ISOINDOLINOTRIAZOLE DERIVATIVES: SYNTHESIS BY THE AZIDE- ALKYNE CYCLOADDITION CLICK CHEMISTRY

A novel series of isoindolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 2-( meta - or para -ethynylphenyl)-4,6-dimethoxyisoindolin-1-ones and several azides. The synthesized triazoles were characterized by IR, 1 H NMR, 13 C NMR and mass spectral techniques.

In medicinal chemistry, the triazoles are known to possess a number of desirable features including sufficient stability to acidic/basic hydrolysis and reductive/oxidative conditions, indicative of a high aromatic stabilization [7]. This moiety is relatively resistant to metabolic degradation. Tazobactam, a b-lactamase inhibitor is among the best-known examples of triazole containing structures with the broad-spectrum antibiotic piperacillin [8]. Also several members of the 1,2,3-triazole family have indeed shown interesting biological properties, such as anti-allergic, anti-bacterial and anti-HIV activity [9,10].
The coupling of two or more molecular entities with distinct properties to form novel conjugates with combined properties of parent components, has emerged as a fast growing technology in recent years [11,12]. Several new conjugates arising via such bioconjugation have been found to exhibit unusual biological properties and activities as the different molecular segments act cooperatively [13]. In this prospective, the 'Click'-chemistry [14] is a newer approach for the synthesis of drug-like molecules that can accelerate the drug discovery process by utilizing a few practical and reliable reactions [15]. Among the reactions comprising the click universe, the perfect example is the Huisgen 1,3-dipolar cycloaddition of terminal alkynes and organic azides to form 1,4-disubstituted-1,2,3-triazoles [16,17].
In this study, we report the high-yielding synthesis of novel isoindolinotriazoles 3a-h using 1,3-dipolar cycloaddition reaction of ethynylisoindolinones 2a-b with several azides in the presence of Cu(I) catalyst at room temperature. All the synthesized isoindolinones and 1,4-disubstituted-1H-1,2,3-triazoles were characterized by IR, 1 H NMR, 13 C NMR spectroscopy and mass spectrometry.

RESULTS AND DISCUSSION
Isoindolinone derivatives were obtained using methods developed by Yoo et al. [18] (Scheme 1). The reaction between methyl 2-formyl-3,5-dimethoxybenzoate 1 with the appropriate amines in methanol was carried at room temperature over 1 h. The resulting solution was mixed with sodium borohydride at 0 °C and reacted overnight at room temperature to produce isoindolinone compounds 2a-d (Table 1)

CONCLUSION
In summary, various isoindolinones were synthesized and utilized as starting materials in the 'click' reaction to attach azido residues. Consequently, we have employed these, in house synthesized precursors, to prepare a new class of hybrid molecules 1,4-disubstituted-1H-1,2,3-triazoles employing already known chemistry of (3 + 2) cycloaddition of azides and alkynes in good to very good yields. All products that we have obtained were hitherto unknown. A number of them are presently under pharmacological screening.

EXPERIMENTAL General
Melting points were determined with an Electrothermal 9300 capillary melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer PARAGON 1000 FT-IR spectrometer. 1 H and 13 C NMR spectra were recorded on an AC Bruker spectrometer at 300 MHz ( 1 H) and 75 MHz ( 13 C) using (CD3)2SO or CDCl3 as solvents. High resolution mass spectra (HRMS) were recorded on a Bruker Maxis spectrometer (Service Commun Toulouse, France). Silica Gel 60 (Merck 70-230) was used for column chromatography. The progress of the reactions was monitored by thin layer chromatography (TLC) on Kieselgel 60 F254 (Merck) plates. Compound purity was determined by an LC-PDA-MS method and was found to be in the range 96-99%.

General experimental procedure for preparation of 2-substitued-4,6dimethoxyisoindolin-1-ones
To a solution of methyl 2-formyl-3,5-dimethoxybenzoate 1 (2.5 mmol) in methanol (20 mL) was added the appropriate amine (2.5 mmol). The mixture was stirred at room temperature until the appearance of a suspension. NaBH4 (5 mmol) was then added at 0 °C and the mixture allowed to react at room temperature for 20 h with stirring. The precipitate thus formed was filtered through a glass filter to give a solid compound.