Nitronate as 1,3-dipole

Structure B is of most interest. It is responsible for the activity of nitronates as 1,3-dipoles in [3+ 2]-cycloaddition reactions. This is the most important aspect of the reactivity of nitronates determining the significance of these compounds in organic synthesis (see e.g., Ref. 267). In addition, this structure suggests that nitronates can show both, O -nucleophilic properties, that is, react at the oxygen atom with electrophiles, and a-C-electrophilic properties, that is, add nucleophiles at the a-carbon atom. 

Intramolecular [3+2]-Cycloaddition ofNitronates These reactions are more efficient than analogous intermolecular transformations of nitronates as [1,3]-dipoles, and, consequently, activation of the dipolarophilic fragment is not required. However, another problem arises, that is, the construction of the starting substrate combining the nitronate fragment and the C,C double bond in the required positions. 

If nitrones have been widely used as 1,3-dipoles in the synthesis of hexahydro-isoxazolo[2,3- ]pyridines, the use of nitroacetates such as 92 in the cycloaddition sequence allows for an efficient access to hexahydro-isoxazolo[2,3-tf] pyridin-7-ones such as 93 after spontaneous dehydration (Scheme 30) <2000JOC499>. 

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. 

Allylsilanes act as good acceptors of nitrones and oxyallyl cations. The 1,3-dipole species arising from electronically activated cyclopropanes can be trapped by allylsilanes.203 204 2043 Epoxides as well as aziridines act as 1,3-dipole precursors for inter- and intramolecular [3 + 2]-cycloadditions with allylsilanes.205 2053 206 2063... 

As mentioned above, nitro compounds are obviously of great importance in organic chemistry and aryl nitro compounds are an important source of aniline derivatives (secs. 4.2.C.V, 4.8.D). Both amine oxides and nitrones have been synthetically exploited. Alkyl nitroso derivatives, however, usually cannot be isolated since they decompose in solution, although the aromatic derivatives are more stable in solution and can be used in synthesis (sec. 2.1 l.E). Treatment of a primary amine with excess peroxyacid is a useful preparative route to alkyl nitro compounds.588 Yields are highest for tertiary alkyl primary amines next come secondary, followed by primary alkyl. Peroxyacid oxidation of oximes also provides a route to alkyl nitro compounds.589 This method is convenient for preparing aromatic nitro compounds as in the oxidation of 2,6-dichloroaniline to 2,6-dichloronitrobenzene (441).590 Nitrones are 1,3-dipoles and have been used in 1,3-dipolar cycloaddition reactions (sec. ll.ll.D). 

The same patent and publication (07W0106818,15JFC121) mentioned the preparation of 4-SF5-2,3,5-trisubstituted-4-isoxazolines 171a—d in case when nitrones 170a—c were used as 1,3-dipoles in cycloaddition reactions with SFs-alkynes 129a,c,d (Scheme 53). 

The 1,3-dipolar systems involved in the cycloaddition reaction with cumulenes include azides, nitrile oxides, nitrile imines, nitrones, azomethine imines and diazo compounds. However, some 1,3-dipolar systems are also generated in the reaction of precursors with catalysts. Examples include the reaction of alkylene oxides, alkylene sulfldes and alkylene carbonates with heterocumulenes. Carbon cumulenes also participate as 1,3-dipols in [3+2] cycloaddifion reactions. Examples include thiocarbonyl sulfides, R2C=S=S, and l-aza-2-azoniaallenes. 

The formation of isoxazolidines was explained by the [2,3]-sigmatropic rearrangement of the initial O-allyl ketoximes [318]. The nitrones primarily formed add as 1,3-dipoles to the second molecule of O-allyl ketoxime. 

Nitroalkenes 1 behave as heterodienes in [4+2] inverse electron demand cycloadditions with simple unactivated alkenes, enamines, or enol ethers (2) as dieno-philes. These reactions require the presence of a Lewis acid to enhance the reactivity of the nitroalkene and accelerate the process. The products obtained in such reactions are six-membered cyclic compounds called nitronates (3) (Scheme 22.1). These compounds can be used in turn, as 1,3-dipoles in [3+2] cycloaddition reactions. 

The commonly accepted mechanism for these isoxazole syntheses assumes the formation of intermediate mixed anhydrides between nitronic acid 6a and the acyl moiety. Many authors have illustrated these intermediates 6b (Scheme 8.2) where the acyl group (X = acyl) in turn is PhNHCO [5], MeCO [31,32,47,48], t-BuCO [32], t-BuOCO [42], EtOCO [37], PhCHaOCO [32], ArCO [32], PhSOa [37], p-TsO [36]. These nitronic mixed anhydrides are intermediates that usually carmot be isolated, unlike die esters alkyl nitronates 6c and silylnitronates 6d (Scheme 8.2). These esters 6c [49,50] and 6d [51-54] behave as 1,3-dipoles toward suitable dipolarophiles, and the resulting cycloadducts 7c and 7d are then converted into the final isoxazole derivatives by elimination of alcohol or silanol respectively in these cases cycloadditions precede elimination. 

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. 

Nitrones are a rather polarized 1,3-dipoles so that the transition structure of their cydoaddition reactions to alkenes activated by an electron-withdrawing substituent would involve some asynchronous nature with respect to the newly forming bonds, especially so in the Lewis acid-catalyzed reactions. Therefore, the transition structures for the catalyzed nitrone cydoaddition reactions were estimated on the basis of ab-initio calculations using the 3-21G basis set. A model reaction indudes the interaction between CH2=NH(0) and acrolein in the presence or absence of BH3 as an acid catalyst (Scheme 7.30). Both the catalyzed and uncatalyzed reactions have only one transition state in each case, indicating that the reactions are both concerted. However, the synchronous nature between the newly forming 01-C5 and C3-C4 bonds in the transition structure TS-J of the catalyzed reaction is rather different from that in the uncatalyzed reaction TS-K. For example, the bond lengths and bond orders in the uncatalyzed reaction are 1.93 A and 0.37 for the 01-C5 bond and 2.47 A and 0.19 for the C3-C4 bond, while those in... 

Chlordiazepoxide functions as a 1,3-dipole (a nitrone) in the reaction with ethyl propiolate to give the cycloadduct 20.247... 

Alkoxy)alkynylcarbene complexes have been shown to react with nitrones to give dihydroisoxazole derivatives [47]. Masked 1,3-dipoles such as 1,3-thia-zolium-4-olates also react with alkynylcarbene complexes to yield thiophene derivatives. The initial cycloadducts formed in this reaction are not isolated and they evolve by elimination of isocyanate to give the final products [48]. The analogous reaction with munchnones or sydnones as synthetic equivalents of... 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Nitronates show a similar reactivity to that of nitrones, and nitrones are one of 1,3-dipoles that have been successfully developed to catalyzed asymmetric versions, as discussed in the section on nitrones (Section 8.2.1). However, asymmetric nitronate cycloadditions catalyzed chiral metal catalysts have not been reported. Kanemasa and coworkers have demonstrated that nitronate cycloaddition is catalyzed by Lewis acids (Eq. 8.93).146 This may open a new way to asymmetric nitronate cycloaddition catalyzed by chiral catalysts. 

Mckillop (223) confirmed the existence of acetyl nitronate A derived from nitroethane by its trapping as a 1,3-dipole in the reaction with dimethyl acetyl-enedicarboxylate (Scheme 3.65). 

The nitrone PhCH=N(Me)—O was successfully applied as a 1,3-dipole to MesB=NMes and to Me3Si-(iBu)N—B=N[Pg.164]

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