Dihydrofurans, intermolecular asymmetric Heck reactions

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... 

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. 

Hennessy, A.J., Malone, Y.M. and Gurry, P.J. (1999) 2,2-Dimethyl-2,3-dihydrofuran, a new substrate for intermolecular asymmetric Heck reactions. Tetrahedron Lett., 40,9163-6. 

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 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... 

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). 

While 2,3-dihydrofuran (1) was the initial test substrate of choice for the intermolecular asymmetric Mizoroki-Heck reaction, the reaction was also applied to 2,3-dihydropyrrole 12, which shows similar patterns of both regio- and stereoselectivity to 2,3-dihydrofuran (1) [16], The intermolecular Mizoroki-Heck reaction with substituted 2,3-dihydropynole 12 and aryl triflates 13 gave mixtures of the 2-aryl-2,3-dihyropym)les 14 and the 2-aryl-2,5-dihydropyrroles 15, with the 2,3-product being the major product formed with a 74% ee (Scheme 11.9). 

Keay and coworkers [22-24] synthesized the novel furan-derived diphosphine ligands, TetFuBINAP (29) and BlNAPFu (30) and applied them to the asymmetric intermolecular Mizoroki-Heck reaction of 2,3-dihydrofuran (1) and phenyl triflate (2) (Scheme 11.15). 

Scheme 11.6 Mechanism of intermolecular asymmetric Mizoroki-Heck reaction of 2,3-dihydrofuran (1).

While BDSfAP (5) has been one of the most successful ligands employed in the intermolecular asymmetric Mizoroki-Heck reaction, many other diphosphine ligands have also been synthesized and tested. Sannicolo and coworkers [20] synthesized novel thiophene-derived axially chiral diphosphine ligands 24 and 25 and applied these to the intermolecular Mizoroki-Heck reactiou of 2,3-dihydrofuran (1) (Scheme 11.13). 

As tdready mentioned above, the intermolecular asymmetric catalytic Heck-Mizoroki reaction was first reported by Hayashi [12d,e, 13,15] and since then various groups have made contributions in this area. Of note was the report in 2009 by Guiry s group [57] who achieved enantioselectivities of up to 96% ee, using novel HetPHOX ligands 7a—f for the benchmark reaction with cydohexenyl, phenyl, and 2-naphthyl triflate with 2,3-dihydrofuran (Scheme 1.21). The problem with this reaction is the extensive reaction time (7 days) at the elevated temperature of 80 °C. The kinetic product 8 (or... 

In an intermolecular Heck reaction, the nucleophilic component and the alkene are on different molecules. Until now, few applications of asymmetric intermolecular Heck reaction have been conducted, mainly because of problems related to the regioselectivity of this transformation. The first example reported by Hayashi and co-workers in 1991 involved the catalytic asymmetric arylation of 2,3-dihydrofuran 46. Aryl triflates afforded 2-aryl-2,3-dihydrofurans with enantioselectivities of up to 93% ee in the presence of the Pd(OAc)2/BINAP catalytic system. In a... 

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