Carbohydrates to Functionalized Pyridines: A New Synthetic Approach via Enol-Driven Ring Transformations

Lal Dhar Singh Yadav; Ankita Rai; Vijai Kumar Rai; Chhama Awasthi

doi:10.1055/s-2008-1042760

LETTER

Carbohydrates to Functionalized Pyridines: A New Synthetic Approach via Enol-Driven Ring Transformations

Lal Dhar Singh Yadav*, Ankita Rai, Vijai Kumar Rai, Chhama Awasthi
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, Uttar Pradesh, India
Fax: +91(532)2460533; e-Mail: ldsyadav@hotmail.com;

Abstract

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Abstract

An expeditious synthetic protocol for polyhydroxyalkylpyridines and their 3-amino/mercapto-2-pyridinone analogues using unprotected aldoses as biorenewable resources is reported. The synthesis involves enol-driven Michael-type addition of lactones/ketones to aldose-derived 1,3-oxazin-2-ones followed by decarboxylative ring transformation to yield various novel polyhydroxyalkylpyridines. This is a one-pot nanoclay (K-10 clay)-catalyzed process proceeding under conditions of solvent-free microwave irradiation.

Key words

carbohydrates - mineral-catalyzed - microwaves - 1,3-oxazin-2-ones - pyridines - solvent-free

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References and Notes

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15 Yadav LDS. Kapoor R. J. Org. Chem. 2004, 69: 8118

16

General Procedure for the Synthesis of 6-Polyhydroxy-alkyl-1,3-oxazin-2-ones 3 Thoroughly mixed aldose semicarbazone 11 (2.0 mmol) and Montmorillonite K-10 clay (0.20 g) were taken in a 20 mL vial and subjected to MW irradiation in a CEM Discover Focused Microwave Synthesis System at 90 °C for 10 min. After completion of the reaction as indicated by TLC, H₂O (10 mL) was added to give the crude product, which was recrystallized from EtOH to obtain an analytically pure sample of 3 as a white solid.
Characterization Data for Synthesized Compounds Compound 3a: white solid; mp 145-148 °C. IR (KBr): 3392, 3386, 3011, 1692 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.11 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.1 Hz, J ₁ _′ _H,2 _′ _Ha = 5.4 Hz, 1 H, 2′H_a), 4.30 (dd, J ₁ _′ _H,2 _′ _Ha = 5.4 Hz, J ₁ _′ _H,2 _′ _Hb = 2.9 Hz, 1 H, 1′H), 4.63 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.1 Hz, J ₁ _′ _H,2 _′ _Hb = 2.9 Hz, 1 H, 2′H_b), 4.93-5.21 (br s, 2 H, 2 × OH, exch. D₂O), 7.48 (d, J _4H,5H = 8.1 Hz, 1 H, 5-H), 7.89 (d, J _4H,5H = 8.1 Hz, 1 H, 4-H). ¹³C NMR (100 MHz, DMSO-d ₆/TMS): δ = 64.5, 65.3, 73.7, 86.2, 105.9, 174.5. MS (FAB): m/z = 158 [MH⁺]. Anal. Calcd for C₆H₇NO₄: C, 45.86; H, 4.49; N, 8.91. Found: C, 46.17; H, 4.58; N, 8.79.
Compound 3b: white solid; mp 153-155 °C. IR (KBr): 3399-3382, 3008, 1689 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.88 (ddd, J ₂ _′ _H,3 _′ _Ha = 5.4 Hz, J ₁ _′ _H,2 _′ _H = 4.6 Hz, J ₂ _′ _H,3 _′ _Hb = 2.7 Hz, 1 H, 2′H), 4.03 (dd, J ₃ _′ _Ha,3 _′ _Hb = 10.5 Hz, J ₂ _′ _H,3 _′ _Ha = 5.4 Hz, 1 H, 3′H_a), 4.37 (d, J ₁ _′ _H,2 _′ _H = 4.6 Hz, 1 H, 1′H), 4.59 (dd, J ₃ _′ _Ha,3 _′ _Hb = 10.5 Hz, J ₂ _′ _H,3 _′ _Hb = 2.7 Hz, 1 H, 3′H_b), 5.01-5.37 (br s, 3 H, 3 × OH, exch. D₂O), 7.51 (d, J _4H,5H = 8.1 Hz, 1 H, 5-H), 7.85 (d, J _4H,5H = 8.1 Hz, 1 H, 4-H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 64.3, 65.9, 71.7, 73.5, 86.5, 106.3, 174.8. MS-FAB: m/z = 188 [MH⁺]. Anal. Calcd for C₇H₉NO₅: C, 44.92; H, 4.85; N, 7.48. Found: C, 44.69; H, 4.73; N, 7.73.

17 Audrieth LF. Ogg BA. The Chemistry of Hydrazines John Wiley and Sons, Inc.; New York: 1951.

18

General Procedure for the Synthesis of 4-Polyhydroxy-alkyl-1 H -pyridin-2-ones 7, 8, and 2-Aryl-4-polyhydroxyalkylpyridines 9 An intimate solvent-free mixture of 1,3-oxazin-2-one 3 (2.4 mmol) and 1,3-oxathiolan-5-one 4 (2.4 mmol), or 1,3-oxazol-5-one 5 (2.4 mmol), or ketone 6 (2.4 mmol) in the presence of Montmorillonite K-10 clay (0.25 g) was taken in a 20 mL vial and subjected to MW irradiation in a CEM Discover Focused Microwave Synthesis System at 90 °C for 7-11 min. After completion of the reaction as indicated by TLC, H₂O (10 mL) was added to give the crude product, which was recrystallized from EtOH to obtain an analytically pure sample of 7, 8, or 9 as a white solid.
Characterization Data for Representative Compounds Compound 7a: white solid; mp 178-180 °C. IR (KBr): 3388-3361, 3015, 2550, 1692 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.57 (s, 1 H, SH, exch. D₂O), 3.71 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.3 Hz, J ₁ _′ _H,2 _′ _Ha = 5.4 Hz, 1 H, 2′H_a), 4.19 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.3 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 2′H_b), 4.27 (dd, J ₁ _′ _H,2 _′ _Ha = 5.4 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 1′H), 4.97-5.06 (br s, 2 H, 2 × OH, exch. D₂O), 7.98 (d, J _5H,6H = 7.8 Hz, 1 H, 5-H), 8.13 (d, J _5H,6H = 7.8 Hz, 1 H, 6-H), 8.51 (br s, 1 H, NH, exch. D₂O). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 65.1, 74.2, 107.8, 124.9, 131.3, 136.4, 173.2. MS-FAB: m/z = 188 [MH⁺]. Anal. Calcd for C₇H₉NO₃S: C, 44.91; H, 4.85; N, 7.48. Found: C, 44.79; H, 4.48; N, 7.73.
Compound 8a: white solid; mp 156-158 °C. IR (KBr): 3398-3367, 3013, 1691, 1665, 1607, 1579, 1454 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.75 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.5 Hz, J ₁ _′ _H,2 _′ _Ha = 5.5 Hz, 1 H, 2′H_a), 4.17 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.5 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 2′H_b), 4.31 (dd, J ₁ _′ _H,2 _′ _Ha = 5.5 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 1′H), 5.03-5.12 (br s, 2 H, 2 × OH, exch. D₂O), 7.09-7.58 (m, 5 H_arom), 7.93 (d, J _5H,6H = 7.2 Hz, 1 H, 5-H), 8.09 (d, J _5H,6H = 7.2 Hz, 1 H, 6-H), 8.49-8.61 (br s, 2 H, 2 × NH, exch. D₂O). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 65.5, 73.6, 105.8, 124.9, 126.9, 128.7, 129.4, 130.5, 131.9, 136.7, 172.5, 173.3. MS-FAB: m/z = 275 [MH⁺]. Anal. Calcd for C₁₄H₁₄N₂O₄: C, 61.31; H, 5.14; N, 10.21. Found: C, 61.63; H, 5.35; N, 10.03.
Compound 9a: white solid; mp 118-120 °C. IR (KBr): 3393, 3385, 3015, 1608, 1581, 1458 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.73 (dd, 1 H, J ₂ _′ _Ha,2 _′ _Hb = 10.2 Hz, J ₁ _′ _H,2 _′ _Ha = 5.2 Hz, 2′H_a), 4.05 (dd, 1 H, J ₁ _′ _H,2 _′ _Ha = 5.2 Hz, J ₁ _′ _H,2 _′ _Hb = 2.7 Hz, 1′H), 4.21 (dd, 1 H, J ₂ _′ _Ha,2 _′ _Hb = 10.2 Hz, J ₁ _′ _H,2 _′ _Hb = 2.7 Hz, 2′H_b), 4.95-5.13 (br s, 2 H, 2 × OH, exch. D₂O), 7.05-7.51 (m, 5 H_arom), 7.67-7.99 (m, 3 H_arom). ¹³C NMR (DMSO-d ₆/TMS): δ = 65.7, 67.1, 107.8, 126.8, 128.5, 129.7, 131.8, 133.6, 147.5, 149.2, 152.7. MS-FAB:
m/z = 216 [MH⁺]. Anal. Calcd for C₁₃H₁₃NO₂: C, 72.54; H, 6.09; N, 6.51. Found: C, 72.25; H, 6.27; N, 6.69.

19

General Procedure for the Synthesis of 3-Amino-4-polyhydroxyalkyl-1 H -pyridin-2-ones 10 Compound 8 (2.0 mmol) was refluxed in H₂SO₄-H₂O (15 mL, 4:3, v/v) for 45 min in an oil bath. The reaction mixture was cooled, and the desired product 10 was precipitated by adding concentrated NH₄OH (specific gravity 0.88) under ice cooling and recrystallized from EtOH to obtain an analytically pure sample of 10.
Characterization Data for Synthesized Compounds Compound 10a: white solid; mp 141-143 °C. IR (KBr): 3391-3367, 3015, 1692 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.77 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.3 Hz, J ₁ _′ _H,2 _′ _Ha = 5.5 Hz, 1 H, 2′H_a), 4.13 (dd, J ₂ _′ _Ha,2 _′ _Hb = 10.3 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 2′H_b), 4.35 (dd, J ₁ _′ _H,2 _′ _Ha = 5.5 Hz, J ₁ _′ _H,2 _′ _Hb = 2.8 Hz, 1 H, 1′H), 4.96-5.18 (br s, 2 H, 2 × OH, exch. D₂O), 7.95 (d, J _5H,6H = 7.5 Hz, 1 H, 5-H), 8.13 (d, J _5H,6H = 7.5 Hz, 1 H, 6-H), 8.33-8.59 (br s, 3 H, 3 × NH, exch. D₂O). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 65.2, 73.6, 105.3, 124.9, 131.3, 136.4, 173.2. MS-FAB: m/z = 171 [MH⁺]. Anal. Calcd for C₇H₁₀N₂O₃: C, 49.41; H, 5.92; N, 16.46. Found: C, 49.72; H, 5.73; N, 16.19.
Compound 10b: white solid; mp 127-128 °C. IR (KBr): 3398-3365, 3009, 1691 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 3.51 (ddd, J ₂ _′ _H,3 _′ _Ha = 5.3 Hz, J ₁ _′ _H,2 _′ _H = 4.2 Hz, J ₂ _′ _H,3 _′ _Hb = 2.4 Hz, 1 H, 2′H), 3.69 (dd, J ₃ _′ _Ha,3 _′ _Hb = 10.3 Hz, J ₂ _′ _H,3 _′ _Ha = 5.3 Hz, 1 H, 3′H_a), 4.06 (dd, J ₃ _′ _Ha,3 _′ _Hb = 10.3 Hz, J ₂ _′ _H,3 _′ _Hb = 2.4 Hz, 1 H, 3′H_b), 4.17 (d, J ₁ _′ _H,2 _′ _H = 4.2 Hz, 1 H, 1′H), 5.06-5.37 (br s, 3 H, 3 × OH, exch. D₂O), 7.99 (d, J _5H,6H = 7.8 Hz, 1 H, 5-H), 8.12 (d, J _5H,6H = 7.8 Hz, 1 H, 6-H), 8.29-8.65 (br s, 3 H, 3 × NH, exch. D₂O). ¹³C NMR (100 MHz, DMSO-d ₆/TMS): δ = 68.5, 71.1, 73.5, 112.9, 124.7, 129.9, 134.8, 172.9. MS-FAB: m/z = 201 [MH⁺]. Anal. Calcd for C₈H₁₂N₂O₄: C, 48.00; H, 6.04; N, 13.99. Found: C, 48.21; H, 5.89; N, 14.16.