Isoxazoles1 and 2H-azirines2 are widely used in the synthesis of various heterocyclic compounds. Since isoxazoles under certain conditions can be transformed into 2-carbonyl-substituted 2H-azirines, these two types of compounds can be viewed as synthetically equivalent. This allows to select isoxazole or azirine as the starting material or intermediate in a route of synthesis depending on their relative availability, stability, specific reactivity, tolerance to substituents, and other considerations. Isoxazoles in many cases are much more stable than azirines with respect to many reagents,1 allowing to modify substituents without ring opening. On the other hand, azirines tend to undergo ring opening much more readily, enabling the use of less reactive reagents of better selectivity while relying on milder reaction conditions.2 The combination of these two different reactivity modes of isoxazoles and azirines, taking into account the possibility of isoxazole–azirine interconversion, presents additional opportunities to synthetic chemists for building complex molecular systems. In this review article we consider the trends of thermal, photochemical, and catalytic isoxazole-azirine isomerization, as well as the possibilities for using such reactions in the synthesis of nitrogen-containing heterocycles.

Thermally initiated isoxazole–2 H -azirine interconversion

Thermal conversion of isoxazole to 2H-azirine was first demonstrated by Nishiwaki3 in 1969, using the isomerization of 5-alkoxy-3-arylisoxazoles 1a–g to 2-alkoxycarbonyl-3-aryl-2H-azirines 3a–g as example (Scheme 1). It was shown that, due to the thermal lability of azirines, the isomerization process must be carefully controlled.4 The efforts to increase the conversion of isoxazole by prolonged heating in the absence of solvent led to a significant resinification of the reaction mixture and a decreased yield of the azirine. The reaction temperature and conversion rate of the respective isoxazoles during heating directly depended on the substituent in the benzene ring. Thus, azirines 3a–c were obtained in 50–70% yields by heating the respective isoxazoles 1a–c at 200°C for 0.5 h, while heating of isoxazole 1d at 180°C resulted in complete resinification. Azirine 3d was obtained in merely 33% yield when isoxazole 1d was slowly heated from 130 to 190°C. Heating of isoxazoles 1e–g at 200°C was successfully used to prepare azirines 3e–g in 50, 62, and 18% yields, respectively.

scheme 1

Scheme 1

As a thio analog of 5-alkoxyisoxazoles, 5-mercaptoisoxazole 4 begins to isomerize to azirine 5 with noticeable rate at higher temperature (230°C) (Scheme 2).4 It was proposed by Nishiwaki and coworkers in 19704 that isomerization of isoxazoles to azirines results from a homolytic cleavage of N–O bond with the formation of biradical 2, followed by its recyclization (Scheme 1).

scheme 2

Scheme 2

The study of thermal isomerization kinetics of isoxazoles 1a,d,e,f, and 1h (R1 = Me, R2 = Br) showed that electron-donating substituents in the benzene ring facilitated the isomerization, while the rate constants of isomerization correlated with the σ+-constants of para substituents.5 Based on this, a conclusion was reached that isomerization proceeds through nitrene, instead of biradical, since it was assumed that only in this case the substituent in aromatic ring would be linked by direct polar conjugation with the positive charge created at the reaction site in the transition state.5

A domino reaction including a Knoevenagel condensation of formylpyrazole 6 with isoxazolone 7 followed by intramolecular hetero-Diels–Alder reaction of heterocycle 8 has been used in the synthesis of condensed isoxazole 9 (Scheme 3).6 It was found that increasing the reaction duration (refluxing for 5 days in acetonitrile or 3 days in toluene) led to nonselective isomerization of the tetracyclic intermediate 9 containing 5-alkoxyisoxazole moiety, forming mixtures of stereoisomeric spiro-fused azirines 10. In analogous reaction of isoxazolone 7 with compounds 11a,b that can be considered as pyrimidine analogs of compounds 6, the intermediate isoxazoles could not be detected, as they isomerized to azirines 12a,b under the reaction conditions7 (Scheme 4).

scheme 3

Scheme 3

scheme 4

Scheme 4

Isoxazoles containing a 5-amino substituent also isomerized relatively easily, giving the respective azirines. For example, 2H-azirines 14 containing an amide group at position 2 were generated by thermolysis of 5-aminoisoxazoles 13 and used for the synthesis of tetrahydro-1,2,4-triazin-6-ones 15 8 (Scheme 5). 2-Carbamoyl-2H-azirines 14 were thermally unstable and could be obtained only by careful optimization of the thermolysis temperature for isoxazoles 13: refluxing in tetralin at 207°C (R = H (yield 73%), Cl (yield 36%)); refluxing in decalin at 186°C (R = Me (yield 52%)). Azirines 14 were formed from isoxazoles 13 also during photolysis, but the yields were significantly lower in this case.8

scheme 5

Scheme 5

Thermal transformation of isoxazoles to azirines was used in the synthesis of key structural motifs of cyclic peptide alkaloids, amides of amino acids.9 Brief heating of isoxazoles 16 under inert atmosphere in the absence of solvent at 175–260°C was found to produce azirines 17 in 52–90% yields (Scheme 6). At the same time, thermolysis or photolysis of compounds 16 in solution resulted in resinification of reaction mixture and significantly lower yields of azirines 17.

scheme 6

Scheme 6

The isoxazoles 18a,b containing a morpholine substituent at position 5 isomerized to the respective azirines in refluxing anisol at 154°C10 (Scheme 7). Thus, heating of isoxazole 18a for 14 h led to the formation of azirine 19a in 43% yield. The epimer of azirine 19 underwent intramolecular (4+2) cycloaddition to the enol form of cyclopentenone moiety, giving 2-azatetracyclo-[4.3.0.02,4.03,7]nonane 20a in 3% yield. Refluxing of compound 18b in anisol for 4 h led to compounds 19b (17% yield) and 20b (10% yield).

scheme 7

Scheme 7

Only one example is known where thermal isomerization was accomplished by using an isoxazole substituted with a carbon-containing group at the azirine ring position 5 (Scheme 8). Flash vacuum pyrolysis (FVP) of isoxazole 21 at 300–500°C led to the formation of azirine 22 and dimer 23.11 The conversion degree of isoxazole 21 and yields of products 22, 23 depended on the pyrolysis temperature: the optimum temperature for the formation of azirine 22 was 350°C. It was established that higher temperatures (≥400°C) led to isomerization of azirine 22 to the oxazole 24. Dimer 23 was the main product at 500°C (the ratio of compounds 23:24 was 7:3).

scheme 8

Scheme 8

Thermal isomerization of 4-acylisoxazoles 25a–c to oxazoles 27a–c was expected to proceed via the formation of 2,2-diacyl-2H-azirines 26a–c 12 as intermediates (Scheme 9). Azirine 26b was later synthesized, and refluxing it in MeOH actually led to the oxazole 27b in 50% yield.13

scheme 9

Scheme 9

Thermal isomerization of isoxazoles to oxazoles usually requires high temperatures and is used much less frequently than photochemical isomerization. Thus, flash vacuum pyrolysis of 3-phenylisoxazole (750°C)14 and 5-ethyl-3-methylisoxazole (500–600°C)15 led to 2-phenyloxazole and 5-ethyl-2-methyloxazole, respectively. As a result of flash vacuum pyrolysis of isoxazolo[4,5-d]pyrimidinones 28, the respective oxazolo[4,5-d]pyrimidinones 29 were formed (Scheme 10).16 One example of thermal isomerization of nitroisoxazole 30 to oxazole 31 has also been reported.17

scheme 10

Scheme 10

The thermal conversion of 3,5-dimethylisoxazole (32) by flash pyrolysis using matrix isolation of products showed that 2-acetyl-3-methyl-2H-azirine (34) and 2,5-dimethyloxazole 36 were formed at 600°C, while only compound 36 was detected at higher temperatures18 (Scheme 11). Quantum-chemical calculations with the CASSCF multiconfigurational method showed that the carbonylsubstituted vinyl nitrene 33 played a key role in the rearrangements occurring during pyrolysis. According to the calculations, vinyl nitrene is a singlet biradicaloid with open electron shell. Ring cleavage of the azirine 34 at the C–C bond producing the nitrile ylide 35 had ~50 kcal/mol activation barrier. On the other hand, 1,5-electrocyclization of nitrile ylide 35 to oxazole 36, occurring most likely by pseudopericyclic mechanism, was strongly exothermic and had a very low activation barrier (~4 kcal/mol).

scheme 11

Scheme 11

A few examples of the reverse process – thermal conversion of 2-acyl-2H-azirines to isoxazoles also have been described in the literature. Thus, heating of 2-formyl-3-phenyl-2H-azirine (37) for 24 h in toluene at 200°C led to the formation of 3-phenylisoxazole (38) in 80% yield19 (Scheme 12).

scheme 12

Scheme 12

Thermolysis of 2-acyl-2-halo-2H-azirines produced 4-halo-substituted isoxazoles.20 , 21 For example, the heating of azirines 39a,b in refluxing toluene for 5 h allowed to obtain isoxazoles 41a,b in nearly quantitative yields (97 and 96%, respectively) (Scheme 13). It was proposed that thermal conversion of 2-carbonyl-2H-azirines occurs via the formation of vinyl nitrene intermediates 40a,b.19 – 21

scheme 13

Scheme 13

An indirect confirmation of vinyl nitrene formation during thermal conversion of azirines to isoxazoles was the formation of triphenyliminophosphoranes 43 by the treatment of 2,3-diaryl-2H-azirine-2-carboxamides 42 with Ph3P in CCl4 22 (Scheme 14).

scheme 14

Scheme 14

Photochemical transformations of isoxazoles to 2 H -azirines

Even though photochemical isoxazole–2H-azirine interconversion has been known for a long time,23 this process continues to be studied with various substrates, using modern research methods. Irradiation of 3,5-diphenylisoxazole (44a) in ether solution with 254 nm UV light led to the formation of 2,5-diphenyloxazole (46a) in 50% yield (Scheme 15). When the conversion of starting material was incomplete, the reaction mixture contained azirine 45a, which was isolated in 12% yield. Azirine 45a was converted to oxazole 46a upon UV irradiation at the same wavelength (82% yield).

scheme 15

Scheme 15

Irradiation of azirine 45a with light at longer wavelength than 300 nm caused the reverse transformation to isoxazole 44a. The same research group published additional results one year later that built upon the previous data, in particular by optimizing the irradiation wavelengths for interconversions of compounds 44a,b–46a,b.24

The study of photoinduced interconversions in naphthyl - substituted derivatives of isoxazole 47, azirine 48, and oxazole 49 showed that irradiation of azirine 48 with light corresponding to the longwave maximum of absorption spectrum (304 nm) induced transformations only to isoxazole 47 25 (Scheme 16). At the same time, irradiation at shorther wavelength (238 nm) gave isoxazole 47 and oxazole 49 as 1:3 mixture.

scheme 16

Scheme 16

Thermolysis and photolysis of 4-unsubstituted 5-aminoisoxazoles 50 was studied with the goal of obtaining 2H-azirine-2-carboxamides 51 26 (Scheme 17). Thermolysis of isoxazoles 50,26 in contrast to the thermolysis of 5-aminoisoxazoles 13 and 16 substituted at position 4,8 , 9 led to low and inconsistent yields of products 51. At the same time, azirines 51 were obtained in 50–70% yields by irradiation of isoxazoles 50 with >300 nm wavelength light.

scheme 17

Scheme 17

It has been reported27 that irradiation of compounds 52a,b in ether solution with the light of mercury lamp gave azirines 53a,b in 52 and 30% yields, respectively, while only a 40% yield of azirine 53a could be isolated after thermolysis of derivative 52a at 200–250°C (Scheme 18).

scheme 18

Scheme 18

Irradiation of (3,5)[9]isoxazolophanes 54 with the light of high pressure mercury lamp resulted in isoxazole group transformation into azirine group.28 Azirines 55 were isolated in moderate yields and used in synthesis of the respective [9]imidazolophanes 56 (Scheme 19).

scheme 19

Scheme 19

Irradiation of 3-acetylisoxazole 57 with UV light at 254 nm wavelength led to the formation of diacetylacetonitrile 58 and diacetylazirine 59 29 (Scheme 20). Azirine 59 could not be isolated as pure compound, and its structure was confirmed by spectral data and transformation to oxazole 60 upon prolonged irradiation.

scheme 20

Scheme 20

Irradiation of isoxazole 61a in acetonitrile, MeOD, benzene, dioxane, and 1,2-dimethoxyethane at 254, 300, and 350 nm wavelength led to azirine 62a (Scheme 21). At the same time, azirine 62b was only obtained by irradiation of isoxazole 61b in acetonitrile with UV light at 254 nm wavelength. The irradiation of azirine 62b or isoxazole 61b in acetonitrile with UV light at 300 nm wavelength led to a photoequilibrium mixture of products 61b:62b in 95:5 ratio.13

scheme 21

Scheme 21

A mixture of 3-phenyl-substituted isoxazoles 63 and aldehydes 64 (R = Ph, Et) upon irradiation did not produce the expected Paternò–Büchi reaction products 65, giving instead the 2H-azirines 66 in good yields,30 while trimethylisoxazole 67 under analogous conditions was converted to the bicyclic oxetanes 68 (Scheme 22).

scheme 22

Scheme 22

Photoirradiation of ketone 69 not only resulted in the formation of azirine 70, but also oxetane 71 31 (Scheme 23).

scheme 23

Scheme 23

The transformation of isoxazoles 72 to 2-acylazirines 73, initiated by irradiation, has been used in a threecomponent one-pot synthesis of tetrasubstituted imidazoles 74 32 (Scheme 24). Condensation of α-aminonitriles 75 with aldehydes 64 led to the formation of α-(alkylideneamino)-nitriles 76, which reacted under basic conditions with acylazirines 73 that were generated in situ by irradiation of isoxazoles 72.

scheme 24

Scheme 24

Photochemical isomerization of isoxazoles to oxazoles, which according to mechanistic studies occurs via the respective azirines, has been widely used for the synthesis of oxazoles from synthetically more available isoxazoles33 (Scheme 25). Photolysis of 4-acetyl-3-methyl(phenyl)-5-methylisoxazoles 25b,c led to the formation of 4-acetyl-2-methyl(phenyl)-5-methyloxazoles 27b,c in high yields.12 Photolysis of 3,5-disubstituted isoxazoles 77 in acetonitrile by using low pressure mercury lamp gave 2,5-disubstituted oxazoles 78.34

scheme 25

Scheme 25

Analogous photochemical isomerization has been frequently used for the synthesis of various condensed oxazoles from the respective isoxazoles (Scheme 26). Photolysis of benzisoxazole led to benzoxazole with up to 50% yield,35 while photolysis of 4,5,6,7-tetrahydrobenzisoxazole provided quantitative yield of the respective oxazole.36 Irradiation of usnic acid isoxazole derivative 79 with high pressure mercury lamp, accompanied by the formation of spiroazirine 80, led to the oxazole derivative 81.37

scheme 26

Scheme 26

Various oxazoles condensed with pyridine (compounds 82,38 83,39 84,40 85 41), pyrimidine (compound 86 42), and pyridazine (compound 87 43) rings were obtained through photolysis of the respective isoxazoles (Scheme 27).

scheme 27

Scheme 27

Photolysis of 5-phenylisoxazole 88 and 4-phenylisoxazole 91 led to isomerization of these compounds to 5-phenyloxazole 89 and 4-phenyloxazole 92, respectively.44 As confirmed by deuterium labeling or introduction of a methyl group, the N-2 and C-3 atoms simply changed places during the isomerization. Thus, 4-deutero-5-phenylisoxazole 93, 4-methyl-5-phenylisoxazole 95, and 5-methyl-4-phenylisoxazole 98 were converted to 4-deutero-5-phenyloxazole 94 (without loosing the isotopic label), 4-methyl-5-phenyloxazole 96, and 5-methyl-4-phenyloxazole 99, respectively. In addition, isoxazoles 88, 95, and 98 were transformed by ring photocleavage into benzoylacetonitrile 90, α-benzoylpropionitrile 97, and aceto-α-phenylacetonitrile 100, respectively (Scheme 28).

scheme 28

Scheme 28

Based on these and literature data, the authors proposed44 a reaction mechanism that included O–N bond cleavage in the photoexcited isoxazole 101 with the formation of vinyl nitrene 102, which could rearrange to the ketonitrile 104 via the ketenimine 103 or produce the azirine 105. Opening of the azirine ring at C–C bond followed by pseudopericyclic 1,5-electrocyclization of nitrile ylide 106 led to oxazole 107 (Scheme 29).

scheme 29

Scheme 29

In accordance with this mechanism, photolysis of isoxazole 108 in methanol gave not only oxazole 110, but also the stereoisomeric aziridines 111 resulting from the reaction of azirine 109 with methanol, while photolysis of compound 108 in acetonitrile gave only the oxazole 110 44 (Scheme 30).

scheme 30

Scheme 30

Photochemical isoxazole–azirine–oxazole transformations were recently studied in detail by such methods as low temperature matrix isolation, laser flash photolysis, etc., as well as quantum-chemical calculations.45 – 48 Photolysis of 3,5-dimethylisoxazole (32) at 222 nm wavelength in argon matrix at 15 K led to the formation of 2-acetyl-3-methyl-2H-azirine (34) and 3-acetyl-N-methylketenimine (112) as primary products, which were most probably formed via a common intermediate, acetyl vinyl nitrene 33 (Scheme 31). Prolonged irradiation gave rise to two other products: acetylnitrile ylide 35 and then 2,5-dimethyloxazole (36).46 The identification of the latter was supported by an additional experiment – irradiation of azirine 34 at 340 nm wavelength, resulting in the transformation of nitrile ylide 35 to oxazole 36, while the starting isoxazole 32 did not react.

scheme 31

Scheme 31

The interconversion of 3,5-diphenylisoxazole (44a) and 2-benzoyl-3-phenyl-2H-azirine (45a) was studied by the method of laser flash photolysis, and it was found that both isoxazole and azirine can serve as precursors of the shortlived triplet vinyl nitrene 113 (Scheme 32). According to quantum-chemical calculations, the triplet vinyl nitrene had significant spin density at the β-carbon atom, pointing to the significant degree of biradical character in nitrene 113.47

scheme 32

Scheme 32

The photochemical transformation of chloroisoxazole 114 to oxazole 117 in argon and xenon matrices was studied by FT-IR spectroscopy. The presence of azirine 115 and nitrile ylide 116 was detected, in accordance with the reported mechanism of isoxazole–oxazole isomerization48 (Scheme 33).

scheme 33

Scheme 33

Catalytic and base-initiated isoxazole–azirine transformations

The catalytic effects of transition metal salts and complexes on the isomerization of isoxazoles and 2-acyl-2H-azirines often can be used for performing this reaction at substantially lower temperatures. This not only creates optimum reaction conditions for syntheses based on isoxazoles and 2-acyl-2H-azirines, but also enables the use of thermally labile compounds. For example, it is known that thermal transformation of isoxazole 1a to azirine 3a occurs at about 200°C temperature.3 , 4 However, it was later shown that the addition of copper stearate in catalytic amounts allows to perform this reaction at 60°C in 30 min, with the azirine 3a formed in 60% yield49 (Scheme 34).

scheme 34

Scheme 34

The rearrangement of isoxazoles 118 to azirines 119 occurs in the presence of molecular hydrogen and poisoned Pd/C catalyst in dioxane at 80°C, with the reaction time of 5–8 min.50 The catalyst poisoning and interruption of reaction after several minutes allows to avoid the reduction of azirines to enaminoesters 120 and to achieve nearly quantitative yields of azirines 119 (Scheme 35).

scheme 35

Scheme 35

Further research revealed catalysts and conditions that enabled similar transformations in high yields even at room temperature. The effects of various transition metal salts and complexes (FeCl2·4H2O, NiCl2, NiCl2·6H2O, Fe(acac)2, and CuCl) on isoxazole 1a conversion was investigated,51 and azirine 3a was formed in all of the cases (Scheme 36). It was shown that iron(II) chloride tetrahydrate was a highly effective catalyst for isoxazole-azirine isomerization. For example, the conversion of isoxazoles 121a–d to azirines 122a–d occurred already at room temperature and gave quantitative yields. The presence of an electron-donating group (the methoxy group in compound 121b) at the benzene ring of the substituent at position 3 accelerated the reaction, while a nitro group (compound 121a) slowed the reaction 4-fold compared to the unsubstituted substrate 1a. 5-Amino-substituted isoxazoles reacted much slower and required a larger amount of catalyst, even compared to azirine 122a. Unfortunately, isoxazoles containing an alkyl or aryl group at position 5 were not reactive under these conditions. More forcing conditions (refluxing in acetonitrile in the presence of 3.5–5-fold molar excess of FeCl2·4H2O) led to reductive cleavage of N–O bond, which gave enamines 123 and their cyclic dimers. The kinetic study of Fe(II)-promoted isoxazole 1a isomerization to azirine 3a showed that this was a first order reaction with k 5.8·10–4·s–1 at 25°C. Based on analysis of the obtained data, a mechanism was proposed that included a single electron transfer from metal atom to the azirine molecule.51 Catalysis by Fe(acac)2 and NiCl2 also accelerated the reaction, but a fivefold molar excess of Fe(II) acetylacetonate was needed for completion of the process. When nickel chloride was used as catalyst for this reaction, it had to be anhydrous, because the isoxazole starting material was not isomerized in the presence of crystal hydrate NiCl2·6H2O. Copper chloride was much less effective and its use in a fivefold molar excess resulted in only partial conversion of isoxazole over several days.

scheme 36

Scheme 36

The isomerization of nitroisoxazoles 124 to oxazoles 125 through azirine intermediate was catalyzed by a Lewis acid, anhydrous FeCl3–SiO2 52 (Scheme 37).

scheme 37

Scheme 37

Two examples of base-induced isoxazole-azirine isomerization have been described.53 , 54 Recently it was found that 3-aryltetrahydrobenzisoxazoles 126 rearrange in refluxing toluene in the presence of Cs2CO3 and give, as a rule, high yields of 2-aryltetrahydrobenzoxazoles 130 53 (Scheme 38). It has been assumed that the reaction proceeded through a base-initiated Boulton–Katritzky rearrangement of isoxazole 126 to isoxazole 127, followed by a Neber rearrangement to azirine 128. The cleavage of azirine ring at C–C bond gave the nitrile ylide 129, which underwent 1,5-electrocyclization to oxazole 130.

scheme 38

Scheme 38

A key difference of another base-initiated isomerization compared to the aforementioned example was the participation of exocyclic carbon atom of isoxazole molecule in this reaction, which eventually became a part of the azirine system54 (Scheme 39). This rearrangement was achieved with benzisoxazoles 131, which formed enolates 132 in the presence of strong bases (NaH, t-BuOK, MeONa) in DMF. The latter initiated a Neber rearrangement, producing 2-(2H-azirin-3-yl)phenolate 133. Its protonation led to azirines 134, which were isolated in 60–90% yields.

scheme 39

Scheme 39

Isoxazole-azirine isomerization as a method for endocyclic C=N bond activation toward nucleophilic attack was recently successfully used in the synthesis of 4-acylpyrrole-2-carboxylic, 4,5,6,7-tetrahydro-4-oxo-1H-indole-2-carboxylic, and pyrrole-2,4-dicarboxylic acids.55 These compounds were obtained by a domino reaction of 5-alkoxy- or 5-aminoisoxazoles 135 with 1,3-dicarbonyl compounds 136 under the conditions of relay catalysis with a Fe(II)/Ni(II) system (Scheme 40). The process started with FeCl2·4H2O catalyzed isomerization of isoxazole 135 to azirine 137, which further reacted in the presence of NiCl2·6H2O catalyst with the 1,3-dicarbonyl compound 136, forming the pyrrole 138. This method was particularly effective when symmetrical 1,3-diketones were used, including cyclic diketones, such as dimedone (139). Esters and amides of acylacetic acid reacted regioselectively, forming pyrrole-2,4-dicarboxylic acid derivatives as the main products.

scheme 40

Scheme 40

The same principle was employed for an original method used to synthesize a whole series of 3-hetaryl-substituted pyrroles, in which azolium and pyridinium ylides were used as nucleophilic components. A mixed catalytic system of Fe(II)/Et3N was required for the synthesis of 4-imidazolylpyrrole-2-carboxylic acids 145–148 in a reaction of the readily available 5-methoxyisoxazoles 140 with phenacylimidazolium salts 141 56 (Scheme 41). The process included: 1) generation of azirines 142 from isoxazoles 140 in the presence of FeCl2 catalyst; 2) the formation of phenacylimidazolium ylide 143, induced by Et3N; 3) the activation of azirine 142 by the action of Et3NH+Br–; 4) the reaction of activated azirine 144 with imidazolium ylide 143.

scheme 41

Scheme 41

The same catalytic system was used for the synthesis of N-pyrrolylpyridinium salts 150 from 5-methoxyisoxazoles 140 and pyridinium ylides 149.57 The conversion of salts 150 to pyrrolylpyridinium ylides 151 followed by catalytic hydrogenation enabled the synthesis of methyl 4-piperidinopyrrole-2-carboxylates 152 in high yields (Scheme 42). This reaction was of particular interest for the synthesis of 3-aminopyrroles 154, which were formed by hydrazinolysis of pyridinium salts. The N-unsubstituted aminopyrroles 154 could be conveniently obtained directly from isoxazoles 140 and pyridinium salts 149 by a one-pot procedure.57 , 58 The introduction of a substituent at the pyrrole ring nitrogen atom in aminopyrrole 154 can be achieved in good yields by alkylation of pyrrolylpyridinium ylides 151, followed by hydrazinolysis of the pyridinium substituent in compound 153.57

scheme 42

Scheme 42

Catalytic azirine–isoxazole transformations

As demonstrated by several studies, the reverse process, conversion of azirines to isoxazoles, also can be achieved in the presence of catalysts. Such procedures can provide isoxazoles that lack heteroatom-containing substituents at position 5. For example, iron(II) chloride was successfully used for the isomerization of 2-acylazirines 156, obtained by conversion of enaminones 155, to isoxazoles 157 59 by the action of PhI(OAc)2 (Scheme 43).

scheme 43

Scheme 43

The treatment of 2-formyl-3-phenyl-2H-azirine (37) with Mo(CO)6 in THF at room temperature gave 3-phenylisoxazole (38) in 81% yield.60 When cyclopentadienyl dicarbonyl iron or Grubbs catalysts were used, azirine 37 was converted to isoxazole 38 in 84 or 90% yields, respectively61 – 63 (Scheme 44). It has been proposed60 that the transformation occurs through the formation of a metal –vinyl nitrene complex as an intermediate.

scheme 44

Scheme 44

3-Monosubstituted and 3,4-disubstituted isoxazoles 159 were obtained in good yields from 2-formylazirines 158 in the presence of dirhodium tetraacetate catalyst.64 Bisazirines 160 also were converted by the action of dirhodium tetraacetate and second generation Grubbs catalysts in nonpolar solvents to the respective bisisoxazoles 161. At the same time, the use of polar solvents and Lewis acids as catalysts allowed to transform the same azirines to the respective oxazole64 derivatives (Scheme 45).

scheme 45

Scheme 45

Many thermal and catalytic isomerization reactions of isoxazoles to azirines can occur reversibly. The equilibrium of these processes is set by the relative thermodynamic stability of isoxazole and azirine. In order to characterize the feasibility of isomerization in one or the other direction, as well as to estimate the possibilities for trapping the isomerization product by a reagent for involving it in subsequent useful reactions, we performed a quantum computational study of the relative Gibbs free energy values in a series of isoxazole and 2-carbonyl-2H-azirine model compounds. The calculations were performed by the DFT B3LYP/6-31g(d) method using polarized continuum solvation model (PCM), selecting acetonitrile as the most appropriate solvent for catalytic isoxazole-azirine isomerization (Table 1). As shown by the presented data, only isoxazoles 157 with such heteroatomcontaining substituents as SR, NR2, OR, or halogen at position 5 (Table 1) were capable of isomerization under equilibrium conditions to azirines 156, or at least generated sufficient concentrations of azirines 156 for participation in further reactions. At the same time, the reversible isomerization of 5-unsubstituted isoxazoles and isoxazoles with C-substituent at position 5 most likely did not produce azirine in sufficient concentrations for effective trapping by suitable reagents, examples of which were listed above, and thus the sequence of azirine ring transformations was not extended. The obtained computational data about the effect of substituents were in accordance with experimentally performed isomerizations, which were described above.

Table 1 The relative Gibbs free energy values of substituted azirines 156 and isoxazoles 157 (kcal/mol, 298 K, PCM solvation model for MeCN), calculated by the DFT B3LYP/6-31G(d) method.*
Full size table

Thus, isoxazole-azirine isomerization, which allowed to perform a single-stage transformation from five-membered heterocyclic system to a three-membered ring and back, can be used as an effective tool for fine-tuning of the endocyclic C=N bond reactivity that may be required for specific molecular transformations. The fairly wide range of principally different mechanistic schemes of this transformation allows not only to select optimum conditions for thermolysis, photolysis, base-promoted or metal-catalyzed reactions of each substrate, but often offers opportunities for including this isomerization in a domino sequence leading to a target heterocyclic system in one synthetic procedure. Obviously, the better availability of isoxazoles and higher reactivity of azirines gives particular synthetic significance to the isomerization of isoxazole to azirine. In addition, new transformations of isoxazoles were discovered, including the syntheses of pyrroles 162 66 and 163,67 pyridines 164,68 1,3-oxazines 165,69 and syn-2,6-diaryl-3,7-diazatetracyclo[4.2.0.02,5]octane-4,8-diones 166,70 for which azirine-isoxazole isomerization may serve as one of the methods providing access to the starting compounds. On the other hand, the reverse isoxazole-azirine isomerization most frequently serves as the first step in a multistage domino process, leading to such systems as compounds 20, 74, 138, 145, 150, and 154 (Scheme 46).

scheme 46

Scheme 46

In recent years, the main efforts of researchers working in this area of heterocyclic synthesis have been focused in two directions, one of which is the search for new routes of isoxazole ring functionalization and efficient functional group transfer via isoxazole-azirine isomerization to azirine ring, which can be used for the construction of 2H-azirines. The second direction is associated with the development of new methods for the construction of important heterocyclic systems by including a catalytic variant of isoxazoleazirine isomerization in various domino reaction sequences, occurring by relay reaction, cooperative, or sequential catalytic mechanisms.