Oxetanes: formation, reactivity and total syntheses of natural products

• Peter Gabko,
• Martin Kalník and
• Maroš Bella

Beilstein J. Org. Chem. 2025, 21, 1324–1373, doi:10.3762/bjoc.21.101

• conditions and exhibits excellent functional group tolerance (demonstrated by synthesising a large library of azetidine analogues), but tends to deliver the oxetane products in rather low yields due to fragmentation of the biradical intermediate 67 through a Norrish-type II process. 1.3 [2 + 2

Giese-type alkylation of dehydroalanine derivatives via silane-mediated alkyl bromide activation

• Perry van der Heide,
• Michele Retini,
• Fabiola Fanini,
• Giovanni Piersanti,
• Francesco Secci,
• Daniele Mazzarella,
• Timothy Noël and
• Alberto Luridiana

Beilstein J. Org. Chem. 2024, 20, 3274–3280, doi:10.3762/bjoc.20.271

• like the azetidine in compound 16 (56%) and the piperidine in compound 17 (67%) also resulted in good yields. Concerning tertiary alkyl substrates, acyclic alkyl substrates used in compound 19 (68%) and 20 (53%) as well as cyclic alkyl substrates like bromomethylcyclohexane used in compound 21 (61

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• single-crystal X-ray diffraction analysis. The reaction of azetidine with diacyl chloride 2a gave a complex mixture of products, and O-methyl hydroxylamine did not react. Diacyl chloride 2a reacts with methanol and ethanol to give diesters 11a,b (Scheme 5). An experiment with isoxazole 1a and methanol on

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• . Key to the successful development of this two-step process is the identification of a benzhydryl-protecting group, which orchestrates the photochemical Norrish–Yang cyclization and facilitates the subsequent ring opening. Keywords: azetidine; Norrish–Yang cyclization; ring-opening reaction; ring

• synthesis of azetidinols. Mechanistically, the Norrish–Yang cyclization involves a 1,5-hydrogen abstraction (HAT) step followed by ring closure to forge the azetidine scaffold (Scheme 2a, 1 → 3, via 1,4-biradical 2) [26]. The respective α-aminoacetophenones 1 were synthesized using a modular approach

• chosen as a preferred solvent because it is known to facilitate Norrish–Yang-cyclizations and allows simple analysis by nuclear magnetic resonance (NMR) spectroscopy [10]. Our results are summarized in Table 1. When p-toluenesulfonyl (Ts) was used as a PG at nitrogen, azetidine 3a was obtained in 81

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• (2e) were used. The corresponding products 5nb, 5ob and 5ec were achieved in 63, 51 and 49% yields, respectively. 1-Boc-azetidine-3-carboxylic acid (2i) also gave the corresponding product 5ib in 54% yield. Considering the carbonyl component, 1-chloropropan-2-one (3a) was used to access the

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• approximately 1 hour of continuous electrolysis; therefore, we then attempted to synthesize pyrrolidine and azetidine derivatives (3b and 3c) using the same procedure (entries 2 and 3 of Table 8). 3b was obtained from imine 1 and dihaloalkane 2d with a good isolated yield (57%, 75.8 mg). However, the azetidine

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• blocks was developed. Regioisomeric methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC

• ). The 1H NMR spectrum of compound 3a showed the appearance of a new downfield enamine proton signal which resonated at δ 7.80 ppm. The connectivity of the β-enamino ketoester moiety and the N-Boc-protected azetidine fragment were easily confirmed based on long-range 1H,13C correlations, obtained from gs

• -HMBC spectra. The aforementioned enamine proton and protons 2’(4’)-H (δ 4.00-4.09 ppm) from the azetidine ring system shared the HMBC cross-peak with the ketone carbonyl carbon (δ 195.4 ppm). Finally, in the 1H,15N-HMBC spectrum of 3a, an expected long-range correlation between the enamine proton (δ

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• azetidines Azetidine [76][77] has attracted less attention than aziridines, pyrrolidines and piperidines, among small and medium size aza-heterocycles, because there are no general methods for their preparation. However, four-membered nitrogen-containing heterocycles have recently found applicability in

• this case from 1-Boc-azetidine-3-carboxylate 46, instead of ethyl cyclobutanecarboxylate 43 [82]. This structural motif was found to have similar physicochemical properties as 2-substituted piperazines, which are key intermediates in drug discovery. The applied protocol was found to be practical for

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• achiral aldehydes (azetidine cores 25 and 27). Furthermore, key to success of the Horner–Wadsworth–Emmons olefination was premixing of the aldehyde and phosphonate 7 prior to the addition of KOt-Bu. Upon deprotonation, phosphonate 7 (in the absence of aldehyde) underwent dimerisation to olefin 28. While

Synthesis of a dihalogenated pyridinyl silicon rhodamine for mitochondrial imaging by a halogen dance rearrangement

• Jessica Matthias,
• Thines Kanagasundaram,
• Klaus Kopka and
• Carsten S. Kramer

Beilstein J. Org. Chem. 2019, 15, 2333–2343, doi:10.3762/bjoc.15.226

• quantum yields up to 0.67. As described previously, azetidine substituents at the xanthene moiety of 5, 7, and 9 lead to an improved quantum yield and to a red shift in comparison to the N,N-dimethylaniline analogues 1, 3, and 4 (Table 1, entry 1 vs 5, 3 vs 7, and 4 vs 9). In contrast, the 4

• -fluoroazetidine moiety in 10 (“JF635”) causes a hypsochromic shift without affecting the high quantum yield compared to the azetidine analogue 9 (“JF646”) (Table 1, entry 9 vs 10). Comparing the phenyl substituted rhodamine 2 with its 2’-methyl substituted analogue 3, restricted rotation around the xanthene

• above, the pyridinyl-substituted silicon rhodamines 13 and 14 are dyes with spectral properties in the near-infrared region. Dye 14 possess the higher quantum yield not only due to the azetidine substituents at the xanthene moiety, but also because of the restricted bond rotation owing to the 3’-methyl

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• protonation using a fully substituted alkene. Nitroalkenes that were activated by the incorporation of an oxetane or N-Boc-azetidine ring at the β-position reacted well with both thioacetic acid and thiobenzoic acid (Scheme 38a). Various R2 substituents were compatible with the reaction, including an

• isopropyl group and a pendent methyl ester. Generally, the azetidine nitroalkenes provided the 1,2-nitrothioacetates in higher yields and enantioselectivity (81–99% yield, 95:5 to 98:2 er). The oxetane and N-Boc azetidine nitroalkenes were activated toward conjugate addition by the release of ring-strain

cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57

• Pro structural analogues, azetidine-2-carboxylic acid (norproline) and pipecolic acid (homoproline) [4], it appears that the high isomerization barrier is a feature associated with the 5-membered pyrrolidine ring of Pro [5]. The pyrrolidine ring of Pro can be found in several conformations, designated

Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• reacted with azetidine-2,3-diones 176 under eco-friendly reaction conditions to generate bis(allene) 177. Compound 177 was then converted into bis(dihydrofuran) 178 by using AuCl3. Macrocyclization of 178 was carried out by using a Ru(II) or Ru(III) catalyst to generate 179 as a mixture of E/Z isomers

Metal-free one-pot synthesis of 2-substituted and 2,3-disubstituted morpholines from aziridines

• Hongnan Sun,
• Binbin Huang,
• Run Lin,
• Chao Yang and
• Wujiong Xia

Beilstein J. Org. Chem. 2015, 11, 524–529, doi:10.3762/bjoc.11.59

• . Furthermore, a range of optically pure morpholines could be achieved by the use of chiral aziridines. Experimental General procedure for the one-pot synthesis of morpholines: A 10 mL round bottom flask equipped with a magnetic stirring bar was charged with aziridine/azetidine 1 (0.3 mmol, 1 equiv), (NH4)2S2O8

Stereocontrolled synthesis of 5-azaspiro[2.3]hexane derivatives as conformationally “frozen” analogues of L-glutamic acid

• Beatrice Bechi,
• David Amantini,
• Cristina Tintori,
• Maurizio Botta and
• Romano di Fabio

Beilstein J. Org. Chem. 2014, 10, 1114–1120, doi:10.3762/bjoc.10.110

• rotation around the C3–C4 bond present in the azetidine derivative Ia by incorporating an appropriate spiro moiety. The cyclopropyl moiety was introduced by a diastereoselective rhodium catalyzed cyclopropanation reaction. Keywords: Amino acids; carbenes; cyclopropanation; rhodium; spiro compounds

• bioactive conformations [19]. Following the latter approach, Ib, shown in Figure 1, was designed as a novel potential ligand of the L-Glu receptors and building block for peptidomimetics. To the best of our knowledge, few structurally related azetidine derivatives 10a,b,11a,b and Ia [20][21][22], have been

• reported to date. The preparation of compound Ib appears challenging due to both the need to control the stereochemistry of three contiguous chiral centers and the presence of a [2.3]-spiro junction connecting the cyclopropane moiety with a highly functionalized azetidine ring. Here, we describe the

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• with Triton B and TBHP yielded the epoxide resulting from top-face attack. The surplus Cbz-group was then deprotected using TMSI [167][168]. The final azetidine formation took place upon refluxing in ethanol to give gelsemoxonine (197). Further synthetic applications The group of Wender applied the

Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

• Ouldouz Ghashghaei,
• Consiglia Annamaria Manna,
• Esther Vicente-García,
• Marc Revés and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2014, 10, 12–17, doi:10.3762/bjoc.10.3

• interest in the azetidine scaffold in medicinal chemistry [9], we decided to study in detail the formation of bis(imino)azetidines 3 from the interaction of imines 1 and isocyanides 2 (Scheme 1), including the scope of the reaction and mechanistic features of this interesting ABB’ process [10]. Results and

• corresponding aldehyde and aniline. It was found that the best conditions were obtained using BF3·Et2O as the activating agent in stoichiometric amounts in THF, at rt for 24 hours or under MW irradiation for 30 min at 65 °C, allowing the formation of the expected azetidine 3a in 43% and 48%, respectively

• ]. In a different experiment, the addition of a 9-fold excess of isocyanide 2a to the imine 1a under the usual conditions led to detection of tris(imino)pyrrolidine 5 (9%) as the minor product, and azetidine 3a as the major component (24%, Scheme 2). Structural elucidation Although we could confirm the

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• the conformations of N-heterocycles 3.1 Four-membered rings O’Hagan and co-workers observed an interesting conformational effect in a computational study of fluorinated azetidine derivatives (Figure 2) [20]. The neutral molecule 6 was calculated to prefer a ring pucker which placed the fluorine atom

• ]. More generally however, it seems safe to predict that the unique properties of stereoselectively fluorinated N-heterocycles will ensure that their importance and utility continue to grow in the future. Fluorination alters the reactivity of aziridines. The ring pucker in azetidine derivatives can be

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• -step sequence yielded azetidine 107. After oxidation with hydrogen peroxide, the resulting N-oxide cleanly underwent a [1,2]-Meisenheimer rearrangement upon heating in tetrahydrofuran. The so-formed azocine 108 was converted to amine 109 by hydrogenolysis of the N–O bond. Amide formation with acid

Cation affinity numbers of Lewis bases

• Christoph Lindner,
• Raman Tandon,
• Boris Maryasin,
• Evgeny Larionov and
• Hendrik Zipse

Beilstein J. Org. Chem. 2012, 8, 1406–1442, doi:10.3762/bjoc.8.163

• kJ/mol. In the case of saturated, acyclic substituents the trend ‘longer alkyl chains – higher MCA values’ is again observed (Figure 6). For saturated, cyclic substituents, however, the MCA values increase from aziridine (134) to azetidine (140) and pyrrolidine (148), but then decrease again for

Carbohydrate-auxiliary assisted preparation of enantiopure 1,2-oxazine derivatives and aminopolyols

• Marcin Jasiński,
• Dieter Lentz and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2012, 8, 662–674, doi:10.3762/bjoc.8.74

• –carbon bonds [52][53][54], the cleavage of N–O bonds in a chemoselective fashion is also well documented [55][56][57]. The application of samarium diiodide for 1,2-oxazine ring opening allowed efficient syntheses of numerous polyhydroxylated heterocycles, such as pyrrolidine [46], azetidine [47], furan