Tsuji alkylation

Enol carbonates react with alkylating agents in the presence of a palladium catalyst. The decarboxylative alkylation of allyl enol carbonates to the corresponding aUylcyclohexanone derivatives is known as the Tsuji alkylation. An asymmetric version of this reaction has been reported. The same reaction can be done using enolate anion and aUylic acetates with a palladium catalyst. ... 

Asymmetric Tsuji Alkylation in the Synthesis of Natural Products. 302... 

In addition to the applications reported in detail above, a number of other transition metal-catalyzed reactions in ionic liquids have been carried out with some success in recent years, illustrating the broad versatility of the methodology. Butadiene telomerization [34], olefin metathesis [110], carbonylation [111], allylic alkylation [112] and substitution [113], and Trost-Tsuji-coupling [114] are other examples of high value for synthetic chemists. 

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. 

As mentioned above nonconjugated dienes give stable complexes where the two double bonds can form a chelate complex. A common pathway in palladium-catalyzed oxidation of nonconjugated dienes is that, after a first nucleophilic addition to one of the double bonds, the second double bond inserts into the palladium-carbon bond. The new (cr-alkyl)palladium complex produced can then undergo a /(-elimination or an oxidative cleavage reaction (Scheme 2). An early example of this type of reaction, although not catalytic, was reported by Tsuji and Takahashi (equation 2)12. 

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. 

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... 

By 1984, the palladium-catalyzed aUyhc alkylation reaction had been extensively studied as a method for carbon-carbon bond formation, whereas the synthetic utility of other metal catalysts was largely unexplored [1, 2]. Hence, prior to this period rhodium s abihty to catalyze this transformation was cited in only a single reference, which described it as being poor by comparison with the analogous palladium-catalyzed version [6]. Nonetheless, Yamamoto and Tsuji independently described the first rhodium-catalyzed decarboxylation of allylic phenyl carbonates and the intramolecular decarboxylative aUylation of aUyl y9-keto carboxylates respectively [7, 8]. These findings undoubtedly laid the groundwork for Tsuji s seminal work on the regiospecific rho-... 

Ketone and ester enolates have historically proven problematic as nucleophiles for the transition metal-catalyzed allylic alkylation reaction, which can be attributed, at least in part, to their less stabilized and more basic nature. In Hght of these limitations, Tsuji demonstrated the first rhodium-catalyzed allylic alkylation reaction using the trimethly-silyl enol ether derived from cyclohexanone, albeit in modest yield (Eq. 4) [9]. Matsuda and co-workers also examined rhodium-catalyzed allylic alkylation, using trimethylsilyl enol ethers with a wide range of aUyhc carbonates [22]. However, this study was problematic as exemplified by the poor regio- and diastereocontrol, which clearly delineates the limitations in terms of the synthetic utihty of this particular reaction. 

Beside the Friedel-Crafts-type alkylation of arenes, the direct functionalization of 2,4-pentanediones is of great interest in Lewis acid catalysis. Although Pd-catalyzed Tsuji-Trost type allylations of 1,3-diketones are known, direct benzylation procedures catalyzed by Lewis acids are less explored [40-43]. Based on the previously described Friedel-Crafts alkylation of arenes and heteroarenes, the Rueping group developed a Bi(OTf)3-catalyzed benzylation of 2,4-pentanediones. Alcohols such as benzyl, allyl or cinnamyl alcohols were used as the electrophilic component to yield important 2-alkylated 1,3-dicarbonyl compounds. Initially, different Bi(III) salts were screened. In contrast... 

Many organic chemical transformations have been carried out in ionic hquids hydrogenation [4, 5], oxidation [6], epoxidation [7], and hydroformylation [8] reactions, for example. In addition to these processes, numerous synthetic routes involve a carbon-carbon (C-C) bond-forming step. As a result, many C-C bondforming procedures have been studied in ambient-temperature ionic Hquids. Among those reported are the Friedel-Crafts acylation [9] and alkylation [10] reactions, allylation reactions [11, 12], the Diels-Alder reaction [13], the Heck reaction [14], and the Suzuki [15] and Trost-Tsuji coupHng [16] reactions. 

Although not discussed in this chapter, the Tsuji-Trost reaction159 is undoubtedly the most extensively investigated Pd-catalyzed allylation with allyl electrophiles. There have also been some uncatalyzed and Cu-catalyzed reactions of allyl electrophiles with alkyl metals and metal cyanides. On the other hand, the Pd- or Ni-catalyzed reactions of allyl electrophiles with organometals containing allyl-, benzyl-, propargyl- and other alkylmetals do not appear to have been extensively investigated. 

The Pd(0)-catalyzed allylic alkylation developed by Tsuji and Trost is useful for creating organic frameworks that have a variety of polar functional groups (197). The reaction is formally viewed as a combination of an allylic cation and a carbanion. A number of allylic compounds that have an electronegative leaving group can be coupled with stabilized cafbanions of pKa less than 16 under mild reaction conditions (Scheme 84). Nucleophilic attack of Pd(0) species on an allylic substrate... 

The preparation of a-lithio aldehydes, o -lithio ketones, and related compounds and their applications to organic synthesis has been reviewed.10 The Tsuji-Trost allylic alkylation with ketone enolates has been highlighted.11... 

The effect of alkyl group substitution on the tunneling splitting in A2Bj state of tropolone has been studied by Sekiya et al. [1990a] and Tsuji et al. [1991] using laser-induced fluorescence in supercooled jets. In iso-... 

Palladium(0)-catalyzed allylation of nucleophiles (the Tsuji-Trost reaction) is a versatile synthetic method that has gained immense popularity in recent years. Rarely applied to ambident nucleophilic aromatic heterocycles before 1991, the Tsuji-Trost reaction has been extensively used in the chemistry of these compounds since 1991. Two factors have played decisive roles in this increased interest in the Pd(0)-catalyzed allylation of such heterocyclic rings one is that, unlike other alkylation procedures, the Pd(0)-catalyzed allylation can sometimes give the product of thermodynamic control when applied to ambident nucleophiles and the second is that the Tsuji-Trost allylation has become one of the standard methods for synthesizing carbanucleosides, which are important antiviral compounds (93MI1, 93MI2). Of course, the double bond of an allylic system can be modified in different directions, thus adding versatility to the Tsuji-Trost reaction. 

We include in Sections I,A and I,B some general features of the Tsuji-Trost reaction with comments on kinetic versus thermodynamic control in allylations and in alkylations in general. Then we review in Sections II, III, and IV all cases known to the authors of the application of the Tsuji-Trost reaction to ambident nucleophilic aromatic heterocycles. This leaves out of the review the allylation of such heterocyclic ambident nucleophiles as 2-piperidone and the like. By aromatic, we mean any heterocycle for which a tautomeric or mesomeric formula can be written that is aromatic in the normal structural sense of having 4n + 2n- electrons cyclically conjugated. 

In 1965, Tsuji et al. observed that palladium could catalyze the allylic alkylation reaction [18]. This discovery, which is a very attractive way to expand the scope of the allylic amination reactions mentioned above, has stimulated an intense research in this field, and even though complexes of nickel, platinum, rhodium, iron, ruthenium, molybdenum, cobalt, and tungsten have been found also to catalyze the alkylation, palladium complexes have received by far the greatest attention [19]. 

Ohsumi K, Ohishi K, Morinaga Y, Nakagawa R, Suga Y, Sekiyama T, Akiyama Y, Tsuji T, Tsuruo T (1995) N-alkylated 1,4-dihydropyridines new agents to overcome multidrug resistance. Chem Pharm Bull 43 818-828... 

Tsuji-Trost allylation reactions offer multiple pathways to tetrahydrofuran synthesis including C-C bond-formation steps. A palladium-catalyzed sequence of allylic alkylation and Hiyama cross-coupling provides a convenient synthesis of 4-(styryl)-lactones (Scheme 67) <2006SL2231>. 

Ito and coworkers [122] found that allylsulfides can be alkylated intramolecularly by epoxides in the presence of a proper base to form macrocycles. Tsuji and... 

Figure 3.85 The use of the mixed NHC/phosphane ligand system in the Tsuji-Trost allylic alkylation reaction.

The catalyst is not only active in the Tsuji-Trost reaction (allylic alkylation), but also in the corresponding amination reaction. This was shown by the reaction of (ii)-l,3-diphenylprop-... 

Both 1,4- and 1,5-dienes form stable complexes with Pd. For most 1,3-dienes, such as 1,3-butadiene, reaction with Pd° compounds leads to 7r-allyl formation. These reactions are described in Section 7. The coordinated double bonds in palladium diene complexes are reactive toward attack by many nucleophiles, and the resulting chelating alkene palladium alkyls are easily isolated. Many useful reactions of dienes were discovered by Jiro Tsuji in the 1960s and 1970s. These have been recently reviewed in a historical memoir. ... 

Intramolecular alkylations of nitrile-stabilized carbanions have been used to synthesize large rings such as those with 10 and 14 members. Tsuji and coworkers carried out a synthesis of the macrocy-clic antibiotic zearalenone by this route. As shown in Scheme 70, conversion of either of the protected cyanohydrins (144) or (145) to the corresponding dianions, resulting from deprotonation at the benzylic positions and a to the nitrile groups, gave the same cyclization product (146) in excellent yields. Dianion formation (i) provided control of the conformation of the side chain (ii) protected the ester from nucleophilic attack and (iii) appeared to increase the rate of the intramolecular cyclization. 

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... 

The second Tsuji synthesis, which appeared (see Scheme 1.6) in the latter part of 1978, employed a strategy similar to his earlier work for construction of the basic carbon framework. Ketal diene 19 was transformed to halo alcohol 22 by the use of chemistry established in his previous synthesis. Acylation with phenylthioacetyl chloride readily afforded ester 23. Intramolecular alkylation resulting in ring closure was brought about by deprotonation with sodium hexa-methyldisilazane to give lactone 24 in 71% yield. Synthetic 1 was then obtained in 90% yield following Raney nickel reduction. 

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