Carbopalladation reductive elimination

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. 

Insertion of palladium into the Si-Sn bond generates intermediate 428 that undergoes m-addition on the triple bond (Scheme 108). The resulting vinylpalladium 429 ensures the carbopalladation of the second triple bond followed by reductive elimination with retention of stereochemistry.376... 

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). 

The palladium(0)-catalyzed cyclization of amide-allenes via a carbopalladation has been developed by several groups. The reaction proceeds through the carbopalladation of the allene moiety with an organopalladium species (R-Pd-X), generated by oxidative addition of R-X to palladium(O), and subsequent reductive elimination of the resultant 7r-allylpalladium intermediate.47,47a 47f... 

The possibility of Jt-allylpalladium complex formation through carbopalladation is excluded from the observation that no four- and/or six-membered rings are produced. The reaction apparently proceeds via an alternative pathway which involves a sequence of Jt-coordination of PhPdl to an allenic terminal double bond, oxypallada-tion and ensuing reductive elimination (Scheme 16.9). 

Triple bonds are in general more reactive than double bonds as is exemplified in the following process (1.2.).13 The active catalyst is HPdOAc, which is formed by the oxidative addition of acetic acid onto Pd(0). The organic substrate is attached to the palladium in a regio- and stereospecific step that is followed by an oxidative addition (N.B. Pd(II)-Pd(IV) transition) and reductive elimination, or alternatively carbopalladation and reductive elimination, to give the indole derivative. 

The first step in the cycle, analogous to the cross-coupling reactions, is the oxidative addition of an aryl (vinyl) halide or sulfonate onto the low oxidation state metal, usually palladium(O). The second step is the coordination of the olefin followed by its insertion into the palladium-carbon bond (carbopalladation). In most cases palladium is preferentially attached to the sterically less hindered end of the carbon-carbon double bond. The product is released from the palladium in a / -hydrogen elimination and the active form of the catalyst is regenerated by the loss of HX in a reductive elimination step. To facilitate the process an equivalent amount of base is usually added to the reaction mixture. 

In spite of its formal similarity to the above mentioned annulation processes, the reaction shown in 4.37. includes a unique migration step. Oxidative insertion of the palladium into the phenyl-iodine bond is followed by the migration of the palladium onto the more electron rich indole ring. The 2-indolylpalladium complex than carbopalladates the pendant alkync moiety and the process ends by the formal activation of a C-H bond of the phenyl substituent and subsequent reductive elimination, furnishing the pentacyclic product.48 The same strategy has been utilised in the preparation of the indoloindolone framework from /V-bcnzoyl-3-(o-iodophcnyl)-indolc in an oxidative addition - palladium migration - C-H activation sequence.49... 

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. 

The use of a relatively soluble base such as CS2CO3 allows good product yield. No products are formed via carbopalladation. Therefore the reaction is considered to occur on a dienolate anion generated from the enal to give an aryl(7r-allyl)palladium intermediate. The regioselectivity seems to be determined in the reductive elimination of the product. Treatment of aliphatic aldehydes with aryl bromides brings about aldol condensation followed by y-aryla-tion to afford 2 1 coupling products (Eq. 27). Note that y-arylation products are also produced in the arylation of a tin-masked dienolate [65,66]. 

Requirements for this type of reaction are a stabilized carbanionic center and a metal unit which can be reductively eliminated. Alkenepalladium complexes can be attacked by carbanion nucleophiles, for example, dimethyl malonate carbanion addition to cycloocta-l,5-dienepal-ladium(II) chloride leads to a carbopalladated adduct 1 which upon treatment with base gives 9,9-dicarbomethoxybicyclo[6.1.0]non-4-ene (2). ... 

Presumably, the oxidative cyclization of 1 commences with direct palladation at the orfAo-position, forming o-arylpalladium(II) complex 3 in a fashion analogous to a typical electrophilic aromatic substitution (this notion is useful in predicting the regiochemistry of oxidative cyclizations). The mechanism of the second formal C—H bond functionalization step is not fully elucidated, but may occur either via (a) an intramolecular carbopalladation reaction (migratory insertion) followed by czHft-P-hydride elimination from 4 (Path A) (b) by o-bond metathesis (through a four-centered transition state) followed by reductive elimination (Path B) (c) by electrophilic aromatic substitution followed by C—C bond-forming reductive elimination (PathC) [9]. 

Arai et al. reported that asymmetric tandem cyclization of the dialkenyl alcohol 182 in the presence of Pd(II)— spiro bis(isoxazoline) catalyst gave the bicyclic heterocycle 183 in 89% yield with 82% ee (Scheme 61).132d The reaction proceeds through Wack-er-type oxypalladation, formation of the palladacycle 185 by carbopalladation of the resulting alkylpalla-dium intermediate 184, elimination of HX, and subsequent reductive elimination of Pd(0) to give the product 183. 

Due to the higher reactivity of the allene moiety toward hydropalladation in 1,6-allenynes, the reaction may proceed via a hydropalladation of the allene moiety of 146 affording a vinylic palladium intermediate 147. Subsequent intramolecular carbopalladation of the C-C triple bond moiety would lead to the 1,3-dienyl palladium formate 148. Releasing of CO2 and reductive elimination afford the final product 149 and Pd(0). Pd(0) would react with HCO2H to afford HC02PdH, which is the catalytically active species (Scheme 61) [36]. 

The reaction is thought to proceed by co-ordination of the alkene with the organopalladium(II) species, followed by carbopalladation. Subsequent p-hydride elimination regenerates an alkene and releases palladium(II). This is reduced (reductive elimination) to palladium(O) in the presence of a base, to allow further oxidative addition and continuation of the cycle (1.211). The carbopalladation and p-hydride elimination steps occur syn selectively. Excellent regioselectivity, even for intermolecular reactions, is often observed, with the palladium normally adding to the internal position of terminal alkenes (except when the alkene substituent is electron-rich as in enamines or enol derivatives), thereby leading to linear substitution products. 

Oxidative carbonylation of alkenes is a unique reaction of Pd(II). Three types of oxidative carbonylation to give -substituted acid derivatives 130, a, -unsaturated esters 132 and succinate derivatives 134 are known, which can be understood by the following mechanism. Palladation of alkenes with PdX2, followed by CO insertion, generates the acylpalladium intermediate 129 whose reductive elimination affords -substituted carboxylic acid derivatives 130 (path a). Reaction in alcohol in the presence of a base starts by the formation of the alkoxycarbonylpalladium 128. Carbopalladation of alkene with 128 generates 131. Then y3-H elimination of the intermediate 131 yields the a-unsaturated ester 132 (path b). Further CO insertion to 131 gives the acylpalladium intermediate 133 and its alcoholysis yields the succinate derivative 134 (path c). Formation of the jS-alkoxy ester 130 (X-OR) is regarded as nucleophilic substitution of Pd-X in 131 with alcohols. 

Different regioselectivities were observed in the reaction of 3,4-pentadien-l-ols 387 with aryl iodides. The expected products 390 and 391 from the tt-allylpalladium intermediates 389 were not formed [151]. Exclusive formation of the dihydrofuran 388 is explained by concerted inter- and intramolecular exo-oxypalladation as shown by 392 to give 7r-allylpalladium 393, and reductive elimination gives rise to the dihydrofuran 394, showing that the intramolecular oxypalladation is faster than the intermolecular carbopalladation with Ar-Pd-I. 

The reaction is explained by the following mechanism. At first, Cul activates 1-alkynes 1 by forming the Cu acetylides 6, which undergo transmetallation with arylpalladium halides to form the alkynylarylpalladium species 7, and reductive elimination to give 2 is the final step. However, the coupling proceeds even in the absence of Cul under certain conditions, and it may be possible to form the alkynylarylpalladium species 7 directly from 1-alkynes. As another less likely possibility, carbopalladation of a triple bond with Ar-Pd-X (or insertion of the triple bond to Ar-Pd-X) generates the alkenylpalladium 8 which undergoes dehydropal-ladation to afford disubstituted alkynes 2. In this mechanism, Cul plays no role. The mechanism of -H elimination of alkenylpalladium to form alkynes is not clearly known. 

The l-(l-alkynyl)cyclobutanol 120 was expanded by Pd-catalyzed reaction with aryl- and alkenyl halides to produce the 2-(2-arylidene)cyclopentanones 123. The reaction can be understood formally by carbopalladation to give 121, and migration of an electron-rich carbon to Pd to form the palladacyclohexanone 122, and the cyclopentanone 123 is obtained by reductive elimination of 122 (see Chapter 3.8.2) [40],... 

Reaction of 140 with vinyltin reagent yields the cyclized product 141. The conversion can be understood by cis carbopalladation, transmetallation with the Sn reagent, and reductive elimination [45,46]. This reaction is overall cis addition to the triple bond. The intramolecular version of furan synthesis was plied to the preparation of the key intermediate of halenaquinone and halenaquinol syntheses from 142 [47]. 

The reaction of 17 (or 25) to give 19 (or 31) can not be explained by the oxidative addition-transmetallation-reductive elimination mechanism. In the reaction of 25, carbopalladation to form 26 and 27 is the first step. Desilylpalladation of 26 affords the expected ipso product 28. On the other hand, the intermediate 27 undergoes syn dehydropalladation to give 29, to which syn addition of H-PdX occurs to generate 30. Then anti desilylpalladation provides the cine product 31. This reaction is not completely fluoride-free, because the Bp4 anion is present. 

As another possibility, the reaction of 44 might be explained by the formation of palladium alkoxide 49, followed by jS-carbon elimination to afford 50. Carbopalladation (5-exo cyclization) of 50 gives 51, and reductive elimination produces 45 via 48. However, this route seems to be less likely, since more substituted carbon migrates in this type of reactions as demonstrated by the following examples [9]. 

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