Dipolarophiles general reactivity

CL973 87BCJ4079). In other words, the competitive ylide trappings in general favor olehnic dipolarophiles rather than carbonyl dipolarophiles, indicating that olefins would be better dipolarophiles toward azomethine ylides. Padwa has established a more quantitative estimate of the relative reactivity of C-unsubstituted azomethine ylide 43 (R = PhCHj) toward a variety of dipolarophiles (87JOC235). Reactivities relative to that of benz-aldehyde (1.0) are shown in parentheses benzaldehyde is less reactive than thiobenzophenone (1.2), dimethyl fumarate (1.9), and Al-phenylmaleimide... 

The 2n component 2, the so-called dipolarophile (analogously to the dieno-phile of the Diels-Alder reaction) can be an alkene or alkyne or a heteroatom derivative thereof. Generally those substrates will be reactive as dipolarophiles, that also are good dienophiles. 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631... 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

Diazoazoles, because of charge polarization and potential bifunctional reactivity of the derived betaine, react with dipolarophiles to give cycloaddition products. Generally all the diazoazoles react with electron-rich, unsaturated derivatives. The cycloaddition reaction with isocyanates is readily observed in the case of the reactive 3-diazopyrazoles, but it is much slower with other diazoazoles. By contrast, reaction with ylides and diazoalkanes is only observed for 3-diazopyrazoles and 3-diazoindazoles. 

The ozonolyses of enol ethers has been reviewed <91MI 4l6-0l>. The relative dipolarophilicity of certain species to attack by carbonyl oxides has been investigated and, in general, the order of reactivity is aldehydes > enol ethers > esters ss ketones. It is apparent that enol ethers are very reactive towards carbonyl oxides, so much so that 1,2-dioxolane formation can be a major reaction pathway (especially for formaldehyde-O-oxide) <85JOC3365>. 

The meso-ionic l,3-dithiol-4-ones (134) participate - in 1,3-dipolar cycloaddition reactions giving adducts of the general type 136. They show a remarkable degree of reactivity toward simple alkenes including tetramethylethylene, cyclopentene, norbomene, and norbor-nadiene as well as toward the more reactive 1,3-dipolarophilic olefins dimethyl maleate, dimethyl fumarate, methyl cinnamate, diben-zoylethylene, A -phenylmaleimide, and acenaphthylene. Alkynes such as dimethyl acetylenedicarboxylate also add to meso-ionic 1,3-dithiol-4-ones (134), but the intermediate cycloadducts are not isolable they eliminate carbonyl sulfide and yield thiophenes (137) directly. - ... 

The relative rate constants (fe ) do not account for the fact that approach of the nitrile oxide to the 7i-bond can occur from both olefinic diastereofaces with two regioisomeric modes of reaction (Scheme 6.14). In the case of achiral 1-alkenes, only one regioisomer is formed. With chiral dipolarophiles, preference for one of the two is usually found (diastereodifferentiation). The relative diastereofacial reactivity (fejH) is used to evaluate this effect (121). With ethylene, there are four possibilities of attack (two for each face corresponding to the different regio-isomers), and the of each is set as 0.25. In diastereodifferentiating cycloadditions, such as those with a-chiral alkenes, the major isomer generally results... 

The highly effective desilylation routes to nonstabihzed azomethine ylides have provided the basis for much of this chemistry. Thus, the reaction of A-(silylmethyl)-thioimidates (30) with AgF in the presence of a range of dipolarophiles (electron-deficient alkenes and alkynes, and aldehydes) led to the isolation of nitrile ylide adducts in generally high yields (20,21). Differences in reactivity and regioselectivity... 

The thiocarbonyl group is a highly reactive dipolarophile and in general this group dominates the reactivity of nonenolisable exocyclic thioketones as illustrated for the systems shown 5-methylene-2-thioxo-l,3-thiazolinin-4-one (260) (161), pyrimidone-2- and -4-thiones (261, 262) (134), pyrazolo[l,5,4-e/][l,5]benzodi-azepin-6-thione (263) (162). 2-Thiono-4-imidazolidinone (264) also gave a C=S cycloadduct as expected but, in the case of the analogue 265 with an additional exocyclic methylene group, the latter proved to be more reactive (163). 

In general, LiBr and NEt3 are employed in 1.5 and 1.2 equiv, respectively. Although the reaction becomes rather slower, catalytic amounts of LiBr/NEt3 (0.1 equiv each) are also sufficient. In reactions with the highly reactive dipolarophile N-methylmaleimide, the catalytic reaction results in a better yield. A similar lithiation is possible with a-substituted (alkylideneamino)acetates and (alkylideneamino)-acetamides to generate lithium enolates (86). Cycloadditions with a variety of a,(3-unsaturated carbonyl compounds leads to endo cycloadducts. However, the reaction with acrylonitrile is again nonstereoselective. 

A major advantage of this indolizine synthesis is that the procedures are generally very simple and the process requires two steps at the most. Since the reactivities of 1,3-dipoles as well as dipolarophiles are sensitive to electronic and steric influences, the substituents in the 1-, 2- and 3-positions of the indolizine nucleus are restricted mostly to electron withdrawing and relatively small groups. If unsymmetric dipolarophiles have almost similar groups in polar and steric character at both ends of the reaction center, a mixture of the two possible isomers is often obtained. 

From the discussion in the foregoing section, it should be clear that the structure of the product(s) from the cycloaddition reactions is dependent on the nature of the reactants as well as reaction conditions. In this section an attempt will be made to look at the general factors influencing the selectivity and reactivity of the nonclassical A,B-diheteropentalenes. In simple terms, cycloaddition or bond formation between terminal carbon atoms occurs when the topology and symmetry of the orbitals of the reacting ylide system and the dipolarophile allow parallel approach (Figure 2). 

The general chemistry of the type B heteropentalenes (90) has not been widely explored. Like type A systems (Section 4.37.3.1) they are electron rich (high energy HOMO) and can be regarded as masked 1,3-dipolarophiles. They are reactive towards electron-deficient species and the main features of their known chemistry are (i) electrophilic substitution (e.g. 90 -> 89) and (ii) cycloaddition reaction with electron-deficient 1,3-dipolarophiles (e.g. 90 -> 91). Reactivity is reduced by aza substitution. 

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