Cycloadditions reactions specific type

A very powerful and elegant methodology intensely developed in recent years for the construction of five-membered ring systems, e.g. of cyclopentanoid natural products, is based on the in situ formation of highly reactive Cj intermediates from a variety of synthetic precursors. These intermediates 1 can then serve as three-earbon, 2n-electron (Y = Hj) or 4 -electron (Y = CH, O) components in cycloaddition reactions, specifically of the [3-1-2] type, with various carbon-carbon - or carbon-heteroatom multiple bonds as 2rt-components. 

This chapter is the first review whose sole focus is only on metal-catalyzed and metal-mediated higher-order cycloaddition reactions where all of the reaction types are discussed. Previous reviews have focused on specific types of higher-order cycloadditions (referenced in individual chapters), on the general topics of metal-mediated and metal-catalyzed cycloaddition reactions,5-8 and on methods for forming medium-sized rings.9... 

A specific type of [3 -I- 2] cycloaddition reaction is the crisscross cycloadditioii between the electron-deficient hexafluoroacetone azine (6) and an electron-rich, terminal alkene or al-kyne. - Reactions can be performed under thermal or photochemical conditions and 2 1 adducts are obtained in good yields. 

Additional aspects of regioselectivity which arise for substituted methylenecyclopropanes are closely related to both the thermodynamic stability or kinetic availability of competing intermediates within the cycloaddition sequences. A variety of products can, in principle, be expected from a [3 + 2] cycloaddition between a monosubstituted MCP and a nonsymmetrical, disubstituted alkene (XHC = CHY). This can be attributed to variability arising in several different steps of the overall reaction. From a topological point of view, these structural features of the product methylenecyclopentanes can be classified as shown in Table 1. Only one selected example for the specific type of isomerism is given in each case. 

Furan has been found to form oxetanes with a variety of carbonyl compounds, e.g., ketones,202-205 aldehydes,206 and ethyl cyanofor-mate.207 In most reactions the (2 + 2)-cycloaddition occurred specifically to give a 2,7 dioxabicyclo[3.2.0]hept-3-ene (175) rather than the 2,6-isomer (176). Only the addition of ethyl cyanoformate yielded mixtures of 175 and 176 (R = OEt and R2 = CN), in a ratio of 2 l.207 Two subsequent (2 + 2)-cycloadditions of benzophenone and furans have been reported to give two isomeric products, 177 and 178.205 Substituted furans yielded similar oxetanes.203 Benzo[ >]furans, furo-coumarins, and furochromones also proved to undergo (2 + 2)-cyclo-addition reactions with carbonyl compounds such as ketones, aldehydes, and quinones. Invariably one type of oxetane was formed (179).,37,u3 ,44 200-202 208,20, In the case of 2-methoxycarbonylbenzo[6)-furan, evidence has been provided that the oxetane was produced by addition of the excited triplet state of the olefinic reactant to the ground state of the ketone.208... 

Our first specific Wessely oxidation approach is outlined in Scheme 2. Following an aldol-type reaction between an appropriately protected resorcinol fragment and an aldehyde, we expected the Wessely oxidation to selectively dearomatize at the ortho position of both phenols. The intramolecular Diels-Alder cycloaddition reaction was then expected to form the tricyclic core, which could then be converted to the critical tetracyclic cage via a samarium diiodide(II)-type 6-exo-trig ketyl radical cyclization reaction. 

In connection with cycloaddition reactions it is convenient to mention yet another interesting possibility of the exploitation of the Fukui s approach. This possibility concerns the rationalization of the so-called endo addition in Diels-Alder reactions. In order to demonstrate the preference of this specific reaction mode let us assume a simple addition of two butadiene molecules resulting in the formation of vinylcyclohexene. For this reaction there are two alternative 4s + 2s reaction paths differing in the stereochemical arrangement of the corresponding products. One of these products is of the so-called exo type, whereas for the other the name endo is reserved. 

A firm understanding of concerted cycloaddition reactions developed as a result of the formulation of the mechanism within the framework of molecular orbital theory. Consideration of the molecular orbitals of reactants and products revealed that in some cases a smooth transformation of the orbitals of the reactants to those of products is possible. In other cases, reactions that appear feasible if no consideration is given to the symmetry and spatial orientation of the orbitals are found to require high-energy transition states when the orbitals are considered in detail. (Review Section 11.3 of Part A for a discussion of the orbital symmetry analysis of cycloaddition reactions.) These considerations permit description of various types of cycloaddition reactions as allowed or forbidden and permit conclusions as to whether specific reactions are likely to be energetically feasible. In this chapter, the synthetic applications of cycloaddition reactions will be emphasized. The same orbital symmetry relationships that are informative as to the feasibility of a reaction are often predictive of the regiochemistry and stereochemistry of the process. This predictability is an important feature for synthetic purposes. Another attractive feature of cycloaddition reactions is the fact that two new bonds are formed in a single reaction. This can enhance the efficiency of a synthetic process. 

Click chemistry is a chemical concept enunciated by Barry Sharpless, Scripps Research Institute, USA, in 2001, which highlights the importance of using a set of powerful, highly reliable, selective reactions under simple reaction conditions to join small molecular units together quickly for the rapid synthesis of new compounds via heteroatom links and create molecular diversity. Several types of reactions have been identified that fulfill the criteria- thermodynamically favored reactions that lead specifically to one product such as nucleophilic ring opening reactions of epoxides and aziridines, nonaldol type carbonyl reactions, additions to carbon-carbon multiple bonds, Michael additions, and cycloaddition reactions. The best-known cHck reactions are the copper-catalyzed reaction of azides and alkynes or the so-called CuAAC reaction and the thiol-ene reaction. 

A very large number of these systems with ring junction heteroatoms exists, and this number is constantly increasing. Only illustrative examples of the preparation of such systems can be given here. The synthetic methods for the formation of this type of heterocycle can be usefully classified as follows (i) various cyclocondensations between the corresponding heterocyclic derivatives and bifunctional units, (ii) intramolecular cyclizations of electrophilic, nucleophilic or (still rare) radical type, (iii) cycloadditions, (iv) intramolecular oxidative coupling, (v) intramolecular insertions, (vi) cyclization of open-chained predecessors, (vii) various reactions (quite often unusual) which are specific for each type of system. Examples given below illustrate all these cases. 

An interesting aspect of the type A heteropentalenes is the fact that each molecule is associated with two 1,3-dipolar fragments (45a<->45b) and, in principle, unsymmetrical systems can form two types of cycloadduct (46 or 47). In some cases the kinetically controlled product (46) is obtained at low temperature and the thermodynamically controlled product (47) is obtained at higher temperatures (see thieno[3,4-c]pyrroles, Chapter 3.18). For a given set of reaction conditions cycloaddition is usually site specific. For example, the non-classical thiophene derivatives of general structure (48) usually add across the thiocar-bonyl ylide fragment. This site selectivity is probably determined by the relative size of the HOMO coefficients at the alternative sites of addition. 

The complete omission of specific material on allene cycloadditions in the Woodward and Hoffmann review article 142> emphasizes the ticklish theoretical situation there may be no violations to the principle of maximum bonding 142>, but sure applications of the theory in its present early stage of development are more easily made for some types of reaction than for others. 

With the exception of vinylcyclopropane-cyclopentene rearrangements (cf. Section VII) radical reactions have so far rather rarely been used synthetically. This is also true for pericyclic modes of cyclopropane cleavage which are mainly restricted to divinylcyclopropane-cycloheptadiene type expansions. Cycloadditions, whether concerted or stepwise, occur only with very specific compounds. ... 

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