6718
L. Liu et al. / Tetrahedron Letters 50 (2009) 6715–6719
O
I
PdCl2(PPh3)2, CuI,
Et2NH, DMF, rt
N
N
O
+
NH2
NH2
5
7
6
O
O
THF, 0 oC, 2 h,
H
O
87% for two steps
8
O
O
N
1. POCl3, DIPEA, DCM;
2. n-Bu4NCl, 60%
N
N
Cl
10
NHCHO
9
Pd(OAc)2, KOAc,
PPh3, DMF, 120 oC,
0.5 h, 91%
O
O
N
N
N
N
12 Camptothecin
O
11
OH
O
Scheme 2. Synthesis of the core structure of camptothecin 11.
Steric hindrance as well as electronic effect may contribute to its
stability.
References and notes
1. For reviews on quinoline synthesis, see: (a) Claret, P. A.. In Comprehensive
Organic Chemistry; Barton, D., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979;
Vol. 4, pp 1479–1489; (b) Jones, G.. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, pp 167–300; (c) Larsen, R. D.. In Science of Synthesis; Black,
D. S., Ed.; Thieme: Stuttgart, 2005; Vol. 15, pp 389–549; (d) Larsen, R. D.. In
Science of Synthesis; Black, D. S., Ed.; Thieme: Stuttgart, 2005; Vol. 15, pp 551–
660; (e) Kouznetsov, V. V.; Vargas Me´ndez, L. Y.; Mele´ndez Go´mez, C. M. Curr.
Org. Chem. 2005, 9, 141–161; (f) Madapa, S.; Tusi, Z.; Batra, S. Curr. Org. Chem.
2008, 12, 1116–1183; (g) Arisawa, M.; Terada, Y.; Theeraladanon, C.; Takahashi,
K.; Nakagawa, M.; Nishida, A. J. Organomet. Chem. 2005, 690, 5398–5406; (h) Ila,
H.; Baron, O.; Wagner, A. J.; Knochel, P. Chem. Commun. 2006, 583–593; (i)
Yamashkin, S. A.; Oreshkina, E. A. J. Heterocycl. Chem. 2006, 42, 701–718; (j)
Marco-Contelles, J.; Perez-Mayoral, E.; Samadi, A.; Carreiras, M. C.; Soriano, E.
Chem. Rev. 2009, 109, 2652–2671.
Camptothecin (CPT, 12, Scheme 2) is a naturally occurring quin-
oline alkaloid having remarkable antitumoral and antileukemic
activity targeting DNA topoisomerase I.9 The core structure of
camptothecin family 11 can be constructed efficiently by intramo-
lecular Heck reaction of the key intermediate 1-((2-chloroquinolin-
3-yl)methyl)pyridinone 10.10 Compound 10 was obtained in 60%
overall yield from formamide 9 by applying the current one-pot
strategy. Sonogashira coupling of o-iodoaniline 5 with N-propargy-
lated-2-pyridinone 6 afforded 7, followed by formamide formation
in high yield.
In summary, we have demonstrated a highly efficient one-pot
two-step strategy for the synthesis of 2-chloro-3-substituted
quinolines from in situ dehydration of N-(2-ethynylphenyl)forma-
mides, followed by tetrabutylammonium chloride-triggered 6-
endo cyclization of the resulting o-alkynylisocyanobenzenes. A
wide range of substituents and functionalities can survive under
the reaction conditions and the yields are excellent. The current
strategy avoids using excess phosphorus oxychloride and multi-
step preparation of starting materials. The chloride on C-2 of
quinolines is active enough to undergo palladium-catalyzed
cross-couplings, such as intramolecular Heck reaction, to make
the core structure of camptothecin.
2. (a) Suginome, M.; Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977–1979; (b) Lu, X.;
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Partridge, J. J.; Sharp, M. J.; Xie, S. Tetrahedron 1997, 53, 10953–10970; (e)
Kimber, M.; Anderberg, P. I.; Harding, M. M. Tetrahedron 2000, 56, 3575–3581;
(f) Inada, K.; Miyaura, N. Tetrahedron 2000, 56, 8657–8660; (g) Inada, K.;
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Acknowledgments
6. The instability of 2a has also been described: Minozzi, M.; Nanni, D.; Zanardi,
G.; Calestani, G. ARKIVO 2006, vi, 6–14.
This work was financially supported by the National Science
Foundation of China (20942001) and Start-up Foundation for
New Investigators from Guangzhou Institutes of Biomedicine and
Health (GIBH).
7. Armesto, D.; Gallego, M. G.; Horspool, W. M. J. Chem. Soc., Perkin Trans. 1 1989,
9, 1623–1626. The spectra data of 4 agrees with the reported data: 1H NMR
(400 MHz, CDCl3): d 8.20 (d, J = 8.4 Hz, 1H), 8.11 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H),
7.71–7.67 (m, 1H), 7.52–7.49 (m, 1H), 7.45–7.44 (m, 2H), 7.26–7.20 (m, 8H);
13C NMR (100 MHz, CDCl3): d 158.4, 147.4, 140.5, 140.1, 137.6, 134.6, 130.1,
129.8, 129.7, 129.5, 128.3, 128.1, 128.0, 127.5, 127.3, 127.2, 126.8.
Supplementary data
8. General procedure for the synthesis of 3 from 1: To a stirred solution of N-(2-
ethynylphenyl)formamides
1
(0.5 mmol) and diisopropylethylamine
(3.0 mmol) in dry DCM (10 mL), POCl3 (1.0 mmol) was added dropwise
within 5 min under argon atmosphere. The reaction mixture was stirred at
0 °C for 1–2 h and monitored by TLC. After the dehydration was complete, n-
Supplementary data associated with this article can be found, in