Dipolarophiles enol ethers

Apart from the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity norbornene, for example, is consistently more reactive than cyclohexene in 1,3-DCA reactions. Conjugated functional groups usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enol ethers, enamines, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with several 1,3-dipoles are given in Table 10.6 of Part A. Additional discussion of these reactivity trends can be found in Section 10.3.1 of Part A. 

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>. 

Cyclic nitrone (52) has a cyclic bridge and cyclic enol ether dipolarophile thus all three elements are present in rings (Scheme 13).24 Models show that direct cyclization of (52) is not possible because of the relative positions of the dipole and dipolarophile. However, a pentacyclic cage isoxazolidine was formed by heating (52) presumably epimerization at the phenyl-bearing bridgehead carbon preceded cycloaddition. 

Olefinic double bonds substituted with one or more electron-withdrawing groups show significant dipolarophilic activity in cycloaddition reactions with organic azides,43,276-278 similar to the electron-rich double bonds of enamines and enol ethers the reactivity is less pronounced in azide additions compared to that observed in diazomethane reactions.7 The first triazolines reported resulted by the action of aryl azides on benzoquinones.1,279-281 As a rule, stereospecific cis additions occur,32 which are usually unidirectional except in the case of methacrylic derivatives67 and certain alkenes bearing... 

The reactivity of acyl cyanides versus carbonyl oxides could be compared in competition experiments with other 1,3-dipolarophiles. Thus when enol ether 109 was ozonized in the presence of an equimolar amount of benzoyl cyanide and 2,2,2-trifluoroacetophenone in diethyl ether at —70°C, a mixture of two ozonides 110 and 111 was obtained in yields of 32% and 45%, respectively, as shown by Equation (11). 

The tandem carbonyl ylide/cycloaddition reaction is also observed when crotonaldehyde or acetone is used instead of benzaldehyde (dimethyl fumarate as dipolarophile), whereas with cyclohexanone, an enol ether derived from the carbonyl ylide is isolated [19] (Scheme 9). 

Enamines, enol ethers and related compounds again encompass one-site nucleophiles and two-site dipolarophiles. Where the adducts are acyclic or where a coelectrophile is involved these appear to be examples of equation (1). In equations (217)-(219), the paths to the major products seem straightforward. While a competing... 

Enantioselective [3+2] cycloaddition of halohydrazones 692 with dipolarophile 691 in the presence of ligand 693 under Lewis acid conditions, followed by reduction, provided an entry to chiral dihydropyrazole scaffolds 694 in excellent yields and good ees (Scheme 86) <2005JA8276>. Highly enantioselective synthesis of pyrazolidines 698 was achieved by the [3+2] acylhydrazone-enol ether cycloadditions of 695 and 696 in the presence of a chiral silicon Lewis acid 697 (Equation 148) <2005JA9974>. 

Triphenylhydrazine reacts in a similar way with enol ethers to cinnoline derivatives (Table 12, number 5). The electrooxidation of A -alkylhydrazines leads to an iminium ion, which can react with olefins to five-membered rings [Eq. (28)] [254]. The anodic oxidation of phenylhydrazones of benzaldehyde affords diphenylnitrilimines, which add to dipolarophilic compounds [255]. 

The reactions of p-nitrostyrene (81a) with both acyclic and cyclic enol-ethers have been studied. In general, when electron-rich alkenes interact at 1.5 GPa with p-nitrostyrene (81a), mixtures of bicyclic or tricyclic regioisomers are obtained. For example, the reaction of 81a with enol ether 86 (Scheme 7.21) led to a 7 3 mixture of compounds 87 and 88. p-Nitrostyrene (81a) first reacts as an electron-poor diene in an inverse electron demand Diels-Alder reaction with the enol ether, and then as an electron-poor dipolarophile with the formed monoadduct in a 1,3-dipolar cycloaddition. 

The components were chosen based on the fact that (i) nitronates react faster with electron-poor alkene than with electron-rich alkenes and (ii) methyl acrylate reacts as an electron-poor dipolarophile because it does not react with the enol ether under high pressure conditions. The reaction of 81a, 82 and 89 afforded a 2.5 1 mixture of two main products, 90 and 91, in 62% yield (Scheme 7.22). 

The use of styrene as the dipolarophile in the reaction with either enol ether (10 or 14) and nitroalkene (31a or 31d) readily produced the corresponding nitroso acetals (33a, 33b and 33d), each as diastereomeric mixtures in 74, 65 and 77 % yield respectively (15 kbar, RT, 18 h. Scheme 9.11). 

A nice demonstration of the powerful effect of high pressure is the one-pot formation of nitroso acetals from stericaUy-hindered and low-activated dipolarophiles such as )ff-tra s-substituted a, -unsaturated esters. The di-substituted acrylates 42 and 44 reacted with enol ether (14) and nitrostyrene (15b) at 15 kbar and 50 °C in 18 h, producing nitroso acetals 43 and 45 as diastereomeric mixtures in yields of 82 and 74 %, respectively (Scheme 9.14). Seebach and coworkers previously reported that, although some modifications of the acrylate are tolerated (e.g. a-substitution), -substituted a,yS-unsaturated esters did not react with nitronates in refluxing toluene [24]. 

Nitrostyrene (15a) can react as a dienophile in the Diels-Alder reaction with 2-alkoxy butadienes producing cyclic enol ethers (Scheme 9.23). By using an excess of nitrostyrene a domino reaction should take place with the in situ-generated enol ether. j -Nitrostyrene (15a) may react subsequently as a dienophile in the Diels-Alder reaction with a 2-alkoxy butadiene, as a heterodiene in the inverse Diels-Alder reaction of alkoxy cyclohexene which is formed primarily, and as a di-substituted dipolarophile in the 1,3-dipolar cycioaddition of the nitronate formed in the inverse Diels-Alder reaction. 2-Methoxy-l,3-butadiene (61) was selected for the Diels-Alder reaction, since it reacted in a completely regioselective manner with nitroalkenes. 

Since three building blocks are involved in the domino cydoaddition reactions, adaptation to the solid phase can be performed either with a resin-bound enol ether, a resin-bound nitroalkene or a resin-botmd dipolarophile (Scheme 9.26). Some applications of the latter two possibilities will be discussed in this section [27]. 

The solid phase synthesis of nitroso acetals via a resin-bound dipolarophile will be described first. It has already been mentioned that nitronates react much faster with electron-poor alkenes than with electron-rich alkenes. The reaction of the nitronate formed in situ with the resin-bound acrylate is therefore expected to be faster than its reaction with the enol ether in solution. An acrylate was selected as dipolarophile and coupled to the resin via an ester linkage, which allows the facile cleavage of the resin-bound nitroso acetals by several methods (hydrolysis, reduc-... 

In related work, this same group found that isomunchnones 5 2 and 503 also react with electron-rich enol ethers to give the corresponding cycloadducts 504 in high yield (Fig. 4.152). In each case, a single diastereomer is isolated and the order of dipolarophilicity is CH2=CHOR > ( )-RCH=CHOR > (Z)-RCH=CHOR > CR2=CH0R CH2=CR(0R). 

The area of reactions of phosphate derivatives has been dominated by highly stereoselective reactions in which the latter were used as chiral catalysts or achiral reagents. Among this group of reactions, it is worthy to note several asymmetric reactions ring opening of w 50-aziridinium and episulfonium ions, addition of alcohols to imines, 1,3-dipolar addition of aldehydes, amino esters and dipolarophiles, protonation of silyl enol ethers, epoxidation of a,p-unsaturated aldehydes, aza-ene-type reactions as well as asymmetric versions of named reactions Mannich, Friedel-Crafts, Kabachnik-Fields, aza-Darzens and aza-Henry. 

Some monofluoro amino derivatives have been prepared with excellent stereocontrol exploiting the potential of inter- and intra-molecular 1,3-dipolar cycloadditions (72) with fluorinated dipolarophiles. An intermolecular application is shown in Scheme 19 (73J4). Nitrile oxides 78 were reacted with fluorinated chiral enol ethers 79 4,5-dihydroisoxazoles 80 were obtained with total regio- and stereo-selectivity. By subsequent elimination of methanol and reductive opening of the isoxazole ring 81, fluoroiminoalcohol 82 was obtained in fair yield. 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

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