Cycloaddition of nitrones

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

The reaction of nitrones with allenes produced three main products an azepine, a pyrrolidinone and an isoxazolidine (Scheme 155) (79JOC4213). The intramolecular cycloaddition of nitrones (529) produced different products depending on the length of n (Scheme 156) (78H(10)257). 

The cycloaddition of nitrones with ketenes produced 5-isoxazolidinones as well as oxazolones, as shown in Scheme 162 (78H(9)457, 79JOC2961). In a similar fashion, nitrones also react with ketenimines to generate the 5-isoxazolidinone imines (75JHC175, 68JHC881). 

The cycloaddition of nitrones to enamines results in the formation of an isoxazolidine (179,180). The reaction of l-(N-pyrrolidino)- -phenyl-ethylene (133) with nitrone 134 producing isoxazolidine 135 illustrates this type of cycloaddition (180). 

Cationic complexes of rran.s-chelating tridentate ligand, (/ ,/ )-4,6-dibenzo-furandiyl-2,2 -bis(4-phenyloxazoline), with transition metal(II) perchlorates as effective catalysts for asymmetric cycloaddition of nitrones 98YGK368. 

Application in organic synthesis of optically active isoxazolidones obtained by asymmetric cycloaddition of nitrones with allenes 97T403. 

Furukawa et al. also applied the above described palladium catalyst to the inverse electron-demand 1,3-dipolar cycloaddition of nitrones with vinyl ethers. However, all products obtained in this manner were racemic [81]. 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Cycloaddition of nitrones and of nitrile oxides to a, /J-ethylenic sulfoxides have been recorded102. 

Cycloadditions of nitrones, nitrile oxides or diazo compounds to thiete dioxides do not show the high stereoselectivity observed with acyclic vinyl sulfones, and mixtures of the two possible adducts are formed . The charge-transfer stabilization energy calculated according to the Klopman-Salem perturbational approach is able to account for the experimental trends of the isomer ratio in terms of the major stereochemical structural differences between the acyclic vinyl sulfones and the four-membered ring sulfones (see Section IV.B.3). 

Scheme 10.7 1,3-Dipolar cycloadditions of nitrones with 1,1-diethoxypropene catalysed by oxazaborolidines derived A-tosyl-L-a-amino acids.

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-0-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-0-allyl-D-glucose and -D-altrose (both with threo-configuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man-nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80... 

A series of 3-substituted-2-isoxazoles are prepared by the following simple procedure in situ conversion of nitroalkane to the silyl nitronate is followed by 1,3-dipolar cycloaddition to produce the adduct, which undergoes thermal elimination during distillation to furnish the isoxazole (Eq. 8.74). 5 Isoxazoles are useful synthetic intermediates (discussed in the chapter on nitrile oxides Section 8.2.2). Furthermore, the nucleophilic addition to the C=N bond leads to new heterocyclic systems. For example, the addition of diallyl zinc to 5-aryl-4,5-dihydroi-soxazole occurs with high diastereoselectivity (Eq. 8.75).126 Numerous synthetic applications of 1,3-dipolar cycloaddition of nitronates are summarized in work by Torssell and coworker.63a... 

Asymmetric 1,3-dipolar cycloaddition of nitronates using chiral alkenes has been reported,... 

The dipolar cycloadditions of nitrone (—)-353 prepared from protected glyceraldehyde 347 (Scheme 74), to dipolar-ophiles 354, 356, and 358 afforded the heterocycles 355, 357, 359-361, respectively (Table 14) <2005JOC3157>. 

The cycloadditions of nitrones to alkylidenecyclopropanes are, by far, the most studied reactions of this class. The first example reported in the literature refers to the cycloaddition of ZV-(phenylaminooxoethylidene)aniline iV-oxide (249) to 2,2-dimethylmethylenecyclopropane (250). The authors report about the formation of a single 5-spirocyclopropane fused regioisomer 251 (Scheme 41) [63]. 

Table 22. Regioselectivity of the cycloadditions of nitrone 256 to alkylidenecyclopropanes substituted with phenyl, electron-releasing and electron-withdrawing groups [67,68]...

The cycloadditions of nitrones to methylenecyclopropanes 285-287 (Table 23), 299 (Table 24, entry 3), and 311 (Table 25, entry 7) substituted on the ring occur with very high diastereofacial selectivity. Nitrone 256 gives with 1-methyl-ene-2-phenylcyclopropane (285) a mixture of four isomers in a 2 2 1 1 ratio... 

A remarkable switch in selectivity was observed by Wagner and coworkers in the cycloaddition of nitrones to free and coordinated ( )-cinnamonitrile (Scheme 6.208)... 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

Inter- and intramolecular 1,3-dipolar cycloadditions of nitrones under microwave irradiation have been reported to give heterocyclic derivatives. 

Microwave irradiation induces 1,3-dipolar cycloadditions of nitrones, such as 152, with aliphatic and aromatic nitriles in the absence of solvent. The products of these reactions are the corresponding 2,3-dihydro-l,2,4-oxadiazoles 156 (Scheme 9.48). The use of microwaves led to yields that were always higher than those obtained with classical heating, with the differences being more significant with the less reactive nitriles [99]. 

The intramolecular cycloaddition of nitrones derived from iV-allyl-2-indolecarbaldehyde was used to an entry to pyrrolo- and pyrido[ 1,2-a]indole skeletons . For instance, the cinnamyl-substituted aldehyde 157 upon treatment with benzylhydroxylamine affords to the nitrone 158, which upon heating in refluxing toluene leads to mainly the cycloadduct 159. 

With a terminal double bond to the nitrone group in the a-hydroxymethyl derivative (309), a typical 1,3-dipolar cycloaddition of nitrones gives compound... 

The tricyclic compound (441) is a key compound in the synthesis of enan-tiomerically pure indolizidine (442). It was obtained in an intramolecular 1,3-cycloaddition of nitrone (440), by retro-cycloaddition from isoxazolidine (439) (Scheme 2.215) (708). 

Regiospecilic intramolecular cycloadditions of nitrones to sulfur-substituted dienes, with 3-sulfolene precursors, has been realized (Scheme 2.217). The stereochemical outcome of these reactions is affected by the structure of the substituent (sulfide or sulfone) in the diene and by the chain length connecting the diene and nitrone (a) and (b) (see Scheme 2.211). The bicyclic products obtained from these reactions have been converted to interesting heterocyclic compounds (709). 

In agreement with Schemes 2.211b and 2.211c, intramolecular cycloadditions of nitrones to 5-allyl- (Scheme 2.225) or 5-homoallylproline (Scheme 2.226), are fully regio- and stereoselective. These reactions are the key steps in the synthesis of functionalized azaoxobicyclo[X.3.0] alkane amino acids, mimics of a homoSer-Pro dipeptide (721). 

Dipolarophiles D1 and D2. In the study of steric and electronic factors on regioselectivity and stereoselectivity of 1,3-cycloaddition of nitrones to olefins, 1-decene (734) and styrene derivatives (735) have been used. By comparative analyses of the kinetic and thermodynamic parameters in the 1,3-cycloadditions... 

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