Carbopalladation intramolecular cyclization

We reported that the palladium-catalyzed intramolecular cyclization of the A/L(o-alkynylphenyl)-imines 54 gave the 3-alkenylindoles 55 in good to high yields (Scheme 19).100 A hydridopalladium species, generated in situ through the reaction of Pd-(OAc)2, P(n-Bu)3, and H20, reacts with alkynes to produce 56, which undergoes the cycloisomerization via the carbopalladation— -elimination—olefin isomerization. 

Catalytic carbopalladation is a ubiquitous process and alkynes are viable substrates. Alkenyl tellurides couple efficiently with alkynes with retention of the double bond geometry. Relatively large amounts of palladium catalyst are required.Oxidative dimerization of monoterpenes has been assumed to involve alkenylpalladium(ii) intermediates. Alkenylpalladium(ii) and di(alkenyl)palladium(iv) complexes have been put forward as intermediates in a similar reaction of halogenoterpenes. The subject has been reviewed concerning the formation of heterocycles by intramolecular cyclization of intermediate alkenylpalladium intermediates. ... 

The Buchwald-Hartwig reaction ( 5.1) can be combined with an intramolecular cyclization i.e., carbopalladation). In particular, an allene can serve as suitable starter molecules see the Experimental Procedure below. "" Depending on the reaction conditions, either the C-N or the C-C coupling proceeds first. 

A variety of 3-vinyl-substituted imidazo[l,5-a]indole derivatives were synthesized by intramolecular Pd catalyzed cyclization of the indole-2-carboxylic acid al-lenamides through either a domino carbopalladation/exo-cyclization process or a novel hydroamination reaction that proceeds smoothly under microwave irradiation. Both the observed pathways involve a Tu-allyl-palladium (II) complex arising from insertion of the allene group into a palladium (II) species, the latter being formed in situ by the intervention of an aryl iodide or of the N-H group. In both these cases, the role of nucleophile is covered by the indole nitrogen (Beccalli et al., 2010). 

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. 

Cyclizations Proceeding with Inter- and Intramolecular Carbopalladations of Allenes 327... 

A different reaction mode was observed in the Pd-catalyzed co-cyclization of the 2-bromo-l-en-6-yne 76 and 4-octyne 77. After an intramolecular carbopalladation of the triple bond in 76, the formed alkenylpalladium bromide carbopalladates 77 and this is followed by another intramolecular carbopalladation or 67r-electrocyclization and dehydropalladation to yield the oligosubstituted indane derivative (Scheme 22). ... 

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 37 Two cascade cyclizations involving inter- or intramolecular carbopalladations of allenes.

The intramolecular nucleophilic attack of a nitrogen atom on an allylpalladium complex was also used to construct a five and a six membered heterocycle in the same step. TV-substituted 2-iodobenzamides bearing an allene function in the appropriate distance from the iodine underwent cyclization through the carbopalladation of the allene moiety by the arylpalladium complex, formed in the first step of the catalytic cycle. The intermediate allylpalladium complex, part of a nine membered ring, cyclized readily to give the pyrroloisoquinolone derivative in excellent yield (4.23.). The nature of the added ligand and the solvent both had a marked influence on the efficiency of the transformation.26... 

Whereas the intermolecular Heck reaction is limited to unhindered alkenes, the intramolecular version permits the participation of even hindered substituted alkenes, and many cyclic compounds can be prepared by the intramolecular Heck reaction [37]. The stereospecific synthesis of an A ring synthon of la-hydroxyvitamin D has been carried out. Cyclization of the (7T)-alkene 88 gives the (fT)-exo-diene 90, and the (Z)-alkene 91 affords the (Z)-exo-diene 92 [38]. These reactions are stereospecific, and can be understood by cis carbopalladation to form 89 and the. sun-elimination mechanism. 

Selective synthesis of benzene derivatives via partially intramolecular cyclic carbopalladation is considerably more complex than the corresponding all-intramolecular processes. As it is generally difficult to specify the cascade-initiation point in the Type Ha cyclization process, it would generally be the least selective path. A priori, the most favorable might be the intra-inter cascade cyclization process (Type lib), since both the point of initiation and the queuing order between the two alkynes is sharply differentiated by the fact that one is intramolecular, while the other is intermolecular. Still, in-... 

Based upon the studies on the mechanism of the Cl sequence we rationalized that the elusive allenol intermediate 19 (Chap. 2.2) could participate in intramolecular trapping reactions as an allenyl ether. Furthermore, vinyl allenes are perfectly suited as dienes in Diels-Alder reactions. Considering both reactive functionalities, allenyl ethers and vinyl allenes, which are perfectly suited for domino processes, we designed an insertion sequence based upon cyclizing carbopalladation [76], where the vinyl aUene results from an isomerization of an alkynylation of a vinyl... 

The propagation steps of the zipper -mode cascade cyclization are by definition all-intramolecular processes. Some prototypical examples of the zip-per -mode cascade cyclic carbopalladation producing two to five fused rings in one step are summarized in Scheme 40 [11,113-116,122]. One of the major attractive features of this synthetic methodology is the ease of retrosynthetic analysis, which involves finding a linear line of dissection indicated in bro-... 

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]. 

Even in cases where the topology of a given substrate renders cyclization a priori rather unlikely, it is potentially misleading to invoke a template effect without appropriate control experiments. An illustrative example was reported by Negishi and co-workers (Scheme 9-5) [7]. Intramolecular carbopalladation reactions of m-haloallenes provide a... 

In the Pd-catalyzed cyclization of allenes with a nucleophihc functionaUty, there are two types of reactions (1) the carbopalladation of the allene 1 leading to a n-allyl intermediate 2, and (2) intramolecular nucleopalladation leading to the intermediates 6,8,10, or 11 depending on the nature of the catalyst and the starting allenes (Scheme 1). 

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]. 

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