Dipole structures nitrones/nitronates

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... 

Relative contribution of each of these structures differs significantly and is determined by internal structural characteristics of the nitrones and by the influence of external factors, such as changes in polarity of solvent, formation of a hydrogen bond, and complexation and protonation. Changes in the electronic stmcture of nitrones, effected by any of these factors, which are manifested in the changes of physicochemical properties and spectral characteristics, can be explained, qualitatively, by analyzing the relative contribution of A-G structures. On the basis of a vector analysis of dipole moments of two series of nitrones (355), a quantum-chemical computation of ab initio molecular orbitals of the model nitrone CH2=N(H)0 and its tautomers, and methyl derivatives (356), it has been established that the bond in nitrones between C and N atoms is almost... 

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. 

Nitronates are among the most readily available and rather reactive 1,3-dipoles. The structure B in Scheme 3.84 is responsible for the reactivity of nitronate molecules. 

It has long been recognized that nitrone cycloadditions may allow access to spirocyclic ring systems. Such systems are inherently difficult to synthesize by conventional methods, yet are a structural component of a number of biologically active natural materials. Two common strategies have emerged for spirocycle generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic version, the carbon atom (arrowed) of the nitrone C=N double bond of dipole 209 carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will... 

Because of the intrinsic structural asymmetry of this dipole, there exist two possible regioisomers resulting from the cycloaddition with unsymmetrical dipo-larophiles. The reaction of a monosubstituted dipolarophile with a nitronate, in a head-to-head fashion provides a 5-substituted isoxazolidine (Scheme 2.4). Alternately, the head-to-tail combination of the coupling partners results in a 4-substituted isoxazolidine. With only a few exceptions (92), the 5-substituted isoxazolidine is formed exclusively. 

Fig. 2.3 shows the core structures of the most important 1,3-dipoles, and what they are all called. As with dienes, they can have electron-donating or withdrawing substituents attached at any of the atoms with a hydrogen atom in the core structure, and these modify the reactivity and selectivity that the dipoles show for different dipolarophiles. Some of the dipoles are stable compounds like ozone and diazomethane, or, suitably substituted, like azides, nitrones, and nitrile oxides. Others, like the ylids, imines, and carbonyl oxides, are reactive intermediates that have to be made in situ. Fig. 2.4 shows some examples of some common 1,3-dipolar cycloadditions, and Fig. 2.5 illustrates two of the many ways in which unstable dipoles can be prepared. 

Nitrone derivatives of a unique structure were prepared recently130. The two stereoisomers 43a and 43b are in equilibrium in solution configuration was determined by means of NMR spectroscopy. Dipole moments were calculated by MNDO for both stereoisomers, but were not measured. In our opinion one suitable approach has thus been omitted. 

One important nitrone is a cyclic compound that has the structure below and adds to dipolarophiles (essentially any alkene ) to give two five-membered rings fused together. The stereochemistry comes from the best approach with the least steric hindrance, as shown. There is no endo rule in these cycloadditions as there is no conjugating group to interact across space at the back of the dipole or dipolarophile. The product shown here is the more stable exo product. 

Examples of 1,3-dipoles include diazoalkanes, nitrones, carbonyl ylides and fulminic acid. Organic chemists typically describe 1,3-dipolar cycloaddition reactions [15] in terms of four out-of-plane 71 electrons from the dipole and two from the dipolarophile. Consequently, most of the interest in the electronic structure of 1,3-dipoles has been concentrated on the distribution of the four Jt electrons over the three heavy atom centres. Of course, a characteristic feature of this class of molecules is that it presents awkward problems for classical valence theories a conventional fashion of representing such systems invokes resonance between a number of zwitterionic and diradical structures [16-19]. Much has been written on the amount of diradical character, with widely differing estimates of the relative weights of the different bonding schemes. 

In the case of cycloadditions with allyl-type" dipoles1, either one e.g., with nitrones, azomethine imines or two e.g., with azomethine ylides, additional stereocenters can be created depending on the structure of the dipole ... 

Scheme 10.7 gives some other examples of 1,3-DPCA reactions. Entries 1 to 3 are typical intermolecular 1,3-DPCA. The 1,3-dipoles in each instance are isolatable compounds. Entries 4 and 5 are intramolecular nitrone cycloadditions. The product from Entry 5 was used in the synthesis of the alkaloid pseudotropine. The proper stereochemical orientation of the hydroxyl group is ensured by the structure of the isoxazoline from which it is formed. 

Cycloadditions are stereospecific cis additions, as has been shown in several cases using geometric isomers as dipolarophiles . In addition to the rigid structure of norbornene, as well-defined approach is preferred, namely the one that gives an exo adduct, as is shown in (a) above for azides, but also occurs with C-phenyl-N-methyl-nitrone and for diphenylnitrilimine -. The alternative approach of the reactants is sterically hindered in the case of norbornene the steric course of reactions of norbornadiene can be different, as was found using phenyl azide as the 1,3-dipole . 

It is possible to compare the reactivity of some 1,3-dipoles inserted in cyclic structures with that of the same dipoles in open chains. This comparison, recalling that between cyclic and open-chain dienes (Section 4.1.3), is limited to two classes of 1,3-dipoles without a double bond , namely azomethine imines and oxides. For the former, there are data in Table 12 for the reaction with dimethyl acetylene dicarboxylate (iii) the cyclic azomethine imine (sydnone) is about 300 times less reactive than the open-chain cyanoazo-methine imine. In the case of nitrones, a typical comparison is. for reaction with ethyl crotonate in toluene at 100°C "... 

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