234
W. Zeghida, M. Demeunynck
PAPER
Anal. Calcd for C21H19Cl3N2O4·0.25 H2O: C, 54.49; H, 3.94; N,
10.59. Found: C, 54.56; H, 4.11; N, 10.55.
Troc Deprotection; General Procedures
Method A
Activated Zn (392 mg, 6 mmol) was added to a solution of the Troc-
protected compound (0.05 mmol) in glacial AcOH (5 mL). The sus-
pension was stirred at r.t. until all the starting material had reacted
(monitored by HPLC), then the mixture was filtered and the solid
was washed with AcOH (2 × 2 mL). The filtrate was diluted with aq
NH4OH (10 mL, pH 10) and extracted with EtOAc (2 × 15 mL).
The organic layers were collected, washed with H2O (2 × 10 mL),
brine (5 mL) and then evaporated to dryness.
Introduction of the Boc Group; General Procedure
Boc2O (0.31 mmol) was added to a solution of 3a,b (0.13 mmol) in
pyridine (5 mL) and the solution was stirred at r.t. overnight. The
solvent was then evaporated under reduced pressure and the oily
residue was stirred in aq NH4OH (10 mL, pH 10). The resulting pre-
cipitate was filtered and washed with H2O (3 × 10 mL).
3-[N-tert-Butoxycarbonyl-N-(2,2,2-trichloroethoxycarbon-
yl)]aminoacridine (5)
Light yellow solid; yield: 92%; mp 154–156 °C.
Method B
Cd (581 mg, 5.17 mmol) was added to a solution of Troc-protected
compound (0.05 mmol) in a mixture of DMF and glacial AcOH
(1:1, 6 mL). The suspension was stirred at r.t. until all the starting
material had reacted (monitored by HPLC), then the mixture was
filtered and the solid was washed with DMF (2 × 2 mL). The solvent
was evaporated to dryness under reduced pressure and the residue
was dissolved in aq NH4OH (10 mL, pH 10) and extracted with
EtOAc (3 × 10 mL). The organic layers were collected, washed
with H2O (2 × 10 mL), brine (5 mL) and then evaporated to dryness.
1H NMR (300 MHz, DMSO-d6): d = 9.17 (s, 1 H, H-9), 8.24–8.15
(m, 3 H, H-5, H-1, H-8), 8.08 (s, 1 H, H-4), 7.90–7.86 (m, 1 H, H-7
or H-6), 7.68–7.63 (m, 1 H, H-7 or H-6), 7.56 (dd, J = 8.9, 1.8 Hz,
1 H, H-2), 4.94 (s, 2 H, CH2), 1.40 (s, 9 H, t-Bu).
13C NMR (75 MHz, DMSO-d6): d = 150.7, 150.5, 149.1, 148.6,
139.9, 136.6, 131.3, 129.4, 129.2, 129.0, 127.6, 127.0, 126.7, 126.6,
125.5, 95.1, 84.1, 75.1, 27.8.
Anal. Calcd for C21H19Cl3N2O4: C, 53.70; H, 4.08; N, 5.97. Found:
C, 53.35; H, 4.18; N, 6.02.
Method C
Cd/Pb amalgam (10%, 394 mg, 3.5 mmol) was added to a solution
of the Troc-protected compound (0.23 mmol) in a mixture of am-
monium acetate (1 M, pH 7) and THF (1:1, 20 mL). The mixture
was stirred at r.t. until all the starting material had reacted (moni-
tored by HPLC), then filtered, and the solid was washed with THF
(5 mL) and EtOAc (5 mL). The filtrate was extracted with EtOAc
(2 × 10 mL) and the organic layer was washed with H2O (5 mL),
brine (5 mL) and then evaporated to dryness.
3-(N-Acetyl-N-tert-butoxycarbonyl)amino-6-[N-tert-butoxycar-
bonyl-N-(2,2,2-trichloroethoxycarbonyl)]aminoacridine (6)
Beige solid; yield: 77%; mp 100–105 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.20 (s, 1 H, H-9), 8.25–8.18
(m, 2 H, H-8, H-1), 8.09 (s, 1 H, H-4), 7.95 (s, 1 H, H-5), 7.58 (dd,
J = 8.9, 1.7 Hz, 1 H, H-7), 7.46 (dd, J = 8.9, 1.6 Hz, 1 H, H-2), 4.94
(s, 2 H, CH2), 2.58 (s, 3 H, CH3), 1.40–1.35 (m, 18 H, 2 × t-Bu).
13C NMR (75 MHz, DMSO-d6): d = 172.7, 152.2, 150.6, 150.5,
149.1, 148.8, 141.5, 140.1, 136.6, 129.5, 129.2, 128.1, 127.8, 127.5,
127.3, 125.7, 125.6, 95.1, 84.1, 83.5, 75.1, 27.9, 26.7.
References
(1) Charmantray, F.; Demeunynck, M.; Carrez, D.; Croisy, A.;
Lansiaux, A.; Bailly, C.; Colson, P. J. Med. Chem. 2003, 46,
967.
HRMS (EI): m/z [M+] calcd for C28H30Cl3N3O7: 626.1222 (35Cl);
found: 626.1222 (35Cl).
(2) Hancock, G.; Galpin, I. J.; Morgan, B. A. Tetrahedron Lett.
1982, 23, 249.
(3) Dong, Q.; Anderson, C. E.; Ciufolini, M. A. Tetrahedron
Lett. 1995, 36, 5681.
(4) Somsak, L.; Czifrak, K.; Veres, E. Tetrahedron Lett. 2004,
45, 9095.
(5) Doi, T.; Numajiri, Y.; Munakata, A.; Takahashi, T. Org.
Lett. 2006, 8, 531.
(6) Valluri, M.; Mineno, T.; Hindapur, R. M.; Avery, M. A.
Tetrahedron Lett. 2001, 42, 7153.
(7) Tokimoto, H.; Fukase, K. Tetrahedron Lett. 2005, 46, 6831.
(8) Zhu, X.; Schmidt, R. R. Synthesis 2003, 1262.
(9) Ando, H.; Koike, Y.; Ishida, H.; Kiso, M. Tetrahedron Lett.
2003, 44, 6883.
3-tert-Butoxycarbonylaminoacridine (7)
Yellow solid; yield: 98%; mp 181–182 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.84 (s, 1 H, NH), 8.93 (s, 1 H,
H-9), 8.30 (s, 1 H, H-4), 8.11–8.04 (m, 3 H, H-5, H-1, H-8), 7.81–
7.77 (m, 1 H, H-7 or H-6), 7.68 (dd, J = 9.1, 1.6 Hz, 1 H, H-2),
7.66–7.50 (m, 1 H, H-7 or H-6), 1.54 (s, 9 H, t-Bu).
13C NMR (75 MHz, DMSO-d6): d = 153.1, 149.9, 149.2, 141.6,
135.9, 130.7, 128.9, 128.8, 125.6, 125.1, 123.2, 121.0, 112.8, 80.1,
28.5.
HRMS (EI): m/z [M+] calcd for C18H18N2O2: 295.1428; found:
295.1433.
(10) Xue, J.; Khaja, S. D.; Locke, R. D.; Matta, K. L. Synlett
2004, 861.
3-(N-Acetyl-N-tert-butoxycarbonyl)amino-6-tert-butoxycar-
bonylaminoacridine (8)
(11) Overman, L. E.; Freerks, R. L. J. Org. Chem. 1981, 46, 2833.
(12) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: London,
1999. (b) Kociensky, P. J. Protecting Groups, 3rd ed.; Georg
Thieme Verlag: Stuttgart, 2005.
(13) Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.;
Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbrüggen,
H. J. Am. Chem. Soc. 1966, 88, 852.
Yellow solid; yield: 92%; mp 182–185 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.88 (s, 1 H, NHBoc), 8.97 (s,
1 H, H-9), 8.31 (s, 1 H, H-4), 8.12–8.05 (m, 2 H, H-8, H-1), 7.83 (s,
1 H, H-5), 7.63 (d, J = 9.0 Hz, 1 H, H-7), 7.31 (d, J = 8.8 Hz, 1 H,
H-2), 2.57 (s, 3 H, CH3), 1.55 (s, 9 H, t-Bu), 1.35 (s, 9 H, t-Bu).
13C NMR (75 MHz, DMSO-d6): d = 172.7, 153.1, 152.3, 150.1,
149.1, 141.9, 140.9, 135.9, 129.4, 129.1, 127.5, 126.6, 124.6, 127.3,
123.3, 121.2, 83.4, 80.2, 28.5, 27.9, 26.8.
(14) Mineno, T.; Choi, S.-R.; Avery, M. A. Synlett 2002, 883.
(15) Semmelhack, M. F.; Heinsohn, G. E. J. Am. Chem. Soc.
1972, 94, 5139.
HRMS (EI): m/z [M+] calcd for C25H29N3O5: 452.2182; found:
452.2180.
Synthesis 2007, No. 2, 231–234 © Thieme Stuttgart · New York