Reductive Heck reactions, palladium

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. 

Now the Heck reaction. Palladium (0) inserts oxidatively into the pyridinebromine bond, reduction of Pd(0Ac)2 by one of the... 

The intermediate 591a was also used in a synthesis of tabersonine. Alkylation of 591a by Z-l,3-di-iodopropene followed by elimination of the phenylselenyl group gave a ring C diene 594, which was cyclized by a reductive Heck reaction with palladium acetate, sodium formate, triphenyl-phosphine, and base, with formation of tabersonine (78) in 43% yield (Scheme 77) (346). 

With their efficient procedure for deracemization of MBH adducts, Trost and coworkers have applied dynamic asymmetric kinetic transformation (DYKAT) to the total synthesis of furaquinodn E. As shown in Scheme 5.28, the asymmetric palladium-catalyzed alkylation of phenols combined with a reductive Heck reaction delivered an effident approach to the synthesis of the key synthon, which is the core structure of the furaquinocins. A general synthetic route to furaquinocin E was established in 14 steps from MBH adduct 159. Their work highlighted the ability to use racemic MBH adducts for asymmetric synthesis. They further extended the scope of their strategy by developing the synthesis of three more analogs of... 

After the initial reports by Banerjee et al. on the intramolecular reductive Heck reaction in the synthesis of abeo-abietane-type diterpenoids, " Node et al. adopted the intramolecular asymmetric Heck reaction for the synthesis of (—)-dichroanal B, (—)-dichroanone, and taiwaniaquinone H. Palladium cyclization of triflate 18 using (/ )-Synphos as ligand and successive hydrogenation afforded the key intermediate (5)-19 in 86% yield and 94% ee. Significantly, both E/Z triflates of 18 gave the desired Heck product 19 indicating an equilibrium between the two isomers (Scheme 13.7). 

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. 

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. 

Rawal s group developed an intramolecular aryl Heck cyclization method to synthesize benzofurans, indoles, and benzopyrans [83], The rate of cyclization was significantly accelerated in the presence of bases, presumably because the phenolate anion formed under the reaction conditions was much more reactive as a soft nucleophile than phenol. In the presence of a catalytic amount of Herrmann s dimeric palladacyclic catalyst (101) [84], and 3 equivalents of CS2CO3 in DMA, vinyl iodide 100 was transformed into ortho and para benzofuran 102 and 103. In the mechanism proposed by Rawal, oxidative addition of phenolate 104 to Pd(0) is followed by nucleophilic attack of the ambident phenolate anion on o-palladium intermediate 105 to afford aryl-vinyl palladium species 106 after rearomatization of the presumed cyclohexadienone intermediate. Reductive elimination of palladium followed by isomerization of the exocyclic double bond furnishes 102. 

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

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]. 

Vinylation or arylation of alkenes with the aid of a palladium catalysts is known as the Heck reaction. The reaction is thought to proceed through the oxidative addition of an organic halide, RX onto a zero-valent [PdL2] species followed by coordination of the olefin, migratory insertion of R, reductive elimination of the coupled product and dehydrohalogenation of the intermediate [HPdXL2] (Scheme 6.1). 

The Heck reaction yields the final product through a p-hydride elimination whereas hydroarylation or hydrovinylation generates the final product via a reductive elimination. Nonetheless, both reactions share a common first step, that is, addition of an aryl or a vinyl palladium species to an alkene, and thus are briefly discussed here. Norbornene 595 is the most studied alkene to evaluate an the... 

The arylation shown in Figure 5.3 is a rare example of a palladium-mediated hydro-arylation of an alkene. Because of the polycyclic structure of the alkene, the intermediate formed by insertion of the alkene into the Pd-Ar bond does not undergo 13-elimination (to yield the product of a normal Heck reaction), but remains unchanged. Reduction of this stable alkylpalladium intermediate with formic acid furnishes the formally hydrogenated Heck product [38],... 

The reaction sequence in the vinylation of aromatic halides and vinyl halides, i.e. the Heck reaction, is oxidative addition of the alkyl halide to a zerovalent palladium complex, then insertion of an alkene and completed by /3-hydride elimination and HX elimination. Initially though, C-H activation of a C-H alkene bond had also been taken into consideration. Although the Heck reaction reduces the formation of salt by-products by half compared with cross-coupling reactions, salts are still formed in stoichiometric amounts. Further reduction of salt production by a proper choice of aryl precursors has been reported (Chapter III.2.1) [1]. In these examples aromatic carboxylic anhydrides were used instead of halides and the co-produced acid can be recycled and one molecule of carbon monoxide is sacrificed. Catalytic activation of aromatic C-H bonds and subsequent insertion of alkenes leads to new C-C bond formation without production of halide salt byproducts, as shown in Scheme 1. When the hydroarylation reaction is performed with alkynes one obtains arylalkenes, the products of the Heck reaction, which now are synthesized without the co-production of salts. No reoxidation of the metal is required, because palladium(II) is regenerated. 

A system for the Heck reaction between methyl acrylate and iodobenzene has been developed comprising an imidazolium-functionalized polystyrene monolith, initially for use in batch. This system could be reused six times before any reduction in yield was observed. Accordingly, a continuous-flow reactor system was developed using DMF at 200 °C with a residence time of 3-4 min to achieve full conversion. This system was characterized by very low palladium loadings (0.02 mol%), and ICP-MS of the solution aliquots showed leaching of less than 1 ppm. Attempts at using EtOH as solvent to provide a more environmentally and procedurally benign protocol resulted in maximum yields of 85% [144]. 

A general catalytic cycle proposed for Heck reaction is shown in Fig. 7.17. While all the steps in the catalytic cycle have precedents, the proposed reaction mechanism lacks direct evidence. The basic assumption is that under the reaction conditions, the precatalyst is converted to 7.64, a coordinatively unsaturated species with palladium in the zero oxidation state. Oxidative addition of ArX, followed by alkene coordination, leads to the formation of 7.65 and 7.66, respectively. Alkene insertion into the Pd-C bond followed by /3-H abstraction gives 7.67 and 7.68, respectively. Reductive elimination of HX, facilitated by the presence of base B, regenerates 7.64 and completes the catalytic cycle. The C-C coupled product is formed in the 7.67 to 7.68 conversion step. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

The proposed mechanism for a standard Heck reaction is depicted in Scheme 6.5. Generally, a haloalkene or haloarene undergoes oxidative addition to an in situ generated, coordinatively unsaturated 14-electron palladium(O) complex, but other substrates such as tosylates, triflates or diazonium salts can also be applied. Subsequent, sy -insertion into the C=C double bond of a complexed olefin yields a t7-(j -alkenyl) or (j- aryl)alkylpalladium complex. If no hydrogen atom in a pseudo cis-position relative to the palladium is present, an internal rotation step is required prior to syw-elimination of the olefin to afford the traws-olefin product and a palladium(II) hydride complex. The latter is restored to the initial Pd(0) species by base-induced reductive elimination.137"401... 

Eberlin also studied the Heck reaction of aryltellurides [45] and Svennebring [19] reported the identification of three types of cationic, catalytic intermediates (Fig. 4A-C) in the microwave-assisted, phosphine-containing Heck arylation of electron rich olefins. In the latter case the authors support a Pd(0)/Pd(II) cycle as opposed to a Pd(II)/Pd(IV) cycle based on ESI-MS evidence for reduction of the palladium(II) precatalyst to Pd(0) by the ligand, and oxidative addition of the aryl substrate to a Pd(0) species. None of the expected Pd-bound olefin intermediates were observed however, this is often the case either because the olefin-bound species is neutral or because OA (oxidative addition) is the turnover-limiting step and the subsequent steps occur too quickly to be observed by the sampling method (in this case sampling included quenching and dilution of samples from a reaction vessel). 

These reactions are commonly interpreted to be composed of three main steps, namely a) oxidative addition of an aryl-X species to palladium(0) with formation of an arylpalladiumffi) bond b) insertion of a terminal olefin and c) reductive elimination regenerating palladium(0). To achieve a catalytic cycle, the rates of these steps have to match each other. The basic process was discovered by Heck in 1968. The mechanism has not yet been well defined and several variants have been proposed. A widely accepted scheme is reported in Figure 6. 

Bulky ligands as above have also proved to be effective in other palladium-catalyzed reactions of aryl halides, e.g., amination [16-19], Suzuki-Miyaura reaction [20-22], Mizoroki-Heck reaction [23, 24], Migita-Kosugi-Stille reaction [25], and aryloxylation and alkoxylation [26-28] as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products [29, 30]. The effectiveness of the commercially available simple ligand, P(f-Bu)3, was first described for the amination by Nishiyama et al. [16]. 

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