in boiling acetic acid, two
Scheme 2

Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines
219
Scheme 3
products were formed; the expected acetamido derivative 11b and 5. The formation
of the latter resulted from a trace of water present in acetic acid. Alternatively, 11b,
11c, and 11d were obtained by the reaction of acyl- or aroylchloride with 8 in
pyridine at room temperature. The chloroacetyl derivative 10 was obtained upon
treating 8 with chloroacetyl chloride in boiling dioxane. The target pyrazolo
[4,3-e]pyrrolo[1,2-a]pyrazines 12a–12d were obtained upon cyclodehydration of
the 11a–11d in boiling POCl3. However, all attempts to ring close 10 into 13 using
phosphoryl chloride alone or admixed with phosphorus trichoride were unsuccess-
ful. Moreover, other pyrazine derivatives 14a–14c (Scheme 4) bearing substituted
Scheme 4

220
A.-R. Farghaly and H. El-Kashef
anilino groups in position 5 as potential adenosine receptor antagonist candidates
could be obtained by cyclodehydration reaction of 3c–3e in boiling POCl3.
Antibacterial and Antifungal Activities
Some of the prepared compounds were screened for the in-vitro antibacterial activ-
ity against four species of bacteria: Staphylococcus aureus, Escherichia coli,
Bacillus cereus, and Pseudomonas aeruginosa as well as eight fungi species: Peni-
cillium chrysogenum AUMC 530-15, Aspergillus flavus AUMC 164-5, Aspergillus
fumigatus AUMC 170-3, Aspergillus ochraceus AUMC 230-2, Aspergillus niger
AUMC 210-1, Curvulana lunata AUMC 2310-1, Fusarium solani AUMC 2690-6,
and Trichothecium roseum AUMC 7410-2.
In the series 3a–3i, only the 3-chloro derivative 3g was found to be active. It
showed a strong activity (þþþ) against B. cereus and (þþ) S. aureus, a moderate
activity (þ) against Escherichia coli whereas all the remainder of this series
showed no activity against both bacteria and fungi. On the other hand, 7d exhibited
a moderate to weak activity against four species of fungi; P. chrysogenum, A. niger,
C. lunala, and F. solani with inhibition zones of 12, 8, 17, 9 mm. Also it showed
activity (þþ) against the Gram-negative bacterium B. cereus.
Furthermore, the compound that showed a wide spectrum of activity against
bacteria and fungi was found to be the methyl pyrazine derivative 12a. Except
against T. roseum, 12a showed a moderate to weak activity against all the other
tested fungal species P. chrysogenum, A. falvus, A. fumigatus, A. ochracus, A. niger,
C. lunala, and F. solani, with inhibition zones 15, 8, 7, 12, 8, 12, 7 mm. Compound
12b showed a strong activity (þþ) against E. coli and B. cereus and a moderate
activity (þ) against S. aureus. When the 5-methyl group of 12b was substituted by
aryls, no activity was observed.
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 wafer technique. 1H NMR spectra were recorded
on a Varian EM 390, 90MHz 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. 1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazole-4-carbohydrazide (1) was prepared as described
earlier [2].
1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazole-4-carboazide (2) [2]
To a suspension of 5.30 g of 1 (20 mmol) in 50cm3 of glacial acetic acid, a cold solution of 3.30g of
NaNO2 (10 cm3, 33%) was added dropwise with stirring at rt. After completion of the addition, stir-
ring was continued for 1 h. The solid precipitate obtained was filtered off, washed with H2O, dried by
suction, and used in the next reaction without purification. Yield 5.22g (95%) of yellow powder of 2;
1
mp (decomp) 102–104ꢁC [2]; IR (KBr): ꢁꢀ¼ 2120 (CON3), 1680 (C¼O) cmꢂ1; H NMR (CDCl3):
ꢀ ¼ 6.25 (m, H3,4pyrrole), 6.65 (m, H2,5pyrrole), 7.10 (m, 2Harom), 7.27 (m, 3Harom), 8.10 (s, 1Hpyrazole
)
ppm.

Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines
221
Reaction of 2 with Hydrazine Hydrate and Amines (General Procedure)
A mixture of 0.278 g of 2 (1mmol) and hydrazine hydrate or the appropriate amine (1mmol) in 10cm3
of dry benzene was heated under reflux for 1 h. Then the reaction mixture was concentrated and the
solid product formed was filtered off and recrystallized from the solvent indicated below to give 3a
or 3b–3i.
4-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)semicarbazide (3a, C14H14N6O)
Buff crystals; mp 194–196ꢁC (ethanol); yield 0.24g (85%); IR (KBr): ꢁꢀ¼ 3300, 3100 (NH and
1
NHNH2), 1660 (C¼O)cmꢂ1; H NMR (CDCl3): ꢀ ¼ 3.63 (s, br, NH2), 6.40 (m, H3,4pyrrole), 6.60
(s, NH), 6.73 (m, H2,5pyrrole), 7.10 (m, 2Harom), 7.23 (m, 3Harom), 8.20 (s, 1Hpyrazole) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(2-hydroxyethyl)urea (3b, C16H17N5O2)
White plates; mp 142–144ꢁC (ethanol); yield 0.25g (80%); IR (KBr): ꢁꢀ¼ 3420–3100 (OH and NH),
1
1650 (C¼O)cmꢂ1; H NMR (CDCl3): ꢀ ¼ 2.57 (s, NH), 3.53 (m, 2CH2), 5.67 (s, OH), 6.37 (m,
H3,4pyrrole), 6.72 (m, H2,5pyrrole), 7.13 (m, 2Harom), 7.30 (m, 3Harom), 8.17 (s, 1Hpyrazole), 8.32 (s, NH)
ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(p-tolyl)urea (3c, C21H19N5O)
White crystals; mp 215–217ꢁC (ethanol); yield 0.29g (81%); IR (KBr): ꢁꢀ¼ 3300 (NH), 1650
1
(C¼O)cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 2.23 (s, CH3), 6.30 (m, H3,4pyrrole), 6.88 (m, H2,5pyrrole),
7.03 (m, 4Harom), 7.27 (m, 5Harom), 7.80 (s, NH), 8.11 (s, 1Hpyrazole), 8.67 (s, NH) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(o-tolyl)urea (3d, C21H19N5O)
Yellowish buff needles; mp 225–227ꢁC (ethanol); yield 0.25 g (70%); IR (KBr): ꢁꢀ¼ 3300 (NH), 1640
(C¼O) cmꢂ1; 1H NMR (DMSO-d6): ꢀ ¼ 2.22 (s, CH3), 6.33 (m, H3,4pyrrole), 6.91 (m, H2,5pyrrole), 7.07
(m, 4Harom), 7.30 (m, 5Harom), 7.80 (s, NH), 8.17 (s, 1Hpyrazole), 8.33 (s, NH) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(m-tolyl)urea (3e, C21H19N5O)
White crystals; mp 198–200ꢁC (ethanol:H2O ¼ 3:1); yield 0.27 g (76%); IR (KBr): ꢁꢀ¼ 3320 and 3250
1
(NH), 1640 (C¼O)cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 2.28 (s, CH3), 6.30 (m, H3,4pyrrole), 6.88 (m,
H2,5pyrrole), 7.17 (m, 9Harom), 7.87 (s, NH), 8.17 (s, 1Hpyrazole), 8.80 (s, NH) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(2-chlorophenyl)urea (3f, C20H16N5OCl)
Yellowish buff crystals; mp 214–116ꢁC (ethanol); yield 0.30 g (80%); IR (KBr): ꢁꢀ¼ 3350 and 3280
1
(NH), 1640 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.30 (m, H3,4pyrrole), 6.90 (m, H2,5pyrrole), 7.03
(m, 4Harom), 7.33 (m, 5Harom), 8.20 (s, 1Hpyrazole), 8.60 (s, NH), 8.77 (s, NH) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(3-chlorophenyl)urea (3g, C20H16N5OCl)
Buff fluffy crystals; mp 105–108ꢁC (ethanol); yield 0.32g (85%); IR (KBr): ꢁꢀ¼ 3350 and 3280 (NH),
1
1640 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.27 (m, H3,4pyrrole), 6.86 (m, H2,5pyrrole), 6.96 (m,
4Harom), 7.23 (m, 5Harom), 7.93 (s, NH), 8.07 (s, 1Hpyrazole), 9.00 (s, NH) ppm.

222
A.-R. Farghaly and H. El-Kashef
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(morpholin-4-yl)urea (3h, C18H19N5O2)
Buff crystals; mp 150–152ꢁC (ethanol); yield 0.26g (77%); IR (KBr): ꢁꢀ¼ 3450 (NH), 1620 (C¼O)
1
cmꢂ1; H NMR (CDCl3): ꢀ ¼ 3.47 (m, 4CH2), 6.30 (m, H3,4pyrrole), 6.67 (m, H2,5pyrrole), 7.13 (m,
2Harom), 7.33 (m, 3Harom), 7.87 (s, 1Hpyrazole), 9.30 ( s, NH) ppm.
1-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-3-(piperidin-1-yl)urea (3i, C19H21N5O)
White crystals; mp 142–144ꢁC (ethanol); yield 0.30g (90%); IR (KBr): ꢁꢀ¼ 3450 (NH), 1620 (C¼O)
cmꢂ1
.
1H NMR (CDCl3): ꢀ ¼ 1.40 (m, 3CH2), 3.37 (m, 2CH2), 6.27 (m, H3,4pyrrole), 6.67 (m,
H2,5pyrrole), 7.17 (m, 2Harom), 7.33 (m, 3Harom), 7.87 (s, 1Hpyrazole), 9.28 (s, NH) ppm.
Alkyl N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)carbamates (General Procedure)
A solution of 0.556 g of 2 (2mmol) in 5 cm3 of ethanol, 2-propanol, n-butanol, or benzyl alcohol was
heated under reflux for 2 h. The reaction mixture was concentrated and allowed to cool. The residue
obtained was triturated with ethanol. The solid product formed was filtered off and recrystallized from
the same alcohol used to give 4a–4d.
Ethyl N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)carbamate (4a)
Fluffy buff crystals; mp 126–128ꢁC (ethanol, Ref. [2] 134–135ꢁC); yield 0.55g (93%, Ref. [2] 85%);
1
IR (KBr): ꢁꢀ¼ 3250 (NH), 1690 (C¼O) cmꢂ1; H NMR (CDCl3): ꢀ ¼ 1.26 (t, J ¼ 7.5 Hz, CH2CH3),
4.16 (q, J ¼ 7.5 Hz, CH2CH3), 6.23 (s, NH), 6.30 (m, H3,4pyrrole), 6.63 (m, H2,5pyrrole), 7.11 (m,
2Harom), 7.23 (m, 3Harom), 8.03 (s, 1Hpyrazole) ppm.
Prop-2-yl N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)carbamate (4b, C17H18N4O2)
Buff crystals; mp 120–122ꢁC (isopropanol); yield 0.40g (65%); IR (KBr): ꢁꢀ¼ 3250 (NH), 1680
1
(C¼O)cmꢂ1; H NMR (CDCl3): ꢀ ¼ 1.27 (m, 2CH3), 4.87 (m, COOCH), 6.03 (s, NH), 6.27 (m,
H3,4pyrrole), 6.60 (m, H2,5pyrrole), 6.97 (m, 2Harom), 7.17 (m, 3Harom), 8.00 (s, 1Hpyrazole) ppm.
Butyl N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)carbamate (4c, C18H20N4O2)
Buff needles; mp 94–96ꢁC (n-butanol); yield 0.50g (77%); IR (KBr): ꢁꢀ¼ 3280 (NH), 1680 (C¼O)
cmꢂ1; 1H NMR (CDCl3): ꢀ ¼ 0.97 (t, J ¼ 7.0 Hz, CH3), 1.45 (m, 2CH2), 4.12 (t, J ¼ 6.9 Hz, COOCH2),
6.17 (s, NH), 6.30 (m, H3,4pyrrole), 6.63 (m, H2,5pyrrole), 7.03 (m, 2Harom), 7.20 (m, 3Harom), 8.03 (s,
1Hpyrazole) ppm.
Benzyl N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)carbamate (4d, C21H18N4O2)
Buff crystals; mp 133–135ꢁC (ethanol); yield 0.54g (75%); IR (KBr): ꢁꢀ¼ 3280 (NH), 1700 (C¼O)
cmꢂ1
;
1H NMR (CDCl3): ꢀ ¼ 5.13 (m, CH2), 6.17 (s, NH), 6.27 (m, H3,4pyrrole), 6.57 (m, 2H,
H2,5pyrrole), 7.00 (m, 2Harom), 7.16 (m, 3Harom), 7.30 (m, 5Harom), 8.03 (s, 1Hpyrazole) ppm.
1,3-Bis-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)urea (5, C27H22N8O)
A suspension of 0.55g of 2 (2mmol) in 20cm3 of H2O was refluxed for 3 h. After cooling, the prod-
uct formed was filtered off and recrystallized from ethanol:dioxane (1:1) to afford 0.40g (84%) of 5
1
as buff crystals; mp 255–257ꢁC; IR (KBr): ꢁꢀ¼ 3380, 3100 (NH), 1690 (C¼O) cmꢂ1; H NMR
(CDCl3): ꢀ ¼ 6.30 (m, H3,4pyrrole), 6.87 (m, H2,5pyrrole), 7.03 (m, 2Harom), 7.30 (m, 3Harom), 8.13 (s,

Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines
223
1Hpyrazole), 8.22 (s, 1H, NH) ppm; MS: m=z (%) ¼ 474 [Mþ] (96), 369 (56), 301 (36), 224 (21), 169
(51), 128 (28), 111 (25), 104 (100), 103 (57), 79 (40), 67 (30), 62 (19), 51 (42).
1-Arylidene-4-(1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)semicarbazide (General Procedure)
A mixture of 0.282g of 3a (1mmol) and the appropriate aromatic aldehyde (1mmol) in 10cm3 of
absolute ethanol was heated under reflux for 4 h. The reaction mixture was concentrated and left to
cool. After cooling, the solid product formed was filtered off and recrystallized from the solvent
indicated to give 7a–7c.
1-Benzylidene-4-(1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)semicarbazide (7a, C21H18N6O)
Yellow needles; mp 223–225ꢁC (ethanol); yield 0.28g (75%); IR (KBr): ꢁꢀ¼ 3350 (NH), 3250 (NH),
1
1650 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.17 (m, H3,4pyrrole), 6.83 (m, H2,5pyrrole), 7.40 (m,
10Harom), 8.30 (s, NH), 8.37 (s, 2Hpyrazole þ N¼CH), 11.63 (s, NH) ppm.
1-(4-Chlorobenzylidene)-4-(1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)semicarbazide
(7b, C21H17N6OCl)
Buff crystals; mp 218–220ꢁC (methanol); yield 0.34g (84%); IR (KBr): ꢁꢀ¼ 3300 (NH), 3180 (NH),
1
1640 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.16 (m, H3,4pyrrole), 6.86 (m, H2,5pyrrole), 7.52 (m,
9Harom), 8.30 (s, NH), 8.34 (s, 1Hpyrazole), 8.72 (s, N¼CH), 11.63 (s, NH) ppm.
1-(2-Hydroxybenzylidene)-4-(1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)semicarbazide
(7c, C21H17N6O2)
White crystals; mp 213–215ꢁC (ethanol); yield 0.35g (91%); IR (KBr): ꢁꢀ¼ 3300 (NH), 3100 (NH),
1
1670 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.05 (m, H3,4pyrrole), 6.90 (m, H2,5pyrrole þ 2Harom),
7.20 (m, 2Harom), 7.38 (m, 5Harom), 8.32 (s, NH), 8.38 (s, 1Hpyrazole), 8.53 (s, N¼CH), 11.03 (s, OH),
11.66 (s, NH) ppm.
1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (8, C13H12N4)
A mixture of 4a or 4d (1mmol) and 15 cm3 of aqueous ethanolic NaOH (20%) was heated under reflux
for 48 h. The solvent was evaporated and the residue was triturated with H2O. The solid product
obtained was filtered off and recrystallized from ethanol to afford 0.17 g (75%) or 0.204g (90%) of 8 as
yellow crystals; mp 140–142ꢁC (Ref. [2] 144–145ꢁC).
N-Arylidene-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (General Procedure)
A mixture of 0.224 g of 8 (1mmol) and the appropriate aromatic aldehyde (1 mmol) in 10 cm3 of
absolute ethanol was heated under reflux in presence of two drops of piperidine for 3 h, then the
reaction mixture was concentrated. After cooling, the solid product formed was collected by filtration
and recrystallized from the proper solvent to give the corresponding derivatives 9a–9e.
N-Benzylidene-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (9a, C20H16N4)
Pale yellow crystals; mp 171–173ꢁC (ethanol); yield 0.17g (55%); IR (KBr): ꢁꢀ¼ 1610 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 6.27 (m, H3,4pyrrole), 6.85 (m, H2,5pyrrole), 7.13 (m, 3Harom), 7.40 (m,
5Harom), 7.73 (m, 2Harom), 8.23 (s, 1Hpyrazole), 8.77 (s, N¼CH) ppm.

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A.-R. Farghaly and H. El-Kashef
N-(4-Chlorobenzylidene)-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (9b, C20H15N4Cl)
Yellowish white crystals; mp 176–178ꢁC (benzene:dioxane ¼ 2:1); yield 0.21g (61%); IR (KBr):
1
ꢁꢀ¼ 1620 (C¼N) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.27 (m, H3,4pyrrole), 6.90 (m, H2,5pyrrole), 7.17
(m, 2Harom), 7.40 (m, 3Harom), 7.56 (d, J ¼ 8.9 Hz, 2Harom), 7.83 (d, J ¼ 8.9 Hz, 2Harom), 8.26 (s,
1Hpyrazole), 8.83 (s, N¼CH) ppm.
N-(4-Nitrobenzylidene)-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (9c, C20H15N4Cl)
Yellow crystals; mp 192–194ꢁC (ethanol); yield 0.12g (34%); IR (KBr): ꢁꢀ¼ 1610 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 6.30 (m, H3,4pyrrole), 6.90 (m, H2,5pyrrole), 7.16 (m, 2Harom), 7.43 (m,
3Harom), 8.03 (d, J ¼ 9 Hz, 2Harom), 8.35 (s, 1Hpyrazole), 8.36 (d, J ¼ 9 Hz, 2Harom), 9.01 (s, N¼CH) ppm.
N-[4-(Dimethylamino)benzylidene]-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine
(9d, C22H21N5)
Yellow needles; mp 182–184ꢁC (ethanol); yield 0.153g (43%); IR (KBr): ꢁꢀ¼ 1600 (C¼N) cmꢂ1
;
1H NMR (CDCl3): ꢀ ¼ 3.03 (s, 2CH3), 6.30 (m, H3,4pyrrole), 6.67 (d, 2Harom), 6.73 (m, H2,5pyrrole), 7.23
(m, 5Harom), 7.67 (m, 2Harom), 7.87 (s, 1Hpyrazole), 8.36 (s, N¼CH) ppm.
N-(4-Methoxybenzylidene)-1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-ylamine (9e, C21H18N4O)
Yellow crystals; mp 147–150ꢁC (benzene:ethanol ¼ 1:1); yield 0.25g (73%); IR (KBr): ꢁꢀ¼ 1610
1
(C¼N) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 3.83 (s, CH3), 6.30 (m, H3,4pyrrole), 6.76 (m, H2,5pyrrole),
6.91 (d, 2Harom), 7.25 (m, 5Harom), 7.73 (m, 2Harom), 7.90 (s, 1Hpyrazole), 8.43 (s, N¼CH) ppm.
2-Chloro-N-(1-phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)acetamide (10, C15H13N4OCl)
To a solution of 0.44g of 8 (2mmol) in 10cm3 of dry dioxane, 0.225 g of chloroacetyl chloride
(2mmol) were added dropwise, and the reaction mixture was refluxed for 4 h. After cooling, the
reaction mixture was poured into ice-H2O and the solid product formed was collected by filtration
and recrystallized from ethanol to give 0.13g (22%) of 10 as bright white flakes; mp 180–182ꢁC; IR
1
(KBr): ꢁꢀ¼ 3250 (NH), 1650 (C¼O) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 4.26 (s, CH2Cl), 6.30 (m,
H3,4pyrrole), 6.80 (m, H2,5pyrrole), 7.00 (m, 2Harom), 7.30 (m, 3Harom), 8.06 (s, 1Hpyrazole), 9.80 (s,
NH) ppm.
N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)formamide (11a, C14H12N4O)
A mixture of 0.56 g of 2 (2mmol) and 5 cm3 of formic acid was heated under reflux for 3 h. After
cooling the reaction mixture was poured into ice-H2O, the solid precipitate formed was collected by
filtration and recrystallized from ethanol into buff crystals. Yield 0.38 g (76%, Ref. [2] 96%);
mp 200–202ꢁC (Ref. [2] 209–210ꢁC); IR (KBr): ꢁꢀ¼ 3200 (NH), 1640 (C¼O) cmꢂ1
;
1H NMR
(DMSO-d6): ꢀ ¼ 6.28 (m, H3,4pyrrole), 6.86 (m, H2,5pyrrole), 7.08 (m, 2Harom), 7.33 (m, 3Harom), 8.20
(s, 2Hpyrazole þ CHO), 9.80 (s, NH) ppm; MS: m=z (%) ¼ 253 [Mþ þ1] (31), 252 [Mþ] (100), 235 (7),
224 (30), 223 (20), 196 (22), 170 (11), 169 (30), 104 (12), 77 (46), 68 (11), 51 (12).
N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)acetamide (11b, C15H14N4O)
Method A: A mixture of 0.44 g of 8 (2mmol) and 0.16g of acetyl chloride (2mmol) in 10cm3 of
pyridine was stirred at rt for 2 h. Then, the reaction mixture was poured into ice-H2O and the solid

Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines
225
product formed was filtered off and recrystallized from ethanol to give 0.34g (79%) of 11b as bright
1
white flakes; mp 202–204ꢁC; IR (KBr): ꢁꢀ¼ 3200 (NH), 1640 (C¼O) cmꢂ1; H NMR (DMSO-d6):
ꢀ ¼ 2.00 (s, CH3), 6.23 (m, H3,4pyrrole), 6.78 (m, H2,5pyrrole), 7.03 (m, 2Harom), 7.30 (m, 3Harom), 8.03
(s, 1Hpyrazole), 9.40 (s, NH) ppm.
Method B: A mixture of 0.50 g of 2 (1.8mmol) and 10cm3 of acetic acid in presence of 0.5 g of
fused NaOAc was heated under reflux for 3 h. After cooling the reaction mixture was poured into ice-
H2O, the solid product formed was filtered off and recrystallized from ethanol to afford 0.13 g of 11b
(27%).
N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)benzamide (11c, C20H16N4O)
To a well stirred cooled suspension of 0.44g of 8 (2mmol) in 10cm3 of pyridine, 0.28g of benzoyl
chloride (2mmol) were added dropwise with stirring. The reaction mixture was stirred at rt for 2 h and
the solid precipitate obtained was filtered off and recrystallized from ethanol to give 0.50 g (76%) of
11c as white crystals; mp 128–130ꢁC; IR (KBr): ꢁꢀ¼ 3220 (NH), 1640 (C¼O) cmꢂ1
;
1H NMR
(CDCl3): ꢀ ¼ 6.23 (m, H3,4pyrrole), 6.70 (m, H2,5pyrrole), 7.22 (m, 5Harom), 7.46 (m, 3Harom), 7.80
(m, 2Harom), 8.41 (s, 1Hpyrazole), 9.96 (s, NH) ppm; MS: m=z (%) ¼ 328 [Mþ] (37), 224 (10), 223 (11),
222 (9), 195 (10), 152 (12), 132 (9), 106 (12), 105 (100), 104 (12), 77 (52), 75 (11), 67 (18), 51 (15),
50 (10).
N-(1-Phenyl-5-(pyrrol-1-yl)-1H-pyrazol-4-yl)-4-chlorobenzamide (11d, C20H15N4OCl)
A mixture of 0.44 g of 8 (2mmol) and 0.35 g of 4-chlorobenzoyl chloride (2mmol) in 10cm3 of
pyridine was stirred at rt for 2 h. The reaction mixture was then poured into ice-H2O and the solid
product formed was collected by filtration and recrystallized from ethanol to give 0.72g (99%) of 11d
as fluffy white crystals; mp 172–174ꢁC; IR (KBr): ꢁꢀ¼ 3320 (NH), 1632 (C¼O), 1590 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 6.21 (m, H3,4pyrrole), 6.81 (m, H2,5pyrrole), 7.02 (m, 2Harom), 7.32 (m,
3Harom), 7.56 (d, J ¼ 8.52 Hz, 2Harom), 7.87 (d, J ¼ 8.52Hz, 2Harom), 7.99 (s, 1Hpyrazole), 9.98 (s,
NH) ppm; MS: m=z (%) ¼ 362 [Mþ] (100), 345 (23), 223 (84), 169 (40), 141 (56), 139 (100), 113
(16), 111 (47), 103 (12), 77 (52), 46 (10), 45 (23).
1-Phenyl-5-substitued-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines (General Procedure)
A mixture of 11a–11d (1mmol) in 5 cm3 of phosphoryl chloride was heated under gentle reflux for 3 h.
After cooling the reaction mixture was poured into ice-H2O and neutralized with NaOH solution
(20%). The solid precipitate formed was collected by filtration and recrystallized from the proper
solvent.
1-Phenyl-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (12a)
This compound was prepared according to the general procedure and the analytical data are in
accordance with that of the reported procedure [2].
1-Phenyl-5-methyl-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (12b, C15H12N4)
Buff needles; mp 120–122ꢁC (petroleum ether (40–60): benzene ¼ 1:1); yield: 0.15g (60%); IR (KBr):
1
ꢁꢀ¼ 1600 (C¼N) cmꢂ1; H NMR (CDCl3): ꢀ ¼ 2.37 (s, CH3), 6.67 (m, 1Hpyrrole), 6.90 (m, 1Hpyrrole),
6.96 (m, 1Hpyrrole), 7.53 (m, 5Harom), 8.10 (s, 1Hpyrazole) ppm; MS: m=z (%) ¼ 249 [Mþ þ1] (25), 248
[Mþ] (100), 247 [Mþ ꢂ1] (23), 220 (11), 144 (7), 118 (7), 92 (10), 77 (18), 51 (15).

226
A.-R. Farghaly and H. El-Kashef
1,5-Diphenyl-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (12c, C20H14N4)
Yellowish brown crystals; mp 175–177ꢁC (ethanol); yield 0.10g (32%); IR (KBr): ꢁꢀ¼ 1600 (C¼N)
1
cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 6.90 (m, 1Hpyrrole), 7.03 (m, 2Hpyrrole), 7.53 (m, 3Harom), 7.67 (m,
5Harom), 7.90 (m, 2Harom), 8.37 (s, 1Hpyrazole) ppm; MS: m=z (%) ¼ 311 [Mþ þ1] (45), 310 [Mþ] (100),
309 [Mþ ꢂ1] (33), 283 (5), 282 (11), 188 (17), 154 (13), 127 (5), 77 (20), 51 (11).
1-Phenyl-5-(4-chlorophenyl)-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (12d, C20H13N4Cl)
White crystals; mp 187–189ꢁC (ethanol); yield 0.34g (99%); IR (KBr): ꢁꢀ¼ 1592 (C¼N) cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 6.90 (m, 1Hpyrrole), 7.01 (m, 1Hpyrrole), 7.07 (m, 1Hpyrrole), 7.62 (d,
J ¼ 8.52Hz, 2Harom), 7.69 (m, 3Harom), 7.71 (m, 2Harom), 7.94 (d, J ¼ 8.52 Hz, 2Harom), 8.39 (s,
1Hpyrazole) ppm; MS: m=z (%) ¼ 343 [Mþ ꢂ1] (100), 342 (10), 316 (76), 307 (37), 290 (27), 280
(38), 178 (87), 171 (29), 76 (66), 51 (35).
1-Phenyl-5-substitued-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (General Procedure)
A mixture of 3c–3e (1mmol) in 5 cm3 of phosphoryl chloride was heated under reflux for 2 h. After
cooling the reaction mixture was poured into ice-H2O and neutralized with NH4OH. The solid white
precipitate formed was collected by filtration and recrystallized from the proper solvent to give the
corresponding compounds 14a–14c.
1-Phenyl-5-(p-tolylamino)-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (14a, C21H17N5)
White crystals; mp 220–222ꢁC (ethanol); yield: 0.30 g (88%); IR (KBr): ꢁꢀ¼ 3425 (NH), 1629 (C¼N)
cmꢂ1
;
1H NMR (DMSO-d6): ꢀ ¼ 2.36 (s, CH3), 6.84 (m, 1Hpyrrole), 6.98 (m, 1Hpyrrole), 7.41 (d,
J ¼ 8.32Hz, 2Hp-tolyl), 7.64 (d, J ¼ 8.32Hz, 2Hp-tolyl), 7.74 (m, 5Harom), 7.98 (m, 1Hpyrrole), 8.01 (s,
1Hpyrazole), 10.82 (s, NH, exchangeable) ppm.
1-Phenyl-5-(o-tolylamino)-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (14b, C21H17N5)
Colorless needles; mp 212–215ꢁC (ethanol); yield 0.32 g (94%); IR (KBr): ꢁꢀ¼ 3340 (NH), 1595
1
(C¼N) cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 2.23 (s, CH3), 6.71 (m, 1Hpyrrole), 6.86 (m, 1Hpyrrole), 7.13
(m, 1Hpyrrole), 7.26 (m, 4Ho-tolyl), 7.54 (m, 3Harom), 7.60 (m, 2Harom), 7.79 (s, 1Hpyrazole), 8.53 (s, NH,
exchangeable) ppm.
1-Phenyl-5-(m-tolylamino)-1H-pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazine (14c, C21H17N5)
White crystals; mp 222–224ꢁC (ethanol); yield 0.28g (82%); IR (KBr): ꢁꢀ¼ 3420 (NH), 1630 (C¼N)
1
cmꢂ1; H NMR (DMSO-d6): ꢀ ¼ 2.40 (s, CH3), 6.80 (m, 1Hpyrrole), 6.94 (m, 1Hpyrrole), 7.03 (m,
1Hpyrrole), 7.29 (m, 4Hm-tolyl), 7.65 (m, 5Harom), 7.98 (s, 1Hpyrazole), 10.12 (s, NH, exchangeable) ppm.
Antibacterial and Antifungal Assay
The tested compounds and the control antibiotic were dissolved in DMSO as stock solutions, and
dilutions were made using sterile distilled H2O. The in vitro anti-microbial activities of the tested
compounds were carried out using the filter paper disc diffusion method [14]. Filter paper discs (5 mm)
saturated with the solution of each tested compound (20 mg=2 cm3 DMSO) were placed on the surface
of the media (Nutrient agar for bacteria and Dextrose Agar for the fungi). The inhibition zones were

Pyrazoles and Pyrazolo[4,3-e]pyrrolo[1,2-a]pyrazines
227
measured in mm at the end of an incubation period of 48 h at 37ꢁC for the bacteria and at 28ꢁC for the
fungi. Discs saturated with DMSO were used as control; Clotrimazole was used as an anti-fungal and
Cloxacillin as an anti-bacterial reference. Both control (þþþ) in the test (inhibition zones >25 mm).
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