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The [3 + 2] annulation reaction between a thiourea, an ambident dinucleophile, and a 2-(phenacylethylidene)cyclobutanone, containing a novel pull-pull alkene system, could in principle proceed with several chemo- and regioselectivity profiles. Here we describe a convenient synthesis of the functionalized cyclobutanone substrates and show that they react with thioureas in a manner that is rationalized mechanistically in terms of the steric and electronic effects at play. The [3 + 2] annulation proceeds in mild, additive-free conditions to provide access to previously unknown cyclobutane-fused imidazolidine-2-thione and thiazolidine-2-imine derivatives in good yields.

This concept review describes the recent achievements on the Heyns rearrangement appeared in literature over the last decade and aims to provide the reader with a general overview of the fundamental synthetic advances in this research area., (© 2024 Wiley-VCH GmbH.)

The potential of aerogels as catalysts for the synthesis of a relevant class of bis-heterocyclic compounds such as bis(indolyl)methanes was investigated. In particular, the studied catalyst was a nanocomposite aerogel based on nanocrystalline nickel ferrite (NiFe 2 O 4 ) dispersed on amorphous porous silica aerogel obtained by two-step sol-gel synthesis followed by gel drying under supercritical conditions and calcination treatments. It was found that the NiFe 2 O 4 /SiO 2 aerogel is an active catalyst for the selected reaction, enabling high conversions at room temperature, and it proved to be active for three repeated runs. The catalytic activity can be ascribed to both the textural and acidic features of the silica matrix and of the nanocrystalline ferrite. In addition, ferrite nanocrystals provide functionality for magnetic recovery of the catalyst from the crude mixture, enabling time-effective separation from the reaction environment. Evidence of the retention of species involved in the reaction into the catalyst is also pointed out, likely due to the porosity of the aerogel together with the affinity of some species towards the silica matrix. Our work contributes to the study of aerogels as catalysts for organic reactions by demonstrating their potential as well as limitations for the room-temperature synthesis of bis(indolyl)methanes.

A novel Brønsted acid catalyzed tandem reaction provides highly functionalized cyclobuta-fused tetrahydroquinoline carboxylic esters from anilines and 2-alkylenecyclobutanones in good to high yield. During the reaction a dynamic diastereoselective cyclization is achieved, resulting in the formation of three contiguous stereocenters with high stereoselectivity.

The reaction between configurably stable α-lithiated oxiranes and 3-substituted cyclobutanones allows obtaining enantiomerically enriched cyclobutanols (er > 98 : 2). These adducts, subjected to base-mediated Payne rearrangement, lead to the synthesis of a new class of oxaspirohexanes, useful precursors of 2,4-disubstituted cyclopentanones.

The continuous flow Norrish-Yang photocyclization of 1,2-diketones has been developed and used for the synthesis of a large number of functionalized 2-hydroxycyclobutanones, under blue light irradiation and employing acetone as a solvent. This eco-friendly procedure represents a valid alternative to the reactions carried out in batches thus reducing the reaction times, the formation of secondary products and simplifying the purification steps. The use of differently substituted diketone compounds has allowed us to obtain a wide range of 2 and 3-functionalized cyclobutanones, thus allowing the evaluation of the scope and limitations of this procedure.

An original tandem reaction consisting of a Wittig reaction-ring contraction process between α-hydroxycyclobutanone and phosphonium ylides has been developed. Highly functionalized cyclopropanecarbaldehydes are obtained in good to high yield.

A general strategy for the synthesis of indolyl cyclopropanecarbaldehydes and ketones via a Brønsted acid-catalyzed indole nucleophilic addition/ring-contraction reaction sequence has been exploited. The procedure leads to a wide panel of cyclopropyl carbonyl compounds in generally high yields with a broad substrate scope.

An original tandem reaction consisting of a thermal elimination-addition process was developed. Highly substituted β-sulfinyl cyclobutane carboxylic acid derivatives were obtained from isomeric α-sulfinyl derivatives in a single operation in good to high yields and with high trans diastereoselectivity.

A general strategy for the synthesis of arylthio cyclopropyl carbaldehydes and ketones via a Brønsted acid catalyzed arylthiol addition/ring contraction reaction sequence has been exploited. The procedure led to a wide panel of cyclopropyl carbaldehydes in generally high yields and with broad substrate scope. Mechanistic aspects and synthetic applications of this procedure were investigated.

A unified protocol for the construction of 3-(2-bromoethyl)benzofurans and 2-(benzofuran-3-yl)ethylamines from bis[(trimethylsilyl)oxy]cyclobutene has been developed. This mild and facile strategy was applied for the synthesis of a series of 5-HT serotonin receptor agonists, underlining its potential for the syntheses of bioactive compounds and natural products.

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The acid-promoted syntheses of 2-(benzyloxy)cyclobutanones and bis(benzyloxy)dioxatricyclo decanes were achieved starting from 2-hydroxycyclobutanone and variously functionalized benzyl alcohols. The reaction sequences afforded the desired products in good to high yields and in a solvent-dependent chemoselective fashion.

A two-step protocol is presented for the preparation of 5-(pyridin-2-ylamino)dihydrofuran-2(3H)-ones from 2-hydroxycyclobutanone and some 2-aminopyridines via a catalyst-free synthesis of 2,2-bis(pyridin-2-ylamino)cyclobutanols followed by Dess-Martin periodinane mediated ring expansion.

Organocatalyzed Michael addition reactions of 2-(arylthio)cyclobutanones with trans-β-nitrostyrenes have been carried out using a bifunctional thiourea-primary amine catalyst, providing diastereoisomerically and enantiomerically enriched 2-alkyl-2-(arylthio)cyclobutanones having two contiguous stereocenters of which one is a chiral quaternary center. The absolute configuration of these novel adducts was assigned by X-ray diffraction analysis and a transition-state model is proposed to explain the observed stereoselectivities.

An original synthetic protocol has been developed for the preparation of highly functionalized tryptamines from 2-hydroxycyclobutanone and secondary arylamines via a solvent-free Brønsted acid catalysed two-step reaction sequence.

Background: The gypsy moth Lymantria dispar L. is a widespread pest that causes economic damage to cork oak forests. Females produce the sex pheromone (+)-(7R,8S)-epoxy-2-methyloctadecane, known as (+)-disparlure [(+)D], for long-distance attraction of conspecific males. A (+)D analogue, 2-decyl-1-oxaspiro[2.2]pentane (OXP-01), neither stimulating nor attractive by itself, causes short-time inhibition of male response in a 1:1 blend with (+)D. The authors investigated whether and how the biological activity of the natural pheromone is affected by OXP-01 on a long-time basis (up to 16 days), also by looking at possible physicochemical reciprocal interactions., Results: Blending of (+)D with OXP-01 decreased, under low evaporation rate, the pheromone effectiveness, as assessed by electroantennogram recordings. In male trappings, within the first 24 h, OXP-01 decreased and later enhanced the blend attractiveness, but only under high evaporation rate. Gas chromatography-mass spectroscopy indicates that quantitative retrieval of (+)D from blend cartridges is higher than for pure pheromone, and nuclear magnetic resonance measurements show that OXP-01 produces, possibly by Van der Waals interactions, a bimolecular entity with pheromone causing retention and lengthening of its attractiveness over time., Conclusion: The biological and physicochemical interactions between (+)D and OXP-01 may provide valuable information for the optimisation of pheromone-based control strategies for gypsy moths., (© 2013 Society of Chemical Industry.)

In the last decade a certain number of new cyclobutane and cyclobutanone synthesis and functionalization protocols have been published. Organo- and biocatalyzed eco-friendly approaches to cyclobutane-containing molecules have been developed with interesting results. Also, successful new total synthesis of bioactive compounds and drugs have been recently reported where a four membered ring represented the key intermediate. Therefore, the rising interest in this field represents a great point of discussion for the scientific community, disclosing the synthetic potential of strained four membered ring carbocyclic compounds. Herein we report a critical survey on the literature concerning the enantiocontrolled synthesis and functionalization of cyclobutane derivatives, with particular attention to metal-free, low impact methodologies, published during the period 2000-2013.

A novel synthesis of optically active α-arylamino ketones through an organocatalytic enantioselective Amadori-Heyns rearrangement is described.

N-Phenylsulfonyl (S)-proline catalyzes the direct aldol reaction of 3-substituted cyclobutanones and aryl aldehydes in good yield and with excellent diastereoselectivity and enantioselectivity. This desymmetrization process provides highly functionalized cyclobutanones with control over three contiguous stereogenic centers.

An unprecedented and conceptually novel chiral Brønsted base/Brønsted acid catalytic method for the enantioselective synthesis of α-amino thioesters through a tandem condensation-intramolecular rearrangement-protonation has been developed which provides a number of important synthetic building blocks in good yield and with moderate to good enantioselectivities.

The high versatility of 1-phenylsulfenyl- or 1-phenylsulfonyl-cyclopropylketones has been exploited for the regioselective synthesis of trans-2,3-disubstituted cyclobutanones, 2,4,5-trisubstituted 3,6-dihydro-2H-pyrans and cis-2-alkyl- or cis-2-aryl-cyclopropylphenylsulfones.

A number of oxaspiropentane derivatives (OXPs) were tested as potential (+)-disparlure analogues, with the aim of identifying any possible interaction of these compounds, be it additive, synergetic, or inhibitory, with the pheromone response in the male gypsy moth Lymantria dispar. As assessed by male electroantennograms, 2 OXPs, 2-decyl-1-oxaspiro[2.2]pentane (OXP-01) and 4-(1-oxaspiro[2.2]pent-2-yl)butan-1-ol (OXP-04), were found to be effective. OXP-01 had no stimulatory effect but strongly decreased the response to (+)-disparlure in a blend in a 1:1 ratio. By contrast, OXP-04 proved to be more stimulating than (+)-disparlure and also had an additive effect in the blend. Single-cell recordings from the sensilla trichoidea showed the activity of 2 cells, one of which responded to (+)-disparlure. OXP-01 reduced the stimulating effectiveness of pheromone by silencing the pheromone-responding unit when the 2 compounds were presented in blend, whereas OXP-04 mimicked the pheromone response, evidenced by exciting the pheromone-responding neuron when tested alone. Behavioral observations are in agreement with electrophysiological results.

The structure of a series of I-O bonded bis(acyloxy)iodoarenes and benzoiodoxolones in chloroform solution has been investigated by 17O NMR spectroscopy and by density functional theory (DFT) calculations, employing the PBE0 functional together with the LANL2DZ basis set extended with polarization (d) and diffuse (p) functions. This combined approach allowed us to ascertain that, although these classes of lambda(3) iodanes maintain in chloroform solution their solid state "T-shaped" structure, a degenerate [1,3] sigmatropic shift of iodine between the two oxygens of the acyloxy groups occurs in solution. The energy barrier involved in this process differs in the two classes, thus causing significant differences in the 17O NMR spectra, at room temperature, of the two classes of compounds.

[reaction: see text] Acid-catalyzed ring expansion of chiral cyclopropyl and cyclobutyl derivatives for the synthesis of carbo- and heterocyclic compounds is reported. The starting materials have been successfully prepared by l-proline-catalyzed direct asymmetric aldol reactions of 1-phenylthiocycloalkyl carboxaldehydes with ketones.

[reactions: see text] Regioselective synthesis of 2,4,5- or 3,4,5-trisubstituted 2,3-dihydrofurans has been realized by using donor-acceptor cyclopropanes or by a Corey ylide reaction with alpha-sulfenyl-, alpha-sulfinyl-, or alpha-sulfonylenones. The method allowed a straightforward synthesis of the natural product calyxolane B.

2,2-dimethyl cyclopentanones are readily prepared by acid catalyzed ring expansion of isopropenylcyclobutanols; the method allows ready access to the family of sesquiterpenes cuparanes and herbertanes, as demonstrated by the synthesis of (+/-)-alpha-cuparenone and the direct precursor of (+/-)-herbertene.

[reaction: see text] The stereochemistry of the cyclobutanones 3, obtained by lithium salt catalyzed ring expansion of the optically pure oxaspiropentanes 2, depends not only on the lithium salt but also on the stereochemistry of 2. They constitute the starting material for the syntheses of the acetogenin (-)-(4R,5R)-muricatacin and the pheromone (R)-japonilure.

[reaction: see text] The thionium ion, generated through a cyclopropylcarbinyl-cyclobutyl ring expansion, is, for the first time, intramolecularly intercepted by activated aromatic rings to generate new versatile 2a-methyl-8b-(phenylsulfanyl-1,2a,3,8b-tetrahydro-2H-cyclobuta[c]chromenes.