DBU mediated one-pot synthesis of triazolo triazines via Dimroth type rearrangement

Herein we report an efficient one-pot synthesis of [1,2,4]triazolo[1,5 a][1,3,5]triazines from commercially available substituted aryl/heteroaryl aldehydes and substituted 2-hydrazinyl-1,3,5-triazines via N-bromosuccinimide (NBS) mediated oxidative C–N bond formation. Isomerisation of [1,2,4]triazolo[4,3-a][1,3,5]triazines to [1,2,4]triazolo[1,5-a][1,3,5]triazines is driven by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70–96%).


Experiment:
The reaction was performed in 10 ml glass reaction tube at room temperature. 4,4'-(6hydrazinyl-1,3,5-triazine-2,4-diyl)dimorpholine and simple benzaldehyde resulted in schiff base formation in 10mins and was monitored by TLC. Addition of NBS led to spontaneous reaction forming isomer 1 and it took 20 mins for its completion. The spot was isolated and characterised by NMR. Next step was addition of DBU which resulted in formation of isomer 2 in 2-4h. The progress of the reaction was monitored by TLC. The isomer 2 on TLC appeared as bluish rather than its isomer 1.
The equivalents of DBU influenced the reaction rate drastically, the 2 eq. of DBU gave the isomer 2 in about 45 mins. The progress of reaction using different equivalents of DBU was studied for isomer 2 as shown in Figure S1. Addition of water caused precipitation the product (isomer 2) and followed by the filtration.
1.5 eq. of DBU resulted in high yield % as compared to 2.0 eq. of DBU and it saved the super-equivalents of reagent.

General consideration
All the required chemicals and solvents used in this research work were purchased from commercial suppliers Sigma Aldrich, Alfa Aesar and Merck. For Thin-layered chromatography (TLC) precoated with silica gel plates were used for monitoring the progress of the reaction which was procured from E.
Merck and Co. (Darmstadt, Germany) and visualized under UV lamp (254 or 365 nm). Melting point for the synthesized compounds was obtained from digital Stuart SMP10 melting point apparatus. The compounds were characterized by Bruker Alpha FT-IR spectrometer using the ATR technique in the 400-4000cm -1 spectral range. The NMR ( 1 H & 13 C) spectra were obtained Bruker AVANCE III 400 MHz spectrometer using deuterated solvents-CDCl 3 and DMSO. Tetramethylsilane (TMS) was used as an internal standard at δ 0.0 parts per million (ppm) and the coupling constants (J) were stated in Hertz. The NMR multiplicities were abbreviated as s for singlet, d for doublet, dd for doublet of doublet, t for triplet, q for quartet and m for multiplet.

Synthesis and spectral characterization of 1a, 3a and 4a.
The starting materials 1a, 3a and 4a were synthesised by the previously reported method. 1

A General procedure for synthesis and spectral characterization of 2 (a-o), 5(a-e), 6(a-c)
and 7 (a-b);

S4
In a 10 mL glass reaction tubes equipped with a magnetic stirrer 1a, 3a, or 4a (200mg, 1 eq.) was placed in 2ml of methanol. To this solution was added aldehydes (1 eq.) and allowed to stir at room temperature (20-30 mins), resulting in respective Schiff base and the same was monitored by the TLC. To the Schiff base NBS (1eq.) was slowly added to the reaction mixture and allowed to stir at room temperature for 5-30 mins, yielding isomer-1, which when treated with 1.5 eq. of DBU resulted in isomerisation to give isomer-2. After the completion of reaction, 2-3 ml of ice-cold water was added to the crude reaction mixture leading to the Precipitation, which was filtered, washed with pentane and vacuum dried to afford the final products in good to excellent yields 65-95%.

3.3.B General procedure for synthesis and spectral characterization of 1b, 3(b, c) and 4(bd);
In a 10 mL glass reaction tubes equipped with a magnetic stirrer 1a, 3a, or 4a (200mg, 1 eq.) was placed in 2ml of methanol. To this solution was added aldehydes (1 eq.) and allowed to stir at room temperature for 10-30 mins, resulting in the formation of respective Schiff bases.
Further slow addition of NBS (1eq.) to this reaction mixture and stirred at room temperature (5-30 mins) yielded isomer-1. The crude reaction mixture was poured onto an ice-clod water (2-3ml) resulting in a precipitate. The precipitate was then filtered and washed with pentane and vacuum dried to afford the final products with yields ranging 83-89%.