Intramolecular cycloadditions reactivity

Feringa-butenolide 114, in the presence of Dess-Martin periodinane reagent and 2,6-lutidine, gave the bis-ketone 115 which underwent intramolecular cycloaddition to afford endo-selectively the desired decalin-based lactone 116 (Equation 2.32) [114]. Double activation of butenolidic double bond strongly increases the reactivity of dienophile 115. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

Allenes as versatile synthons including Diels-Alder reactions and especially intramolecular cycloadditions of this type were reviewed by Aso and Kanematsu [338], In some cases of intramolecular Diels-Alder reactions of open-chain starting materials such as 340 [339], 342 [339] and similar acceptor-substituted allenes [156], the formation of two new six-membered rings seems to be favorable if possible (Scheme 7.48). The non-activated cumulated C=C bond of 340 takes part in the [4+ 2]-cycloaddition and hence the necessary reaction temperature is high. On the other hand, the progressive truncation of the tether and the electron deficiency of the allenic C=C bond involved give rise to a remarkable Diels-Alder reactivity of the sulfone 346 generated in situ from sulfoxide 345 [339]. 

However, by considering models of the anti configured ylide (Fig. 3.18), it was concluded that the inclusion of a three-carbon tether forces the reactive centers to be too sterically constrained to suffer intramolecular cycloaddition with an alkyne dipolarophile. Conversely, the syn ylide is able to achieve the correct approach for such a process, despite the steric interaction with the phenyl ring. Extension of the interim chain by one methylene unit using 6-heptynal, introduced a greater degree of flexibility into the system, allowing for the formation of the expected diaster-eoisomers (Scheme 3.101). 

Side reactions that occur with intramolecular cycloaddition, such as linear oligomerization or dimerization of the nitrile oxide, are not very common when shorter chain lengths n < 1) are used due to the entropically favored intramolecular process. A rather unusual result in this regard involves the formation of a fused cyclooctane instead of the less-strained six-membered ring (also fused) in the cycloaddition of the nitrile oxide derived from p-naphthoquinone (Scheme 6.43). This result is consistent with the effect of electron-withdrawal in the enedione part, leading to increased reactivity (247), and also reflects the known sluggishness of cyclohexenes towards nitrile oxides (cf. Section 6.2.1.2). 

In this case, the exojendo selection coincides with the ratio of cis and trans annulation of ring A (formed by the cycloaddition) and ring B (formed from the tether which connects the reactive sites in the starting material). By means of the intramolecular cycloaddition, the exojendo selection may be significantly improved in a predictable manner (Section 2.3.6.). The exojendo problem is characteristic of all types of cycloadditions and enc reactions for instance, nitrone-olefin cycloaddition. 

Ketene reactivity in intramolecular cycloadditions parallel those in intermolecular reactions in which chloro-, vinyl-, aryl- and alkoxyketenes are more reactive than the alkylketenes. In most instances the ketene is generated by amine dehydrohalogenation of an acid chloride. There are, however, a few examples of ketenes prepared along less conventional routes as by the examples for the formation of 11.150 12,151 and 13.151... 

Diazo compounds can often be isolated, although many intramolecular cycloadditions occur at room temperature. Thus, the diazo compounds have typically been treated as reactive intermediates. Both 1,3-cycloaddition and 1,1-cycloaddition reactions have been observed, depending on the substrate geometry. 

The photochemical reactivity of alkenes is also of great interest [1,2]. Studies in this area have led to an expansion of the synthetic utility of these substances. Typical photochemical reactions include cis-trans isomeriza-tions, inter- and intramolecular cycloadditions, photooxidations, and electrocyclic ring opening and closing of conjugated dienes and polyenes. Many of these photoreactions have thermal counterparts. In contrast,... 

The reactivity and selectivity of cycloaddition can be considerably increased in intramolecular versions. The protocol was first demonstrated in the Diels-Alder reaction between anthrone 253416,417 and 4-hydroxy-2-butenoate mediated by phenylboronic acid (Equation (73)).418,419 Another method developed for the intramolecular cycloaddition is the synthesis of trienylboranes 256 by hydroboration of terminal alkynes (Equation (74)).419-422... 

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