Tsuji-Trost reaction enolate allylation

The Tsuji-Trost Reaction (or Trost Allylation) is the palladium-catalyzed allylation of nucleophiles such as active methylenes, enolates, amines and phenols with allylic compounds such as allyl acetates and allyl bromides. 

The Tsuji-Trost reaction involves Pd-catalyzed allylation of stabilized enolates and related compounds, such as malonate and acetoacetate anions. Since most of the counterions have been alkali metals, such as Li and Na, this vast topic is mostly outside the scope of this... 

A wide variety of nucleophiles add to an -rf-allyl ligand. Desirable nucleophiles typically include stabilized carbanions such as CH(COOR)2 or 1° and II0 amines. Unstabilized nucleophiles such as MeMgBr or MeLi often attack the metal first and then combine with the n-allyl by reductive elimination. The Tsuji-Trost reaction, which is typified by the addition of stabilized carbanions to T 3—allyl ligands complexed to palladium followed by loss of the resulting substituted alk-ene, comprises an extremely useful method of constructing new C-C bonds, and many applications of this reaction have appeared in the literature.61 Equation 8.43 illustrates an example of a Pd-catalyzed addition of a stabilized enolate to an allyl acetate.62 The initial step in the catalytic cycle is oxidative addition of the allyl acetate to the Pd(0) complex, followed by nq1 to nq3—allyl isomerization, and then attack by the nucleophile to a terminal position of the T 3—allyl ligand. We will discuss the Tsuji-Trost reaction, especially in regard to its utility in chiral synthesis,63 more extensively in Chapter 12. 

The stereochanistry at the allylic CspS center is also a very intricate issue. In the 1970s it was demonstrated that Pd-catalyzed allylation of doubly stabilized enolates, that is, the Tsuji-Trost reaction, proceeded with retention at that C pS center, resulting from double... 

With ample supplies of 38 provided through this protocol, the Sorensen group could next attempt to attach the atoms needed to prepare 37, the projected intermediate for a second reaction based on 7T-allyl palladium complexes (a Tsuji—Trost reaction) that would hopefully lead to the 19-membered macrocycle 36. In essence, this requirement boiled down to only two key synthetic objectives generating a ketoester moiety from the Weinreb amide, and converting the allylic TES-protected alcohol function at Cl into a methyl carbonate. Neither of these tasks ultimately proved to be overly challenging to carry out, with the first accomplished by treating 38 with excess quantities of the lithium enolate of t-butyl acetate to provide 54, and the second requiring three rela-... 

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. 

A complementary functional cyclopropane assembly relies on the utilization of the Tsuji-Trost reaction [101], A highly enantio and diastereoselective cou-pling/cyclopropanation sequence of acyclic amides 85 with allyl carbonates 86 is illustrated in Scheme 5.30 [102], In this reaction, a scarcely described addition of the nucleophilic enolate intermediate onto the central carbon of the i-allyl palladium is involved, which affords the corresponding cyclopropane. 

The first diastereoselective and enantioselective allylic alkylation of cyclohexanone (through the magnesium enolate 18a) with diphenylallyl acetate 19a was reported in 2000 by Braun and coworkers [16a]. (7J)-BINAP (23) served as the optimum chiral ligand, and the alkene 20 was obtained as an almost pure diastereomer with an enantiomeric excess of 99% ee. The relative configuration was proven by the crystal structure analysis the absolute configuration was assigned unambiguously by chemical correlation. A first diastereoselective and enantioselective Tsuji-Trost reaction of a lithium enolate derived from... 

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. 

The formation of diastereomeric product 67 from the substrate E)-65 is plausibly rationalized by a twofold inversion firstly in the formation of the Jt-complex 66 and secondly by an approach of the nucleophilic enolate. In this case, there is no need for a thermodynamically controlled (Z)- to ( )-interconversion, and thus, a net retention in the allylic alkylation results (Scheme 5.22). Analogous stereochemical outcome was observed for the reaction of the lithium enolate of cyclohexanone with the allylic substrates (Z)-60 and ( )-65. The results shown in Schemes 5.21 and 5.22 clearly prove the outer-sphere mechanism for the Tsuji-Trost reaction of ketone lithium enolates [16c]. 

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 Tsuji-Trost reaction is the palladinum-catalyzed substitution of allylic leaving groups by carbon nucleophiles. The nucleophile can be carbon-, nitrogen-, or oxygen- based compounds such as alcohols, enolates, phenols, and enamines, and the leaving group can be a halide or an acetate. This emerged as a powerful procedure for the formation of C—C, C—O and C—N bonds. The reaction, also known as Trost allylation or allylic alkylation, was named after Jiro Tsuij, who first reported the method in 1965 [42], and Barry Trost, who introduced an asymmetric version in 1973 [43]. 

Negishi, E.-i. Palladium-catalyzed cross-coupling involving 3-hetero-substituted compounds. Palladium-catalyzed a-substitution reactions of enolates and related derivatives other than the Tsuji-Trost allylation reaction. Handbook of Organopalladium Chemistry for Organic Synthesis 2002, 1, 693-719. 

The enantioselectivity associated with quaternary allylation is connected with scenario 5 above (one of the five points associated in the catalytic cycles shown by Schemes 12.10a and b where chirality could be induced), which is where enantioselection of one of two faces of the nucleophile (the enolate ion) occurs. Theoretical studies of the transformation using the PHOX ligand have shown support for an inner sphere mechanism, where nucleophilic attack of the enolate onto the rf-allyl ligand occurs from the Pd-bound enolate and not from an external nucleophile.74 These studies have not been able to definitively determine the step that defines the enantioselectivity of the reaction, and it is not clear how these results would carry over to reactions involving the Trost ligands. At this time, selection of which ligand one should use not only to induce enantioselectivity but also to predict the sense of absolute configuration of any asymmetric Tsuji-Trost allylation is mostly based on empirical results. Work continues on this... 

The Tsuji-Trost allylation of enolates can be viewed as a variant of Pd-catalyzed cross-coupling involving aUylic electrophiles (Sects, ni.2.9 and III.2.10). In recognition of the widely accepted mechanism involving a nucleophilic attack by enolates at the TT-allyl ligand of an allylpalladium derivative on the side opposite to Pd, however, it is discussed separately in Part V together with the Wacker and related reactions, which are... 

III.2.14.1 Palladium-Catalyzed of-Substitution Reactions of Enolates and Related Derivatives Other than the Tsuji-Trost Allylation Reaction... 

In this section, attention is focused on the Pd-catalyzed a-substitution reactions of enolates and related derivatives represented by Method I in Scheme 1, other than Tsuji-Trost allylation and propargylation. Additionally, its charge-affinity inverted version represented by Method II in Scheme 1 is also discussed. In general, it is advisable to consider simultaneously various other alternatives including those shown in Scheme 1, especially Method III. Indeed, Method III discussed in the following section provides the currently most... 

The Tsuji-Trost protocol has been successfiilly employed for the allyUc alkylation of preformed lactone enolates. It has been demonstrated that this Pd-catalysed reaction can be carried out in an enantio- and diastereo-selective manner. The use of additives, such as LiCl, was found to be crucial for reaching high levels of product selectivity. Among the five pathways investigated by DFT methods, the reaction between an (allyl)Pd(BINAP) (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) complex and a LiCl-lithium enolate adduct was predicted to be the most likely route for C-C bond formation. 

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. 

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