4168
T. Pospieszny et al. / Tetrahedron Letters 51 (2010) 4166–4169
4. Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc., Perkin Trans. 1 2000, 3155–
3184.
CH3-19, and CH3-21, respectively. The protons of the CO2CH3 group
gave signals in the range 3.66 ppm. Moreover, the 1H NMR spectra
of compounds 4a–e showed characteristic singlets in the range
3.88–3.92 ppm assigned to the S–CH2–CO protons. Two doublets
at 6.22 and 7.80 ppm for C50-H and C60-H of the 2-thiouracil ring
of compound 4a and a singlet at 6.00 ppm due to C50-H of the 6-
methyl-2-thiouracil ring of compound 4b were present. Diagnostic
singlets for compounds 4b–e in the range 2.16–2.23 ppm were as-
signed to the C60-CH3 protons of the 6-methyl-2-thiouracil ring.
The13CNMRspectraofcompounds4a–einCDCl3 showedcharac-
teristic signals in the ranges 12.00–12.02 ppm, 23.26–23.28 ppm,
and 18.24–18.26 ppm assigned to CH3-18, CH3-19, and CH3-21,
respectively. The carbons of the CO2CH3 group gave signals in the
ranges 174.78–174.81 ppm and 51.48–51.49 assigned to CO2 and
CH3, respectively. Two diagnostic signals for C26@O and S-CH2 were
present at 167.60–168.66 ppm and 33.13–33.38 ppm, respectively.
The thiouracil ring exhibited signals in the range 107.95–
111.39 ppm and 154.64–161.07 ppm assigned to C50@C60, respec-
tively. The 13C NMR spectra of compounds 4b–e showed the
presence of a methyl group from the 6-methyl-2-thiouracil ring at
23.85–24.13 ppm.
5. For example, see: (a) Willimann, P.; Marti, T.; Fürer, A.; Diederich, F. Chem. Rev.
1997, 97, 1567–1608. and references cited therein; (b) Davis, A. P. Chem. Soc.
Rev. 1993, 22, 243–253; (c) Li, Y.; Dias, R. Chem. Rev. 1997, 97, 283–304; (d)
Tamminen, J.; Kolehmainen, E. Molecules 2001, 6, 21–46; (e) Guthrie, J. P.; Ueda,
Y. Can. J. Chem. 1976, 54, 2745–2758. and references cited therein; (f) McKenna,
J.; McKenna, J. M.; Thornthwaite, D. W. J. Chem. Soc., Chem. Commun. 1977, 809–
811.
Filimonov, D. A.; Borodina, Y. V.; Lagunin, A. A.; Kos, A. J. Chem. Inf. Comput.
Sci. 2000, 40, 1349–1355; (c) Poroikov, V. V.; Filimonov, D. A. J. Comput. Aided
Mol. Des. 2003, 16, 819–824; (d) Poroikov, V. V.; Filimonov, D. A. In Predictive
Toxicology; Helma, Christopher, Ed.; Taylor and Francis, 2005; pp 459–478; (e)
Stepanchikova, A. V.; Lagunin, A. A.; Filimonov, D. A.; Poroikov, V. V. Curr. Med.
Chem. 2003, 10, 225–233.
7. For example, see: (a) Snyder, H. R.; Foster, H. M.; Nussberger, G. A. J. Am. Chem.
Soc. 1953, 76, 2441–2444; (b) Kamalakannan, P.; Venkappayya, D.;
Balasubramanian, T. Dalton Trans. 2002, 3381–3391; (c) Pospieszny, T.;
Wyrzykiewicz, E. Tetrahedron Lett. 2008, 49, 5319–5321.
´
8. Opsenica, D.; Pocsfalvi, G.; Juranic, Z.; Tinant, B.; Declercq, J.-P.; Kyle, D. E.;
Milhous, W. K.; Šolaja, B. A. J. Med. Chem. 2000, 43, 3274–3282.
9. For example, see: (a) Chattopadhyay, P.; Pandey, P. S. Bioorg. Med. Chem. Lett.
2007, 17, 1553–1557; (b) On, J. H.; Cho, K. T.; Park, Y.; Hahm, S.; Kim, W.; Cho, J.
Y.; Hwang, J. H.; Jun, Y. M.; Cha, G. S.; Nam, H.; Kim, B. H. Tetrahedron 2009, 65,
1415–1423.
10. (a) General procedure for the synthesis of 5-morpholinomethyl-6-methyl-
2-thiouracil, 5-piperidinomethyl-6-methyl-2-thiouracil, and 5-(4-methylpi
The FT-IR spectra of all the compounds (KBr discs) revealed
peridino)methyl-6-methyl-2-thiouracil:
a mixture of 6-methyl-2-thiouracil
two strong characteristic bands in the region 1666–1639 cmꢀ1 and
(5.0 g, 35.21 mmol), paraformaldehyde (3.0 g, 35.21 mmol), and morpholine
(3.07 mL, 35.21 mmol), or piperidine (3.46 mL, 35.21 mmol), or 4-
methylpiperidine (4.15 mL, 35.21 mmol) was suspended in 300 mL of EtOH
(99.8%) and heated at reflux for 48 h. The obtained homogeneous solution was
filtered and concentrated on a rotary evaporator to 150 mL. The reaction
mixture was kept at room temperature for 24 h. The precipitated solid was
isolated by filtration, dried at room temperature, and recrystallized from
methanol. (b) General procedure for the synthesis of 4a and 4b: a mixture of 2-
thiouracil (54.81 mg, 0.42 mmol) or 6-methyl-2-thiouracil (60.81 g,
0.42 mmol) and K2CO3 (59.10 mg, 0.42 mmol) in dry DMF (5 mL) was stirred
1587–1546 cmꢀ1, assigned to (C40@O) and (C50@C60), respectively.
m m
The most characteristic peaks in the FT-IR spectra of water-free 4a–e
in KBr were the bands at 1746–1730 cmꢀ1 and 1272-1263 cmꢀ1
2870–2865 cmꢀ1, and 1445–1432 cmꢀ1, assigned to
(C24@O) and
(C24O2), (S–CH2), and d(S–CH2), respectively.
In conclusion, five new compounds 4a–e were prepared from
methyl 3 -chloroacetoxy-5b-cholan-24-oate (3) in dry DMF in
,
m
m
m
a
at room temperature for 2 h. Next, methyl 3a-chloroacetoxy-5b-cholan-24-
the presence of K2CO3 at room temperature for 24 h by reaction
with 2-thiouracil, 6-methyl-2-thiouracil, 5-morpholinomethyl-6-
methyl-2-thiouracil, 5-piperidinomethyl-6-methyl-2-thiouracil, or
5-(4-methylpiperidino)methyl-6-methyl-2-thiouracil.10
oate (3) (200 mg, 0.42 mmol) was added and the mixture was stirred for 24 h
at room temperature (TLC). It was then poured onto crushed ice and extracted
with benzene/Et2O (1:1, 3 ꢁ 15 mL). The extract was washed with H2O
(3 ꢁ 15 mL) and brine (20 mL) and then dried over MgSO4. The solvent was
evaporated under reduced pressure to afford the crude product. (c) General
procedure for the synthesis of 4c–e: A mixture of 5-piperidinomethyl-6-methyl-
2-thiouracil (145.18 mg, 0.42 mmol) or 5-morpholinomethyl-6-methyl-2-
thiouracil (103.21 mg, 0.42 mmol) or 5-(4-methylpiperidino) methyl-6-
methyl-2-thiouracil (108.35 mg, 0.42 mmol) and K2CO3 (59.10 mg,
0.42 mmol) in dry DMF (10 mL) was stirred at room temperature for 2 h. Next,
Acknowledgements
This work was supported by the Ministry of Science and Higher
Education (Project No. N N204 166 836).
methyl
3a-chloroacetoxy-5b-cholan-24-oate (3) (200 mg, 0.42 mmol) was
added and the mixture was stirred for 24 h at room temperature (TLC). It was
then poured onto crushed ice and extracted with benzene/Et2O (1:1, 3 ꢁ 20 mL).
The extract was washed with H2O (3 ꢁ 20 mL), brine (30 mL), and dried over
MgSO4. The solvent was evaporated under reduced pressure to afford the crude
product. The spectral and ES-HRMS data of compounds 4a–e are given below.
Compound 4a (isolated yield 79%, mp 175–176 °C): 1H NMR (300 MHz, CDCl3,
TMS, ppm): d 12.10 (1H, br s, N1-H), 7.80 (1H, d, J = 7.8 Hz, C60-H), 6.22 (1H, d,
J = 7.8 Hz, C50-H), 4.81 (1H, m, Cb3–H), 3.92 (2H, s, 27-CH2), 3.66 (3H, s,
–CO2CH3), 2.40–0.98 (27H, m, steroid skeleton), 0.92 (3H, s, 19-CH3), 0.90 (3H, d,
J = 6.4 Hz, 21-CH3), 0.64 (3H, s, 18-CH3). 13C NMR (75 MHz, CDCl3, TMS, ppm):
174.78 (C24), 167.60 (C26), 164.28 (C20), 160.45 (C40), 154.64 (C60), 111.39 (C50),
76.48 (C3), 56.40 (C14), 55.94 (C17), 51.49 (C25), 42.70 (C13), 41.85 (C5), 40.36
(C9), 40.06 (C12), 35.75 (C8), 35.34 (C20), 34.91 (C1), 34.55 (C10), 33.13 (C27),
32.01 (C4), 31.04 (C23), 30.97 (C22), 28.16 (C2), 26.97 (C16), 26.44 (C6), 26.38
(C7), 24.25 (C15), 23.26 (C19), 20.80 (C11), 18.24 (C21), 12.01 (C18). FT-IR (KBr,
Supplementary data
Supplementary data associated with this article can be found, in
References and notes
1. For example, see: (a) De Clercq, E.; Balzarini, J. Il Farmaco 1995, 50, 735–747;
(b) Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye, N.; Baba, M.;
Shigeta, S.; Walker, R. T.; De Clercq, E. J. Med. Chem. 1995, 38, 2860–2865; (c)
Crooks, J. In Side Effects of Drugs; Meyler, L., Herzheimer, A., Eds.; Expertia
Medica; Elsevier: Amsterdam, 1972; p 573; (d) Barth, R. F.; Soloway, A. H.;
Fairchild, R. G. Cancer Res. 1990, 50, 1061–1070; (e) Tjarks, W.; Gabel, D. J. Med.
Chem. 1991, 34, 315–319; (f) Hawthorne, M. F. Angew. Chem. 1993, 105, 997–
1033; (g) Nugent, R. A.; Schlachter, S. T.; Murphy, M. I.; Cleek, G. J.; Poel, T. J.;
Wishka, D. G.; Graber, D. R.; Yagi, Y.; Kaiser, B. J.; Olmsted, R. A.; Kopta, L. A.;
Swaney, S. M.; Poppe, S. M.; Morris, J.; Tarpley, W. G.; Thomas, R. C. J. Med.
Chem. 1998, 41, 3793–3803.
2. For example, see: (a) Raj, C. R.; Behera, S. Biosens. Bioelectron. 2005, 21, 949–
956; (b) Chu, X.; Duan, D.; Shen, G.; Yu, R. Talanta 2007, 71, 2040–2047; (c)
Herak, J. N.; Sankovic, K.; Huttermann, J. Int. J. Radiat. Biol. 1994, 66, 3–9.
3. For example, see: (a) Civcir, P. Ü. J. Mol. Struct. (Theochem) 2000, 532, 157–169;
(b) Moustafa, H.; El-Taher, S.; Shibil, M. F.; Hilal, R. Int. J. Quantum Chem. 2002,
cmꢀ1): (C40@O) 1664,
CH2) 2870, d(S–CH2) 1445,
m
m
(C50@C60) 1552,
(C26@O) 1749, m(C26O2) 1271. EI MS (m/z, % int.):
m(C24@O) 1733, m(C24O2) 1265, m(S–
m
558 (M+Å, 8), 372 (100), 215 (72). ES-HRMS [C31H46N2O5S+H]+: calcd 559.3203,
found 559.3208.
Compound 4b (isolated yield 84%, yellow oil): 1H NMR (300 MHz, CDCl3, TMS,
ppm): d 12.15 (1H, br s, N1-H), 6.00 (1H, s, C50-H), 4.79 (1H, m, Cb3–H), 3.88 (2H,
s, 27-CH2), 3.66 (3H, s, –CO2CH3), 2.41–0.98 (28H, m, steroid skeleton), 2.16 (3H,
s, C60-CH3), 0.92 (3H, s, 19-CH3), 0.91 (3H, d, J = 6.4 Hz, 21-CH3), 0.64 (3H, s, 18-
CH3). 13C NMR (75 MHz, CDCl3, TMS, ppm): 174.78 (C24), 168.66 (C26), 165.30
(C20), 163.43 (C40), 161.07 (C60), 107.95 (C50), 76.32 (C3), 56.36 (C14), 55.92
(C17), 51.48 (C25), 42.69 (C13), 41.86 (C5), 40.35 (C9), 40.04 (C12), 35.76 (C8),
35.34 (C20), 34.93 (C1), 34.56 (C10), 33.38 (C27), 32.06 (C4), 31.04 (C23), 30.97
(C22), 28.16 (C2), 27.01 (C16), 26.44 (C6), 26.27 (C7), 24.17 (C15), 23.85 (C60-
CH3), 23.27 (C19), 20.79 (C11), 18.24 (C21), 12.00 (C18). FT-IR (KBr, cmꢀ1):
´
87, 378–381; (c) Leszczynski, J. Int. J. Quantum Chem.: Quant. Biol. Symp. 1991,
m
(C40@O) 1659,
m
(C50@C60) 1549,
(C26@O) 1748, m(C26O2) 1269. EI MS (m/z, % int.): 572
m(C24@O) 1738, m(C24O2) 1272, m(S–CH2)
18, 9–18; (d) Les´, A.; Adamowicz, L. J. Am. Chem. Soc. 1990, 112, 1504–1509; (e)
Marino, T.; Russo, N.; Sicilia, E.; Toscano, M. J. Quantum Chem. 2001, 82, 44–52;
(f) Civcir, P. U. J. Phys. Org. Chem. 2001, 14, 171–179; (g) Contreras, J. G.;
Alderete, J. B. J. Phys. Org. Chem. 1995, 8, 395–399; (h) Nowak, M. J.;
Rostkowska, H.; Lapinski, L.; Leszczynski, J.; Kwiatkowski, J. S. Spectrochim.
Acta, Part A 1991, 47, 339–353.
2869, d(S–CH2) 1443,
m
(M+Å, 10), 372 (100), 215 (45). ES-HRMS [C32H48N2O5S+H]+: calcd 573.8068,
found 573.8063.
Compound 4c (isolated yield 87%, mp 157–157 °C): 1H NMR (300 MHz, CDCl3,
TMS, ppm): d 12.15 (1H, br s, N1-H), 4.81 (1H, m, Cb3–H), 3.88 (2H, s, 27-CH2),