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Formation of 1-methyl[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-ones by reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone

  • Svitlana Yuriyivna Danylchenko , Oleksandr Grygorovych Drushlyak EMAIL logo , Svitlana Sergiyivna Kovalenko and Sergiy Mykolayovych Kovalenko
Published/Copyright: July 18, 2015
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 21 Issue 4

Abstract

Reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone results in the formation of 1-methyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones instead of 2-(3,5-dimethyl-1H-pyrazol-1-yl)quinazolin-4(3H)-ones. Under similar conditions, the 7-hydrazinocarbonyl group in quinazolin-4(3H)-one moiety is transformed into a pyrazole derivative, which can be replaced by amine with the amide formation.

Keywords: acetylacetone; amide formation; 2-hydrazinoquinazolin-4(3H)-one; pyrazole; [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one

Introduction

The reaction of hydrazines with β-dicarbonyl compounds is the common approach to the synthesis of pyrazoles [1, 2]. However, in the case of heterocyclic hydrazines, such as 2-hydrazino-3-methylquinoxaline, the formation of a triazole has been reported [3, 4]. 1,4-Dimethyl-1,2,4-triazolo[4,3-a]quinoxaline has been identified as the side product of the reaction of 2-hydrazino-3-methylquinoxaline with 1-phenyl-1,3-butanedione [4].

Results and discussion

Our attempt to obtain pyrazole derivatives by treatment of 2-hydrazinoquinazolin-4(3H)-ones 4, 5 with acetylacetone led to the formation of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones 6, 7 as main products. Under similar conditions, the 7-hydrazinocarbonyl group in 2-hydrazino-7-hydrazinocarbonyl-4-oxo-3-phenyl-3,4-dihydroquinazoline (5) was converted into a pyrazole derivative 6 (Scheme 1). In a full agreement with this result, the treatment of 6 with 2-methylbutylamine gave the expected amide 7.

Scheme 1
Scheme 1

The purity and structures of synthesized compounds were confirmed by LC/MS and 1H NMR spectroscopy data. The singlet for 1-CH3 group at 2.36 ppm is characteristic for [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones 6, 7. Other singlets at 2.12 and 2.55 ppm are attributed to the respective 3-CH3 and 5-CH3 groups of the pyrazole. The singlet at 6.26 ppm in the 1H NMR spectrum of 6 belongs to 4-H of the pyrazole. The signal of the NHCO proton of amides 3, 4, 7 appears as triplet at 8.55 ppm.

The formation of [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones by reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone is consistent with the suggestion that heterocyclic hydrazines may react with β-diketones via intermediate dihydro[1,2,4]triazole, such as 8 followed by cleavage of the ketone residue, as shown in Scheme 2 [4].

Scheme 2
Scheme 2

Conclusion

Reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone results in the formation of triazole derivatives instead of pyrazole.

Experimental

1H NMR-spectra were recorded in DMSO-d6 on Varian WXR-400 (400 MHz) spectrometer. 13C NMR spectra were recorded in DMSO-d6 on a Bruker DRX-300 spectrometer (100 MHz). Elemental analysis was performed on a Euro EA-3000 apparatus. Melting points were measured with a Buchi B-520 melting point apparatus and were not corrected. LC/MS spectra were recorded with a PE SCIEX API 150EX liquid chromatograph equipped with a UV detector (λmax 215 and 254 nm) and using a Luna-C18 column, Phenomenex (100×4 mm). Elution started with water and ended with acetonitrile/water (95:5, v/v) using a linear gradient at a flow rate of 0.15 mL/min and an analysis cycle time of 25 min. Starting 2-hydrazinoquinazolin-4-ones 4, 5 were obtained from commercially available methyl 4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1) according to a published method [5].

4-Oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (2)

To an agitated suspension of methyl 4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1, 3.12 g, 10 mmol) in 30 mL of isopropanol, 20% aqueous solution of NaOH (5 mL) was added. The solution was heated under reflux for 3 h then diluted with 50 mL of water and neutralized with 3 mL of 10% aqueous HCl. The precipitate was filtered and crystallized from a mixture of DMF (5 mL) and isopropanol (20 mL): yield 2.56 g (86%); a creamy solid; mp>300°C (dec.); 1H NMR: δ 7.08 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.80 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.95 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 13.10 (s, 1H, NH), 13.50 (br s, 1H, OH); 13C NMR: δ 118.8, 123.8, 125.1, 126.8, 128.3, 129.2, 130.4, 139.00, 139.3, 146.2, 153.6, 167.1, 170.0. Anal. Calcd for C15H10N2O3S: C, 60.39; H, 3.38; N, 9.39. Found: C, 60.47; H, 3.36; N, 9.34.

N-(3-Methylbutyl)-4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (3)

The mixture of 4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylic acid (2, 1.79 g, 6 mmol) and 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole (CDІ, 1.05 g, 6.5 mmol) in 30 mL of anhydrous dioxane was heated under reflux with stirring for 1 h. Then 2-methylbutylamine (0.52 g, 6 mmol) was added. The mixture was heated under reflux for 2 h. After cooling, the mixture was diluted with water (50 mL) and allowed to stand overnight to form a precipitate, which was filtered, washed with water, and crystallized from a mixture of dimethylformamide (10 mL) and isopropanol (20 mL): yield 1.92 g (87%); a white solid; mp 290–292°C; 1H NMR: δ 0.88 (d, J = 7.0 Hz, 6H), 1.40 (q, J = 7.0 Hz, 2H), 1.52–1.72 (m, 1H), 3.25 (q, J = 7.0 Hz, 2H), 7.08 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.80 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.95 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 8.55 (t, J = 7.0 Hz, 1H, CONH), 13.10 (s, 1H, NH); 13C NMR: δ 22.7, 25.1, 38.4, 41.2, 118.7, 123.9, 125.0, 126.3, 128.3, 129.2, 130.3, 139.0, 139.6, 146.3, 153.6, 166.8, 169.9. Anal. Calcd for C20H21N3O2S: C, 65.37; H, 5.76; N, 11.44. Found: C, 65.43; H, 5.74; N, 11.48.

2-Hydrazino-N-(3-methylbutyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxamide (4)

A mixture of dioxane (10 mL), hydrazine hydrate (3 mL), and N-(3-methylbutyl)-4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (3, 1.84 g, 5 mmol) was heated under reflux with stirring for 3 h. The lower dioxane layer was separated and diluted with water (20 mL). The precipitate was filtered, washed with isopropanol (10 mL), and crystallized from mixture of DMF (10 mL) and isopropanol (20 mL): yield 1.29 g (68%); a white solid; mp>300°C (dec.); 1H NMR: δ 0.88 (d, J = 7.0 Hz, 6H), 1.40 (q, J = 7.0 Hz, 2H), 1.52–1.72 (m, 1H), 3.25 (q, J = 7.0 Hz, 2H), 5.70 (s, 2H, NHNH2-2), 7.06 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.57 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H), 8.55 (t, J = 7.0 Hz, 1H, CONH), 9.33 (s, 1H, NHNH2-2); 13C NMR: δ 22.7, 25.0, 38.4, 41.2, 118.8, 123.9, 125.6, 126.8, 128.4, 129.1, 130.0, 139.1, 139.7, 146.1, 154.1, 159.2, 166.8. Anal. Calcd for C20H23N5O2 : 65.73; H, 6.34; N, 19.16. Found: C, 65.79; H, 6.31; N, 19.21.

2-Hydrazino-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carbohydrazide (5)

A mixture of dioxane (10 mL), hydrazine hydrate (4 mL), and methyl 4-oxo-3-phenyl-2-thioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (1, 1.56 g, 5 mmol) was heated and stirred under reflux for 3 h. The lower dioxane layer was separated and diluted with water (20 mL). The resultant precipitate was filtered, washed with isopropanol (10 mL), and crystallized from a mixture of DMF (10 mL) and isopropanol (20 mL): yield 1.21 g (78%); a white solid; mp>300°C (dec.); 1H NMR: δ 4.55 (br. s, 2H, CONHNH2), 5.70 (s, 2H, NHNH2-2), 7.08 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 2H), 7.57 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.88 (d, J = 7.8 Hz, 2H), 8.00 (d, J = 7.8 Hz, 1H), 9.40 (s, 1H, NHNH2-2), 10.02 (s, 1H, CONHNH2); 13C NMR: δ 118.6, 123.4, 125.7, 126.9, 128.3, 129.1, 130.4, 139.1, 140.0, 144.2, 155.5, 161.7, 166.0. Anal. Calcd for C15H14N6O2: C, 58.06; H, 4.55; N, 27.08. Found: C, 57.97; H, 4.58; N, 27.13.

8-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-1-methyl-4-phenyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (6)

The suspension of 2-hydrazino-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carbohydrazide 5 (1.55 g, 5 mmol) in acetylacetone (20 mL) was heated at 100ºC with stirring for 5 h. After cooling, the mixture was diluted with isopropanol (50 mL). The resultant precipitate was filtered, washed with isopropanol (10 mL), and crystallized from a mixture of DMF (10 mL) and isopropanol (20 mL): yield 1.47 g (74%); a creamy solid; mp 296–298°C; 1H NMR: δ 2.12 (s, 3H), 2.36 (s, 3H, CH3-1), 2.55 (s, 3H), 6.26 (s, 1H), 7.52–7.76 (m, 6H), 8.00 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 7.8 Hz, 1H); 13C NMR: δ 12.6, 13.3, 14.1, 113.6, 118.8, 123.5, 125.8, 126.9, 128.3, 129.2, 130.8, 135.3, 139.0, 139.9, 141.8, 144.3, 152.3, 155.3, 161.5, 166.1; LC/MS: m/z 399.3 [M+H+] (64%). Anal. Calcd for C22H18N6O2: C, 66.32; H, 4.55; N, 21.09. Found: C, 66.39; H, 4.52; N, 21.16.

1-Methyl-N-(3-methylbutyl)-5-oxo-4-phenyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinazoline-8-carboxamide (7): Protocol A

The suspension of 2-hydrazino-N-(3-methylbutyl)-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxamide 4 (1.83 g, 5 mmol) in acetylacetone (20 mL) was heated at 100ºC with stirring for 5 h. After cooling, the mixture was diluted with isopropanol (50 mL). The resultant precipitate was filtered, washed with isopropanol (10 mL), and crystallized from a mixture of DMF (10 mL) and isopropanol (20 mL): yield 1.29 g (68%), a white solid; mp>300°C; 1H NMR: δ 0.88 (d, J = 7.0 Hz, 6H), 1.40 (q, J = 7.0 Hz, 2H), 1.52–1.72 (m, 1H), 2.36 (s, 3H, CH3-1), 3.25 (q, J = 7.0 Hz, 2H), 7.42–7.56 (m, 5H), 7.74 (dd, J = 7.8 Hz, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 8.55 (t, J = 7.0 Hz, 1H, CONH); 13C NMR: δ 13.4, 22.7, 25.1, 38.36, 4.2, 118.6, 123.4, 125.8, 126.9, 128.3, 129.1, 130.7, 135.4, 139.0, 139.9, 144.2, 155.5, 161.6, 166.9; LC/MS: m/z 390.4 [M+H+] (62%). Anal. Calcd for C22H23N5O2: C, 67.85; H, 5.95; N, 17.98. Found: C, 67.78; H, 5.99; N, 18.03.

Protocol B

A solution of 8-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-1-methyl-4-phenyl[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (6, 0.80 g, 2 mmol) and 2-methylbutylamine (0.26 g, 3 mmol) in anhydrous DMF (10 mL) was heated under reflux for 8 h. After cooling, the mixture was diluted with water (30 mL) and the resultant precipitate was filtered, washed with isopropanol (10 mL), and crystallized from a mixture of DMF (5 mL) and isopropanol (10 mL): yield 0.64 g (84%); a white solid; mp>300°C (dec.). This sample was identical to the sample obtained by protocol A both by 1H NMR spectrum and LC/MS data.

Corresponding author: Oleksandr Grygorovych Drushlyak, The National University of Pharmacy, Kharkiv, Pushkinska Street, 53, Kharkiv 61002, Ukraine, e-mail:

References

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Received: 2015-5-21
Accepted: 2015-6-19
Published Online: 2015-7-18
Published in Print: 2015-8-1

©2015 by De Gruyter

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/hc-2015-0104
Keywords for this article
acetylacetone; amide formation; 2-hydrazinoquinazolin-4(3H)-one; pyrazole; [1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one
Creative Commons
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Articles in the same Issue

  1. Frontmatter
  2. Preliminary Communications
  3. Montmorillonite K10 catalyzed multi component reactions (MCR): synthesis of novel thiazolidinones as anticancer agents
  4. Synthesis, antibacterial, and antifungal activities of new pyrimidinone derivatives
  5. Research Articles
  6. Formation of 1-methyl[1,2,4]triazolo[4,3-a] quinazolin-5(4H)-ones by reaction of 2-hydrazinoquinazolin-4(3H)-ones with acetylacetone
  7. Synthesis of new 4′-(N-alkylpyrrol-2-yl)-2,2′: 6′,2″-terpyridines via N-alkylation of a pyrrole moiety
  8. Efficient synthesis of 3-(bromomethyl)-5-methylpyridine hydrobromide
  9. One-pot synthesis of 5-[1-substituted 4-acetyl-5-methyl-1H-pyrrol-2-yl)]-8-hydroxyquinolines using DABCO as green catalyst
  10. A new on-fluorescent sensor for Ag+ based on benzimidazole bearing bis(ethoxycarbonylmethyl)amino groups
  11. Synthesis of new derivatives of 10H-benzo[b]pyridazino[3,4-e][1,4]thiazines
  12. Efficient and convenient synthesis of pyrido [2,1-b]benzothiazole, pyrimidopyrido[2,1-b]benzothiazole and benzothiazolo[3,2-a][1,8]naphthyridine derivatives
  13. Synthesis of 3-benzylidene-dihydrofurochromen-2-ones: promising intermediates for biflavonoid synthesis
  14. Synthesis and antitumor activities of piperazine- and cyclen-conjugated dehydroabietylamine derivatives
  15. Synthesis, characterization, and antimicrobial evaluation of novel spiropiperidones
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