Intermolecular Alkene-Alkyne Coupling

In the reaction of allyl esters and ethers bearing monosubstituted alkenes with propargyl esters, (Z,Z)-1,3-dienes result - the only such cases observed (Equation 1.40) [37]. 

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Scheme 10.66 Regioselective intramolecular carbotitanation of alkenes leading to the products of intermolecular alkene-alkyne coupling [52].

As noted in the introduction, in contrast to attack by nucleophiles, attack of electrophiles on saturated alkene-, polyene- or polyenyl-metal complexes creates special problems in that normally unstable 16-electron, unsaturated species are formed. To be isolated, these species must be stabilized by intramolecular coordination or via intermolecular addition of a ligand. Nevertheless, as illustrated in this chapter, reactions of significant synthetic utility can be developed with attention to these points. It is likely that this area will see considerable development in the future. In addition to refinement of electrophilic reactions of metal-diene complexes, synthetic applications may evolve from the coupling of carbon electrophiles with electron-rich transition metal complexes of alkenes, alkynes and polyenes, as well as allyl- and dienyl-metal complexes. Sequential addition of electrophiles followed by nucleophiles is also viable to rapidly assemble complex structures. 

An interesting sequential reaction, consisting of an intermolecular alkene carbometallation and subsequent intermolecular alkyne cross-coupling, has been reported (Scheme 8.87) [601]. Starting from an immobihzed tropane framework 459, stoichiometric carbopalladation yields a stable organopalladium intermediate, which in the presence of copper(I) iodide undergoes coupling with an added terminal acetylene. 

An interesting sequential reaction consisting of an intermolecular alkene carbometallation and subsequent intermolecular alkyne cross-coupling has been reported by... 

Indole and isoquinolone nuclei are prominent structural units frequently found in numerous natural products and pharmaceutically active compounds. Thus, the search for new methodologies to obtain these scaffolds with different substitution patterns is a current major objective in organic synthesis. Similar to benzofuran synthesis, Aluraez et al. observed that the palladium-catalyzed cascade intramolecular alkyne aminopaUadation/intermolecular Heck-type coupling reaction under oxidative conditions is an efficient methodology for the synthesis of indole 217 and isoquinolone 219 derivatives, starting from readily available aniline 216 or benzamide 218 substrates and functional alkenes [77] (Scheme 6.60). 

The 121/Cl3SiH combination selectively cross-couples alkenes with alkynes intermolecularly to give acyclic homoallylic silanes 127 and 128 (Eq. 22) [73]. 

The moderate level of regioselectivity seen in the alkyne insertion is dependent on added PPI13, but the alkene insertion occurs with excellent regioselectively. This is the only catalytic, late transition metal system shown to intermolecularly couple alkenes with alkynes. 

Although a fair number of examples of the Ti-promoted intermolecular alkyne-alkene coupling reactions are known, those that display high pair selectivity and regioselectivity are still relatively limited. Some representative examples are shown in Scheme 18 51 53>53a... 

Scheme 18 Ti-promoted intermolecular alkyne-alkene coupling.

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

Macrolactone synthesis 6,51, 71, 72, 94, 124,131,163,187,195 McMurry coupling 43 Medium ring synthesis 43,45,75, 77 Metathesis, Alkene (see Grubbs) Metathesis, Alkyne (see alkyne metathesis) Michael addition Intramolecular 166,166, 167,201 Intermolecular 57,84, 153, 166,204... 

Many cyclization reactions via formation of metallacycles from alkynes and alkenes are known. Formally these reactions can be considered as oxidative cyclization (coupling) involving oxidation of the central metals. Although confusing, they are also called the reductive cyclization, because alkynes and alkenes are reduced to alkenes and alkanes by the metallacycle formation. Three basic patterns for the intermolecular oxidative coupling to give the metallacyclopentane 94, metallacyclopentene 95 and metallacyclopentadiene 96 are known. (For simplicity only ethylene and acetylene are used. The reaction can be extended to substituted alkenes and alkynes too). Formation of these metallacycles is not a one-step process, and is understood by initial formation of an tj2 complex, or metallacyclopropene 99, followed by insertion of the alkyne or alkene to generate the metallacycles 94-96, 100 and 101-103 (Scheme 7.1). 

Radical coupling of organic halides with alkenes or alkynes takes place intermolecularly (Equation (12)).54 Tin hydride-mediated radical additions to a series of a-methyleneglutarates furnish 2,4-dialkyl-substituted glutarates.55 Using MgBr2-OEt2 as an additive, exclusive yy/t-selectivities are achieved upon tert-butyl radical addition at —78 °C. 

Drawn from these examples it is apparent that controlling the chemose-lectivity in inter-intermolecular Heck-Diels-Alder reactions of two different alkenes can be tedious if the alkenes show comparable reactivities. Nevertheless, the stepwise approach was realized in several other cases. In a synthesis of a derivative of cephalostatin 1 containing a central benzene instead of the pyrazine ring, Winterfeldt et al. linked two steroidal systems by a Heck coupling and subsequently performed high pressure Diels-Alder reactions of the conjugated diene with electron-deficient alkynes [34], Another example, reported by Hayashi et al., involves a selective Heck reaction of a bromoglu-cal with ethylene or acrylic acid derivatives followed by cycloadditions with maleic anhydride or N-phenylmaleimide [35]. 

Other synthetic routes to alkene-metal complexes reported in the literature involve bridge cleavage reactions of halogeno complexes (method F), facile intermolecular scrambling reactions involving metal-alkene and metal-PF3 complexes (18, 81) (method G) (Scheme 4), and the coupling together of two alkyne units to afford a metallo-cyclopentadiene derivative (method H). 

In a similar manner, cyclopropane-containing benzvalene can be used as the alkene component in intermolecular Pauson-Khand reactions.Several examples of intermolecular Pauson-Khand cyclizations of methylenecyclopropanes and alkynes are reported to give bicyclic car-bocycles. Ethynylcyclopropyl-substituted chromium carbonyl complexes have also been used in palladium-catalyzed coupling reactions. 

As was the case for the intermolecular coupling reactions, activated alkenes and alkynes constitute one important class of acceptors for the ketyl radical anions. Notably, even highly strained four-membered rings can be accessed via a 4-exo cyclization process (Eq. 56) [65]. 

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