Azidation in the Difunctionalization of Olefins - Semantic Scholar

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Azidation in the Difunctionalization of Olefins Kai Wu, Yujie Liang and Ning Jiao * State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China; [email protected] (K.W.); [email protected] (Y.L.) * Correspondence: [email protected]; Tel.: +86-10-8280-5297 Academic Editor: Klaus Banert Received: 13 November 2015 ; Accepted: 9 March 2016 ; Published: 16 March 2016

Abstract: 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. Keywords: azides; difunctionalization; olefins

1. Introduction The first organic azide, phenyl azide, discovered by Griess in 1864 opened the door for the use of organic azides in synthesis [1]. Since then, numerous elegant approaches have been developed, such as the aza-Wittig reaction [2], Sundberg rearrangement, Curtius rearrangement [3,4], Schmidt rearrangement [5], Hemetsberger rearrangement [6] and click chemistry [7–12]. Organic azides are important building blocks and intermediates, not only due to the fact they are potential precursors of N-containing structural motifs [13–19], but also for their remarkable biological activity in pharmaceutical chemistry [20]. Moreover, organic azides have also received great attention in other fields, such as supramolecular chemistry [21–24], medicinal chemistry [25], biotechnology and materials science [26]. Olefins are readily available starting materials in organic synthesis. Recently, the difunctionalization of olefins [27–42] which could introduce two chemical bonds into substrates simultaneously, has attracted considerable attention. Organic azide-driven difunctionalization of olefins has been a hot topic in this area in recent years. Herein, we summarize the recent developments in the use of azidation reactions in the difunctionalization of olefins. 2. The Application of Organic Azides in Difunctionalization of Olefins 2.1. Construction of C-N3 Bond and C-C Bond In the past decade, the hydroazidation of olefins has been significantly developed [43–48], 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-N3 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, Csp2 -Csp3 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.

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Scheme Scheme 1. 1. Arylheterofunctionalization Arylheterofunctionalization of of activated activated alkenes. alkenes. Scheme 1. Arylheterofunctionalization of activated alkenes.

The proposed mechanism is illustrated in Scheme 2. In the first step, the generated azido radical The proposed mechanism is in Scheme 2. In the first step, the generated azido The with proposed mechanism is illustrated illustrated in Scheme 2. bond In theand firstan step, the generated azido radical radical interacts the activated alkene to give a new C(sp3)-N alkyl radical intermediate A. A 3 3)-N interacts with the the activated activatedalkene alkenetotogive giveaanew newC(sp C(sp )-N bond and an alkyl radical intermediate A. interacts with bond and an alkyl radical intermediate A. to A 5-ipso cyclization then takes place on the aromatic ring generating aryl radical B, which leads A 5-ipso cyclization then takes place on the aromatic ring generating aryl radical B, which leads 5-ipso cyclization then takes place onwith the concomitant aromatic ring generating aryl B, which leads to amidyl radical C upon rearomatization desulfonylation. Theradical subsequent H-abstraction to amidyl radical C upon rearomatization with concomitant desulfonylation. TheH-abstraction subsequent amidyl radical C upon rearomatization with concomitant desulfonylation. The subsequent step produces the desired product 2 (Scheme 2). H-abstraction produces the desired product step produces step the desired product 2 (Scheme 2). 2 (Scheme 2).

Scheme 2. The proposed mechanism of the arylheterofunctionalization of alkenes. Scheme Scheme2.2.The Theproposed proposedmechanism mechanismofofthe thearylheterofunctionalization arylheterofunctionalizationofofalkenes. alkenes.

Wang and co-workers reported a copper-catalyzed intermolecular Markovnikov-type azidocyanation Wang and co-workers reported a copper-catalyzed intermolecular Markovnikov-type azidocyanation reaction of alkenes 3 to construct C-N 3 andaC-CN bonds simultaneously (Scheme 3) [50], which gives Wang and co-workers reported copper-catalyzed intermolecular Markovnikov-type reaction of alkenes 3 to construct C-N 3 and C-CN bonds simultaneously (Scheme 3) [50], which gives aazidocyanation series of 3-azido-2-arylpropanenitriles 4 in moderate toC-CN good bonds yields.simultaneously These compounds may3)serve reaction of alkenes 3 to construct C-N3 and (Scheme [50], 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 which gives a series of 3-azido-2-arylpropanenitriles 4 in moderate to good yields. These compounds as potential precursors of the corresponding 3-amino-2-arylpropanoic acids. This reaction employs PhI(OAc) 2 as 3 as N3 of source, TMSCN as CN source and it proceeds atacids. room temperature. may serve asoxidant, potentialTMSN precursors the corresponding 3-amino-2-arylpropanoic This reaction 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 employs PhI(OAc) as oxidant, TMSN as N source, TMSCN as CN source and it proceeds at room 2 3 3 A mechanistic study revealed that the addition of process 2,6-di-tert-butyl-4-methylphenol (BHT) significantly suppressed the reaction, suggesting that a radical may be involved in this reaction. temperature. A mechanistic study revealed that the addition of 2,6-di-tert-butyl-4-methylphenol (BHT) suppressed the reaction, suggesting that a radical process may be involved in this reaction. significantly suppressed the reaction, suggesting that a radical process may be involved in this reaction.

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Scheme3.3.Azidocyanation Azidocyanation of Scheme ofaryl arylalkenes. alkenes. Scheme 3. Azidocyanation of aryl alkenes.

On the basis of the above results, a plausible mechanism is proposed. First, TMSN3 could react

On basis of the above the results, a 3.plausible mechanism is proposed. First,Then TMSN could react Scheme Azidocyanation of aryl alkenes. withthe PhI(OAc) 2 to generate N3 radical under the standard reaction conditions. the3 radical On the basis of the above results, a plausible mechanism is proposed. First, TMSN3 could react with addition PhI(OAc) to generate the N3 radical the standard reaction conditions. the radical to2alkene gives intermediate A. Inunder the presence of copper(II) catalyst, A could beThen oxidized to with On PhI(OAc) 2 to generate the N3 radical under the standard reaction conditions. Then the radical the basis of the a In plausible mechanism is proposed. First, TMSN 3 could react formto the intermediate Babove with results, a carbocation center, whichofiscopper(II) trapped bycatalyst, TMSCN tocould give the final addition alkene gives intermediate A. the presence A be oxidized addition to alkene gives intermediate A. In the presence of copper(II) catalyst, A could be oxidized to with PhI(OAc) 2 to the N3 radical under the standard reaction conditions. Then the radical product (Scheme 4).generate to form the intermediate B with center,which which trapped TMSCN to give the final form the intermediate with a a carbocation carbocation is is trapped by by TMSCN to be give the final addition to alkene givesBintermediate A. In thecenter, presence of copper(II) catalyst, A could oxidized to product (Scheme 4). 4). product (Scheme form the intermediate B with a carbocation center, which is trapped by TMSCN to give the final product (Scheme 4).

Scheme 4. Plausible mechanism of the reaction. Scheme Plausible mechanism mechanism ofofthe Scheme 4.4.Plausible thereaction. reaction. A radical mediated azidosulfonylation of various 1-en-6-ynes 5 or 1,6-dienes 6 that are able to Scheme 4. Plausible mechanism the reaction. undergo a rapid radical rearrangement was reported by of Renaud and co-workers (Scheme 5) [51]. A radical mediated azidosulfonylation of various 1-en-6-ynes 5 or 1,6-dienes 6 that are able to This reaction is initiated by di-tert-butyldiazene upon irradiation with5aor 3001,6-dienes W sun lamp. Under the A radical azidosulfonylation various 1-en-6-ynes 6 that are able to undergo a mediated rapid radical rearrangement wasof by Renaud and [51]. A radical mediated azidosulfonylation ofreported variouscompleted 1-en-6-ynes 5 or co-workers 1,6-dienes 6(Scheme that are 5) able to standard reaction conditions, the reaction is generally within 2–4 h. undergo areaction rapid is radical rearrangement was reported by Renaud and co-workers (Scheme 5) [51]. This initiated by di-tert-butyldiazene upon irradiation with a 300 W sun lamp. Under the undergo a rapid radical rearrangement was reported by Renaud and co-workers (Scheme 5) [51]. standard reaction conditions, the reaction is generally completed within 2–4 h. This reaction is initiated by di-tert-butyldiazene upon irradiation with a 300 W sun lamp. Under This reaction is initiated by di-tert-butyldiazene upon irradiation with a 300 W sun lamp. Under the the standard reaction conditions, thethe reaction within 2–4 standard reaction conditions, reactionisisgenerally generally completed completed within 2–4 h. h.

Scheme 5. Azidoarylation of alkenes. Scheme 5. Azidoarylation of alkenes.

2-Oxindoles not only have unique biological activity, but also are important building blocks in Scheme 5. In Azidoarylation of alkenes. drug design and organic synthesis [52,53]. order to synthesize these useful intermediates, a rapid 5. Azidoarylation alkenes. 2-Oxindoles not only haveScheme unique biological activity,of but also are important building blocks in approach to oxindoles through C-N3 and C-C bond construction was reported by Antonchick and drug design and organic synthesis [52,53]. In order to synthesize these useful intermediates, a rapid 2-Oxindoles not only have unique biological activity, but also areconditions, importantgiving building blocks in co-workers [54]. This chemistry proceeds under mild and metal-free biologically approach to and oxindoles C-N 3 and C-C bond construction was reported by Antonchick and 2-Oxindoles notorganic onlythrough have unique biological activity, but also are important building blocks in drug design synthesis [52,53]. In order to synthesize these useful intermediates, a rapid interesting 2-oxindoles 10 in good yields (Scheme 6). co-workers [54]. This chemistry proceeds under mild and metal-free conditions, giving biologically to oxindoles through C-N 3 and In C-C bondtoconstruction reported Antonchick and drug approach design and organic synthesis [52,53]. order synthesizewas these useful by intermediates, a rapid interesting 2-oxindoles 10 in good yields (Scheme 6). co-workers [54]. Thisthrough chemistry proceeds under mild and metal-free conditions, giving biologically approach to oxindoles C-N and C-C bond construction was reported by Antonchick and 3 interesting 10 in good yields (Scheme 6). and metal-free conditions, giving biologically co-workers [54].2-oxindoles This chemistry proceeds under mild

interesting 2-oxindoles 10 in good yields (Scheme 6).

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Scheme 6. Azidoarylation of alkenes.

Scheme 6. Azidoarylation of alkenes. Scheme 6. Azidoarylation of alkenes. 6. Azidoarylation of alkenes. A plausible mechanism forScheme this transformation is illustrated in Scheme 7. This reaction begins with a doublemechanism ligand exchange PhI(OCOCF3)2is TMSN3 toin intermediate A, which A for this illustrated Scheme 7. begins A plausible plausible mechanism for between this transformation transformation isand illustrated inprovide Scheme 7. This This reaction reaction begins A plausible mechanism for this transformation is and illustrated into Scheme 7.intermediate This reaction begins undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to with a double ligand exchange between PhI(OCOCF ) TMSN provide A, 3 2 3 with a double ligand exchange between PhI(OCOCF3)2 and TMSN3 to provide intermediate A, which which with give a double ligand exchange between 3)2intermediate and radical. TMSNC. 3 to provide intermediate A, which intermediate B, which is trapped to byPhI(OCOCF arene to give Rearomatization of attacks C provides undergoes thermal homolytic cleavage generate anazido azido This azidoradical radical alkene 9 undergoes thermal homolytic cleavage to generate an radical. This azido attacks alkene 9 to product 10. Similar approaches using different catalysts and oxidants were also reported by the undergoes thermal homolytic cleavage to generate an azido radical. This azido radical attacks alkene 9 to to give intermediate B, which is trapped by arene give intermediate C. Rearomatization of C give intermediate B, which is trapped by arene to givetointermediate C. Rearomatization of C provides of Zhang Yang [56], andby Jiaoarene [57] (Scheme give groups intermediate B, [55], which is trapped to give 8). intermediate C. Rearomatization of C provides

provides product 10. approaches Similar approaches using different catalysts and oxidants reported by product 10. Similar using different catalysts and oxidants were were also also reported by the product 10. Similar approaches using different catalysts and oxidants were also reported by the the groups of Zhang Yang [56], (Scheme groups of Zhang [55],[55], Yang [56], andand JiaoJiao [57][57] (Scheme 8). 8). groups of Zhang [55], Yang [56], and Jiao [57] (Scheme 8).

Scheme 7. Proposed mechanism for the azidoarylation of alkenes.

Scheme 7. Proposed mechanism for the azidoarylation of alkenes. Scheme Proposed mechanism Scheme 7. 7. Proposed mechanism for for the the azidoarylation azidoarylation of of alkenes. alkenes.

Scheme 8. Azidoarylation of alkenes.

Scheme 8. Azidoarylation of alkenes. Scheme 8. 8. Azidoarylation Azidoarylation of of alkenes. alkenes. Scheme

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The introduction introduction of a trifluoromethyl trifluoromethyl group into chemical compounds compounds is an important way to modify their activities [58]. In light of their importance in in medicinal medicinal chemistry, chemistry, and biocompatibilities [58]. In light of their importance Molecules 2016, 21, 352 5 of 20 a novel alkenes hashas been developed by novel copper-catalyzed copper-catalyzedintermolecular intermolecularazidotrifluoromethylation azidotrifluoromethylationofof alkenes been developed Molecules 2016, 21, 352 5 of 20 Theco-workers introduction of ausing trifluoromethyl into various chemical compounds is anorganoazides important way Liu and and co-workers [59]. [59]. By this method, various CF3 -containing organoazides 11 were obtained by Liu By using this group method, CF 3-containing 11to were modify activities andreaction biocompatibilities [58]. In light of importance in medicinal chemistry, in good yields under mild (Scheme 9).their Besides, the resulting products can be obtained in their good yields under mild conditions reactiongroup conditions (Scheme 9). Besides, resulting products The introduction of a trifluoromethyl into chemical compounds is anthe important way to a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed readily transformed into other valuable CF3 -containing 3-containing amine compounds. can be readily transformed other valuable CFIn modify their activities andinto biocompatibilities [58]. lightamine of theircompounds. importance in medicinal chemistry, by Liu and co-workers [59]. By using this method, various CF3-containing organoazides 11 were a novel copper-catalyzed intermolecular azidotrifluoromethylation of alkenes has been developed obtained in good yields under mild reaction conditions (Scheme 9). Besides, the resulting products by Liu and co-workers [59]. By using this method, various CF3-containing organoazides 11 were can be readily transformed into other valuable CF3-containing amine compounds. 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. Scheme 9. Azidotrifluoromethylation of alkenes. Scheme 9. Azidotrifluoromethylation of alkenes.

A photoredox-catalyzed azidotrifluoromethylation of enecarbamates 12 was reported by Magnier, A photoredox-catalyzed azidotrifluoromethylation of enecarbamates Scheme 9. Azidotrifluoromethylation of alkenes. 12 was reported by Magnier, A photoredox-catalyzed azidotrifluoromethylation of reagent enecarbamates was reported by Magnier, 3 source, and was proposed to Masson and coworkers [60]. This reaction used Tongi’s as CF12 Masson and coworkers [60]. This reaction used Tongi’s reagent asCFCF and was proposed to 3 source, 3 source, and was proposed to Masson and coworkers [60]. This reaction used Tongi’s reagent as follow a radical/cationic pathway. Under the optimized a wide range of substrates can be A photoredox-catalyzed azidotrifluoromethylation ofconditions, enecarbamates 12 was reported by Magnier, follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be follow a radical/cationic pathway. Under the optimized conditions, a wide range of substrates can be readily difunctionalized (Scheme 10). Masson and coworkers [60]. This reaction used Tongi’s reagent as CF3 source, and was proposed to readily difunctionalized (Scheme 10). readily difunctionalized (Scheme 10). 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. Scheme 10. Azidotrifluoromethylation of enecarbamates. Scheme 10. Azidotrifluoromethylation of enecarbamates.

A possible mechanism is shown in Scheme 11. Visible light excites Ru(bpy)32+ into *Ru(bpy)32+,

2+, 2+ A possible possible mechanism mechanism is is shownin inScheme Scheme11. 11. Visiblelight lightexcites excitesRu(bpy) Ru(bpy) 32+ into into*Ru(bpy) *Ru(bpy)332+ A , 3 which is a strong reductantshown species that performs Visible a SET to generate trifluoromethyl radical from A possible mechanism is shown in Scheme 11. Visible light excites Ru(bpy) 32+ into *Ru(bpy)32+, which strong reductant species that performs a to SET toenecarbamate generate trifluoromethyl radical from which isisaastrong reductant species that performs a SET generate trifluoromethyl from Togni’s Togni’s reagent. Then, addition of trifluoromethyl radical to 14 leadsradical to an α-amido which is a strong species that performs radical a SET totogenerate trifluoromethyl radical from Togni’s reagent. Then,reductant addition of trifluoromethyl enecarbamate 14toleads to α-amido radical intermediate A, can be oxidized intotoN-acyliminium cation intermediate B an by SET reagent. Then, addition of which trifluoromethyl radical enecarbamate 14 leads an α-amido radical Togni’s reagent. Then,3+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 . Final nucleophilic trapping by NaN 3 forms the products 15. intermediate A, which can oxidized into N-acyliminium cation intermediate B by SETBprocess radical intermediate A, be which can be oxidized into N-acyliminium cation intermediate by SET from 3+ process from Ru(bpy) 33+. Final nucleophilic trapping by NaN3 forms the products 15. 3+ Ru(bpy)3 . Final nucleophilic trapping by NaN3 forms the products 15.

process from Ru(bpy)3 . Final nucleophilic trapping by NaN3 forms the products 15.

Scheme 11. Proposed mechanism. Scheme 11. Proposed mechanism.

Scheme 11. Proposed mechanism. Scheme 11. Proposed mechanism.

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Inspired by their above work, this group also developed a photoredox-catalyzed photoredox-catalyzed 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 azidotrifluoromethylation of alkenes 16. Under the optimized conditions, using Umemoto’s reagent azidotrifluoromethylation of alkenes 16. Under the optimized conditions, using Umemoto’s reagent thethe CFCF a wide range of of alkenes cancan be be readily difunctionalized (Scheme 12)12) [61]. as 3 source, a wide range alkenes readily difunctionalized (Scheme [61]. 3 source, as the CF3 source, a wide range of alkenes can be readily difunctionalized (Scheme 12) [61].

Scheme Scheme 12. 12. Azidotrifluoromethylation Azidotrifluoromethylation of of alkenes. alkenes. Scheme 12. Azidotrifluoromethylation of alkenes.

A similar mechanism is proposed based on their above work (Scheme 13). Firstly, visible light A similar similar mechanism mechanism is is proposed proposed based on on their their above above work work (Scheme 13). 13). Firstly, Firstly, visible visible light light A excites the Ru(bpy)32+ into *Ru(bpy) 32+,based which performs a SET to (Scheme generate trifluoromethyl radical 2+ into *Ru(bpy) 2+ , which performs a SET to generate trifluoromethyl radical excites the Ru(bpy) 2+ 2+ 33 into *Ru(bpy)33 , which performs a SET to generate trifluoromethyl radical excites the Ru(bpy) from Umemoto’s reagent 17. Then addition of trifluoromethyl radical to alkenes 16 produces carbon from Umemoto’s Umemoto’s reagent reagent 17. 17. Then Then addition addition of of trifluoromethyl trifluoromethyl radical radical to to alkenes alkenes 16 16 produces produces carbon carbon from radical intermediate A, which can be oxidized into β-trifluoromethylated carbocation intermediate radical intermediate A, can oxidized into β-trifluoromethylated carbocation intermediate B. radical intermediate A,Bwhich which canbe be β-trifluoromethylated carbocation intermediate B. Finally, carbocation is trapped by oxidized TMSN3 tointo form the product 18. Finally, carbocation B is trapped by TMSN to form the product 18. 3 3 to form the product 18. B. Finally, carbocation B is trapped by TMSN

Scheme 13. Plausible reaction mechanism. Scheme 13. Plausible reaction mechanism. Scheme 13. Plausible reaction mechanism.

Due to the importance of these compounds, a copper-catalyzed three-component Due to the importance of was these compounds, a copper-catalyzed three-component azidotrifluoromethylation of alkenes designed by Yang (Scheme 14) [62]. This reaction proceeded Due to the importance of was these compounds, a copper-catalyzed three-component azidotrifluoromethylation of alkenes designed by Yang (Scheme 14) [62]. This reaction proceeded under mild conditions and gave the corresponding product 20 in good yields. A possible mechanism azidotrifluoromethylation alkenes was designed by Yang (Scheme 14) [62]. This reactionmechanism proceeded under mild conditions andof gave the19corresponding 20 in good Aspecies possible was also proposed. Togni’s reagent is activated byproduct CuBr, leading to theyields. radical A by reaction under mild conditions and gave the corresponding product 20 in good yields. A possible mechanism was Togni’s reagent 19 A is activated by to CuBr, leading to B, thewhich radicalisspecies by reaction withalso the proposed. alkene. Then, intermediate is oxidized intermediate furtherA trapped by was also proposed. Togni’s reagent 19 is activated by CuBr, leading to the radical species A by reaction with the intermediate is oxidized tointermediate intermediateA B, which is TMSN further3 and trapped TMSN 3 toalkene. lead to Then, the product (Path a).AAlternatively, reacts with CuBrby to with the alkene. Then, intermediate AAlternatively, is oxidized to intermediate B, which isTMSN further trapped by TMSN 3 to lead to the product (Path a). intermediate A reacts with 3 and CuBr to afford complex C, further reductive elimination of complex C affords the product 20. TMSN3complex to lead to product (Path a). Alternatively, intermediate A reacts with TMSN afford C,the further reductive elimination of complex C affords the product 20. 3 and CuBr to afford complex C, further reductive elimination of complex C affords the product 20.

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Scheme 14. Azidotrifluoromethylation of alkenes.

Scheme 14. Azidotrifluoromethylation of alkenes. Scheme 14.Azidotrifluoromethylation Azidotrifluoromethylation ofof alkenes. Scheme 14. alkenes. 2.2. Construction of C-N3 Bond and C-O Bond

2.2. Construction of C-N3 Bond and C-O Bond 2.2. Construction of C-N 3 Bond and C-OBond Bond Shibasaki co-workers reported the first example of (Cl2SnO)n-catalyzed synthesis of trans 2.2. Construction of and C-N 3 Bond and C-O Shibasaki and co-workers reported the first of(Cl (Cl -catalyzed synthesis of trans β-azido alcohols by using readily available as substrates (Scheme [63]. n15) 2 SnO) Shibasaki and co-workers reported thealkenes first example example of 2SnO) n-catalyzed synthesis of trans Shibasaki and co-workers reported thealkenes first example of (Cl(Scheme 2SnO)n-catalyzed synthesis of trans β-azido alcohols by using readily available as substrates 15) [63]. β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63]. β-azido alcohols by using readily available alkenes as substrates (Scheme 15) [63].

Scheme 15. Synthesis of trans β-azido alcohols. Scheme 15. Synthesis of trans β-azido alcohols.

Synthesis of trans The authors proposed aScheme catalytic15. cycle that involves theβ-azido insertionalcohols. of a C=C double bond to dichlorotin oxideThe to afford intermediate A, which could react with TMSN 3 to afford B. Subsequent nucleophilic attack authors proposed aScheme catalytic15. cycle that involves theβ-azido insertionalcohols. of a C=C double bond to dichlorotin Synthesis of trans of BTSP (bis(trimethylsilyl) oncycle Sn gives the intermediate regeneration of (Cl 2SnO)n The authors proposed A, aperoxide) catalytic that involves the C. insertion of nucleophilic a C=C double oxide to afford intermediate which could react with TMSN 3 to afford B.The Subsequent attackbond by S N2 attack with TMSN3 gives D as the precursor of the product (Scheme 16). of BTSP (bis(trimethylsilyl) peroxide) on Sn gives the intermediate C. The regeneration of (Cl2SnO)n

to dichlorotin to aafford intermediate A, which could of react with TMSN todichlorotin afford B. The authorsoxide proposed catalytic cycle that involves the insertion a C=C double bond 3 to by S N 2 attack with TMSN 3 gives D as the precursor of the product (Scheme 16). Subsequent nucleophilic attack of BTSP (bis(trimethylsilyl) Sn gives the intermediate C. oxide to afford intermediate A, which could react with TMSN3 peroxide) to afford B.on Subsequent nucleophilic attack The regeneration of (Cl2 SnO)n by SN 2onattack withthe TMSN gives D as the precursor of the product of BTSP (bis(trimethylsilyl) peroxide) Sn gives intermediate C. The regeneration of (Cl 2 SnO)n 3 (Scheme 16). with TMSN3 gives D as the precursor of the product (Scheme 16). by SN2 attack

Scheme 16. Plausible reaction mechanism. Scheme 16. Plausible reaction mechanism.

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)hydroxyazidation [64]. This chemistry Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative of was notable for its mild reaction conditions, broad substrate scope, and high reaction olefins for the synthesis of β-azido alcohols 23 using air as the oxidant (Scheme 17) [64]. This efficiency. chemistry was notable for its mild reaction conditions, broad substrate scope, and high reaction efficiency. Scheme 16. reaction mechanism. Scheme 16. Plausible Plausible reaction mechanism.

Recently, the Jiao group reported an efficient Mn-catalyzed aerobic oxidative hydroxyazidation of 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 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.

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Molecules 2016, 21, 352 of 20 was notable for its mild reaction conditions, broad substrate scope, and high reaction 8efficiency. Moreover, the resulting β-azido alcohols precursorsofofβ-amino β-amino alcohols, aziridines, and Moreover, the β-azido alcoholsare areuseful useful precursors alcohols, aziridines, Molecules 2016, 21, resulting 352 8 and of 20 otherother O- and N-containing heterocyclic O- and N-containing heterocycliccompounds. compounds. Molecules 2016, 21, 352 of 20 Moreover, the resulting β-azido alcohols are useful precursors of β-amino alcohols, aziridines,8 and other O- and N-containing heterocyclic compounds. Moreover, the resulting β-azido alcohols are useful precursors of β-amino alcohols, aziridines, and other O- and N-containing heterocyclic compounds.

Scheme 17. β-Azido alcohol construction.

Scheme 17. β-Azido alcohol construction.

On the basis of the mechanistic study density functional theory (DFT) calculations, a favored Scheme 17. and β-Azido alcohol construction.

On theprocess basis ofis the mechanistic and density functional theoryto(DFT) calculations, a favored radical proposed (Schemestudy 18). Firstly, the MnII is readily oxidized MnIII or MnIV by molecule Scheme 17. β-Azido alcohol construction. II III oxidizes TMSN3 to generate azido radical. MnIV can also oxidize oxygen the then TMSN radical process isair, proposed (Scheme 18). Firstly, the functional Mn is readily oxidized to MnIIIa favored or Mn3IV by Onin the basis of theMn mechanistic study and density theory (DFT) calculations, III catalyst. Radical III Mn IV less to form the N3 in radical A and generate A attacks anazido alkene at sterically radical process is proposed (Scheme Firstly, theTMSN MnII is readily oxidized to MnIIIradical. or the MnIV by molecule molecule oxygen the air, then Mn18). oxidizes Mn can also 3 to generate On the basis oftothe mechanistic study andB,density functional theory (DFT) calculations, a peroxyl favored III IV III hindered position form the carbon radical which is trapped by oxygen to generate the oxygen in the air, thenthe MnN3oxidizes TMSN 3 to generate azido radical. MnRadical canIII alsoAoxidize TMSN 3 oxidize TMSN to form radical A and generate Mn catalyst. attacks an alkene 3 II IV radical process is proposedthe (Scheme 18). Firstly, the is readily oxidized to Mnradical or MnC by molecule III catalyst. DFT calculations, it Mn is Radical favored for the peroxyl to undergo tosterically form C. theAccording N 3 radical to A and generate Mn A attacks an alkene at the sterically less at theradical less hindered position to form the carbon radical B, which is trapped by oxygen to III oxidizes TMSN3 to generate azido radical. MnIV can also oxidize TMSN3 oxygen in the air,SET then Mnprotonation Mn-participated and processes to afford β-azido by peroxy alcohols E. In comparison, hindered position to form the carbon radical B, which is trapped oxygen to generate the peroxyl generate the the peroxyl radical C. According toIIIthe DFT calculations, it is favored C to form N3 radical A and generate Mn catalyst. Radical A attacks an alkenefor at the peroxyl stericallyradical less the pathway through Ftoisthe disfavored. Finally, β-azido peroxyfor alcohol E is reduced byCPPh to form radical C. According DFT calculations, it is favored the peroxyl radical to 3undergo hinderedMn-participated position to form the carbon radical B, which is trappedtobyafford oxygenβ-azido to generate the peroxyl to undergo SET and protonation processes peroxy alcohols E. the β-azido alcohol 23.and protonation processes to afford β-azido peroxy alcohols E. In comparison, Mn-participated SET radical C. According to the DFT calculations, it is favored for the peroxyl radical C to undergo In comparison, the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by the pathway through F is disfavored. Finally, β-azido peroxy alcohol E is reduced by PPh3 to form Mn-participated SET and protonation processes to afford β-azido peroxy alcohols E. In comparison, PPh3 the to form the β-azido β-azido alcohol 23. alcohol 23. 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 I18. 2-catalyzed synthesis of 1,2-azidoalcohols by employing Scheme Proposed mechanism. Scheme 18. Proposedrespectively mechanism. (Scheme 19) [65]. This approach NaN3 as N-nuclepohiles and DMF as O-nuclepohiles Scheme 18. Proposed mechanism. 18O displayed broad scope and high efficiency with regio- and stereoselectivity. Sudalai and substrate co-workers reported an I2reaction -catalyzed synthesis of 1,2-azidoalcohols by employing labelling studies proved that DMF the O-nucleophile. Sudalai co-workers reported Ias synthesis of 1,2-azidoalcohols employing NaN3 as and N-nuclepohiles and DMFserved asan O-nuclepohiles respectively (Scheme 19) [65]. Thisby approach 2 -catalyzed Sudalai and co-workers reported an I2-catalyzed synthesis of 1,2-azidoalcohols by employing 18O broad substrate high reaction efficiency with regioand stereoselectivity. NaN3displayed as N-nuclepohiles and scope DMF and as O-nuclepohiles respectively (Scheme 19) [65]. This approach NaN3 as N-nuclepohiles and DMF as O-nuclepohiles respectively (Scheme 19) [65]. This approach labelling studies proved that DMF served as the O-nucleophile. displayed broad substrate highreaction reaction efficiency and stereoselectivity. 18O displayed broad substratescope scope and and high efficiency with with regio-regioand stereoselectivity. 18 O labelling studies proved that DMF served as the O-nucleophile. labelling studies proved that DMF served as the O-nucleophile.

Scheme 19. Synthesis of 1,2-azidoalcohols. Scheme 19. Synthesis of 1,2-azidoalcohols. Scheme19. 19.Synthesis Synthesis of Scheme of 1,2-azidoalcohols. 1,2-azidoalcohols.

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A possible mechanism was was proposed proposed (Scheme (Scheme 20). 20). Firstly, Firstly, an an iodonium iodonium ion ion is is formed formed by by the the A possible mechanism 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 reaction of iodine with alkene, which undergoes subsequent regioselective ring opening with DMF reaction of iodine with alkene, which undergoes subsequent regioselective ring opening with DMF afford the the corresponding iodo iodo intermediate A, followed by stereoselective displacement with NaN 3 to to afford corresponding intermediate A, followed by stereoselective displacement with to afford the corresponding iodo intermediate A, followed by stereoselective displacement with give intermediate B. Intermediate B on hydrolysis gives syn azido alcohols 24. Alternatively, under aq. NaN3 to give intermediate B. Intermediate B on hydrolysis gives syn azido alcohols 24. Alternatively, NaN 3 to give intermediate B. Intermediate B on hydrolysis gives syn azido alcohols 24. Alternatively, H O conditions, the iodo intermediate A is hydrolyzed in situ to form iodoformate C. The proposed 2 2 aq. H2O2 conditions, the iodo intermediate A is hydrolyzed in situ to form iodoformate C. The under under H O2 conditions, iodo intermediate A is hydrolyzed situ to iodoformate The speciesaq. D species is2formed from Cthe byfrom the anchimeric assistance from theinformate group, it group, reacts with the proposed D is formed C by the anchimeric assistance from theform formate itC. reacts proposed species D is formed from C by the anchimeric assistance from the formate group, it reacts azide anion in a regioselective manner to give anti azido alcohols 25 with the liberation of the iodide with the azide anion in a regioselective manner to give anti azido alcohols 25 with the liberation of with the azide anion in a regioselective manner to give anti azido alcohols 25 with the liberation of ion,iodide which is then reoxidized with TBHP/H I2 in the catalytic cycle. 2O 2 to regenerate the ion, which is then reoxidized with TBHP/H 2O2 to regenerate I2 in the catalytic cycle. the iodide ion, which is then reoxidized with TBHP/H2O2 to regenerate I2 in the catalytic cycle. Me2N Me2N

O

R1

O R

R1 I

H2O H2O

R A I O

NaN3

N

NaN3 Me2N Me2N

O

R1

O R

R1 N3

R

B

N

A H

R

H

R

R1

O

R1

O

I2

R1

O O R

I2

N3

B

O

R

C C

R1 I I

oxidant

H2O

base

I

H2O HO

base

I

HO R

R1 N3

oxidant

R1

R 24 N3

O

24

O R

O O R1

R D R1

NaN3 H2O NaN

N3

H2O base

N3 R

3

base

D

R1 R1 OH

R 25 OH 25

Scheme Scheme 20. 20. Possible Possible mechanism. mechanism. Scheme 20. Possible mechanism.

An effective [Cu(dap)2]Cl catalyzed azide addition of styrene-type alkenes 26 using the Zhdankin An effective effective [Cu(dap) ]Cl catalyzed catalyzed azide azide addition of of styrene-type styrene-type alkenes alkenes 26 26 using using the the Zhdankin Zhdankin 2]Cl An [Cu(dap) was reported by Greaney addition and co-workers [66]. This is a light-controlled reaction, reagent as N3 source reagent as as N N33 source source was was reported reported by by Greaney Greaney and and co-workers co-workers [66]. [66]. This This isis aa light-controlled light-controlled reaction, reaction, reagent and in the presence of light, a photoredox cycle is implicated with polar components such as methanol and in the presence of light, a photoredox cycle is implicated with polar components such as methanol andbromide in the presence of light, a photoredox cycle is implicated with polar components such as methanol or adding to a benzylic cation. By contrast, in the absence of light, a double azidation takes or bromide bromide adding to aa benzylic cation. By contrast, contrast, in in the the absence absence of of light, light, aa double azidation takes or adding to benzylic cation. By double azidation takes place, leading to diazide products. Thus, the degree of azidation can be controlled by switching place, leading to diazide products. Thus, Thus, the the degree degree of of azidation azidation can be controlled by switching between light and dark conditions (Scheme 21). between light and dark conditions (Scheme 21).

Scheme 21. Azidation of styrene-type double bonds. Scheme 21. Azidation of styrene-type double bonds. Scheme 21. Azidation of styrene-type double bonds.

Studer and co-worker achieved oxyazidation reactions of alkenes using sodium TEMPO as O Studer and29co-worker achieved alkenes30using sodium O source, reagent as N3 source under oxyazidation mild conditionreactions affordingofproduct in good yieldsTEMPO (Schemeas22) Studer and29co-worker achieved oxyazidation reactions of alkenes using sodium TEMPO as source, reagent 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 O source, 29 asthat N3 the source under mild affording productwell 30 in good yields [67]. It is reagent noteworthy oxyazidation of condition cyclic systems proceeded with excellent diastereoselectivity. (Scheme 22) [67]. It is noteworthy that the oxyazidation of cyclic systems proceeded well with diastereoselectivity. excellent diastereoselectivity.

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Scheme 22. Oxyazidation of alkenes. Scheme Scheme 22. 22. Oxyazidation Oxyazidation of of alkenes. alkenes. Scheme 22. Oxyazidation of alkenes.

Inspired by their previous work that TEMPONa could reduce CF3-iodine reagent (Togni reagent) Inspired by their previous work that TEMPONa could reduce CF3-iodine -iodine reagent reagent (Togni (Togni reagent) to generate CFby 3-radical [68], a radical process was suggested by the 23). Under the Inspired their previous work that TEMPONa could reduce CFauthors 3-iodine(Scheme reagent (Togni reagent) to generate CF3-radical -radical [68], [68], a radical process was suggested by the authors (Scheme 23). Under the generate authors (Scheme 23).and standard reaction conditions, TEMPONa reduced Togni reagent to generate an N 3 radical, release 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 an and release Togni reagent to generate generate an N N33 radical, TEMPO, the N 3 radical is TEMPONa trapped by reduced an olefinTogni to generate species A, which reacts with and TEMPO to standardthen reaction conditions, reagent to generate an N 3 radical, release TEMPO, then the N33 radical radicalisistrapped trappedby byan anolefin olefintotogenerate generatespecies species which reacts with TEMPO A,A, which reacts with TEMPO to form products 30.N3 radical is TEMPO, then the trapped by an olefin to generate species A, which reacts with TEMPO to to form products form products 30.30. form products 30.

Scheme 23. Radical oxyazidation of alkenes. Scheme 23. 23. Radical Radical oxyazidation oxyazidation of of alkenes. alkenes. Scheme Scheme 23. Radical oxyazidation of alkenes.

Recently, an efficient oxyazidation of alkenes under metal-free conditions was reported Recently, an efficient oxyazidation of alkenes under metal-free conditions was by reported by Xia and co-workers. This reaction form andmetal-free C-N bonds in one step using Recently, efficient oxyazidation of alkenes under conditions wasby reported Recently, ananefficient oxyazidation of could alkenes underC-O metal-free conditions was reported Xia and by Xia and co-workers. This reaction could form C-O and C-N bonds in one step by using N-hydroxyphthalimide an oxygen-radical and TMSN 3 by asbonds the NN-hydroxyphthalimide 3 source. A number of by Xia and This co-workers. This reaction form C-O C-N in one step by using co-workers. reactionascould form C-O could and precursor C-N bonds in and one step using N-hydroxyphthalimide as antolerated oxygen-radical precursor and (Scheme TMSN3 as the N3 source. A number of aryl-substituted alkenes was in this transformation 24) [69]. N-hydroxyphthalimide as an oxygen-radical precursor and TMSN 3 as the N 3 source. A number of as an oxygen-radical precursor and TMSN as the N source. A number of aryl-substituted alkenes 3 3 aryl-substituted alkenes was tolerated in this transformation (Scheme 24) [69]. aryl-substituted alkenes was tolerated in this 24) transformation (Scheme 24) [69]. was tolerated in this transformation (Scheme [69].

Scheme 24. Oxyazidation of alkenes. Scheme 24. Oxyazidation of alkenes. Scheme 24. Oxyazidation Scheme 24. Oxyazidation of of alkenes. alkenes.

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Molecules 2016,mechanism 21, 352 11 of 20 A possible is outlined in Scheme 25. In the presence of PIDA, N-hydroxyphthalimide A possible mechanism is outlined in Scheme 25. In the presence of PIDA, N-hydroxyphthalimide (NHPI) 31 could be oxidized to generate an N-oxyl (PINO) radical, which attacks alkenes to form (NHPI) 31 couldmechanism be oxidized to generate an N-oxyl (PINO) radical,ofwhich alkenes to form A possible is outlined in Scheme 25. In the presence PIDA,attacks N-hydroxyphthalimide Molecules 2016, 21, 352 11 of 20 intermediate A. Intermediate A can be oxidizedtotocation cation intermediate by PIDA. Finally, intermediate A. Intermediate befurther further oxidized intermediate B byB PIDA. Finally, (NHPI) 31 could be oxidized Atocan generate an N-oxyl (PINO) radical, which attacks alkenes to form intermediate B isBtrapped byby TMSN 32. 3 3to intermediate is trapped TMSN togive give products products 32.

intermediate A.mechanism Intermediate A can beinfurther cation intermediate B by PIDA. Finally, A possible is outlined Schemeoxidized 25. In thetopresence of PIDA, N-hydroxyphthalimide intermediate B is be trapped by TMSN 3 to give 32. (NHPI) 31 could oxidized to generate anproducts N-oxyl (PINO) radical, which attacks alkenes to form intermediate A. Intermediate A can be further oxidized to cation intermediate B by PIDA. Finally, intermediate B is trapped by TMSN3 to give products 32.

Scheme 25. Possible mechanism. Scheme 25. Possible mechanism. Scheme 25. Possible mechanism.

The simultaneous addition of oxygen and nitrogen across an alkene is a convenient way to The simultaneous addition of oxygen and nitrogen across an alkene is acopper-catalyzed convenient way to construct the precursor of 2-aminomethylmorpholines 34.across Remarkably, through The simultaneous addition ofScheme oxygen25.and nitrogen an alkene is a convenient way to Possible mechanism. oxyamination alkene, synthetic method for the 34. preparation of 34through was reported by Chemler construct the precursor of a2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed construct the of precursor ofnovel 2-aminomethylmorpholines Remarkably, copper-catalyzed and co-workers Under the reaction conditions, obtained inof good with oxyamination of alkene, a novel synthetic method for thewas preparation 34 reported by Chemler oxyamination of[70]. alkene, a novel synthetic method for34 the preparation of 34 was reported by excellent Chemler The simultaneous addition of oxygen and nitrogen across an alkene iswas ayields convenient way to diastereoselectivity (Scheme 26). and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent construct the precursor of 2-aminomethylmorpholines 34. Remarkably, through copper-catalyzed

diastereoselectivity 26).26).synthetic method for the preparation of 34 was reported by Chemler diastereoselectivity (Scheme oxyamination of(Scheme alkene, a novel and co-workers [70]. Under the reaction conditions, 34 was obtained in good yields with excellent diastereoselectivity (Scheme 26).

Scheme 26. Oxyazidation of alkenes. Scheme 26. Oxyazidation of alkenes.

26. in Oxyazidation alkenes. A plausible mechanism is Scheme illustrated Scheme 27. ofCoordination of alcohol 33 to copper(II) 2-ethylhexanoate gives monomer A. Thermal conditions promote cis-oxycupration via 33 TS-A, then give A plausible mechanism is illustrated Scheme 27.of Coordination of alcohol to copper(II) Scheme 26.in Oxyazidation alkenes. the copper(II) intermediate B. The diastereoselectivity is rationalized by a chair-like transition state 2-ethylhexanoate gives monomer A. Thermal promote cis-oxycupration via TS-A, give A plausible mechanism is illustrated inconditions Scheme 27. Coordination of alcohol 33 then to copper(II) where tosyl and benzyl substituents adopt pseudoaxial positions. B undergoes the copper(II) intermediate B.isThe diastereoselectivity ispromote rationalized by of aIntermediate chair-like transition state give A vicinal plausible mechanism in Scheme 27. Coordination alcohol 33 toTS-A, copper(II) 2-ethylhexanoate gives monomer A.illustrated Thermal conditions cis-oxycupration via then C-Cu(II) homolytic cleavage to substituents give carbon adopt radicalpseudoaxial C. promote In the presence ofIntermediate an azide an where vicinal tosyl andmonomer benzyl positions. Btransition undergoes 2-ethylhexanoate gives A. Thermal conditions cis-oxycupration via nucleophile, TS-A, then give the copper(II) intermediate B. TheD diastereoselectivity isundergo rationalized by aelimination chair-like state organocopper(III) intermediate is formed, which can reductive to form the C-Cu(II) homolytic cleavageB.toThe give carbon radical C.isInrationalized the presence azide nucleophile, an the copper(II) intermediate diastereoselectivity byofa an chair-like transition state where vicinal34.tosyl and benzyl substituents adopt pseudoaxial positions. Intermediate B undergoes product organocopper(III) D is formed,adopt whichpseudoaxial can undergo reductive eliminationBtoundergoes form the where vicinal tosylintermediate and benzyl substituents positions. Intermediate

C-Cu(II) homolytic cleavage to give carbon radical C. In the presence of an azide nucleophile, an product 34. C-Cu(II) homolytic cleavage to give carbon radical C. In the presence of an azide nucleophile, an organocopper(III) intermediate D is formed, which can undergo reductive elimination to form the organocopper(III) intermediate D is formed, which can undergo reductive elimination to form the product 34. product 34.

Scheme 27. Proposed oxyamination reaction mechanism. Scheme 27. Proposed oxyamination reaction mechanism. Scheme 27. Proposed oxyamination reaction mechanism. Scheme 27. Proposed oxyamination reaction mechanism.

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12 of 20 to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed enantioselective radical oxyfunctionalization of alkenes was developed by Buchwald and A new approach to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed A new approach to synthesize a wide range of chiral lactones 36 based on Cu-catalyzed co-workers [71]. radical This method provides a straightforward approach to various lactone and building blocks enantioselective oxyfunctionalization of alkenes was developed by Buchwald co-workers enantioselective radical oxyfunctionalization of alkenes was developed by Buchwald and co-workers containing tetrasubstituted stereogenic centers, which are hard to access through traditional methods [71]. This method provides a straightforward approach to various lactone building blocks containing [71]. This28). method provides a straightforward approach to various lactone building blocks containing (Scheme tetrasubstituted stereogenic centers, which are hard to access through traditional methods (Scheme 28). tetrasubstituted stereogenic centers, which are hard to access through traditional methods (Scheme 28).

Scheme Scheme 28. 28. Synthesis Synthesis of of chiral chiral lactones. lactones. Scheme 28. Synthesis of chiral lactones.

Isoxazolines are useful building blocks in organic chemistry [72]. Recently, an efficient Isoxazolines are useful building building blocks blocks in organic chemistry chemistry [72]. Recently, an efficient Isoxazolines Cu(OAc)2-catalyzed oxyazidation of alkenes 37 was developed by Wang, Xu and co-workers Cu(OAc)22-catalyzed -catalyzed oxyazidation oxyazidation of of alkenes alkenes 37 37 was was developed developed by by Wang, Xu and co-workers (Scheme 29) [73]. This reaction occurs under mild conditions, forming the azido-substituted isoxazolines (Scheme 29)[73]. [73]. This reaction occurs mild conditions, forming the azido-substituted (Scheme 29) This reaction occurs underunder mild conditions, forming the azido-substituted isoxazolines 38 in good yields, although the mechanism of this chemistry is still unclear. isoxazolines 38 in good yields, although the mechanism of this chemistry is still unclear. 38 in good yields, although the mechanism of this chemistry is still unclear.

Scheme 29. Oxyazidation of alkenes. Scheme Scheme 29. 29. Oxyazidation Oxyazidation of of alkenes. alkenes.

2.3. Construction of C-N3 Bond and C-N Bond 2.3. 2.3. Construction Construction of of C-N C-N33 Bond Bond and and C-N C-N Bond Bond Olefin diamination methods provide powerful access to vicinal diamines that are useful in Olefin diamination methods provide powerful access to diamines that useful in in Olefin diamination methods provide powerfulscience. access Recently, to vicinal vicinalan diamines that are are useful chemical biology, medicinal chemistry and materials novel copper(II)-promoted chemical biology, medicinal chemistry and materials science. Recently, an novel copper(II)-promoted chemical biology, medicinal chemistry and39 materials science.byRecently, novel copper(II)-promoted intramolecular azidoamination of alkenes was reported Chemleran and co-workers (Scheme 30) intramolecular azidoamination of alkenes 39 was reported by Chemler and co-workers (Scheme[74]. 30) intramolecular azidoamination of alkenes 39 was reported by Chemler and co-workers [74]. This method could tolerate a wide range of internal and external amine (Scheme sources 30) for the [74]. This method could tolerate a wide range of internal and external amine sources for the This method could tolerate a wide range of internal and external formation of differently functionalized nitrogen heterocycles 40. amine sources for the formation of formation differently functionalized nitrogen 40. heterocycles 40. differentlyof functionalized nitrogen heterocycles

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Scheme Scheme 30. 30. Intermolecular Intermolecular alkene alkene azidoamination. azidoamination. Schemean 30. intramolecular Intermolecular alkene azidoamination. Yu and co-workers reported azidation reaction through copper-mediated Yu and co-workers reported an30.intramolecular azidation reaction through copper-mediated Scheme Intermolecular alkene azidoamination. N-O cleavage and subsequent C-N bond forming 5-exo cyclization. The forming intermediate is N-O cleavage and subsequent C-N an bond forming 5-exo cyclization. forming intermediate is Yu and co-workers reported intramolecular azidation reaction The through copper-mediated subsequently azidated to afford the corresponding dihydropyrroles (Scheme 31)copper-mediated [75]. To understand Yu and co-workers reported an intramolecular azidation reaction through N-O cleavage and subsequent C-N bond formingdihydropyrroles 5-exo cyclization. (Scheme The forming intermediate is subsequently azidated to afford the corresponding 31) [75]. To understand this reaction mechanism, compound 43bond was treated standard reaction conditions. However, N-O cleavage and subsequent C-N formingunder 5-exo cyclization. The forming is in subsequently azidated to afford the corresponding 31)conditions. [75]. intermediate To understand this reaction mechanism, compound 43 was treateddihydropyrroles under standard(Scheme reaction However, in this case 44 and mechanism, 45 are mainly obtained with only trace amounts ring opening formation, subsequently azidated to compound afford the corresponding dihydropyrroles (Scheme 31) [75].product ToHowever, understand this reaction 43 with was treated underamounts standardof reaction conditions. in this case 44 and 45 are mainly obtained only trace of ring opening product formation, this reaction mechanism, compound 43 was treated under standard reaction conditions. However, in suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction 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 freetrace radical process. Based on these results, a reaction this case 44 and 45 are mainly obtained with only amounts of ring opening product formation, mechanism is proposed (Scheme 32). The first step involves the oxidative addition of Cu(I) to the suggesting that the cyclization step is unlikely a free radical process. Based on these results, a reaction N-O mechanism is proposed (Scheme 32). The firsta free stepradical involves the Based oxidative addition of Cu(I) to the suggesting that theA, cyclization step unlikely process. on these a the reaction mechanism is proposed (Scheme 32).isThe first step involves the oxidative ofresults, Cu(I) tocyclization N-O to give intermediate which undergoes ligand exchange and then addition intramolecular to N-O to to give intermediate intermediate whichundergoes undergoes ligand exchange and then intramolecular to mechanism is proposed (Scheme The first step involves the oxidative addition tocyclization the N-O give A,A, which ligand exchange and then intramolecular cyclization to afford intermediate C, followed by32). reductive elimination to afford products 42.of Cu(I) to give intermediate A, which undergoes ligand exchange and then intramolecular cyclization to afford intermediate C, followed by reductive elimination to afford products 42. afford intermediate C, followed by reductive elimination to afford products 42.

afford intermediate C, followed by reductive elimination to afford products 42.

Scheme 31. Azidation of unsaturated O-acyl oximes and radical clock experiments.

Scheme Azidation of ofof unsaturated O-acyl Scheme 31. Azidation unsaturated oximesand andradical radical clock experiments. Scheme 31. Azidation unsaturatedO-acyl O-acyl oximes clock experiments. OC(O)Ph N OC(O)PhR2 OC(O)Ph 2 N 1N R2 R 3 R R 1 3 R3 R1 R R 41 41

OC(O)Ph

Cu(I) Cu(I) Cu(I)

N3 N3 N3 Cu(III) N Cu(III) R2 Cu(III) TMSN3 N R2 R2 N 3 3 R1 R3 TMSN TMSN R3 3 1 RR3 R3 R3 RR 1 B

OC(O)Ph OC(O)Ph Cu(III) 2 N Cu(III) Cu(III) R 2 N R R2 1N

R

A A

1

RR1

A

41

B

2

R1 R1

R1

3

R R 3 N R2 R N33 N R2 R N3

N

42 42

N3

B

3 R2 R 3 N R2 RCu(III) 3 2 R R1 N RCu(III) N3 1 N - Cu(I) R N3 Cu(III) R1C N3 C

- Cu(I) - Cu(I)

Scheme 32. Proposed 42 mechanism.

C

Scheme32. 32. Proposed Proposed mechanism. Scheme mechanism. Scheme 32. Proposed mechanism. Studer and co-workers described a novel methodology for the efficient synthesis of the precursors Studer and co-workers described33) a novel for the synthesis the precursors of vicinal amino azides 46 (Scheme [76], methodology which can easily be efficient transformed into of other important Studer and co-workers described a33) novel methodology for be thetransformed efficient synthesis of important the precursors of vicinal amino azides 46 (Scheme [76], which can easily into other amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN 3 as N 3 source and available 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 N3 source and available N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in of vicinal amino azides 46 (Scheme 33) [76], which can easily be transformed into other important N-fluorobenzenesulfonimide (NFSI) asdiastereoselectivity. nitrogen-radical precursor TMSN leading3toasthe in amine derivatives. This yields chemistry employed Cu(I) as catalyst, N3desired sourceproducts and available moderate to excellent with high amine derivatives. This chemistry employed Cu(I) as catalyst, TMSN3 as N3 source and available moderate to excellent yields(NFSI) with high diastereoselectivity. N-fluorobenzenesulfonimide as nitrogen-radical precursor leading to the desired products in

N-fluorobenzenesulfonimide (NFSI) as nitrogen-radical precursor leading to the desired products in moderate to excellent yields with high diastereoselectivity. moderate to excellent yields with high diastereoselectivity.

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Scheme 33. Aminoazidation of alkenes.

Scheme 33. Aminoazidation of alkenes.

A plausible reaction mechanism based the reported of processes Scheme 33. on Aminoazidation alkenes. is outlined in Scheme 34 [77,78]. A plausible mechanism based on the reported processes outlined in Schemewith 34 [77,78]. Firstly, Cu(I) reaction reacts with NFSI to form Cu(III) species A, which couldisexist in equilibrium a A plausible reaction mechanism on the reported processes outlined in Scheme 34adds [77,78]. Cu(II)-stabilized radical B.based It Cu(III) is the precursor ofA, bis-sulfonylamidyl radical, to with Firstly, Cu(I) reactsN-centered with NFSI to form species which iscould exist in which equilibrium Firstly, Cu(I) reacts with NFSI to form Cu(III) species could exist in equilibrium withadds a the alkene to generate carbon radical Cu(II) speciesA,D. Also B species could react as N-radicals a Cu(II)-stabilized N-centered radical B.CItand is the precursor ofwhich bis-sulfonylamidyl radical, which to Cu(II)-stabilized N-centered radical B. It is the precursor of bis-sulfonylamidyl radical, which adds to with the alkene. Then two pathways are suggested. In path a, trapping of C with D provides Cu(III) the alkene to generate carbon radical C and Cu(II) species D. Also B species could react as N-radicals the alkene to generate carbon radical C and Cu(II) species D. Also B species could react as N-radicals species E, which exchanges ligand with TMSN 3 to give Cu(III) complex F. Reductive elimination of F with the alkene. Then two pathways are suggested. In path a, trapping of C with D provides Cu(III) with thethe alkene. Thenalong two pathways suggested.ofInthe path a, trapping with b, DD provides Cu(III) affords products with the are regeneration Cu(I) catalyst.ofInCpath oxidizes C to species E, which exchanges ligand with TMSN3 to give Cu(III) complex F. Reductive elimination of F species E, which exchanges ligand with TMSN 3 to give complex F. Reductive elimination of F cationic intermediate G, which is trapped by TMSN 3 to Cu(III) form the products. affords the products along with of the the Cu(I) Cu(I)catalyst. catalyst. In path D oxidizes affords the products along withthe theregeneration regeneration of In path b, Db,oxidizes C to C to cationic intermediate G, which is trapped by TMSN to form the products. cationic intermediate G, which is trapped by TMSN33 to form the products.

Scheme 34. Proposed reaction mechanism.

Snider and co-workers reported diazidation of alkenes and glycals for Scheme a34.Mn(OAc) Proposed3-mediated reaction mechanism. Scheme 34. Proposed reaction mechanism. the formation of 1,2-diazides compounds [79]. Very recently, Xu and co-workers reported a novel Snider anddiastereoselective co-workers reported Mn(OAc)3-mediated diazidation of aalkenes and glycals for iron-catalyzed olefina diazidation method which tolerates broad range of olefins Snider and co-workers reported a Mn(OAc) diazidation of alkenes anda glycals the formation of This 1,2-diazides compounds [79]. Very recently, Xu and co-workers reported novel (Scheme 35) [80]. method also provides a convenient approach to vicinal primary diamines and for 3 -mediated iron-catalyzed diastereoselective olefin diazidation method which a broad range of olefins other synthetically valuable compounds nitrogen-containing compounds. the formation of 1,2-diazides [79]. Very recently, Xutolerates and co-workers reported a novel (Scheme 35)diastereoselective [80]. This method also provides a convenient approach vicinal primary diamines and iron-catalyzed olefin diazidation method whichtotolerates a broad range of olefins other synthetically valuable nitrogen-containing compounds. (Scheme 35) [80]. This method also provides a convenient approach to vicinal primary diamines and

other synthetically valuable nitrogen-containing compounds.

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Scheme 35. Diazidation of olefins. Scheme 35. Diazidation of olefins. Scheme 35. Diazidation of olefins.

A proposed mechanism is shown in Scheme 36. TMSN3 reacts with 47 to give intermediate A, A proposed mechanism isTMSN shown in Scheme 36. TMSN reacts with 47 to giveofintermediate A, which further activated byis 3 to intermediate B. Inwith the 47 presence iron catalysts, A is proposed mechanism shown ingenerate Scheme 36. TMSN33 reacts to give intermediate A, which is further activated by TMSN to generate intermediate B. In the presence of iron catalysts, 3 intermediate B reacts with by alkene to3 afford intermediate C andB.release D. Itcatalysts, is likely which is further activated TMSN to generate intermediate In theintermediate presence of iron intermediate B reacts with alkene to afford intermediate C and release intermediate D. It is likely that that the high-valent iron species may be further oxidize intermediate C through inner-sphere azido intermediate B reacts with alkene to afford intermediate C and release intermediate D. It is likely the high-valent to iron species may be further oxidize intermediate C through inner-sphere azido ligand ligand afford diazide product. that thetransfer high-valent ironthe species may be further oxidize intermediate C through inner-sphere azido transfer to afford the diazide product. ligand transfer to afford the diazide product.

Scheme 36. Possible mechanism. Scheme 36. 36. Possible Possible mechanism. mechanism. Scheme

2.4. Construction of C-N3 Bond and C-P Bond Bond andsynthesis C-P Bond Bond of β-azidophosphonates 49 through Mn(OAc)3-mediated 2.4. Construction C-N33 Bond and C-P An efficientofmethod for the radical phosphonation-azidation ofβ-azidophosphonates alkenes under relatively mild reaction conditions was Anoxidative efficient method for the 49 through Mn(OAc) the synthesis synthesis of of β-azidophosphonates through Mn(OAc) 33-mediated reported by Tangphosphonation-azidation and co-workers. This reaction displayed a broad substrate scope and can be easily phosphonation-azidation radical oxidative of alkenes under relatively mild reaction conditions was scaled up.by The products can be obtained in a one-pot operation (Scheme 37) [81]. reported 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].

Scheme 37. Phosphonation–azidation of alkenes. Scheme Scheme 37. 37. Phosphonation–azidation Phosphonation–azidation of of alkenes. alkenes.

Based on their previous studies in P–C bond formation, and reaction of organophosphorus radicals [82],on a possible mechanism was in proposed (Scheme 38). Theand reaction is initiated by the addition Based their previous studies P–C bond formation, reaction of organophosphorus of phosphorous radical mechanism A to alkene was to generate radical B, which undergoes oxidation afford radicals [82], a possible proposed (Scheme 38). The reaction further is initiated by the to addition cationic intermediate C. The intermediate C is then trapped by TMSN 3 to afford the final product 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

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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 16 afford Molecules 2016, 21, 352 of 20 Molecules 2016, 21, 352 16 of 20 cationic intermediate C. The intermediate C is then trapped by TMSN3 to afford the final product (path radical B could be directly trapped by anby azido to form to theform product (path a). a).Alternatively, Alternatively,the the radical B could be directly trapped an radical azido radical the (path a). Alternatively, the radical B could be directly trapped by an azido radical to form the (path b) (Scheme 38). product (path b) (Scheme 38). product (path b) (Scheme 38).

Scheme 38. Possible Scheme Possible reaction reaction pathways. pathways. Scheme 38. 38. Possible reaction pathways.

2.5. Construction C-N3 Bond 2.5. Construction of of Bond and and C-Se C-Se Bond Bond 2.5. Construction of C-N C-N33 Bond and C-Se Bond Tiecco and and co-workers reported reported the first first example of of a highly asymmetric asymmetric electrophilic Tiecco Tiecco and co-workers co-workers reported the the first example example of aa highly highly asymmetric electrophilic electrophilic azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. This This reaction reaction azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. azidoselenenylation of olefins for the preparation of azido selenium derivatives 51. This reaction occurs with with a high level of facial which was was made possible possible by the the use of of chiral, non-racemic occurs facial selectivity, selectivity, which occurs with aa high high level level of of facial selectivity, which was made made possible by by the use use of chiral, chiral, non-racemic non-racemic selenium reagents (Scheme 39) [83]. selenium reagents (Scheme 39) [83]. selenium reagents (Scheme 39) [83].

Scheme 39. Azidoselenenylation of alkenes. Scheme 39. 39. Azidoselenenylation of alkenes. alkenes. Scheme Azidoselenenylation of

2.6. Construction of C-N3 Bond and C-Halogen Bond 2.6. Construction of C-N3 Bond and C-Halogen Bond 2.6. Construction of C-N3 Bond and C-Halogen Bond 1,2-Haloazidation of alkenes represents an important transformation in organic synthesis. By 1,2-Haloazidation of alkenes represents an important transformation in organic synthesis. By 1,2-Haloazidation of alkenes representsbromoazidation an important of transformation in organic synthesis. using Zn(OTf)2 as catalyst, a metal-catalyzed alkenes was reported by Hajra and using Zn(OTf)2 as catalyst, a metal-catalyzed bromoazidation of alkenes was reported by Hajra and By using Zn(OTf) metal-catalyzedproducts bromoazidation of alkenes wasyields reported by Hajra 2 as catalyst, abromoazidation co-workers. The corresponding were obtained in good by using this co-workers. The corresponding bromoazidation products were obtained in good yields by using this and co-workers. bromoazidation products were obtained in good yields by by using protocol (SchemeThe 40, corresponding a) [84]. Phukan’s group also achieved the bromoazidation of alkenes using protocol (Scheme 40, a) [84]. Phukan’s group also achieved the bromoazidation of alkenes by using this (Scheme [84]. Moreover, Phukan’s group also the bromoazidation of alkenes by using otherprotocol bromine sources40a) [85,86]. a route to achieved 1,2-azidochlorides from alkenes was developed other bromine sources [85,86]. Moreover, a route to 1,2-azidochlorides from alkenes was developed other bromine sources [85,86]. Moreover, a route to 1,2-azidochlorides from alkenes was developed by by Finn and co-workers (Scheme 40, b) [87]. by Finn and co-workers (Scheme 40, b) [87]. Finn and co-workers (Scheme 40b) [87].

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Scheme Scheme 40. 40. Bromoazidation Bromoazidation or or chloroazidation chloroazidation of of alkenes. alkenes.

3. Conclusions 3. Conclusions In has summarized summarized recent recent difunctionalization difunctionalization reactions In conclusion, conclusion, this this review review has reactions of of olefins olefins with with organic and inorganic azides through C-N 3 bond formation. An oxidative single electron transfer (SET) 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 process is involved in most cases. These approaches provide efficient protocols for the preparation various organic azido compounds, which can then be further applied in many transformations to of various organic azido compounds, which can then be further applied in many transformations to synthesize various valuable nitrogen-containing compounds. synthesize various valuable nitrogen-containing compounds. Acknowledgment：Financial support from National Basic Research Program of China (973 Program) (grant No. FinancialNatural supportScience from National BasicofResearch Program of China (973 Program) (grant Acknowledgments: 2015CB856600) and National Foundation China (Nos. 21325206, 21172006), and National No. 2015CB856600) and National Natural Science Foundation of China (Nos. 21325206, 21172006), and National Young Top-notch Talent Support Program are greatly appreciated. Young Top-notch Talent Support Program are greatly appreciated. Conflict ConflictsofofInterest: Interest:Declare Declareconflicts conflictsofofinterest interestor orstate state“The “Theauthors authorsdeclare declareno noconflict conflictof ofinterest." interest."

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