3-Substituted Benzo[e][1,2,4]triazines: Synthesis and Electronic Effects of the C(3) Substituent

Abstract

A series of 19 structurally diverse C(3)substituted derivatives of benzo [e][1,2,4]triazine were synthesized from 3-chloro-(1c) and 3-iodobenzo[e][1,2,4]triazine (1d) obtained in three steps from 2-nitroaniline in 37−55% yields. Nucleophilic aromatic substitution and metal-catalyzed (Pd, Cu) reactions led to functional derivatives that include alkyl (C 5 H 11 ), (het)aryl (Ph, 2-thienyl, ferrocenyl), ArCC, amine (NHPh and morpholine), PO(OEt) 2 , sulfanyl (SBu-t), alkoxide (OEt, OMe), and CN. The synthesis of C(3)−CF 3 derivative 1g via the Ruppert reaction with 1d and its 1-oxide analogue 2d led to the substitution followed by formal addition of HCF 3 to the CN bond. Pd-catalyzed carbonylation reactions of 1d and 2d did not give the corresponding C(3)-carboxylic acids. Therefore, acid 1f was obtained through hydrolysis of the CN. The substituent effect on the electronic structure of the benzo[e][1,2,4]triazine ring was investigated by spectroscopic methods (UV−vis and NMR) augmented with density functional theory calculations. Results show significant effect of the C(3) substituent on the π−π*(1) transition energy and good correlation of the 1 H NMR chemical shift with the substituent constant σ p . Molecular and crystal structures of six derivatives were established with the single-crystal X-ray diffraction method, and the substituent impact on the molecular geometry was investigated.

Trifluoroacetimidoyl halides: a potent synthetic origin

“…A series of structurally different C(3)-substituted benzo [e][1,2,4]triazine derivatives were synthesized by Kaszynski and co-workers (Scheme 89). 106 Among these compounds, 3-(trifluoromethyl)-benzo [e][1,2,4]triazines were constructed by the Ruppert reaction of 3-iodobenzo [e][1,2,4]triazine with TMSCF 3 . An alternative synthetic pathway was the oxidative cyclization of amidrazone, which was obtained from the reaction of trifluoroacetimidoyl chlorides with 1,2-di( propan-2-ylidene) hydrazine and hydrazine hydrate.…”

C(3) Functional Derivatives of the Blatter Radical

“…Functionalization of the C(3) atom is, however, much less developed. Arguably, this is a particularly important position since it is the only functionalizable position with a sizable negative spin density in the benzo­[ e ]­[1,2,4]­triazinyl system, and the substituent is expected to have a significant impact on electronic properties of the radical. A literature search demonstrates that only a handful of substituents have been introduced into this position using mainly methods A and B, and they include aromatic (Ph, substituted Ph, − , 2-pyridinyl, and 2-thienyl , ), aliphatic (CH 3 , t -butyl, , and adamantyl), CF 3 , and NHAr (in method A′ after basic hydrolysis of NH­(CHO)­Ar) .…”

“…Here, we present the preparation of C(3)-substituted 1-phenyl-1,4-dihydrobenzo­[ e ]­[1,2,4]­triazin-4-yl radicals 1 by addition of PhLi to the readily available benzo­[ e ]­[1,2,4]­triazines 2 followed by oxidation of the resulting anions 3 (method C, Figure ). The scope of the substituents X is investigated, stability of radicals 1 is assessed, and the impact of the C(3) substituent X on spectroscopic and electrochemical properties in series 1 is analyzed.…”

Cobalt-Catalyzed, Directed Intermolecular C–H Bond Functionalization for Multiheteroatom Heterocycle Synthesis: The Case of Benzotriazine

“…11 The initial screening of a metal catalyst in trifluoroethanol (TFE), with 1-adamantanecarboxylic acid (AdCOOH, 20 mol %) and KOAc (30 mol %) as the additives, indicates that [RhCp*Cl 2 ] 2 (2 mol %) and [Ru(pcymene)Cl 2 ] 2 (5 mol %) fail to effect any transformation after 20 h reaction at 120 °C in N 2 , whereas [CoCp*(CO)I 2 ] (10 mol %) enables the formation of 3-phenyl-1,2,4-benzotriazine (3aa) in 5% yield. 16 The change of AdCOOH to AgOAc (20 mol %) increases the yield to 28%. The further addition of AgSbF 6 (20 mol %) leads to a 35% yield.…”

“…We commence our study by investigating the coupling reaction between 1-methyl-1-phenylhydrazine ( 1a ) and 3-phenyl-1,2,4-oxadiazol-5­(4 H )-one ( 2a ), drawn upon previously used metal/halide abstraction reagent/base/acid combinations . The initial screening of a metal catalyst in trifluoroethanol (TFE), with 1-adamantanecarboxylic acid (AdCOOH, 20 mol %) and KOAc (30 mol %) as the additives, indicates that [RhCp*Cl 2 ] 2 (2 mol %) and [Ru­( p -cymene)­Cl 2 ] 2 (5 mol %) fail to effect any transformation after 20 h reaction at 120 °C in N 2 , whereas [CoCp*­(CO)­I 2 ] (10 mol %) enables the formation of 3-phenyl-1,2,4-benzotriazine ( 3aa ) in 5% yield . The change of AdCOOH to AgOAc (20 mol %) increases the yield to 28%.…”