Preparation The 1,2,3-triazole

Preparation:

The 1,2,3-triazole ring system has been the subject of considerable research mainly due to its usefulness in synthetic organic chemistry and also because of the pharmacological properties shown by some of its derivatives. In this context, we decided to explore the 1,2,3-triazole ring system as a new scaffold for cannabinoid ligands.²⁰ Cannabinoids are compounds belonging to different structural families that elicit diverse biological responses by interacting with the cannabinoid receptors, of which two have been identified so far, CB1 and CB2. These receptors are involved in many biochemical processes and are thus interesting therapeutic targets.^21-24 In particular, the CB1 receptor is involved in many different food-intake related disorders such as bulimia or obesity.^25-26 Unfortunately, rimonabant (Figure 1), the first potent and selective CB1 antagonist to reach the pharmaceutical market as antiobesity agent, has been recently withdrawn

due to possible depressive effects Our group reported a series of cannabinoid 1,2,4-triazoles resulting in the identification of LH-21 (Figure 1) [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole].²⁸ LH-21 displays selective and neutral CB1 receptor antagonism properties with lower penetration in the brain than rimonabant.^29-30

Preparation:

 1-we have synthesized a series of 1,2,3-triazoles as LH-21 analogues. In the course of our research three reports dealing with cannabinoid 1,2,3-triazoles have appeared very recently. In one of them the 1,2,3-triazole group is reported as peptidomimetic element of mixed CB1/TRPV1 antagonists.^[11] The two other reports focused on 4-alkoxycarbonyl-1,5-diaryl-1,2,3-triazoles^[12] and 2-(phenoxy-carbonyl)methyl-1,2,3-triazoles^[13] as CB1 cannabinoid antagonists. The results reported here deal with the preparation of 2-alkyl-1,2,3-triazoles as LH-21 analogues

Concerning synthetic issues^[14] the most classical approach to the synthesis of 1,2,3-triazoles involves thermal 1,3-dipolar cycloaddition of azides with alkynes, as initially proposed by Huisgen.^[15] This reaction suffered from a lack of selectivity yielding a mixture of N1/N3- and N2-substituted 1,2,3-triazoles when azides react with unsymmetrical disubstituted alkynes.^[16] The discovery of copper (I)^[17] and ruthenium (II)^[18] catalyzed cycloadditions opened the field of highly efficient "click chemistry" between azides and alkynes However, using these conditions only N1/N3-substituted 1,2,3-triazole isomers can be prepared. Few methods are available for the selective preparation of N2-substituted-1,2,3-triazoles and they are limited to N2-hydroxymethyl-,^[19] N2-allyl-^[,21,21] or N2-aryl-1,2,3-triazoles^.[22,23] We finally prepared and isolated the regioisomer N2-alkyl-1,2,3-triazoles by alkylation of NH-1,2,3-triazoles. N2-[N-(piperidin-1-yl)acetamide]-1,2,3-triazole derivatives are also reported here by comparison to rimonabant. The structural assignment of the different regioisomers was fully illustrated using NMR techniques.

Result:

The synthesis of NH-1,2,3-triazoles ^[2-6] was achieved in acceptable yield (30-67%) by cycloaddition of tri-n-butyltin azide with mono- or disubstituted alkynes 1 under pressure and heating conditions (Scheme 1).^[24] This procedure was convenient regarding the safety issues using tri-n-butyltin azide compared to the highly explosive hydrazoic acid. The tributylstannyl group could be subsequently replaced by a proton under mild conditions. The starting alkynes 1a-1d were obtained from commercial sources and 1e was prepared^[25] in excellent yield from the corresponding 1-ethylnyl-4-methyl benzene  

Triazoles 2-6 were then alkylated with the corresponding alkylbromide under basic conditions using the phase transfer catalyst Bu4NBr26 to afford the desired N-substituted-1,2,3-triazoles 7-17 (Scheme 2). N-Alkylation of unsymmetrical 4,5-disubstituted-1,2,3-triazoles produces a mixture of three possible regioisomers: a N2-, b N-1 and c N-3. Under the alkylation conditions used here two or three regioisomers have been isolated depending on the nature of the triazole substituents.

2-1H-1,2,3-triazole can be prepared by the following methods:
One method utilizes the reaction of Cl2CHCH=NNHSO2C6H4CH3 with NH3. A solvent of 41.5g p-MeC6H4SO2NHNH2 in MeCH2CO2H was treated with 25g Cl2CHCHO at 15°C for ~1h to give 37.2g Cl2CHCH=NNHSO2C6H4CH3, which was treated with NH3-saturated.MeOH at 22±5°C for 2h to give 50.5% 1,2,3-triazole .
Another method: 2,2-dichloroacetaldehyde was treated with hydroxylamine hydrochloride to give 80.5% 2,2-dichloroacetaldoxime, which was treated with hydrazine to give 70.1% glyoxal monoxime hydrazon. Stirring it in CHCl3 in the presence of SOCl2 and Et3N gave 61.6% 1,2,3-triazole [5].
The third method: 1H-1,2,3-triazole was prepared by adding tosylhydrazide to a mixture of ammonia and glyoxal in methanol and water in a sealed container, and the reaction mixture was stirred for 15h at room temperature to give 53.4% 1,2,3-triazole, which was isolated by the residue distillation[8, 9].
The fourth method: 538g MeCONHN=CHCH=NOH and 74.8g AcONa were dissolved in 2.4L toluene, followed by adding 930.2g Ac2O, and the reaction mixture was stirred at 90-93°CC for 4h,cooled,and filtered to give a filtrate solvent. MeOH(730g) was added drop-wise to the latter solvent at <40°C and the resulting mixture was stirred for 4h, concentrated in vacuum, and distillated to give 80% 1,2,3-triazole[8, 9].
The fifth method: Autoclaving benzyltriazole with 5% Pd/C in AcOH at 50°C and 6kg/cm2 for 4h gave 89.8% 1,2,3-triazole, whereas hydrogenation in EtOH was unsuccessful[8].
In view of price of raw materials, conditions demanded and yield of the product in the concerned procedures, we selected the third method as the most suitable procedure for preparation of 1,2,3-triazole for study.