Palladium-catalyzed arylation enolates

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

Intramolecular palladium catalyzed thio-enolate S-arylation has been used in a route to a set of fused benzo[ ]thiophenes, as illustrated by the conversion of the substrate 10 into the product 11 <06T11513>. 

For Heck reactions catalysed by Pd(OAc)2 associated with dppp, see Ref. [Ig] and (a) Cabri, W., Candiani, I. and Bedeshi, A. (1990) Ligand-controlled a-regioselectivity in palladium-catalyzed arylation of butyl vinyl ether. J. Org. Chem., 55, 3654-5 (b) Cabri, W., Candiani, L, De-Bernardinis, S. et al. (1991) Heck reaction on anthraquinone derivatives ligand, solvent, and salts effects. J. Org. Chem., 56, 5796-800 (c) Cabri, W., Candiani, L, Bedeshi, A. and Santi, R. (1991) Palladium-catalyzed a-arylation of vinyl butyl ether with aryl halides. Tetrahedron Lett., 32, 1753-6 (d) Cabri, W., Candiani, L, Bedeshi, A. et al. (1992) a-Regioselectivity in palladium-catalyzed arylation of acyclic enol ethers. J. Org. Chem., 57, 1481-6 (e) Cabri, W.,... 

Heck, R.F. (1968) The palladium-catalyzed arylation of enol esters, ethers, and halides. A new synthesis of 2-aryl aldehydes and ketones. J. Am. Chem. Soc., 90, 5535-8. 

Cabri, W., Candiani, L, Bedeschi, A. et al. (1992) Alpha-regioselectivity in palladium-catalyzed arylation of acyclic enol ethers. J. Org. Chem., 57,1481-6. 

The first attempts to use transition metal-catalyzed cross-coupling methodology to couple enolates with aryl halides were far from being broadly applicable, and involved less-attractive preformed zinc- or tin-enolates [210]. In addition, only ketones or acetates could be employed as enolate precursors. At that time, nickel was the predominant transition metal to mediate these couplings [211]. In an early contribution, CiufoHni arylated soft enolates in an intramolecular fashion with aryl halides using Pd(PPh3)4, along with NaH, in DMF at elevated temperatures [212]. This represented one of the first palladium-catalyzed arylations of enolates. 

In 2004, Willis s group demonstrated that in situ-generated enolates can be used as intramolecular nucleophiles in palladium-catalyzed aryl-carbonylation reactions to give the corresponding isocoumarins [274]. At 1 bar of CO, good yields were achieved with both cyclic and acyclic ketones as substrates. Later on, they also used this methodology in a concise synthesis of the natural product thunberginol A (Scheme 2.40). 

SCHEME 19.29 Nickel- and Palladium-catalyzed arylation of zinc ester enolate (1977). 

After the intermolecular palladium-catalyzed arylation of enolates had been discovered by the research groups of Buchwald, Hartwig, and Miura [63], it was an obvious idea to explore a stereoselective variant that was based on the reliable Evans auxiliaries, while catalytic, enantioselective protocols (cf. Section 5.2) were developed at the same time. However, only relatively moderate diastereoselectivity in the formation of arylation products 133 was achieved when the silyl ketenimine (S)-132 derived from Af-propionyl oxazolidinone was coupled with aryl bromides under palladium catalysis, as disclosed by Hartwig and Liu [64]. The additive zinc(ll) f-butoxide permitted to lower the temperature to 25 °C so that the diastereoselectivity could be enhanced (Scheme 4.26). The authors noticed that Ley s chiral dioxanone 134 proves itself as an auxiliary that induced excellent diastereoselectivity and led to the formation of arylated compounds 135 in very high diastereomeric ratios. The chiral auxiliary group was readily removed by treatment with chlorotrimethylsUane and methanol, so... 

Scheme 5.50 Enantioselective palladium-catalyzed arylation of enolates derived from racemic oxindoles 152, mediated by the axially chiral and P-stereogenic ligand 153.

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. 

On the other hand, the use of [Rh(CO)2Cl]2 as a catalyst results in ring opening of the siloxycyclopropanes 13 to the silyl enol ethers 14 with high stereoselectivity [10]. The 2-siloxyrhodacyclobutane 15a is proposed to undergo j8-elimination to give jr-allylrhodium 16a followed by reductive elimination to the silyl enol ether 14a. 1-Trimethylsiloxybicyclo[n.l.0]alkanes serve as / -metallo-carbonyl compounds via desilylation with a variety of transition metals [11]. The palladium-catalyzed reaction of the siloxycyclopropanes 17 under carbon monoxide in chloroform provides a route to the 4-keto pimelates 18. In the presence of aryl triflates, the 1,4-dicarbonyl compounds 19 are... 

Vinyl-l//-isochromenes can be prepared in moderate yield by a palladium-catalyzed coupling of ( )-(3-(2-bromo-phenyl)allyloxy)tenM)i i r l)si Iyl derivatives 157 with ketones. The reaction proceeds via initial ketone arylation to furnish the intermediate 158 followed by intramolecular cyclization of the ketone enolate onto the tethered allylic system (Scheme 50) <2000CG1675>. 

Relatively less acidic ketones compared to 1,3-dicarbonyl compounds are also suitable substrates for the palladium catalyzed coupling. a-Aryl ketones are obtained as products. In the early examples, masked ketone enolates such as silyl enol ethers [42] and enol acetates [43-45] were used in the presence of a tin source. These reactions involve tin enolates or acylmethyltins as intermediates and thus proceed by transmetalation (mechanism B in Scheme 1). 

In the last years several publications appeared describing palladium-catalyzed a-arylations of ketone enolates for the synthesis of a-aryl ketones, involving ketone eno-lates, silyl enol ethers and intramolecular a-aiylation of ketone enolates . In this process, an enolate is generated from a ketone in the presence of an aryl halide, and a palladium catalyst couples this enolate with the aryl halide. Iwama and Rawal proposed... 

Silyl enol ethers (CHj = CROSiMe3) react with cyanuryl chloride and replace only one chlorine with a carbon substituent (CH2COR R = cyclopropyl, 70 /o, R = Ph, 90 /o). Friedel-Crafts arylation <83KGS1125,92EUP497734>, the Ullmann reaction of 2-iodo-1,3,5-triazine to form 2,2 -bis-1,3,5-triazine <82NKK1425>, and a palladium-catalyzed cross-coupling reaction of 2-substituted 4,6-dichloro-... 

Nucleophilic displacement of chlorine, in a stepwise manner, from cyanuric chloride leads to triazines with heteroatom substituents (see Section 6.12.5.2.4) in symmetrical or unsymmetrical substitution patterns. New reactions for introduction of carbon nucleophiles are useful for the preparation of unsymmetrical 2,4,6-trisubstituted 1,3,5-triazines. The reaction of silyl enol ethers with cyanuric chloride replaces only one of the chlorine atoms and the remaining chlorines can be subjected to further nucleophilic substitution, but the ketone produced from the silyl enol ether reaction may need protection or transformation first. Palladium-catalyzed cross-coupling of 2-substituted 4,6-dichloro-l,3,5-triazine with phenylboronic acid gives 2,4-diaryl-6-substituted 1,3,5-triazines <93S33>. Cyanuric fluoride can be used in a similar manner to cyanuric chloride but has the added advantage of the reactions with aromatic amines, which react as carbon nucleophiles. New 2,4,6-trisubstituted 1,3,5-triazines are therefore available with aryl or heteroaryl and fluoro substituents (see Section 6.12.5.2.4). 

For related palladium-catalyzed cyclizations of enolates, see Ciufolini, M.A. Qi, H.B. Browne, M.E. Intramolecular arylations of soft enolates catalyzed by zerovalent palladium. J. Org. Chem. 1988, 53, 4149 151. Muratake, H. Natsume, M. Nakai, H. Palladium-catalyzed intramolecular -arylation of aliphatic ketone, formyl, and nitro groups. Tetrahedron 2004, 60, 11783-11803. Muratake, H. Natsume, M. Palladium-catalyzed intramolecular -arylation of aliphatic ketones. Tetrahedron Lett. 1997, 38, 7581-7582. 

In connection with a total synthesis of frondosin B, the key intermediate shown below was synthesized by a sequential reaction of the phenol, the enyne and the bromide in a one-pot operation as shown <04OL457>. The palladium-catalyzed intramolecular C-0 bond formation between aryl halides and enolates was employed to make 2,3-disubstituted benzo[i> furans <04OL4755>. 

---