Intramolecular palladation

Palladation of an arene is a very facile reaction when, before the C-H activation step, coordination of palladium to a nearby ligand functionality in the molecule occurs. The first report of a stoichiometric intramolecular palladation is probably the reaction of diazobenzene and palladium chloride by Cope in 1967 [6a], Intramolecular palladation is a widespread reaction that has often been used as a starting point for synthesizing new molecules using insertion reactions in the arylpal-... 

Fast intramolecular palladation to VII iii) Oxidative addition of alkyl halide forms Pd(IV) complex IV... 

The outcome of these annulation reactions could be rationalized by a Pd(II)-Pd (IV)-Pd(II)-Pd(0) cycle consisting of oxidative addition giving palladium(IV) complexes (highlighted in Scheme 18) followed by reductive elimination and intramolecular 6-exo or 7-endo or 5-exo Heck reactions. Incorporation of two equivalents of the allyl into the annulation products suggests the involvement of two distinct palladium(IV) complexes (Scheme 18), the second one arising via an intramolecular palladation of the aromatic ring followed by an oxidative addition of a second equivalent of the allyl bromide. 

It has been shown that in the presence of a palladium catalyst the carbonylation, with carbon monoxide, of diaryl ethers may yield xanthone derivatives such as (111), The reaction involves two carbon-hydrogen functionalizations. After the first, the insertion of carbon monoxide gives an intermediate (110) and a second intramolecular palladation... 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

Butyrolactones are prepared by intramolecular reaction of haloallylic 2-alkynoates. The a-chloromethylenebutyrolactone 301 is prepared by the intramolecular reaction of300[150,151]. 4 -Hydroxy-2 -alkenyl 2-alkynoates can be used instead of haloallylic 2-alkynoates, and in this reaction, Pd(II) is regenerated by elimination of the hydroxy group[152]. As a related reaction, the q-(chloromethylene)-7-butyrolactone 304 is obtained from the cinnamyl 2-alkynoate 302 in the presence of LiCl and CuCbflSS]. Isohinokinin (305) has been synthesized by this reaction[l 54]. The reaction is explained by chloro-palladation of the triple bond, followed by intramolecular alkene insertion to generate the alkylpalladium chloride 303. Then PdCb is regenerated by attack of CuCb on the alkylpalladium bond as a key step in the catalytic reaction. 

Based on a /rarcr-acetoxypalladation of the triple bond, Lu has developed a highly enantioselective (up to 87% ee) synthesis of 7-butyrolactones with Pd(n) catalysis (Scheme 73).280 Following the initial /ra/w-acetoxy-palladation, a plausible mechanism for this sequence involves an intramolecular carbopalladation of the pendant olefin, and deacetoxypalladation instead of the common /3-hydride elimination in the final step. 

The oxidative coupling/cyclization process occurs via stoichiometric carbo-palladation using a Pd(II) species, typically Pd(OAc)2. In an early example, submission of diphenylamines 3 to the palladium(II)-promoted oxidative intramolecular cyclization conditions yielded carbazoles 4 [15-... 

Presumably, the oxidative cyclization of 3 commences with direct palladation at the a position, forming o-arylpalladium(II) complex 5 in a fashion analogous to a typical electrophilic aromatic substitution (this statement will be useful in predicting the regiochemistry of oxidative additions). Subsequently, in a manner akin to an intramolecular Heck reaction, intermediate 5 undergoes an intramolecular insertion onto the other benzene ring, furnishing 6. (i-Hydride elimination of 6 then results in carbazole 4. 

Palladium(0)-catalyzed cross-coupling of aryl halides and alkenes (i.e., the Heck reaction) is widely used in organic chemistry. Oxidative Heck reactions can be achieved by forming the Pd -aryl intermediate via direct palladation of an arene C - H bond. Intramolecular reactions of this type were described in Sect. 4.1.2, but considerable effort has also been directed toward the development of intermolecular reactions. Early examples by Fu-jiwara and others used organic peroxides and related oxidants to promote catalytic turnover [182-184]. This section will highlight several recent examples that use BQ or dioxygen as the stoichiometric oxidant. 

Cardenas, D. J. Echavarren, A. M. Selectivity in the aliphatic palladation of ketone hydra-zones. An example of Pd-promoted intramolecular addition of a N, N-dimethylhydrazone to an alkene. Organometattics 1995, 14, 4427— 4430. 

Although mechanistically ambiguous, Williams and co-workers, synthesis of (-p)-paraherquamide B (79) could exemplify an alternative strategy for initiating a Heck cyclization (Scheme 6-13) [281. In this case, indole 77 was exposed to a stoichiometric amount of PdCl2, which potentially generated a 2-palladated intermediate [29]. Intramolecular insertion of the disubstituted alkene and reduction of the resulting neopentyl cr-alkylpalladium intermediate with sodium borohydride provided 78 in 63-80% yield. 

Scheme 6-13 Sequential palladation-intramolecular Heck reaction.

Formation of cyclopropane-containing oligocyclic systems such as nortricyclenes from nor-bornadienes also proceed via intramolecular insertion of homoallylmetal complexes. Palladated nortricyclene 19 can be converted with lithium aluminum hydride, chlorine or bromine to give 3-exo-methoxynortricyclene (20) and the en(/o-3-halo-exo-5-methoxy analogs 21 and 22, respectively. Intramolecular alkene insertion into the Pd — C bond is assumed to form the nortricyclene skeleton. ... 

We found that the intramolecular hydroamination of the aminoallenes 220 took place in the presence of catalytic amounts of palladium, phosphine, and acetic acid to give the 2-alkenylpyrrolidine and -piperidine 221 in good to high yields (Scheme 71).142 The reaction proceeds through formation of hydri-dopalladium species by the oxidative addition of an N—H bond to palladium(O) and subsequent hydro-palladation of the allene moiety, as mentioned in Scheme 70, type b. 

Alkenylation and arylation. Alkenyl triflates are highly active in intramolecular alkenylation of both electron-rich and electron-poor arenes. 2-Alkynylbiaryls give 9-aIkylidenefluorenes via palladation of the o -position [the benzene ring bearing electron-withdrawing group(s)]. ... 

Intramolecular Heck-type reaction initiated by palladation of alkenyl Inflates to generate... 

Intramolecular ort/zo-palladation of N-donor ligands with formation of N,Pd-cycles 00MI52. 

Another Wacker-type oxidation is the oxidative cyclization reaction, which is the intramolecular union of two arenes with formal loss of H2 promoted by a Pd(II) species [typically Pd(OAc)2].33-36 In an early example of this transformation, treatment of diphenylamines 45 with Pd(OAc)2 in acetic acid yielded carbazoles 46.37 The role of acetic acid in such oxidative cyclization processes is to protonate one of the acetate ligands, which affords a more electrophilic cationic Pd(II) species, thereby promoting the initial electrophilic palladation of the aromatic ring. 

Abstract Palladium readily catalyzes the cross-coupling of functionally substituted aryl or vinylic halides and alkynes to afford a wide variety of heterocycles and carbocycles in one efficient step. Terminal alkynes presumably initially generate aryl (vinylic) alkynes, which under the reaction conditions are rapidly cyclized by the palladium or copper salts employed in the first step to produce the final product. Internal alkynes apparently react by carbo-palladation of the alkyne and subsequent intramolecular nucleophilic substitution of the palladium moiety to generate the observed products. A variety of other closely related processes have also been reported, including the simultaneous annulation of alkynes and car-... 

---