Click Chemistry Approach to Isoindole-1,3-dione Tethered 1,2,3-Triazole Derivatives

Abstract A convenient and efficient approach for the synthesis of novel 1,2,3-triazole tethered isoindol-1,3-dione conjugates by a nucleophilic substitution reaction of phthalic anhydride with 1,2,3-triazole containing carbohydrazide is described. The latter were prepared by using click chemistry.

The desire to construct biologically relevant molecules starting from simple molecules leads to a constant demand for new synthetic methodologies. [10][11][12] A simple and straightforward strategy to access the desired isoindole-1,3-dione-tethered 1,2,3-triazole derivatives would involve click chemistry (Scheme 1), with the fragments being connected by following either path A or Path B. In the present work, we followed Path A as it helps to generate and introduce diversity in the final product. Diversity in the final products can be introduced at three points by varying the azide, alkyne, and the phthalic anhydride, thus permitting access to multifunctional, highly substituted derivatives.

Letter Syn Open
To start with, aromatic amines 9 were converted into the corresponding azides 6 via reaction of their respective diazonium salt with sodium azide by following reported procedures (Scheme 2). 13,14 The azides were used without further purification and were subjected to 1,3-dipolar cycloaddition 15 with a ethyl propynoate 10 using Cu(OAc) 2 /sodium ascorbate (10 mol% and 20 mol%, respectively) in H 2 O/t-BuOH (1:1) to yield the corresponding cycloaddition products 5 in good to excellent yields (Scheme 2). 16 These compounds were fully characterized by 1 H and 13 C NMR spectroscopy. For instance, compound 5a showed eleven resonances in its 13 C NMR spectrum and, in its 1 H NMR spectrum, a resonance at  = 9.62 ppm could be assigned to the C-5 proton of the triazole. Next, hydrazides 11 were prepared by reacting carboxylate derivatives 5 with hydrazine hydrate in ethanol at reflux (Scheme 3). 17 The absence of resonances at  = 61.6 and 14.3 ppm in the 13 C NMR spectra of hydrazides 11 supported their formation. The 1 H NMR spectra of hydrazides 11ad still exhibited the characteristic resonance due to the C-5 proton of the triazole moiety, but the ethyl ester resonances had been replaced by NH and NH 2 resonances at  = 9.91 (bs, 1H) and 4.53 ppm (bs, 2H).

Scheme 3 Preparation of hydrazide 11a-d
After synthesizing 1,2,3-triazole carbohydrazides 11, preparation of isoindole-1,3-dione derivatives 4 was performed (Scheme 4). 1,2,3-Triazole carbohydrazides 11 were treated with the phthalic anhydride 8 under a range of reaction conditions; the results are summarized in Table 1. These studies revealed that a catalytic amount of glacial acetic acid is required for complete amidation. Reactions without glacial acetic acid were slower and lower yielding. This sluggishness is presumably due to the lower nucleophilicity of the NH 2 group attached to a 1,2,3-triazole compared with aliphatic and aromatic amines.

Table 1 Reaction Conditions for Amidation Reaction
Thus, the reaction of compounds 11 with phthalic anhydride in toluene using a catalytic amount of glacial acetic acid at 110 °C to afford isoindole-1,3-dione derivatives 4 was found to be optimal (Scheme 4). 18 All compounds were fully characterized spectroscopically.  Table 2 summarizes the yields of the various compounds synthesized. The infrared spectra of carboxylates 5 exhibited a characteristic peak for an ester carbonyl group; whereas there was a sharp decrease in the IR frequency for the carbohydrazide carbonyl group in 11 due to the amide linkage.

Letter Syn Open
These molecules were subjected to in vitro antibacterial activity against Mycobacterium smegmatis and were found to be inactive. 19 In conclusion, a methodology to prepare triazole-isoindole-1,3-dione derivatives is described. The methodology tolerates various functional groups and provides a way to introduce three points of diversity into the core skeleton. The molecules were designed to be active against tuberculosis; however, the experimental results did not show the predicted activity.

Funding Information
Science and Engineering Research Board, New Delhi (Grant / Award Number: CS-017/2014). R.K. thanks SERB New Delhi for a Fellowship.i e n c e a n d E n g i n e e r i n g R e s e a r c h B o a r d ( C S -0 1 7 / 2 0 1 4 )