A Versatile Protocol for theSynthesis of Oxazole and 3-Nitro/3-Carbethoxy Pyrrole C-Nucleosides using TOSMIC [1]

Abstract

The synthesis of oxazole and pyrrole C-nucleosides usingTOSMIC in moderate to good yields is reported.

oxazole - pyrrole - C-nucleosides - TOSMIC - sugar derivatives

References

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IICT Communication number 030312.

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General ExperimentalProcedures: Method A: To a stirred solution of aldehyde 1 (0.08 g, 0.39 mmol) in MeOH (2 mL), K₂CO₃ (0.16g, 1.18 mmol) and TOSMIC (0.077 g, 0.39 mmol) were added and stirredat reflux for 1 h. The reaction mixture was diluted with EtOAc (20mL), washed with H₂O (10 mL), brine (10 mL), dried (Na₂SO₄)and concentrated. The residue was subjected to column chromatography(silica gel, 25% EtOAc:hexane) to afford 1a (0.030g, 33%) as a syrup. [α]_D -35.2(c 1.0, CHCl₃). ¹H NMR(200 MHz, CDCl₃): δ = 1.30 (s, 3 H,-CH₃), 1.50 (s, 3 H, -CH₃), 3.12 (s, 3 H,OMe), 3.80 (d, J _3,4 = 3.7Hz, 1 H, H-3), 4.60 (d, J _2,1 = 7.4Hz, 1 H, H-2), 5.20 (d, J _4,3 = 3.5 Hz, 1 H, H-4),5.96 (d, J _1,2 = 6.7Hz, 1 H, H-1), 7.03 (s, Ar-H, 1 H), 7. 89 (s, Ar-H, 1 H). ¹³CNMR (50 MHz, CDCl₃): δ = 26.09, 26.75,58.05, 74.11, 81.96, 84.89, 104.61, 111.96, 125.93, 146.64, 150.70.IR (KBr): 3380, 2760, 1510, 1380 cm^-1. Method B: To a stirred solution of potassium t-butoxide (0.046 g, 0.41mmol) in dryTHF (1 mL) was added TOSMIC (0.053 g, 0.27 mmol) followed by 8 (0.1 g, 0.27 mmol) in dry THF (2 mL)at -78 °C and stirred for 30 min. After the completionof the reaction, sat. NH₄Cl (2 mL) was added and thereaction mixture was allowed to come to r.t. and stirred for 15min. The organic compound was extracted into EtOAc (2 × 20mL), washed with H₂O (10 mL), brine (10 mL), dried (Na₂SO₄)and concentrated. The residue was subjected to column chromatography(silica gel, 20% EtOAc:hexane) to afford the product 8a (0.049 g, 44%) as a syrup. [α]_D -61.6(c 1.0, CHCl₃). ¹HNMR (CDCl₃, 200 MHz): δ = 0.09 (s,6 H), 0.95 (s, 9 H, 3 × CH₃),1.23 (s, 6 H_, 2 × CH₃),3.65 (br. s, 2 H, CH₂OTBS), 4.05 (t, J _4,5 = 3.8Hz, 1 H, H-4), 4.87 (d, J _2,1 = 5.2Hz, 1 H, H-2), 5.01 (dd, J _3,4 = 4.2, J _3,2 = 5.7Hz, 1 H, H-3), 5.55 (d, J _1,2 = 4.0Hz, 1 H, H-1), 6.70 (s, 1 H, Ar-H) 7.53 (s, Ar-H, 1 H). ¹³CNMR (75 MHz, CDCl₃): δ = 18.12, 24.90,25.81, 26.12, 29.65, 64.92, 78.99, 81.74, 83.23, 83.71, 112.07,117.54, 118.36, 120.56, 134.37. MS-FAB: m/z (%) = 399(19) [M⁺ + 1], 355(24), 281 (12), 221 (14), 147 (32), 73 (100). IR (neat): 3140, 2930, 2870,1570, 1380 cm^-1. Anal. Calcd for C₁₈H₃₀N₂O₆Si:C, 54.25; H, 7.59; N, 7.03. Found: C, 54.22; H, 7.55; N, 7.01. Compound 4a. [α]_D -52.4(c 1.0, CHCl₃). ¹HNMR (300 MHz, CDCl₃): δ = 1.36 (s,3 H, CH₃), 1.55 (s, 3 H, CH₃), 3.20 (s, 3H, -OMe), 4.19 (d, J _3,4 = 3.6Hz, 1 H, H-3), 4.61 (d, J _2,1 = 6.0Hz, 1 H, H-2), 5.61 (d, J _4,3 = 3.6Hz, 1 H, H-4), 5.95 (d, J _1,2 = 6.0Hz, 1 H, H-1), 6.88 (s, Ar-H, 1 H), 7.61 (Ar-H, 1 H). ¹³CNMR (50 MHz, CDCl₃): δ = 26.32, 26.81, 29.62,58.17, 82.83, 84.15,104.23, 111.94, 115.64, 118.90, 120.86, 134.45.IR (KBR): 3480, 2960, 1490, 1340 cm^-1. MS-FAB: m/z (%) = 385(25) [M + 1], 281 (2), 221 (2), 147 (6),111 (16), 97 (32), 57 (100). Mp146-148 °C. Anal.Calcd for C₁₂H₁₆N₂O₆:C, 50.70; H, 5.67; N, 9.85. Found: C, 50.64; H, 5.62; N, 9.78. Method C: To a stirred solution of TOSMIC(0.05 g, 0.26 mmol) in dry THF (2 mL) was added n-BuLi(0.24 mL, 1.6 M solution in hexane) followed by 9 (0.1g, 0.26 mmol) dissolved in dry THF (2 mL) at -78 °C andstirred for 30 min. After the completion of the reaction, the reactionmixture was quenched with aq sat. NH₄Cl solution (2 mL)and allowed to attain r.t. in 15 min. The organic compound was extractedinto EtOAc (2 × 20 mL), washed with H₂O(10 mL), brine (10 mL), dried (Na₂SO₄) andconcentrated. The residue was subjected to column chromatography(silica gel, 20% EtOAc:hexane) to afford 9a (0.058g, 53%) as a syrup. [α]_D -34.0(c 1.0, CHCl₃). ¹H NMR(200 MHz, CDCl₃): δ = 0.09 (s, 6 H),0.95 (s, 9 H, 3 × CH₃), 1.20-1.40(9 H), 3.74 (d, J _5,4 = 4.6Hz, 2 H, -CH₂OTBS), 4.10 (t, J _4,5 = 4.8Hz, 1 H, H-4), 4.19-4.3 (m, 2 H, -OCH₂CH₃),4.82 (d, J _2,1 = 4.8 Hz, 1 H, H-2),5.01 (dd, J _3,4 = 4.6, J _3,2 = 5.8Hz, 1 H, H-3), 5.55 (d, J _1,2 = 3.9Hz, 1 H, H-1), 6.82 (s, Ar-H, 1 H), 7.30 (s, Ar-H, 1 H), 8.30 (br.s, 1 H, NH). ¹³C NMR (75 MHz, CDCl₃): δ = 14.47,18.28, 25.14, 25.91, 26.33, 59.43, 63.35, 78.88, 81.91, 83.84, 83.71,111.96, 118.43, 124.06, 128.33. MS-FAB: m/z (%) = 426 (52) [M⁺ + 1],380 (23), 366 (46), 281 (48), 222 (54), 218(100). Anal. Calcd forC₂₁H₃₅NO₆Si: C, 59.26; H, 8.29; N,3.29. Found: C, 59.21; H, 8.22; N, 3.25. Compound 5a. [α]_D -69.3(c 1.0, CHCl₃). ¹HNMR (300 MHz, CDCl₃): δ = 1.30-1.60(m, 6 H) 1.55 (s, 3 H), 3.21 (s, 3 H, OMe), 4.10 (d, J _3,4 = 6.0Hz, 1 H, H-3), 4.22-4.30 (m, 2 H, -OCH₂CH₃), 4.60(d, J _2,1 = 6.0 Hz, 1 H, H-2),5.65 (d, J _4,3 = 5.6Hz, 1 H, H-4), 5.94 (d, J _1,2 = 6.0Hz, 1 H, H-1), 6.82 (s, Ar-H, 1 H), 7. 33 (s, Ar-H, 1 H). ¹³CNMR (75 MHz, CDCl₃): δ = 14.40, 26.33,26.85, 58.26, 59.60, 84.10, 84.53, 104.10, 111.47, 113.12, 118.64,119.47, 124.53, 164.90. IR (KBr): 3350, 2980, 1710, 1340, 1070 cm^-1.MS-FAB: m/z (%) = 312 [M + 1],281 (2), 221 (2), 147 (6), 111 (16), 97 (32), 57 (100). Mp 90-93 °C.Anal. Calcd for C₁₅H₂₁NO₆: C, 57.87;H, 6.80; N, 9.85. Found: C, 57.81; H, 6.77; N, 9.83.