Carbopalladation alkylation

The transmetallation of various organometallic compounds (Hg, Tl, Sn, B, Si, etc.) with Pd(II) generates the reactive cr-aryl, alkenyl, and alkyl Pd compounds. These carbopalladation products can be used without isolation for further reactions. Pd(II) and Hg(II) salts have similar reactivity toward alkenes and aromatic compounds, but Hg(II) salts form stable mercuration products with alkenes and aromatic rings. The mercuration products are isolated and handled easily. On the other hand, the corresponding palladation products are too reactive to be isolated. The stable mercuration products can be used for various reactions based on facile transmetallation with Pd(II) salts to generate the very reactive palladation products 399 and 400 in rim[364,365]. 

The carbopalladation is extended to homoallylic amines and sulfides[466. Treatment of 4-dimethylamino-l-butene (518) with diethyl malonate and Li2PdCl4 in THF at room temperature leads to the oily carbopalladated complex 519, hydrogenation of which affords diethyl 4-(dimethylamino) butylmalonate (520) in an overall yield of 91%. Similarly, isopropyl 3-butenyl sulfide (521) is carbopalladated with methyl cyclopentanonecarboxylate and Li2PdCl4. Reduction of the complex affords the alkylated keto ester 522 in 96% yield. Thus functionalization of alkenes is possible by this method. 

In the alkylative cyclization of the 1,6-enyne 372 with vinyl bromide, formation of both the five-membered ring 373 by exn mode carbopalladation and isomerization of the double bonds and the six-membered ring 374 by endo mode carbopalladation are observed[269]. Their ratio depends on the catalytic species. Also, the cyclization of the 1,6-enyne 375 with /i-bromostyrene (376) affords the endo product 377. The exo mode cyclization is commonly observed in many cases, and there are two possible mechanistic explanations for that observed in these examples. One is direct endo mode carbopalladation. The other is the exo mode carbopalladation to give 378 followed by cyclopropana-tion to form 379, and the subsequent cyclopropylcarbinyl-homoallyl rearrangement affords the six-membered ring 380. Careful determination of the E or Z structure of the double bond in the cyclized product 380 is crucial for the mechanistic discussion. 

A clean twofold Heck coupling of unsubstituted butadiene 46 (R = H) in the 1- and 4-positions has not been reported. However, the initial carbopalladation product from 46 (R = H) and an in situ formed arylpalladium halide, the cr-allylpalladium halide 47 equilibrating with the corresponding 7r-allylpalladium halide, can efficiently be trapped with the anion formed by arylation of malononitrile or cyanoacetate to give 48, a product of reductive 1,4-arylation-alkylation of 1,3-butadiene 46 (R = H)." /3-Hydride elimination from the intermediate 47 (R H) can be accomplished when the reaction is carried out in the presence of silver acetate or thallium acetate, leading to the... 

A mechanistic rationale for the Pd-catalyzed addition of a C-H bond at nitriles to allenes is outlined in Scheme 3. The oxidative insertion of Pd(0) into the C-H bond of nitrile 1 produces the Pd(II) hydride species 16 (or alternatively a tautomeric structure E E2C=C=N PdH Ln may be more suitable, where E = H, alkyl, aryl and/or EWG). Carbopalladation of the allene 2 would afford the alkenylpalladium complex 17 (carbopalladation mechanism), which would undergo reductive coupling to give the addition product 3 and regenerates Pd(0) species. As an alternative mechanism, it may be considered that the hydropalladation of allenes with the Pd(II) intermediate 16 gives the jr-allylpalladium complex 18 which undergoes reductive coupling to afford the adduct 3 and a Pd(0) species (hydropalladation mechanism). 

Step 5 of the mechanism shown in Figure 16.35 (part II) is new. It consists of the cw-selec-tive addition of the aryl-Pd complex to the C=C double bond of the acrylic acid methyl ester, i.e., a carbopalladation of this double bond. A related reaction, the cw-selective car-bocupratlon of C=C triple bonds, was mentioned in connection with Figure 16.17. The regioselectivity of the carbopalladation is such that the organic moiety is bonded to the methylene carbon and Pd to the methyne carbon of the reacting C=C double bond. The addition product is an alkyl-Pd(II) complex. 

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. 

Palladium-catalyzed vinylations of aryl halides are generally referred to as the Heck reaction (for reviews on the Heck reaction see [34-40]), a versatile process that can be performed inter- and intramolecularly [41]. In the Heck reaction the carbon-carbon single bond forming step is an insertion of an al-kene into the aryl-Pd bond, i.e., a carbopalladation, giving rise to an alkyl-Pd species. If this insertion is terminated by /1-hydride elimination the expected vinylation product is the outcome of the classical Heck reaction. Likewise, reversible insertion of a highly strained olefin where the /1-hydride elimination is suppressed leads to an entry to multiple Pd-catalyzed bond forming processes. 

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. 

Although the belief that steric factors influence norbomene extrusion is reasonable and supported by Catellani s studies, it is entirely possible that norbomene carbopalladation and extrusion are reversible processes. If so, a species related to 4 may be trapped as the mono-o/t/to-alkylated product. Although mono-functionalization has been observed in stoichiometric studies by Catellani [31, 42], catalytic reactions generally do not afford monoalkylated products. Interestingly, Lautens has shown that in some particular systems mono-alkylation is possible, which may occur as a result of a sterically congested system (Scheme 14) [44], This does lend some evidence to the possibility that norbomene carbopalladation and extrusion are reversible steps, and may occur between ortho functionalization steps. 

While the PNP dimer was an efficient catalyst for the ort/toalkylation/ Mizoroki-Heck reaction, the practicality of the transformation is lessened by the fact that the PNP dimer is not commercially available, and can be quite difficult to prepare. Thus, Catellani adapted the reaction conditions to include commercially available and air-stable Pd(OAc)2 as the catalyst source [46], Under these conditions, the ortho-u kylation/Mizoroki-I Ieck coupling of aryl iodides containing a pre-existing ortho substituent could be carried out. The reaction required higher temperatures, and the addition of KOAc to promote the carbopalladation of norbomene [47] and encourage the o/t/zo-alkylation pathway vs a direct Mizoroki-Heck coupling. 

Under the reaction conditions, phenylacetylene was found to be a much more reactive coupling partner than arylboronic acids in the analogous Suzuki-Miyaura coupling, as in addition to the desired product (38), alkynylation and further addition reactions occurred with a variety of transient palladium(II) species (Scheme 27). Despite these undesired side reactions, Catellani was able to fine-tune the reaction conditions to form predominantly product 38 or 39. The formation of the desired product 38 (and suppression of product 39) is promoted by acceleration of norbomene carbopalladation by KOAc [47] and by using an excess of alkyl halide affording several structurally similar unsymmetrical alkyne products in good yields (Scheme 28). 

More recently, Lautens has also employed l-(2-iodophenyl)-pyrrole as a bifunctional aryl iodide/acceptor for the synthesis of substituted pyrrolo[l,2]quinolines (Scheme 34)[82], During Catellani s application of the Cassar-Sonogashira reaction to the ort/m-alkylation sequence [70] it was found that alkynes can undergo further carbopalladation reactions with arylpalladium(II) species. It was this reactivity which led Lautens to explore the use of bromoalkylalkynes as species which can undergo an ort/zo-alkylation, followed by a cyclocarbopalladation onto the alkyne,... 

This unusual strategy is thought to make use of the different reactivities of palladium(O), palladium(II) and palladium(IV) intermediates. Mechanistically, the reaction is proposed to occur via initial oxidative addition of palladium(O) to the aryl iodide, followed by carbopalladation with norbomene to afford alkyl palladium species II (Scheme 18). 

A similar reaction of Ar-allyl-Ar-(2,3-allenyl)mesitylenesulfonamides 79A with aryl halides in dioxane afforded c/s-2-alkyl-3-(r-arylethenyl)-4-meth-ylenepyrrolidines 86 via carbopalladation-stereoselective intramolecular car-bopalladation-dehydropalladation (Scheme 41) [28]. Here the diastereose-lectivity may be determined by the unfavorable steric interaction between the pseudoaxial hydrogens and the aromatic group in intermediate 88, which would lead to the formation of the trans product 86 (Scheme 42). This chemistry has been extended to the carbon-tethered allenenes 89 (Scheme 43) [28]. In cases of more substituted C=C bonds, further cyclization with the aromatic ring from Arl was observed to afford fused tricyclic products 91 or tetracyclic products 92 (Scheme 44) [29]. 

Pd(rV) intermediate. The alkylated Pd(II)-aryl thus generated performs an intramolecular C2-arylation on the indole. The authors suggest that this occurs via electrophilic addition at C3 followed by a C3-C2 Pd migration, as proposed by Sames and co-workers (05JA8050), although the possibility of a Heck-type carbopalladation cannot be excluded. 

Intramolecular carbopalladation of the unsaturated jS-diketone 126 catalyzed by the combination of PdCl2 with CuCb at room temperature provided the cyclo-hexenone 127 in very high yield (97 %). In other words, facile oxidative alkylation of an unactivated alkene with a carbon nucleophile took place [54],... 

HR consists of three elemental reactions (1) oxidative addition of an organic halide to form arylpalladium halides (2) insertion of an alkene to form the alkyl-palladium 17 (or carbopalladation of alkene) and (3) dehydropalladation (jS-H elimination) to give the arylalkenes 18 or conjugated dienes. 

The reactivity of the C—Pd bond is very diverse. In addition to the previously discussed j8-elimination and reductive elimination, alkyl-, benzyl-, aryl-, alkenyl-, and alkynyl-Pd complexes can undergo syn addition of the C—Pd bond across the C—C bond of alkenes and alkynes, that is, carbopalladation. This reaction can generate alkyl- or alkenyl-Pd complexes and is occasionally used as a preparative method, as exemplified in Scheme 31.Closely related is the hydropalladation of alkenes and alkynes. However, these processes are mostly observed under catalytic conditions. 

Two types of reactions are summarized in this section (i) the intermolecular carbopalladation leads to a Pd functionality such as alkyl-, alkenyl-, or allylpalladium complexes, which is intramolecularly trapped by a heteroatom (again Wacker-type processes are mechanistic alternatives) (ii) the palladium catalyst is not directly involved in the hetero-cyclization step, but the carbopalladation builds up a suitable functionality or changes bond angles so that the heterocyclization can take place. 

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