Triene cycloisomerizations

The [4+ 4]-homolog of the [4 + 2]-Alder-ene reaction (Equation (48)) is thermally forbidden. However, in the presence of iron(m) 2,4-pentanedioate (Fe(acac)3) and 2,2 -bipyridine (bipy) ligand, Takacs57 found that triene 77 cyclizes to form cyclopentane 78 (Equation (49)), constituting an unprecedented formal [4 + 4]-ene cycloisomerization. The proposed mechanism for this transformation involves oxidative cyclization followed by /3-hydride elimination and reductive elimination to yield the cyclized product (Scheme 18). 

Malacria and co-workers76 were the first to report the transition metal-catalyzed intramolecular cycloisomerization of allenynes in 1996. The cobalt-mediated process was presumed to proceed via a 7r-allyl intermediate (111, Scheme 22) following C-H activation. Alkyne insertion and reductive elimination give cross-conjugated triene 112 cobalt-catalyzed olefin isomerization of the Alder-ene product is presumed to be the mechanism by which 113 is formed. While exploring the cobalt(i)-catalyzed synthesis of steroidal skeletons, Malacria and co-workers77 observed the formation of Alder-ene product 115 from cis-114 (Equation (74)) in contrast, trans-114 underwent [2 + 2 + 2]-cyclization under identical conditions to form 116 (Equation (75)). 

PtCl2 was shown to catalyze a similar Alder-ene transformation, as in the cycloisomerization of allenyne 117 to triene 118 (Equation (76)).78 In the same study, it was noticed that tetrasubstituted allenes cyclized to bicyclic compounds, such as 120 (Scheme 23), under identical PtCl2 conditions, presumably due to A(1,3) strain in intermediate 119. 

Brummond and Shibata independently reported the Rh(i)-catalyzed cycloisomerization of allenynes to cross-conjugated trienes. The rhodium conditions were shown to have broad functional group tolerance. Brummond et al 9 observed rate and selectivity enhancements when they switched to an iridium catalyst (Equation (77)). The rate acceleration observed in the Alder-ene cyclization of aminoester containing allenyne 121 (Equation (78)) was attributed to the Thorpe-Ingold effect.80... 

Wilkinson s catalyst also allows the intramolecular cycloisomerization of allenynes 243 to interesting cross-conjugated trienes 244 (Scheme 15.76) [146], Similar compounds are observed as side-products in Pauson-Khand reactions of allenynes [147]. 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

A two-step one-pot synthesis of 2,3,5-trisubstituted furans from epoxyalkynyl esters was reported, in which a facile Sml -mediated reduction was used for the generation of the 2,3,4-trien-l-ols, and the reduction was followed by a Pd(ll)-catalyzed cycloisomerization <01JOC564>. An attractive variant of this reaction was extended to the preparation of tetrasubstituted furans. Thus, when electrophilic Pd(ll) complexes were generated in situ by an oxidative addition of aryl halides or triflates to Pd(0), the oxypalladation process was followed by a reductive elimination and tetrasubstituted furans were formed <01TL3839>. 

There has been broad scientific interest in the synthesis of analogs of la,25-dihydrox-yvitamin D3 193 due their potential clinical applications. A concise entry into the triene-containing tricyclic core structure from simple precursors is available using an enyne cycloisomerization. The precursors of the central cascade reaction are the alkenyl bromide 188 and enyne 189, which are easily obtained in enantiomerically pure form (Scheme 29).[66].[6v] In iiie key reaction, alkenyl bromide 188 and enyne 189 are converted into a 10 1 mixture of triene 191 and the thermally rearranged product 194. After recycling of 194 to 191, a yield of 76% was reahzed. Alkenyl bromide 188 undergoes regiospecific intramolecular carbopalladation of enyne 189 to provide the dienylpalladium complex 190. 

Dichloro(p-diphenylphosphinopolystyrene)nickel(II) jchromous chloride 2-VinylmethyIenecyclopentanes from 1,2,7-trienes Stereospecific cycloisomerization via catalytic intramolecular carbametalation... 

Cycloisomerization of l,2,n-trienes with acoxy group migration O... 

A variety of allenynamides undergo cycloisomerization reactions in the presence of silver triflate leading to the formation of A-containing heterocycles incorporating cross-conjugated trienes (Scheme 160). ... 

Cycloisomerization of Aiienenes and Alleneynes. Allenes are a special class of compounds that possess cumulated double-bond systems. For a long period of time, the development of the chemistry of allenes was impaired under the false notion that such cumulated double-bond systems are highly unstable (90-92). Unlike the chemistry of alkene and alkyne that have been comprehensively developed, allenes only started to emerge in recent decades as versatile precursors in organic synthesis. The Brummond Laboratory was the first to illustrate that cross-conjugated trienes 83 could be prepared by Rh-catalyzed allenic Alder-ene reaction of allenyne 82 (Scheme 42) (93). 

Five years ago, Houk, Toste, and coworkers [31] suggested a fascinating new reaction mechanism. The cycloisomerization of 1,5-allenynes 23 by the [(Ph3PAu)30]Bp4 catalyst delivers cross-conjugated trienes 24 (Scheme 4.8). 

Brummond s group [23] and independentlythe group of Shibata [24] discovered that rhodium(I) complexes are excellent catalysts in the formal Alder-ene cycloisomerization of allenynes to give cross-conjugated trienes under mild conditions... 

Taking advantage of the rich chemistry of transition-metal-catalyzed cycloisomerization of 1,6-enynes, the electron-rich, conformationally blocked cyclohepta-1,3, 5-triene has been envisioned as a 6-% nucleophilic component [59]. Thus, cycloisomerization of l-(pent-4-ynyl)cyclohepta-l,3,5-trienes in the presence of catalytic amounts of platinum(II) chloride led to a formal intramolecular [64-2] cycloaddition in good to excellent yields [60]. These reactions are conducted at room temperature in toluene as the solvent. A heteroatom in the tether between the unsaturated subunits is tolerated, although in these cases other catalytic pathways were also observed. A mechanism involving cationic intermediates resulting from the nucleophilic attack of the triene on the metal-alkyne moiety has been proposed (Scheme 8.38). The occurrence of ionic intermediates was supported with... 

Analogous 1,2-alkyl migration of an intermediary metal carbene complex is proposed in catalytic cycloisomerization reactions of o-alkynylbenzaldehyde acetal [36], alkynyl azides [37], 1,2,4-trienes [38], allenyl ketones [39], and o-alkynylanilides [40]. 

The earliest example of cycloisomerization in conjugated dienes was reported by Takacs et al. in 1980 [68]. In their study a low-valent iron bipyridine complex was prepared by reducing Fe(acac>3 with EtjAl and used for the cycloisomerization of trienes (Schane 7.49). 

SCHEME 7.50 Application of cycloisomerization of trienes in the total synthesis of iridoids. 

The reaction mechanism leading to advanced intermediate 85 starts with rhodium insertion into the aldehyde moiety. Rhodacycle formation follows to promote hydroacylation into the 4,6-diene providing cycloheptene compound 86. Then, rhodium catalyze a highly regioselective cycloisomerization reaction on the resulting triene to produce the final product 87 (Scheme 7.54 please refer also to Scheme 7.51). 

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