Site-selective synthesis of arylated pyridines by Suzuki–Miyaura reactions of 2,3,5,6-tetrachloropyridine

Tetrahedron 71 (2015) 5371e5384

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Site-selective synthesis of arylated pyridines by SuzukieMiyaura reactions of 2,3,5,6-tetrachloropyridine Sebastian Reimann a, b, Peter Ehlers a, b, Silvio Parpart a, Annette Surkus b, Anke Spannenberg b, Peter Langer a, b, * a b

€t Rostock, A.-Einstein-Str. 3a, 18059 Rostock, Germany € r Chemie, Universita Institut fu €t Rostock e.V., A.-Einstein-Str. 29a, 18059 Rostock, Germany € r Katalyse an der Universita Leibniz-Institut fu

a r t i c l e i n f o

a b s t r a c t

Article history: Received 23 April 2015 Accepted 29 May 2015 Available online 5 June 2015

Site-selective arylation of commercially available 2,3,5,6-tetrachloropyridine has been accomplished, using the SuzukieMiyaura reaction. The reaction conditions were thoroughly optimized, allowing the selective synthesis of mono-, di-, tri- and tetraarylated pyridines in good to quantitative yields. In addition, we studied the electrochemical properties of selected tetraarylpyridines by DPV-measurements. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Pyridine SuzukieMiyaura reaction Site-selectivity Cross-coupling Catalysis

1. Introduction Owing to their widespread incorporation in biological systems and their application in medicinal- and chemical science, pyridines belong to one of the most studied heterocycles to date.1 In particular, pyridines are common structural motives in natural products2 and relevant pharmaceuticals3 (Fig. 1). Moreover, pyridine possessing molecules are of central importance in organometallic chemistry and catalysis,4 as well as material science5 and supramolecular chemistry.6 The ubiquitous significance of pyridines in various research areas underlines the importance and requirement of new synthetic methodologies for the synthesis of functionalized pyridines. Generally, synthetic access to substituted pyridine derivatives relies either on the functionalization of appropriate precursors and a final ring closing step or by the systematic introduction of substituents on the preformed pyridine ring. The first strategy is mainly based on traditional condensation reactions,7 [3þ3] aza-DielseAlder and related reactions8 or transition metal based condensations.9 These procedures lack mostly on the availability of only constricted substitution pattern. The latter strategy includes, for example, aromatic substitutions,10 direct metallation or metalhalogen-exchange reactions11 as well as transition metal catalyzed Fig. 1. Choice of natural products and drugs possessing a pyridine core. * Corresponding author. Fax: þ49 (381) 4986412; e-mail address: peter.langer@ uni-rostock.de (P. Langer). http://dx.doi.org/10.1016/j.tet.2015.05.114 0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

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cross-coupling reactions.12 Notably, the primary selective introduction of activating groups on the substrate is the main drawback of these procedures. Several research groups focused on site selective cross-coupling reactions on heterocycles13 including ours.14 Different electron density distribution in heterocycles allows the facile introduction of versatile functionalities by palladium catalyzed cross-coupling reactions with high selectivity. Recently, we have described the synthesis of pentaalkynyl-15 and pentaarylpyridines16 as well as the synthesis of 2,3,5,6-tetraalkynyl- and tetraalkenylpyridines12c using cheap and commercially available pentachloropyridine or 2,3,5,6tetrachloropyridine as substrates, respectively. These examples impressively proofed the access of highly functionalized pyridines by cross-coupling methodologies. We also reported the site-selective synthesis of 3,4,5-trichloro-2,6-diarylpyridines from PCP.14e

R Cl

B(OH)2

Cl

i

+ Cl

N

Cl

R

N

R R

1

R

2

Scheme 2. Synthesis of 2aem. i, 1 (1.0 equiv), boronic acid (7.0 equiv), Pd2(dba)3 (1.25 mol %), cataCXium A (5 mol %), K3PO4 (7.5 equiv), toluene, 100  C, 22 h.

Table 2 Synthesis of 2aem 2

Boronic acid

Yield (%)a

a

99

b

96

c

94

d

90

e

99

f

84

g

73

h

57

i

56

j

75

k

47

l

55

m

60

2. Results and discussion Initially we thouroughly optimized the reaction conditions for the synthesis of tetraarylpyridines starting from 1 (Scheme 1, Table 1). Successfully applied conditions for the pentafold arylation of pentachloropyridine gave only moderate yields of the desired product (entry 1).16 In comparison to several tested bulky, electronrich phosphine ligands, the cataCXium A ligand17 showed in the presence of Pd2(dba)3 the best results (entry 6). The amount of catalyst and ligand could be reduced to 1.25 mol % of Pd2(dba)3 and 5 mol % of ligand, while further reduction to 0.5 mol % of the palladium gave a diminished yield of product 2a (entry 8). Finally, increasing the amount of the phenylboronic acid to 7 equiv led to a quantitative yield using toluene as solvent and K3PO4 as base. R Cl

B(OH)2

Cl

i

+ Cl

N

Cl

R

N

R R

1

R

2a

Scheme 1. Optimization of the tetrafold SuzukieMiyaura reaction of 1.

Table 1 Optimizationetetrafold SuzukieMiyaura reaction of 1

1 2 3 4 5 6 7 8 9 a

Equiv of Ph-B(OH)2

Pd source (mol %)

Ligand (mol %)

Yielda [%]

5 5 5 5 5 5 5 5 7

PdCl2(CH3CN)2 (5) PdCl2(CH3CN)2 (5) PdCl2(CH3CN)2 (5) PdCl2(CH3CN)2 (5) Pd(OAc)2 (5) Pd2(dba)3 (2.5) Pd2(dba)3 (1.25) Pd2(dba)3 (0.5) Pd2(dba)3 (1.25)

SPhos (10) XPhos (10) cataCXium A P(Cy)3 (10) cataCXium A cataCXium A cataCXium A cataCXium A cataCXium A

51 30 68 49 43 95 97 88 99

(10) (10) (10) (5) (5) (5)

Isolated yield.

With our optimized conditions in hand, various boronic acids provided the corresponding 2,3,5,6-tetraarylpyridines in high to quantitative yield. Boronic acids containing substituents in two- or three-position led to lower yields (47e73%). Furthermore, n-hexylboronic acid was successfully converted to the corresponding tetraalkyl-derivative 2j in 75% yield. (Scheme 2 and Table 2). The structure of compound 2a was additionally confirmed by Xray crystal analysis (Fig. 2). The phenyl rings, located opposite to each other, are twisted out of the pyridine ring plane (N1eC1eC6eC7¼37.0(2), C3eC4eC18eC19¼38.5(3) and N1eC5eC24eC29¼67.5(2), C1eC2eC12eC13¼68.9(2) , respectively).

a

Isolated yield.

Our next step was to evaluate the regioselective synthesis of monoarylated trichloropyridines. During our optimization, Pd(PPh3)4 proved to be the most appropriate catalyst for this reaction, while bulkier ligands, such as SPhos19 and cataCXium A, gave predominately tri- and tetraarylated pyridines as main

S. Reimann et al. / Tetrahedron 71 (2015) 5371e5384

5373

Table 3 Synthesis of compounds 3aek 3

Yield (%)a

Boronic acid

a

65

b

64

c

65

d

55

e

67

f

71

g

41

h

57

i

51

j

54

k

43

Fig. 2. Molecular structure of 2a. Displacement ellipsoids are drawn at the 50% probability level.18

products. Thus, the synthesis of the desired 2,3,5-trichloro-6arylpyridines was accomplished by using 5 mol % of Pd(PPh3)4, 3 equiv of KF as base in toluene at 100  C (Scheme 3, Table 3). The arylation exclusively took place at position 5. The synthesis of other isomers was not observed.

Cl

B(OH)2

Cl

i

+ Cl

N 1

Cl

R

Cl Cl

Cl N

R

3

Scheme 3. Synthesis of compounds 3aek: i, 1 (1.0 equiv), boronic acid (1.1 equiv), Pd(PPh3)4 (5.0 mol %), KF (3.0 equiv), toluene, 100  C, 22 h.

a

Using the same conditions, while adjusting the amounts of base (KF) and boronic acid, 2,6-diarylated products could be obtained in good yields (Scheme 4, Table 4). Arylation on position three or five was not observed. The structure of compound 4i was independently confirmed by X-ray crystal structure analysis (Fig. 3). Compounds 4a and 4i were chosen as model compounds for the synthesis of tetraarylpyridines containing two different aryl moieties. Using the optimized catalyst system for the tetraarylation reaction the corresponding 2,3,5,6-tetraaryl-pyridines were synthesized in excellent yields (Scheme 5, Table 5). The amounts of base (K3PO4) and boronic acid were reduced as compared to the synthesis of the tetraarylated pyridines. Finally, the trifold arylation of tetrachloropyridine 1 was investigated (Scheme 6, Table 6). Again, application of the cataCXium A ligand led to the desired products in 38e58 % yield. The formation of the corresponding 2,3,5,6-tetraarylproduct 2 as main by-product explain the moderate yields. However, choosing other ligands like XPhos, SPhos and P(Cy)3 or reducing the amount of the boronic acid, temperature or reaction time resulted in no improvement of the product yield. The electrochemical activity of selected compounds was studied using DPV measurements. Compounds 2a, 2b, 2d and 2e exhibit distinct reductions within the range of 2.18 V to 2.2 V. Compound 2f reveals its first reduction potential at 1.55 V and subsequent reductions until 2.2 V (Fig. 4). However, the influence by different substitution patterns can be brought into correlation with the Hammett substituent constants spara.20 Thus, the potential of

Isolated yield.

Cl

B(OH)2

Cl +

Cl

N

Cl

1

Cl

i

Cl N

R R

R

4

Scheme 4. Synthesis of compounds 4aei. i, 1 (1.0 equiv), boronic acid (2.5 equiv), Pd(PPh3)4 (5 mol %), KF (6.0 equiv) toluene, 100  C, 22 h.

compounds containing electron donating groups are cathodically shifted, whereas compound 3f with an electron withdrawing group is anodically shifted. 3. Conclusions In conclusion, we developed a convenient and high yielding protocol for the synthesis of 2,3,5,6-tetraarylpyridines from commercially available 2,3,5,6-tetrachloropyridine. Furthermore, we studied the site-selective arylation of this starting material, giving access to mono-, di- and triarylated pyridines. The obtained products are useful substrates in demand for subsequent cross-coupling reactions to construct tetraarylpyridines with two different arylmoieties.

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Table 4 Synthesis of compounds 4aei 4

Table 5 Synthesis of compounds 5aef Yield (%)a

Boronic acid

a

77

b

77

c

72

d

71

e

73

f

77

g

68

h

69

4

a

a

90

b

a

93

c

a

98

d

a

90

e

i

86

f

i

97

a

a

Boronic acid

Isolated yields.

R Cl

i

Yield (%)a

5

B(OH)2

Cl +

71

Cl

N

Cl

N

R R

1

Isolated yields.

Cl

i

R

6

Scheme 6. Synthesis of compounds 6aee. Conditions: i, 1 (1.0 equiv), boronic acid (3.5 equiv), Pd(dba)2 (2.5 mol %), cataCXium A (5.0 mol %), K3PO4 (5.0 equiv), toluene, 100  C, 20 h.

Table 6 Synthesis of compounds 6aee 6

Fig. 3. Molecular structure of 4i. Displacement ellipsoids are drawn at the 50% probability level.18

R Cl

B(OH)2

Cl N

Ar

4a, 4i

Yield (%)a

a

42

b

58

c

55

d

38

e

41

i

+ Ar

R

Boronic acid

R

Ar

N

Ar

5 a

Scheme 5. Synthesis of compounds 5aef. Conditions: i, 4a or 4i (1.0 equiv), boronic acid (4.0 equiv), Pd(dba)2 (2.5 mol %), cataCXium A (5.0 mol %), K3PO4 (4.0 equiv), toluene, 100  C, 22 h.

4. Experimental 4.1. General All reactions were carried out in oven-dried pressure tubes under argon atmosphere. Solvents for reactions were dried and

Isolated yields.

distilled by standard methods or purchased in extra dry quality from Sigma Aldrich. Solvents for liquid chromatography and extraction were always distilled prior to use (n-heptane, n-hexane, ethyl acetate, dichloromethane). All chemicals employed, including halogenated pyridines, ligands, boronic acids and bases, were purchased from a commercial source (Sigma Aldrich, Alfa Aesar) and used without further purification.

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www.ccdc.cam.ac.uk/data_request/cif. Elemental Analysis (EA): C/H/ N/SeMicroanalysator TruSpec CHNS (Leco). Melting point determination (mp): Micro-Hot-Stage GalenÔ III Cambridge Instruments. The melting points have not been corrected. Thin layer chromatography (TLC): Merck Silica 60 F254 on aluminum tin foil from MachereyeNagel. Detection with UV light at 254 nm and/or 366 nm without dipping reagent. Column Chromatography: Separation on Fluka silica gel 60 (0.063e0.200 mm, 70e320 mesh). Eluents were distilled before use. 4.2. General procedure for the synthesis of 2,3,5,6-tetraarylsubstituted pyridines 2aem

Fig. 4. Reductive DPVs of 1, 2a, 2b, 2d, 2e and 2f in DMF (0.1 mol,L1 TBAPF6); working electrode: platinum; [Fc/Fcþ]¼0.6 V.

1 H NMR Spectroscopy: Bruker AV 300 (300 MHz) and Bruker AV 400 (400 MHz). All NMR spectra presented in this work were recorded in CDCl3 solution. All chemical shifts are given in ppm. All coupling constants are indicated as J. References: TMS (d¼0.00 ppm) or residual CHCl3 (d¼7.26 ppm) were taken as internal standard. Peak characterization: s¼singlet, br s¼broad singlet, d¼doublet, br d¼broad doublet, t¼triplet, dd¼doublet of doublet, q¼quartet, m¼multiplet. The spectra were measured with a standard number of scans (NS¼32). In case of unclear assignment all possible hydrogen atoms were stated. 13C NMR Spectroscopy: Bruker AV 300 (75 MHz) and Bruker AV 400 (100 MHz). All NMR spectra presented in this work were recorded in CDCl3 solution. All chemical shifts are given in ppm. All coupling constants are indicated as J. References: TMS (d¼0.00 ppm) or residual CHCl3 (d¼70.00 ppm) were taken as internal standard. Peak characterization: d¼doublet, t¼triplet, q¼quartet. DEPT method was used for determining the presence of primary, secondary, tertiary and quaternary carbon atoms. All spectra were measured with a standard number of scans (NS¼256). In case of unclear assignment all possible carbon atoms were stated. In some cases the number of scans was increased to 2000e8000 scans in order to detect carbonefluorine couplings. 19F-NMR Spectroscopy: Bruker AV 300 (282 MHz). Spectra were measured with a standard number of scans (NS¼128). Mass Spectrometry (MS): Finnigan MAT 95 XP (electron ionization EI, 70 eV); 6890 N/5973 (Agilent), 6210 Timeof-Flight LC/MS (Agilent). Gas Chromatography MS (GCeMS): Agilent HP-5890 with an Agilent HP-5973 Mass Selective Detector (EI) and HP-5 capillary column using helium carrier gas. Only the measurements with an average deviation from the theoretical mass of 2 mDa were accounted as correct. High resolution MS (HRMS (ESI)): Agilent 1969A TOF. Only the measurements with an average deviation from the theoretical mass of 2 mDa were accounted as correct. Infrared Spectroscopy (IR): Nicolet 550 FTIR spectrometer with ATR sampling technique for solids as well as liquids. Signal characterization: w¼weak, m¼medium, s¼strong. X-ray Crystallography: Data were collected on a Bruker Kappa APEX II Duo diffractometer. The structure was solved by direct methods and refined by full-matrix least-squares procedures on F2 with the SHELXTL software package (Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112.). XP (Bruker AXS) was used for graphical representation. CCDC 986651-986652 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via

An oven-dried and argon-flushed pressure tube was charged with 2,3,5,6-tetrachloropyridine 1 (0.25 mmol), Pd2(dba)3 (1.25 mol %), cataCXium A (5.0 mol %), boronic acid (1.8 mmol) and K3PO4 (1.9 mmol) followed by anhydrous toluene (4.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at 100  C for 22 h. The cooled reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography. 4.2.1. 2,3,5,6-Tetraphenylpyridine (2a). Starting with 2,3,5,6tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), phenylboronic acid (213 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2a was isolated as a colorless solid (95 mg, 99%); mp¼244e246  C. 1H NMR (300 MHz, CDCl3): d¼7.15e7.22 (m, 16H, CH), 7.41e7.44 (m, 4H, CH), 7.69 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼127.2 (CH), 127.8 (CH), 127.8 (CH), 128.3 (CH), 129.5 (CH), 130.2 (CH), 134.3 (C), 139.6 (C), 139.9 (C), 141.2 (CH), 155.3 (C). IR (ATR, cm1): ṽ¼3080 (w), 3054 (w), 3023 (w), 2927 (w), 2857 (w), 1444 (m), 1416 (s), 1386 (m), 1179 (w), 1072 (w), 1017 (w), 908 (m), 854 (w), 779 (m), 757 (s), 732 (m), 690 (s), 537 (m), 528 (m), 499 (m), 409 (w), 390 (w). GCeMS (EI, 70 eV): m/z (%): 384 (Mþ, 16), 383 (66), 382 (100), 306 (3), 305 (3), 304 (10), 303 (7), 302 (6), 276 (8), 190 (7), 189 (5), 188 (3), 183 (13), 77 (4). HRMS (ESI, 70 eV): calcd for C29H22N ([MþH]þ): 384.17468, found 384.17447. Anal. Calcd for C29H21N (383.48): C, 90.83; H, 5.52; N, 3.65. Found: C, 90.50; H, 5.329; N, 3.431. 4.2.2. 2,3,5,6-Tetra-p-tolylpyridine (2b). Starting with 2,3,5,6tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), p-tolylboronic acid (238 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2b was isolated as a colorless solid (105 mg, 96%); mp¼284e286  C. 1H NMR (300 MHz, CDCl3): d¼2.31 (s, 6H, CH3), 2.34 (s, 6H, CH3), 7.03e7.17 (m, 12H, CH), 7.38e7.41 (m, 4H, CH), 7.69 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼21.2 (CH3), 21.3 (CH3), 128.5 (CH), 129.1 (CH), 129.3 (CH), 130.0 (CH), 133.8 (C), 136.8 (C), 137.0 (C), 137.2 (C), 137.4 (C), 141.2 (CH), 154.8 (C). IR (ATR, cm1): ṽ¼3119 (w), 3021 (w), 2859 (w), 1607 (w), 1568 (w), 1496 (m), 1426 (s), 1380 (w), 1308 (w), 1181 (m), 1112 (m), 1089 (w), 1014 (w), 1004 (m), 926 (w), 880 (w), 818 (s), 781 (m), 728 (m), 718 (w), 681 (w), 645 (w), 621 (m), 556 (m), 530 (m), 516 (m), 462 (m), 433 (w), 408 (m), 382 (w). GCeMS (EI, 70 eV): m/z (%): 440 (Mþ, 18), 439 (72), 438 (100), 331 (4), 315 (2), 220 (3), 211 (2), 207 (3), 204 (8), 197 (7), 196 (6), 182 (4). HRMS (ESI, 70 eV): calcd for C33H30N ([MþH]þ): 440.23728, found 440.23695. Anal. Calcd for C33H29N (439.59): C, 90.83; H, 5.52. Found: C, 90.61; H, 5.950. 4.2.3. 2,3,5,6-Tetrakis(4-ethylphenyl)pyridine (2c). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 4ethylphenylboronic acid (262 mg, 1.75 mmol), K3PO4 (398 mg,

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1.88 mmol) and toluene (4.0 mL), 2c was isolated as a colorless solid (116 mg, 94%); mp¼237e239  C. 1H NMR (300 MHz, CDCl3): d¼1.20 (t, 3JHeH¼7.6 Hz, 6H, CH3), 1.23 (t, 3JHeH¼7.6 Hz, 6H, CH3), 2.61 (q, 3 JHeH¼7.7 Hz, 4H, CH2), 2.64 (q, 3JHeH¼7.7 Hz, 4H, CH2), 7.05e7.20 (m, 12H, CH), 7.41e7.43 (m, 4H, CH), 7.71 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼15.4 (CH3), 15.4 (CH3), 28.5 (CH2), 28.6 (CH2), 127.3 (CH), 127.8 (CH), 129.4 (CH), 130.1 (CH), 133.7 (C), 137.2 (C), 137.4 (C), 141.3 (CH), 143.1 (C), 143.7 (C), 154.8 (C). IR (ATR, cm1): ṽ¼3026 (w), 2962 (m), 2930 (m), 2872 (w), 1907 (w), 1609 (w), 1582 (w), 1513 (w), 1499 (w), 1456 (m), 1429 (s), 1405 (m), 1383 (w), 1331 (w), 1182 (w), 1117 (w), 1004 (w), 969 (w), 834 (s), 795 (m), 626 (m), 537 (m). GCeMS (EI, 70 eV): m/z (%): 495 (Mþ, 75), 494 (100), 478 (7), 466 (9), 465 (2), 464 (5), 450 (5), 449 (3), 436 (4), 420 (3), 390 (2), 329 (2), 81 (3), 57 (4), 55 (33), 44 (4), 43 (15), 41 (4), 39 (2). HRMS (ESI, 70 eV): calcd for C37H38N ([MþH]þ): 496.29988, found 496.3007.

was isolated as a colorless solid (137 mg, 84%); mp¼253e254  C. 1H NMR (300 MHz, CDCl3): d¼7.37e7.40 (m, 4H, CH), 7.52e7.62 (m, 12H, CH), 7.80 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼124.0 (q, 4 JCeF¼271.8 Hz, CF3), 124.1 (q, 4JCeF¼271.7 Hz, CF3), 125.2 (q, 3 JCeF¼3.6 Hz, CH), 125.8 (q, 3JCeF¼3.8 Hz, CH), 129.8 (CH), 130.4 (CH), 130.4 (q, 2JCeF¼32.0 Hz, C), 130.4 (q, 2JCeF¼32.2 Hz, C), 134.0 (C), 141.4 (C), 142.2 (C), 142.4 (CH), 154.8 (C). 19F NMR (282.4 MHz, CDCl3): d¼62.2 (CF3), 62.2 (CF3). IR (ATR, cm1): ṽ¼2937 (w), 1617 (m), 1572 (w), 1439 (m), 1406 (m), 1322 (s), 1164 (s), 1104 (s), 1061 (s), 1014 (s), 934 (w), 843 (s), 795 (m), 714 (m), 697 (w), 630 (m), 500 (w), 470 (m), 413 (m), 402 (w). GCeMS (EI, 70 eV): m/z (%): 655 (Mþ, 51), 654 (100), 652 (6), 636 (7), 468 (5), 281 (2), 248 (3), 224 (3), 181 (3), 169 (3), 119 (4), 69 (13), 44 (12), 43 (10). HRMS (ESI, 70 eV): calcd for C33H18F12N ([MþH]þ): 656.12421, found 656.12529. Anal. Calcd for C33H17F12N (655.48): C, 60.47; H, 2.61. Found: C, 60.24; H, 2.555.

4.2.4. 2,3,5,6-Tetrakis(4-tert-butylphenyl)pyridine (2d). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 4-tertbutylphenylboronic acid (312 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2d was isolated as a colorless solid (137 mg, 90%); mp¼314e316  C. 1H NMR (300 MHz, CDCl3): d¼1.28 (s, 18H, CH3 tBu), 1.32 (s, 18H, CH3 tBu), 7.16e7.31 (m, 12H, CH), 7.42e7.46 (m, 12H, CH), 7.73 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼31.3 (CH3 tBu), 31.3 (CH3 tBu), 34.5 (CtBu), 34.5 (CtBu), 124.6 (CH), 125.1 (CH), 129.1 (CH), 129.8 (CH), 133.7 (C), 136.9 (C), 137.1 (C), 141.3 (CH), 150.0 (C), 150.5 (C), 154.7 (C). IR (ATR, cm1): ṽ¼3030 (w), 2962 (s), 2902 (m), 2865 (m), 1609 (w), 1584 (w), 1512 (m), 1474 (m), 1460 (m), 1430 (m), 1391 (m), 1361 (m), 1268 (m), 1204 (m), 1203 (m), 1118 (s), 1015 (m), 1003 (m), 927 (w), 835 (s), 794 (m), 756 (w), 667 (w), 629 (m), 580 (m), 563 (m), 508 (w), 411 (w). GCeMS (EI, 70 eV): m/z (%): 608 (Mþ, 38), 607 (100), 606 (88), 592 (9), 591 (6), 590 (9), 576 (5), 495 (11), 494 (17), 464 (2), 289 (7), 169 (2), 165 (2), 151 (3), 145 (3), 139 (3), 125 (6), 123 (5), 111 (9), 109 (7), 105 (3), 97 (13), 95 (10), 83 (12), 81 (9), 71 (14), 69 (13), 57 (25), 55 (14), 44 (12), 43 (12), 41 (19). HRMS (ESI, 70 eV): calcd for C45H54N ([MþH]þ): 608.42508, found 608.42535.

4.2.7. 2,3,5,6-Tetrakis(2-methoxyphenyl)pyridine (2g). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2methoxyphenylboronic acid (266 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2g was isolated as a colorless solid (73 mg, 73%); mp¼228e230  C. 1H NMR (300 MHz, CDCl3): d¼3.34 (s, 6H, MeO), 3.57 (s, 6H, MeO), 6.64 (br d, 3JHeH¼8.3 Hz, 2H, CH), 6.66e7.21 (m, 12H, CH), 7.53 (dd, 3JHeH¼7.7 Hz, 4JHeH¼1.8 Hz, 2H, CH), 7.80 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼54.7 (MeO), 55.0 (MeO), 110.4 (CH), 110.4 (CH), 119.8 (CH), 120.8 (CH), 128.2 (CH), 128.8 (CH), 129.1 (C), 130.4 (C), 131.1 (CH), 132.0 (CH), 140.8 (CH), 154.1 (C), 156.2 (C). IR (ATR, cm1): ṽ¼2997 (w), 2956 (w), 2832 (m), 1599 (m), 1580 (m), 1494 (m), 1459 (m), 1434 (m), 1416 (m), 1386 (w), 1253 (m), 1180 (m), 1161 (w), 1118 (w), 1079 (m), 1023 (s), 919 (m), 805 (m), 795 (w), 754 (s), 670 (m), 643 (w), 585 (w), 500 (m), 432 (w), 385 (w). GCeMS (EI, 70 eV): m/z (%): 504 (Mþ, 16), 503 (48), 502 (35), 488 (7), 474 (15), 473 (34), 472 (100), 458 (7), 442 (9), 398 (29), 397 (12), 396 (40), 350 (4), 252 (7), 244 (5), 199 (7), 191 (6), 183 (10), 176 (6). HRMS (EI, 70 eV): calcd for C33H29NO4 (Mþ): 503.20911, found 503.20812. Anal. Calcd for C33H29NO4 (503.59): C, 78.71; H, 5.80; N, 2.78. Found: C, 78.55; H, 5.560; N, 2.734.

4.2.5. 2,3,5,6-Tetrakis(4-methoxyphenyl)pyridine (2e). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 4methoxyphenyl-boronic acid (266 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2e was isolated as a colorless solid (125 mg, 99%); mp¼246e248  C. 1H NMR (300 MHz, CDCl3): d¼3.78 (s, 6H, MeO), 3.80 (s, 6H, MeO), 6.75e6.85 (m, 8H, CH), 7.15e7.20 (m, 4H, CH), 7.41e7.46 (m, 4H, CH), 7.64 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.2 (MeO), 55.2 (MeO), 113.2 (CH), 113.8 (CH), 130.6 (CH), 131.4 (CH), 132.3 (C), 133.1 (C), 141.1 (CH), 147.0 (C), 154.3 (C), 158.7 (C), 159.2 (C). IR (ATR, cm1): ṽ¼3085 (w), 2990 (w), 2954 (w), 2834 (w), 2536 (w), 1605 (s), 1576 (s), 1512 (s), 1426 (s), 1292 (s), 1244 (s), 1208 (m), 1168 (s), 1110 (m), 1030 (s), 998 (m), 829 (s), 804 (m), 786 (m), 738 (w), 667 (m), 616 (m), 561 (m), 530 (w), 491 (m), 415 (w). GCeMS (EI, 70 eV): m/z (%): 504 (Mþ, 29), 503 (100), 502 (94), 488 (5), 458 (6), 415 (6), 329 (4), 252 (9), 244 (8), 214 (13), 207 (10), 198 (7), 192 (20), 187 (11), 185 (14), 183 (16), 180 (10), 178 (13), 176 (24), 171 (34), 170 (17), 158 (21), 157 (9), 140 (6), 120 (6). HRMS (ESI, 70 eV): calcd for C33H30NO4 ([MþH]þ): 504.21693, found 504.21764. Anal. Calcd for C33H29NO4 (503.59): C, 78.71; H, 5.80. Found: C, 78.65; H, 5.802.

4. 2. 8 . 2 , 3, 5, 6 -Tetrakis (3-( triflu oro methyl) phenyl) pyr idin e (2h). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.8 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 3-(trifluoromethyl)phenylboronic acid (333 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2h was isolated as a colorless solid (93 mg, 57%); mp¼119e121  C. 1H NMR (300 MHz, CDCl3): d¼7.39e7.65 (m, 16H, CH), 7.85 (s, 1H, CH). 13 C NMR (75 MHz, CDCl3): d¼123.7 (q, 4JCeF¼274.3 Hz, CF3), 123.7 (q, 4JCeF¼272.3 Hz, CF3), 124.7 (q, 3JCeF¼4.1 Hz, CH), 125.1 (q, 3 JCeF¼3.8 Hz, CH), 126.2 (q, 3JCeF¼3.8 Hz, CH), 127.0 (q, 3JCeF¼4.0 Hz, CH), 128.7 (CH), 129.3 (CH), 130.6 (q, 2JCeF¼32.9 Hz, C), 131.3 (q, 2 JCeF¼32.9 Hz, C), 132.8 (CH), 133.2 (CH), 134.0 (C), 139.2 (C), 139.4 (C), 140.9 (CH), 154.8 (C). 19F NMR (282.4 MHz, CDCl3): d¼62.5 (CF3), 62.6 (CF3). IR (ATR, cm1): ṽ¼1411 (m), 1374 (w), 1324 (s), 1276 (w), 1250 (m), 1213 (w), 1180 (m), 1214 (m), 1180 (m), 1162 (m), 1069 (s), 1001 (m), 899 (m), 836 (m), 802 (s), 727 (m), 700 (s), 536 (m), 465 (m), 436 (m), 416 (w), 399 (w). GCeMS (EI, 70 eV): m/z (%): 655 (Mþ, 61), 654 (100), 652 (2), 544 (12), 488 (4), 468 (4), 281 (2), 207 (3), 137 (2), 125 (3), 123 (3), 111 (5), 109 (5), 95 (6), 81 (6), 71 (8), 69 (10), 57 (15), 55 (10), 43 (11), 41 (11), 39 (5). HRMS (ESI, 70 eV): calcd for C33H18F12N ([MþH]þ): 656.12421, found 656.12419. Anal. Calcd for C33H17F12N (655.48): C, 60.47; H, 2.61. Found: C, 60.67; H, 2.232.

4. 2 .6 . 2, 3, 5 , 6-Tetrak is(4 -(tr iflu orom et hyl) phenyl )p yrid ine (2f). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 4-(trifluoromethyl)phenylboronic acid (332 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2f

4.2.9. 2,3,5,6-Tetrakis(biphenyl-3-yl)pyridine (2i). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), biphenyl-3-

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ylboronic acid (347 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2i was isolated as a colorless solid (97 mg, 56%); mp¼235e237  C. 1H NMR (300 MHz, CDCl3): d¼7.27e7.45 (m, 26H, CH), 7.51e7.59 (m, 6H, CH), 7.62e7.67 (m, 2H, CH), 7.73e7.74 (m, 2H, CH), 7.97 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼126.1 (CH), 126.7 (CH), 127.1 (CH), 127.1 (CH), 127.4 (CH), 128.4 (CH), 128.5 (CH), 128.5 (CH), 128.5 (CH), 128.7 (CH), 128.7 (CH), 129.0 (CH), 129.1 (CH), 129.5 (CH), 134.5 (C), 140.1 (C), 140.6 (C), 140.7 (C), 140.8 (CH), 141.0 (C), 141.5 (C), 155.5 (C). IR (ATR, cm1): ṽ¼3057 (w), 3029 (w), 2926 (w), 1597 (m), 1572 (m), 1535 (w), 1387 (m), 1207 (w), 1037 (w), 893 (m), 799 (m), 750 (s), 700 (s), 617 (m), 513 (m), 442 (w). GCeMS (EI, 70 eV): m/z (%): 688 (Mþ, 36), 687 (95), 686 (100), 532 (3), 344 (3), 208 (2), 207 (9), 105 (4), 97 (2), 96 (2), 91 (11), 84 (4), 77 (4), 66 (5), 60 (4), 57 (4), 55 (4), 44 (54), 43 (12), 42 (3), 41 (5), 39 (3). HRMS (ESI, 70 eV): calcd for C53H38N ([MþH]þ): 688.29988, found 688.30015. Anal. Calcd for C53H37N (687.87): C, 92.54; H, 5.42; N, 2.04. Found: C, 92.48; H, 5.054; N, 1.644. 4.2.10. 2,3,5,6-Tetra-n-hexylpyridine (2j). Starting with 2,3,5,6tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), n-hexylboronic acid (228 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2j was isolated as a colorless oil (95 mg, 75%). 1H NMR (300 MHz, CDCl3): d¼0.92 (t, 3JHeH¼7.1 Hz, 6H, CH3), 0.94 (t, 3 JHeH¼6.5 Hz, 6H, CH3), 1.35e1.46 (m, 24H, CH2), 1.55e1.75 (m, 8H, CH2), 2.58 (t, 3JHeH¼7.8 Hz, 4H, CH2), 2.77 (t, 3JHeH¼7.8 Hz, 4H, CH2), 7.16 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼14.1 (CH3), 14.1 (CH3), 22.6 (CH2), 22.6 (CH2), 29.3 (CH2), 29.5 (CH2), 30.2 (CH2), 30.9 (CH2), 31.7 (CH2), 31.8 (CH2), 31.8 (CH2), 34.7 (CH2), 132.2 (C), 137.6 (CH), 156.7 (C). IR (ATR, cm1): ṽ¼2955 (w), 2923 (s), 2855 (s), 1558 (m), 1450 (s), 1378 (m), 1301 (w), 1115 (w), 915 (w), 888 (w), 724 (s), 502 (w), 459 (w), 397 (w). GCeMS (EI, 70 eV): m/z (%): 416 (Mþ, 2), 415 (6), 414 (8), 386 (6), 372 (14), 358 (29), 345 (20), 344 (12), 331 (17), 330 (67), 316 (5), 302 (24), 289 (15), 288 (28), 276 (21), 275 (100), 244 (4), 204 (7), 188 (4), 172 (4), 161 (5), 160 (5), 158 (3), 43 (11). HRMS (ESI, 70 eV): calcd for C29H54N ([MþH]þ): 416.42508, found 416.4258. Anal. Calcd for C29H53N (415.74): C, 83.78; H, 12.85; N, 3.37. Found: C, 84.11; H, 12.43; N, 2.998. 4.2.11. 2,3,5,6-Tetrakis(2,5-dimethoxyphenyl)pyridine (2k). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2,5dimethoxy-phenylboronic acid (319 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2k was isolated as a slightly yellow solid (73 mg, 47%); mp¼244e245  C. 1H NMR (300 MHz, CDCl3): d¼3.32 (s, 6H, MeO), 3.54 (br s, 6H, MeO), 3.57 (br s, 6H, MeO), 3.70 (s, 6H, MeO), 6.59e6.75 (m, 10H, CH), 7.06e7.07 (m, 2H, CH), 7.82 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.4 (MeO), 55.7 (MeO), 55.7 (MeO), 55.8 (MeO), 111.6 (CH), 111.7 (CH), 114.0 (CH), 114.7 (CH), 116.3 (CH), 116.9 (CH), 129.4 (C), 131.0 (C), 131.9 (C), 141.0 (C), 150.6 (C), 150.8 (C), 152.9 (C), 153.4 (C). IR (ATR, cm1): ṽ¼3052 (w), 2991 (w), 2937 (m), 2831 (m), 1607 (w), 1586 (m), 1499 (s), 1451 (s), 1430 (s), 1396 (w), 1373 (w), 1278 (m), 1233 (w), 1215 (s), 1173 (m), 1144 (m), 1071 (w), 1043 (s), 1018 (s), 873 (m), 801 (s), 729 (m), 691 (m), 501 (w), 432 (w). GCeMS (EI, 70 eV): m/z (%): 624 (Mþ, 12), 623 (28), 593 (38), 592 (100), 578 (5), 489 (13), 488 (39), 486 (26), 458 (6), 312 (7), 266 (7), 236 (8), 214 (6), 126 (3), 108 (3). HRMS (ESI, 70 eV): calcd for C37H38NO8 ([MþH]þ): 624.25919, found 624.26022. Anal. Calcd for C37H37NO8 (623.69): C, 71.25; H, 5.98; N, 2.25. Found: C, 70.84; H, 5.623; N, 2.010. 4.2.12. 2,3,5,6-Tetrakis(2,3-dimethoxyphenyl)pyridine (2l). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2,3dimethoxyphenylboronic acid (319 mg, 1.75 mmol), K3PO4

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(398 mg, 1.88 mmol) and toluene (4.0 mL), 2l was isolated as a colorless solid (86 mg, 55%); mp¼224e226  C. 1H NMR (300 MHz, CDCl3): d¼3.66 (br s, 6H, MeO), 3.73 (s, 6H, MeO), 3.76 (br s, 6H, MeO), 3.79 (br s, 6H, MeO), 6.67e6.79 (m, 8H, CH), 6.91e6.93 (m, 4H, CH), 7.95 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.7 (MeO), 55.8 (MeO), 60.4 (MeO), 60.8 (MeO), 122.9 (CH), 123.2 (CH), 123.3 (CH), 123.4 (CH), 131.5 (C), 133.1 (C), 135.7 (C), 141.2 (CH), 146.6 (C), 146.8 (C), 152.4 (C), 152.5 (C), 153.7 (C). IR (ATR, cm1): ṽ¼3074 (w), 3002 (w), 2931 (w), 2831 (m), 1599 (w), 1577 (m), 1464 (m), 1412 (s), 1384 (s), 1300 (s), 1258 (s), 1222 (s), 1169 (m), 1143 (m), 1115 (w), 1083 (m), 1051 (s), 1024 (m), 996 (m), 844 (m), 785 (s), 748 (s), 670 (m), 649 (m), 606 (w), 563 (w), 514 (w), 447 (w), 412 (w). GCeMS (EI, 70 eV): m/z (%): 624 (Mþ, 7), 623 (17), 622 (9), 608 (17), 594 (11), 593 (36), 592 (100), 488 (9), 486 (12), 281 (6), 207 (11), 111 (6), 83 (10), 73 (8), 71 (12), 69 (15), 57 (19), 55 (16), 45 (11), 44 (36), 43 (49), 42 (9), 41 (15). HRMS (EI, 70 eV): calcd for C37H37NO8 (Mþ): 623.25137, found 623.249812. Anal. Calcd for C37H37NO8 (623.69): C, 71.25; H, 5.98. Found: C, 70.97; H, 5.845. 4 . 2 .13 . 2 , 3 , 5 , 6 -Te t ra k i s ( 2 , 3 , 4 - t r i m e t h o x y p h e n yl ) p y r i d i n e (2m). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd2(dba)3 (2.9 mg, 1.25 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2,3,4-trimethoxy-phenylboronic acid (371 mg, 1.75 mmol), K3PO4 (398 mg, 1.88 mmol) and toluene (4.0 mL), 2m was isolated as a colorless solid (112 mg, 60%); mp¼190e192  C. 1H NMR (300 MHz, CDCl3): d¼3.59 (br s, 6H, MeO), 3.64 (br s, 6H, MeO), 3.73 (br s, 6H, MeO), 3.76 (br s, 12H, MeO), 3.79 (br s, 6H, MeO), 6.44 (d, 3JHeH¼8.7 Hz, 2H, CH), 6.58 (d, 3JHeH¼8.7 Hz, 2H, CH), 6.69 (d, 3JHeH¼8.7 Hz, 2H, CH), 7.04 (d, 3JHeH¼8.4 Hz, 2H, CH), 7.81 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.8 (MeO), 55.9 (MeO), 60.6 (MeO), 60.7 (MeO), 60.7 (MeO), 60.8 (MeO), 106.2 (CH), 106.8 (CH), 125.5 (CH), 125.7 (CH), 126.0 (C), 128.3 (C), 131.4 (C), 141.1 (CH), 141.7 (C), 141.8 (C),151.4 (C), 151.4 (C), 152.8 (C), 153.2 (C), 153.5 (C). IR (ATR, cm1): ṽ¼2932 (w), 2837 (w), 1598 (m), 1498 (m), 1459 (s), 1407 (s), 1374 (m), 1289 (s), 1232 (m), 1201 (m), 1170 (m), 1084 (s), 1006 (s), 920 (w), 800 (s), 699 (m), 609 (m), 436 (m). GCeMS (EI, 70 eV): m/z (%): 744 (Mþ, 19), 743 (46), 742 (11), 730 (8), 729 (32), 728 (78), 714 (13), 713 (40), 712 (100), 696 (10), 682 (14), 666 (7), 576 (21), 356 (13), 325 (3), 281 (6), 267 (4), 207 (13), 105 (11), 84 (7), 77 (6), 69 (9), 57 (8), 44 (41), 43 (14), 41 (6). HRMS (ESI, 70 eV): calcd for C41H46NO12 ([MþH]þ): 744.30145, found 744.30009. Anal. Calcd for C41H45NO12 (743.80): C, 66.21; H, 6.10; N, 1.88. Found: C, 66.27; H, 6.329; N, 1.708. 4.3. General procedure for the synthesis of 2,3,5-trichloro-6aryl-substituted pyridines 3aek An oven-dried and argon-flushed pressure tube was charged with 2,3,5,6-tetrachloropyridine 1 (0.5 mmol), Pd(PPh3)4 (5.0 mol %), boronic acid (0.55 mmol) and KF (1.5 mmol) followed by anhydrous toluene (8.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at 100  C for 22 h. The cooled reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography. 4.3.1. 2,3,5-Trichloro-6-phenylpyridine (3a). Starting with 2,3,5,6tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), phenylboronic acid (67.0 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3a was isolated as a colorless solid (84 mg, 65%); mp¼60e61  C. 1H NMR (300 MHz, CDCl3): d¼7.44e7.49 (m, 3H, CH), 7.71e7.75 (m, 2H, CH), 7.89 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼128.2 (CH), 128.6 (C), 129.0 (C), 129.3 (CH), 129.6 (CH), 135.9 (C), 140.0 (CH), 146.6 (C), 154.4 (C). IR (ATR, cm1): ṽ¼3057 (w), 2924 (w), 1523 (w), 1492 (w), 1445 (m), 1398 (s), 1376

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(m), 1336 (m), 1315 (m), 1209 (w), 1160 (s), 1096 (s), 1097 (m), 1046 (s), 1021 (m), 898 (s), 873 (s), 778 (s), 732 (m), 694 (s), 668 (m), 597 (m), 550 (m), 484 (w), 468 (w), 407 (w). GCeMS (EI, 70 eV): m/z (%): 259 (Mþ, 89), 258 (15), 257 (91), 226 (10), 225 (9), 224 (68), 223 (156), 222 (100), 189 (17), 188 (16), 187 (48), 186 (30), 160 (7), 152 (19), 151 (24), 125 (9), 112 (11), 111 (15), 99 (10), 77 (10), 76 (10), 75 (12), 74 (13), 51 (18), 50 (13). HRMS (EI, 70 eV): calcd for C11H6Cl3N (Mþ): 256.95603, found 256.956186 and calcd for C11H6Cl37 2 ClN (Mþ): 258.95308, found 258.953312 and calcd for C11H6NCl37Cl2(Mþ): 260.95013, found 260.950344. Anal. Calcd for C11H6Cl3N (258.53): C, 51.10; H, 2.34. Found: C, 51.23; H, 2.495. 4.3.2. 2,3,5-Trichloro-6-p-tolylpyridine (3b). Starting with 2,3,5,6tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), p-tolylboronic acid (74.8 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3b was isolated as a colorless solid (87 mg, 64%); mp¼84e86  C. 1H NMR (300 MHz, CDCl3): d¼2.40 (s, 3H, CH3), 7.24e7.27 (m, 2H, CH), 7.61e7.65 (m, 2H, CH), 7.87 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼21.4 (CH3), 128.4 (C), 128.6 (C), 128.9 (CH), 129.2 (CH), 133.0 (C), 139.7 (C), 139.9 (CH), 146.5 (C), 154.5 (C). IR (ATR, cm1): ṽ¼3057 (w), 2919 (w), 2851 (w), 2712 (w), 1612 (m), 1562 (m), 1505 (m), 1393 (s), 1335 (s), 1309 (m), 1207 (m), 1160 (s), 1119 (m), 1094 (s), 1044 (s), 1021 (m), 899 (s), 883 (m), 817 (s), 744 (s), 695 (m), 649 (m), 580 (m), 541 (s), 488 (s), 459 (m), 448 (w), 405 (w). GCeMS (EI, 70 eV): m/z (%): 273 (Mþ, 96), 272 (49), 271 (100), 270 (38), 238 (22), 236 (35), 235 (9), 202 (10), 201 (14), 200 (27), 166 (10), 164 (16), 139 (10), 118 (13), 99 (10), 91 (20), 75 (5), 63 (9), 51 (6), 39 (8). HRMS (ESI, 70 eV): calcd for C12H9Cl3N ([MþH]þ): 271.9795, found 271.9797. Anal. Calcd for C12H8Cl3N (272.56): C, 52.88; H, 2.96. Found: C, 52.93; H, 2.993.

(%): 315 (Mþ, 18), 314 (5), 313 (20), 302 (32), 301 (15), 300 (94), 299 (16), 298 (100), 285 (5), 272 (15), 270 (15), 269 (7), 200 (6), 177 (4), 151 (5), 150 (5), 117 (8), 41 (19), 39 (8). HRMS (ESI, 70 eV): calcd for C15H15Cl3N ([MþH]þ): 314.0265, found 314.0261. Anal. Calcd for C15H14Cl3N (314.64): C, 57.26; H, 4.48; N, 4.45. Found: C, 57.10; H, 4.386; N, 4.279. 4.3.5. 2,3,5-Trichloro-6-(4-ethoxyphenyl)pyridine (3e). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 4-ethoxyphenylboronic acid (91.3 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3e was isolated as a colorless solid (101 mg, 67%); mp¼92e93  C. 1H NMR (300 MHz, CDCl3): d¼1.42 (t, 3JHeH¼7.0 Hz, 3H, CH3), 4.07 (q, 3 JHeH¼7.0 Hz, 2H, CH2), 6.92e6.97 (m, 2H, CH), 7.68e7.74 (m, 2H, CH), 7.85 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼14.7 (CH3), 63.5 (CH2), 114.0 (CH), 128.1 (C), 128.1 (C), 130.9 (CH), 140.0 (CH), 146.3 (C), 154.0 (C), 160.0 (C). IR (ATR, cm1): ṽ¼3055 (w), 2986 (w), 2928 (w), 2877 (w), 1614 (s), 1578 (m), 1506 (s), 1413 (m), 1401 (s), 1333 (m), 1298 (m), 1254 (s), 1206 (m), 1180 (m), 1160 (m), 1115 (s), 1097 (m), 1046 (s), 1010 (m), 924 (m), 903 (m), 882 (m), 840 (m), 824 (s), 798 (m), 752 (m), 666 (m), 598 (m), 504 (m), 481 (m), 440 (w), 404 (w). GCeMS (EI, 70 eV): m/z (%): 303 (Mþ, 62), 302 (10), 301 (63), 277 (33), 276 (13), 275 (98), 274 (16), 273 (100), 240 (25), 238 (36), 211 (8), 209 (11), 203 (25), 185 (4), 174 (15), 148 (5), 140 (7), 139 (5), 138 (5), 119 (3), 86 (4), 63 (5), 62 (3), 29 (10). HRMS (EI, 70 eV): calcd for C13H10Cl3NO (Mþ): 300.98225, found 300.982496 and calcd for þ C13H10Cl37 2 ClNO (M ): 302.97930, found 302.979724. Anal. Calcd for C13H10Cl3NO (302.58): C, 51.60; H, 3.33; N, 4.63. Found: C, 51.70; H, 3.197; N, 4.312.

4.3.3. 2,3,5-Trichloro-6-(4-ethylphenyl)pyridine (3c). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 4-ethylphenylboronic acid (82.5 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3c was isolated as a colorless solid (92 mg, 65%); mp¼28e29  C. 1H NMR (300 MHz, CDCl3): d¼1.25 (t, 3JHeH¼7.5 Hz, 3H, CH3), 2.70 (q, 3 JHeH¼7.8 Hz, 2H, CH2), 7.27e7.29 (m, 2H, CH), 7.64e7.60 (m, 2H, CH), 7.87 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼15.4 (CH3), 28.7 (CH2), 127.7 (CH), 128.4 (C), 128.6 (C), 129.3 (CH), 133.3 (C), 139.9 (CH), 146.0 (C), 146.5 (C), 154.5 (C). IR (ATR, cm1): ṽ¼3056 (w), 2965 (w), 2931 (w), 2872 (w), 1612 (w), 1505 (m), 1458 (m), 1399 (s), 1334 (m), 1302 (w), 1208 (m), 1160 (s), 1094 (m), 1042 (s), 1018 (m), 966 (w), 896 (m), 879 (m), 837 (s), 748 (s), 671 (m), 646 (m), 594 (m), 580 (m), 542 (w), 511 (w), 466 (w), 408 (w). GCeMS (EI, 70 eV): m/z (%): 287 (Mþ, 86), 286 (56), 285 (90), 284 (48), 274 (33), 273 (17), 272 (100), 271 (24), 270 (100), 269 (13), 222 (5), 202 (8), 200 (25), 187 (7), 177 (5), 164 (16), 151 (8), 117 (10), 105 (9), 99 (11), 77 (7), 75 (8), 50 (5). HRMS (EI, 70 eV): calcd for C13H10Cl3N (Mþ): þ 284.98733, found 284.987445 and calcd for C13H10Cl37 2 ClN (M ): 286.98438, found 286.984879. Anal. Calcd for C13H10Cl3N (286.58): C, 54.48; H, 3.52; N, 4.89. Found: C, 54.60; H, 3.339; N, 5.260.

4.3.6. 2,3,5-Trichloro-6-(4-biphenyl)pyridine (3f). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 4-biphenylboronic acid (100.1 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3f was isolated as a colorless solid (119 mg, 71%); mp¼142e144  C. 1H NMR (300 MHz, CDCl3): d¼7.34e7.39 (m, 1H, CH), 7.42e7.49 (m, 2H, CH), 7.60e7.71 (m, 4H, CH), 7.81e7.85 (m, 2H, CH), 7.91 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼126.9 (CH), 127.2 (CH), 127.8 (CH), 128.6 (C), 128.9 (CH), 128.9 (C), 134.7 (C), 140.1 (CH), 140.3 (C), 142.4 (C), 146.7 (C), 154.0 (C). IR (ATR, cm1): ṽ¼3051 (w), 1606 (w), 1559 (w), 1510 (w), 1486 (m), 1447 (w), 1402 (s), 1346 (m), 1208 (m), 1157 (m), 1095 (m), 1042 (m), 1017 (m), 1004 (w), 902 (m), 879 (w), 846 (m), 772 (m), 740 (s), 688 (m), 663 (m), 599 (m), 562 (w), 538 (w), 484 (m), 449 (m), 396 (w). GCeMS (EI, 70 eV): m/z (%): 335 (Mþ, 98), 334 (21), 333 (100), 300 (10), 298 (16), 263 (17), 227 (23), 200 (8), 152 (11), 131 (9), 113 (9), 100 (8). HRMS (EI, 70 eV): calcd for C17H10Cl3N (Mþ): 332.98733, found 332.986985 and calcd for þ C17H10Cl37 2 ClN (M ): 334.98438, found 334.984192 and calcd for C17H10Cl37Cl2N (Mþ): 336.98143, found 336.981836 and calcd for þ C17H37 10 Cl3N (M ): 338.97848, found 338.979430. Anal. Calcd for C17H10Cl3N (334.63): C, 61.02; H, 3.01; N, 4.19. Found: C, 60.89; H, 2.827; N, 4.177.

4.3.4. 2,3,5-Trichloro-6-(4-tert-butylphenyl)pyridine (3d). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 4-tert-butylphenylboronic acid (97.9 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3d was isolated as a colorless oil (87 mg, 55%). 1H NMR (300 MHz, CDCl3): d¼1.33 (s, 9H, CH3 tBu), 7.45e7.48 (m, 2H, CH), 7.66e7.70 (m, 2H, CH), 7.87 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼31.2 (CH3 tBu), 34.8 (CtBu), 125.2 (CH), 128.4 (C), 128.6 (C), 129.0 (CH), 139.9 (CH), 146.5 (C), 152.8 (C), 154.4 (C). IR (ATR, cm1): ṽ¼3056 (w), 2961 (m), 2903 (w), 2868 (w), 1610 (m), 1507 (m), 1462 (w), 1403 (s), 1364 (m), 1336 (m), 1269 (m), 1206 (m), 1159 (s), 1119 (m), 1089 (m), 1043 (m), 1016 (m), 896 (m), 838 (s), 758 (m), 721 (m), 695 (m), 671 (m), 626 (m), 583 (m), 541 (m), 529 (m), 471 (w). GCeMS (EI, 70 eV): m/z

4.3.7. 2,3,5-Trichloro-6-(4-fluorophenyl)pyridine (3g). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 4-fluorophenylboronic acid (76.9 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3g was isolated as a colorless solid (57 mg, 41%); mp¼94e96  C. 1H NMR (300 MHz, CDCl3): d¼7.10e7.17 (m, 2H, CH), 7.68e7.76 (m, 2H, CH), 7.88 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼115.3 (d, 2 JCeF¼21.8 Hz, CH), 128.4 (d, 4JCeF¼2.6 Hz, C), 128.6 (C), 129.1 (C), 131.5 (d, 2JCeF¼8.7 Hz, CH), 132.0 (C), 140.1 (CH), 146.6 (C), 153.3 (C), 163.4 (d, JCeF¼251.4 Hz, CF). 19F NMR (282.4 MHz, CDCl3): d¼110.4 (F). IR (ATR, cm1): ṽ¼3063 (w), 1897 (w), 1603 (m), 1505 (m), 1407 (m), 1396 (m), 1332 (m), 1300 (m), 1231 (m), 1205 (m), 1167 (s), 1095 (m), 1044 (m), 1014 (m), 895 (m), 834 (s), 810 (m), 751 (m), 720 (m),

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659 (m), 580 (m), 543 (m), 500 (m), 451 (m), 421 (m), 396 (m). GCeMS (EI, 70 eV): m/z (%): 277 (Mþ, 99), 276 (12), 275 (100), 242 (46), 241 (12), 240 (64), 239 (6), 207 (17), 206 (12), 205 (50), 204 (20), 170 (14), 169 (17), 150 (7), 145 (5), 138 (5), 121 (13), 120 (13), 119 (9), 102 (8), 95 (6), 74 (7). HRMS (EI, 70 eV): calcd for C11H5Cl3FN (Mþ): 274.94661, found 274.946744 and calcd for C11H5Cl37 2 ClFN (Mþ): 276.94366, found 276.943877 and calcd for C11H5Cl37Cl2FN (Mþ): 278.94071, found 278.941109. Anal. Calcd for C11H5Cl3FN (276.52): C, 47.78; H, 1.82; N, 5.07. Found: C, 47.75; H, 1.872; N, 4.775. 4.3.8. 2,3,5-Trichloro-6-m-tolylpyridine (3h). Starting with 2,3,5,6tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 3-methylphenylboronic acid (74.8 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3h was isolated as a colorless solid (78 mg, 57%); mp¼42e44  C. 1H NMR (300 MHz, CDCl3): d¼2.41 (s, 3H, CH3), 7.26e7.34 (m, 2H, CH), 7.49e7.52 (m, 2H, CH), 7.88 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼21.4 (CH3), 126.4 (CH), 128.0 (CH), 128.6 (C), 128.8 (C), 129.9 (CH), 130.3 (CH), 135.8 (C), 138.0 (C), 139.9 (CH), 146.5 (C), 154.7 (C). IR (ATR, cm1): ṽ¼3057 (w), 2913 (m), 2857 (m), 1607 (w), 1521 (m), 1489 (m), 1421 (m), 1402 (m), 1388 (m), 1332 (s), 1195 (m), 1156 (s), 1106 (m), 1054 (s), 994 (m), 892 (m), 788 (m), 742 (m), 697 (s), 666 (s), 610 (m), 560 (s), 541 (m), 500 (w), 454 (m), 402 (w). GCeMS (EI, 70 eV): m/z (%): 273 (Mþ, 93), 272 (49), 271 (100), 270 (37), 238 (34), 237 (14), 236 (52), 235 (11), 234 (5), 202 (11), 201 (16), 200 (30), 166 (12), 165 (9), 164 (19), 139 (10), 99 (11), 91 (13), 86 (7), 82 (6), 63 (8), 39 (7). HRMS (ESI, 70 eV): calcd for C12H9Cl3N ([MþH]þ): 271.9795, found 271.9792. Anal. Calcd for C12H8Cl3N (272.56): C, 52.88; H, 2.96; N, 5.14. Found: C, 52.50; H, 2.607; N, 4.893. 4.3.9. 2,3,5-Trichloro-6-(2-methoxyphenyl)pyridine (3i). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 2-methoxyphenylboronic acid (83.6 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3i was isolated as a colorless oil (69 mg, 51%). 1H NMR (300 MHz, CDCl3): d¼3.78 (s, 3H, MeO), 6.96 (dd, 3JHeH¼8.4 Hz, 4JHeH¼0.9 Hz, 1H, CH), 7.04 (ddd, 3JHeH¼7.7 Hz, 3JHeH¼7.5 Hz, 4JHeH¼1.2 Hz, 1H, CH), 7.28 (dd, 3JHeH¼7.7 Hz, 4JHeH¼1.7 Hz, 1H, CH), 7.42 (ddd, 3JHeH¼8.4 Hz, 3 JHeH¼7.8 Hz, 4JHeH¼1.8 Hz, 1H, CH), 7.85 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.5 (MeO), 111.0 (CH), 120.6 (CH), 125.7 (C), 129.1 (C), 130.3 (CH), 130.9 (CH), 131.0 (C), 138.9 (CH), 146.2 (C), 153.9 (C), 156.7 (C). IR (ATR, cm1): ṽ¼3059 (w), 3004 (w), 2936 (w), 2727 (w), 1602 (m), 1582 (m), 1524 (m), 1493 (m), 1460 (m), 1435 (m), 1402 (s), 1329 (s), 1263 (s), 1238 (s), 1208 (m), 1157 (s), 1099 (s), 1053 (m), 1035 (s), 1023 (s), 895 (m), 792 (m), 749 (s), 667 (m), 606 (m), 556 (m), 468 (m), 436 (w), 387 (w). GCeMS (EI, 70 eV): m/z (%): 289 (Mþ, 22), 287 (22), 256 (12), 253 (21), 252 (100), 251 (13), 239 (11), 237 (18), 226 (17), 222 (18), 219 (19), 218 (15), 217 (56), 216 (17), 189 (15), 188 (11), 187 (13), 174 (17), 138 (6), 111 (11), 86 (8), 63 (12), 39 (10). HRMS (EI, 70 eV): calcd for C12H8Cl3NO (Mþ): 286.96660, found 286.966752 and calcd for þ C12H8Cl37 2 ClNO (M ): 288.96365, found 288.963947. Anal. Calcd for C12H8Cl3NO (288.56): C, 49.95; H, 2.79. Found: C, 49.96; H, 2.915. 4 . 3 .10 . 2 , 3 , 5 -Tr i c h l o r o - 6 - ( 2 , 5 - d i m e t h o x y p h e nyl ) p y r i d i n e (3j). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 2,5dimethoxyphenylboronic acid (100.1 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3j was isolated as a slightly yellow solid (85 mg, 54%); mp¼66e67  C. 1H NMR (300 MHz, CDCl3): d¼3.73 (s, 3H, MeO), 3.77 (s, 3H, MeO), 6.83e6.97 (m, 3H, CH), 7.85 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.7 (MeO), 56.0 (MeO), 112.3 (CH), 115.5 (CH), 116.2 (CH), 126.1 (C), 129.2 (C), 131.0 (C), 138.9 (CH), 146.2 (C), 150.9 (C), 153.4 (C), 154.5 (C). IR (ATR, cm1): ṽ¼3061 (w), 3014 (w), 2999 (w), 2969

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(w), 2935 (w), 2837 (w), 1521 (w), 1500 (s), 1469 (m), 118 (m), 1419 (s), 1388 (s), 1329 (m), 1271 (m), 1224 (s), 1179 (m), 1156 (m), 1085 (m), 1051 (m), 1032 (s), 926 (m), 882 (m), 855 (m), 824 (m), 812 (m), 745 (m), 723 (m), 683 (m), 669 (m), 638 (w), 584 (m), 565 (m), 529 (m), 469 (m). GCeMS (EI, 70 eV): m/z (%): 319 (Mþ, 86), 318 (15), 317 (87), 304 (10), 286 (14), 285 (10), 284 (63), 283 (24), 282 (100), 281 (17), 271 (12), 269 (62), 268 (17), 267 (98), 256 (23), 255 (9), 254 (50), 252 (35), 249 (19), 248 (20), 247 (55), 246 (34), 233 (13), 232 (11), 231 (13), 226 (11), 224 (18), 211 (11), 210 (11), 208 (10), 198 (15), 196 (24), 161 (17), 135 (11), 82 (11), 54 (17), 53 (9). HRMS (ESI, 70 eV): calcd for C13H11Cl3NO2 ([MþH]þ): 317.98499, found 317.98535. Anal. Calcd for C13H10Cl3NO2 (318.58): C, 49.01; H, 3.16; N, 4.40. Found: C, 48.79; H, 2.876; N, 4.094. 4.3.11. 2,3,5-Trichloro-6-(3,5-difluorophenyl)pyridine (3k). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29.0 mg, 5.0 mol %), 3,5-difluorophenylboronic acid (86.8 mg, 0.55 mmol), KF (87.0 mg, 1.5 mmol) and toluene (8.0 mL), 3k was isolated as a colorless solid (63 mg, 43%); mp¼139e141  C. 1H NMR (300 MHz, CDCl3): d¼6.85e6.94 (m, 1H, CH), 7.27e7.30 (m, 2H, CH), 7.91 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼105.0 (dd, 2 JCeF¼26.6 Hz, 2JCeF¼25.4 Hz, CH), 112.6 (d, 3JCeF¼11.6 Hz, CH), 112.6 (d, 2JCeF¼26.6 Hz, CH), 128.6 (C), 130.2 (C), 138.6 (dd, 3JCeF¼10.3 Hz, C), 140.3 (CH), 146.9 (C), 151.6 (dd, 4JCeF¼3.3 Hz, C), 162.5 (dd, JCeF¼248.6 Hz, 3JCeF¼11.3 Hz, CF), 162.6 (dd, JCeF¼248.7 Hz, 3 JCeF¼11.1 Hz, CF). 19F NMR (282.4 MHz, CDCl3): d¼108.6 (F). IR (ATR, cm1): ṽ¼3088 (w), 3063 (w), 1626 (m), 1595 (m), 1525 (m), 1434 (m), 1411 (m), 1391 (s), 1348 (m), 1304 (m), 1234 (m), 1200 (m), 1160 (m), 1119 (s), 1099 (m), 1063 (s), 986 (s), 939 (s), 901 (m), 864 (s), 850 (s), 811 (m), 748 (m), 691 (s), 670 (m), 655 (m), 630 (m), 581 (s), 531 (m), 509 (m), 460 (m). GCeMS (EI, 70 eV): m/z (%): 295 (Mþ, 98), 294 (14), 293 (100), 260 (54), 259 (13), 258 (84), 225 (18), 224 (12), 223 (57), 222 (14), 196 (5), 188 (15), 187 (18), 168 (9), 162 (8), 129 (12), 111 (14), 98 (8), 94 (5), 88 (4), 84 (9), 81 (6), 75 (6), 74 (5), 63 (7). HRMS (EI, 70 eV): calcd for C11H4Cl3F2N (Mþ): 292.93719, þ found 292.937449 and calcd for C11H4Cl37 2 ClF2N (M ): 294.93424, 37 found 294.934554 and calcd for C11H4Cl Cl2F2N (Mþ): 296.93129, found 296.931821. Anal. Calcd for C11H4Cl3F2N (294.51): C, 44.86; H, 1.37; N, 4.76. Found: C, 44.49; H, 1.249; N, 4.520. 4.4. General procedure for the synthesis of 3,5-dichloro-2,6diaryl-substituted pyridines 4aei An oven-dried and argon-flushed pressure tube was charged with 2,3,5,6-tetrachloropyridine 1 (0.5 mmol), Pd(PPh3)4 (5.0 mol %), boronic acid (1.25 mmol) and KF (3.0 mmol) followed by anhydrous toluene (8.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at 100  C for 22 h. The cooled reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography. 4.4.1. 3,5-Dichloro-2,6-diphenylpyridine (4a). Starting with 2,3,5,6tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), phenylboronic acid (152 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4a was isolated as a colorless solid (116 mg, 77%); mp¼135e137  C. 1H NMR (300 MHz, CDCl3): d¼7.43e7.51 (m, 6H, CH), 7.80e7.83 (m, 4H, CH), 7.94 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼128.0 (CH), 128.3 (C), 129.0 (CH), 129.4 (CH), 137.2 (C), 139.3 (CH), 154.2 (C). IR (ATR, cm1): ṽ¼3057 (w), 1580 (w), 1521 (w), 1446 (m), 1401 (m), 1337 (m), 1207 (m), 1159 (m), 1097 (m), 1047 (s), 1022 (w), 896 (w), 779 (m), 729 (m), 695 (s), 669 (m), 618 (s), 552 (m), 542 (m), 482 (m), 467 (m), 408 (w), 389 (w). GCeMS (EI, 70 eV): m/z (%): 300 (Mþ, 19), 299 (84), 266 (34), 265 (20), 264 (100), 229 (16), 228 (27), 227 (27), 226 (5), 202 (9),

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201 (9), 149 (5), 136 (9), 132 (12), 126 (19), 125 (6), 114 (15), 101 (10), 100 (8), 99 (5), 77 (10), 75 (7), 74 (6). HRMS (EI, 70 eV): calcd for C17H11Cl2N (Mþ): 299.02631, found 299.02622 and calcd for C17H11Cl37ClN (Mþ): 301.02336, found 301.02362. Anal. Calcd for C17H11Cl2N (300.18): C, 68.02; H, 3.69; N, 4.67. Found: C, 67.98; H, 3.585; N, 4.742. 4.4.2. 3,5-Dichloro-2,6-di-p-tolylpyridine (4b). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), p-tolylboronic acid (170 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4b was isolated as a colorless solid (122 mg, 77%); mp¼134e136  C. 1H NMR (300 MHz, CDCl3): d¼2.41 (s, 6H, CH3), 7.25e7.28 (m, 4H, CH), 7.69e7.73 (m, 4H, CH), 7.90 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼21.3 (CH3), 127.8 (C), 128.7 (CH), 129.3 (CH), 134.4 (C), 139.0 (C), 139.2 (CH), 154.0 (C). IR (ATR, cm1): ṽ¼3060 (w), 2917 (w), 1896 (w), 1784 (w), 1647 (w), 1610 (w), 1504 (m), 1435 (m), 1417 (m), 1402 (m), 1373 (w), 1354 (m), 1309 (m), 1252 (w), 1200 (m), 1109 (m), 1080 (s), 1010 (m), 957 (m), 874 (m), 817 (s), 755 (m), 716 (s), 638 (m), 592 (m), 512 (m), 487 (m), 454 (m), 389 (w). GCeMS (EI, 70 eV): m/z (%): 328 (Mþ, 27), 327 (100), 326 (11), 294 (18), 293 (13), 292 (59), 257 (7), 256 (7), 241 (11), 240 (10), 164 (9), 139 (13), 127 (8), 121 (6), 91 (8). HRMS (EI, 70 eV): calcd for C19H15Cl2N (Mþ): 327.05761, found 327.057624 and calcd for C19H15Cl37ClN (Mþ): 329.05466, found 329.055034. 4.4.3. 3,5-Dichloro-2,6-bis(4-ethylphenyl)pyridine (4c). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-ethylphenyl-boronic acid (187 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4c was isolated as a colorless solid (128 mg, 72%); mp¼50e52  C. 1H NMR (300 MHz, CDCl3): d¼1.29 (t, 3JHeH¼7.9 Hz, 6H, CH3), 2.71 (q, 3 JHeH¼7.7 Hz, 4H, CH2), 7.30e7.33 (m, 4H, CH), 7.75e7.79 (m, 4H, CH), 7.92 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼15.4 (CH3), 28.7 (CH2), 127.5 (CH), 127.8 (C), 129.4 (CH), 134.7 (C), 139.2 (CH), 145.3 (C), 154.0 (C). IR (ATR, cm1): ṽ¼3027 (w), 2960 (m), 2930 (w), 2867 (w), 1914 (w), 1610 (m), 1503 (m), 1419 (s), 1404 (s), 1351 (m), 1199 (m), 1107 (m), 1118 (m), 1030 (m), 1020 (m), 965 (w), 874 (m), 840 (s), 763 (s), 660 (m), 637 (m), 592 (w), 553 (w), 513 (w), 486 (m), 455 (w), 386 (w). GCeMS (EI, 70 eV): m/z (%): 356 (Mþ, 43), 355 (100), 354 (34), 342 (32), 341 (13), 340 (52), 326 (5), 325 (7), 290 (4), 254 (5), 163 (10), 162 (13), 126 (3), 120 (3), 89 (3). HRMS (EI, 70 eV): calcd for C21H19Cl2N (Mþ): 355.08891, found 355.088200 and calcd for C21H19Cl37ClN (Mþ): 357.08596, found 357.085937 þ and calcd for C21H37 19 Cl2N (M ): 359.08301, found 359.083695. Anal. Calcd for C21H19Cl2N (356.29): C, 70.79; H, 5.38; N, 3.93. Found: C, 70.71; H, 5.107; N, 4.068. 4.4.4. 3,5-Dichloro-2,6-bis(4-methoxyphenyl)pyridine (4d). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-methoxy-phenylboronic acid (189 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4d was isolated as a colorless solid (128 mg, 71%); mp¼174e176  C. 1H NMR (300 MHz, CDCl3): d¼3.78 (s, 6H, MeO), 6.89e6.92 (m, 4H, CH), 7.70e7.73 (m, 4H, CH), 7.80 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.3 (MeO), 113.4 (CH), 127.4 (C), 129.8 (C), 130.9 (CH), 139.9 (CH), 153.5 (C), 160.2 (C). IR (ATR, cm1): ṽ¼3054 (w), 3005 (w), 2834 (w), 2034 (w), 1609 (s), 1579 (m), 1504 (m), 1451 (m), 1421 (s), 1406 (s), 1355 (m), 1304 (m), 1243 (s), 1174 (s), 1080 (m), 1024 (s), 1005 (m), 829 (s), 788 (w), 763 (m), 631 (m), 537 (m), 448 (m), 434 (m), 415 (w). GCeMS (EI, 70 eV): m/z (%): 360 (Mþ, 24), 359 (100), 318 (5), 316 (8), 309 (13), 274 (5), 246 (4), 203 (4), 202 (4), 180 (12), 162 (2), 158 (2), 147 (2), 141 (2), 123 (2), 113 (3), 107 (3), 101 (2), 87 (2), 75 (2), 63 (2). HRMS (ESI, 70 eV): calcd for C19H16Cl2NO2 ([MþH]þ):

360.0548, found 360.0553. Anal. Calcd for C19H15Cl2NO2 (360.23): C, 63.35; H, 4.20; N, 3.89. Found: C, 63.45; H, 3.883; N, 3.649. 4.4.5. 3,5-Dichloro-2,6-bis(4-ethoxyphenyl)pyridine (4e). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-ethoxyphenyl-boronic acid (207 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4e was isolated as a colorless solid (142 mg, 73%); mp¼97e99  C. 1H NMR (300 MHz, CDCl3): d¼1.42 (t, 3JHeH¼7.4 Hz, 6H, CH3), 4.07 (q, 3 JHeH¼7.5 Hz, 4H, CH2), 6.92e6.97 (m, 4H, CH), 7.74e7.79 (m, 4H, CH), 7.85 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼14.8 (CH3), 63.5 (CH2), 113.9 (CH), 127.3 (C), 129.7 (CH), 130.9 (C), 139.3 (CH), 153.6 (C), 159.6 (C). IR (ATR, cm1): ṽ¼3067 (w), 2980 (m), 2928 (w), 2869 (w), 1611 (m), 1578 (m), 1506 (m), 1410 (m), 1389 (s), 1353 (w), 1314 (m), 1297 (m), 1247 (s), 1172 (m), 1110 (m), 1080 (m), 1050 (s), 1006 (w), 951 (w), 921 (m), 892 (m), 821 (s), 797 (m), 731 (m), 673 (m), 600 (m), 529 (m), 506 (m), 476 (m), 410 (w). GCeMS (EI, 70 eV): m/z (%): 388 (Mþ, 24), 387 (100), 359 (11), 333 (28), 332 (12), 331 (43), 330 (5), 296 (20), 261 (6), 260 (3), 232 (6), 231 (4), 214 (4), 203 (4), 202 (4), 176 (4), 165 (11), 148 (4), 113 (3), 29 (10). HRMS (EI, 70 eV): calcd for C21H19Cl2NO2 (Mþ): 387.07874, found 387.076976 and calcd for C21H19Cl37ClNO2 (Mþ): 389.07579, found 389.076421. 4.4.6. 3,5-Dichloro-2,6-bis(4-fluorophenyl)pyridine (4f). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-fluorophenyl-boronic acid (175 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4f was isolated as a colorless solid (129 mg, 77%); mp¼146e148  C. 1H NMR (300 MHz, CDCl3): d¼7.10e7.18 (m, 4H, CH), 7.75e7.81 (m, 4H, CH), 7.92 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼115.1 (d, 2 JCeF¼22.1 Hz, CH), 128.3 (C), 131.4 (d, 3JCeF¼8.2 Hz, CH), 133.1 (d, 4 JCeF¼2.9 Hz, C), 139.5 (CH), 153.1 (C), 163.3 (d, 1JCeF¼249.4 Hz, CF). 19 F NMR (282.4 MHz, CDCl3): d¼111.3 (F). IR (ATR, cm1): ṽ¼3066 (w), 1889 (w), 1600 (s), 1501 (s), 1439 (s), 1416 (s), 1399 (s), 1347 (m), 1299 (m), 1225 (s), 1155 (s), 1110 (m), 1081 (s), 1015 (m), 954 (w), 880 (m), 834 (s), 806 (s), 762 (s), 660 (m), 597 (m), 529 (m), 482 (s), 455 (m), 415 (m). GCeMS (EI, 70 eV): m/z (%): 336 (Mþ, 22), 335 (100), 302 (26), 301 (16), 300 (77), 265 (20), 264 (18), 263 (17), 245 (8), 244 (5), 238 (9), 237 (5), 167 (5), 154 (12), 150 (9), 145 (4), 144 (24), 140 (5), 132 (8), 123 (6), 122 (7), 118 (5), 98 (3), 94 (6), 75 (7), 74 (4), 57 (2). HRMS (EI, 70 eV): calcd for C17H9Cl2F2N (Mþ): 335.00746, found 335.007509 and calcd for C17H9Cl37ClF2N (Mþ): þ 337.00451, found 337.004698 and calcd for C17H37 9 Cl2F2N (M ): 339.00156, found 339.002442. Anal. Calcd for C17H9Cl2F2N (336.16): C, 60.74; H, 2.70; N, 4.17. Found: C, 60.59; H, 2.600; N, 4.281. 4.4.7. 3,5-Dichloro-2,6-bis(4-(trifluoromethoxy)phenyl)pyridine (4g). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 4-(trifluoro-methoxy) phenylboronic acid (257 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4g was isolated as a colorless solid (159 mg, 68%); mp¼60e62  C. 1H NMR (300 MHz, CDCl3): d¼7.28e7.31 (m, 4H, CH), 7.79e7.85 (m, 4H, CH), 7.95 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼120.3 (q, 1JCeF¼259.5 Hz, CF3), 120.4 (CH), 128.7 (C), 131.1 (CH), 135.5 (C), 139.7 (CH), 149.8 (q, 3JCeF¼1.8 Hz, C), 152.9 (C). 19F NMR (282.4 MHz, CDCl3): d¼57.3 (CF3). IR (ATR, cm1): ṽ¼3055 (w), 1901 (w), 1608 (m), 1503 (m), 1403 (m), 1301 (m), 1205 (s), 1168 (s), 1109 (s), 1046 (m), 1029 (w), 1014 (m), 923 (m), 899 (m), 875 (m), 808 (m), 767 (m), 754 (m), 668 (m), 603 (m), 532 (m), 389 (w). GCeMS (EI, 70 eV): m/z (%): 468 (Mþ, 23), 467 (100), 434 (23), 433 (14), 432 (65), 400 (2), 397 (6), 384 (5), 382 (8), 335 (7), 311 (6), 300 (6), 210 (4), 202 (4), 123 (3), 113 (5), 87 (3), 69 (22). HRMS (ESI, 70 eV): calcd for C19H10Cl2F6NO2 ([MþH]þ): 467.9987, found

S. Reimann et al. / Tetrahedron 71 (2015) 5371e5384

467.9997. Anal. Calcd for C19H9Cl2F6NO2 (468.18): C, 48.74; H, 1.94; N, 2.99. Found: C, 48.66; H, 1.861; N, 2.949. 4.4.8. 3,5-Dichloro-2,6-di-m-tolylpyridine (4h). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), m-tolylboronic acid (170 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4h was isolated as a colorless solid (113 mg, 69%); mp¼81e83  C. 1H NMR (300 MHz, CDCl3): d¼2.44 (s, 6H, CH3), 7.26e7.40 (m, 4H, CH), 7.60e7.61 (m, 4H, CH), 7.93 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼21.5 (CH3), 126.5 (CH), 127.8 (CH), 128.3 (C), 129.8 (CH), 130.0 (C), 137.2 (C), 137.7 (C), 139.1 (C). IR (ATR, cm1): ṽ¼2914 (w), 1788 (w), 1529 (m), 1408 (m), 1340 (m), 1201 (w), 1110 (w), 1088 (m), 1037 (s), 993 (w), 923 (m), 886 (m), 814 (m), 785 (m), 747 (s), 697 (s), 652 (w), 532 (w), 512 (w), 502 (m), 457 (m), 430 (w). GCeMS (EI, 70 eV): m/z (%): 328 (Mþ, 27), 327 (100), 326 (11), 294 (34), 293 (22), 292 (96), 256 (11), 255 (8), 241 (14), 240 (12), 227 (5), 163 (12), 139 (16), 138 (6), 127 (12), 120 (11), 115 (9), 114 (6), 113 (5), 91 (7), 89 (5), 87 (3), 65 (7), 63 (5), 51 (3), 39 (5). HRMS (EI, 70 eV): calcd for C19H15Cl2N (Mþ): 327.05761, found 327.057678 and calcd for C19H15Cl37ClN (Mþ): 329.05466, found 329.055137. Anal. Calcd for C19H15Cl2N (328.29): C, 69.52; H, 4.61; N, 4.27. Found: C, 69.55; H, 4.507; N, 4.310. 4.4.9. 3,5-Dichloro-2,6-bis(3-methoxyphenyl)pyridine (4i). Starting with 2,3,5,6-tetrachloropyridine 1 (108 mg, 0.5 mmol), Pd(PPh3)4 (29 mg, 5.0 mol %), 3-methoxyphenylboronic acid (189 mg, 1.25 mmol), KF (174 mg, 3.0 mmol) and toluene (8.0 mL), 4i was isolated as a colorless solid (128 mg, 71%); mp¼152e154  C. 1H NMR (400 MHz, CDCl3): d¼3.83 (s, 6H, MeO), 6.95e6.98 (m, 2H, CH), 7.29e7.30 (m, 2H, CH), 7.34e7.36 (m, 4H, CH), 7.91 (s, 1H, CH). 13 C NMR (100 MHz, CDCl3): d¼55.3 (MeO), 114.8 (CH), 115.1 (CH), 121.9 (CH), 128.5 (C), 129.1 (CH), 138.5 (C), 139.3 (CH), 153.9 (C), 159.2 (C). IR (ATR, cm1): ṽ¼3002 (w), 2961 (w), 2924 (w), 2830 (w), 1952 (w), 1740 (w), 1598 (m), 1587 (m), 1493 (m), 1458 (m), 1415 (s), 1317 (m), 1272 (m), 1176 (m), 1033 (m), 993 (w), 895 (m), 870 (m), 796 (m), 762 (m), 703 (s), 524 (m), 469 (w), 434 (w). GCeMS (EI, 70 eV): m/z (%): 360 (Mþ, 77), 359 (78), 358 (100), 332 (11), 331 (20), 330 (21), 329 (26), 328 (8), 272 (3), 250 (3), 238 (3), 215 (4), 214 (4), 202 (4), 180 (9), 125 (2), 114 (2), 113 (4), 101 (4), 75 (2). HRMS (ESI, 70 eV): calcd for C19H16Cl2NO2 ([MþH]þ): 360.05526, found 360.0551. Anal. Calcd for C19H15Cl2NO2 (360.23): C, 63.35; H, 4.20; N, 3.89. Found: C, 63.46; H, 4.211; N, 3.923.

5381

7.73 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): d¼55.2 (MeO), 113.8 (CH), 127.6 (CH), 127.8 (CH), 130.1 (CH), 130.6 (CH), 131.9 (C), 133.9 (C), 140.1 (C), 140.9 (CH), 154.9 (C), 158.9 (C). IR (ATR, cm1): ṽ¼3055 (w), 3032 (w), 3003 (w), 2951 (w), 2930 (w), 2835 (w), 1606 (m), 1574 (m), 1511 (s), 1458 (m), 1428 (s), 1405 (m), 1387 (m), 1290 (m), 1248 (s), 1176 (s), 1030 (m), 1017 (m), 918 (m), 831 (s), 762 (m), 750 (m), 695 (s), 660 (m), 560 (m), 548 (m), 537 (m), 518 (m), 417 (w). GCeMS (EI, 70 eV): m/z (%): 444 (Mþ, 23), 443 (86), 442 (100), 428 (3), 399 (9), 398 (8), 355 (7), 354 (4), 222 (4), 177 (5), 176 (3), 171 (3), 164 (2). HRMS (EI, 70 eV): calcd for C31H24NO2 (Mþ): 442.18016, found 442.18055. Anal. Calcd for C31H25NO2 (443.53): C, 83.95; H, 5.68; N, 3.16. Found: C, 83.87; H, 5.576; N, 3.061. 4.5.2. 3,5-Bis(4-(trifluoromethyl)phenyl)-2,6-diphenylpyridine (5b). Starting with 3,5-dichloro-2,6-diphenylpyridine 4a (100 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), 4-(trifluoromethyl)-phenylboronic acid (252 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5b was isolated as a colorless solid (159 mg, 93%); mp¼188e189  C. 1H NMR (400 MHz, CDCl3): d¼7.25e7.30 (m, 6H, CH), 7.39 (d, 3 JHeH¼8.1 Hz, 4H, CH), 7.43e7.48 (m, 4H, CH), 7.55e7.58 (m, 4H, CH), 7.74 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): d¼124.3 (q, 1 JCeF¼272.4 Hz, CF3), 125.4 (q, 3JCeF¼3.7 Hz, CH), 128.1 (CH), 128.3 (CH), 129.6 (q, 2JCeF¼32.5 Hz, C), 129.8 (CH), 130.1 (CH), 133.0 (C), 139.1 (C), 140.9 (C), 143.1 (C), 156.1 (CH). 19F NMR (282.4 MHz, CDCl3): d¼62.1 (CF3). IR (ATR, cm1): ṽ¼3058 (w), 3039 (w), 2931 (w), 1617 (m), 1574 (w), 1518 (w), 1491 (w), 1430 (m), 1403 (m), 1321 (s), 1244 (w), 1165 (m), 1108 (m), 1065 (s), 1016 (s), 1004 (m), 956 (w), 908 (w), 843 (s), 805 (w), 843 (s), 778 (m), 760 (m), 718 (m), 696 (s), 628 (s), 604 (m), 547 (w), 484 (w), 409 (w), 381 (w). GCeMS (EI, 70 eV): m/z (%): 519 (Mþ, 58), 518 (100), 500 (4), 420 (5), 371 (2), 250 (6), 214 (4), 190 (4), 189 (2), 176 (2). HRMS (EI, 70 eV): calcd for C31H18F6N (Mþ): 518.13380, found 518.13388.

An oven-dried and argon-flushed pressure tube was charged with the appropriate 3,5-dichloro-2,6-diaryl-substituted pyridine 4a or 4i (0.33 mmol), Pd(dba)2 (2.5 mol %), cataCXium A (5.0 mol %), boronic acid (1.3 mmol) and K3PO4 (1.3 mmol) followed by anhydrous toluene (4.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at 100  C for 22 h. The cooled reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography.

4.5.3. 3,5-Di(biphenyl-4-yl)-2,6-diphenylpyridine (5c). Starting with 3,5-dichloro-2,6-diphenylpyridine 4a (100 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), biphenyl-4-ylboronic acid (263 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5c was isolated as a colorless solid (173 mg, 98%); mp¼264e266  C. 1H NMR (300 MHz, CDCl3): d¼7.25e7.29 (m, 6H, CH), 7.33e7.37 (m, 6H, CH), 7.40e7.45 (m, 4H, CH), 7.53e7.62 (m, 12H, CH), 7.86 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼127.0 (CH), 127.0 (CH), 127.4 (CH), 127.9 (CH), 127.9 (CH), 128.8 (CH), 130.0 (CH), 130.2 (CH), 134.0 (C), 138.5 (C), 139.7 (C), 140.0 (C), 140.4 (C), 141.2 (CH), 155.3 (C). IR (ATR, cm1): ṽ¼3081 (w), 3031 (w), 2217 (w), 1580 (w), 1488 (m), 1428 (m), 1401 (m), 1383 (m), 1263 (m), 1205 (m), 1183 (m), 1163 (m), 1121 (m), 1099 (m), 1074 (m), 1017 (w), 1004 (m), 917 (m), 836 (s), 807 (w), 784 (m), 762 (s), 749 (m), 724 (s), 697 (m), 643 (m), 624 (m), 560 (w), 526 (w), 511 (w), 488 (m), 455 (w), 438 (w), 418 (w), 410 (w), 382 (w). GCeMS (EI, 70 eV): m/z (%): 536 (Mþ, 12), 535 (36), 534 (39), 246 (2), 172 (4), 154 (2), 143 (6), 129 (35), 125 (2), 115 (11), 112 (7), 111 (4), 110 (5), 101 (10), 98 (10), 97 (8), 96 (3), 89 (5), 88 (3), 87 (17), 85 (11), 84 (11), 83 (15), 73 (88), 71 (30), 70 (11), 69 (24), 67 (6), 61 (11), 60 (100), 59 (6), 57 (40), 56 (13), 55 (32), 54 (4), 46 (7), 45 (29), 44 (35), 43 (38), 42 (11), 41 (34), 40 (8), 39 (9). HRMS (ESI, 70 eV): calcd for C41H30N ([MþH]þ): 536.23728, found 536.2371.

4.5.1. 3,5-Bis(4-methoxyphenyl)-2,6-diphenylpyridine (5a). Starting with 3,5-dichloro-2,6-diphenylpyridine 4a (100 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), 4methoxyphenyl-boronic acid (202 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5a was isolated as a colorless solid (131 mg, 90%); mp¼204e206  C. 1H NMR (400 MHz, CDCl3): d¼3.80 (s, 6H, MeO), 6.83e6.85 (m, 4H, CH), 7.18e7.21 (m, 4H, CH), 7.24e7.28 (m, 6H, CH), 7.51e7.54 (m, 4H, CH),

4.5.4. 3,5-Bis(2-methoxyphenyl)-2,6-diphenylpyridine (5d). Starting with 3,5-dichloro-2,6-diphenylpyridine 4a (100 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), 2methoxyphenylboronic acid (202 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5d was isolated as a colorless solid (131 mg, 90%); mp¼179e181  C. 1H NMR (400 MHz, CDCl3): d¼3.38 (s, 6H, MeO), 6.77e6.80 (m, 2H, CH), 6.97 (ddd, 3 JHeH¼8.3 Hz, 3JHeH¼7.5 Hz, 4JHeH¼1.2 Hz, 2H, CH), 7.20e7.22 (m,

4.5. General procedure for the synthesis of 2,3,5,6-tetraarylsubstituted pyridines 5aef

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6H, CH), 7.26e7.31 (m, 4H, CH), 7.48e7.52 (m, 4H, CH), 7.74 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): d¼55.0 (MeO), 111.1 (CH), 120.8 (CH), 127.4 (CH), 127.4 (CH), 128.9 (C), 129.0 (CH), 129.0 (CH),130.6 (C), 131.4 (CH), 141.0 (C), 142.2 (CH), 156.0 (C), 156.2 (C). IR (ATR, cm1): ṽ¼3079 (w), 3055 (w), 2951 (w), 2929 (w), 2832 (w), 1651 (w), 1598 (m), 1493 (m), 1418 (m), 1383 (m), 1280 (m), 1242 (m), 1180 (m), 1160 (m), 1024 (m), 1002 (m), 917 (m), 787 (m), 766 (m), 749 (s), 698 (s), 680 (m), 558 (m), 542 (m), 515 (m), 494 (m). GCeMS (EI, 70 eV): m/z (%): 444 (Mþ, 26), 443 (87), 442 (100), 428 (11), 427 (4), 426 (8), 413 (10), 412 (31), 411 (2), 396 (15), 384 (3), 380 (3), 366 (3), 350 (5), 336 (2), 320 (4), 307 (2), 198 (2), 183 (13), 177 (4), 176 (3), 170 (2), 169 (2). HRMS (ESI, 70 eV): calcd for C31H26NO2 ([MþH]þ): 444.19581, found 444.19648. 4.5.5. 3,5-Diphenyl-2,6-bis(3-methoxyphenyl)pyridine (5e). Starting with 3,5-dichloro-2,6-bis(3-methoxyphenyl)pyridine 4i (119 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), phenylboronic acid (161 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5e was isolated as a colorless solid (126 mg, 86%); mp¼105e107  C. 1H NMR (400 MHz, CDCl3): d¼3.62 (s, 6H, MeO), 6.79e6.82 (m, 2H, CH), 7.03e7.17 (m, 6H, CH), 7.27e7.32 (m, 10H, CH), 7.77 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): d¼55.1 (MeO), 114.3 (CH), 115.2 (CH), 122.8 (CH), 127.3 (CH), 128.4 (CH), 128.8 (CH), 129.5 (CH), 134.5 (C), 139.7 (C), 141.1 (C), 141.2 (CH), 155.0 (C), 159.0 (C). IR (ATR, cm1): ṽ¼3010 (w), 2959 (w), 2938 (w), 2832 (w), 1598 (m), 1574 (m), 1523 (w), 1418 (m), 1381 (m), 1287 (m), 1271 (m), 1241 (m), 1202 (m), 1180 (m), 1154 (m), 1031 (m), 1007 (w), 994 (m), 906 (m), 864 (m), 782 (s), 768 (s), 733 (m), 694 (s), 652 (m), 526 (m), 484 (w), 442 (w), 398 (w). GCeMS (EI, 70 eV): m/z (%): 444 (Mþ, 15), 443 (65), 442 (100), 427 (3), 426 (3), 400 (3), 399 (7), 398 (4), 384 (3), 368 (2), 366 (2), 355 (4), 354 (3), 183 (8), 177 (4), 176 (3), 171 (3), 164 (2), 158 (2). HRMS (ESI, 70 eV): calcd for C31H26NO2 ([MþH]þ): 444.19581, found 444.19667. 4.5.6. 3,5-Bis(4-(trifluoromethyl)phenyl)-2,6-bis(3-methoxyphenyl) pyridine (5f). Starting with 3,5-dichloro-2,6-bis(3methoxyphenyl)-pyridine 4i (119 mg, 0.33 mmol), Pd(dba)2 (4.7 mg, 2.5 mol %), cataCXium A (5.9 mg, 5.0 mol %), 4-(trifluoromethyl)phenylboronic acid (251 mg, 1.32 mmol), K3PO4 (282 mg, 1.32 mmol) and toluene (4.0 mL), 5f was isolated as a colorless solid (185 mg, 97%); mp¼143e144  C. 1H NMR (400 MHz, CDCl3): d¼3.65 (s, 6H, MeO), 6.83e6.86 (m, 2H, CH), 6.99e7.03 (m, 4H, CH), 7.15e7.19 (m, 2H, CH), 7.40e7.41 (m, 4H, CH), 7.57e7.59 (m, 4H, CH), 7.75 (s, 1H, CH). 13C NMR (100 MHz, CDCl3): d¼55.1 (MeO), 114.5 (CH), 115.3 (CH), 122.7 (CH), 124.2 (q, 1 JCeF¼272.3 Hz, CF3), 125.4 (q, 3JCeF¼4.2 Hz, CH), 129.1 (CH), 129.6 (q, 2JCeF¼32.5 Hz, C), 129.8 (CH), 133.1 (C), 140.3 (C), 140.8 (CH), 143.2 (C), 155.8 (C), 159.2 (C). 19F NMR (282.4 MHz, CDCl3): d¼62.2 (CF3). IR (ATR, cm1): ṽ¼3055 (w), 3063 (w), 3007 (w), 2936 (w), 2840 (w), 1606 (m), 1578 (m), 1529 (w), 1488 (w), 1402 (w), 1386 (w), 1322 (s), 1288 (m), 1219 (m), 1160 (m), 1122 (s), 1109 (m), 1066 (s), 1018 (m), 1006 (m), 906 (m), 881 (m), 846 (s), 777 (m), 730 (m), 715 (s), 696 (m), 687 (m), 642 (m), 607 (m), 571 (w), 553 (w), 511 (w), 476 (w), 445 (w), 405 (w). GCeMS (EI, 70 eV): m/z (%): 580 (Mþ, 15), 579 (60), 578 (100), 536 (3), 535 (8), 534 (5), 520 (2), 491 (4), 280 (4), 217 (3), 211 (2), 183 (2), 176 (2). HRMS (ESI, 70 eV): calcd for C33H24F6NO2 ([MþH]þ): 580.17028, found 580.17057. 4.6. General procedure for the synthesis of 3-chloro-2,5,6triaryl-substituted pyridines 35aee An oven-dried and argon-flushed pressure tube was charged with 2,3,5,6-tetrachloropyridine 1 (0.25 mmol), Pd(dba)2 (2.5 mol %), cataCXium A (5.0 mol %), boronic acid (0.9 mmol) and K3PO4 (1.25 mmol), followed by anhydrous toluene (4.0 mL). The tube was sealed with a Teflon valve and the reaction mixture was stirred at

100  C for 20 h. The cooled reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography. 4.6.1. 3-Chloro-2,5,6-triphenylpyridine (6a). Starting with 2,3,5,6tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd(dba)2 (3.6 mg, 2.5 mol %), cataCXium A (5.1 mg, 5.0 mol %), phenylboronic acid (107 mg, 0.88 mmol), K3PO4 (265 mg, 1.25 mmol) and toluene (4.0 mL), 6a was isolated as a colorless solid (36 mg, 42%); mp¼174e176  C. 1H NMR (300 MHz, CDCl3): d¼7.11e7.25 (m, 8H, CH), 7.30e7.44 (m, 5H, CH), 7.77 (s, 1H, CH), 7.79e7.83 (m, 2H, CH). 13 C NMR (75 MHz, CDCl3): d¼127.7 (CH), 127.9 (CH), 128.0 (CH), 128.0 (CH), 128.3 (C), 128.5 (CH), 128.8 (CH), 129.4 (CH), 129.6 (CH), 130.0 (CH), 135.7 (C), 138.0 (C), 138.4 (C), 139.1 (C), 140.1 (CH), 154.4 (C), 154.9 (C). IR (ATR, cm1): ṽ¼3054 (w), 3029 (w), 1598 (w), 1566 (w), 1528 (w), 1489 (w), 1420 (m), 1365 (m), 1304 (w), 1175 (w), 1114 (m), 1014 (s), 906 (m), 767 (m), 757 (m), 721 (m), 695 (s), 665 (m), 624 (m), 608 (m), 546 (m), 504 (m), 419 (w). GCeMS (EI, 70 eV): m/z (%): 342 (Mþ, 45), 341 (61), 340 (100), 305 (9), 304 (14), 303 (7), 302 (5), 276 (4), 227 (10), 202 (8), 201 (5), 200 (6), 153 (9), 152 (8), 151 (8), 77 (3). HRMS (ESI, 70 eV): calcd for C23H17ClN ([MþH]þ): 342.1044, found 342.1044. 4.6.2. 3-Chloro-2,5,6-tris(4-methoxyphenyl)pyridine (6b). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd(dba)2 (3.6 mg, 2.5 mol %), cataCXium A (5.1 mg, 5.0 mol %), 4methoxyphenylboronic acid (132 mg, 0.88 mmol), K3PO4 (265 mg, 1.25 mmol) and toluene (4.0 mL), 6b was isolated as a colorless solid (63 mg, 58%); mp¼123e125  C. 1H NMR (300 MHz, CDCl3): d¼3.76 (s, 3H, MeO), 3.80 (br s, 3H, MeO), 3.85 (s, 3H, MeO), 6.73e6.85 (m, 4H, CH), 6.96e7.00 (m, 2H, CH), 7.10e7.15 (m, 2H, CH), 7.32e7.37 (m, 2H, CH), 7.73 (s, 1H, CH), 7.83e7.87 (m, 3H, CH). 13 C NMR (75 MHz, CDCl3): d¼55.2 (MeO), 55.2 (MeO), 55.3 (MeO), 113.3 (CH), 113.3 (CH), 114.0 (CH), 127.4 (C), 130.5 (CH), 130.6 (C), 131.0 (CH), 131.3 (CH), 131.8 (C), 134.5 (C), 140.0 (CH), 142.0 (C), 153.3 (C), 154.3 (C), 159.1 (C), 159.4 (C), 160.0 (C). IR (ATR, cm1): ṽ¼3000 (w), 2957 (w), 2931 (w), 2836 (w), 1606 (s), 1515 (m), 1426 (m), 1403 (m), 1370 (m), 1292 (s), 1244 (s), 1172 (s), 1108 (m), 1029 (m), 1003 (m), 906 (m), 830 (s), 779 (s), 728 (m), 659 (m), 605 (s), 535 (s), 489 (w), 450 (w), 416 (w). GCeMS (EI, 70 eV): m/z (%): 432 (Mþ, 56), 431 (93), 430 (100), 416 (6), 415 (2), 389 (4), 388 (4), 387 (9), 373 (2), 344 (4), 278 (2), 266 (2), 265 (2), 216 (5), 198 (2), 177 (2), 176 (2), 168 (2), 145 (2), 139 (3), 133 (4). HRMS (EI, 70 eV): calcd for C26H22ClNO3 þ (Mþ): 431.12827, found 431.12737 and calcd for C26H37 22ClO3N (M ): 433.12532, found 433.12537. 4.6.3. 3-Chloro-2,5,6-tris(3-methoxyphenyl)pyridine (6c). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd(dba)2 (3.6 mg, 2.5 mol %), cataCXium A (5.1 mg, 5.0 mol %), 3methoxyphenylboronic acid (132 mg, 0.88 mmol), K3PO4 (265 mg, 1.25 mmol) and toluene (4.0 mL), 6c was isolated as a colorless solid (71 mg, 55%); mp¼122e124  C. 1H NMR (300 MHz, CDCl3): d¼3.51 (s, 3H, MeO), 3.54 (s, 3H, MeO), 3.74 (s, 3H, MeO), 6.63e6.74 (m, 4H, CH), 6.85e6.91 (m, 3H, CH), 7.00e7.12 (m, 2H, CH), 7.24e7.36 (m, 3H, CH), 7.72 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.0 (MeO), 55.1 (MeO), 55.3 (MeO), 113.6 (CH), 114.3 (CH), 114.5 (CH), 114.7 (CH), 114.9 (CH), 115.1 (CH), 121.7 (CH), 122.0 (CH), 122.4 (CH), 128.3 (C), 128.8 (CH), 128.9 (CH), 129.5 (CH), 135.6 (C), 139.2 (C), 139.7 (C), 140.0 (CH), 140.3 (C), 154.1 (C), 154.6 (C), 159.1 (C), 159.2 (C), 159.4 (C). IR (ATR, cm1): ṽ¼3079 (w), 3056 (w), 3011 (w), 2837 (w), 1585 (s), 1568 (s), 1528 (m), 1492 (m), 1462 (m), 1426 (s), 1360 (s), 1316 (m), 1286 (m), 1250 (m), 1225 (m), 1170 (m), 1111 (m), 1083 (w), 1039 (s), 1026 (s), 992 (w), 859 (m), 840 (w), 799 (w), 786 (s), 769 (s), 713 (m), 703 (s), 690 (m), 666 (m), 626 (w), 557 (m), 511 (m), 495 (m), 420 (w). GCeMS (EI, 70 eV): m/z (%): 432

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(Mþ, 48), 431 (70), 430 (100), 416 (6), 415 (5), 401 (5), 344 (2), 278 (2), 266 (2), 265 (2), 215 (3), 169 (2), 161 (2), 145 (4), 133 (4), 119 (2). HRMS (ESI, 70 eV): calcd for C26H23ClNO3 ([MþH]þ): 432.13628, found 432.1361. Anal. Calcd for C26H22ClNO3 (431.91): C, 72.30; H, 5.13; N, 3.24. Found: C, 72.06; H, 4.989; N, 2.915. 4.6.4. 3-Chloro-2,5,6-tris(2-methoxyphenyl)pyridine (6d). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd(dba)2 (3.6 mg, 2.5 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2methoxyphenylboronic acid (132 mg, 0.88 mmol), K3PO4 (265 mg, 1.25 mmol) and toluene (4.0 mL), 6d was isolated as a colorless solid (41 mg, 38%); mp¼48e50  C. 1H NMR (300 MHz, CDCl3): d¼3.33 (s, 3H, MeO), 3.60 (br s, 3H, MeO), 3.85 (s, 3H, MeO), 6.59e6.62 (m, 1H, CH), 6.79e6.83 (m, 2H, CH), 6.89e7.08 (m, 4H, CH), 7.14e7.23 (m, 2H, CH), 7.36e7.47 (m, 3H, CH), 7.81 (s, 1H, CH). 13 C NMR (75 MHz, CDCl3): d¼54.7 (MeO), 55.0 (MeO), 55.5 (MeO), 110.3 (CH), 110.3 (CH), 111.0 (CH), 119.9 (CH), 120.3 (CH), 120.5 (CH), 127.5 (C), 128.1 (C), 128.9 (CH), 129.2 (CH), 129.4 (C), 130.0 (CH), 130.9 (CH), 131.1 (CH), 131.6 (CH), 134.0 (C), 138.8 (CH), 153.4 (C), 153.9 (C), 154.0 (C), 156.0 (C), 156.1 (C), 157.1 (C). IR (ATR, cm1): ṽ¼3000 (w), 2918 (w), 2849 (w), 2833 (w), 1600 (m), 1580 (m), 1529 (m), 1491 (m), 1459 (m), 1434 (m), 1417 (m), 1364 (m), 1272 (m), 1243 (s), 1179 (m), 1120 (m), 1100 (m), 1014 (s), 906 (m), 803 (m), 748 (s), 726 (s), 656 (m), 626 (w), 505 (m), 469 (m), 388 (m). GCeMS (EI, 70 eV): m/z (%): 432 (Mþ, 15), 431 (31), 430 (19), 416 (3), 402 (22), 401 (13), 400 (49), 398 (5), 397 (28), 396 (100), 386 (6), 380 (7), 378 (4), 370 (6), 364 (5), 350 (8), 326 (30), 324 (22), 320 (9), 288 (5), 209 (3), 208 (7), 153 (8), 145 (11), 132 (4). HRMS (EI, 70 eV): calcd for C26H22ClNO3 (Mþ): 431.12827, found 431.12754 and calcd þ for C26H37 22ClNO3 (M ): 433.12532, found 433.12562. 4 . 6 . 5 . 3 - C h l o r o - 2 , 5 , 6 - t r i s ( 2 , 5 - d i m e t h o x y p h e nyl ) p y r i d i n e (6e). Starting with 2,3,5,6-tetrachloropyridine 1 (54 mg, 0.25 mmol), Pd(dba)2 (3.6 mg, 2.5 mol %), cataCXium A (5.1 mg, 5.0 mol %), 2,5-dimethoxyphenylboronic acid (159 mg, 0.88 mmol), K3PO4 (265 mg, 1.25 mmol) and toluene (4.0 mL), 6e was isolated as a slightly yellow solid (54 mg, 41%); mp¼152e154  C. 1H NMR (300 MHz, CDCl3): d¼3.31 (s, 3H, MeO), 3.54 (s, 3H, MeO), 3.59 (s, 3H, MeO), 3.68 (s, 3H, MeO), 3.77 (br s, 3H, MeO), 3.79 (s, 3H, MeO), 6.56e6.59 (m, 2H, CH), 6.70e6.75 (m, 3H, CH), 6.91e6.92 (m, 2H, CH), 6.98e7.02 (m, 2H, CH), 7.84 (s, 1H, CH). 13C NMR (75 MHz, CDCl3): d¼55.3 (MeO), 55.5 (MeO), 55.5 (MeO), 55.6 (MeO), 55.6 (MeO), 56.1 (MeO), 111.4 (CH), 111.6 (CH), 112.3 (CH), 114.4 (CH), 114.7 (CH), 115.2 (CH), 116.0 (CH), 116.2 (CH), 116.6 (CH), 127.7 (C), 128.6 (C), 129.8 (C), 129.9 (C), 133.8 (C), 138.9 (CH), 150.2 (C), 150.4 (C), 151.3 (C), 152.8 (C), 153.1 (C), 153.2 (C), 153.3 (C), 153.5 (C). IR (ATR, cm1): ṽ¼3070 (w), 2996 (m), 2934 (w), 2832 (w), 1586 (w), 1531 (w), 1497 (s), 1456 (s), 1415 (m), 1361 (m), 1308 (m), 1272 (s), 1214 (s), 1177 (s), 1148 (m), 1095 (m), 1049 (s), 1022 (s), 861 (m), 803 (s), 755 (m), 722 (m), 696 (m), 681 (m), 666 (m), 600 (w), 504 (w), 480 (w), 404 (w). GCeMS (EI, 70 eV): m/z (%): 522 (Mþ, 18), 521 (48), 520 (11), 492 (30), 491 (23), 490 (74), 487 (31), 486 (100), 484 (5), 460 (9), 456 (11), 446 (5), 430 (9), 388 (18), 387 (15), 386 (61), 385 (9), 384 (26), 261 (14), 228 (3), 220 (5), 213 (5), 205 (5), 187 (3), 176 (5), 161 (3). HRMS (EI, 70 eV): calcd for C29H28ClNO6 (Mþ): þ 521.15997, found 521.15991 and calcd for C29H37 28ClNO6 (M ): 523.15702, found 523.15832. Acknowledgements Financial support by the state Mecklenburg-Vorpommern (scholarship of the Interdisciplinary faculty of the University of Rostock/Dept. LL&M for S.R.) is gratefully acknowledged. Furthermore we would like to thank Prof. R. Ludwig (IfCh University of € hn (IfPh University of Rostock) for scientific Rostock) and Prof. O. Ku discussion.

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