Pyridine–hydrazone ligands in enantioselective palladium-catalyzed Suzuki–Miyaura cross-couplings

Graphical Abstract To create your abstract, type over the instructions in the template box below. Fonts or abstract dimensions should not be changed or altered. Pyridine– hydrazone ligands in enantioselective palladium –catalyzed SuzukiMiyaura cross –couplings Yolanda Álvarez-Casao,a Beatriz Estepa,a David Monge,a, * Abel Ros,b Javier Iglesias-Siguenza,a Eleuterio Álvarez,b Rosario Fernándeza,* and José M. Lassalettab,* a Departamento de Química Orgánica, Universidad de Sevilla, and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/ Prof. García González, 1, 41012 Sevilla, Spain b Instituto de Investigaciones Químicas (CSIC-USe) and Centro de Innovación en Química Avanzada (ORFEOCINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain Leave this area blank for abstract info. 1 Tetrahedron Pyridine–hydrazone ligands in enantioselective palladium-catalyzed Suzuki-Miyaura cross–couplings Yolanda Álvarez-Casao,a Beatriz Estepa,a David Monge,a,* Abel Ros,b Javier Iglesias-Siguenza,a Eleuterio Álvarez,b Rosario Fernándeza,* and José M. Lassalettab,∗ a Departamento de Química Orgánica, Universidad de Sevilla, and Centro de Innovación en Química Avanzada (ORFEO-CINQA), C/ Prof. García González, 1, 41012 Sevilla, Spain b Instituto de Investigaciones Químicas (CSIC-US) and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Avda. Américo Vespucio, 49, 41092 Sevilla, Spain ——— ∗ Corresponding author. Fax: +34 954624960; Tel: +34 954551518; e-mail: [email protected] Fax: +34 954460565; Tel: +34 954489563; e-mail: [email protected] The geometries and coordination properties of modular pyridine–hydrazone N,N-ligands containing C2-symmetric trans-2,5-diphenylpyrrolidine and trans-2,5-diphenylpiperidine as the terminal dialkylamino units have been analyzed by X-ray diffraction analysis of [PdCl2(N,N)] complexes [(N,N) = pyridine hydrazone ligand]. In combination with Pd(OAc)2 as the precatalyst, these ligands provide high enantioselectivities (up to 95:5 er) in asymmetric SuzukiMiyaura cross couplings of 2-methoxy-1-naphthyl bromides with 1-naphthyl and 2-tolyl boronic acids. . Keywords: Cross-coupling N-Ligands Asymmetric Catalysis Palladium Biaryls Tetrahedron 2 1. Introduction Palladium catalyzed asymmetric Suzuki-Miyaura cross coupling is one of the most useful C-C bond forming reactions for the synthesis of axially chiral biaryl compounds.1 Since seminal communications by Buchwald2 and Cammidge3 relatively few catalytic systems enabling efficient control of axial chirality in biaryls synthesis have been described. To date, most of the successful examples are based on palladium complexes containing chiral phosphine ligands [mono-phosphine (P), biphosphine (P,P) and heterobidentate P,X ligands (X = O or N)]. The most recent studies include also the use of phosphine-free dienes4 and N-heterocyclic carbenes.5 On the other hand, based in previous results by Nolan6 and Mino,7 we reported on the use of electron–rich glyoxal bis-hydrazone I (Scheme 1) as a phosphine–free ligand in this reaction. This type of ligand class, had been previosly used in asymmetric Cu(II)–catalyzed DielsAlder cycloadditions,8 exhibiting a high level of enantiocontrol based on a related square–planar geometry. In fact, the use of I/PdCl2 complex as the precatalyst enabled the obtention of a series of biaryls, particularly unfunctionalized binaphtalenes, with unprecedented enantioselectivities at low temperatures.9 Scheme 1. Hydrazone based ligands in the asymmetric SuzukiMiyaura reaction. The high efficiency of I/PdCl2 system was associated with the intrinsic features of the ligand I: (a) C2 symmetry of the terminal dialkylamino group (2,5-diphenylpyrrolidino). This property makes the rotation arond N–N bonds inconsequential (maintaining a suitable chiral environment in the proximity of the Pd center) and proved to be essential for reaching high enantioselectivities; (b) limited flexibility arounds the conjugated C=N-N system, providing an adequate chiral environment for square-planar 5-membered palladacycles; (c) a considerable steric crowding for the stabilization of the intermediate Pd(0) species, (d) a relatively high electron density (n→π conjugation) in the system which normally favor the oxidative addition step and finally (e) the potential hemilabile behavior which might be essential for the transmetalation event, as recently outlined by Denmark and Houk.10 In spite of the excellent results achieved with ligand I, there are still limitations related with the lower enantioselectivities achieved with electron poor electrophiles and the long reaction times required in some cases for reaction completion. In an attempt to overcome these limitations, the original design was later extended to 6-membered palladacyclic complexes containing phosphino-hydrazone P,N ligands II which, interestingly, exhibited excellent catalytic activities and good stereocontrol with complementary families of substrates.11 Aiming to expand the strategy of combining a C2–symmetric hydrazone ligand with a different highly-tunable coordinating functionality we have recently developed a new family of heterofunctional N,N´ pyridine–hydrazone ligands III, which have been succesfully tested in Pd(II)-catalyzed arylations of cyclic sulphonylketimines12 and Ru(II)-catalyzed decarboxylative allylic etherification reactions.13 In this paper, we present new palladium complexes based on pyridine–hydrazone ligands III (forming 5-membered palladacycles), their structural analysis and their use in asymmetric Suzuki-Miyaura reactions. N N N R2 R2 [Pd] R1n NN N N Ph Ph [Pd] Ph Ph I/PdCl2 5-membered palladacycles Up to 99% yield; up to 98% ee Ref. 5 NN R R Ar2P [Pd] II/PdCl2 6-membered palladacycles Up to 91% yield; up to 84% ee Ref. 6 Z III/PdX2 5-membered palladacycles (This work) Electronically and sterically tunable pyridine ligand R = Ph, i-Pr L*/PdX2 (5 mol%) B(OH)2 X + R R' X = Halide, OTf L*/[Pd] R R' 3 Scheme 2. Synthesis of pyridine–hydrazone ligands L1-L15 2. Results and discussion 2.1. Synthesis of ligands and Palladium (II) complexes A first set of the suggested pyridine–hydrazone ligands L1-L15 were synthesized in 43-95% yield by simple condensation of a variety of readily available 2-formylpyridines 2 with different substitution patterns and C2–symmetric hydrazines such as (2S,5S)-1-amino-2,5-diphenylpyrrolidine (1A),8 (2R,5R)-1amino-2,5-diphenyl-pyrrolidine (ent-1A),8 (2S,6S)-1-amino-2,6diphenylpiperidine (1B),8 and (2S,5S)-1-amino-2,5diisopropylpyrrolidine (1C)11 (Scheme 2). Reactions of representative pyridine–hydrazone ligands L1, L2, L6 and L14 with [PdCl2(CH3CN)2] in dry CH2Cl2 at room temperature afforded the corresponding [PdCl2(N,N)] neutral complexes C1C4 in 74-94% yields (Scheme 3). The complexes were characterized in solution by 1H and 13C NMR spectroscopy. Additionally, good quality crystals of these complexes could be grown by slow difussion of n-hexane into a solution of the complexes in CH2Cl2. Therefore, their solid state structural analysis was also performed by single–crystal X-ray diffraction, to obtain valuable information about the coordination features and geometries of pyridine–hydrazone ligands. Scheme 3. Synthesis of Pd(II) complexes C1-C4 NR R NH2 MeOH, rt n 1A: R = Ph, n = 1 1B: R = Ph, n = 2 1C: R = iPr, n = 1 N O H XN NN R R n Y Z N NN Ph Ph MeO2C N NN iPr iPr N NN Ph Ph N NN Ph Ph N NN Ph Ph L1, 75% L2, 85%ent-L1, 75% L3, 48% L7, 43% N NN Ph Ph Me N NN Ph Ph N NN Ph Ph F3C CF3 Me Me N NN Ph Ph Me N NN Ph Ph O X O L14, 90% L15, 75%L12, 88% L13, 95% L1-L15 N NN Ph Ph OMe N NN Ph Ph NMe2 N NN Ph Ph Cl L4, 81% L5, 65% L6, 62% L8, 75% N NN Ph Ph Ph L9, 85% L10, 73% N NN Ph Ph MeO N NN Ph Ph F L11, 79% + Y Z 2a-m N NN R R n Z X C1-C4 N N N Ph Ph Pd Cl Z Xn L1, L2, L6, L14 [Pd(CH3CN)2Cl2] CH2Cl2, rt Cl C1, 74% N N N Ph Ph Pd Cl Cl N Ph Ph C4, 92% N N Pd Cl Cl C2, 94% N N N Ph Ph Pd Cl Cl MeO C3, 91% N N N Ph Ph Pd Cl Cl F3C CF3 Tetrahedron 4 Figure 1. ORTEP drawings of complexes C1-C4: Thermal ellipsoids are drawn at the 30% probability level. Hydrogen atoms are omitted for clarity. The structure shown for C1 corresponds to one out of three independent molecules in the molecular cell. The structure shown for C2 corresponds to one out of two independent molecules in the molecular cell. Selected crystallographic data for all structures are colleted in Table 1. Table 1. Selected bond lengths (Å) and bond angles (deg) for complexes C1-C4 shown in Figure 1 Structure C1(M1) C1(M2) C1(M3) C2(M1) C2(M2) C3 C4 Square planar distortion (deg) 11.5 6.3 8.3 6.2 5.3 12.8 8.0 Angle between ligand and coordination planes (deg) 21.0 12.5 19.4 12.5 11.3 29.6 12.0 Virtual angle N2-N3-C7-C10/11 (deg) 151.0 149.4 159.3 149.0 150.4 144.5 143.8 √(360 −Σ) 2.67 2.74 1.87 2.76 2.60 3.12 3.06 Dihedral C=N-N-C (deg) -5.4(12) -15.1(12) -13.0(12) -10.3(9) -22.9(10) -12.2(5) -21.7(5) Pd–N(Py) (Å) 2.013(8) 2.017(5) 1.989(8) 2.036(6) 2.016(6) 2.050(3) 2.035(4) Pd–N(Hyd) (Å) 2.049(7) 2.047(6) 2.075(7 2.084(6) 2.073(6) 2.043(3) 2.041(4) Pd–Cl (trans to Py) (Å) 2.283(2) 2.2769(17) 2.286(3) 2.278(2) 2.289(2) 2.2937(9) 2.2825(12) Pd–Cl (trans to Hyd) (Å) 2.284(2) 2.2734(19) 2.271(3) 2.2874(19) 2.293(2) 2.2826(9) 2.2799(13) 2.2. Structural analysis The solid state structure of diphenylpirrolidine(or piperidine) derivatives C1-C414 reveals the expected square-planar geometry around the palladium center, although a slight distortion was observed in all cases. This distortion, presumably caused by the steric repulsion with the bulky 2,5diphenylpyrrolidino(piperidino) group, has been measured as the torsion angle between the planes defined by N(2)−Pd−N(1) and Cl(1)−Pd−Cl(2), respectively, reaching low to moderate values (5.3–11.5 deg) in most cases (Table 1). In the case of C3, however, the presence of the additional aromatic ring at C(6) originates a steric repulsion between the chlorine atom trans to the hydrazone N(sp2) and the 3,5-(CF3)2-C6H3 group, forcing a slightly higher deviation from the square planar geometry (torsion angle 12.8 deg). As one of the remarkable characteristics, the structures of C1C4 show a relatively low deviation of coplanarity between ligand plane (defined as the plane fitting through N(1)-C(1)-C(6)-N(2) and the coordination plane (defined as the plane fitting through N(1)-N(2)-Pd-Cl(1)-Cl-(2). Again, the presence of an aryl group at position C(6) makes this deviation more significant in C3 (angle between planes 29.6 deg). Nevertheless, there is a sharp contrast between these geometries and those of related phosphino–hydrazone complexes II/[Pd]11,15 which, having six– membered geometries, are characterized by a much larger deviation angle (54.1 to 62.6). Interestingly, this comparison reveals also that phosphino–hydrazone ligands regularly exhibit a more efficient n→π conjugation in the hydrazone system. Thus, the pyramidalization degree, measured either as the virtual dihedral angle N(2)-N(3)-C(7)-C(10)16 or using the √360 −Σ descriptor,17 is regularly lower in phosphino-hydrazone complexes than in complexes C1-C4. Thus, the average virtual angle in II/PdCl2 complexes11 is 161.7 deg, while the average value for comparable pyrrolidine derivatives C1-C3 is 150.6 deg. Additionally, the average values for the √(360−Σ descriptor is 1.49 for II/PdCl2 complexes, much lower than the corresponding average values of 2.26 calculated for C1-C3. Not surprisingly, the largest value of 3.12 was observed in the sterically distorted complex C3. The planarity degree in the 2,6-diphenylpiperidine derivative C4 (not included in the above discussed comparison), is also relatively low (virtual angle = 143.8 deg; √(360−Σ = 3.06) as expected for the lower tendency of the piperidine N(sp3) atom to reach planar conformations. The structures show also typical Pd–N distances, being the Pd– N(Py) bond (average 2.02 Å) shorter in general than the Pd– N(Hyd) one (average 2.06 Å), which is in accordance with the higher basicity of the pyridine fragment. Unexpectedly, though, the Pd–Cl(1) and Pd–Cl(2) bond distances are very similar in all cases, not reflecting a significant trans influence by any of the N atoms. This is in sharp contrast with the previously reported allyl complex,12 in which the Pd−C bond trans to the pyridine N is significantly longer [2.150(5) Å] compared to the Pd−C bond trans to the hydrazone N [2.099(5) Å], reflecting in this case the higher trans influence of the more basic pyridine nitrogen. C1 C3 C4C2 5 2.3. Asymmetric Suzuki-Miyaura cross-coupling Complexes prepared in situ from L1-L15 and [PdCl2(CH3CN)2] were then tested in the asymmetric Suzuki– Miyaura cross-coupling reaction between 1-bromo-2methoxynaphthalene (3a) and 1-naphthyl boronic acid (4a) (Table 2). The reactions carried out at 80 °C for 4 days employing L1-L3/PdCl2 as precatalyst, Cs2CO3 as the base and toluene as the solvent, afforded (S)-2-methoxy-1,1'-binaphthyl [(S)-5a] in moderate conversions (50-65%) and enantioselectivities (63:37-85:15 er) (entries 1-3). The analysis of these results indicates that the pyrrolidine-derived L1 provides a better chiral environment than the piperidine-derived L2, a fact that has been repeteadly obverved in related catalsyts8,9,11,12 and that is presumably related with the higher conformational flexibility of the piperidine moiety, in turn associated with the weaker n→π conjugation. 2,5-Diisopropylpyrrolidine derivative L3, lacking possible preferred orientations of aryl groups in oxidative addition intermediates due to stabilizing π-π interactions, was also less efficient. Next, it was explored the influence of substituents on the pyridine moiety. The presence of electron-donating [4-MeO, L4 and 4-NMe2, L5] and electronwithdrawing [4-Cl, L6 and 5-CO2Me, L7] groups had a detrimental effect on catalytic activities (entries 4-7), affording (S)-5a in lower conversions (35-50%) and similar enantioselectivities. The effect of the steric properties of ligands containing substituents at C-6 of the pyridine ring (L8-L15) was Table 2. Pd-catalyzed asymmetric Suzuki-Miyaura reactions: ligand screeninga entry Precatalystb Conv. (%)c er (S:R)d 1 L1/[Pd] 65 85:15 2 L2/[Pd] 60 78:22 3 L3/[Pd] 50 63:37 4 L4/[Pd] 36 84:16 5 L5/[Pd] 35 82:18 6 L6/[Pd] 55 84:16 7 L7/[Pd] 50 84:16 8 L8/[Pd] 60 80:20 9 L9/[Pd] 50 59:41 10 L10/[Pd] >95 68:32 11 L11/[Pd] 62 68:32 12 L12/[Pd] >95 58:42 13 L13/[Pd] 65 61:39 14 L14/[Pd] 85 35:65 15 L15/[Pd] 82 56:44 16 C1 70 84:16 17 C2 60 84:16 18 C3 90 35:65 19 C4 67 78:22 a Reactions were carried at 0.1 mmol scale. b [Pd] = PdCl2(CH3CN)2. c Determined by 1H-NMR. d Determined by HPLC using chiral columns. subsequently investigated. Methylsubstituted ligand L8 gave a similar level of conversion and slightly lower enantioselectivity (80:20 er, entry 8). The introduction of aryl groups at C(6) in ligands L9-L15 had also a negative effect on the performance of the catalyst, affording (S)-5a in moderate (50-65%, entries 9, 11 and 13) to good conversions (82->95%, entries 10, 12, 14 and 15), albeit lower enantioselectivities (up to 68:32 er for L10 and L11). It is worth mentioning that enantioinversion was observed with the ligand L14 (entry 14), and the coupling product (R)-5a was obtained in full conversion and 35:65 er. Finally, reactions carried out with preformed complexes C1-C4 afforded the same level of enantioselectivity and similar conversions than those accomplished with in situ formed precatalysts. Having identified the simplest L1 as the most selective ligand, experiments with different Pd sources were conducted. Surprisingly, Pd(0) precursors [Pd(dba)2 and Pd2(dba)3] showed no catalytic activity (<5% conversion after 4 days), while Pd(II) sources containing less coordinating anions such as Pd(OAc)2 afforded (S)-5a in 54% conversion and an improved 95:5 er. (Table 3, entry 1). A screening of different bases (entries 2-5) and solvents (entries 6-9) revealed CsF in toluene as a good alternative to Cs2CO3, reaching 71% conversion and 94:6 er (entry 5 vs 1), although the reaction time remained relatively long (96 h). Finally, reactions were made in Toluene/H2O mixtures, being 9:1 the optimal ratio (entries 10 and 11). To our delight, this solvent combination had a positive effect on the catalytic activity, possibly associated with solubility issues, and afforded high conversions (>95%) and still good enantioselectivities. Remarkably, employing Cs2CO3 as the base Table 3. Pd-catalyzed asymmetric Suzuki-Miyaura reactions: reaction optimization and scopea entry Base Solvent t (h) 5, Conv. (%)b er (S:R)c 1 Cs2CO3 Toluene 96 (S)-5a, 54 95:5 2 tBuOK Toluene 96 (S)-5a, 16 91:9 3 Ba(OH)2 Toluene 96 (S)-5a, 40 84:16 4 K3PO4 Toluene 96 (S)-5a, 44 90:10 5 CsF Toluene 96 (S)-5a, 71 94:6 6 Cs2CO3 DCE 96 (S)-5a, 26 93:7 7 Cs2CO3 Dioxane 96 (S)-5a, 60 91:9 8 Cs2CO3 MeOH 96 (S)-5a, 32 92:8 9 Cs2CO3 H2O 96 (S)-5a, 42 75:25 10d Cs2CO3 Toluene/H2O, 9/1 15 (S)-5a, >95 (99) 94:6 11 CsF Toluene/H2O, 9/1 96 (S)-5a, 93 93:7 12d,e Cs2CO3 Toluene/H2O, 9/1 15 (R)-5a, >95 (99) 9:91 13d Cs2CO3 Toluene/H2O, 9/1 48 (S)-5b, >95 (99) 94:6 14d Cs2CO3 Toluene/H2O, 9/1 96 (S)-5c, >95 (99) 84:16 Br OMe B(OH)2 +OMe L*/[Pd] (5 mol%) 3a 4a (S)-5a Cs2CO3,Toluene, 80 °C 4 days L1 (7.5 mol%) Pd(OAc)2 (5 mol%) Base Solvent, 80 °C Br OMe B(OH)2 +OMe 3a: X = H 3b: X = OMe 4a 5 X R R OMe (S)-5a OMe OMe (S)-5b OMe (S)-5c Me OMe (R)-5a Tetrahedron 6 a Reactions were carried at 0.1 mmol scale. b Isolated yield are given in brackets. c Determined by HPLC using chiral stationary phases. d Reactions were carried at 0.2 mmol scale. e Employing ent-L1. the reaction took place in 15 hours, yielding (S)-5a in quantitative yield and 94:6 er (entry 10). Unfortunately the enantioselectivity could not be further improved at lower temperatures. The opposite (R)-5a enantiomer was obtained applying ent-L1 (entry 12), thereby highlighting the availability of both enantiomers of the ligand. Under optimized conditions, other biaryl compounds (S)-5b and (S)-5c were synthesized in quantitative yields and enantioselectivities from good (94:6 er for (S)-5b, entry 13) to moderate (84:16 er for (S)-5c, entry 14), albeit in longer reaction times (48 and 96 hours, respectively). 3. Conclusion In summary, pyridine–hydrazone ligands form neutral fivemembered Pd(II) complexes showing geometries that exhibit significant differences with those previously found in related sixmembered phosphino–hydrazones. Under optimized conditions, these complexes behave as efficient catalysts for the asymmetric Suzuki–Miyaura cross–coupling of 2-methoxy-1-naphthyl bromides with 1-naphthyl and 2-tolyl boronic acids. Together with the results collected in the asymmetric 1,2–addition of boronic acids to cyclic sulphonylketimines12 and Ru(II)-catalyzed decarboxylative allylic etherification reactions,13 these results suggest that this type of ligands is an interesting alternative to better established chiral N,N ligands such as bis–oxazolines or pyridine–oxazolines. 4. Experimental Section General experimental methods. 1H NMR spectra were recorded at 300 MHz, 400 MHz or 500 MHz; 13C NMR spectra were recorded at 75 MHz, 100 MHz or 125 MHz, with the solvent peak used as the internal reference. Flash chromatography was carried out on silica-gel (40-63 µm or 15-40 µm). Melting points were recorded in a metal block and are uncorrected. Optical rotations were measured on a Perkin-Elmer 341 MC polarimeter. The enantiomeric excesses (ee) were measured by HPLC on chiral stationary phase with iPrOH/n-hexane mixtures as the eluents. Solvents were purified and dried by standard procedures. 6-bromo-2-formylpyridine, 2-formylpyridine (2a), 6-methyl-2formylpyridine (2f), 6-(4-fluorophenyl)-2-formylpyridine (2i), 6- (benzo[d][1,3]dioxol-5-yl)-2-formylpyridine (2m), [Pd(CH3CN)2Cl2], 1-bromo-2-methoxynaphthalene (3a), 1bromo-2,3-dimethoxynaphthalene (3b), 1-naphthylboronic acid (4a) and 2-tolylboronic acid (4b) were purchased from Aldrich and used as received. (2S,5S)-1-Amino-2,5-diphenylpyrrolidine (1A),8 (2R,5R)-1-amino-2,5-diphenylpyrrolidine (ent-1A),8 (2S,6S)-1-amino-2,6-diphenylpiperidine (1B),8 (2S,5S)-1-amino2,5-diisopropylpyrrolidine (1C),11 pyridine aldehydes 2b,d18 2c,19 and 2e,20 and pyridine–hydrazones L1-L812 were prepared according to the literature procedures. General Procedure for the synthesis of pyridine–aldehydes 2: 6-Bromo-2-formylpyridine (5.4 mmol, 1.0 g) was added to a solution of Pd(PPh3)4 (3 mol%, 186 mg) in deoxygenated DME (10 mL), under Argon. After 10 min, stirring at rt, the corresponding boronic acid (7.5 mmol) and a Na2CO3 (2M aq., 5.5 mL) solution were added and the reaction mixture was stirred at 90 °C for 16 h. H2O was added and the layers were separated. The aqueous portion was extracted with CH2Cl2 (3 × 30 mL) and the combined organics were dried, concentrated and the resulting residue was purified by flash chromatography. Yields and characterization data for compounds 2 are as follows: 6-Phenylpicolinaldehyde (2g). Following the general procedure using phenyl boronic acid (7.5 mmol, 919 mg), flash chromatography (EtOAc:hexane 1:30) gave 2g (772 mg, 78%) as a yellow solid. M.P. = 68-69 °C. 1H NMR (300 MHz, CDCl3): δ 10.18 (s, 1H), 8.11-8.09 (m, 2H), 7.98-7.90 (m, 3H), 7.56-7.48 (m, 3H). 13C NMR (125 MHz, CDCl3): δ 193.9, 158.0, 152.8, 138.2, 137.8, 129.7, 128.9, 127.0, 124.4, 119.8. HRMS (CI) m/z calcd for C12H9NO 183.0684, found 183.0687. 6-(2,6-Dimethylphenyl)picolinaldehyde (2j). Following the general procedure using 2,6-dimethylphenyl boronic acid (7.5 mmol, 1.13 g), flash chromatography (EtOAc:hexane 1:15) gave 2j (1.0 g, 97%) as a white solid. M.P. = 75-77 °C. 1H NMR (300 MHz, CDCl3): δ 10.12 (s, 1H), 7.96 (d, 2H, J = 7.5 Hz), 7.497.47 (m, 1H), 7.24 (t, 1H, J = 7.8 Hz), 7.14 (d, 2H, J = 7.8 Hz), 2.06 (s, 6H). 13C NMR (100 MHz, CDCl3): δ 193.8, 160.7, 152.8, 139.2, 137.4, 135.7, 128.9, 128.4, 127.8, 119.6, 20.2. HRMS (CI) m/z calcd for C14H13NO 211.0997, found 211.0997. 6-(4-(Tert-butyl)phenyl)picolinaldehyde (2k). Following the general procedure using 4-(tert-butyl)phenyl boronic acid (7.5 mmol, 1.34 g), flash chromatography (EtOAc:hexane 1:8) gave 2k (1.12 g, 87%) as a yellow solid. M.P. = 78-80 °C. 1H NMR (300 MHz, CDCl3): δ 10.17 (s, 1H), 8.04-8.00 (m, 2H), 7.93-7.88 (m, 3H), 7.56-7.53 (m, 2H), 1.38 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 194.0, 158.0, 153.0, 152.7, 137.6, 135.4, 126.7, 125.9, 124.2, 119.4, 34.7, 31.2. HRMS (CI) m/z calcd for C16H17NO 239.1310, found 239.1318. 6-(3,5-Bis(trifluoromethyl)phenyl)picolinaldehyde (2l). Following the general procedure using 3,5-bis(trifluoromethyl)- phenyl boronic acid (7.5 mmol, 1.94 g), flash chromatography (EtOAc:hexane 1:8) gave 2l (1.16 g, 71%) as a yellow solid. M.P. = 92-93 °C. 1H NMR (300 MHz, CDCl3): δ 10.2 (s, 1H), 8.58 (s, 2H), 8.08-7.98 (m, 4H). 13C NMR (125 MHz, CDCl3): δ 193.2, 154.5, 153.1, 140.1, 138.5, 132.5 (q, JC-F = 33 Hz), 127.1, 127.0, 124.4, 123.3 (q, JC-F = 271 Hz), 121.2. HRMS (CI) m/z calcd for C14H7NOF6 319.0432, found 319.0437. General procedure for the synthesis of pyridine–hydrazones L9-L15: A solution of the corresponding aldehyde 2 (1 mmol) in MeOH (1 mL) was dropwise added to a solution of (2S,5S)-1amino-2,5-diphenylpyrrolidine 1a (1.1 mmol, 263 mg) in MeOH (1 mL). The reaction mixture was stirred at rt for 3 hours. A partial precipitation of the product was observed and the formed pyridine–hydrazone was filtered, and the mother liquor containing product was concentrated to dryness and purified by flash chromatography. Yields and characterization data for compounds L9-L15 are as follows: Pyridine-hydrazone (L9). Following the general procedure, flash chromatography (EtOAc:n-hexane 1:20, 1% Et3N) gave L9 (342 mg, 85%) as a yellow-orange foam. [α]20D –259.5 (c 0.54, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.87 (m, 2H), 7.62-7.22 (m, 16H), 7.09 (s, 1H), 5.23 (d, 2H, J = 6.8 Hz), 2.59-2.52 (m, 2H), 1.91-1.81 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 156.5, 156.4, 143.0, 139.8, 136.3, 132.3, 128.6, 128.5, 128.4, 126.9, 126.8, 126.2, 117.9, 116.8, 65.2, 31.4. HRMS (CI) m/z calcd for C28H25N3 403.2048, found 403.2061. 7 Pyridine-hydrazone (L10). Following the general procedure, flash chromatography (Et2O:n-hexane 1:8→1:4, 1% Et3N) gave L10 (314 mg, 73%) as a white solid. M.P. = 112-113 °C. [α]20D – 310.2 (c 0.83, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J = 8.8 Hz), 7.56-7.42 (m, 2H), 7.40-7.19 (m, 11H), 7.10 (s, 1H), 6.93 (d, 2H, J = 8.8 Hz), 5.23 (d, 2H, J = 6.7 Hz), 3.82 (s, 3H), 2.70-2.45 (m, 2H), 1.95-1.75 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 160.1, 156.3, 156.1, 143.0, 136.3, 132.5, 132.4, 128.5, 128.1, 126.8, 126.2, 117.2, 116.1, 113.9, 65.2, 55.3, 31.5. HRMS (CI) m/z calcd for C29H28N3O 434.2232 (M+ + 1), found 434.2234. Pyridine-hydrazone (L11). Following the general procedure, flash chromatography (toluene:n-hexane 1:1→2:1, 1% Et3N) gave L11 (334 mg, 79%) as a yellow solid. M.P. = 115-117 °C. [α]20D –58.8 (c 0.90, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.88-7.81 (m, 2H), 7.54 (dd, 1H, J = 7.9, 0.9 Hz), 7.47 (t, 1H, J = 7.9 Hz), 7.38-7.32 (m, 4H), 7.30 (dd, 1H, J = 7.9, 0.9 Hz), 7.287.21 (m, 6H), 7.12-7.04 (m, 3H), 5.24 (d, J = 7.0 Hz), 2.62-2.49 (m, 2H), 1.97-1.78 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 163.3 (q, J = 249.0 Hz), 156.4, 155.3, 142.9, 136.4, 132.0, 128.7, 128.6, 126.9 (q, J = 7.8 Hz), 126.6, 126.2, 117.5, 116.7, 115.4 (q, J = 23.2 Hz), 65.3, 31.6 HRMS (CI) m/z calcd for C28H25N3F (M+ + 1) 422.2028, found 422.2033. Pyridine-hydrazone (L12). Following the general procedure, flash chromatography (toluene, 1% Et3N) gave L12 (352 mg, 88%) as a yellow foam. [α]20D –330.9 (c 0.80, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.58 (dd, 1H, J = 8.1, 2.0 Hz), 7.50 (t, 1H, J = 7.4 Hz), 7.36-7.33 (m, 4H), 7.26-7.24 (m, 6H), 7.14-7.10 (m, 1H), 7.06-7.00 (m, 3H), 7.03 (s, 1H), 6.88 (dd, 1H, J = 7.4, 1.1 Hz), 5.22 (d, 2H, J = 7.0 Hz), 2.60-2.51 (m, 2H), 1.99 (s, 6H), 1.90-1.84 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 158.6, 156.5, 142.8, 140.6, 135.9, 135.8, 132.2, 128.5, 127.6, 127.5, 126.8, 126.3, 121.5, 116.1, 65.2, 31.4, 20.2. HRMS (CI) m/z calcd for C30H30N3 432.2440 (M+ + 1), found 432.2435. Pyridine-hydrazone (L13). Following the general procedure, flash chromatography (EtOAc:n-hexano 1:20, 1% Et3N) gave L13 (437 mg, 95%) as a yellow foam. [α]20D –256.8 (c 0.62, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.81-7.77 (m, 2H), 7.577.23 (m, 15H), 7.11 (s, 1H), 5.25 (dd, 2H, J = 6.8, 1.2 Hz), 2.592.51 (m, 2H), 1.91-1.80 (m, 2H), 1.33 (s, 9H). 13C NMR (125 MHz, CDCl3): δ 156.6, 156.3, 151.5, 143.0, 137.1, 136.2, 132.5, 128.6, 128.5, 126.8, 126.6, 126.2, 125.5, 116.4, 65.2, 34.6, 31.4, 31.2. HRMS (CI) m/z calcd for C32H33N3 459.2674, found 459.2662. Pyridine-hydrazone (L14). Following the general procedure, flash chromatography (toluene:n-hexane 1:2, 1% Et3N) gave L14 (486 mg, 90%) as a yellow solid. M.P. = 122-124 °C. [α]20D – 229.2 (c 0.80, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.34 (s, 2H), 7.84 (s, 1H), 7.68-7.25 (m, 13H), 7.07 (s, 1H), 5.25 (d, 2H, J = 6.7 Hz), 2.61-2.55 (m, 2H), 1.94-1.84 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 157.1, 153.1, 142.8, 141.7, 136.8, 132.3 (q, JC-F = 34.0 Hz), 131.4, 128.7, 127.1, 127.0, 126.9, 126.3, 122.3 (q, JCF = 272.0 Hz), 122.1, 118.4, 117.9, 65.4, 31.6. HRMS (CI) m/z calcd for C30H24N3F6 540.1874 (M+ + 1), found 540.1882. Pyridine-hydrazone (L15). Following the general procedure, flash chromatography (EtOAc:n-hexane 1:8, 1% Et3N) gave L15 (334 mg, 75%) as a white solid. M.P. = 137-138 °C. [α]20D – 260.9 (c 0.90, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.52-7.23 (m, 15H), 7.07 (s, 1H), 6.82 (d, 1H, J = 8.1 Hz), 5.94 (s, 2H), 5.23 (d, 2H, J = 6.7 Hz), 2.58-2.53 (m, 2H), 1.87-1.85 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 156.2, 155.9, 148.0, 143.0, 136.3, 134.2, 132.2, 128.6, 128.5, 126.9, 126.2, 120.8, 117.3, 116.3, 108.3, 107.4, 101.1, 65.2, 31.4. HRMS (CI) m/z calcd for C29H25N3O2 447.1947, found 447.1949. General Procedure for the synthesis of palladium complexes C1-C4: Under an argon atmosphere, [Pd(CH3CN)2Cl2] (75 mg, 0.3 mmol) was added to solution of L (0.3 mmol) in dry CH2Cl2 (5 mL). The reaction mixture was stirred at room temperature for 2h, concentrated to dryness, washed with dry Et2O and dried in vacuo to give the palladium dichloride complex. Yields and characterization data for compounds C1-C4 are as follows: Palladium complex C1. Following the general procedure, C1 was obtained as a red solid (112 mg, 74%). X-ray quality crystals were grown by slow diffusion of AcOEt into a solution of C1 in CH2Cl2. M.P. = 160-162 °C (dec.). [α]20D= 235.4° (c 0.57, CHCl3). 1H NMR (500 MHz, C2D6CO): δ 8.89 (d, 1H, J = 5.4 Hz), 7.95 (t, 1H, J = 7.4 Hz), 7.73-7.18 (m, 10H), 6.91-6.74 (m 2H), 5.48-5.33 (m, 1H), 2.78-2.53 (m, 2H), 2.11-1.90 (m, 2H). 13C NMR (125 MHz, CDCl3): δ 156.9, 150.65, 147.8, 143.9, 141.3, 139.5, 130.0, 129.4, 129.0, 128.9, 128.4, 127.6, 125.1, 125.0, 69.1, 66.0, 35.0, 32.6. HRMS m/z calcd for C22H20N3Pd 432.0674. Found 432.0678. Palladium complex C2. Following the general procedure, C2 was obtained as an orange solid (151 mg, 94%). X-ray quality crystals were grown by slow diffusion of n-hexane into a solution of C2 in CH2Cl2. M.P. = 234-235 °C (dec.). [α]20D= 177.5° (c 0.60, CHCl3).!1H NMR (300 MHz, CDCl3): δ 8.42 (d, 1H, J = 6.8 Hz), 7.58-7.17 (m, 11H), 6.93-6.81 (m, 2H), 6.64 (d, 1H, J = 2.5 Hz), 6.53 (dd, 1H, J = 6.8, 2.5 Hz), 5.06-4.86 (m, 1H), 3.83 (s, 3H), 2.78-2.54 (m, 2H), 2.17-1.92 (m, 2H). 13C NMR (75 MHz, CDCl3): 167.8, 156.7, 151.2, 144.4, 142.3, 137.5, 129.6, 128.8, 128.5, 128.0, 127.8, 126.3, 110.0, 108.6, 68.4, 65.5, 56.5, 34.1, 31.2. HRMS m/z calcd for C23H23ON3ClPd 498.0557. Found 498.0559. Palladium complex C3. Following the general procedure, C3 was obtained as an orange solid (194 mg, 91%). X-ray quality crystals were grown by slow diffusion of n-hexane into a solution of C3 in CH2Cl2. M.P. = 143-145 °C. 1H NMR (300 MHz, CDCl3): δ 7.91 (bs, 1H), 7.85-7.74 (m, 3H), 7.64-7.35 (m, 11H), 7.58-7.17 (m, 11H), 7.29-6.92 (m, 1H), 7.11 (d, 1H, J = 7.9 Hz), 6.91 (s, 1H), 6.65-6.50 (m, 1H), 5.04-4.80 (m, 1H), 2.80-2.53 (m, 2H), 2.25-1.96 (m, 2H). 13C NMR (175 MHz, CDCl3): 160.0, 157.5, 142.4, 140.1, 139.9, 139.6, 137.1, 131.3 (q, JC-F = 34.4 Hz), 129.9, 129.0, 128.8, 128.3, 128.2, 126.1, 124.7, 123.1 (q, JCF = 272.3 Hz), 123.4, 123.3, 121.9, 69.6, 66.7, 35.1, 33.1. HRMS (CI) m/z calcd for C30H23N3F6Pd (M+ - 2Cl) 645.0831, found 645.0841. Palladium complex C4. Following the general procedure, C4 was obtained as an orange solid (167 mg, 92%). X-ray quality crystals were grown by slow diffusion of n-hexane into a solution of C4 in CH2Cl2. M.P. = 232-234 °C (dec.). [α]20D= 472.6° (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3): δ 8.92 (d, 1H, J = 5.5 Hz), 7.75 (t, 1H, J = 7.8 Hz), 7.65-7.54 (m, 4H), 7.44-7.32 (m, 5H), 7.30-7.15 (m, 4H), 7.06 (s, 1H), 6.53 (m, 1H), 2.62-2.27 (m, 2H), 2.16-1.95 (m, 2H), 1.95-1.74 (m, 2H). 13C NMR (75 MHz, CDCl3): 154.7, 152.8, 150.6, 140.2, 139.7, 129.1, 128.5, 127.8, 127.7, 124.7, 124.5, 63.9, 18.2. HRMS m/z calcd for C23H23N3Cl2NaPd 504.0196. Found 540.0180 [M++Na]. General procedure for the asymmetric Suzuki coupling: A Schlenk flask containing a magnetic stir bar was charged with Pd(OAc)2 (2.4 mg, 0.01 mmol), L1 (4 mg, 0.015 mmol), Cs2CO3 (130 mg, 0.4 mmol), boronic acid (0.3 mmol), and aryl bromide (0.2 mmol) under argon atmosphere. Mixture Toluene:H20 9:1 (1 Tetrahedron 8 mL) was added, and the reaction was stirred at 80 °C during the indicated time for each case. The reaction mixture was filtered through a short pad of Celite and the Celite pad was washed with DCM. The combined organic layers were concentrated and the resulting residue was purified by flash chromatography using hexane–EtOAc mixtures as eluents. (S)-2-methoxy-1,1'-binaphthyl (S)-5a (Table 3, entry 10). Following the general procedure after 15 hours. Flash chromatography (n-hexane→n-hexane:EtOAc 200:1) afforded 5a (55 mg, 97%) as a white solid. [α]20D +8.0 (c 1.0, CHCl3) for 88% ee. [Lit.21: [α]25D= –31.4 (c 2.1, THF) for the (R)-enantiomer (99 % ee)]. Spectroscopic and physical data matched those reported in the literature.9 HPLC (Chiracel OJ-H, 2-propanol/nhexane 20:80, flow 1.0 mL/min, T = 30 °C): tR 7.7 min (major) and 12.1 min (minor). (R)-2-methoxy-1,1'-binaphthyl (R)-5a (Table 3, entry 12). [α]20D –7.9 (c 1.0, CHCl3) for 82% ee. [Lit.21: [α]25D= –31.4 (c 2.1, THF) for the (R)-enantiomer (99 % ee)]. Spectroscopic and physical data matched those reported in the literature.9 HPLC (Chiracel OJ-H, 2-propanol/n-hexane 20:80, flow 1.0 mL/min, T = 30 °C): tR 7.7 min (minor) and 12.1 min (mayor). (S)-2,3-dimethoxy-1,1'-binaphthyl (5b) (Table 3, entry 13). Following the general procedure after 48 hours. Flash chromatography (n-hexane→n-hexane:EtOAc 200:1) afforded 5b (56 mg, 89%) as a white solid. [α]20D +7.3 (c 0.58, CHCl3) for 87% ee. [Lit.9: [α]25D= 7.3 (c 0.33, CHCl3) for the (S)-enantiomer (92% ee)]. Spectroscopic and physical data matched those reported in the literature.9 HPLC (Chiracel OJ-H, 2-propanol/nhexane 30:70, flow 1.0 mL/min, T = 30 °C): tR 6.1 min (major) and 9.2 min (minor). (S)-2-Methoxy-1-(2-methylphenyl)-naphthalene (5c) (Table 3, entry 14). Following the general procedure after 96 hours. Flash chromatography (n-hexane→n-hexane:EtOAc 200:1) afforded 5c (49 mg, 98%) as a white solid. [α]20D +24.7 (c 1.0, CHCl3) for 67 % ee. [Lit.22: [α]25D= +19.4 (c 1.0, DCM) for the (S)-enantiomer (46% ee)]. Spectroscopic and physical data matched those reported in the literature.23 HPLC (Chiracel OJ-H, 2-propanol/nhexane 10:90, flow 1.0 mL/min, T = 30 °C): tR 5.4 min (major) and 6.6 min (minor). Acknowledgments We acknowledge financial support by the Ministerio de Economía y Competitividad of Spain (CTQ2013-48164-C2-1-P, CTQ2013-48164-C2-2-P, CTQ2014-51912-REDC, contract RYC-2013-12585 for A.R. and predoctoral fellowship to Y. A.), European FEDER funds and the Junta de Andalucía (Grant 2012/FQM 1078). D. M. acknowledges Universidad de Sevilla for a postdoctoral contract. 5. References and notes 1. Recent reviews: a) Zhang, D.; Wang, Q. Coord. Chem. Rev., 2015, 286, 1–16. b) Wencel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Chem. Soc. Rev. 2015, 44, 3418–3430. c) Pauline, L.; Manoury, E.; Poli, R.; Deydier, E.; Labande, A. Coord. Chem. Rev. 2015, DOI:10.1016/j.ccr.2015.07.006 2. Yin, J.; Buchwald, S. L. J. 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