Two-step syntheses of 3-methyl and 3-phenyl-1,2,4-benzotriazines

Khodja, Mohamed; Moulay, Saâd; Boutoumi, Hocine; Wilde, H.

doi:10.1002/hc.20200

Cited by 9 publications

(6 citation statements)

References 23 publications

(18 reference statements)

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“…23,31,32 Although the reaction allows for the formation of a wide range of 3-aryl 23 and 3trifluoromethyl-substituted 32 benzo [e] [1,2,4]triazines in moderate yields, the method suffers from demanding synthesis of amidrazones and use of HgO. 23 Another method for the preparation of the benzo [e][1,2,4]triazine ring relies on reductive cyclization of 2-nitrophenylhydrazones, 21,22 2-nitrophenylhydrazono esters, 33 and 2-nitrophenylhydrazides 34 (method D, Figure 2). This route allows for the formation of benzo [e] [1,2,4]triazine derivatives with H, Me, Et, CH 2 Ph, Ph, and CH 2 COOEt groups at C(3) position in low to moderate yields.…”

Section: ■ Introductionmentioning

confidence: 99%

“…In spite of such a broad application of benzo[ e ][1,2,4]triazine derivatives, there are surprisingly few investigations of their molecular and electronic structures. Thus, only five experimental solid-state structures have been reported to date, − and UV–vis spectroscopy has been limited to the parent , and a few members of 3-phenyl, 3-aryl, 3-amino, and 3-alkyl derivatives. There has been no systematic investigation of the effect of 3-substituent on the electronic properties of the benzo[ e ][1,2,4]triazine ring.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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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.

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Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2019

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“…Compound 5 and its expected bioreductive metabolites, 8 and 11 , were synthesized by literature routes involving either BF 3 -catalyzed cyclization of a formazan precursor55 or PtO 2 -catalyzed cyclization of the 2-nitrophenylhydrazone of pyruvic acid,56 followed by N -oxidation using m -chloroperbenzoic acid 54. We employed either NADPH:cytochrome P450 reductase or xanthine/xanthine oxidase enzyme systems for the one-electron reductive activation of 5 .…”

Section: Resultsmentioning

confidence: 99%

Initiation of DNA Strand Cleavage by 1,2,4-Benzotriazine 1,4-Dioxide Antitumor Agents: Mechanistic Insight from Studies of 3-Methyl-1,2,4-benzotriazine 1,4-Dioxide

et al. 2008

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The antitumor agent 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1) gains medicinal activity through its ability to selectively damage DNA in the hypoxic cells found inside solid tumors. This occurs via one-electron enzymatic reduction of TPZ to yield an oxygen-sensitive drug radical (2) that leads to oxidatively generated DNA damage under hypoxic conditions. Two possible mechanisms have been considered to account for oxidatively generated DNA damage by TPZ. First, homolysis of the N-OH bond in 2 may yield the well known DNA-damaging agent, hydroxyl radical. Alternatively, it has been suggested that elimination of water from 2 generates a benzotriazinyl radical (4) as the ultimate DNA-damaging species. In the studies described here, the TPZ analogue 3-methyl-1,2,4-benzotriazine 1,4-dioxide (5) was employed as a tool to probe the mechanism of DNA damage within this new class of antitumor drugs. Initially, it was demonstrated that 5 causes redoxactivated, hypoxia-selective oxidation of DNA and small organic substrates in a manner that is completely analogous to TPZ. This suggests that 5 and TPZ damage DNA by the same chemical mechanism. Importantly, the methyl substituent in 5 provides a means for assessing whether the putative benzotriazinyl intermediate 7 is generated following one-electron reduction. Two complementary isotopic labeling experiments provide evidence against the formation of the benzotriazinyl radical intermediate. Rather, a mechanism involving the release of hydroxyl radical from the activated drug radical intermediates can explain the DNA-cleaving properties of this class of antitumor drug candidates.The compound 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine, TPZ, 1, Scheme 1) is currently undergoing a variety of phase I, II, and III clinical trials for the treatment of human cancers. 1 TPZ gains medicinal activity from its ability to selectively damage DNA in the oxygen-poor (hypoxic) cells found inside solid tumors. [2][3][4][5][6][7][8] This DNA-damage process begins with intracellular enzymatic reduction of TPZ to yield the drug radical intermediate (2 , Scheme 1). [9][10][11][12] In normally-oxygenated cells, 2 undergoes relatively harmless oxidation back to the parent drug (Scheme 1), 9,10,13 while, under hypoxic conditions, the drug radical intermediate 2 leads to oxidatively generated DNA damage including hydroxylation of the nucleobases 22,23 and strand breaks initiated by the abstraction of hydrogen atoms from the sugar-phosphate backbone of DNA. [7][8][9][24][25][26][27][28] In the recent literature, two mechanisms have been considered to explain TPZ-mediated DNA damage. We have presented evidence [22][23][24]26,29 supporting a mechanism involving homolysis of the N-OH bond in the neutral drug radical (2) to yield the mono-N-oxide metabolite 3 and the well known DNA-damaging agent hydroxyl radical (Scheme 1, upper branch). 30 This *To whom correspondence should be addressed: gatesk@missouri.edu; phone: (573) FAX: (573) NIH-PA Author ManuscriptNIH-PA ...

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“…When the hydrazines (52) were treated with ethyl benzimidate (56) the hydrazono-ethers (57) were formed, and a similar hydrogenation led to the 3-phenylbenzotriazines (58) (Scheme 7). 49 Scheme 7. Synthesis of 6,7-disubstituted 3-methyl and 3-phenyl-1,2,4-benzotriazines (55) and (58).…”

Section: Scheme 5 Reductive Cyclization Of 2-nitrophenylhydrazone (44)mentioning

confidence: 99%

The synthesis of 1,2,4-benzotriazines

Ziarani¹,

Mostofi²,

Gholamzadeh³

et al. 2019

Arkivoc

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The 1,2,4-benzotriazine nucleus fused to a benzene ring is a prominent heterocyclic substructure present in numerous pharmacologically active compounds. To date, many 1,2,4-benzotriazine analogues possessing a wide spectrum of potent pharmacological activities are known. This review compiles information on the synthesis, chemical reactions, medicinal chemistry aspects and applications of 1,2,4-benzotriazines.

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Two-step syntheses of 3-methyl and 3-phenyl-1,2,4-benzotriazines

Abstract: 2,

Cited by 9 publications

References 23 publications

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

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

Initiation of DNA Strand Cleavage by 1,2,4-Benzotriazine 1,4-Dioxide Antitumor Agents: Mechanistic Insight from Studies of 3-Methyl-1,2,4-benzotriazine 1,4-Dioxide

The synthesis of 1,2,4-benzotriazines

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