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DOI: 10.1055/a-2157-5782
Synthetic Utility of N-Acylbenzotriazoles
Abstract
N-Acylbenzotriazoles are valuable synthons in organic synthesis. They are particularly used as acylating agents and an alternative to acyl chlorides. They have been widely explored for a diverse range of applications. This review summarizes methods for the preparation of N-acylbenzotriazole derivatives and their diverse applications, in particular demonstrating their ability to serve as alternative acylating agents in organic transformations such as N-, O-, C-, and S-acylating agents for the convenient synthesis of a wide range of biologically important organic compounds. We also emphasize the synthesis of diverse compounds using benzotriazole ring cleavage (BtRC) methodology, including its pharmacophore study and some notable utilities as valuable starting materials, ligands, and intermediates in the field of organic synthesis.
1 Introduction
2 Synthesis of N-Acylbenzotriazoles
3 Applications of N-Acylbenzotriazoles in Organic Synthesis
3.1 N-Acylation Using N-Acylbenzotriazoles
3.2 C-Acylation of Heterocycles Using N-Acylbenzotriazoles
3.3 Preparation of β-Keto Esters and β-Diketones by Acylative Deacetylation
3.4 N-Acylbenzotriazoles Used for the Preparation of Other Valuable Intermediates
3.5 Benzotriazole Ring Cleavage (BtRC) Reactions
4 N-Acylbenzotriazoles as Catalysts and Ligands
5 Pharmacological Applications of N-Acylbenzotriazoles
6 Conclusions and Future Outlook
#
Key words
N-acylbenzotriazole - acylation - denitrogenative ring cleavage - acylative deacetylation - benzotriazole ring cleavage reactionsBiographical Sketches
Mangal Singh Yadav, born in Azamgarh, U.P., India (in 1992) is currently working as extended SRF under the supervision of Prof. Vinod K. Tiwari, Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, India. He completed his B.Sc. and M.Sc. (in Chemistry) from T. D. P. G. College Jaunpur. He qualified Graduate Aptitude Test in Engineering (GATE)-2017 and NET-CSIR with JRF-2017 and then, in 2018, he joined doctoral research under the supervision of Prof. Vinod K. Tiwari at Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, India. Through his dedicated research, he significantly contributed over 15 scientific contributions in peer-reviewed journals and just submitted his doctoral thesis on the topic ‘development of novel benzotriazole methodologies and their application’. His present research work is focused on the development of novel synthetic methodologies and Cu(I)-catalyzed click chemistry in glycoscience.
Abhishek Gupta, born in Bhadohi, U.P., India (in 1997), is at present Lecturer of Chemistry at the Govt. Polytechnic Mohammadpur, Bahraich, U.P. India. He obtained his B.Sc. (2017) and M.Sc. (Organic Chemistry, 2020) degrees in chemistry from the University of Allahabad, Allahabad, India. He qualified CSIR-JRF in 2020 and GATE in 2021 and completed his doctoral research under the guidance of Prof. V. K. Tiwari at the Department of Chemistry, Banaras Hindu University. His research interest is focused on the development of carbohydrate-containing molecules of chemotherapeutic potential.
Priyanka Bose, born in Kolkata, India (in 1992) has just submitted her Ph.D. thesis under the supervision of Prof. V. K. Tiwari at Department of Chemistry, Institute of Science, Banaras Hindu University and in April 2023, she joined Pharma Industry in Hyderabad as research Scientist. She earned her M.Pharma (Medicinal Chemistry as specialization) in 2017 from Dr. H. S. Gour Central University, Sagar, India and has qualified GPAT and on the same year joined the laboratory of Prof. V. K. Tiwari for her doctoral research as SERB-JRF. She was awarded the ‘1st Prize in SPIRIT-15’, organized by the Department of Pharmaceutical Engineering, IIT-BHU. Her current research is focused on click chemistry mediated glycohybrids, computational chemistry, and molecular series synthesis having potent bioactivities including anticancer activity.
Anoop Shyam Singh was born in Varanasi, Uttar Pradesh, India (in 1986). He obtained his M.Sc. degrees in chemistry (specializing in organic chemistry, 2010) from the U. P. College Autonomous Institution, Varanasi, India and completed his Ph.D. degree in 2018 on the topic ‘Development of Novel Synthetic Methodology through Benzotriazole Ring Cleavage’ under the guidance of Prof. V. K. Tiwari, at Department of Chemistry, Banaras Hindu University India. He has contributed significantly to about 30 publications 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, i10 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.
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. This mild, regioselective, and regiospecific reagent provides an alternative route to Friedel–Craft and Vilsmeier–Haack acylation strategies and can be used to obtain better results.[1] [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.
# 2
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. 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]
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]
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]).[6] In 2002, they developed a notable method in an extension of this methodology when 1-(methylsulfonyl)benzotriazole was treated N-Boc-α-amino acids for the synthesis of stable N-(Boc-α-aminoacyl)benzotriazoles (see Scheme [14]).[7]
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 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]
In 2014, Phakhodee and co-workers introduced a new method to obtain N-acylbenzotriazoles 3 by utilizing I2/PPh3 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 I2/PPh3, 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 Et3N 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 NaHCO3, 1 M HCl, and water ascertained the process to be economic and environment friendly.[10] Whereas, 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 NaHCO3 and benzotriazole in aqueous medium (Scheme [6b]).[11]
In 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.[12]
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.[13] The 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.[8] To achieve the target N-(1,2;3,4-di-O-isopropylidene-α-d-galactopyranuronosyl)benzotriazole 11, 1,2;3,4-di-O-isopropylidene-α-d-galacturonic acid (10) was first synthesized via the isopropylidene protection of d-(+)-galactose to yield compound 9, followed by oxidation. When this sugar acid 10 was treated with SOCl2 in the presence of benzotriazole and dichloromethane, a crystalline white solid of 11 was obtained in appreciable yield (Scheme [8]).
However, for the synthesis of N-3-O-benzyl- or 3-O-ethyl-1,2-O-isopropylidene-α-d-xylofuranuronyl)benzotriazoles, a six-step reaction was performed on d-(+)-glucose. First, isopropylidene protection was carried out on d-(+)-glucose to obtain 1,2;5,6-di-O-isopropylidene-glucofuranose 12, followed by 3-O-alkylation and selective isopropylidene deprotection to obtain compound 13. Compound 13 on selective oxidation with NaIO4 furnished the corresponding aldehyde and finally, treatment of this aldehyde with freshly prepared AgNO3/KOH catalyzed oxidation afforded 3-O-benzyl- or 3-O-ethyl-1,2-O-isopropylidene-α-d-xylofuranuronic acids 14 as the target product. Reaction of furanuronic acids 14 with SOCl2 and BtH in anhydrous DCM furnished N-(3-O-benzyl- or 3-O-ethyl-1,2-O-isopropylidene-α-d-xylofuranuronyl)benzotriazoles 15 in good yields (Scheme [9]).[13]
In 2018, the Tiwari group explored work of Phakhodee and co-workers[9a] and utilized it for the synthesis of glycoconjugated N-acylbenzotriazoles and achieved excellent results.[9b] The Tiwari group played an active role in the development of various methodologies for the synthesis of N-acylbenzotriazoles 3 and illustrated it by the exploration and use of various reagents such as triphenylphosphine, NBS, PySSPy, or TClCA (trichloroisocyanuric acid) with diverse carboxylic acids 5 in the presence of dichloromethane as the solvent to obtain diverse N-acylbenzotriazole derivatives in appreciable yields (Scheme [10]).[14] [15] [16]
In 2021, the Tiwari group developed a new technique to synthesize aromatic and aliphatic derivatives of N-acylbenzotriazoles. The reaction was based on the activation of different carboxylic acids 5 with trichloroacetonitrile (CCl3CN) to produce an imidate intermediate, which reacts in situ with benzotriazole to furnish the desired N-acylbenzotriazoles 3.[17] The methodology is feasible for the synthesis of both aromatic as well as aliphatic N-acylbenzotriazoles (Scheme [11]).
In 2019, Laconde et al. demonstrated propylphosphonic anhydride solution T3P as an efficient reagent for the one-pot synthesis of Bt amino acid derivatives starting from N-protected 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 avoid tedious purification and toxic reagents. In addition, T3P was used for the synthesis of biotin and N-Fmoc polyethylene glycol derivatives.[18]
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]).[19] The reaction of diaryliodonium salts in the presence of BtH under one atmospheric pressure of carbon monoxide produced average-to-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]
Acid chlorides of N-protected amino acids have been known for a long time.[21] Most 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-α-aminoacyl)benzotriazoles 19 from Boc-α-amino acids 18 and BtSO2Me as the benzotriazole source (Scheme [14]).[7] N-(Boc-α-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-α-aminoacyl)benzotriazoles was considered for the synthesis of chiral α-(N-protected amino acid) amides without racemization.[7]
By 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.
# 3
Applications of N-Acylbenzotriazoles in Organic Synthesis
3.1N-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-to-good yields (Scheme [15]).[23]
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 solid-phase synthesis.[24] The synthetic pathway for amides 25 from amines 24 and N-acylbenzotriazoles is depicted in Scheme [16].
α-Methoxy-α-(trifluoromethyl)phenylacetic acid (MTPA, 26), also known as Mosher’s reagent, is used as a chiral derivatizing agent for defining both absolute configurations and enantiomeric excess of natural and synthetic amines and alcohols by NMR spectroscopy.[25] [26] MTPA 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]).[27]
In 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 isolated 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]).[28] In 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% H2O2 in the presence of n-Bu4N+HSO4 – in dichloromethane at 25 °C (Scheme [18b]).[29]
Amidines 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 N-imidoylbenzotriazoles (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]
(α-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 C-terminal N-protected dipeptidoyl amides in moderate-to-good 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 reaction 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]).[31]
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]).[32]
Peptide bond formation through the activation of carboxylic acid functional group of N-protected α-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-α-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]).[33]
The 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.[34] They 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]).[35]
The 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 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]
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.[37] A 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 β-N-glycoamino acids.[38] The group utilized easily available N-(Cbz- or Fmoc-α-aminoacyl)benzotriazoles 61 for the acylation of tetra-O-pivaloyl-β-d-galactopyranosylamine (60) under microwave irradiation conditions to afford the desired β-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 β-N-glycodipeptides from N-Cbz-protected peptidoyl benzotriazoles under similar reaction conditions in 3.5 h in good-to-high yields. 1D and 2D NMR techniques were used to reveal the regiospecific β-N-linkage.
The Katritzky group further used a chromene-based N-acylbenzotriazole 63 for the preparation of 2H-chromene-based conjugates 66 and 67 of natural amino acids 64 and N-acyl-1,ω-amino acids 65, respectively, at 20 °C in aqueous media (Scheme [27]).[39] The 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 ω-amino acid conjugates in DMF and DMSO with different chain lengths.
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 2-hydroxybenzaldehydes 69 in the presence of triethylamine under neat conditions (Scheme [28]).[40]
The Katritzky group also explored the chemistry of N-acylbenzotriazoles 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]).[41] The 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 Et3N 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-benzotriazolylpropanamides 77, and aliphatic amines react exclusively through the 1,2-addition pathway to afford good-to-high yields of cinnamides 76 (Scheme [30]).[42]
Simple synthesis of substituted 1,3,4,5-tetrahydro-1,5-benzodiazepine-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]).[42]
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-1,5-benzodiazepine-2-ones, in good-to-high yields. The desired product was obtained from the reaction of α,β-unsaturated 1-acylbenzotriazoles 80 with 2-aminobenzothiol (81) under similar reaction conditions (Scheme [32]).[43]
1,2,4-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.[44] The Katritzky group developed a convenient method for the synthesis of these biologically relevant 1,2,4-oxadiazoles 85 derived from chiral α-amino acids using N-protected N-(α-aminoacyl)benzotriazoles 83 (Scheme [33a]).[45] N-Protected N-(α-aminoacyl)benzotriazoles 83 reacted with p-tolyl-, 4-pyridinyl-, and benzylamidoximes in refluxing ethanol in the presence of catalytic Et3N 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 Et3N 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 1,2,4-oxadiazoles 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 SOCl2. Using a similar protocol, thiazolines 88 were synthesized using 2-aminoethanethiol hydrochloride in the presence of Et3N. 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.
N-Acylbenzotriazoles were applied for the efficient and high-yielding synthesis of biologically active 5-substituted-2-ethoxy-1,3,4-oxadiazoles 92 by Pattarawarapan and co-workers (Scheme [35]).[47] Their synthetic procedure involved a one-pot N-acylation/dehydrative cyclization between ethyl carbazate (91) and N-acylbenzotriazoles in the presence of Ph3P-I2 as a dehydrating agent. A variety of 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-ones 93 were also prepared in excellent yields from 5-substituted 2-ethoxy-1,3,4-oxadiazoles 92 by allowing them to react with a stoichiometric 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.[48]
The Katritzky group developed a novel benzotriazole-mediated methodology for the efficient synthesis of chiral oligoesters 96 and depsipeptides 99 through the reaction of O-Pg-(α-hydroxyacyl)benzotriazoles 94 and 97, respectively, by using unprotected α-hydroxycarboxylic acids 95 in the former and depsides 98 in the latter reaction (Scheme [36]).[49] The methodology also elaborated for the synthesis of amide conjugates by the reaction of O-Pg-(α-hydroxyacyl) with amines in satisfactory outcome.
An efficient methodology for O-acylation of various isopropylidene-protected monosaccharides with readily available N-(Cbz-α-aminoacyl)benzotriazoles 100 was established by the Katritzky group (Scheme [37]).[50] The reaction was performed under microwave irradiation in the presence of a catalytic amount of DMAP in THF solvent at 65 °C to afford the desired α-amino acid–sugar conjugates in good yields. Chiral O-(Cbz-α-aminoacyl) sugar products 101 and 102 were synthesized from 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (9) and 1,2:5,6-di-O-isopropylidene-d-glucose (12), respectively.
In a similar way, the Katritzky group reported the fluorescent labeling of various monosaccharides under microwave irradiation using N-(coumarin-3-carbonyl)benzotriazole 103.[51] The group achieved the convenient synthesis of various O-(coumarin-3-carbonyl) diisopropylidene sugars 104 and 105 through the O-acylation of isopropylidene-protected monosaccharides in the presence of catalytic amount of DMAP in DCM solvent at 60 °C. The preparation of O-(coumarin)diacetonide sugars 104 and 105 from 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (9) and 1,2:5,6-di-O-isopropylidene-d-glucose (12) is presented in Scheme [38].[51]
Similarly, l-lysine-scaffold based coumarin-labeled sugars were also prepared via O-and N-acylation using N ε-coumarin-3-carbonyl-N α-Cbz-l-lysine benzotriazoles 106 as the acylating agents. The synthesis of l-lysine-scaffold based coumarin-labeled monosaccharide product 107 and 108 from 1,2:3,4-di-O-isopropylidene-α-d-galactopyranose (9) and tetra-O-pivaloyl-β-d-galactopyranosylamine 60, respectively (Scheme [39]).[51]
Schick and co-workers devised a novel 1-acylbenzotriazole-mediated one-step synthesis of β-lactones 111 by the aldolization of carbonyl compounds (Scheme [40]).[52] N-Acylbenzotriazoles 109 containing one hydrogen atom in the α-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 O-lithiated β-hydroxyalkanoic acids 110. The carboxamide derivatives 110 then underwent cyclization followed by the elimination of lithium benzotriazolide to produce the desired di- and trisubstituted β-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 substrate-specific 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 good-to-excellent yields (76–99%).[3f] N-Acylbenzotriazoles reacted with thiophenol, benzyl mercaptan, ethyl mercaptoacetate, and mercaptoacetic acid in the presence of Et3N 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 Cbz-protected amino acid and dipeptide based N-acylbenzotriazoles 113 under similar reaction conditions (Scheme [41b]).
The Katritzky group demonstrated a novel methodology for the synthesis of aryl benzyl sulfoxides 116 in good-to-excellent yields (70–90%) from the reaction of N-(arylacetyl)benzotriazoles 68 with sodium sulfinates (Scheme [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.
# 3.2
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]).[54]
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 TiCl4 (at 23 °C) or ZnBr2 (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.[56] Synthesis of acylpyrroles can be easily achieved through the acylation of pyrroles. The Katritzky group performed the reaction of unsubstituted/1-substituted pyrroles with N-acylbenzotriazoles 3 in the presence of TiCl4, 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]
A convenient route for the synthesis of 1-substituted 2-azinylethanones 125 was reported by the Katritzky group through the acylation of alkylated azines 124 with N-acylbenzotriazoles. Various alkylazines (2-methylpyridine, 2-benzylpyridine, 4-benzylpyridine, 2-methylquinoline, 4-methylquinoline, or 4-methylpyrimidine) reacted with readily available N-acylbenzotriazoles in THF at –78 °C with LDA to furnish acylated products 125 in 50–95% yields (Scheme [46]).[57]
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-α-aminoacyl)benzotriazoles 126 and afforded N-(α-Cbz-aminoacyl)methylene heterocycles 127, 128, and 129, respectively (Scheme [47]).[58]
C-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 β-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 β-ketonitriles and α-mono- and α,α-disubstituted β-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] In addition, sulfones were also converted into β-keto sulfones 132 (Scheme [48]). Aliphatic, aromatic, and heteroaromatic β-keto sulfones were prepared in 70–96% yields using n-butyllithium. β-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 β-keto sulfones show evidence of fungicidal activity,[69] and some are used as precursors for synthesis of optically active β-hydroxy sulfones.[70]
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 step involves 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)-2,2-dimethyl-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.
β- and γ-Amino acid derivatives are the key motifs for several biologically relevant compounds as well as in natural products.[72] A versatile approach was developed for the synthesis of ω-aryl-substituted β- and γ-amino acid derivatives (Scheme [50]).[73] The treatment of N-Tfa-amino acid monoesters 136 (Tfa = trifluoroacetyl) with thionyl chloride and benzotriazole in dichloromethane afforded 1-(N-Tfa-α-aminoacyl)benzotriazoles 137, which on Friedel–Crafts reaction with aromatic compounds provided α-amino ketones 138. The reduction of α-amino ketones with sodium borohydride or with triethylsilane afforded the corresponding ω-aryl-substituted β- and γ-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 α-position with respect to the carbonyl carbon provides specificity this type of molecule. Their existence offers viable reactivity patterns to compounds like α-nitro ketones. α-Nitro ketones are important precursors used in the synthesis of compounds with chemotherapeutic applications. The Katritzky group established a method for the synthesis of α-nitro ketones by the application of N-acylbenzotriazoles (Scheme [51]).[3h] The reaction of nitro alkanes 140 with 2.0 equiv potassium tert-butoxide resulted in the generation of a doubly metalated complex 141 that reacted with various substituted N-acylbenzotriazoles to furnish functionalized α-nitro ketones 142 in up to 86% yields.
Other intermediates involving C-acylation were explored with N-acylbenzotriazole derivatives such as the acylation of metalated ketimines 143 (1.0 equiv) was accomplished in the presence of LDA (2.0 equiv) in anhydrous THF at 0 °C using N-acylbenzotriazoles as acylating agents, producing enaminones 144 (Scheme [52]).[74] Enaminones are very important compounds and used as synthetic intermediates in various heterocyclic moieties, e.g., carbazolequinone alkaloids[75] pyrroles,[76] isoxazoles,[77] tricyclic benzo[a]quinolizines,[78] and benzodiazepines.[79]
# 3.3
Preparation of β-Keto Esters and β-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 β-keto esters in high yields (Scheme [53]).[80] This one-pot, two-step 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 the reaction with NH4Cl in the second step. The crude product was then exposed to silica gel column chromatography, and β-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 α-substituted β-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 β-keto esters is not available proficiently in previous reports.
Similarly, by acylative deacetylation, α-acetyl ketones were transformed into more complex β-diketones 148 (Scheme [55]).[80] In this type of reaction, triketones are the expected intermediates, which subsequently undergo reaction by Japp–Klingemann mechanism with loss of the acetyl group.[81] In 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 β-diketone in which only the central carbon atom of acetylacetone is preserved. Symmetrical β-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.
# 3.4
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.[82] Preparation 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]).[83] Thus, by using benzotriazole and easily available starting materials, auxiliary 1,2-diketones 149 were synthesized under mild reaction conditions.
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]
Further, the Katritzky group reported synthesis of predominantly trans-isomers 155 of 3-alkyl-4,6-diaryl-3,4-dihydropyran-2-ones in good yields (Scheme [58]).[85] In this reaction, lithiated aliphatic unbranched N-acylbenzotriazoles undergo 1,4-addition with α,β-unsaturated aromatic ketones 153 to produce 154, which afforded the diastereomeric mixture of 3,4-dihydropyran-2-ones 155 and 156 with predominance of trans-isomer 155 in 70% yield.
Coltart and co-workers further explored N-acylbenzotriazoles in the acylation of enolizable thioesters to give β-keto thiolesters 158 (Scheme [59]).[86] In the presence of MgBr2·OEt2 and i-Pr2NEt, the thiolesters 157 undergo chemoselective soft enolization followed by acylation by N-acylbenzotriazoles in DCM in air to afford β-keto thiolesters 158. The obtained β-keto thiolesters 158 are very stable and also these are synthetic equivalents of β-keto acids and can be transformed directly into β-keto esters 159 and β-keto amides 160 after treatment with an alcohol or an amine, respectively, in the presence of silver trifluoroacetate in THF. The β-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 2-morpholino-8-phenyl-4H-chromen-4-one (165), an important PI3-K inhibitor, by utilizing the C–C bond forming protocol. First, the β-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]).[86]
Chafuroside 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 β-diketone intermediate 168 in 95% yield. Under acidic conditions, using the Amberlyst 15 catalyst, derivative 168 undergoes a ring-closing 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.[87]
In another investigation, a group from Roche used an N-acylbenzotriazole for the construction of the 1H-pyrido[2,3-d]pyrimidine system (Scheme [62]).[88] Efficient 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 β-keto ester 173, which undergoes cyclocondensation reaction on treatment with DBU and N,N-diisopropylethylamine at 120 °C to furnish 174 in 97% yield.
The synthesis of a variety of heterocyclic compounds has frequently utilized aryl isocyanates.[89] [90] The Katritzky group further demonstrated the versatility of benzotriazoles by establishing a protocol for N-acylbenzotriazole-mediated synthesis of various polycyclic heteroaromatic compounds (Scheme [63]).[91] In 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]).[91] These products 175–179 were constructed through the incorporation of 3, 3, 4, 2, and 2 molecules, respectively, of aryl isocyanate per N-acylbenzotriazole molecule.
Barrett and co-workers reported a N-acylbenzotriazole-mediated synthesis of an isoquinolone 184, a part of the antifungal agent Sch 56036 (Scheme [64]).[93] Acetal 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.
Bicyclic pyrrolizines were synthesized by the Katritzky group starting from N-acylbenzotriazole 185, obtained through the reaction of N-Cbz-l-proline with benzotriazole and thionyl chloride (Scheme [65]).[94] The reaction of N-acylbenzotriazole 185 with ethyl (triphenylphosphoranylidene)acetate afforded (2S)-1-Cbz-2-[(ethoxycarbonyl)(triphenylphosphoranylidene)acetyl]pyrrolidine 186 in 66% yield. Deprotection of pyrrolidine 186 by H2/Pd(C) followed by ring closure resulted in formation of pyrrolizine-1,3-dione 188. In a similar way, reaction of N-acylbenzotriazole 185 with (triphenylphosphoranylidene)acetonitrile gave (2S)-1-Cbz-2-[cyano(triphenylphosphoranylidene)acetyl]pyrrolidine 187. Deprotection of pyrrolidine 187 with 33% HBr in acetic acid followed by cyclization afforded 3H-1-ammonio-2-(triphenylphosphonio)-5,6,7,7a-tetrahydropyrrolizin-3-one dibromide 189 in 66% yield.
The Katritzky group exploited a practical route using benzotriazole-mediated methodology for an efficient and high yielding synthesis of 1,3-benzodioxin-4-ones 191, 1,3-benzoxazine-2,4-diones 192, naphtho-1,3-dioxinones 194, and naphthoxazine-1,3-diones 195 (Scheme [66]).[95] The reaction of N-(o-hydroxyarylcarbonyl)benzotriazoles 190 and 193 with various aldehydes in anhydrous THF as solvent in the presence of base furnished 1,3-benzodioxin-4-ones 191 and naphtho-1,3-dioxinones 194, respectively at room temperature, whereas, under the similar reaction conditions, their reaction with suitable isocyanates produced 1,3-benzoxazine-2,4-diones 192 and naphthoxazine-1,3-diones 195, respectively, in excellent yields. Both aromatic and aliphatic aldehydes and isocyanates were well tolerated as substrates in this methodology.
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]).
The reaction was carried out between N-(phenylpropynoyl)benzotriazole 202 and substituted 2-aminopyridines in acetonitrile solvent in a sealed tube at 120 °C for 12 h which furnished the pyrido[1,2-a]pyrimidin-2-ones 200 in good yields (71–73%) (Scheme [67]).[100] Similarly, the reaction of N-(phenylpropynoyl)benzotriazole 202 with substituted 2-picolines under same reaction conditions afforded 2H-quinolizin-2-ones 201 in moderate-to-good yields (39–81%).
The group also applied this methodology to the preparation of fused ring systems of pyrido[1,2-a]quinolin-3-one 203 and thiazolo[3,2-a]pyrimidin-7-one 204. The reaction of 2-methylquinoline with N-(phenylpropynoyl)benzotriazole 202 in acetonitrile in a sealed tube at 120 °C afforded pyrido[1,2-a]quinolin-3-one 203 in 40% yield. Likewise, the 5-phenyl-7H-thiazolo[3,2-a]pyrimidin-7-one (204) was obtained in 54% yield from the reaction of 2-aminothiazole with N-(phenylpropynoyl)benzotriazole 202 under similar reaction conditions (Scheme [67]).[100]
In their next investigation, the Katritzky group utilized N-acylbenzotriazoles of various aliphatic and aromatic α,β-unsaturated carboxylic acids as stable and easily accessible acylating agents for the regioselective C-acylation of various ketones 205 in order to synthesize medicinally active γ,δ-unsaturated β-diketones (Scheme [68]).[101] The desired γ,δ-unsaturated β-diketones 207 and 208 were prepared from the reaction N-(α,β-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]).[102] N-Protected l-glutamic acid 209 was used for the acylation of 1H-benzotriazole 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.
Mintas, Zorc, and co-workers reported a benzotriazole-mediated methodology for synthesis of 3,5-disubstituted hydantoin (imidazolidine-2,4-dione) derivatives 216 through cyclization of the corresponding N-(benzotriazol-1-ylcarbonyl)-l- and d-amino acid amides 215 in the presence of a base (Scheme [70]).[103] 1-(Chloroformyl)benzotriazoles 212 were prepared from benzotriazole using a previously reported method.[104] The 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.
A general and convenient method for the synthesis of 4-carbamoyl-1,2,3-triazoles 219 from N-(phenylpropynoyl)benzotriazole 202 under microwave irradiation has been reported by the Katritzky group (Scheme [71]).[105] First, the condensation of phenylpropynoic acid with 1-(methylsulfonyl)benzotriazole produced N-(phenylpropynoyl)benzotriazole 202, which on [3+2] cycloaddition reaction with benzyl azide (217) in toluene under microwave irradiation furnished substituted 4-(benzotriazol-1-ylcarbonyl)-1,2,3-triazole 218. The treatment of 218 with various amines in DCM at room temperature provided corresponding 4-carbamoyl-1,2,3-triazoles 219 in 54–91% yields after elimination of the benzotriazole moiety.
A novel protocol was devised by the Katritzky group for one-step synthesis of various important bicyclic compounds with fused pyrrole, indole, oxazole, and imidazole rings (Scheme [72]).[106] Easily available and stable benzotriazol-1-yl(1H-pyrrol-2-yl)methanone 220 reacted with various ketones, isocyanates, and isothiocyanates in the presence of a strong, non-nucleophilic base such as DBU in THF to give pyrrolo[1,2-c]oxazol-1-ones 221 and pyrrolo[1,2-c]imidazoles 222 and 223, respectively, in a simple one-step method. This protocol was also utilized for the synthesis of oxazolo[3,4-a]indol-1-ones 225 and related imidazo[1,5-a]indoles 226 and 227 from benzotriazol-1-yl(1H-indol-2-yl)methanone 224 in one-step.
In 2016, the Tiwari group implemented a plan for the synthesis of diverse urea, carbamates and thiocarbamates via the Curtius rearrangement in different solvent compositions at elevated temperatures (Scheme [73]).[107] Readily available N-acylbenzotriazoles reacted with NaN3 in THF/water (85:15) at 90 °C, H2O/alcohol (1:19) at 90 °C for 4 h, and thiol/water (90:10) at 100 °C to afford the symmetrical ureas 228, carbamates 229, and thiocarbamates 230, respectively.
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 TMSN3 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 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.[108]
Furthermore 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.[109] The 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/H2O (3:1) at room temperature afforded N-acylcysteines 235 exclusively in 51–86% yields, whereas, S-acylcysteines 236 were obtained 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 α,β-unsaturated derivatives, side reactions such as Curtius rearrangements and racemization of the chiral center in case of amino acid derivatives.
The Katritzky group utilized the fascinating chemistry of N-acylbenzotriazoles for the preparation of amidines from the condensation reaction of readily available mono- and diisocyanates and N-acylbenzotriazoles (Scheme [78]).[110] The one-pot reaction was performed at 200 °C in a sealed tube under neat conditions for 24 h to afford various aryl 238a–d, heteroaryl 238e, bulky aliphatic 238f, and difunctionalized 1-imidoylbenzotriazoles 239 in 71–99% yields. This protocol was also efficiently utilized for the direct synthesis of (arylamino)heterocycles, such as 4-(arylamino)quinoline 241 from quinolin-4(1H)-one (240), in 71–96% yields
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-acylbenzotriazole intermediates were obtained by the activation of hydroxy carboxylic acids without prior protection of the hydroxy substituent.[111]
Furthermore, 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]).[112] They also utilized sulfonyl azide 249 as an efficient diazo transfer reagent for the convenient preparation of N-(α-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]).
# 3.5
Benzotriazole Ring Cleavage (BtRC) Reactions
Natural products and pharmaceuticals both frequently contain fused heterocycles that contain nitrogen.[113] [114] [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.[116] Nowadays, benzotriazole ring cleavage (BtRC) reaction have become an indispensable tool for the synthesis of various types of heterocyclic and amides derivatives.[117]
In 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 cycloaddition 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 2-haloanilides in metal-catalyzed coupling reactions.[117a]
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.
A similar but modified approach came from the Glorius group for the efficient preparation of ortho-alkylated N-arylbenzamides 262 (R = aroyl) (Scheme [85]).[118] They 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.
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.[119] Various 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.[120]
By using a denitrogenative process, the Glorius group reported a novel visible-light-promoted borylation and thiolation of benzotriazoles using B2pin2 264 and alkyl disulfides 266, respectively, to produce ortho-functionalized N-arylbenzamide derivatives 265 (Scheme [87]) and 267 (Scheme [88]).[118] On 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-light-induced denitrogenative phosphorylation of N-aroylbenzotriazoles with phosphites under mild conditions (Scheme [89]).[121] N-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 furnished 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.[117`] [j] [k] [l] [m] [n] [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 ring-opening process in the presence of n-Bu3SnH/AIBN.[117o] In addition, the byproduct tin dimer was reduced by using NaBH4 to regenerate the n-Bu3SnH reagent. This reduces the consumption of n-Bu3SnH 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.[122] The synthesis of the benzimidazole system goes through ring cleavage of benzotriazoles followed by successive ring closure. 1-Acylamido-2-alkyl/aryl-substituted benzimidazoles 272 were synthesized by the reduction of 1-acylbenzotriazoles 3 using samarium(II) iodide (2 equiv) in 43% (R = 4-ClC6H4) to 82% (R = c-C6H11) yields (Scheme [92]). Different results were obtained by varying substitution in substrate and solvents, for instance, in case of R = 4-MeOC6H4, 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 SmI2. However, there is not any certain clear mechanism regarding the transformation.
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]).[123] They 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 SNAr substitution of a 2-haloheterocycle, in situ oxidation, and amine displacement. N-Containing heteroaryl amides can be synthesized efficiently from the corresponding halides in a prompt one-pot 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-1-ylacetonitrile (281) in the presence of sodium hexamethyldisilazanide (NaHMDS) at room temperature (Scheme [94]).[124] The 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.
#
# 4
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.[125] Several ligand-mediated approaches were reported for the synthesis of heterocycles via coupling reactions.[126]
In 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]).[127] Both complexes were capable of catalyzing the hydrogenation of styrene and oct-1-ene and were fully soluble in 1-butyl-3-methylimidazolium tetrafluoroborate [bmim][BF4]. 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][BF4] 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, H2 (g) pressure, and catalyst amount was investigated, and it was observed that the conversion increased in tandem with the rising temperature and H2 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]
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 K2CO3 (1.2 equiv) in DMF at 120 °C for 8 h to obtain benzoxazoles 290 in up to 93% yield (Scheme [96]).[128] The 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.
# 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.[130] The structures of some biologically potent N-acylbenzotriazoles are depicted in Figure [3]. For example, N-acyl/aroylbenzotriazoles 291 (IC50 = 1.7 nM) and 292 (IC50 = 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.[131] Furthermore, compound 291 has moderate HDAC inhibitory activity. It depicts the necessity of more series and molecular library exploration.
The antidiabetic activity of compound 293 (IC50 = 2.99 ± 1.43 mM against α-amylase and IC50 = 3.00 ± 1.21 mM against α-glucosidase) was reported by Khan and co-workers.[132] Molecular 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 α-amylase and noncompetitive mode of inhibition against α-glucosidase enzyme. The NHE-1 inhibitory via in vitro platelet swelling assay of N-aroylbenzotriazoles with an oxygen atom in benzoyl 294 (IC50 = 51.57 mM) and a sulfonyl group 295 (IC50 = 50.89 mM) and 296 (IC50 = 49.95 mM) was reported by Singh and Silakari.[133]
In a free radical scavenging study, N-acylbenzotriazole analogue 297 exhibited appreciable DPPH (2,2-diphenyl-1-picrylhydrazyl) 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.[134] Bis-N-aroylbenzotriazole 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 anti-inflammatory 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%.[135] Tasneem et al. reported the antitubercular activity of compound 299 (minimal inhibitory concentration, MIC = 4.5 μg/mL against M. tuberculosis compared to first line drugs, streptomycin (MIC = 7.5 μg/mL) and pyrazinamide (MIC = 10 μg/mL).[136]
Interestingly, Cu(II) coordinated N-aroylbenzotriazole complex 300 displayed potent antibacterial activity.[137] This 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 N-acyl/aroylbenzotriazole agents against other diseases along with opening up new prospects for the motif.
# 6
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 important 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.
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Conflict of Interest
The authors declare no conflict of interest.
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Corresponding Author
Publication History
Received: 14 May 2023
Accepted after revision: 16 August 2023
Accepted Manuscript online:
21 August 2023
Article published online:
27 September 2023
© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by/4.0/)
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