DBU mediated one-pot synthesis of triazolo triazines via Dimroth type rearrangement |
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| Authors: | Ab Majeed Ganai Tabasum Khan Pathan Nisar Sayyad Babita Kushwaha Narva Deshwar Kushwaha Andreas G Tzakos Rajshekhar Karpoormath |
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| Institution: | Department of Pharmaceutical Chemistry, Discipline of Pharmaceutical Sciences, College of Health Sciences, University of KwaZulu-Natal (Westville), Durban 4000 South Africa.; Section of Organic Chemistry and Biochemistry, Department of Chemistry, University of Ioannina, Ioannina 45110 Greece |
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| Abstract: | Herein we report an efficient one-pot synthesis of 1,2,4]triazolo1,5 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]triazolo4,3-a]1,3,5]triazines to 1,2,4]triazolo1,5-a]1,3,5]triazines is driven by 1,8-diazabicyclo5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70–96%).We demonstrate a simple yet efficient one-pot synthesis of two triazolotriazine isomers via DBU mediated Dimroth type rearrangement with excellent yields.Purines are nitrogen-containing heterocycles and are structural motifs in the nucleobases adenine and guanine of DNA as well as RNA. Purine nucleotides (ATP, GTP, cAMP, cGMP, NAD, FAD) also act as co-factors, substrates, or mediators in the functioning of numerous proteins.1 Therefore, bioisosteres of purines are widely explored and exploited by pharmaceutical chemists in developing new drug entities. Heterocycles containig the 1,3,5-triazine ring act as bioisosteres of purine, which exist as two isomers, namely 1,2,4]triazolo4,3-a]1,3,5]triazine and 1,2,4]triazolo1,5-a]1,3,5]triazine (), which have been extensively studied as adenosine receptor antagonists,2,3 as well as for other pharmacological activities1,4,5 (). Literature reports suggest that 1,2,4]triazolo1,5-a]1,3,5]triazine has been exploited extensively in drug discovery as compared to its corresponding isomer. Further, from the literature it is evident that symmetrical disubstituted triazines,6–9 especially morpholine10–12 substituted, have displayed broad pharmacological activities.Open in a separate windowStructure of isomers of triazolo–triazine.Open in a separate windowBiologically active molecules of 1,2,4]triazolo4,3-a]1,3,5]triazine (1) and 1,2,4]triazolo1,5-a]1,3,5]triazine (2, 3, 4).Various synthetic methods have been reported for the C–N bond formation by employing different starting materials13–15via oxidative cyclisation,16 high temperature condition17–19 and/or metal-catalysed reactions.20 However, the current reported protocols were environmentally unfriendly as they suffered from drawbacks such as, multistep, and tedious procedures, use of carcinogenic solvents, high-temperature, expensive and toxic metal-catalysts, and other hazardous reagents.Furthermore, there is very less reported research on these heterocycles, and that can be because of the unavailability of the efficient and cheaper methods. Thus, there is a need to develop new versatile synthetic method for the synthesis of disubstituted triazolotriazine heterocycles of pharmacological interest.In 1970, for the first time Kobe21et al. (scheme a) reported the synthesis of 1,2,4]triazolo4,3-a]1,3,5]triazine utilizing lead tetraacetate in benzene under reflux conditions (). However, no further Isomerization was carried out and resulted low to moderate yield. Deshpande22et al. reported (scheme b) the reaction of 2-hydrazinyl-1,3,5-triazine with various substituted benzoic acids. The product formed was treated with P2O5, refluxed in xylene for 10h to yield 1,2,4]triazolo4,3-a]1,3,5]triazine. Further, Isomerization of the resulting product was carried out in 2% methanolic-NaOH solution resulting in poor yields. Recently, Stefano23et al. (scheme c) reported, a multistep protocol by reacting the intermediate with bis(methyl-sulfanyl)methylenecyanamide at 180 °C under N2 for 3h resulting in low yield due to the formation of several side products. In addition no isomerization studies were carried out, and only the 1,2,4]triazolo1,5-a]1,3,5]triazine analogs were reported.Open in a separate windowDifferent approaches for the synthesis of triazolo triazines.Herein, we report an economical one-pot synthesis of 1,2,4]triazolo1,5-a]1,3,5]triazine analogs via Dimroth type rearrangement of 1,2,4]triazolo4,3-a]1,3,5]triazine derivatives. This one pot novel methodology was carried out by reacting readily available, inexpensive starting materials such as substituted aryl/heteroaryl benzaldehydes and substituted 2-hydrazinyl-1,3,5-triazine in methanol (a mild solvent)24 at room temperature giving excellent yields of the desired product. For cyclization reaction, an eco-friendly reagent NBS25 was used and the resulting product was treated with DBU to yield its corresponding desired isomer. To the best of our knowledge this is the first report for the greener synthesis of symmetric disubstituted triazolotriazine heterocycles via Dimroth type rearrangement. We believe that this simple, yet novel methodology could be further exploited by the researchers in pharmaceutical industries and academics settings in drug discovery.Formation of the Schiff base was initiated reacting 4,4′-(6-hydrazinyl-1,3,5-triazine-2,4-diyl)dimorpholine 1a and unsubstituted benzaldehyde as shown in | Open in a separate windowaConditions: 1a (1 mmol), benzaldehyde (1 mmol), solvent, rt, 20 min, then oxidant (1 mmol), 5 min, rt, then DBU, stir at rt till completion of the reaction.Meanwhile, equivalents of DBU were adjusted (entry 12, 13) to attain the highest yield %. Reaction with 1.5 eq. showed drastic improvement in yields in 2 h whereas 2.0 eq. resulted in good yields with less reaction time. Considering the yield factor (entry 12), the oxidant optimization was achieved (entry 14–17). Using N-chlorosuccinimide (NCS) and N-iodosuccinimide (NIS) (entry 14, 15) offered 56% and 61% yield respectively. When the reaction was performed using phenyliodine(iii) diacetate (PIDA) and KI/I2 (entry 16, 17) it provided 2a in 63% and 53% yields, respectively. Finally, methanol–water and ethanol–water systems in 3 : 1 were used, which gave approximately 70% yield, concluding that entry 12 gives the best result, demanding alcoholic solvents especially methanol as a key factor for Dimroth type rearrangement. Additionally, it was supported by the observation that reaction goes well in methanol, a little worse in ethanol (. The reaction involves a Schiff base formation (II) by 1a and benzaldehydes, the addition of NBS results in oxidative cyclization reaction to produce isomer 1. The addition of DBU in isomer-1 initiates a famous Dimroth type rearrangement, protonation of III results in ring-opening with the formation of unstable intermediate V. It undergoes tautomerism by 1,3 proton shift, bond rotation and proton abstraction by methoxide ion facilitating the intramolecular cyclization to afford the isomer 2. This reaction mechanism is supported by the formation of the Schiff base, isomer-1, and its conversion to isomer-2, which were easily monitored by TLC, isolated, and characterized (ESI†). In addition to that, a single crystal of compound 2e was obtained, which further supports the Dimorth type of rearrangement (ESI†).Open in a separate windowPlausible mechanism of the reaction pathway.Having in hand the optimized conditions, the substrate scope was further explored by using different aldehydes (). The reaction was carried out using 1a with benzaldehydes having electron-donating groups (2a-f) followed by NBS and DBU additions. The reaction was allowed to stir at room temperature till reaction completion, as monitored by TLC, which would approximately take 2 h. The reaction could smoothly give final products in excellent reaction yields (79 to 96%). Electron withdrawing groups such as chlorobenzaldehydes (2g-i) despite the position of substitution gave excellent yields (93–95%). With the 4-bromo and different fluoro-benzaldehydes, the reaction resulted in 2j (89%) and 2k-m (84–90%) with very good yields. Also, reaction afforded 70% and 77% yields with heterocyclic aldehydes such as 3-pyridinecarboxyaldehyde (2n) and thiophene-2-carbaldehyde (2o), respectively.Open in a separate windowSubstrate scope for different aldehydes.The gram scale reaction was performed to further validate this synthetic procedure. The reaction was carried out using 1a (1 g) with benzaldehyde (0.38 g) and stirred for 30 min. The NBS (1.26 g, 1 eq.) was added slowly and stirred till new spot appeared on TLC followed by the slow addition of DBU (1.5 eq.) resulted in isomerisation to give 2a in good yields (1.1 g, 84%) (ESI†).Encouraged from the potency of the reaction to generate in good to excellent yields 1,2,4]triazolo1,5-a]1,3,5]triazine analogues, we shifted our investigation to isolate 1,2,4]triazolo4,3-a]1,3,5]triazine derivatives (isomer-1) as described in . Different aldehydes were reacted with hydrazinyl-1,3,5-triazine analogs (1a, 3a, and 4a) and followed by the addition of NBS, stirred at room temperature till the completion of reaction as monitored by TLC. Compound 1a on reaction with 4-bromobenzaldehyde and NBS resulted in 1b with 90% yield. Similarly, 3a with 4-bromobenzaldehydes and thiophene-2-carbaldehyde afforded 3b and 3c with 84% and 83% yields, respectively. The same reaction was carried out with 4a and 4-bromobenzaldehyde bearing an electron-withdrawing group gave 3d with 87% yield. Further, 4a with aldehydes bearing electron-donating groups resulted 4c and 4d, with 88% and 84% yields, respectively ().Open in a separate windowSubstrate scope for 1,2,4]triazolo4,3-a]1,3,5]triazine analogues.Open in a separate windowSubstrate scope for different disubstituted triazinyl-hydrazine and aldehydes.With these promising results, we explored the scope of aldehydes and 2-hydrazinyl-1,3,5-triazine analogs for the synthesis of 1,2,4]triazolo1,5-a]1,3,5]triazine derivatives. Compound 3a, when reacted with different aldehydes and employing the optimized protocols gave 5a-e with excellent yields (86–92%) in 2–4 h. Similarly compounds 6a, 6b and 6c, synthesized from 4a also afforded excellent yields 88%, 86% and 90% respectively. Further, substituted cinnamaldehydes were also explored and reacted with 1a followed by the addition of NBS and DBU resulted in 7a and 7b in appreciable yields of 84% and 82%, respectively.Finally, we investigated both the isomers (3b and 5d) spectroscopically, to elucidate the change in proton chemical shifts during rearrangement. Interestingly, it was observed that the proton chemical shift for 5d at the 7th position () was not affected. However, 5th position of 5d suffers a downfield shift due to change in its electronic environment as compared to its corresponding isomer 3b. In general, the proton chemical shifts for the substitution at 5th position and for the aromatic region was found to be more for isomer-2 as compared to isomer-1. |
