Cycloaddition reactions synthons

The quiaones have excellent redox properties and are thus important oxidants ia laboratory and biological synthons. The presence of an extensive array of conjugated systems, especially the a,P-unsaturated ketone arrangement, allows the quiaones to participate ia a variety of reactioas. Characteristics of quiaoae reactioas iaclude nucleophilic substitutioa electrophilic, radical, and cycloaddition reactions photochemistry and normal and unusual carbonyl chemistry. 

All around this chapter, we have seen that a,/J-unsaturated Fischer carbene complexes may act as efficient C3-synthons. As has been previously mentioned, these complexes contain two electrophilic positions, the carbene carbon and the /J-carbon (Fig. 3), so they can react via these two positions with molecules which include two nucleophilic positions in their structure. On the other hand, alkenyl- and alkynylcarbene complexes are capable of undergoing [1,2]-migration of the metalpentacarbonyl allowing an electrophilic-to-nucleophilic polarity change of the carbene ligand /J-carbon (Fig. 3). These two modes of reaction along with other processes initiated by [2+2] cycloaddition reactions have been applied to [3+3] cyclisation processes and will be briefly discussed in the next few sections. 

Several examples of [5C+1S] cycloaddition reactions have been described involving in all cases a 1,3,5-metalahexatriene carbene complex as the C5-syn-thon and a CO or an isocyanide as the Cl-synthon. Thus,Merlic et al. described the photochemically driven benzannulation of dienylcarbene complexes to produce ortho alkoxyphenol derivatives when the reaction is performed under an atmosphere of CO, or ortho alkoxyanilines when the reaction is thermally performed in the presence of an isonitrile [111] (Scheme 63). In related works, Barluenga et al. carried out analogous reactions under thermal conditions [36a, c, 47a]. Interestingly, the dienylcarbene complexes are obtained in a first step by a [2+2] or a [3S+2C] process (see Sects. 2.3 and 2.5.1). Further reaction of these complexes with CO or an isonitrile leads to highly functionalised aromatic compounds (Scheme 63). 

Trimethylenemethane is a special type of alkene that does not exist as the free compound. Various synthetic equivalents to the synthon 43 shown below have been reported. Trost, in particular, has exploited these compounds in 1,3-dipolar cycloaddition reactions.138 139 A metal-bound, isolated trimethylenemethane species was recently reported by Ando (Scheme 6). It resulted from the complexation of an ero-methylenesila-cyclopropene with group 8 carbonyls (Fe, Ru).140,140a The structure was proved by X-ray crystal structure analysis.29Si NMR data were consistent with the -structure shown. 

Thus, nitroheterocycles are important synthons of five-membered heteroarynes in cycloaddition reactions, which are generally difficult to be generated.38... 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

The 4-phospha-1,3-butadiene 77/80 serves as an effective synthon for the unknown H-substituted nitrile ylide 79 in [3+ 2]-cycloaddition reactions with a range of electron-poor dipolarophUes (e.g., reaction with DMAD gave 78 in 80% yield). Similar yields were also obtained using methyl propiolate, azodicaboxylic esters, ethyl acrylate, and acrylonitrile (39). The reactant was generated under very mild conditions from 75 as shown below. 

Phosphites and 2,2-bis(trifluoromethyl)-5(2//)-oxazolone 71 react with elimination of carbon dioxide to give 2-aza-4-phospha-l,l-bis(trifluoromethyl)-l,3-butadiene 72 that can be used as a synthon for the previously unknown hydrogen-substituted nitrile ylide 72a in [3 + 2]-cycloaddition reactions. Examples of cycloadditions of 72a with dipolarophiles to give heterocyclic compounds 12t-ll are shown in Scheme 7.18. 

There is a rich synthetic potential for enamines in heterocyclic synthesis. Enamines can react as electrophiles or nucleophiles and as new partners in cycloaddition reactions. Various derivatives of nitrogen-, oxygen-, and sulfur-containing heterocycles have been prepared, and these, in turn, are of interest as starting materials for additional syntheses. They represent potential synthons for the development of various new directions in organic chemistry. 

The 3 + 2-cycloaddition of nitrile oxides to 2-crotyl-l,3-dithiane 1-oxides produces exclusively 5-acyldihydroisoxazoles.92 Lewis acid addition to 1,3-dipole cycloaddition reactions of mesityl nitrile oxide with a, /i-unsaturated 2-acyl-1,3-dithiane 1-oxides can reverse the sense of induced stereoselectivity.93 The 1,3-dipolar cycloaddition of 4-t-butylbenzonitrile oxide with 6A-acrylainido-6A-deoxy-/i-cyclodextrin (68) in aqueous solution favours the formation of the 4-substituted isoxazoline (69) rather than the 5-substituted regioisomer (Scheme 24).94 Tandem intramolecular cycloadditions of silyl nitronate, synthons of nitrile oxides, yield functionalized hydrofurans.95... 

Similarly to [1+6] cycloaddition reactions (see Scheme 27), [2+5] cycloaddition reactions are generally based on connecting the appropriately located functional groups of a complex molecule with a 2-carbon synthon. As such a synthon, 1,2-dibromoethane was used in the synthesis of the parent 1,3,5-trithiepane from bis(2-mercaptomethyl)... 

In [3 + 2]-cycloaddition reactions a-ketoenamines serve as synthons, reacting with phenyl azide as the 1,3-dipole component. The resulting tetrahydrophenylcyclopenta-triazol-4-ones are interesting and easily accessible heterocycles329 (equation 247). 

Evans DA, Chapman KT, Bisaha J (1984) New asymmetric Diels-Alder cycloaddition reactions. Chiral a,fS-unsaturated carboximides as practical chiral acrylate and crotonate dienophile synthons. J Am Chem Soc 106 4261-4263... 

Heptafluoro-2-butene, which is readily available in a laboratory synthesis from hexa-chlorobutadiene, may be used as a synthon for perfluoro-2-butyne in cycloaddition reactions where in situ elimination occurs [322] (Figure 7.92). 

Bicyclic oxiranes in the synthesis of prostanoid synthons 87MI21. Cycloaddition reactions of oxiranes 89YGK102. 

The Pd -catalyzed [3 + 2] cycloaddition reactions of (97) exhibit very different selectivities from those of the corresponding methylenecyclopropane codimerizations. One major distinction is the chemoselec-tivity only electron-deficient alkenes will react to form methylenecyclopentane. The nucleophilic nature of this TMM synthon is indicated in the exclusive annulation of the electron-poor double bond of 2,3-di-methoxycarbonylnorbomadiene (equation 109). - No such differentiation of alkenes is evident in the methylenecyclopropane codimerization with the same diene (equation 65). 

It has been demonstrated that cycloadducts (129), which are enolphosphates obtained by regio- and stereospecific [4 + 2] cycloaddition reactions of dienes (130) to a variety of dienophiles, are functionalized versatile synthons having fixed stereochemistry. Their [2,3] sigmatropic rearrangement via allylic sulfoxides and selenoxides (131) provides a direct sterospecific entry to new functionalized bi- and tricyclic allylic alcohol systems (133). The latter has been transformed into the corresponding a-hydroxy ketones (132), key structural subunits of natural products and valuable synthetic intermediates (examples are given in Scheme 32). ... 

Cyclopropene, methylenecyclopropane and their derivatives have proved to be valuable reagents in transition metal-catalyzed cycloaddition reactions. Small and medium carbocycles can be prepared by this method. The chemoselectivity observed in some of these reactions is quite remarkable. In addition, high degree of regio- and stereoselectivity is obtained in most cases. In particular the new [3+2] cycloaddition described here and which involves methylenecyclopropane and its derivatives as trimethylenemethane synthones, shows great synthetic promise as a method for constructing fivemembered rings. 

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