Endocyclic reactions cycloadditions

Exocyclic double bonds at cyclic systems, which contain cross-conjugated double bonds, cannot be considered as a subgroup of radialenes and shall therefore be treated separately, although many of the structural features are comparable. However, in these systems the exocyclic and endocyclic double bonds are competing with each other as sites for Diels-Alder reactions, cycloadditions and electrophilic attacks. The double bond character of both, as measured by its distance, can provide some evidence for the selec-tivities. If no strain and conjugation are expected, the double bonds should be comparable... 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

Reaction of the aldehyde-tethered furanone 244 with pipecolinic acid results in the formation of the oxazolopyr-idine derivative 245, which undergoes spontaneous decarboxylation to give the ylide 246. This in turn undergoes an intramolecular cycloaddition with the tethered exomethylene group to give 247, or with the endocyclic alkene to give the furoindolizine 248 <1997T10633> (Scheme 66). 

These phenomena can be illustrated by the cycloaddition reactions of fulvenes with electron-deficient a-pyrones. In general, the Diels-Alder reactions of electron-deficient dienes such as 458 with 6-alkyl substituted fulvenes favor addition across one of the endocyclic... 

Niggli and Neuenschwander294 studied the reaction of fulvene (461) with cyclopen-tadiene. The main product fraction consisted of three 1 1 adducts, as illustrated in equation 138. Diels-Alder Adducts 462 and 463 resulted from attack of cyclopentadiene at the endocyclic and exocyclic double bonds of fulvene, respectively. The formation of 464 was rationalized by a [6 + 4] cycloaddition reaction followed by two [1,5] hydrogen shifts. It was stated that due to the absence of electron-donating and electron-withdrawing groups on both triene and diene, fulvene may have reacted via its HOMO as well as its LUMO. 

Cycloaddition to endocyclic unsaturation has been used by many researchers for the preparation of isoxazoUdinyl adducts with y-lactams derived from pyrogluta-minol and is discussed later in this chapter as a synthesis of unusual amino acids (Scheme 1.20, Section 1.6) (79,80). A related a,p-unsaturated lactam has been prepared by a nitrone cycloaddition route in the total synthesis of the fungal metabolite leptosphaerin (81). A report of lactam synthesis from acyclic starting materials is given in the work of Chiacchio et al. (82) who prepared isoxazolidine (47) via an intramolecular nitrone cycloaddition reaction (Scheme 1.11). 

It has long been recognized that nitrone cycloadditions may allow access to spirocyclic ring systems. Such systems are inherently difficult to synthesize by conventional methods, yet are a structural component of a number of biologically active natural materials. Two common strategies have emerged for spirocycle generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic version, the carbon atom (arrowed) of the nitrone C=N double bond of dipole 209 carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will... 

Further examples of the endocyclic nitrone route to spirocyclic adducts are the total syntheses of (—)-histrionicotoxin (230) by Holmes and of cylindricines by Weinreb. Histrionicotoxin is one of many spiropiperidine alkaloids isolated from the poison-arrow frog Dendrobates histrionicus and has been the subject of many attempted total syntheses by a nitrone cycloaddition strategy that failed to provide the desired regioisomer, possibly through unfavorable steric interactions (265-268). Unlike these reports, Holmes and co-workers (101) found that the intermolecular reaction of nitrone (231), prepared by the 1,3-APT of the corresponding alkynyl-hydroxylamine carrying Oppolzer s chiral sultam auxiliary, afforded the styrene... 

The Cu(I)-catalyzed decomposition of (alkynyloxysilyl)diazoacetates 119 furnishes the silaheterocycles 120 and/or 121 (equation 30) in modest yield63. In these cases, the photochemical extrusion of nitrogen from 119 does not lead to defined products and the thermal reaction is dominated by the 1,3-dipolar cycloaddition ability of these diazo compounds. In mechanistic terms, carbene 122 or more likely a derived copper carbene complex, is transformed into cyclopropene 123 by an intramolecular [1 + 2] cycloaddition to the triple bond. The strained cyclopropene rearranges to a vinylcarbene either with an exo-cyclic (124) or an endocyclic (125) carbene center, and typical carbene reactions then lead to the observed products. Analogous carbene-to-carbene rearrangements are involved in carbenoid transformations of other alkynylcarbenes64. 

The endocyclic and exo-endo diene systems of 2-vinylfuran la participate in cycloaddition reactions with dimethyl acetylenedicarboxylate... 

The initially formed bicyclic compound 38 has a highly strained and very reactive bridgehead endocyclic Si—Si bond. It can easily react with a second molecule of benzaldehyde by the insertion pathway to form a new bicyclic compound 40 with a norbornane type skeleton (Scheme 14 and Figure 12). Although this last reaction closely resembles the previous case of phenylacetylene22, the mechanism is evidently different in the case of phenylacetylene the final product 36 is a result of [2 + 2] cycloaddition of the second molecule of phenylacetylene across the new Si=Ge double bond, whereas in the case of benzaldehyde the final norbornane 40 is a result of the insertion of the second molecule of benzaldehyde into the strained Si—Si single bond. Apparently, the reactions of disi-lagermirenes with phenylacetylene and benzaldehyde have the same initial steps to form bicyclic compounds, but then the reaction pathways become different due to the different nature of these intermediate bicyclic compounds. 

The reaction of 1-disilagermirene 22 with ketones is similar to the benzaldehyde case. Thus, reaction with butane-2,3-dione gives a final bicyclic product 41, which also has a norbornane type skeleton (Scheme 15, Figure 13)50. Formation of this compound can be reasonably explained by the initial [2 + 2] cycloaddition of one carbonyl group across the Si=Si bond to form the three- and four-membered ring bicyclic compound 42, followed by the isomerization of disilaoxetane 42 to an enol ether derivative 43. The intramolecular insertion of the second carbonyl group into the endocyclic Si—Ge single bond in 43 completes this reaction sequence to produce the final norbornane 41. In this case, C=0 insertion occurred into the Si—Ge bond rather than the Si—Si bond, which is reasonable due to the weakness of Si—Ge bond. 

In response to a more fundamental question, a qualitative understanding of the origins of the treble diastereoselectivity exhibited in each cycloaddition has been developed. Arguments based on discussions in the literature have been combined with synthetic observations made in our own laboratories to assess the factors which control the reactivities and selectivities of exocyclic r-m-butadiene units, and endocyclic bisdienophilic units incorporating the (2.2. l]bicycloheptane skeleton. The syn/endo-H stereochemistry generated across each newly-formed cyclohexene ring in the cycloadditions between bisdiene and bisdienophilic building blocks is, we believe, a consequence of transition state considerations, and therefore a result of kinetic control. In spite of the sometimes tacitly assumed reversibility of the Diels-Alder reaction, evidence is provided in this review that confirms here at least the unidirectional nature of the cycloadditions under discussion. 

Methylenecyclopropenes can function as the 2n addend in Diels-Alder cycloadditions, and it is only the endocyclic double bond that is involved (Section II.G) thus, reaction of 85 with cyclopentadiene affords endo adduct 379 (opposite) exclusively... 

Alkylidenecycloproparenes (benzotriafulvenes) are more strained than triafulvenes and readily undergo ring opening or rearrangement upon reaction with electrophiles and nucleophiles. For cycloadditions, different reactivity has been observed between diarylmethylenecyclopropa-benzenes 12 and -naphthalenes 13. While the former compounds give Diels-Aldcr adducts at the endocyclic double bond with diphenylisobenzofuran, the latter compounds produce rearrangement products via Diels-Alder adducts from reaction at the exocyclic C —C double bond. A [2-1-2] cycloaddition has also been observed for a naphtbo compound. 

Cyclic enones carrying an endocyclic stereogenic center reliably undergo cycloadditions of 1,3-dienes to the sterically less-hindered face, as exemplified by the AlCb-catalyzed reaction of (285) with butadiene which yielded (286 84%) as the sole cycloadduct (Scheme 68). ... 

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