Asymmetric Palladium-Catalyzed Intramolecular α-Arylation of Aldehydes†

The prevalence of chiral quaternary stereocenters in many natural products has attracted a growing interest in the development of methods for their construction with absolute stereocontrol.[1,2] In recent years, the α-arylation of carbonyl compounds has received a great deal of attention.[3] Despite substantial advances, the asymmetric metal-catalyzed α-arylation of carbonyl compounds remains a formidable challenge, and few examples have been described.[4-7] To the best our knowledge, no examples of asymmetric metal-catalyzed α-arylation of aldehydes have yet been reported.[8] Herein, we present the first asymmetric metal-catalyzed α-arylation of aldehydes forming all-carbon-substituted chiral centers in high yields and enantioselectivities. (Scheme 1). Scheme 1 General scheme for the asymmetric intramolecular α-arylation of aldehydes. The racemic α-arylation of aldehydes remains challenging due to competing aldol condensation under the reaction conditions.[9] In 2007 our group described a general method for the α-arylation of aldehydes with both ArBr and ArCl.[9d] It was found that the catalytic system based upon Pd(OAc)2/BINAP provided the best results when aryl bromides were used. Given that BINAP has been successfully used as a ligand in related α-arylation methodologies[4-7] we decided to examine the utility of this ligand for the asymmetric α-arylation of 1a (Table 1). After some initial systematic screening of palladium sources, bases and solvents,[10] we obtained the desired compound 2a in 54% yield and 49% ee using DME as a solvent and Cs2CO3 as a base (Table 1, entry 1). Table 1 Screening of reaction conditions.[a] Encouraged by the initial results, we next examined the use of different chiral ligands in this transformation. Our experiments with other axially-chiral ligands such as CyBINAP (L2), CyMOP (L3), KenPhos (L4) and DTMB-SEGPHOS (L5), however, did not provide results with improved enantioselectivity (Table 1, entries 2-5). The use of of Josiphos (L6) or DIOP (L7) gave rise to 2a in 9 and 44% GC yield respectively (Table 1, entries 6 and 7), with very low enantioselectivity. Notably, the use of phosphinooxazoline-base ligands such as iPr-PHOX (L8)[11] provided the desired α-aryl aldehyde 2a in 68% ee, albeit in only 25% yield. Further optimization showed that higher enantioselectivities could be achieved by carrying out the process in polar solvents (Table 1, entries 9-12), with tBuOH providing the best results. It is well known that the substituent of the oxazoline moiety plays an important role in the enantioselectivity.[12] Indeed, the use of a more sterically encumbered tBu-PHOX (L9a) increased the optical purity of the product to 81% ee (Table 1, entry 14). Particularly significant is the effect of the α-substituent to the aldehyde (see below), thus, 1b afforded the desired compound 2b in 85% yield and 86% ee (Table 1, entry 15). We next focused our attention on the influence of both steric and electronic effects of the phosphine moiety of the PHOX ligands (Table 2). Although we observed no clear trend in electronic effects of the phosphine in the enantioselectivity and the yield of the reaction (Table 2, entry 7 vs 8), the size of the substituents has a substantial impact. Along these lines, the use of bulkier phosphine substituents resulted in lower enantioselectivity (Table 2, entry 2 vs 6). As depicted in Table 2, the best results were obtained when the reagents were stirred at 80 °C for 24 h using Cs2CO3 as the base and ligand L9i in tBuOH (0.1 M) affording the desired indane derivative 2b in 94% ee and 93% yield, respectively (Table 1, entry 9). Table 2 Screening of different PHOX ligands[a] With the optimized reaction conditions in hand, we further investigated the influence of the α-substituent to the aldehyde on the reaction outcome (Table 3). Substrates containing both α-alkyl and α-aryl substituents yielded the product aldehydes in high enantioselectivity. Generally, substrates with α-aryl substituents gave rise to products with higher optical purity than these with α-alkyl analogues (Table 3, entries 1-5 vs entries 6-8). In regard to the nature of the alkyl substituent, enantioselectivity increased with the size of the α-substituent to the carbonyl group (Table 3, entries 1-5). Under our reaction conditions, o-tolyl derivative 1h prove to be a difficult case, in which even higher catalysts loadings produced the desired product 2h in only 36% isolated yield, but with 98% ee (Table 3, entry 8).[14] The efficiency of the method dropped significantly for substrates in which a six-member ring was being formed; tetrahydronapthalene derivatives were prepared in moderate to good yields with moderate enantioselectivities (Table 2, entries 9-10). The absolute configuration of two of the products was established by X-ray crystallography of 2g (Figure 1)[15] and by comparison with a reported compound derived from 2a.[16,17] Figure1 Molecular structure of 2g with ellipsoids set at 50% probability. Hydrogen atoms are omitted for clarity. Table 3 Scope of the asymmetric Pd-catalyzed intramolecular α-arylation.[a] The fact that products with both aryl as well as alkyl α-substituents were of the same absolute configuration suggests that the enantioselectivity-limiting step in the catalytic system is common for both classes of substrates. The influence of the substitution pattern in the aromatic ring on the outcome reaction is shown in Table 4. The enantiomeric purity of the reaction product is not affected by the electronic character density of the aryl moiety (Table 4, entry 1 vs 4). Table 4 Scope of the asymmetric Pd-catalyzed intramolecular α-arylation.[a] Some representative applications of this methodology are illustrated in Scheme 2. For example, compound 5 was obtained from 2b by means of Lindgren oxidation,[18,19] Curtius rearrangement[20] and reaction of the resulting isocyanate with NaOtBu in 70% overall yield with no loss of the optical activity. This result is particulary interesting given the wide variety of pharmacologically active compounds with a chiral tertiary amine scaffold.[21] Alternatively, a one-pot oxidation or reduction of the corresponding aldehyde afforded the alcohol 6 or the carboxylic acid 7 in excellent overall yield. Scheme 2 Synthesis of different derivatives from 1b. In summary, we have developed the first asymmetric metal-catalyzed α-arylation of aldehydes. The high yields and enantioselectivities achieved make this process particularly attractive for further synthetic applications. Further investigations into this reaction and the development of an intermolecular protocol are currently underway in our laboratories.