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Article

Regioselective Oxidation of 3-Substituted Pyridinium Salts

1
Centro de Química del Instituto de Ciencias. BUAP. Puebla, Pue. México
2
Instituto de Química. UNAM. Cd. Universitaria. D.F. 04510. México
3
Department of Chemistry, University of Toronto, Toronto, M5S BHG Canada
*
Author to whom correspondence should be addressed.
Molecules 2000, 5(10), 1175-1181; https://doi.org/10.3390/51001175
Submission received: 18 August 2000 / Revised: 3 October 2000 / Accepted: 4 October 2000 / Published: 31 October 2000

Abstract

:
(1'R)-(+)-3-Hydroxymethyl-1-(1'-phenyl-ethyl)-pyridinium chloride (1), 1-benzyl- 3-[1', 3']-dioxolan-2'-yl-pyridinium chloride (2) and (2'S, 4'S, 5'R)-(-)-1-benzyl-3-(3',4'- dimethyl-5'-phenyl-oxazolidin-2'-yl)-pyridinium bromide (3), were transformed by oxidation with potassium ferricyanide into the corresponding 1H-pyridin-2-ones in excellent yields with high regioselectivity.

Introduction

The oxidation of chiral pyridinium salts is an area of research with wide interest because enantiopure 1H-pyridin-2-ones obtained can be used in the asymmetric synthesis of alkaloids. The synthesis of chiral 1H-pyridin-2-ones is useful, because the starting material is easily obtained and the regioselectivities of the reactions can attain high values depending on the substituent at position 3. [1,2,3,4,5,6,7,8]. In a preliminary communication [9], we reported the oxidation of 3-(methyl and ethyl) pyridinium salts, where in all cases, the oxidation at the 2-position in the starting material was favored. Now, we report three different examples of pyridinium salts differently substituted at position 3, incorporating chiral substituents in the quaternary nitrogen or at position 3, which were oxidized with potassium ferricyanide. We observe an increasing percentage of oxidation at position 6 when the bulkiness of the substituent was increased. The products obtained were characterized by NMR and in one case, by X-ray diffraction.

Results and Discussion

For this purpose, we prepared pyridinium salt (1) from the corresponding 1-(2,4-dinitro-phenyl)-3- hydroxymethyl-pyridinium chloride and (R)-(+)-1-phenyl-ethylamine [10]. The salts (2) and (3) were obtained from pyridin-3-carbaldehyde with ethane-1, 2-diol or (1R, 2S)-(-)-2-methylamino-1-phenyl- propan-1-ol followed of quaternisation with benzyl bromide [11]. See Experimental.
The oxidation of chiral non-racemic pyridinium salt (1) with potassium ferricyanide produced a mixture of (1'R)-(+)-5-hydroxymethyl-1-(1'-phenyl-ethyl)-1H-pyridin-2-one (4) and (1'R)-(+)-3- hydroxymethyl-1-(1'-phenyl-ethyl)-1H-pyridin-2-one (5) (Scheme 1); the overall yield was 90% with a ratio of (4):(5) = 70:30 after column chromatography (SiO2, gradient dichloromethane-methanol). The products all gave satisfactory spectroscopic data.
Similarly, the oxidation of (2) afforded a mixture of 1-benzyl-5-[1',3']-dioxolane-2'-yl-1H-pyridin-2- one (6) and 1-benzyl-3-[1',3']-dioxolane-2'-yl-1H-pyridin-2-one (7) (Scheme 2); overall yield 92% with a ratio of (6):(7) = 80:20 after column chromatography (SiO2, gradient dichloromethane-methanol). The products all gave satisfactory spectroscopic data.
Finally, the oxidation of chiral non-racemic pyridinium salt (3) exclusively afforded the (2'S, 4'S, 5'R)-(-)-1-benzyl-5-(3',4'-dimethyl-5'-phenyl-oxazolidin-2'-yl)-1H-pyridin-2-one (8) (Scheme 3) in a yield of 97% after column chromatography (SiO2, gradient dichloromethane-methanol). The product gave satisfactory spectroscopic data. This compound was crystallized from Et2O/CHCl3 and submitted to X-ray studies. The ORTEP [12] view of (8) is shown in Fig 1.

Conclusions

These results show that the steric hindrance exerted by the substituent at position 3 plays a key role in the extent of 6-oxidation in the starting material. In particular, we found that the size of the substituent in (2'S, 4'S, 5'R)-(-)-1-benzyl-3-(3',4'-dimethyl-5'-phenyl-oxazolidin-2'-yl)-pyridinium bromide (3) results in the exclusive generation of the chiral, non-racemic (2'S, 4'S, 5'R)-(-)-1-benzyl-5-(3',4'-dimethyl-5'- phenyl-oxazolidin-2'-yl)-1H-pyridin-2-one (8).

Experimental

General.

Melting points were determined in open capillaries and are uncorrected. IR spectra were recorded in KBr on a Nicolet Magna-750 spectrophotometer. NMR spectra were measured on a Jeol 400 MHz. spectrometer, using TMS as the internal standard. 1H-NMR assignments were confirmed by extensive use of 13C-1H correlation techniques. Optical rotation was measured on a Perkin-Elmer Polarimeter M241. X-ray diffractions were measured on a Siemens P4/PC diffractometer.

Preparation of Chiral Pyridinium Salt (1).

To a solution of 1-(2,4-dinitro-phenyl)-3-hydroxymethyl-pyridinium chloride at 70°C (3.0 g, 9.64 mmol) in vigorously stirred n-butanol (150 mL), a solution of (R)-(+)-1-phenyl-ethylamine (1.16 g, 9.64 mmol) in n-butanol (50 mL) was added dropwise over a period of 15 min and the mixture was then refluxed for 12 h. Thereafter, the solvent was removed in vacuo, affording a viscous residue, which was dissolved in water (50 mL), filtered and the water solution washed with dichloromethane (5x20 mL). To the 2,4-dinitroaniline-free water solution, toluene (75 mL) was added. The toluene-water azeotrope was removed under reduced pressure, affording 1 (2.40g, 80% yield), after column chromatography (SiO2, CH2Cl2/MeOH, 100:0; 99:1; 98:2; 97:3 and 95:5 v/v).

Spectral Data.

Chiral Pyridinium Salt (1). Oil; [α]D +12.3 (c= 2, MeOH); IR: (KBr, cm-1) 3345-3300, 2923, 1636, 1058. 1H NMR: δ (ppm, CD3OD, JHz): 8.97 (H-2, s); 8.91 (H-6, d, 6.05); 8.56 (H-4, d, 7.97); 8.08 (H-5, t, 7.97, 6.05); 7.55-7.40 (5H, φ-H); 6.20 (H-1', q, 7.03); 4.85 (2H-7, s); 2.02 (3H-2', d, 7.03). 13C NMR: δ (ppm, CD3OD): C-2, 145.98; C-6, 145.23; C-3, 143.21; C-4, 142.48; C-3', 138.79; C-6', 131.78; 2C-4', 130.90; C-5, 129.50; 2C-5', 128.78; C-1', 72.50; C-7, 61.38; C-2', 21.03.

General Procedure for Synthesis of Pyridinium Salts (2) and (3).

A solution of pyridine-3-carbaldehyde protected with ethane-1,2-diol or (1R, 2S)-(-)-2- methylamino-1-phenyl-propan-1-ol (1.0 eq) in anhydrous CH2Cl2, was cooled to O°C and a solution of benzyl bromide (1.1 eq) in anhydrous CH2Cl2 was added dropwise over a period of 30 min with stirring. After maintaining the temperature at 35°C for 12h the reaction was complete, as evidenced by by TLC monitoring (Al2O3, CH2Cl2/MeOH, 97:3 v/v). Average yields of pyridinium salts (2) and (3) were 85% and 90% respectively after column chromatography (SiO2, CH2Cl2/MeOH, 100:0; 99:1 and 98:2 v/v).

Spectral Data.

Pyridinium Salt (2). Oil. IR: (KBr, cm-1) 3422-3400, 2897, 1636, 1105; 1H NMR: δ (ppm, CD3OD, JHz): 9.91 (H-6, d, 5.1); 9.57 (H-2, s); 8.42 (H-4, d, 7.7); 8.08 (H-5, t, 6.0); 7.72 (2H-9, m); 7.34 (2H-10 and H-11, m); 6.36 (2H-7, m); 6.02 (H-2', s); 4.08 (2H-4', 2H-5', td, 11.2, 8.0). 13C NMR: δ (ppm, CD3OD): C-2, 146.20; C-6, 143.80; C-3, 140.10; C-8, 132.80; C-11, 129.87; 2C-10, 129.71; 2C-9, 129.50; C-4; C-5, 128.34; C-2', 99.80; C-4'; C-5', 66.00; C-7, 64.20.
Chiral Pyridinium Salt (3). Crystallized from Et2O/CHCl3, mp. 153-155°C; [α]D = -58.4 (c= 2, MeOH); IR: (KBr, cm-1) 3445-3400, 2977, 2937, 1457; 1H NMR: δ (ppm, CDCl3, JHz): 10.04 (H-6, d, 5.60); 9.69 (H-2, s); 8.63 (H-4, d, 7.60); 8.12 (H-5, dd, 6.40, 1.30); 7.75 (2H-9, m); 7.39 (2H-10 and H-11, m); 7.30 (2H-9', H-11', m); 7.18 (2H-10', m); 6.38 (2H-7, AB, 22.4, 13.2); 5.14 (H-5', d, 8.0); 5.07 (H-2', s); 3.11 (H-4', m); 2.32 (3H-6', s); 0.71 (3H-7', d, 6.24). 13C NMR: δ (ppm, CDCl3): C-2, 145.93; C-6, 144.80; C-3, 144.18; C-4, 140.80; C-8, 138.23; C-8', 132.94; C-5, 130.10; 2C-9, 2C-10, C-11, 2C-9', 2C-10', C-11', 129.79 to 127.59; C-2', 93.82; C-5', 83.22; C-7, 64.44; C-4', 63.88; C-6', 36.59; C-7', 15.28.

General Procedure for Synthesis of 1H-pyridin-2-ones (4+5), (6+7) and (8).

A stirred solution of the corresponding pyridinium salt (4.0 mmol) in water (25 mL) was cooled to 5°C and a solution of K3Fe(CN)6 (11.0 eq) in water (30 mL) was added dropwise over a period of 1h. Then, a solution of KOH (15.8 eq) in water (10 mL) was added dropwise over 30 min. Toluene (40 mL) was added and the mixture warmed at 40°C for 30 min. After maintaining the temperature at 40°C for 2h the reaction was complete, as indicated by TLC (Al2O3, CH2Cl2/MeOH, 99:1 v/v). The organic layer was separated and the aqueous solution extracted with dichloromethane (4x50 mL). The combined organic layers were dried over Na2SO4 and the solvent was removed in vacuo. The mixture was purified and separated by column chromatography (SiO2, CH2Cl2/MeOH, 100:0; 99:1 and 98:2 v/v). Overall yields: (4+5), 90% (4, 63% / 5, 27%); (6+7), 92% (6, 73.6% / 7, 18.4%) and 97% (8).

Spectral Data.

Chiral 1H-pyridin-2-one (4): Oil. [α ]D = +15.82 (c = 1, CH2Cl2). IR (KBr, cm-1): 3550-3200, 2926, 1662, 1580, 1539. 1H NMR: δ (ppm, CDCl3, J Hz): 7.35-7.28 (φ-H, 5H, m); 7.23 (H-4, d, 9.52); 7.10 (H-6, d, 1.80); 6.51 (H-3, d, 9.12); 6.36 (H-1', q, 7.32); 4.26 (2H-7, s); 1.66 (3H-2', d, 7.32). 13C NMR: δ (ppm, CDCl3): C-2, 162.00; 2C-4', 140.03; C-4, 139.51; C-6, 132.25; 2C-4', 128.93; C-6', 128.12; 2C-5', 127.47; C-3, 120.55; C-5, 119.88; C-7, 61.90; C-1', 52.65 and C-2', 19.13.
Chiral 1H-pyridin-2-one (5): Oil. [α ]D = +27.61 (c = 1, CH2Cl2). IR (KBr, cm-1): 3500-3200, 3062, 2979, 1645, 1581, 1555. 1H NMR: δ (ppm, CDCl3, J Hz): 7.36-7.28 (φ-H, 5H, m); 7.25 (H-4, d, 6.24); 7.08 (H-6, d, 6.96); 6.42 (H-1', q, 7.32); 6.14 (H-5, t, 6.96); 4.58 (2H-7, s); 1.70 (3H-2', d, 7.32). 13C NMR: δ (ppm, CDCl3): C-2, 162.39; C-3', 140.02; C-4, 135.46; C-6, 133.14; C-3, 131.23; 2C-4', 128.96; C-6', 128.15; 2C-5', 127.46; C-5, 106.54; C-7, 62.97; C-1', 52.68 and C-2', 19.21.
1H-Pyridin-2-one (6): Oil. IR (KBr, cm-1): 3450-3400, 2925, 2880, 1669, 1607, 1544. 1H NMR: δ (ppm, CDCl3 , J Hz): 7.41 (H-4, dd, 9.16, 2.56); 7.31 (H-6, s); 7.30 (2H-9, m); 7.29 (2H-10, m); 7.28 (H-11, m); 6.63 (H-3, d, 9.16); 5.49 (H-2', s); 5.12 (2H-7, s); 3.97 (2H-4', 2H-5', A2X2, 8.8). 13C NMR: δ (ppm, CDCl3): C-2, 162.51; C-4, 137.82; C-6, 136.29; C-8, 136.20; 2C-10, 129.0; 2C-9; C-11, 128.19; C-3 121.39; C-5, 115.55; C-2', 101.54; C-4'; C-5', 65.35; C-7, 53.52.
1H-Pyridin-2-one (7): Oil. IR (KBr, cm-1): 3450-3400, 2925, 2880, 1650, 1591, 1559. 1H NMR: δ (ppm, CDCl3, JHz): 7.59 (H-4, dd, 6.76, 2.2); 7.31 (H-11, m); 7.30 (2H-9 and 2H-10, m); 7.28 (H-6, dd, 6.76, 1.84); 6.16 (H-5, t, 6.76); 6.00 (H-2', s); 5.14 (2H-7, s); 4.05 (2H-4' and 2H-5', dt, 15.4, 4.03, 1.84). 13C NMR: δ (ppm, CDCl3): C-2, 161.51; C-4, 137.74; C-3, C-6, 136.41; 2C-10, 128.97; 2C-9, C-11, 128.51; C-8, 128.16; C-5, 105.56; C-2', 99.51; C-4'; C-5', 65.37 and C-7, 51.93.
Chiral 1H-pyridin-2-one (8): Crystallized from Et2O/CHCl3, mp = 144°C. [α ]D = -6.1 (c = 1, CH2Cl2). IR (KBr, cm-1): 3450-3400, 2947, 2892, 1667, 1610, 1541. 1H NMR: δ (ppm, CDCl3, J Hz): 7.67 (H-4, dd, 9.32, 2.2); 7.45 (H-6, d, 2.2); 7.33- 7.30 (2φ-H, 10H, m); 6.69 (H-3, d, 9.52); 5.16 (2H-7, AB, 23.98, 14.28); 5.06 (H-5', d, 8.04); 4.41 (H-2', s); 2.90 (H-4', qd, 8.4, 6.6); 2.13 (3H-6', s); 0.73 (3H-7', d, 6.6). 13C NMR: δ (ppm, CDCl3): C-2, 163.03; C-4, 139.33; C-6, 137.65; C-8, C-8', 136.25; C-11, C-11', 129.02; 2C-10, 2C-10', 128.18; 2C-9, 2C-9', 128.10; C-3, 121.47; C-5, 116.79; C-2', 95.96; C-5', 82.28; C-4', 63.67; C-7, 52.13; C-6', 35.74; C-7', 15.14.
X-ray structure of (8) Crystal data: C23H24N2O2, Mw = 360.44, monoclinic, space group P21, Z = 2, a= 5.443 (1) Å, b =8.634 (1) Å, c = 21.073 (2) Å, β = 96.23 (1)•, V = 984.4 (2) Å3, Dcalc = 1.216 g cm-3 , T= 293 K, R1 = 0.041, wR2 = 0.101 for 2608 reflections with I>2σ(I). [R1= 0.043, wR2 = 0.104 for all 3120 independent reflections].

Acknowledgements

D.G and A.G acknowledge the financial support from CONACyT (project # 28906). J.L.T gratefully acknowledges a Ph.D. scholarship awarded by CONACyT (grant #112584).

References and Notes

  1. Coffen, D. L.; Hengartner, U.; Katonak, A.; Mulligan, M. E.; Burdick, D. C.; Olson, G. L.; Todaro, L. J. J. Org. Chem. 1984, 49, 5109. Amat, M.; Llor, N.; Hidalgo, J.; Hernández, A.; Bosch, J. Tetrahedron Asymmetry 1996, 7, 4, 977. and references cited therein; Kuethe, J. T.; Padwa, A. Tetrahedron Lett. 1997, 38, 1505. and references cited therein; Mabic, S.; Castagnoli, N., Jr. J. Org. Chem. 1996, 61, 309. Munchhof, M. J.; Meyers, A. I. J. Org. Chem. 1995, 60, 7086. Möhrle, H.; Weber, H. Tetrahedron 1970, 26, 2953. and references cited therein.
  2. Micouin, L.; Bonin, M.; Cherrier, M.-P.; Mazurier, A.; Tomas, A.; Quirion, J.-Ch.; Husson, H.-P. Tetrahedron 1996, 52(22), 7719. and references therein.
  3. Prill, E. A. McElvain. Org. Syn. 1943, 2, 419. [Google Scholar]
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  8. Uchida, H.; Nishida, A.; Nakagawa, M. Tetrahedron Letters 1999, 40, 113.
  9. Gnecco, D.; Marazano, C.; Enríquez, R. G.; Terán, J.L.; Sanchez, M. R.; Galindo, A. Tetrahedron Asymmetry 1998, 9, 2027.
  10. Wong, Y. S.; Marazano, C.; Gnecco, D.; Genisson, Y.; Das, B. C. J. Org. Chem. 1997, 62, 729. [PubMed]Genisson, Y.; Marazano, C.; Mehmandoust, M.; Gnecco, D.; Das, B.C. Synlett. 1992, 431.
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  • Sample Availability: Available from the authors.
Scheme 1.  
Scheme 1.  
Molecules 05 01175 sch001
Scheme 2.  
Scheme 2.  
Molecules 05 01175 sch002
Scheme 3.  
Scheme 3.  
Molecules 05 01175 sch003
Fig. 1. ORTEP view of the crystal structure of compound (8).
Fig. 1. ORTEP view of the crystal structure of compound (8).
Molecules 05 01175 g001

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MDPI and ACS Style

Terán, J.L.; Gnecco, D.; Galindo, A.; Juárez, J.R.; Enríquez, R.G.; Soriano, M.; Reynolds, W.F. Regioselective Oxidation of 3-Substituted Pyridinium Salts. Molecules 2000, 5, 1175-1181. https://doi.org/10.3390/51001175

AMA Style

Terán JL, Gnecco D, Galindo A, Juárez JR, Enríquez RG, Soriano M, Reynolds WF. Regioselective Oxidation of 3-Substituted Pyridinium Salts. Molecules. 2000; 5(10):1175-1181. https://doi.org/10.3390/51001175

Chicago/Turabian Style

Terán, Joel L., Dino Gnecco, Alberto Galindo, Jorge R. Juárez, Raúl G. Enríquez, Manuel Soriano, and W. F. Reynolds. 2000. "Regioselective Oxidation of 3-Substituted Pyridinium Salts" Molecules 5, no. 10: 1175-1181. https://doi.org/10.3390/51001175

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