Heck reaction intramolecular carbopalladation

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

The transformations of 136 proceed cleanly upon treatment with a catalytic amount of Pd(PPh3)4, in the presence of triethylamine and molecular sieve (MS) 4 A it apparently is initiated by oxidative addition of the N(sp )-0 bond of 136 to the Pd(0) complex, and this is succeeded by two or even three intramolecular carbopalladations followed by / -hydride elimination. This Heck-type reaction is not affected by the configuration of the oxime derivatives probably due to a facile enough if/Z-isomerization of the alkylideneaminopalladium intermediate. 

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. 

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. 

Even the early concepts concerning the mechanism of the Heck reaction served as reasonable working hypotheses (for details see Sect. IV.2.1.1). The actual C—C bondforming reaction is a carbopalladation of C,C double bond, and it can be used to bind alkenyl, aryl, allyl (the intramolecular carbometallation of an allyhc substrate is called a... 

Cascade reactions arising from sequential carbopalladations are especially valuable for the construction of various carbo- and heterooligocyclic systans with three, four, or even more annelated rings. The Heck reaction has successfully been employed in various inter-inter-, intra-inter-, as well as all-intramolecular reaction cascades (Sect. IV.3). In the carbopalladation step of the Heck reaction (Scheme 6) a new metal-carbon bond is formed, which, in principle, can undergo any of the typical reactions of a hydride elimination is not too fast. When the /S-hydride elimination is totally suppressed, the palladium species can undergo a number of reactions with the formation... 

The product in Scheme 8, reminiscent of a prostaglandin, is the result of an intramolecular carbopalladation followed by an intermolecular Heck reaction, which becomes possible because the decisive intermediary alkylpalladium complex is lacking an appropriate hydrogen in synperiplanar position for the /3-H-elimination.f ... 

Compared to Figure 1, the substructures of Figure 3 have side chains elongated by one carbon atom. Heck-type cyclization of substrates that match these substructures should lead to six-membered heterocycles because the intramolecular carbopalladation in the sense of a 6-exo-trig reaction should clearly be favored against the 1-endo-trig pathway. 

D.i.b. Insertion of Another Alkenyl Unit In certain cases, however, the 3-exo-trig process may be retarded and an additional alkene moiety participates in the cascade carbopalladation. A pioneering example of this kind has been demonstrated by Overman and co-workers in their total synthesis of scopadulcic acid A, starting from an iodoaUcenyl-substituted methylenecycloheptene derivative (Scheme 24). The first intramolecular carbopalladation occurs across the disubstituted double bond of the exomethylene group, and the trisubstituted endocyclic double bond acts as the terminator to give a tricyclic system, which was further elaborated to the natural product (Scheme 24). It is remarkable that all three quaternary carbon centers can be created by intramolecular Heck reactions. 

Intramolecular carbopalladations, as in the Heck reaction, with subsequent reduction by a hydride source have established themselves as an indispensable tool for the construction of various carbocyclic and heterocyclic skeletons. Such a reaction comes about when the iyn-addition of an aryl- or alkenylpalladium species to a multiple bond leads to an intermediate that does not or cannot undergo a rapid 5yn-/3-hydride elimination such as certain cycloalkyl- (Scheme 21, Eq. 1), " neopentyl- (Eq. Eq. Eq. or TT-afiylpaUadium intermediates (Eq. The most efficient reagents for the reduction are formic acid in the presence of secondary or tertiary amines and alkali metal formates such as sodium formate. In some cases tin hydrides have successfully been employed (Scheme 33, Eqs. 3-5). 

Intramolecular carbopalladation has widely been used to assemble the polycyclic frameworks of natural products. The majority of these carbopalladations are intramolecular Heck reactions and examples of 5-exo, 6-exo, 1-exo, -exo, 6-endo, S-endo, and macro-cyclic ring closures will be presented (Scheme 12). Examples fall into two basic categories vinylic substitution (75- 76) and quaternary center construction (77- 78). Investigation of domino reactions like polyene cyclizations (79- 80) and asynunetric Heck reactions (81 82) has been fruitful. 

The 5-exo intramolecular Heck reaction has been employed to construct both meso-chimonanthine 105 and (-)-chimonanthine 106 (Scheme 16). The synthetically most challenging structural features of these bispyrroloindoline alkaloids are their vicinal quaternary centers. The synthetic plan relies on two sequential 5-exo carbopallada-tions to stereoselectively produce pentacycles 102 and 104 from closely related intermediates. Heck cyclization of 100 requires a challenging tetrasubstituted alkene insertion to provide 101. A second 5-exo carbopalladation reaction adjacent to the newly formed quaternary center installs the second quaternary center and oxindole unit. The tartrate-derived ene-diamide 100 underwent bis-5-cJct) carbopalladation when... 

Asymmetric intramolecular carbopalladation is an effective reaction for producing enantioenriched polycycles. Most examples are intramolecular Heck reactions. One seminal example from natural product synthesis is the 5-exo carbopalladation of eneamide 201 to oxindole 202 (after acid treaunent) from a total synthesis of ( )-physostigmine 203 (Scheme The reaction occurs in 84% yield with 95% ee,... 

Treatment of aryl bromide 272 with Pd resulted in an oxidative addition, which was followed by an intramolecular carbopalladation of the triple bond, resulting in with formation of the oxepine ring containing a vinyl-palladium species, i.e. 276 (Scheme 14.42). This functionality probably underwent a Heck-type reaction initiated by insertion into the aUyl silane to give intermediate 277. As shown by Tietze et al. [Ill] in earHer studies, the following P-ehmination occurred in a... 

G. S. and Lu, X.Y. (2002) Palladium(II)-catalyzed coupling reactions of alkynes and allylic compounds initiated by intramolecular carbopalladation of alkynes. Tetrahedron Lett., 43, 6791-6794 (d) de Meijere, A. and Meyer, F.E. (1995) Fine feathers make fine birds - the Heck reaction in modem garb. Angew. Chem. Int. Ed., 33, 2379-2411, and references therein. 

TABLE 4. Synthesis of Triquinanes through Intramolecular Carbopalladation and Cross-CoupUng of Cyclopentenyl Derivatives versus Heck Reaction. 

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