Intermolecular asymmetric Heck reactions

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

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,... 

The use of cyclic alkenes as substrates or the preparation of cyclic structures in the Heck reaction allows an asymmetric variation of the Heck reaction. An example of an intermolecular process is the addition of arenes to 1,2-dihydro furan using BINAP as the ligand, reported by Hayashi [23], Since the addition of palladium-aryl occurs in a syn fashion to a cyclic compound, the 13-hydride elimination cannot take place at the carbon that carries the phenyl group just added (carbon 1), and therefore it takes place at the carbon atom at the other side of palladium (carbon 3). The normal Heck products would not be chiral because an alkene is formed at the position where the aryl group is added. A side-reaction that occurs is the isomerisation of the alkene. Figure 13.20 illustrates this, omitting catalyst details and isomerisation products. 

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... 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

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... 

Ozawa et al. reported the Pd(OAc)2-BlNAP catalysed asymmetric intermolecular Heck reaction of aryl triflate and 2,3-dihydrofiiran in the presence of a base [34]. In this reaction, the enantiomeric excess was significantly affected by the base, and Proton Sponge (1) gave the best results among the various bases, such as triethylamine, diisopropylethylamine, pyridine derivatives and inorganic bases (Table 8.9). 

Table 8.9 Asymmetric intermolecular Heck reaction of aryl triflate... 

Hennessy, A.J., Malone, Y.M. and Guiry, PJ. (1999) 2,2-Dimethyl-2,3-dihydrofuran, a new substrate for intermolecular asymmetric Heck reactions. Tetrahedron Letters, 40, 9163-9166 Hennessy, A.J., Malone, Y.M. and Guiry, P.J. (2000) The asymmetric cyclohexenylation of 2,2-dimethyl-2,3-dihydrofuran. Tetrahedron Letters, 41,2261-2264 Hennessy, A.J., Connolly, D.J., Malone, Y.M. and Guiry, PJ. (2000) Intermolecular asymmetric Heck reactions with 2,2-diethyl-2,3-dihydrofuran. Tetrahedron Letters, 41, 7757-7761. 

The microwave-assisted asymmetric Heck reaction has also been used with success for intermolecular bond formation (Scheme 2.28). Using 2,3-dihydrofuran and phenyl triflate as model substrates, the most active catalyst screened was a combination of Pd2dba3 and a phosphine-thiazole supporting ligand. Heating a THF/DIPEA... 

Asymmetric intermolecular Mizoroki—Heck reaction From phosphine/ phosphinite-nitrogen to phosphite-nitrogen hgands 12IJC572. Asymmetric palladium-catalyzed intramolecular Wacker-type cycliza-tions of unsaturated alcohols and amino alcohols to give O- and N-het-erocycles 13MOL6173. 

Ligand Design for Intermolecular Asymmetric Mizoroki-Heck Reactions... 

This chapter provides a survey of the literature up to the end of 2007 dealing with the asymmetric intermolecular Mizoroki-Heck reaction, specifically focusing on ligand design for this important transformation. 

The first example of the asymmetric intermolecular Mizoroki-Heck reaction was reported by Hayashi and coworkers [8] in 1991. This involved the asymmetric arylation of 2,3-dihydrofuran (1) with aryl triflates using a palladium/(7 )-BINAP (BINAP = 2,2 -bis(diphenylphosphino)-l,F-binaphthyl) catalytic system (Scheme 11.4). 

Scheme 11.4 First catalytic asymmetric intermolecular Mizoroki-Heck reaction.

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