Asymmetric Intermolecular Arylations

The catalytic cycle starts with oxidative addition of 73b to palladium(O) (77 78), followed by enantiofacial alkene-coordination to form the diastereomeric complexes (R)-79 and (S)-79 (78 (R)-79 and 78- (S)-79). In both cases, sy -selective migratory insertion R)-79— R)-S0 and (S)-79 (S)-80) and subsequent stereospecific P-hydride elimination furnishes a pair of diastereomeric alkene-hydridopaUadium(II) complexes (R)-81 and (S)-81 ((R)-80 (R)-81 and (S)-80— (S)-81). The Ji-bound Pd—H fragment in complex (S)-81 dissociates rapidly ((S)-81— 77), whereas (R)-81 undergoes hydropaUadation but with reversed regjoselec-tivity ((R)-81— (R)-82) P-hydride elimination and alkene dissociation then affords 

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An Ir(l)-catalyzed asymmetric intermolecular hydroarylation of norbornene with benzamide was reported in good to excellent enantiomeric excess, albeit in low yields, via the aryl C—H activation (Scheme 5.14). In some cases, the hydroami-nation products of norbornene were also formed in high enantioselectivities. 

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates <07ASC2595>. Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

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... 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

Houk, Rovis, and their co-workers later extended the scope of the asymmetric intermolecular Stetter reaction of p-nitrostyrenes to unactivated aliphatic aldehydes, which have rarely been utilized in this reaction due to their relatively lower electrophilicity compared with aryl aldehydes. Comparing to known scaffolds, tert-leucine derived trans-fluorinated catalyst leads to improved reactivity and enantioselectivity in this transformation. Computational studies show that the optimized catalyst is the most stereoselective one because the Re-face attack is stabilized by favorable electrostatic interactions between the phenyl group and the fluorine on the catalyst backbone (Scheme 7.31). 

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). 

Figure 7.1 Chiral ligands tested in asymmetric intermolecular Mizoroki-Heck arylations (nd = not determined).

Scheme 3.46 Asymmetric intermolecular a-arylation using NHC as chiral modifiers of nanoparticles.

Davies et al. carried out a comparative study on the catalytic activities of Rh2(S-DOSP)4 (3), RhjlR-BNP)4 (4), and Rh2(S-PTAD)4 (5) toward asymmetric cyclopropanation reactions (Table 9.2, entries 3-9) [94]. In general, Rh2(S-DOSP)4 was found to be the most effective catalyst for asymmetric intermolecular cyclopropanation of methyl aryldiazoacetates with styrene. Rh2(S-PTAD)4 exhibited lower levels of enantioinduction with 4-substituted aryldiazoacetates but it proved to be superior with the 4-methoxy substituted aryldiazoacetate (Table 9.2, entry 4, 96% ee) [94, 98]. Rh2(i -BNP)4, however, functions as an extremely effective catalyst with all the aryldiazoacetates substituted with three methoxy groups (88-97% ee). The asymmetric inductions varied with the aryl groups on the aryl diazoacetate but the choice of olefin had no effect on the selectivity. 

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... 

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... 

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. 

Intermolecular Stereoselective Aryl Coupling 2.1.1. Internal Asymmetric Induction with Chiral Substrates 2.1.1.1. Dimerization of Chiral Aryl Compounds... 

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... 

Intermolecular a-arylation of the ketone 399 with o-tolyl bromide (398) gives 400 under selected conditions using f-BuONa or KN(SiMe2)2 as suitable bases, and BINAP or DPPF (XLIX) as a bulky ligand [194], Furthermore, asymmetric arylation of the ketone 402 with the bromide 401 gave 403 with 98% ee efficiently by using chiral BINAP [195]. 

Intermolecular insertion to aryl C—H bonds is possible. The asymmetric intramolecular reaction of the a-diazo compound 354 catalysed by Rh2[(S)-PTTL]4, Rh2[(S)—PTTL]4 = dirhodium tetrakis[N-phthaloyl(S)—t—leucinate], afforded indane... 

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 thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

The first example of the intermolecular AHR was reported by Hayashi et al. and involved the asymmetric arylation of 2,3-dihydrofurans using aryl triflates [18]. Although little or no enantiomeric excess was obtained when aryl iodide/silver salt combinations were used, the use of triflates along with the familiar Pd(OAc)2/ BINAP catalyst system resulted in the formation of the 2-aryl-2,3-dihydrofuran product 54, together with minor amounts of the 2, 5-dihydrofuran isomer 55. The rationale proposed by the authors for this outcome is shown in Scheme 12 it is hypothesized that addition of the catalytic complex to either face of the sub-... 

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