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Rhodium-catalyzed C –H activation involves mild reaction conditions, high efficiency, versatility, and regioselectivity. Consequently, this strategy is gradually becoming a powerful tool for constructing diverse heterocyclic scaffolds. In fact, N -heterocycles, especially indoles, are ubiquitous in natural products and pharmaceuticals. The present review summarizes recent advances (2019–2023) in Rh-catalyzed annulation of various substrates for the synthesis of indole skeletons. Annulations involving substrates, such as, anilines, anilides, amidines, N -nitrosoanilines, ortho -alkynylanilines, aryl hydrazines, nitrones/nitroarenes, 1-phenylpyrazolidinones etc. with suitable reaction partner efficiently afforded functionalized indoles. The reactions discussed in this review employed readily available starting materials that are environmentally benign and easy to handle. Moreover, mechanistic rationale for most of the reactions was highlighted for clear understanding of the readers. [Display omitted] • This review summarizes recent advances (2019–2023) in Rh-catalyzed reactions for the synthesis of indole skeletons. • Annulation involving anilines, anilides, amidines, N -nitrosoanilines, ortho -alkynylanilines, aryl hydrazines, nitrones/nitroarenes etc. Was described. • Mechanistic rationale for most of the reactions was highlighted for better understanding of reaction pathway. • Some of the reactions are practical for the synthesis of biologically active heterocycles. [ABSTRACT FROM AUTHOR]

Abstract The base-induced formal [4 + 3] annulation reactions of N -(ortho -chloromethyl)aryl amides with nitrones or hydrazonoyl chlorides have been reported. When nitrones are used as the 1,3-dipole, the corresponding reaction afforded a series of 1,2,3,5-tetrahydrobenzo[ e ][1,2,4]oxadiazepine derivatives. Highly functionalized 2,3-dihydro-1 H -benzo[ e ][1,2,4]triazepine derivatives were also synthesized via an unprecedented tandem aza-Michael addition/rearrangement aromatization between N -(ortho -chloromethyl)aryl amides and hydrazonoyl chlorides. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

Abstract The addition of Lewis acids changes the path of the reaction of N -vinylpyrroles with 3,4-dihydroisoquinoline- N -oxides: formal (3 + 3)-cycloaddition proceeds instead of (3 + 2)-cycloaddition. In the case of benzoyl(3,4-dihydroisoquinolin-2-ium-2-yl)amides, reaction path does not change in the same conditions, but changing of the diastereoselectivity occurs and other diastereomer of (3 + 2)-cycloaddition became predominant. Graphical abstract Image 1 [ABSTRACT FROM AUTHOR]

An efficient, and metal-free approach for the ʟ-proline mediated synthesis of nitrones from nitrosobenzene and benzaldehydes has been established. The reaction undergoes very efficiently at room temperature in methanol as a solvent. The reaction is assumed to involve that the initial formation of azomethine ylide and [2 + 3] cycloaddition of nitrosobenzene, followed by the subsequent retro [2 + 3] cycloaddition could offer the desired nitrone. [ABSTRACT FROM AUTHOR]

A novel method of SiCl 4 -catalyzed/PR 3 -mediated β -C(sp 3 )−H functionalization of nitrones with aldehydes/ketones to α,β -unsaturated imines was developed. The synthesis of α,β -unsaturated imines mainly invovles deoxygenation and aldol condensation, each proceeding under a cooperation effect between Lewis acid and Lewis base. In addition, both the acidity and hydrolytic stability of the weak SiCl 4 were supposed to be enhanced by coordination with phosphine oxide (R = Et) or phosphoric triamide (R = NMe 2 ) that originated from deoxygenation of nitrones by PR 3 . In the case of 6-membered nitrone, a [1,3]-hydride shift within the resulted α,β -unsaturated imines renders the aromatization leading to 3,5-dialkylpyridines. [ABSTRACT FROM AUTHOR]

The first synthesis of a recently isolated antiproliferative diarylindolizidine alkaloid, (+)-fistulopsine B, was achieved. The synthesis features the use of an organocatalytic ketone-nitrostyrene Michael addition as the key step. [ABSTRACT FROM AUTHOR]

Four histrionicotoxin analogues were prepared in an efficient manner utilizing a nitrone dipolar cycloaddition reaction as the key step in forming tricyclic intermediate 13 . The nitrile in intermediate 13 was reduced with DIBAL to an aldehyde which then underwent Z -selective Wittig reactions to produce intermediates containing the Z -alkene side-chain. Hydrogenation of the Z -alkenes produced saturated histrionicotoxin analogues whereas reduction with SmI 2 afforded the unsaturated histrionicotoxin analogues. The histrionicotoxin analogues were shown to be potent non-competitive antagonists of the α4β2 and α7 nAChR's with the most potent analogue 3 displaying IC 50 's of 0.10 μM and 0.45 μM against the α4β2 and α7 nAChR's, respectively. The unsaturated analogues 15 and 18 displayed Hill slope ( n H ) of approximately 1 whilst the saturated analogues 16 and 3 had a n H of approximately 0.5, which may indicate that the saturated analogues are binding to more than one binding site. [ABSTRACT FROM AUTHOR]

The 1,3-dipolar cycloaddition of nitrones to N -propadienyl indoles and pyrroles proceeds predominantly via the C1-C2 bond to form 4-methyleneisoxazolidines. In the case of aldonitrones, the cis -isomers are predominantly formed. [ABSTRACT FROM AUTHOR]

Density functional theory (DFT) calculations were performed to study the mechanism of bioorthogonal strain-promoted dibenzocyclooctyne (DIBO)-nitrone and DIBO-nitrile oxide cycloaddition (CA) reactions at B3LYP/6-31G(d,p), M06-2X/6-31G(d,p) and B3LYP-D3/6-31G(d,p) levels of theory. The potential energy surface analysis, synchronicity indices and global electron density transfer (GEDT) calculations at the transition states (TSs) show that these cycloadditions take place through a nearly synchronous mechanism with non-polar character. The strain and electronic effects on the reactivity of DIBO with nitrone and nitrile oxide were studied using a distortion/interaction transition state model and compared with CA reactions of these dipoles with acetylene as a strain-free reaction. The electron-reorganizations along these CA reactions have been studied using the topological analysis of the electron localization function (ELF) at the B3LYP/6-31G(d,p) level. The ELF topological patterns indicate a one-step two-stage mechanism for both reactions in which the formation of C O single bonds takes place after the formation of C C bonds. [ABSTRACT FROM AUTHOR]

1,3-Dipolar cycloaddition of benzylidenecyclopropane with various aldonitrones proceeds regioselectively giving good yields of 4-spirocyclopropane isoxazolidines. In the case of aldonitrones, bearing carbamoyl- or aryl-groups on the carbon atom, only the cis -isomer is formed. The compounds synthesized were tested for their virus-inhibiting activity. [ABSTRACT FROM AUTHOR]

A highly enantioselective 1, 3-dipolar cycloaddition of nitrone with α, β-unsaturated acyl phosphonate was developed for the first time by using a chiral indane-bis(oxazoline)-copper(II) complex. The reaction proceeded smoothly under mild conditions to provide isoxazolidines with multi-stereocenters in good yields with high to excellent diastereo- (>20:1 dr) and enantioselectivities (up to 99% ee). The resulting products were readily converted to multi-functional isoxazolidines or γ-amino alcohol compounds. [ABSTRACT FROM AUTHOR]

Molecular mechanism of catalytic Kinugasa reaction of a cyclic nitrone and acetylene, derived from d -glyceraldehyde acetonide, using acetonitrile as a ligand and solvent is studied with density functional theory methods. Possible pathways of Cu(L) catalyzed 1,3-diploar cycloaddition/rearrangement cascade reaction are investigated. For a cycloaddition process, two possible mechanisms have been characterized: the first one corresponds to a one-step cycloaddition with a high activation barrier. The second one corresponds to the mono- or di-copper catalyzed stepwise process that in terms of calculated energy barriers, di-copper path is the most favorable. The reaction proceeds by rearrangement with two competitive mechanisms, formation of bicyclic oxaziridinium intermediate or ketene intermediate. Our calculations show that formation of ketene intermediate is the lowest energy pathway for the rearrangement process. [ABSTRACT FROM AUTHOR]

The addition of Lewis acids change the reaction mechanism of the cycloaddition of N -vinylpyrroles with azomethine imine and C,N -diarylnitrones. The formal (3+3)-cycloaddition is observed instead of (3+2)-dipolar cycloaddition, which take place in the absence of catalysts. This unusual (3+3)-cycloaddition leads to heterocyclic compounds with pyrazolo[1,2- a ]pyrrolo[1,2- d ][1,2,4]triazine- and pyrrolo[2,1- d ][1,2,5]oxadiazine cores, which are difficultly achievable by other methods. [ABSTRACT FROM AUTHOR]

Isoxazolidine analogues of homonucleos(t)ides were synthesized from nucleobase-derived nitrones 20a-20e (uracil, 5-fluorouracil, 5-bromouracil, thymine, adenine) employing 1,3-dipolar cycloadditions with allyl alcohol as well as with alkenylphosphonates (allyl-, allyloxymethyl- and vinyloxymethyl- and vinylphosphonate). Besides reactions with vinylphosphonate the additions proceeded regioselectively to produce mixtures of major cis and minor trans 3,5-disubstituted isoxazolidines (d.e. 28–82%). From vinylphosphonate up to 10% of 3,4-disubstituted isoxazolidines was additionally produced. Vicinal couplings, shielding effects and 2D NOE correlations were employed in configurational assignments as well as in conformational analysis to find out preferred conformations for several isoxazolidines and to observe anomeric effects (pseudoaxial orientation of phosphonylmethoxy groups) for those obtained from vinyloxymethylphosphonate. None of the tested compounds were endowed in vitro with antiviral activity against a variety of DNA and RNA viruses at subtoxic concentrations (up to 250 μM) nor exhibited antiproliferative activity towards L1210, CEM, and HeLa cells (IC 50 = ≥100 μM). [ABSTRACT FROM AUTHOR]

The regioselective reactions of fluorinated nitrones with selected terminal alkynes (Kinugasa reaction) was studied in the presence of Cu(I) iodide and TEA as a base. After chromatographic purification the desired β-lactams were obtained in high yields (up to 93%) and high diastereoselectivities (up to 9:1). The reactions performed in the presence of chiral, enantiomerically pure ligands led to enantiomerically enriched products ( ee values up to 26%) obtained as one of the possible diastereoisomers depending on the type of chiral ligand used. [ABSTRACT FROM AUTHOR]

In our series of investigations to expand the understanding of the gold(I) catalysis chemistry of propargyl acetals, a gold(I) catalysed [3+3] cycloaddition reaction of propargyl acetals with nitrones has been studied. A series of 5-methoxy-3,6-dihydro-2 H -1,2-oxazine products with two stereogenic centres were obtained in a cis -stereoselective manner. The formal [3+3] cycloaddition reaction is supposed to go through O-nucleophilic attack of the nitrone on the C 1 position of the gold complex generated from propargyl acetal followed by a final ring closure. An alternative C3 oxidation by nitrone affords aldehyde products and represents a competing pathway. The chemoselectivity of the cycloaddition reaction is discussed in order to demonstrate the potential and limitations of the reaction. [ABSTRACT FROM AUTHOR]

1,3-Dipolar cycloadditions of nitrones with pentafluorosulfanyl-substituted acrylic ester and amides afforded new trisubstituted pentafluorosulfanylated isoxazolidines in moderate yields as 4-SF 5 -regioisomers. Theoretical calculations were carried out and the regioselectivity could be explained by the fact that the 5-SF 5 -regioisomer probably undertook a spontaneous degradation in the reaction medium via the loss of pentafluorosulfanyl anion. Diastereoselectivity of the 1,3-dipolar cycloadditions was also assessed according to NMR and X-ray diffraction analysis. [ABSTRACT FROM AUTHOR]

A facile preparation of nitrones has been achieved by use of unsupported nanoporous gold (AuNPore) as a heterogeneous catalyst through aerobic oxidation of N,N -disubstituted hydroxylamines with molecular oxygen as an oxidizing agent under mild conditions. A variety of amines were oxidized to the corresponding nitrones in high chemical yields. The catalyst is robust enough to be reused without leaching. [ABSTRACT FROM AUTHOR]

A synthetic method has been developed for diastereoselective de novo synthesis of pyrroloindolines using readily available α,β-unsaturated N -aryl ketonitrones and amino acid derived activated alkynes. The reaction likely proceeded by initial formation of C3-quaternary indolenines followed by N-cyclization of the pendent nitrogen atom to give the complex heterocyclic system from simple starting materials in one step. Pyrroloindolines with substituents that may be difficult to introduce via other approaches have been prepared using this method. [ABSTRACT FROM AUTHOR]

A general method for accessing 5-alkyl-5-aryl-1-pyrroline N-oxides (AAPOs) has been established using readily available aryl bromides, nitroalkanes, and acrolein as the starting materials. The palladium-catalyzed arylation of nitroalkanes gave the 1-aryl-substituted nitroalkanes, which underwent the Et3N-catalyzed Michael addition with acrolein at room temperature to afford the 4-aryl-4-nitroaldehydes. The latter were then subjected to the nitro reductive cyclization using Zn-HOAc in EtOH at 0 °C followed by warming the reaction mixture to room temperature for 24 h, furnishing the 5-alkyl-5-aryl-1-pyrroline N-oxides in good overall yields. Selected examples of 1,3-dipolar cycloaddition of the cyclic nitrones with methyl methacrylate were also described. [ABSTRACT FROM AUTHOR]

Abstract: The stereoselective synthesis of two epimeric penta-hydroxylated indolizidines was accomplished from 2,3:5,6-di-O-isopropylidene-α-d-mannofuranose and N-(2-methylpent-4-en-2-yl)hydroxylamine. The transformation of these substrates into the corresponding 7-oxa-1-azabicyclo[2.2.1]heptane by the intramolecular 1,3-dipolar cycloaddition was the key step of the synthesis. The adduct was transformed into the tricyclic ammonium salt by intramolecular N-alkylation. The tricyclic ammonium salt was converted to the target compounds by: (route 1) the catalytic hydrogenation; or (route 2) the reaction with sodium azide, followed by the enantioselective reduction of the resulting indolizidinone. [Copyright &y& Elsevier]

Abstract: Diastereoselective asymmetric 1,3-dipolar cycloadditions of N-(alkoxycarbonylmethyl) nitrones derived from glycine, alanine and phenylalanine have been studied both experimentally and theoretically. Asymmetric induction is evaluated by either introducing a chiral group at the nitrone nitrogen atom or by using Oppolzer's sultam acrylamide. In both cases the sense of the asymmetric induction is the same, the (3R,5R)-isomer being preferentially obtained. The best results were observed with the chiral dipolarophile, which afforded an only isomer in all cases. The obtained isoxazolidines are easily transformed into the corresponding 5-substituted-3-hydroxypyrrolidin-2-ones. DFT studies are in a qualitative agreement with the observed experimental results. [Copyright &y& Elsevier]

Abstract: Polyhydroxylated pyrrolizidines bearing a methyl group at C-5 have been synthesized by 1,3-dipolar cycloaddition of five membered cyclic nitrones with methyl vinyl ketone followed by a N–O reductive cleavage and in situ intramolecular reductive amination. The stereochemistry of the obtained compounds is examined in relation to the reactions mechanism. [Copyright &y& Elsevier]

Abstract: A facile one-pot protocol for synthesis of nitrone–spiro-oxindole frameworks via alkylation of nitromethane with carbonates of Baylis–Hillman alcohols, derived from isatins and cyclohex-2-enone derivatives, followed by reductive cyclization is described. [Copyright &y& Elsevier]

Abstract: The hydroxyl radical addition onto 3-aryl-2H-benzo[1,4]oxazin-4-oxides spin traps yielded very persistent nitroxides. Their EPR spectra showed unusually large splitting due to the trapped OH proton, whose assignment has been possible by means of the isotope exchange technique. A proper DFT study revealed isomeric molecular geometries with possible intramolecular hydrogen bonds (IHB) forming five- and/or six-membered rings, allowing to be envisioned relationships between EPR hyperfine coupling constants (h.f.c.c.) and IHB strengths. [Copyright &y& Elsevier]

Abstract: One-pot thermal-induced [3+2] cycloaddition/silica gel-promoted fragmentation sequence between isatin ketonitrones and electron-deficient alkynes affords spiro[indoline]oxindoles in moderate to excellent yields along with good diastereoselectivities. The detailed mechanism of silica gel-promoted fragmentation has been clarified by experiment and DFT calculations. [Copyright &y& Elsevier]

Abstract: DFT calculations have proven clearly the polar nature of gem-dinitroethene cycloaddition to (Z)-C,N-diphenylnitrone. The formation of the azolidine ring on both analysed [2+3] cycloaddition pathways occurs in the gas phase according to the one-step mechanism. When toluene is added as the reaction medium, the kinetic pathway preference does not change. However, the mechanism for the formation of the 2,3-diphenyl-4,4-dinitroisoxazolidine heterocyclic ring does change. In the first reaction stage, a zwitterionic intermediate forms, which is only later cyclized to the [2+3] cycloadduct. [Copyright &y& Elsevier]

Abstract: Kinugasa reactions between terminal acetylenes and six-membered ring nitrones when one or both components are chiral, proceed in a low to moderate yield and with a high diastereoselectivity affording mostly one, dominant β-lactam product. The first step of the reaction is controlled by the configuration of the nitrone, whereas the protonation of the C-7 center of the carbacepham skeleton in the second step depends on: a) the configuration of the bridgehead carbon atom formed in the first step, b) epimerization process in the presence of a base, and c) on the configuration of the stereogenic center in the acetylenic partner. In the case of the nitrone derived from dihydroisoquinoline, the reaction proceeds in a more complex way affording not only β-lactams, but also products derived from the alternative regio-1,3-cycloaddition, or nucleophilic addition of the acetylene to the double bond of the nitrone. [Copyright &y& Elsevier]

Abstract: The role of the trifluoromethyl group in reactivity, regio-, and stereoselectivity in cycloaddition reactions has been analyzed by studying the 1,3-dipolar cycloaddition (13DC) reactions of nitrone 4 with 3,3,3-trifluoro-1-nitropropene 7b and 3,3,3-trifluoro-2-nitropropene 14 using density functional theory (DFT) methods at the B3LYP/6-311G(d) level. The recent M06-2X functional has also been evaluated but, although the thermodynamic performance is improved, the kinetic data are not necessarily better than those obtained by the popular B3LYP functional for cycloaddition reactions. Four reactive channels associated with the meta and ortho regio- and endo and exo stereoselective approach modes of the nitro group of these disubstituted ethylenes relative to nitrone 4 have been explored and characterized. Unlike other electron-withdrawing groups, the trifluoromethyl group increases the reactivity of the nitroethylene, but it does not modify the meta and endo selectivities when it is located at the β conjugated position of nitroethylene. Analysis of the global and local electrophilicity indices allows for an explanation of the role of the trifluoromethyl group in reactivity and regioselectivity of electrophilically activated ethylenes. [Copyright &y& Elsevier]

Abstract: Reactions of the nitrones −O+N(Me)e:bold>1 (Ar=phenyl 1a, 4-methylphenyl 1b, 2,4,6-trimethylphenyl 1c, and anthracen-9-yl 1d) with the cyclic β-diketones 1,3-indandione 2 or barbituric acid 3 in CH2Cl2, afford the corresponding endiones 2′a–2′d or 3′a–3′d. In contrast, dimedone 4 reacts with 1a or 1b to give the endione 4′a or 4′b and the bis-adduct 4″a or 4″b. Nevertheless, reaction of 4 with 1c or 1d in CH2Cl2 furnishes only the endione adducts 4′c or 4′d. However, the reaction of 4 with 1a or 1b in methanol gives only 4″a or 4″b, respectively. Among acyclic β-diketones only malonic acid 7 reacts with 1a–1c. Reaction of 7 with 1a in CH2Cl2 forms cinnamic acid 7″a, whereas in the case of 1b, the endione 7′b and (E)-3-p-tolylacrylic acid 7″b are obtained. The nitrone 1c reacts with 7 in CH2Cl2 to afford the endione 7′c or with acetone yielding (E)-4-mesitylbut-3-en-2-one 8. X-ray analyses are reported for 4′c, 5, and 7″b. In addition, the calculated acidity of the hydrogen at the α-C atom is shown to correlate with the reactivity of the β-diketones with nitrones. [Copyright &y& Elsevier]

Abstract: A new straightforward route to glycomimetics containing a piperidine unit is reported. The key step of the methodology is the intramolecular 1,3-dipolar cycloaddition of easily accessible glycosyl alkenyl nitrones. The reaction takes place in most cases with a complete selectivity in favor of the exo–exo adduct, which facilitates the synthesis of all-cis piperidines bearing the glycosyl units. The direct transformation of adducts into the final imino-C-di and trisaccharide analogues is achieved in one step using simple reagents. Inhibition properties against two glycosidases have been tested but no positive results have been found. [Copyright &y& Elsevier]

Abstract: A flexible enantioselective approach to polyhydroxylated prolinol derivatives was described, which is based on the samarium diiodide-mediated reductive coupling of the chiral nitrone (3S,4R)-8, derived from d-isoascorbic acid with aldehydes/ketones. Thereby, polyhydroxyprolinol derivatives 9a–e and 9h–j were obtained from aromatic ketones and aliphatic aldehydes in good to excellent yields of 65–91%. These reductive hydroxyalkylations are highly diastereoselective in establishing the C-4 stereogenic center. By this way, the asymmetric syntheses of (−)-8a-epi-swainsonine (4) and (−)-8,8a-di-epi-swainsonine (5) have been achieved. [Copyright &y& Elsevier]

Abstract: Chiral tris(oxazoline)/Cu(I) complexes are demonstrated as a type of efficient catalysts for the asymmetric Kinugasa reaction of terminal alkynes with C-arylnitrones, providing a highly enantio- and diastereoselective access to optically active β-lactams. [Copyright &y& Elsevier]

Abstract: A new family of five-membered cyclic nitrones bearing functional groups at positions 2 and 5 were tested in 1,3-cycloadditions with various dipolarophiles. These reactions gave the corresponding cycloadducts as single diastereomers in high yields. The reaction scope was examined, 23 compounds were isolated and fully characterized. The comparison of the reactivity was carried out by a study of reaction conversions while different nitrones or dipolarophiles were used. In addition, the exceptional reactivity of nitrone bearing benzylamino group in position 2 was studied. The formation of the nitrone complex and evaluation of its reactivity in 1,3-DC is presented. [Copyright &y& Elsevier]

Abstract: A concise synthesis of zanamivir (GG167, 1) has been accomplished utilizing the adduct of a highly diastereoselective 1,3-dipolar cycloaddition between methyl acrylate and the nitrone derived from d-glucono-δ-lactone. Azide-free introduction of C4 nitrogen functionality and one-pot selective O-acetylation followed by straightforward generation of dihydropyran moiety are two advantages in this synthesis. Using the established methodology and common intermediate, two representative C4-thiocarbamido derivatives of zanamivir were also synthesized. [Copyright &y& Elsevier]

Abstract: Synthesis of trihydroxylated pyrrolizidines, the enantiomer of 2-epihyacinthacine A2 and indolizidine analogues of the natural alkaloids is reported. The key step of these syntheses is the stereoselective samarium diodide-induced coupling of the chiral nitrone prepared from d-ribose with methyl acrylate. The nitrone derived from d-ribose possessing C2/C3 syn configuration reacted with methyl acrylate in the presence of samarium diiodide in excellent yield and diastereoselectivity, with only the anti-diastereomer being detected. [Copyright &y& Elsevier]

Abstract: Pyrrolidine analogues of C-nucleosides related to pseudouridine have been synthesized by 1,3-dipolar cycloaddition reactions of uracil-5 and 2,4-dimethoxypyrimidine-5 nitrones with allyl alcohol and methyl acrylate, and subsequent reductive cleavage of the isoxazolidine cycloadducts. The dimethoxy derivatives have been easily deprotected to the corresponding uracils bearing the pyrrolidine ring instead of a sugar moiety. The regio and stereoselectivity of the reactions are discussed. [Copyright &y& Elsevier]

Abstract: The synthesis of 4-isoxazolines via 1,3-dipolar cycloaddition of nitrones generated from allenoates and the subsequent thermal rearrangement to pyrroles is reported. The selection of the reaction conditions allowed the isolation of the initial 1,3-dipolar cycloadducts, the 4-isoxazolines, or the pyrrole derivatives. The isomerization of the parent system (4-isoxazoline) was examined by carrying out quantum chemical calculations and corroborated the favourability of the 4-isoxazoline rearrangement to five-membered heterocycles via 2-acylaziridine intermediates. [Copyright &y& Elsevier]

Abstract: The tricyclic-isoxazolidine analogues tetrahydrothiochromenoisoxazoles, hexahydroisoxazolequinolines and tetrahydroisoxazolepyranopyridines were prepared by an intramolecular 1,3-dipolar cycloaddition reaction of a nitrone with an alkene. For N-alkylated hexahydroisoxazolequinolines, reduction of the reaction time from two days to 40min was achieved using microwave heating. The cyclization to form tetrahydroisoxazolepyranopyridines only proceeded when the alkene was substituted with an electron withdrawing group. [Copyright &y& Elsevier]

Abstract: A new approach to five-membered cyclic nitrones connected with the incorporation of a planar aromatic ring system into the structure is described. This procedure is based on an allenyloxime one-pot domino transformation under simple base catalysis in alcoholic and aqueous solvents. The structure of obtained nitrones was studied by X-ray analysis and the reactivity of products in 1,3-dipolar cycloadditions was tested. [Copyright &y& Elsevier]

Abstract: Several new polyhydroxylated alkaloids including pyrrolidines with a long side chain and 3-(hydroxymethyl) indolizidines were prepared from a common nitrone easily obtained from d-arabinose. In addition, a total synthesis of hyacinthacine A2 has been achieved in five steps and 67.7% overall yield starting from the same d-arabino-derived nitrone. All synthesized compounds have a common structural feature consisting of a pyrrolidine ring with d-arabino configuration. [Copyright &y& Elsevier]

Abstract: Novel polyhydroxylated indolizidine derivatives containing an amino group have been efficiently and divergently synthesized from azasugar aldehyde. The key steps of the strategy involved an effectively microwave assisted 1,3-dipolar cycloaddition of azasugar nitrone and methacrylate for installing a potential amino group and an ester group with a extended chain, and a structurally controlled intramolecular cyclo-amidation for constructing the indolizidine ring system via a key tricyclic indolizinone-containing intermediate. [Copyright &y& Elsevier]

Abstract: A variety of conditions including reductive and/or basic reagents in aqueous or alcoholic solution was applied to 2,2-dimethylpenta-3,4-dienal oxime. Formation of various five-membered heterocycles with excellent chemical selectivity was observed. Most of the reactions yielded cyclic nitrones with stable dipolar structure and unique functionalities present. All products of cyclization were isolated and fully characterized. [Copyright &y& Elsevier]

Abstract: The stereoselective synthesis of novel spiro-oxazinanone nucleosides 9 and 10 has been achieved by microwave assisted 1,3-dipolar cycloaddition of exo-glucal (1) and nitrones (2), and followed by reduction, stereospecific recyclization, and catalytic deprotection. The structures of the spironucleosides were determined according to the 1H NMR, 13C NMR, 2D NMR, MS, and X-ray analyses, and the biological activities of the title compounds against glycosidases (α-amylase, α-glucosidase, and β-glucosidase) and cytotoxicity were also evaluated. [Copyright &y& Elsevier]

Abstract: Various C-aryl and C-alkyl-nitrones were synthesized within 0.5–2h via condensation of an equimolar amount of aldehydes and N-substituted-hydroxylamines under solvent-free conditions in a ball-mill apparatus. Reactions can be performed without the need of excluding air and moisture and yields the expected products with no need for further purification. The study has been complemented by Differential Scanning Calorimetry (DSC) and solid-state 13C MAS nuclear magnetic resonance experiments. We have also studied the temperature profile during the reaction. A comparative study with the corresponding solvent-free microwave activated reaction showed the superiority of the ball-milling method; 31 examples are described, including the synthesis of the anti-aging agent C-phenyl-N-tert-butyl nitrone (PBN) and one of its analogues C-2-pyridyl-N-tert-butylnitrone (2-PyBN). [Copyright &y& Elsevier]

Abstract: A number of quantum chemical and density functional methods have been used to study the chemo- and regioselectivity of the uncatalysed and Lewis acid mediated cycloaddition of the nitrone PhCHth the CC (E)-cinnamonitrile. In agreement with experimental evidence, Lewis acid coordination to the nitrile strongly promotes reaction at the Cer reaction at the alkene moiety. The main factors responsible for this inversion of the chemoselectivity were identified as the following: (i) the Lewis acid strongly stabilises the product of Cn and the transition state leading to it, thus favouring this reaction both kinetically and thermodynamically. Addition across the Cn contrast, only receives weak kinetic activation; (ii) the cycloaddition to the C:glyph name="tbnd" />N bonds involves different molecular orbitals at the cinnamonitrile, and the Lewis acid influences the orbital involved in Cn to a larger extent; (iii) the Lewis acid has a stronger effect on the electron distribution of the Cs an overall result, the Lewis acid not only promotes the cycloaddition, but also alters the order of functional group reactivity and brings about a complete change in chemoselectivity. [Copyright &y& Elsevier]

Abstract: Diastereo- and regioselelective intra-molecular nitrone–olefin cycloaddition reaction of in situ generated N-benzylnitrones, obtained from d-glucose derived precursors 5a/5b furnished dihydroxy functionalized isoxazolidines. The N–O bond reductive cleavage and removal of N/O-benzyl groups led to the formation of stereochemically well defined aminocyclohexitols. [Copyright &y& Elsevier]

Abstract: The synthesis of some novel 3′-spirocyclic-oxindole compounds, based on the spiro[indole-3,5′-isoxazolidin]-2(1H)-one, the 2′H-spiro[indole-3,6′-[1,3]oxazinane]-2,2′(1H)-dione and the 2′H-spiro[indoline-3,3′-pyrrolo[1,2-c][1,3′]oxazine]-1′,2(1H)-dione heterocyclic structures, is described. These compounds were prepared from methyl α-(2-nitrophenyl)acrylate via [1,3]-dipolar cycloaddition reactions with two acyclic nitrones and one cyclic nitrone followed by reduction of the cycloadducts and then treatment with triphosgene. Two of these compounds showed significant cytostatic activity on three cancer cell lines with GI50 values of 2.6–4.1μM on the human breast cancer cell line, MCF-7. [Copyright &y& Elsevier]

Abstract: The Lewis acid (LA) catalyzed 1,3-dipolar cycloaddition of N-benzylideneaniline N-oxide with acrolein has been studied using DFT calculations. Coordination of AlCl3 to the acrolein oxygen atom produces a drastic change in the mechanism along the more favorable meta reactive channel. The process is characterized by a strong nucleophile/electrophile interaction allowing the formation of a zwitterionic intermediate, a Michael-type addition. The subsequent ring closure constitutes the rate-determining step. The energies obtained with the inclusion of solvent effect by means of the polarizable continuum model are in good agreement with experimental findings. Analysis of the global and local electrophilicity allows to explain correctly the reactivity and regioselectivity of the LA catalyzed cycloaddition. [Copyright &y& Elsevier]