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Synlett 2007(12): 1905-1908  
DOI: 10.1055/s-2007-984527
LETTER
© Georg Thieme Verlag Stuttgart · New York

Biorenewable Resources in the Biginelli Reaction: Cerium(III)-Catalyzed Synthesis of Novel Iminosugar-Annulated Perhydropyrimidines

Lal Dhar Singh Yadav*, Ankita Rai, Vijai Kumar Rai, Chhama Awasthi
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
Fax: +91(532)2461157; e-Mail: ldsyadav@hotmail.com;
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Publication History

Received 7 May 2007
Publication Date:
25 June 2007 (online)

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Abstract

An unprecedented version of the Biginelli reaction using an unprotected aldose as a biorenewable aldehyde component and 2-phenyl-1,3-oxazol-5-one as a novel active methylene building block with urea/thiourea is reported. The reaction is cerium(III)-­catalyzed, expeditious, and effected under solvent-free microwave irradiation conditions to yield diastereoselectively, iminosugar-annulated polyfuntionalized perhydropyrimidines via ring transformation of an isolable intermediate followed by cyclodehydration.

Key words

Biginelli reaction - iminosugars - perhydropyrimidines - microwaves - stereoselective - solvent-free

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General Procedure for Iminosugar-Annulated Perhydropyrimidines 4 and 5: A solvent-free mixture of oxazolone 1 (2.0 mmol), aldose 2 (2.0 mmol), urea/thiourea 3 (2.0 mmol) and Ce2(SO4)3 (0.114 g, 10 mol%) was taken in a 20-mL vial and subjected to MW irradiation for 8-13 min (Table [1] ). After completion of the reaction as indicated by TLC, H2O (10 mL) was added to the reaction mixture and stirred for 10 min. The yellowish precipitate thus obtained was washed with H2O to give the crude product which was recrystallized from EtOH to afford a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by 1H NMR spectroscopy). The product on second recrystallization from EtOH furnished an analytically pure sample of a single diastereomer 4 or 5 (Table [1] ). On the basis of comparison of J values with the literature ones, [24] [30-36] the trans stereochemistry was assigned to 4 and 5, as the coupling constant (J 1,9a = 9.6 Hz) of the major trans isomer was higher than that for the minor cis diastereomer (J 1,9a = 4.8 Hz).
Characterization Data of Representative Compounds: Compound 4a: pale yellow powder; mp 115-117 °C. IR (KBr): 3341, 3315, 3009, 1685, 1670, 1675, 1603, 1581, 1455 cm-1. 1H NMR (400 MHz, DMSO-d 6 + D2O): δ = 2.65 (dd, J 6ax,eq = 13.1 Hz, J 6ax,7 = 9.7 Hz, 1 H, H-6ax), 3.34 (ddd, J 7,8 = 9.3 Hz, J 6ax,7 = 9.7 Hz, J 6eq,7 = 3.7 Hz, 1 H, H-7), 3.70 (dd, J 7,8 = 9.3 Hz, J 8,9 = 9.2 Hz, 1 H, H-8), 3.92 (dd, J 6ax,eq = 13.1 Hz, J 6eq,7 = 3.7 Hz, 1 H, H-6eq), 4.11 (dd, J 8,9 = 9.2 Hz, J 9,9a = 9.5 Hz, 1 H, H-9), 5.05 (dd, J 1,9a = 9.6 Hz, J 9,9a = 9.5 Hz, 1 H, H-9a), 6.17 (d, J 1,9a = 9.6 Hz, 1 H, H-1), 7.19-7.83 (m, 5 H, ArH). 13C NMR (DMSO-d 6/TMS): δ = 25.5, 59.7, 69.5, 73.5, 74.5, 80.5, 126.9, 127.7, 129.2, 130.8, 132.5, 165.7, 167.8, 169.3. MS (FAB): m/z = 336 [MH+]. Anal. Calcd for C15H17N3O6: C, 53.73; H, 5.11; N, 12.53. Found: C, 53.47; H, 5.33; N, 12.89.
Compound 5a: pale yellow powder; mp 125-128 °C. IR (KBr): 3343, 3319, 3008, 1683, 1667, 1673, 1604, 1585, 1449 cm-1. 1H NMR (400 MHz, DMSO-d 6 + D2O): δ = 3.13 (ddd, J 6,7 = 9.7 Hz, J 1 ′ a,6 = 5.8 Hz, J 1 ′ b,6 = 2.5 Hz, 1 H, H-6), 3.35 (dd, J 7,8 = 9.4 Hz, J 6,7 = 9.7 Hz, 1 H, H-7), 3.50 (dd, J 1 ′ a,1 ′ b = 12.2 Hz, J 1 ′ a,6 = 5.8 Hz, 1 H, Ha-1′), 3.69 (dd, J 7,8 = 9.4 Hz, J 8,9 = 9.3 Hz, 1 H, H-8), 3.81 (dd, J 1 ′ a,1 ′ b = 12.2 Hz, J 1 ′ b,6 = 2.5 Hz, 1 H, Hb-1′), 4.14 (dd, J 8,9 = 9.3 Hz, J 9,9a = 9.4 Hz, 1 H, H-9), 4.99 (dd, J 1,9a = 9.5 Hz, J 9,9a = 9.4 Hz, 1 H, H-9a), 6.21 (d, J 1,9a = 9.5 Hz, 1 H, H-1), 7.08-7.85 (m, 5 H, ArH). 13C NMR (DMSO-d 6/TMS): δ = 25.9, 61.1, 66.9, 70.3, 73.5, 74.5, 79.9, 127.2, 128.3, 129.7, 131.5, 133.1, 165.2, 166.9, 169.1. MS (FAB): m/z = 366 [MH+]. Anal. Calcd for C16H19N3O7: C, 52.60; H, 5.24; N, 11.50. Found: C, 52.89; H, 5.59; N, 11.33.

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General Procedure for 5-Aminoperhydropyrimidine-dione Analogues 9 and 10: Compound 4 or 5 (2.0 mmol) was refluxed in H2SO4-H2O (15 mL, 4:3) for 45 min in an oil bath. The reaction mixture was cooled, the desired products 9 or 10 were precipitated by adding concd NH4OH (specific gravity 0.88) under ice cooling and recrystallized from EtOH to obtain analytically pure samples of 9 and 10, respectively.
Characterization Data of Representative Compounds:
Compound 9a: pale yellow powder; mp 134-135 °C. IR (KBr): 3345, 3011, 1683, 1669, 1605, 1579, 1451 cm-1. 1H NMR (400 MHz, DMSO-d 6 + D2O): δ = 2.67 (dd, J 6ax,eq = 13.1 Hz, J 6ax,7h = 9.8 Hz, 1 H, H-6ax), 3.35 (ddd, J 7,8 = 9.3 Hz, J 6ax,7h = 9.8 Hz, J 6eq,7h = 3.8 Hz, 1 H, H-7), 3.73 (dd, J 7,8 = 9.3 Hz, J 8,9 = 9.3 Hz, 1 H, H-8), 3.95 (dd, J 6ax,eq = 13.1 Hz, J 6eq,7h = 3.8 Hz, 1 H, H-6eq), 4.09 (dd, J 8,9 = 9.3 Hz, J 9,9a = 9.5 Hz, 1 H, H-9), 5.04 (dd, J 1,9a = 9.7 Hz, J 9,9a = 9.5 Hz, 1 H, H-9a), 6.18 (d, J 1,9a = 9.7 Hz, 1 H, H-1). 13C NMR (DMSO-d 6/TMS): δ = 25.6, 60.1, 69.3, 73.7, 74.6, 80.8, 165.8, 167.9. MS (FAB): m/z = 232 [MH+]. Anal. Calcd for C8H13N3O5: C, 41.56; H, 5.67; N, 18.17. Found: C, 41.92; H, 5.49; N, 18.32.
Compound 10a: pale yellow powder; mp 151-153 °C. IR (KBr): 3344, 3009, 1685, 1671, 1601, 1583, 1453 cm-1. 1H NMR (400 MHz, DMSO-d 6 + D2O): δ = 3.15 (ddd, J 6,7 = 9.7 Hz, J 1 ′ a,6 = 5.9 Hz, J 1 ′ b,6 = 2.4 Hz, 1 H, H-6), 3.36 (dd, J 7,8 = 9.4 Hz, J 6,7 = 9.7 Hz, 1 H, H-7), 3.57 (dd, J 1 ′ a,1 ′ b = 12.1 Hz, J 1 ′ a,6 = 5.9 Hz, 1 H, Ha-1′), 3.71 (dd, J 7,8 = 9.4 Hz, J 8,9 = 9.2 Hz, 1 H, H-8), 3.79 (dd, J 1 ′ a,1 ′ b = 12.1 Hz, J 1 ′ b,6 = 2.4 Hz, 1 H, Hb-1′), 4.11 (dd, J 8,9 = 9.2 Hz, J 9,9a = 9.5 Hz, 1 H, H-9), 5.02 (dd, J 1,9a = 9.6 Hz, J 9,9a = 9.5 Hz, 1 H, H-9a), 6.23 (d, J 1,9a = 9.6 Hz, 1 H, H-1). 13C NMR (DMSO-d 6/TMS): δ = 26.0, 61.5, 67.0, 70.5, 73.6, 74.7, 80.2, 165.3, 167.2. MS (FAB): m/z = 262 [MH+]. Anal. Calcd for C9H15N3O6: C, 41.38; H, 5.79; N, 16.09. Found: C, 41.18; H, 5.58; N, 16.21.

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General Procedure for Isolation of Michael Adducts 7a ( n = 3, X = O, R = H) and 7j ( n = 4, X = S, R = Ph) and Their Conversion into the Corresponding Sugar-Annulated Products 4a and 5d:
The procedure followed was the same as described above for the synthesis of 4 and 5 except that the time of MW irradiation in this case was 4-6 min instead of 8-13 min. The adducts 7 were recrystallized from EtOH to give a diastereomeric mixture (>94:<6; in the crude products the ratio was >91:<9, as determined by 1H NMR spectroscopy) which was again recrystallized from EtOH to obtain an analytical sample of 7a and 7j. The adducts 7a and 7j were assigned the anti stereochemistry as their 1H NMR spectra exhibited higher values of coupling constant (J cyclicNCH,acyclicNCH = 9.9 Hz) than that of the very minor (<6%) diastereomer (syn, J cyclicNCH,acyclicNCH = 4.4 Hz). [24] [30-36] Finely powdered intermediate compounds 7a and 7j were MW irradiated for 4-7 min in the same way as described for the synthesis of 4 and 5 to give the corresponding sugar-annulated products 4a and 5d quantitatively.
Characterization Data of Representative Compounds:
Compound 7a: pale yellow powder; mp 102-104 °C. IR (KBr): 3148, 3011, 1773, 1677, 1603, 1585, 1455 cm-1. 1H NMR (400 MHz, DMSO-d 6 + D2O): δ = 4.07 (dd, J 1 ′ ,2 ′ = 6.9 Hz, J 1 ′ ,acyclicNCH = 5.4 Hz, 1 H, H-1′), 4.19 (dd, J 4 ′ Ha,Hb = 10.5 Hz, J 4 ′ Hb,3 ′ = 5.3 Hz, 1 H, Hb-4′), 4.39 (dd, J 1 ′ ,2 ′ = 6.9 Hz, J 2 ′ , 3 ′ = 4.1 Hz, 1 H, H-2′), 4.67 (ddd, J 3,4 ′ Hb = 5.3 Hz, J 3,4 ′ Ha = 5.3 Hz, J 2 ′ , 3 ′ = 4.1 Hz, 1 H, H-3′), 4.85 (dd, J 4 ′ Ha,Hb = 10.5 Hz, J 3,4 ′ Ha = 5.3 Hz, 1 H, 4′-Ha), 5.03 (dd, J 1 ′ ,acyclicNCH = 5.4 Hz, J cyclicNCH,acyclicNCH = 9.9 Hz, 1 H, acyclic NCH), 6.74 (d, J cyclicNCH,acyclicNCH = 9.9 Hz, 1 H, cyclic NCH), 7.12-7.69 (m, 5 H, ArH). 13C NMR (DMSO-d 6): δ = 35.8, 64.9, 70.5, 71.5, 72.7, 73.5, 73.5, 74.6, 127.5, 128.3, 130.2, 132.9, 133.6, 167.5, 170.2. MS (FAB): m/z = 354 [MH+]. Anal. Calcd for C15H19N3O7: C, 50.99; H, 5.42; N, 11.89. Found: C, 50.79; H, 5.78; N, 11.63.