The possibility of ligand-controlled, catalytic, asymmetric synthesis of biaryls was first reported by Kumada and co-workers in 1975 and 1977 (Scheme 28).88,89 Although low yield and enantiopurity were obtained for (S)-2,2'-dimethyl-1,1'-binaphthalene, these reports inspired other research groups to strive for improvements.
Scheme 28
Interestingly, no major report emerged until 1988, perhaps due to the limited options for other chiral ligands at that time. Hayashi, Ito and co-workers showed that a monodentate phosphine ligand with a ferrocene framework dramatically improved the efficiency of the nickel catalyst (Scheme 29).90 Crucially, the methoxy group in the ligand was required for the asymmetric induction presumably through coordination to the magnesium ion of the Grignard reagent to form an organized complex at the transmetalation step. Replacement of the methoxy group with a hydrogen atom resulted in a total loss of asymmetric induction. The substitution patterns on the coupling partners can also influence the enantiomeric ratio (er) of the products. Higher enantioselectivity was observed for 2,2’-dimethyl substituted binaphthalene than the monosubstituted 2-methylbinaphthalene.
Scheme 29
The next major development appeared a decade later; the catalytic asymmetric Suzuki- Miyaura coupling of binaphthyls was independently reported by the Cammidge91 and Buchwald92 research groups in 2000. The dimethylamino analogue of the ferrocenyl phosphine ligand (S)-(R)-PPFNMe is found to be more efficient than the methoxy substituted analogue (S)- (R)-PPFOMe for asymmetric induction (Scheme 30). This result is interpreted in terms of the weaker coordinating ability of the oxygen compared to nitrogen atom, which may be required to activate the organoboron reagents toward transmetalation. However, this hypothesis cannot explain the higher yield obtained using (S)-(R)-PPFOMe ligand.
Scheme 30
The dimethylamino substituent is also an essential feature of the KenPhos ligand to catalyze the asymmetric Suzuki-Miyaura reaction (Scheme 31). Various chiral binaphthalenes bearing a phosphonate or a nitro group were synthesized in good enantiomeric purity. For the first time, chiral biaryls with these polar functional groups were employed and significant asymmetric induction was observed for the coupling of non-naphthyl derived substrates such as 2-substituted phenylboronic acids and –halides. After a decade, the scope of this reaction was extended to include the amide functionality. Most importantly, a detailed computational study was performed to rationalize the origin of enantioselectivity.
Scheme 31
In 2001, Miura et. al. reported palladium-catalyzed arylative carbon−carbon bond cleavage of α,α-disubstituted arylmethanols to yield sterically hindered biaryls (Scheme 32).93 The extrusion of an acetone molecule provides the driving force for β-carbon elimination. In the absence of a 2-substituent on aryldimethylcarbinol, the alcohol hydroxyl group directs the C−H activation to give the corresponding products. Importantly, if a methoxy group is the 2- substituent on the aryl bromide, the rate of reaction is enhanced. An example of the use of aryldimethylcarbinol in the synthesis of a chiral biaryl is illustrated using (R)-BINAP as the ligand (Scheme 32).
Scheme 32
In 2008, Fernández et. al. reported C2-symmetric bis-hydrazones as ligands for the cross-
coupling reaction of arylboronic acids (Scheme 33).94 Excellent enantioselectivities are achieved for a number of biaryls when the reactions are conducted at 20 °C. Although a prolonged reaction time (7 days) and an excess amount of the aromatic bromide (2.5 equiv) are needed. The undesired processes such as deborylation or homocoupling are not an issue at this temperature. The slow conversion was addressed simply by heating the reaction at 80 °C (< 17 h), albeit with some erosion in the selectivity.
Scheme 33
Noting the relatively low catalytic activity at room temperature and the limited scope in this work, the same group designed a novel class of P/N-hybrid ligand derived from C2-
symmetric hydrazine (Scheme 34).95 A number of challenging monocyclic and bicyclic aromatic bromides with ester and aldehyde groups afford moderate to good successes (77:23 - 92:8 er). The coupling of some aromatic triflates is also demonstrated. Compared to the bis-hydrazone catalyst system94, the present system is more efficient but is not necessarily more selective (Scheme 34).
Scheme 34
As described in the introduction, the existence of axial chirality in biaryl compounds arises from hindered rotation. In terms of their preparation by cross-coupling reactions, a consequence is a high reaction barrier because of the congested substitution pattern of the coupling partners. In 2010, Tang et. al. described the preparation of extremely hindered biaryls such as 2,4,6-triisopropyl-2'-phenylbiphenyl in 95% yield at a 1 mol % palladium loading.96 The success was enabled by a P-stereogenic monophosphorus ligand and the non-racemic form was employed in the asymmetric Suzuki-coupling (Scheme 35).97 This ligand features a rigid oxaphosphole framework which defines the configuration of the phosphorous atom. This protocol allows the coupling of a number of aromatic bromides bearing polar functional groups.
Scheme 35
In the preceding examples, the study of asymmetric coupling reaction either focuses on non-polar coupling partner or requires a polar functionality to maintain high enantioselectivity. None of the examples has demonstrated the ability to satisfy both demands with a single catalytic system. This feat was achieved to some degrees through the use of a polymer supported chiral imidazoindole phosphines (Scheme 36).98 For example, the highly hindered but non-polar 2,2’- dimethylbinaphthalene was obtained in 95% yield and 97:3 er. The less hindered but more polar 2-methyl-1-(2-nitrophenyl)naphthalene was obtained in 96% yield and 96:4 er. The catalyst PS- PEG-L*-Pd can be recovered and reused four times without significant loss of catalytic activity or stereoselectivity. Aromatic iodides, bromides and even some chlorides are competent coupling partners. The PEG-free ligand is also effective under conditions in toluene. However, high loadings of reagents including arylboronic acid (5 equiv), palladium source/ligand (10 mol %) and TBAF (10 equiv) are required.
Scheme 36
Reports on the use of chiral-diene ligands in palladium-catalyzed reactions are rare, possibly due to the perception of the low stability of diene-palladium complexes in the solution which can result in fast catalyst death.99,100 In addition, inadvertent functionalization of the alkene moiety of the ligand via Heck-type pathway could also be a concern. Nevertheless, stable diene-PdCl2 complex has been isolated for X-ray crystal structure characterization and used in
the catalytic, asymmetric Suzuki-Miyaura coupling (Scheme 37).101 A number of aromatic halides having a 2-formyl group were studied because of its value in subsequent transformation. The reaction was conducted at 25 °C and moderate enantioselectivities are observed. An additional amount of chiral diene (15 mol %) is added to the reaction possibly due to the lability of the ligand. When an equimolar amount of the enantiomeric ligand is included in the reaction mixture, a racemic product was obtained indicating a fast ligand exchange.
Interest in the use of metal nanoparticles (NPs) to promote catalytic transformations has increased in recent years.102,103 A first example in the realm of asymmetric aryl−aryl coupling appeared in 2008 (Scheme 38).104 The (S)-BINAP stabilized Pd-NPs are prepared by the reduction of K2PdCl4 with NaBH4 in the presence of this chiral ligand. This “nanocatalyst” is
stable for several months. Notably, the superb catalytic activity of this system allows the coupling to proceed at a low catalyst loading (0.1 mol %) and at room temperature, thereby slightly improving the enantioselectivity compared to a catalytic system that depends on the use of palladium precatalyst (Scheme 38).105
Scheme 38
An interesting study using helically chiral polymer in the asymmetric Suzuki-coupling was disclosed in 2011 (Scheme 39).106 The 1000mer-based ligand was prepared by living, random copolymerization of a chiral spacer bearing chiral (R)-2-butoxymethyl side chains and a phenylquinoxaline derived phosphine in ~950:50 ratio. The helical sense of the this polymeric ligand can be switched from (P) to (M) by simply heating it in a solution of 1,1,2- trichloroethane/THF for 24 h. The reversed helicity inverts the asymmetric induction thus providing an easy access to the enantiomeric product, albeit with slight erosion in selectivity. In one example, the use of an aromatic chloride as the coupling partner is demonstrated.
Scheme 39
To date, the study of catalytic asymmetric aryl-aryl coupling usually focuses on aromatic bromides. The use of aromatic chlorides poses significant challenges because of increased carbon−halide bond strength19 in addition to overcoming the hindrance of the substrate. Therefore, catalyst loading is usually high. A catalytic system employing a chiral biaryl-based phosphine ligand with a pendent pentatolylbenzene moiety has shown high turnover numbers for the coupling of hindered biaryls (Scheme 40).107 Although limited scope was demonstrated, the catalyst loading is typically at the 0.5 mol % Pd level. Head-to-head substrate comparison to other system may be needed to justify the efficacy of this protocol.
In pursuit of more atom-economical carbon−carbon bond formation reactions, C−H activation has garnered tremendous interest from the chemical community in recent years.108,109 The major benefit from such reaction is the elimination of the process involved in the preparation of halides or pseuodohalides required in the traditional cross-coupling. Perhaps because of the relatively low catalytic activity and the issue of site selectivity, the preparation of hindered chiral biaryls by this technology is particularly challenging, especially in the absence of a directing group. In 2012, Yamaguchi et. al. reported the first palladium-catalyzed asymmetric C-H/C-B coupling of various sulfur-containing heterocycles (Scheme 41).85 The reaction occurred regioselectively at the C(4) position. The addition of trifluoroacetic acid enhanced the enantioselectivity from the chiral ligand 2,2’-bis(2-oxazoline) 32.
Scheme 41
In the same year, a novel class of biaryl-based monophosphine ligands was employed in asymmetric Suzuki-Miyaura coupling reactions (Scheme 42).110,111 The atropisomeric property of these ligands is engendered by a chiral-linker instead of steric obstruction of rotation. The preparation of these ligands is enabled by desymmetrization of 2,2’,6,6’-tetrahydroxybiphenyl via SN2 displacement of (R,R)-2,3-butanediol bis(mesylate) or related analogs. The streamlined
synthetic route expedites the identification of the optimal ligand (R = Me, Aryl = 3,5-t-Bu2C6H3).
An enantiomeric ratio up to 98.5:1.5 was reported which is a significant improvement from the KenPhos system (85.5:14.5 er).112
Scheme 42
3.2.2 Mechanistic Hypotheses of the Stereodetermining Step and the Origin of