One-Pot Synthesis of 1,3,5-Triazine Derivatives via Controlled Cross-Cyclotrimerization of Nitriles: A Mechanism Approach

Abstract

The reaction of equimolecular amounts of a nitrile and triflic anhydride or triflic acid at low temperature produces an intermediate nitrilium salt that subsequently reacts with 2 equiv of a different nitrile at higher temperature to form 2,4-disusbstituted-6-substituted 1,3,5-triazines in moderate to good yields. This synthetic procedure has also been applied to the preparation of a 1,3,5-triazine having three different substituents. The results are explained in terms of a mechanism based on the relative stability of the intermediate nitrilium salts that are formed through a reversible pathway. The formation of a substituted isoquinoline using benzyl cyanide as the second nitrile supports the postulated mechanism as well as the structure of derivatives of the proposed intermediate when the reaction is carried out in the presence of different nucleophiles other than nitriles. Theoretical calculations and the monitoring of the reaction using (1)H and (13)C NMR spectroscopy are in agreement with the proposed mechanism pathway.

Polar Hinges as Functionalized Conformational Constraints in (Bi)cyclic Peptides

“…Next, a more recent procedure for the synthesis of 2,4‐disubstituted 6‐substituted 1,3,5‐triazines by the same authors was attempted. It involved treatment of bromoacetonitrile with triflic anhydride or triflic acid in toluene at reflux . Surprisingly, in both cases the only isolated product was 2‐bromo‐4′‐methylacetophenone ( 7 ), resulting from electrophilic aromatic substitution of the solvent (Scheme B).…”

Recent Advances on the s‐Triazine Scaffold with Emphasis on Synthesis, Structure‐Activity and Pharmacological Aspects: A Concise Review

“…Sun et al in 2013, introduced the synthesis of pyrazolo‐1,3,5‐triazine hybrid ( P16 ) via reaction of ethoxycarbonyl thiocyanate/ethoxycarbonyl isothiocyanate with amines to form urea intermediate, which further reacted with sodium methoxide to form desired product P16 in quantitative yield (60–91 %) (Scheme 15). [22] Herrera et al in 2014, reported the novel one pot synthesis of s ‐triazine analogues P17 by controlled cross‐cyclotrimerization of nitriles in the presence of triflic anhydride at low temperatures (Scheme 16 ) [23] . This procedure was applied for the preparations of 1,3,5‐triazines having three different substituents in good yields (39–82 %).…”

Greener approach toward synthesis of biologically active s‐Triazine (TCT) derivatives: A recent update

“…These nitriles can be prepared from aldehydes (109) and alcohols (110) on their reaction with iodine in aqueous ammonia under microwave irradiation. The reaction time was reduced to 15–30 min, without using any base, most of the time used in classical heating methods 51 …”