Palladium-catalyzed synthesis substrates

In 1985, Xu and Zhang reported a palladium-catalyzed synthesis of ben-zoxaphosphacycloalkanes via intramolecular cyclization. By using the corresponding alkane or benzenephosphonous acid mono(a-o-bromophe-nylalkyl)esters as substrates, moderate yields of the desired products were... 

The palladium-catalyzed synthesis of functionalized indoles through intramolecular nitrogen-carbon(sp ) bond formation has been reported (Scheme 3.55) [61], This was an oxidative cycloisomerization process, and the authors found that molecular oxygen (1 atm) was an effective oxidant for the process. The substrate scope for this reaction was quite... 

SCHEME 4.182 Using arenediazonium salts as substrates for the palladium-catalyzed synthesis of... 

SCHEME 4.277 Use of vinyl Inflates as substrates in the palladium-catalyzed synthesis of vinylphosphines [439, 440]. 

In summary, palladium-mediated reactions, especially cross-coupling reactions have found many applications in quinoline synthesis. It is noteworthy that due to the a and S activation for the C(2) and C(4) positions, even 2-chloro- and 4-chloro-quinolines are viable substrates for palladium-catalyzed reactions under standard conditions. With the advent of the palladium chemistry and more commercially available organometallic substrates, more palladium-mediated quinoline syntheses are to be added to the repertoire of quinoline chemistry. 

Additions of carbon nucleophiles to vinylepoxides are well documented and can be accomplished by several different techniques. Palladium-catalyzed allylic alkylation of these substrates with soft carbon nucleophiles (pKa 10-20) proceeds under neutral conditions and with excellent regioselectivities [103, 104]. The sul-fone 51, for example, was cyclized through the use of catalytic amounts of Pd(PPh3)4 and bis(diphenylphosphino)ethane (dppe) under high-dilution conditions to give macrocycle 52, an intermediate in a total synthesis of the antitumor agent roseophilin, in excellent yield (Scheme 9.26) [115, 116]. 

Following the pioneering work by Alterman, several microwave-assisted palladium-catalyzed aminations have been reported for a number of different substrates, using different types of palladium sources and ligands. The examples shown in Scheme 6.59 include bromoquinolines [124], aryl triflates [125], and intramolecular aminations in the synthesis of benzimidazoles [126]. In all cases, the use of micro-wave irradiation dramatically reduced the required reaction times and in many cases also improved the yields. Several authors have also found that the microwave-driven reaction required significantly less catalyst than its conventionally heated counterpart [126]. 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

Thus, the sole remaining stereocenter after epoxide opening controls the formation of three other stereocenters. It should be noted that the synthesis of enantiomerically pure substrates via palladium-catalyzed allylic alkylation [80] is possible and offers an access to the products in enantiomerically pure form. This possibility and the diastereoconvergent course of our reaction are extremely attractive for the synthesis of complex molecules. 

Mixed trialkylstannyl and silyl derivatives have also been used in coupling reactions, with subsequent replacement of the silyl substituent by bromine, leading to species that are capable of undergoing further coupling reactions. This process was amply demonstrated by the recent synthesis of micrococcinic acid 203, which involved four palladium-catalyzed crosscoupling reactions on stannylated substrates, two palladium-catalyzed trimethylstannane replacements of bromine, two trimethylsilyl displacements by bromine, and a total of four bromine-lithium exchange reactions, on three different thiazole derivatives and one pyridine derivative (91-TL4263). 

Palladium-catalyzed, Wacker-type oxidative cycHzation of alkenes represents an attractive strategy for the synthesis of heterocycles [139]. Early examples of these reactions typically employed stoichiometric Pd and, later, cocat-alytic palladium/copper [140-142]. In the late 1970s, Hegedus and coworkers demonstrated that Pd-catalyzed methods could be used to prepare nitrogen heterocyles from unprotected 2-allylanilines and tosyl-protected amino olefins with BQ as the terminal oxidant (Eqs. 23-24) [143,144]. Concurrently, Hosokawa and Murahashi reported that the cyclization of allylphenol substrates can be accomplished by using a palladium catalyst with dioxygen as the sole stoichiometric reoxidant (Eq. 25) [145]. 

The (diastereoselective) conjugate addition of silylcuprate reagents to a variety of chiral derivatives of a,(3-unsaturated carboxylic acids can be used to prepare optically active p-silyl esters.258 259 Best results are obtained with substrates of type (25). The (related) p-silyl ketones, which also constitute valuable building blocks for (acyclic) stereoselective synthesis, are now accessible in high ee via palladium-catalyzed enantioselective 1,4-disiiylation of a,p-unsaturated ketones (Scheme 76).260... 

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