2814
S. Lucarini et al. / Tetrahedron Letters 52 (2011) 2812–2814
Table 1
Reagents, conditions and yields for the synthetic procedures leading to CTet and CTr
Entry
Note
Reagents
Conditions
CTet/CTr ratioa
Yield (%)
1
2
3
4
5
6
7
8
9
6
Indole/HC(O)H
2 and 3
4
5
4
2 and 3
2 and 6
2 and 6
2 and 6
H2SO4/MeOH/rfx/2 h
15:85
35:65
25:75
15:85
—
10:90
33:67
45:55
40:60
35
28
27
42
—
35
37
25
36
13
17
18
19
MeOH/rfx/7 h, AcOH/PtO2/H2/60 °C/4 h
AcOH/PtO2/H2/60 °C/6 h
AcOH/60 °C/1.5 h
AcOH/PtO2/H2/60 °C/5 h
AcOH/PtO2/H2/60 °C/16 h
AcOH/PtO2/H2/60 °C/16 h
AcOH/PtO2/H2/60 °C/2 h
AcOH/PtO2/H2/60 °C/4 h
20
b
nd
21
a
The CTet/CTr ratio was determined by HPLC/MS.
The synthetic procedure is the same reported in note 21. nd = not described.
b
by recrystallization from (CH3)2CO. HPLC/UV and 1H NMR are according to the
literature.6
3. Conclusion
14. This is borne out by the fact that treating 2 and 3 in AcOH at 60 °C for 30 h
under N2 atmosphere a small amount of 4 was isolated, together with the
unreacted starting compounds, 4-acetamidophenylsulfonamide [Mp, MS, and
1H NMR are according to those reported by Wang, F.; Liu, H.; Fu, H.; Jiang, Y.;
Zhao, Y. Adv. Synth. Cat. 2009, 351, 246–252] and unidentified by-products.
15. 4-Amino-N-[1-(1H-indol-3-yl)methylidene]benzenesulfonamide (4)11: Mp 186 °C
[(CH3)2CO/H2O]; MS (EI): m/z 299 (M+), 92 (100); 1H NMR (DMSO-d6) d: 6.08 (s,
2H), 6.63 (d, 2H, J = 8.5 Hz), 7.23–7.29 (m, 2H), 7.52 (d, 3H, J = 8.5 Hz), 8.05–
8.10 (m, 1H), 8.43 (s, 1H), 8.99 (s, 1H), 12.42 (br s, 1H) ppm; 13C NMR (DMSO-
d6) d: 112.6, 113.2, 113.3, 122.1, 123.0, 124.4, 124.7, 124.8, 129.5, 138.0, 141.2,
153.6, 162.8 ppm.
A new and convenient method for the synthesis of the antican-
cer agent CTet employing 1H-indole-3-carboxaldehyde, sulfamide
and platinum oxide in catalytic amounts was developed. This pro-
tocol works better than those previously described in terms of
CTet/CTr ratio and yield, and permits a good accessibility of CTet
for in vivo biological tests.
Acknowledgments
16. 4-Amino-N-[(1H-indol-3-yl)methyl]benzenesulfonamide (5)11
:
Mp 177 °C
(MeOH) [lit. 175–176 (i-PrOH)]11; MS (EI): m/z 301 (M+), 92 (100); 1H NMR
(DMSO-d6) d: 4.00 (d, 2H, J = 6.0 Hz), 5.49 (s, 2H), 6.63 (d, 2H, J = 8.5 Hz), 6.93–
7.11 (m, 2H), 7.15–7.17 (m, 1H), 7.31–7.37 (m, 2H), 7.46–7.52 (m, 3H), 10.92
(br s, 1H) ppm; 13C NMR (DMSO-d6) d: 38.8, 111.0, 111.8, 113.1, 119.0, 119.1,
121.6, 124.4, 126.0, 126.9, 129.0, 136.7, 152.9 ppm.
The authors thank Professor Giorgio Tarzia and Dr. Giovanni
Piersanti for their helpful hints.
References and notes
17. To a suspension of 4 (0.763 g, 2.55 mmol) in AcOH (27 mL), PtO2 (0.09 g) was
added. The mixture was hydrogenated at 5 atm and 60 °C for 6 h, cooled and
filtered on Celite, and the filtrate was concentrated. Purification was conducted
as described in note 13 (cyclohexane/EtOAc 1:1, CTet/CTr 25:75). Yield 27%
(0.09 g).
18. A suspension of 5 (0.497 g, 1.65 mmol) in AcOH (25 mL) was stirred at 60 °C for
1.5 h under a N2 atmosphere, cooled, diluted with H2O (250 mL), poured onto a
saturated Na2CO3 aqueous solution, and extracted with EtOAc. The combined
organic layers were washed with brine, dried (Na2SO4), and concentrated.
Purification was conducted as described in note 13 (cyclohexane/EtOAc 7:3,
CTet/CTr 15:85). Yield 42% (0.09 g).
1. Grose, K. R.; Bjeldanes, L. F. Chem. Res. Toxicol. 1992, 5, 188–193.
2. Virtanen, A. I. Phytochemistry 1965, 4, 207–228.
3. Wattenberg, L. W.; Loub, W. D. Cancer Res. 1978, 38, 1410–1413.
4. Weng, J.-R.; Tsai, C.-H.; Kulp, S. K.; Chen, C.-S. Cancer Lett. 2008, 269, 153–163.
5. Brandi, G.; Paiardini, M.; Cervasi, B.; Fiorucci, C.; Filippone, P.; De Marco, C.;
Zaffaroni, N.; Magnani, M. Cancer Res. 2003, 63, 4028–4036.
6. Lucarini, S.; De Santi, M.; Antonietti, F.; Brandi, G.; Diamantini, G.; Fraternale,
A.; Paoletti, M. F.; Tontini, A.; Magnani, M.; Duranti, A. Molecules 2010, 15,
4085–4093.
7. Bergman, J.; Högberg, S.; Lindström, J.-O. Tetrahedron 1970, 26, 3347–3352.
8. Staub, R. E.; Bjeldanes, L. F. J. Org. Chem. 2003, 68, 167–169.
9. De Kruif, C. A.; Marsman, J. W.; Venekamp, J. C.; Falke, H. E.; Noordhoek, J.;
Blaauboer, B. J.; Wortelboer, H. M. Chem. Biol. Interact. 1991, 80, 303–315.
10. Lee, C.-H.; Kohn, H. J. Org. Chem. 1990, 55, 6098–6104.
19. To a solution of 2 (0.581 g, 4 mmol) in AcOH (40 mL), PtO2 (0.07 g) was added
and the mixture was hydrogenated at 5 atm and 60 °C for 5 h. A TLC analysis of
the mixture showed that, apart from a consistent amount of unreacted 2, only
traces of unidentifiable products are present.
20. A mixture of 2 (1.45 g, 10 mmol) and 3 (3.44 g, 20 mmol) and PtO2 (0.1 g) in
AcOH (100 mL) was hydrogenated at 5 atm and 60 °C for 16 h, cooled and
filtered upon Celite. Work-up and purification were conducted as described in
note 13 (cyclohexane/EtOAc 7:3, CTet/CTr 1:9). Yield 35% (0.45 g).
21. To a suspension of 2 (0.5 g, 3.45 mmol) and 6 (0.662 g, 6.9 mmol) in AcOH
(35 mL), PtO2 (0.035 g) was added and the mixture was hydrogenated at 5 atm
and 60 °C for 4 h. Work-up and purification were conducted as described in
note 13 (cyclohexane/EtOAc 7:3, CTet/CTr 4:6). Total yield 36% (0.16 g). CTet
was obtained by recrystallization from (CH3)2CO, yield 15% (0.068 g).
22. Pink solid. Mp 171–172 °C (benzene) [lit. 170–171.5 °C (benzene)23]; MS (EI):
m/z 260 (M+, 100); 1H NMR (DMSO-d6) d: 2.26 (s, 3H), 4.11 (s, 2H), 6.86–7.49
(m, 9H), 10.60 (br s, 1H), 10.85 (br s, 1H).
11. Gaedke, F.; Knorr, R.; Zymalkowski, F. Arch. Pharm. 1980, 313, 166–173.
12. Stokker, G. E.; Deana, A. A.; deSolms, S. J.; Schultz, E. M.; Smith, R. L.; Cragoe, R.
L.; Baer, J. E.; Russo, H. F.; Watson, L. S. J. Med. Chem. 1982, 25, 735–742.
13. To a suspension of 3 (4.8 g, 28 mmol) in MeOH (25 mL), a suspension of 2
(1.45 g, 10 mmol) in MeOH (50 mL) was added dropwise; the mixture was
stirred under reflux for 7 h and concentrated. The yellow residue was then
suspended in AcOH (100 mL), added of PtO2 (0.1 g) and the resulting mixture
was hydrogenated at 5 atm and 60 °C for 4 h, then cooled and filtered on Celite.
The solid was washed with (CH3)2CO and the filtrate concentrated. H2O
(500 mL) was added and the pink precipitate separated by filtration.
Purification of the solid by short, protected from light, and fast Al2O3 column
chromatography (cyclohexane/EtOAc 6:4) gave a white solid consisting (HPLC/
UV)6 in a 35:65 mixture of CTet and CTr. Yield: 28% (0.36 g). CTet was obtained
23. Hino, T.; Nakamura, T.; Nakagawa, M. Chem. Pharm. Bull. 1975, 23, 2990–2997.