The effect of hydrogen bond donors in asymmetric organocatalytic conjugate additions

A series of primary amine organocatalysts with various hydrogen bond donors were prepared and examined in the conjugate addition of isobutyraldehyde and acetone to trans-β-nitrostyrene and (E)-methyl 2-oxo-4-phenylbut-3-enoate. The effect of N–H acidity and hydrogen-bonding modes of the catalysts on the catalytic activity and enantioselectivity was studied. The experimental results did not support a general correlation of N–H acidity and hydrogen-bonding modes with catalytic activity and enantioselectivity. The catalysts with double hydrogen-bonding interactions provided better catalytic activities and enantioselectivities than the catalysts with single hydrogen-bonding interactions for the reaction of trans-β-nitrostyrene. The catalyst with the most acidic N–H bond showed the best catalytic activity and enantioselectivity for the reaction of (E)-methyl 2-oxo-4-phenylbut-3-enoate. These results suggest that the effect of hydrogen bond donors in organocatalytic reactions may be highly dependent on the substrates and the reaction conditions.     

The role of the trifluoromethyl group in reactivity and selectivity in polar cycloaddition reactions. A DFT study

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.     

An expedient approach for the regio- and stereoselective synthesis of novel spiroindolizidines via [3+2] cycloaddition

A new series of spiroindolizidines was synthesized by one-pot, three-component condensation of azomethine ylides, generated from 1,2,3,4-tetrahydroisoquinoline with ninhydrin or isatin derivatives by a 1,5-prototropic shift route, with various derivatives of trans-β-nitrostyrene in a regio- and stereoselective manner. X-ray crystal structure analysis and NMR spectroscopic data confirmed the structure outcome of the cycloaddition reaction.     

A highly diastereoselective Tandem radical reaction. Facile three-component routes to protected (E)-polysubstituted homoallylic alcohols

A facile synthesis of geometrically pure (E)-1,2,4-trisubstituted and (E)-1,2,4-tetrasubstituted homoallylic benzoates was developed. Various Lewis acids were subsequently evaluated in the diastereoselective radical substitution of (E)-β-nitrostyrene, and Titanium (IV) 2-ethylhexoxide emerged as the best Lewis acid in terms of yield and diastereoselectivity (up to 98% de). These reactions occurred with high regio-, diastereo- and stereoselectivity, and a possible mechanism to explain this transformation was proposed.     

Synthesis and regiochemistry of spiro indane-1,3-dione compounds

Spiro indane-1,3-dione compounds have been synthesized by 1,3-dipolar cycloaddition of ninhydrin, l-proline, and an alkene (either a chalcone or an (E)-??-arylnitrostyrene). All these reactions proceed with good yield and with high regioselectivity and stereoselectivity. The structures were studied by NMR spectroscopy, MS, and X-ray diffraction analysis. It was found that these two kinds of alkene lead to different regioselectivity. This study has provided information about the regioselectivity of 1,3-dipolar cycloaddition reactions: regioselectivity may be controlled by ?ШC?? stacking state; the order of stability of stacking of the Ar and EWG part with the indane-1,3-dione part is: benzoyl group?>?phenyl group?>?nitro group.     

Are any non-stereospecific 1,3-dipolar cycloadditions known? A revision

The cycloaddition of 1-benzylidenepyrazolid-3-one betaine to (E)-β-nitrostyrene, which has been claimed to furnish 15–30% non-stereospecific product, revealed stereospecificity up to 99.92% in a renewed study; (Z)-β-nitrostyrene stereoisomerizes under the influence of the 1,3-dipole.     

Nitroalkylation and nitroalkenylation reactions of γ-lactone enolates. A facile ring switch from polysubstituted γ-lactones to polysubstituted γ-lactams

Michael addition of lithium enolates of γ-butyrolactone 1 and α-methyl-γ-butyrolactone 1′ to (E)-1-nitropropene 2, (E)-β-nitrostyrene 3 and (E)-2-nitro-1-phenylpropene 4 is described. Reactions of the lithium enolate of 1′ with 2 and 4 occurred with high diasteroselectivity (80 and 92% d.e., respectively). Reactions of the zinc enolate of 1′ with two β-nitroenamines and two methylthio-substituted 1-amino-2-nitro-1,3-dienes were also examined. Catalytic reduction of the nitroalkylated and nitroalkenylated products allowed the achievement of functionalized γ-lactams and/or cyclic hydroxamic acids.     

Ag/ThioClickFerrophos catalyzed highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with alkenes

A silver(I)/ThioClickFerrophos complex catalyzed the endo selective asymmetric 1,3-dipolar cycloaddition reaction of methyl N-benzylideneglycinate (the source of azomethine ylides) with α,β-unsaturated esters and maleimides to give the endo-2,4,5- and 2,3,4,5-substituted pyrrolidines in good yields with high enantioselectivities (up to 99% ee). The complex also effectively catalyzed the endo selective reactions with β-nitrostyrene to give the 4-nitropyrrolidine in a high enantioselectivity.     

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20-100 °C, 10-60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77-83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59-63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.     

Efficient asymmetric selenocyclizations of alkenyl oximes into cyclic nitrones and 1,2-oxazines promoted by sulfur containing diselenides

Treatment of the di-2-[(1S)-1-(methylthio)ethyl]phenyl diselenide or of the di-2-methoxy-6-[(1S)-1-methylthio)ethyl]phenyl diselenide with bromine and silver triflate afforded the corresponding electrophilic selenylating triflates which were used in situ to promote the asymmetric selenocyclization of γ-alkenyl oximes and δ-phenyl-γ-alkenyl oximes. The course of these reactions and hence the structures of the cyclization products were dictated by the (E)- or (Z)-geometry of the starting oximes. The two types of cyclization products were either the cyclic nitrones or the 1,2-oxazines; in both cases the reactions proceeded with excellent yields, complete regioselectivity and good diastereoselectivity.     

Cycloaddition of a 1,2-diaza-1,3-butadiene to phenylpropiolic acid: an efficient route to pyridazinoquinolone derivatives

Diazocoupling of dihydroquinolin-4-ones with aryldiazonium nitrates gave the corresponding diazo derivatives, which undergo facile (4+2) cycloaddition reactions with phenylpropiolic acid to afford 2-aryl-4a-methyl-10-oxo-4-phenyl-2,4a,5,10-tetrahydropyridazino[4,3-b]quinoline-3-carboxylic acid derivatives 3. However, with β-nitrostyrene a mixture of three isomeric products 4a-c was obtained.     

Reactions of (E)-3,3,3-trichloro(trifluoro)-1-nitropropenes with enamines derived from cycloalkanones. A new type of ring-chain tautomerism in a series of cyclobutane derivatives and stereochemistry of the products

Depending on the reaction conditions, the reactions of (E)-3,3,3-trichloro-1-nitropropene with cyclohexanone enamines led to bicyclo[4.2.0]octanes or trisubstituted enamines, which are the ring-chain tautomers capable of reversible transformations. Diastereoselectivity of the reactions of (E)-3,3,3-trichloro(trifluoro)-1-nitropropenes with cycloalkanone enamines were studied, a series of hitherto unknown CX₃-containing nitroalkylated enamines and γ-nitro ketones were synthesized, the structures of novel compounds were determined by NMR spectroscopy and X-ray diffraction.     

Regio- and stereoselectivity of the 1,3-dipolar cycloaddition of azomethine ylides to (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones: A combined experimental and theoretical study

Functionalized oxindoles and pyrrolizidines form the central structural framework for numerous natural products with extensive biological and pharmacological applications. The requirement for high regio- and stereoselectivity is the main obstacle in the synthesis of such five-membered heterocycles. Multicomponent cycloaddition reactions often provide an efficient and straightforward approach for the preparation of specific regio- and stereoisomers. In this article, the regio- and stereochemistry of the polar [3 + 2]-cycloaddition (32CA) reaction of azomethine ylides prepared by the reaction of isatin derivatives and L-proline with a series of (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-ones was investigated by experimental and theoretical methods. Among the isatin and (E)-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one derivatives, a remarkable inversion of regioselectivity was observed in the 32CA reaction of azomethine ylide generated by the reaction of L-proline and 5-chloroisatin or N-methyl-5-chloroisatin with (E)-5-chloro-3-(2-oxo-2-(pyren-1-yl)ethylidene)indolin-2-one. The regio- and stereochemical assignment of the structures of the cycloaddition products was determined by one- and two-dimensional (1D&2D) homonuclear and heteronuclear correlation nuclear magnetic resonance spectroscopy. The molecular mechanism as well as the regio- and stereoselectivity of the cycloaddition were investigated by means of global and local reactivity indices and a density functional theory (DFT) and explained in detail on the basis of the transition state stabilities of the reactants.     

Study of two diastereomeric pairs of regiosomeric 2-isoxazolines by tandem mass spectrometry with electron impact ionization

On electron impact (EI) ionization, two cis/trans pairs of 4-methyl-5-phenyl and 4-phenyl-5-methyl regioisomeric 3-carbethoxy-2-isoxazolines showed normal mass spectra and mass-analysed ion kinetic energy (MIKE) spectra of metastable (MI) and collision-activated (CA) molecule ions, allowing unequivocal differentiation of the regioisomers. The cis/trans stereoisomers of each regioisomer showed very similar normal mass spectra. Very interestingly, the cis- and trans-4-phenyl-5-methyl stereoisomers appeared reasonably differentiated by the molecule ion MIKE spectra, whereas the 4-methyl-5-phenyl regioisomeric pair of stereoisomers did not. The influence of the phenyl substituent to the fragmentation processes was notable. Some fragments of interest were studied by comparison of their MIKE spectra with those of model ions, generated by EI from suitable substrates, including (i) the isomeric α,β-unsaturated oxime, namely ethyl (Z)-2-(hydroxymino)-3-methyl-4-phenylbut-3-enoate, a by-product of importance for the mechanism(s) of the addition/cycloaddition reactions of nitrile oxides to alkenes and (ii) trans-β-methylstyrene, a dipolarophilic reactant in the same reactions. The favoured heterocyclic C(5)–O(1) bond cleavage occurred only for the ionized 4-methyl-5-phenyl 2-isoxazoline pair, leading to a distonic ion of relevance, as it can represent either a reasonable precursor for both the isomerization to the ionized α,β-unsaturated oxime and the EI-induced cycloreversion yielding ionized β-methylstyrene, or the ionized form of a zwitterionic intermediate, which had been proposed previously for the addition/cycloaddition mechanism(s) in the solution phase, currently under study.     

Conformational analysis of some (E)-α-phenyl-β-(2-thienyl)- and -(2-furyl_acrylic acids

NMR spectral data of some (E)-α-phenyl-β-(2-thienyl) acrylic acids indicate that these compounds exist in the preferred s-trans conformation. In the case of (E)-α-phenyl-β-(2-furyl)acrylic acids and their methyl esters the presence of only s-cis rotamer has been established.     

Nitrilimine cycloaddition onto 2-azetidinones bearing alkenyl dipolarophile(s)

Silver acetate-promoted nitrilimines cycloaddition onto 3(R*)-phenyl-4(R*)-cinnamoyl-2-azetidinone 1 were highly stereoselective giving 4-(4,5-dihydropyrazol-5-yl) carbonyl-2-azetidinones 5 as the major products and regioisomeric 4-(4,5-dihydropyrazol-4-yl) carbonyl-2-azetidinones 6 as the minor one. When the same protocol was applied to the novel 3(R*)-phenyl-4(S*)-(4-benzoyl-E,E-1,3-butadienyl)-2-azetidinone 2 it resulted in site- and regioselective but not stereoselective cycloaddition, involving the formation of the four cycloadducts 10-13.     

A new synthesis of the 2,2,3,5,6,6-substituted tetrahydropyran aplysiapyranoid A and its 5-epimer

The vanadium(V)-catalyzed oxidation of bromide in the presence of methyl (E)-2-(1-hydroxy-1-methylethyl)-5-phenyl-4-hexenoate furnished 5,6-trans-5-bromo-6-phenyl-2,2,6-trimethyl-3-methyloxycarbonyltetrahydropyran, which was converted into the marine natural product aplysiapyranoid A and its 5-epimer, via a short sequence of decarboxylative bromination and transition metal-based procedures for transforming a phenyl into a chlorovinyl substituent.     

Stereoselectivity, periselectivity, and regioselectivity in the cycloadditions of 8-(p-chlorophenyl)-8-azaheptafulvene with cyclopentadiene and fulvenes

The stereoselectivity, periselectivity, and regioselectivity in the cycloaddition reactions of 8-(p-chlorophenyl)-8-azaheptafulvene with cyclopentadiene and symmetrical/unsymmetrical fulvenes is described.     

Diasteroselective synthesis of oxazolidines and imidazolidines via the Lewis acid catalyzed C-C cleavage of aziridines

In this work, cis-2,5-disubstitutedoxazolidines were efficiently constructed via a regioselective C-C bond cleavage of N-tosylaziridine 2,2-dicaboxylates and a subsequent [3+2] cycloaddition with aromatic aldehydes in the presence of Zn(OTf)₂. The reactions were highly diastereoselective to form oxazolidines in cis configurations. trans-2,5-Disubstituted imidazolidines were also diastereoselectively synthesized in the similar manner using imines as substrates and AgOTf as catalyst. Based on the detailed investigation of the substrate diversity for both reactions, including the electronic effects and the steric effects of the substituted groups on the aziridines, aldehydes, and imines, a stepwise mechanism was postulated for the diastereoselective formation of cis-2,5-disubstitutedoxazolidines and trans-2,5-disubstituted imidazolines.     

Enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by a bis(oxazoline)-Cu(II) complex

The catalytic enantioselective Friedel-Crafts reaction of indole with trans-β-nitrostyrene is reported in the presence of copper triflate-bisoxazoline complexes. The reaction furnished nitroalkylated indoles in excellent yields (up to 95%) and high enantioselectivities up to an 86% ee.