Azidation in the Difunctionalization of Olefins

Organic azides are key motifs in compounds of relevance to chemical biology, medicinal chemistry and materials science. In addition, they also serve as useful building blocks due to their remarkable reactivity. Therefore, the development of efficient protocols to synthesize these compounds is of great significance. This paper reviews the major applications and development of azidation in difunctionalization of olefins using azide reagents.


Construction of C-N 3 Bond and C-C Bond
In the past decade, the hydroazidation of olefins has been significantly developed [43][44][45][46][47][48], although this kind of addition reaction has not been generally classified as a traditional difunctionalization of olefins. Therefore, we start here from the construction of C-N 3 bonds and C-C bonds.
An interesting radical-mediated arylazidation of activated alkenes 1 was reported by Nevado and co-workers (Scheme 1) [49]. This process involves radical addition, Csp 2 -Csp 3 and C-N bond formation, 1,4-aryl migration, and further desulfonylation, producing in good yields the corresponding products 2 bearing a quaternary stereocenter when the substituent on the nitrogen atom is an aryl group.

Scheme 1. Arylheterofunctionalization of activated alkenes.
The proposed mechanism is illustrated in Scheme 2. In the first step, the generated azido radical interacts with the activated alkene to give a new C(sp 3

)-N bond and an alkyl radical intermediate A.
A 5-ipso cyclization then takes place on the aromatic ring generating aryl radical B, which leads to amidyl radical C upon rearomatization with concomitant desulfonylation. The subsequent H-abstraction step produces the desired product 2 (Scheme 2). Scheme 2. The proposed mechanism of the arylheterofunctionalization of alkenes.
Wang and co-workers reported a copper-catalyzed intermolecular Markovnikov-type azidocyanation reaction of alkenes 3 to construct C-N3 and C-CN bonds simultaneously (Scheme 3) [50], which gives a series of 3-azido-2-arylpropanenitriles 4 in moderate to good yields. These compounds may serve as potential precursors of the corresponding 3-amino-2-arylpropanoic acids. This reaction employs PhI(OAc)2 as oxidant, TMSN3 as N3 source, TMSCN as CN source and it proceeds at room temperature. A mechanistic study revealed that the addition of 2,6-di-tert-butyl-4-methylphenol (BHT) significantly suppressed the reaction, suggesting that a radical process may be involved in this reaction. The proposed mechanism is illustrated in Scheme 2. In the first step, the generated azido radical interacts with the activated alkene to give a new C(sp 3

)-N bond and an alkyl radical intermediate A.
A 5-ipso cyclization then takes place on the aromatic ring generating aryl radical B, which leads to amidyl radical C upon rearomatization with concomitant desulfonylation. The subsequent H-abstraction step produces the desired product 2 (Scheme 2).

Scheme 1. Arylheterofunctionalization of activated alkenes.
The proposed mechanism is illustrated in Scheme 2. In the first step, the generated azido radical interacts with the activated alkene to give a new C(sp 3

)-N bond and an alkyl radical intermediate A.
A 5-ipso cyclization then takes place on the aromatic ring generating aryl radical B, which leads to amidyl radical C upon rearomatization with concomitant desulfonylation. The subsequent H-abstraction step produces the desired product 2 (Scheme 2). Scheme 2. The proposed mechanism of the arylheterofunctionalization of alkenes.
Wang and co-workers reported a copper-catalyzed intermolecular Markovnikov-type azidocyanation reaction of alkenes 3 to construct C-N3 and C-CN bonds simultaneously (Scheme 3) [50], which gives a series of 3-azido-2-arylpropanenitriles 4 in moderate to good yields. These compounds may serve as potential precursors of the corresponding 3-amino-2-arylpropanoic acids. This reaction employs PhI(OAc)2 as oxidant, TMSN3 as N3 source, TMSCN as CN source and it proceeds at room temperature. A mechanistic study revealed that the addition of 2,6-di-tert-butyl-4-methylphenol (BHT) significantly suppressed the reaction, suggesting that a radical process may be involved in this reaction. A plausible mechanism for this transformation is illustrated in Scheme 7. This reaction begins with a double ligand exchange between PhI(OCOCF3)2 and TMSN3 to provide intermediate A, which undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to give intermediate B, which is trapped by arene to give intermediate C.
Rearomatization of C provides product 10. Similar approaches using different catalysts and oxidants were also reported by the groups of Zhang [55], Yang [56], and Jiao [57] (Scheme 8). A plausible mechanism for this transformation is illustrated in Scheme 7. This reaction begins with a double ligand exchange between PhI(OCOCF 3 ) 2 and TMSN 3 to provide intermediate A, which undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to give intermediate B, which is trapped by arene to give intermediate C. Rearomatization of C provides product 10. Similar approaches using different catalysts and oxidants were also reported by the groups of Zhang [55], Yang [56], and Jiao [57] (Scheme 8). A plausible mechanism for this transformation is illustrated in Scheme 7. This reaction begins with a double ligand exchange between PhI(OCOCF3)2 and TMSN3 to provide intermediate A, which undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to give intermediate B, which is trapped by arene to give intermediate C. Rearomatization of C provides product 10. Similar approaches using different catalysts and oxidants were also reported by the groups of Zhang [55], Yang [56], and Jiao [57] (Scheme 8).  A plausible mechanism for this transformation is illustrated in Scheme 7. This reaction begins with a double ligand exchange between PhI(OCOCF3)2 and TMSN3 to provide intermediate A, which undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to give intermediate B, which is trapped by arene to give intermediate C. Rearomatization of C provides product 10. Similar approaches using different catalysts and oxidants were also reported by the groups of Zhang [55], Yang [56], and Jiao [57] (Scheme 8). The introduction of a trifluoromethyl group into chemical compounds is an important way to modify their activities and biocompatibilities [58]. In light of their importance in medicinal chemistry, a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed by Liu and co-workers [59]. By using this method, various CF 3 -containing organoazides 11 were obtained in good yields under mild reaction conditions (Scheme 9). Besides, the resulting products can be readily transformed into other valuable CF 3 -containing amine compounds.
The introduction of a trifluoromethyl group into chemical compounds is an important way to modify their activities and biocompatibilities [58]. In light of their importance in medicinal chemistry, a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed by Liu and co-workers [59]. By using this method, various CF3-containing organoazides 11 were obtained in good yields under mild reaction conditions (Scheme 9). Besides, the resulting products can be readily transformed into other valuable CF3-containing amine compounds.

Scheme 9. Azidotrifluoromethylation of alkenes.
A photoredox-catalyzed azidotrifluoromethylation of enecarbamates 12 was reported by Magnier, Masson and coworkers [60]. This reaction used Tongi's reagent as CF3 source, and was proposed to follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be readily difunctionalized (Scheme 10).

Scheme 10. Azidotrifluoromethylation of enecarbamates.
A possible mechanism is shown in Scheme 11. Visible light excites Ru(bpy)3 2+ into *Ru(bpy)3 2+ , which is a strong reductant species that performs a SET to generate trifluoromethyl radical from Togni's reagent. Then, addition of trifluoromethyl radical to enecarbamate 14 leads to an α-amido radical intermediate A, which can be oxidized into N-acyliminium cation intermediate B by SET process from Ru(bpy)3 3+ . Final nucleophilic trapping by NaN3 forms the products 15. Scheme 11. Proposed mechanism. Scheme 9. Azidotrifluoromethylation of alkenes.
A photoredox-catalyzed azidotrifluoromethylation of enecarbamates 12 was reported by Magnier, Masson and coworkers [60]. This reaction used Tongi's reagent as CF 3 source, and was proposed to follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be readily difunctionalized (Scheme 10). The introduction of a trifluoromethyl group into chemical compounds is an important way to modify their activities and biocompatibilities [58]. In light of their importance in medicinal chemistry, a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed by Liu and co-workers [59]. By using this method, various CF3-containing organoazides 11 were obtained in good yields under mild reaction conditions (Scheme 9). Besides, the resulting products can be readily transformed into other valuable CF3-containing amine compounds.

Scheme 9. Azidotrifluoromethylation of alkenes.
A photoredox-catalyzed azidotrifluoromethylation of enecarbamates 12 was reported by Magnier, Masson and coworkers [60]. This reaction used Tongi's reagent as CF3 source, and was proposed to follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be readily difunctionalized (Scheme 10).

Scheme 10. Azidotrifluoromethylation of enecarbamates.
A possible mechanism is shown in Scheme 11. Visible light excites Ru(bpy)3 2+ into *Ru(bpy)3 2+ , which is a strong reductant species that performs a SET to generate trifluoromethyl radical from Togni's reagent. The introduction of a trifluoromethyl group into chemical compounds is an important way to modify their activities and biocompatibilities [58]. In light of their importance in medicinal chemistry, a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed by Liu and co-workers [59]. By using this method, various CF3-containing organoazides 11 were obtained in good yields under mild reaction conditions (Scheme 9). Besides, the resulting products can be readily transformed into other valuable CF3-containing amine compounds.

Scheme 9. Azidotrifluoromethylation of alkenes.
A photoredox-catalyzed azidotrifluoromethylation of enecarbamates 12 was reported by Magnier, Masson and coworkers [60]. This reaction used Tongi's reagent as CF3 source, and was proposed to follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be readily difunctionalized (Scheme 10).

Scheme 10. Azidotrifluoromethylation of enecarbamates.
A possible mechanism is shown in Scheme 11. Visible light excites Ru(bpy)3 2+ into *Ru(bpy)3 2+ , which is a strong reductant species that performs a SET to generate trifluoromethyl radical from Togni's reagent. Then, addition of trifluoromethyl radical to enecarbamate 14 leads to an α-amido radical intermediate A, which can be oxidized into N-acyliminium cation intermediate B by SET process from Ru(bpy)3 3+ . Final nucleophilic trapping by NaN3 forms the products 15. Scheme 11. Proposed mechanism. Scheme 11. Proposed mechanism. Inspired by their above work, this group also developed a photoredox-catalyzed azidotrifluoromethylation of alkenes 16. Under the optimized conditions, using Umemoto's reagent as the CF 3 source, a wide range of alkenes can be readily difunctionalized (Scheme 12) [61]. Inspired by their above work, this group also developed a photoredox-catalyzed azidotrifluoromethylation of alkenes 16. Under the optimized conditions, using Umemoto's reagent as the CF3 source, a wide range of alkenes can be readily difunctionalized (Scheme 12) [61].

Scheme 12. Azidotrifluoromethylation of alkenes.
A similar mechanism is proposed based on their above work (Scheme 13 Due to the importance of these compounds, a copper-catalyzed three-component azidotrifluoromethylation of alkenes was designed by Yang (Scheme 14) [62]. This reaction proceeded under mild conditions and gave the corresponding product 20 in good yields. A possible mechanism was also proposed. Togni's reagent 19 is activated by CuBr, leading to the radical species A by reaction with the alkene. Then, intermediate A is oxidized to intermediate B, which is further trapped by TMSN3 to lead to the product (Path a). Alternatively, intermediate A reacts with TMSN3 and CuBr to afford complex C, further reductive elimination of complex C affords the product 20.

Scheme 12. Azidotrifluoromethylation of alkenes.
A similar mechanism is proposed based on their above work (Scheme 13 Due to the importance of these compounds, a copper-catalyzed three-component azidotrifluoromethylation of alkenes was designed by Yang (Scheme 14) [62]. This reaction proceeded under mild conditions and gave the corresponding product 20 in good yields. A possible mechanism was also proposed. Togni's reagent 19 is activated by CuBr, leading to the radical species A by reaction with the alkene. Then, intermediate A is oxidized to intermediate B, which is further trapped by TMSN3 to lead to the product (Path a). Alternatively, intermediate A reacts with TMSN3 and CuBr to afford complex C, further reductive elimination of complex C affords the product 20.

Scheme 13. Plausible reaction mechanism.
Due to the importance of these compounds, a copper-catalyzed three-component azidotrifluoromethylation of alkenes was designed by Yang (Scheme 14) [62]. This reaction proceeded under mild conditions and gave the corresponding product 20 in good yields. A possible mechanism was also proposed. Togni's reagent 19 is activated by CuBr, leading to the radical species A by reaction with the alkene. Then, intermediate A is oxidized to intermediate B, which is further trapped by TMSN 3 to lead to the product (Path a). Alternatively, intermediate A reacts with TMSN 3 and CuBr to afford complex C, further reductive elimination of complex C affords the product 20.

Construction of C-N3 Bond and C-O Bond
Shibasaki and co-workers reported the first example of (Cl2SnO)n-catalyzed synthesis of trans β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63].  Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for the synthesis of β-azido alcohols 23 using air as the oxidant (Scheme 17) [64]. This chemistry was notable for its mild reaction conditions, broad substrate scope, and high reaction efficiency. Scheme 14. Azidotrifluoromethylation of alkenes.

Construction of C-N 3 Bond and C-O Bond
Shibasaki and co-workers reported the first example of (Cl 2 SnO) n -catalyzed synthesis of trans β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63].

Construction of C-N3 Bond and C-O Bond
Shibasaki and co-workers reported the first example of (Cl2SnO)n-catalyzed synthesis of trans β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63].  Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for the synthesis of β-azido alcohols 23 using air as the oxidant (Scheme 17) [64]. This chemistry was notable for its mild reaction conditions, broad substrate scope, and high reaction efficiency. The authors proposed a catalytic cycle that involves the insertion of a C=C double bond to dichlorotin oxide to afford intermediate A, which could react with TMSN 3 to afford B. Subsequent nucleophilic attack of BTSP (bis(trimethylsilyl) peroxide) on Sn gives the intermediate C.
The regeneration of (Cl 2 SnO)n by S N 2 attack with TMSN 3 gives D as the precursor of the product (Scheme 16).

Construction of C-N3 Bond and C-O Bond
Shibasaki and co-workers reported the first example of (Cl2SnO)n-catalyzed synthesis of trans β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63]. Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for the synthesis of β-azido alcohols 23 using air as the oxidant (Scheme 17) [64]. This chemistry was notable for its mild reaction conditions, broad substrate scope, and high reaction efficiency. Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative hydroxyazidation of olefins for the synthesis of β-azido alcohols 23 using air as the oxidant (Scheme 17) [64]. This chemistry was notable for its mild reaction conditions, broad substrate scope, and high reaction efficiency. Moreover, the resulting β-azido alcohols are useful precursors of β-amino alcohols, aziridines, and other O-and N-containing heterocyclic compounds. On the basis of the mechanistic study and density functional theory (DFT) calculations, a favored radical process is proposed (Scheme 18). Firstly, the Mn II is readily oxidized to Mn III or Mn IV by molecule oxygen in the air, then Mn III oxidizes TMSN3 to generate azido radical. Mn IV can also oxidize TMSN3 to form the N3 radical A and generate Mn III catalyst. Radical A attacks an alkene at the sterically less hindered position to form the carbon radical B, which is trapped by oxygen to generate the peroxyl radical C. According to the DFT calculations, it is favored for the peroxyl radical C to undergo Mn-participated SET and protonation processes to afford β-azido peroxy alcohols E. In comparison, the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by PPh3 to form the β-azido alcohol 23.

Scheme 18. Proposed mechanism.
Sudalai and co-workers reported an I2-catalyzed synthesis of 1,2-azidoalcohols by employing NaN3 as N-nuclepohiles and DMF as O-nuclepohiles respectively (Scheme 19) [65]. This approach displayed broad substrate scope and high reaction efficiency with regio-and stereoselectivity. 18 O labelling studies proved that DMF served as the O-nucleophile. On the basis of the mechanistic study and density functional theory (DFT) calculations, a favored radical process is proposed (Scheme 18). Firstly, the Mn II is readily oxidized to Mn III or Mn IV by molecule oxygen in the air, then Mn III oxidizes TMSN 3 to generate azido radical. Mn IV can also oxidize TMSN 3 to form the N 3 radical A and generate Mn III catalyst. Radical A attacks an alkene at the sterically less hindered position to form the carbon radical B, which is trapped by oxygen to generate the peroxyl radical C. According to the DFT calculations, it is favored for the peroxyl radical C to undergo Mn-participated SET and protonation processes to afford β-azido peroxy alcohols E. In comparison, the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by PPh 3 to form the β-azido alcohol 23. On the basis of the mechanistic study and density functional theory (DFT) calculations, a favored radical process is proposed (Scheme 18). Firstly, the Mn II is readily oxidized to Mn III or Mn IV by molecule oxygen in the air, then Mn III oxidizes TMSN3 to generate azido radical. Mn IV can also oxidize TMSN3 to form the N3 radical A and generate Mn III catalyst. Radical A attacks an alkene at the sterically less hindered position to form the carbon radical B, which is trapped by oxygen to generate the peroxyl radical C. According to the DFT calculations, it is favored for the peroxyl radical C to undergo Mn-participated SET and protonation processes to afford β-azido peroxy alcohols E. In comparison, the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by PPh3 to form the β-azido alcohol 23.

Scheme 18. Proposed mechanism.
Sudalai and co-workers reported an I2-catalyzed synthesis of 1,2-azidoalcohols by employing NaN3 as N-nuclepohiles and DMF as O-nuclepohiles respectively (Scheme 19) [65]. This approach displayed broad substrate scope and high reaction efficiency with regio-and stereoselectivity. 18 O labelling studies proved that DMF served as the O-nucleophile. Sudalai and co-workers reported an I 2 -catalyzed synthesis of 1,2-azidoalcohols by employing NaN 3 as N-nuclepohiles and DMF as O-nuclepohiles respectively (Scheme 19) [65]. This approach displayed broad substrate scope and high reaction efficiency with regio-and stereoselectivity. 18 O labelling studies proved that DMF served as the O-nucleophile. On the basis of the mechanistic study and density functional theory (DFT) calculations, a favored radical process is proposed (Scheme 18). Firstly, the Mn II is readily oxidized to Mn III or Mn IV by molecule oxygen in the air, then Mn III oxidizes TMSN3 to generate azido radical. Mn IV can also oxidize TMSN3 to form the N3 radical A and generate Mn III catalyst. Radical A attacks an alkene at the sterically less hindered position to form the carbon radical B, which is trapped by oxygen to generate the peroxyl radical C. According to the DFT calculations, it is favored for the peroxyl radical C to undergo Mn-participated SET and protonation processes to afford β-azido peroxy alcohols E. In comparison, the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by PPh3 to form the β-azido alcohol 23.

Scheme 18. Proposed mechanism.
Sudalai and co-workers reported an I2-catalyzed synthesis of 1,2-azidoalcohols by employing NaN3 as N-nuclepohiles and DMF as O-nuclepohiles respectively (Scheme 19) [65]. This approach displayed broad substrate scope and high reaction efficiency with regio-and stereoselectivity. 18  The proposed species D is formed from C by the anchimeric assistance from the formate group, it reacts with the azide anion in a regioselective manner to give anti azido alcohols 25 with the liberation of the iodide ion, which is then reoxidized with TBHP/H 2 O 2 to regenerate I 2 in the catalytic cycle.
A possible mechanism was proposed (Scheme 20). Firstly, an iodonium ion is formed by the reaction of iodine with alkene, which undergoes subsequent regioselective ring opening with DMF to afford the corresponding iodo intermediate A, followed by stereoselective displacement with NaN3 to give intermediate B. Intermediate B on hydrolysis gives syn azido alcohols 24. Alternatively, under aq. H2O2 conditions, the iodo intermediate A is hydrolyzed in situ to form iodoformate C. The proposed species D is formed from C by the anchimeric assistance from the formate group, it reacts with the azide anion in a regioselective manner to give anti azido alcohols 25 with the liberation of the iodide ion, which is then reoxidized with TBHP/H2O2 to regenerate I2 in the catalytic cycle. An effective [Cu(dap)2]Cl catalyzed azide addition of styrene-type alkenes 26 using the Zhdankin reagent as N3 source was reported by Greaney and co-workers [66]. This is a light-controlled reaction, and in the presence of light, a photoredox cycle is implicated with polar components such as methanol or bromide adding to a benzylic cation. By contrast, in the absence of light, a double azidation takes place, leading to diazide products. Thus, the degree of azidation can be controlled by switching between light and dark conditions (Scheme 21). Studer and co-worker achieved oxyazidation reactions of alkenes using sodium TEMPO as O source, reagent 29 as N3 source under mild condition affording product 30 in good yields (Scheme 22) [67]. It is noteworthy that the oxyazidation of cyclic systems proceeded well with excellent diastereoselectivity. An effective [Cu(dap) 2 ]Cl catalyzed azide addition of styrene-type alkenes 26 using the Zhdankin reagent as N 3 source was reported by Greaney and co-workers [66]. This is a light-controlled reaction, and in the presence of light, a photoredox cycle is implicated with polar components such as methanol or bromide adding to a benzylic cation. By contrast, in the absence of light, a double azidation takes place, leading to diazide products. Thus, the degree of azidation can be controlled by switching between light and dark conditions (Scheme 21). An effective [Cu(dap)2]Cl catalyzed azide addition of styrene-type alkenes 26 using the Zhdankin reagent as N3 source was reported by Greaney and co-workers [66]. This is a light-controlled reaction, and in the presence of light, a photoredox cycle is implicated with polar components such as methanol or bromide adding to a benzylic cation. By contrast, in the absence of light, a double azidation takes place, leading to diazide products. Thus, the degree of azidation can be controlled by switching between light and dark conditions (Scheme 21). Studer and co-worker achieved oxyazidation reactions of alkenes using sodium TEMPO as O source, reagent 29 as N3 source under mild condition affording product 30 in good yields (Scheme 22) [67]. It is noteworthy that the oxyazidation of cyclic systems proceeded well with excellent diastereoselectivity.

Scheme 21. Azidation of styrene-type double bonds.
Studer and co-worker achieved oxyazidation reactions of alkenes using sodium TEMPO as O source, reagent 29 as N 3 source under mild condition affording product 30 in good yields (Scheme 22) [67]. It is noteworthy that the oxyazidation of cyclic systems proceeded well with excellent diastereoselectivity.

Scheme 22. Oxyazidation of alkenes.
Inspired by their previous work that TEMPONa could reduce CF3-iodine reagent (Togni reagent) to generate CF3-radical [68], a radical process was suggested by the authors (Scheme 23). Under the standard reaction conditions, TEMPONa reduced Togni reagent to generate an N3 radical, and release TEMPO, then the N3 radical is trapped by an olefin to generate species A, which reacts with TEMPO to form products 30.

Scheme 23. Radical oxyazidation of alkenes.
Recently, an efficient oxyazidation of alkenes under metal-free conditions was reported by Xia and co-workers. This reaction could form C-O and C-N bonds in one step by using N-hydroxyphthalimide as an oxygen-radical precursor and TMSN3 as the N3 source. A number of aryl-substituted alkenes was tolerated in this transformation (Scheme 24) [69]. Inspired by their previous work that TEMPONa could reduce CF 3 -iodine reagent (Togni reagent) to generate CF 3 -radical [68], a radical process was suggested by the authors (Scheme 23). Under the standard reaction conditions, TEMPONa reduced Togni reagent to generate an N 3 radical, and release TEMPO, then the N 3 radical is trapped by an olefin to generate species A, which reacts with TEMPO to form products 30.

Scheme 22. Oxyazidation of alkenes.
Inspired by their previous work that TEMPONa could reduce CF3-iodine reagent (Togni reagent) to generate CF3-radical [68], a radical process was suggested by the authors (Scheme 23). Under the standard reaction conditions, TEMPONa reduced Togni reagent to generate an N3 radical, and release TEMPO, then the N3 radical is trapped by an olefin to generate species A, which reacts with TEMPO to form products 30.

Scheme 23. Radical oxyazidation of alkenes.
Recently, an efficient oxyazidation of alkenes under metal-free conditions was reported by Xia and co-workers. This reaction could form C-O and C-N bonds in one step by using N-hydroxyphthalimide as an oxygen-radical precursor and TMSN3 as the N3 source. A number of aryl-substituted alkenes was tolerated in this transformation (Scheme 24) [69]. Recently, an efficient oxyazidation of alkenes under metal-free conditions was reported by Xia and co-workers. This reaction could form C-O and C-N bonds in one step by using N-hydroxyphthalimide as an oxygen-radical precursor and TMSN 3 as the N 3 source. A number of aryl-substituted alkenes was tolerated in this transformation (Scheme 24) [69]. Inspired by their previous work that TEMPONa could reduce CF3-iodine reagent (Togni reagent) to generate CF3-radical [68], a radical process was suggested by the authors (Scheme 23). Under the standard reaction conditions, TEMPONa reduced Togni reagent to generate an N3 radical, and release TEMPO, then the N3 radical is trapped by an olefin to generate species A, which reacts with TEMPO to form products 30.

Scheme 23. Radical oxyazidation of alkenes.
Recently, an efficient oxyazidation of alkenes under metal-free conditions was reported by Xia and co-workers. This reaction could form C-O and C-N bonds in one step by using N-hydroxyphthalimide as an oxygen-radical precursor and TMSN3 as the N3 source. A number of aryl-substituted alkenes was tolerated in this transformation (Scheme 24) [69]. The simultaneous addition of oxygen and nitrogen across an alkene is a convenient way to construct the precursor of 2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed oxyamination of alkene, a novel synthetic method for the preparation of 34 was reported by Chemler and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent diastereoselectivity (Scheme 26). The simultaneous addition of oxygen and nitrogen across an alkene is a convenient way to construct the precursor of 2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed oxyamination of alkene, a novel synthetic method for the preparation of 34 was reported by Chemler and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent diastereoselectivity (Scheme 26). The simultaneous addition of oxygen and nitrogen across an alkene is a convenient way to construct the precursor of 2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed oxyamination of alkene, a novel synthetic method for the preparation of 34 was reported by Chemler and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent diastereoselectivity (Scheme 26). The simultaneous addition of oxygen and nitrogen across an alkene is a convenient way to construct the precursor of 2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed oxyamination of alkene, a novel synthetic method for the preparation of 34 was reported by Chemler and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent diastereoselectivity (Scheme 26). A new approach to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes was developed by Buchwald and co-workers [71]. This method provides a straightforward approach to various lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access through traditional methods (Scheme 28). A new approach to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes was developed by Buchwald and co-workers [71]. This method provides a straightforward approach to various lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access through traditional methods (Scheme 28).

Scheme 28. Synthesis of chiral lactones.
Isoxazolines are useful building blocks in organic chemistry [72]. Recently, an efficient Cu(OAc)2-catalyzed oxyazidation of alkenes 37 was developed by Wang, Xu and co-workers (Scheme 29) [73]. This reaction occurs under mild conditions, forming the azido-substituted isoxazolines 38 in good yields, although the mechanism of this chemistry is still unclear. Scheme 29. Oxyazidation of alkenes.

Construction of C-N3 Bond and C-N Bond
Olefin diamination methods provide powerful access to vicinal diamines that are useful in chemical biology, medicinal chemistry and materials science. Recently, an novel copper(II)-promoted intramolecular azidoamination of alkenes 39 was reported by Chemler and co-workers (Scheme 30) [74]. This method could tolerate a wide range of internal and external amine sources for the formation of differently functionalized nitrogen heterocycles 40.

Scheme 28. Synthesis of chiral lactones.
Isoxazolines are useful building blocks in organic chemistry [72]. Recently, an efficient Cu(OAc) 2 -catalyzed oxyazidation of alkenes 37 was developed by Wang, Xu and co-workers (Scheme 29) [73]. This reaction occurs under mild conditions, forming the azido-substituted isoxazolines 38 in good yields, although the mechanism of this chemistry is still unclear. A new approach to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes was developed by Buchwald and co-workers [71]. This method provides a straightforward approach to various lactone building blocks containing tetrasubstituted stereogenic centers, which are hard to access through traditional methods (Scheme 28).

Scheme 28. Synthesis of chiral lactones.
Isoxazolines are useful building blocks in organic chemistry [72]. Recently, an efficient Cu(OAc)2-catalyzed oxyazidation of alkenes 37 was developed by Wang, Xu and co-workers (Scheme 29) [73]. This reaction occurs under mild conditions, forming the azido-substituted isoxazolines 38 in good yields, although the mechanism of this chemistry is still unclear. Scheme 29. Oxyazidation of alkenes.

Construction of C-N3 Bond and C-N Bond
Olefin diamination methods provide powerful access to vicinal diamines that are useful in chemical biology, medicinal chemistry and materials science. Recently, an novel copper(II)-promoted intramolecular azidoamination of alkenes 39 was reported by Chemler and co-workers (Scheme 30) [74]. This method could tolerate a wide range of internal and external amine sources for the formation of differently functionalized nitrogen heterocycles 40. Scheme 29. Oxyazidation of alkenes.

Construction of C-N 3 Bond and C-N Bond
Olefin diamination methods provide powerful access to vicinal diamines that are useful in chemical biology, medicinal chemistry and materials science. Recently, an novel copper(II)-promoted intramolecular azidoamination of alkenes 39 was reported by Chemler and co-workers (Scheme 30) [74]. This method could tolerate a wide range of internal and external amine sources for the formation of differently functionalized nitrogen heterocycles 40.

Scheme 30. Intermolecular alkene azidoamination.
Yu and co-workers reported an intramolecular azidation reaction through copper-mediated N-O cleavage and subsequent C-N bond forming 5-exo cyclization. The forming intermediate is subsequently azidated to afford the corresponding dihydropyrroles (Scheme 31) [75]. To understand this reaction mechanism, compound 43 was treated under standard reaction conditions. However, in this case 44 and 45 are mainly obtained with only trace amounts of ring opening product formation, suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction mechanism is proposed (Scheme 32). The first step involves the oxidative addition of Cu(I) to the N-O to give intermediate A, which undergoes ligand exchange and then intramolecular cyclization to afford intermediate C, followed by reductive elimination to afford products 42.  Studer and co-workers described a novel methodology for the efficient synthesis of the precursors of vicinal amino azides 46 (Scheme 33) [76], which can easily be transformed into other important amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN3 as N3 source and available N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in moderate to excellent yields with high diastereoselectivity. Yu and co-workers reported an intramolecular azidation reaction through copper-mediated N-O cleavage and subsequent C-N bond forming 5-exo cyclization. The forming intermediate is subsequently azidated to afford the corresponding dihydropyrroles (Scheme 31) [75]. To understand this reaction mechanism, compound 43 was treated under standard reaction conditions. However, in this case 44 and 45 are mainly obtained with only trace amounts of ring opening product formation, suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction mechanism is proposed (Scheme 32). The first step involves the oxidative addition of Cu(I) to the N-O to give intermediate A, which undergoes ligand exchange and then intramolecular cyclization to afford intermediate C, followed by reductive elimination to afford products 42. Yu and co-workers reported an intramolecular azidation reaction through copper-mediated N-O cleavage and subsequent C-N bond forming 5-exo cyclization. The forming intermediate is subsequently azidated to afford the corresponding dihydropyrroles (Scheme 31) [75]. To understand this reaction mechanism, compound 43 was treated under standard reaction conditions. However, in this case 44 and 45 are mainly obtained with only trace amounts of ring opening product formation, suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction mechanism is proposed (Scheme 32). The first step involves the oxidative addition of Cu(I) to the N-O to give intermediate A, which undergoes ligand exchange and then intramolecular cyclization to afford intermediate C, followed by reductive elimination to afford products 42. Studer and co-workers described a novel methodology for the efficient synthesis of the precursors of vicinal amino azides 46 (Scheme 33) [76], which can easily be transformed into other important amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN3 as N3 source and available N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in moderate to excellent yields with high diastereoselectivity. Yu and co-workers reported an intramolecular azidation reaction through copper-mediated N-O cleavage and subsequent C-N bond forming 5-exo cyclization. The forming intermediate is subsequently azidated to afford the corresponding dihydropyrroles (Scheme 31) [75]. To understand this reaction mechanism, compound 43 was treated under standard reaction conditions. However, in this case 44 and 45 are mainly obtained with only trace amounts of ring opening product formation, suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction mechanism is proposed (Scheme 32). The first step involves the oxidative addition of Cu(I) to the N-O to give intermediate A, which undergoes ligand exchange and then intramolecular cyclization to afford intermediate C, followed by reductive elimination to afford products 42. Studer and co-workers described a novel methodology for the efficient synthesis of the precursors of vicinal amino azides 46 (Scheme 33) [76], which can easily be transformed into other important amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN3 as N3 source and available N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in moderate to excellent yields with high diastereoselectivity. Studer and co-workers described a novel methodology for the efficient synthesis of the precursors of vicinal amino azides 46 (Scheme 33) [76], which can easily be transformed into other important amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN 3 as N 3 source and available N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in moderate to excellent yields with high diastereoselectivity.

Scheme 33. Aminoazidation of alkenes.
A plausible reaction mechanism based on the reported processes is outlined in Scheme 34 [77,78]. Firstly, Cu(I) reacts with NFSI to form Cu(III) species A, which could exist in equilibrium with a Cu(II)-stabilized N-centered radical B. It is the precursor of bis-sulfonylamidyl radical, which adds to the alkene to generate carbon radical C and Cu(II) species D. Also B species could react as N-radicals with the alkene. Then two pathways are suggested. In path a, trapping of C with D provides Cu(III) species E, which exchanges ligand with TMSN3 to give Cu(III) complex F. Reductive elimination of F affords the products along with the regeneration of the Cu(I) catalyst. In path b, D oxidizes C to cationic intermediate G, which is trapped by TMSN3 to form the products. Snider and co-workers reported a Mn(OAc)3-mediated diazidation of alkenes and glycals for the formation of 1,2-diazides compounds [79]. Very recently, Xu and co-workers reported a novel iron-catalyzed diastereoselective olefin diazidation method which tolerates a broad range of olefins (Scheme 35) [80]. This method also provides a convenient approach to vicinal primary diamines and other synthetically valuable nitrogen-containing compounds.

Scheme 33. Aminoazidation of alkenes.
A plausible reaction mechanism based on the reported processes is outlined in Scheme 34 [77,78]. Firstly, Cu(I) reacts with NFSI to form Cu(III) species A, which could exist in equilibrium with a Cu(II)-stabilized N-centered radical B. It is the precursor of bis-sulfonylamidyl radical, which adds to the alkene to generate carbon radical C and Cu(II) species D. Also B species could react as N-radicals with the alkene. Then two pathways are suggested. In path a, trapping of C with D provides Cu(III) species E, which exchanges ligand with TMSN 3 to give Cu(III) complex F. Reductive elimination of F affords the products along with the regeneration of the Cu(I) catalyst. In path b, D oxidizes C to cationic intermediate G, which is trapped by TMSN 3 to form the products. A plausible reaction mechanism based on the reported processes is outlined in Scheme 34 [77,78]. Firstly, Cu(I) reacts with NFSI to form Cu(III) species A, which could exist in equilibrium with a Cu(II)-stabilized N-centered radical B. It is the precursor of bis-sulfonylamidyl radical, which adds to the alkene to generate carbon radical C and Cu(II) species D. Also B species could react as N-radicals with the alkene. Then two pathways are suggested. In path a, trapping of C with D provides Cu(III) species E, which exchanges ligand with TMSN3 to give Cu(III) complex F. Reductive elimination of F affords the products along with the regeneration of the Cu(I) catalyst. In path b, D oxidizes C to cationic intermediate G, which is trapped by TMSN3 to form the products. Snider and co-workers reported a Mn(OAc)3-mediated diazidation of alkenes and glycals for the formation of 1,2-diazides compounds [79]. Very recently, Xu and co-workers reported a novel iron-catalyzed diastereoselective olefin diazidation method which tolerates a broad range of olefins (Scheme 35) [80]. This method also provides a convenient approach to vicinal primary diamines and other synthetically valuable nitrogen-containing compounds. Snider and co-workers reported a Mn(OAc) 3 -mediated diazidation of alkenes and glycals for the formation of 1,2-diazides compounds [79]. Very recently, Xu and co-workers reported a novel iron-catalyzed diastereoselective olefin diazidation method which tolerates a broad range of olefins (Scheme 35) [80]. This method also provides a convenient approach to vicinal primary diamines and other synthetically valuable nitrogen-containing compounds.

Construction of C-N3 Bond and C-P Bond
An efficient method for the synthesis of β-azidophosphonates 49 through Mn(OAc)3-mediated radical oxidative phosphonation-azidation of alkenes under relatively mild reaction conditions was reported by Tang and co-workers. This reaction displayed a broad substrate scope and can be easily scaled up. The products can be obtained in a one-pot operation (Scheme 37) [81]. Based on their previous studies in P-C bond formation, and reaction of organophosphorus radicals [82], a possible mechanism was proposed (Scheme 38). The reaction is initiated by the addition of phosphorous radical A to alkene to generate radical B, which undergoes further oxidation to afford cationic intermediate C.

Construction of C-N3 Bond and C-P Bond
An efficient method for the synthesis of β-azidophosphonates 49 through Mn(OAc)3-mediated radical oxidative phosphonation-azidation of alkenes under relatively mild reaction conditions was reported by Tang and co-workers. This reaction displayed a broad substrate scope and can be easily scaled up. The products can be obtained in a one-pot operation (Scheme 37) [81]. Based on their previous studies in P-C bond formation, and reaction of organophosphorus radicals [82], a possible mechanism was proposed (Scheme 38). The reaction is initiated by the addition of phosphorous radical A to alkene to generate radical B, which undergoes further oxidation to afford cationic intermediate C.

Construction of C-N 3 Bond and C-P Bond
An efficient method for the synthesis of β-azidophosphonates 49 through Mn(OAc) 3 -mediated radical oxidative phosphonation-azidation of alkenes under relatively mild reaction conditions was reported by Tang and co-workers. This reaction displayed a broad substrate scope and can be easily scaled up. The products can be obtained in a one-pot operation (Scheme 37) [81].

Construction of C-N3 Bond and C-P Bond
An efficient method for the synthesis of β-azidophosphonates 49 through Mn(OAc)3-mediated radical oxidative phosphonation-azidation of alkenes under relatively mild reaction conditions was reported by Tang and co-workers. This reaction displayed a broad substrate scope and can be easily scaled up. The products can be obtained in a one-pot operation (Scheme 37) [81]. Based on their previous studies in P-C bond formation, and reaction of organophosphorus radicals [82], a possible mechanism was proposed (Scheme 38). The reaction is initiated by the addition of phosphorous radical A to alkene to generate radical B, which undergoes further oxidation to afford cationic intermediate C. The intermediate C is then trapped by TMSN3 to afford the final product Based on their previous studies in P-C bond formation, and reaction of organophosphorus radicals [82], a possible mechanism was proposed (Scheme 38). The reaction is initiated by the addition of phosphorous radical A to alkene to generate radical B, which undergoes further oxidation to afford cationic intermediate C. The intermediate C is then trapped by TMSN 3 to afford the final product (path a). Alternatively, the radical B could be directly trapped by an azido radical to form the product (path b) (Scheme 38).

Construction of C-N3 Bond and C-Se Bond
Tiecco and co-workers reported the first example of a highly asymmetric electrophilic azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. This reaction occurs with a high level of facial selectivity, which was made possible by the use of chiral, non-racemic selenium reagents (Scheme 39) [83].

Construction of C-N3 Bond and C-Halogen Bond
1,2-Haloazidation of alkenes represents an important transformation in organic synthesis. By using Zn(OTf)2 as catalyst, a metal-catalyzed bromoazidation of alkenes was reported by Hajra and co-workers. The corresponding bromoazidation products were obtained in good yields by using this protocol (Scheme 40, a) [84]. Phukan's group also achieved the bromoazidation of alkenes by using other bromine sources [85,86]. Moreover, a route to 1,2-azidochlorides from alkenes was developed by Finn and co-workers (Scheme 40, b) [87].

Construction of C-N 3 Bond and C-Se Bond
Tiecco and co-workers reported the first example of a highly asymmetric electrophilic azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. This reaction occurs with a high level of facial selectivity, which was made possible by the use of chiral, non-racemic selenium reagents (Scheme 39) [83].

Construction of C-N3 Bond and C-Se Bond
Tiecco and co-workers reported the first example of a highly asymmetric electrophilic azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. This reaction occurs with a high level of facial selectivity, which was made possible by the use of chiral, non-racemic selenium reagents (Scheme 39) [83].

Construction of C-N3 Bond and C-Halogen Bond
1,2-Haloazidation of alkenes represents an important transformation in organic synthesis. By using Zn(OTf)2 as catalyst, a metal-catalyzed bromoazidation of alkenes was reported by Hajra and co-workers. The corresponding bromoazidation products were obtained in good yields by using this protocol (Scheme 40, a) [84]. Phukan's group also achieved the bromoazidation of alkenes by using other bromine sources [85,86]. Moreover, a route to 1,2-azidochlorides from alkenes was developed by Finn and co-workers (Scheme 40, b) [87]. 2.6. Construction of C-N 3 Bond and C-Halogen Bond 1,2-Haloazidation of alkenes represents an important transformation in organic synthesis. By using Zn(OTf) 2 as catalyst, a metal-catalyzed bromoazidation of alkenes was reported by Hajra and co-workers. The corresponding bromoazidation products were obtained in good yields by using this protocol (Scheme 40a) [84]. Phukan's group also achieved the bromoazidation of alkenes by using other bromine sources [85,86]. Moreover, a route to 1,2-azidochlorides from alkenes was developed by Finn and co-workers (Scheme 40b) [87].

Conclusions
In conclusion, this review has summarized recent difunctionalization reactions of olefins with organic and inorganic azides through C-N3 bond formation. An oxidative single electron transfer (SET) process is involved in most cases. These approaches provide efficient protocols for the preparation of various organic azido compounds, which can then be further applied in many transformations to synthesize various valuable nitrogen-containing compounds.