Laccase-catalyzed oxidation of Hantzsch 1,4 ... · Laccase-catalyzed oxidation of Hantzsch 1,4-dihydropyridines to pyridines and a new one pot synthesis of pyridines Heba T. Abdel-Mohsen,

1

Laccase-catalyzed oxidation of Hantzsch 1,4-dihydropyridines to

pyridines and a new one pot synthesis of pyridines

Heba T. Abdel-Mohsen, Jürgen Conrad and Uwe Beifuss*

Bioorganische Chemie, Institut für Chemie, Universität Hohenheim

Garbenstr. 30, D-70599 Stuttgart, Germany

Fax: (+49) 711 459 22951; Tel: (+49) 711 459 22171

E-mail: [email protected]

Electronic Supplementary Information Table of contents

1. General remarks

2

2. General procedure I for the synthesis of Hantzsch 1,4-dihydropyridines 4a-k

2

3. Synthesis and analytical data of 1,4-dihydropyridines 4a-k

3

4. General procedures II and III for the laccase-catalyzed oxidation of 1,4-

dihydropyridines 4a-k to the corresponding pyridines 5a-k

19

5. General procedures IV and V for the one pot synthesis of pyridines 5a-k

20

6. Synthesis and analytical data of pyridines 5a-k

21

7. Determination of the laccase activity

48

8. References 48

Electronic Supplementary Material (ESI) for Green ChemistryThis journal is © The Royal Society of Chemistry 2012

2

1. General remarks

All chemicals and the laccase from Trametes versicolor (Fluka) were purchased from

commercial suppliers. Solvents used in extraction and purification were distilled prior to use.

Aldehydes and 1,3-dicarbonyl compounds used in the reactions were freshly distilled before use.

The pH of the buffer was adjusted using a pH 330/SET-1 pH-meter. Reaction temperatures are

reported as bath temperatures. Analytical thin layer chromatography (TLC) was performed on

precoated silica gel 60 F245 aluminium plates (Merck) with visualization under UV light and by

immersion in ethanolic vanillin solution followed by heating. Flash chromatography was carried

out on silica gel MN 60, 0.04-0.053 mm (Macherey & Nagel). Melting points were determined

on a Büchi melting point apparatus B-545 with open capillary tubes and are uncorrected. UV/VIS

spectra were recorded with a Varian Cary 50. IR spectra were measured on a Perkin-Elmer

Spectrum One (FT-IR-spectrometer). 1H and 13C NMR spectra were recorded at 300 (75) MHz

on a Varian UnityInova using CDCl3 or DMSO-d6. The chemical shifts were referenced to the

solvent signals at δH/C 2.49 / 39.50 ppm (DMSO-d6) and 7.26 / 77.00 ppm (CDCl3) relative to

TMS as internal standards. Coupling constants J [Hz] were directly taken from the spectra and

are not averaged. Splitting patterns are designated as s (singlet), d (doublet), t (triplet), q

(quartet), sep (septet) and m (multiplet). Low resolution electron impact mass spectra (EI-LRMS)

and exact electron impact mass spectra (HRMS) were recorded at 70 eV on a Finnigan MAT 95

instrument. The intensities are reported as percentages relative to the base peak (I = 100%).

2. General procedure I for the synthesis of Hantzsch 1,4-dihydropyridines 4a-k 1

An oven-dried 10 mL vial with a magnetic stirrer bar was charged with a mixture of an aldehyde

1 (1 mmol), a 1,3-dicarbonyl compound 2 (2 mmol) and ammonium acetate (3) (1.5 mmol). The

vial was sealed and the reaction mixture was stirred at 80 oC for the time given. After completion

of the reaction, the solid crude product was isolated upon addition of ice-cold water (10 mL)

followed by scratching. The precipitate was filtered and further purified by recrystallization from

methanol to yield the 1,4-dihydropyridines 4a-k.


3

3. Synthesis and analytical data of 1,4-dihydropyridines 4a-k

3.1. Synthesis and analytical data of dimethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4a). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), methyl acetoacetate (2a) (232 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5

mmol) were reacted for 10 min. Purification afforded dimethyl-1,4-dihydro-2,6-

dimethylpyridine-3,5-dicarboxylate (4a) (160 mg, 71%) as canary yellow powder; mp 210 - 212 oC (from MeOH) (lit.,2,3 208 - 210 oC); Rf = 0.29 (petroleum ether / EtOAc = 2:1); ṽmax (atr)/cm-1

3350 (NH), 2982, 2962 and 2873 (C_H), 1698 and 1647 (C=O), 1626 (C=C), 1203 and 1073

(C_O); δH (300 MHz; DMSO-d6) 2.10 (6H, s, 1´-H), 3.12 (2H, s, 4-H), 3.57 (6H, s, 2´´-H) and

8.30 (1H, s, 1-H); δC (75 MHz; DMSO-d6) 17.80 (C-1´), 24.78 (C-4), 50.60 and 50.62 (C-2´´),

96.88 (C-3 and C-5), 146.77 (C-2 and C-6) and 167.45 (C-1´´), m/z (EI, 70 eV) 225 (M+, 23%),

224 (50, M+ - 1), 210 (100, M+ - CH3) and 194 (33).

1.000

5.429

2.057

5.678

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.3005

3.5700

3.3261

3.1170

2.0991

NH

OO

O O

1

2

34

5

6

1´´1´´ 2´´2´´

1´1´


4

PPM 180 160 140 120 100 80 60 40 20 0

167.4506

146.7672

96.8813

50.617850.5995

40.333740.056139.778139.500039.221738.943338.6647

24.7765

17.8019

Fig. 1 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4a in DMSO-d6. 3.2. Synthesis and analytical data of dimethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4b). According to the general procedure I, acetaldehyde (1b) (66 mg, 1.5 mmol),

methyl acetoacetate (2a) (232 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were

reacted for 30 min. Purification afforded dimethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4b) (180 mg, 75%) as white crystals; mp 153 - 155 oC (from MeOH) (lit.,2,3 152 -

154 oC); Rf = 0.41 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3340 (NH), 2950 (C_H), 1677

and 1647 (C=O), 1630 (C=C), 1222 and 1054 (C_O); δH (300 MHz; CDCl3) 0.95 (3H, d, 3J 1´´´-H,

4-H 6.6 Hz, 1´´´-H), 2.27 (6H, s, 1´-H), 3.71 (6H, s, 2´´-H), 3.80 (1H, q, 3J 4-H, 1´´´-H 6.6 Hz, 4-H)

and 5.65 (1H, s, 1-H); δC (75 MHz; CDCl3) 19.40 (C-1´), 22.25 (C-1´´´), 28.41 (C-4), 50.94 and

50.95 (C-2´´), 104.41 (C-3 and C-5), 144.63 (C-2 and C-6) and 168.23 (C-1´´); m/z (EI, 70 eV)

239 (M+, 2%), 224 (100, M+ - CH3), 208 (37, M+ - OCH3) and 192 (17).


5

1.000

1.1325.653

5.829

3.100

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

5.6542

3.81503.79333.7097

2.2646

0.96110.9394

0.0603

PPM 180 160 140 120 100 80 60 40 20 0

168.2299

144.6245

104.4104

77.423877.000076.5761

50.954450.9407

28.4051

22.253419.3960

0.9877

Fig. 2 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4b in CDCl3.

NH

OO

O O

1

2

34

5

6

1´´1´´ 2´´2´´

1´1´

1´´´


6

3.3. Synthesis and analytical data of diethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4c). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), ethyl acetoacetate (2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol)

were reacted for 15 min. Purification afforded diethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4c) (200 mg, 79%) as canary yellow powder; mp 172 - 174 oC (from MeOH)

(lit.,2,3 170 - 172 oC); Rf = 0.39 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3347 (NH), 2988,

2939 and 2897 (C_H), 1691 and 1647 (C=O), 1629 (C=C), 1220 and 1055 (C_O); δH (300 MHz;

CDCl3) 1.28 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.19 (6H, s, 1´-H), 3.26 (2H, s, 4-H), 4.17 (4H, q, 3J 2´´-H, 3´´-H 7.2 Hz, 2´´-H) and 5.20 (1H, s, 1-H); δC (75 MHz; CDCl3) 14.45 (C-3´´), 19.15 (C-

1´), 24.78 (C-4), 59.64 (C-2´´), 99.51 (C-3 and C-5), 144.78 (C-2 and C-6) and 168.05 (C-1´´);

m/z (EI, 70 eV) 253 (M+, 21%), 252 (30, M+ - 1), 224 (100) and 196 (86).

1.000

3.292

1.810

4.957

8.287

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

4.20274.17904.15534.1316

3.2642

2.1896

1.5669

1.30621.28251.2586

0.06710.0551

3´´ 3´´1´´1´´ 2´´2´´

1´1´ 1

2

34

5

6

NH

OO

O O


7

PPM 180 160 140 120 100 80 60 40 20 0

168.0457

144.7844

99.5064

77.424377.000076.5758

59.6358

24.7766

19.1503

14.4491

Fig. 3 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4c in CDCl3. 3.4. Synthesis and analytical data of diethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4d). According to the general procedure I, acetaldehyde (1b) (66 mg, 1.5 mmol),

ethyl acetoacetate (2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were

reacted for 15 min. Purification afforded diethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4d) (188 mg, 70%) as white crystals; mp 128 - 130 oC (from MeOH) (lit.,2,3 128 -

130 oC); Rf = 0.43 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3343 (NH), 2984, 2963 and

2905 (C_H), 1695 (C=O), 1639 (C=C), 1222 and 1056 (C_O); δH (300 MHz; CDCl3) 0.96 (3H, d, 3J 1´´´-H, 4-H 6.6 Hz, 1´´´-H), 1.29 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.26 (6H, s, 1´-H), 3.83 (1H, q, 3J 4-H, 1´´´-H 6.6 Hz, 4-H), 4.15 (2H, dq, 2J 2´á-H, 2´´b-H 10.9 Hz,

3J 2´á-H, 3´´H 7.2 Hz, 2´á-H), 4.21 (2H,

dq, 2J 2´á-H, 2´´b-H 10.9 Hz, 3J 2´´b-H, 3´´H 7.2 Hz, 2´´b-H) and 5.55 (1H, s, 1-H); δC (75 MHz; CDCl3)

14.41 (C-3´´), 19.48 (C-1´), 22.22 (C-1´´´), 28.50 (C-4), 59.56 and 59.57 (C-2´´), 104.70 (C-3

and C-5), 144.21 (C-2 and C-6) and 167.83 (C-1´´); m/z (EI, 70 eV) 265 (M+ - 2, 5%), 252 (100,

M+ - CH3), 224 (34) and 196 (37).


8

1.000

3.908

0.963

5.984

6.139

3.495

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

5.5543

4.24374.23134.21994.20754.18354.18034.15654.14404.13284.12033.83773.8161

2.25812.1655

1.6255

1.31221.28851.26481.24950.97590.9543

0.0630

PPM 180 160 140 120 100 80 60 40 20 0

167.8329

144.2099

104.6986

77.423677.043477.000076.5763

59.571359.5584

28.4992

22.220819.4747

14.4135

0.9919

Fig. 4 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4d in CDCl3.

3´´ 3´´1´´1´´

2´á

1´1´ 1

2

34

5

6

NH

OO

O O HH2´´b

H H2´á2´´b 1´´´


9

3.5. Synthesis and analytical data of diethyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (4e). According to the general procedure I, benzaldehyde (1c) (106 mg, 1 mmol),

ethyl acetoacetate (2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were

reacted for 180 min. Purification afforded diethyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-

3,5-dicarboxylate (4e) (148 mg, 45%) as white crystals; mp 160 - 162 oC (from MeOH) (lit.,2,3

158 - 160 oC); Rf = 0.49 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3339 (NH), 3060 and

2982 (C_H), 1686 and 1649 (C=O), 1620 (C=C), 1207 and 1090 (C_O); δH (300 MHz; CDCl3)

1.22 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.33 (6H, s, 1´-H), 4.07 (2H, dq, 2J 2´á-H, 2´´b-H 10.9 Hz, 3J

2´á-H, 3´´H 7.0 Hz, 2´á-H), 4.10 (2H, dq, 2J 2´á-H, 2´´b-H 10.9 Hz, 3J 2´´b-H, 3´´H 7.1 Hz, 2´´b-H), 4.99

(1H, s, 4-H), 5.63 (1H, s, 1-H), 7.11-7.14 (1H, m, 4´´´-H), 7.18-7.22 (2H, m, 3´´´-H and 5´´´-H)

and 7.26-7.30 (2H, m, 2´´´-H and 6´´´-H); δC (75 MHz; CDCl3) 14.22 (C-3´´), 19.58 (C-1´),

39.62 (C-4), 59.70 (C-2´´), 104.19 (C-3 and C-5), 126.07 (C-4´´´), 127.80 (C-3´´´ and C-5´´´),

127.99 (C-2´´´ and C-6´´´), 143.77 (C-2 and C-6), 147.73 (C-1´´´) and 167.60 (C-1´´); m/z (EI,

70 eV) 329 (M+, 12%), 300 (15, M+ - C2H5), 284 (18, M+ - OC2H5), 252 (100, M+ - C6H5), 224

(36) and 196 (45).

1.000

1.165

4.496

6.948

6.466

1.7832.1011.031

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.29487.28967.28337.26627.26237.26007.22387.21747.20037.19527.17527.14227.13747.13267.1135

5.6248

4.9886

4.13784.12554.11484.10174.09154.07794.06794.05444.0442

2.3265

1.6014

1.23971.21591.1922

3´´ 3´´1´´1´´

2´á

1´1´ 1

2

34

5

6

NH

OO

O O HH2´´b

H H2´á2´´b

1´´´

2´´´

5´´´

4´´´

3´´´

6´´´


10

PPM 180 160 140 120 100 80 60 40 20 0

167.5962

147.7269143.7665

127.9878127.8043126.0706

104.1934

77.423577.000076.5757

59.6950

39.616139.6062

19.5775

14.2235

Fig. 5 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4e in CDCl3. 3.6. Synthesis and analytical data of di-isopropyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4f). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), isopropyl acetoacetate (2c) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5

mmol) were reacted for 30 min. Purification afforded di-isopropyl-1,4-dihydro-2,6-

dimethylpyridine-3,5-dicarboxylate (4f) (196 mg, 70%) as pale yellow crystals; mp 119 - 121 oC

(from MeOH) (lit.,4 123 - 125 oC); Rf = 0.48 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3359

(NH), 2979, 2935 and 2878 (C_H), 1667 and 1644 (C=O), 1630 (C=C), 1232 and 1106 (C_O); δH

(300 MHz; CDCl3) 1.25 (12H, d, 3J 3´´-H, 2´´-H 6.3 Hz, 3´´-H), 2.18 (6H, s, 1´-H), 3.24 (2H, s, 4-H),

5.03 (2H, sep, 3J 2´´-H, 3´´-H 6.3 Hz, 2´´-H) and 5.06 (1H, s, 1-H); δC (75 MHz; CDCl3) 19.23 (C-

1´), 22.08 (C-3´´), 24.84 (C-4), 66.78 and 66.80 (C-2´´), 99.86 (C-3 and C-5), 144.36 (C-2 and C-

6) and 167.63 (C-1´´); m/z (EI, 70 eV) 281 (M+, 4%), 280 (17, M+ - 1), 279 (84, M+ - 2) and 28

(100).


11

1.000

1.320

2.873

5.861

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

5.06055.03965.0188

3.2353

2.1748

1.26461.2438

PPM 180 160 140 120 100 80 60 40 20 0

167.6289

144.3645

99.8563

77.424277.000076.5759

66.796766.7843

24.835622.080819.2299

Fig. 6 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4f in CDCl3.

1

2

34

5

6

NH

OO

O O3´´ 3´´

1´´1´´2´´ 2´´

1´1´

3´´3´´


12

3.7. Synthesis and analytical data of di-tert-butyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4g). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), tert-butyl acetoacetate (2d) (316 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5

mmol) were reacted for 30 min. Purification afforded di-tert-butyl-1,4-dihydro-2,6-

dimethylpyridine-3,5-dicarboxylate (4g) (246 mg, 80%) as white crystals; mp 151 - 153 oC (from

MeOH) (lit.,4 152 - 154 oC); Rf = 0.64 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 3336 (NH),

2958 (C_H), 1694 and 1650 (C=O), 1639 (C=C), 1203 and 1092 (C_O); δH (300 MHz, CDCl3)

1.48 (18H, s, 3´´-H), 2.14 (6H, s, 1´-H), 3.17 (2H, s, 4-H) and 5.02 (1H, s, 1-H); δC (75 MHz,

CDCl3) 19.20 (C-1´), 25.42 (C-4), 28.19 and 28.36 (C-3´´), 79.41 (C-2´´), 100.89 (C-3 and C-5),

143.72 (C-2 and C-6) and 167.57 (C-1´´); m/z (EI, 70 eV) 309 (M+, 68%), 308 (100, M+ - 1), 307

(59, M+ - 2) and 292 (60).

1.000

2.745

8.647

0.479

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

3.1723

2.1433

1.60381.4769

1

2

34

5

6

NH

OO

O O3´´ 3´´

1´´1´´2´´ 2´´

1´1´

3´´3´´

3´´3´´


13

PPM 180 160 140 120 100 80 60 40 20 0

167.5719

143.7198

100.8852

79.406577.423877.000076.5758

28.363428.188125.4161

19.1955

1.0016

Fig. 7 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4g in CDCl3.

3.8. Synthesis and analytical data of diallyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4h). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), allyl acetoacetate (2e) (284 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol)

were reacted for 10 min. Purification afforded diallyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4h) (200 mg, 72%) as yellow powder; mp 164 - 166 oC (from MeOH); Rf = 0.50

(petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 366 (log ε, 3.81) and 228 (4.18); ṽmax(atr)/cm-1

3345 (NH), 3085, 2985, 2941 and 2879 (C_H), 1694 and 1655 (C=O), 1627 (C=C), 1211 and

1085 (C_O); δH (300 MHz; CDCl3) 2.20 (6H, s, 1´-H), 3.33 (2H, s, 4-H), 4.62 (4H, dt, 3J 2´´-H, 3´´-H

5.4 Hz, 4J 1.6 Hz, 2´´-H), 5.20 (2H, dq, 2J 1.4 Hz, 3Jcis 4´á-H, 3´´-H 10.5 Hz, 4J 1.4 Hz, 4´á-H), 5.31

(2H, dq, 2J 1.7 Hz, 3Jtrans 4´´b-H, 3´´-H 17.4 Hz, 4J 1.7 Hz, 4´´b-H) and 5.96 (2H, ddt, 3J 3´´-H, 2´´-H 5.4

Hz, 3Jcis 3´´-H, 4´á-H 10.5 Hz, 3Jtrans 3´´-H, 4´´b-H 17.4 Hz, 3´´H); δC (75 MHz; CDCl3) 19.21 (C-1´),

24.73 (C-4), 64.38 (C-2´´), 99.33 (C-3 and C-5), 117.17 (C-4´´), 132.92 (C-3´´), 145.26 (C-2 and

C-6) and 167.50 (C-1´´); ´´); m/z (EI, 70 eV) 277 (M+, 7%), 275 (15, M+ - 2), 236 (44, M+ -

CH2CHCH2), 218 (75), 191 (23), 41 (93, CH2CHCH2) and 28 (100); HRMS (EI, M+) found:

277.1275 calcd. for C15H19NO4: 277.1314 .


14

1.000

2.755

2.398

1.321

3.767

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

5.99805.98075.96315.95885.94495.94065.92325.90575.34325.33815.33285.32765.28565.28065.27535.27025.22355.21925.21465.21025.18865.18435.17975.17534.63304.62824.62334.61504.61024.6053

3.3297

2.1975

PPM 180 160 140 120 100 80 60 40 20 0

167.4955

145.2580

132.9191

117.1717

99.3286

77.423977.000076.5760

64.3664

24.7260

19.1885

Fig. 8 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4h in CDCl3.

1

2

34

5

6

3´´ 3´´

1´´1´´ 2´´2´´

1´1´ NH

OO

O O4´´b4´´b

H

H

H

H

H

H4´á4´á


15

3.9. Synthesis and analytical data of dimethyl-2,6-diethyl-1,4-dihydropyridine-3,5-

dicarboxylate (4i). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), methyl propionyl acetate (2f) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5

mmol) were reacted for 15 min. Purification afforded dimethyl-2,6-diethyl-1,4-dihydropyridine-

3,5-dicarboxylate (4i) (227 mg, 90%) as yellow powder; mp 129 - 131 oC (from MeOH); Rf =

0.64 (petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 363 (log ε, 3.64), 230 (4.14) and 206

(4.14); ṽmax(atr)/cm-1 3350 (NH), 2982, 2962 and 2873 (C_H), 1697 and 1646 (C=O), 1625

(C=C), 1203 and 1072 (C_O); δH (300 MHz; CDCl3) 1.15 (6H, t, 3J 2´H, 1´H 7.5 Hz, 2´-H), 2.61

(4H, q, 3J 1´H, 2´H 7.5 Hz, 1´-H), 3.27 (2H, s, 4-H), 3.70 (6H, s, 2´´-H) and 5.31 (1H, s, 1-H); δC

(75 MHz; CDCl3) 12.54 (C-2´), 24.86 (C-4), 25.62 (C-1´), 50.98 (C-2´´), 98.21 (C-3 and C-5),


(100, M+ - CH3), 222 (35, M+ - OCH3) and 194 (13, M+ - COOCH3); HRMS (EI, M+) found:

253.1308 calcd. for C13H19NO4: 253.1314.

0.999

6.029

2.195

4.354

5.995

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

5.3113

3.6955

3.2655

2.64942.62422.59912.5740

1.17021.14511.1199

0.0603

1

1´´1´´2´´2´´

1´1´

2

34

5

6

NH

OO

O O

2´ 2´


16

PPM 180 160 140 120 100 80 60 40 20 0

167.8558

150.9587

98.2131

77.424377.000076.5762

50.9784

25.614524.8553

12.5421

Fig. 9 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4i in CDCl3. 3.10. Synthesis and analytical data of diethyl-2,6-diethyl-1,4-dihydropyridine-3,5-

dicarboxylate (4j). According to the general procedure I, paraformaldehyde (1a) (30 mg, 1

mmol), ethyl propionyl acetate (2g) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5

mmol) were reacted for 40 min. Purification afforded diethyl-2,6-diethyl-1,4-dihydropyridine-

3,5-dicarboxylate (4j) (196 mg, 70%) as yellow powder; mp 106 - 108 oC (from MeOH); Rf =

0.70 (petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 363 (log ε, 3.67), 229 (4.13) and 203

(4.05); ṽmax(atr)/cm-1 3344 (NH), 2980, 2935 and 2873 (C_H), 1694 and 1645 (C=O), 1625

(C=C), 1193 and 1071 (C_O); δH (300 MHz; CDCl3) 1.14 (6H, t, 3J 2´H, 1´H 7.5 Hz, 2´-H), 1.27

(6H, t, 3J 3´´H, 2´´H 6.9 Hz, 3´´-H), 2.59 (4H, q, 3J 1´H, 2´H 7.8 Hz, 1´-H), 3.26 (2H, s, 4-H), 4.16 (4H,

q, 3J 2´´H, 3´´H 7.2 Hz, 2´´-H) and 5.33 (1H, s, 1-H); δC (75 MHz; CDCl3) 12.62 (C-2´), 14.39 (C-

3´´), 24.85 (C-4), 25.72 (C-1´), 59.58 (C-2´´), 98.44 (C-3 and C-5), 150.62 (C-2 and C-6) and

167.55 (C-1´´); m/z (EI, 70 eV) 281 (M+, 9%), 238 (48), 220 (28) and 195 (100); HRMS (EI, M+)

found: 281.1581 calcd. for C15H23NO4: 281.1627.


17

1.000

3.610

2.048

3.988

5.4245.464

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

5.3276

4.19164.16794.14414.1204

3.2552

2.63152.60642.58132.5562

1.29321.26941.24571.16631.14131.1161

PPM 180 160 140 120 100 80 60 40 20 0

167.5539

150.6212

98.4410

77.424177.000076.5757

59.5844

25.722024.8541

14.392712.6175

Fig. 10 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4j in CDCl3.

1

3´´ 3´´1´´1´´ 2´´2´´

1´1´

2

34

5

6

NH

OO

O O

2´ 2´


18

3.11. Synthesis and analytical data of 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (4k).

According to the general procedure I, paraformaldehyde (1a) (30 mg, 1 mmol), acetylacetone

(2h) (200 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted for 15 min.

Purification afforded 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (4k) (145 mg, 75%) as

yellow powder; mp 213 - 215 oC (from MeOH) (lit.,5 216 - 220 oC); Rf = 0.25 (petroleum ether /

EtOAc = 1:2); ṽmax(atr)/cm-1 3382 (NH), 2920 (C_H), 1668 and 1643 (C=O) and 1588 (C=C); δH

(300 MHz; DMSO-d6) 2.09 (6H, s, 1´-H), 2.12 (6H, s, 2´´-H), 3.25 (2H, s, 4-H) and 8.27 (1H, s,

1-H); δC (75 MHz; DMSO-d6) 18.67 (C-1´), 26.39 (C-4), 30.10 (C-2´´), 107.62 (C-3 and C-5),


(50, M+ - CH3), 150 (23, M+ - COCH3), 106 (23) and 43 (38, COCH3).

1.000

5.4302.013

11.45

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.2667

3.33203.2493

2.12072.0875

NH

O O

2

34

5

6

1´´1´´2´´2´´

1´1´1


19

PPM 180 160 140 120 100 80 60 40 20 0

196.6439

145.2339

107.6176

40.331540.056339.777739.500039.221738.941038.666330.094626.3835

18.6688

Fig. 11 1H (300 MHz) and 13C (75 MHz) NMR spectra of 4k in DMSO-d6.

4. General procedures II and III for the laccase-catalyzed oxidation of 1,4-dihydropyridines

4a-k to the corresponding pyridines 5a-k

4.1. General procedure II for the laccase-catalyzed oxidation of 1,4-dihydropyridines 4a-k

to the corresponding pyridines 5a-k (method A)

A 100 mL round bottomed flask with a magnetic stirrer bar was charged with a solution of 1,4-

dihydropyridine 4 (1 mmol) in methanol (3 - 6 mL). Acetate buffer (0.2 M, pH 4.37, 30 mL),

laccase from Trametes versicolor (168 U, 12 mg) and ABTS diammonium salt (6.9 mg, 0.0125

mmol) were added and the reaction mixture was stirred at 50 oC for the time given. After

extraction with CH2Cl2 (7 × 20 mL), the combined organic phases were dried over anhydrous

Na2SO4, filtered and the solvents were evaporated in vacuo. The crude product was purified by

flash chromatography on SiO2 (petroleum ether / EtOAc = 6:1). It was found that 2-butanone can

be also used for extraction.


20

4.2. General procedure III for the laccase-catalyzed oxidation of 1,4-dihydropyridines 4a-k

to the corresponding pyridines 5a-k (method B)

A 100 mL round bottomed flask with a magnetic stirrer bar was charged with a solution of 1,4-

dihydropyridine 4 (1 mmol) in methanol (3 - 6 mL). Acetate buffer (0.2 M, pH 4.37, 30 mL),

laccase from Trametes versicolor (168 U, 12 mg) and ABTS diammonium salt (54.9 mg, 0.1

mmol) were added and the reaction mixture was stirred at 50 oC for the time given. After

extraction with CH2Cl2 (7 × 20 mL), the combined organic phases were dried over anhydrous

Na2SO4, filtered and the solvents were evaporated in vacuo. The crude product was purified by

flash chromatography on SiO2 (petroleum ether / EtOAc = 6:1). It was found that 2-butanone can

be also used for extraction.

5. General procedures IV and V for the one pot synthesis of pyridines 5a-k

5.1. General procedure IV for the one pot synthesis of pyridines 5a-k (method C)

A 100 mL round bottomed flask with a magnetic stirrer bar was charged with an aldehyde 1 (1

mmol), a 1,3-dicarbonyl compound 2 (2 mmol) and ammonium acetate (3) (1.5 mmol). The

mixture was stirred at 80 oC until the starting materials were consumed (TLC). After cooling to

room temperature, the mixture was dissolved in methanol (3 - 6 mL). Acetate buffer (0.2 M, pH

4.37, 30 mL), laccase from Trametes versicolor (168 U, 12 mg) and ABTS diammonium salt (6.9

mg, 0.0125 mmol) were added and the mixture was stirred at 50 oC for the time given. The

reaction mixture was extracted with CH2Cl2 (7 × 20 mL) and the combined organic phases were

dried over anhydrous Na2SO4, filtered and the solvents were evaporated in vacuo. The crude

product was purified by flash chromatography on SiO2 (petroleum ether / EtOAc = 6:1). It was

found that 2-butanone can be also used for extraction.

5.2. General procedure V for the one pot synthesis of pyridines 5a-k (method D)

A 100 mL round bottomed flask with a magnetic stirrer bar was charged with an aldehyde 1 (1

mmol), a 1,3-dicarbonyl compound 2 (2 mmol) and ammonium acetate (3) (1.5 mmol). The

mixture was stirred at 80 oC until the starting materials were consumed (TLC). After cooling to


21

room temperature, the mixture was dissolved in methanol (3 - 6 mL). Acetate buffer (0.2 M, pH

4.37, 30 mL), laccase from Trametes versicolor (168 U, 12 mg) and ABTS diammonium salt

(54.9 mg, 0.1 mmol) were added and the mixture was stirred at 50 oC for the time given. The

reaction mixture was extracted with CH2Cl2 (7 × 20 mL) and the combined organic phases were

dried over anhydrous Na2SO4, filtered and the solvents were evaporated in vacuo. The crude

product was purified by flash chromatography on SiO2 (petroleum ether / EtOAc = 6:1). It was

found that 2-butanone can be also used for extraction.

6. Synthesis and analytical data of pyridines 5a-k

6.1. Synthesis and analytical data of dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5a)

Synthesis of 5a

According to the general procedure II, dimethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4a) (225 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),

laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt (6.9 mg, 0.0125 mmol)

were reacted for 5 h. Purification afforded dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5a)

(209 mg, 94%).

According to the general procedure III, dimethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4a) (225 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 5 h. Purification afforded dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5a)

(212 mg, 95%).

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), methyl

acetoacetate (2a) (232 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted

for 10 min. The reaction mixture was treated with methanol (3 mL), acetate buffer (0.2 M, pH

4.37, 30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt (6.9 mg,

0.0125 mmol) for 7 h. Purification afforded dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5a) (133 mg, 60%).


22

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), methyl



4.37, 30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt (54.9

mg, 0.1 mmol) for 6 h. Purification afforded dimethyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5a) (130 mg, 58 %).

Analytical data of 5a

White powder; mp 98 - 100 oC (lit.,6 101 - 103 oC); Rf = 0.49 (petroleum ether / EtOAc = 2:1);

ṽmax(atr)/cm-1 2970 (C_H), 1721 (C=O), 1595 and 1547 (C=C, C=N), 1227 and 1104 (C_O); δH

(300 MHz; CDCl3) 2.84 (6H, s, 1´-H), 3.92 (6H, s, 2´´-H) and 8.69 (1H, s, 4-H); δC (75 MHz;

CDCl3) 24.92 (C-1´), 52.28 (C-2´´), 122.60 (C-3 and C-5), 141.04 (C-4), 162.61 (C-2 and C-6)

and 166.21 (C-1´´); m/z (EI, 70 eV) 223 (M+, 98%), 192 (100, M+ - OCH3) and 164 (61).

1.000

8.271

8.127

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.6920

3.9200

2.8423

N

OO

O O

2

34

5

6

1´´1´´ 2´´2´´

1´1´


23

PPM 180 160 140 120 100 80 60 40 20 0

166.2060162.6093

141.0348

122.5999

77.424177.000076.5760

52.2779

24.9179

Fig. 12 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5a in CDCl3.

6.2. Synthesis and analytical data of dimethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5b) Synthesis of 5b According to the general procedure II, dimethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4b) (239 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 4 h. Purification afforded dimethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate

(5b) (213 mg, 90%).

According to the general procedure III, dimethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4b) (239 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 8 h. Purification afforded dimethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate

(5b) (189 mg, 80%).


24

According to the general procedure IV, acetaldehyde (1b) (66 mg, 1.5 mmol), methyl




0.0125 mmol) for 7 h. Purification afforded dimethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate

(5b) (142 mg, 60%).

According to the general procedure V, acetaldehyde (1b) (66 mg, 1.5 mmol), methyl acetoacetate

(2a) (232 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted for 30 min.

The reaction mixture was treated with methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


for 9 h. Purification afforded dimethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5b) (118 mg,

50%).

Analytical data of 5b


ṽmax(atr)/cm-1 2980 (C_H), 1713 (C=O), 1558 (C=C, C=N), 1220 and 1043 (C_O); δH (300 MHz;

CDCl3) 2.24 (3H, s, 1´´´-H), 2.50 (6H, s, 1´-H) and 3.92 (6H, s, 2´´-H); δC (75 MHz; CDCl3)

17.11 (C-1´´´), 23.01 (C-1´), 52.40 (C-2´´), 127.27 (C-3 and C-5), 142.35 (C-4), 155.22 (C-2 and

C-6) and 168.84 (C-1´´); m/z (EI, 70 eV) 237 (M+, 30%), 222 (33, M+ - CH3), 206 (56) and 28

(100).


25

1.000

2.206

2.189

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.2600

3.9231

2.4990

2.2398

PPM 180 160 140 120 100 80 60 40 20 0

168.8429

155.2195

142.3494

127.2738

77.424177.000076.576576.5351

52.3966

23.0112

17.1054

Fig. 13 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5b in CDCl3.

N

OO

O O

2

34

5

6

1´´1´´ 2´´2´´

1´1´

1´´´


26

6.3. Synthesis and analytical data of diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5c)

Synthesis of 5c

According to the general procedure II, diethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4c) (253 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 5 h. Purification afforded diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5c)

(208 mg, 83%).

According to the general procedure III, diethyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4c) (253 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 5 h. Purification afforded diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5c)

(225 mg, 90%).

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), ethyl

acetoacetate (2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



0.0125 mmol) for 5 h. Purification afforded diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5c)

(133 mg, 53%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), ethyl

acetoacetate (2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



mg, 0.1 mmol) for 5 h. Purification afforded diethyl-2,6-dimethylpyridine-3,5-dicarboxylate (5c)

(168 mg, 67%).

Analytical data of 5c




27

CDCl3) 1.40 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.83 (6H, s, 1´-H), 4.38 (4H, q, 3J 2´´-H, 3´´-H 7.2 Hz,

2´´-H) and 8.66 (1H, s, 4-H); δC (75 MHz; CDCl3) 14.25 (C-3´´), 24.94 (C-1´), 61.38 (C-2´´),

123.05 (C-3 and C-5), 140.88 (C-4), 162.20 (C-2 and C-6) and 165.95 (C-1´´); m/z (EI, 70 eV)

251 (M+, 82%), 206 (100) and 195 (22).

1.000

5.205

8.124

7.649

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.08.6601

7.2600

4.42094.39714.37334.3495

2.8342

1.7122

1.42751.40371.3799

0.0604

3´´ 3´´1´´1´´ 2´´2´´

1´1´

2

34

5

6

N

OO

O O


28

PPM 180 160 140 120 100 80 60 40 20 0

165.9472162.1957

140.8770

123.0463

77.423877.000076.5759

61.3756

24.9353

14.2503

Fig. 14 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5c in CDCl3.

6.4. Synthesis and analytical data of diethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5d)

Synthesis of 5d

According to the general procedure II, diethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4d) (267 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 6 h. Purification afforded diethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5d)

(230 mg, 87%).

According to the general procedure III, diethyl-1,4-dihydro-2,4,6-trimethylpyridine-3,5-

dicarboxylate (4d) (267 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 5 h. Purification afforded diethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5d)

(238 mg, 90%).


29

According to the general procedure IV, acetaldehyde (1b) (66 mg, 1.5 mmol), ethyl acetoacetate

(2b) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted for 15 min.


laccase (168 U, 12 mg, Trametes versicolor), ABTS diammonium salt (6.9 mg, 0.0125 mmol) for

6 h. Purification afforded diethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5d) (148 mg, 56%).

According to the general procedure V, acetaldehyde (1b) (66 mg, 1.5 mmol), ethyl acetoacetate



laccase (168 U, 12 mg, Trametes versicolor), ABTS diammonium salt (54.9 mg, 0.1 mmol) for 6

h. Purification afforded diethyl-2,4,6-trimethylpyridine-3,5-dicarboxylate (5d) (161 mg, 61%).

Analytical data of 5d

Colourless oil (lit.,6 oil); Rf = 0.66 (petroleum ether / EtOAc = 2:1); ṽmax(atr)/cm-1 2981 and 2962

(C_H), 1721 (C=O), 1565 (C=C, C=N), 1214 and 1038 (C_O); δH (300 MHz; CDCl3) 1.36 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.24 (3H, s, 1´´´-H), 2.49 (6H, s, 1´-H) and 4.40 (4H, q, 3J 2´´-H, 3´´-H

7.2 Hz, 2´´-H); δC (75 MHz; CDCl3) 14.11 (C-3´´), 16.88 (C-1´´´), 22.86 (C-1´), 61.50 (C-2´´),

127.51 (C-3 and C-5), 141.97 (C-4), 154.86 (C-2 and C-6) and 168.33 (C-1´´); m/z (EI, 70 eV)

265 (M+, 35%), 220 (74) and 28 (100).


30

1.000

1.301

1.974

1.990

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

4.41854.39464.3708

2.4884

2.2424

1.38581.36201.3382

PPM 180 160 140 120 100 80 60 40 20 0

168.3292

154.8588

141.9704

127.5073

77.423977.000076.5754

61.5035

22.8621

16.879714.1094

Fig. 15 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5d in CDCl3.

N

OO

O O

2

34

5

6

1´´1´´ 2´´2´´

1´1´

1´´´

3´´ 3´´


31

6.5. Synthesis and analytical data of diethyl-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (5e)

Synthesis of 5e

According to the general procedure II, diethyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (4e) (329 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 24 h. Purification afforded diethyl-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (5e) (88 mg, 27%).

According to the general procedure III, diethyl-1,4-dihydro-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (4e) (329 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 9 h. Purification afforded diethyl-2,6-dimethyl-4-phenylpyridine-3,5-

dicarboxylate (5e) (261 mg, 80%).

According to the general procedure V, benzaldehyde (1c) (106 mg, 1 mmol), ethyl acetoacetate




for 24 h. Purification afforded diethyl-2,6-dimethyl-4-phenylpyridine-3,5-dicarboxylate (5e) (65

mg, 20%).

Analytical data of 5e



CDCl3) 0.90 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 2.60 (6H, s, 1´-H), 3.99 (4H, q, 3J 2´´-H, 3´´-H 7.2 Hz,

2´´-H), 7.23-7.25 (3H, m, 3´´´-H, 4´´´-H and 5´´´-H) and 7.35-7.37 (2H, m, 2´´´-H and 6´´´-H); δC

(75 MHz; CDCl3) 13.50 (C-3´´), 22.88 (C-1´), 61.29 (C-2´´), 126.89 (C-4´´´), 128.04 and 128.05

(C-3´´´ and C-5´´´), 128.08 and 128.37 (C-2´´´ and C-6´´´), 136.55 (C-1´´´), 146.08 (C-4), 155.38

(C-2 and C-6) and 167.84 (C-1´´); m/z (EI, 70 eV) 327 (M+, 100 %), 282 (56, M+ - OC2H5), 236

(79) and 209 (24).


32

0.9991.324

1.863

2.943

2.748

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

7.36707.35667.34537.26007.25497.25137.24547.23927.2278

4.02954.00573.98193.9581

2.5986

0.91990.89610.8723

PPM 180 160 140 120 100 80 60 40 20 0

167.8415

155.3831

146.0805

136.5486128.3718128.0808128.0518128.0389126.8851

77.423977.000076.5757

61.2901

22.8813

13.5044

0.9790

Fig. 16 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5e in CDCl3.

3´´ 3´´1´´1´´ 2´´2´´

1´1´

2

34

5

6

3´´´

2´´´

1´´´

4´´´

N

OO

O O6´´´

5´´´


33

6.6. Synthesis and analytical data of di-isopropyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5f)

Synthesis of 5f

According to the general procedure II, di-isopropyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4f) (281 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 20 h. Purification afforded di-isopropyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5f) (226 mg, 81%).

According to the general procedure III, di-isopropyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4f) (281 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 8 h. Purification afforded di-isopropyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5f) (260 mg, 93%).

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), isopropyl

acetoacetate (2c) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



0.0125 mmol) for 21 h. Purification afforded di-isopropyl-2,6-dimethylpyridine-3,5-

dicarboxylate (5f) (159 mg, 57%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), isopropyl

acetoacetate (2c) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



mg, 0.1 mmol) for 9 h. Purification afforded di-isopropyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5f) (189 mg, 68%).

Analytical data of 5f


ṽmax(atr)/cm-1 3020, 2984 and 2936 (C_H), 1712 (C=O), 1591 (C=C, C=N), 1221 and 1100


34

(C_O); δH (300 MHz; CDCl3) 1.38 (12H, d, 3J 3´´-H, 2´´-H 6.0 Hz, 3´´-H), 2.82 (6H, s, 1´-H), 5.25

(2H, sep, 3J 2´´-H, 3´´-H 6.0 Hz, 2´´-H) and 8.60 (1H, s, 4-H); δC (75 MHz; CDCl3) 21.88 (C-3´´),

24.96 (C-1´), 69.10 (C-2´´), 123.55 (C-3 and C-5), 140.77 (C-4), 161.74 (C-2 and C-6) and

165.65 (C-1´´); m/z (EI, 70 eV) 279 (M+, 10 %), 250 (22, M+ - C2H5), 220 (21), 195 (55) and 31

(100); HRMS (EI, M+) found: 279.1451 calcd. for C15H21NO4: 279.1471.

1.000

2.298

8.586

17.43

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.08.5982

5.27375.25285.2319

2.8200

1.39131.3704

0.0621

2

34

5

6

N

OO

O O3´´ 3´´

1´´1´´2´´ 2´´

1´1´

3´´3´´


35

PPM 180 160 140 120 100 80 60 40 20 0

165.6498161.7389

140.7670

123.5539

77.423877.000076.5762

69.0976

24.956421.8793

Fig. 17 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5f in CDCl3.

6.7. Synthesis and analytical data of di-tert-butyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5g)

Synthesis of 5g

According to the general procedure II, di-tert-butyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4g) (309 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 15 h. Purification afforded di-tert-butyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5g) (185 mg, 60%).

According to the general procedure III, di-tert-butyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4g) (309 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 7 h. Purification afforded di-tert-butyl-2,6-dimethylpyridine-3,5-dicarboxylate

(5g) (275 mg, 90%).


36

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), tert-butyl

acetoacetate (2d) (316 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



0.0125 mmol) for 24 h. Purification afforded di-tert-butyl-2,6-dimethylpyridine-3,5-

dicarboxylate (5g) (93 mg, 30%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), tert-butyl

acetoacetate (2d) (316 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



mg, 0.1 mmol) for 24 h. Purification afforded di-tert-butyl-2,6-dimethylpyridine-3,5-

dicarboxylate (5g) (190 mg, 62%).

Analytical data of 5g


ṽmax(atr)/cm-1 3003, 2980 and 2937 (C_H), 1709 (C=O), 1595 (C=N, C=C), 1150 and 1105

(C_O); δH (300 MHz; CDCl3) 1.59 (18H, s, 3´´-H), 2.79 (6H, s, 1´-H) and 8.51 (1H, s, 4-H); δC

(75 MHz; CDCl3) 24.95 (C-1´), 28.18 (C-3´´), 82.08 (C-2´´), 124.61 (C-3 and C-5), 140.74 (C-

4), 161.11 (C-2 and C-6) and 165.44 (C-1´´); m/z (EI, 70 eV) 279 (M+- C2H4, 23%), 264 (100)

and 251 (77).


37

1.000

8.080

25.24

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.5078

2.7885

1.5937

0.0596

PPM 180 160 140 120 100 80 60 40 20 0

165.4401

161.1124

140.7424

124.6132

82.083677.423077.000076.5757

28.183724.9476

0.9957

Fig. 18 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5g in CDCl3.

2

34

5

6

N

OO

O O3´´ 3´´

1´´1´´2´´ 2´´

1´1´

3´´3´´

3´´3´´


38

6.8. Synthesis and analytical data of diallyl-2,6-dimethylpyridine-3,5-dicarboxylate (5h)

Synthesis of 5h

According to the general procedure II, diallyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4h) (277 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 7 h. Purification afforded diallyl-2,6-dimethylpyridine-3,5-dicarboxylate (5h)

(236 mg, 86%).

According to the general procedure III, diallyl-1,4-dihydro-2,6-dimethylpyridine-3,5-

dicarboxylate (4h) (277 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 8 h. Purification afforded diallyl-2,6-dimethylpyridine-3,5-dicarboxylate (5h)

(220 mg, 80%).

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), allyl

acetoacetate (2e) (284 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



0.0125 mmol) for 24 h. Purification afforded diallyl-2,6-dimethylpyridine-3,5-dicarboxylate (5h)

(167 mg, 61%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), allyl

acetoacetate (2e) (284 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted



mg, 0.1 mmol) for 9 h. Purification afforded diallyl-2,6-dimethylpyridine-3,5-dicarboxylate (5h)

(136 mg, 49 %).

Analytical data of 5h

White powder; mp 64 - 66 oC; Rf = 0.80 (petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 272

(log ε, 3.60), 235 (4.07) and 207 (4.54); ṽmax(atr)/cm-1 3091 and 2928 (C_H), 1716 (C=O), 1591

(C=N, C=C), 1219 and 1106 (C_O); δH (300 MHz; CDCl3) 2.85 (6H, s, 1´-H), 4.83 (4H, dt, 3J 2´´-


39

H, 3´´-H 5.6 Hz, 4J 1.3 Hz, 2´´-H), 5.32 (2H, dq, 2J 1.3 Hz, 3Jcis 4´á-H, 3´´-H 10.5 Hz, 4J 1.3 Hz, 4´á-H),

5.40 (2H, dq, 2J 1.4 Hz, 3Jtrans 4´´b-H, 3´´-H 17.2 Hz, 4J 1.4 Hz, 4´´b-H), 6.03 (2H, ddt, 3J 3´´-H, 2´´-H 5.7

Hz, 3Jcis 3´´-H, 4´á-H 10.4 Hz, 3Jtrans 3´´-H, 4´´b-H 17.3 Hz, 3´´-H) and 8.73 (1H, s, 4-H); δC (75 MHz;

CDCl3) 25.00 (C-1´), 65.99 (C-2´´), 118.85 (C-4´´), 122.73 (C-3 and C-5), 131.79 and 131.81 (C-

3´´), 141.02 (C-4), 162.60 (C-2 and C-6) and 165.47 (C-1´´); m/z (EI, 70 eV) 275 (M+, 5%), 234

(15), 218 (33) and 41 (100); HRMS (EI, M+) found: 275.1146 calcd. for C15H17NO4: 275.1158.

1.000

2.015

4.491

5.363

8.333

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.7302

7.2600

6.08386.04906.02666.00755.99185.44385.43915.43465.38645.38175.37735.33195.32805.29725.29334.84124.83704.83284.82214.81784.8137

2.8496

0.0639

2

34

5

6

3´´ 3´´

1´´1´´ 2´´2´´

1´1´ N

OO

O O4´´b4´´b

H

H

H

H

H

H4´á4´á


40

PPM 180 160 140 120 100 80 60 40 20 0

165.4684162.6043

141.0227

131.8115131.7885

122.7249118.8486

77.424277.000076.5762

65.9881

24.9955

0.9942

Fig. 19 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5h in CDCl3.

6.9. Synthesis and analytical data of dimethyl-2,6-diethylpyridine-3,5-dicarboxylate (5i)

Synthesis of 5i

According to the general procedure II, dimethyl-2,6-diethyl-1,4-dihydropyridine-3,5-

dicarboxylate (4i) (253 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 20 h. Purification afforded dimethyl-2,6-diethylpyridine-3,5-dicarboxylate (5i)

(200 mg, 80%).

According to the general procedure III, dimethyl-2,6-diethyl-1,4-dihydropyridine-3,5-

dicarboxylate (4i) (253 mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 14 h. Purification afforded dimethyl-2,6-diethylpyridine-3,5-dicarboxylate (5i)

(179 mg, 71%).


41

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), methyl

propionyl acetate (2f) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were

reacted for 15 min. The reaction mixture was treated with methanol (3 mL), acetate buffer (0.2

M, pH 4.37, 30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt

(6.9 mg, 0.0125 mmol) for 26 h. Purification afforded dimethyl-2,6-diethylpyridine-3,5-

dicarboxylate (5i) (186 mg, 74%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), methyl

propionyl acetate (2f) (260 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were

reacted for 15 min. The reaction mixture was treated with methanol (3 mL), acetate buffer (0.2

M, pH 4.37, 30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt

(54.9 mg, 0.1 mmol) for 20 h. Purification afforded dimethyl-2,6-diethylpyridine-3,5-

dicarboxylate (5i) (167 mg, 67%).

Analytica data of 5i

White powder; mp 50 - 52 oC; Rf = 0.84 (petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 272

(log ε, 3.52), 235 (3.99) and 207 (4.47); ṽmax(atr)/cm-1 2976, 2958 and 2938 (C_H), 1716 (C=O),

1593 (C=N, C=C), 1229 and 1048 (C_O); δH (300 MHz; CDCl3) 1.30 (6H, t, 3J 2´-H, 1´-H 7.5 Hz,

2´-H), 3.20 (4H, q, 3J 1´-H, 2´-H 7.5 Hz, 1´-H), 3.92 (6H, s, 2´´-H) and 8.63 (1H, s, 4-H); δC (75

MHz, CDCl3) 13.69 (C-2´), 30.36 (C-1´), 52.29 (C-2´´), 122.03 (C-3 and C-5), 141.22 (C-4),

166.35 (C-1´´) and 167.23 (C-2 and C-6); m/z (EI, 70 eV) 251 (M+, 83%), 236 (100, M+ - CH3)

and 220 (25, M+ - OCH3); HRMS (EI, M+) found: 251.1157 calcd. for C13H17NO4: 251.1158.


42

1.000

8.148

5.708

8.858

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.6297

7.2600

3.9199

3.23193.20693.18193.1570

1.32261.29771.2727

0.0646

PPM 180 160 140 120 100 80 60 40 20 0

167.2279166.3453

141.2213

122.0306

77.423877.000076.5760

52.2909

30.3636

13.6921

Fig. 20 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5i in CDCl3.

1´´1´´2´´2´´

1´1´

2

34

5

6

N

OO

O O

2´ 2´


43

6.10. Synthesis and analytical data of diethyl-2,6-diethylpyridine-3,5-dicarboxylate (5j)

Synthesis of 5j

According to the general procedure II, diethyl-2,6-diethyl-1,4-dihydropyridine-3,5-dicarboxylate

(4j) (281 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL), laccase (168

U, 12 mg, Trametes versicolor) and ABTS diammonium salt (6.9 mg, 0.0125 mmol) were

reacted for 24 h. Purification afforded diethyl-2,6-diethylpyridine-3,5-dicarboxylate (5j) (200

mg, 72%).

According to the general procedure III, diethyl-2,6-diethyl-1,4-dihydropyridine-3,5-

dicarboxylate (4j) (281 mg, 1 mmol), methanol (6 mL), acetate buffer (0.2 M, pH 4.37, 30 mL),


were reacted for 9 h. Purification afforded diethyl-2,6-diethylpyridine-3,5-dicarboxylate (5j)

(237 mg, 85%).

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), ethyl propionyl

acetate (2g) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted for

40 min. The reaction mixture was treated with methanol (6 mL), acetate buffer (0.2 M, pH 4.37,

30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt (6.9 mg,

0.0125 mmol) for 24 h. Purification afforded diethyl-2,6-diethylpyridine-3,5-dicarboxylate (5j)

(162 mg, 58%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), ethyl propionyl

acetate (2g) (288 mg, 2 mmol) and ammonium acetate (3) (116 mg, 1.5 mmol) were reacted for

40 min. The reaction mixture was treated with methanol (6 mL), acetate buffer (0.2 M, pH 4.37,

30 mL), laccase (168 U, 12 mg, Trametes versicolor) and ABTS diammonium salt (54.9 mg, 0.1

mmol) for 8 h. Purification afforded diethyl-2,6-diethylpyridine-3,5-dicarboxylate (5j) (155 mg,

56%).

Analytical data of 5j

Colourless solid; mp 35 - 37 oC; Rf = 0.83 (petroleum ether / EtOAc = 2:1); λmax(MeCN)/nm 272

(log ε, 3.58), 235 (4.05) and 206 (4.52); ṽmax(atr)/cm-1 2977, 2936 and 2874 (C_H), 1717 (C=O),

1590 (C=N or C=C), 1224 and 1044 (C_O); δH (300 MHz; CDCl3) 1.30 (6H, t, 3J 2´-H, 1´-H 7.5 Hz,


44

2´-H), 1.40 (6H, t, 3J 3´´-H, 2´´-H 7.2 Hz, 3´´-H), 3.18 (4H, q, 3J 1´-H, 2´-H 7.5 Hz, 1´-H), 4.39 (4H, q, 3J 2´´-H, 3´´-H 7.2 Hz, 2´´-H) and 8.59 (1H, s, 4-H); δC (75 MHz; CDCl3) 13.80 (C-2´), 14.22 (C-

3´´), 30.42 (C-1´), 61.35 (C-2´´), 122.55 (C-3 and C-5), 141.02 (C-4), 166.13 (C-1´´) and 166.78

(C-2 and C-6); m/z (EI, 70 eV) 279 (M+, 19%), 250 (100, M+ - C2H5) and 222 (43); HRMS (EI,

M+) found: 279.1446 calcd. for C15H21NO4: 279.1471.

1.000

0.199

5.364

5.821

7.8467.899

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.5869

7.2600

4.42064.39694.37314.3494

3.21673.19183.16693.1420

1.42551.40171.37791.31961.29481.2698

3´´ 3´´1´´1´´ 2´´2´´

1´1´

2

34

5

6

N

OO

O O

2´ 2´


45

PPM 180 160 140 120 100 80 60 40 20 0

166.7820166.1288

141.0229

122.5495

77.423677.000076.5756

61.3461

30.4192

14.222713.7998

Fig. 21 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5j in CDCl3.

6.11. Synthesis and analytical data of 2,6-dimethyl-3,5-diacetylpyridine (5k)

Synthesis of 5k

According to the general procedure II, 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (4k) (193

mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL), laccase (168 U, 12 mg,

Trametes versicolor) and ABTS diammonium salt (6.9 mg, 0.0125 mmol) were reacted for 10 h.

Purification by flash chromatography on SiO2 (petroleum ether / EtOAc = 2:1) afforded 2,6-

dimethyl-3,5-diacetylpyridine (5k) (165 mg, 86%).

According to the general procedure III, 2,6-dimethyl-3,5-diacetyl-1,4-dihydropyridine (4k) (193

mg, 1 mmol), methanol (3 mL), acetate buffer (0.2 M, pH 4.37, 30 mL), laccase (168 U, 12 mg,

Trametes versicolor) and ABTS diammonium salt (54.9 mg, 0.1 mmol) were reacted for 10 h.

Purification by flash chromatography on SiO2 (petroleum ether / EtOAc = 2:1) afforded 2,6-

dimethyl-3,5-diacetylpyridine (5k) (172 mg, 90%).


46

According to the general procedure IV, paraformaldehyde (1a) (30 mg, 1 mmol), acetylacetone




for 14 h. Purification by flash chromatography on SiO2 (petroleum ether / EtOAc = 2:1) afforded

2,6-dimethyl-3,5-diacetylpyridine (5k) (112 mg, 59%).

According to the general procedure V, paraformaldehyde (1a) (30 mg, 1 mmol), acetylacetone




for 10 h. Purification by flash chromatography on SiO2 (petroleum ether / EtOAc = 2:1) afforded

2,6-dimethyl-3,5-diacetylpyridine (5k) (115 mg, 60%).

Analytical data of 5k

White crystals; mp 65 - 67 oC (lit.,6 68 - 70 oC); Rf = 0.29 (petroleum ether / EtOAc = 2:1);

ṽmax(atr)/cm-1 2980 (C-H), 1673 (C=O) and 1578 (C=N, C=C); δH (300 MHz; CDCl3) 2.61 (6H, s,

2´´-H), 2.75 (6H, s, 1´-H) and 8.22 (1H, s, 4-H); δC (75 MHz; CDCl3) 24.95 (C-1´), 29.32 (C-

2´´), 130.11 (C-4), 137.73 (C-3 and C-5), 160.23 (C-2 and C-6) and 199.19 (C-1´´); m/z (EI, 70

eV) 191 (M+, 37 %), 176 (77, M+ - CH3), 106 (39) and 28 (100).


47

1.000

6.6626.034

PPM 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

8.2155

2.74842.6095

PPM 180 160 140 120 100 80 60 40 20 0

199.1881

160.2342

137.7302

130.1092

77.481177.423977.000076.5762

29.3237

24.9484

Fig. 22 1H (300 MHz) and 13C (75 MHz) NMR spectra of 5k in CDCl3.

N

O O

2

34

5

6

1´´1´´2´´2´´

1´1´


48

7. Determination of the laccase activity8

A 0.1 M solution of ABTS (0.3 mL) in 0.2 M acetate buffer (pH 4.37) was diluted with 0.2 M

acetate buffer (2.6 mL, pH 4.37) and treated with a solution of laccase in the same buffer (0.1

mL). The change in absorption was followed via UV spectroscopy (λ = 414 nm). One unit was

defined as the amount of laccase (Trametes versicolor, Fluka) that converts 1 mmol of ABTS per

minute at pH 4.37 at rt.

8. References

[1] M. A. Zolfigol and M. Safaiee, Synlett, 2004, 827.

[2] Suresh, D. Kumar and J. S. Sandhu, Synth. Commun., 2009, 39, 1957.

[3] H. Salehi and Q.-X. Guo, Synth. Commun., 2004, 34, 4349.

[4] J. Uldrikjis, G. Duburs, I. Dipans, B. Cekavicius, Khimiya Geterotsiklicheskikh Soedinenii,

1975, 9, 1230.

[5] K. Kikugawa, T. Nakahara and K. Sakurai, Chem. Pharm. Bull., 1987, 35, 4656.

[6] J.-J. Xia and G.W. Wang, Synthesis, 2005, 2379.

[7] A. Ghorbani-Choghamarani and J. Zeinivand, Synth. Commun., 2010, 40, 2457.

[8] S. Nicotra, A. Intra, G. Ottolina, S. Riva and B. Danieli, Tetrahedron: Asymmetry,

2004, 15, 2927.


Documents

Laccase-catalyzed oxidation of Hantzsch 1,4 ... · Laccase-catalyzed oxidation of Hantzsch 1,4-dihydropyridines to pyridines and a new one pot synthesis of pyridines Heba T. Abdel-Mohsen,