Hydroarylation directed

Scheme 5.65 Ir-catalyzed intramolecular direct hydroarylation of a-keto amides reported by Yamamoto.

The first example of direct enantioselective addition of a C—H bond to a ketone was reported by Shibata and co-workers in 2009 using the cationic Ir/ (S)-Hg-BINAP as the catalyst in the synthesis of a chiral 4-acetyl-3-hydroxy-3-methyl-2-oxindole with 72% ee. Recently, Yamamoto and co-workers developed a cationic Ir/(R,R)-Me-BIPAM catalyzed asymmetric intramolecular direct hydroarylation of a-keto amides 178 affording the chiral 3-substi-tuted 3-hydroxy-2-oxindoles 179 in high yields with complete regioselectivity and high enantioselectivity (84-98% ee). In their proposed reaction mechanism, the aryl iridium complex formed via C—H bond activation is coordinated with the two carbonyl groups of the amide (Scheme 5.65). 

In parallel with the directed hydroarylation of olefins, a series of papers described the formation of ketones from heteroarenes, carbon monoxide, and an alkene. Moore first reported the reaction of CO and ethylene with pyridine at the position a to nitrogen to form a ketone (Equation 18.28). Related reactions at the less-hindered C-H bond in the 4-position of an A/-benzyl imidazole were also reported (Equation 18.29). - Reaction of CO and ethylene to form a ketone at the ortho C-H bond of a 2-arylpyridine or an N-Bu aromatic aldimine has also been reported (Equations 18.30 and 18.31). Reaction at an sp C-H bond of an N-2-pyridylpiperazine results in both alkylative carbonylation and dehydrogenation of the piperazine to form an a,p-unsaturated ketone (Equation 18.32). The proposed mechanism of the alkylative carbonylation reaction is shown in Scheme 18.6. This process is believed to occur by oxidative addition of the C-H bond, insertion of CO into the metal-heteroaryl linkage, insertion of olefin into the metal-acyl bond, and reductive elimination to form the new C-H bond in the product. 

In 1993, Murai reported the reactions of aryl ketones witti ethylene and vinylsilanes to form the product from the addition of the C-H bond ortho to the carbonyl group to the olefin (Equation 18.49). This finding led to subsequent work on the addition of the C-H bonds of a variety of aromatic groups to a series of olefins. Catalysts that react under milder conditions than the original ones and extensions of the C-H activation to intramolecular cyclizations to form heterocyclic structures have made this reaction capable of being used in the synthesis of complex molecules. For example, alkylated diterpe-noids and (+)-lithospermic acid (Equations.18.50 and 18.51) have been synthesized using directed hydroarylation. ... 

The intramolecular hydroarylation of A-propargylpyrrole-2-carboxamides under AuCls-catalyzed conditions affords substituted pyrrolo[2,3-c]pyridinone and pyrrolo[3,2-c]pyridinone derivatives arising from direct hydroarylation or from a formal rearrangement of the carboxamide group (Scheme 18.39) [34]. The ratio of these products depends on the polarity of the solvent. The AuCls-catalyzed intramolecular... 

Scheme 1. Conventional (top) and direct (bottom) hydroarylation of alkynes.

These catalytic reactions provide a unique pathway for addition of aromatic C-H bonds across C=C bonds. In contrast with Friedel-Crafts catalysts for olefin hydroarylation, the Ru-catalyzed hydrophenylation reactions of a-olefins selectively produce linear alkyl arenes rather than branched products. Although the selectivity is mild, the formation of anti-Markovnikov products is a unique feature of the Ru(II) and Ir(III) catalysts discussed herein. Typically, the preferred route for incorporation of long-chain linear alkyl groups into aromatic substrates is Friedel-Crafts acylation then Clemmensen reduction, and the catalysts described herein provide a more direct route to linear alkyl arenes. 

The hydroarylation of olefins is relatively uncommon in photochemistry, despite a high interest in this process which allows the formation of an aryl-carbon bond via the direct activation of an aromatic, with no need for leaving groups in both components of the reaction. The process follows a photo-EOCAS (Electrophile-Olefin Combination Aromatic Substitution) mechanism [32], and is initiated by a PET reaction between an electron-rich aromatic and an electron-poor olefin, as illustrated in Scheme 3.14. 

Stoichiometric cycloruthenation reactions, as well as the early example of catalytic deuteration of phenol (see above) [38] served for the development of efficient catalytic strategies for C-C bond formations through C-H bond functionalizations. Indeed, ruthenium-catalyzed atom-economical [51] addition reactions of arenes onto C-C multiple bonds, hydroarylations [52-57], were found to be very useful. In an early example, Lewis and Smith disclosed a regioselective alkylation of phenol through in situ formation of its phosphite, and subsequent directed C-H bond functionalization (Scheme 8) [58],... 

While this protocol relied on the in situ generation of the relevant phosphite for catalytic hydroarylation reactions, Murai and coworkers developed effective methodologies for the direct use of Lewis-basic substrates, such as acetophenone 20 (Scheme 9) [18, 59], Thereby, regioselective ruthenium-catalyzed anti-Markovnivkov alkylations and alkenylations were accomplished using alkenes or alkynes [60] as substrates, respectively. Recently, an extension of this protocol to terminal alkynes was reported, which involved a phosphine ligand-free catalytic system (see below), along with stoichiometric amounts of a peroxide [61]. 

In 1986, a highly regioselective catalytic hydroarylation [118] ofalkenes was disclosed by Lewis, whereby a cyclometaUated ruthenium catalyst 94 allowed for a directed (hence ortho-selective) alkylation of phenols through the in situ formation of the corresponding phosphites (Scheme 1.36) [119]. 

Ruthenium(II)-Catalyzed Regio- and Stereoselective Hydroarylation of Alkynes via Directed C-H Functionalization... 

A series of arylations of olefins by C-H bond cleavage without direction by an ortho functional group has also been reported, and these reactions can be divided into two sets. In one case, the C-H bond of an arene adds across an olefin to form an alkylarene product. This reaction has been called hydroarylation. In a second case, oxidative coupling of an arene with an olefin has been reported. This reaction forms an aryl-substituted olefin as product, and has been called an oxidative arylation of olefins. The first reaction forms the same t)q)es of products that are formed from Friedel-Crafts reactions, but with selectivity controlled by the irietal catalyst. For example, the metal-catalyzed process can form products enriched in the isomer resulting from anti-Markovnikov addition, or it could form the products from Markovnikov addition with control of absolute stereochemistry. Examples of hydroarylation and oxidative arylation of olefins are shown in Equations 18.63 - and 18.64. ... 

The syntheses of isolable five-coordinate Pt(IV) complexes have allowed the direct study of C-C and Si-H reductive elimination processes. Rate constants can now be determined for these bond-forming reactions that do not include contributions from preliminary dissociation of ligands as is generally the case when the reactions occur from octahedral complexes. In additimi, reductive elimination from five-coordinate Pt(IV) complexes allows access to highly reactive Pt(II) species, which have been shown to perform intra- and intermolecular C-H activation and to provide entry points into catalytic hydroarylation and hydrosilylation reactions. 

The use of aryloxazolines (n = 0) or aryloxazines (n = 1) as directing groups has also been reported (Scheme 19.60) [80]. The selectivity of these groups with respect to the formation of hydroarylation and dehydrogenative alkenylation products was found to depend on the structure of the N,0-heterocycle. 

Phosphine oxide directing groups enable both redox-neutral and oxidative C-H olefinations (Scheme 23.17) [76, 77], In combination with [Ru(p-cymene)Clj]j, cw-selective hydroarylations of alkynes can be achieved. Furthermore, in the presence of [Cp RhCy/AgSbF, Cu(OAc)j, and AgjCOj, oxidative C-H olefinations are possible with electron-poor olefins as coupling partners. The latter reactions proceed with complete selectivity for the fran -product. 

To date, most research on NHCP transition-metal catalysis has been devoted to cross-couplings [13] or related reactions such as hydroarylation of alkenes [18], direct arylation of alkynes [17], or oxidative homocoupling of terminal alkynes [19]. All NHCP systems used in these studies feature one or two... 

Insertions of alkynes into palladium-hydride complexes have been reported to take place as part of catalytic cycles, resulting in circumstantial yet credible evidence for the occurrence of alkenylpalladium complexes. The first example of palladium-catalyzed hydroarylation of alkynes with organoboronic acids B(OH)2R has been given. The mechanistic interpretation based on labeling studies involves hydropalladation of the alkyne to give an intermediate alkenylpalladium(ii) species that reacts with the organoboronic acid (Scheme 11). Similar direct coupling reactions... 

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