Pyrazolones as building blocks in heterocyclic synthesis: Synthesis of new pyrazolopyran, pyrazolopyridazine and pyrazole derivatives of expected antifungicidal activity

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Article

Pyrazolones as Building Blocks in Heterocyclic Synthesis: Synthesis of New

Pyrazolopyran, Pyrazolopyridazine and Pyrazole Derivatives of Expected

Antifungicidal Activity

Mahmoud. M. M. Ramiz,^a* Ibrahim. S. Abdel Hafiz,^b

Mohamed. A. M. Abdel Reheim^band Hatem M. Gaber^c

^aFaculty of Electronic Engineering, Minufiya University, Menouf, Egypt

^bDepartment of Chemistry, Faculty of Education, Suez Canal University, Arish, Egypt

^cNational Organization for Drug Control and Research (NODCAR), P.O. Box 29, Cairo, Egypt

(Received April 3, 2011; Accepted August 23, 2011; Published Online August 31, 2011; DOI: 10.1002/jccs.201100194)

A series of new pyrazolone and pyrazole derivatives with expected antifungicidal activity have been pre-

pared through the reactions 3-phenyl-1-H-pyrazol-5(4H)-one (3) and 4-(dimethylaminomethylene)-3-

phenyl-1H-pyrazol-5(4H)-one (5) with a variety of electrophilic reagents and nucleophilic reagents. The

newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral studies.

Keywords: Pyrazolone; Pyrazolopyran and pyrazolopyridazine and pyrazole derivatives.

INTRODUCTION

Heterocycles, containing the pyrazolone nucleus,

derivatives received great attention due to their biological

activities as potential HIV-1 inhibitors,¹⁹insecticides,²⁰

fungicides,²⁰antiviral agents,²¹and due to their anticancer

activity.²²Also, the chemistry of fused pyrazoles such as

pyrazolopyrimidines and related fused heterocycles has

drawn great attention due to the pharmacological impor-

tance and their structural resemblance to purines.²³Several

substituted pyrazolo-pyrimidine derivatives demonstrated

significant antimicrobial²⁴and antiviral activities,²⁵also

they have been identified as adenosine antagonists, tyro-

sine kinase, and Src-kinase inhibitors.^26–30In continuation

of this work and as apart of our biological chemistry pro-

gramme,^31–33we report here the utility of 3 in the synthesis

of unique heterocycles of expected biological interest.

have attracted much attention due to their interesting bio-

logical activities.^1–4The synthesis of a large number of

heterocycles containing pyrazolone nucleus led to very in-

teresting and useful antitumorally,⁵antibacterially,⁶and

agrochemically active products.⁷Pyrazolone-5 derivatives

form an important class of organic compounds and repre-

sent a major scientific and applied interest in biological, an-

alytical applications, catalysis, dye and extraction metal-

lurgy.^8–11Furthermore, they have the potential to form dif-

ferent types of coordination compounds due to the several

electron-rich donor centers.^12,13Well-known medicinal

pyrazolone dipyrone, has shown to inhibit the activities in

a dose-dependent manner of cyclooxygenase enzyme

COX-1 and its variant COX-3,¹⁴which catalyze the rate-

limiting step of prostaglandin synthesis. Pyrazolones are

also well-known as an active moiety in the class of NSAIDs

and used in the treatment of arthritis, musculo skeletal and

joint disorder.^15–165-Pyrazolone derivatives are widely

used in medical practice (antipyrine, amidopyrine, analgin,

etc.).¹⁷Most of the compounds belonging to this series of

drugs are characterized by the presence of phenyl substitu-

ents in position 1 of the pyrazoline ring. Thus, the biologi-

cal activities of pyrazol-5-ones depend on the nature of the

substituents.¹⁸On the other hand, the chemistry of pyrazole

RESULTS AND DISCUSSION

It has been reported that ethyl benzoylacetate (1) re-

acted with hydrazine hydrate in domestic microwave oven

to yield the pyrazolone derivative 3 via intermediacy of

hydrazide derivative 2.³⁴Trials to isolate the acyclic inter-

mediate 2 were failed under a variety of mild conditions

(Scheme I).

Pyrazol-5-one derivative 3 was exploited as a key in-

termediate for the synthesis of hitherto unknown fused

pyrazoles through its reaction with some reagents. Thus,

fusion of pyrazolone 3 with dimethylformamide dimethyl

* Corresponding author. E-mail: dr.m.ramiz@gmail.com

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Pyrazolones as Building Blocks in Heterocyclic Synthesis

acted with 5 to give pyrazolones 8b,c respectively(Scheme

III). The structure of the latter product 8 was established on

the basis of its elemental analysis and spectral data. For ex-

ample, the mass spectrum of 8a showed a molecular ion

peak at m/z = 263 in agreement with its molecular formula

C₁₆H₁₃N₃O. The reactivity of 5 towards some nitrogen

nucleophiles was investigated. Thus, when 5 was treated

with ammonia, the transamination adduct 10 was formed in

a good yield via intermediacy of 9.³⁵Treatment of 10 with

triethylorthoformate in refluxing acetic anhydride for 3 hr

afforded Ethyl N-((5-oxo-3-phenyl-1H-pyrazol-4(5H)yli-

dene)methyl)-formimidate (11) which could be cyclized to

3-phenylpyrazolo[4,3-e][1,3]oxazine (12), upon boiling in

pyridine. Structures of compounds 11 and 12 were estab-

Scheme I

acetal (DMF-DMA) in domestic microwave oven afforded

the pyrazolone 4. Establishing structure 4 was based on its

spectral analyses. The mass spectrum of 4 showed a molec-

ular ion peak at m/z = 330 in agreement with its molecular

formula C₁₉H₁₄N₄O₂. Refluxing prazolone 3 with dimeth-

ylformamide dimethyl acetal in dry dioxane for about 6 hrs

afforded the pyrazolone derivative 5. Establishing struc-

ture 5 was based on its elemental analyses and spectral

data. Thus, ¹H NMR spectrum of compound 5 revealed an

intense singlet signal at d = 3.25, 3.29 ppm corresponding

to two methyl functions, the olifinic proton and NH group

appeared as two singlet signals at d = 7.31 and 10.87 ppm

respectively. The ¹³C NMR data of compounds 5 showed

chemical shift values conform to the suggested structure.

The mass spectrum of the same compound is in accordance

with the proposed structure. Thus, it showed a very intense

molecular ion peak at m/z 215 and a number of fragments

agree with the proposed structure (Scheme II).

Scheme III

Compound 5 was examined as a key precursor toward

a variety of nucleophilic reagents aiming at exploring its

synthetic potentiality. Thus, when compound 5 is allowed

to reflux with aniline 6 in ethanol containing a catalytic

amount of piperidine, pyrazolone derivative 8a was ob-

tained via intermediacy of 7. Similarly, anilines 6b,c re-

Scheme II

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Ramiz et al.

lished on the basis of elemental analysis and spectral data.

For example, the ¹H NMR of compound 11 showed a triplet

at d = 1.22 ppm and quarter at d = 3.61 ppm corresponding

to ethyl function, while the aromatic and alkenyl protons

appeared as multiples at d = 7.43-7.53, and a single singlet

at d = 12.84 corresponds to NH group. The IR spectrum of

12 was free from the absorption bands for carbonyl and

amino groups and the ¹H NMR of 12 revealed only the sig-

nals for the aromatic proton at d = 7.46-9.76 (Scheme III).

Treatment of pyrazolone 5 with hydrazine and phenyl

hydrazine in refluxing ethanol afforded the acyclic hydra-

zide derivatives 15a,b respectively. Establishing structure

15 was based on its elemental analyses and spectral data.

For example, the ¹H NMR of 15a revealed the presence of

singlet signal at d = 5.95 ppm corresponding to the olifinic

protons and a multiplet signal at d = 7.32-7.74 ppm corre-

sponding to aromatic protons and the amine proton ap-

peared as a singlet signal at d = 8.53 ppm.

Scheme IV

data. For example the IR spectrum of compound 24a re-

vealed the absence of OH group absorption band, in addi-

tion it revealed the presence of an amino function at n_max

=

3367 and 3300 cm^–1. The ¹H NMR spectrum showed a sin-

glet signal at d = 5.22 ppm corresponding to H-4 pyran, a

multiplet signals at d = 7.01-7.64 ppm corresponding to ar-

omatic protons and NH₂and a singlet signal at d = 11.82

characteristic of NH group. Formation of 24 is believe to be

formed via initial addition of the methylene group of 3 on

the double bond of the arylidene 20 to give the Michael

adduct 21 that underwent tautomerism followed by intra-

molecular cyclization to give 24.

Treatment of 15a,b with sodium ethoxide solution af-

forded the cyclic pyrazolo[3,4-c]pyrazole 16a,b (Scheme

III). Establishing structure 16 was based on its elemental

analyses and spectral data. For example, the IR spectrum of

16a revealed the absence of carbonyl group indicating that

compound 16 is formed from 15 via tautomerism, cycliza-

tion and subsequent elimination of water molecule. The

mass spectrum of the same product is in accordance with

the proposed structure. The reaction of hydroxyl amine

with pyrazolone 5 in refluxing pyridine afforded the fused

isoxazole 19. Formation of 19 from the reaction of pyr-

azolone 5 and hydroxyl amine is believed to be formed via

initial addition of hydroxyl amine to the double bond sys-

tem of 5 to give the intermediate 17 that loses diethyl amine

giving the non isolable intermediate 18 that loses water to

give isoxazole 19 (Scheme III). Establishing structure 19

was based on its elemental analysis and spectral data.

The foregoing results prompt us to investigate the

synthetic potentiality of pyrazolone 3 toward a variety of

electrophilic reagents as potential precursors for fused

heterocyclic systems. Thus, treatment of pyrazolone 3 with

arylidenemalononitrile 20 in refluxing ethanol containing a

catalytic amount of piperidine afforded either pyranopyr-

azole derivative 24 or its isomeric pyrazolo-pyridine 25

(Scheme IV). Structure 25 was ruled out and structure 24 was

established as a sole reaction product based on its spectral

The behavior of pyrazolone 3 towards isothiocyanate

reagents was also investigated. Thus, the reaction of pyra-

zolone 3 with acetyl isothiocyanate and benzoyl isothio-

cyanate 26a,b respectively in dry acetone for 24 h afforded

the acyclic structures 27a,b. Structures 27a,b were con-

firmed by its correct elemental analyses and spectral data.

For example, the mass spectrum of compound 27a revealed

the molecular ion peak at m/z = 261 (M⁺) corresponding to

the molecular formula C₁₂H₁₁N₃O₂S. Compounds 27a,b

could be cyclized to the corresponding pyrazolo[4,3-e]

oxazine derivatives 29a,b via intermediacy of 28 upon

boiling in sodium ethoxide through elimination of water

molecule. The structure of compounds 29a,b was estab-

lished on the basis of elemental analyses and spectral data

of the isolated reaction product (Scheme V). For example,

the IR spectrum of 29a revealed no absorption bands due to

carbonyl groups.

The reaction of pyrazolone 3 with aryl diazonium

salts was also investigated. Thus, coupling of 3 with ben-

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Pyrazolones as Building Blocks in Heterocyclic Synthesis

CONCLUSION

Scheme V

In conclusion, compounds 3 and 5 were used as effi-

cient precursors for the synthesis of new heterocycles in-

cluding the pyrazole moiety with expected biological activ-

ities.

EXPERIMENTAL

All melting points are uncorrected. IR spectra (KBr)

were recorded on a FTIR 5300 spectrometer (n, cm^–1). The

¹H NMR and ¹³C NMR spectra were recorded in DMSO-d₆

at 200 MHz on a Varian Gemini NMR spectrometer (d,

ppm) using TMS as an internal standard. Mass spectra were

obtained on GC Ms-QP 1000 EX mass spectrometer at 70

ev. Thin layer chromatography (TLC) was used to monitor

the course of reactions and ascertain the purity of com-

pounds, and detection of the components was made by ex-

posure to ultraviolet light. Elemental analyses were carried

out by the Micro analytical Research Center, Faculty of

Science, Cairo University and Micro analytical Research

Center. Compound 3 was prepared following literature pro-

cedure.³⁴

zenediazonium salt 30a in ethanol containing sodium ace-

tate afforded the corresponding hydrazone 31a that tauto-

merizes into 32a based on its spectral data. For example,

1

the H NMR spectrum of compound 32a recorded in

DMSO-d₆revealed a signal at d = 12.11 ppm which could

be attributed to hydrazone NH group. Similarly, pyra-

zolone 3 coupled readily with aryl diazonium chlorides

30b-d in the same reaction conditions to give the corre-

sponding hydrazones 32b-d. Fusion of aryl hydrazones

32a with malononitrile in domestic microwave oven gave a

product with a molecular formula C₁₈H₁₂N₆which was

considered to be the pyrazolopyridazine derivative 35a.

Formation of 35 is believed to be formed via initial addition

of malononitrile on the carbonyl group of 32 to give the in-

termediate 33 which cyclizes into 34 which readily losses a

molecule of water to give 35a. Similarly, aryl hydrazones

32b-d fused with malononitrile to give pyrazolopyridazine

derivatives 35b-d as demonstrated in Scheme VI.

Preparation of 4-((5-oxo-3-phenyl-1H-pyrazol-4(5H)-

ylidene)methyl)-3-phenyl-1H-pyrazol-5(4H)-one (4)

A mixture of compound 3 (0.01 mole), DMF-DMA

(0.01 mole) and ammonium acetate (0.5 g) was exposed to

microwave irradiation (power input 20%) for 4.0 min, the

reaction mixture was allowed to reach room temperature,

then diluted with ethanol with stirring and the solid product

that formed, was filtrated and crystallized from ethanol to

give pale red crystals; yield 81%; m.p. 285-286 °C; IR

(KBr) n cm^–13150 (NH), 3056 (CH arom), 1685, 1730 (2

1

C=O); H NMR (DMSO-d₆) d = 3.96 (s, 1H, CH), 7.43-

Scheme VI

7.95 (m, 11H, aromatic and alkenyl H), 9.76 (s, 1H, NH),

12.83 (s, 1H, NH); MS: m/z (%) = 330 (M⁺). Anal. Cacld

for C₁₉H₁₄N₄O₂(330.34): C, 69.08; H, 4.27; N, 16.96%.

Found: C, 69.15; H, 4.35; N, 17.10%.

Preparation of 4-((dimethylamino)methylene)-3-

phenyl-1H-pyrazol-5(4H)-one (5)

To a solution of compound 3 (0.01 mole) in dioxane

(30 mL), DMF-DMA (0.01 mole) was added. The reaction

mixture was refluxed for 6 hrs. The solid product, so

formed, was collected by filtration and crystallized from

ethanol to give yellow crystals; yield 76%; m.p. 210-211

°C; IR (KBr) n cm^–13432 (NH), 2919 (CH-aliph), 1672

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(C=O); ¹H NMR (DMSO-d₆) d = 3.25 (s, 3H, CH₃), 3.29 (s,

3H, CH₃), 7.31 (s, 1H, olifinic proton), 7.37-7.43 (m, 5H,

aromatic protons), 10.87 (s, 1H, NH); ¹³C NMR (DMSO-

d₆) d 43.90, 43.90, 103.50, 127.10, 127.65, 127.65, 128.90,

128.90, 135,70, 145.95, 153.70, 173.25; MS: m/z (%) =

215 (M⁺). Anal. Cacld for C₁₂H₁₃N₃O (215.25): C, 66.96;

H, 6.09; N, 19.52%. Found: C, 66.90; H, 6.00; N, 19.60%.

Preparation of compounds (8a-c)

Preparation of 4-(aminomethylene)-3-phenyl-1H-

pyrazole-5(4H)-one (10)

To a solution of the compound 5 (0.01 mole) in etha-

nol (20 mL), concentrated aqueous ammonia (0.7 mL) was

added. The reaction mixture was refluxed for 6 h, and then

cooled. The solid products so formed was filtered off,

washed with dry ether, dried, it was obtained as bright red

crystals from ethanol yield 76%; m.p. 270-272 °C; IR

1

(KBr) n cm^–13441, 3272 (NH₂), 1675 (C=O); H NMR

General procedure

(DMSO-d₆) d = 7.35-9.39 (m, 8H, aromatic protons, al-

kenyl proton and NH₂), 11.15 (s, 1H, NH); MS: m/z (%) =

187 (M⁺). Anal. Cacld for C₁₀H₉N₃O(187.20): C, 64.16; H,

4.85; N, 22.45%. Found: C, 64.25; H, 4.90; N, 22.53%.

Ethyl N-((5-oxo-3-phenyl-1H-pyrazol-4(5H)-ylidene)-

methyl)formimidate (11)

Equimolar amounts of compound 5 (0.01 mole) and

compounds 6a-c (0.01 mole) in ethanol (30 mL) containing

a few drops of piperidine were refluxed for 12 hrs and

poured into cold water (30 mL) and acidified with HCl. The

solid product that formed was filtered and crystallized from

the proper solvent to give (8a-c).

A solution of compound 10 (0.01 mole) in a mixture

of triethylorthoformate (0.01 mole) and acetic anhydride

(2.5 mL) were heated under reflux for 3 hr during which the

product partially separated. The reaction mixture was al-

lowed to cool at room temperature and the separated prod-

uct was filtered off, washed with ethanol, dried, and crys-

tallized from the proper solvent to give 11. It was obtained

as pale yellow crystals from benzene; m.p. 238-239 °C;

yield 78%; IR (KBr) n cm^–13227 (NH), 2924 (CH-aliph),

1725 (C=O); ¹H NMR (DMSO-d₆) d = 1.22 (t, 3H, CH₃),

3.61 (q, 2H, CH₂), 7.43-7.53 (m, 7H, aromatic and alkenyl

protons), 12.84 (s, 1H, NH); MS: m/z (%) = 243 (M⁺). Anal.

Cacld for C₁₃H₁₃N₃O₂(243.26): C, 64.19; H, 5.39; N,

17.27%. Found; C, 64.28; H, 5.45; N, 17.45%.

3-Phenyl-4-((phenylamino)methylene)-1H-pyrazol-

5(4H)-one (8a)

It was obtained as yellow crystals from ethanol; m.p.

250-252 °C; yield 68%; IR (KBr) n cm^–13138 (NH), 1671

(C=O); ¹H NMR (DMSO-d₆) d = 7.21-7.75 (m, 11H, aro-

matic protons + alkenyl-H), 8.52 (s, 1H, NH), 11.59 (s, 1H,

NH); ¹³C NMR (DMSO-d₆) d 102.95, 117.45, 117.45,

123.15, 128.35, 128.35, 128.50, 129.55, 129.55, 130.10,

130.10, 136.55, 140.60, 149.00, 155.10, 173.20; MS: m/z

(%) = 263 (M⁺). Anal. Cacld for C₁₆H₁₃N₃O (263.29): C,

72.99; H, 4.98; N, 15.96%. Found: C, 72.90; H, 4.92; N,

15.90%.

4-(((4-Chlorophenyl)amino)methylene)-3-phenyl-1H-

pyrazol-5(4H)-one (8b)

3-Phenylpyrazolo[4,3-e][1,3]oxazine (12)

It was obtained as pale yellow crystals from benzene;

m.p. 220-222 °C; yield 71%; IR (KBr) n cm^–13133 (NH),

1667 (C=O); ¹H NMR (DMSO-d₆) d = 7.46-7.75 (m, 10H,

aromatic protons and alkenyl proton), 8.47 (s, 1H, NH),

11.61 (s, 1H, NH); MS: m/z (%) = 297 (M⁺). Anal. Cacld

for C₁₆H₁₂ClN₃O (297.74): C, 64.54; H, 4.06; Cl, 11.91; N,

14.11%. Found: C, 64.60; H, 4.14; Cl, 12.00; N, 13.90%.

3-Phenyl-4-((pyridin-3-ylamino)methylene)-1H-pyr-

azol-5(4H)-one (8c)

A solution of compound 11 (0.01 mole) in pyridine

(20 mL) was refluxed for 8 h. The solution was evaporated

under vacuum and triturated with ethanol. The precipitated

product was filtered off, washed with ethanol and crystal-

lized from a mixture of EtOH/DMF (1:1) to give 12. It was

obtained as pale yellow crystals; m.p. 180-182 °C; yield

53%; IR (KBr) n cm^–13050 (CH-arom); ¹H NMR (DMSO-

d₆) d = 7.46-9.76 (m, 7H, aromatic protons); ¹³C NMR

(DMSO-d₆) d 123.45, 129.44, 130.90, 130.90, 131.95,

131.95, 133.87, 149.55, 153.00, 153.85, 171.00; MS: m/z

(%) = 197 (M⁺). Anal. Cacld for C₁₁H₇N₃O (197.19): C,

67.00; H, 3.58; N, 21.31%. Found: C, 67.08; H, 3.65; N,

21.40%.

It was obtained as pale yellow crystals from ethanol;

m.p. 210-212 °C; yield 72%; IR (KBr) n cm^–13200 (NH),

1638 (C=O); ¹H NMR (DMSO-d₆) d = 7.21-7.80 (m, 11H,

aromatic protons, alkenyl-H and NH), 9.77 (s, 1H, NH);

MS: m/z (%) = 264 (M⁺). Anal. Cacld for C₁₅H₁₂N₄O

(264.28): C, 68.17; H, 4.58; N, 21.20%. Found: C, 68.30;

H, 4.60; N, 21.25%.

Preparation of compounds (15a,b)

General procedure

To a solution of compound 5 (0.01 mole) in ethanol

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(20 mL), hydrazine hydrate (80%, 0.2 mL) or phenyl

hydrazine (0.2 mL) was added. The reaction mixture was

refluxed for 4 hrs, and then cooled. The solid product so

formed was filtered off washed with ethanol, dried and

crystallized from the proper solvent to give (15a,b).

4-(Hydrazinylmethylene)-3-phenyl-1H-pyrazol-5(4H)-

one (15a)

(CH-arom); ¹H NMR (DMSO-d₆) d = 7.7-8.9 (m, 11H, aro-

matic protons and alkenyl proton), 11.90 (s, 1H, NH); MS:

m/z (%) = 260 (M⁺). Anal. Cacld for C₁₆H₁₂N₄(260.29): C,

73.83; H, 4.65; N, 21.52%. Found: C, 73.90; H, 4.70; N,

21.59%.

Preparation of 4-phenyl-2H-pyrazolo[4,3-d]isoxazole

(19)

It was obtained as yellow crystals from benzene; m.p.

110-112 °C; yield 49%; IR (KBr) n cm^–13250, 3151 (NH),

1659 (C=O); ¹H NMR (DMSO-d₆) d = 5.95 (s, 1H, alkenyl

proton), 7.32-7.74 (m, 8H, aromatic protons, NH and NH₂),

8.53 (s, 1H, NH); MS: m/z (%) = 202 (M⁺). Anal. Cacld for

C₁₀H₁₀N₄O (202.21): C, 59.40; H, 4.98; N, 27.71%. Found:

C, 59.49; H, 5.10; N, 27.80%.

A mixture of compound 5 (0.01 mole) and hydroxyl

amine hydrochloride (0.01 mole) in 30 mL pyridine was

refluxed for 12 hr. The solution was evaporated under vac-

uum and triturated with ice cold water (20 mL). The solid

product so formed was collected by filtration, washed with

water, dried, it was obtained as yellow crystals from etha-

nol yield 73%; m.p. 270-272 °C; IR (KBr) n cm^–13214

1

3-Phenyl-4-((2-phenylhydrazinyl)methylene)-1H-pyr-

azol-5(4H)-one (15b)

(NH); 3066 (CH-arom); H NMR (DMSO-d₆) d = 7.35-

8.75 (m, 7H, aromatic protons and NH); MS: m/z (%) = 185

(M⁺). Anal. Cacld for C₁₀H₇N₃O (185.18): C, 64.86; H,

3.81; N, 22.69%. Found: C, 64.90, H, 3.85, N, 22.74%.

Preparation of compounds (24a-c)

It was obtained as pale yellow crystals from benzene;

m.p. 90-92 °C; yield 58%; IR (KBr) n cm^–13205 (NH),

1660 (C=O); ¹H NMR (DMSO-d₆) d = 6.65-7.96 (m, 13H,

aromatic protons, alkenyl proton and 2NH), 9.87 (s, 1H,

NH); MS: m/z (%) = 278 (M⁺). Anal. Cacld for C₁₆H₁₄N₄O

(278.31): C, 69.05 ; H, 5.07; N, 20.13%. Found: C, 69.12;

H, 5.17; N, 20.19%.

General procedure

A mixture of 3 (0.01 mole), and benzylidene malono-

nitrile derivatives 20a-c (0.01 mole) in ethanol (30 mL)

was treated with a few drops of piperidine and heated under

reflux for 4 hr. The reaction mixture allowed to cool,

poured into crushed ice and acidified with HCl. The solid

product was filtered off and crystallized from the proper

solvent to give (24a-c).

Preparation of compounds (16a,b)

General procedure

A solution of compound 15a and 15b (0.01 mole) in

sodium ethoxide solution (prepared by dissolving 0.23 g of

sodium in 20 mL absolute ethanol) was refluxed for 12 hr,

and was allowed to cool to room temperature and diluted

with ice-cold water (40 mL) containing few drops with

HCl. The solid product so formed was filtered off washed

with water, dried and crystallized from the proper solvent

to give (16a,b).

6-Amino-3,4-diphenyl-1,4-dihydropyrano[2,3-c]pyra-

zole-5-carbonitrile (24a)

It was obtained as brown crystals from benzene; yield

81%; m.p. 200-202 °C; IR (KBr) n cm^–13367, 3300 (NH₂)

3260 (NH), 2192 (CºN); ¹H NMR (DMSO-d₆) d = 5.22 (s,

1H, H-4 pyran), 7.01-7.64 (m, 12H, aromatic protons and

NH₂), 11.82 (s, 1H, NH); MS: m/z (%) = 314 (M⁺). Anal.

Cacld for C₁₉H₁₄N₄O (314.34): C, 72.60; H, 4.49; N,

17.82%. Found C, 72.69; H, 4.57; N, 17.90%.

4-Phenyl-1,2-dihydropyrazolo[3,4-c]pyrazole (16a)

It was obtained as green crystals from ethanol; m.p.

250-252 °C; yield 69%; IR (KBr) n cm^–13214 (NH); ¹H

NMR (DMSO-d₆) d = 7.44-8.53 (m, 7H, aromatic protons

and NH), 12.08 (s, 1H, NH); ¹³C NMR (DMSO-d₆) d 99.90,

127.90, 127.90, 128.55, 131.60, 131,60, 133.90, 134.90,

150.00, 169.90; MS: m/z (%) = 184 (M⁺). Anal. Cacld for

C₁₀H₈N₄(184.20): C, 65.21; H, 4.38; N, 30.42%. Found: C,

65.33; H, 4.44; N, 30.50%.

6-Amino-4-(3-chlorophenyl)-3-phenyl-1,4-dihydro-

pyrano[2,3-c]pyrazole-5-carbonitrile (24b)

It was obtained as brown crystals from benzene; yield

92%; m.p. 280-282 °C; IR (KBr) n cm^–13300, 3250 (NH₂),

3061 (CH-arom), 2206 (CºN), ¹H NMR (DMSO-d₆) d =

5.07 (s, 1H, H-4 pyran), 6.99-7.47 (m, 11H, aromatic pro-

tons and NH₂), 12.18 (s, 1H, NH); MS: m/z (%) = 348 (M⁺).

Anal. Cacld for C₁₉H₁₃ClN₄O (348.79): C, 65.43; H, 3.76;

Cl, 10.16; N, 16.06%. Found: C, 65.50; H, 3.82; Cl, 10.00;

2,4-Diphenyl-1,2-dihydropyrazolo[3,4-c]pyrazole(16b)

It was obtained as yellow crystals from ethanol; m.p.

207-209 °C; yield 59%; IR (KBr) n cm^–13300 (NH), 3056

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Ramiz et al.

N, 16.10%.

H₂O and acidified with HCl. The solid product so formed

was collected by filtration, washed with water, dried, and

crystallized from the proper solvent to give compound

(29a,b).

6-Amino-4-(4-methoxyphenyl)-3-phenyl-1,4-dihydro-

pyrano[2,3-c]pyrazole-5-carbonitrile (24c)

It was obtained as green crystals from ethanol; yield

88%; m.p. 276-278 °C; IR (KBr) n cm^–13344, 3300 (NH₂),

2932 (CH-arom), 2215 (CºN), ¹H NMR (DMSO-d₆) d =

3.88 (s, 3H, OCH₃), 5.11 (s, 1H, H-4 pyran), 6.83-7.56 (m,

9H, aromatic protons), 8.65 (s, 2H, NH₂), 11.82 (s, 1H,

NH); MS: m/z (%) = 344 (M⁺). Anal. Cacld for C₂₀H₁₆N₄O₂

(344.37): C, 69.76; H, 4.68; N, 16.27%. Found; C, 69.80;

H, 4.76; N, 16.32%.

6-Methyl-3-phenylpyrazolo[4,3-e][1,3]oxazine-4(1H)-

thione (29a)

It was obtained as pale yellow crystals from benzene;

yield 70%; m.p. 128-130 °C; IR (KBr) n cm^–13190 (NH),

3054 (CH-arom), 2924 (CH-aliph); 1590 (C=S); ¹H NMR

(DMSO-d₆) d = 1.17 (s, 3H, CH₃), 7.10-7.61 (m, 5H, aro-

matic protons), 11.95 (s, 1H, NH); ¹³C NMR (DMSO-d₆) d

20.50, 110.40, 128.70, 129.10, 129.10, 129.25, 129.25,

134.00, 147.00. 147.90, 159.20, 205.50; MS: m/z (%) =

243 (M⁺). Anal. Cacld for C₁₂H₉N₃OS (243.28): C, 59.24;

H, 3.73; N, 17.27; S, 13.18%. Found; C, 59.26; H, 3.75; N,

17.28; S, 13.20%.

Preparation of compounds (27a,b)

General procedure

Amixture of compound 3 (0.01 mole) and methyl car-

bonyl or benzoyl isothiocyanate (0.01 mole) in dry acetone

(50 mL) was heated under reflux for 24 hr, then left to cool.

The solid product that formed was filtered and crystallized

from the proper solvent to give (27a,b).

3,6-Diphenylpyrazolo[4,3-e][1,3]oxazine-4(1H)-thione

(29b)

N-(5-Oxo-3-phenyl-4,5-dihydro-1H-pyrazole-4-car-

bonothioyl)acetamide (27a)

It was obtained as brown crystals from ethanol; yield

64%; m.p. 120-122 °C; IR (KBr) n cm^–13422 (NH), 3040

(CH-arom), 1585 (C=S); ¹H NMR (DMSO-d₆) d = 6.98-

7.92 (m, 10H, aromatic protons), 12.00 (s, 1H, NH); MS:

m/z (%) = 305 (M⁺) Anal. Cacld for C₁₇H₁₁N₃OS (305.35):

C, 66.87; H, 3.63; N, 13.76; S, 10.50%. Found: C, 66.93;

H, 3.70; N, 13.80; S, 10.58%.

It was obtained as pale yellow crystals from benzene;

yield 77%; m.p. 180-182 °C; IR (KBr) n cm^–13328, 3266

(2 NH), 3054 (CH-arom), 2922 (CH-aliph), 1722, 1684 (2

C=O), 1580 (C=S); ¹H NMR (DMSO-d₆) d = 2.2 (s, 3H,

CH₃), 3.60 (s, 1H, CH), 6.90-8.90 (m, 5H, aromatic pro-

tons), 8.16 (s, 1H, NH), 13.16 (s, 1H, NH); MS: m/z (%) =

261 (M⁺). Anal. Cacld for C₁₂H₁₁N₃O₂S (261.30): C, 55.16;

H, 4.24; N, 16.08; S, 12.27%. Found: C, 55.22; H, 4.30; N,

16.09; S, 12.21%.

Preparation of compounds (32a-d)

General procedure

To a stirred cold solution of diazonium chloride (0.01

mole, prepared by treating of aniline derivatives (0.01

mole) with sodium nitrite (0.01 mole) in HCl, ethanol (30

mL) and catalytic of sodium acetate, the active methylene

reagent 3 was added gradually. The stirring was continued

for two hrs. The sold product so formed was filtered of,

washed with water several times, dried and crystallized

from the proper solvent to give (32a-d).

N-(5-Oxo-3-phenyl-4,5-dihydro-1H-pyrazole-4-car-

bonothioyl)benzamide (27b)

It was obtained as pale yellow crystals from benzene;

yield 53%; m.p. 150-152 °C; IR (KBr) n cm^–13306, 3152

(2 NH), 1744, 1682 (2C=O), 1585 (C=S); ¹H NMR (DMSO-

d₆) d = 3.33 (s, 1H, CH), 6.68-8.16 (m, 10H, aromatic pro-

tons), 8.16 (s, 1H, NH), 13.16 (s, 1H, NH); MS: m/z (%) =

323 (M⁺). Anal. Cacld for C₁₇H₁₃N₃O₂S (323.37): C, 63.14;

H, 4.05; N, 12.99; S, 9.92%. Found; C, 63.20; H, 4.12; N,

13.10; S 9.95%.

3-Phenyl-4-(2-phenylhydrazinylidene)-1H-pyrazol-

5(4H)-one (32a)

It was obtained as pale red crystals from ethanol;

yield 92%; m.p. 180-182 °C; IR (KBr) n cm^–13435 (NH),

1636 (C=O); ¹H NMR (DMSO-d₆) d = 7.19-8.08 (m, 11H,

aromatic protons and NH), 12.11 (s, 1H, NH); MS: m/z

(%) = 264 (M⁺). Anal. Cacld for C₁₅H₁₂N₄O (264.28): C,

68.17; H, 4.58; N, 21.20%. Found: C, 68.18; H, 4.59; N,

21.21%.

Preparation of compounds (29a,b)

General procedure

Asolution of compound 27a or 27b (0.01 mole) in so-

dium ethoxide solution (prepared by dissolving 0.23 g of

sodium in 20 mL absolute ethanol) was refluxed for 8 hr,

then left to cool at room temperature and poured in to ice/

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JOURNAL OF THE CHINESE

CHEMICAL SOCIETY

Pyrazolones as Building Blocks in Heterocyclic Synthesis

4-(2-(4-Methoxyphenyl)hydrazono)-3-phenyl-1H-pyra-

zol-5(4H)-one (32b)

6-Imino-5-(4-methoxyphenyl)-3-phenyl-5,6-dihydro-

1H-pyrazolo[4,3-c]pyridazine-7-carbonitrile (35b)

It was obtained as orange crystals from ethanol; yield

67%; m.p. 170-172 °C; IR (KBr) n cm^–13300 (NH), 2925

(CH-aliph), 2206 (CºN); ¹H NMR (DMSO-d₆) d = 3.78 (s,

3H, OCH₃), 7.05-8.06 (m, 10H, aromatic protons and NH),

12.01 (s, 1H, NH). MS: m/z (%) = 342 (M⁺). Anal. Cacld

for C₁₉H₁₄N₆O (342.35): C, 66.66; H, 4.12; N, 24.55%.

Found: C, 66.73; H, 4.20; N, 24.62%.

It was obtained as brown crystals from ethanol; yield

88%; m.p. 212-214 °C; IR (KBr) n cm^–13184 (NH), 1651

(C=O); ¹H NMR (DMSO-d₆) d = 3.80 (s, 3H, OCH₃), 7.09-

8.07 (m, 10H, aromatic protons and NH), 12.03 (s, 1H,

NH); MS: m/z (%) = 294 (M⁺). Anal. Cacld for C₁₆H₁₄N₄O₂

(294.31): C, 65.30; H, 4.79; N, 19.04%. Found: C, 65.39;

H, 4.85; N, 19.10%.

5-(3-Chlorophenyl)-6-imino-3-phenyl-5,6-dihydro-1H-

pyrazolo[4,3-c]pyridazine-7-carbonitrile (35c)

4-(2-(3-Chlorophenyl)hydrazono)-3-phenyl-1H-pyrazol-

5(4H)-one (32c)

It was obtained as red crystals from ethanol; yield

72%; m.p. 220-222 °C; IR (KBr) n cm^–13191 (NH), 2187

(CºN); ¹H NMR (DMSO-d₆) d = 7.49-8.04 (m, 10H, aro-

matic protons and NH), 12.06 (s, 1H, NH). MS: m/z (%) =

346 (M⁺). Anal. Cacld for C₁₈H₁₁ClN₆(346.77): C, 62.34;

H, 3.20; Cl, 10.22; N, 24.23%. Found: C, 62.42; H, 3.27;

Cl, 10.25; N, 24.20%.

It was obtained as orange crystals from ethanol; yield

91%; m.p. 250-252 °C; IR (KBr) n cm^–13192 (NH), 3070

(CH-arom), 1659 (C=O); ¹H NMR (DMSO-d₆) d = 7.44-

8.05 (m, 10H, aromatic protons and NH), 12.05 (s, 1H, NH);

MS: m/z (%) = 298 (M⁺). Anal. Cacld for C₁₅H₁₁ClN₄O

(298.73): C, 60.31; H, 3.71; Cl, 11.87; N, 18.76. Found: C,

60.40; H, 3.79; Cl, 11.99; N, 18.82%.

6-Imino-5-(4-nitrophenyl)-3-phenyl-5,6-dihydro-1H-

pyrazolo[4,3-c]pyridazine-7-carbonitrile (35d)

4-(2-(4-Nitrophenyl)hydrazono)-3-phenyl-1H-pyrazol-

5(4H)-one (32d)

It was obtained as brown crystals from ethanol; yield

81%; m.p. 240-242 °C; IR (KBr) n cm^–13217 (NH), 2201

(CºN); ¹H NMR (DMSO-d₆) d = 7.50-8.27 (m, 10H, aro-

matic protons and NH), 12.20 (s, 1H, NH); MS: m/z (%) =

357 (M⁺). Anal. Cacld for C₁₈H₁₁N₇O₂(357.33): C, 60.50;

H, 3.10; N, 27.44%. Found: C, 60.59; H, 3.17; N, 27.50%.

It was obtained as pale red crystals from ethanol;

yield 76%; m.p. 260-262 °C; IR (KBr) n cm^–13209 (NH),

1671 (C=O); ¹H NMR (DMSO-d₆) d = 7.46-8.31 (m, 9H,

aromatic protons), 12.21 (s, 1H, NH), 13.60 (s, 1H, NH);

MS: m/z (%) = 309 (M⁺). Anal. Cacld for C₁₅H₁₁N₅O₃

(309.28): C, 58.25; H, 3.58; N, 22.64%. Found: C, 58.27;

H, 3.60; N, 22.66%.

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Pyrazolones as building blocks in heterocyclic synthesis: Synthesis of new pyrazolopyran, pyrazolopyridazine and pyrazole derivatives of expected antifungicidal activity

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