S. F. Vasilevsky et al. / Tetrahedron Letters 48 (2007) 1867–1870
1869
(benzene) IR, m/cmꢀ1 (KBr): 1621 (C@O); 3416 (NH).
1H NMR, dH (CDCl3-d): 2.38 (s, 3H, PhCH3); 6.58 (s, 1H,
3-H); 6.96 (d, J = 7 Hz; 1H, 40-Htoluid); 7.1–7.3 (m, 3H,
50-, 60-, 20-Htoluid); 7.3–7.5 (m, 3H, 4-H, m-, m-HPh); 7.6–
7.3 (m, 5H, 8-, 9-H, o-, o-, p-HPh); 8.1–8.4 (m, 2H, 7-,
10-H). HRMS, m/z (%): 428.0 [M]+ (100.00), 427.1 (5.71),
413.0 (4.56), 212.0 (8.05), 411.0 (3.25), 213.9 (7.53), 206.4
(4.68), 177.9 (3.24), 28.0 (3.88). Found: m/z 428.15350
[M]+. C29H20N2O2. Calcd: M = 428.15247.
The overall transformation is tightly choreographed—
the isoxazole ring opening furnishes a keto amine moiety
in which the carbonyl group activates the atom of iodine
for the cross-coupling reaction (C–C bond formation),
whereas the amino group provides the nitrogen atom
for the C–N bond formation in the subsequent cycliza-
tion. Remarkably, in the Castro-based version of this
process, all the three-steps in the reaction cascade are
promoted through copper catalysis. The mechanism of
the copper salt effect at the isoxazole ring opening and
further synthetic explorations are under investigation.
8. Gornostaev, L. M.; Es’kin, A. P.; Korniets, E. D. Zh. Org.
Khim. 1981, 11, 2344–2346.
9. Experimental procedure for the cross-coupling reaction with
phenylacetylene: A mixture of 5-(p-toluidino)-3-iodo-6H-
anthra[1,9-cd]isoxazol-6-one 1b (130 mg, 0.3 mmol), Et3N
(5 mL), PdCl2(PPh3)2 (10 mg), PPh3 (10 mg), CuI (10 mg),
and phenylacetylene (46 mg, 0.45 mmol) in 10 mL of
benzene was stirred under an argon stream at 45–50 ꢁC
for 9.5 h until iodide 1b is consumed (TLC control:
Silufolꢂ). CHCl3 (30 mL) and water (40 mL) were added.
The organic layer was separated, the water layer was
extracted with CHCl3 (2 · 25 mL). The combined organic
layers were washed with 25% aqueous NH3 (2 · 15 mL),
dried over sodium sulfate, and filtered through alumina
(1 · 0.5 cm). The crude product was recrystallized from
toluene, 4-(p-toluidino)-1-amino-2-phenylethynylanthra-
cene-9,10-dione 5b (80 mg, 65%), mp 207–208 ꢁC (diox-
ane). IR, m/cmꢀ1 (KBr): 3458 (NH2); 2203 (C„C); 1612
Acknowledgments
This work was supported by a grant from the Ministry
of Education and Science of Russian Federation
(2006–2007) and grants ‘Integration’ of SB of Russian
Academy of Sciences 132 and 154. Research at Florida
State University was sponsored by the National Science
Foundation (CHE-0316598) and Material Research and
Technology (MARTECH) Center.
1
(C@O). H NMR, dH (DMSO-d6): 2.35 (s, 3H, PhCH3);
References and notes
3.0 (br s, 1H, NH2) 7.2–7.3 (m, 4H, o-, o-, m-, m-Htoluid);
7.4 (m, 3H, m-, m-, p-HPh); 7.62 (s, 3-H); 7.7 (m, 2H, o-, o-
1. Vasilevsky, S. F.; Tretyakov, E. V.; Elguero, J. Adv.
Heterocycl. Chem. 2002, 82, 1–99.
2. Dax, S. L.; Cook, S. L. Bioorg. Med. Chem. Lett. 1996, 6,
797.
3. Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne,
G. D.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715–3716;
For the latest discussion see: Tuttle, T.; Kraka, E.;
Cremer, D. J. Am. Chem. Soc. 2005, 127, 9469–9484.
4. Anne, A.; Moiroux, J. J. Chem. Soc., Perkin Trans. 2 1989,
2097–2102.
H
Ph); 7.9 (m, 2H, 6-, 7-H); 8.3 (m, 2H, 5-, 8-H); 11.93 (s,
1H, NH). HRMS, m/z (%): 428.1 [M]+ (100.00), 427.2
(6.76), 412.2 (5.36), 214.1 (5.53), 73.1 (7.72), 43.2 (11.50),
41.1 (6.64), 32.0 (6.73), 29.0 (5.07), 28.0 (34.67). Found:
m/z 428.15058 [M]+. C29H20N2O2. Calcd: M = 428.15247.
Compound 5b was also prepared through an alternative
route from aminobromide 6b (Scheme 1, 3 h, 70 ꢁC, 86%).
4-(m-Toluidino)-1-amino-2-phenylethynylanthracene-9,10-
dione 5a was obtained from isoxazole 2a (3 h, 180 mg,
65%), mp 189–190 ꢁC (toluene). IR, m/cmꢀ1 (KBr): 3449
5. Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28,
3313–3315.
1
(NH2); 2203 (C„C); 1620 (C@O). H NMR, dH (CDCl3-
d): 2.37 (s, 3H, PhCH3); 6.99 (d, J = 7 Hz, 1H, 4-Htoluid);
7.0–7.1 (m, 2H, 2-, 6-Htoluid); 7.3–7.4 (m, 4H, 5-Htoluid, m-,
m-, p-HPh); 7.5–7.6 (m, 2H, o-, o-HPh); 7.7–7.8 (m, 3H, 3-,
6-, 7-H); 8.3–8.4 (m, 2H, 5-, 8-H). HRMS, m/z (%): 428.3
[M]+ (100.00), 427.3 (14.32), 413.3 (11.69) 212.3 (22.56),
411.3 (11.76), 214.1 (15.14), 206.6 (13.67), 178.2 (10.43).
Found: m/z 428.15651 [M]+. C29H20N2O2. Calcd:
M = 428.15247. Compound 5a is prepared independently
from aminobromide 6a (Scheme 1, 23 h, 70 ꢁC, 92%).
10. A mixture of 4-(p-toluidino)-1-amino-2-(phenylethyn-
yl)anthracene-9,10-dione (430 mg, 1 mmol) and CuI
(150 mg) in 10 mL of DMF was stirred under the stream
of argon at 50 ꢁC for 2 h until all 5b is consumed (TLC
control). CHCl3 (20 mL) and water were added, the
organic layer was separated, the water layer extracted
with CHCl3 (2 · 5 mL), and the combined organic layer
was washed with 25% NH3aq (3 · 35 mL), dried over
sodium sulfate, and filtered off through alumina
(1 · 0.5 cm). The crude product was purified by recrystal-
lization from dioxane, 5-(p-toluidino)-2-phenyl-1H-naph-
tho[2,3-g]indole-6,11-dione 4b (420 mg, 97.6%) mp 256–257
ꢁC (benzene). 5-(m-Toluidino)-2-phenyl-1H-naphtho[2,3-g]-
indole-6,11-dione 4a was obtained under analogous
conditions (750 mg, 58%), mp 247–248 ꢁC (benzene).
11. Shvartsberg, M. S.; Barabanov, I. I.; Fedenok, L. G. Russ.
Chem. Rev. 2004, 73, 161–184.
6. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467–4471.
7. All new compounds are fully characterized on the basis of
IR, 1H, and HRMS data. Selected experimental proce-
dures: Cross-coupling reaction with PhC„CCu [copper(I)
phenylacetylide]: Iodide 1b (280 mg, 0.62 mmol) and
PhC„CCu (220 mg, 1.36 mmol) in 5 mL of pyridine were
boiled (6 h) under argon atmosphere (TLC control:
Silufolꢂ). The reaction mixture was cooled, poured into
chloroform, and washed with aqueous ammonium
hydroxide. Chloroform solution was dried over sodium
sulfate and filtered through alumina (height/diameter of
the column: 1 · 1 cm). After the solvent was removed in
vacuo, the product was recrystallized from 1,4-dioxane. 5-
(p-Toluidino)-2-phenyl-1H-naphtho[2,3-g]indole-6,11-dione
4b (200 mg, 74%); mp 256–257 ꢁC (dioxane). IR, m/cmꢀ1
(KBr): 1623 (C@O); 3420 (NH). 1H NMR, dH (CDCl3-d):
2.37 (s, 3H, PhCH3); 6.53 (s, 1H, 3-H); 7.2–7.3 (m, 4H,
H
toluid); 7.4–7.5 (m, 3H, 4-H, m-, m-HPh); 7.6–7.8 (m, 5H,
8-, 9-H, o-, o-, p-HPh) 8.22 (d, J = 7 Hz; 1H, 10-H); 8.32
(d, J = 7 Hz; 1H, 7-H); 10.77 (s, 1H, NHtoluid); 11.16 (s,
1H, NHPyr). HRMS, m/z (%): 428.3 [M]+ (100.00), 427.5
(9.52), 412.4 (7.03), 214.3 (9.07), 32.1 (7.09), 28.1 (30.57).
Found: m/z 428.15260 [M]+. C29H20N2O2. Calcd: M =
428.15247.
5-(m-Toluidino)-2-phenyl-1H-naphtho[2,3g]indole-6,11-
dione 4a was obtained under the same conditions (8 h,
from 695 mg of 1b) (440 mg, 66%), mp 247–248 ꢁC
12. Opening of the isoxazole ring in the cross-coupling
reaction with PhC„CCu [copper(I) phenylacetylide]: