Huisgen 1,4-dipoles

DMAP has been incorporated into dispirooxindole-fused heterocycles via a domino 1,4-dipolar addition and Diels-Alder reaction of DMAP, acetylenedicarboxylates, and 3-phenacylideneoxindoles. The reactive intermediate is an in situ generated Huisgen 1,4-dipole. 

A review of organocatalytic asymmetric 2-1-2- and 4 -1- 2-cycloaddition reactions of ketenes has been published. The domino 1,4-dipolar addition and the Diels-Alder reaction of in situ generated Huisgen 1,4-dipoles (4), from dimethyl acetylenedicarboxy-late (DMAD) and 4-dimethylaminopyridine to 3-phenylacyhdeneoxindole (5), formed complex dispirooxindole-fused heterocyclic compounds (6) (Scheme 2). A multicat-alytic one-pot Diels-Alder/benzoin reaction sequence has been developed for the synthesis of complex tetrahydrocarbazoles possessing four stereogenic centres. ... 

This type of reaction is represented by 1,3-dipolar cycloadditions, corresponding to one of the Huisgen categories (69MI1). The 1,3-dipolar cycloaddition corresponds to the interaction between a 1,3-dipole and a multiple system five-membered ring closure (Scheme 1). 

No single examples have been reported so far for the catalyzed asymmetric diazoalkane cydoadditions. Based on the kinetic data on the relative reaction rates observed by Huisgen in the competitive diazomethane cydoadditions between 1-alkene and acrylic ester (Scheme 7.32), it is found that diazomethane is most nu-deophilic of all the 1,3-dipoles examined (kaciyiate/fci-aikene = 250000) [78]. Accordingly, the cydoadditions of diazoalkanes to electron-defident alkenes must be most efficient when catalyzed by a Lewis acid catalyst. The author s group has become aware of this possibility and started to study the catalyzed enantioselective diazoalkane cydoadditions of 3-(2-alkenoyl)-2-oxazolidinones. 

The class of 1,3-dipolar cycloadditions embraces a variety of reactions that can accomplish the synthesis of a diverse array of polyfunctional and stereochemically complex five-membered rings.3 The first report of a 1,3-dipolar cycloaddition of a nitrone (a 1,3-dipole) to phenyl isocyanate (a dipolarophile) came from Beckmann s laboratory in 1890,4 and a full 70 years elapsed before several investigators simultaneously reported examples of nitrone-olefin [3+2] cycloadditions.5 The pioneering and brilliant investigations of Huisgen and his coworkers6 have deepened our under-... 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

The 2 + 3 cycloaddition implies a reaction between 1, 3 dipole and an unsaturated compound called dipolarophile. The product of the reaction is a five membered heterocycle. Its theory has been develoed by R. Huisgen. According to him there are four classes of dipoles distinguished by then-bonds and the way they are stabilized by conjugation. 

Two recent publications feature metal vinylidenes functioning as 1,3-dipole equivalents, as in the Cu-catalyzed Huisgen cyclization (Section 9.4.5). Fiirstner and coworkers described intramolecular Diels-Alder reactions of unactivated die-nynes catalyzed via a proposed [4+3]-diene/copper vinylidene cycloaddition [59]. 

In principle, cycloadditions of 1,3-dipoles with dipolarophiles may occur in a concerted or stepwise manner (108). On the basis of intensive, meticulous experimental work, Huisgen and his group unequivocally established the concerted course for this reaction (15,109,110). A model was proposed for the transition state, whereby the 47i-electron system present in 1,3-dipoles interacts with the 71-bond of the dipolarophile (Scheme 6.12). 

The characteristics of the 1,3-dipolar cycloaddition mechanism of azides and other 1,3-dipoles (such as diazoalkanes, azo-methine imines, nitrones, nitrile imines, nitrile oxides) have been described in detail by Huisgen.191 19 According to the author, the addition of a 1,3-dipole (a b c) to a dipolarophile (d e) occurs by a concerted mechanism in which the two new a bonds are formed simultaneously although not necessarily at equal rates (32). As a consequence, a stereoselective cis addition is observed. Thus, the addition of p-methoxyphenyl azide to dimethyl fiynarate (33) yields l-(p-methoxyphenyl)-4,5-froiw-dicarbomethoxy-AMriazoline (34),194 and 4-nitrophenyl azide gives exclusively the respective cis-addition products 35 and 36 on addition to irons- and cis-propenyl propyl ether.196... 

Cycloaddition par Dipoles-1,3, Retrospective et Progres R. Huisgen, Bull. Soc. Chim. Fr., 1965, 3431-3440. 

The 1,3-dipolar additions (Equation 11.5), studied extensively by Huisgen and co-workers,9 also fit in the cycloaddition category. The 1,3-dipole, which... 

A number of reactions are known in which a three-atom chain bearing four electrons in a n system adds to an olefin. These transformations, explored extensively by Huisgen and his collaborators,57 are known as 1,3-dipolar additions. The 1,3 dipoles are characterized by a structure for which at least one contributing form is of the dipolar type 24. Huisgen has identified two types of 1,3... 

Recently, Huisgen and coworkers have reported on the first unequivocal example of a nonconcerted 1,3-dipolar cycloaddition.27 Sustmann s FMO model of concerted cycloadditions envisions two cases in which the stepwise mechanism might compete with the concerted one.21 Two similar HOMO-LUMO interaction energies correspond to a minimum of rate and a diradical mechanism is possible, especially if stabilizing substituents are present. A second case is when the HOMO (l,3-dipole)-LUMO (dipolarophile) is strongly dominant in the transition state. The higher the difference in rr-MO energies of reac-... 

Thiocarbonyl ylides are the 1,3-dipoles with the highest ir-MO energies.28,29 Huisgen described the cycloadditions of 2,2,4,4-tetramethyl-l-oxocyclobutane-3-thione S-methylide (10) and of adamantane-thione S-methylide (11) to dimethyl 2,3-dicyanofumarate which proceed in a nonstereospecific manner (Scheme 4).27 The presence of four electron-attracting substituents in the dipolarophile significantly lowers the MO energy of the ethylenic dipolarophile. Thus, in this particular case, the pair of reactants ful-... 

Huisgen and coworkers have also described the cycloaddition behavior of the munchnones , unstable mesoionic A2-oxazolium 5-oxides with azomethine ylide character.166 Their reactions closely parallel those of the related sydnones. These mesoionic dipoles are readily prepared by cyclodehydration of N-acyl amino acids (216) with reagents such as acetic anhydride. The reaction of munchnones with alkynic dipolarophiles constitutes a pyrrole synthesis of broad scope.158-160 1,3-Dipolar cycloaddition of alkynes to the A2-oxazolium 5-oxide (217), followed by cycloreversion of carbon dioxide from the initially formed adduct (218), gives pyrrole derivative (219 Scheme 51) in good yield. Cycloaddition studies of munchnones with other dipolarophiles have resulted in practical, unique syntheses of numerous functionalized monocyclic and ring-annulated heterocycles.167-169... 

Huisgen et al. have reported [260] evidence for sulfines playing the role of dipole in [3+2] cycloaddition. The reaction of thiobenzophenones with the S-oxide of a cyclobutanethione proceeds at room temperature to yield crystals of 1,2,4-oxadithiolanes, in a process in which reversibility was demonstrated. 

A 1,3-dipole is a compound of the type a—Het—b that may undergo 1,3-dipolar cycloadditions with multiply bonded systems and can best be described with a zwitter-ionic all-octet Lewis structure ( Huisgen ylid ). An unsaturated system that undergoes 1,3-dipolar cycloadditions with 1,3-dipoles is called dipolarophile. Alkenes, alkynes, and their diverse hetero derivatives may react as dipolarophiles. Since there is a considerable variety of 1,3-dipoles—Table 12.2 shows a small selection—1,3-dipolar cycloadditions represent not only a general but also the most universal synthetic approach to five-membered heterocycles. 

There are two common forms of mesoionic compound that belong to the oxazole ring system mlinchnones (1,3-oxazolium-5-olates) 86, named by Huisgen for the city Miinchen, and isomilnchnones (l,3-oxazolium-4-olates) 87 (Figure 4). These are highly versatile compounds which are often used as 1,3-dipoles in cycloaddition chemistry <2002HC(59)681>. 

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