Efficient Synthesis of 5-Hydroxymethyl Pyrimidines and their Nucleosides Using Microwave Irradiation

Abstract

Hydroxymethylation of uracil (1), cytosine (3), 5-hydroxymethyl-2′,3′-O-isopropylideneuridine (5), 5′-O-tert-butyldiphenylsilyl-2′,3′-O-isopropylideneuridine (7), 2′,3′-O-isopropyl-idenecytidine (9) and 2′,3′-O-isopropylidene-5′-O-tritylcytidine (11) was efficiently carried out with paraformaldehyde in alkaline medium under microwave irradiation in very high yield.

Key words

microwave - uracil - cytosine - 5-hydroxymethyluracil - uridine - cytidine - formaldehyde addition

References

• 1 Gedye RN. Smith FE. Westaway KC. Can. J. Chem.  1988,  66:  17 
• 2 Mingos DMP. Baghurst DR. Chem. Soc. Rev.  1991,  20:  1 
• 3 Abramovitch RA. Org. Prep. Proced. Int.  1991,  23:  683 
• 4 Jahngen EGE. Lentz RR. Pesheck PS. Sackett PH. J. Org. Chem.  1990,  55:  3406 
• 5 Pollington SD. Bond G. Moyes RB. Whan DA. Candlin JP. Jennings JR. J. Org. Chem.  1991,  56:  1313 
• 6 Raner KD. Strauss CR. J. Org. Chem.  1992,  57:  6231 
• 7 Sun WC. Guy PM. Jahngen JH. Rossomando EF. Jahngen EGE. J. Org. Chem.  1988,  53:  4414 
• 8a Lewis DA. Ward TC. Summers JS. McGrath JE. Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.)  1988,  29:  174 
• 8b Lewis DA. Summers JD. Ward TC. McGrath JE. J. Polym. Sci. Part A: Polym. Chem.  1992,  30:  1647 
• 9 Bose AK. Manhas MS. Ghosh M. Raju VS. Tabei K. Urbanczyk-Lipkowska Z. Heterocycles  1990,  30:  741 
• 10 Berlan J. Giboreau P. Lefeuvre S. Marchand C. Tetrahedron Lett.  1991,  32:  2363 
• 11 Adamek F. Hajek M. Tetrahedron Lett.  1992,  33:  2039 
• 12 Wyatt GR. Cohen SS. Biochem. J.  1953,  55:  774 
• 13 Flaks JG. Cohen SS. Biochim Biophys. Acta  1957,  25:  667 
• 14 Dosmar M. Witmer H. Curr. Microbiol.  1979,  2:  361 
• 15 Cline RE. Fink RM. Fink K. J. Am. Chem. Soc.  1959,  81:  2521 
• 16 Alegria AH. Biochim. Biophys. Acta.  1967,  149:  317 
• 17 Scheit KH. Chem. Ber.  1966,  3884 
• 18 Fourrey J.-L. Henry G. Jouin P. J. Chem. Res., Synop.  1979,  226 
• 19 Fromageot HPM. Grieffin BE. Reese CB. Sulston JE. Tetrahedron  1967,  23:  2315 

20

Selected Physical Data: 2: White powder; mp >300 °C (H₂O); TLC (CHCl₃-MeOH, 8.5:1.5 v/v): R_f 0.59. ¹H NMR (DMSO-d ₆, 300 MHz): δ = 4.11 (s, 2 H, CH₂), 7.24 (s, 1 H, H-6), 10.71 (br s, 1 H, NH), 11.05 (br s, 1 H, NH). ¹³C NMR (DMSO-d ₆, 75.04 MHz): δ = 55.7 (CH₂), 112.6 (C-5), 138.1 (C-6), 151.3 (C-2), 163.7 (C-4). 4: White powder; mp >300 °C (H₂O); TLC (CHCl₃-MeOH, 8:2 v/v): R_f 0.35. ¹H NMR (DMSO-d ₆, 300 MHz): δ = 3.51 (s, 2 H, CH₂), 7.12 (br s, 2 H, NH₂), 8.15 (s, 1 H, H-6), 11.18 (br s, 1 H, NH). 6: White powder; mp 170-172 °C (H₂O); TLC (CHCl₃-MeOH, 8.5:1.5 v/v): R_f 0.50. ¹H NMR (DMSO-d ₆, 300 MHz): δ = 1.36 (s, 3 H, CH₃), 1.57 (s, 3 H, CH₃), 3.85 (d, 1 H, J _gem = 12.1 Hz, H-5′_a), 3.97 (d, 1 H, J _gem = 12.1 Hz, H-5′_b), 4.12 (s, 1 H, CH₂), 4.80 (dd, 1 H, J _{3 ′ ,4 ′} = 3.0 Hz, J _{4 ′ ,5 ′} = 2.4 Hz, H-4′), 4.95 (dd, 1 H, J _{3 ′ ,4 ′} = 3.0 Hz, J _{2 ′ ,3 ′} = 6.2 Hz, H-3′), 4.98 (brs, 1 H, OH), 5.01 (dd, 1 H, J _{2 ′ ,3 ′} = 6.2 Hz, J _{1 ′ ,2 ′} = 2.5 Hz, H-2′), 5.67 (d, 1 H, J _{1 ′ ,2 ′} = 2.5 Hz, H-1′), 7.57 (s, 1 H, H-6), 9.01 (br s, 1 H, NH). 7: White foam; TLC (CHCl₃-MeOH, 9.5:0.5 v/v): R_f 0.61. ¹H NMR (CHCl₃, 300 MHz): δ = 1.08 (s, 9 H, 3 CH₃), 1.34 (s, 3 H, CH₃), 1.57 (s, 3 H, CH₃), 3.94 (d, 1 H, J _gem = 12.4 Hz, H-5′_a), 3.96 (d, 1 H, J _gem = 12.4 Hz, H-5′_b), 4.26 (dd, 1 H, J _{3 ′ ,4 ′} = 3.3 Hz, J _{4 ′ ,5 ′} = 2.6 Hz, H-4′), 4.75 (m, 1 H, H-3′), 4.82 (m, 1 H, H-2′), 5.44 (d, 1 H, J _{1 ′ ,2 ′} = 3.1 Hz, H-1′), 5.97 (d, 1 H, J _5,6 = 5.0 Hz, H-5), 7.34-7.41 (m, 5 H, Ar-H), 7.44-7.65 (m, 6 H, Ar-H, H-6), 9.51 (br s, 1 H, NH). ¹³C NMR (CHCl₃, 75.04 MHz): δ = 19.3 (Me₃ C), 25.3 (CH₃), 26.9 (Me ₃ C), 27.2 (CH₃), 63.9 (C-5′), 80.1 (C-3′), 84.9 (C-2′), 86.4 (C-4′), 91.5 (C-1′), 102.4 (Me₂ C), 114.3 (C-5), 127.8, 127.9, 129.9, 130.0, 132.2, 132.7, 135.3, 135.5 (Ar-Carbons), 140.6 (C-6), 150.1 (C-2), 163.3 (C-4). 8: White foam; TLC (CHCl₃-MeOH, 9:1 v/v): R_f 0.58. ¹H NMR (CHCl₃, 300 MHz): δ = 1.10 (s, 9 H, 3 CH₃), 1.35 (s, 3 H, CH₃), 1.60 (s, 3 H, CH₃), 3.90 (d, 1 H, J _gem = 12.2 Hz, H-5′_a), 3.94 (d, 1 H, J _gem = 12.2 Hz, H-5′_b), 4.15 (s, 2 H, CH₂), 4.15 (dd, 1 H, J _{3 ′ ,4 ′} = 3.0 Hz, J _{4 ′ ,5 ′} = 2.7 Hz, H-4′), 4.77 (dd, 1 H, J _{3 ′ ,4 ′} = 3.0 Hz, J _{2 ′ ,3 ′} = 6.3 Hz, H-3′), 4.80 (dd, 1 H, J _{2 ′ ,3 ′} = 6.3 Hz, J _{1 ′ ,2 ′} = 3.2 Hz, H-2′), 5.50 (d, 1 H, J _{1 ′ ,2 ′} = 3.2 Hz, H-1′), 7.35-7.44 (m, 5 H, Ar-H), 7.50-7.60 (m, 5 H, Ar-H), 8.01 (s, 1 H, H-6), 10.32 (br s, 1 H, NH). 10: Pale yellow foam; TLC (CHCl₃-MeOH, 9:1 v/v): R_f 0.45.
¹H NMR (DMSO-d ₆, 300 MHz): δ = 1.36 (s, 3 H, CH₃), 1.63 (s, 3 H, CH₃), 3.49 (s, 2 H, CH₂), 4.01 (m, 2 H, H-5′), 4.31 (m, 1 H, H-4′), 4.39 (m, 1 H, H-3′), 4.78 (m, 1 H, H-2′), 5.51 (d, 1 H, J _{1 ′ ,2 ′} = 2.8 Hz, H-1′), 7.21 (br s, 2 H, NH₂), 8.01 (s,
1 H, H-6). 12: Yellow foam; TLC (CHCl₃-MeOH, 9:1 v/v): R_f 0.65. ¹H NMR (CDCl₃, 300 MHz): δ = 1.37 (s, 3 H, CH₃), 1.63 (s, 3 H, CH₃), 3.50 (s, 2 H, CH₂), 3.79 (m, 2 H, H-5′), 4.33 (m, 1 H, H-4′), 4.95 (m, 1 H, H-3′), 5.09 (m, 1 H, H-2′), 5.60 (d, 1 H, J _{1 ′ ,2 ′} = 2.9 Hz, H-1′), 7.09-7.25 (m, 8 H, NH₂, Ar-H), 7.29-7.38 (m, 9 H, Ar-H), 8.06 (s, 1 H, H-6).