Copper-catalyzed domino cyclization of anilines and cyclobutanone oxime: a scalable and versatile route to spirotetrahydroquinoline derivatives

• Qingqing Jiang,
• Xinyi Lei,
• Pan Gao and
• Yu Yuan

Beilstein J. Org. Chem. 2025, 21, 749–754, doi:10.3762/bjoc.21.58

• the desired product. Keywords: copper catalysis; cyclobutane-fused tetrahydroquinolines; domino cyclization reaction; green synthesis; Introduction Tetrahydroquinolines (THQs) represent a privileged scaffold in medicinal chemistry, exhibiting a broad spectrum of biological activities and serving as

• utility and scalability [9][10][11][12][13][14][15][16][17][18][19][20]. Cyclobutane-fused tetrahydroquinolines (THQs) have garnered significant attention in drug discovery due to their inherent structural rigidity and enhanced pharmacological profiles [21], which render them highly desirable for

• therapeutic development. The strained cyclobutane ring, in particular, acts as a versatile and conformationally constrained building block, enabling the construction of complex molecular architectures with potent biological activities [22]. Despite their promise, the synthesis of cyclobutane-fused THQs

Photomechanochemistry: harnessing mechanical forces to enhance photochemical reactions

• Francesco Mele,
• Ana M. Constantin,
• Andrea Porcheddu,
• Raimondo Maggi,
• Giovanni Maestri,
• Nicola Della Ca’ and
• Luca Capaldo

Beilstein J. Org. Chem. 2025, 21, 458–472, doi:10.3762/bjoc.21.33

• surface area exposed to light but also to allow the motions within the crystal. In another instance, MacGillivray and colleagues reported the synthesis of rctt-tetrakis(4-pyridyl)cyclobutane (2.3) via [2 + 2] photodimerization of trans-1,2-bis(4-pyridyl)ethylene (2.1) via supramolecular catalysis by 4,6

• -dichlororesorcinol (2.2) in the solid state (Scheme 2) [64]. The authors noticed that single crystals of 2.1·2.2 (1:1 stoichiometry) produced by mortar-and-pestle grinding undergo a single-crystal-to-single-crystal (SCSC) transformation when exposed to UV light (medium-pressure Hg lamp). The cyclobutane 2.3 was

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• aryl ((±)-54a) and heteroaryl ((±)-54b) substituted 1,2-BCHs. As an alternative synthesis of 1,2-BCHs, and importantly also enantioenriched examples, Qin and co-workers developed an intramolecular coupling of cyclobutane-tethered sulfonylhydrazones and boronic esters (not shown) [41]. They also

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• Astericus aquaticus (Asteraceae) which possesses a unique backbone featuring a cyclobutane moiety fused to a cyclopentane ring, a γ-lactone, and an eight-membered enone [60][61]. Zhang and Gu achieved its preparation through the use of a late-stage intramolecular NHK reaction (Scheme 23) [62]. Thus, when

• articulated around a ring expansion of a fused cyclobutane/perhydroindanone fragment, leading to the cyclooctane motif. Interestingly, and unlike the previously reported strategies, the perhydroindanone precursor was prepared starting from achiral building blocks 157 and 158. They were engaged in a selective

• formation of the fused cyclobutane acid 162 as the desired precursor for the cyclooctane formation. The ring expansion was achieved in the presence of an iridium catalyst and under blue LED irradiation, via the trapping by TEMPO or O2 of the cyclobutyl radical resulting from decarboxylation, which allowed a

Radical cation Diels–Alder reactions of arylidene cycloalkanes

• Kaii Nakayama,
• Hidehiro Kamiya and
• Yohei Okada

Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112

• decrease the steric hindrance at the β-position and improve the reaction. Unfortunately, the arylidene cyclopropane 4 was found to be totally unreactive under both conditions (Scheme 3). However, to our surprise, the arylidene cyclobutane 5 was found to be productive and the corresponding spiro ring

• electrochemistry in many cases for these dienophiles, which accords well with our previous reports. The ring size effect of cycloalkanes was also clearly observed and cyclobutane was much more effective than the others. A similar trend was observed using some heterocycles, which also accorded well with the

• material is reported in parentheses. Scope of the radical cation Diels–Alder reaction of arylidene cycloalkanes (recovered starting material is reported in parentheses). Control studies for the radical cation Diels–Alder reaction of the arylidene cyclobutane 5. Supporting Information Supporting

Unusual highly diastereoselective Rh(II)-catalyzed dimerization of 3-diazo-2-arylidenesuccinimides provides access to a new dibenzazulene scaffold

• Anastasia Vepreva,
• Alexander S. Bunev,
• Andrey Yu. Kudinov,
• Grigory Kantin,
• Mikhail Krasavin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2022, 18, 533–538, doi:10.3762/bjoc.18.55

• ortho-methyl substituent in the benzylidene fragment. In this case, along with conventional reaction products ‒ dimer 2r and indene 3r, unexpectedly the cyclobutane 5, a product of the formal [2 + 2] cycloaddition, was isolated in low yield (Scheme 1); its structure was confirmed by single-crystal X-ray

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• ) [13]. Interestingly, when this mixture was subjected to silica gel chromatography, not only could the isomers of 38 not be separated, they also underwent silica-catalyzed α-ketol rearrangement to cyclobutane 39. This rearrangement, however, was of no consequence because addition of sodium methoxide to

• ring strain from cyclobutane derivatives has been developed by Cheng et al. to prepare functionalized α-amino cyclopentanones [31]. In the presence of a palladium catalyst, an electron-rich heteroarene 115 first adds to the nitrile group in a 1-cyanocyclobutyl ester 116 to give a tetrahedral imine

• cyclobutane derivatives (Figure 21b), highlighting the importance of the relief of ring strain in driving the rearrangement [31]. Like their α‑ketol counterparts, rearrangements of α‑iminols have also been used in total syntheses. In their total synthesis of four eburnane-type alkaloid natural products 122

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• efficiently utilized for the synthesis of highly strained tricyclo[5.2.1.01,6]decene intermediate 214 containing a cyclobutane ring (Scheme 64). Compound 213 is an important precursor for the asymmetric total synthesis of solanoeclepin A. The formation of β-hydroxyketone 213 was achieved by Hg(TFA)2-mediated

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

• , appears to be the most promising conformationally constrained PNA analogue. Vilaivan and co-workers developed pyrrolidinyl PNA based on an α/β-dipeptide backbone that is one atom longer than the canonical PNA and contains two amide bonds and two cyclic moieties in one monomer (Figure 4) [61]. Cyclobutane

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• hydrogen atoms from thiophenol to produce the final product 47 (Scheme 17). In 2020, Alemán and colleagues [53] proposed an approach in which ketene 48 and diene 49 condense with the help of diamine 51 to afford cyclobutane product 50 (Scheme 18). The reaction could be catalyzed by a simple diamine due to

• initiated by an EDA complex. Mechanism of the synthesis of spirocyclic indoline derivative 47. Synthesis of cyclobutane product 50 initiated by an EDA complex. Mechanism of the synthesis of spirocyclic indoline derivative 50. Synthesis of 1,3-oxazolidine compound 59 initiated by an EDA complex. Synthesis of

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

• Minzan Zuo,
• Krishnasamy Velmurugan,
• Kaiya Wang,
• Xueqi Tian and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• + and crown ether, leading to the formation of cyclobutane in a high yield. D’Souza et al. constructed a photosynthetic triad 4 to mimic the photosynthetic reaction center [19]. A BODIPY, an ammonium-functionalized fullerene, and a zinc porphyrin functioned as the energy donor, electron acceptor, and

• photochemical synthesis of an unsymmetrical cyclobutane” by O. Fedorova et al., Photochem. Photobiol. Sci. vol. 6, issue 10, © 2007); permission conveyed through Copyright Clearing Center, Inc. Energy transfer system constructed of a BODIPY–zinc porphyrin–crown ether triad assembly bound to a fulleropyrrolidine

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• to allenes 80 to give complex bicyclic products 81 in moderate yields and good enantioselectivities (20 examples, up to 92:8 er) (Scheme 9b) [47]. The Bach group recently developed an enantioselective synthesis of cyclobutane 82 from enal 83 and diene 84 (Scheme 11a) [48]. Most of the examples

• energy charge transfer state that can be photoexcited to generate singlet intermediate 89*. Subsequent enantioselective photocycloaddition with 88 via diradical 90 gives iminium ion intermediate 91, which after hydrolysis affords the desired cyclobutane products 92 in excellent yields and good

• ] photocycloaddition of quinolone 170. The proposed mechanism proceeds via hydrogen-bonded complex 171, which is sensitised by the pendant benzophenone to its triplet excited state 171*. The following cycloaddition completes the cycle and generates the desired cyclobutane product 173 in excellent conversion but poor

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• 1а with pinacol 2-phenylethynyl boronate. The meta-methoxystyryl derivative 5c was found to easily undergo photodimerization in solid state upon sunlight exposure, leading to the formation of compound 8 with a central cyclobutane ring (see Supporting Information File 1). As proved previously for

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

• from that of enones. The latter underwent the [2 + 2] annulation with olefins at their olefinic center to yield cyclobutane derivatives, and rarely undergo oxetane formation completely. The reaction parameters such as solvent affected the balance between the cyclobutane and oxetane formation. Whereas

Photocatalysis with organic dyes: facile access to reactive intermediates for synthesis

• Stephanie G. E. Amos,
• Marion Garreau,
• Luca Buzzetti and
• Jerome Waser

Beilstein J. Org. Chem. 2020, 16, 1163–1187, doi:10.3762/bjoc.16.103

Synthesis of esters of diaminotruxillic bis-amino acids by Pd-mediated photocycloaddition of analogs of the Kaede protein chromophore

• Esteban P. Urriolabeitia,
• Pablo Sánchez,
• Alexandra Pop,
• Cristian Silvestru,
• Eduardo Laga,
• Ana I. Jiménez and
• Carlos Cativiela

Beilstein J. Org. Chem. 2020, 16, 1111–1123, doi:10.3762/bjoc.16.98

• -face arrangement, which is optimal for their [2 + 2] photocycloaddition. Irradiation of dimers 3 in CH2Cl2 solution with blue light (465 nm) promoted the chemo- and stereoselective [2 + 2] photocycloaddition of the exocyclic C=C bonds and the formation of cyclobutane-containing ortho-palladated

• , harsh irradiation conditions and low yields) [16][20], or (b) the direct [2 + 2] cycloaddition does not take place and it is necessary to synthesize a cyclobutane precursor and then functionalize it, thus increasing the number of reaction steps, the waste material, and decreasing the global yield [16

• -palladated cyclobutane derivatives 4a–f and 4h–j, as shown in Scheme 2. Complexes 4a–f and 4h–j were obtained as air- and moisture-stable solids in good to very good yields. This also applied to the synthesis of 4h, which was performed at scale of 2 mmol (instead of 0.2 mmol in most of the other cases) and

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• chiral cyclobutene 180, providing highly functionalized cyclobutanes 182 and an access to the enantioenriched cyanosulfones 183, resulting from cyclobutane ring opening, or the new tetrasubstituted cyclobutanes 184 (Scheme 42). The cyclobutenes 180 were subjected to a photocatalyzed radical addition, and

Reversible photoswitching of the DNA-binding properties of styrylquinolizinium derivatives through photochromic [2 + 2] cycloaddition and cycloreversion

• Sarah Kölsch,
• Heiko Ihmels,
• Jochen Mattay,
• Norbert Sewald and
• Brian O. Patrick

Beilstein J. Org. Chem. 2020, 16, 111–124, doi:10.3762/bjoc.16.13

• Information File 1). However, it was observed that further irradiation of the nitro-substituted derivative 3d furnished the dimer in acetonitrile, as shown by the development of the characteristic cyclobutane protons at 4.85–4.95 ppm. In contrast, the NMR-spectroscopic analysis in D2O showed that the

• )bisquinolizinium 4b and 4c as photoproducts in quantitative yield. The products 4b and 4c were fully characterized by NMR spectroscopy (1H, 13C, COSY, HSQC, HMBC, and ROESY) and mass spectrometry, which revealed a cyclobutane structure, specifically by the appearance of the characteristic NMR signals of the

• cyclobutane at 4.89–5.00 ppm [42][43][44][45][46]. Unfortunately, detailed 2D NMR and spectroscopic analyses did not allow a conclusive assignment of the configuration of the products. Even in the ROESY NMR spectra, only unspecific correlations were detected. However, as both products could be obtained as

Synthesis of acremines A, B and F and studies on the bisacremines

• Nils Winter and
• Dirk Trauner

Beilstein J. Org. Chem. 2019, 15, 2271–2276, doi:10.3762/bjoc.15.219

• starting material. Next, we tried to trigger the cyclization through a [2 + 2] cycloaddition followed by vinyl cyclobutane rearrangement [19][20]. We reasoned that the initially formed divinyl cyclobutane [21] should undergo an allylic rearrangement to furnish the decalin system [22][23]. Condensation

Azologization and repurposing of a hetero-stilbene-based kinase inhibitor: towards the design of photoswitchable sirtuin inhibitors

• Christoph W. Grathwol,
• Nathalie Wössner,
• Sören Swyter,
• Adam C. Smith,
• Enrico Tapavicza,
• Robert K. Hofstetter,
• Anja Bodtke,
• Manfred Jung and
• Andreas Link

Beilstein J. Org. Chem. 2019, 15, 2170–2183, doi:10.3762/bjoc.15.214

• oxidized to phenantrene in the presence of oxygen [48]. In high concentrations, (E)-stilbene furthermore undergoes photocyclodimerization to cyclobutane derivatives [49]. Photoisomerization and photocyclization are also reported for 3-styrylpyridines, forming two regioisomeric dihydroazaphenanthrenes that

Cyclobutane dication, (CH₂)₄²⁺: a model for a two-electron four-center (2e-4c) Woodward–Hoffmann frozen transition state

• G. K. Surya Prakash and
• Golam Rasul

Beilstein J. Org. Chem. 2019, 15, 1475–1479, doi:10.3762/bjoc.15.148

• G. K. Surya Prakash Golam Rasul Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, University Park, Los Angeles, CA 90089-1661, USA 10.3762/bjoc.15.148 Abstract The structures of the elusive cyclobutane dication, (CH2)42+, were investigated at the

• considered as a prototype for a 2e-4c Woodward–Hoffmann frozen transition state. The planar rectangular shaped structure 2 with a 2e-4c bond was found not to be a minimum. Keywords: cyclobutane dication; 2e-4c bond; frozen transition state; Woodward–Hoffmann rule; Introduction The protonated hydrogen

• +, v) and the cyclobutane dication (CH2)42+ (vi)? The structures of H42+ (including v) were previously analyzed at various theoretical levels including CISD/6-311++G(d,2pd) by von Ragué Schleyer, Koch and co-workers [9]. No structure with four connected hydrogens, however, was found to be a minimum on

Synthesis of aryl cyclopropyl sulfides through copper-promoted S-cyclopropylation of thiophenols using cyclopropylboronic acid

• Emeline Benoit,
• Ahmed Fnaiche and
• Alexandre Gagnon

Beilstein J. Org. Chem. 2019, 15, 1162–1171, doi:10.3762/bjoc.15.113

• with hydrobromic acid and zinc bromide leads to 1-arylthiocyclobutenes 7 [13] and 2-alkyl-substituted cyclobutanones 8 [11][12], respectively. Treatment of 6 with hydrobromic acid and zinc bromide in the presence of a thiophenol provides the 1,1-di(arylthio)cyclobutane 9 which, upon reaction with

Mechanochemistry of supramolecules

• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2019, 15, 881–900, doi:10.3762/bjoc.15.86

• 1,2-di(pyridin-4-yl)ethylene and 4,6-dichlororesorcinol in the transition state (Figure 24). Finally the cyclobutane derivative 43 was observed after the release of catalyst for the next cycle. In 2012, again the MacGillivray group reported an improved version of the above mentioned [2 + 2