Cycloisomerization reductive elimination

Copper(I) catalysis is very well established to promote intramolecular [2+2] photocycloaddition reactions of l,n-dienes (review [351]). The methodology recently enjoyed a number of applications [352-354], It is assumed that CuOTf, which is commonly applied as the catalyst, coordinates the diene and in this way mediates a preorganization. The Ghosh group recently reported a number of CuOTf-catalyzed photochemical [2+2] cycloaddition reactions, in which an organocopper radical complex was proposed as a cyclization intermediate (which should, however, have a formal Cu(II) oxidation state) (selected references [355-357]). A radical complex must, however, not be invoked, since the process may either proceed by a [2+2] photocycloaddition in the coordination sphere of copper without changing the oxidation state or according to a cycloisomerization/reductive elimination process. 

Silane reduces the palladium acetate in 119 to the palladium hydride 120, which undergoes reductive elimination to provide the organic product and the catalytic Pd(II) species. This mechanistic hypothesis was supported by the use of EtsSiD as the reductant product was formed with D incorporation at only the methyl group [70]. This reaction is best performed with a Pd(0) precatalyst in the presence of acetic acid and 10 eq. of silane, which suppresses the competitive cycloisomerization reaction [70]. 

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)). 

The proposed mechanism of the above cycloisomerizations are depicted in Scheme 11.30. The oxidative coupling of a metal to an enyne yields a bicyclic metaUacyclopentene, which is a common intermediate. The reductive elimination and subsequent retro-[2+2] cycloaddition gave vinylcyclopentene derivatives, while the two patterns of P-elimination and subsequent reductive eUmination gave cychc 1,3- and 1,4-dienes, respectively. The existence of a carbene complex intermediate might explain the isomerization of the olefinic moiety. 

Cycloisomerization or metathesis also occurs, which can be understood as the formation of cyclobutene 326 by reductive elimination of 321. The metathesis product 327 is formed by isomerization of 326. The metatheses involving metal-carbene complexes are discussed in Section 7.2.6. They are closely related, but somewhat different from the metathesis explained here. Balance between the ene and the metathesis reactions seems to be delicate. 

Of the two mechanistic pathways, i.e., via palladacyclization or via hydropalladation-cyclic carbopalladation, the latter seems to be more suitable for the development of sequentially catalyzed processes. Considering cycloisomerizations via the hydropalladation-cyclic carbopalladation route the catalytic reaction can terminate by /1-hydride elimination giving rise to the formation of dienes and derivatives thereof (Scheme 79). Alternatively, the alkyl-Pd species formed in the cyclic carbopalladation can be susceptible to subsequent transmetallation with organometallic substrates. Then, a reductive elimination could conclude this second Pd-mediated step releasing the Pd(0) species for a new catalytic cycle. 

An illustration of the preparation of six-membered rings by enyne cycloisomerizations is found in Trost s total synthesis of (-t-)-cassiol (113) (Scheme 6-19) [44]. The key step of this synthesis involved conversion of enyne 111 to 1,4-diene 112. Although a mixture of diastereomers is produced, the offending stereocenter is not found in the natural product, allowing both diastereomers of 112 to be used. A reductive diyne cyclization (114 115) was recently described as the key step in a total synthesis of ( )-siccanin (116) [45]. Hydropalladation of the terminal alkyne, insertion of the internal alkyne, hydride transfer to palladium, and reductive elimination are proposed to account for the observed reaction. 

Shortly after the discovery of enyne metathesis, Trost began developing cycloisomerization reactions of enynes using Pd(ll) and Pt(ll) metallacyclic catalysts (429-433), which are mechanistically divergent from the metal-carbene reactions. The first of these metal catalyzed cycloisomerization reactions of 1,6-enynes appeared in 1985 (434). The reaction mechanism is proposed to involve initial enyne n complexation of the metal catalyst, which in this case is a cyclometalated Pd(II) cyclopentadiene, followed by oxidative cyclometala-tion of the enyne to form a tetradentate, putative Pd(IV) intermediate [Scheme 42(a)]. Subsequent reductive elimination of the cyclometalated catalyst releases a cyclobutene that rings opens to the 1,3-diene product. Although this scheme represents the fundamental mechanism for enyne metathesis and is useful in the synthesis of complex 1,3-cyclic dienes [Scheme 42(fe)], variations in the reaction pathway due to selective n complexation or alternative cyclobutene reactivity (e.g., isomerization, p-hydride elimination, path 2, Scheme 40) leads to variability in the reaction products. Strong evidence for intermediacy of cyclobutene species derives from the stereospecificity of the reaction. Alkene... 

An example of palladium-catalyzed furan synthesis utilizing allenes as starting materials was reported, in which 2,4-disubstituted-2,3-butadienoic acids and 1,2-propadienyl ketones were used and 2,4-disubstituted furans were produced. The reaction may proceed via a matched double oxypalladation-reductive elimination process <04CEJ2078>. In a similar cycloisomerization of substituted allenes to tri- and tetrasubstituted furans with regioselectivity, the allenes were produced in situ from acyloxy-, phosphatyloxy- and sulfonyloxy-substituted alkynylketones via a 1,2-migration of such substituents catalyzed by CuCl or AgBF <04AG(E)2280>. 

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>. 

Whereas these transformations require stoichiometric gold compounds, catalytic amounts of both gold and palladium are sufficient for the cycloisomerization of allyl allenoates to allyl-substituted butenolides. Blum and co-workers reported this tandem C-O/C-C bond formation, which is initiated by activation of the distal allenic double bond with PhaPAuOTf (Scheme 4-107). This induces cyclization to an allyl oxonium intermediate, which undergoes deallylation in the presence of Pd2dba3. Nucleophilic attack of the resulting a-vinylgold intermediate at the ti-allylpalladium species and reductive elimination furnish the allylated butenolide and regenerate both catalysts. 

A synthesis of bicyclo[5.3.0]decatrienes through a Rh(I)-catalysed cycloisomerization of 3-acyloxy-4-ene-l,9-diynes has been reported " to proceed by [l,2]-acyloxy migration, 6n electrocyclization, migratory insertion, and reductive elimination. The overall process viewed as a intramolecular 5 -I- 2-cycloaddition with concomitant [l,2]-acyloxy migration (Scheme 146). 

With the help of deuterium-labehng experiments, a mechanism was proposed that involves initial C-H activation followed by hydrometallation with complete transfer of the deuterium atom to the cyclopropane ring (Scheme 19.84). Cycloisomerization and reductive elimination affords the final compound. 

Evidence for such metallacyclopentene intermediates includes the isolation of cyclobutene products arising from reductive elimination at this stage, in a formal [2 + 2] cycloaddition (Scheme 11.72). Indeed, a small change of ligand may be enough to switch the course of the reaction between the cycloisomerization and [2 + 2] pathways (Scheme 11.73). ... 

The direct reductive elimination from intermediates 2 leads to the formation of products 5 which present a very constrained structure. Usually, a con-rotatory thermal opening leads to the formation of vinylcycloalkenes 6. Only when the electrocyclic opening of the cyclobutene is not favoured, due to geometrical, steric or electronic reasons, the cyclobutene derivative can be isolated. This is the case with a substrate such as 9 which undergoes cycloisomerization via a formal [2+2] cycloaddition to give the polycyclic compound 10 (Eq. 2) [5],... 

Another possibility would be the use of allylic esters, which after a gold-catalyzed cycloisomerization with the carbonyl oxygen atom as the nucleophile deliver activated allylic intermediates which at the same time contain a vinylgold substructure. After transfer of an allyl cation to palladium(O), an oxidative addition to palladium, the vinylgold intermediate could transfer the organic moiety to palladium(II). A final reductive elimination would close the catalytic cycle. At the same time, no halide that potentially could deactivate the cationic gold(I) catalyst would be present. Indeed, Blum et al. [30] presented such systems. But... 

With the electTOTi-poor allenic esters, palladium(0) is able to catalyze the reaction without gold. The reactiOTi then is initiated at the other end, after oxidative addition of the aryl halide to the electrophilic palladium(II) species cycloisomerizes the allenic ester and then forms the product by reductive elimination. With o-alkynylbenzoates, the intermediate vinylgold species contains an enol ether substructure and is able to directly intercept the activated allyl donors, even in the absence of palladium. In both cases, by careful trace analysis (ICP), the presence of the other metal was excluded [78]. 

The seven-memberedring product was obtained by tandem rhodium-catalyzed C-H bond activation/cycloisomerization of MCPs. Pyridine-directed C-H activation, intramolecular addition to the C=C bond, ring expansion by P-carbon elimination, and reductive elimination gave the 5-(2-pyridylmethylene)cycloheptene derivative 90 (Scheme 2.63) [102]. Analogous cycloisomerization employing an... 

Mukai et al. have found scission of a cyclopentane ring of allenyne 34 in the rhodium-catalyzed cycloisomerization (Scheme 7.11) [14]. When 34 was treated with a rhodium catalyst, the bicyclo [7.4.0]tridecatriene 37 was formed. Mechanistically, initial coordination of 34 to rhodium(I) would occur between an allenic distal double bond and an alkyne to form the intermediary ir-coordinating complex, which undergoes oxidative cyclization to form the rhodabicyclo[4.3.0]nonadiene intermediate 35. Subsequent P-carbon elimination, presumably assisted by release of the ring strain of the cyclopentane (6.3 kcal mol ), results in the formation of the 10-membered rhodacycle 36. Reductive elimination ensues to give the final product 37. 

A rhodium-catalyzed cycloisomerization reaction of triyne 137 to 141 involves cleavage of the C=C triple bond (Scheme 7.49) [68]. The following reaction pathway is proposed initially, oxidative cyclization produces the rhodacycle 138, which then undergoes reductive elimination. The rhodium cyclobutadiene complex 139 is thus generated, and then undergoes oxidative addition to produce the rhodacycle 140. This isomerization from 138 to 140 would reduce the steric congestion of the heUcal structure. Subsequently, a cycloaddition reaction between the rhodacycle and the pendant alkyne moiety takes place to afford 141. 

Reductive Elimination Pathway On the other hand, interesting cycloisomerizations promoted by palladium... 

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