Journal of the Korean Chemical Society (대한화학회지)

Korean Chemical Society (대한화학회)
권호 표지
DOI QR코드

DOI QR Code

Oxidative Cyclisation Based One-Pot Synthesis of 3-Substituted[1,2,4]triazolo[4,3-b]pyridazines Using Me4NBr/Oxone

  • Received : 2013.06.11
  • Accepted : 2013.09.01
  • Published : 2013.10.20
Download PDF
⟨ Previous Next ⟩

Abstract

A facile one-pot syhthesis of 3-substituted triazolopyridazine and thieno-triazolopyridazine derivatives is described. This protocol involves the preparation of heteroaryl hydrazone from the aldehyde and pyridazinohydrazine derivative followed by subjecting the intermediate directly to oxidative cyclization to assemble the desired 1,2,4-triazloe moiety by employing the mixture of Me4NBr and oxone. This condition is efficient and is able to tolerate wide range of functional groups.

Keywords

INTRODUCTION

1,2,4-Triazole is an important class of heterocyclic unit which found to have extensive use in organocatalysis and material science. Moreover, 1,2,4-triazole embedded systems display a broad spectrum of biological properties such as antimicrobial, antitubercular, serotonergic, anti-allergy, CNS depressant, anti-inflammatory, anticonvulsants and anti-cancer activities.1 Recent studies reveal that 1,2,4-triazoles based derivatives are found to be inhibitor of HIV integrase and methionine aminopeptidase-2.2 Owing to their diverse applications, it gained a great deal of interest among the synthetic chemist. Most common and widely used method to construct 1,2,4-triazole system is the oxidative cyclization of hydrazone. In order to set up the such cyclization reagents such as POCl3, Br2, PhI(OAc)2, Chloramine -T, Pb(OAc)4, and CuCl2 have been successfully employed on heteroaryl hydrazone.3 However this protocol suffer by the disadvantages such as the requirement of stiochiometric amount of reagents and the employment of hazardous materials or metal reagents. Further the intermediate hydrazone needs to be isolated and then purified prior to oxidative cyclization. Thus, it is highly desirable to find a new reagent which should be non-toxic and metalfree. Furthermore, one-pot protocol is more convenient since it avoids the unnecessary work up and purification of the intermediate.

In addition, pyridazine represents another important class of heterocyclic compound found to display a variety of biological activities such as antimicrobial, antifungal, antiviral, antitumor, antihypertensive, antitubercular and anticancer agents.4 Besides, pyridazines and heterocyclic-fused pyridazines are considered to be an important pharmacorein biological research5 and in particular, thieno skeleton embedded core was found to further enhance the physiological and pharmacological activity.6 Evidently, triazolopyridazine, a hybrid of pyridazine and 1,2,4-triazole, is a structurally interesting and biologically important unit. Representative examples of this kind are depicted in Fig. 1, wherein analogs 1a−1c act as ligand for GABAA receptor whereas 1d displayed anti-HIV activity and 1e was found to act as c-Met kinase inhibitor.7

Figure 1.Some biologically active [1,2,4] triazolo [4,3-b] pyridazine derivatives.

Bearing the biological activities in mind, we planned to devise a viable synthetic route for the triazolopyridazine derivative and thieno-triazolopyridazine derivative. To realize this task, it was decided to construct 1,2,4-triazole unit by keeping the pyridazine moiety as the starting point.

 

EXPERIMENTAL

All reagents were purchased from commercial suppliers and were used without purification. Melting points were determined in Buchi B-545melting point apparatus and were uncorrected. 1H NMR and 13C NMR spectra were recorded on a Bruker Advance-400 & 300 NMR MHZ spectrometer in DMSO-d6 & CDCl3 solution using TMS as an internal reference and 13C NMR were recorded at 100 & 75 MHz. Mass spectra were recorded on LC-MS-Agilent 1200 series, Carbon, Hydrogen, Nitrogen and Sulphur were analyzed on Elementor instrument. All these compounds were purified by flash column Chromatography using 230−400 mesh silica gel.

Typical Procedure for the Synthesis of 3-Substituted Triazolopyridazine

A mixture of corresponding hydrazinylpyridazine 1 or 5 (1 mmol) and aldehyde 2 (1.1 mmol) in ethanol (5 mL) was heated at 60 ℃ for 0.5 h. The formation of hydrazone was checked by TLC and the reaction mixture was cooled to rt. Oxone (1.5 mmol) was added to the mixture at rt followed by tetramethyl ammonium bromide (0.2 mmol) and the resulting mixture was heated at 60 ℃ for another 5 h. The mixture was cooled to rt and extracted with dichloromethane (2 × 25 mL), dried over anhydrous sodium sulphate and concentrated to obtain a residue which was purified by column chromatography using hexane/ethyl acetate as eluent to furnish the desired triazolopyridazines 4 and 7.

Data: 1(4a−4o)

3-(3-Bromophenyl)-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4a

Yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1H), 8.47 (d, J = 7.89 Hz, 1H), 8.06 (d, J = 9.48 Hz, 1H), 7.63−7.60 (m,1H), 7.43−7.38 (m, 1H), 7.06 (d, J = 7.98 Hz, 1H) 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 154.2, 146.2, 144.4, 132.8, 130.9, 130.2, 128.2, 125.9, 124.6, 122.6, 121.8, 21.9.

MS: m/z 290 (M++1).

3-(2-Bromo-6-chlorophenyl)-6-methyl[1,2,4]triazolo[4,3-b] pyridazine: 4b

White solid; 1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J= 9.5 Hz, 1H), 7.69−7.66 (m, 1H), 7.56−7.53 (m,1H), 7.40 (d, J = 8.1 Hz, 1H), 7.08−7.05 (d, J = 9.5 Hz, 1H), 2.56 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 154.8, 146.2, 143.3, 137.1, 132.4, 131.1, 128.5, 127.5, 126.4, 124.2, 122.5, 21.6.

MS: m/z324 (M++1).

3-(2,6-Dichlorophenyl)-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4c

White solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.11 (d, J = 9.6 Hz, 1H), 7.53−7.48 (m, 3H), 7.08 (d, J = 9.6 Hz, 1H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 154.8, 144.8, 143.5, 137.1, 132.1, 128.0, 125.5, 124.2, 122.5, 21.6.

MS: m/z 282(M++2).

3-(4-Bromo-2-fluorophenyl)-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4d

Pale yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 9.5 Hz, 1H), 7.85−7.81 (m, 1H), 7.53−7.50 (m, 2H), 7.08 (d, J = 9.5 Hz), 2.62 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.5, 158.9, 154.8, 144.1, 132.7, 127.8, 125.5, 124.4, 122.5, 120.3, 113.7, 21.8.

MS: m/z 308(M++1).

3-[2-Chloro-3-(1,1,1-trifluoromethyl)phenyl]-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4e

Off white solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 9.5 Hz, 1H), 7.94 (dd, J = 1.08, 1.08 Hz, 1H), 7.85 (dd, J = 1.10, 1.14 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 9.5 Hz), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 154.9, 146.4, 143.8, 135.9, 133.4, 129.5, 128.4, 128.3, 126.6, 124.3, 122.6, 120.7, 21.6.

MS: m/z 327(M++1).

Methyl 4-(6-methyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)benzoate: 4f

White solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.62 (d, J = 8.5 Hz, 2H), 8.19 (d, J = 8.5 Hz, 2H), 8.07 (d, J = 9.5 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 3.95 (s, 3H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 166.2, 154.8, 146.7, 144.5, 131.0, 130.4, 129.7, 127.2, 124.6, 121.9, 52.2, 21.9.

MS: m/z 269(M++1).

4-(6-Methyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)benzoic acid: 4g

Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 13.1 (br, 1H), 8.51 (d, J = 8.3 Hz, 2H), 8.3 (d, J = 9.5 Hz, 1H), 8.11 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 9.5 Hz), 2.59 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 167.2, 156.1, 146.1, 145.0, 132.0, 130.6, 130.1, 127.3, 124.9, 123.6, 22.0.

MS: m/z 235(M++1).

4-(6-Methyl[1,2,4]triazolo[4,3-b]pyridazin-3-yl)benzonitrile: 4h

Plae yellow solid; 1H NMR (300 MHz, CDCl3): δ = 8.70 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 9.5 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.1 (d, J = 9.5 Hz, 1H), 2.69 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 155.1, 145.9, 144.7, 132.3, 130.5, 127.7, 124.7, 122.2, 118.4, 113.1, 21.9.

MS: m/z 236 (M++1).

6-Methyl-3-(3-nitrophenyl)[1,2,4]triazolo[4,3-b]pyridazine: 4i

Yellow solid; yield; 1H NMR (300 MHz, CDCl3): δ = 9.53 (s, 1H), 8.92−8.88 (m, 1H), 8.39−8.83 (s, 1H), 8.16 (d, J = 9.5 Hz, 1H), 7.78−7.72 (m, 1H), 7.11 (d, J = 9.5 Hz, 1H), 3.8 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 160.8, 156.2, 148.3, 145.5, 137.3, 133.1, 130.1, 129.7, 127.9, 124.7, 122.1, 22.0.

MS: m/z 256 (M++1).

3-(4-Ethynylphenyl)-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4j

Yellow solid; yield; 1H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.04 (d, J = 9.4 Hz), 3.22 (s, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 154.7, 132.3, 127.3, 126.6, 124.7, 123.6, 121.8, 83.2, 78.9, 22.0.

MS: m/z 2365 (M++1).

6-Methyl-3-[(E)-2-phenylethenyl][1,2,4]triazolo[4,3-b]pyridazine: 4k

White solid; yield; 1H NMR (300 MHz, DMSO-d6): 8.27 (d, J = 8.3 Hz, 2H), 8.01 (d, J = 16.6 Hz, 1H), 7.76−7.73 (m, 2H), 7.53−7.33 (m, 4H), 7.30 (d, J = 9.5 Hz, 1H), 2.60 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ = 155.9, 146.7, 144.1, 136.2, 134.6, 129.4, 127.6, 127.1, 124.7, 123.4, 111.5, 21.8.

MS: m/z 237(M++1).

6-Methyl-3-(thiophen-3-yl)[1,2,4]triazolo[4,3-b]pyridazine: 4l

White solid; yield; 1H NMR (400 MHz, CDCl3): 8.64− 8.63 (m, 1H), 8.13−8.11 (m, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.50−7.48 (m, 1H), 7.03 (d, J = 9.5 Hz, 1H), 2.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 154.5, 145.0, 143.5, 126.9, 126.8, 125.8, 125.5, 124.4, 121.5, 21.9.

MS: m/z201(M++1).

6-Methyl-3-(pyridin-4-yl)[1,2,4]triazolo[4,3-b]pyridazine: 4m

White solid; yield; 1H NMR (300 MHz,CDCl3): 8.78 (d, J = 5.3 Hz, 2H), 8.44−8.42 (m, 2H), 8.08 (d, J = 9.5 Hz, 1H), 7.08 (d, J = 9.5 Hz, 1H), 2.67 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 155.2, 150.2, 145.3, 144.8, 133.5, 124.6, 122.3, 120.8, 21.9.

MS: m/z212(M++1).

3-Cyclopropyl-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4n

White solid; yield; 1H NMR (300 MHz, CDCl3): 7.90 (d, J = 9.5 Hz, 1H), 6.91 (d, J = 9.5 Hz, 1H), 2.58 (s, 3H), 2.50−2.47 (m, 1H), 1.35−1.31 (m, 2H), 1.28−1.25 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 153.8, 151.5, 143.3, 124.0, 121.4, 21.6, 7.5, 4.9.

MS: m/z 175(M++1).

3-Cyclohexyl-6-methyl[1,2,4]triazolo[4,3-b]pyridazine: 4o

White solid; yield; 1H NMR (400 MHz, CDCl3): 7.96 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 9.4 Hz, 1H), 3.39−3.32 (m, 1H), 2.60 (s, 3H), 2.15−2.12 (d, J = 9.5 Hz, 2H), 2.19−2.17 (m, 6H), 1.56−1.52 (m, 2H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 153.5, 143.2, 124.2, 121.4, 34.0, 29.9, 25.9, 25.8, 21.6.

MS: m/z 217(M++1).

Data: 2 (Selected compounds)

3-(3-Bromophenyl)-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7a

Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 8.7 (s, 1H), 8.5 (s, 1H), 8.46 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.41 (m, 1H), (s, 1H), 7.22.95−2.89 (m, 4H). 1.98−1.94 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 162.8, 146.7, 143.1, 142.3, 139.5, 132.8, 130.8, 130.3, 130.1, 130.0, 128.4, 126.1, 122.5, 25.3, 23.4, 22.9, 21.6.

MS: m/z 386(M++1).

3-(4-Bromophenyl)-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7b

Yellow solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.58 (s, 1H), 8.40 (d, J = 8.5 Hz, 2H), 7.67 (d, J = 8.5 Hz, 2H), 2.95−2.89 (m, 4H), 1.98−195 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 161.1, 147.3, 143.0, 142.4, 139.5, 131.9, 130.8, 130.3, 129.1, 125.4, 124.4, 25.3, 23.4, 22.9, 21.6.

MS: m/z 386(M++1).

3-(4-Bromo-2-methoxyphenyl)-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7e

White solid; 1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.65−7.62 (m, 1H), 7.51−7.48 (m, 1H), 7.72 (s, 1H), 6.99−6,96 (d, J = 8.8 Hz, 1H), 3.79 (s, 3H), 2.99−2.97 (m, 2H), 2.91−2.89 (m, 2H), 1.99−1.96 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 157.0, 157.4, 156.4, 146.4, 141.9, 139.3, 134.7, 134.4, 130.5, 129.8, 117.5, 113.2, 112.7, 56.0, 25.3, 23.4, 22.9, 21.7.

MS: m/z 415(M++1).

3-(2,4,6-Trimethoxyphenyl)-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7f

Yellow solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.43 (s, 1H), 6.25 (s, 2H), 3.88 (s, 3H), 3.70 (s, 6H), 3.95 (s, 3H), 2.96−2.86 (m, 4H), 1.96−1.98 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 163.5, 160.7, 144.6, 142.3, 141.2, 139.0, 130.5, 130.2, 130.3, 96.8, 90.7, 55.8, 55.3, 25.3, 23.4, 23.0, 21.7.

MS: m/z 397(M++1).

3-[4(4-Fluorophenoxy)phenyl]-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7g

White solid; 1H NMR (400 MHz, CDCl3): δ = 8.45 (d, J= 8.8 Hz, 1H), 7.52−7.48 (m, 1H), 7.30−7.27 (m, 1H), 7.04− 6.95 (m, 5H), 3.95 (s, 3H), 2.97−2,95 (m, 2H), 2.89−2.87 (m, 2H), 2.00−1.98 (m, Hz, 4H); 13C NMR (75 MHz, CDCl3): δ = 156.7, 152.0, 147.3, 142.6, 141.9, 139.2, 132.4, 131.9, 130.7, 130.4, 130.0, 123.0, 121.1,117.6,117.4, 116.2, 115.9, 25.3, 23.4, 22.9, 21.7.

MS: m/z 447(M++1).

Methyl 4-(7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine-3-yl)benzoate: 7h

Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 8.68 (s, 1H), 8.59 (d, J = 6.7 Hz, 2H), 8.19 (d, J = 8.3 Hz, 2H), 3.95 (s, 3H), 2.95−2.89 (m, 4H), 1.98−1.97 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 166.5, 147.2, 143.2, 142.4, 139.6, 131.0, 130.8, 130.5, 130.2, 129.7, 127.3, 52.2, 25.3, 23.4, 22.9, 21.6.

MS: m/z 365(M++1).

3-(4-Allyloxy)phenyl)-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7i

White solid; 1H NMR (300 MHz, CDCl3): δ = 8.49 (s, 1H), 8.42 (d, J = 11.7Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.14−6.03 (m, 1H), 5.49 (d, J = 1.2Hz, 2H), 5.34−5.29 (m, 1H), 4.62 (d, J = 5.2 Hz, 2H), 2.93−2.86 (m, 4H), 1.96−194 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 159.8, 148.1, 142.6, 141.6, 139.1, 132.8, 130.7, 130.3, 129.8, 119.2, 117.8, 114.7, 68.7, 25.3, 23.4, 22.9, 21.6.

MS: m/z 363(M++1).

(E)-3-Styryl-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7j

Yellow solid; yield; 1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1H), 8.14 (d, J = 16.5 Hz, 1H), 7.64 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 16.6 Hz, 1H), 7.44−7.39 (m, 2H), 7.36−7.32 (m, 1H), 2.93−2.87 (m, 4H), 1.97−1.96 (m, 4H); 13C NMR (100 MHz, CDCl3): δ = 147.8, 142.5, 142.0, 139.3, 136.2, 135.2, 130.8, 130.2, 128.9, 128.8, 127.2, 111.1, 25.4, 23.5, 23.0, 21.7.

MS: m/z 333(M++1).

3-Cyclopropyl-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7k

White solid; yield; 1H NMR (300 MHz, CDCl3): δ = 8.48 (s, 1H), 2.96−2.95 (m, 2H), 2.93−2.88 (m,2H), 2.54−2.05 (m, 1H), 1.99−1.97 (m, 4H), 1.41−1.36 (m, 2H), 1.32−1.26 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 151.9, 142.1, 141.2, 139.0, 130.6, 130.0, 128.9, 25.2, 23.4, 23.9, 21.6, 7.4, 5.4.

MS: m/z 271(M++1).

3-Hexyl-7,8,9,10-tetrahydrobenzo[4,5]thieno[2,3-d][1,2,4]triazolo[4,3-b]pyridazine: 7l

Pale yellow solid; 1H NMR (400 MHz, CDCl3): δ = 8.42 (s, 1H), 3.21−3.31 (m, 2H), 2.91−2.89 (m, 2H), 2.85−2.84 (m, 2H), 1.95−1.85 (m, 8H), 1.48−1.43 (m, 2H), 1.41−139 (m, 6H), 1.12−1.22 (m, 3H); 13C NMR (100 MHz, CDCl3): δ = 150, 142.0, 141.4, 139.1, 130.7, 130.1, 130.0, 31.4, 28.9, 26.7, 25.3, 24.6, 23.5, 23.0, 22.5, 21.7, 14.0.

MS: m/z 315(M++1).

 

RESULTS AND DISCUSSION

Scheme 1 illustrates our plan for the synthesis of triazolopyridazine derivative 4a. At first, 3-hydrazinyl-6- methylpyridazine 1 was treated with the model substrate, 3-bromobenzaldehyde 2a in EtOH at 60 ℃ for 0.5 h to obtainthe heteroaryl hydrazones 3a which was subjected directly to oxidative cyclization to acquire the triazolopyridazine 4a. To perform the oxidative cyclization, various conditions were screened as shown in the Table 1. Molecular iodine, potassium iodide and sodium iodide furnished 4a in poor yield whereas in association with oxidant such as TBHP, DMP, H2O2 and mCPBA did not improve the yield, however, oxone showed improvement in the yield. Similarly, the reaction was unclean with NBS alone whereas in the presence oxone, 4a was obtained in moderate yield. Combination of stiochiomentric amount of nBu4NBr/oxone and Me4NBr/oxone worked well. The mixture of Me4NBr (20 mol%) and oxone (1.5 equiv.) was found to be the best condition (92%).

Scheme 1.Synthesis of triazolopyridazine derivative 4a.

Having the optimized condition in hand, various aldehydes were subjected to the one-pot condition to afford the corresponding triazolopyridazine 4 as shown in Table 2. Halo substituted aryl aldehydes delivered 4b−4f in good yield. Both, electron donating and electron withdrawing group containing aryl aldehydes worked well. Interestingly, alkyne substituted aldehyde gave 4k and cinnamaldehyde provided 4l without affecting C−C multiple bond present in the substituent demonstrates that this oxidative condition is mild and highly efficient. Similarly, hetero aromatic aldehydes and aliphatic aldehydes such as cyclopropyl and cyclohexylcarboxaldehydes smoothly underwent oxidative cyclization in good yield.8

Table 1.a1 equiv. of reagent was used. b1.5 equiv. of oxidant was used. cIsolated yield. d20 mol% of reagent and 1.5 equiv. of oxidant were used.

Table 2.One-pot oxidative cyclization of various aldehydes with 4-methylhydrazinopyridazine

In order to further build complexity in the triazolopyridazine framework especially with hetereocyclic unit, thieno substituted pyridazine derivative 5 was prepared and then subjected to this one-pot process. Accordingly, treatment of 5 with aldehydes 2 furnished the heteroaryl hydrazones 6 and then in situ oxidative cyclization under the optimized condition afforded the thieno-triazolopyridazines 7 (Table 3). Halo, electron donating and electron withdrawing group containing aryl aldehydes smoothly underwent to this one-pot process. Towards the end, aliphatic alde-hydes led to 7 in high yield.8

Table 3.One-pot oxidative cyclization of various aldehydes with 4-hydrazinyl-6,7,8,9-tetrahydro[1]benzothieno[2,3-d]pyridazine

 

CONCLUSION

In conclusion, one-pot synthesis of 3-substituted triazolopyridazine derivatives was developed from the readily available aldehydes and hydrazinopyridazine derivatives. Similarly, the thieno analogs were obtained from the corresponding thienohydrazinopyridazine derivatives. Our method to construct 1,2,4-triazole moiety is based on oxidative cyclization which was successfully executed by Me4NBr and oxone, a non-toxic, metal-free and environmentally benign condition. Also, this condition is mild and thus displayed a wide functional group tolerance. Halo, nitro and related functional groups present in the triazolopyridazine derivative can be used for further elaboration.

References

  1. Ulusoy, N.; Gursoy, A.; Otuk, G. II Farmaco 2001, 56, 947-952 https://doi.org/10.1016/S0014-827X(01)01128-4
  2. Papakostantinou, S.; Garoufalias, N.; Pouli, P.; Marakos, A.; Ladas, A.C. II Farmaco 2002, 57, 973-977 https://doi.org/10.1016/S0014-827X(02)01227-2
  3. Kucukguzel, I. I.; Kucukguzel, S. G.; Rollas, S.; Kiraz, M. Bioorg. Med. Chem. Lett. 2001, 11, 1703-1707 https://doi.org/10.1016/S0960-894X(01)00283-9
  4. Patel, N. B.; Khan, I. H.; Rajani, S. D. Eur. J. Med. Chem. 2010, 45, 4293-4299 https://doi.org/10.1016/j.ejmech.2010.06.031
  5. Shiradkar, M.; Kumar, G. V. S.; Dasari, V.; Tatikonda, S.; Akula, K.C.; Shah, R. Eur. J. Med. Chem. 2007, 42, 807-816 https://doi.org/10.1016/j.ejmech.2006.12.001
  6. Parmar, S. S.; Gupta, G. A. K.; Singh, H. H.; Gupta, T. K. J. Med. Chem. 1972, 15, 999-1000 https://doi.org/10.1021/jm00279a033
  7. Wang, L. C.; Tu, C. H.; Wang, J. H.; Lee, G. H. Molecules 2006, 11, 169-176 https://doi.org/10.3390/11020169
  8. Zitouni, G. T.; Kaplanciki, Z. A.; Ozdemir, A.; Chevallet, P.; Kandilci, H. B.; Gumusel, B. Arch. Pharm. Chem. Life. Sci. 2007, 11, 586-590
  9. Sarva, M. C.; Romeo, G.; Guerrera, F.; Siracusa, M.; Alerno, L.; Russo, F.; Cagnotto, A.; Goegan, M.; Mennin, T. Cheminform. 2010, 33, 2002-2004
  10. Holla, B. S.; Veerendra, B.; Poojary, M. K. Eur. J. Med. Chem. 2003, 38, 759-767 https://doi.org/10.1016/S0223-5234(03)00128-4
  11. Parmar, S. S.; Chaudhary, M.; Chaudhary, S. K.; Kumar, S.; Spiro, H. R. J. Pharm. Sci. 1977, 66, 971-975. https://doi.org/10.1002/jps.2600660717
  12. Shimizu, S.; Endo, T.; Izumi, K.; Mikamiyama, H. Org. Process Res. Dev. 2007, 11, 1055-1058 https://doi.org/10.1021/op700116y
  13. Marino, J. P. Jr.; et al. J. Med. Chem. 2007, 50, 3777-3785. https://doi.org/10.1021/jm061182w
  14. Bower, J. D.; Doyle, F. P. J. Chem. Soc. 1957, 727-732 https://doi.org/10.1039/jr9570000727
  15. Gibson, M. S. Tetrahedron 1963, 19, 1587-1589 https://doi.org/10.1016/S0040-4020(01)99232-4
  16. Pollak, A.; Ti-sler, M. Tetrahedron 1966, 22, 2073-2079 https://doi.org/10.1016/S0040-4020(01)82127-X
  17. El-Gazzar, A. B.; Hassan, N. A. Molecules 2000, 5, 835-850 https://doi.org/10.3390/50600835
  18. Abdel-Fattah, B.; Kandeel, M. M.; Abdel-Hakeem, M.; Fahmy, Z. M. J. Chin. Chem. Soc. 2006, 53, 403-412 https://doi.org/10.1002/jccs.200600051
  19. Shawali, A. S.; Hassaneen, H. M.; Shurrab, N. K. Tetrahedron 2008, 64, 10339-10558 https://doi.org/10.1016/j.tet.2008.08.082
  20. Shawali, A. S.; Hassaneen, H. M.; Shurrab, N. K. Heterocycles 2008, 75, 1479-1488 https://doi.org/10.3987/COM-07-11311
  21. Shawali, A. S.; Gomha, S. M. Tetrahedron 2002, 58, 8559-8564 https://doi.org/10.1016/S0040-4020(02)00946-8
  22. Son. Y. H.; Son. H. Y. Bull. Korean Chem. Soc. 2010, 31, 2242-2246 https://doi.org/10.5012/bkcs.2010.31.8.2242
  23. Mogilaiah, K.; Chandra, A. V.; Srivani, N. Indian J. Chem. 2011, 50B, 1187-1191
  24. Thiel, O. R.; Achmatowicz, M. M.; Reichelt, A.; Larsen, R. D. Angew. Chem. Int. Ed. 2010, 49, 8395-8398 https://doi.org/10.1002/anie.201001999
  25. Staben, S.; Blaquiere, N. Angew. Chem. Int. Ed. 2010, 49, 325-328. https://doi.org/10.1002/anie.200905897
  26. Unqureanu, M.; Mangalagiu, I.; Grosu, G.; Petrovanu, M. Ann. Pharm. Fr. 1997, 55, 69-72
  27. Galtie, C.; Mavel, S.; Snoeck, R.; Andre, G.; Pannecouque, C.; Witvrouw, M.; Balzarini, J.; Clercq, E. D.; Gueiffier, A. Antivir. Chem. & Chemother. 2003, 14, 177-182 https://doi.org/10.1177/095632020301400402
  28. Islam, M.; Siddiqui, A. A.; Rajesh, R. Acta Pol Pharm. 2008, 65, 441-447
  29. Yas sin, F. A. Chem. Heterocycl. Comp. 2009, 45, 997-1003 https://doi.org/10.1007/s10593-009-0381-9
  30. Zhou, J.; Fan, H. T.; Song, B. A.; Jin, L. H.; Bhadury, P. S.; Hu, D. Y.; Yang, S. Phosphorus. Sulfur. Silicon Relat. Elem. 2010, 186, 81-87 https://doi.org/10.1080/10426507.2010.482543
  31. Bloomer, L.C.; Wotring, L. L.; Townsend, L. B. Cancer Res. 1982, 42, 100-106
  32. Katz, D. J.; Wise, D. S.; Townsend, L. B. J. Med. Chem. 1982, 25, 813-321. https://doi.org/10.1021/jm00349a009
  33. Corina, M.; Casiraghi, G.; Zetta, L.C. J. Org. Chem. 1991, 56, 5466-5468 https://doi.org/10.1021/jo00018a053
  34. Abubshait, S. A. Molecules 2007, 12, 25-42 https://doi.org/10.3390/12010025
  35. Yokoyama, M.; Tanabe, T.; Toyoshima, A.; Togo, H. Chem Lett. 1994, 517, 265-268
  36. Mantu, D.; Luca, M. C.; Moldoveanu, C.; Zbancioc, G.; Mangalagiu, I. Eur. J. Med. Chem. 2010, 45, 5164-5168 https://doi.org/10.1016/j.ejmech.2010.08.029
  37. Malinka, W.; Redizicka, A.; Lozach, O. II Farmaco 2004, 59, 457-462. https://doi.org/10.1016/j.farmac.2004.03.002
  38. Albright, J. D.; Moran, D. P.; Wright, W. B.; Collins, J. P.; Beer, B.; Lipa, A. S.; Greenblatt, E. N. J. Med. Chem. 1981, 24, 592-600 https://doi.org/10.1021/jm00137a020
  39. Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni, V.; Lucacchini, A.; Senatore, G. II Farmaco 1996, 51, 601-608
  40. Atack, J. R. et al. J. Pharmacol Exp Ther. 2010, 332, 17-25 https://doi.org/10.1124/jpet.109.157909
  41. Licata, S. C.; Platt, D. M.; Ruedi-Bettschen, D. R.; Atack, J. R.; Dawson, G. R.; Van Linn, M. L.; Cook, J. M.; Rowlett, J. K. Neuropharmacology 2010, 58, 357-364. https://doi.org/10.1016/j.neuropharm.2009.10.004
  42. El-Dean, A. M. K.; Gaber, A. E. M.; El-Gaby, M. S. A.; Eyada, H. A. Cheminform. 2004, 35, 321-344
  43. Singh, A. K.; Hedge, G. L.; Khanum, S. A.; Shashikanth, S. Indian J. Pharm. Sci. 2005, 67, 210-215
  44. Pieretti, S.; Ominici, L. D.; Di Giannuario, A.; Cesari, N.; Dal Piaz, V. Life Sci. 2006, 79, 791-800 https://doi.org/10.1016/j.lfs.2006.02.026
  45. Zaher, A. F. A.; Refaat, H. M.; Fawzy, O. M. Bull. Fac. Pharm. Cairo. Univ. 2009, 47, 69-75.
  46. Street, L. J. et al. J. Med. Chem. 2004, 47, 3642-3657 https://doi.org/10.1021/jm0407613
  47. Shamroukh, A. H.; Ali, M. A. Arch. Pharm. 2008, 341, 223-230 https://doi.org/10.1002/ardp.200700181
  48. Albrecht, B. K. et al. J. Med. Chem. 2008, 51, 2879-2882. https://doi.org/10.1021/jm800043g

Cited by

  1. Antimicrobial Activities of Novel 3-Substituted [1,2,4] Triazolo[4,3-b]pyridazines Derivatives vol.58, pp.4, 2014, https://doi.org/10.5012/jkcs.2014.58.4.377