Carbopalladation alkynes

Intramolecular reaction can be used for polycyclization reaction[275]. In the so-called Pd-catalyzed cascade carbopalladation of the polyalkenyne 392, the first step is the oxidative addition to alkenyl iodide. Then the intramolecular alkyne insertion takes place twice, followed by the alkene insertion twice. The last step is the elimination of/3-hydrogen. In this way, the steroid skeleton 393 is constructed from the linear diynetriene 392(276]. 

Termination of cyclic carbopalladation of alkynes via caibonylative lactamization can be achieved more satisfactorily with alkenyl or aryl halides containing an oo-caiboxamido or co-sulfonamido group than with those containing an 0)-amino group. The method appears to be satisfactory for the preparation of certain piperidines (e.g., 102) <96T(52)11529>. 

Recently, Larock and coworkers used a domino Heck/Suzuki process for the synthesis of a multitude of tamoxifen analogues [48] (Scheme 6/1.20). In their approach, these authors used a three-component coupling reaction of readily available aryl iodides, internal alkynes and aryl boronic acids to give the expected tetrasubsti-tuted olefins in good yields. As an example, treatment of a mixture of phenyliodide, the alkyne 6/1-78 and phenylboronic acid with catalytic amounts of PdCl2(PhCN)2 gave 6/1-79 in 90% yield. In this process, substituted aryl iodides and heteroaromatic boronic acids may also be employed. It can be assumed that, after Pd°-cata-lyzed oxidative addition of the aryl iodide, a ds-carbopalladation of the internal alkyne takes place to form a vinylic palladium intermediate. This then reacts with the ate complex of the aryl boronic acid in a transmetalation, followed by a reductive elimination. 

Tietze and coworkers [60] observed a combination of a Heck reaction and a C-H-activation by treatment of the alkyne 6/1-111 with Pd°. These authors aimed at compound 6/1-112, but 6/1-110 was obtained as a single product in high yield (Scheme 6/1.29). It can again be assumed that after oxidative addition a cis-carbopalladation of the triple bond takes place to give an alkenyl Pd intermediate which undergoes the C-H-insertion into the neighboring naphthalene and not into the aryl ether moiety. 

Because of their high reactivity and their low steric demand, alkynes are highly versatile partners. The resulting vinylmetal species are also important reactive entities. Accordingly, the intermolecular carbopalladation of alkynes has attracted the interest of organic chemists for years.42-45... 

Palladium-catalyzed cyclization of alkenes and alkynes were reported by Balme and co-workers.143 144 Intramolecular carbopalladation occurs to give polycyclic compounds. It has been shown that the nucleophile type has a large influence on the cyclization process. Both 5-exo- and 6-endo-cyclization are observed for substrates with nitrile (116 and 118) and ester (120, 122, and 124) substituents, respectively (Scheme 36). When a mixed nucleophile (CN and C02Me) is used, a mixture of 5-exo and 6-endo products is obtained. The chemoselectivity is controlled by the size of the nucleophile used. The stereochemistry of the initial double bond plays an important role on the stereoselectivity of the cyclization. (Z)-olefins (118 and 120) and (/. )-olefins (116 and 124) afford as- (119 and 121) and trans-cyclization products (117 and 123), respectively. 

Cyclization of 2-(l-alkynyl)XV-alkylidene anilines is catalyzed by palladium to give indoles (Equation (114)).471 Two mechanisms are proposed the regioselective insersion of an H-Pd-OAc species to the alkyne moiety (formation of a vinylpalladium species) followed by (i) carbopalladation of the imine moiety and /3-hydride elimination or (ii) oxidative addition to the imino C-H bond and reductive coupling. 

To probe the reaction mechanism of the silane-mediated reaction, EtjSiD was substituted for PMHS in the cyclization of 1,6-enyne 34a.5 The mono-deuterated reductive cyclization product 34b was obtained as a single diastereomer. This result is consistent with entry of palladium into the catalytic cycle as the hydride derived from its reaction with acetic acid. Alkyne hydrometallation provides intermediate A-7, which upon cw-carbopalladation gives rise to cyclic intermediate B-6. Delivery of deuterium to the palladium center provides C-2, which upon reductive elimination provides the mono-deuterated product 34b, along with palladium(O) to close the catalytic cycle. The relative stereochemistry of 34b was not determined but was inferred on the basis of the aforementioned mechanism (Scheme 24). 

In analogy to the mechanism of the palladium-catalyzed enyne cyclization, it is postulated that exposure of palladium(O) to acetic acid promotes in situ generation of hydridopalladium acetate LnPd"(H)(OAc). Alkyne hydrometallation affords the vinylpalladium complex A-10, which upon r-carbopalladation of the appendant alkyne provides intermediate B-7. Silane-mediated cleavage of carbon-palladium bond liberates the cyclized product along palladium(O), which reacts with acetic acid to regenerate hydridopalladium acetate to close the cycle (Scheme 33). 

Mechanistically, a (silyl)(stannyl)palladium initially formed undergoes regioselective silylpalladation to the alkyne moiety of the enyne (Scheme 66). Then, two possible pathways are conceivable for addition to the alkene moiety, that is, stannylpalladation and carbopalladation. It has not been established that which pathway operates. 

The alkyne relay, in particular, has frequently been used for cascade carbopaliadations with ring formation, because a carbon-carbon triple bond is more reactive toward carbopalladation than a carbon-carbon double bond. Thus, methyl -iodocinnamate 70 reacts with diphenylacetylene 71 to yield the methylenediphenylindene derivative 72 (Scheme 22). ... 

Scheme 22 Alkyne relays in inter-intramolecular carbopalladation cascades leading to ring-annelated alkylidenecyclopenta-dienes and cyclopentenes. ...

Scheme 23 Highly convergent assembly of calcitriol 83 employing an alkyne-relayed inter-intramolecular carbopalladation cascade.

Tricyclic skeletons such as 85, 87, 89 with a central benzene ring are formed in the fully intramolecular Pd-catalyzed cascade cyclization of 2-bromo-l-ene-//,w-diynes 84, 86, 88 and analogs (Scheme 24). This process involves two alkyne relays in a row and a final 67r-electrocyclization or 6-endo-trig carbopalladation with ensuing / -dehydropalladation. 

Scheme 24 Two alkyne relays in sequence in intra-intramolecular carbopalladation cascades. ...

Regarding efficiency in terms of achieving a maximum increase of molecular complexity in a minimum number of operational steps, the zipper-mode tetracyclization of the open-chain trienediyne 102 leading to the tetracyclic steroidal skeleton 103, as accomplished by Negishi et al. is particularly impressive (Scheme 28). This transformation involves four intramolecular carbopalladations with two alkyne relays forming four new G,G-bonds with the creation of four rings. 

The final option available to a u-alkylpalladium intermediate from Heck alkylation occurs if another alkene or alkyne function is situated properly to participate in a further Heck-type carbopalladation (equation 161)318,319. In properly constructed systems, more than one further carbopalladation is feasible, and many examples of these cascade car-bopalladations have been reported. Several have been quite spectacular (equation 162)320. Fused, spirocyclic and bridged bicyclic ring systems have been prepared in this manner. The process may also create as many as five rings in one step, with five-,six- and three-membered rings321 being the most suitable for preparation (equation 163). Alternatively, the proper orientation of double and triple bonds allows cyclotrimerization to highly functionalized arenes or fulvenes (equation 164)322,279. 

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