Supporting Information Metal-Free Synthesis of C-4 Substituted Pyridine Derivatives Using Pyridine-boryl Radicals via a Radical Addition/Coupling Mechanism: A Combined Computational and Experimental Study Guoqiang Wang, a Jia Cao, a,c Liuzhou Gao, a Wenxin Chen, b Wenhao Huang, b Xu Cheng b,d,* and Shuhua Li a,* a Key Laboratory of Mesoscopic Chemistry of Ministry of Education, Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China b Institute of Chemistry and Biomedical Sciences, Jiangsu Key Laboratory of Advanced Organic Material, School of Chemistry and Chemical Engineering, Nanjing University 210023, P. R. China c College of Chemistry and Chemical engineering, Yan an University, Yan an 716000, P. R. China d State Key Laboratory of Elemento-organic Chemistry, Nankai University, P. R. China Emails: shuhua@nju.edu.cn, chengxu@nju.edu.cn Table of Contents CONTENTS 1. Computational Investigations... S2 2. Experimental Studies on Substrare Scopes... S9 3. Experimental Studies on the Mechanism... S12 4. Spectroscopic Characterization of the 4-Substituted Pyridines... S18 5. NMR Spectra... S50 6. Cartesian Coordinates and Energies of the Optimized Structures... S103 7. References... S142 S1
1. Computational Investigations 1.2 Computational Details All calculations were performed with the Gaussian 09 package. [1] Geometries of all stationary points were fully optimized and characterized by vibrational frequency calculations at the M06-2X [2] /6-31G(d,p) level of theory. To get more accurate energies, we performed single-point energy calculations for all the species at the M06-2X/cc-pVTZ level. The calculated gas-phase Gibbs free energies refer to 298.15 K and 1 atm. A broken-symmetry guess was used for calculations on open-shell systems. For each transition state, the intrinsic reaction coordinate (IRC) [3] analysis was performed to verify whether the transition state truly connects the reactant and the product. The solvent effect was treated with the polarizable continuum model (PCM). [4] In calculating the free energies for species in the benzene solvent, we have used the method developed by Whitesides et al. [5] to calculate the entropic contributions. This method was designed to better describe the suppression of the translational entropy upon moving from gas phase to a solvent for each species. [6] Activation free energy barriers here are defined as the free energy difference between the transition state and the lowest-energy stationary point before it in the reaction pathways. 1.2 Spin Density Calculations on the Pyridine-Boryl Radical The calculated spin density distribution on 1 is shown in Figure S1. One can see that the spin density is mainly localized at C4 (0.448), C2 (0.218), and N1 (0.139), and only a small spin density on B (0.048). This distribution of spin density is mainly S2
due to the resonance stabilization effect of the pyridinyl group. Carbon radical character is dominant in 1, which indicates that radical 1 may act as a carbon radical for the development of other new reactions, in particular reactions that lead to the synthesis of pyridine derivatives via the radical carbon-carbon coupling reactions. Figure S1. DFT-optimized structure and the calculated spin density in the pyridine-boryl radical 1. 1.3 Theoretical Investigations on Possible Substrates for Radical C-C Coupling Reactions Before verifying our hypothesis, we performed calculations to investigate the possibility for the addition of the boryl radical from radical 1 to other substrates for subsequent radical coupling reactions. As shown in Scheme S1, the addition of the boryl radical from radical 1 to 2-cyclohexenone, benzaldehyde and N-phenyl-1-(p-tolyl) methanimine were only endothermic by 2.2, 0.5 and 3.4 kcal/mol, respectively. These results indicate that the generation of new radicals with above mentioned substrates is feasible. In the following studies, the reaction between radical 1 and 2-cyclohexenone was selected as the model reaction to investigate the reactivity of the pyridine-boryl radical 1 in radical C-C coupling reactions. S3
Scheme S1. Thermodynamical calculations for the reactions between 1 and some potential substrates (kcal/mol, in gas phase). 1.4 Theoretical Investigations on Dimerization of the Pyridine-boryl Radical The homo-coupling reaction of the radical 1 may generate three possible C-C coupling intermediates (IntC4-C4, IntC4-C4, and IntC2-C4), as listed in Scheme S2 and Figure S2. Although the formation of these three dimers are exothermic by 2.9, 4.6, and 3.7 kcal/ml, respectively, the corresponding barrier of these processes are about only 10-14 kcal/mol, suggesting that the homo-coupling reactions of radical 1 are all reversible. Thus, the radical 1 may be considered as a persistent radical for subsequent radical cross-coupling reactions. The existence of the dimeric species of 1 was further verified by 1 H NMR and HRMS analysis (see experimental section, Figure S8). S4
Scheme S2. Possible pathways for the dimerization of pyridine-boryl radical (1). Figure S2. Computed Gibbs free energy (in kcal/mol) profile for the homo-coupling reaction of the pyridine-boryl radical 1 in the solvent (benzene). 1.5 Comparison between Radical C-C and C-B Coupling Reactions As shown in Figures S3 and S4, in addition to the radical C-C coupling pathway (Figure S3a), the radical coupling reaction between 1 and Int2 can also generate a C-B coupling intermediate (Int6) via TS5, with a barrier of 13.7 kcal/mol (Figure S3b), which is 2.2 kcal/mol higher than that of the C-C coupling transition state (TS3). The generation of Int6 is only exothermic by 17.0 kcal/mol (with respect to the radical 1 and reactant 2b). Hence, the formation of the C-B coupling product is less favorable both thermodynamically and kinetically. These results are consistent with the observed fact that only the C-C coupling products were detected in the following experimental sections. S5
Figure S3. Computed Gibbs free energy (in kcal/mol) profile for the reaction of the pyridine-boryl radical (1) and 2-cyclohexenone (2b) in the solvent (benzene) along C-C radical coupling pathway (a) and the C-B radical coupling pathway (b). Figure S4. The optimized transition state and the product involved in the C-B coupling reaction. Distances are in Å 1.6 Homo-coupling of Enone-B radical S6
Figure S5. Computed Gibbs free energy (in kcal/mol) profile for the homocoupling of enone-boryl radical (Int1) in the solvent (benzene). As shown in Figure S5, the homo-coupling of enone-boryl radical is exothermic by 37.7 kcal/mol (with respect to separated 1 and 2b). However, no homo-coupling product of Int2 was detected, which may be attributed by the persistent radical effect. [7] As shown in Eq. (a), the generation of the new radical Int2 is endothermic by 1.8 kcal/mol, which suggests that the concentration of the radical 1 is much higher that of Int2. Thus, the formation of cross-coupling product of 1 and Int2 is dominant in our system. 1.7 1, 2- and 1, 4-Addition of Pyridine-boryl Radical to the 2-Cyclohexenone S7
Figure S6. Computed Gibbs free energy (in kcal/mol) profile for the direct addition reaction of the pyridine-boryl radical (1) to 2-cyclohexenone (2b) in the solvent (benzene) along 1, 4-addition pathway (a) and the 1, 2-addition pathway (b). The direct 1, 2- or 1, 4-addition of pyridine-boryl radical (1) to enone 2b could also generate the same C4-substituted pyridines. As shown in Figure S6, the relative free energy of Int8 and Int9 is 22.6 and 50.0 kcal/mol higher than that of separated 1 and 2b, respectively, suggesting that the 1,4- or 1,2-addition of 1 to 2-cyclohexenone (2b) is unlikely to occur. S8
2. Experimental Studies on Substrate Scopes 2.1 General Information All reactions were carried out under nitrogen atmosphere. Anhydrous CH3CN, CH2Cl2, toluene, THF and methyl tert-butyl ether (MTBE) were purchased from Acros and used as received. Other solvents were dried by distillation over the appropriate drying reagents. All NMR spectra were recorded on a Bruker AVANCE Ⅲ 400 spectrometer at room temperature with CDCl3 as the solvent and TMS as the internal standard. Chemical shifts (δ) were reported in ppm with respect to the residue solvent peak. Coupling constant (J) were reported in Hert (Hz), abbreviations for signal couplings are indicated as follows: s, singlet; d, doublet; t, triplet; m, multiplet. Infrared spectra were recorded on a ThermoFisher Nicolet is5 FTIR using neat thin film technique. High-resolution mass spectra (HRMS) were recorded on Thermo Quest Finnigan LCQDECA system equipped with an ESI ionization source. Enones 2l, [8] 2m and 2o, [9] 2n, [10] 2h, [11] 2j, [12] 2A, [13] 2p, [14] 2r, [15] 2t and 2u, [16] 3-(methylthio)isonicotinonitrile, [17] and 6, [18] were synthesized according to the reported procedure. All other commercially available reagents were used without further purification. 2.2 Optimization Studies Using aryl Aldehydes as the Coupling Partner Table S1 Optimization studies. a S9
Entry t (h) T ( C) Benzaldehyde (equiv.) B 2(pin) 2 (equiv.) Yield b 1 24 70 2.0 2.4 54% 2 24 70 2.0 1.2 35% 3 18 70 2.0 2.4 52% 4 12 70 2.0 2.4 53% 5 6 70 4.0 2.4 51% 6 6 90 4.0 2.4 66% 7 6 40 4.0 2.4 43% 8 12 70 4.0 12 62% 9 12 90 4.0 2.4 70% (54%) c a Reaction conditions: 4-cyanopyridine (0.2 mmol), B 2(pin) 2 (0.24-0.48 mmol), MTBE (1.0 ml), benzaldehyde (0.4-0.8 mmol). b Yields were determined by 1 H NMR analysis of the crude reaction mixture with CH 3NO 2 as an internal standard. c Isolated yield. 2.3 General Procedures for the Synthesis of 4-Substituted Pyridines A: Using enones, arylimines, alkyn-ketone, aliphatic aldehyde or ketone as the coupling partner S10
A sealed reaction tube charged with a magnetic stir bar, B2(pin)2 (0.24 mmol, 1.2 equiv), 4-cyanopyridine (0.3 mmol, 1.5 equiv), MTBE (1 ml) and the corresponding coupling partner (2, 11, 13, 15, 17) was placed in a heated oil bath (25-70 C). After 24-48 hours the reaction was cooled and quenched with 2M Na2CO3 aqueous solution (3 ml). The reaction tube was stirred under air for another 15 minutes. 10 ml of brine was added to the reaction mixture and the aqueous layer was extracted with EtOAc (3 10mL). The combined organic layer was dried over Na2SO4 and then concentrated in vacuo to afford the crude product. This crude material was purified by preparative TLC or chromatography on silca gel to afford the desired 4-substituted pyridines. B: Using Aryl Aldehydes and Ketone as the Coupling Partner A sealed reaction tube charged with a magnetic stir bar, B2(pin)2 (0.48 mmol, 2.4 equiv), 4-cyanopyridine (0.2 mmol, 1.0 equiv), MTBE (1 ml) and the corresponding aryl aldehydes or ketone (9) was placed in a heated oil bath (90 C). After 24 hours the reaction was cooled and the reaction was quenched by 2M Na2CO3 aqueous solution (3 ml). The mixture was stirred under air for another 15 minutes. 10 ml of brine was added to the reaction mixture and the product was extracted with EtOAc (3 10mL). The organic layer was collected, dried over Na2SO4, and then concentrated in vacuo to afford the crude product. This crude material was purified by preparative TLC to afford the desired 4-substituted pyridines. The yields were referred to 4-cyanopyridine. S11
2.4 Effect of Substituents on the Pyridine Ring The effect of substituents on the pyridine ring was investigated, as shown in Scheme S3a. 4-cyanopyridines bearing substituents such as F, Cl, and methyl, at C-3 position could afford the corresponding 1, 4-addition products (3v, 3w, and 3x) in moderate yield. However, for the 4-cyanopyridines bearing a substituent at C-2 position, no product was detected, suggesting that the 2-substitued-4-cyanopyridine failed to activate the B-B bond of B2(pin)2 to generate the corresponding boryl radical, which is mainly due to the steric effect of the substituents at C-2 position (Scheme S3b). Scheme S3. Reactions of 2-cyclohepten-1-one (2c) with the substituted 4-cycano pyridines. 3. Experimental Studies on the Mechanism 3.1 Detecting the Boron-enolate Intermediate by HRMS Analysis In order to verify the involvement of the boron-enolate intermedate under the proposed radical addition/coupling addition conditions, HRMS analysis was S12
performed to detect the possible intermediate. Experimental procedure: A sealed reaction tube was charged with a magnetic stir bar, B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv), MTBE (1 ml) and cyclohept-2-en-1-one (2c) (24.7 μl, 0.2 mmol, 1.0 equiv.). The mixture was stirred at 25 C for 12h, after which, the ESI-MS analysis of the crude reaction mixture was carried out immediately. The mass for an aromatized boron-enolate intermediate (Int3 ) is C18H26BNNaO3 + [M+Na] + calc. 338.1898, found 338.1902 (Figure S7). However, the direct detection of Int3-like structure was not successful, possibly due to its rapid aromatization. Figure S7. Mass spectrum of the crude reaction mixture of 4-cycanopyridine, B2(pin)2 and cyclohept-2-en-1-one. 3.2 Trapping the boron-enolate with Cyano Group S13
Experimental procedure: The trapping of B-enolate intermediate with a cyano group was carried out following general procedure A using the cyclohept-2-en-1-one (2c) (24.7 μl, 0.2 mmol, 1.0 equiv.), 3, 4-dicyanopyridine (39.5 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 1:2) to afford compound 5 with fused ring scaffold (8 mg, 19% yield), indicating that an intramolecular trapping of the boron-enolate via a nucleophilic addition reaction occurred. The computed relative free energy of imine-isomer 5 or 5 is higher about 14 kcal/mol than that of enamine-isomer 5, suggesting that the generation of 5 is favorable (See Scheme S4). The 13 C NMR spectrum in a CDCl3 solution displays only five peaks at upfield (and with eight peaks at downfield), indicating that 5 is the predominant species. Scheme S4. The calculated relative free energy change for imine-enamine tautomerism of 5 (with respect to 5 ) 5: Yellowish-brown solid, decomposed at >200 o C. 1 H NMR (400 MHz, CDCl3) S14
δ 8.85 (s, 1H), 8.65 (d, J = 5.1 Hz, 1H), 7.41 (d, J = 5.1 Hz, 1H), 3.62 (dd, J = 12.1, 2.4 Hz, 1H), 2.71-2.64 (m, 1H), 2.56 (dd, J = 13.9, 7.2 Hz, 1H), 2.45 (dd, J = 13.4, 3.3 Hz, 1H), 2.20 (d, J = 13.8 Hz, 1H), 2.03-1.96 (m, 1H), 1.82-1.71 (m, 1H), 1.46 (q, J = 12.8 Hz, 1H), 1.08 (qd, J = 13.0, 3.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 200.4 158.1, 155.4, 150.0, 142.3, 133.5, 119.8, 113.9, 47.6, 45.5, 34.4, 31.8, 24.6; IR (film): 3363, 3294, 1752, 1630, 1498, 1426, 953, 842 cm 1 ; HRMS (ESI-TOF) calculated for C13H15N2O [M+H] + 215.1179, found 215.1179. 3.3 Intermediacy of Radical in Carbon-Carbon Coupling The involvement of a radical intermediate was probed with the rigid cycloprop[a]inden-6(1h)-one 6 as radical clock. In the presence of 3-chloro-4-cycano pyridine and B2(pin)2 at 70 o C, the product 7 is generated from the opening of fused cyclopropyl group in 13% yield. This result also supported the involvement of radical intermediate in the proposed pathways. Experimental procedure: Following general procedure A, a mixture of 6 (28.9 mg, 0.2 mmol, 1.0 equiv.), 3-chloro-4-cyano pyridine (42.4 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) was stirred at 70 C. After 24 hours, with the described workup procedure, the reaction mixture was S15
purified by preparative TLC on silica gel (PE/EtOAc = 5:1) to afford compound 7 (6.7 mg, 13% yield) (and the 1, 2-addition product 8 was also obtained in 15% yield). 7: off-white solid, 100-102.3 C. 1 H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.36 (d, J = 5.0 Hz, 1H), 8.16 (dd, J = 7.7, 1.2 Hz, 1H), 7.50 (td, J = 7.5, 1.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 5.0 Hz, 1H), 4.81 (t, J = 6.4 Hz, 1H), 2.68-2.64 (m, 2H), 2.52-2.47 (m, 1H), 2.40-2.31 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 197.4, 150.3, 149.9, 148.3, 143.6, 134.4, 133.5, 132.4, 129.4, 128.2, 127.9, 124.8, 41.6, 36.3, 28.9; IR (film): 2923, 1686, 1598, 1398, 1033, 913, 840 cm 1 ; HRMS (ESI-TOF) calculated for C15H13ClNO [M+H] + 258.0680, found 258.0678. 8: off-white solid, mp 135.6-137.2 C. 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.42 (s, 1H), 7.40 (d, J = 4.4 Hz, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.27 (td, J = 7.4, 1.3 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 3.11 (brs, 1H), 2.66 (ddd, J = 7.7, 5.9, 3.7 Hz, 1H), 2.26 (ddd, J = 8.2, 5.9, 4.1 Hz, 1H), 1.25 (td, J = 7.9, 4.9 Hz, 1H), 0.93 (q, J = 4.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 151.8, 151.2, 148.2, 147.4, 143.3, 129.1, 127.2, 125.9, 124.3, 122.8, 84.8, 27.7, 25.6, 19.9; (one carbon was not observed due to the incidental equivalence) IR (film): 3220, 3070, 3042, 1585, 1399, 1044, 912, 840 cm 1 ; HRMS (ESI-TOF) calculated for C15H13ClNO [M+H] + 258.0680, found 258.0677. 3.4 Spectroscopic Study of the Dimerization of Pyridine-boryl Radical As shown in Scheme S5, three possible dimeric isomers may be generated via the dimerization of pyridine-boryl radical. Since these species are highly moisture and air sensitive, 1 H NMR and HRMS analysis were carried out to detect the presence of S16
these intermediates. Scheme S5. DFT-optimized three possible isomers of the homo-coupling of pyridine-boryl radical. Experimental procedure: Bis(pinacolato)diboron (30.5 mg, 0.12 mmol) and 4-cycanopyridine (15.7 mg, 0.15 mmol) were mixed in 0.5 ml THF-d8 in a NMR tube. The NMR tube was sealed with a cap before removal from the glove box. The mixture was allowed to heat for 12 h at 40 C, 1 H NMR analysis was carried out to determine the generation of the dimerization product. As shown in Figure S8, the peaks in the 1 H NMR spectrum of the 4-cyanopyridine/B2(pin)2 reaction mixture are significantly different from those of 4-cyanopyridine. The signals at 4.3-6.7 ppm may be attributed to the 1,2 or (and) 1,4-dihydropyridine moiety, which are similar to the previously reported peaks of the 1,2 or 1,4-dearomatized pyridine. [19, 20] In addition, the mass for dimeric isomers IntC4-C4 (or IntC2-C2, IntC2-C4) is C24H33B2N4O4 + [M+Na] + calc. 463.2682, found 463.2674. These results suggested that the dimeric species of pyridine-boryl radical was formed in the mixture of 4-cyanopyridine and B2(pin)2. The direct observation of dimeric isomers is consistent with our DFT calculations. S17
Figure S8. Up: 1 H NMR spectrum of 4-cyanopyridine in THF-d8; Down: 1 H NMR spectrum of the reaction mixture of 4-cyanopyridine and B2(pin)2 in THF-d8. 4. Spectroscopic Characterization of the Corresponding 4-substituted Pyridines 4.1: Using enones as the coupling partner 3a and 4a: Prepared following general procedure A using 2a (20.2 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the two pyridines (15 mg, 43% combined yield, 3a/4a = 1.8:1). And the resulting mixture was further isolated with preparative TLC on silica gel (PE/isopropanol = 6:1) to afford 3a and 4a separately. 3a: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.5 Hz, 2H), 7.21 (dd, J = 4.7, 1.5 Hz, 2H), 2.65-2.47 (m, 2H), 2.46-2.23 (m, 2H), 2.30-2.23 (m, 2H), 1.39 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 217.2, 157.7, 150.3, 121.2, 51.6, 43.9, S18
36.8, 35.5, 28.9; IR (film): 2961, 1743, 1597, 1409, 994, 823 cm 1 ; HRMS (ESI-TOF) calculated for C11H14NO [M+H] + 176.1070, found 176.1070. 4a: Gum; 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 5.7 Hz, 2H), 7.37 (d, J = 5.7 Hz, 2H), 5.42 (s, 1H), 2.95 (brs, 1H), 2.62-2.54 (m, 1H), 2.44-2.33 (m, 1H), 2.27-2.23 (m, 2H), 1.86 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 157.6, 149.5, 147.3, 130.3, 120.8, 86.7, 43.2, 36.0, 17.1; IR (film): 3218, 2966, 2937, 1600, 1411, 1240, 1065, 1003, 825 cm 1 ; HRMS (ESI-TOF) calculated for C11H14NO [M+H] + 176.1070, found 176.1070. 3b and 4b: Prepared following general procedure A using 2b (20 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 1:1) to afford the two pyridines (24.5 mg, 70% combined yield, 3b/4b=3.7:1). And the resulting mixture was further isolated by preparative TLC on silica gel (PE/isopropanol = 6:1) to afford 3b and 4b separately. 3b: Gum; 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 2H), 7.15 (d, J = 4.4 Hz, 2H), 3.03-2.97 (m, 1H), 2.58-2.31 (m, 4H), 2.15-2.06 (m, 2H), 1.88-1.72 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 209.9, 153.6, 150.2, 122.4, 47.9, 44.0, 41.3, 32.1, 25.5; IR (film): 2939, 2866, 1714, 1600, 1416, 993, 822 cm 1 ; HRMS (ESI-TOF) calculated for C11H14NO [M+H] + 176.1070, found 176.1071. 4b: White solid, mp 108-109 C; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 2.5 S19
Hz, 2H), 7.41 (d, J = 3.6 Hz, 2H), 6.26-5.99 (m, 1H), 5.72 (d, J = 10.0 Hz, 1H), 2.63 (brs, 1H), 2.21-2.08 (m, 2H), 2.00-1.93 (m, 1H), 1.86-1.74 (m, 2H), 1.68-1.65 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 157.5, 149.6, 132.4, 130.9, 121.1, 71.7, 39.4, 25.2, 19.1; IR (film): 3199, 3022, 2934, 1601, 1064, 1411, 982, 820 cm 1 ; HRMS (ESI-TOF) calculated for C11H14NO [M+H] + 176.1070, found 176.1070. 3c: Prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the pyridine 3c as the sole product (23.3 mg, 62% yield). 3c: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 5.9 Hz, 2H), 7.10 (d, J = 6.0 Hz, 2H), 2.93-2.84 (m, 2H), 2.63-2.55 (m, 3H), 2.09-1.97 (m, 3H), 1.75-1.66 (m, 2H), 1.54-1.47 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 212.5, 155.8, 150.3, 122.2, 50.3, 44.2, 42.3, 38.6, 29.3, 24.3; IR (film): 2928, 2856, 1698, 1596, 1414, 993, 817 cm 1 ; HRMS (ESI-TOF) calculated for C12H16NO [M+H] + 190.1226, found 190.1227. 3d and 4d: Prepared following general procedure A using 2d (17.8 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 S20
mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 1:1) to afford the two pyridines (12.9 mg, 40% combined yield, 3d/4d=1.2:1). And the resulting mixture was further purified by preparative TLC on silica gel (PE/isopropanol = 6:1) to afford 3d and 4d separately. 3d: Gum; 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 6.0 Hz, 2H), 7.18 (d, J = 6.1 Hz, 2H), 3.46-3.37 (m, 1H), 2.72-2.65 (m, 1H), 2.51-2.44 (m, 2H), 2.37-2.28 (m, 2H), 2.01-1.95 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 216.9, 152.6, 150.2, 122.5, 45.0, 41.8, 38.8, 30.7; IR (film): 2994, 1742, 1415, 993, 820 cm 1 ; HRMS (ESI-TOF) calculated for C10H12NO [M+H] + 162.0913, found 162.0914. 4d: White solid, mp 115-116 C; 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 6.1 Hz, 2H), 7.35 (d, J = 6.2 Hz, 2H), 6.16 (dt, J = 5.2, 2.4 Hz, 1H), 5.80 (m, J = 5.2, 2.4 Hz, 1H), 2.95 (brs, 1H), 2.75-2.60 (m, 1H), 2.55-2.42 (m, 1H), 2.26-2.21 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 156.5, 149.8, 136.2, 136.1, 120.5, 86.4, 42.4, 31.9; IR (film): 3218, 2965, 2935, 1600, 1411, 1240, 1003, 824 cm 1 ; HRMS (ESI-TOF) calculated for C10H12NO [M+H] + 162.0913, found 162.0915. 3e and 4e: Prepared following general procedure A using 2e (23.2 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 1:1) to afford the two pyridines (32.5 mg, 86% combined yield, 3e/4e=1.9:1). And the resulting mixture were further purified by preparative TLC on silica gel S21
(PE/isopropanol = 6:1) to afford 3e and 4e separately. 3e: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.9 Hz, 2H), 7.19 (d, J = 5.4 Hz, 2H), 2.75 (d, J = 12.0 Hz,1H), 2.37 (d, J = 12.0 Hz, 1H), 2.27-2.21 (m, 2H), 2.12-2.04 (m, 1H), 1.90-1.81 (m, 2H), 1.62-1.50 (m, 1H), 1.24 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 210.5, 157.5, 150.1, 121.6, 52.4, 43.2, 40.9, 37.5, 29.4, 22.2; IR (film): 2958, 2871, 1711, 1616, 1410, 995, 820 cm 1 ; HRMS (ESI-TOF) calculated for C12H16NO [M+H] + 190.1226, found 190.1227. 4e: Gum; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 4.4 Hz, 2H), 7.43 (d, J = 5.8 Hz, 2H), 5.44 (s, 1H), 2.77 (brs, 1H), 2.07-2.03 (m, 2H), 1.92-1.78 (m, 5H), 1.71-1.65 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 159.1, 149.3, 140.8, 125.5, 121.5, 72.4, 39.1, 30.2, 24.2, 19.5; IR (film): 3201, 2934, 2866, 1616, 1424, 1080, 977, 824 cm 1 ; HRMS (ESI-TOF) calculated for C12H16NO [M+H] + 190.1226, found 190.1226. 3f and 4f: Prepared following general procedure A using 2f (30.5 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the two pyridines (35.7 mg, 82% combined yield, 3f/4f=2.2:1). And the resulting mixture was further purified by preparative TLC on silica gel (PE/isopropanol = 6:1) to afford 3f and 4f separately. 3f: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 4.9, 1.4 Hz, 2H), 7.30 (dd, J = 4.7, 1.6 Hz, 2H), 2.99 (d, J = 14.0 Hz 1H), 2.40 (dd, J = 14.0, 1.0 Hz, S22
1H), 2.24 (d, J = 13.2 Hz, 2H), 2.08 (d, J = 13.4 Hz, 1H), 1.94 (d, J = 14.3 Hz, 1H), 1.33 (s, 3H), 1.03 (s, 3H), 0.36 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 210.7, 157.9, 149.9, 121.8, 54.6, 51.2, 50.7, 42.9, 36.6, 34.8, 33.2, 28.7; IR (film): 2958, 2926, 1715, 1595, 1412, 995, 823 cm 1 ; HRMS (ESI-TOF) calculated for C14H20NO [M+H] + 218.1539, found 218.1539. 4f: Gum; 1 H NMR (400 MHz, CDCl3) δ 8.50 (dd, J = 4.6, 1.6 Hz, 2H), 7.35 (dd, J = 4.6, 1.6 Hz, 2H), 5.43 (s, 1H), 2.53 (brs, 1H), 1.95 (d, J = 17.4 Hz, 1H), 1.84-1.80 (m, 5H), 1.60 (d, J = 14.3 Hz, 1H), 1.14 (s, 3H), 0.93 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 159.2, 149.6, 138.6, 124.3, 120.9, 73.5, 51.5, 44.6, 31.9, 30.8, 27.5, 24.5; IR (film): 3219, 2950, 2865, 1599, 1411, 1240, 1054, 1002, 831 cm 1 ; HRMS (ESI-TOF) calculated for C14H20NO [M+H] + 218.1539, found 218.1540. 3g and 4g: Prepared following general procedure A using 2g (27.1 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the two pyridines (33.6 mg, 83% combined yield, 3g/4g=1:2.6). And the resulting mixture was further purified by preparative TLC on silica gel (PE/isopropanol = 4:1) to afford 3g and 4g separately. 3g: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.1 Hz, 2H), 7.08 (d, J = 5.5 Hz, 2H), 2.89-2.80 (m, 2H), 2.62-2.53 (m, 1H), 2.43-2.35 (m, 2H), 1.88-1.73 S23
(m, 2H), 1.03 (s, 3H), 0.91 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 210.5, 150.6, 149.6, 124.5, 52.8, 42.9, 40.7, 38.5, 34.0, 29.5, 20.0; IR (film): 2960, 2870, 1716, 1595, 1416, 1240, 994, 831 cm 1 ; HRMS (ESI-TOF) calculated for C13H18NO [M+H] + 204.1383, found 204.1383. 4g: White solid, mp 89-90 C; 1 H NMR (400 MHz, CDCl3) δ 8.49 (dd, J = 4.6, 1.6 Hz, 2H), 7.38 (dd, J = 4.6, 1.6 Hz, 2H), 5.77 (d, J = 10.0 Hz, 1H), 5.54 (d, J = 10.0, 1H), 2.75 (brs, 1H), 1.96-1.80 (m, 2H), 1.72-1.65 (m, 1H), 1.40-1.36 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H); 13 C NMR (101 MHz, CDCl3) δ 157.5, 149.6, 142.2, 128.4, 121.2, 71.8, 36.7, 33.5, 32.1, 29.9, 28.2; IR (film): 3206, 2954, 2864, 1600, 1411, 1244, 1050, 1001, 823 cm 1 ; HRMS (ESI-TOF) calculated for C13H18NO [M+H] + 204.1383, found 204.1384. 3h: Prepared following general procedure A using 2h (34.4 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 25 C. After 48 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 1:1) to afford the pyridine 3h as the sole product with trans configuration (26.6 mg, 53% yield). 3h: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 4.1 Hz, 2H), 7.21-7.07 (m, 3H), 6.99 (d, J = 6.0 Hz, 2H), 6.90 (dd, J = 5.2, 3.2 Hz, 2H), 3.78 (d, J = 12.3 Hz, 1H), 3.29-3.18 (m, 1H), 2.73-2.57 (m, 2H), 2.30-2.24 (m, 1H), 2.14-1.93 S24
(m, 3H); 13 C NMR (100 MHz, CDCl3) δ 208.4, 152.7, 149.9, 136.0, 129.6, 128.5, 127.4, 123.2, 62.8, 51.9, 42.1, 34.0, 26.4; IR (film): 2932, 1758, 1596, 1417, 993, 823 cm 1 ; MS (ESI) exact mass calculated for C17H18NO [M+H] + 252.1383, found 252.1382. The relative stereochemistry between α- and β-position of 3h was assigned as a trans-configuration based on 2D NOESY spectra. 3i and 4i: Prepared following general procedure A using 2i (26.5 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the two pyridines (21.9 mg, 54% combined yield, 3i/4i=1.6:1). And the resulting mixture was further purified by preparative TLC (PE/isopropanol = 6:1) to afford 3i (with trans configuration as predominant species, d.r.>10:1) and 4i separately. 3i: White solid, mp 51-53 C; 1 H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.8 Hz, 2H), 7.17 (d, J = 5.1 Hz, 2H), 3.10 (dd, J = 8.7, 4.3 Hz, 1H), 2.86-2.81 (m, 1H), 2.43-2.14 (m, 1H), 2.07-2.01 (m, 1H), 1.88-1.72 (m, 6H), 1.60-1.49 (m, 2H), 1.42-1.36 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 210.6, 154.1, 149.7, 123.6, 52.3, 44.1, 30.9, 28.4, 26.4, 25.6, 21.9; IR (film): 2930, 2857, 1707, 1597, 1416, 993, 816 S25
cm 1 ; HRMS (ESI-TOF) calculated for C13H18NO [M+H] + 204.1383, found 204.1383. The relative stereochemistry between α- and β-position of 3i was assigned as a trans-configuration based on 2D NOESY spectra. 4i: White solid, mp 119-121 C; 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 6.3 Hz, 2H), 7.36 (d, J = 6.2 Hz, 2H), 5.93-5.88 (m, 1H), 2.84 (brs, 1H), 2.14-2.09 (m, 2H), 2.02-1.95 (m, 1H), 1.66-1.52 (m, 8H); 13 C NMR (100 MHz, CDCl3) δ 156.9, 149.6, 141.7, 123.2, 121.1, 76.6, 28.9, 25.5, 24.6, 23.1, 22.4; IR (film): 3207, 2928, 2855, 1600, 1411, 1024, 1064, 1002, 828 cm 1 ; HRMS (ESI-TOF) calculated for C13H18NO [M+H] + 204.1383, found 204.1383. 3j: Prepared following general procedure A using 2j (32.3 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the pyridine 3j with trans configuration as predominant species (28.4 mg, 62% yield, trans/cis = 10:1). 3j: White solid, mp 75-76 C; 1 H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.7 Hz, 2H), 7.18 (d, J = 5.4 Hz, 1.84H, trans), 7.10 (d, J = 5.1 S26
Hz, 0.17H, cis), 3.30-3.27 (m, 1H), 2.87-2.82 (m, 1H), 2.40-2.30 (m, 1H), 2.20-2.14 (m, 1H), 1.88-1.55 (m, 5H), 1.50-1.31 (m, 2H), 0.83-0.48 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 211.9, 154.7, 149.8, 149.4, 123.7, 123.3, 57.0, 52.7, 45.5, 44.2, 33.9, 29.9, 28.7, 26.4, 26.2, 25.8, 25.8, 25.1, 21.9, 21.1, 20.8, 11.1, 11.1, 10.6; IR (film): 2929, 2857, 1693, 1596, 1413, 994, 815 cm 1 ; HRMS (ESI-TOF) calculated for C15H20NO [M+H] + 230.1539, found 230.1540. The relative stereochemistry between α- and β-position of 3j was assigned as a trans-configuration based on 2D NOESY spectra. 3k: Prepared following general procedure A using 2k (39.2 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (n-pentane/etoac = 1:1) to afford the pyridine 3k as the sole product (31 mg, 59% yield). 3k: White solid, mp 130.6-132.1 C; 1 H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 5.8 Hz, 2H), 7.42 (d, J = 6.4 Hz, 2H), 6.14 (d, J = 16.1 Hz, 1H), 5.70 (d, J = 16.8 Hz, 1H), 3.19 (brs, 1H), 1.95 (t, J = 6.1 Hz, 2H), 1.68 (s, 3H), 1.65-1.55 (m, 5H), 1.47-1.39 (m, 2H), 0.96 (s, 3H), 0.95 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 156.9, S27
149.7, 139.7, 136.7, 129.4, 127.4, 120.8, 74.4, 39.6, 34.4, 32.9, 29.9, 29.1 (two C have the same chemical shift at 29.1 ppm), 21.6, 19.5; IR (film): 3181, 2924, 1600, 1412, 1063, 826 cm 1 ; HRMS (ESI-TOF) calculated for C18H26NO [M+H] + 272.2009, found 272.2009. 3l and 4l: Prepared following general procedure A using 2l (22 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford the two pyridines (23 mg, 60% combined yield, 3l/4l = 2.3:1). And the resulting mixture was further purified by preparative TLC on silica gel (PE/isopropanol = 7:1) to afford 3l and 4l separately. 3l: Cloorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 5.2 Hz, 2H), 7.20 (d, J = 6.0 Hz, 2H), 2.97-2.86 (m, 2H), 2.46-2.38 (m, 1H), 2.09 (s, 3H), 1.02-0.93 (m, 1H), 0.60 (tt, J = 8.9, 5.1 Hz, 1H), 0.45 (tt, J = 9.1, 5.1 Hz, 1H), 0.27 (dq, J = 9.8, 4.9 Hz, 1H), 0.14 (dt, J = 9.5, 4.8 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 206.9, 154.8, 149.8, 123.4, 49.8, 45.4, 31.1, 17.1, 5.7, 4.7; IR (film): 3000, 2922, 1714, 1599, 1415, 993, 817 cm 1 ; HRMS (ESI-TOF) calculated for C12H16NO [M+H] + 190.1226, found 190.1226. 4l: White solid, mp 96.1-98.4 C; 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 6.1 Hz, 2H), 7.42 (d, J = 6.2 Hz, 2H), 5.80 (d, J = 15.5 Hz, 2H), 5.19 (dd, J = 15.5, 9.0 Hz, 1H), 2.71 (brs, 1H), 1.60 (s, 3H), 1.44-1.36 (m, 1H), 0.77-0.71 (m, 2H), 0.41-0.34 (m, S28
2H); 13 C NMR (100 MHz, CDCl3) δ 157.6, 149.6, 134.9, 133.3, 121.1, 73.9, 30.0, 13.90, 7.2 (two C atoms have the same chemical shift at 7.2 ppm); IR (film): 3194, 3003, 2978, 1455, 1416, 1063, 965, 913, 872 cm 1 ; HRMS (ESI-TOF) calculated for C12H16NO [M+H] + 190.1226, found 190.1224. 3m: Prepared following general procedure A using 2m (35.1 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford 3m (26.1 mg, 52% yield). 3m: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 2H), 7.92 (d, J = 7.1 Hz, 2H), 7.56 (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.28 (d, J = 6.1 Hz, 2H), 3.53-3.42 (m, 2H), 2.66-2.60 (m, 1H), 1.12-1.03 (m, 1H), 0.64-0.57 (m, 1H), 0.52-0.45 (m, 1H), 0.30 (dq, J = 9.8, 4.9 Hz, 1H), 0.19 (dq, J = 9.9, 5.0 Hz, 1H); 13 C NMR (100 MHz, CDCl3) δ 198.3, 155.3, 149.7, 137.1, 133.6, 128.9, 128.3, 123.6, 45.8, 44.8, 17.2, 5.8, 4.9; IR (film): 2919, 2850, 1685, 1597, 1448, 1415, 993, 872 cm 1 ; HRMS (ESI-TOF) calculated for C17H18NO [M+H] + 252.1383, found 252.1387. 3n: Prepared following general procedure A using 2n (50.5mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 S29
mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the pyridine 3n as the sole product (29.2 mg, 44% yield). 3n: Gum; 1 H NMR (400 MHz, CDCl3)δ 8.52 (d, J = 5.9 Hz, 2H), 7.92-7.90 (m, 2H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.32-7.20 (m, 7H), 4.48 (s, 2H), 3.75-3.63 (m, 3H), 3.61-3.51 (m, 1H), 3.34-3.28 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 198.1, 152.5, 149.8, 138.1, 137.1, 133.6, 128.9, 128.7, 128.3, 127.9, 127.9, 123.9, 73.5, 72.9, 40.9, 40.8; IR (film): 3028, 2858, 1786, 1598, 1416, 1001, 818 cm 1 ; HRMS (ESI-TOF) calculated for C22H22NO2 [M+H] + 332.1645, found 332.1646. 3o: Prepared following general procedure A using 2o (47.4 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 4:1) to afford the pyridine 3o as the sole product (32 mg, 50% yield). 3o: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 5.6 Hz, 2H), 7.86 (d, J = 7.2 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.7 Hz, 2H), 7.30-7.21 (m, 4H), 7.16 (t, J = 7.3 Hz, 1H), 7.08 (d, J = 7.0 Hz, 2H), 3.46-3.39 (m, 1H), 3.31 (dd, J = 6.9, 1.4 Hz, 2H), 2.53-2.45 (m, 2H), 2.15-2.08 (m, 1H), 2.02-1.92 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 197.8, 155.3, 149.9, 141.4, 136.9, 133.6, 128.9, 128.7, 128.6, 128.2, 126.3, 123.9, 45.1, 40.4, 37.5, 33.8; IR (film): 3025, 2921, 1715, 1597, 1414, 993, 872 cm 1 ; HRMS (ESI-TOF) calculated for C22H22NO [M+H] + 316.1696, found S30
316.1692. 3p and 4p: Prepared following general procedure A using 2p (35 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford the two pyridines (36 mg, 71% combined yield, 3p/4p=4:1). And the resulting mixture was further purified by preparative TLC (PE/isopropanol = 6:1) to afford 3p and 4p separately. 3p: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 5.2 Hz, 2H), 7.27 (t, J = 6.9 Hz, 2H), 7.19 (d, J = 7.1 Hz, 1H), 7.16 (d, J = 5.2 Hz, 2H), 7.09 (d, J = 7.3 Hz, 2H), 3.20 (dq, J = 12.3, 6.8 Hz, 1H), 2.77 (d, J = 7.0 Hz, 2H), 2.45 (t, J = 7.9 Hz, 2H), 2.05 (s, 3H), 2.03-1.83 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 206.6, 153.7, 150.3, 141.5, 128.7, 128.5, 126.3, 123.4, 50.1, 40.1, 37.4, 33.7, 30.8; IR (film): 2921, 1685, 1597, 1448, 1001, 749 cm 1 ; HRMS (ESI-TOF) calculated for C17H20NO [M+H] + 254.1539, found 254.1540. 4p: White solid, mp 77-79 C; 1 H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.5 Hz, 2H), 7.33-7.25 (m, 4H), 7.21 (t, J = 7.3 Hz, 1H), 7.16 (d, J = 7.3 Hz, 2H), 5.78-5.68 (m, 2H), 2.88 (brs, 1H), 2.72 (t, J = 7.2 Hz, 2H), 2.45-2.37 (m, 2H), 1.59 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 156.3, 149.9, 141.7, 136.8, 129.8, 128.9, 128.7, 126.3, 120.8, 74.0, 35.7, 34.2, 29.9; IR (film): 3357, 2920, 2848, 1470, 1412, 872, 745 cm 1 ; HRMS (ESI-TOF) calculated for C17H20NO [M+H] + 254.1539, found 254.1539. S31
3q and 4q: Prepared following general procedure A using 2q (23.3 μl, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1:1) to afford the two pyridines (25.8 mg, 73% combined yield, 3q/4q=6.7:1). And the resulting mixture was further purified by preparative TLC on silica gel (PE/isopropanol = 6:1) to afford 3q and 4q separately. 3q: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 3.2 Hz, 2H), 7.28 (d, J = 4.6 Hz, 2H), 2.81 (s, 2H), 1.95 (s, 3H), 1.40 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 206.6, 158.9, 149.7, 121.5, 55.7, 37.3, 31.8, 28.6; IR (film): 2966, 1716, 1616, 1410, 996, 822 cm 1 ; HRMS (ESI-TOF) calculated for C11H16NO [M+H] + 178.1226, found 178.1228. 4q: White solid, mp 124-126 C; 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 6.2 Hz, 2H), 7.43 (dd, J = 4.6, 1.6 Hz, 2H), 5.69 (s, 1H), 2.36 (s, 1H), 1.73 (d, J = 1.2 Hz, 3H), 1.56 (s, 3H), 1.44 (d, J = 1.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 159.4, 149.5, 139.4, 131.3, 121.1, 73.4, 34.4, 26.9, 19.8; IR (film): 3194, 2975, 2926, 1615, 1241, 1063, 1002, 827 cm 1 ; HRMS (ESI-TOF) calculated for C11H16NO [M+H] + 178.1226, found 178.1228. 3r: Prepared following general procedure A using 2r (35.2 mg, 0.2 mmol, 1.0 S32
equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford the 3r as the sole product (35 mg, 69% yield). 3r: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 5.2 Hz, 2H), 7.35-7.29 (m, 3H), 7.18 (d, J = 5.2 Hz, 2H), 7.08 (d, J = 6.9 Hz, 2H), 3.51 (s, 2H), 2.85 (s, 2H), 1.41 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 205.9, 157.8, 149.9, 133.9, 129.6, 129.0, 127.4, 121.2, 53.8, 51.8, 37.3, 28.7 (two C atoms have the same chemical shift at 28.7 ppm); IR (film): 2964, 1715, 1596, 1409, 913, 821 cm 1 ; HRMS (ESI-TOF) calculated for C17H20NO [M+H] + 254.1539, found 254.1538. 3s: Prepared following general procedure A using 2s (28 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc/ i PrOH/AcOH = 50:10:1:1) to afford the pyridine 3s as the sole product (30.5 mg, 70% yield). 3s: Yellowish-brown oil; 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 6.3 Hz, 2H), 7.30 (d, J = 6.4 Hz, 2H), 5.85 (s, 1H), 2.78 (s, 2H), 2.02 (s, 3H), 1.79 (s, 3H), 1.41 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 198.9, 158.4, 1555.7, 149.9, 125.0, 121.3, 56.5, 37.7, 28.8, 27.9, 20.9; IR (film): 2968, 2933, 1682, 1597, 1428, 1046, 995, 822 cm 1 ; HRMS (ESI-TOF) calculated for C14H20NO [M+H] + 218.1539, found 218.1535. S33
3t: Prepared following general procedure A using 2t (32 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford the pyridine 3t as the sole product (38.7 mg, 81% yield). 3t: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 6.3 Hz, 2H), 7.84 (d, J = 7.1 Hz, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.32 (d, J = 6.3 Hz, 2H), 3.39 (s, 2H), 1.48 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 197.8, 159.7, 149.5, 137.6, 133.4, 128.8, 128.2, 121.7, 50.3, 37.5, 29.1; IR (film): 3025, 2965, 1685, 1596, 1410, 1003, 822 cm 1 ; HRMS (ESI-TOF) calculated for C16H18NO [M+H] + 240.1383, found 240.1385. 3u: Prepared following general procedure A using 2u (45 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 24 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc/AcOH = 40:20:1) to afford the pyridine 3u as the sole product (43.5 mg, 71% yield). 3u: Pale-yellow oil; 1 H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 6.2 Hz, 2H), 7.83 S34
(d, J = 8.0 Hz, 2H), 7.52 (t, J = 7.4 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 6.2 Hz, 2H), 5.02-4.99 (m, 1H), 3.51 (d, J = 17.0 Hz, 1H), 3.29 (d, J = 17.0 Hz, 1H), 1.90-1.75 (m, 3H), 1.69-1.62 (m, 4H), 1.54 (s, 3H), 1.47 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 197.7, 158.6, 149.6, 137.8, 133.4, 132.4, 128.9, 128.1, 123.9, 122.3, 49.2, 43.1, 40.8, 25.9, 23.9, 22.9, 17.9; IR (film): 3025, 2969, 2924, 1689, 1596, 1447, 1410, 1218, 821, 753 cm 1 ; HRMS (ESI-TOF) calculated for C21H26NO [M+H] + 308.2009, found 308.2012. 3v: Prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 equiv.), 3-fuloro-4-cyanopyridine (24.7 μl, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 4:1) to afford the pyridine 3v as the sole product (24.8 mg, 60% yield). 3v: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.34-8.29 (m, 2H), 7.10 (t, J = 5.6 Hz, 1H), 3.20 (t, J = 11.6 Hz, 1H), 2.90 (dd, J = 13.9, 12.8 Hz, 1H), 2.59-2.54 (m, 3H), 2.07-1.96 (m, 3H), 1.77-1.61 (m, 2H), 1.55-1.45 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 212.1, 157.3 (d, J = 254.8 Hz), 146.3 (d, J = 5.0 Hz), 141.9 (d, J = 12.3 Hz), 138.4 (d, J = 25.3 Hz), 122.37 (d, J = 1.9 Hz), 48.9, 44.0, 37.2, 35.7, 29.5, 24.3; 19 F NMR (376 MHz, CDCl3) δ -132.63 (d, J = 6.1 Hz); IR (film): 2931, 2858, 1702, 1604, 1414, 1241, 937, 840 cm 1 ; HRMS (ESI-TOF) calculated for C12H15FNO [M+H] + S35
208.1132, found 208.1127. 3w: Prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 equiv.), 3-chloro-4-cyanopyridine (41.6 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 4:1) to afford the pyridine 3w as the sole product (28 mg, 63% yield). 3w: Yellowish white solid, mp 62-64 C; 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.40 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 5.1 Hz, 1H), 3.38 (t, J = 11.2 Hz, 1H), 2.81 (dd, J = 14.8, 11.8 Hz, 1H), 2.62-2.58 (m, 3H), 2.10-1.98 (m, 3H), 1.71-1.51 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 212.1, 152.5, 149.9, 148.5, 131.2, 121.9, 49.0, 44.0, 38.1, 37.1, 29.6, 24.5; IR (film):2930, 2857, 1702, 1582, 1399, 1241, 937, 842 cm 1 ; HRMS (ESI-TOF) calculated for C12H15ClNO [M+H] + 224.0837, found 224.0831. 3x: prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 equiv.), 3-methyl-4-cyanopyridine (35.4 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 1/1) to afford the pyridine 3x as the sole product (20.7 mg, 51% yield). S36
3x: Colorless oil; 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 7.06 (d, J = 5.2 Hz, 1H), 3.03 (t, J = 11.5 Hz, 1H), 2.92-2.86 (m, 1H), 2.62-2.46 (m, 3H), 2.29 (s, 3H), 2.13-1.96 (m, 3H), 1.77-1.62 (m, 2H), 1.52-1.42 (m, 1H); 13 C NMR (100 MHz, CDCl3) δ 212.7, 154.5, 151.1, 148.1, 130.7, 120.5, 49.7, 441, 37.9, 37.8, 29.6, 24.3, 16.4; IR (film):2931, 2858, 1702, 1582, 1415, 1240, 937, 842 cm 1 ; HRMS (ESI-TOF) calculated for C13H18NO [M+H] + 204.1383, found 204.1390. 3y: prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 equiv.), 3-bromo-4-cyano pyridine (56 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 40 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 4:1) to afford the pyridine 3y as the sole product (18 mg, 38% yield). 3y: Yellow solid, mp 58.6-61.9 C; 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.44 (d, J = 5.0 Hz, 1H), 7.12 (d, J = 5.0 Hz, 1H), 3.36 (t, J = 10.9 Hz, 1H), 2.81 (dd, J = 14.6, 12.0 Hz, 1H), 2.65-2.62 (m, 3H), 2.11-1.97 (m, 3H), 1.72-1.59 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 212.1, 154.2, 152.4, 149.0, 122.5, 122.3, 49.2, 44.0, 40.6, 37.3, 29.7, 24.5; IR (film): 2929, 2856, 1701, 1579, 1398, 1239, 937, 842 cm 1 ; HRMS (ESI-TOF) calculated for C12H15BrNO [M+H] + 268.0332, found 268.0333. 3z: prepared following general procedure A using 2c (24.7 μl, 0.2 mmol, 1.0 S37
equiv.), 3-methylthio-4-cyanopyridine (45 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 40 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC on silica gel (PE/EtOAc = 2:1) to afford the pyridine 3z as the sole product (23 mg, 48% yield). 3z: Yellow amorphous solid; 1 H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 8.34 (d, J = 5.1 Hz, 1H), 7.03 (d, J = 5.1 Hz, 1H), 3.37 (t, J = 11.2 Hz, 1H), 2.82 (dd, J = 14.9, 11.7 Hz, 1H), 2.67-2.59 (m, 3H), 2.51 (s, 3H), 2.11-1.99 (m, 3H), 1.70-1.53 (m, 3H); 13 C NMR (100 MHz, CDCl3) δ 212.6, 153.8, 148.1, 147.3, 133.2, 120.3, 49.6, 44.1, 38.1, 37.6, 29.8, 24.6, 16.7; IR (film): 3378, 2924, 2855, 1703, 1574, 1443, 1266, 972, 870 cm 1 ; HRMS (ESI-TOF) calculated for C13H18NOS [M+H] + 236.1104, found 236.1108. 3A: prepared following general procedure A using 2A (31.6 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 40 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by preparative TLC (PE/EtOAc = 2:1) to afford the pyridine 3A as the sole product (20 mg, 40% yield). NMR spectrums of the compounds 3A are consistent with previous reported results. [21] 3A: gum; 1 H NMR (400 MHz, CDCl3) δ 8.50 (dd, J = 4.4, 1.6 Hz, 2H), 8.04 (dd, J = 7.9, 1.1 Hz, 1H), 7.46 (td, J = 7.5, 1.4 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.21 (d, J S38
= 7.7 Hz, 1H), 7.17 (dd, J = 4.5, 1.5 Hz, 2H), 3.45 (dd, J = 13.6, 4.3 Hz, 1H), 2.99-2.91 (m, 2H), 2.83-2.65 (m, 2H), 2.11-2.05 (m, 1H), 1.84-1.73 (m, 1H); 13 C NMR (101 MHz, CDCl3) δ 198.8, 149.9, 149.8, 144.1, 133.8, 132.5, 129.1, 127.9, 127.1, 125.1, 48.9, 35.6, 29.1, 28.4. 3B: prepared following general procedure A using 2B (81 mg, 0.2 mmol, 1.0 equiv.), 4-cyanopyridine (31.2 mg, 0.3 mmol, 1.5 equiv.), B2(pin)2 (61.9 mg, 0.24 mmol, 1.2 equiv) and MTBE (1 ml) at 70 C. After 36 hours, following the described workup procedure, the reaction mixture was purified by flash column chromatography on silica gel (PE/EtOAc = 3:1 PE/EtOAc/TEA = 1:2:0.03) to afford the pyridine 3B (2.6:1 mixture of diastereomers as determined by 1 H NMR, 43 mg, 44% yield). Separation of the diastereomers was accomplished by recrystallization from acetonitrile to afford the 3B as one diasteroisomer (23 mg, 24% yield, d.r. = 95:5). However, the relative configuration of the major isomer could not be assigned by NMR method. 3B: White solid, mp 246.2-247.3 C; 1 H NMR (400 MHz, (CD3)2SO) δ 8.51 (d, J = 5.4 Hz, 2H), 7.38 (d, J = 5.8 Hz, 1.9H), 7.33 (d, J = 5.9, 0.1H), 5.41 (s, 1H), 5.32 (s, 1H), 5.14 (s, 1H), 5.08 (d, J = 17.6 Hz, 1H), 4.72 (d, J = 17.5 Hz, 1H), 4.16 (s, 2H), 2.55-2.45 (m, 1H) (one of the H overlap in the solvent peak), 2.33 (t, J = 12.1 Hz, 1H), 2.08-1.99 (m, 4H), 1.92-1.86 (m, 4H), 1.76-1.58 (m, 5H), 1.48-1.41 (m, 1H), S39