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Synlett 2008(4): 529-534  
DOI: 10.1055/s-2008-1042760
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publication History

Received 20 November 2007
Publication Date:
12 February 2008 (online)

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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

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′Ha), 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′Hb), 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′Ha), 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′Hb), 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.

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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′Ha), 4.19 (dd, J 2 ′ Ha,2 ′ Hb = 10.3 Hz, J 1 ′ H,2 ′ Hb = 2.8 Hz, 1 H, 2′Hb), 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′Ha), 4.17 (dd, J 2 ′ Ha,2 ′ Hb = 10.5 Hz, J 1 ′ H,2 ′ Hb = 2.8 Hz, 1 H, 2′Hb), 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 Harom), 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′Ha), 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′Hb), 4.95-5.13 (br s, 2 H, 2 × OH, exch. D2O), 7.05-7.51 (m, 5 Harom), 7.67-7.99 (m, 3 Harom). 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′Ha), 4.13 (dd, J 2 ′ Ha,2 ′ Hb = 10.3 Hz, J 1 ′ H,2 ′ Hb = 2.8 Hz, 1 H, 2′Hb), 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′Ha), 4.06 (dd, J 3 ′ Ha,3 ′ Hb = 10.3 Hz, J 2 ′ H,3 ′ Hb = 2.4 Hz, 1 H, 3′Hb), 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.