Palladium -catalyzed reactions intermolecular

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

The silyl group in 311, prepared by intramolecular silylformylation, is intermolecularly substituted by a phenyl group by a palladium-catalyzed reaction with Phi to give coupled product 312 (Equation (56)). ... 

The palladium-catalyzed reaction of allyl chloride 11 with the benzyne precursor 104 to produces phenanthrene derivatives 131 is also known [83]. A plausible mechanism for this intermolecular benzyne-benzyne-alkene insertion reaction is shown in Scheme 38. Initially n-allyl palladium chloride la is formed from Pd(0) and 11. Benzyne 106, which is generated from the reaction of CsF and 104, inserted into la to afford the aryl palladium intermediate 132. A second benzyne insertion into 132 produce 133 and subsequent carbopalladation to the alkene afford the cyclized intermediate 134. f>- Iydride elimination from 134 followed by isomerization gave 9-methylphenanthrene 131. 

Palladium-catalyzed reaction of conjugated dienes in the presence of a halide anion can be controlled to give a l-acyloxy-4-halo-2-alkene selectively under appropriate reaction conditions. The catalyst for this system is a palladium(II) salt, usually Pd(OAc)2 or Li2PdCl4. The reaction may be intermolecular or intramolecular. In most cases, it is stereoselective and results in a 1,4-cis addition to the diene. The products obtained from such reactions are useful synthetic intermediates since they have two allylic leaving groups with a large difference in reactivity (see below, under Synthetic applications ). 

Intramolecular or intermolecular Heck-type reactions were also used in the synthesis of poly-substituted quinoline compounds. Palladium-catalyzed reaction between vinyl or aryl halides and ortAo-allyl-substituted-A -tosyl-anilides produces dihydroquinolines in an intermolecular fashion, where reaction of acrylates intramolecularly affords 4-quinolones. ° ° ... 

Fagnou and co-workers succeeded to combine Heck cyclization with direct arylation in 2009. This interesting domino palladium-catalyzed Heck-intermolecular direct arylation reaction gave new access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene could be employed as the direct arylation coupling partner as well and resulted in yields up to 99% (Scheme 2.35). As the authors demonstrated, in addition to... 

The use of benzyne derivatives in intermolecular carbo-palladation processes has stood out as a powerful tool for the preparation of 1,2-functionalized arenes in the last decade. Since the pioneering work by Yamamoto in 2000 [34], which introduced arynes as reactive partners in palladium-catalyzed reactions, several groups have exploited the carbopallada-tion of benzyne in three-component couplings. In general, 2-(trimethylsilyl)phenyl triflate derivatives, in combination with a fluoride salt such as CsF, are used as benzyne precursors. 

Pena et al. reported the synthesis of double helicenes by the palladium-catalyzed complete intermolecular homo-[2- -2-1-2] cycloaddition of 3,4-didehydrophenanthrene (Scheme 10.12) [13a]. 1,2-Didehydrotriphenylene could also be employed for this reaction to give the corresponding triphenylene-based double helicene, although the product yield was low (Scheme 10.12) [13b]. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

The vinylcyclopropane 144, bearing two electron-withdrawing groups, undergoes the intermolecular palladium-catalyzed [3 + 2]cycloaddition reaction of the Jt-allylpalladium intermediate 145 with a,/ -unsaturated esters or ketones to provide a useful method for forming the cyclopentane ring of 146 [74], (Scheme 51)... 

The Heck reaction, a palladium-catalyzed vinylic substitution, is conducted with olefins and organohalides or pseudohalides are frequently used as reactants [15, 16], One of the strengths of the method is that it enables the direct monofunctionalization of a vinylic carbon, which is difficult to achieve by other means. Numerous elegant transformations based on Heck chemistry have been developed in natural and non-natural product synthesis. Intermolecular reactions with cyclic and acyclic al-kenes, and intramolecular cyclization procedures, have led to the assembly of a variety of complex and sterically congested molecules. 

Attempts to employ allenes in palladium-catalyzed oxidations have so far given dimeric products via jr al lyI complexes of type 7i62.63. The fact that only very little 1,2-addition product is formed via nucleophilic attack on jral ly I complex 69 indicates that the kinetic chloropalladation intermediate is 70. Although formation of 70 is reversible, it is trapped by the excess of allene present in the catalytic reaction to give dimeric products. The only reported example of a selective intermolecular 1,2-addition to allenes is the carbonylation given in equation 31, which is a stoichiometric oxidation64. 

The same type of bis-functionalization has been reported for the palladium-catalyzed borylstannylative carbocy-cyclization of 1,6-, 1,5-, 1,7-diynes, bis-propargylamine, and ether.377 It should be noted that even 1,2-dialkylidene cyclobutane can be obtained in reasonable yield. Ito has proposed the related silaborative reaction involving nickel(O) catalysis.378 This reaction has been performed in an intra- and intermolecular fashion. The intramolecular reaction allows the formation of cyclic dienes and the intermolecular process proceeds through a dimerization of alkynes to give acyclic dienes. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

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. 

Li and Yue also reported the intermolecular palladium catalyzed cross coupling reactions of bromo quinoxalines 214 and 216 with aryl boronic acids and heterocyclic stannanes, respectively <99TL4507>. The Suzuki couplings (i.e., 214 215) required the use of a... 

The same group developed an interesting intermolecular palladium-catalyzed alienation of aryliodide with N-tosyl o-iodoanilines with nucleophiles in combination with two palladium-coupling reactions [69]. In this reaction, the N-allyl(2-iodopalladium)aniline intermediate 52 underwent an intramolecular Heck reaction followed by a cross-coupling reaction with phenyl boronic acid to give the 3,3-disubstituted indoline 53 in 78% yield (Scheme 8.27). 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

The same authors also reported on palladium-catalyzed domino cycli-zation-anion capture reactions employing allene (69) as a relay switch (Scheme 10) [52], Such a reaction of the alkynyl-tethered aryl iodide 68 starts with an oxidative addition to the catalytic metal species, and is followed by an intramolecular carbopalladation of the triple bond. An intermolecular car-... 

The palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a [42] and aziridine 20b [39] with the activated olefin 4a for the formation of five membered cyclic ether 21a and pyrrolidine derivative 21b has also been reported in our laboratories. The mechanistic issue is very much similar to that discussed in Scheme 9. Pd(0) catalyst added oxidatively to 20 to produce the 7r-allylpalladium complex 22. The Michael addition of a hetero nucleophile in 22 to the activated olefin 4a gives 23 which undergoes intramolecular nucleophilic attack on the inner 7r-allylic carbon atom to give the cy-clized products 21 and Pd(0) species is generated (Scheme 10). Similarly, the palladium-catalyzed [3 + 2] cycloaddition of vinylic oxirane 20a with the N-losylimincs 24 is also known (Scheme 11) [43]. Intermolecular cycloaddition of vinyl epoxides and aziridines with the heterocumulenes such as isocyanates, carbodiimides and isothiocyanates is also known [44,45]. Alper et al. reported the regio- and enatioselective formation of the thiaolidine, oxathiolane, and dithiolane derivatives by the palladium-catalyzed cyclization reaction of 2-vinylthiirane with heterocumulenes [46]. 

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