Intramolecular 1,2-disubstituted alkenes

A interesting and useful reaetion is the intramolecular polycyclization reaction of polyalkenes by tandem or domino insertions of alkenes to give polycyclic compounds[l 38]. In the tandem cyclization. an intermediate in many cases is a neopentylpalladium formed by the insertion of 1,1-disubstituted alkenes, which has no possibility of /3-elimination. The key step in the total synthesis of scopadulcic acid is the Pd-catalyzed construction of the tricyclic system 202 containing the bicyclo[3.2. Ijoctane substructure. The single tricyclic product 202 was obtained in 82% yield from 201 [20,164). The benzyl chloride 203 undergoes oxidative addition and alkene insertion. Formation of the spiro compound 204 by the intramolecular double insertion of alkenes is an exam-ple[165]. 

The intramolecular inverse electron demand Diels-Alder reaction between the azadiene and the tethered alkene of compound 176 gives the corresponding benzoxazolo- and benzothiazolopyranopyridines. Terminal alkenes (RZ = H) give the tvr-products 177, whereas 1,2-disubstituted alkenes (R2 = Me or Ph) give the /ram-products 178 (Equation 46) <1995J(P1)1759>. 

In more recent work, Chiu and co-workers [167, 168] have reported an intramolecular 1,3-dipolar cycloaddition approach toward the pseudolaric acids 85, in which the di-polarophile is an unactivated 1,1-disubstituted alkene. Hence, treatment of the diazo ketone 86 with catalytic Rh2(OAc)4 furnished a mixture of tricyclic products 87 and 88 in nearly equal proportions (Scheme 19.13). The synthesis of 2-pyridones [169] and their application to the ipalbidine core [170] has been described. The pentacyclic skeleton of the aspidosperma alkaloids was prepared via the cycloaddition of a push-pull carbonyl ylide [171]. The dehydrovindorosine alkaloids 89 have also been investigated, in which the a-diazo-/ -ketoester 90 undergoes a facile cycloaddition to furnish 91 in... 

Cascade carbopalladation sequences after attack on an alkene are most commonly terminated by dehydropallada-tion, if a / -hydride is available in a yy//-orientation. The intramolecular carbopalladation starting from the monocyclic diene 122 with a geminally disubstituted alkene terminator leads to a neopentylpalladium intermediate 123, which cannot undergo /J-dehydropalladation, but continue the cascade by a carbopalladation to eventually form the... 

For such cascades with intramolecular carbopalladations, smaller ring sizes (5 and 6) are preferred due to the entropic term thus, 1,1-disubstituted alkenes suitably located in the substrate preferably serve as the relay without formation of the larger ring size resulting from insertion into the terminal alkene moiety. 

Thiiranes can be formed directly and stereospecifically from 1,2-disubstituted alkenes by addition of trimethylsilylsulfenyl bromide, formed at -78 C from reaction of bromine with bis(trimethylsilyl) sulfide (Scheme 7).12 A two-step synthesis of thiiranes can be achieved by addition of succinimide-A/-sulfe-nyl chloride or phthalimide-A -sulfenyl chloride to alkenes followed by lithium aluminum hydride cleavage of the adducts (Scheme 8).13 Thiaheterocycles can also be formed by intramolecular electrophilic addition of sulfenyl chlorides to alkenes, e.g. as seen in Schemes 914 and 10.13 Related examples involving sulfur dichloride are shown in Schemes 1116 and 12.17 In the former case addition of sulfur dichloride to 1,5-cyclooctadiene affords a bicyclic dichloro sulfide via regio- and stereo-specific intramolecular addition of an intermediate sulfenyl chloride. Removal of chlorine by lithium aluminum hydride reduction affords 9-thiabicyclo[3.3.1]nonane, which can be further transformed into bicyclo[3.3.0]oct-1,5-ene.16... 

Another type of carbopalladation is observed in the oxidation of the 2,2-disubstituted alkene attached to the cyclobutanol 104. The shift of the carbon-carbon bond as shown by 105 and ring expansion generate 106. Intramolecular alkene insertion gives the bicyclo[4.3.0]nonane system 107. Finally, 108 is obtained [78],... 

Although mechanistically ambiguous, Williams and co-workers, synthesis of (-p)-paraherquamide B (79) could exemplify an alternative strategy for initiating a Heck cyclization (Scheme 6-13) [281. In this case, indole 77 was exposed to a stoichiometric amount of PdCl2, which potentially generated a 2-palladated intermediate [29]. Intramolecular insertion of the disubstituted alkene and reduction of the resulting neopentyl cr-alkylpalladium intermediate with sodium borohydride provided 78 in 63-80% yield. 

Intramolecular asymmetric Heck insertions of acyclic disubstituted alkenes are complicated by y8-hydride elimination to provide substitution products. In a potentially... 

The rate of the alkene insertion step is quite sensitive to steric effects, and intermolecular reactions are generally limited to mono- and disubstituted alkenes. However, intramolecular reactions of tri- and tetra-substituted olefins are well precedented [61b]. 

This intramolecular bis-silylation has been extended to terminal and 2,2-disubstituted alkenes. 1,2-Disubstituted alkenes do not undergo this reaction. The substrates, unsat-urated disilanyl ethers, arc prepared by silylation of allylic and homoallylic alcohols. 

In Scheme 21, the regioselective (and stereoselective) intramolecular addition of a 1,2-unsymmetrically disubstituted alkene to an Al-acylindole is used to achieve a formal synthesis of the alkaloid vindorosine 59 [53]. The key step is formation of cycloadduct 60, which undergoes in situ retro-aldol opening to 61. The face selectivity of attack of the alkene on the indole is governed by the size of the R2 substituent. 

Characteristic behaviors of several functionalized alkenes in HR are summarized as follows. HR of monosubstituted alkenes usually proceeds satisfactorily. Inter-molecular HR is sensitive to steric factors of alkenes, and reactions of 1,1- and 1,2-disubstituted alkenes are slower than those of monosubstituted alkenes. Although intermolecular reactions of congested double bonds are slow, intramolecular reactions of even very hindered double bonds proceed smoothly. 

As mentioned above, although some examples of intramolecular MBH reactions have been reported in the literature, this aspect is still in its infancy. Most known reports are based on the cyclizations of combinations of enone-enone, enone-acrylate, enone-aldehyde, unsaturated thioester-aldehyde, enone-allylic carbonate frameworks, etc. More recently, Krafft et al. have developed a novel, entirely organo-mediated intramolecular MBH reaction by using allyl chloride 277 as an alternative electrophile to afford densely functionalized cyclic enones 278. This reaction tolerates modification of the enone and the use of primary and secondary allylic chlorides and generates both five-and six-membered rings in excellent yields. Both mono- and disubstituted alkenes are formed with excellent selectivity in the absence of a transition metal catalyst (Scheme 1.100). ... 

The enantioselective intramolecular [2+2+2] cycloaddition of 1,4-dienynes 429 gave the bicyclo[2.2,l]heptene skeleton 430, accompanied by a small amormt of 431 (Scheme 2-43). For Ais reaction, dienynes cormecting the alkyne and the other alkene components with 1,1-disubstituted alkene moieties were employed. For this reaction, dienynes connecting the alkyne and the other alkene components with 1,1-disubstituted alkene moieties were employed. Each product of this reaction represents a unique class of cycloadducts that possess two quaternary carbon stereocenters. 

Monosubstituted alkenes are also good partners. Disubstituted alkenes are distinctly less reactive and trisubstituted alkenes are usually limited to intramolecular reactions. A very special case of a tetrasubstituted alkene is cyclopropylidene cyclopropane 5.65 (Scheme 5.21). Due to the special chemistry associated with strained rings, ring opening and 3-hydride elimination follows insertion to give a diene 5.66, which may be trapped in a Diels-Alder reaction. 

An analogous 5-exo-dig carbopalladation, performed on an iodoarene with an ortho-alkynylamino substituent in the presence of hexabutyldistannane, produces an alkenyl-stannane, which undergoes a second cyclization by intramolecular Stille cross-coupling with the second o-iodoaniline moiety in the molecule. The hnal product, though, arises by double bond migration (Scheme 25, Eq. 1). Alternatively, a 1,1-disubstituted alkene... 

Disubstituted alkenes are generally less reactive towards coupling than are monosubstituted alkenes. However, the use of the more reactive aryl iodides can result in reasonable yields of the coupled product, usually as a mixture of (E) and (Z) isomers. The reaction has been applied to a coupling of 2-iodoaniline derivatives with dimethyl maleate (eq 18), the product of which spontaneously cyclizes to form quinolone derivatives in 30-70% yield. If, instead, the 2-iodoaniline is coupled with isoprene or cyclohexadiene in the presence of palladium acetate, triphenylphosphine, and triethylamine, indole and carbazole derivatives are obtained by a coupling followed by intramolecular nucleophilic attack by the heteroatom. ... 

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

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