Aryl nitrones, cycloaddition

This homoenolate methodology has been extended to the use of nitrones 170 as electrophiles [72]. Scheldt and co-workers have shown that enantiomerically enriched y-amino esters 172 can be prepared with excellent levels of stereocontrol from an enal 27 and a nitrone 170 using the NHC derived from triazolium salt 164 (Scheme 12.37). The oxazinone product 171, formally a result of a [3-1-3] cycloaddition, is cleaved to afford the y-amino ester product 172. The reaction shows broad substrate scope, as a range of substituted aryl nitrones containing electron donating and withdrawing substituents are tolerated, while the enal component is tolerant of both alkyl and aryl substituents. 

As for the regioselectivity of the nitrone cycloaddition to MCP and its alkyl or aryl derivatives, a tendency of the three-membered ring to end up at the 4-position of the final isoxazolidine ring clearly emerges from the experimental findings. This result is particularly noteworthy if compared to regiospecific formation of the 5,5-disubstituted isoxazolidines in the reactions of nitrones, not... 

The one step domino cycloaddition-rearrangement process of A-aryl nitrones 78 to BCP (79) afforded spirocyclopropane-annelated pyridones 81 and benzazocinones 82 in good overall isolated yields <00SL1034>. 

An addition to the earlier cycloadditions is the self condensation of an N-methyl-C-aryl nitrone (18) in the presence of potassiunt cyanide (Scheme 4.2.8) [22, 23[. The reactions are carried out in mild conditions (room temperature overnight in aqueous ethanol), but although the yields are good there arc no obvious advantages over other methods which are available for making 4,5-diarylimidazoles. Oie nitrones (18) are, however, readily available from Af-aryl- or iV-alkylhydroxylamines and aryl aldehydes [24], and so there may be occasions when the approach could be useful. 

CsMes)M (i )-l,2-bis(diphenylphosphino)propane (H20)] were found to catalyze the 1,3-dipolar cycloaddition of some acyclic and cyclic nitrones with methacrolein with complete diastereoselectivity and good enantioselec-tivity. Some intermediates involved in the process were isolated and characterized and a catalytic cycle involving [M]-aldehyde, [M]-nitrone, and [M]-adduct species was proposed <2005JA13386>. The reactions of A -phenyl C-aryl nitrones with the electron-poor a-bromoacrolein were effectively catalyzed by Zn(ll) complexes such as 534 and afforded isoxazolidine-4-carboxaldehydes, with high diastereo- and enantioselectivity, that were reduced to the corresponding alcohols (Scheme 123) <2004TL4061>. 

Another C-C-C-X fragment is shikimic acid-derived 4,5-epoxy-3-hydroxycy-clohex-l-ene-l-carboxylic acid [270]. The latter can be bound onto an amino group which is bound to TentaGel via a Gysen Linker (367) [322]. Subsequent esterification with alkyl or aryl nitrone acids according to Tamura et al. [323] was concurrent with [2 -i- 3]-cycloadditions to the allylic double bond. As a result, tricyclic lactones (370) were obtained, which could readily be modified in many ways to yield a wide variety of polyfunctional structures (Scheme 77). 

MacMillan s imidazolidinone salts, used successfully in the organocatalysed Diels-Alder reaction (see Section 8.1) also function as effective catalysts in the asymmetric nitrone cycloaddition with simple monodentate dipolarophiles. Thus acrolein (8.63) and crotonaldehyde (8.99) both react with acyclic C-aryl, N-benzyl nitrones and C-aryl N-alkyl nitrones such as (8.198) with high ees ranging from 90 to 99% in the presence of the perchlorate salt of imidazolidinone (8.91). 

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... 

Cycloaddition of a-aryl-A-phenylnitrones to the C16-C17 n-bond in 16-dehydropregnenolone-3P-acetate (545) involves only the minor rotamer (A-form) of the nitrones. It proceeds regio-, stereo- and Jt-facial-selectively to give steroido[16,17-d]isoxazolidines (546) in high yield (Scheme 2.257), (Table 2.24) (760). Similarly the cycloaddition of a,N -diphenylnitrones proceeds with five-membered heterocyclic enones (761). 

In 2008, Yamamoto et al. disclosed an asymmetric 1,3-dipolar cycloaddition of diarylnitrones 156 with ethyl vinyl ether (157) (Scheme 66). Under the influence of the bulky chiral A-triflyl phosphoramide (5)-4s (5 mol%, R = 2,6- Prj-4-Ad-C Hj), the enrfo-products 158 were formed as the major diastereomers in good yields and enantioselectivities (66 to >99%, 7 1-32 1 endolexo, 70-93% ee(endo)) [86]. High asymmetric induction was achieved only with electron-deficient aryl groups on the nitrones. 

The reaction is versatile and proceeds with a variety of cyclic and acylic alkenes substituted with alkyl, aryl, vinyl and heteroatom substituents. Allene derivatives also undergo cycloaddition with nitrones ". A variety of cyclic and acyclic aliphatic nitrones bearing aliphatic and aromatic substituents has been tested. The reaction is, however, relatively sensitive to steric constraints and proceeds easily only for mono- and disubstituted alkenes. Steric requirements for a nitrone molecule are similar and, although several reactions with R, R2 are known, good yield has been achieved only with R = H (equation 105). 

The intermolecular alkylation of metallo nitronates with various alkyl halides is limited. The addition of methyl iodide to the silver salt of an aryl nitro-methane provides the corresponding methyl nitronate in moderate yield (Eq. 2.13) (150), which has also been extended to the silver salt of trinitromethane (Scheme 2.16) (151-153). However, in the case of primary halides, both O- and C-alkylation are observed. For secondary and tertiary halides, only O-alkylation is observed, but in low yields. Unfortunately, under the reaction conditions, the starting alkyl halide can undergo dehydrohalogenation to provide the corresponding alkene, which then undergoes [3+2] cycloaddition with the alkyl nitronate. 

Chiral exocyclic alkenes such as 112, also having the chiral center two bonds away from the reacting alkene moiety, have been used in highly diastereoselective reactions with azomethine ylides, and have been used as the key reaction for the asymmetric synthesis of (5)-(—)-cucurbitine (Scheme 12.37) (169). The aryl sulfone 113 was used in a 1,3-dipolar cycloaddition reaction with acyclic nitrones. In 113, the chiral center is located four bonds apart from alkene, and as a result, only moderate diastereoselectivities of 36-56% de were obtained in these reactions (170). 

Nitrogen heterocycles continue to be valuable reagents and provide new synthetic approaches such as NITRONES FOR INTRAMOLECULAR -1,3 - DIPOLAR CYCLOADDITIONS HEXAHYDRO-1,3,3,6-TETRAMETHYL-2,l-BENZISOX AZOLINE. Substituting on a pyrrolidine can be accomplished by using NUCLEOPHILIC a - sec - AM IN O ALKYL ATION 2-(DI-PHENYLHYDROXYMETHYL)PYRROLIDINE. Arene oxides have considerable importance for cancer studies, and the example ARENE OXIDE SYNTHESIS PHENANTHRENE 9,10-OXIDE has been included. An aromatic reaction illustrates RADICAL ANION ARYLATION DIETHYL PHENYLPHOSPHONATE. 

Chiral crotonates derived from S-citronellol, l-(—)-menthol, and 5-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active trifluoromethylated a, /i-unsaturated aryl sulfones (43) with nitrones yield the corresponding isoxazolidines (44) and (45) with high regio- and... 

The chemo-, regio-, and stereo-selective 1,3-dipolar cycloaddition of C-aryl-iV-phenylnitrones with 3,5-bis(arylidine)-l-methylpiperidin-4-ones produced mono- and bis-spiroisoxazolidines, with the former predominating.52 The 1,3-dipolar cycloaddition of five-membered cyclic nitrones with a, fl-unsaturated y-lactones provides an interesting example of a double asymmetric induction.53 Eu(fod)3 catalysed the ... 

A method was proposed [196] for the production of 4-phosphazenyl-2,3-dihydropyrrol-2-ones and 5-phosphazenyl-2-pyridones from p-(N-acylphosphazenyl)enamines of dimethyl acetylenedicarboxylate. The authors of [197] examined the chemoselective cycloaddition of C-aryl-N-phenyl nitrones at the 1,2 double bond of allenylphosphonates, leading to a mixture of adducts possessing pyrrolidine and isoxazolidine structures. 

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