Synthesis of 1,3,5-Triazepines and Benzo[f][1,3,5]triazepines and Their Biological Activity: Recent Advances and New Approaches

This review article discusses the recent progress in synthesizing seven-membered ring 1,3,5-triazepine and benzo[f][1,3,5]triazepine derivatives. These derivatives can be either unsaturated, saturated, fused, or separated. This review covers strategies and procedures developed over the past two decades, including cyclo-condensation, cyclization, methylation, chlorination, alkylation, addition, cross-coupling, ring expansions, and ring-closing metathesis. This review discusses the synthesis of 1,3,5-triazepine derivatives using nucleophilic or electrophilic substitution reactions with various reagents such as o-phenylenediamine, 2-aminobenzamide, isothiocyanates, pyrazoles, thiazoles, oxadiazoles, oxadiazepines, and hydrazonoyl chloride. This article systematically presents new approaches and techniques for preparing these compounds. It also highlights the biological importance of benzo[f][1,3,5]triazepine derivatives, which have been used as drugs for treating nervous system diseases. This review aims to provide researchers with the necessary information to create and develop new derivatives of these compounds as quickly as possible.

The benzotriazepine class is of great interest due to its ability to affect the central nervous system and its use as psychoactive agents.For example, compounds (I) and (II) are effective neuroleptic agents used to treat psychotic disorders such as schizophrenia [14].Compound (III) exhibits moderate antisecretory activity in rats [15], while compound (IV) acts as a CCK2 receptor antagonist with better selectivity than CCK1 receptors [17].Compound (V) has been found to have analgesic activity in white mongrel mice [19].Finally, compound (VI) has shown antipsychotic activity comparable to that of the reference drug clozapine [20], as demonstrated in (Figure 1).
Molecules 2024, 29, x FOR PEER REVIEW 2 of 3 Compound (V) has been found to have analgesic activity in white mongrel mice [19].F nally, compound (VI) has shown antipsychotic activity comparable to that of the referenc drug clozapine [20], as demonstrated in (Figure 1).It has recently been discovered that seven-membered ring heterocycles have significan biological activities [24][25][26], especially considering the increasing cancer problem worldwid Chemotherapy is often not completely effective due to its toxicity to other tissues.As a re sult, scientific researchers have turned their attention to developing various pharmaceutica drugs.Benzodiazepine derivatives are widely used in many pharmaceutical drugs, includ ing alprazolam, bromazepam, clorazepate, and diazepam (valium).
Cancer has become a widespread disease among humans in recent years.As a resul many scientists have been working hard to find a cure for this disease.They have been pre paring numerous heterocyclic compounds and studying their effects and toxicity on cance cells.Among these compounds are the 1,3,5-triazepine and 1,2,4-triazolo [3,4-b][1,3,5]tr azepine derivatives that have been found to be effective as anticancer agents [40].You ca find additional details in (Figure 3), which displays the reagents as follows: 0.015 mol N,N bis(p-chlorobenzyl) ethylenediamine and 0.015 mol Et carboethoxy carbamate were re fluxed in xylene for 5 h to give a triazepine-dione derivative VII (R 1 = p-chlorobenzyl, R It has recently been discovered that seven-membered ring heterocycles have significant biological activities [24][25][26], especially considering the increasing cancer problem worldwide.Chemotherapy is often not completely effective due to its toxicity to other tissues.As a result, scientific researchers have turned their attention to developing various pharmaceutical drugs.Benzodiazepine derivatives are widely used in many pharmaceutical drugs, including alprazolam, bromazepam, clorazepate, and diazepam (valium).
Cancer has become a widespread disease among humans in recent years.As a result, many scientists have been working hard to find a cure for this disease.They have been preparing numerous heterocyclic compounds and studying their effects and toxicity on cancer cells.Among these compounds are the 1,3,5-triazepine and 1,2,4triazolo [3,4-b][1,3,5]triazepine derivatives that have been found to be effective as anticancer agents [40].You can find additional details in (Figure 3), which displays the reagents as follows: 0.015 mol N,N ′ -bis(p-chlorobenzyl) ethylenediamine and 0.015 mol Et carboethoxy carbamate were refluxed in xylene for 5 h to give a triazepine-dione derivative VII (R 1 = p-chlorobenzyl, R 2 = R 4 = O, and R 3 = H) which was refluxed with Lawesson's reagent in toluene to give triazepinethione VIII (R 1 = p-chlorobenzyl, R 2 = S, R 3 = H, and R 4 = O) (V).[ 3 H]-vinblastine at 10 n M showed a 14.0-fold increase in the accumula-tion of adriamycin-resistant P388/ADR cells in the presence of 50 µ M V. Pharmaceutical formulations, e.g., tablets containing V, were prepared as detailed in [40] (Figure 3).
Molecules 2024, 29, x FOR PEER REVIEW 3 of 34 = R 4 = O, and R 3 = H) which was refluxed with Lawesson's reagent in toluene to give triazepinethione VIII (R 1 = p-chlorobenzyl, R 2 = S, R 3 = H, and R 4 = O) (V).[ 3 H]-vinblastine at 10 n M showed a 14.0-fold increase in the accumulation of adriamycin-resistant P388/ADR cells in the presence of 50 µ M V. Pharmaceutical formulations, e.g., tablets containing V, were prepared as detailed in [40] (Figure 3).= R 4 = O, and R 3 = H) which was refluxed with Lawesson's reagent in toluene to give triazepinethione VIII (R 1 = p-chlorobenzyl, R 2 = S, R 3 = H, and R 4 = O) (V).[ 3 H]-vinblastine at 10 n M showed a 14.0-fold increase in the accumulation of adriamycin-resistant P388/ADR cells in the presence of 50 µ M V. Pharmaceutical formulations, e.g., tablets containing V, were prepared as detailed in [40] (Figure 3).In this review article, different safe and environmentally friendly methods for preparing 1,3,5-triazepine derivatives have been discussed.These methods are cost-effective, time-saving, and have potential applications in both medical and industrial fields.By adopt-ing these methods, we can achieve sustainable development in all aspects of society.Thus, different methods for synthesizing fused triazepines are described in the literature [41,42].
We have shown and described a four-component reaction using oxalyl chloride ( 27), aniline derivatives, and two molecules of ammonium thiocyanate in acetone under ultrasound irradiation to synthesize 3-aryl-2,4-dithioxo-1,3,5-triazepane-6,7-diones (51).Several triazepanes were synthesized by reacting oxalyl chloride (27) with different aniline derivatives and two equivalents of NH 4 SCN.The reaction was conducted under two different conditions: (i) reflux in acetone and (ii) ultrasound irradiation at 60 • C in water.The initial step of the reaction was carried out at 0-5 • C due to the fast release of chlorine atoms from oxalyl chloride.Oxalyl diisothiocyanate (50) was created by mixing two equivalents of NH 4 SCN with one equivalent of oxalyl chloride (27).The color of the mixture turned red during the reaction.Afterwards, (50) reacted with aniline derivatives to form intermediates (50 ′ ).These intermediates then underwent intramolecular cyclization, resulting in the production of 1,3,5-triazepane derivatives (51a-g).The reaction also changed color from red to brown [69].Based on the MTT analysis and cellular images, the cyclic urea compounds (51a-g) showed higher toxicity compared to the control sample.This is because the selected cells used in this study are MKN-45 gastric adenocarcinoma cells.As a result, the synthesized compounds (51a-g) are more effective in inducing cancer cell toxicity than the Paclitaxel drug [69], as shown in Scheme 13.
We have shown and described a four-component reaction using oxalyl chloride ( 27), aniline derivatives, and two molecules of ammonium thiocyanate in acetone under ultrasound irradiation to synthesize 3-aryl-2,4-dithioxo-1,3,5-triazepane-6,7-diones (51).Several triazepanes were synthesized by reacting oxalyl chloride (27) with different aniline derivatives and two equivalents of NH4SCN.The reaction was conducted under two different conditions: (i) reflux in acetone and (ii) ultrasound irradiation at 60 °C in water.The initial step of the reaction was carried out at 0-5 °C due to the fast release of chlorine atoms from oxalyl chloride.Oxalyl diisothiocyanate (50) was created by mixing two equivalents of NH4SCN with one equivalent of oxalyl chloride (27).The color of the mixture turned red during the reaction.Afterwards, (50) reacted with aniline derivatives to form intermediates (50′).These intermediates then underwent intramolecular cyclization, resulting in the production of 1,3,5-triazepane derivatives (51a-51g).The reaction also changed color from red to brown [69].Based on the MTT analysis and cellular images, the cyclic urea compounds (51a-51g) showed higher toxicity compared to the control sample.This is because the selected cells used in this study are MKN-45 gastric adenocarcinoma cells.As a result, the synthesized compounds (51a-51g) are more effective in inducing cancer cell toxicity than the Paclitaxel drug [69], as shown in Scheme 13.Scheme 12.The reaction of substituted anilines, oxalyl chloride, and two molecules of potassium seleno-cyanate in acetone at room temperature give 3-substituted-phenyl-2,4-diselenoxo-1,3,5triazepane-6,7-dione.The reaction of acyl isoselenocyanates, produced from acyl chlorides and KSeCN, with benzene-1,2-diamine in acetone at room temperature produced 1,3,5-triazepineselone derivatives in moderate to good yields.A possible explanation for how 1,3,5-triazepineselone derivatives (54) are formed can be given as follows.It involves the acyl isoselenocyanate (53), which is created from (52) and KSeCN.This compound then reacts with o-phenylenediamine, resulting in the formation of an intermediate product (53′).Finally, this intermediate is transformed into the desired product, 4-phenyl-1,3-dihydro-2H-benzo[f] [1,3,5]triazepine-2-selenone (54) derivatives, through cyclization and elimination of H2O [70].In this study, benzene-1,2-diamine is used to react with acyl isoselenocyanate intermediates, which are generated from acyl chlorides and KSeCN, resulting in the formation of 1,3,5-triazepineselone derivatives.This methodology offers great potential diversity and available starting materials [70].This process is illustrated in Scheme 14.The reaction of acyl isoselenocyanates, produced from acyl chlorides and KSeCN, with benzene-1,2-diamine in acetone at room temperature produced 1,3,5-triazepineselone derivatives in moderate to good yields.A possible explanation for how 1,3,5-triazepineselone derivatives (54) are formed can be given as follows.It involves the acyl isoselenocyanate (53), which is created from (52) and KSeCN.This compound then reacts with o-phenylenediamine, resulting in the formation of an intermediate product (53 ′ ).Finally, this intermediate is transformed into the desired product, 4-phenyl-1,3-dihydro-2H-benzo[f ] [1,3,5]triazepine-2-selenone (54) derivatives, through cyclization and elimination of H 2 O [70].In this study, benzene-1,2-diamine is used to react with acyl isoselenocyanate intermediates, which are generated from acyl chlorides and KSeCN, resulting in the formation of 1,3,5-triazepineselone derivatives.This methodology offers great potential diversity and available starting materials [70].This process is illustrated in Scheme 14.

From Pyrazole Derivatives
Using microwave techniques to prepare heterocyclic compounds has been previously reported.Microwave irradiation is considered one of the green chemistry techniques due to improved yield, a safer environment, and reduced reaction times.Thus, when 5-amino-3-( 4

Summary of Biological Activity
This article provides a comprehensive review of more than 140 compounds of 1,3,5triazepine and benzo[f] [1,3,5]triazepine derivatives, including information on their preparation, reactions, and biological activity.This review is based on over 85 scientific references published in international journals.To make it easier to refer to, the biological activity of some compounds is presented in Tables 1 and 2.

Summary of Biological Activity
This article provides a comprehensive review of more than 140 compounds of 1,3,5triazepine and benzo[f ] [1,3,5]triazepine derivatives, including information on their preparation, reactions, and biological activity.This review is based on over 85 scientific references published in international journals.To make it easier to refer to, the biological activity of some compounds is presented in Tables 1 and 2.

Conclusions
This review discusses the recent strategies in drug design that utilize seven-membered rings with three nitrogen atoms.By analyzing a few literature examples, it has been found that derivatives of seven-membered rings such as 1,3,5-triazepine and benzo[f ] [1,3,5] triazepine can act as bioisosteres to mono ortho-substituted biaryl systems.These rings offer new structures and vectors to explore in drug design.This review presents a comprehensive survey of the synthesis procedure, chemical reactions, and biological activities of 1,3,5-triazepine and benzo[f ] [1,3,5]triazepine derivatives.We have discussed several methods for the synthesis of these compounds, including 2-phenyl-benzo[f ] [1,3,5] We have referenced over (85) sources to provide a comprehensive overview.In the final part of this study, derivatives of quinazoline, pyrazole, thiazole, oxadiazole, triazolopyrimidine,

Figure 1 .
Figure 1.Derivatives of triazepine that are biologically active.

Figure 1 .
Figure 1.Derivatives of triazepine that are biologically active.