Stereoselectivity Heck reaction

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

To date, only double Heck reactions have been described, but triple Heck reactions are also possible [39]. Reaction of the alkynyl aryl iodide 6/1-55 with norbor-nene in the presence of Pd(OAc)2, triphenylphosphane and triethylamine as base led to the cyclopropanated norbornene derivate 6/1-59 as a single diastereomer in 40% yield (Scheme 6/1.13). It can be assumed that the alkenyl Pd-species 6/1-56 is first formed stereoselectively, and this undergoes a Heck reaction with norbornene... 

Regio- and enantioselective Heck reactions of 2 3-dihydrofuran with aryl and alkenyl triflates in the presence of the chiral ligand (R)-BITIANP provides 2-substituted 23-dihydro-furans with complete regioselectivity, high enantioselectivity (86-96% ee) and good yields (76-93%) <99CC1811>. A catalytic oxyselenylation-deselenylation reaction of alkenes offers a stereoselective one-pot conversion of alkenes into 2 -dihydrofurans <99EF0797>. 

A twofold intramolecular Heck reaction has been employed as a key step for the synthesis of the skeleton of the natural product (—)-chimonanthine 58 (Scheme 19). The synthetically most challenging structural features of this bispyrro-loindoline alkaloid are its two adjacent quaternary centers. They were both built up by intramolecular double-bond carbopalladations, which stereoselectively produced the pentacycle 57 from the f72-symmetrical bis[A-(2-iodophenyl)-cyclohexane-1,2-dicarboxamide 55 via the intermediate 56. The key intermediate 57 was thus obtained as a single enantiomer in 90% yield. 

A ir,o domino-Heck reaction under concomitant rearrangement of the tetracyclic allylcyclopropane endo,exo-bishomobarrelene has been reported 138 the stereoselective reaction proceeds via an intramolecular insertion of a primarily formed carbopallada-tion intermediate into a strained cyclopropane C-C cr-bond (Scheme 96). 

With the spirocycle in hand, a regioselective and stereoselective Heck reaction was used to install the substituted aromatic portion of the molecule (Scheme 28.5). It is interesting that the addition of water to the reaction provided the high selectivity. The remaining olefin was reduced over Pearlman s catalyst, and the protecting groups were removed to provide the desired NK-1 antagonist 14 in 7 overall steps.33... 

A haloalkene that contains a stereogenic C=C double bond can usually be coupled with alkenes via the Heck reaction without isomerization. This is illustrated with the three reaction pairs in Figure 16.36. As can be seen, both the as- and the /raw-configured iodoalkenes react with acrolein or methyl vinyl ketone or acrylic acid methyl ester with complete retention of the C=C double bond configuration. These coupling reactions are thus stereoselective and— when considered as a pair—stereospecific. 

Once a chiral silane is synthesized, intramolecular reaction such as the Heck reaction and the radical cyclization reaction with transfer of chirality from the silicon center can be pursued. Other reactions of interest include the stereoselective hydrosilylation of aldehydes and ketones. Our method could be used to tether chiral silanes to solid support for uses in solid support... 

Another gain in diversity is achieved by the combination of these cross couplings with uncatalyzed reactions. Because of their oligounsaturated character, the coupling products are obviously well suited for subsequent peri-cyclic reactions leading to additional cyclizations. These atom-efficient processes are especially attractive since they typically proceed with high chemo-, regio- and stereoselectivity [18]. This review is intended to cover Heck reactions and related palladium-catalyzed processes followed by Diels-Alder reactions, 1,3-dipolar cycloadditions or 6 -electrocyclizations. 

Control over regioselectivity and stereoselectivity in the formation of new C-C a-bond is required to utilize the Heck reaction in complex molecule synthesis. For the intramolecular Heck reaction, the size of the ring formed in the insertion step controls the regiochemistry, with 5-exo and 6-exo cyclization favoured. A mixture of regioisomers is formed from Heck insertions of acyclic alkenes, whereas cyclic alkenes such as cycloalkenes as a Heck substrate produce a a-arkylpalladium(II) intermediate A, which has only one syn-P-hydrogen. Syn-elimination of the hydrogen provides only product B (Scheme 5.6). 

Mizorokf and Heck reported independently in the early 1970s the first palladium-mediated coupling of an aryl or vinyl halide or triflate with an alkene. This reaction is generally referred to as the Heck reaction. From the first reports on asymmetric intramolecular Heck reactions by Overman and Shibasakf in 1989 the asymmetric Heck reaction has emerged as a reliable method for the stereoselective formation of tertiary and quaternary stereogenic centers by C-C bond formation in polyfunctionalized molecules. ... 

Overman and co-workers have demonstrated the feasibility of using a chiral ligand to cause asymmetric induction in an elegant enantioselective synthesis of (- -)- and (—)-physostigmine (237) (Scheme 3-53) [23a]. An intramolecular Heck reaction of the aryl iodide 234 proceeds smoothly, even though a trisubstituted double bond is being linked to the aryl moiety. This strategy allows the assembly of quaternary carbon centers in a stereoselective manner [214]. 

In the Heck reaction, aryl, heterocyclic and vinyl halides - " or aryl triflates react with excess carbon monoxide and primary or secondary amines to give substituted amides, in the presence of a palla-dium(II) catalyst (equation 41). Cis- and trans-vinyl halides react stereoselectively. 

Under modified Heck reaction conditions, coupling diethyl (Z)-2-iodovinylphosphonate with acrolein in MeCN at room temperature produces the diethyl (lZ,3 )-dienylphosphonate in 92% yield with high stereoselectivity (Scheme 5.47). ... 

Hu et al. [104] disclosed that the spiro phosphine oxide ligand (/ )-30a is highly efficient for the Pd-catalyzed Heck reaction of cyclic and heterocyclic olefins with aryl triflates. An asymmetric domino Heck cyclization was established using catalyst Pd/(/ )-30a to form fused carbo- and heterocycles with excellent stereoselectivity (Scheme 42) [105]. This method was used in a short synthesis of (-)-martinellic acid, a primary ingredient in traditional eye medicine in South America. 

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