Intramolecular 1,3-dipolar cycloadditions of norbornadiene-tethered nitrones.

Efficient routes to the synthesis of norbornadiene-tethered nitrones have been developed, and their intramolecular 1,3-dipolar cycloadditions were studied. The cycloadditions occurred in moderate to good yields for a variety of substrates and were found to be highly regio- and stereoselective, giving single regio- and stereoisomers in most cases.     

Intramolecular 1,3-dipolar cycloadditions of aliphatic nitrile oxides

Treatment of functionalized 1-chloro-oximes ( 3c and 4a,b ) with triethylamine originates nitrile oxides ( 1c and 2a,b ) which undergo an intramolecular cycloaddition providing fused-ring isoxazole derivatives ( 7c and 8a,b ). The latter reaction was not observed for one substrate ( 2c ).     

Highly regio- and stereoselective intramolecular 1,3-dipolar cycloadditions of norbornadiene-tethered nitrile oxides

[reaction: see text] Intramolecular cycloadditions with high regio- and stereocontrol are important methods for the efficient assembly of complex molecular structures. Efficient routes to the synthesis of norbornadiene-tethered nitrile oxides have been developed, and their intramolecular 1,3-dipolar cycloadditions were studied. The cycloadditions occurred in good yields for a variety of substrates and were found to be highly regio- and stereoselective.     

Intramolecular 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides

Intramolecular 1,3-dipolar cycloaddition of cyclo-1,3-diene- and -1,3,5-triene-tethered nitrile oxides gave tricyclic isoxazolines as a single stereoisomer in most cases. The relative stereochemistry of tricycle-fused isoxazolines resulting from 1,3-dipolar cycloaddition of cyclo-1,3-diene-tethered nitrile oxides is cis-cis, whereas from cyclohepta-1,3,5-triene-tethered nitrile oxides the cis-trans isomer predominates.     

Stereoconvergent and stepwise 1,3-dipolar cycloadditions of nitrile oxides and nitrile imines

The first example of stereoconvergent 1,3-dipolar cycloaddition of nitrile oxides and nitrile imines with E/Z isomeric mixture of electron-deficient olefins is reported, delivering isoxazolines and pyrazolines bearing two vicinal stereogenic tertiary and trifluoromethylated quaternary carbon centers with perfect regioand diastereoselectivities. The possibility of concerted cycloaddition/epimerization sequence under basic condition to form the thermodynamically stable diastereomers is excluded th...     

Asymmetric 1,3-dipolar cycloadditions of chiral carboxyloyl nitrile oxides to cycloalkenes

Asymmetric 1,3-dipolar cycloadditions of chiral carboxyloyl nitrile oxides derived from (2R)-bornane-10,2-sultam, (1R)-8-phenylmenthol, N,N-dicyclohexyl-10-sulfamoyl-(2R)-isoborneol, and 7,7-dimethylnorbornane-(1S,2R)-oxazolidinone to four cycloalkenes, leading to the corresponding 2-isoxazolines in both moderate yields and diastereoselectivities, are presented. All cycloadducts were converted into the corresponding alcohols, which were used for the determination of enantiomeric purity via chiral gas chromatography. In the case of the six-membered ring cycloadduct, the absolute configuration was determined by X-ray analysis.     

Transition structures of diastereoselective 1,3-dipolar cycloadditions of nitrile oxides to chiral homoallylic alcohols

Transition structures of the 1,3-dipolar cycloaddition of substituted nitrile oxides with chiral homoallylic alcohols were explored with density functional theory (B3LYP/6-311+G(d,p)+CPCM(dichloromethane)//B3LYP/6-31+G(d)). The diastereoselectivity observed in these reactions was explained. The anti product is favored in both the thermal and magnesium-mediated reactions. Selectivity is predicted to increase in the presence of magnesium, in agreement with experimental results. The energetics of the magnesium-mediated reaction are similar to those previously found for allylic alcohols. [structure: see text].     

Intramolecular 1,3-dipolar ene reactions of nitrile oxides occur by stepwise 1,1-cycloaddition/retro-ene mechanisms

Density functional theory studies of intramolecular ene-like (or the so-called 1,3-dipolar ene) reactions between nitrile oxides and alkenes (Ishikawa, T.; Urano, J.; Ikeda, S.; Kobayashi, Y.; Saito, S. Angew. Chem., Int. Ed. 2002, 41, 1586) show that this reaction is a three-step process involving a stepwise carbenoid addition of nitrile oxide to form a bicyclic nitroso compound, followed by a retro-ene reaction of the nitrosocyclopropane intermediate. The competitive reactions, either the intramolecular (3+2) reactions between nitrile oxides and alkenes or the intermolecular dimerizations of nitrile oxides to form furoxans, can overwhelm the intramolecular 1,3-dipolar ene reactions when the tether joining the nitrile oxide and alkene is elongated or some substituents such as trimethylsilyl are absent.     

Intramolecular 1,3-dipolar cycloaddition of nitrile N-oxide accompanied by dearomatization

Intramolecular 1,3-dipolar cycloaddition of 2-phenoxybenzonitrile N-oxides to benzene rings, accompanied by dearomatization, formed the corresponding isoxazolines in high yields. The X-ray single-crystal structure analysis revealed that the reaction formed the cis-adduct as a single isomer. The substituents on the benzene rings markedly affected the reaction rate, yield, and structure of the final product.     

C-glycosides. 3. 1,3-dipolar cycloaddition on nitrile and nitrilimine oxides

1.3-dipolar cycloaddition of alkenes (or alkynes) on sugars-nitriloxides and nitrilimines led respectively to 3-glycosyl-isoxazolines (or isoxazoles) and 3-glycosyl-pyrazolines (or pyrazoles). 5-glycosyl-isoxazolines were similarly prepared from arylnitriloxides and α- or ω-unsaturated sugars. These new C-glycosides are potential antiviral and anti-tumor agents.     

Intramolecular low-temperature 1,3-dipolar cycloadditions of nitrones: synthesis of chromano-heterocycles

In contrast to the reported facile intramolecular 1,3-dipolar cycloadditions of in-situ generated nitrone on heterocyclic systems, reactions of 2-(N-allyl/crotyl/cinnamyl-anilino)-3-formylchromones with N-phenyl-/methylhydroxylamine under comparable conditions, afford fused isoxazolidines only in low to moderate yields; the corresponding amides derived from rearrangement of in situ generated nitrones are formed as major products. However, when reactions were carried by stirring the reactants at an ice-cold temperature in dichloromethane, highly stereoselective intramolecular 1,3-dipolar cycloadditions lead to novel fused isoxazolidines in high yields (80-90%).     

Regioselectivity in the 1,3-dipolar cycloaddition of nitrile oxides to alkylidenecyclopropanes.

The 1,3-dipolar cycloaddition of nitrile oxides to methylenecyclopropanes substituted on the exocyclic double bond gives prevalently or exclusively 4-spirocyclopropane isoxazolines when the substituent is arylic or alkylic group, 5-spirocyclopropane isoxazolines when the substituent is an electron-withdrawing group. Adducts 16 and 17 selectively rearrange photochemically to the enaminoenone 19.     

1,3-dipolar cycloadditions to oxidopyraziniums

1,5-Dimethyl-3-oxidopyrazinium (6) undergoes cycloadditions with methyl acrylate, acrylonitrile, diethyl maleate, maleimide, methyl propiolate and diethyl acetylenedicarboxylate.     

Optically active nitrile oxides: synthesis and 1,3-dipolar cycloaddition reactions

Baker’s yeast-promoted reduction of the CC bond in 2-aryl-1-nitropropenes gave the corresponding optically active (R)-2-aryl-1-nitropropanes of high enantiomeric purity (ee >90%). They were next converted with the aid of the Mukaiyama and Hoshino method into the optically active nitrile oxides, which were made to react in situ with ethyl propiolate, methylvinyl ketone and (R)-1-phenyl-2-(phenylsulfonyl)ethyl acrylate to yield the appropriate, enantiomerically enriched, isoxazoles or 4,5-dihydroisoxazoles as diastereomeric mixtures, respectively.     

Hydrazide-catalyzed 1,3-dipolar nitrone cycloadditions

The triflate salts of cyclic hydrazides function as asymmetric catalysts for the [3+2]cycloadditions of nitrones with α,β-unsaturated aldehydes. The camphor-derived hydrazides show a preference for the exo isomers during these reactions, providing a compliment to other organically catalyzed dipolar cycloadditions. Enantiomeric excesses as high as 93% were realized for the exo isomers, while some endo products were obtained in 94% ee.     

1,3-Dipolar cycloadditions of prop-1-ene-1,3-sultone with nitrile oxides/nitrones

The scope and limitations of dipolar cycloaddition reactions between nitrile oxides/nitrones and prop-1-ene-1,3-sultone have been investigated. A remarkably high degree of regioselectivity and stereoselectivity was observed. The homochiral sultam 8e was synthesized in a four-step reaction sequence starting from the substituted isoxazoline 4e obtained from the cycloaddition. The absolute stereochemistry of this material was assigned by an X-ray crystallographic investigation of the intermediate 7e.     

Asymmetric 1,3-dipolar cycloaddition of nitrile oxides with optically active vinylboronic ester

Pinanyldioxy styrylboronic ester (1) was employed for asymmetric 1,3-dipolar cycloaddition with nitrile oxides, optically active △2-isoxazolines (3) or 4-hydroxy-△2-isoxazolines (4) were obtained. The effect of different bases on the selectivity of the cycloaddition reaction was studied.