Reductive Heck reactions

Felpin et al. developed a palladium-catalyzed tandem Heck reaction-reduction-cyclization synthesis of oxindoles (n=0) and dihydroquinolones (n= 1) using different 2-(2-nitrophenyl)aaylates (n=0) or 2-(2-nitrobenzyl)aaylates (n=l) and aryldiazonium salts 36 in good yield [15] (Scheme 6.7). However, a complementary approach was developed by the same group using diazonium salts 40 and substituted acrylates 41 to access a larger substitution pattern on the C3 position (Scheme 6.8). It is noteworthy that a different solvent was required and the charcoal had to be added after the Heck reaction. C3-unsubstituted, arylated, and alkylated dihydroquinolones 42 can be obtained efficiently using this protocol. 

SCHEME 6.7 Tandem Heck reaction/reduction/cyclization. 

SCHEME 6.8 Synthesis of dihydroquinolones by tandem Heck reaction/reduction/ cyclization. 

Use of Qi-acetamidoacrylate esters in the Heck reaction allows for the introduction of a dehydroalanine side-chain. The dehydrotryptophans can be reduced catalytically, and this reduction can be done enantioselectively[17]. 

Palladium(II) complexes provide convenient access into this class of catalysts. Some examples of complexes which have been found to be successful catalysts are shown in Scheme 11. They were able to get reasonable turnover numbers in the Heck reaction of aryl bromides and even aryl chlorides [22,190-195]. Mechanistic studies concentrated on the Heck reaction [195] or separated steps like the oxidative addition and reductive elimination [196-199]. Computational studies by DFT calculations indicated that the mechanism for NHC complexes is most likely the same as that for phosphine ligands [169], but also in this case there is a need for more data before a definitive answer can be given on the mechanism. 

Although sulfur is unHkely to chelate the metal in this case, it is worth mentioning the axially chiral diphosphine Hgands, based on hz-thienyl systems which increase the electronic density at phosphorus such as 159 (used in Ru-catalyzed reduction of /1-keto esters with 99% ee) [llla],BITIANP 160,andTMBTP 161 (in a Pd-catalyzed Heck reaction, the regio- and enantioselectivity are high with 160 but low with 161) [mb]. 

The Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

Novel C2-symmetric thiophene-containing ligands have recently been prepared and utilized in asymmetric synthesis. Dithiophene 158 was utilized as a ligand in the asymmetric reduction of p-ketoesters (prostereogenic carbonyl) and acrylic acids (carbon-carbon double bond) <00JOC2043>. Dibenzo[b]thiophene 159 was utilized as a ligand in enantioselective Heck reactions of 2-pyrrolines <00SL1470>. 

A key feature of PdCys as precursors of Pd(0) nanoparticles is that reduction of Pd(II) -> Pd(0) involving C-Pd bond cleavage is required. This accounts for both the high temperatures invariably required and the induction period in the absence of reductants. Rosner et al. have developed a detailed kinetic model of a Heck reaction catalyzed by dimeric palladacycles (Rosner et al. 2001 a,b). This model explains the experimental observations and is consistent with an active species... 

A related Heck reaction of substituted o-bromoacetanilides with styrenes followed by selenium-induced cyclization of the resulting o-styiylacetanilides gives 2-arylindoles [378], Substituted o-bromonitrobenzenes react with ethyl vinyl ether under the influence of Pd(OAc)2 to give the corresponding o-ethoxyethenylnitrobenzenes. Zinc reduction then yields indoles [379]. The one-step Pd-catalyzed conversion of o-bromoanilines to indoles 302 with enamines (or with A/-vinyl-2-pyrrolidone) has been reported [380]. 

The intermolecular Heck reaction of halopyridines provides an alternative route to functionalized pyridines, circumventing the functional group compatibility problems encountered in other methods. 3-Bromopyridine has often been used as a substrate for the Heck reaction [124-126]. For example, ketone 155 was obtained from the Heck reaction of 3-bromo-2-methoxy-5-chloropyridine (153) with allylic alcohol 154 [125]. The mechanism for such a synthetically useful coupling warrants additional comments oxidative addition of 3-bromopyridine 153 to Pd(0) proceeds as usual to give the palladium intermediate 156. Subsequent insertion of allylic alcohol 154 to 156 gives intermediate 157. Reductive elimination of 157 gives enol 158, which then isomerizes to afford ketone 155 as the ultimate product This tactic is frequently used in the synthesis of ketones from allylic alcohols. 

The catalytic Pd complex and the aryl bromide together suggest the first step is oxidative addition of Pd(0) to the C5-Br bond. (The reduction of Pd(II) to Pd(0) can occur by coordination to the amine, p-hydride elimination to give a Pd(II)-H complex and an iminium ion, and deprotonation of Pd(IE)-H to give Pd(0).) The C10-C11 k bond can then insert into the C5-Pd bond to give the C5-C10 bond. P-Hydride elimination then gives the Cl 1-C12 n bond and a Pd(II)-H, which is deprotonated by the base to regenerate Pd(0). The overall reaction is a Heck reaction. 

In Figure 13.19 we have shown a route to L-699,392 published by Merck involving three steps based on homogeneous catalysts, viz. two Heck reactions and one asymmetric hydrogen transfer reaction, making first an alcohol and subsequently a sulphide [21], Stoichiometric reductions for the ketone function have been reported as well [22] and the Heck reaction on the left-hand side can be replaced by a classic condensation reaction. L-699,392 is used in the treatment of asthma and related diseases. 

We recently focused on processes involving the reductive Heck and Domino-Heck reactions [3] in a single synthetic operation by treating aryl iodides in conjimction with this work. 

Synthesis of Different Epibatidine Analogues with Domino- and Reductive Heck Reactions... 

Abstract New epibatidine analogues were synthesized by palladium catalyzed reductive Heck and Domino-Heck reactions and regioselective results were obtained. 

We continued our work with the reductive Heck and Domino-Heck reactions [1, 7J of new bicyclic compound (3) by treating it with different aryl- and hetaryl-iodides, as a result a series of new epibatidine analogues were synthesized, continuously separated and purificated by column chromatography on silica gel. Treatment of 3 with iodobenzene, 2-iodothiophene, 1-iodonapthalene and 2-chloro-5-iodopy-ridine under reductive Heck conditions gave new compounds 4a-d and 5b, 5d as exo-regioisomers after chromatographic separations. The reactions with iodobenzene and 1-iodonapthalene gave only 5-exo- products. The use of trimethylsily-lacetylene under Domino-Heck conditions provided alkynic bicyclic systems 6e andf. 

It has been proven that palladium catalyzed reductive Heck reactions are versatile and high-yield approach for preparing of new bioactive alkaloid epibatidine (1) analognes fromN-benzoylated 2-aza-bicyclo[2.2.1]hept-5-ene (3) and it has been shown that in case of aryl- groups reaction progresses regioselectively. All Heck type reactions proceed exo-selectively, leading to the same stereochemistry as fonnd in 1. 

The cyclodehydrohalogenation of 2-halo-Ar,AT-diarylamines is analogous to the classical Heck reaction [114-116] and represents a palladium(0)-catalyzed process (Scheme 28). Cyclization of the diarylamine 78 with a palladium(O) catalyst, generated in situ by reduction of palladium(II) with triethylamine, affords carbazole-1-carboxylic acid 79 in 73% yield [122]. 

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