Reactivities of vinyl azides and their recent applications in nitrogen heterocycle synthesis

Abstract

Nitrogen heterocycles are abundant in natural products and pharmaceuticals. An emerging interest among synthetic chemists is to apply vinyl azides as a pivotal three-atom synthon for the construction of structurally complex and diverse N-heterocyclic skeletons. The unique features of the azide group connected to an alkene moiety permit vinyl azides to function as electrophiles, nucleophiles, or radical acceptors; their access to diverse reaction pathways provides great opportunities to generate highly reactive intermediates with often unusual or unconventional reactivities. This tutorial review will systematically illustrate the reactivities of vinyl azides and describe recent breakthroughs in the development of new transformations that create N-heterocycles.

1. Introduction

Since the discovery of phenyl azides by Peter Grieβ in 1864,¹ numerous novel transformations of azide derivatives have emerged as rapid and versatile methods for the synthesis of a variety of complex N-heterocyclic systems.² However, vinyl azides have been regarded as “sleepers” among the reactive azido species, and they drew little attention over the course of the last century. Until recently, efforts to employ vinyl azides have focused largely on their use as a pivotal three-atom synthon for the formation of diverse N-heterocycles. The unique properties of the azide group connected to an alkene moiety permit this functional group to act as an electrophile, a nucleophile, or a radical acceptor, have turned these compounds into indispensable building blocks for organic synthesis.

One of the intriguing chemical features of vinyl azides is their ability to undergo thermolysis or photolysis to give highly strained three-membered 2H-azirines, 3, which can be regarded as equivalents of vinyl nitrenes, 2 (Scheme 1, eq. a).³ Transition metal-catalysed reactions of vinyl azides can form metal nitrenoids, 5, with release of molecular nitrogen (Scheme 1, eq. b).^2d,4 Alternatively, vinyl azides can be reduced by transition metal species to afford iminyl metal radicals, 6, which equilibrate with iminyl metal species, 7 (Scheme 1, eq. c).⁵ In the syntheses of N-heterocycles, a radical pathway might also be involved, in which α-azido radicals, 8, generated from radical species (R^·), add to vinyl azides, to produce iminyl radicals, 9 (Scheme 1, eq. d).⁶ Moreover, the C=C bonds of vinyl azides can be used for the formation of new C-C or C-X (X = heteroatom) bonds with appropriate electrophiles (R⁺), which results in the generation of iminodiazonium ions 10. Subsequent Schmidt-type rearrangements might create nitrilium ions, 11 (Scheme 1, eq. e).⁷ Also, vinyl azides can react with PPh₃ to furnish vinyl iminophosphoranes, 12, via the Staudinger reaction (Scheme 1, eq. f).⁸ Vinyl azides can also lead to new iminyl anions, 14, by a process that involves Michael addition-elimination of incipient anions (R⁻). The elimination is driven by the excellent leaving-group ability of nitrogen (Scheme 1, eq. g).⁹ Recently, it was shown that an intramolecular cyclization of a vinyl azide (R₁ = H) takes place to generate triazoline 15, which undergoes a 1,5-hydrogen shift to give triazoline 16. Loss of nitrogen leads to zwitterionic (17) or diradical (18) reactive intermediates (Scheme 1, eq. h).¹⁰

Scheme 1.

Chemical reactive intermediates generated from vinyl azides.

One of the attractive chemical properties of vinyl azides is their ability to undergo manifold transformations. Arguably, the most important applications of vinyl azides are directed toward the synthesis of various N-heterocycles, and yet no comprehensive recent review categorizes the great number of transformations which vinyl azides undergo in the construction of different N-heterocycles.¹¹ Even this seemingly large topic encompasses a relatively small subset of the types of reactions open to vinyl azides.^2,11 The present Review, therefore, is intended to enumerate and classify the types of possible reactive intermediates that can be generated from vinyl azides under different reaction conditions. Furthermore, this Review highlights how these diverse reaction pathways make vinyl azides outstanding building blocks in N-heterocycle synthesis.

2. Thermal- or photo-induced reactions of vinyl azides

Vinyl azides are often used as precursors to vinyl nitrenes and 2H-azirines. These reactive intermediates are accessible by thermolysis or photolysis, and they can react further in cyclization reactions or by other processes to generate nitrogenated heterocycles. In 1961, Smolinsky¹² reported the first example of the vapor phase pyrolysis of α-phenyl vinyl azide 19. This vinyl azide furnished 2-phenylazirine 20 in 65% yield, together with a small amount of the Curtius rearrangement side product 21 (Scheme 2). Although 2H-azirines have been studied extensively for their great synthetic potential in the synthesis of functionalized amino derivatives and N-containing heterocycles, most 2H-azirines were found to be difficult to prepare and to handle because these highly strained reactive intermediates tend to be unstable.¹³ The transformation of vinyl azides into 2H-azirines is currently the most frequently used reaction to access these strained heterocycles.

Scheme 2.

Generation of 2H-azirine from a vinyl azide by pyrolysis.

For example, continuous flow thermolysis of β-aryl vinyl azides 22 in toluene has been applied to prepare indoles and related heterocycles via 2H-azirines intermediates 23 (Scheme 3).^14a However, thermolysis of β-aldehyde, ketone, or ester substituted vinyl azides 25 usually led to isoxazoles 27 through the corresponding 2H-azirine intermediates 26 (Scheme 4).¹⁵

Scheme 3.

Indole formation from thermolysis of vinyl azides via 2H-azirines.

Scheme 4.

Isoxazole formation from thermolysis of vinyl azides via 2H-azirines.

Intermolecular, thermally induced reactions of vinyl azides are also possible. Chiba and Narasaka recently described the pyrolysis of vinyl azides 28 in the presence of 1,3-dicarbonyl compounds to give 2,3,4,5-tetrasubstituted N-H pyrroles, 29. These products were proposed to arise from nucleophilic attack of the 1,3-diketone enol on the 2H-azirines 30 followed by ring opening of the resulting aziridines 31, and recyclization of the intermediates to form 32 (Scheme 5).¹⁶

Scheme 5.

Synthesis of pyrroles from vinyl azides and acetylacetone.

Condensation of α-cyano derivatives with vinyl azides has also been reported as an efficient method for the synthesis of 2-aminopyrroles (Scheme 6).¹⁷ The proposed mechanism featured the addition of α-cyano derivatives 34 onto 2H-azirines 36, generated from pyrolysis of vinyl azides 33, to form azirine intermediates 37. Ring expansion to form pyrrolidine intermediates 38, was followed by tautomerization and oxidation to furnish the 2-aminopyrrole products, 35 (Scheme 6).

Scheme 6.

Synthesis of 2-aminopyrroles from vinyl azides and α-cyano derivatives.

The use of visible light activated transition metal catalysts in synthesis is currently attracting increased attention.¹⁸ Important recent studies from Yoon and co-workers demonstrated that photolytic conversion of dienyl azides 39 into reactive nitrenes 40, with visible light in the presence of a Ru photocatalyst was an attractive approach to the construction of pyrroles 41 (Scheme 7).¹⁹ The use of low-energy visible light precludes competitive photodecomposition processes typically associated with UV irradiation, and makes this approach more attractive and useful.

Scheme 7.

Synthesis of pyrroles from vinyl azides by transition-metal photocatalysis.

As mentioned above, vinyl azides are typically employed as precursors to 2H-azirines, which are themselves photochemically active substances. Under photochemical conditions, the highly strained 2H-azirines 29 underwent ring-opening to yield the nitrile ylides 42.²⁰ These 1,3-dipolar intermediates proved to be excellent [3 + 2] cycloaddition substrates for dipolarophiles 43. The cyclization provided 3,4-dihydro-2H-pyrroles 44 in reasonable yields (Scheme 8).²¹

Scheme 8.

Photo-induced cycloadditions of vinyl azides and electron-deficient alkenes.

3. Transition metal-catalyzed reactions of vinyl azides

Thermolysis of vinyl azides has been applied frequently in indole synthesis, however, the excessive heating often required to promote this reaction can lead to side reactions, thereby diminishing the attractiveness of this approach.¹⁴ In contrast, transition metal catalysts can generate highly reactive radical ion or metal nitrenoid intermediates under relatively mild reaction conditions. The Driver group described a Rh(II)-catalyzed intramolecular C-H bond insertion reaction that transforms vinyl azides 45 into indoles 47. This process likely involves evolution of N₂ to form rhodium nitrenoid intermediates 46 (Scheme 9).²² Bolm and co-workers recently showed that a first row transition metal salt, Fe(II) triflate, was also a competent catalyst for heterocyclic ring closures of vinyl azides 45.²³ More recently, this chemistry was extended to the formation of pyrroles 49, from dienyl azides 48. It was found that a range of transition metal salts, including Rh(II) carboxylates, Cu(OTf)₂, ZnI₂, and RuCl₃ can promote this process efficiently (Scheme 10).²⁴

Scheme 9.

Rhodium-catalyzed indole formation.

Scheme 10.

Transition metal-catalyzed pyrrole formation.

For transition metal-catalyzed intermolecular reactions of vinyl azides, significant advances have been achieved by the Chiba group, who developed a Cu(II)-catalyzed synthesis of polysubstituted pyrroles 56 from vinyl azides 50 and ethyl acetoacetate (Scheme 11).^16a The proposed reaction mechanism included the 1,4-addition of copper enolate 52 to vinyl azides 51, followed by elimination of dinitrogen leading to alkylideneaminocoppers 53. Cyclization via an intramolecular nucleophilic attack on the carbonyl group, followed by dehydration, readily afforded pyrroles 56 (Scheme 11).

Scheme 11.

Cu(II)-catalyzed pyrrole formation.

Similar efforts from the same research group revealed that highly substituted isoquinolines could be synthesized from α-aryl vinyl azides and internal alkynes under rhodium/copper bimetallic catalysis (Scheme 12).⁵ Preliminary mechanistic investigations indicated that both rhodium and copper are prerequisites for achieving catalytic activity. It was also found that benzylic radical intermediates were trapped by 2,6-di-tert-butyl-4-methylphenol (TEMPO), when it was added instead of HOAc (Scheme 12). Based on this and other experimental observations, the authors proposed a reaction mechanism that involved the reduction of Cu(OAc)₂ by DMF to generate a Cu(I) species. Vinyl azide 57 expelled N₂ to produce 2H-azirine 61, which was reduced by the Cu(I) species and underwent C-N bond cleavage, affording iminyl Cu(II) radical 62. Intermediate 62 was further reduced by a Cu(I) species and protonated to yield iminyl Cu(II) species 64. Transmetalation with Rh(III) afforded 65, which was proposed to form rhodacycle 66, by C-H insertion. Subsequent insertion of diphenylethyne and C-N reductive elimination from rhodacycle 67 provided isoquinoline 58, with generation of Rh(I) species. A redox reaction between Rh(I) and Cu(II) species was proposed as a method to regenerate the resting oxidation states of the transition metal catalysts (Rh(III) and Cu(I), Scheme 12).

Scheme 12.

Isoquinoline formation by Rh–Cu bimetallic cooperation.

Recently, the Adimurthy group reported a Cu(I)-catalyzed, oxidative C-H functionalization of pyridine derivatives with vinyl azides 68 to give imidazo[1,2-α]pyridines 69 under aerobic conditions (Scheme 13).²⁵ Similarly, thermal treatment of vinyl azides 68 led to 2H-azirines 70, which underwent C-N bond cleavage in the presence of Cu(I) to generate iminylcopper(II) radicals 71. Formation of 6-membered cyclic copper complexes 73 from reaction of pyridine derivatives and iminylcopper(II) radicals 71 occurred with the assistance of Cu(I) via iminyl copper intermediates 72. Subsequent C-N reductive elimination of Cu(III) intermediates 73 and oxidation of 74 provided imidazo[1,2-α]pyridines 69 (Scheme 13).

Scheme 13.

Cu(I)-catalyzed C−H functionalization of pyridines with vinyl azides.

A recent study by the research group of Jiao demonstrated that 2,4- and 3,4-disubsituted pyrroles can be prepared in a regioselective fashion from vinyl azides and aryl acetaldehydes. Intriguingly, the regioselectivity could be switched by the choice of transition metal catalyst (Cu(OAc)₂ or NiCl₂, Scheme 14).²⁶ The authors proposed plausible mechanisms for these highly regioselective transformations. In the Cu-catalyzed formation of 2,4-disubsituted pyrroles, an iminylcopper(II) radical intermediate 78, generated by pyrolysis to form the azirine 20 and reductive ring opening was proposed. A coupling reaction of Cu(II) phenylacetaldehyde enolate 79 with iminylcopper(II) radical 78 furnished γ-formyl iminylcopper(II) intermediate 80. Intramolecular cyclization provided 2H-pyrrole Cu(II) intermediate 81, which underwent dehydration and tautomerized to afford 2,4-diphenyl pyrrole 76 with regeneration of the Cu(II) catalyst. In contrast, when Ni(II), a transition metal ion less likely to support one-electron reduction, was used as a catalyst, 2H-azirine 20 remained intact long enough to undergo nucleophilic attack by the Ni(II) enolate of phenylacetaldehyde, 83, giving nickel aziridine 84. Ring-expansion and tautomerization led to the 2,5-dihydropyrrole intermediate 85. Subsequent β-OH elimination and tautomerization produced 3,4-diphenylpyrrole 77 with regeneration of the free Ni(II) catalyst (Scheme 14).

Scheme 14.

Pyrrole synthesis switched by copper and nickel catalysts

Copper complexes not only catalyze C-H amination reactions of vinyl azides, they can promote N-N bond forming reactions as well. The Rao group has recently developed a two-step protocol for the synthesis of 1H-pyrazoles 89 from vicinal vinyl azidoaldehydes 87 and aryl amines (Scheme 15).²⁷ This tandem process involves a copper-catalyzed intramolecular cyclization that occurs with loss of N₂.

Scheme 15.

1H-pyrazoles formation from vicinyl vinyl azidoaldehydes and aryl amines.

4. Radical-initiated reactions of vinyl azides

Vinyl azides participate in several different types of radical-initiated processes. Once generated, radicals add readily to the alkenyl group to produce the corresponding iminyl radicals, which in certain cases are able to undergo subsequent cyclizations to give heterocyclic amines. Pioneering research in this area was reported by Chiba group.^28,29 Manganese(III) salts, such as Mn(OAc)₃,³⁰ are excellent one-electron oxidants, which have been widely employed to generate free radicals for cyclization reactions. Recently, Chiba and Narasaka demonstrated Mn(III)-catalyzed pyrrole formation from variously substituted vinyl azides and β-keto esters or 1,3-diketones (Scheme 16).²⁸ The reaction is thought to proceed through the addition of manganese(III) enolate 91 to vinyl azide 19 via a radical pathway, giving iminyl radical 92 with the release of a reduced Mn(II) species and dinitrogen. The resulting iminyl radical 92 undergoes an intramolecular addition to a carbonyl group to give alkoxyl radical 93, which is reduced by Mn(II) species to create Mn(III) alkoxide 95 (path a). Alternatively, reaction of iminyl radical 92 with a Mn(II) species could generate alkylideneaminomanganese(III) 94, which can close upon the carbonyl group to give intermediate 95 (path b). Finally, protonation of 95 with acetic acid followed by dehydration of 96 produced pyrrole 90 along with regeneration of Mn(III) (Scheme 16).

Scheme 16.

Mn(III)-catalyzed formal [3+2]-annulation reactions of vinyl azides and 1,3-dicarbonyl compounds.

In addition to the above-mentioned Mn(III)-catalyzed [3+2] annulations of vinyl azides and 1,3-dicarbonyl compounds, the Chiba and co-workers also demonstrated [3+3] annulation reactions of vinyl azides 28 with cyclopropanols 97 for the synthesis of a series of azaheterocycles, such as pyridines 98 (Scheme 17).²⁹ The reaction likely involved the formation of a β-carbonyl radical 100, generated by one-electron oxidation of cyclopropanol by Mn(III). Subsequent addition of β-carbonyl radical 100 to vinyl azide 28 afforded iminyl radical 101 with extrusion of dinitrogen. Subsequent intramolecular cyclization of iminyl radical 101 onto the carbonyl group would give alkoxyl radical 102. Reduction, protonation, dehydration and further oxidation afforded the pyridine product 98 (Scheme 17).

Scheme 17.

Mn(III)-mediated Formal [3+3]-annulation reactions of vinyl azides and cyclopropanols.

Furthering their efforts directed toward the synthesis of azaheterocyles based on radical reactions of vinyl azides, Chiba and co-workers recently disclosed a PhI(OAc)₂-mediated radical trifluoromethylation of vinyl azide 19 to generate a trifluoromethyl azine 106 (Scheme 18).³¹ The dimerization product 106 could be transformed to 5-fluoropyrazole 107, trifluoroethyl isoquinolines 108, and other valuable trifluoromethylated heterocycles. Mechanistically, this reaction was likely initiated by a single-electron oxidation of Me₃SiCF₃ by PhI(OAc)₂, leading to CF₃ radical. The CF₃ radical subsequently added to the C=C bond of vinyl azide 19 to form trifluoromethyl iminyl radical 105, with release of a dinitrogen. Dimerization of CF₃ iminyl radical 105 gave α-CF₃ azine 106 (Scheme 18).

Scheme 18.

Radical trifluoromethylation of vinyl Azides with Me₃SiCF₃.

Drawing inspiration from these findings, the Chiba group developed an intramolecular radical cyclization of α-(biaryl-2-yl)vinyl azides 109 to construct trifluoroethyl phenanthridines 111 (Scheme 19).³² A similar mechanism was proposed: CF₃ radical generation preceded addition to the C=C bond of α-(biaryl-2-yl)vinyl azides 109 to form trifluoromethyl iminyl radicals 110. The iminyl radicals 110 were added to the aryl group ortho-position to afford trifluoroethyl phenanthridines 111 after aromatization (Scheme 19).

Scheme 19.

Formation of trifluoroethyl phenanthridine via a radical cyclization.

5. Lewis acid-mediated reactions of vinyl azides

Vinyl azides can act as nucleophilic enamine equivalents. Nucleophilic attack of vinyl azides onto various electrophilic species can form iminodiazonium ions I (Scheme 20), which are in equilibrium with α-azido ions II. The intermediates I can lose dinitrogen and undergo Schmidt-type rearrangements to form nitrilium ions III, which can be used for further transformations (Scheme 20). Having recognized that hydrolysis of nitrilium ions III provided a facile route into amides,^33a the Chiba group proposed a tethering strategy in which a second intramolecular nucleophile could trap α-azido ions II before Schmidt-type rearrangements could occur. This quite different reaction manifold ultimately relies upon azide acting as a leaving group in the construction of azaheterocycles (Scheme 21). Highly functionalized quinolines and pyridines were synthesized by a BF₃·OEt₂-mediated formal [4+2]-annulation of vinyl azides and N-unsaturated aldimines (Scheme 21 ).^33b In the proposed mechanism, the reaction was initiated by complexation of N-unsaturated aldimine 112 with BF₃·OEt₂, activating it to nucleophilic attack by vinyl azide 19. This process provided iminodiazonium ion intermediate 115, which underwent an intramolecular cyclization to form 4-azido-tetrahydroquinoline 116. Subsequent aromatization of 116 via hydrogen transfer to another molecule of aldimine 112, and elimination of HN₃ delivered the corresponding quinoline 113 and N-benzyl aniline 114 (Scheme 21).

Scheme 20.

Chemical intermediates generated from nucleophilic reaction of vinyl azides with electrophilic species.

Scheme 21.

Formal [4+2] annulation of vinyl azides with N-unsaturated aldimines.

6. PPh₃-triggered reactions of vinyl azides

Aza-Wittig reactions of iminophosphoranes have received increased attention because of their utility in the synthesis of nitrogen heterocyclic compounds.³⁴ Vinyl azides very often appear in the form of their readily accessible synthons, vinyl iminophosphoranes, which are generated from the Staudinger reaction. The use of vinyl iminophosphoranes has been advanced significantly by the Wang group.

In 2008 and 2009, Wang and co-workers disclosed a one-pot synthesis of isoquinolines 119, or pyridines 121 by condensation of vinyl azides 117 or 120 with α-diazocarbonyl compounds 118 (Scheme 22).³⁵ Addition of a stoichiometric amount of triphenylphosphine initiated the tandem Wolff rearrangement and aza-Wittig reactions, which was followed by a thermally-allowed electrocyclic ring closure to afford the heterocyclic core structures.

Scheme 22.

A tandem Wolff rearrangement/aza-Wittig/electrocyclic reaction.

A recent study by the same research group demonstrated that vinyl azides 50 engaged benzynes 126 in an interesting transformation to furnish indoles 127 with the assistance of PPh₃ and CsF (Scheme 23).³⁶ This annulation was thought to proceed through a mechanism that involved a tandem cyclization of benzyne, generated by elimination of TMS fluoride, and vinyl iminophosphorane 128, formed by the Staudinger reaction of vinyl azide 50 with PPh₃, to give the tricyclic intermediate 129. Hydrolysis of 129 afforded dihydroindole 132 and triphenylphosphine oxide, presumably with the intermediacy of 130 and 131. Dihydroindole 132 was oxidized in air to afford indole products 127 (Scheme 23). The proposed mechanism was supported by the isolation of Ph₃PO and detection of reactive intermediate 129 by both HRMS and ³¹P NMR in trapping experiments.

Scheme 23.

Indoles formation from vinyl azides and ortho-silyl aryltriflates.

In another example of the use of vinyl azides 133 and 135 as precursors to vinyl iminophosphoranes 136, Ding and co-workers reported syntheses of imidazole derivatives. This process proceeded through carbodiimide intermediates 138, which could add various amines 139 or phenols 143 under base catalysis to give 1,2,4,5-tetrasubstituted imidazoles 142 (Scheme 24).³⁷ Carbodiimides 138 were derived from aza-Wittig reactions of iminophosphoranes 136 with aryl isocyanates 137. Surprisingly, when phenols 143 were used as nucleophiles to trap the carbodiimide intermediate, 4-acylimidazoles 146 were obtained. Presumably, the expected products, 145, were susceptible to benzylic oxidation under these basic, aerobic conditions (Scheme 24).

Scheme 24.

Formation of 1,2,4,5-substituted imidazoles.

The coupled Staudinger/aza-Witting strategy has also been used for the preparation of 4-arylidene-1H-imidazol-5(4H)-ones 150 (Scheme 25).³⁸ Ding and co-workers used a 4-component Ugi reaction, starting from 2-azido-3-arylacrylic acids 147, aldehydes, secondary amines, and isocyanides to provide an elaborated vinyl azide, 148. Upon addition of triphenylphosphine, the key vinyl iminophosphorane intermediate 149 underwent an intramolecular aza-Wittig reaction to form the densely functionalized heterocycle 150 (Scheme 25).

Scheme 25.

A sequential Staudinger and intramolecular aza-Wittig reaction.

Similarly, treatment of vinyl azides 151 with isocyanates in the presence of PPh₃ led to the construction of dihydropyrimidines 154 (Scheme 26).³⁹ This process involved sequential Staudinger, aza-Wittig, and intramolecular cyclization reactions.

Scheme 26.

A sequential Staudinger/aza-Wittig/cyclization reaction.

Triphenylphosphine and dialkyl azodicarboxylates were utilized for the formation of a Huisgen zwitterion,⁴⁰ an intermediate that plays an important role in Mitsunobu reaction.⁴¹ Recently, Lin and Wang reported a synthesis in which zwitterion 159 condensed with vinyl azides 155 to afford 1,2,4-triazolines 157 (Scheme 27).⁴² Preliminary mechanistic studies suggested that an no intermediate iminophosphorane was involved. Attempts to prepare the desired 1,2,4-triazoline product 157 (Ar = PMP, R = Et) from the reaction of diethyl azodicarboxylate (DEAD) and vinyl iminophosphorane 158 (prepared from the corresponding vinyl azide and PPh₃) failed. Because the product was not accessible directly from 158, the authors proposed a mechanism in which the reaction is initiated by nucleophilic attack of the nitrogen of the Huisgen zwitterion 159 at the β-position of vinyl azides 155. A subsequent cyclization of 160 released PPh₃ and gave the 1,2-diazetidine intermediate 161, which underwent a Curtius-type rearrangement giving rise to 1,2,4-triazolines 157 with the release of a dinitrogen (Scheme 27).

Scheme 27.

A cascade reaction of the Huisgen zwitterion with vinyl azides.

7. Base-mediated reactions of vinyl azides

Huisgen 1,3-dipolar cyloaddition is a classic reaction in organic chemistry; the addition of 1,3-dipolar compounds to alkynes and alkenes permits facile construction of five-membered heterocyclic compounds.⁴³ The base-catalyzed cycloaddition of 1,3-dipolar compounds with electron-deficient vinyl azides 33 is an area that has seen significant progress over the last several years (Scheme 28). This approach has provided many straightforward and operationally simple protocols for the syntheses of various heterocyclic compounds, including 1H-pyrazoles 162,^44a pyrazoles 163,^44b,c isoxazoles 164,^44d and pyrroles 165^44e (Scheme 28). In the above syntheses, vinyl azides function as a two-atom synthon. The azide group of vinyl azides serves as a leaving group, which is crucial for the final aromatization of the intermediate to the product. In addition, vinyl azides have been employed as three-atom (C-C-N) synthons to construct N-heterocyclic skeletons under basic conditions. Such reactions typically involve loss of molecular nitrogen.

Scheme 28.

[3+2] Cycloaddition of vinyl azides 33 with 1,3-dipolar compounds.

Nucleophilic species are competent to add (β-addition) to the C=C bond of vinyl azides to give anionic intermediates. The reactive intermediates, in turn, provide an opportunity for cyclization to N-heterocycles if an appropriate and accessible electrophilic functional group is present in the same molecule. In their preparation of 5-aminopyrimidine-2(1H)-thiones 172, Yu and Zhang described the Michael addition of thiourea to vinyl azides 33 affording intermediates 168 (Scheme 29).⁴⁵ Following loss of dinitrogen, 168 formed 169, which subsequently underwent intramolecular cyclization, dehydration, and rearrangement to provide the products 172.

Scheme 29.

Reactions of vinyl azides with thiourea.

Analogously, thiophenes 174⁴⁶ and anilines 176⁴⁷ have been synthesized by employing 1,4-dithiane-2,5-diol 173 (Scheme 30) and phosphorus ylide/dimethyl allylphosphonates 175 (Scheme 31) as nucleophiles for vinyl azides 33.

Scheme 30.

Reactions of vinyl azides with 1,4-dithiane-2,5-diol.

Scheme 31.

Reactions of vinyl azides with phosphorus ylide/dimethyl allylphosphonate.

In above processes iminyl anions, generated from the addition of nucleophilic reagents to vinyl azides and subsequent loss of N₂, were protonated and were not available as nucleophiles for further transformations. However, it was recently demonstrated that iminyl anions can be trapped by various intramolecular electrophilic groups to construct the corresponding N-heterocycles. For example, Michael addition of cyanimide anion 178 to 33, followed by elimination of N₂ afforded iminyl anions 179, which were capable of intramolecular nucleophilic addition to the cyano group. Protonation followed by tautomerization provided 2-aminoimidazole products 181 (Scheme 32).⁴⁸

Scheme 32.

A [3+2] cyclization of vinyl azides and cyamide.

Other nucleophiles, for example the anion derived from deprotonation of pyrrole-2-carboxaldehyde, also act as a nucleophiles toward vinyl azides 33. In this case addition initiates a [3+3] cascade process for the generation of functionalized pyrrolo[1,2-α]pyrazines 185 (Scheme 33).⁹

Scheme 33.

A [3+3] cyclization of vinyl azides and pyrrole-2-carboxaldehyde.

Similarly, treatment of isobenzofuranone 186 with LHMDS and vinyl azides 33 resulted in the formation of 5-hydroxy-2-benzazepinones 187 from a [4+3] annulation (Scheme 34).⁴⁹ The proposed mechanism involved Michael addition of the benzylic anion 186 to the C=C bond of vinyl azide 33, creating the new anion species 188. Loss of dinitrogen gave rise to iminyl anion 189, which underwent an intramolecular nucleophilic addition to the lactone carbonyl to generate 7-membered lactam 191 (path a). A plausible alternative second sequence leading to the same product is attack by the azido anion 188 on the lactone carbonyl prior to ring cleavage and N₂ expulsion to form intermediate 191 (path b). Tautomerization of 191 followed by protonation furnished the benzazepinone product 187 (Scheme 34).

Scheme 34.

A [4+3] cyclization of vinyl azides and phthalides.

8. Other miscellaneous reactions of vinyl azides

With the interest of developing a new [3+3] cycloaddition reactions of nitrones,⁵⁰ Hu et al. investigated the reaction of vinyl azides 33 with nitrones 192 and found that 1,2,4,5-tetrasubstituted imidazoles 193 were obtained instead of the possible [3+2] cycloaddition isoxazolidine products (Scheme 35).^10a Preliminary mechanistic investigations suggested that this reaction did not proceed through a 2H-azirine intermediate. The assignment of a radical mechanism was supported by the observation that no imidazole 193 products were obtained when 2H-azirine replaced vinyl azide 33, or when the radical-trapping reagent, TEMPO (1.0 equiv) was added to the reaction of vinyl azide 33 (R₁ = Ph, R₂ = OEt) and nitrone 192 (R₃ = R₄ = Ph, Scheme 35).

Scheme 35.

Cascade reactions of nitrones and vinyl azides.

On the basis of these results, a tentative mechanism for the domino reaction was proposed (Scheme 35). An intramolecular cyclization of vinyl azide 33 formed triazoline 194, which underwent a 1,5-hydrogen shift to give triazoline 195. The zwitterionic intermediate 196a, (or biradical intermediate 196b), was generated from the triazoline intermediate 195 by thermal elimination of dinitrogen. It was believed that the key intermediate 196 participated in a formal [3+3] cycloaddition with nitrone 192 via the zwitterionic pathway or by sequential two-electron processes, giving intermediate 197 with high regioselectivity. Homolytic cleavage of the N-O bond in 197, followed by a hydrogen shift resulted in the formation of 5-amino ketomalonate 199. The intermediate 200 was readily obtained via an intramolecular cyclization of 199 through nucleophilic addition of the amino nitrogen to the carbonyl group. Finally, dehydration of intermediate 200 afforded the desired product 193 (Scheme 35).

Although the proposed mechanism is quite involved, several lines of evidence support it. The key zwitterionic intermediate 202 is generated in the Er(OTf)₃-catalyzed reaction of vinyl azides 33 with N-unsaturated aldimines 201. This reaction leads to 1,2,4,5-tetrasubstituted imidazoles 205 (Scheme 36).⁵¹ In this case the domino reaction also involves triazoline formation, a 1,5-hydrogen shift, and loss of N₂ to form zwitterionic 202. Condensation of 202 with Lewis acid-coordinated imines 201 resulted in dihydroimidazoles 204 that were readily oxidized to furnish the imidazole products 205 (Scheme 36).

Scheme 36.

A domino reaction of imines and vinyl azides.

Conclusions

In summary, vinyl azides have proven to be particularly powerful and versatile building blocks for the preparation of diverse nitrogen-containing heterocycles. The synthetic utility of vinyl azides is due mostly to their high chemical reactivity, which is driven by the excellent leaving-group ability of dinitrogen. Different timing of dinitrogen loss opens a wide variety of reaction pathways that originate from a very simple functional group. The reactions discussed in this review demonstrate that vinyl azides can generate different types of reactive intermediates for novel transformations, and that the choice of particular pathway may be influenced by heating, photolysis, transition metal catalysts, radical generation, Lewis acid coordination, and addition of PPh₃ or base. Notably, vinyl azides can undergo the intramolecular [3+2] cycloaddition, 1,5-H shift and denitrogenation to generate zwitterionic intermediates or biradical intermediates. We believe the formation of such intermediates from an unusual nitrogen transfer process represents a new concept for the construction of N-heterocycles, as well as a new reactivity pattern for vinyl azides. Although great progress has been made in vinyl azide chemistry over the last few years, there is little doubt that studies of the use of versatile vinyl azide startings material in the development of N-heterocycle synthesis will continue to bear fruit.

Handling azides - Warning!

Vinyl azides are classified as organic azides, which are valuable intermediates in organic synthesis. However, one should keep in mind the inherent toxicity, instability, shock sensitivity, and explosive power of azides. All users should exercise appropriate caution. Generally, the explosion danger of organic azides decreases with diminishing fraction of N₃ in the molecular mass. For organic azides to be safely handled or non-explosive, “Smith’s rules” must be followed: i) the number of nitrogen atoms (N_N) must not exceed that of carbon (N_C), and ii) (N_C + N_O)/N_N ≥ 3 (N = number of atoms).⁵²

In general, any azides synthesized should be stored below room temperature and in the dark. Most vinyl azides and other azides are prepared directly or indirectly from sodium azide. Sodium azide is toxic [LD₅₀ oral (rats) = 27 mg/Kg] and can be absorbed through the skin. Sodium azide should not be allowed to come into contact with any Brønsted acids, water, heavy metals such as Pb, Cu, Ba, Zn, Cd, Ni, or chlorinated solvents (CH₂Cl₂ and CHCl₃). Sodium azide reacts also vigorously with CS₂, Br₂, and dimethyl sulfate.

Biographies

Bao Hu was born in Hunan, China in 1982. He studies chemistry at Hunan University of Science and Technology in 2001 and began his graduate studies in 2005 under the supervision of Prof. Zhongwen Wang at Nankai University, where he worked on the methylene cyclopropane 1,1-diesters chemistry and total synthesis of (±)-bruguierol A. In 2010, he joined the faculty at Zhejiang University of Technology as an assistant professor. After a short independent research on vinyl azide chemistry, he moved to US in 2012 as a Postdoctoral Fellow with Prof. Stephen G. DiMagno at the University of Nebraska–Lincoln. His current research in DiMagno group focuses on preparation and use of diaryliodonium salts in the creation of new radiotracers for PET imaging applications.

Stephen G. DiMagno is a Professor of Organic Chemistry at the University of Nebraska-Lincoln. He was born in Philadelphia, Pennsylvania in 1962. His training in organic chemistry included a BA from Swarthmore College in 1985, and a PhD in organic chemistry from UC Berkeley, under the direction of Prof. Andrew Streitwieser in 1991. His undergraduate and graduate work focused on the physical organic chemistry of radical species. During postdoctoral studies with Prof. Michael J. Therien at the University of Pennsylvania, DiMagno’s research emphasis was in the synthesis and ultrafast electron transfer properties of metalloporphyrins and related heterocyclic pigments. Upon joining the University of Nebraska-Lincoln faculty in 1993, Professor DiMagno’s began a research program in organofluorine chemistry that has continued to this day. Most recently, his research has particularly focused upon the introduction of fluoride (19F and 18F) into pharmaceutically relevant aromatic and heteroaromatic compounds.