Pd -catalyzed transformation

Asymmetric nucleophilic allylic substitution has rarely been studied in its heterogeneous version, probably because of the difficulties encoimtered in properly stabilizing and recycling Pd(0) species. Nevertheless, some promising examples have been pubhshed. Lemaire et al. [143] studied the activity and enantioselectivity of various chiral C2-diamines for the asymmetric Pd-catalyzed transformation of various allyl acetates. The structures tested are represented in Scheme 58. 

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. 

In a similar manner, cross-coupling reactions have been used as the first step, followed by a second Pd-catalyzed transformation or other reactions. 

Another cyclotrimerization was observed in the Pd°-catalyzed transformation of substrates of type 6/1-51 which led to annulated naphthalenes 6/1-52, as described by Grigg and coworkers [37] (Scheme 6/1.11). The reaction can also be performed as a two-component transformation involving a combination of an intra- and an in-termolecular process. 

Helmchen and coworkers employed a,co-amino-1,3-dienes as substrates [51]. By using palladium complexes with chiral phosphino-oxazolines L as catalysts, an enantiomeric excess of up to 80 % was achieved. In a typical experiment, a suspension of Pd(OAc)2, the chiral ligand L, the aminodiene 6/1-90 and an aryltriflate in dimethylformamide (DMF) was heated at 100 °C for 10 days. Via the chiral palladium complex 6/1-91, the resulting cyclic amine derivative 6/1-92 was obtained in 47% yield and 80% ee (Scheme 6/1.23). Using aryliodides the reaction time is shorter, and the yield higher (61 %), but the enantiomeric excess is lower (67% ee). With BINAP as a chiral ligand for the Pd°-catalyzed transformation of 6/1-90 and aryliodide, an ee-value of only 12% was obtained. 

The most common combination of a Heck reaction in a domino process with a non-Pd-catalyzed transformation is that with a pericydic reaction, especially a Diels-Alder cycloaddition. This is reasonable, since a Heck reaction allows an easy formation of a 1,3-butadiene. 

Heck reactions can also be combined with anion capture processes, animations, metatheses, aldol and Michael reactions, and isomerizations. The anion capture process has also been widely used with other Pd-catalyzed transformations. Outstanding examples of many different combinations have been developed by Grigg and coworkers, though not all of them match the requirements of a domino process. All of these reactions will be detailed here, despite the fact the nature of these intermediate transformations would also have permitted their discussion in Chapter 2. 

Domino transition metal-catalyzed processes can also start with a cross-coupling reaction most often, Suzuki, Stille and Sonogashira reactions are used in this context They can be combined with another Pd-catalyzed transformation, and a number of examples have also been reported where a pericydic reaction, usually a Diels-Alder reaction, follows. An interesting combination is also a Pd-catalyzed borina-tion followed by a Suzuki reaction. 

The Pd°-catalyzed transformation of enediynes represents a highly efficient and effective approach for the synthesis of polycyclic compounds, with different ring sizes being obtained by a variation of the tether [129]. In this respect, reaction of 6/1-270 led to the tricyclic product 6/1-271 as a single diastereomer. The initial step is a chemoselective hydropalladation of the propargylic ester moiety in 6/1-270 to give an alkenyl-Pd-species, according to the mechanism depicted in Scheme 6.71. A hexatriene is formed as a byproduct. 

Scheme 6/1.75. Pd-catalyzed transformation of organic halides or triflates with alkynes or allenes containing a nucleophilic functionality.

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

Organometallic methods, with the possible exception of those involving the stoichiometric generation of enolates and other stabilized carbanionic species 140], have seldom been used in carbohydrate chemistry for the synthesis of cyclohexane and cyclopentane derivatives. The present discussion will not cover these areas. The earliest of the examples using a catalytic transition metal appears in the work of Trost and Runge [41], who reported the Pd-catalyzed transformation of the mannose-derived intermediate 22 to the functionalized cyclopentane 23 in 98% yield (Scheme 10). Under a different set of conditions, the same substrate gives a cycloheptenone 24. Other related reactions are the catalytic versions of the Ferrier protocol for the conversion of methylene sugars to cyclohexanones (see Chap. 26) [40,42,43]. 

In a route towards new estrogens which bind to the /1-unit of the K+-channel located on the surface of the endothelium, L.F. Tietze et al. described the synthesis of a novel enantiopure B-Nor-steroid, applying multiple Pd-catalyzed transformations [141] (Scheme 38). A combination of a Suzuki-Miyaura and a Heck reaction using a 2-bromobenzylchloride derivative and a boronic ester, derived from the enantiopure Hajos-Wiechert ketone [142-... 

In a synthesis of tetronomycin (45) published in 1994 [14], Semmelhack et al. probe the scope of intramolecular alkoxypalladations. The retro-synthetic analysis (Scheme 4) shows that the chosen strategy exploits such Pd-catalyzed transformations even twice. The pre-target structure 46 is formally derived from 47 by Pd-mediated cy-clization. Compound 47 can be traced back via 48 to the tetrahydrofuran derivative 49, which in turn should be available by alkoxycarbonyla-tion from a precursor of type 50. 

The use of aryl triflates or other sulfonates in the amine arylation reaction is highly desirable from a synthetic standpoint since a large variety of phenols are easily accessed and derivatized. Aryl and vinyl triflates have enjoyed great utility in other Pd-catalyzed transformations such as the Stille [77] and Suzuki [78] couplings, and the Heck [79] reaction. 

Bolm and co-workers have described the arylation of sulfoximes with aryl bromides, iodides, triflates, and nonaflates [124]. The BINAP/Pd-catalyzed transformation proceeds in moderate to excellent yields, Eq. (152). The resulting N-arylsulfoximines were used to prepare new chiral ligands. Harmata and Pavri have used similar transformations to prepare several benzothiazines [125]. 

Walden inversion, on the other hand, is observed in the reaction of alkanols with diethyl azodicarboxylate, triphenylphosphine and HN3 (c/. the Mitsunobu reaction).There is also some interest in the Pd-catalyzed transformation of allyl acetates into the corresponding azido derivatives. Primary amines can be generated in a one-pot procedure without isolation of these azides, by further treatment with PhsP and subsequent hydrolysis (Scheme 45). 

Transmetalation and CO insertion reactions play key roles in the following Pd-catalyzed transformation, shown below in general form.217... 

Along with the Suzuki reaction, the Stille reaction is one of the most popular Pd-catalyzed transformations involving furans [1, 34]. Furans participate as both the stannane and halogen component, although the former is more popular. As previously highlighted, reaction at the 2-position is more common and convenient, although functionalization at the 3-position is well-known. 

Recently, Liu extended further the variety of orf/io-phenylene phosphine-boranes and Pd-catalyzed transformations The boron center was incorporated in a 1,4-azaborine... 

The general reaction mechanism has been shown to involve typical steps for cross-coupling [98, 113]. Oxidative addition of an aryl halide generates a Pd(II) species that undergoes transmetalation to form a Pd(II)-thiolate. C-S reductive elimination provides the aryl sulfide and regenerates the Pd(0) catalyst. More recently, Hartwig reported a detailed mechanistic analysis of the Pd/Josiphos system derived from different Pd precursors. The dominant Pd species were found to be off the catalytic cycle, which accounted for differences in rates between stoichiometric and catalytic reactions [114]. Thioketones are also effective thiolate nucleophiles for C-S bond formation. The reaction involves tandem Pd-catalyzed thioenolate alkylation, followed by 5-arylation (8) [102]. Presumably, the arylation process proceeds by a similar mechanism to related Pd-catalyzed transformations. 

This Pd-catalyzed transformation uses two imines an acid chloride and CO. Mechanistically, this reaction is proposed to proceed via Pd addition to the activated imine, followed by CO insertion. Reductive elimination of Pd with HCl provides the ketene, which undergoes formation of the Munchnone. Miinchnones are known to undergo cycloaddition reactions with electron-deficient imines to yield cycloaddition adducts, which lose CO2 and TsH to yield imidazole. 

Jia and coworkers [71] reported a very nice palladium-catalyzed domino reaction involving a C-H activation process (Scheme 12.47). The regioselectivity of the attack of the nucleophile at the intermediately formed palladacyle 121 is solely controlled by the reaction conditions using the same substrate. In the Pd-catalyzed transformation of 120 in DMF in the absence of water, the aryl-substituted product 122 was obtained in 47-95% yield, and, in the presence of water, the alkyl-substituted product 123 in 60-95% yield. However, it should be noted that the reaction temperature has also some influence. The paUadacycle intermediate 121 was successfully trapped by cyanation, Heck reaction, secondary C-H activation, and Suzuki coupling. 

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