Chiral ligands asymmetric Heck reaction

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). ... 

One active field of research involving the Heck reaction is asymmetric Heck reactions (AHR). The objective is to achieve enantiomerically-enriched Heck products from racemic substrates using a catalytic amount of chiral ligands, making the process more practical and economical Although intermolecular Heck reactions that occurred onto carbocyclic arenes are rare, they readily take place onto many heterocycles including thiophenes, furans, thiazoles, oxazoles,... 

A fluorous version of the chiral bis-phosphine BINAP has been developed for asymmetric Heck reactions [5], Several fluorous-derivatized binaphthols and BINAP derivatives have been reported, (Scheme 10.4) [6], The silane spacer group present in one of the ligands was used to maximize the percentage fluorine on the molecule. Even so, the partition coefficient1 between FC-72 (see Chapter 3) and benzene was only 2.85, and not surprisingly, the reuse of the catalyst was poor. 

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>. 

The remarkable affinity of the silver ion for hahdes can be conveniently applied to accelerate the chiral palladium-catalyzed Heck reaction and other reactions. Enantioselectivity of these reactions is generally increased by addition of silver salts, and hence silver(I) compounds in combination with chiral ligands hold much promise as chiral Lewis acid catalysts for asymmetric synthesis. Employing the BINAP-silver(I) complex (8) as a chiral catalyst, the enantioselective aldol addition of tributyltin enolates (9) to aldehydes (10) has been developed." This catalyst is also effective in the promotion of enantioselective allylation, Mannich, ene, and hetero Diels-Alder reactions. 

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>. 

A variety of chiral phosphine ligands are frequently used for asymmetric Heck reactions. The oxidative insertion is favored by basic ligands whereas bidentate ligands with a small bite angle enable good to excellent chirality transfer (>90 % ee). Some selected ligands which meet these requirements for asymmetric Heck reactions are shown in the margin. 

Figure 3-1 Some chiral ligands used in asymmetric Heck reactions (see Table 3-8).

The intramolecular asymmetric Heck reaction has featured in the synthesis of complex heterocyclic compounds. Bidentate ligands, such as diphosphines (especially BINAP) and phosphine—oxazolines, have been used as a chiral ligand of the asymmetric Heck reaction. Imbos et al. demonstrated that the mono-dentate phosphoramidite 513 was an effective ligand for the asymmetric Heck reaction of the prochiral cyclohexadienone 511 (Scheme 153).227 The reaction of 511 in the presence of catalytic amounts of Pd-(OAc)2 and the chiral phosphoramidite 513 gave the 4a-methoxy-4a//-benzo[c]chromen-2(6E/)-one 512 in 71% yield with 96% ee. By contrast, the reaction of... 

Chiral spirooxindoles. An asymmetric Heck reaction of the acryloyl 2 -iodoaniline (2) effected with tris(dibenzylideneacetone)dipalladium and (R)-l as the chiral ligand can provide either enantiomer of the spiroindole 3 depending upon an added promotor. Thus the presence of a silver salt provides (S)-(+)-3, whereas addition of a basic tertiary amine can favor formation of (R)-(-)-3. The most effective amine is 1,2,2,6,6-pentamethylpiperidine (PMP). 

Compared to very extensive studies on Heck reactions, examples of successful asymmetric Heck reactions (abbreviated to AHR in this section) are rather limited, showing that AHRs are not easy to carry out, and careful tuning of conditions is crucial. Most of the HRs proceed by using monodentate ligands. On the other hand, chiral bidentate ligands are mainly required for AHRs. This may be a reason for the difficulty in achieving efficient AHRs. The ligands most extensively used are BINAP, its derivatives, and phosphinooxazolines [116]. 

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. 

Mata, Y, Dieguez, M., Pamies, O. and Claver, C. (2005) Chiral phosphite oxazolines class of ligands for asymmetric Heck reactions. Org. Lett., 7, 5597-9. 

Hou, X.-L., Dong, D.X. and Yuan, K. (2004) Synthesis of new chiral benzytically substituted P,N-ligands and their applications in the asymmetric Heck reaction. Tetrahedron Asymmetry, 15, 2189-91. 

Shibasaki (Equation 19.36) and Overman first reported the enantioselective Heck reaction. A few substrate combinations react intermolecularly with high enantiose-lectivity (Equation 19.37),but most enantioselective Heck reactions used in S)mthetic applications have been conducted intramolecularly. The asymmetric Heck reaction in Equation 19.37 has begun to be a test-bed for new chiral ligands. Although most Heck reactions that occur with high enantioselectivity have been conducted with BINAP as ligand, a phosphinooxazoline ligand has been used successfully (vide infra). Overman has applied an intramolecular version of the Heck reaction to form oxindoles (Equation 19.38) in the synthesis of a variety of natural products. ... 

Syntheses of Heterocycles, Natural Products, and Other Biologically Active Compounds 619 Table 8.9 Some chiral ligands used in asymmetric Heck reactions [421] (Figure 8.5). 

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