Azides in the Synthesis of Various Heterocycles

In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal, catalyzed, or noncatalyzed reaction conditions. The aforementioned reactions in the aim to prepare basic five-, six-, organometallic heterocyclic-membered systems and/or their fused analogs. This review article also provides a report on the developed methods describing the synthesis of various heterocycles from organic azides, especially those reported in recent papers (till 2020). At the outset, this review groups the synthetic methods of organic azides into different categories. Secondly, the review deals with the functionality of the azido group in chemical reactions. This is followed by a major section on the following: (1) the synthetic tools of various heterocycles from the corresponding organic azides by one-pot domino reaction; (2) the utility of the chosen catalysts in the chemoselectivity favoring C−H and C-N bonds; (3) one-pot procedures (i.e., Ugi four-component reaction); (4) nucleophilic addition, such as Aza-Michael addition; (5) cycloaddition reactions, such as [3+2] cycloaddition; (6) mixed addition/cyclization/oxygen; and (7) insertion reaction of C-H amination. The review also includes the synthetic procedures of fused heterocycles, such as quinazoline derivatives and organometal heterocycles (i.e., phosphorus-, boron- and aluminum-containing heterocycles). Due to many references that have dealt with the reactions of azides in heterocyclic synthesis (currently more than 32,000), we selected according to generality and timeliness. This is considered a recent review that focuses on selected interesting examples of various heterocycles from the mechanistic aspects of organic azides.


Introduction
Organic azides are organic compounds containing the azide (N 3 ) functional group. Due to the hazards associated with their use, few azides are commercially used, although

Introduction
Organic azides are organic compounds containing the azide (N3 Due to the hazards associated with their use, few azides are commerci they display interesting applications in organic chemistry. Organic az someric structures (1a-1d, Figure 1), and their structure is also describ with carbon dioxide. The polar character of the azido group has a remarkable effect on and angles. In methyl azide, as an example, the angles of CH3-N 1 -N 2 N 3 are approximately 115. 28 and 172.58 Å, respectively [1]. Aromatic a shorter bond lengths between N 2 and N 3 [1]. Accordingly, an almost lin is present, with sp 2 hybridization at N 1 . The polar resonance structur that strong IR absorption by a band at nearly 2114 cm −1 (phenyl azid show absorption in the UV region at 287 nm and 216 nm [2]. They also e moment (1.44 D for phenyl azide) [2]. Azido group in aromatic substi rects to ortho-and para-positions.
Organic azides engage in useful organic reactions, as the termina nucleophilic. Generally, nucleophiles attack the azide at the terminal electrophiles react at the internal atom Nα [3]. Azides easily extrude d tendency that is engaged in many reactions, such as the Staudinger liga rearrangement [4]. Azides can be reduced to amines by hydrogenolysis phine (e.g., triphenylphosphine) in the Staudinger reaction [5]. Organ with phosphines to give iminophosphoranes, which can be hydrol amines (the Staudinger reaction) [6]. They react with carbonyl compou (the aza-Wittig reaction) [7,8] or undergo other transformations. Ther of azides gives nitrenes, which participate in various reactions; vinyl into 2H-azirines [9].
Since organic azides are highly reactive and have been long esta building blocks in assembling structurally diverse N-containing heter organic azides into high-value compounds, such as heterocycles, woul and a subject of enormous current interest. Currently, well over 32,0 1000 in 2021 showed interest in this type of chemistry.

From Diazonium Salts
The aryl diazonium salts were decomposed readily on reacting wi or Me3SiN3) to the corresponding aryl azide without a catalyst. As an conversion of 5-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dion (2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (2) via a two-step reactio tization followed by azidation using sodium azide as a precursor of azi The polar character of the azido group has a remarkable effect on their bond lengths and angles. In methyl azide, as an example, the angles of CH 3 -N 1 -N 2 N 3 and CH 3 N 1 -N 2 -N 3 are approximately 115. 28 and 172.58 Å, respectively [1]. Aromatic azides show slightly shorter bond lengths between N 2 and N 3 [1]. Accordingly, an almost linear azide structure is present, with sp 2 hybridization at N 1 . The polar resonance structures Ib-Id illustrated that strong IR absorption by a band at nearly 2114 cm −1 (phenyl azide [2]). Alkyl azides show absorption in the UV region at 287 nm and 216 nm [2]. They also exhibit weak dipole moment (1.44 D for phenyl azide) [2]. Azido group in aromatic substitution reactions directs to orthoand para-positions.
Organic azides engage in useful organic reactions, as the terminal nitrogen is mildly nucleophilic. Generally, nucleophiles attack the azide at the terminal nitrogen N γ , while electrophiles react at the internal atom N α [3]. Azides easily extrude diatomic nitrogen, a tendency that is engaged in many reactions, such as the Staudinger ligation or the Curtius rearrangement [4]. Azides can be reduced to amines by hydrogenolysis [5] or with a phosphine (e.g., triphenylphosphine) in the Staudinger reaction [5]. Organic azides can react with phosphines to give iminophosphoranes, which can be hydrolyzed into primary amines (the Staudinger reaction) [6]. They react with carbonyl compounds to give imines (the aza-Wittig reaction) [7,8] or undergo other transformations. Thermal decomposition of azides gives nitrenes, which participate in various reactions; vinyl azides decompose into 2H-azirines [9].
Since organic azides are highly reactive and have been long established as versatile building blocks in assembling structurally diverse N-containing heterocycles, converting organic azides into high-value compounds, such as heterocycles, would be greatly valued and a subject of enormous current interest. Currently, well over 32,000 total and nearly 1000 in 2021 showed interest in this type of chemistry.
Organic azides engage in useful organic reactions, as the terminal nitroge nucleophilic. Generally, nucleophiles attack the azide at the terminal nitroge electrophiles react at the internal atom Nα [3]. Azides easily extrude diatomic tendency that is engaged in many reactions, such as the Staudinger ligation or rearrangement [4]. Azides can be reduced to amines by hydrogenolysis [5] or w phine (e.g., triphenylphosphine) in the Staudinger reaction [5]. Organic azide with phosphines to give iminophosphoranes, which can be hydrolyzed in amines (the Staudinger reaction) [6]. They react with carbonyl compounds to (the aza-Wittig reaction) [7,8] or undergo other transformations. Thermal dec of azides gives nitrenes, which participate in various reactions; vinyl azides into 2H-azirines [9].
Since organic azides are highly reactive and have been long established building blocks in assembling structurally diverse N-containing heterocycles, organic azides into high-value compounds, such as heterocycles, would be gre and a subject of enormous current interest. Currently, well over 32,000 total 1000 in 2021 showed interest in this type of chemistry.
Molecules 2022, 27, x FOR PEER REVIEW 5 of 81 the reactions proceeded smoothly to give the target products 12a-r in high yields ranging from 72 to 99%. Moreover, different aryl azides were selected to react with tryptophol (2-(5-chlorobenzofuran-3-yl)ethanol) (11e) under the optimized reaction conditions to investigate the effect of substituents on the products' yields. The suggested mechanism describes the formation of furroindole 12a, as shown Scheme 9 [16]. Firstly, the azide moiety reacted with copper complex to produce cop nitrene complex A, which abstracts a hydrogen atom from compound 11a to form copper aminyl species B and imine radical C, which combines to produce the intermedi D. The catalyst moiety was then excluded from the intermediate D to form the imine s cies E. Finally, E was converted to the desired product 12a via an intramolecular nucl philic addition [16]. The suggested mechanism describes the formation of furroindole 12a, as shown in Scheme 9 [16]. Firstly, the azide moiety reacted with copper complex to produce copper nitrene complex A, which abstracts a hydrogen atom from compound 11a to form the copper aminyl species B and imine radical C, which combines to produce the intermediate D. The catalyst moiety was then excluded from the intermediate D to form the imine species E. Finally, E was converted to the desired product 12a via an intramolecular nucleophilic addition [16].
Molecules 2022, 27, x FOR PEER REVIEW 7 of 81 Scheme 9. A plausible mechanism described the formation of compound 12a.

Organic Azides in the Synthesis of Heterocycles
Organic azides have synthesized various heterocycles of the five-member ring with one heteroatom, such as pyrroles. They are also involved in synthesizing heterocycles with two heteroatoms, such as pyrazole and isoxazole, oxazole, thiazole, oxazine, and pyrimidine. In addition, heterocycles containing three heteroatoms, such as 1,2,3-triazoles and thiadiazole, are also included. Furthermore, organic azides are used in synthesizing An interest application of previously reported work, was directed towards synthesizing a large family of botanical natural products group named husbanan [17]. Husbanan was synthesized from ethyl 2-phenethylcyclohex-1-enecarboxylate (21), which initially underwent reduction followed by partial re-oxidation to the aldehyde 22 (i.e., from ester to alcohol then aldehyde using tetrapropylammonium perruthenate (TPAP), and N-methylmorpholine N-oxide (NMO)). Aldehyde 22 was elaborated by Corey-Chaykovsky epoxidation. Epoxide 23 was opened with NaN 3 in acetone/water yielding the allylic azide 24. Imidate 25 was isolated after activation with trichloroacetonitrile. Finally, reduction of imidate 25 gave 26 on the presence of dicyclohexyl borane ring closer to the hasubanan product 27 [17] (Scheme 14). Finally, the tetraline 14a was converted into pyrrolidine 19 [17]. At the same time, the cycloaddition reaction of the tetraline 14a with dimethyl acetylene dicarboxylate gave the triazole 20 (Scheme 13). An interest application of previously reported work, was directed towards synthesizing a large family of botanical natural products group named husbanan [17]. Husbanan was synthesized from ethyl 2-phenethylcyclohex-1-enecarboxylate (21), which initially underwent reduction followed by partial re-oxidation to the aldehyde 22 (i.e., from ester to alcohol then aldehyde using tetrapropylammonium perruthenate (TPAP), and Nmethylmorpholine N-oxide (NMO)). Aldehyde 22 was elaborated by Corey-Chaykovsky epoxidation. Epoxide 23 was opened with NaN3 in acetone/water yielding the allylic azide 24. Imidate 25 was isolated after activation with trichloroacetonitrile. Finally, reduction of imidate 25 gave 26 on the presence of dicyclohexyl borane ring closer to the hasubanan product 27 [17] (Scheme 14).

Organic Azides in the Synthesis of Heterocycles
Organic azides have synthesized various heterocycles of the five-member ring with one heteroatom, such as pyrroles. They are also involved in synthesizing heterocycles with two heteroatoms, such as pyrazole and isoxazole, oxazole, thiazole, oxazine, and pyrimidine. In addition, heterocycles containing three heteroatoms, such as 1,2,3-triazoles and thiadiazole, are also included. Furthermore, organic azides are used in synthesizing

Organic Azides in the Synthesis of Heterocycles
Organic azides have synthesized various heterocycles of the five-member ring with one heteroatom, such as pyrroles. They are also involved in synthesizing heterocycles with two heteroatoms, such as pyrazole and isoxazole, oxazole, thiazole, oxazine, and pyrimidine. In addition, heterocycles containing three heteroatoms, such as 1,2,3-triazoles and thiadiazole, are also included. Furthermore, organic azides are used in synthesizing heterocycles of six-membered rings and with one heteroatom, such as pyridine, isoquinoline, and phenanthridine. Heterocycles with four heteroatoms, such as tetrazole, are also discussed.
Synthetic interest applications of organometal heterocycles (i.e., phosphorus-, boron-, and aluminum-containing heterocycles) were also investigated. Figure 2 indicates the contribution of organic azides in heterocyclic synthesis. heterocycles of six-membered rings and with one heteroatom, such as pyridine, isoquinoline, and phenanthridine. Heterocycles with four heteroatoms, such as tetrazole, are also discussed. Synthetic interest applications of organometal heterocycles (i.e., phosphorus-, boron-, and aluminum-containing heterocycles) were also investigated. Figure 2 indicates the contribution of organic azides in heterocyclic synthesis.

Synthesis of the Pyrrole Ring
Dong and others [18] reported that dipyrrin-supported nickel catalyst ( AdF L)Ni(py) ( AdF L: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) catalyzed the productive intramolecular C−H bond amination to give N-heterocyclic products 28a-k using aliphatic azide substrates. The catalytic amination conditions were mild, requiring 0.1−2 mol% catalyst, and occurred at room temperature. The amination process occurred using different substrates having multiple activatable C−H bonds (Schemes 15 and 16). The selective catalyst showed high chemoselectivity favoring C−H bonds in ethers, halides, thioethers, esters, etc. (Scheme 17). Sequential cyclization of substrates with ester groups was achieved to provide facile preparation of indolizidine derivatives found in various alkaloids [18].

Synthesis of the Pyrrole Ring
Dong and others [18] reported that dipyrrin-supported nickel catalyst ( AdF L)Ni(py) ( AdF L: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine) catalyzed the productive intramolecular C−H bond amination to give N-heterocyclic products 28a-k using aliphatic azide substrates. The catalytic amination conditions were mild, requiring 0.1−2 mol% catalyst, and occurred at room temperature. The amination process occurred using different substrates having multiple activatable C−H bonds (Schemes 15 and 16). The selective catalyst showed high chemoselectivity favoring C−H bonds in ethers, halides, thioethers, esters, etc. (Scheme 17). Sequential cyclization of substrates with ester groups was achieved to provide facile preparation of indolizidine derivatives found in various alkaloids [18]. The amination cyclization reaction mechanism is illustrated in Scheme 18. Benzene (4-azido-4-methyl pentyl), as an example, releases pyridine and N2 from L to give the corresponding nickel iminyl species A. The next step would be a hydrogen atom abstraction to give radical B, followed by radical recombination to give the cyclized product 28a [18]. The amination cyclization reaction mechanism is illustrated in Scheme 18. Benzene (4-azido-4-methyl pentyl), as an example, releases pyridine and N 2 from L to give the corresponding nickel iminyl species A. The next step would be a hydrogen atom abstraction to give radical B, followed by radical recombination to give the cyclized product 28a [18].
The amination cyclization reaction mechanism is illustrated in Scheme 18. (4-azido-4-methyl pentyl), as an example, releases pyridine and N2 from L to give responding nickel iminyl species A. The next step would be a hydrogen atom abs to give radical B, followed by radical recombination to give the cyclized product Scheme 18. The postulated reaction mechanism for the formation of pyrroles and C-H am Scheme 18. The postulated reaction mechanism for the formation of pyrroles and C-H amination.

Entry
Energy The reaction mechanism was described as a result of the denitrogenative decomposition process of α-keto vinyl azides, 1,3-amino group migration, and c of intermediates 43-48 with secondary amines, as shown in Scheme 25 [22]. The reaction mechanism was described as a result of the denitrogenative photodecomposition process of α-keto vinyl azides, 1,3-amino group migration, and coupling of intermediates 43-48 with secondary amines, as shown in Scheme 25 [22]. The reaction mechanism was described as a result of the denitrogenative photodecomposition process of α-keto vinyl azides, 1,3-amino group migration, and coupling of intermediates 43-48 with secondary amines, as shown in Scheme 25 [22].

Synthesis of the Pyrazole Ring
Quiclet-Sire et al. [23] reported syntheses of tetrahydropyrrolo-pyrazole from hydrazones of pendant alkene using iodine in a basic medium as a catalyst. In contrast, Jahn et al. [24]
Previously, a cycloaddition reaction was reported between cinnamyl azide and methyl acrylates to obtain the tetrahydro-pyrrole-pyrazole [26,27]. Recently, Carlson et al. [28] developed the previously mentioned procedure via stereoselective interaction between allylic azides and acrylates in high yields. The development includes (i) secondary and tertiary azides, (ii) the use of an enantioenriched azide, (iii) cinnamyl azides substituted at the α or β-carbon, (iv) derivatization of the products, and (v) additional Michael acceptors. Interestingly, it was found the following sequences: (A) the reaction was not completed during the reaction with cinnamoyl azide 66a, (B) 1 equivalent of acrylate 43 did not consume the azide at room temperature for three d, and (C) quantitative intermediates 67a-69a were obtained (Scheme 31). Optimization of acrylates 43 with cinnamoyl azides with aryl group of electrons withdrawing character has been investigated in Scheme 32. Re-optimization of reaction conditions such as (i) solvent, (ii) concentration, (iii) temperature, (iv) equivalents of acrylate, (v) time, and (vi) addition of DIPEA. It was found that the reaction proceeds well with a variety of cinnamoyl azides and the yields were improved. When DIPEA was used as a solvent compound, 70b was obtained with a 94% yield (Scheme 33). Optimization of the reaction in the scope of the substrate, incorporating methyl or phenyl group adjacent to the azide, for compound 70o a diastereomer was observed. Furthermore, cyclic azide resulted in the formation of tricyclic compounds 70u-w, as demonstrated in Scheme 34 [28]. Previously, a cycloaddition reaction was reported between cinnamyl azide and methyl acrylates to obtain the tetrahydro-pyrrole-pyrazole [26,27]. Recently, Carlson et al. [28] developed the previously mentioned procedure via stereoselective interaction between allylic azides and acrylates in high yields. The development includes (i) secondary and tertiary azides, (ii) the use of an enantioenriched azide, (iii) cinnamyl azides substituted at the α or β-carbon, (iv) derivatization of the products, and (v) additional Michael acceptors. Interestingly, it was found the following sequences: (A) the reaction was not completed during the reaction with cinnamoyl azide 66a, (B) 1 equivalent of acrylate 43 did not consume the azide at room temperature for three d, and (C) quantitative intermediates 67a-69a were obtained (Scheme 31). Optimization of acrylates 43 with cinnamoyl azides with aryl group of electrons withdrawing character has been investigated in Scheme 32. Re-optimization of reaction conditions such as (i) solvent, (ii) concentration, (iii) temperature, (iv) equivalents of acrylate, (v) time, and (vi) addition of DIPEA. It was found that the reaction proceeds well with a variety of cinnamoyl azides and the yields were improved. When DIPEA was used as a solvent compound, 70b was obtained with a 94% yield (Scheme 33). Optimization of the reaction in the scope of the substrate, incorporating methyl or phenyl group adjacent to the azide, for compound 70o a diastereomer was observed. Furthermore, cyclic azide resulted in the formation of tricyclic compounds 70u-w, as demonstrated in Scheme 34 [28]. Scheme 31. Synthesis of tetrahydro-pyrrole-pyrazoles 67a-70a. Reagents and conditions: (a) THF 5 mL, r.t 3 d.

Solvent
Additive

Synthesis of Oxazole, Thiazole, and Oxazine Derivatives
The reaction of substituted vinyl azides 74 with a combination of substoichiometric amounts of iron(II) chloride and Togni's trifluomethylating reagent 75 resulted in the formation of 2,2,2-trifluoroethyl-substituted 3-oxazolines 76, 3-thiazolines 77, and 5,6-dihydro-2H-1,3-oxazines 78. It was found that the optimal reaction conditions clarified that DCM, DCE, DMF, and 1,4-dioxane were solvents of choice, and the temperature varied from 80 • C to ambient temperature (Scheme 36) [30]. The proposed mechanism described the formation of compound 76a. It showed the role of Fe II in the reaction steps and its activation of Togni's reagent via the formation of intermediates A-C; deprotonation was then achieved by the Fe III iodobenzoate complex (D) to give compound 76a and iodobenzoic acid 79 (Scheme 37) [30].
The proposed mechanism described the formation of compound 76a. It showed the role of Fe II in the reaction steps and its activation of Togni's reagent via the formation of intermediates A-C; deprotonation was then achieved by the Fe III iodobenzoate complex (D) to give compound 76a and iodobenzoic acid 79 (Scheme 37) [30].
Regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazoles 86a-p from the catalyzed reaction between enaminones 85 and aryl azides using 1-methyl pyridinium trifluoromethanesulfonate [mPy]OTf as the ionic liquid in basic medium via 1,3-dipolar cycloaddition (Scheme 40). Herein, the reaction selectively generates only the 1,5-disubstituted triazoles as the only possible product over 1,4-disubstituted triazoles. As illustrated in Scheme 41, the proposed mechanism demonstrated that the formation of triazoles 86a-n from the reaction of the aryl azides and enaminones 85a-g was taken via the formation of intermediate 87a-n [33]. The reaction was described as retro-Michael addition to give two regioisomers. Elimination of aniline from the two regiosomers afforded the corresponding triazoles 86a-n. Moreover, the reaction took place with complete regioselectivity yielding the regioisomer with the electron-deficient group of the enaminone in position 4 and the alkyl substituent in position 5 as the only product of the reaction. Ionic liquid/iron(III) chloride as a homogeneous catalyst was applied in the synthesis of 1 1,2,3-triazoles 84a-n from the reaction of substituted azides and substituted styrenes 83a-g [32] (Scheme 39). Regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazoles 86a-p from t lyzed reaction between enaminones 85 and aryl azides using 1-methyl pyridinium romethanesulfonate [mPy]OTf as the ionic liquid in basic medium via 1,3-dipolar dition (Scheme 40). Herein, the reaction selectively generates only the 1,5-disub triazoles as the only possible product over 1,4-disubstituted triazoles. As illust Scheme 41, the proposed mechanism demonstrated that the formation of triazole from the reaction of the aryl azides and enaminones 85a-g was taken via the form intermediate 87a-n [33]. The reaction was described as retro-Michael addition to g regioisomers. Elimination of aniline from the two regiosomers afforded the corres triazoles 86a-n. Moreover, the reaction took place with complete regioselectivity the regioisomer with the electron-deficient group of the enaminone in position 4 alkyl substituent in position 5 as the only product of the reaction.  Zhang et al. [34] reporoom temperatureed the one-pot multicomponent rea the syntheses of 5-thiotriazoles 89a-u, 91a-m, and 5-selenotriazole 92a-l scaffold sulfur and selenium elements. Firstly, the reaction was displayed between methy olate, benzyl bromide, S8, and 4-methoxybenzyl azide (PMBN3) and was selected mize the reaction conditions. It was clear that the optimized condition was achi 89a in the following conditions: CuI (1.3 equiv), K2CO3 (2.0 equiv), and S8 (3.0 e MeCN (or DMF), first at 0 °C for 1 h and then at 50 °C for 10 h (Scheme 42). The y increased with an increasing amount of CuI to 1.3 equivalent and at 50 °C using MeCN as a solvent. Accordingly, the yields of compounds 89a-u became good co with the previous method, as shown in Scheme 43. Regioselective synthesis of 1,4,5-trisubstituted-1,2,3-triazoles 86a-p from the cata lyzed reaction between enaminones 85 and aryl azides using 1-methyl pyridinium trifluo romethanesulfonate [mPy]OTf as the ionic liquid in basic medium via 1,3-dipolar cycload dition (Scheme 40). Herein, the reaction selectively generates only the 1,5-disubstituted triazoles as the only possible product over 1,4-disubstituted triazoles. As illustrated in Scheme 41, the proposed mechanism demonstrated that the formation of triazoles 86a-n from the reaction of the aryl azides and enaminones 85a-g was taken via the formation o intermediate 87a-n [33]. The reaction was described as retro-Michael addition to give two regioisomers. Elimination of aniline from the two regiosomers afforded the corresponding triazoles 86a-n. Moreover, the reaction took place with complete regioselectivity yielding the regioisomer with the electron-deficient group of the enaminone in position 4 and the alkyl substituent in position 5 as the only product of the reaction. Zhang et al. [34] reporoom temperatureed the one-pot multicomponent reaction for the syntheses of 5-thiotriazoles 89a-u, 91a-m, and 5-selenotriazole 92a-l scaffolds using sulfur and selenium elements. Firstly, the reaction was displayed between methyl propi olate, benzyl bromide, S8, and 4-methoxybenzyl azide (PMBN3) and was selected to opti mize the reaction conditions. It was clear that the optimized condition was achieved for 89a in the following conditions: CuI (1.3 equiv), K2CO3 (2.0 equiv), and S8 (3.0 equiv) in MeCN (or DMF), first at 0 °C for 1 h and then at 50 °C for 10 h (Scheme 42). The yield was increased with an increasing amount of CuI to 1.3 equivalent and at 50 °C using DMF or MeCN as a solvent. Accordingly, the yields of compounds 89a-u became good compared with the previous method, as shown in Scheme 43.

Scheme 41.
Reaction mechanism for the reaction between enaminones and azides to form triazoles 86a-n.
Zhang et al. [34] reporoom temperatureed the one-pot multicomponent reaction for the syntheses of 5-thiotriazoles 89a-u, 91a-m, and 5-selenotriazole 92a-l scaffolds using sulfur and selenium elements. Firstly, the reaction was displayed between methyl propiolate, benzyl bromide, S 8 , and 4-methoxybenzyl azide (PMBN 3 ) and was selected to optimize the reaction conditions. It was clear that the optimized condition was achieved for 89a in the following conditions: CuI (1.3 equiv), K 2 CO 3 (2.0 equiv), and S 8 (3.0 equiv) in MeCN (or DMF), first at 0 • C for 1 h and then at 50 • C for 10 h (Scheme 42). The yield was increased with an increasing amount of CuI to 1.3 equivalent and at 50 • C using DMF or MeCN as a solvent. Accordingly, the yields of compounds 89a-u became good compared with the previous method, as shown in Scheme 43. Next, the influence of the alkynes and azides was examined using DMF as the solvent at temperatures ranging from room temperature to 70 °C for the generation of the sulfenylating agent (Scheme 44). Aromatic alkynes with methyl, methoxy, and nitro groups on the benzene ring worked well to produce the corresponding 5-thiotriazoles 91a-i. The efficiency of acylacetylenes was demonstrated by the generation of 91j bearing a reactive Scheme 43. Substrate effect on the formation of 5-thiotriazoles 89a-u under the optimal conditions. Next, the influence of the alkynes and azides was examined using DMF as the solvent at temperatures ranging from room temperature to 70 • C for the generation of the sulfenylating agent (Scheme 44). Aromatic alkynes with methyl, methoxy, and nitro groups on the benzene ring worked well to produce the corresponding 5-thiotriazoles 91a-i. The efficiency of acylacetylenes was demonstrated by the generation of 91j bearing a reactive hydroxyl group. Aliphatic alkynes also proved to be effective for this process 91l. The excellent availability of this multistep reaction has been well demonstrated by the generation of products 91i and 91k from α-azidoacetate and 2-phenylethyl azide, respectively. Under the previous mild sequential copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) and thiolization reaction conditions, the estrone derivative of an alkyne was easily transformed into the corresponding 5-thiotriazole 91m in 52% yield. 5-Selenotriazoles 92a-l were prepared using selenium as a reagent under the st ard conditions in DMF or MeCN, as shown in Scheme 45. The examination was exten to synthesize fused bicyclic 5-thiotriazoles 93a-g [34] (Scheme 46). 5-Selenotriazoles 92a-l were prepared using selenium as a reagent under the standard conditions in DMF or MeCN, as shown in Scheme 45. The examination was extended to synthesize fused bicyclic 5-thiotriazoles 93a-g [34] (Scheme 46).
N-Propargylated cinnolinones 145a-c reacted with benzyl azide to afford the corresponding triazole derivatives 146a-c via CuAAC in CHCl 3 . It was noted that the complexes of the [(IPr)CuX] series (X = Cl, Br, I) did not exhibit catalytic activity. However, [(IMes)CuX] complexes (X = Cl, Br, I) containing a less sterically hindered ligand showed higher activity under the same reaction conditions; this was attributed to the electronic nature of the halides, and the catalytic reactivity increased in the order of Cl − < Br − ≈ I − , (Scheme 60) [45]. N-Propargylated cinnolinones 145a-c reacted with benzyl azide to afford the corresponding triazole derivatives 146a-c via CuAAC in CHCl3. It was noted that the complexes of the [(IPr)CuX] series (X = Cl, Br, I) did not exhibit catalytic activity. However, [(IMes)CuX] complexes (X = Cl, Br, I) containing a less sterically hindered ligand showed higher activity under the same reaction conditions; this was attributed to the electronic nature of the halides, and the catalytic reactivity increased in the order of Cl − < Br − ≈ I − , (Scheme 60) [45].
R PEER REVIEW 46 of 81 reaction rate, and the electronic nature of substituted groups in both o-and p-positions showed a limited effect on the reaction rate. In contrast, 2,6-disubstituted phenyl azides had accelerated reaction rates as the size of substituents became bulkier (the lower click ability of adamantyl azide than that of diisopropylphenyl azide was attributed to the stabilization of the azido group by hyper-conjugation with C-H bonds, which decreases the distort ability of the azido group) (Scheme 67) [52]. The click ability of the alkyl and alkenyl azides with Sondheimer diyne (174) afforded the regioisomeric bicyclo adducts 176 (trans/cis). The studies showed that the reaction rate was faster in the case of alkyl azides than in the alkenyl azides, indicating that resonance retarded the reaction rate and that both the inductive effect and hyper-conjugation increased the reaction rate (Scheme 67) [52,53]. The synthesis of triazolyl benzoxazine derivatives 179a-n via one-pot reaction (e.g., Ugi reaction [54]) using the so-called Passerini-azide reactions (a method to prepare tetrazoles by substituting hydrazoic acid generated in situ from NaN3 or TMS-N3 (177), has been reported [54][55][56]. The reaction of 2-azidobenzaldehydes 176, 177, and isocyanides 178 gave 4H-3,1-benzoxazine derivatives by the in-situ formation of azide intermediate (Scheme 68) [56]. The synthesis of triazolyl benzoxazine derivatives 179a-n via one-pot reaction (e.g., Ugi reaction [54]) using the so-called Passerini-azide reactions (a method to prepare tetrazoles by substituting hydrazoic acid generated in situ from NaN 3 or TMS-N 3 (177), has been reported [54][55][56]. The reaction of 2-azidobenzaldehydes 176, 177, and isocyanides 178 gave 4H-3,1-benzoxazine derivatives by the in-situ formation of azide intermediate (Scheme 68) [56].
The type of solvent and Lewis acid affected the yield and the regioselectivity of the product, as in 205a. Additionally, the substituted group affected the yield of the target product in which the presence of electron-donating groups gave higher yields than electron-withdrawing groups. On replacing the phenyl ring with pyridine ring (an electrondeficient) and naphthalene (π-electron delocalized group), the triazoloisoquinolones 205h and 205i were synthesized in moderate yields of 32 and 53%, respectively, as shown in Scheme 77 [68]. Scheme 77. Substituent affected the yields of the synthesized triazoloquinolines 205a-v. The plausible mechanism for the formation of compound 205a is illustrated in Scheme 78 [68]. Scheme 77. Substituent affected the yields of the synthesized triazoloquinolines 205a-v. The plausible mechanism for the formation of compound 205a is illustrated in Scheme 78 [68]. Mn(OAc)3·2H2O were used as catalysts in the syntheses of bicyclic azido alcohol 208 via azide radical addition/cyclization/oxygen insertion reaction of alkyne-tethered cyclohexadienones 208 with TMSN3 under mild conditions. The azido alcohol 209a was led to react with phenylacetylene via Cu-catalyzed click reaction 1,2,3-triazole 210 was obtained in 84% yield (Scheme 79) [69]. The plausible mechanism for forming the azido alcohol 209a is shown in Scheme 80. It was described due to azide radical addition, then radical conjugation, and lastly, oxygen insertion process through the formation of the intermediates A-E [69]. Mn(OAc) 3 ·2H 2 O were used as catalysts in the syntheses of bicyclic azido alcohol 208 via azide radical addition/cyclization/oxygen insertion reaction of alkyne-tethered cyclohexadienones 208 with TMSN 3 under mild conditions. The azido alcohol 209a was led to react with phenylacetylene via Cu-catalyzed click reaction 1,2,3-triazole 210 was obtained in 84% yield (Scheme 79) [69]. The plausible mechanism for forming the azido alcohol 209a is shown in Scheme 80. It was described due to azide radical addition, then radical conjugation, and lastly, oxygen insertion process through the formation of the intermediates A-E [69].

Synthesis of Tetrazole Ring
One-pot syntheses of 5-substituted 1H-tetrazole derivatives 229a-j [75] were achieved using a dimethyl sulfoxide-nitric acid combination in an aldehyde, hydroxyla mine combination hydrochloride, and sodium azide under mild conditions (Scheme 88) The proposed mechanism is illustrated in Scheme 89 [75].

Synthesis of Tetrazole Ring
One-pot syntheses of 5-substituted 1H-tetrazole derivatives 229a-j [75] were achieved using a dimethyl sulfoxide-nitric acid combination in an aldehyde, hydroxylamine combination hydrochloride, and sodium azide under mild conditions (Scheme 88). The proposed mechanism is illustrated in Scheme 89 [75]. (Scheme 87). Compounds 228a-c were found to be the most active antiapoptotic hybrids with significant measurements for the antioxidant parameters (malondialdehyde (MDA), total antioxidant capacity (TAC), and the apoptotic biomarkers (testicular testosterone, tumor necrosis factor (TNFα) and caspase-3) in comparison to the reference. A preliminary mechanistic study was performed in order to improve the antiapoptotic activity through caspase-3 inhibition. A compound assigned as 6-methoxy-4-(4-(((2-oxo-1,2-dihydroquinolin-4-yl)oxy)methyl)-1H-1,2,3-triazol-1-yl)quinolin-2(1H)-one (228c) was selected as a representative of the most active hybrids in comparison to N-acetyl cysteine (NAC). Assay of cytochrome C for 228c revealed a down expression of cytochrome C level by about 3.54 fold, comparable to NAC (4.13 fold). In caspases-3,8,9 assays, 228c was found to exhibit more potency and selectivity toward caspase-3 than other caspases. Testicular histopathological investigation was carried out on all targeted compounds 228a-g, indicating a significant improvement in spermatogenesis process for compounds 228a-c if compare with the reference relative to the control [74].

Synthesis of Tetrazole Ring
One-pot syntheses of 5-substituted 1H-tetrazole derivatives 229a-j [75] were achieved using a dimethyl sulfoxide-nitric acid combination in an aldehyde, hydroxylamine combination hydrochloride, and sodium azide under mild conditions (Scheme 88). The proposed mechanism is illustrated in Scheme 89 [75]. Cobalt nano-particles, a heterogeneous catalyst, catalyzed the synthesis of tetrazoles 236a-j from a multicomponent reaction of amines, sodium azide, and triethyl orthoformate under solvent-free conditions at 100 °C (Scheme 92). The reaction was screened for the effects of the amount of both catalyst and solvent; it was found that carrying the reaction using 50 mg of the catalyst under solvent-free conditions gave the tetrazole 236a a Scheme 89. The proposed mechanism for the formation of tetrazoles 229a-j.

Synthesis of Pyridine and Isoquinoline Derivatives
Singam et al. [82] reported the regioselective arylnicalation of ortho functional diaryl acetylene 254a with Ar(BOH) 2 255a-p to synthesize substituted di-aryl isoquinolines 256a-p (Scheme 98). Pd-PEPPSI-IPr was used as a catalyst to reach the optimal reaction conditions during the reaction of acetophenone-N-acetylhydrazone (259a) and (1-azidovinyl) benzene (260a (Scheme 101) [83]. It was concluded that toluene was the best solvent of choice, and heat ing to 100 °C gave 81% yield of 261a (Scheme 101) Pd-PEPPSI-IPr was used as a catalyst to reach the optimal reaction conditions during the reaction of acetophenone-N-acetylhydrazone (259a) and (1-azidovinyl) benzene (260a) (Scheme 101) [83]. It was concluded that toluene was the best solvent of choice, and heating to 100 • C gave 81% yield of 261a (Scheme 101) Pd-PEPPSI-IPr was used as a catalyst to reach the optimal reaction conditions during the reaction of acetophenone-N-acetylhydrazone (259a) and (1-azidovinyl) benzene (260a) (Scheme 101) [83]. It was concluded that toluene was the best solvent of choice, and heating to 100 °C gave 81% yield of 261a (Scheme 101) The procedure showed that N-acetyl hydrazones 259 were screened to react with (1-azidovinyl)benzene (260a), as shown in Scheme 102. Variation from alkyl aryl ketones to benzophenone and cycloalkyl aryl ketones hydrazones reacted smoothly with 260a to afford isoquinolines 261a-ab in 60-81% yields (Scheme 102) [83]. The C-H functionalization occurred regioselectively at the less hindered site for meta-substituted substrate (Me, 259k), yielding a mixture of two isomers, 261k (major) and 261l [83]. Either electron-donating (Me, Bu, Ph, OMe, OPh) or electron-withdrawing (F, Br, Cl, CN) group on the para-position of the phenyl ring of acetophenone N-acetylhydrazones were transformed to the desired products in moderate yields.

27, x FOR PEER REVIEW 69 of 81
The procedure showed that N-acetyl hydrazones 259 were screened to react with (1azidovinyl)benzene (260a), as shown in Scheme 102. Variation from alkyl aryl ketones to benzophenone and cycloalkyl aryl ketones hydrazones reacted smoothly with 260a to afford isoquinolines 261a-ab in 60-81% yields (Scheme 102) [83]. The C-H functionalization occurred regioselectively at the less hindered site for meta-substituted substrate (Me, 259k), yielding a mixture of two isomers, 261k (major) and 261l [83]. Either electron-donating (Me, Bu, Ph, OMe, OPh) or electron-withdrawing (F, Br, Cl, CN) group on the paraposition of the phenyl ring of acetophenone N-acetylhydrazones were transformed to the desired products in moderate yields. The reaction of various vinyl azides 260a-p with N-acetyl hydrazone 259a under the standard reaction conditions was examined (Scheme 103). Fused isoquinolines 261ac-ap were obtained via the same previous procedure [83]. The reaction of various vinyl azides 260a-p with N-acetyl hydrazone 259a under the standard reaction conditions was examined (Scheme 103). Fused isoquinolines 261ac-ap were obtained via the same previous procedure [83]. The transformations of 1-tetralone, 1-benzosuberone hydrazones 262a-d proceeded smoothly to give the desired polycyclic product 263a,b in moderate yields. Moreover, chroman-4-one and thiochroman-4-one-hydrazone substrates were converted to polyheterocyclic products 263c,d in 88% and 91% yields (Scheme 104).
The proposed mechanistic steps were proposed, as shown in Scheme 108. First, a copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC) takes place to generate intermediate A, which then transforms to ketenimine B by the extrusion of N 2 . Nucleophilic addition of 2-bromoprop-2-en-1-amine (270a) to intermediate B affords carboxamidine C and/or its tautomer. Finally, a consecutive coppercatalyzed C-N coupling reactions proceeds to provide 2,3-dihydro-1H-imidazo[1,2-a]indole 272a (Scheme 108) [85]. The postulated mechanism is illustrated in Scheme 110. Initially, the Mn(OAc) 3 ·2H 2 Oassisted homolysis of tert-butyl hydroperoxide (TBHP) generates the tert-butoxy and the tert-butyl peroxy radicals. Bond cleavage of the C-N in methyl carbazate 274 forms the alkoxycarbonyl radical (B), which loses molecular N 2 . Radical (B) then attacks the R-NC bond of 2-(azidomethyl)phenyl isocyanide (273a) to form an imidoyl radical intermediate (C). The intermediate C then undergoes intermolecular cyclization with the azido group to give a cyclized aminyl radical (D) by nitrogen loss. Finally, a hydrogen abstraction of the radical intermediate (D) leads to the desired product (275a) (Scheme 110) [86]. The postulated mechanism is illustrated in Scheme 110. Initially, the Mn(OAc)3·2H2O-assisted homolysis of tert-butyl hydroperoxide (TBHP) generates the tert-butoxy and the tert-butyl peroxy radicals. Bond cleavage of the C-N in methyl carbazate 274 forms the alkoxycarbonyl radical (B), which loses molecular N2. Radical (B) then attacks the R-NC bond of 2-(azidomethyl)phenyl isocyanide (273a) to form an imidoyl radical intermediate (C). The intermediate C then undergoes intermolecular cyclization with the azido group to give a cyclized aminyl radical (D) by nitrogen loss. Finally, a hydrogen abstraction of the radical intermediate (D) leads to the desired product (275a) (Scheme 110) [86].
Scheme 110. Proposed mechanism for the formation of quinazoline 275a via the radical pathway. Scheme 110. Proposed mechanism for the formation of quinazoline 275a via the radical pathway.

Synthesis of Benzothiazaphosphole
The reaction of ortho-phosphinoarenesulfonyl fluorides 291 with trimethylsilyl azide resulted in benzo-1,2,3-thiazaphosphole 292 [91]. To optimize the reaction condition, it was found that a mixture of acetonitrile and 10 equivalents of trimethylsilyl azide at 60 • C was the optimal reaction chosen condition (Scheme 115) [92]. The three possible mechanistic pathways (A), (B) and (C) for forming the benzo-thiazaphosphole 292a are illustrated in Scheme 116 [91]. The reaction of ortho-phosphinoarenesulfonyl fluorides 291 with trimethylsilyl azide resulted in benzo-1,2,3-thiazaphosphole 292 [91]. To optimize the reaction condition, it was found that a mixture of acetonitrile and 10 equivalents of trimethylsilyl azide at 60 °C was the optimal reaction chosen condition (Scheme 115) [92]. The three possible mechanistic pathways (A), (B) and (C) for forming the benzo-thiazaphosphole 292a are illustrated in Scheme 116 [91]. The reaction of ortho-phosphinoarenesulfonyl fluorides 291 with trimethylsilyl azide resulted in benzo-1,2,3-thiazaphosphole 292 [91]. To optimize the reaction condition, it was found that a mixture of acetonitrile and 10 equivalents of trimethylsilyl azide at 60 °C was the optimal reaction chosen condition (Scheme 115) [92]. The three possible mechanistic pathways (A), (B) and (C) for forming the benzo-thiazaphosphole 292a are illustrated in Scheme 116 [91].

Conclusions
In summary, the azido group in organic substrates are effectively served in the synthesis of various heterocycles through different mechanistic steps, such as one-pot reactions, nucleophilic additions (such as Aza-Michael addition), cycloaddition reactions (such as [3+2] cycloaddition), mixed addition/cyclization/oxygen, and insertion reactions of C-H amination. The selectivity of the chosen catalyst plays an important role in the chemoselectivity favoring C−H and C-N bonds, as it can be seen that organic azides have been used in the synthesis of various types of natural products producing good to excellent yields. Most indicative is the utility of organic azides in the synthetic procedures of fused heterocycles, such as quinazoline derivatives along with organo-metal heterocycles (i.e., phosphorus-, boron-, and aluminum-containing heterocycles). This review focused on synthesizing various heterocycles using azide chemistry and mechanistic aspects.