2- allyl acetate, Tsuji-Trost reaction

The Tsuji-Trost reaction is the Pd(0)-catalyzed allylation of a nucleophile [48-51]. The NH group in imidazole can take part as a nucleophile in the Tsuji-Trost reaction, whose applications are found in both nucleoside and carbohydrate chemistry. Starting from cyclopentadiene and paraformaldehyde, cyclopentenyl allylic acetate 64 was prepared in diastereomerically-enriched form via a Prins reaction [52], Treating 64 with imidazole under Pd(0) catalysis provided the N-alkylated imidazole 65. 

Extending the aforementioned methodology from imidazole to adenine, the Tsuji-Trost reaction between the sodium salt of adenine and allylic acetate 66 gave 67 as a 82 18 mixture of cis trans isomers. Carbocyclic nucleoside 67 was advantageous over normal nucleosides as a drug candidate because it was not susceptible to degradation in vivo by nucleosidases and phosphorylases [52],... 

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. 

In one of the first papers on the subject, Billups et al. (80SC147) reported that the Pd(0)-catalyzed allylation of indole 96 with allyl acetate gave N-allyl- (97) and 3-allylindole (98) plus the diallylation product 99 (Scheme 21). They also showed that the yV-allyl isomer 97 rearranged under Pd(0) catalysis to the C-3 isomer 98, thus indicating that the formation of 98 was thermodynamically controlled (C > N). The work of Billups also includes the use of allyl alcohol instead of allyl acetate in the Tsuji-Trost reaction. 

The Pd(0)-catalyzed allylation of 96 with acrolein dimethyl acetal gives exclusively compound 104. The 7j3-allylpalladium cationic complex (4, R = OMe) is attacked only at the center bearing the substituent MeO (80SC147), thus emphasizing the importance not only of steric effects in the electrophile but also of the electronic effects in the Tsuji-Trost reaction (92T1695). Indole 96 has been also allylated with epoxide 105 under Pd(0) catalysis by Trost and Molander (81JA5969). The intermediate cationic complex is attacked at the exocyclic position, 106 being formed, as shown in Scheme 22. 

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 Tsuji-Trost reaction is the Pd-catalyzed allylation of nucleophiles [105] with allylic halides, acetates, carbonates, etc. This transformation proceeds via intermediate allylpalladium complexes (e.g. 110), and typically proceeds with overall retention of stereochemistry. In addition, the trapping of the intermediate allylpalladium complex usually occurs at the least hindered carbon. A representative example of this transformation is shown below in an application to the formation of an 7V-glycosidic bond. Treatment of 2,3-unsaturated hexopyranoside 109 with imidazole in the presence of a Pd(0) catalyst... 

An ingenious extension of the Tsuji-Trost reaction was the cornerstone of Oppolzer s enantioselective synthesis of a heteroyohimbine alkaloid, (-t-j-B-isorauniticine (267) [117]. Substrate 263 was prepared from a commercially available glycinate equivalent by Malkylation, installation of the sultam chiral auxiliary followed by a sultam-directed C-alkylation. As illustrated in Scheme 48, the crucial double cyclization was accomplished by the treatment of 263 with Pd(dba), Bu,P, in the presence of carbon monoxide (1 atm) in acetic acid to give enone 264 and two other stereoisomers in a 67 22 11 ratio. In this case, an allyl carbonate, rather than an allyl acetate, was used as the allyl precursor. Since carbonate is an irreversible leaving group, formation of the n-allylpalladium complex occurs readily. In the presence of Pd(0), the allylic carbonate is converted into a n-allylpalladium complex with concurrent release of CO, and... 

Leaving groups in the Tsuji-Trost reaction include acetates, halides, ethers, carbonates, sulfones, carbamates, epoxides, and phosphates. Reviews (a) Tsuji, J. In Handbook of Organopalladium Chemistry for Organic Synthesis, Negishi, E. deMeijere, A., Eds. Wiley-lnterscience New York, 2002 Vol II, Palladium-Catalyzed Nucleophile Substitution Involving Allyl Palladium, Propargyl-palladium and Related Derivatives, pp. 1669-1687. (b) Frost C. G. Howarth, J. Williams, J. M. J. Tetrahedron Asymmetry 1992, 3, 1089-1122. 

The allylation of active methylene compounds with allyl alcohols or their derivatives, called the Tsuji-Trost reaction, is a widely used process in academia as well as in industry. Ranu et al. have reported that the reaction of active methylene compounds with allyl acetate catalyzed by palladium(O) nanoparticles (Scheme 5.22) led to mono-allylation in water, whereas the reaction in THF provided the bis-allylated product. This is a remarkable example of controlling the direction of a reaction by water. 

Palladium-catalyzed nucleophilic substitution of allylic substrates (Tsuji-Trost coupling) is a most important methodology in organic synthesis and therefore it is no wonder that such reactions have been developed also in aqueous systems. Carbo- and heteronucleophiles have been found to react with allylic acetates or carbonates in aqueous acetonitrile or DMSO, in water or in biphasic mixtures of the latter with butyronitrile or benzonitrile, affording the products of substitution in excellent yields (Scheme 6.19) [7-11,14,45,46], Generally, K2C03 or amines are used as additives, however in some cases the hindered strong base diazabicycloundecene (DBU) proved superior to other bases. 

Two crucial requirements for any catalytic reactions are (i) that the overall catalytic processes be thermodynamically favorable (i.e., AAG<0) and (ii) that all steps in a given catalytic cycle be kinetically accessible (i.e., of reasonably low activation energies). Moreover, so long as these two requirements are met, one or more of the microsteps in a catalytic cycle can be thermodynamically unfavorable. This is an obvious principle that nonetheless is frequently misunderstood. For example, the stoichiometric oxidative addition reaction of allyl acetate with Pd(0) complexes does not normally give the desired allylpalladium derivative in significant yields, and it may well be thermodynamically unfavorable. And yet, the Tsuji-Trost reaction of allyl acetate with malonates is normally facile. It is very important not to rule out any potentially feasible catalytic processes simply because some microsteps are or appear to be thermodynamically unfavorable. 

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 Pd-catalysed allylation of carbon nucleophiles with allylic compounds via Jt-aUylpaUadium complexes is called the Tsuji-Trost reaction [32]. Typically, an allyl acetate or carbonate (54) reacts with a Pd-catalyst resulting in displacement of the leaving group to generate a Jt-allylpalladium complex (55) that can undergo substitution by a nucleophile (56) (Scheme 4.14). In 1965, Tsuji reported the reaction of ti-aUylpaUadium chloride with nucleophiles such as enamines and anions of diethyl malonate and ethyl acetoacetate. A catalytic variant was soon reported thereafter in the synthesis of allylic amines [33]. In 1973, Trost described the alkylation of alkyl-substituted 7i-aUylpalladium complexes with methyl methylsulfonylacetate... 

One distinguishes palladium(0)- and palladium(ll)-catalysed reactions. The most common palladium(O) transformations are the Mizoroki-Heck and the cross-coupling transformations such as the Suzuki-Miyaura, the Stille and the Sonogashira reactions, which allow the arylation or alkenylation of C=C double bonds, boronic acid derivates, stan-nanes and alkynes respectively [2]. Another important palladium(O) transformation is the nucleophilic substitution of usually allylic acetates or carbonates known as the Tsuji-Trost reaction [3]. The most versatile palladium(ll)-catalysed transformation is the Wacker oxidation, which is industrially used for the synthesis of acetaldehyde from ethylene [4]. It should be noted that many of these palladium-catalysed transformations can also be performed in an enantioselective way [5]. 

The palladium(0)-catalysed nucleophilic substitution of allylic acetates, carbonates or halides, also known as the Tsuji-Trost reaction, is a powerful procedure for the formation of C—C, C—O and C—N bonds. One of the early impressive examples, where this transformation had been combined with a pallada-ene reaction, was developed by Oppolzer and Gaudin [126], Although, in general, the Tsuji-Trost reaction can be combined with other palladium-catalysed transformations, there are only a few examples where it is combined with a Mizoroki-Heck transformation. 

R = allyl, vinyl, aryl, benzyl X = halide, acetate, etc. Tsuji-Trost reaction... 

In the first catalytic Tsuji-Trost reaction, allylic acetate 19 was readily converted into product 21 in good yield. Following this precedent, numerous examples of this allylation reaction have been reported using activating groups such as carbonyl, sulfonyl, cyano, nitro, aryl, olefmic, imino, etc. Readers are referred to the many comprehensive reviews on the topic for extensive examples of the Tsuji-Trost reaction in synthesis. ... 

In the Tsuji-Trost reaction, an allylic acetate first oxidatively adds to the Pd(0) catalyst to give a Tr-allyl complex, which undergoes nucleophilic attack by the carbanion derived from the deprotonated active methylene compound allyl alcohols and aldehydes can be coupled by a related procedure. 

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... 

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]. 

The Tsuji-Trost reaction involves the coupling of allyl electrophiles with nucleophiles with a broad range of metal complexes, including those of nickel, palladium, platinum, rhodium, iron, ruthenium, etc (Scheme 13.37). " In a typical example, an allyl acetate or carbonate reacts with a palladium catalyst by displacement of the leaving group to give 7i-allyl palladium complexes that can undergo substitution by a nucleophile. 

A combination of a Tsuji-Trost and a Michael addition was used for the synthesis of (+)-dihydroerythramine 6/1-269, as reported by Desmaele and coworkers [128]. The Pd-catalyzed reaction of the allylic acetate 6/1-267 with the nitromethylarene 6/1-266 in the presence of Cs2C03 as base led to the domino product 6/1-268 as a 4 1 mixture of two diastereomers in 79% yield. Further manipulation of 6/l-268a yielded the desired dihydroerythramine 6/1-269 (Scheme 6/1.70). Interestingly, using the corresponding allylic carbonate without additional base gave the mono-alkylated product only. 

---