Enolates arylation

Enolate arylation has also been extended to aryl tosylates. The preferred catalyst includes a very bulky biphenyl phosphine D.179... 

A tandem enolate-arylation-allylic cyclisation, in which an essential z-butyldimethylsilyl ether protecting group delays the cyclisation step until the Pd-catalysed arylation is complete, enables 1-vinyl-l//-[2]benzopyrans 54 to be prepared from 2-bromobenzaldehyde (Scheme 32) <00CC1675>. 4-Substituted isochromans 55 are formed from aldehydes by a Pd-catalysed termolecular queuing cascade. The sequence involves cyclisation of an aryl iodide onto a proximate alkyne followed by an allene insertion. Transmetallation with indium then allows addition to the aldehyde (Scheme 33) . 

The synthesis of 1-substituted tetrahydroisoquinolines using an intramolecular Pd-catalyzed a-enolate arylation was described. Treatment of a-amino esters such as 71 and 73 with LiOr-Bu, Pd2(dba)3 and ligand 75 or 76 afforded the corresponding isoquinolines 72 and 74. Investigations to develop an asymmetric version of this reaction were reported to be ongoing <02JOC465>. 

Bonjoch has just begun to explore a novel intramolecular annulation of 2-haloanilines with pendant ketones 95 which can lead to indolic products 96 by either of two different and competitive cyelization pathways, namely, enolate arylation or addition of the organometallic intermediate to the ketone carbonyl group <01CC1888>. 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

Metal Enolates. In parallel with additives, transition metals may be added to enolates to give transmetallated species which can undergo cross-coupling chemistry. Perhaps the earliest example of metal-catalyzed enolate reactions is the Reformatsky reaction. Transition metal-catalyzed enolate chemistry has been recently revived in the literature, particularly in the field of asymmetric catalysis. The transition metal-catalyzed coupling reactions of aryl halides, allyl epoxides, and allylic esters with alkyl enolates have been recently investigated. Generally the choice of base employed depends on the substrate and on the reaction performed. For enolate arylation, KHMDS seems to be the most... 

To investigate whether an enolate arylation was occurring, the authors prepared enantioenriched cyclopropane substrate 45 and submitted it to the reaction conditions (Scheme 11). After 3 h, all starting material was consumed, and spirooxindole product 46 showed little erosion of enantioselectivity. Furthermore, the kinetic isotope effect was determined via parallel reactions to be 3.9, identifying C-H cleavage as a rate-determining step. This observation is not consistent with an enolate-like pathway. Furthermore, the use of a weak base (K2CO3) makes the enolate pathway quite unlikely. 

As far as the influence of the phosphine ligand in the catalyzed reactions is concerned, P(tBu)j is effective in most cases. The rate of the reductive elimination of enolate complexes containing this and other bulky phosphines is faster, and the scope of many couplings catalyzed by complexes with these ligands is broader. Recently, it has been found that a catalytic quantity of phenol causes a remarkable increase in the efficiency of ketone enolate arylation [382]. 

An intramolecular enolate arylation of ketone 2.490 was employed in a synthesis of lennoxamine 2.492 and related alkaloids (Scheme 2.140). ° The carbonyl group, having served the purpose of activating the a-protons in ketone 2.490, was subsequently removed by a double reduction sequence, including a Kursanov-Parnes reaction. 

Scheme 8.29 Intramolecular cyclization reaction employing enolate arylation, as described by Muratake and Nakai [64].

Scheme 2.53 In situ formation of palladium enolates 180 and/or 181 in catalytic enolate arylation reactions.

Despite the key role that has been attributed to copper enolates as postulated intermediates in additions to enones [78], structural information is very rare for enolates of copper as well as the higher elements in group 11. A recent crystal structure of a copper(I) ester enolate 46, which functions as a relevant intermediate in catalytic enolate arylation reactions, features a cationic Cu(I) center coordinated to two phenanthroline ligands and a free unligated enolate anion (Figure 3.13) [79]. A gold(I) enolate of acetophenone is a C-bound tautomer, as expected by the low oxophilic character of the noble metal and confirmed by a crystal structure analysis [80]. 

Scheme 5.46 General, simplified catalytic cycle of enolate arylation, mediated by [L Pd°]. The intermediate palladium enolates are assumed to exist as equilibrium of C- and O-bound tautomers 140 and 141, respectively.

Scheme 5.47 Enantioselective palladium-catalyzed enolate arylation of racemic aminomethylene ketones 143 mediated by chiral ligands 144.

The concept of enantioselective intramolecular enolate arylation was also applied to obtain indanyl aldehydes 168, according to a protocol of Buchwald and Garda-Fortanet, from aryl bromides 167. A screening of ligands revealed the... 

Scheme 5.53 Enantioselective intramolecular enolate arylation of racemic ortho-bromoanilides 161, 163, and 165.

Continuing their investigation of tandem cascade reactions toward indole synthesis, Barluenga et al. reported a process combining palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation (Scheme 24.1, disconnection D-7) [51]. The process is outlined in Scheme 24.9 initial palladium-catalyzed aza-enolate arylation generates intermediate imine 23 and then palladium-catalyzed intramolecular amination, presumably via intermediate enamine 24, results in the product indole in excellent 86% yield. An XPhos-derived catalyst facilitated both steps of the cascade, and a wide range of imines could be incorporated. 

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