Enantioselectivity asymmetric Heck reaction

Other enantioselective reactions performed by microwave heating include asymmetric Heck reactions (Scheme 6.53 a) [109] and ruthenium-catalyzed asymmetric hydrogen-transfer processes (Scheme 6.53 b) [110]. 

As mentioned previously, the partially reduced forms of five membered heteroaromatic systems might act as olefins in insertion reactions. This behaviour is characteristic particularly of dihydrofuranes. The olefin insertion and the following / hydride elimination should in principle lead to a trisubstituted olefin, which is rarely observed, however. Typical products of this reaction are 2-aryl-2,3-dihydrofuranes. A characteristic example of such a reaction is presented in 6.54. The coupling of 4-iodoanisole and dihydrofurane led to the formation of the chiral 2-anisyl-2,3-dihydrofurane in excellent yield.83 The shift of the double bond, which leads to the creation of a new centre of chirality in the molecule, opens up the way for enantioselective transformations. Both intermolecular and intramolecular variants of the asymmetric Heck reaction have been studied extensively.84... 

It is the intent of this chapter to outline the major synthetic developments of the intramolecular asymmetric Heck reaction as well as to examine the mechanistic factors that have been revealed to date that effect enantioselectivity. 

A key feature of the cationic mechanism is that removal (or dissociation) of an anionic ligand from the palladium coordination sphere allows alkene complexation to occur while maintaining coordination of both phosphines of a bisphosphine ligand. That both phosphines can be accommodated in a square-planar four-coordinate intermediate during the insertion step has provided a simple rationalization for the higher enantioselectivities often observed for the cationic pathway. Concrete information on the enantioselective step of asymmetric Heck reactions proceeding by the cationic pathway has not been reported to date. It is likely to be either coordination of the alkene to generate 20.S or the insertion step (20.5 —> 20.6, Scheme 8G.20). 

The cyclohexadienone 10 undergoes an intramolecular asymmetric Heck reaction in the presence of a chiral monodentate phosphoramidate ligand to give the benzo[c]chromene derivative 11 with excellent enantioselectivity and conversion <02JA184>. 

Excellent enantioselectivity and double-bond regioselectivity can be achieved in an asymmetric Heck reaction between 2,3-dihydrofuran and aryl triflates by using a combination of chiral diphosphine-oxazoline ferrocenyl ligand and Pd catalyst <03CEJ3073>, as shown below. Chiral diphosphine-containing (arene)tricarbonylchromium(O) complexes were also used as ligands for this reaction to obtain the 2,3-isomer, however, both the yield and enantioselectivity were modest <03TA1455>. 

To account for the differences in reactivity and enantioselectivity observed in Heck reactions of unsaturated triflates and halides, two distinct mechanistic pathways have been proposed (as shown in the margin). The "cationic" pathway is generally invoked to describe asymmetric Heck reactions of unsaturated triflates or halides in the presence of Ag(I) or T1(I) additives. In the absence of such additives the Heck reaction is expected to proceed through a "neutral" reaction pathway. The modest enantioselectivity often observed in Heck reactions of this type has been attributed to the formation of a neutral palladium-alkene complex by partial ligand dissociation. ... 

For intermolecular asymmetric Heck reaction between aryl triflates and 2,3-dihydrofuran the hindered diphosphine 1 is superior to BINAP. Improved enantioselectivity is due to the bulky f-butyl substituents to create a more ideal chiral pocket in the metal complexes. 

The intermolecular asymmetric Heck reaction, a palladium-catalysed carbon-carbon bond forming process, is an efficient method for the preparation of optically active cyclic compounds.[1] Very recently, a new catalytic system has been developed based on palladium complexes having l-[4-(5)-tert-butyl-2-oxazolin-2-yl]-2-(5)-(diphenylphosphino)ferrocene (1) as the chiral ligand121 (Figure 5.2), which we have shown to be efficient catalysts for the enantioselective intermolecular Heck reaction of 2,3-dihydrofuran (2).[3] In contrast to complexes derived... 

Kiely, D. and Guiry, PJ. (2003) Palladium complexes of phosphinamine ligands in the intramolecular asymmetric Heck reaction. Journal of Organometallic Chemistry, 687, 546-561. Dounary, A.B., Hatanaka, K., Kodanko, J.J. et al. (2003) Catalytic asymmetric synthesis of quaternary carbons bearing two aryl substituents. Enantioselective synthesis of 3-alkyl-3-aryl... 

In the presence of a chiral ligand, asymmetric Heck reactions can be carried out. The axially-chiral bisphosphine ligand (/ )- or (5)-BINAP promotes good to excellent levels of enantioselectivity in intramolecular Heck reactions. For example, insertion of palladium into the aryl iodide 214 followed by cyclization gave the indolinone 215 in high enantiomeric excess, used in a synthesis of physostigmine (1.215). ... 

The asymmetric Heck reaction is catalysed by enantiomerically pure palladium catalysts formed with chelatingbiphosphines, especially BINAP, and this has proved an effective method for the synthesis of sterically constrained carbon centres, including quaternary centres. This chapter concludes with a brief discussion of enantioselective alkylmetallations using Grignard and organoaluminium species, which have proved useful in the diastereo- and enantioselective synthesis of polyene systems. 

Dihydrofuran (10.137) has also proved to be a popular substrate for the asymmetric Heck reaction. Hayashi has reported that using a Pd/BINAP catalyst not only is the initial addition enantioselective, but that the diastereomeric intermediates, i.e. of structure (10.119) preferentially give different regioisomeric products (10.138) and (10.139). This effect is similar to that of a kinetic resolution (see Section 4.1). ... 

Deng, W.-P, Hou, X.-L., Dai, L.-X. and Dong, X.-W. (2000) Efficient planar chiral 2 -substituted l,l -P,N-ferrocene ligands for the asymmetric Heck reaction control of enantioselectivity and configuration by planar chiral substituent. Chem. Commun., 1483-4. 

Overman, L.E. and Poon, D.J. (1997) Asymmetric Heck reactions via neutral intermediates enhanced enantioselectivity with halide additives gives mechanistic insights. Angew. Chem., Int. Ed. Engl., 36,518-21. 

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