Dipolarophiles maleic anhydride

Dipolarophiles most frequently employed in trapping of azomethine ylides are acetylenedicarboxylates and maleimides because they are much more reactive than most other dipolarophiles. Maleic anhydride is almost equal to maleimides in reactivity toward azomethine ylides, and furmarates and maleates rank next. These dipolarophiles are so highly reactive in 1,3-dipolar cycloadditions that most of the azomethine ylides cited in this article can be smoothly trapped as the corresponding cycloadducts. Accordingly, less reactive dipolarophiles are selected in this section in order to evaluate the reactivity of azomethine ylide 1,3-dipoles. 

However, at least one example is known of acetylated nitronic acids 9 (Scheme 8.3) supposed to react directly with a dipolarophile (dimethyl acetylenedicarboxylate) to give the expected isoxazole derivatives 11 via the unstable intermediate adducts 10 (R = Ph) rather than via nitrile oxides. In fact, isolated 9 (R = Ph), in standard reaction conditions but in the absence of dipolarophile, decomposed to benzoic acid, with no diphenylfuroxan being detected [30]. Notice that this result refers only to the mentioned dipolarophile, whereas attempted reaction with other dipolarophiles (maleic anhydride or diphenylacetylene) failed. 

In the reaction of fused aziridines with alkene dipolarophiles, the opportunity for stereoselectivity as well as facial selectivity arises since exo- or entfo-isomers can be formed (Scheme 10). In practice, maleic anhydride 6, A-methyl maleimide and JV-phenyl maleimide each reacted exo-stereoselectively with TV-benzyl aziridine 69 to form adducts of type 71 (Scheme 10b), the stereochemistries of which were confirmed by NOE measurement between Hb and He. Similar reaction of the Y-phenyl aziridine 67 with N-Ph maleimide gave a 1 1 mixture of endo-adduct 72 and exo-adduct 73 (Scheme 10c). Adducts 68, 71-73 all exhibited a low-field methano-bridge proton (Ha) in the range 5 3.06-3.60 confirming the syn-facial stereochemistry of the two bridges. 

In addition to the regioselectivity of the cycloaddition, there also exists a question of stereoselectivity. This issue involves the location of the substituent X on the dipolarophile in either an exo or endo fashion (Scheme 2.3). In the case of simple alkyl nitronates bearing an electron-withdrawing substituent, the stereoselectivity is highly dependent on both the nature of the dipolarophile and the configuration of the nitronate (Scheme 2.5) (96). In the case of nitronate 47, either a mixture of diastereomers or only the exo adduct is observed. However, the cycloaddition of maleic anhydride with 47 provides only the endo stereoisomer (97). 

The stereoselectivity of monosubstituted dipolarophiles has also been studied with cyclic nitronates (Table 2.30) (84). In most cases, an exo selectivity was observed. The ratio between the endo and exo adducts can be correlated to the size of the substituents on the dipolarophile. Because of the endo preference observed with acrolein, it is believed that there is a slight electronic preference for the endo orientation in the transition state, in the absence of steric hindrance. In line with these results is the observation that, for 49, maleic anhydride reacts with complete exo selectivity, in contrast the cycloaddition with 47 (69). 

Unsymmetrical dipolarophiles led to the formation a single regioisomeric product acrylonitrile delivered adduct 19 exclusively while maleic anhydride... 

An example of 2,4,6-triphenylpyrylium-3-olate (65 R = R = R = Ph, R = H) reacting as a 1,3-dipole was first provided by Suld and Price who obtained a maleic anhydride adduct (C25HigO5). Subsequently, an extensive study of the cycloadditions of this species has been published by Potts, Elliott, and Sorm. With acetylenic dipolarophiles, compound 65 (R = R = R = Ph, R = H) gives 1 1 adducts that have the general structure 74 and that isomerize to 6-benzoyl-2,4-cyclohexadienones (76) upon thermolysis. This thermal rearrangement (74 -> 76) has been interpreted in terms of an intermediate ketene 75. The 2,3-double bond of adduct 74 (R = Ph) is reduced by catalytic hydrogenation. Potential synthetic value of these cycloadducts (74) is demonstrated by the conversion of compound 74 (R = Ph) to l,2,3,4,6-pentaphenylcyclohepta-I,3,5-triene (79 R= Ph) via the alcohol 78 (Scheme 1). ... 

In its reaction toward aryl azides, /V-phenylmaleimide is found more active than maleic anhydride with rate constants for phenyl azide addition at 25°C being 72 and 2.8 x 10 6, respectively,28 although on the basis of orbital donor-acceptor interactions between dipoles and dipolarophiles, the reverse should be the case.315 Such anomalies can be explained by taking into consideration not only orbital donor-acceptor interactions but also localization energies thus maleic anhydride with a higher localization energy than V-phenylmaleimide is the less reactive of the two.315... 

When maleic anhydride is used as the dipolarophile, simple condensation occurs with benzothiazole giving a hve-membered cycloadduct as a mixture of cis and trans... 

Maleimides and maleic anhydride have been most frequently employed as cyclic cis-olefin dipolarophiles in the stereochemical investigation of 1,3-dipolar cycloadditions, especially on the endo and exo selection of the reaction. They are one of the most reactive dipolarophiles toward many kinds of azomethine ylide 1,3-dipoles. Because of their structural simplicity, the only stereochemical variation possible in cycloadditions is an endo and exo selection. If a strong attractive interaction exists between the extended conjugation of these dipolarophiles and azomethine ylides, an endo-selective cycloaddition results. 

Addition of electron deficient aUcenes, such as tetracyanoethylene to the dipole 20, generated by addition of diazomethane to methyl [(diaIkoxy)phosphinyl]dithioformates, gave the tetrahydrothiophene 21 in good yield. The application of cyclic dipolarophiles, such as maleic anhydride or A -phenylmaleimide in similar cycloadditions, provided access to the corresponding fused tetrahydrothiophene systems <05HCA2582>. 

In a related effort, Petrovanii et a/. 3,234 showed that when stabilized ylide 205 was generated in the absence of a dipolarophile only a dimer (206) could be isolated. Compound 205 was also shown to react with maleic anhydride to afford a 4a,5,6,7-tetrahydropyrrolo[ 1,2-6]-pyridazine (207) [Eq. (75)1. 

Since the discovery of the very remarkable 100% endo selectivity of the reactions of nitronic esters with dimethyl maleate, maleic anhydride and maleimides secondary orbital interactions involving the nitrogen atom of the 1,3-dipole and the substituents on the dipolarophile have been postulated as strong endo-orienting factors, able to overwhelm the contrasting steric factors (Figure 1). 

The synthesis of highly substituted furopyrroles, which are found in many biologically interesting natural products, has attracted considerable attention in recent years. Changing the dipolarophile from maleic anhydride to NPM... 

The 1,3-dipolar retro-cycloaddition reaction turned out to be quite general and occurs in the presence of an excess of a highly efficient dipolarophile (30 equiv), such as maleic anhydride, which traps the corresponding ylide resulting from the thermal retro-cycloaddition. In the absence of the metal salts, the reaction yields depend on the refluxing temperature, the pyrrolidine substitution pattern [unsubstituted (16a), monosubstituted (16b, c, e), and disubstituted (16d)] (Scheme 34.6), and the nature of the substituents on the pyrrolidine ring, which influence the stability of the thermally generated 1,3-dipole. 

Pyrrolidines and related compounds are readily available by 1,3-dipolar cycloaddition reactions of imines derived from a-amino-acid esters. The imines have now been shown to undergo a wider range of 1,3-dipolar cycloadditions with dipolarophiles such as maleic anhydride, N-phenylmaleimide, acrylonitrile, acrylate, and other activated olefins (Scheme 47). This study is an extension of earlier work which led to triazolidines. ... 

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