Tsuji-Trost reaction allyl esters

Ester enolates, much more sensitive and capricious than ketone and amide enolates, seemed to be unsuitable for palladium-catalyzed allylic alkylations. Thus, Hegedus and coworkers [24] reported on low yields and predominant side reactions in the allylation of the lithium enolate of methyl cyclohexanecarboxylate. It seems that so far the only reliable and efficient version of a Tsuji-Trost reaction with ester enolates is based on the chelated zinc enolates 41 derived from N-protected glycinates 40 - a procedure that was developed by Kazmaier s group. 

For further details of this reaction, the reader is referred to Chapter 9. The catalytic allylation with nucleophiles via the formation of Ti-allyl metal intermediates has produced synthetically useful compounds, with the palladium-catalyzed reactions being known as Tsuji-Trost reactions [31]. The reactivity of Ti-allyl-iridium complexes has been widely studied [32] for example, in 1997, Takeuchi idenhfied a [lrCl(cod)]2 catalyst which, when combined with P(OPh)3, promoted the allylic alkylation of allylic esters 74 with sodium diethyl malonate 75 to give branched... 

The catalytic version of allylation of nucleophiles via 7r-allylpaUadium intermediates was discovered in 1970 using allylic esters and aUyl phenyl ethers as substrates (Scheme Formation of 7r-allylpaUadium complexes by oxidative addition of various allylic compounds to Pd(0) and subsequent reaction of electrophilic rr-allylpalladium complexes with soft carbon nucleophiles are the basis of the catalytic allylation. After the reaction, Pd(0) is regenerated, which undergoes oxidative addition to the allylic compounds again, making the whole reaction catalytic. The efficient catalytic cycle is ascribed to the characteristic feature that Pd(0) is more stable than Pd(II). Allylation of carbon nucleophiles with allyhc compounds via TT-allylpalladium complexes is called the Tsuji-Trost reaction. The reaction has wide synthetic applications, particularly for cyclization. " ... 

The advent of the catalytic Tsuji-Trost reaction in the early 1970s " (Sects. V.2.1.1 and V.2.1.2) has significantly expanded the scope of enolate allylation and related reactions. Noteworthy among others is that the range of allylic electrophiles was vastly expanded from allylic halides, such as chlorides and bromides, to a much wider range of derivatives including not only halides but also O, S, N, and other heteroatom-containing derivatives. Curiously, however, the scope of the Tsuji-Trost reaction had essentially been limited to the Pd-catalyzed allylation of extra-stabilized enolates, such as those derived from malonate and acetoacetate esters, until around 1980. 

Contrary to earlier notions that the Pd-catalyzed a-allylation of carbonyl compounds would be limited to those carbonyl compounds that are extrastabilized (the Tsuji-Trost reaction), the use of Zn, B in the forms of BRjK or Li + 2 BR3, where R = Et, and so on, Si, and Sn has been shown to permit the use of those enolates of ordinary ketones, aldehyde esters, and so on, where the pATj of the carbonyl compounds may be 20. In some cases, however, even lithium enolates can provide satisfactory results. Since most of the enolates mentioned above are derived via alkali metal enolates containing Li, Na, or K, these parent enolates should be tested before converting or modilying them with reagents containing other metals. 

Allylic esters are among the most versatile substrate in organic synthesis. They are popular substrates for many transition metal-catalyzed reactions, such as dihydroxylation, the Tsuji-Trost reaction, hydrogenation, and isomerization, inter alia In this context, the Heck arylation can be considered a privileged reaction for the formation of such esters in a regio- and stereoselective way. However, this transformation has been a challenging one due to the... 

The protocols for the utilization of ketone-derived silyl enol ethers in Tsuji-Trost reactions were preceded by a report of Morimoto and coworkers on the enantioselective allylation of sUyl ketene acetals 88. Without external activation, they reacted with the allylic substrate 19d in the presence of the palladium complex derived from the amidine ligand 89 to give y,5-unsaturated esters 90 in moderate chemical yield but high enantiomeric excess (Scheme 5.29) [46]. Presumably, the pivalate anion hberated during the oxidative addition functions as an activator of the silyl ketene acetal. The protocol is remarkable in view of the fact that asymmetric allylic alkylations of carboxylic esters are rare. Interestingly, the asymmetric induction originates from a ligand with an uncomplicated structure. The protocol seems however rather restricted with respect to the substitution pattern of allylic component and sUyl ketene acetal. 

The Overman esterification is a palladium-catalyzed formation of enantioenriched allyl esters from carboxylic esters with primary allyl imidates. From a mechanistic point of view, it is related to the Tsuji-Trost reaction. It proceeds under quite mild conditions with high enantiomerically access if the COP ([Ti -(5)-2-(4-methylethyl)-oxazolinylcyclo-pentadienyl]-(T] -tetraphenylcyclobutadiene)cobalt) complex is used. For example, Kirsch and co-workers used the Pd-catalyzed Overman esterification " in their approach to 1,3-polyols starting from (Z)-allylic trichloroacetimidates to build up the stereogenic centers. By choice of the required enantiomer of COP-OAc catalyst, every possible diastereoisomer is accessible in high stereoselectivity (Experimental Procedure below). 

In the laboratory of B.M. Trost, the second generation asymmetric synthesis of the potent glycosidase inhibitor (-)-cyclophellitol was completed using a Tsuji-Trost allylation as the key step. The synthetic plan called for the conversion of the a-nitrosulfone allylation product to the corresponding carboxylic acid or ester. Numerous oxidative Nef reaction conditions were tested, but most of them caused extensive decomposition of the starting material or no reaction at all. Luckily, the nitrosulfone could be efficiently oxidized with dimethyidioxirane under basic conditions (TMG) to afford the desired carboxylic acid in high yield. 

The allylic alcohol products from Morita-Baylis-Hillman reactions were shown to participate in a DMAP-mediated Tsuji-Trost-type reaction with /3-diketones or /3-ketoesters, forming the C-allylation product without requiring the use of palladium. Previously, it was shown that allylic alcohols combined with /8-ketoesters and DMAP afforded the transesterification products, in which the allylic alcohol displaced the ester substituent. The difference between these diverging reaction pathways is likely due to the electron-withdrawing group on the allylic alcohol in the MBH adducts vs. just alkyl substituents in the latter case. 

Although it is mechanistically different from the Tsuji-Trost allylation, indirect allyla-tions of ketones, aldehydes, and esters via their enolates are briefly summarized here. Related reactions are treated in Sect V.2.1.4. Pd-catalyzed allylation of aldehydes, ketones, and esters with aUyhc carbonates is possible via the Tr-allylpaUadium enolates of these carbonyl compounds. Tr-AUylpalladium enolates can be generated by the treatment of silyl and stannyl enol ethers of carbonyl compounds with allyl carbonates, and the allylated products are obtained by the reductive elimination of the Tr-allylpalladium enolates. 

Transition metal-catalyzed allylic substitution reactions with carbon nucleophiles are among the most important carbon-carbon bond formation methods in modem organic synthesis, because of their broad substrate scope under mild reaction conditions. In addition, they are applicable to enantioselective reactions, as well as exhibiting versatility towards the alkene functionality adjacent to the chiral centre for stereoselective derivatization. Tsuji-Trost allylic substitution, involving a (Ti-allyl) metal intermediate, has provided a particular advance in this regard [34, 35]. Most recently, Sawamura et al. [36, 37] have improved the regioselectivity of this reaction with unsymmetrically substituted allylic esters, and thus opened a new approach to sertraline. 

The research groups of Trost and Tsuji have shown that in the presence of a palladium(O) catalyst vinyl epoxides can be regio- and stereo-selectively alkylated with various carbon acids under neutral conditions the main products are E-allylic alcohols resulting from 1,4-addition, e.g. (107) - (108). The reaction tolerates ester and ether groups. In the presence of a base, alkyl-lithiums... 

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