Regioselective hydroarylation

Periana and coworkers have recently made computational studies with respect to the mechanism of regioselective hydroarylation of alkenes reported by Periana, Matsumoto, and coworkcrs- " induced by the Ph-Ir(acac)2L catalyst in the formation of ethylbenzene. Iridium inserts into the benzene C-H bond, resulting in an oxidative hydrogen migration through transition... 

As a typical intermolecular carbopalladation and termination, hydroarylation of alkynes are carried out extensively in the presence of HCO2H as a hydride source. Formation of regioisomers is observed in the reaction of asymmetric alkynes, and ratios depend on the nature of the substituents. High regioselectivity was observed in the reaction of the tertiary propargylic alcohol 14 to give 15 as a major product [5]. The (Z)-2-arylcinnamates 17, rather than 3-arylcinnamate 18, was obtained by the hydroarylation of methyl phenylpropiolate (16) [6]. 3-Substituled quinoline 21 was prepared by the regioselective hydroarylation of 19, followed by treatment of 20 with an acid without isolation [6]. 

A TFA-promoted regioselective hydroarylation of 2,3-allenoates R C=C=C (R )C02Et with N-Ts- or A-Ac-indoles has been reported to occur at the electron-rich C=C bond, giving rise to 4-indolyl-4-arylbut-2-enoates. The E Z selectivity was found to be dependent on the reaction temperature and time. A mechanism involving the formation of ( )- and (Z)-allylic carbocations generated in situ on protonation of the allenoate with TEA, followed by Friedel-Crafts attack at the 3-position of the indoles, was proposed. ... 

Compared to the hydroamination of alkynes, the protocols for more readily available olefins were rather limited. Ackermann presented a TiCU-catalyzed hydroamination reaction of norbornene using a variety of functionalized amines. Regioselective hydroarylation occurs as a competing reaction and the chemose-lectivity for hydroamination products ranges from poor to excellent [312]. This protocol can also be utilized in the hydroamination of vinylarenes with some electron-deficient amines [313] and the hydroamination of enyne compound. In the latter reaction, a subsequent rearrangement gives rise to a tetrahydroisoquinoline derivative (Scheme 14.134). 

Yoshikai and coworkers used their regioselective hydroarylation to demonstrate that their N-heterocyclic carbene cobalt catalyst could be used to perform the ortho-arylation of aromatic imines with aryl chlorides under mild conditions. Their work was inspired by previous studies by Li and coworkers with 2-arylpyridine derivatives. Treatment of aryl imines 191-193 with CoBrj, IMesHCl, t-BuCH2MgBr in THF, followed by aqueous HCl gave the corresponding ketones 194-196 in modest to good yields. The authors were able to generate various imine derivatives such as 197-199 to show the utility of their catalytic system. 

The allylic alcohols 41 derived from the propynols 40 by either a regioselective Pd-catalysed hydroarylation or hydrovinylation are readily cyclised to 4-aryl or 4-vinyl 2//-chromenes in high yield (Scheme 27) <00EJO4099>. 

Dinuclear palladium complexes catalyze m-hydroarylation of alkynes with arenes.56 The reaction of 3-hexyne with benzene in the presence of a dinulear palladium complex Pd2R2(M-OH)(//-dpfam) [dpfam = j/V,Ar -bis[2-(diphenyl-phosphino)phenyl]formamidinate, R=/>-Tol] and tri(/z-butyl)borane at 100 °C for 4h affords ( )-3-phenyl-3-hexene quantitatively (Equation (53)). The hydroarylation of 3-hexyne with monosubstituted benzenes ( )-3-aryl-3-hexenes with a 2 1 ratio of the meta- and ra -isomers. This regioselectivity is different from that of the hydroarylation of diphenylacetylene catalyzed by Rh4(GO)12.57... 

Ir(III) complexes can also be used to catalyze the hydroarylation of olefins [5, 6], The catalyst precursors (acac-0,0)2Ir(Ph)(L) (L= pyridine or H20) and [Ir(w-acac-0,0,C3)(acac-0,0)(acac-C3)]2 have been reported and are depicted in Scheme 3, with representative catalytic reactions. Among these catalyst precursors, (acac-0,0)2Ir(Ph)(H20) has been demonstrated to be the most active system [5], The lin-ear-to-branched ratios observed for Ir(III) catalyzed reactions of a-olefins are remarkably similar to those obtained using TpRu(CO)(NCMe)(Ph). For example, hydrophenylation of propene using 11 r (a-acac- O, O,C ) (acac-O, O) (acac-C3) ]2 as catalyst produces a 1.6 1 ratio of linear propylbenzene to cumene (identical to the ratio observed using the Ru(II) catalyst). Similar to the TpRu(CO)(NCMe)(R) catalysts, the regioselectivity of hydroarylation of ethylene that incorporates monoalkyl arenes produces meta- and para-disubstituted alkyl arenes in approximately 2 1 ratio without observation of ortho-disubstituted products. 

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]. 

Palladium(II) catalysts can also be applied to stereo- and regioselective syn hydroarylation and hydrovinylation of symmetrically and unsymmetrically substituted alkynes8 9. Thus, alkyl 4-hydroxy-2-alkynoates in the presence of Pd(OAc)2(PPh3)2, formic acid, and tributylamine in dimethyl formamide or acetonitrile are converted with aryl iodides in a one-pot syn hydroary-lation/cyclization reaction to give functionalized substituted butenolides. The reactions occur with high syn stereoselectivities and with good regioselectivities8. 

Hydroarylation can also be mediated by Au(I) and Au(III) (Scheme 33) (384). In the case of aryl substituted alkynes, the Au(III) Ji complex undergoes electrophilic aromatic substitution with the electron-rich arene to give aLkenyl-Au(III) complex, which is immediately protonated by the H generated upon C C bond formation. For the Au(I)-catalyzed hydroarylation, the cationic gold complex k coordinates the alkyne, with subsequent nucleophilic attack by the arene from the opposite face leading to an alkenyl-gold complex, which is protonated to the desired products. The nature of the reaction causes the regioselectivity of this reaction to be sensitive to electronic rather than steric factors. 

A novel green process for intermolecular hydroarylation of in situ generated o-QMs with electron-rich arenes in aqueous medium under catalyst-free conditions at room temperature has been developed. The reaction is efficient and highly regioselective (Scheme 7.62). 

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). 

Intermolecular hydroarylations of terminal allenes with highly nucleophilic methoxyarenes are catalyzed by cationic phosphite gold(l) complexes. The addition takes place regioselectively at the unsubstituted allene terminus and affords ( )-allylated benzene derivatives with moderate-to-high yields. 

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]. 

Cobalt-phosphine and cobalt-carbene catalysts have been developed for the hydroarylation of styrene with (91) via a chelation-assisted C-H bond activation. The regioselectivity can be controlled in favour of the branched (92) or linear product (93) at will by the ligand. Deuterium-labelling studies demonstrated a reversible C-H bond cleavage and alkene insertion steps and reductive elimination as the rate-and regioselectivity-determining step. ... 

Lautens and Yoshida reported a similar rhodium-catalyzed hydroarylation of alkynes with arylboronic acids, where ortho nitrogen heteroaromatic alkynes were employed to favor a high regioselectivity [43]. The reaction of 2-(l-hexynyl)pyridine (67a) with 2-methylphenylboronic acid (2v) and [RhCl(cod)]2/69 catalyst in the presence of sodium carbonate and sodium dodecyl sulfate (SDS) in water gave a 84% yield of the addition product 68av with high regioselectivity (Scheme 4.31). Under these conditions, the addition of arylboronic acids was also observed for several other or-... 

Synthetic strategy Regioselective tandem intramolecular hydroarylation of 1,3-dienes Catalyst Bimuth triflate [Bi(OTf)3]... 

Keywords Electron-deficient arenes, unactivated 1,3-dienes, bismuth triflate, nitromethane, room temperature, intramolecular double hydroarylation of 1,3-dienes, regioselectivity, substituted indanes... 

The gold-catalyzed intermolecular hydroarylation of electron-rich alkynes leads to 1,1-disubstituted alkenes [116]. The inverse regioselectivity in favor the 1,2-disubstituted alkenes is observed for alkynes with electron-withdrawing groups (Scheme 1.5) [117]. 

Hydroarylation of Alkynes. Hydroarylation of propynoic acid derivatives with indoles was achieved via an intermolecu-lar Fe-catalyzed, Ag-mediated process, providing access to 3,3 -bis(indolyl)propanoic acid derivatives. A catalytic system of 5 mol % FeCls and 15 mol% AgOTf in AcOH at 40 °C for 36 h regioselectively produced ethyl 3,3-bis( l//-indol-3-yl)propanoate in 86% yield (eq 71). 

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