Palladium -catalyzed nucleophilic additions, alkenes

Coordinated alkenes and alkynes undergo two kinds of reactions substitution reactions and nucleophilic additions to the coordinated ligand. While a relahvely few examples of nucleophihc attack exist for stable Pd -alkene complexes, a far larger number of examples can be inferred from the palladium-catalyzed reactions of alkenes. 

The transformations in eqs 1 and 2 ultimately produce palla-dium(0), whilepaUadium(II) is required to activate alkenes (eq 1). Thus, if such a process is to be run using catalytic amounts of the noble metal, a way to rapidly regenerate palladium(II) in the presence of both substrate and product is required. Often this reoxidation step is problematic in palladium(II)-catalyzed nucleophilic addition processes, and reaction conditions have to be tailored to fit a particular type of transformation. A number of very useful catalytic processes, supplementing the processes that employ stoichiometric amounts of the metal, have been developed. " ... 

Palladium-catalyzed addition of oxygen nucleophiles to alkenes dates back to the Wacker process and acetoxylation of ethylene (Sects. 1 and 2). In contrast, catalytic methods for intermolecular oxidative amination of alkenes (i.e., aza-Wacker reactions) have been identified only recently. Both O2 and BQ have been used as oxidants in these reactions. 

As an alternative to addition of anionic nucleophiles followed by reoxidation, rhodium(l)-catalyzed C-H activation allowed the nucleophilic addition of alkenes to the intermediate Rh(i) carbene complex <2002JA13964, 2004JOC7329>. Purine behaved anomalously compared to other heterocycles, for which selective monoalkylation was observed, and underwent sequential substitution first at C-8 and then at C-6 (Equation 8). Caffeine was monoalkylated at C-8 in low yield (15%). Selectivity for C-8-arylation was also observed in the palladium-catalyzed C-H activation of 6-phenyl-9-benzylpurine (aryl iodides, 0.05 equiv Pd(OAc)2, 3 equiv Cul, 2.5 equiv CS2CO3, DMF, 160 °C, 60 h, 48-95% yields) <2006OL5389>. 

A similar but conceptually distinct approach to difunctionalization of terminal alkynes consists of sequential carboboration-palladium-catalyzed cross-coupling 137 equation (33) illustrates that this method also provides alkenes of high stereochemical purity by net syn Markovnikov addition. Benzyne-contain-ing molecules can act as highly activated substrates for vicinal difunctionalizations initiated by nucleophiles 138-140 thus, nucleophilic addition-electrophilic trapping can serve as an alternative to sequential directed metallation for the production of 1,2-disubstituted and 1,2,3-trisubstituted aromatic systems (equation 34).141... 

Finally, a,[3-unsaturated carbonyl compounds are converted to [3-keto systems when treated with 20% Na2PdCl4 catalyst in 50% acetic acid as solvent and r-butyl hydroperoxide or hydrogen peroxide as reoxidant (equation 3).9 It is not clear if the mechanism of this process is related to the other palladium(II)-catalyzed addition of oxygen nucleophiles to alkenes. 

Palladium chemistry has been used in the synthesis of tetrahydroisoquinolines. Different combinations of iodoaryl-amine-alkene can be used in these multicomponent reactions. For example, the metal-mediated o-alkylated/alkenyl-ation and intramolecular aza-Michael reaction (Scheme 109) give moderate yields of heterocycle <2004TL6903>, whereas the palladium-catalyzed allene insertion-nucleophilic incorporation-Michael addition cascade (Equation 172) produces good yields of tetrahydroisoquinolines in 15 examples <2003TL7445> with further examples producing tetrahydroquinolines (Scheme 110) <2000TL7125>. 

Palladium salts also promote the addition of nucleophiles to alkenes and alkynes. The Pd-catalyzed additions of nucleophiles to alkynes, which is useful for intramolecular cyclizations such as the isomerization of 2-alkynylphenols to benzofurans, proceeds by exactly the same mechanism as does the Hg-catalyzed reaction. However, the Pd-catalyzed additions of nucleophiles to alkenes takes the course of substitution rather than addition because alkylpalladium complexes are unstable toward /3-hydride elimination. The Pd-catalyzed nucleophilic substitutions of alkenes are discussed later in this chapter (Section 6.3.6). 

The mechanisms of these reactions begin the same way as Hg-mediated nucleophilic addition to alkenes. The alkene coordinates directly to Pd(II) to form an electrophilic 77 complex. The nucleophile attacks one of the carbons of the 77 complex, and the electrons from the C=C 77 bond move to form a other carbon to give an alkylpalladium(II) compound. The alkylpalladium(II) compound then undergoes /I-hydride elimination to give the observed product and a palladium(II) hydride. Loss of H+ from the palladium(II) hydride gives Pd(0), which is oxidized back to Pd(II) by the stoichiometric oxidant. The Pd(II)-H sometimes catalyzes the migration of the 77 bond by a series of insertions and /3-hydride eliminations. 

In principle, palladium-catalyzed alkene functionalization can be carried out by employing a series of different nucleophiles. Within the scope of the present chapter, oxygen- and nitrogen-based nucleophiles will be considered, and the discussion will be extended to metals other than palladium where appropriate for synthetic reasons. Addition of heteroatoms to alkenes in the presence of palladium catalysts can proceed through two different fundamental pathways of syn- and anti-nucleopalladation (Figure 16.1) [6]. 

Palladium-catalyzed addition of heteroatom compounds bearing heteroatom-heteroatom bond (X—X) or heteroatom-hydrogen bond (X—H) to carbon-carbon unsaturated bonds, such as aUcynes, alkenes, and allenes, is one of the most useful methods for introducing heteroatom functions into organic molecules. The reaction may involve the formation of the species bearing a heteroatom-palladium bond as a key intermediate and proceed via heteropalladation of unsaturated compounds (or alternatively via hydropalla-dation by a palladium hydride species (H—Pd— X) formed in situ). The following two processes can be operative for the heteropalladation (Scheme 1). While the former process, that is, anh-addition process, proceeds by the attack of the heteroatom nucleophile (X ) to the unsaturated bond coordinated by palladium, the later process involves the i yn-addition of X—PdL to the unsaturated bonds. Whereas the onh-addition process is widely known, 5yn-heteropalladation has been rare. 

The oxidative addition reactions to alkenes promoted or catalyzed by PdCl2(CH3CN)2 have been classified based on the nature of the attacking species. Oxygen nucleophiles such as water, alcohols and carboxylic acids undergo oxypalladation, while ammonia, amines and their derivatives are typical nucleophiles for aminopalladation. Carbopalladation with active methylene compounds is also discussed The palladium-catalyzed intramolecular hetero- and carbopalladation of olefins is extensively used as the ring-forming step in the synthesis of a variety of heterocyclic and carbocyclic systems, and representative examples are provided. 

In Fig. 4.35 the nucleophile depicted is anionic, but Nu may also be a neutral nucleophile, such as an amine or H2O. There are many alkene complexes of middle and late transition elements which undergo this type of reaction, e.g. M = Pd2+, Pt2, Hg2+, Zn2+, FeCp(CO)2+. The addition reaction of this type is the key step in the Wacker-type processes catalyzed by palladium. 

In addition to the most important 1,2-difunctionalization assisted or catalyzed by palladium(II) complexes, a catalytic 1,1-arylamination process of alkenes, applied to the construction of nitrogen heterocycles from 4-pentenylamides, was realized29,30. The mechanism involves the formation of arylpalladium chloride from alkyl(aryl)stannanes, the addition to the alkene, the isomerization of the adduct to the more stable benzylic palladium complex, and the displacement of palladium by an internal nitrogen nucleophile. In the presence of a substituent, mixtures of diastereomers were generally obtained. 

Interestingly, Widenhoefer reported a similar palladium(II) catalyzed cycliza-tion of indoles onto alkenes (Scheme 58) [72]. This mild protocol for cyclization/ carboxylation of 2-alkenyl indoles makes possible catalytic addition of a carbon-nucleophile and carbonyl group across a C-C bond. The mechanism, however, is thought to involve outer-sphere attack of indole onto a palladium-olefin complex rather than the electrophilic C-H activation of the indole C(3)-H bond, exhibited by the Stoltz carbocyclization. 

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