Dipolarophiles relative reactivity

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

TABLE 6.3. RELATIVE REACTIVITIES (k,) AND RELATIVE DIASTEREOFACIAL RATES (k,K) OF CHIRAL DIPOLAROPHILES" ... 

The many successful applications of nitrile oxide cycloadditions in synthesis are intimately linked with theory, both the simple FMO variety as well as the more sophisticated ab initio treatment, where the work of Sustmann and subsequently of Houk and his group has been seminal. We, the practitioners, have thus been supplied with a consistent view on the nature of 1,3-dipoles, their reactivity toward dipolarophiles, and the origin and interpretation of stereoselectivity of cycloaddition chemistry. It is of course desirable that our understanding of the relative reactivities of alkenes as well as of many 1,3-dipoles would be also improved, thereby leading to simple, extended recipes for the chemist practicing synthetics. We hope that this account will stimulate further advances in this field of cycloaddition chemistry and promote further uses of nitrile oxides in organic synthesis. 

The most widely applied interpretation of substituent effects on relative reactivity is based on FMO theory. According to FMO theory, interacting orbitals are most stabilized when they are closest in energy. Substituent effects on dipolar cycloadditions can be interpreted in terms of matching of HOMO and LUMO orbitals of the two reactants.This is the same concept used in applying FMO theory to D-A reactions (see p. 844-848). In the D-A reaction, it is fairly clear which reactant is electrophilic and which is nucleophilic, and the interpretation of substituent effects follows directly. This choice is not always so obvious for 1,3-DPCA reactions. In fact, for several of the 1,3-dipoles both EWGs and ERGs in the dipolarophile enhance reactivity. These 1,3-dipoles are called ambiphilic. Let us look carefully to see why they have this property. 

Much of the relative reactivity data on 1,3-DPCA reactions has been tabulated and discussed in reviews by R. Huisgen, a pioneer researcher in the field.Some representative data are presented in Table 10.3. The dipolarophiles are shown in decreasing order of electrophilicity. The data from these monosubstituted dipolarophiles should be relatively free of steric influences on reactivity. Note that for phenyl azide and benzonitrile oxide, reactivity is at a minimum for unfunctionalized alkenes and is increased by both donor and acceptor substituents. 

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... 

Dipolarophiles which contain an electron-deficient substituent undergo smooth cycloaddition reactions with nitrile ylides. The relative reactivity of the nitrile ylide toward a series of dipolarophiles is determined primarily by the extent of stabilization afforded the transition state by interaction of the dipole highest-occupied (HO) and dipolarophile lowest-unoccupied (LU) orbitals. Substituents which lower the dipolarophile LU energy accelerate the 1,3-dipolar cycloaddition reaction. For example, fumaronitrile undergoes cycloaddition at a rate which is 189,000 times faster than methyl crotonate. Ordinary olefins react so sluggishly that their bimolecular rate constants cannot be measured. 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

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>. 

However, use of a less reactive reagent where [R = R =(CH2)4, (CH2)s, (CH2)20(CH2)2] led to the isolation of products 61 and 62, with a reduction in the yields of the desired cycloadducts. The product 62 arises from Michael addition of the liberated methanethiol to A-methylmaleimide. The protocol was further extended to olefinic dipolarophiles with dimethyl fiimurate, dimethyl maleate, fumaronitrile, and 2-chloroacrylonitrile leading to the corresponding adducts, although these dipolarophiles proved somewhat less reactive with reduced yields being observed. Where applicable, the alkene configuration was reflected in the relative stereochemistry of the cycloadducts (Fig. 3.5). 

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... 

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