Heck reaction trapping

So-called domino or cascade reactions have become more and more important for the efficient synthesis of complex organic molecules [1211. In this respect methyl 2-chloro-2-cyclopropylideneacetate (1-Me) has been used as a dieno-phile to trap cyclic dienes which were produced by intramolecular Heck reactions in Diels-Alder cycloadditions. Thus, the spirocyclopropanated functionalized bicyclo[4.3.0lnonenes 248,250 (Fig. 11) were obtained from the bromo-diene 247 or enynes 249 in 56-83% yield (Scheme 71) [122,1231. 

Next, palladadihydrofuran intermediate 51 is trapped by the cross-coupling reagents leading to compounds 47-49. For example, the palladium species 51 can then form the intermediate 52 in a subsequent Heck reaction with acrylate, which leads to the final spirocycles 49a and 49b and Pd(0) in a p-hydride elimination [61]. It is necessary for the catalytic cycle that Pd(0) is reoxidized to Pd(II) this is achieved by the addition of Cu(OAc)2, which does not interfere with the course of the reaction. 

Multiple-component difunctionalization reactions of a,/ -unsaturated carbonyl systems have been achieved by catalytic conjugate addition/aldol sequences. As Scheme 8.13 illustrates, an efficient method reported by Montgomery [46] allows regioselective addition of an aryl iodide to the /i-position of an unsaturated ester under nickel catalysis and subsequent trapping with an aldehyde to give / -hydroxyesters (e.g. 33). Significantly, premature termination of the sequence by the /Miydride elimination process that is usually observed in Pd-catalyzed Heck reactions does not occur here. 

A further evidence on the acceleration enjoyed by a typical Pd-catalysed reaction, the Heck reaction, in an ionic phase ( V-mcthyl-Y.Y. V.-trioctylammonium chloride or Aliquat 336) is found in a triphasic protocol developed by Tundo and coworkers. 7b.The arylation of electron poor olefins is catalysed by palladium supported on charcoal (Pd/C) and is carried out in the heterogeneous isooctane/Aliquat 336/water system (Figure 27). Under this multiphasic condition, Aliquat 336 forms a third liquid phase between the organic and the aqueous phase that traps the catalyst. The use of phosphines is not necessary. As a matter of fact, Aliquat 336 incorporates the solid-supported catalyst and ensures an efficient mass transfer between the bulk phases resulting in an increase of the reaction rate of an order of magnitude compared to the reaction in the absence of the ionic liquid. A determing role is played by the base while I LN drives the reaction towards the formation of ethyl cinnamate, reaction carried out in the presence of KOH lead to formation of Ullmann dimerisation products. 

This reaction type differs from die three-component reaction reported by Grigg et al. Thus, Grigg et al. [53] (Scheme 7) immobihzed 3-iodo-4-(N-acetyl-N-(2-methyl-2-propenyl)amino)benzoate (36) onto a sohd support. In the presence of suitable Pd salts, Pd substituted the iodide function of the aromatic. The proximal isopropyhdene group trapped the resulting metalated species in an intramolecular Heck reaction. The resulting alkyl palladium species (37) could then react with a suitable carbanion equivalent. The authors used vinylstaimanes or boronates for this purpose, which they obtained in situ from alkynes by hydroboration or hydro-starmylation. The latter procedure allowed them to attach the same vinylic species via its terminal carbon (boronate) (41) and its subterminal carbon (stannane) (39). 

The palladium-catalyzed arylation of alkenes and arenes offers one of the conceptually most intelligent solutions for the synthesis of PAHs from the appropriate aryl halides or triflates. The reaction is usually carried out in a polar solvent (AT,AT-dimethylformamide (DMF) or AT,AT-dimethylacetamide (DMA)) at relatively high temperatures (100-170°C) with a base to trap the acid formed, and a phase transfer catalyst. Most often Pd(II) acetate or a Pd(II) complex are used, that are converted to a catalytically active Pd(0) species in the course of the reaction. The mechanisms of these Heck reactions have been discussed widely throughout the pertinent literature [78,79]. 

Asymmetric Heck reaction. The chiral product from an intramolecular process can he trapped. Thus, the method has been applied to a synthesis of (-)-A -capnellene and halenaquinone. Hypervalent alkenyliodonium salts can be used instead of triflates. 

A cascade Heck reaction with termination by nucleophiles is considered to start with an oxidative addition of a heteroatom-carbon bond (starter) onto a palladium(O) species (startup reaction), followed by carbopalladation of a nonaromatic carbon-carbon double or triple bond without subsequent dehydropalladation (relay), a second and possibly further carbopalladation of a carbon-carbon double or triple bond (second etc. relay). The terminating step is a displacement of the palladium residue by an appropriate nucleophile. It is crucial for a successful cascade carbopalladation that no premature dehydropalladation takes place, and that can be prevented by using alkynes and 1,1-disubstituted alkenes (or certain cycloalkenes) as relay stations since they give kinetically stable alkenyl- or neopentylpalladium intermediates, respectively. In addition, reaction of haloalkenes with alkenes in certain cases may form rr-allyl complexes, which are then trapped by various nucleophiles. 

Alkenes that can provide hydrogen atoms /3 and syn to Pd, such as monosubstituted alkenes, may not be used in the cyclic carbopalladation-carbonylative trapping process, as the reaction is dominated by the cyclic Heck reaction. The difference between this process and the Type II Ac—Pd process (Sect. VI.4.1.1) may be attributable to a chelation effect in the latter preventing otherwise competitive dehydropalladation. 

Shibasaki and coworkers [40] also demonstrated the use of soft carbanionic nucleophiles, initially sodium dimethyl malonate, in cascade asymmetric Mizoroki-Heck cyclization- j -allyl trapping sequences. This conversion succeeds with various soft carbanionic nucleophiles to provide functionalized bicyclo[3.3.0]octane derivatives 55 in excellent yields (72-92%) and up to 94% ee (Scheme 16.13). The enantioselectivity of these Mizoroki-Heck reactions is significantly diminished in the absence of NaBr a speculative rationale to account for the effect of the NaBr additive has been advanced [40]. 

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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