Synthetic Utility of N -Acylbenzotriazoles

Abstract


Introduction
N-Acylbenzotriazoles are versatile neutral acylating agents; they have been extensively used in the preparation of diverse pharmacologically important scaffolds.Because of the high stability of benzotriazole-containing intermediates, the benzotriazole methodology has been proven to be an effective method to prepare alternatives of unstable organic intermediates and hence attracted much interest in organic synthesis for a plethora of organic transformations.Benzotriazole, commonly used as a good leaving group, has been extensively used as a novel synthetic auxiliary in various organic reactions.Particularly, N-acylbenzotriazoles are more stable than the corresponding acid chlorides, and they can be used as acylating agents in acylation reactions without diacylation or other side reactions, unlike traditional methods.2][3] This review summarizes the emerging methods for the preparation of N-acylbenzotriazole derivatives, their pharmacophore study, and their utilities in the field of organic chemistry as a starting material, ligand, and intermediates involved in the important organic reactions as well functional group transformations.

Synthesis of N-Acylbenzotriazoles
N-Acylbenzotriazole motifs are, in general, prepared from acyl chlorides, aldehydes, and carboxylic acid as the starting chemicals via numerous synthetic pathways.

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Therefore, in this section, a comprehensive summary of the methods for synthesizing a diverse range of N-acylbenzotriazoles is presented (Figure 1).
In 1954, Gaylord tried to reduce 1-(hydroxymethyl)benzotriazole 2 to form 1-methylbenzotriazole in the presence of acyl chloride 1 and pyridine in dioxane.However, the reaction afforded N-acylbenzotriazoles 3, for example N-benzoylbenzotriazole as the sole product.This became the first step in the history of N-acylbenzotriazoles (Scheme 1). 4

Scheme 1 Synthesis of N-benzoylbenzotriazole
In 1980, Gasparini et al. successfully synthesized various derivatives of N-acylbenzotriazoles through the reaction of N-(trimethylsilyl)benzotriazole 4 with acid chlorides 1, thus selectively producing 1-substituted acylbenzotriazoles 3 in good yields (Scheme 2). 5 Scheme 2 Synthesis of N-acylbenzotriazoles by the reaction of N-(trimethylsilyl)benzotriazole with acid chlorides (R = alkyl, aryl, (hetero)aryl) The efforts of the Katritzky group over 11 years (1992-2003) led to substantial progress in the development of methods for the synthesis of N-acylbenzotriazoles.In 1992, the Katritzky group reported two methods for the synthesis of a diverse range of N-acylbenzotriazoles.In the first method, acyl chloride 1 and 1H-benzotriazole (BtH) were fused together under solvent-free conditions (Scheme 3a); in the second method, carboxylic acid 5 was refluxed with N-(methylsulfonyl)benzotriazole 6 in basic medium to afford the final products 3 (Scheme 3b). 6In 2002, they developed a notable method in an extension of this methodology when 1-(methylsulfonyl)benzotriazole was treated N-Boc--amino acids for the synthesis of stable N-(Boc--aminoacyl)benzotriazoles (see Scheme 14). 7 Scheme 3 Synthesis of N-acylbenzotriazoles using carboxylic acid chloride or 1-(1-methylsulfonyl)benzotriazole In 2003, the Katritzky group reported an improved and modern one-pot methodology for the synthesis of N-acylbenzotriazoles.The method comprised of reaction of carboxylic acids 5 with 1.0 equiv thionyl chloride (7) in the presence of 3.5 to 4 equiv benzotriazole in dichloromethane

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at room temperature for 2 h.This method is the most efficient, and economical, and involves an easy workup process for converting a wide range of carboxylic acids into N-acylbenzotriazoles 3 in excellent yields (Scheme 4). 8

Scheme 4 Conversion of carboxylic acids into N-acylbenzotriazoles with thionyl chloride
In 2014, Phakhodee and co-workers introduced a new method to obtain N-acylbenzotriazoles 3 by utilizing I 2 /PPh 3 and benzotriazole in the presence of triethylamine (Scheme 5).In this reaction, the sequence of addition of triethylamine and benzotriazole plays a key role to achieve good yields.When first triethylamine and then benzotriazole were added to a round-bottom flask containing carboxylic acid 5 and I 2 /PPh 3 , the acid anhydride was the sole product; whereas, addition of benzotriazole followed by triethylamine, afforded N-acylbenzotriazoles in good-to-excellent yields.9a In 2018, the Tiwari group extended this methodology and applied it to carbohydrate chemistry for the preparation of glycoconjugated N-acylbenzotriazoles and found the reagent to be equally effective in producing glycoconjugated N-acylbenzotriazoles in good-to-excellent yields with sugar acids without affecting the sugar stereochemistry.9b In 2015, Phakhodee and co-workers reported two eloquent N-acylbenzotriazole syntheses that are advantageous from economic and environmental perspectives using 2,4,6-trichloro-1,3,5-triazine (8).In the first report, 0.33 equiv 2,4,6-trichloro-1,3,5-triazine was reacted with 1.0 equiv Et 3 N at 0 °C followed by the addition of 1.0 equiv carboxylic acid and 1.0 equiv benzotriazole to obtain N-acylbenzotriazoles 3 as the final product (Scheme 6a).Extraction of the product from the crude reaction mixture using the separation technique with saturated NaHCO 3 , 1 M HCl, and water ascertained the process to be economic and environment friendly. 10Whereas, in another investigation, N-acylbenzotriazoles 3 were synthesized by the reaction of a carboxylic acid with 2,4,6-trichloro-1,3,5-triazine (8) in the presence of NaHCO 3 and benzotriazole in aqueous medium (Scheme 6b). 11n 2016, Abo-Dya et al. utilized tosyl chloride/DMAP to promote the synthesis of a diverse range of N-acylbenzotriazole derivatives 3. The reaction of carboxylic acid 5 with tosyl chloride afforded the corresponding intermediate 5′, which was subsequently attacked by 1H-benzotriazole to furnish the respective N-acylbenzotriazole derivatives 3 (Scheme 7).This method was also applied to synthesize Vorinostat (SAHA), a well-known differentiating agent for prostate and breast cancers. 12Scheme 7 Conversion of carboxylic acids into N-acylbenzotriazoles utilizing tosyl chloride/DMAP The Tiwari group developed three novel methods for the synthesis of diverse range of N-acylbenzotriazoles besides extending two previously reported procedures for synthesizing glycoconjugated N-acylbenzotriazole derivatives. 13he furanose-and pyranose-based glycoconjugated N-acylbenzotriazoles were used as coupling reagents for the synthesis of novel sugar amides by exploring 2003 method of the Katritzky group. 8To achieve the target N-(1,2;3,4-di-O-
In 2019, Laconde et al. demonstrated propylphosphonic anhydride solution T3P as an efficient reagent for the onepot synthesis of Bt amino acid derivatives starting from Nprotected amino acids (Scheme 12).This method is applicable to substrates with various side-chain protecting groups including highly sensitive trityl group and can be used to

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avoid tedious purification and toxic reagents.In addition, T3P was used for the synthesis of biotin and N-Fmoc polyethylene glycol derivatives. 18

Scheme 12 Conversion of carboxylic acids into N-acylbenzotriazoles utilizing T3P
N-Acylbenzotriazoles are mainly synthesized from acyl derivatives, as this method is advantageous in producing a large number of N-acylbenzotriazoles.However, there are a few examples of critical exceptions, where acyl derivatives were not used as the starting materials.In 2001, Wang and Chen first accomplished the synthesis of N-acylbenzotriazoles through the Pd(OAc) 2 -catalyzed carbonylation of several diaryliodonium salts (Scheme 13). 19The reaction of diaryliodonium salts in the presence of BtH under one atmospheric pressure of carbon monoxide produced averageto-good yields of N-acylbenzotriazoles as the final product.In a simple yet classic reaction methodology developed by the Katritzky group, refluxing aldehydes 16 with N-chlorobenzotriazole 17 in the presence of AIBN in benzene yielded N-acylbenzotriazoles (in up to ~80% yield) as the major product (Scheme 13). 20

Scheme 13 Synthesis of N-acylbenzotriazoles without using acyl derivatives
Acid chlorides of N-protected amino acids have been known for a long time. 21Most of them cannot be stored under normal conditions because of their highly sensitive nature and reactivity; 22 they undergo racemization and decomposition on storage.The Katritzky group developed innovative methodology for the synthesis of stable N-(Boc-aminoacyl)benzotriazoles 19 from Boc--amino acids 18 and BtSO 2 Me as the benzotriazole source (Scheme 14). 7N-(Boc--aminoacyl)benzotriazoles were found to be stable at 20 °C and no detectable amount of change was observed for six months.Also, the application of N-(Boc--aminoacyl)benzotriazoles was considered for the synthesis of chiral -(N-protected amino acid) amides without racemization. 7y utilizing the methods discussed, the synthesis of a wide variety of desired N-acylbenzotriazoles can be achieved.Hence, we summarized all the methodology discussed and their selective starting chemical components in Figure 1 to show all the possibilities of N-acyl-and N-aroylbenzotriazole synthesis.

N-Acylation Using N-Acylbenzotriazoles
The Katritzky group reported a novel protocol for the synthesis of N-aroylindoles 20 and 21 by the application of N-aroylbenzotriazoles.The developed methodology was applied to the reaction of N-aroylbenzotriazoles with indole (22) and also with substituted indoles 23 in the presence of NaH to afford the desired N-aroylindole in moderate-togood yields (Scheme 15). 23heme 15 Synthesis of N-aroylindoles using N-acylbenzotriazoles N-Acylbenzotriazoles are acylating agents that react with ammonia, primary amines, and secondary amines to produce high yields of the corresponding primary, secondary, and tertiary amides, respectively, by the elimination of BtH.The procedure predominantly provides a way for solidphase synthesis. 24The synthetic pathway for amides 25 from amines 24 and N-acylbenzotriazoles is depicted in Scheme 16.

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and enantiomeric excess of natural and synthetic amines and alcohols by NMR spectroscopy. 25,26MTPA chloride enantiomers used as chiral derivatizing agents are commercially available, but these are expensive, moisture sensitive, and stored at a low temperature.To overcome these limitations, the Katritzky group established a protocol for the synthesis of enantiomeric and racemic form of 1-benzotriazol-1-yl-3,3,3-trifluoro-2-methoxy-2-phenylpropan-1-one (Mosher-Bt reagent) 27 in (R)-27, and (S)-27, rac-27 forms by refluxing the MTPA 26 with BtH and thionyl chloride in acetonitrile/water (2:1) for 50 h.The prepared Mosher-Bt reagent 27 was reacted with various chiral amino acids 28 and peptides to obtain the corresponding amides 29 to prove the efficacy of the developed Mosher-Bt reagent over the sensitive MTPA chloride (Scheme 17). 27n 1997, the Katritzky group reported a versatile method for the synthesis of various substituted symmetrical and unsymmetrical urea derivatives 32 via the N-acylation of 1,1′-carbonylbisbenzotriazole 30 with primary and secondary amines.BtH was obtained as a byproduct, which can be easily removed from reaction product during workup.When secondary amines were used as the first component in the reaction, benzotriazole-1-carboxamides 31 were iso-lated as reaction intermediates.This method provides a useful and benign route for the synthesis of numerous urea derivatives that could not be successfully afforded by other protocols (Scheme 18a). 28In 2003, they developed a proficient route for the synthesis of mono-and disubstituted ureas 35 by the reaction of benzotriazole-1-carboxamide 34 with primary and secondary aliphatic amines under mild reaction conditions.Benzotriazole-1-carboxamide 34 was obtained by the reaction of N-cyanobenzotriazole 33 with 30% H 2 O 2 in the presence of n-Bu 4 N + HSO 4 -in dichloromethane at 25 °C (Scheme 18b). 29midines are a significant class of motifs with biological importance, and also, they are widely used in the synthesis of heterocycles.A microwave-assisted versatile route was developed for the synthesis of amidines by the reaction of various substituted primary and secondary amines with Nimidoylbenzotriazoles (Scheme 19).The synthesis of N-imidoylbenzotriazoles 37 was achieved in two steps.In the first step, amides 36 were synthesized from N-acylbenzotriazoles 3 under microwave (MW) conditions.In the second step, N-imidoylbenzotriazoles 37 were obtained in good yields by the one-pot reaction of amides 36, thionyl chloride, and benzotriazole.The N-imidoylbenzotriazoles reacted with various substituted primary and secondary amines to furnish the respective amidines 38. 30-Aminoacyl)amino-substituted heterocycles are an important class of scaffolds with substantial biological properties.A new type of derivative of N-substituted amide was synthesized from N-(protected-aminoacyl)benzotriazoles in 40-98% yields when the reaction was carried out under microwave irradiation conditions for 30 min.This method was also efficiently utilized for the synthesis of Cterminal N-protected dipeptidoyl amides in moderate-togood yields.The N-protected dipeptidoyl amides 41 were synthesized from the corresponding N-protected peptidoylbenzotriazoles 39 under microwave irradiation conditions.Compound 41a was obtained in 60% yield when the reac-  Scheme 19 Microwave-assisted synthesis of amidines from N-imidoylbenzotriazoles M. S. Yadav et al.

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tion of Cbz-L-Met-L-Trp-Bt was carried out with 2-aminothiazole 40a, and 41b was obtained by the coupling of Cbz-L-Phe-L-Ala-Bt with 2-amino-6-methoxybenzothiazole 40b in anhydrous DMF (Scheme 20). 31heme 20 Microwave-assisted synthesis of N-protected dipeptidoyl amides from N-protected peptidoylbenzotriazoles N-Acylation was also utilized for the synthesis of dipeptides and tripeptides from N-(Cbz-aminoacyl)benzotriazoles.The corresponding N-(Cbz-aminoacyl)benzotriazoles were obtained from alanine, phenylalanine, and valine.Synthesis of tripeptide 44 was achieved in two different ways: first by the reaction of N-(Cbz-aminoacyl)benzotriazoles 42 with free dipeptides 43 through stepwise coupling and second by the reaction of N-(Cbz-aminopeptidoyl)benzotriazoles 46 obtained from acid precursors 45.The reaction of 46 with free amino acids 47 through fragment coupling afforded tripeptides 44 (Scheme 21). 32ptide bond formation through the activation of carboxylic acid functional group of N-protected -amino acids is very important and has attracted much attention recently.Therefore, various scientists have contributed towards this endeavor of peptide bond construction.In this regard, the Katritzky group demonstrated a convenient protocol for the synthesis of dipeptides 49 from the corresponding crystalline and chirally stable N-(Cbz-and Fmoc--aminoacyl)benzotriazole-activated derivatives 42 and 48 of Tyr, Trp, Cys, Met, and Gln amino acids.These benzotriazole-activated derivatives of amino acids undergo peptide coupling in aqueous acetonitrile with unprotected L-Ala-OH and L-Phe-OH to furnish the chiral dipeptides in 70-98% yield.The NMR and HPLC studies showed no racemization in the process (Scheme 22). 33he Katritzky group explored the utility of N-acylbenzotriazoles for the efficient conversion of carboxylic acids into N-methoxy-N-methylamides 52 (Weinreb amides).Weinreb amides 52 were synthesized directly from N-acylbenzotriazoles by the reaction with N,O-dimethylhydroxylamine hydrochloride 51 in THF. 34They further investigated the scope of N-acylbenzotriazoles for the synthesis of various O-alkyl-, N-alkyl-, and O,N-dialkylhydroxamic acids 53 by using an appropriate hydroxylamine hydrochloride under similar reaction conditions (Scheme 23). 35he reactivity of N-acylbenzotriazoles was further utilized by the Katritzky group for the N-acylation of sulfonamides to synthesize biologically active N-acylsulfonamides 54.The reaction was carried out first by treating

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various sulfonamides with NaH in THF for 1.5 h to produce the sodium salt of the sulfonamides, which then reacted with diverse N-acylbenzotriazoles in THF under reflux conditions followed by acidification with 2 N HCl solution to produce the desired N-acylsulfonamides 54 in 76-98% yields (Scheme 24). 36

Scheme 24 Synthesis of various biologically active N-acylsulfonamides from N-acylbenzotriazoles
The Katritzky group developed a straightforward synthetic approach towards the preparation of taurine-containing water-soluble peptidomimetics, which are very attractive scaffolds for the application in drug delivery systems. 37A number of taurine-containing peptides were efficiently synthesized through the acylation of N-terminal taurine using benzotriazole methodology.Synthesis of taurine-containing dipeptides 57 was accomplished by utilizing taurine (55) and benzotriazoles 56 as the starting materials in the presence of DIPEA as the base in acetonitrile solvent.A few drops of water were also added to dissolve taurine.The reaction was completed within 1-2 h to afford the desired products 57 in 76-90% yields.Similarly, the preparation of taurine-containing tri-and tetrapeptides 59 was achieved in 73-93% yields from various peptidoyl benzotriazoles 58 under similar reaction conditions (Scheme 25).The group also synthesized various taurine sulfonopeptides and taurine N-and O-conjugates using similar reaction conditions from the coupling of N-Cbz-taurine sulfonyl benzotriazole and several amino esters, dipeptide esters, and N-and O-nucleophilic compounds, respectively.
In another study, the Katritzky group established a protocol for the exclusive and diastereoselective synthesis of -N-glycoamino acids. 38The group utilized easily available N-(Cbz-or Fmoc--aminoacyl)benzotriazoles 61 for the acylation of tetra-O-pivaloyl--D-galactopyranosylamine (60)  under microwave irradiation conditions to afford the desired -N-linked glycoamino acids 62 in excellent yields.This stereoselective glycosylation reaction was carried out in anhydrous DCM solvent in the presence of DMAP as the base at 100-W microwave irradiation for 75 min to furnish the desired glycoamino acids 62 (Scheme 26).The group also accomplished the regiospecific synthesis of -N-glycodipeptides from N-Cbz-protected peptidoyl benzotriazoles under similar reaction conditions in 3.5 h in good-tohigh yields. 1 D and 2 D NMR techniques were used to reveal the regiospecific -N-linkage.
The Katritzky group further used a chromene-based Nacylbenzotriazole 63 for the preparation of 2H-chromenebased conjugates 66 and 67 of natural amino acids 64 and N-acyl-1,-amino acids 65, respectively, at 20 °C in aqueous media (Scheme 27). 39The group also synthesized an example of 2H-chromene-based conjugate of dipeptide.They also studied the variation in the gelation properties of the sodium salts of the corresponding chromene-2H natural and -amino acid conjugates in DMF and DMSO with different chain lengths.

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Pattarawarapan and co-workers developed a rapid, simple, and one-pot methodology for the synthesis of substituted 3-arylcoumarins 70 under ultrasound assistance.Their synthetic strategy involved a one-pot acylation/cyclization reaction between N-acylbenzotriazoles 68 and 2hydroxybenzaldehydes 69 in the presence of triethylamine under neat conditions (Scheme 28). 40

Scheme 28 Ultrasound-assisted synthesis of substituted 3-arylcoumarins using N-acylbenzotriazoles
The Katritzky group also explored the chemistry of Nacylbenzotriazoles for the synthesis of amino acid conjugates of quinolone antibiotics, such as oxolinic acid 72 and nalidixic acid 74, through the coupling of their respective benzotriazole-activated derivatives 71 and 73 with free amino acids under basic conditions (Scheme 29). 41The cinoxacin-and flumequine-amino acid conjugates were also synthesized with their respective benzotriazole-activated derivatives.The coupling reaction was carried out in the presence of Et 3 N base for 3 h in aqueous acetonitrile.They also prepared dipeptide conjugates of the corresponding quinolones by coupling of the dipeptide Gly-Gly with benzotriazole derivatives of quinolone antibiotics.
Wang and co-workers proposed a synthetic pathway for the preparation of 3-benzotriazolylpropanamides 77 and cinnamides 76 from aromatic and aliphatic amines, respectively.Their work showed that aromatic amines react with N-cinnamoylbenzotriazoles 75 to give 3-benzotriazolylpro-Scheme 26 Diastereoselective synthesis of -N-glycoamino acids and -N-glycodipeptides using benzotriazole methodology

Scheme 30 N-Cinnamoylbenzotriazole-mediated synthesis of 3-benzotriazolylpropanamides and cinnamides
Simple synthesis of substituted 1,3,4,5-tetrahydro-1,5benzodiazepine-2-ones 79 was also carried out via further acylation of the 1,4-addition product obtained from the reaction of o-phenylenediamine (78) with N-cinnamoylbenzotriazoles 75 (Scheme 31). 42heme 31 N-Cinnamoylbenzotriazole-mediated synthesis of 1,3,4,5tetrahydro-1,5-benzodiazepin-2-ones Wang and co-workers extended their previous work towards the facile synthesis of 2,3,4,5-tetrahydro-1,5-benzothiazepin-4-ones 82, analogous to 1,3,4,5-tetrahydro-1,5benzodiazepine-2-ones, in good-to-high yields.The desired product was obtained from the reaction of ,-unsaturated 1-acylbenzotriazoles 80 with 2-aminobenzothiol (81) under similar reaction conditions (Scheme 32). 43,2,4-Oxadiazole rings are a crucial part of various biologically active synthetic heterocyclic compounds, and they are useful precursors in drug discovery processes.They are potential drug candidates in the form of hydrolysis-resisting bioisosteric replacements for ester or amide functionalities. 44The Katritzky group developed a convenient method for the synthesis of these biologically relevant 1,2,4-oxadiazoles 85 derived from chiral -amino acids using N-protected N-(-aminoacyl)benzotriazoles 83 (Scheme 33a). 45-Protected N-(-aminoacyl)benzotriazoles 83 reacted with p-tolyl-, 4-pyridinyl-, and benzylamidoximes in refluxing ethanol in the presence of catalytic Et 3 N to afford good yields of 1,2,4-oxadiazoles 85; the intermediate O-acylated N-protected amidoxime was instantly produced from the reaction of 83 with various amidoximes 84 after the addition of Et 3 N in ethanol at room temperature, followed by cyclization within 5 min under reflux conditions to give 1,2,4-oxadiazoles 85 in good yields.The NMR and HPLC analysis showed that the chirality preserved in the product.The Katritzky group also demonstrated that the reaction of suitable amidoximes 86 with N-aroylbenzotriazoles under similar reaction conditions produced 1,2,4oxadiazoles 87 in 73-82% yields (Scheme 33b).45 Similarly, the synthesis of important heterocycles, such as thiazolines 88 and oxazolines 89, was carried out from readily available N-acylbenzotriazoles by the Katritzky group using a similar synthetic methodology under microwave assistance (Scheme 34).46 In the preparation of oxazolines, the N-acylation of N-acylbenzotriazoles was performed in a sealed tube for 10 min, followed by the cyclization of intermediates in the presence of SOCl 2 .Using a similar protocol, thiazolines 88 were synthesized using 2aminoethanethiol hydrochloride in the presence of Et 3 N.They also accomplished the synthesis of 5,6-dihydro-4H-1,3-oxazines 90 from the reaction of N-acylbenzotriazoles with 3-aminopropan-1-ol under similar reaction conditions.

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amount of alkyl halides.Electron-donating as well as electron-withdrawing group containing substrates were well tolerated in this synthetic approach.
Depsipeptides are the analogues of peptides comprising both amino acids and hydroxy acids linked by amide and ester bonds.Several natural depsipeptides display a range of biological activities such as antimicrobial, antifungal, and anti-inflammatory activities, and they are also highly valuable therapeutic agents in the form of anticancer and anti-HIV candidates. 48he Katritzky group developed a novel benzotriazolemediated methodology for the efficient synthesis of chiral oligoesters 96 and depsipeptides 99 through the reaction of O-Pg-(-hydroxyacyl)benzotriazoles 94 and 97, respective-

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ly, by using unprotected -hydroxycarboxylic acids 95 in the former and depsides 98 in the latter reaction (Scheme 36). 49The methodology also elaborated for the synthesis of amide conjugates by the reaction of O-Pg-(-hydroxyacyl) with amines in satisfactory outcome.

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(9) and tetra-O-pivaloyl--D-galactopyranosylamine 60, respectively (Scheme 39). 51chick and co-workers devised a novel 1-acylbenzotriazole-mediated one-step synthesis of -lactones 111 by the aldolization of carbonyl compounds (Scheme 40). 52N-Acylbenzotriazoles 109 containing one hydrogen atom in the position to the carboxamide group were used as the substrates.These are easily deprotonated with lithium diisopropylamide to afford amide enolates that undergo condensation with carbonyl compounds at -90 to -95 °C to give Olithiated -hydroxyalkanoic acids 110.The carboxamide derivatives 110 then underwent cyclization followed by the elimination of lithium benzotriazolide to produce the desired di-and trisubstituted -lactones in good yields.
Thiolesters play a substantial role in many different syntheses, including those of heterocycles, various ketones, and biologically active substances.The majority of S-acylations that have been previously reported used an activated acyl derivative, such as an acyl halide with thiol sodium salts.The methods using activated acyl derivatives frequently have low yields, are constrained by the need for substratespecific catalysts, or demand harsh conditions and lengthy workup procedures.Carbodiimides like N,N′-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) are frequently used to couple carboxylic acids with thiols in chemical reactions.The processes produce thiolesters in good yields, but because ureas are solvent-soluble, it can be challenging to remove them from the reaction mixture.3f The utility of N-acylbenzotriazoles 3 was exploited as novel S-acylating agents by the Katritzky group and applied for the effective synthesis of a range of thiolesters in goodto-excellent yields (76-99%).3f N-Acylbenzotriazoles reacted with thiophenol, benzyl mercaptan, ethyl mercaptoacetate, and mercaptoacetic acid in the presence of Et 3 N in DCM at room temperature to afford the corresponding thiolesters 112 (Scheme 41a).Moreover, preparation of chiral thiolesters 114 was also accomplished from N-Boc-or Cbzprotected amino acid and dipeptide based N-acylbenzotriazoles 113 under similar reaction conditions (Scheme 41b).

Scheme 41 Preparation of diverse thiolesters utilizing N-acylbenzotriazoles
The Katritzky group demonstrated a novel methodology for the synthesis of aryl benzyl sulfoxides 116 in good-toexcellent yields (70-90%) from the reaction of N-(arylacetyl)benzotriazoles 68 with sodium sulfinates (Scheme

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42). 53 The reaction is initiated with the elimination of benzotriazole from the N-(arylacetyl)benzotriazoles 68 in basic condition to generate arylketene intermediate 115, which reacts with arenesulfinate anions to furnish aryl benzyl sulfoxides 116 after spontaneous decarboxylation.

C-Acylation of Heterocycles Using N-Acylbenzotriazoles
The Katritzky group further extended the application of N-acylbenzotriazoles to the synthesis of ketones 117 from organometallic compounds.Grignard and heteroaryllithium reagents reacted with N-acylbenzotriazoles 3, derived from a range of aliphatic, unsaturated, (hetero)aromatic, and N-protected (R)-amino carboxylic acids, to furnish the corresponding ketones in good-to-excellent yields (Scheme 43). 54heme 43 N-Acylbenzotriazole-mediated synthesis of ketones from organometallic compounds C-Acylation of heterocyclic compounds, such as furans, thiophenes, pyrroles, and indoles, with N-acylbenzotriazoles under Friedel-Crafts reaction condition was demonstrated by the Katritzky group (Scheme 44).55 Their synthetic protocol furnished C-acylated heterocycles in excellent yields with high regioselectivity.C-Acylation reactions of thiophene and 2-methylfuran were performed in the presence of TiCl 4 (at 23 °C) or ZnBr 2 (at 110 °C) to provide comparable yields of 2-acylated products 118 and 119, respectively.
Acylpyrroles are important motifs with biological significance and also play the role of intermediates in the multistep synthesis of various drug candidates. 56Synthesis of acylpyrroles can be easily achieved through the acylation of pyrroles.The Katritzky group performed the reaction of unsubstituted/1-substituted pyrroles with N-acylbenzotri-azoles 3 in the presence of TiCl 4 , which resulted in an easy replacement of the benzotriazolyl group by the pyrrole, leading to the formation of 2-acylpyrroles 120 and 121.N-Protection of pyrroles with a bulky group like triisopropylsilyl group directs the acylation to C-3 and affords N-triisopropylsilyl-3-acylpyrroles 122.Subsequent deprotection using tetrabutylammonium fluoride gives 3-acylpyrrole 123 in 98% yield (Scheme 45).3b

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The Katritzky group further applied the benzotriazole methodology for the efficient synthesis of amino acyl conjugates of nitrogen heterocycles such as pyridine and quinoline, which act as potential pharmacophores in drug discovery and development.Lithiated substrates 2-methylpyridine, 4-methylpyridine, and 2-methylquinoline reacted with N-(Cbz--aminoacyl)benzotriazoles 126 and afforded N-(-Cbz-aminoacyl)methylene heterocycles 127, 128, and 129, respectively (Scheme 47). 58-Acylations have been widely considered as a valuable technique in C-C bond formation and therefore are synthetically important.[59][60][61] Carbon acylation of simple ketone enolates has been explored for the synthesis of 1,3-keto esters and 1,3-diketones using different acylating reagents such as acid chlorides, 62 acyl cyanides, 63,64 N-acylimidazoles, 65 methyl methoxymagnesium carbonate, 66 formates, and oxalates.60 The Katritzky group synthesized -diketones 130 from N-acylbenzotriazoles in a regioselective manner via C-acylation.The C-acylated products were formed in excellent yields by the reaction of alkyl and aryl N-acylbenzotriazoles derivatives with aliphatic ketones, saturated cyclic ketones, and unsaturated cyclic ketones in the presence of lithium diisopropylamide in THF at -78 °C (Scheme 48).67 The synthesis of -ketonitriles and -monoand ,-disubstituted -ketonitriles 131 was also achieved by the acylation of both primary and secondary alkyl cyanides as depicted in Scheme 48.The reactions were performed using a strong base at different temperatures, either by potassium tert-butoxide at 23 °C or n-butyllithium at -78 °C. 3d Inaddition, sulfones were also converted into keto sulfones 132 (Scheme 48).Aliphatic, aromatic, and heteroaromatic -keto sulfones were prepared in 70-96% yields using n-butyllithium.-Keto sulfones are useful intermediates and have substantial synthetic applications in the synthesis of different moieties such as disubstituted acetylenes, vinyl sulfones, allenes, olefins, and polyfunctionalized 4H-pyrans.68 A few -keto sulfones show evidence of fungicidal activity, 69 and some are used as precursors for synthesis of optically active -hydroxy sulfones.70 Scheme 48 N-Acylbenzotriazole-mediated regioselective C-acylation for the synthesis of -diketones, -ketonitriles, and -keto sulfones Furthermore, pyrones are a significant class of lactone derivatives and are important functionality present in many natural products with diverse range of biological applications.The Katritzky group formulated a two-step synthetic strategy for the preparation of functionalized pyrones (Scheme 49). 71 The first stepinvolves the synthesis of 6-(acylmethyl)-2,2-dimethyl-4H-1,3-dioxin-4-ones 134 by reacting 2,2,6-trimethyl-4H-1,3-dioxin-4-one (133) with N-acylbenzotriazoles using LDA in 37-66% yields.Compounds 134 rapidly undergo cyclization under heating conditions in toluene to afford 6-substituted 4-hydroxy-2-pyrones 135 in up to 86% yield.In the proposed reaction pathway, initially LDA abstracts a proton from compound 133 to afford the corresponding anion A which subsequently attacks the N-acylbenzotriazole to give 6-(acylmethyl)-2,2dimethyl-4H-1,3-dioxin-4-ones 134.Under heating, elimination of acetone results in in situ generation of intermediate B, which tautomerizes to enolic form C, followed by cyclization to obtain the desired pyrone derivatives 135.
-and -Amino acid derivatives are the key motifs for several biologically relevant compounds as well as in natural products. 72A versatile approach was developed for the Scheme 47 Benzotriazole-mediated one-step synthesis of optically pure aminoacyl conjugates of pyridine and quinoline

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synthesis of -aryl-substituted -and -amino acid derivatives (Scheme 50). 73The treatment of N-Tfa-amino acid monoesters 136 (Tfa = trifluoroacetyl) with thionyl chloride and benzotriazole in dichloromethane afforded 1-(N-Tfa-aminoacyl)benzotriazoles 137, which on Friedel-Crafts reaction with aromatic compounds provided -amino ketones 138.The reduction of -amino ketones with sodium borohydride or with triethylsilane afforded the corresponding -aryl-substituted -and -amino acid derivatives 139.The result obtained from chiral HPLC confirms that the chirality was maintained throughout the reaction.
The existence of the nitro group at the -position with respect to the carbonyl carbon provides specificity this type of molecule.Their existence offers viable reactivity patterns to compounds like -nitro ketones.-Nitro ketones are important precursors used in the synthesis of compounds with chemotherapeutic applications.The Katritzky group established a method for the synthesis of -nitro ketones by the application of N-acylbenzotriazoles (Scheme 51).3h The reaction of nitro alkanes 140 with 2.0 equiv potassium tertbutoxide resulted in the generation of a doubly metalated complex 141 that reacted with various substituted N-acylbenzotriazoles to furnish functionalized -nitro ketones 142 in up to 86% yields.

Preparation of -Keto Esters and -Diketones by Acylative Deacetylation
In 2004 in extension of the reactions of N-acylbenzotriazoles, the Katritzky group showed that aromatic N-acylbenzotriazoles react with ethyl acetoacetate to afford keto esters in high yields (Scheme 53). 80This one-pot, twostep reaction was used to demonstrate the C-acylative deacetylation reaction.In the first step, N-acylbenzotriazole 3 and acetoacetic ester were treated with NaH followed by Scheme 51 N-Acylbenzotriazole-mediated synthesis of -nitro ketones

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the reaction with NH 4 Cl in the second step.The crude product was then exposed to silica gel column chromatography, and -keto esters 145 were obtained in 58-85% yields with a keto/enol ratio 80:20; the exception was R = 4-pyridyl where a keto/enol ratio of 39:61 was found.When 2-benzyl-or 2-methyl-substituted acetoacetates 146 were used under similar reaction conditions, the corresponding substituted -keto esters 147 were obtained in 51-76% yields (Scheme 54).The conversions are of specific importance as the direct acylation of esters with N-acylbenzotriazoles to produce -keto esters is not available proficiently in previous reports.

Scheme 53 Synthesis of -keto esters via C-acylative deacetylation
Similarly, by acylative deacetylation, -acetyl ketones were transformed into more complex -diketones 148 (Scheme 55). 80In this type of reaction, triketones are the expected intermediates, which subsequently undergo reaction by Japp-Klingemann mechanism with loss of the acetyl group. 81In this case, acetylacetone undergoes a double C-acylative deacetylation via repeated reactions with 2.0 mol of the same or different N-acylbenzotriazoles, resulting in a -diketone in which only the central carbon atom of acetylacetone is preserved.Symmetrical -diketones (2 examples) were formed in 97% and 100% yields when 2.0 mol of the N-acylbenzotriazoles were utilized.Using this approach, even the unsymmetrical diketones were obtained in good yields.

N-Acylbenzotriazoles Used for the Preparation of Other Valuable Intermediates
N-Acylbenzotriazoles 3 are used as excellent acylating reagents as well as key synthons for synthesizing important intermediates.Baruah et al. synthesized 1,2-diketones through the coupling of keto cyanides catalyzed by samarium diiodide. 82Preparation of keto cyanides required toxic cyanides and high temperatures.Wang and Zhang reported a modified synthesis of 1,2-diketones 149 by coupling two molecules of N-acylbenzotriazole catalyzed by samarium diiodide in THF; the products are stable, crystalline solids (Scheme 56). 83Thus, by using benzotriazole and easily available starting materials, auxiliary 1,2-diketones 149 were synthesized under mild reaction conditions.

Scheme 56 Synthesis of 1,2-diketones form N-acylbenzotriazole
The Katritzky group synthesized arylketenes 151, which can be further used to access other important organic intermediates, from N-(arylacetyl)benzotriazole 150 under basic conditions facilitated by the elimination of benzotriazole.Symmetrical ketones 152 were achieved in good yields from N-(arylacetyl)benzotriazoles via reaction with NaH in THF followed by hydrolysis (Scheme 57). 84

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Coltart and co-workers further explored N-acylbenzotriazoles in the acylation of enolizable thioesters to give -keto thiolesters 158 (Scheme 59). 86In the presence of MgBr 2 •OEt 2 and i-Pr 2 NEt, the thiolesters 157 undergo chemoselective soft enolization followed by acylation by N-acylbenzotriazoles in DCM in air to afford -keto thiolesters 158.The obtained -keto thiolesters 158 are very stable and also these are synthetic equivalents of -keto acids and can be transformed directly into -keto esters 159 and -keto amides 160 after treatment with an alcohol or an amine, respectively, in the presence of silver trifluoroacetate in THF.The -keto thiolesters 158 also reacted with ethylzinc iodide and a palladium complex to give 1,3-diketo derivatives 161.
Coltart and co-workers also reported the synthesis of 2morpholino-8-phenyl-4H-chromen-4-one (165), an important PI3-K inhibitor, by utilizing the C-C bond forming protocol.First, the -keto thiolester 163 was produced by the crossed-Claisen coupling of 162 with S-phenyl thioacetate.Treatment of 163 with morpholine in the presence of silver trifluoroacetate in THF resulted in the replacement of the phenylthio group by a morpholino group to produce amide 164.The derivative 164 undergoes deprotection of the benzyloxy group followed by cyclization of the obtained phenol derivative catalyzed by triflic anhydride to furnish smoothly chromen-4-one 165 (Scheme 60). 86hafuroside A and its regioisomer chafuroside B are flavone C-glycosides, possessing remarkable biological activities against various frontline diseases.Due to their importance in drug discovery and development, continuous efforts have been made for their total synthesis by various scientific communities.In this direction, Kan, Wakimoto, and co-workers developed a novel synthetic strategy for the total synthesis of chafuroside A and B through the assistance of benzotriazole chemistry.A segment of the total synthesis of chafuroside B is shown in Scheme 61; here the crucial step is the acylation of 2-hydroxyacetophenone derivative 166 using 1-(4-benzyloxybenzoyl)benzotriazole (167) in the presence of LHMDS to afford the -diketone intermediate 168 in 95% yield.Under acidic conditions, using the Amberlyst 15 catalyst, derivative 168 undergoes a ringclosing reaction to produce 4H-chromen-4-one 169, which on deprotection of the benzyloxy groups, furnish a naturally occurring flavonoid vitexin (170), which under Mitsunobu conditions furnishes the desired chafuroside B in 63% yield. 87n another investigation, a group from Roche used an Nacylbenzotriazole for the construction of the 1H-pyrido [2,3-d]pyrimidine system (Scheme 62). 88Efficient synthesis of 8-cyclopentyl-5-hydroxy-2-(methylsulfanyl)pyrido [2,3-d]pyrimidin-7(8H)-one (174) was carried out using benzotriazole chemistry in 97% yield.First, treatment of o-(cyclopentylamino) acid 171 with benzotriazole in the presence of EDCI as dehydrating agent in DCM results in the formation of the 1-acylbenzotriazole derivative 172.Reaction of 172 with lithiated ethyl acetate in THF provides -Scheme 58 Ring synthesis of 3-alkyl-4,6-diaryl-3,4-dihydropyran-2ones The synthesis of a variety of heterocyclic compounds has frequently utilized aryl isocyanates. 89,90The Katritzky group further demonstrated the versatility of benzotriazoles by establishing a protocol for N-acylbenzotriazolemediated synthesis of various polycyclic heteroaromatic compounds (Scheme 63). 91In their synthetic strategy, several distinct type of N-acylbenzotriazoles reacted with various aryl isocyanates in a sealed tube for 24 h to furnish five different categories of polycyclic heteroaromatic molecules.Derivatives of quinoline 175, pyrimidino [5,4-c]quinoline 176, benzo[b][1,8]naphthyridine 177, phenanthridine 178, and indolo [2,3-b]quinoline 179 were synthesized in good yield from the reaction of alkanoyl-, acetyl-, acetoacetyl-, aroyl-, and cinnamoylbenzotriazoles, respectively, with various aryl isocyanates (Scheme 63). 91These products 175-179 were constructed through the incorporation of 3, 3, 4, 2, and 2 molecules, respectively, of aryl isocyanate per Nacylbenzotriazole molecule.

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Barrett and co-workers reported a N-acylbenzotriazolemediated synthesis of an isoquinolone 184, a part of the antifungal agent Sch 56036 (Scheme 64). 93Acetal 181, obtained from readily available L-isoleucine, was acylated with N-acylbenzotriazole 180 to give amide 182 in 68% yield.Reaction of amide 182 with KOH under refluxing conditions gave detosylation to give phenol 183.Subsequent reaction of phenol 183 with 4.0 equiv of camphorsulfonic acid in refluxing toluene resulted in cyclization (via Pomeranz-Fritsch mechanism), followed by demethylation to give isoquinolone 184 in a satisfactory outcome.
The fascinating chemistry of benzotriazoles was further extended by the Katritzky group for the synthesis of a diverse range of biologically active heterocyclic compounds.Towards this effort, the group applied the benzotriazole methodology to synthesize fused ring systems of pyrido[1,2-a]pyrimidin-2-ones 200 and 2H-quinolizin-2-ones 201.Pyrido[1,2-a]pyrimidines are biologically potent heterocycles, and they are structural features of several chemotherapeutic drugs such as the tranquilizer pirenperone (196), 96 the antiallergic agent ramastine (197), 97 an antiulcerative agent 198, 98 and an anti-asthmatic agent TBX 199, 99 contain the pyrido[1,2-a]pyrimidine moiety in their structures (Figure 2).

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unsaturated -diketones 207 and 208 were prepared from the reaction N-(,-unsaturated acyl)benzotriazoles 206 and 202 and ketones in the presence of a LDA as base at -78 °C in 3 h.First, the reaction of ketones with LDA produced the corresponding lithium enolate which on reaction with N-acylbenzotriazoles furnished the diketones in good yields.
The Katritzky group demonstrated a convenient synthesis of N-protected-pyroglutamyl pseudopeptides 211a-c from glutamyl-bis-benzotriazole 210 through cyclization of an N-terminal glutamic acid residue (Scheme 69). 102N-Protected L-glutamic acid 209 was used for the acylation of 1Hbenzotriazole in the presence of thionyl chloride in THF to generate glutamyl-bis-benzotriazole 165, which underwent condensation with an L-amino acid in the presence of triethylamine as base in aqueous acetonitrile to furnish pyrrolidin-2-ones 211.The crude products were washed with 4 N HCl to afford pure products 211a-c in 58-88% yields.

Scheme 69 Benzotriazole-mediated synthesis of N-protected-pyroglutamyl pseudopeptides
Mintas, Zorc, and co-workers reported a benzotriazolemediated methodology for synthesis of 3,5-disubstituted hydantoin (imidazolidine-2,4-dione) derivatives 216 through cyclization of the corresponding N-(benzotriazol-1-ylcarbonyl)-Land D-amino acid amides 215 in the presence of a base (Scheme 70). 1031-(Chloroformyl)benzotriazoles 212 were prepared from benzotriazole using a previously reported method. 104The reaction of 212 with amino acids in anhydrous dioxane produced 213 that on treatment with thionyl chloride was converted into acid chlorides 214 which were subsequently reacted with amines to afford amides 215.The cyclocondensation of these amides in the presence of sodium carbonate as base followed by elimination of the benzotriazole moiety furnished hydantoins 216 in 24-88% yields.
In 2019, the Tiwari group devised a new methodology for the synthesis of symmetrical and unsymmetrical ureas from N-acylbenzotriazole 3 (Scheme 74); 108 the route in Scheme 73 was limited to symmetrical ureas.The ureas 232 were obtained in a one-pot reaction when N-acylbenzotriazole 3 was treated with TMSN 3 followed by the addition of amines 231 in toluene at 110 °C for 60 min.Mechanistically, compound 3 reacts with trimethylsilyl azide (as azide source) to give acyl azide A by elimination of benzotriazole.The acyl azide A undergo subsequent rearrangement (Curtius rearrangement) and furnishes isocyanate intermediate B by the evolution of molecular nitrogen.The isocyanate is

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subsequently trapped by the amine nucleophile to afford ureas 232 (25 examples, up to 99% yield).N-Acylureas were also obtained in reasonable yields when 1-(1H-benzotriazol-1-yl)-2-phenylethane-1,2-dione was reacted with various amines under the optimized reaction condition. 108urthermore in 2021, the Tiwari group devised an efficient, one-pot method for the synthesis of N-acylureas, ureas, carbamates, and thiocarbamates using diphenylphosphoryl azide (DPPA) as an azide transfer reagent. 109The synthesis of N-acylurea 233 is depicted in Scheme 75.Initially, N-acylbenzotriazole 3 reacted with DPPA to give an acyl azide that underwent rearrangement under heating to furnish an isocyanate intermediate after the elimination of molecular nitrogen.The reaction of the isocyanate with amides, amines, phenols, and thiophenols resulted in the formation of N-acylureas, ureas, carbamates, and thiocarbamates, respectively.In most of the cases, column chromatography was avoided, and compounds were purified by sequential washing with appropriate solvents.
In their next investigation, the Katritzky group developed a protocol for selective synthesis of S-acylcysteines and N-acylcysteines utilizing N-acylbenzotriazole chemistry under mild reaction conditions (Scheme 76).3n The reaction of N-acylbenzotriazoles with L-cysteine (234) in the presence of triethylamine as base in MeCN/H O (3:1) at room temperature afforded N-acylcysteines 235 exclusively in 51-86% yields, whereas, S-acylcysteines 236 were ob-tained as the sole product in 66-85% yields under similar reaction condition but in the absence of basic medium.The structures of the synthesized compounds were confirmed by using various spectroscopic characterizations and also single-crystal X-ray diffraction techniques.
The Katritzky group reported a general route for preparation of acyl azides 237 by the reaction of N-acylbenzotriazoles with sodium azide in acetonitrile solvent at room temperature (Scheme 77).3i The beauty and advantage of this developed protocol is that along with good yields, it avoids the use of acid activators and NO + equivalents typically employed to synthesize these compounds from acid chlorides and hydrazides, respectively.Also, there is least chance of isomerization of ,-unsaturated derivatives, side reactions such as Curtius rearrangements and racemization of the chiral center in case of amino acid derivatives.

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In their next effort, the Katritzky group presented a facile and economically viable route for the high-yielding synthesis of aliphatic hydroxy carboxamides 243, hydroxy esters 244, and hydroxy thiolesters 245 from aliphatic hydroxy-substituted N-acylbenzotriazole intermediates 242 on treatment with amines, alcohols, and thiols, respectively (Scheme 79), along with the synthesis of aromatic hydroxy carboxamides 247 and aromatic hydroxy esters 248 from N-(o-hydroxybenzoyl)benzotriazoles 246 and amines or alcohols, respectively (Scheme 80).The hydroxy N-acylben-zotriazole intermediates were obtained by the activation of hydroxy carboxylic acids without prior protection of the hydroxy substituent. 111urthermore, the Katritzky group synthesized novel benzotriazol-1-ylsulfonyl azide 249, a crystalline, stable, and easily available compound, and reacted it with active methylene compounds and amines to give a broad range of diazo compounds 250 and azides 251, respectively, in good yields (Scheme 81). 112They also utilized sulfonyl azide 249 as an efficient diazo transfer reagent for the convenient preparation of N-(-azidoacyl)benzotriazoles 252 which are very suitable candidates for N-, O-, S-, and C-acylation reactions and afforded various amides 253, esters 254, thiolesters 255, and ketones 256, respectively The Katritzky group also proposed a plausible mechanistic pathway for formation of diazo compound 250 from an active methylene compounds.The reaction proceeds through a diazo transfer reaction in which the first step is the nucleophilic attack of the generated enolate intermediate A onto the benzotriazol-1-ylsulfonyl azide 249 followed by proton transfer to furnish intermediate B. Further, intermediate B is converted into intermediate C in the presence of base, which undergoes an elimination reaction to afford the desired diazo compound 250 (Scheme 82).

Benzotriazole Ring Cleavage (BtRC) Reactions
4][115] Because of their significant biological and physiological activities, considerable effort has been put into developing new synthetic methods for their preparation.It has been determined that the most helpful transformations among these are cyclization and cycloaddition reactions. 116Nowadays, benzotriazole ring cleavage (BtRC) reaction have become an indispensable tool for the synthesis of various types of heterocyclic and amides derivatives. 117n 2009, Nakamura and co-workers reported a benzotriazole ring cleavage methodology for the synthesis of biologically relevant indole derivatives 258 (Scheme 83).117a The developed strategy included a denitrogenative cycloaddi-tion reaction of N-aroylbenzotriazoles and alkynes 257 in the presence of a Pd catalyst.This methodology does not work with terminal alkynes but despite this it is of great utility in organic synthesis due to its tolerance of a wide variety of benzotriazoles.Also, this reaction displays some excellent features like satisfactory yields, simple purification of indole derivatives, and a solvent-and base-free experimental procedure.It also exhibits good regioselectivity for the asymmetric alkynes by placing the bulkier substituent of asymmetric alkynes at C-2 of the indole ring.This work showed that benzotriazoles could be utilized as the synthetic equivalents of ortho-aminoarenediazoniums or 2haloanilides in metal-catalyzed coupling reactions.117a Scheme 83 Pd-catalyzed synthesis of biologically relevant indole derivatives from N-aroylbenzotriazoles and alkynes The Glorius group also synthesized 2-aryl-substituted indole derivatives 260 by the reaction of N-aroylbenzotriazoles with terminal alkynes 259 in the presence of an Ir catalyst under blue light irradiation (Scheme 84).117b This method also exhibits good-to-excellent regioselectivity for the synthesis of 2-substituted indoles, as well as excellent functional group tolerance and a wide substrate range.Various p-substituted arylacetylenes were utilized and gave the corresponding products in 48-92% yields.In contrast to Nakamura's methodology 117a this reaction is incompatible with internal alkynes and no products were formed.They also investigated the effects of substitution on the benzotriazole ring on the reaction using 5-methyl-or 5-chloro-substituted N-aroylbenzotriazoles and obtained 2-arylated indoles in 52% and 85% yield, respectively.The deprotected indoles could be obtained from substrates containing strong electron-withdrawing groups, such as 4-(trifluoromethyl)benzoyl-substituted benzotriazoles, which delivers a significant route for the synthesis of 2-aryl-substituted indoles without the extra deprotection steps.Stern-Volmer studies and reaction quantum yield determination confirm the proposed photoinduced radical chain pathway.

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A similar but modified approach came from the Glorius group for the efficient preparation of ortho-alkylated N-arylbenzamides 262 (R = aroyl) (Scheme 85). 118They used styrenes 261, in place of terminal alkynes, and employed Ir as the catalyst in the presence of blue LEDs.The reaction proceeds through the denitrogenative alkylation of benzotriazoles and displays compatibility with various substitutions on benzotriazoles and gives moderate-to-good yields in the case of both electron-withdrawing and electron-donating group bearing styrenes.Since aliphatic alkenes are poor radical acceptors in comparison to styrenes, therefore, they do not undergo this reaction, which is the only limitation of this developed protocol.
A novel protocol for the synthesis of 3,1-benzoxazinones 263 was devised by Wu and co-workers in 2017 (Scheme 86).117f The target molecules were synthesized by carbonylative activation of N-acylbenzotriazoles under silver and palladium bimetallic catalysis.This reaction methodology is very beneficial in constructing a series of biologically important 3,1-benzoxazinones 263 in satisfactory yields and also performs well with various substituted benzotriazoles.

Scheme 86 Synthesis of 3,1-benzoxazinones through Pd-catalyzed carbonylative cyclization of benzotriazoles with carbon monoxide
In organic synthesis, one of the transformations of enormous importance is the construction of carbon-heteroatom bonds.Therefore, many scientific groups across the world have developed and reported methods for the construction of carbon-heteroatom bonds, in which one of the important conventional methods is the transition-metal-catalyzed cross coupling reaction. 119Various developments have been made in this field, one of which is the radical oxidative coupling strategy for carbon-heteroatom bond formation.This field of work has gained tremendous attraction in recent years and has become a hot spot in the field of carbon-heteroatom bond construction. 120y using a denitrogenative process, the Glorius group reported a novel visible-light-promoted borylation and thiolation of benzotriazoles using B 2 pin 2 264 and alkyl disulfides 266, respectively, to produce ortho-functionalized Narylbenzamide derivatives 265 (Scheme 87) and 267 (Scheme 88). 118On either the benzotriazole core or the benzoyl fragment, the reaction could tolerate both electron-donating and electron-deficient substituents.Aryl disulfides were unable to provide the thiolation products, whereas a variety of alkyl disulfides 266 were compatible with this transformation.
Yang, Xia, and co-workers established the visible-lightinduced denitrogenative phosphorylation of N-aroylbenzotriazoles with phosphites under mild conditions (Scheme 89). 121N-Aroylbenzotriazoles were treated with 3.0 equiv of phosphite 268, Ir photocatalyst, and 15-W LEDs as light source to give a series of ortho-phosphorylated N-arylbenzamide derivatives 269 in up to 99% yield.Furthermore, this reaction demonstrated perfect functional group tolerance.Several trialkyl phosphites were suitable for the reaction, and the steric hindrance of the phosphite had a significant effect on product yield; the reaction was unsuccessful with triphenyl phosphite as the phosphorylation agent.Furthermore, a gram-scale reaction under standard conditions fur-

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nished good-to-excellent yield of products, demonstrating the synthetic utility of this new protocol.
Significant contributions were made by the Tiwari group towards the development of benzotriazole ring cleavage (BtRC) methodology.117i-o In their first work, they accomplished the synthesis of benzoxazoles 270 from N-acylbenzotriazoles under heating condition in the presence of a Lewis acid using toluene as solvent.; the reaction goes through a denitrogenative ring-opening process followed by cyclization (Scheme 90d).117m This protocol has several advantages such as an excellent tolerance to substitution on the aromatic ring, moderate-to-good yields, use of easily available and economical catalyst, and milligram to gram scale conversion.They also investigated this protocol with aliphatic N-acylbenzotriazoles and found that the reaction undergoes Friedel-Crafts acylation reaction to furnish an excellent yield of ketones.
The Tiwari group also developed a methodology for synthesis of substituted amides 271 from N-aroyl-and N-alkanoylbenzotriazoles via free radical benzotriazole ringopening process in the presence of n-Bu 3 SnH/AIBN.117o In addition, the byproduct tin dimer was reduced by using NaBH 4 to regenerate the n-Bu 3 SnH reagent.This reduces the consumption of n-Bu 3 SnH reagent in this reaction and makes this protocol economic (Scheme 91).
Wang and Zhang reported an interesting methodology for the synthesis of heterocyclic compounds from benzotriazoles without the loss of a nitrogen molecule. 122The synthesis of the benzimidazole system goes through ring cleavage of benzotriazoles followed by successive ring closure.1-Acylamido-2-alkyl/aryl-substituted benzimidazoles 272 Scheme 88 Synthesis of ortho-functionalized N-arylbenzamide derivatives via visible-light-promoted thiolation of benzotriazoles with disulfides

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were synthesized by the reduction of 1-acylbenzotriazoles 3 using samarium(II) iodide (2 equiv) in 43% (R = 4-ClC 6 H 4 ) to 82% (R = c-C 6 H 11 ) yields (Scheme 92).Different results were obtained by varying substitution in substrate and solvents, for instance, in case of R = 4-MeOC 6 H 4 , the diketone 273 was obtained as the sole product in 72% isolated yield whereas in other reactions diketones 273 were isolated as side products.Also, using THF as the solvent in place of acetonitrile gave diketones 273 as the sole product.Therefore, it was concluded that acetonitrile solvent is crucial for exclusive production of 1-acylamido-2-alkyl/aryl-substituted benzimidazoles 222 through reduction of N-acylbenzotriazoles with SmI 2 .However, there is not any certain clear mechanism regarding the transformation.

Scheme 92 Samarium(II) iodide induced ring opening of N-acylbenzotriazoles
A gas-phase pyrolysis (static pyrolysis) technique was devised by Al-Awadi and co-workers to access benzoxazole 274, 1-cyanocyclopentadiene 275, phenanthridin-6(5H)ones 276, substituted N-phenylbenzamide 277, benzamide 278, and benzimidazole 279 from 1-aroylbenzotriazoles at 300-340 °C temperature and 6 × 10 -2 mbar pressure (Scheme 93). 123They also investigated a different pyrolysis technique and found that when pyrolysis of 1-aroylbenzotriazole was carried out by flash vacuum pyrolysis at 600 °C and 0.2 Torr, only the benzoxazole, 1-cyanocyclopentadiene, and phenanthridin-6(5H)-one were obtained.The group also carried out kinetic and mechanistic studies and revealed that biradical or carbene reactive intermediates were involved in the reaction pathway of gas-phase pyrolysis of benzotriazole in the reaction course.
The synthesis of N-containing heteroaryl amides can be achieved by utilizing azole-N-acetonitrile derivatives as substrates through a strategy where they act as synthons for an ambident carbonyl moiety and the course of reaction involves sequential base-mediated S N Ar substitution of a 2haloheterocycle, in situ oxidation, and amine displacement.N-Containing heteroaryl amides can be synthesized efficiently from the corresponding halides in a prompt one-pot Scheme 90 N-Acylbenzotriazoles for the synthesis of diverse biologically relevant molecules including benzothiazoles, benzoxazoles, amides, etc.

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fashion by utilizing this approach.A similar protocol was developed by Wang and co-workers who accomplished the synthesis of N-containing heteroaryl amides through the reaction of 2-chloroquinoxaline (280) and benzotriazol-1ylacetonitrile (281) in the presence of sodium hexamethyldisilazanide (NaHMDS) at room temperature (Scheme 94). 124The reaction proceeded through the intermediate nitrile derivative 282 which was further transformed into amide 285 (66% yield) on treatment with m-CPBA.The desired product 285 is proposed to be formed from 282 through a sequence of steps in which a cyanohydrin 283 is first generated from 282 and this undergoes elimination of HCN to afford 1-acylbenzotriazole 284 that reacts with NaHMDS followed by hydrolysis during workup to furnish amide 285.

N-Acylbenzotriazoles as Catalysts and Ligands
The availability of unique ligation sites on benzotriazole moieties has paved the way for the development of efficient ligands, predominantly for application in coupling reactions. 125Several ligand-mediated approaches were reported for the synthesis of heterocycles via coupling reactions. 126n 2016, Unver and Yılmaz reported the application of N-acylbenzotriazole-based complexes of Rh(I) 286 and Ru(III) 287 as hydrogenation catalysts in ionic liquid media (Scheme 95). 127Both complexes were capable of catalyzing the hydrogenation of styrene and oct-1-ene and were fully soluble in 1-butyl-3-methylimidazolium tetrafluoroborate [bmim][BF 4 ].While ethylbenzene conversion in the styrene hydrogenation process reached 84% when the Ru complex 287 was used, under the same conditions (393 K in 6 h) the Rh complex 286 produced 100% conversion.Additionally, using the Rh complex in [bmim][BF 4 ] media, 100% of the hydrogenation of oct-1-ene was achieved.To compare the impact of the solvent on the catalytic system, the hydrogenation of styrene and oct-1-ene in dimethyl sulfoxide and toluene was also investigated and found to be inferior.The relationship between the conversion and some catalytic parameters, including temperature, H 2 (g) pressure, and cata-lyst amount was investigated, and it was observed that the conversion increased in tandem with the rising temperature and H 2 pressure.It was found that the Rh complex in particular retained its activity for at least 10 cycles when the recyclability of catalysts was examined. 127

Scheme 95 Hydrogenation of alkene by benzotriazole-based rhodium complexes
In 2017, the Tiwari group employed N-acylbenzotriazoles as efficient ligands for the synthesis of diverse benzoxazoles via a copper-catalyzed intramolecular cyclization of N-(2-halophenyl)benzamides.Various substituted N-acylbenzotriazoles were screened amongst which (1H-benzotriazol-1-yl)(2-methoxyphenyl)methanone 288 was found to be satisfactory.After screening, various N-(2-halophenyl)benzamides 289 were reacted with CuI (0.2 equiv), ligand 288 (0.2 equiv), and K 2 CO 3 (1.2equiv) in DMF at 120 °C for 8 h to obtain benzoxazoles 290 in up to 93% yield (Scheme 96). 128The effect on yield with variation of the halo substituent on the N-(2-halophenyl)benzamide was also checked and N-(2-iodophenyl)benzamide was found a more appropriate substrate in contrast to bromo and chloro derivatives.The proposed reaction pathway is by coordination of the ligand with copper iodide which then is tethered to the amido group of the benzamide to afford intermediate A that on subsequent oxidation gives complex B, followed by reductive elimination to give benzoxazoles 290.

Review SynOpen 5 Pharmacological Applications of N-Acylbenzotriazoles
N-Acyl/aroylbenzotriazoles have been widely explored as a leaving group in various synthetic approaches.Also, the benzotriazole ring cleavage (BtRC) methodology is well-established protocol that recently used in modern organic synthesis for an easy access of wide range of biologically relevant scaffolds.1d,129 In addition to the versatile synthetic utilities of N-acylbenzotriazoles, this scaffold possesses some notable bioactivities and explored in medicinal chemistry. 130The structures of some biologically potent Nacylbenzotriazoles are depicted in Figure 3.For example, Nacyl/aroylbenzotriazoles 291 (IC 50 = 1.7 nM) and 292 (IC 50 = 14 nM) with 3,4,5-trimethoxy-substitution exhibited potent activities against oral epidermoid carcinoma KB cells, non-small-cell lung carcinoma H460 cells, and stomach carcinoma MKN45 cells with respect to doxorubicin. 131Furthermore, compound 291 has moderate HDAC inhibitory activity.It depicts the necessity of more series and molecular library exploration.
Scheme 96 Synthesis of benzoxazole from N-(2-halophenyl)benzamides using N-acylbenzotriazoles as ligands in a copper-mediated coupling reaction

Review SynOpen
The antidiabetic activity of compound 293 (IC 50 = 2.99 ± 1.43 mM against -amylase and IC 50 = 3.00 ± 1.21 mM against -glucosidase) was reported by Khan and co-workers. 132Molecular docking revealed that the aryl ring substitution is the key interactive point in this case and the kinetic studies supported that 293 has competitive inhibitory action against -amylase and noncompetitive mode of inhibition against -glucosidase enzyme.The NHE-1 inhibitory via in vitro platelet swelling assay of N-aroylbenzotriazoles with an oxygen atom in benzoyl 294 (IC 50 = 51.57mM) and a sulfonyl group 295 (IC 50 = 50.89mM) and 296 (IC 50 = 49.95mM) was reported by Singh and Silakari. 133n a free radical scavenging study, N-acylbenzotriazole analogue 297 exhibited appreciable DPPH (2,2-diphenyl-1picrylhydrazyl) interaction value (85%) comparable to the reference nordihydroguaiaretic acid (91%).Besides, 297 has lipid peroxidation (LP) inhibition of 31%, which further encourages its efficiency as an antioxidant scaffold. 134Bis-Naroylbenzotriazole 298 displayed notable analgesic and antipyretic activities with minimal side effects, prolonged plasma half-life, increased solubility, and antioxidative potentiality than ketoprofen, a commercial non-steroidal antiinflammatory drug (NSAID).This exhibited interaction with DPPH in iron-free system as well as its reducing activity.Besides, it has significantly higher LP inhibition (98%) with respect to parent motif (69.3%) with remarkable soybean LOX activity of 95%. 135Tasneem et al. reported the antitubercular activity of compound 299 (minimal inhibitory concentration, MIC = 4.5 g/mL against M. tuberculosis compared to first line drugs, streptomycin (MIC = 7.5 g/mL) and pyrazinamide (MIC = 10 g/mL). 136nterestingly, Cu(II) coordinated N-aroylbenzotriazole complex 300 displayed potent antibacterial activity. 137This complex exhibited moderate inhibitions against both Gram-positive (B.subtills and S. aureus) and Gram-negative (E. coli and S. typhi) bacteria.However, in lieu of dependable stability, variation in structural coordination of the complex may vary in the final pharmacological application and cell inhibitory activity.
N-Acyl/aroylbenzotriazoles have exerted great potentiality as versatile pharmacophore including excellent antibacterial, antifungal properties, along with the efficacy as antioxidant agents.Hopefully, these inspiring outcomes will help to investigate more molecular library genesis as Nacyl/aroylbenzotriazole agents against other diseases along with opening up new prospects for the motif.

Conclusions and Future Outlook
In this review, we highlighted the various synthetic methodologies for efficient preparation of N-acylbenzotriazoles which have developed over time.The diverse applications of N-acylbenzotriazoles as N-, O-, C-, and S-acylating agents for the convenient synthesis of a range of im-portant organic compounds and synthesis of diverse compounds has also been incorporated by using benzotriazole ring cleavage (BtRC) methodology in this review.The review also emphasized the role of N-acylbenzotriazoles as a ligand in various transformations and illuminated on the medicinal importance of the N-acylbenzotriazolyl scaffold by including the pharmacological applications of various medicinally active compounds containing the benzotriazolyl framework.For future perspective, theses inspiring outcomes will help to explore the role of N-acylbenzotriazoles in organic synthesis as well as for therapeutic resolutions.
V. K. Tiwari, at Department of Chemistry, Banaras Hindu University India.He has contributed significantly to about 30 publi-cations and several book chapters of international repute.Currently, he is working as a Research Scientist in Jubilant Biosys Limited, Greater Noida, India.Prabhu P. Mohapatra, born in Odisa, India (in 1967) is an adjunct Research Scientist at Augusta University, USA.He completed his M.Sc.from Sambalpur University and earned his doctoral degree in Chemistry at the Department of Chemistry, University of Delhi with Prof. S. M. S. Chauhan.He then joined Ranbaxy Pharma, Delhi, as a research scientist working on development of API.He worked as postdoctoral fellow with Prof. Alan R. Katritzky and since then has an interest in benzotriazole methodology.Dr Mohapatra has contributed to over 45 research publications in peer-reviewed journals of high repute.His research interest is focused on the development of novel synthetic methodology using benzotriazole synthon, catalysis, photochemistry, and medicinal chemistry.Vinod K. Tiwari was born in Bihar, India (in 1976) and is associated with Banaras Hindu University (BHU) as Professor of Organic Chemistry.He earned his M.Sc.degree in Chemistry (in 1998) from BHU and Ph.D. degree from CSIR-Central Drug Research Institute, Lucknow (awarded by Jawaharlal Nehru University, New Delhi, in 2004, Mentor: Dr. R. P. Tripathi) and had postdoctoral experience at the University of Florida (Mentor: (Late) Prof. Alan R. Katritzky, in 2005), University of California-Davis (Mentor: Prof. Xi Chen, in 2007), and Guest Scientist at Universitat Konstanz, Germany (Mentor: Prof. (em.)Richard R. Schmidt, in 2009).He was offered the post of lecturer at Bundelkhand University (in 2004) before being appointed to BHU (in 2005).With over 25 years of research and 20 years of teaching (UG/PG) experience, Dr. Tiwari has supervised 16 Ph.D. and 25 M.Sc.dissertations, and completed 10 major projects (CSIR, DST, SERB, UGC, IoE).He significantly contributed 176 peer-reviewed publications including two Chemical Reviews (Citations: 7569, h-index: 42, i 10 index: 114, Impact Factors: 650), 8 patents, 4 books, and 25 invited book chapters of high repute.Dr. Tiwari has vast editorial experience, and he is presently Guest Editor of 'SYNTHESIS' for a thematic issue on 'Emerging Trends in Glycoscience'.Dr. Tiwari is a highly travelled scientist (delivered 251 invited lectures in India and abroad) and holds Secretary Position, ACCT(I) (2022-2025) and council member of CRSI (2023-2026).His research is well recognized with several prestigious honors/awards/medals/invited contributions from various academic societies including ISCA, CRSI, ICS, ICC, ACCT(I), BHU, NESA, IAPS, UP-CST, Holkar Science College, ACS, RSC, Wiley, Thieme, Bentham, Springer, Elsevier Inc., etc. His current research is focused on synthetic carbohydrate chemistry, novel synthetic methodology, click chemistry in glycoscience, and carbohydrates in drug discovery and development.M. S. Yadav et al.

Figure 1
Figure 1 Some common approaches used for the synthesis of diverse N-acylbenzotriazoles

Scheme 5 Scheme 6
Scheme 5 Conversion of carboxylic acids into N-acylbenzotriazoles using I 2 /PPh 3

Scheme 16 Scheme 14
Scheme 16Formation of primary, secondary, and tertiary amides

N
. Yadav et al.

2 Scheme 46
Scheme 46 Use of N-acylbenzotriazoles as acylating agents of various alkylated azines

Scheme 49 Scheme 50
Scheme 49 Synthesis of biologically relevant pyrone derivatives using N-acylbenzotriazoles

Scheme 61
Scheme 61 Total synthesis of chafuroside B through the application of an N-acylbenzotriazole

Scheme 84 Scheme 81
Scheme 84Ir-catalyzed synthesis of 2-aryl-substituted indole derivatives from N-aroylbenzotriazoles and alkynes under blue light irradiation Scheme 82 Mechanism for the formation of diazo compounds from active methylene compounds by a diazo transfer reaction

Scheme 85 Scheme 87
Scheme 85 Blue LED induced Ir-catalyzed denitrogenative alkylation of benzotriazoles with styrene derivatives 3 261 262 R N N N

Scheme 94
Scheme 94 One-pot synthesis of heteroaryl amide

Figure 3
Figure 3 Structure of some biologically active N-acylbenzotriazoles