WO2013081549A1 - Method for preparing 2h-azirine carboxylic esters - Google Patents

Abstract

The invention relates to a method for preparing 2H-azirine carboxylic esters. More specifically, the invention relates to a method for preparing 2H-azirine carboxylic esters starting from α-diazo-β-keto oxime ethers in the presence of a rhodium (II)-based catalyst.

Description

METHOD FOR PREPARING 2H-AZIRINE CARBOXYLIC ESTERS

Cross-Reference to Related Application

[0001] This application claims the benefit of priority of United States of America Provisional Patent Application No. 61/564,014, filed 28 November 2011, the contents of which being hereby incorporated by reference in its entirety for all purposes.

Technical Field

[0002] The invention relates to a method for preparing 2H-azirine carboxylic esters. More specifically, the invention relates to a method for preparing 2H-azirine carboxylic esters starting from a-diazo-_/8-keto oxime ethers in the presence of a rhodium (Il)-based catalyst.

Background

[0003] 2H-azirines represent a highly valuable class of compounds found in natural products and synthetic intermediates. Derived from the high ring strains present in these smallest heterocycles, their unique reactivity allows for 2H-azirines to serve as a versatile source of nitenes, electrophiles, dienophiles, and dipolarophiles in various reactions. These reactions based on the chemistry of 2H-azirines led to the development of efficient synthetic platforms for various nitrogen containing heterocycles including pyrroles, indoles, pyrazolo[l,5- a]pyridines, isoxazoles, and piperidines. Despite the broad utility of 2H-azirines, the synthesis methods are rather limited, primarily relying on the Neber reaction and thermal/photochemical rearrangement of vinyl azides. [0004] Recently, oxidation of enamines for the synthesis of 2H-azirines has also been reported. While these methods allow for the access to 2H-azirines, the efficiency of these reactions is highly variable and dependent on substrates due to the sensitive nature of azirines that promotes further activation of azirines and subsequent decomposition. Moreover, the Neber reaction often suffers from complications such as Beckmann rearrangement upon activation of oximes and intramolecular cyclization of oximes derived from -keto esters resulting in formation of 2-isoxazolin-5-ones.

[0005] Noting that the current protocols typically involve the use of stoichiometric reagents, harsh reaction conditions including bases and/or high reaction temperature, development of a new synthesis method for 2H-azirines employing catalytic and neutral conditions is highly desirable, and would offer a great opportunity for further expansion of the utility of these versatile synthetic building blocks.

Summary

[0006] Wolff rearrangement, among the fundamental reactions of diazo compounds, has found broad applications in organic synthesis. Metal-catalyzed and thermal/photochemical activation of diazo compounds smoothly produces ketenes which have proven as versatile intermediates in various transformations including nucleophilic addition, cycloaddition, ring contraction, and homologation. The present invention is based on the inventors' discovery that generation of ketenes via metal-mediated Wolff rearrangement gives rise to a cascade rearrangement resulting in the formation of 2H-azirine carboxylic esters.

[0007] Thus, a first aspect of the present invention relates to a method for preparing 2H- azirine carboxylic esters of formula (I)

comprising: reacting a-diazo-|3-keto oxime ether of formula (II)

in the presence of a rhodium (Il)-based catalyst and an organic solvent.

[0008] R¹ may be a substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted C₂- Ci5 alkenyl, substituted or unsubstituted C₂-Ci₅ alkynyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C₃- C₁₅ heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted Q-C 15 aryl, or substituted or unsubstituted C₆-Ci5 heteroaryl.

[0009] R may be a substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C₂-

Ci5 alkenyl, substituted or unsubstituted C₂-Ci₅ alkynyl, substituted or unsubstituted C3-Q5 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C3-

C15 heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci₅ aryl, or substituted or unsubstituted C₆-Ci5 heteroaryl. [0010] R³ may be a substituted or unsubstituted Ci-Cjo alkyl, substituted or unsubstituted C - Ci5 alkenyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C3-C15 heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, substituted or

unsubstituted C₆-C₁₅ heteroaryl, or substituted or unsubstituted C7-C15 alkylaryl.

[0011] In one embodiment, the rhodium (Il)-based catalyst is Rh₂(OAc)₄.

Description

[0012] The following detailed description refers to the accompanying drawings that show, by way of illustration, specific details and embodiments in which the invention may be practised. These embodiments are described in sufficient detail to enable those skilled in the art to practise the invention. Other embodiments may be utilized and changes may be made without departing from the scope of the invention. The various embodiments are not necessarily mutually exclusive, as some embodiments can be combined with one or more other embodiments to form new embodiments.

[0013] Wolff rearrangement, among the fundamental reactions of diazo compounds, has found broad applications in organic synthesis. Metal-catalyzed and thermal/photochemical activation of diazo compounds smoothly produces ketenes which have proven as versatile intermediates in various transformations including nucleophilic addition, cycloaddition, ring contraction, and homologation. The present invention is based on the inventors' discovery that generation of ketenes via metal-mediated Wolff rearrangement gives rise to a cascade rearrangement resulting in the formation of 2H-azirine carboxylic esters as shown in Eq. (1) below:

[0014] Accordingly, an internal redox reaction of a-diazo-(S-keto oxime ethers leading to highly efficient synthesis of 2H-azirine carboxylic esters under catalytic reaction conditions has been developed and described herein.

[0015] Thus, a first aspect of the present invention relates to a method for preparing 2H- azirine carboxylic esters of formula (I)

comprising: reacting odiazo- 3-keto oxime ether of formula (II)

P

in the presence of a rhodium (Il)-based catalyst and an organic solvent. [0016] Without wishing to be bound by any theory, it is hypothesized that Eq. ( 1) proceeded via the following reaction mechanism Eq. (2), wherein the rhodium (Il)-based catalyst may be Rh₂(OAc)₄:

[0017] It is proposed that the rearrangement proceeds through ketene intermediate C. Thus, the rhodium-catalyzed formation of carbenoid B promotes migration of R² to the carbenoid center resulting in the formation of ketene C. Attack of the oxygen atom of the oxime ether moiety on the ketene leads to the formation of ylide D that further undergoes rearrangement to afford the final 2H-azirine carboxylic ester E.

[0018] Various catalyst systems have been explored by the present inventors and it has unexpectedly been found that rhodium salts gave almost an exclusive formation of 2H-azirine carboxylic esters in nearly quantitative yields, even when frequently used Wolff

rearrangement silver salts were tested. Various ligands of the rhodium salts were also explored to determine the effects of the electronic and steric influences caused by the ligands. It has been found that steric influence of rhodium catalysts was minimal while electronic effects of ligands had a pronounced influence on the efficiency of the reaction of Eq. (1).

[0019] Thus, in various embodiments, the rhodium (Il)-based catalyst is rhodium (II) acetate [Rh₂(OAc)₄], rhodium (II) pivalate [Rh₂(Piv)₄], or rhodium (II) perfluorobutyrate [Rh₂(pfb)₄].

[0020] In one embodiment, the rhodium (Il)-based catalyst is Rh₂(OAc)₄.

[0021] In an alternative embodiment, the rhodium (Il)-based catalyst is Rh₂(Piv)₄.

[0022] I addition to exploring various catalyst systems for expedient synthesis of highly substituted 2H-azirine carboxylic esters, the effect of various solvents was also studied. The present inventors have found that the reaction of Eq. (1) is well tolerated in various solvents tested.

[0023] In various embodiments, the organic solvent is dichloroethane, benzene, toluene, 1,4- dioxane, chlorobenzene, (trifluoromethyl)benzene, or tetrahydrofuran.

[0024] In one embodiment, the organic solvent is dichloroethane.

[0025] The reaction of Eq. (1) may be carried out by heating the c-diazo-)3-keto oxime ether of formula (II) at a temperature range of between 50 and 80 °C, such as about 50 °C, about 55 °C, about 60 °C, about 65 °C, about 70 °C, about 75 °C, or about 80 °C.

[0026] In one embodiment, the a-diazo-j3-keto oxime ether of formula (II) is heated at about 60 °C. [0027] In a further embodiment, the a-diazo-)3-keto oxime ether of formula (II) is heated at about 60 °C in the presence of Rh₂(OAc)₄.

[0028] In yet further embodiment, the Oi-diazo- 3-keto oxime ether of formula (II) is heated at about 60 °C in the presence of Rh₂(OAc)₄ and dichloroethane.

[0029] The heating of the a-diazo-|8-keto oxime ether of formula (II) in the presence of the rhodium (Il)-based catalyst and organic solvent may be carried out for a period of between 5 and 15 h, such as about 5 h, about 6 h, about 7 h, about 8 h, about 9 h, about 10 h, about 1 1 h, about 12 h, about 13 h, about 14 h, or about 15 h.

[0030] Advantageously, the catalytic reaction conditions described herein allow a broad spectrum of substrates (i.e. R¹, R² and R³) to be used, and thus a wide variety of 2H-azirine carboxylic esters to be formed. In particular, highly substituted 2H-azirine carboxylic esters can be formed in nearly quantitative yields.

[0031] R¹ may be a substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted C₂- Ci5 alkenyl, substituted or unsubstituted C2-C15 alkynyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C₃- Ci5 heterocycloalkyl, substituted or unsubstituted C₃-Ci5 heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, or substituted or unsubstituted C₆-C₁₅ heteroaryl.

[0032] R may be a substituted or unsubstituted C Ci₀ alkyl, substituted or unsubstituted C₂- Ci5 alkenyl, substituted or unsubstituted C2-C15 alkynyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C₃-C₁₅ cycloalkenyl, substituted or unsubstituted C₃- Ci5 heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci 5 aryl, or substituted or unsubstituted C₆-Ci5 heteroaryl.

[0033] R³ may be a substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C₂- C i5 alkenyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C3-C15 heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, substituted or

unsubstituted C6-C15 heteroaryl, or substituted or unsubstituted C7-C15 alkylaryl.

[0034] The term "aliphatic", alone or in combination, refers to a straight chain or branched chain hydrocarbon comprising at least one carbon atom. Aliphatics include alkyls, alkenyls, and alkynyls. In certain embodiments, aliphatics are optionally substituted, i.e. substituted or unsubstituted. Aliphatics include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, ethynyl, butynyl, propynyl, and the like, each of which may be optionally substituted. As used herein, aliphatic is not intended to include cyclic groups.

[0035] The term "optionally substituted" or "substituted or unsubstituted" refers to a group in which none, one, or more than one of the hydrogen atoms have been replaced with one or more groups such as, but are not limited to, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, alkylaryl, or heteroaryl.

[0036] The term "alkyl", alone or in combination, refers to a fully saturated aliphatic hydrocarbon. In certain embodiments, alkyls are optionally substituted, i.e. substituted or unsubstituted. In certain embodiments, an alkyl comprises 1 to 10 carbon atoms, for example 2 to 8 carbon atoms, wherein (whenever it appears herein in any of the definitions given below) a numerical range, such as "1 to 10" or "Ci-Cio", refers to each integer in the given range, e.g. "Ci-Cjo alkyl" means that an alkyl group comprising only 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like. In certain embodiments, one or more carbon atoms may be replaced by a heteroatom to form a heteroalkyl (see definition below).

[0037] The term "alkeny , alone or in combination, refers to an aliphatic hydrocarbon having one or more carbon-carbon double-bonds, such as two or three carbon-carbon double-bonds. In certain embodiments, alkenyls are optionally substituted, i.e. substituted or unsubstituted. In certain embodiments, an alkenyl comprises 2 to 15 carbon atoms, for example 2 to 10 carbon atoms. "C2-Q5 alkenyl" means that an alkenyl group comprising only 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 11 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, or 15 carbon atoms. Examples of alkenyls include, but are not limited to, ethenyl, propenyl, butenyl, 1,4-butadienyl, pentenyl, hexenyl, 4-methylhex-l-enyl, 4-ethyl-2- methylhex-l-enyl and the like. In certain embodiments, one or more carbon atoms may be replaced by a heteroatom to form a heteroalkenyl (see definition below).

[0038] The term "alkynyl", alone or in combination, refers to an aliphatic hydrocarbon having one or more carbon-carbon triple-bonds, such as two or three carbon-carbon triple-bonds. In certain embodiments, alkynyls are optionally substituted, i.e. substituted or unsubstituted. In certain embodiments, an alkynyl comprises 2 to 15 carbon atoms, for example 2 to 10 carbon atoms. "C₂-Ci 5 alkynyl" means that an alkynyl group comprising only 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 1 1 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, or 15 carbon atoms. Examples of alkynyls include, but are not limited to, ethynyl, propynyl, butynyl, and the like. In certain embodiments, one or more carbon atoms may be replaced by a heteroatom to form a heteroalkynyl (see definition below).

[0039] The term "aromatic" refers to a group comprising a covalently closed planar ring having a delocalized [pi]-electron system comprising 4n+2 [pi] electrons, where n is an integer. Aromatic rings may be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatics may be optionally substituted. Examples of aromatic groups include, but are not limited to phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. The term aromatic includes, for example, benzenoid groups, connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from an aryl, a heteroaryl, a cycloalkyl, a non-aromatic heterocycle, a halo, a hydroxy, an amino, a cyano, a nitro, an alkylamido, an acyl, a Ci-C₆ alkoxy, a Ci-C₆ alkyl, a C -Ce hydroxyalkyl, a Ci-C₆ aminoalkyl, an alkylsulfenyl, an alkylsulfinyl, an alkylsulfonyl, an sulfamoyl, or a trifluoromethyl. In certain embodiments, an aromatic group is substituted at one or more of the para, meta, and/or ortho positions. Examples of aromatic groups comprising substitutions include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4- hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 4-trifluoromethoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, (trifluoromethyl)phenyl, alkoxyphenyl, 4-morpholin-4-ylphenyl, 4-pyrrolidin-l-ylphenyl, 4-pyrazolylphenyl, 4- triazolylphenyl, and 4-(2-oxopyrrolidin-l-yl)phenyl.

[0040] The term "aryl" refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings may be formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups may be optionally substituted.

[0041] The term "heteroaryl" refers to an aromatic heterocycle. Heteroaryl rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Heteroaryls may be optionally substituted. Examples of heteroaryl groups include, but are not limited to, aromatic C3-C8 heterocyclic groups comprising one oxygen or sulfur atom or up to four nitrogen atoms, or a combination of one oxygen or sulfur atom and up to two nitrogen atoms, and their substituted as well as benzo- and pyrido-fused derivatives, for example, connected via one of the ring-forming carbon atoms. In certain embodiments, heteroaryl groups are optionally substituted with one or more substituents, independently selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, Ci-Ce alkoxy, Ci-C₆ alkyl, Ci-C₆

hydroxyalkyl, Ci-C₆ aminoalkyl, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzo thiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, tetrazole, quinoline, isoquinoline, pyridazine, pyrimidine, purine and pyrazine, furazan, 1,2,3-oxadiazole, 1,2,3- thiadiazole, 1 ,2,4-thiadiazole, triazole, benzotriazole, pteridine, phenoxazole, oxadiazole, benzopyrazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. In some embodiments, the substituents are halo, hydroxy, cyano, or Ci-C₆ alkyl.

[0042] The term "non-aromatic ring" refers to a group comprising a covalently closed ring that is not aromatic.

[0043] The term "alicyclic" refers to a group comprising a non-aromatic ring wherein each of the atoms forming the ring is a carbon atom. Alicyclic groups may be formed by three, four, five, six, seven, eight, nine, or more than nine carbon atoms. In certain embodiments, alicyclics are optionally substituted, i.e. substituted or unsubstituted. In certain embodiments, an alicyclic comprises one or more unsaturated bonds, such as one, two or three carbon-carbon double-bonds. Alicyclics include cycloalkyls and cycloalkenyls. Examples of cycloalkyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. Examples of cycloalkenyls include, but are not limited to, cyclopentene, cyclopentadiene, cyclohexene, 1,3-cyclohexadiene, 1 ,4-cyclohexadiene, and cycloheptene.

[0044] The term "heteroatom" refers to an atom other than carbon or hydrogen. Heteroatoms are typically independently selected from oxygen, sulfur, nitrogen, and phosphorus, but are not limited to those atoms. In embodiments in which two or more heteroatoms are present, the two or more heteroatoms may all be the same as one another, or some or all of the two or more heteroatoms may each be different from the others.

[0045] The term "heteroaliphatic", alone or in combination, refers to a group comprising an aliphatic hydrocarbon (such as alkyl, alkenyl, and alkynyl) and one or more heteroatoms. In certain embodiments, heteroaliphatics are optionally substituted, i.e. substituted or

unsubstituted. Certain heteroaliphatics are acylaliphatics, in which the one or more heteroatoms are not within an aliphatic chain. Heteroaliphatics include heteroalkyls, including, but not limited to, acylalkyls, heteroalkenyls, including, but not limited to, acylalkenyls, and heteroalkynyls, including, but not limited acylalkynyls. Examples of heteraliphatics include, but are not limited to, CH₃C(=0)CH₂-, CH₃C(=0)CH₂CH₂-, CH₃CH₂C(=0)CH₂CH₂-, CH₃C(=0)CH₂CH₂CH₂-, CH₃OCH₂CH₂-, CH₃NHCH₂-, and the like.

[0046] The term "heterocycle" refers to a group comprising a covalently closed ring wherein at least one atom forming the ring is a carbon atom and at least one atom forming the ring is a heteroatom. Heterocyclic rings may be formed by three, four, five, six, seven, eight, nine, or more than nine atoms. Any number of those atoms may be heteroatoms (i.e., a heterocyclic ring may comprise one, two, three, four, five, six, seven, eight, nine, or more than nine heteroatoms). Herein, whenever the number of carbon atoms in a heterocycle is indicated (e.g., Ci-C₆ heterocycle), at least one other atom (the heteroatom) must be present in the ring.

Designations such as "C₁-C6 heterocycle" refer only to the number of carbon atoms in the ring and do not refer to the total number of atoms in the ring. It is understood that the heterocylic ring will have additional heteroatoms in the ring. In heterocycles comprising two or more heteroatoms, those two or more heteroatoms may be the same or different from one another. Heterocycles may be optionally substituted. Binding to a heterocycle can be at a heteroatom or via a carbon atom. Examples of heterocycles include heterocycloalkyls (where the ring contains fully saturated bonds) and heterocycloalkenyls (where the ring contains one or more unsaturated bonds) such as, but are not limited to the following:

wherein D, E, F, and G independently represent a heteroatom. Each of D, E, F, and G may be the same or different from one another. [0047] The term "ring" refers to any covalently closed structure. Rings include, for example, carbocycles (e.g., aryls and alicyclics), heterocycles (e.g., heteroaryls and non-aromatic heterocycles), aromatics (e.g., aryls and heteroaryls), and non-aromatics (e.g., alicyclics and non-aromatic heterocycles). Rings may be optionally substituted.

[0048] The term "alkylaryl" refers to a group comprising an aryl group bound to an alkyl group.

[0049] In certain embodiments, R¹ is an alkyl. The alkyl can be a primary alkyl, a secondary alkyl, or a tertiary alkyl. The alkyl can be substituted or unsubstituted. The alkyl can also include one or more heteroatoms in the main chain of the alkyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkyl. The alkyl can also form a ring, i.e. a cycloalkyl. The cycloalkyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocycloalkyl. The alkyl can also be bound to an aryl to form an alkylaryl, such as a benzyl, or to a non-aromatic ring.

[0050] In other embodiments, R¹ is an alkenyl. The alkenyl can have a cis- or trans- configuration. The alkenyl can be substituted or unsubstituted. The alkenyl can also include one or more heteroatoms in the main chain of the alkenyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkenyl. The alkenyl can also form a ring, i.e. a cycloalkenyl. The cycloalkenyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocycloalkenyl. The alkenyl can also be bound to an aryl or to a non-aromatic ring. [0051] In further embodiments, R¹ is an alkynyl. The alkenyl can be substituted or unsubstituted. The alkynyl can also include one or more heteroatoms in the main chain of the alkynyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkynyl. The alkynyl can also be bound to an aryl or to a non-aromatic ring.

[0052] In yet further embodiments, R¹ is an aryl or is aromatic. The aryl can be substituted or unsubstituted. The aryl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heteroaryl.

[0053] In illustrative embodiments of the present invention, R¹ of the a-diazo-/3-keto oxime ether of formula (II) may be, but is not limited to

wherein the symbol " * " denotes the point at which R is connected to the carbon atom adjacent to the oxime ether in formula (II). [0054] In certain embodiments, R² is an alkyl. The alkyl can be a primary alkyl, a secondary alkyl, or a tertiary alkyl. The alkyl can be substituted or unsubstituted. The alkyl can also include one or more heteroatoms in the main chain of the alkyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkyl. The alkyl can also form a ring, i.e. a eycloalkyl. The cycloalkyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocycloalkyl. The alkyl can also be bound to an aryl to form an alkylaryl, such as a benzyl, or to a non-aromatic ring.

[0055] In other embodiments, R² is an alkenyl. The alkenyl can have a cis- or irons- configuration. The alkenyl can be substituted or unsubstituted. The alkenyl can also include one or more heteroatoms in the main chain of the alkenyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkenyl. The alkenyl can also form a ring, i.e. a cycloalkenyl. The cycloalkenyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocyclo alkenyl. The alkenyl can also be bound to an aryl or to a non-aromatic ring.

[0056] In further embodiments, R² is an alkynyl. The alkenyl can be substituted or unsubstituted. The alkynyl can also include one or more heteroatoms in the main chain of the alkynyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkynyl. The alkynyl can also be bound to an aryl or to a non- aromatic ring.

[0057] In yet further embodiments, R² is an aryl or is aromatic. The aryl can be substituted or unsubstituted. The aryl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heteroaryl.

[0058) In illustrative embodiments of the present invention, R² of the odiazo-/3-keto oxime ether of formula (II) may be, but is not limited to

wherein the symbol " * " denotes the point at which R² is connected to the carbon atom of the carbonyl in formula (II).

[0059] In certain embodiments, R³ is an alkyl. The alkyl can be a primary alkyl, a secondary alkyl, or a tertiary alkyl. The alkyl can be substituted or unsubstituted. The alkyl can also include one or more heteroatoms in the main chain of the alkyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkyl. The alkyl can also form a ring, i.e. a cycloalkyl. The cycloalkyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocycloalkyl. The alkyl can also be bound to an aryl to form an alkylaryl, such as a benzyl, or to a non-aromatic ring.

[0060] In other embodiments, R³ is an alkenyl. The alkenyl can have a cis- or trans- configuration. The alkenyl can be substituted or unsubstituted. The alkenyl can also include one or more heteroatoms in the main chain of the alkenyl wherein one or more of the carbon atoms are replaced by the one or more heteroatom, i.e. a heteroalkenyl. The alkenyl can also form a ring, i.e. a cycloalkenyl. The cycloalkenyl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heterocycloalkenyl. The alkenyl can also be bound to an aryl or to a non-aromatic ring.

[0061] In yet further embodiments, R³ is an aryl or is aromatic. The aryl can be substituted or unsubstituted. The aryl can further include one or more heteroatoms in the ring wherein one or more of the carbon atoms in the ring are replaced by the one or more heteroatoms, i.e. a heteroaryl.

[0062] In illustrative embodiments of the present invention, R³ of the a-diazo-/3-keto oxime ether of formula (II) may be, but is not limited to

wherein the symbol " * " denotes the point at which R³ is connected to the oxygen atom in formula (II).

[0063] In summary, the development of highly efficient synthesis of 2H-azirine carboxylic esters has been described. This internal redox reaction has been achieved by rearrangement of a-oximino carbenoids generated from odiazo-jS-keto oxime ethers under rhodium catalysis. A broad substrate scope has been demonstrated enabling the synthesis of 2H-azirines with a wide range of substitutions of distinct electronic and steric characteristics.

[0064] The herein described synthesis of 2H-azirine carboxylic esters is further extended to the synthesis of pyrroles, which are frequently found in natural products, pharmaceuticals, and functional materials. These utilities continue to drive the interest in the development of new synthetic methods for pyrroles which include cycloaddition reactions, multicomponent coupling reactions, and transition metal-mediated reactions.

(0065] Novel rearrangement of a-oximino ketenes derived from odiazo oxime ethers provides 2H-azirines bearing quaternary centers and allows for subsequent rearrangement to highly substituted pyrroles in excellent yields by introduction of vinyl groups on a-diazo oxime ethers (Eq. (3)).

[0066] 2-vinyl-2H-azirines undergo rearrangement to form pyrroles via nitrenes. The rhodium catalyst system used in the formation of 2-vinyl-2H-azirines is further exploited in the synthesis of pyrroles in tandem fashion. It is surprisingly found that that exposure of a-diazo oxime ether 3a to 2 mol % Rh₂(OAc)₄ in refluxing toluene provided tetra-substituted pyrrole 4a in 90% yield. The substrate scope of the reaction of Eq. (3) was studied. As shown in

Table 3, this protocol offers highly flexible synthesis of pyrroles with various substituents. While substrates with alky groups on vinyl substituents required refluxing toluene (4a, 4n, and 41), those with aryl groups for R³ gave the corresponding pyrroles at 60 °C in excellent yields (4b-4h).

Table 3. Synthesis of Pyrroles via Tandem Reaction of

a-Diazo xime Ethers"

4d 96%)^c 41 (85%)⁶ 4e (95%) ^c 4f (96%)^c

4g (94%)^c 4h (74%)' "The reported yields in parentheses are of the isolated products.

''Toluene, 1 10 °C 'DCE, 60 °C. ^i/(E)-3-(3-Cydohexy.-2-methoxy- 2H-azirin-2-yl)-l-phenylprop-2-en- l-one 4 h' (19%) obtained as

byproduct.

[0067] Without wishing to be bound by any theory, it is hypothesized that Eq. (3) proceeded via the following reaction mechanism Eq. (4), wherein the rhodium (Il)-based catalyst may be Rh₂(OAc)₄:

[0068] It is proposed that the rearrangement proceeds through ketene intermediate C. Thus, rhodium-catalyzed formation of carbenoid B promotes migration of the vinyl substitutent to the carbenoid center resulting in formation of ketene C. Attack of the oxygen atom of the oxime ether moiety on the ketene leads to formation of ylides D/E that further undergo rearrangement to afford 2H-azirine-2-carboxylic ester F. Rhodium-nitrene complex G formed via ring-opening of F undergoes C-H insertion to afford pyrrole H. [0069] To investigate the presence of ketenes as intermediates in the reaction pathway as proposed in Eq. (4), it has been demonstrated that the ketene independently prepared from carboxylic acid 5 spontaneously undergoes rearrangement to afford 2t in 85%, Eq. (5).

[0070] In order that the invention may be readily understood and put into practical effect, particular embodiments will now be described by way of the following non-limiting examples.

Examples

Example 1: General methods and materials

[0071] All reactions were carried out in flame or oven-dried glassware under nitrogen atmosphere with freshly distilled dry solvents under anhydrous conditions unless otherwise indicated. Flash column chromatography was performed with silica gel 60 (230 - 400 mesh). Chromatograms were visualized by fluorescence quenching with UV light at 254 nm or by staining with base solution of potassium permanganate and molybdate. NMR spectra were recorded at RT on 400 MHz Bruker spectrometers. The residual solvent signals were taken as the reference (0.00 ppm or 7.26 ppm for 1H NMR spectra and 77.0 ppm for ¹³C NMR spectra in CDCI₃). Chemical shift (δ) is reported in ppm, coupling constants (J) are given in Hz. The following abbreviations classify the multiplicity: s = singlet, d = doublet, t = triplet, m = multiple!, dd = doublet of doublet, q = quartet and br = broad signal. HRMS (ESI) spectra were recorded on a Waters Q-Tof premier™ mass spectrometer.

[0072] All solvents were distilled under nitrogen atmosphere from the following drying agents immediately before use: acetonitrile and dichloroethane were distilled from P₂C>5.

Example 2: Screening of catalysts and Examination of solvent effect

[0073] Various catalyst systems are explored to determine the optimal catalyst system for the reaction of Eq. (1). A reaction employing Cu(OTf) as a catalyst (see Table 1, entry 1) is first evaluated. Exposure of a-diazo-/3-keto oxime ether la to Cu(OTf) at 60 °C resulted in the formation of two products in low yield. The two products were identified to have the structures of products 2a and 2a'. Compound 2a appears to arise from the intended Wolff rearrangement, while compound 2a' arises from N-0 insertion. Screening of various metal salts was continued using catalyst systems illustrated in Table 1. Copper salts in general proved to be inferior, affording poor yields and selectivities (Table 1, entries 1-3). Use of silver salts which are frequently used in the Wolff rearrangement gave improved yield, while the selectivity between the Wolff rearrangement and N-O insertion remained unsatisfactory (Table 1, entries 4-8). It was surprisingly discovered that an exposure of compound la to 2 mol % of Rh2(OAc)₄ led to the exclusive formation of compound 2a in nearly quantitative yield (Table 1, entry 9). Various rhodium salts bearing ligands with different electronic and steric influences were thus examined (Table 1, entries 9-1 1). From these results, it is apparent that steric influence of rhodium catalysts appears to be minimal, while electronic effect of ligands has a pronounced influence on the efficiency of the reaction (Rh(Piv)₄, 99% vs Rh₂(pfb)₄, 60%) (Table 1, entries 10 vs. 1 1). [0074] On the other hand, examination of the solvent effect on the rearrangement revealed that the reaction is well tolerated in various solvents (Table 1, entries 9, 12-14).

Table 1. Screening of catalvsts and solvents.

la

Entry Catalysf Yield [%Y

2a 2a'

1 Cu(OTi) Dichloroeiliane 16 13

2 Cu(OTf}₂ Dicliloroetliane 12 19

3 Cii(hfacac)2 Dichloroetliaue 19 18

4 AgN0₃ Dicliloroetliane 28 28

5 Ag₂C0₃ DichloroeTliane 44 55

6 Ag(OBz) Dichloroetliane 46 54

7 Ag(OTf) Dicliloroetliane 71 20

8 AgBF₄ DichloiOetliane 69 -

9 Rli₂(OAc)₄ Dicfjloroetliane 99 -

10 Rli₂(Piv)₄ Dicliloroetliane 99 -

11 Rli₂(pfb)₄ Dicliloroetliane 60 -

12 Rli₂(OAc)₄ Benzene 95 -

13 Rli₂(OAc)₄ Toluene 94 -

14 Rli₂(OAc) 1,4-dioxane 96 -

= pivalate, pfb = perfluorobutyrate. Yields determined by NMR vs. standard. Example 3: Examination of substrate scope

[0075] The substrate scope (i.e. R¹, R² and R³) of the rearrangement was studied (Table 2).

Consistent with the results in the optimization studies of Example 1, most of the substrates smoothly proceeded to afford 2H-azirine carboxylic esters in good to excellent yields. With the anticipation that electronic and steric influences would play a crucial role in the rearrangement, various types of substituents for each of the three sites (R¹, R² and R³) were examined. For substituent R¹ adjacent to the oxime ethers, a wide range of substitutions including primary, secondary and tertiary alkyl groups was well tolerated (Table 2, entries 1 - 3). Since carbenoids are known to undergo addition with aryl groups, substrate le bearing a benzyl group was subjected to the reaction conditions to determine the preference between the two competing pathways, addition and 2H-azirines formation (Table 2, entry 4). Nevertheless, the reaction led to exclusive formation of 2H-azirine 2e with the benzyl group remaining intact. In additions, substrates with alkenyl, alkynyl and aryl substituents smoothly proceeded to give the corresponding 2H-azirine carboxylic esters in excellent yields (Table 2, entries 5- 10). The electronic effect of substituent R¹ on the rearrangement by varying substituents on phenyl groups was also studied (Table 2, entries 9, 10). Despite the large difference in electronic properties, little impact on the reaction efficiency was observed. For example, the substrates with 4-MeOPh (li) and 4-N0₂Ph (lj) afforded comparable yields of the

corresponding products (92% and 96%, respectively). In addition, those with heteroaryl groups such as 2-furyl group (lk) for R¹ afforded 2k in 87% yield.

[0076] The influence of R² that is involved in migration was next investigated (Table 2, entries 12-22). Examination of the migratory aptitude of R² revealed that the efficiency appears to be in the order of secondary, vinyl ^primary followed by tertiary alkyl groups (cyclohexyl (lm), 94%; trans-alkenyl (lq), 72%; butyl (11), 66%; tBu (lo), 33%). To examine the diastereoselectivity of the rearrangement, a substrate with omethylbenzyl group were subjected to the rearrangement (Table 2, entry 14). However, little selectivity was observed resulting in formation of two diastereomers in a ratio of 1.2: 1 in 96% yield.

[0077] Intrigued by the report that intramolecular allylic C-H insertion is the predominant pathway for carbenoids derived from a-diazo-/3-keto esters bearing allylic substituents, an intramolecular competition reaction with lp was performed (Table 2, entry 16). In contrast to iS-keto ester derived carbenoids, it was suprisingly found that lp afforded 2H-azirine 2p as a sole product in 92% yield. Encouraged by this result, the potential isomerization of (E)~ and (Z)-alkenes during migration was examined (Table 2, entries 17, 18). It was surprisingly found that the geometries of the alkenes were preserved during migration showing free from isomerization. Moreover, compound Is with a cyclohexene moiety also produced the corresponding product in 82% yield (Table 2, entry 19).

[0078] Next, the influence of migrating groups when R² is an aryl group was examined. While the substrates with phenyl (It) and 2-furyl (lv) groups afforded the expected products 2t and 2v (44% and 60%, respectively) along with N-0 insertion products 2t' and 2v' (44% and 31 %, respectively), lu bearing a more electron-rich 4-methoxyphenyl group gave the corresponding product 2u in higher yield (70%).

[0079] Since the rearrangement also involves migration of the alkoxy groups (OR³) of oxime ethers resulting in the transformation of ketones to esters, the electronic as well as steric effects of R³ (Table 2, entries 23-28) were investigated. Overall, a wide range of substitution was well-tolerated for R³. Substrates bearing primary and secondary alkyl groups afforded the corresponding 2H-azirine carboxylic esters in excellent yields. Moreover, electron

withdrawing groups for R³ did not interfere with the efficiency of the rearrangement as observed with substrates ly and lz bearing trifluoroethyl and methoxycarbonylmethyl groups (Table 2, entries 25, 26). Substrate lbb with phenyl group also gave the corresponding phenyl ester 2bb in 93% (Table 2, entry 28).

Table 2. Substrate scope.'

[a] The reported yields in parentheses are of the isolated products, fb] 1 -(2-methoxy-3-phenyl-2H-azirin-2-yi)butan-1 -one 2 (29%) was obtained as a by-product, (c) 1-(2-memoxy-3i3henyi-2H-a2mn-2-y!)-2,2-dimethylpropan- 2o' (46%) and 2,2-dimethyM-(3-phenyi-2H-azirin-2- ^: yl)propan-1 -one 2o" (18%) were obtained as by-products, [d] The product was obtained as an inseparable mixture with (2-methoxy-3-phenyf- 2H-azirin-2-yl)(phenyl>methanone 2V (44%). Yield determined by NMR. [e] furan-2-yl(2-methoxy-3-phenyl-2H-a2irin-2-yi)methanone 2^ (31%) was obtained as a by-product. Example 4: General procedure for g-diazo-ff-oximino ketones

[0080] To a solution of β-oximino ketones (0.5 mmol, 1.0 eq.) and 4-methylbenzenesulfonyl azide (0.55 mmol, 1.1 eq.) in CH₃CN (5 mL) was added DBU (0.55 mmol, 1.1 eq.) dropwise at 0 °C. The resulting orange color solution was stirred at 0 °C for 3 h and^'slowly brought to RT. Upon completion as indicated by TLC, the solvent was removed under reduced pressure, and the crude material was purified by flash chromatography using hexane-ethyl acetate

(19: 1).

Example 5: (Z)-2-diazo-l-(methoxyimino)-4-methyl-l-phenvIpentan-3-one (la)

[0081] The title compound was prepared according to the general procedure. The product was obtained as yellow solid. Mp: 55 - 57 °C. Yield 71%; 1H NMR (400 MHz, CDC1₃) δ 7.61 - 7.59 (m, 2H), 7.44 - 7.38 (m, 3H), 4.08 (s, 3H), 2.47 - 2.41 (m, 1H), 0.98 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 197.4, 144.1, 133.9, 130.2, 128.9, 127.4, 67.3, 62.8, 36.8, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃Hi₆N₃0₂: 246.1243. Found: 246.1244.

Example 6: (Z)-4-diazo-5-(methoxyimino)-2,7-dimethyloctan-3-one (lb)

[0082] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 56%; 1H NMR (400 MHz, CDC1₃) δ 3.88 (s, 3H), 2.89 - 2.74 (m, 1H), 2.45 (d, J= 7.2 Hz, 2H), 1.85 - 1.70 (m, 1H), 1.14 (d, J= 7.2 Hz, 6H), 0.91 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 196.1, 144.8, 61.9, 40.8, 35.9, 26.9, 22.2, 18.7;

HRMS (ESI) m/z [M+H]+: Calcd for Ci,H₂oN₃0₂: 226.1556. Found: 226.1565.

Example 7: (Z)-4-diazo-5-(methoxyimino)-2_<6,6-trimethylheptan-3-one (lc)

[0083] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 66%; Ή NMR (400 MHz, CDC1₃) δ 3.89 (s, 3H), 2.64 - 2.58 (m, 1H), 1.21 (s, 9H), 1.10 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 198.7, 150.2, 61.9, 39.4, 36.0, 28.5, 19.1 ; HRMS (ESI) m/z [M+H]+: Calcd for C_uHi9N₃0₂Na: 248.1375. Found: 248.1372.

Example 8: (5Z,6E)-4-diazo-5-(methoxyimino)-2-methyl-7-phenylhept-6-en-3-one (If)

[0084] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 83%. Ή NMR (400 MHz, CDC1₃) δ 7.47 - 7.45 (m, 2H), 7.38 - 7.29 (m, 3H), 6.90 (s, 2H), 4.04 (s, 3H), 2.79 - 2.73 (m, 1H), 1.10 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 197.7, 144.0, 136.1, 135.6, 129.0, 128.9, 127.1, 122.9, 62.8, 36.7, 19.0; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅Hi₈N₃0₂: 272.1399. Found: 272.1403.

Example 9: (Z)-4-diazo-5-(methoxyimino)-2-methyl-7-phenylhept-6-vn-3-one (lg)

[0085] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 76%. 1H NMR (400 MHz, CDC1₃) δ 7.53 - 7.51 (m, 2H), 7.40 - 7.34 (m, 3H), 4.07 (s, 3H), 3.34 - 3.31 (m, 1H), 1.18 (d, J= 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCI3) δ 196.3, 132.0, 129.6, 129.5, 128.5, 121.2, 91.8, 82.6, 63.4, 36.8, 19.1; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅H₁₆N₃0₂: 270.1243. Found: 270.1247. Example 10: (Z)-2-diazo-l-Cmethoxyimino)-l-(4-methoxyphenyl)-4-methylpentan-3-one

Oil

[0086] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 77%. Ή NMR (400 MHz, CDC1₃) δ 7.56 - 7.52 (m, 2H), 6.94 - 6.90 (m, 2H), 4.05 (s, 3 H), 3.84 (s, 3H), 2.50 - 2.44 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 197.6, 161.3, 143.7, 128.9, 126.2, 114.3, 62.6, 55.4, 36.8, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₄Hi₈N₃0₃: 276.1348. Found: 276.1355.

Example 11: (Z)-2-diazo-l-(methoxyimino)-4-methyl-l-(4-nitrophenyl)pentan-3-one (10

[0087] The title compound was prepared according to the general procedure. The product was obtained as yellow solid. Mp: 93 - 94 °C. Yield: 65%. Ή NMR (400 MHz, CDC1₃) δ 8.26 - 8.23 (m, 2H), 7.74 - 7.71 (m, 2H), 4.13 (m, 3H), 2.63 - 2.59 (m, 1H), 1.08 (d, J= 6.8 Hz, 6H); ¹³C MR (100 MHz, CDC1₃) δ 195.9, 148.5, 142.6, 140.0, 128.1, 123.9, 63.4, 36.5, 18.6; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃Hi₅N₄0₄: 291.1093. Found: 291.1094.

Example 12: (E)-2-diazo-l-(furan-2-yl)-l-(methoxyimino)-4-methylpentan-3-one (lk)

[0088] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 82%; Ή NMR (400 MHz, CDC1₃) δ 7.51 (m, 1H), 6.68 - 6.67 (m, 1H), 6.50 - 6.48 (m, 1H), 4.08 (s, 3H), 2.58 - 2.51 (m, 1H), 1.06 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 197.1, 147.4, 144.5, 135.7, 112.1, 11 1.9, 63.1, 36.7, 18.9; HRMS (ESI) m/z [M+H]+: Calcd for C_nH,₄N₃0₃: 236.1035. Found: 236.1044.

Example 13: (Z)-2-diazo-l-(methoxyimino)-l-phenylhexan-3-one (11) [0089] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 80%. Ή NMR (400 MHz, CDC1₃) ό 7.61 - 7.58 (m, 2H), 7.44 - 7.39 (m, 3H), 4.08 (s, 3H), 2.08 (t, J = 7.2 Hz, 2H), 1.56 - 1.50 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 193.2, 144.2, 133.9, 130.2, 128.9, 127.6, 62.8, 41.4, 18.2, 13.6; HRMS (ESI) m/z [M+H]+: Calcd for C₁₃H₁₆N₃0₂: 246.1243. Found: 246.1249.

Example 14: (Z)-l-cvclohexyl-2-diazo-3-(methoxyimino)-3-phenylpropan-l-one (lm)

[0090] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 82%. 1H NMR (400 MHz, CDC1₃) δ 7.59 - 7.57 (m, 2H), 7.44 - 7.38 (m, 3H), 4.07 (s, 3H), 2.14 - 2.04 (m, 1H), 1.69 - 1.52 (m, 5H), 1.42 - 1.32 (m, 2H), 1.14 - 1.07 (m, 1H), 0.97 - 0.90 (m, 2H); ^l3C NMR (100 MHz, CDC1₃) δ 196.4, 144.3, 134.0, 130.1, 128.8, 127.5, 62.8, 47.2, 28.9, 25.6, 25.6; HRMS (ESI) m z [M+H]+: Calcd for Ci₆H₂₀N₃O₂: 286.1556. Found: 286.1563.

Example 15: (Z)-2-diazo-l-(methoxyimino)-4,4-dimethyl-l-phenylpentan-3-one (lo)

[0091] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 58%. Ή NMR (400 MHz, CDC1₃) δ 7.57 - 7.55 (m, 2H), 7.39 - 7.35 (m, 3H), 4.07 (s, 3H), 1.23 (s, 9H); ¹³C NMR (100 MHz, CDC1₃) δ 197.2, 145.1, 134.0, 129.8, 128.6, 127.1, 62.8, 44.5, 26.8; HRMS (ESI) m/z [M+H]+: Calcd for C₁₄H,₈N₃0₂:

260.1399. Found: 260.1398.

Example 16: (lZ_<4E)-2-diazo-l-(methoxyimino)-l-phenyloct-4-en-3-one (lq)

[0092] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 63%. Ή NMR (400 MHz, CDC1₃) δ 7.61 - 7.58 (m, 2H), 7.42 - 7.36 (m, 3H), 6.82 (dt, Jl = 8.4 Hz, J2 = 6.8 Hz, 1H), 5.30 (d, J= 15.2 Hz, 1H), 4.08 (s, 3H), 1.97 - 1.91 (m, 2H), 1.30 - 1.22 (m, 2H), 0.76 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDClj) δ 182.9, 146.1, 144.1, 134.1, 130.2, 128.8, 127.8, 125.7, 62.8, 34.1, 21.0, 13.5; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅H,8N₃0₂: 272.1399. Found: 272.1404.

Example 17: (lZ,4Z)-2-diazo-l-(methoxyimino)-l-phenylundec-4-en-3-one (lr)

[0093] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 71%. Ή NMR (400 MHz, CDC1₃) δ 7.60 - 7.58 (m, 2H), 7.42 - 7.35 (m, 3H), 5.81 (dt, J7 = 11.6 Hz, J2 = 7.2 Hz, 1H), 5.65 (d, J= 11.6 Hz, 1H), 4.07 (s, 3H), 2.59 - 2.55 (m, 2H), 1.58 - 1.26 (m, 8H), 0.87 (t, J= 6.4 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 184.0, 148.1, 144.1, 134.0, 130.1, 128.7, 127.7, 123.9, 62.8, 31.6, 29.6, 29.1 , 29.0, 22.6, 14.1; HRMS (ESI) m/z [M+H]+: Calcd for Ci₈H₂₄N₃0₂: 314.1869. Found: 314.1868.

Example 18: (Z)-l-cvdohexenyl-2-diazo-3-(methoxyimino)-3-phenylpropan-l-one (Is)

[0094] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 81%. Ή NMR (400 MHz, CDC1₃) δ 7.47 - 7.44 (m, 2H), 7.37 - 7.33 (m, 3H), 6.05 - 6.03 (m, 1H), 4.08 (s, 3H), 2.00 - 1.96 (m, 2H), 1.85 - 1.74 (m, 2H), 1.29 - 1.21 (m, 4H); ¹³C NMR (100 MHz, CDC1₃) δ 189.9, 145.8, 138.0, 136.7, 135.0, 129.6, 128.7, 127.4, 62.7, 25.2, 24.1, 21.6, 21.2; HRMS (ESI) m/z [M+H]+: Calcd for C₁₆H,₈N₃0₂:

284.1399. Found: 284.1393.

Example 19: (Z)-2-diazo-3-(methoxyimino)-l,3-diphenylpropan-l-one (It)

[0095] The title compound was prepared according to the general procedure. The product was obtained as yellow solid. Mp: 87 - 88 °C. Yield: 88%. Ή NMR (400 MHz, CDC1₃) δ 7.51 - 7.47 (m, 4H), 7.34 - 7.29 (m, 1H), 7.26- 7.20 (m, 5H), 3.97 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 187.8, 144.9, 137.6, 133.4, 13 1.9, 129.9, 128.5, 128.1, 127.6, 127.5, 62.6; HRMS (ESI) m/z [M+H]+: Calcd for Ci₆Hi₄N₃0₂: 280.1086. Found: 280.1078.

Example 20: (Z)-2-diazo-3-(methoxyimino)-l-(4-methoxyphenyl)-3-phenylpropan-l-one ilil)

[0096] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 94%. Ή NMR (400 MHz, CDC1₃) δ 7.53- 7.48 (m, 4H), 7.25 - 7.23 (m, 3H), 6.72 - 6.70 (m, 2H), 4.00 (s, 3H), 3.75 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 186.5, 162.6, 145.2, 133.5, 130.2, 129.9, 128.6, 127.6, 1 13.3, 62.7, 55.3; HRMS (ESI) m/z [M+H]+: Calcd for CnH₁₆N₃0₃: 310.1 192. Found: 310.1 194.

Example 21: (Z)-2-diazo-l-(furan-2-yl)-3-(methoxyimino)-3-phenylpropan-l-one (lv)

[0097] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 82%. Ή NMR (400 MHz, CDC1₃) δ 7.62 - 7.60 (m, 2H), 7.35 - 7.32 (m, 4H), 7.01 (d, J= 3.6 Hz, 1H), 6.40 - 6.38 (m, 1H), 4.06 (s, 3H); ^I3C NMR (100 MHz, CDC1₃) 6 173.4, 151.2, 145.0, 144.1, 133.7, 129.8, 128.6, 127.2, 116.8, 112.1, 62.9; HRMS (ESI) m/z [M+H]+: Calcd for C₁₄Hi₂N₃0₂: 254.0930. Found: 254.0920.

Example 22: (Z)-2-diazo-4-methyl-l-phenyl-l-(2,2,2-trifluoroethoxyimino)pentan-3-one

Oil

[0098] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 75%. Ή NMR (400 MHz, CDC1₃) δ 7.54 - 7.51 (m, 2H), 7.42 - 7.33 (m, 3H), 4.56 (q, J = 16.8 Hz, 2H), 2.37 - 2.30 (m, 1H), 0.91 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 196.8, 147.5, 133.0, 130.9, 129.0, 127.8, 123.3 (q, J= 278.2 Hz), 71.6 (q, J= 34.2 Hz), 67.5, 37.0, 18.6; HRMS (ESI) m/z [M+H]+: Calcd for C₁₄Hi₅N₃0₂F₃: 314.1116. Found: 314.1 111.

Example 23: (Z)-2-diazo-4-methyl-l-(phenoxyimino)-l-phenylpentan-3-one (lbb)

[0099] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 69%. Ή NMR (400 MHz, CDC1₃) δ 7.63 - 7.62 (m, 2H), 7.41 - 7.35 (m, 3H), 7.29 - 7.24 (m, 4H), 7.20 - 6.97 (m, 1H), 2.46 - 2.38 (m, 1H), 0.94 (d, J = 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 197.1, 158.7, 147.6, 133.4, 130.9, 129.5, 128.0, 123.1, 1 14.7, 68.0, 37.1, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₈Hi₈N₃0₂: 308.1399. Found: 308.1402.

Example 24: (lE,5Z)-4-diazo-5-(methoxyimino)-2-methyl-l,5-diphenylpent-l-en-3-one

[00100] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 78%; Ή NMR (400 MHz, CDC1₃) 6 7.51 - 7.48 (m, 2H), 7.36 - 7.32 (m, 3H), 7.31 - 7.22 (m, 3H), 6.95 - 6.93 (m, 2H), 6.74 (s, 1H), 4.09 (s, 3H), 1.79 (d, J= 2.0 Hz, 3H); ¹³C NMR (100 MHz, CDCI3) δ 191.0, 145.5, 136.7, 135.8, 135.4, 134.7, 129.8, 129.0, 128.8, 128.2, 128.0, 127.6, 62.8, 14.4; HRMS (ESI) m/z [M+H]+: Calcd for C₁₉Hi₈N₃0₂: 320.1399. Found: 320.1406.

Example 25: (lE,5E)-5-(methoxyimino)-l,5-diphenylpent-l-en-3-one

[00101] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 82%; Ή NMR (400 MHz, CDC1₃) δ 7.66 - 7.65 (m, 2H), 7.56 (d, J= 15.6 Hz, 1H), 7.43 - 7.32 (m, 3H), 7.30 - 7.23 (m, 3H), 7.17 - 7.15 (m, 2H), 6.30 (d, J= 15.6 Hz, 1H), 4.10 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 182.4, 144.0, 140.9, 134.5, 134.2, 130.4, 130.2, 129.0, 128.8, 128.2, 127.9, 122.5, 62.9; HRMS (ESI) m z [M+H]+: Calcd for C|₈Hi₆N₃0₂: 306.1243. Found: 306.1235.

Example 26: (lE,5Z)-4-diazo-l-(furan-2-yl)-5-(methoxyimino)-5-phenylpent-l-en-3-one

[00102] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 93%. 1H NMR (400 MHz, CDC1₃) δ 7.65 - 7.63 (m, 2H), 7.42 - 7.40 (m, 3H), 7.39 - 7.33 (m, 2H), 6.51 (d, J= 3.6 Hz, 1H), 6.39 (dd, Jl = 3.6 Hz, J2 = 1.6 Hz, 1H), 6.26 (d, J= 15.2 Hz, 1H), 4.09 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 182.1, 151.2, 144.7, 143.9, 133.9, 130.3, 128.9, 127.8, 127.5, 1 19.8, 1 15.6, 1 12.4, 62.8;

HRMS (ESI) m/z [M+H]+: Calcd for Ci₆H₁₄N₃0₃: 296.1035. Found: 296.1033.

Example 27: (lZ,4E,6E)-2-diazo-l-(methoxyimino)-l,7-diphenylhepta-4_<6-dien-3-one

[00103] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 94%; ^!H NMR (400 MHz, CDC1₃) 5 7.65 - 7.63 (m, 2H), 7.44 - 7.25 (m, 9H), 6.87 (d, J= 15.6 Hz, 1H), 6.55 (dd, Jl = 15.6 Hz, J2 = 4.4 Hz), 5.89 (d, J= 14.8 Hz, 1H), 4.09 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 182.4, 143.9, 141.6, 141.4, 136.0, 134.0, 130.4, 129.1, 128.9, 128.8, 127.8, 127.2, 126.3, 125.5, 62.9; HRMS (ESI) m/z [M+H]+: Calcd for C₂₀Hi₈N₃O₂: 332.1399. Found: 332.1404.

Example 28: (lE,5E)-4-diazo-5-(furan-2-yl)-5-( methoxyimino)-l-phenylpent-l-en-3-one

[00104] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield: 82%. Ή NMR (400 MHz, CDC1₃) δ 7.65 (d, J = 15.6 Hz, 1H), 7.54 - 7.53 (m, 1H), 7.38 - 7.32 (m, 5H), 6.76 (d, Jl = 3.2 Hz, 1H), 6.63 (d, J = 16.4 Hz, 1H), 6.50 (dd, J7 = 3.6 Hz, J2 = 2.0 Hz, 1H), 6.45 (d, Jl = 15.6 Hz, 1H), 4.10 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 182.1, 147.3, 144.8, 141.4, 135.5, 134.5, 130.3, 128.9, 128.3, 121.7, 112.8, 1 12.0, 63.2; HRMS (ESI) m/z [M+H]+: Calcd for C^H^C^: 296.1035. Found: 296.1024.

Example 29: (lE,5Z,6E)-4-diazo-5-(methoxyimino)-l,7-diphenyIhepta-l,6-dien-3-one

[00105] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 98%; 1H NMR (400 MHz, CDCI3) δ 7.72 (d, J = 15.6 Hz, 1H), 7.46 - 7.44 (m, 4H), 7.36 - 7.29 (m, 6H), 6.97 (s, 2H), 6.72 (d, J= 15.6 Hz, 1H), 4.06 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 182.4, 143.6, 141.6, 137.0, 135.7, 134.5, 130.3,

129.1, 128.9, 128.3, 127.2, 123.0, 121.9, 63.0; HRMS (ESI) m/z [M+H]+: Calcd for

C₂₀Hi8N₃O2: 332.1399. Found: 332.1396.

Example 30: (lE,5Z)-4-diazo-5-(methoxyimino)-l,7-diphenylhept-l-en-6-vn-3-one

[00106] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 92%; 1H NMR (400 MHz, CDC1₃) δ 7.73 (d, J = 15.6 Hz, 1H), 7.52 - 7.50 (m, 2H), 7.42 - 7.38 (s, 3H), 7.35 - 7.22 (m, 6H), 4.09 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 181.6, 141.8, 134.6, 131.9, 130.4, 129.7, 129.4, 128.9, 128.4,

122.2, 121.0, 93.2, 83.1, 63.5; HRMS (ESI) m/z [M+H]+: Calcd for C₂₀Hi₆N₃O₂: 330.1243. Found: 330.1242.

Example 31: (lE,5Z)-5-cvclohexyl-4-diazo-5-rmethoxyimino)-l-phenylpent-l-en-3-one [00107] The title compound was prepared according to the general procedure. The product was obtained as yellow oil. Yield 91%; 1H NMR (400 MHz, CDC1₃) δ 7.69 (d, J = 15.6 Hz, 1H), 7.54 - 7.52 (m, 2H), 7.39 - 7.38 (m, 3H), 6.77 (d, J= 15.6 Hz, 1H), 3.91 (s, 3H), 2.68 - 2.61 (m, 1H), 1.99 - 1.96 (m, 2H), 1.82 - 1.76 (m, 2H), 1.70 - 1.67 (m, 1H), 1.47 - 1.19 (m, 5H); ¹³C NMR (100 MHz, CDC1₃) δ 182.1 , 148.1, 142.0, 134.5, 130.4, 129.0, 128.3, 120.7, 68.5, 62.1 , 42.1, 31.3, 26.3, 26.0; HRMS (ESI) m/z [M+H]+: Calcd for Ci₈H₂₂N₃0₂: 312.1712. Found: 312.1717.

Example 32: General procedure for 2H-azirine-2-carboxylic esters

[00108] To Rh₂(OAc)₄ ( 1.8 mg, 0.004 mmol, 2 mol%) in a flask was added a solution of odiazo-|6-keto oxime ether (0.2 mmol) in dichloroethane (2.0 mL) under nitrogen atmosphere. The solution was stirred at 60 °C overnight, and the solvent was removed under vacuo. The crude material was purified by flash chromatography (hexanes/EtOAc = 9: 1) to give the desired product.

Example 33: Methyl 2-isopropyl-3-phenyl-2H-azirine-2-carboxylate (2a)

[00109] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 95%. 1H NMR (400 MHz, CDC1₃) δ 7.88 - 7.86 (m, 2H), 7.64 - 7.54 (m, 3H), 3.66 (s, 3H), 2.94 - 2.87 (m, 1H), 0.95 (d, J= 6.8 Hz, 3H), 0.83 (d, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 172.9, 162.2, 133.5, 130.1, 129.3, 123.4, 52.3, 44.7, 27.3, 20.4, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃Hi₆N0₂: 218.1 181. Found: 218.1 184.

Example 34: l-(2-Methoxy-3-phenyl-2H-azirin-2-yl)-2-methylpropan-l-one (2a') [00110] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Ή NMR (400 MHz, CDC1₃) δ 7.41 - 7.39 (m, 2H), 7.34 - 7.29 (m, 3H), 3.73 (s, 3H), 2.78 - 2.71 (m, 1H), 1.16 (d, J= 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDC1₃) δ 183.2, 169.3, 138.5, 129.7, 128.2, 124.0, 73.7, 51.6, 25.9, 22.5; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃H,₆N0₂: 218.1 181. Found: 218.1178.

Example 35: Methyl 3-isobutyl-2-isopropyl-2H-azirine-2-carboxylate (2b)

[00111] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 88%. 1H NMR (400 MHz, CDC1₃) δ 3.66 (s, 3H), 2.75 - 2.70 (m, 1H), 2.69 - 2.60 (m, 2H), 2.23 - 2.16 (m, 1H), 1.09 (dd, Jl = 4.0 Hz, J2 = 4.0 Hz, 6H), 0.90 (d, J= 6.8 Hz, 3H), 0.73 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 173.3, 165.2, 52.0, 42.6, 36.3, 27.2, 25.5, 22.6, 22.5, 19.8, 18.6; HRMS (ESI) m/z [M+H]+: Calcd for CiiH₂₀NO₂: 198.1494. Found: 198.1494.

Example 36: Methyl 3-tert-butyl-2-isopropyl-2.H-azirine-2-carboxylate (2d)

[00112] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 93%. 1H NMR (400 MHz, CDC1₃) δ 3.65 (s, 3H), 2.63 - 2.52 (m, 1H), 1.31 (s, 9H), 0.90 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 173.1, 172.0, 51.9, 45.5, 33.4, 27.8, 26.8, 20.6, 19.1 ; HRMS (ESI) m/z [M+H]+: Calcd for CiiH₂₀NO₂: 198.1494. Found: 198.1493.

Example 37: (E)-methyl 2-isopropyl-3-styryl-2H-azirine-2-carboxylate (2f)

[00113] The title compound was prepared according to the general procedure. The product was obtained as white solid. Mp: 70 - 72 °C. Yield: 82%. ^lH NMR (400 MHz, CDC1₃) δ 7.59 - 7.57 (m, 2H), 7.45 - 7.43 (m, 3H), 7.26 (d, J= 16.0 Hz, 1H), 7.17 (d, J= 16.0 Hz, 1H), 3.68 (s, 3H), 2.91 - 2.84 (m, 1H), 0.95 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) 5 172.9, 161.1, 148.2, 134.2, 131.0, 129.1, 128.3, 110.7, 52.3, 43.8, 27.3, 20.3, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅Hi₈N₃0₂: 272.1399. Found:

272.1393.

Example 38: Methyl 2-isopropyI-3-(phenylethvnyl)-2H-azirine-2-carboxylate (2g)

[00114] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 93%. 1H NMR (400 MHz, CDC1₃) δ 7.63 - 7.61 (m, 2H), 7.50 - 7.48 (m, 1H), 7.45 - 7.41 (m, 2H), 3.72 (s, 3H), 2.89 - 2.79 (m, 1H), 0.96 (d, J = 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 171.5, 153.2, 132.6, 131.2, 128.8, 120.0, 113.6, 73.3, 52.5, 46.7, 27.1, 19.6, 18.3; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅H₁₆N0₂: 242.1181. Found: 242.1180.

Example 39: Methyl 2-isopropyl-3-(4-methoxyphenvD-2H-azirine-2-carboxylate (2i)

[00115] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 92%. Ή NMR (400 MHz, CDC1₃) 6 7.82 - 7.80 (m, 2H), 7.07 - 7.05 (m, 2H), 3.90 (s, 3H), 3.65 (s, 3 H), 2.92 - 2.85 (m, 1H), 0.94 (d, J= 6.8 Hz, 3H), 0.80 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 173.2, 163.7, 161.1, 132.1, 115.7, 114.8, 55.6, 52.2, 44.2, 27.4, 20.4, 18.8; HRMS (ESI) m z [M+H]+: Calcd for Ci₄H₁₈N0₃: 248.1287. Found: 248.1287.

Example 40: Methyl 2-isopropyl-3-(4-nitrophenyl)-2H-azirine-2-carboxylate (2j) [00116] The title compound was prepared according to the general procedure. The product was obtained as yellow solid. Mp: 119 - 121 °C. Yield: 96%. Ή NMR (400 MHz, CDC1₃) δ 8.45 - 8.42 (m, 2H), 8.08 - 8.05 (m, 2H), 3.69 (s, 3H), 2.97 - 2.91 (m, 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.83 (d, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 172.0, 162.7, 150.5, 130.8, 129.1, 124.5, 52.5, 46.0, 27.2, 20.5, 18.7; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃H₁₅N₂0₄: 263.1032. Found: 263.1039.

Example 41: Methyl 3-(furan-2-yl)-2-isopropyl-2H-azirine-2-carboxylate (2k)

[00117] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 87%. Ή NMR (400 MHz, CDC1₃) δ 7.79 - 7.79 (m, 1H), 7.21 - 7.19 (m, 1H), 6.67 - 6.66 (m, IH), 3.66 (s, 3H), 2.90 - 2.79 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.83 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCI₃) δ 172.3, 152.4, 148.5, 140.3, 120.6, 1 12.8, 52.4, 44.2, 27.2, 20.1, 18.5; HRMS (ESI) m/z [M+H]+: Calcd for

CnH,₄N0₃: 208.0974. Found: 208.0975.

Example 42: Methyl 3-phenyl-2-propyl-2H-azirine-2-carboxylate (21)

[00118] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 66%. Ή NMR (400 MHz, CDC1₃) δ 7.87 - 7.84 (m, 2H), 7.65 - 7.60 (m, IH), 7.58 - 7.54 (m, 2H), 3.67 (s, 3H), 2.13 - 1.98 (m, 2H), 1.33 - 1.24 (m, 2H), 0.90 (t, J= 7.6 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 173.3, 163.0, 133.6, 130.1, 129.3, 123.1, 52.4, 39.7, 32.7, 19.6, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for Ci₃H_]6N0₂: 218.1181. Found: 218.1 176.

Example 43: Methyl 2-cyclohexyl-3-phenyl-2H-azirine-2-carboxyIate (2m) [00119] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 94%. 1H NMR (400 MHz, CDC1₃) δ 7.87 - 7.85 (m, 2H), 7.64 - 7.54 (m, 3H), 3.65 (s, 3H), 2.61 - 2.55 (m, 1H), 1.81 - 1.72 (m, 2H), 1.67 - 1.60 (m, 3H), 1.35 - 1.27 (m, 2H), 0.99 - 0.89 (m, 2H), 0.76 - 0.72 (m, 1H); ¹³C NMR (100 MHz, CDC1₃) δ 172.9, 162.5, 133.4, 130.1, 129.3, 123.6, 52.3, 44.1, 36.7, 30.9, 29.0, 26.1, 26.0, 25.9; HRMS (ESI) m/z [M+H]+: Calcd for C₁₆H₂oN0₂: 258.1494. Found: 258.1501.

Example 44: Methyl 2-tert-butyl-3-phenyl-2H-azirine-2-carboxylate (2o)

[00120] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 33%. Ή NMR (400 MHz, CDC1₃) δ 7.81 - 7.79 (m, 2H), 7.55 - 7.48 (m, 3H), 3.54 (s, 3H), 1.05 (s, 9H); ¹³C NMR (100 MHz, CDCI3) δ 171.7, 164.4, 133.4, 130.0, 129.3, 123.8, 51.9, 46.6, 33.4, 28.3; HRMS (ESI) m/z [M+H]+: Calcd for C₁₄H₁₈N0₂: 232.1338. Found: 232.1339.

Example 45: (E)-methyl 2-fpent-l-enyl)-3-phenyl-2H-azirine-2-carboxylate (2q)

[00121] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 72%. Ή NMR (400 MHz, CDC1₃) δ 7.87 - 7.85 (m, 2H), 7.63 - 7.55 (m, 3H), 6.50 (dt, Jl = 15.6 Hz, J2 = 1.2 Hz, 1H), 5.30 (dt, Jl = 15.6 Hz, J2 = 7.2 Hz, 1H), 3.72 (s, 3H), 2.04 - 1.98 (m, 2H), 1.36 - 1.30 (m, 2H), 0.83 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCI3) δ 172.1, 157.1 , 133.7, 133.5, 130.4, 129.4, 125.5, 121.6, 52.6, 38.8, 34.3, 22.1, 13.6; HRMS (ESI) m/z [M+H]+: Calcd for Ci₅H₁₈N0₂: 244.1338. Found: 244.1341.

Example 46: (Z)-methyl 2-(oct-l-enyl)-3-phenyl-2H-azirine-2-carboxylate (2r) [00122] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 81%. Ή NMR (400 MHz, CDC1₃) δ 7.88 - 7.86 (m, 2H), 7.64 - 7.56 (m, 3H), 6.02 (dt, Jl = 11.2 Hz, J2 = 1.6 Hz, 1H), 5.63 (dt, Jl = 1 1.2 Hz, J2 = 7.6 Hz, 1H), 3.72 (s, 3H), 2.00 - 1.94 (m, 2H), 1.23 - 1.12 (m, 4H), 1.11 - 1.08 (m, 4H), 0.82 (t, J= 7.2 Hz, 3H); ¹³C NMR ( 100 MHz, CDC1₃) δ 172.4, 161.0, 136.8, 133.7, 130.2, 129.4, 123.1, 122.8, 52.7, 37.9, 31.6, 29.5, 28.9, 28.5, 22.5, 14.0; HRMS (ESI) m/z [M+H]+: Calcd for C₁₈H₂₄N0₂: 286.1807. Found: 286.1802.

Example 47: Methyl 2-cyclohexenyl-3-phenyl-2H-azirine-2-carboxylate (2s)

[00123] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 82%. Ή NMR (400 MHz, CDC1₃) δ 7.91 - 7.89 (m, 2H), 7.65 - 7.55 (m, 3H), 5.87 - 5.85 (m, 1H), 3.69 (s, 3H), 2.23 - 2.19 (m, 2H), 2.03 - 1.99 (m, 2H), 1.68 - 1.55 (m, 4H); ¹³C NMR (100 MHz, CDC1₃) 5 171.9, 161.9, 134.3, 133.6, 130.3, 129.4, 128.0, 122.9, 52.4, 42.8, 26.4, 25.1, 22.5, 21.9; HRMS (ESI) m/z [M+H]+: Calcd for Ci₆Hi₈N0₂: 256.1338. Found: 256.1337.

Example 48: Methyl 2-(4-methoxyphenvO-3-phenyl-2H-azirine-2-carboxylate (2u)

[00124] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 70%. Ή NMR (400 MHz, CDC1₃) δ 7.94 - 7.92 (m, 2H), 7.66 - 7.56 (m, 3H), 7.43 - 7.39 (m, 2H), 6.87 - 6.84 (m, 2H), 3.78 (s, 3H), 3.74 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 171.9, 160.8, 159.2, 133.9, 130.4, 129.6, 129.5, 128.4, 122.2, 1 13.8, 55.3, 52.7, 40.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₇Hi₆N0₃: 282.1130. Found: 282.1134. Example 49: Methyl 2-(furan-2-yl)-3-phenyl-2H-azirine-2-carboxylate (2v)

[00125] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 60%. 1H NMR (400 MHz, CDC1₃) δ 7.95 - 7.93 (m, 2H), 7.69 - 7.65 (m, 1H), 7.62 - 7.58 (m, 2H), 7.27 - 7.26 (m, 1H), 6.83 - 6.82 (m, 1H), 6.40 - 6.38 (m, 1H), 3.77 (s, 3H); ¹³C MR (100 MHz, CDC1₃) δ 170.0, 157.2,^" 149.6, 142.0, 134.0, 130.6, 129.4, 121.7, 1 1 1.0, 1 1 1.0, 52.8, 36.1 ; HRMS (ESI) m z [M+H]+: Calcd for C4H12NO3: 242.0817. Found: 242.0814.

Example 50: 2,2,2-Trifluoroethyl 2-isopropyl-3-phenyl-2H-azirine-2-carboxylate (2y)

[00126] The title compound was prepared according to the general procedure. The product was obtained as colorless oil. Yield: 96%. Ή NMR (400 MHz, CDC1₃) δ 7.80 - 7.77 (m, 2H), 7.57 - 7.52 (m, 1H), 7.51 - 7.49 (m, 2H), 4.56 - 4.46 (m, 1H), 4.35 - 4.26 (m, 1H), 2.83 - 2.80 (m, 1H), 0.89 (d, J= 6.8 Hz, 3H), 0.78 (d, J= 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCI₃) δ 171.0, 162.0, 133.7, 130.1 , 129.4, 126.9, 122.8 (q, J= 144.6 Hz), 60.7 (q, J= 36.3 Hz), 44.3, 27.4, 20.2, 18.7; HRMS (ESI) m/z [M+H]+: Calcd for Ci₄H₁₅N0₂F₃: 286.1055. Found: 286.1048.

Example 51: Phenyl 2-isopropyl-3-phenyl-2H-azirine-2-carboxylate (2x)

[00127] The title compound was prepared according to the general procedure. The product was obtained as white solid. Mp: 106 - 108 °C. Yield: 93%. Ή NMR (400 MHz, CDCI₃) δ 7.87 - 7.85 (m, 2H), 7.59 - 7.50 (m, 3H), 7.26 - 7.22 (m, 2H), 7.12 - 7.08 (m, 1H), 6.95 - 6.92 (m, 2H), 2.93 - 2.90 (m, 1H), 0.95 (d, J= 6.8 Hz, 3H), 0.83 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 171.1 , 162.5, 150.8, 133.7, 130.2, 129.4, 129.3, 125.8, 123.2, 121.5, 44.8, 27.5, 20.4, 18.8; HRMS (ESI) m/z [M+H]+: Calcd for C,₈Hi₈N0₂: 280.1338. Found: 280.1342.

Example 52: General procedure for pyrroles

[00128] A solution of diazo compound (0.2 mmol) and Rh₂(OAc)₄ (0.004 mmol, 2 mol%) in dichloroethane (or toluene) (2.0 mL) was stirred at 60 °C (or 1 10 °C) until the starting material was fully consumed. The reaction mixture was concentrated under reduced pressure to give the crude material which was purified by column chromatography using hexane-ethyl acetate (9: 1) to give the corresponding product.

Example 53: Methyl 4-methyl-2,5-diphenyl-lH-pyrrole-3-carboxylate (4a)

[00129] The title compound was prepared according to the general procedure (reaction at 1 10 °C). The product was obtained as colorless oil. Yield 90%; Ή NMR (400 MHz, CDC1₃) δ 8.26 (s, 1H), 7.54 - 7.51 (m, 2H), 7.44 - 7.31 (m, 8H), 3.72 (s, 3H), 2.43 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) 0 166.2, 136.9, 132.8, 132.5, 129.6, 128.9, 128.8, 128.2, 128.1, 127.5, 127.1, 119.0, 112.9, 50.7, 11.8; HRMS (ESI) m/z [M+H]+: Calcd for Ci₉Hi₈N0₂: 292.1338. Found: 292.1336.

Example 54: Methyl 5-phenyl-2-(phenylethynvD-lH-pyrrole-3-carboxylate (4n)

[00130] The title compound was prepared according to the general procedure (reaction at 110 °C). The product was obtained as white solid. Mp: 126 - 127 °C. Yield 92%; Ή NMR

(400 MHz, CDC1₃) δ 7.94 (s, 1H), 7.52 - 7.50 (m, 2H), 7.40 - 7.36 (m, 2H), 7.34 - 7.31 (m,

1H), 3.70 (s, 3H), 2.76 (t, J= 6.0 Hz, 2H), 2.58 (t, J = 6.0 Hz, 2H), 1.84 - 1.78 (m, 4H); ¹³C

NMR (100 MHz, CDC1₃) 5 166.1, 135.8, 133.0, 128.9, 128.1, 127.8, 127.8, 120.2, 109.9, 50.5, 23.4, 23.4, 22.9, 22.6; HRMS (ESI) m/z [M+H]+: Calcd for Ci₉Hi₈N0₂: 292.1338. Found: 292.1343.

Example 55: Methyl 2,5-diphenyl-lH-pyrrole-3-carboxylate (4b)

[00131] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as white solid. Mp: 172 - 173 °C. Yield 94%; 1H NMR (400 MHz, CDC1₃) δ 8.70 (s, 1H), 7.63 - 7.60 (m, 2H), 7.52 - 7.50 (m, 2H), 7.43 - 7.34 (m, 5H), 7.28 - 7.24 (m, 1H), 6.99 (d, J = 3.2 Hz, 1H), 3.75 (s, 3H); ^l3C NMR (100 MHz, CDC1₃) δ 165.3, 137.9, 131.8, 131.5, 129.0, 128.9, 128.5, 128.3, 127.1, 124.0, 113.3, 109.1, 51.1 ; HRMS (ESI) m/z [M+H]+: Calcd for Ci₈Hi₆N0₂: 278.1181. Found: 278.1177.

Example 56: Methyl 5-(furan-2-yl)-2-phenyl-lH-pyrrole-3-carboxylate (4c)

[00132] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as yellow solid. Mp. 134 - 135 °C. Yield 98%; Ή NMR (400 MHz, CDCI₃) δ 8.72 (s, 1H), 7.64 - 7.62 (m, 2H), 7.45 - 7.36 (m, 4H), 6.92 (d, 16.8 Hz, 1H), 6.90 (d, 1H), 6.90 (d, J= 2.8 Hz, 1H), 6.46 (d, J= 1.2 Hz, 1H), 3.76 (s, 3H); ¹³C MR (100 MHz, CDC1₃) 5 165.0, 146.8, 141.0, 137.2, 131.6, 128.9, 128.5, 128.3, 123.7, 113.1, 111.7, 108.3, 103.8, 51.1; HRMS (ESI) m/z [M+H]+: Calcd for Ci₆H₁₄N0₃: 268.0974. Found: 268.0976.

Example 57: (E)-methyl 2-phenyl-5-styryl-lH-pyrrole-3-carboxylate (4d)

[00133] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as yellow solid. Mp. 125 - 126 °C. Yield 96%; ^!H NMR

(400 MHz, CDCI3) δ 8.58 (s, 1H), 7.64 - 7.62 (m, 2H), 7.44 - 7.22 (m, 9H), 6.92 (d, J= 16.8 Hz, 1H), 6.82 - 6.72 (m, 2H), 3.76 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 165.2, 138.1, 136.9, 131.7, 130.5, 128.9, 128.8, 128.5, 128.2, 127.5, 126.1, 125.4, 117.8, 1 13.1, 1 12.1, 51.1;

HRMS (ESI) m/z [M+H]+: Calcd for C₂₀Hi₈NO₂: 304.1338. Found: 304.1334.

Example 58: Methyl 2-phenyl-5-propyl-lH-pyrrole-3-carboxylate (41)

[00134] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as red oil. Yield 85%; Ή NMR (400 MHz, CDC1₃) δ 8.15 (s, 1H), 7.59 - 7.56 (m, 2H), 7.41 - 7.37 (m, 2H), 7.35 - 7.31 (m, 1H), 6.41 (d, 3.2 Hz, 1H), 3.72 (s, 3H), 2.56 (t, J= 7.6 Hz, 2H), 1.70 - 1.59 (m, 2H), 0.99 (t, J= 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDC1₃) δ 165.5, 135.9, 132.7, 132.3, 128.7, 128.2, 128.0, 1 1 1.6, 108.7, 50.9, 29.4, 22.5, 13.8; HRMS (ESI) m/z [M+H]+: Calcd for C,₅Hi₈N0₂: 244.1338. Found: 244.1334.

Example 59: Methyl 2-(furan-2-yl)-5-phenyl-lH-pyrrole-3-carboxylate (4e)

[00135] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as yellow solid. Mp. 134 - 135 °C. Yield 95%; Ή NMR (400 MHz, CDCI3) δ 9.12 (s, 1H), 7.55 - 7.53 (m, 3H), 7.45 - 7.39 (m, 3H), 7.29 - 7.26 (m, 1H), 6.96 (d, J= 2.8 Hz, 2H), 6.54 (dd, Jl = 3.2 Hz, J2 = 1.6 Hz, 1H), 3.88 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) 0 164.7, 145.8, 141.4, 131.5, 131.2, 129.1, 128.2, 127.2, 124.1, 112.5, 112.1, 1 10.9, 109.1 , 51.2; HRMS (ESI) m/z [M+H]+: Calcd for Ci₆H₁₄N0₃: 268.0974. Found: 268.0980.

Example 60: (E)-methyl 5-phenyl-2-styryl-lH-pyrrole-3-carboxylate (4f)

[00136] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as yellow oil. Yield 96%; Ή NMR (400 MHz, CDC1₃) δ 8.95 (s, 1H), 7.86 (d, J= 16.8 Hz, 1H), 7.56 - 7.54 (m, 4H), 7.51 - 7.23 (m, 6H), 6.93 (d, J = 2.8 Hz, 1H), 6.89 (d, J= 16.8 Hz, 1H), 3.87 (s, 3H); ¹ C NMR (100 MHz, CDC1₃) δ 165.5, 136.8, 135.5, 132.6, 131.3, 129.1, 128.8, 127.9, 127.6, 127.3, 126.6, 124.2, 117.6, 115.2, 109.0, 51.3; HRMS (ESI) m/z [M+H]+: Calcd for C₂₀H,₈NO₂: 304.1338. Found: 304.1336.

Example 61: Methyl 5-phenyl-2-(phenylethvnyn-lH-pyrrole-3-carboxylate(4g)

[00137] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as yellow solid. Mp : 175 - 176 °C. Yield 94%; ^!H NMR (400 MHz, CDC1₃) δ 8.84 (s, 1H), 7.58 - 7.56 (m, 2H), 7.53 - 7.51 (m, 2H), 7.44 - 7.35 (m, 5H), 7.32 - 7.30 (m, 1H), 6.95 (d, J= 2.8 Hz, 1H), 3.91 (s, 3H); ¹³C NMR (100 MHz, CDC1₃) 5 164.4, 133.1, 131.5, 130.8, 129.1, 128.7, 128.4, 127.6, 124.3, 122.6. 120.7, 117.7, 108.2, 95.2, 80.5, 51.4; HRMS (ESI) m/z [M+H]+: Calcd for C₂₀Hi₆NO₂: 302.1 181. Found:

302.1 171.

Example 62: Methyl 2-cyclohexyl-5-phenyl-lH-pyrrole-3-carboxylate (4h)

[00138] The title compound was prepared according to the general procedure (reaction at 60 °C). The product was obtained as white solid. Mp: 132 - 133 °C. Yield 74%; Ή NMR (400 MHz, CDC1₃) δ 8.46 (s, 1H), 7.46 - 7.44 (m, 2H), 7.38 - 7.34 (m, 2H), 7.24 - 7.20 (m, 1H), 6.82 (d, J= 3.2 Hz, 1H), 3.82 (s, 3H), 3.54 - 3.48 (s, 1H), 2.06 - 2.03 (m, 2H), 1.87 - 1.84 (m, 3H), 1.50 - 1.37 (m, 4H), 1.27 - 1.24 (m, 1H); ¹³C NMR (100 MHz, CDC1₃) δ 165.7, 145.8, 131.9, 129.8, 129.0, 126.6, 123.8, 11 1.6, 107.4, 50.8, 36.0, 32.6, 26.5, 26.1; HRMS (ESI) m z [M+H]+: Calcd for Ci₈H₂₂N0₂: 284.1651. Found: 284.1653. [00139] By "comprising" it is meant including, but not limited to, whatever follows the word "comprising". Thus, use of the term "comprising" indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present.

[00140] By "consisting of is meant including, and limited to, whatever follows the phrase "consisting of. Thus, the phrase "consisting of indicates that the listed elements are required or mandatory, and that no other elements may be present.

[00141] The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms "comprising", "including", "containing", etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

[00142] By "about" in relation to a given numberical value, such as for temperature and period of time, it is meant to include numerical values within 10% of the specified value.

[00143] The invention has been described broadly and generically herein. Each of the narrower species and sub-generic groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[00144] Other embodiments are within the following claims and non- limiting examples. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

Claims

Claims

1. A method for preparing 2H-azirine carboxylic esters of formula (I)

comprising: reacting odiazo-|3-keto oxime ether of formula (II)

R³

I

N O

N₂ (I I ) in the presence of a rhodium (Il)-based catalyst and an organic solvent, wherein

R¹ is a substituted or unsubstituted Cj-Cio alkyl, substituted or unsubstituted C₂-Ci₅ alkenyl, substituted or unsubstituted C₂-Ci₅ alkynyl, substituted or unsubstituted C₃-Ci₅ cycloalkyl, substituted or unsubstituted C₃-Ci₅ cycloalkenyl, substituted or unsubstituted C₃-Ci₅ heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, or substituted or unsubstituted C₆-Ci5 heteroaryl; R² is a substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted C₂-Ci₅ alkenyl, substituted or unsubstituted C₂-Ci₅ alkynyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C3-C15 heterocycloalkyl, substituted or unsubstituted C₃-Ci₅ heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, or substituted or unsubstituted C₆-Ci5 heteroaryl; and

R³ is a substituted or unsubstituted CJ -CJO alkyl, substituted or unsubstituted C2-C15 alkenyl, substituted or unsubstituted C3-C15 cycloalkyl, substituted or unsubstituted C3-C15 cycloalkenyl, substituted or unsubstituted C3-C15 heterocycloalkyl, substituted or unsubstituted C3-C15 heterocycloalkenyl, substituted or unsubstituted C₆-Ci5 aryl, substituted or unsubstituted C₆-Ci5 heteroaryl, or substituted or μnsubstituted C7-C 15 alkylaryl.

2. The method of claim 1, wherein the rhodium (Il)-based catalyst is rhodium (II) acetate [Rh₂(OAc)4], rhodium (II) pivalate [Rh₂(Piv)4], or rhodium (II) perfluorobutyrate

[Rh₂(pfb)₄].

3. The method of claim 2, wherein the rhodium (Il)-based catalyst is Rh₂(OAc)₄.

4. The method of claim 2, wherein the rhodium (Il)-based catalyst is Rh₂(Piv)₄.

5. The method of any one of claims 1 to 4, wherein the organic solvent is dichloroethane, benzene, toluene, 1,4-dioxane, chlorobenzene, (trifluoromethyl)benzene, or

tetrahydrofuran.

6. The method of claim 5, wherein the organic solvent is dichloroethane.

7. The method of any one of claims 1 to 6, wherein reacting comprises heating a-diazo-jS- keto oxime ether of formula (II) at a temperature range of between 50 and 80 °C.

8. The method of claim 7, wherein reacting comprises heating a-diazo-j3-keto oxime ether of formula (II) at 60 °C.

9. The method of claim 7 or 8, wherein heating of the odiazo-/3-keto oxime ether of formula (II) is carried out for a period of between 5 and 15 h.

10. The method of claim 9, wherein heating of the a-diazo-|3-keto oxime ether of formula (II) is carried out for 10 h.

11. The method of any one of claims 1 to 10, wherein R¹ of the -diazo-(3-keto oxime ether of formula (II) is

wherein the symbol " * " denotes the point at which R is connected to the carbon atom adjacent to the oxime ether in formula (II).

wherein the symbol " * " denotes the point at which R² is connected to the carbon atom of the carbonyl in formula (II).

The method of any one of claims 1 to 12, wherein R³ of the odiazo-/3-keto oxime ether of formula (II) is

wherein the symbol " * " denotes the point at which R is connected to the oxygen atom in formula (II).

14. The method of any one of claims 1 to 13, wherein the odiazo-/3-keto oxime ether of formula (II) is

59