1.3- Dipolar cycloaddition reactions with alkene

The meso-ionic l,3>2-oxathiazol-5-ones (169) show an interesting range of reactions with nucleophiles including ammonia, primary amines, and aqueous alkali. They also react with l,3-dipolarophiles, including dimethyl acetylenedicarboxylate and methyl propiolate, yielding isothiazoles (171) and carbon dioxide. 1,3-Dipolar cycloaddition reactions with alkenes such as styrene, dimethyl maleate, and methyl cinnamate also lead to isothiazoles (171) directly. BicycUc intermediates (cf. 136) were not isolable these cycloaddition reactions with alkenes giving isothiazoles involve an additional dehydrogenation step. 

Upon heating, aziridine 191 opened in the conrotatory manner to give azomethine yhdes 192 and/or 193, which underwent 1,3-dipolar cycloaddition reactions with alkenes and acetylenes. With styrene, for example, pyrrolidine 194 was formed exclusively in 81 % yield, and the regiochemistry of the cycloaddition was ascribed to control by the LUMO of the electron-deficient azomethine ylide. The cis relationship of the phenyl and benzoyl groups was attributed to secondary orbital interactions between them in the transition state. 

Chiral cyclic nitrones that have been obtained from recoverable chiral sources (e.g. camphor, L-menthone) did provide excellent selectivities in 1,3-dipolar cycloaddition reactions with alkenes. 

Azomethine imines readily undergo 1,3-dipolar cycloaddition reactions with alkenes and alkynes to furnish pyrazoUdines and pyrazolines, respectively (Scheme 5.21). 

Application of azomethine ylides in dipolar cycloaddition reactions with alkenes provides a route to pyrrolidine derivatives, as illustrated by the generation of the intermediate 12, and its subsequent conversion to the target system 13 (Scheme 16) <1995TL9409, CHEC-III(3.03.9)327>. 

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

The normal electron-demand principle of activation of 1,3-dipolar cycloaddition reactions of nitrones has also been tested for the 1,3-dipolar cycloaddition reaction of alkenes with diazoalkanes [71]. The reaction of ethyl diazoacetate 33 with 19b in the presence of a TiCl2-TADDOLate catalyst 23a afforded the 1,3-dipolar cycloaddition product 34 in good yield and with 30-40% ee (Scheme 6.26). 

The triphenyl derivative (91, R = R = R = Ph, R = H) is formed in a mechanistically interesting reaction between benzoyl formic acid anil (Ph-N=CPh-C02H), trifluoroacetic anhydride, and pyridine. Its 1,3-dipolar cycloaddition reactions with alkynes and alkenes have been reported. ... 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

Ramamoorthy et al. (444) found that a-phenyl-A-(4-methylphenyl)nitrone can be the guest molecule in inclusion complexes with a p-cyclodextrin host in 1 1 and 1 2 ratios (guest/host), and that the latter undergoes a 1,3-dipolar cycloaddition reaction with electron-deficient alkenes. In more recent work, they have formed 1 1 inclusion complexes of the bowl-shaped p-cyclodextrin 383 with (3-nitrostyrene 381 or 1-nitrocyclohexene 382, which leave the alkene moiety exposed (Fig. 1.9) (445). Complexes 381 and 382 undergo cycloaddition reaction with ot-phenyl-A-(4-methylphenyl)nitrone in the solid state after thorough homogenization (60 °C, 3 h) to give the 4-substituted products exclusively in 80 and 85% yield, respectively. 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

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). 

Salts of the linear [S=N=S]" cation (isoelectronic with CS2) are readily prepared. This cation undergoes quantitative, 1,3-dipolar cycloaddition reactions with unsaturated molecules such as alkenes, alkynes and nitriles, and also with NS" , to give a variety of ring compounds (Scheme 2.8). The... 

Alkene-functionalized 1,3-diene complexes undergo regio-and stereoselechve 1,3-dipolar cycloaddition reactions with nitrile A-oxides. Related cycloaddihons of nitroalkanes in the presence of triethyl amine and phenylisocyanate afford dihydroisoxazoles. This type of cycloaddition was used in a synthesis toward macrolactin A (Scheme 163). 

Nitrileoxidomethyl)penam sulfone, prepared in a few steps from commercially available (- -)-6-aminopenicilla-nic acid by treatment of oxime 617 with NCS and followed by dehydrochlorination with bis(tributyltin)oxide, underwent smooth 1,3-dipolar cycloaddition reactions with various alkynes, and alkenes, to give cycloadducts 618 in moderate to good yields. Some acid derivatives 618 (R = H) showed potent /3-lactamase inhibitory activity (Scheme 148) <20000L3087>. 

There are essentially two selectivity problems when dealing with 1.3-dipolar cycloaddition reactions to alkenes regioselectivity and stereoselectivity. The issue of regiocontrol has received extensive coverage116 and will not be further discussed here. This chapter will deal with the problem of stereochemistry of the cycloaddition which can be addressed at three different levels. 

Rate accelerations in 1,3-dipolar cycloaddition reactions between alkenes and nitrones as well as improvements in endo/exo selectivity were achieved with certain Lewis acids, such as ZnCl2, TiCl(OiPr)3, TiCl2(OiPr)2, Mg(II) salts or BF3 0Et2, ... 

Dipolar Cycloaddition. The principal use of p-bromobenzenesulfonyl azide is in 1,3-dipolar cycloaddition reactions with functionally substituted alkenes. The reagent has been used at ambient temperature and pressure to convert simple trimethylsilyl and methyl enol ethers of cyclic ketones to ring-contracted p-bromobenzenesulfonimidates, and thence to the corresponding amides, esters, or acids (eqs 1 and 2). 

The interaction of the capsnle with the diazoacetate esters did not lead to their decomposition. In fact, aU snbstrates remained nnaltered both in the presence and in the absence of the capsnle, even at 50°C for 20 h in water saturated chloroform-d. More interestingly, since this class of molecules are good partners for the 1,3-dipolar cycloaddition reactions with a large series of dipolarophiles [60], their interaction with electron-poor alkenes was investigated in the presence and in the absence of the capsule in order to ascertain its snpramolecular catalytic effects. 

Nitrones activated by chiral 2,2 -dihydroxy-l,P-bisnaphthol (BINOL)-AlMe complexes undergo enantioselective inverse-electron-demand 1,3-dipolar cycloaddition reactions with electron-rich alkenes to produce exo-diastereoisomers of isoxazolidines. The diastereoselectivity of the 1,3-dipolar cycloaddition between diphenyl nitrone and 4-(5 )-benzyl-( )-but-2 -enoyl)-l,3-oxazolidin-2-one can be controlled by inorganic salts whose cations behave like Lewis acids.The Cu(OTf)2-bisoxazoline-catalysed asymmetric 1,3-dipolar cycloaddition of nitrones with electron-rich alkenes at room temperature gave isoxazolidines in good yields and diastereoselectivity and with high enantioselectivities of up to 94% ee. ° Kinetic studies have shown that the reaction rate of the 1,3-dipolar cycloaddition of C,tV-diphenyl nitrone with dibutyl fumarate increases dramatically in aqueous solutions... 

Heteroatom Wittig chemistry also includes reactions of N-sulfonyl imines. It was demostrated that these compounds underwent olefination reactions with nonstabilized phosphonium ylides under mild conditions to afford an array of both Z- and E-isomers of 1,2-disubstituted alkenes, allylic alcohols, and allylic amines.Additionally, studies of the reactions of 5-bromo-4,6-dimethyl-2-thioxo-l,2-dihydropyridine-3-carboni-trile and thiazolidinone with phosphorus ylides have proved the formation of new phosphonium ylides. Annulations via P-ylides are a common occurrence in the literature. For example, on photochemical irradiation, phosphonium-iodonium ylides were shown to undergo 1,3-dipolar cycloaddition reactions with triple bonds, via a carbene intermediate, to yield furans. " Even more common are the reactions of Morita-Baylis-Hillman (MBH) acetates and carbonates. Zhou et al. demostrated that these substrates were able to generate very reactive 1,3-dipoles in the presence of tertiary phosphines the dipoles then underwent cycloaddition reactions to yield annulation products (Scheme 16). ... 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

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