Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• acetal group could be used as substrates in an aza-Nazarov cyclization with the intermediacy of in situ-generated N-acyliminium ions (Scheme 1b) [21]. The first catalytic aza-Nazarov reaction was reported by Tius and co-workers in 2010, which involved the kinetic resolution of azirine derivatives via an

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

• Ivan P. Mosiagin,
• Olesya A. Tomashenko,
• Dar’ya V. Spiridonova,
• Mikhail S. Novikov,
• Sergey P. Tunik and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2021, 17, 1490–1498, doi:10.3762/bjoc.17.105

• developed protocol doesn’t require column chromatography for purification of target compounds 3 and can be performed in a gram scale. Pyridinium bromides 1a–l,n–w and iodide 1m were prepared by the reaction of 3-(2-bromophenyl)-2H-azirine (4a) with substituted N-phenacyl pyridinium salts 5a–w according to

• bromide 8, functionalized with an alkoxycarbonyl group at the C1 position, was also synthesized by the developed approach, starting from azirine 4b (Scheme 3). Iodo-substituted salt 2 should be more reactive towards cyclization as compared to its bromo-analogue, and this can be used to control the

A sustainable strategy for the straightforward preparation of 2H-azirines and highly functionalized NH-aziridines from vinyl azides using a single solvent flow-batch approach

• Michael Andresini,
• Leonardo Degannaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2021, 17, 203–209, doi:10.3762/bjoc.17.20

• flow procedures involved acetonitrile, dichloromethane and acetone as solvents, however, incompatible with the utilization of reactive alkali organometals. An exception is made for toluene, used by Kirschning for the photoinduced azirine formation [27]. Therefore, we investigated the thermally induced

• , 3-(o-tolyl)-2H-azirine (2d) and 2,3-diphenyl-2H-azirine (2l) were also obtained in excellent yields. When 1-(1-azidovinyl)-2,3,4,5,6-pentafluorobenzene (1k) was reacted under optimal flow conditions, a mixture of 1k and 2H-azirine 2k (20:80 ratio) was recovered. Unfortunately, it was not possible to

• isolate 3-(perfluorophenyl)-2H-azirine (2k) due to its rapid polymerization in the crude mixture. Interestingly, aliphatic vinyl azides 1h–j were found less reactive, and the corresponding azirines 2h–j were obtained in just 74–77% yield, in mixtures with unreacted starting materials. However, when the

Access to highly substituted oxazoles by the reaction of α-azidochalcone with potassium thiocyanate

• Mysore Bhyrappa Harisha,
• Pandi Dhanalakshmi,
• Rajendran Suresh,
• Raju Ranjith Kumar and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2020, 16, 2108–2118, doi:10.3762/bjoc.16.178

• 058, India Department of Inorganic and Physical Chemistry, Indian Institute of Science (IISc), Bangalore-560 012, India 10.3762/bjoc.16.178 Abstract The reactivity of α-azidochalcones has been explored for the preparation of highly substituted oxazoles via a 2H-azirine intermediate. The

• ; potassium persulfate; thiazole; vinyl azide; Introduction Vinyl azide is one of the most versatile and potent building blocks explored in the synthesis of several heterocycles [1][2][3][4][5]. It can undergo photolysis or thermolysis to afford highly strained three-membered 2H-azirine, which can act as the

• -azirine, an efficient source of nitrogen, was employed as starting material for the synthesis of oxazole with various coupling partners such as aldehyde, trifluoroacetic acid, etc. [8][45][46][47][48][49][50] (Scheme 1). Thiazole is a common structural motif that is found in a wide variety of naturally

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• the [3 + 2]-cycloaddition of electron-poor alkynes and 2H-azirines [60]. The reaction is performed under blue LED irradiation and using acridinium salts as a photocatalyst (Scheme 15). With respect to 2H-azirine the scope of the reaction is demonstrated to be relatively broad, with aromatics

• . Aliphatic and heteroaromatic substituents on the 2H-azirine were not tolerated. The aldehyde substituents are much more diverse, with a variety of substituted benzenes, heteroaromatics, carbonyls and aliphatic side chains undergoing the cycloaddition. Overall, these two methods provide much more mild

Synthesis of trifluoromethylated 2H-azirines through Togni reagent-mediated trifluoromethylation followed by PhIO-mediated azirination

• Jiyun Sun,
• Xiaohua Zhen,
• Huaibin Ge,
• Guangtao Zhang,
• Xuechan An and
• Yunfei Du

Beilstein J. Org. Chem. 2018, 14, 1452–1458, doi:10.3762/bjoc.14.123

• (PhIO)-mediated intramolecular azirination in a one-pot process. Keywords: azirination; 2H-azirine; iodosobenzene; Togni reagent; β-trifluoromethylation; Introduction The trifluoromethyl group is a striking structural motif, which can be widely found in the fields of pharmaceutical and agrochemical

• [52][53][54][55] have been developed for accessing this exclusive class of heterocycles. In our previous works, we have realized the application of hypervalent iodine reagents for the construction of the 2H-azirine skeleton starting from enamines 2 via intramolecular oxidative cyclization (Scheme 1

• , R2 = H) with PhIO in 2,2,2-trifluoroethanol (TFE) afforded 2-trifluoroethoxy-2H-azirines 4 [57]. The latter process involves an intermolecular oxidative trifluoroethoxylation and the subsequent oxidative intramolecular azirination. In continuation of our interest in the construction of the 2H-azirine

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

• Thaís A. Rossa,
• Nícolas S. Suveges,
• Marcus M. Sá,
• David Cantillo and
• C. Oliver Kappe

Beilstein J. Org. Chem. 2018, 14, 506–514, doi:10.3762/bjoc.14.36

• from vinyl azides through an azirine intermediate (Scheme 3). The process starts with the generation of the azirine from the vinyl azide by thermolysis. Formation of azirines from vinyl azides by photolysis and thermolysis in continuous flow has been previously described [38][39]. The azirine

• fully continuous process are described in detail. Results and Discussion Thermolysis of the vinyl azide and oxazole formation. Batch optimization The reaction conditions for the thermolysis of the vinyl azide and the subsequent ring expansion of the intermediate azirine to form the oxazole ring were

• -(bromomethyl)oxazole 6a from azirine 2a was also optimized under batch conditions. All reactions were carried out under an argon atmosphere using a 0.5 M solution of the substrate 2a in acetone. In general, the addition of the reagents was performed at 0 °C in an ice-bath followed by stirring the reaction

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

• Lena Huck,
• Juan F. González,
• Elena de la Cuesta and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2016, 12, 1772–1777, doi:10.3762/bjoc.12.166

• loss of a molecule of methanol, to furnish azirine 5. Finally, addition of the methanol released in the previous step to the highly strained intermediate 5 would take place anti to the R1 substituent, explaining the observed diastereoselection. This proposal was supported by the isolation of one of its

Investigation on the reactivity of α-azidochalcones with carboxylic acids: Formation of α-amido-1,3-diketones and highly substituted 2-(trifluoromethyl)oxazoles

• Kandasamy Rajaguru,
• Arumugam Mariappan,
• Rajendran Suresh,
• Periasamy Manivannan and
• Shanmugam Muthusubramanian

Beilstein J. Org. Chem. 2015, 11, 2021–2028, doi:10.3762/bjoc.11.219

• Abstract The reaction of α-azidochalcones with carboxylic acids has been investigated resulting in the formation of α-amido-1,3-diketones under microwave irradiation via in situ formation of 2H-azirine intermediates. An interesting reaction is described wherein, with trifluoroacetic acid at lower

• . The N-(2-keto)amide skeleton is of particular interest, as it serves as a synthetic precursor for various small heterocyclic compounds such as imidazoles, oxazoles and thiazoles [7][8][9]. Azirine, the smallest nitrogen-containing unsaturated three-membered heterocyclic system, is well known as a

• -azirines are impressive intermediates for the synthesis of various substituted heterocyclic compounds [23][24][25]. Nucleophiles can interact with the electrophilic carbon of the strained 2H-azirine rings and due to the ring strain in the three-membered 2H-azirine ring system A1, the electrophilic

Fe(II)/Et₃N-Relay-catalyzed domino reaction of isoxazoles with imidazolium salts in the synthesis of methyl 4-imidazolylpyrrole-2-carboxylates, its ylide and betaine derivatives

• Ekaterina E. Galenko,
• Olesya A. Tomashenko,
• Alexander F. Khlebnikov,
• Mikhail S. Novikov and
• Taras L. Panikorovskii

Beilstein J. Org. Chem. 2015, 11, 1732–1740, doi:10.3762/bjoc.11.189

• -imidazoles based on the formation of a pyrrole ring via the reaction of 2H-azirines with 1-alkyl-3-phenacyl-1H-imidazolium bromides [29], in which one example of the synthesis of ethyl 4-imidazolylpyrrole-2-carboxylate from ethyl 3-methyl-2H-azirine-2-carboxylate was described. Earlier it was found that

• alkyl 2H-azirine-2-carboxylates can be prepared by isomerization of 5-alkoxyisoxazoles under Fe(II)-salt catalysis [30]. Quite recently this isomerization has been used for the preparation of substituted pyrrole-2-carboxylic acid derivatives by the domino reaction of 3-aryl-5-methoxyisoxazoles with 1,3

• according to Scheme 2, whereby excluding the isolation of often unstable 2H-azirines [34]. Results and Discussion The synthetic scheme (Scheme 2) implies an implementation of all stages (1: generation of azirine 8 from isoxazole 7 under FeCl2 catalysis; 2: formation of phenacylimidazolium ylide 10 induced

Azirinium ylides from α-diazoketones and 2H-azirines on the route to 2H-1,4-oxazines: three-membered ring opening vs 1,5-cyclization

• Nikolai V. Rostovskii,
• Mikhail S. Novikov,
• Alexander F. Khlebnikov,
• Galina L. Starova and
• Margarita S. Avdontseva

Beilstein J. Org. Chem. 2015, 11, 302–312, doi:10.3762/bjoc.11.35

• ; Introduction 2H-Azirines are unique strained compounds which have found various applications in organic synthesis due to their ability to react both with retention and opening of the three-membered ring. Even though each of the three bonds in the azirine ring can be cleaved under certain conditions, the

• at all. Our study of the chemical behavior of 2H-azirines under Rh(II)-catalyzed decomposition of diazoketones was started with searching for optimal conditions for the catalytic reaction of 2,3-diphenyl-2H-azirine (1a) with 1-diazo-1-phenylpropan-2-one (2a), leading to oxazine 4a. The most

• successful procedure involving addition of Rh2(OAc)4 to a boiling 1:1.25 mixture of azirine 1a and diazo compound 2a in 1,2-dichloroethane (DCE) (procedure A) gave rise to oxazine 4a and azadiene Z-3a in 60 and 7% yields, respectively (Scheme 2, Table 1, entry 1). It was also shown that azadiene Z-3a did not

Isoxazolium N-ylides and 1-oxa-5-azahexa-1,3,5-trienes on the way from isoxazoles to 2H-1,3-oxazines

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Yelizaveta G. Gorbunova,
• Ekaterina E. Galenko,
• Kirill I. Mikhailov,
• Viktoriia V. Pakalnis and
• Margarita S. Avdontceva

Beilstein J. Org. Chem. 2014, 10, 1896–1905, doi:10.3762/bjoc.10.197

• isoxazoles capable of providing stable 1-oxa-5-azahexa-1,3,5-trienes D under reaction with diazo esters and by comparing the experimental results of the reactions of carbenoids with a complementary pair of isoxazole and azirine. An analysis of recent literature shows that 2H-1,3-oxazine derivatives exhibit

• “one-step oxazahexatriene mechanism” of carbenoid-mediated isoxazole ring expansion originates from the results of the interaction of diazo compounds 2a–c with the complimentary isoxazole 1a and azirine 5 (Scheme 5). The reaction of isoxazoles with a carbenoid can only give a (3Z)-1-oxa-5-azahexa-1,3,5

• -triene due to geometrical restrictions. (3Z)-1-Oxa-5-azahexa-1,3,5-triene can then cyclize into the corresponding oxazine, so that the products of the reaction of isoxazole 1a with diazo compounds 2a–c were only oxazines 3a–c (Table 2). In contrast, azirinium ylides 6a–c formed by the reaction of azirine

Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Viktoriia V. Pakalnis,
• Roman O. Iakovenko and
• Dmitry S. Yufit

Beilstein J. Org. Chem. 2014, 10, 784–793, doi:10.3762/bjoc.10.74

• compounds, with a new heterocyclic skeleton, are the result of the coupling of two molecules of azirine and two molecules of acylketene and can be prepared only from 3-aryl-2H-azirines having no electron-withdrawing groups in the aryl substituent. Calculations at the DFT B3LYP/6-31G(d) level for the various

• : acylketene; azirine; domino reaction; furandione; Introduction 2H-Azirines, the most strained nitrogen unsaturated heterocyclic systems, are versatile building blocks for the construction of various heterocyclic nitrogen-containing compounds. Because 2H-azirines contain an activated C=N double bond and a

• -azabicyclo[4.4.1]undeca-3,8-diene) derivatives of 4,11-dioxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-5,12-diene, a new heterocyclic system, were formed. Boiling a benzene solution of furan-2,3-dione 1a and azirine 2a (1:1) for 0.5 h gave a mixture of compounds 3a–5a, which were isolated by column

[3 + 2]-Cycloadditions of nitrile ylides after photoactivation of vinyl azides under flow conditions

• Stephan Cludius-Brandt,
• Lukas Kupracz and
• Andreas Kirschning

Beilstein J. Org. Chem. 2013, 9, 1745–1750, doi:10.3762/bjoc.9.201

• pyrex filter. Test reactions conducted either in benzene or in toluene resulted exclusively in the formation of the corresponding 2H-azirine 2a in yields up to 95%, while no formation of the cycloaddition product was encountered (Table 2; entries 1 and 2). 2a could easily be identified by the signal at

Continuous flow photolysis of aryl azides: Preparation of 3H-azepinones

• Farhan R. Bou-Hamdan,
• François Lévesque,
• Alexander G. O'Brien and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2011, 7, 1124–1129, doi:10.3762/bjoc.7.129

• expansion of 12, via 2H-azirine 3, affords didehydroazepine 4, which can be trapped by variety of nucleophiles to provide the corresponding azepine 5. Alternatively, intersystem crossing (ISC) of 12 gives rise to 32, which can dimerize to form diazo compound 6. Performing the reaction in the presence of