Tsuji-Trost reaction reactions

The synthesis of the CG525155 (a neutral endopeptidase inhibitor) required a Pd catalyzed Tsuji-Trost reaction as the key step following the strategy described by Johnson. Starting from the optically active allenyl amino acid methylester 91 (synthesized in several steps from 90), the seco-derivative 92 as the crucial precursor was generated in several steps in high yield. The Pd (0)... 

The above-described structures are the main representatives of the family of nitrogen ligands, which cover a wide spectrum of activity and efficiency for catalytic C - C bond formations. To a lesser extent, amines or imines, associated with copper salts, and metalloporphyrins led to good catalysts for cyclo-propanation. Interestingly, sulfinylimine ligands, with the chirality provided solely by the sulfoxide moieties, have been also used as copper-chelates for the asymmetric Diels-Alder reaction. Amide derivatives (or pyridylamides) also proved their efficiency for the Tsuji-Trost reaction. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

Several Pd-catalyzed domino processes start with a Tsuji-Trost reaction, a pal-ladation of alkynes or allenes [5], a carbonylation [6], an amination [7] or a Pd(II)-cat-alyzed Wacker-type reaction [8]. A novel illustrious example of this procedure is the efficient enantioselective synthesis of vitamin E [9]. 

Transition Metal-Catalyzed Domino Reactions 6.1.1.3 Heck/Tsuji-Trost Reactions... 

Within a total synthesis of the neurotoxin (-)-pumiliotoxin C [52], Minnaard, Fer-inga and coworkers used a domino Heck/Tsuji-Trost reaction of 6/1-93 and 6/1-94 to give the perhydroquinoline 6/1-95 in 26% yield after hydrogenation [53] (Scheme 6/1.24). 

Grigg and coworkers developed bimetallic domino reactions such as the electro-chemically driven Pd/Cr Nozaki-Hiyama-Kishi reaction [69], the Pd/In Barbier-type allylation [70], Heck/Tsuji-Trost reaction/1,3 dipolar cycloaddition [71], the Heck reaction/metathesis [72], and several other processes [73-75]. A first example for an anion capture approach, which was performed on solid phase, is the reaction of 6/1-134 and 6/1-135 in the presence of CO and piperidine to give 6/1-136. Liberation from solid phase was achieved with HF, leading to 6/1-137 (Scheme 6/1.30) [76]. 

Scheme 6/1.64. Domino Tsuji-Trost/Heck reaction.

Scheme 6/1.69. Domino Tsuji-Trost reaction/rearrangement.

The Tsuji-Trost reaction is the palladium-catalyzed allylation of nucleophiles [110-113]. In an application to the formation of an A-glycosidic bond, the reaction of 2,3-unsaturated hexopyranoside 97 and imidazole afforded A-glycopyranoside 99 regiospecifically at the anomeric center with retention of configuration [114], Therefore, the oxidative addition of allylic substrate 97 to Pd(0) forms the rc-allyl complex 98 with inversion of configuration, then nucleophilic attack by imidazole proceeds with a second inversion of configuration to give 99. 

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],... 

Pd(0)-catalyzed allylations of 4(5)-nitroimidazole, 2-methyl-4(5)-nitroimidazole, 4(5)-bromoimidazole and 4(5)-methoxyimidazole resulted in complicated mixtures, which did not necessarily reflect the tautomeric ratios of the starting material [7], For example, poor regioselectivity for the products (70 and 71) was observed in the Tsuji-Trost reaction of 4(5)-bromoimidazole with cinnamyl carbonate. However, the same reaction with 4(5)-nitroimidazole and 2-methyl-4(5)-nitroimidazole led predominantly to the l-allylation products. In addition, removal of the 77-imidazole allyl groups can be selectively effected under mild conditions by Pd-catalyzed ic-allyl chemistry [55],... 

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 Tsuji-Trost reaction, more commonly applied to carbocyclic nucleoside synthesis, has been used in the synthesis of famciclovir 21 (Scheme 5) <2000T4589>. Reaction of 2-amino-6-chloropurine with allylic carbonate 22 in the presence of Pd2DBA3 and bis(diphenylphosphino)ethane (DPPE) gave a 1 1 ratio of 23 to 24 after 1 h (DBA = dibenzylideneacetone). However, a ratio of >95 5 in favor of the thermodynamically favored N-9 isomer 23 was subsequently obtained upon further stirring, highlighting the reversibility of the reaction in this specific instance. 

The Tsuji-Trost-type reaction is applicable to bifunctional vinyl epoxide 144 and 1,3-diketone using a palladium catalyst as demonstrated by Koizumi, who obtained polymer 145 (Equation (67)). The reaction proceeds at 0 °C to a reflux temperature of THE. The resulting polymer 145 is isolated in a quantitative yield. The molecular weight of 145 is ca. 3000 (PDI = 2.0-2.7) when 5 mol% of Pd(PPh3)4 is employed as a catalyst. Use of Pd2(dba)3 with several bidentate phosphines such as dppe, dppp, dppb, and dppf is also effective for the polymerization reaction. Propargyl carbonate 146 also reacts with bisphenols in the presence of a palladium catalyst to afford polyethers 147 via carbon-oxygen bond formation at s - and r/) -carbon atoms (Equation (68)). 

Inspection of Table 1 indicates that acylation, cyanation and enolate substitution represent the other classes of Pd- or Ni-catalyzed cross-coupling. The vast topic of Pd-catalyzed enolate -substitution including the Tsuji-Trost reaction and other -substitution reactions22 is not discussed in this chapter, and the readers are referred to pertinent reviews including that cited above. The other topics are very briefly discussed below. 

The carbon skeleton of natural product galanthamine was prepared by the ring closure of an enantiopure aryl-cyclohexenyl ether. The transformation, run in the presence of a palladium-dppp catalyst and silver carbonate, led to the diastereoselective formation of the tricyclic product (3.25.). It is worth mentioning, that the chiral information in the ether intermediate was introduced in the palladium catalysed Tsuji-Trost reaction (N.B. the synthetic approach depicted in 3.13. and 3.25. are much alike).31... 

The formation of chromane derivatives has also been realised in the palladium catalyzed intramolecular nucleophilic substitution of allyl carbonates (Tsuji-Trost reaction). In most cases the reaction is accompanied by the formation of a new centre of chirality. Using Trost s chiral ligand the ring closure was carried out in an enantioselective manner. The asymmetric allylation of the phenol derivative shown in 4.20. was achieved both in good yield and with excellent selectivity.23... 

The palladium catalyzed intramolecular nucleophilic substitution of allyl alcohol derivatives (Tsuji-Trost reaction) has successfully been extended to the closure of a seven membered ring. The coupling of the allyl alcohol unit and the enamide was the key step in the preparation of the natural product claviciptic acid (5.14.),14... 

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