The Asymmetric Heck Reaction

The asymmetric Heck reaction is often carried out in the presence of silver salts, implying the formation of a cationic palladium intermediate (Section 5.1.3) triflate substrates would be expected to also proceed in this way. There are also examples of Heck reactions carried out without silver, implying that a neutral palladium 

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Pd complexes 9-12 were tested for their catalytic behavior in the asymmetric Heck reaction involving the phenylation of 2,3-dihydrofuran (Scheme 3). The results are summarized in Table 2. The two isomeric products of 2-phenyl-2,5-dihydrofuran are formed with varying yields from 80% to 0%. The obtained ee s are high. Complex 12 is shown to be catalytically inactive. The lack of catalysis in complex 12 is rationalized by differences in the steric requirements between the diphenylphosphinites 1-3 (cone angle >140°) and the more sterically hindered cyclohexyl-phosphinite 4 (cone angle >170°) and the resulting stereochemistry on the Pd center. The ligands in complex 12 adopt a... 

A short five-step synthesis of a bifuran, namely ( )-2,2 -bis(diphenylphosphino)-3,3 -binaphtho[2,l-I>]furan (BINAPFu) from naphthofuranone via a low-valent titanium-mediated dimerization was reported. The newly developed resolution procedure for phosphines was utilized to provide the optically active bidentate phosphine ligands (BINAPFu), which consistently outperforms BINAP in the asymmetric Heck reaction between 2,3-dihydrofuran and phenyl triflate . Another way in which a benzofuranone can be converted into benzo[7 ]furan is by treatment of the former with 1-BU2AIH at -78°C followed by an acidic work up <00TL5803>. 

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... 

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). 

The role of silver salts in the asymmetric Heck reaction is thought to be as in Sch. 29 [57b]. The Ag ion abstracts the iodide from the palladium intermediate 107 to produce the square-planar 16-electron Pd intermediate 108 which is indispensable for high asymmetric induction. 

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. ... 

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... 

The palladium catalyzed arylation of 1,3-dioxin has been used in the preparation of 4-aryldioxins (42). The use of these compounds as )S-formylvinyl synthons means that access to aryl derivatives, inaccessible by lithiation and alkylation, is possible (Scheme 15). Use of the asymmetric Heck reaction allowed the synthesis of optically active dioxin derivatives, albeit in modest enantiomeric excess <92TL6845). 

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. 

The asymmetric Heck reaction can be used to synthesise quaternary carbon centres. During studies towards the synthesis of 3,3-disubstituted oxindoles. Overman and coworkers have shown how the use of silver salts can change the sense of asymmetric induction of the cyclised product. Thus, the iodide (10.131) can be converted into the product (10.132) with the (S)-enantiomer predominating, when the reaction is run in the presence of silver salts. In the absence of silver salts, the (J )-enantiomer is the major product. 

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). ... 

A series of new phosphinooxazoline ligands have been recently prepared and tested in the asymmetric Heck reaction. Synthesis of the ligands involved the aromatic nucleophilic substitution of aryl fluorides with phosphide nucleophile generated from the corresponding phosphine and KHMDS (eq 49). The reaction proceeded in good yields, but proved to be more sluggish with electron-rich aryl fluorides and failed completely when the addition of electron-deficient phosphines was attempted. 

Dounay, A.B. and Overman, L.E. (2003) The asymmetric Heck reaction in natural products total synthesis. Chem. Rev., 103, 2945-63. 

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. 

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. 

For recent reviews of the asymmetric Heck reaction, see (a) Shibasaki, M., Boden, C.D.J. and Kojima, A. (1997) The asymmetric Heck reaction. Tetrahedron, 53, 7371-95 (b) Shibasaki, M. and Vogl, E.M. (1999) Heck reaction, in Comprehensive Asymmetric Catalysis, Vol. 2 (eds E.N. Jacobsen, A. Pfaltz and H. Yamamoto), Springer, Berlin, pp. 457-87 (c) Donde, Y. and Overman, L.E. (2000) Asymmetric intramolecular Heck reactions, in Catalytic Asymmetric Synthesis (ed. I. Ojima), WUey-VCH Verlag GmbH, New York, pp. 675-97 (d) Dounay, A.B. and Overman, L.E. (2003) The as5mmetric intramolecular Heck reaction in natural product total synthesis. Chem. Rev., 103, 2945-64 (e) Shibasaki, M., Vogl, E.M. and Ohshima, T. (2004) Asymmetric Heck reaction. Adv. Synth. Catal., 346,1533-52. 

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