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LETTER
Table 5 Microwave-Assisted Synthesis of Conjugates 5a
(3) Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.;
Quilliam, M. A.; Walter, J. A.; Howlett, S. E. Drug Des.
Discov. 1995, 12, 337.
Entry
5
R1
R2
Yield (%) Mp (°C)b
(4) (a) Coyne, W. E.; Cusic, J. W. J. Med. Chem. 1968, 11,
1158. (b) Sanner, J. H. Arch. Int. Pharmacodyn. Ther. 1969,
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(e) Drower, E. J.; Stapelfeld, A.; Mueller, R. A.; Hammond,
D. L. Eur. J. Pharmacol. 1987, 133, 249. (f) Hallinan, E.
A.; Hagen, T. J.; Husa, R. K.; Tsymbalvo, S.; Rao, S. N.;
vanHoeck, J.-P.; Rafferty, M. F.; Stapelfeld, A.; Savage, M.
A.; Reichman, M. J. Med. Chem. 1993, 36, 3293.
(g) Hallinan, E. A.; Stapelfeld, A.; Savage, M. A.;
Reichman, M. Bioorg. Med. Chem. Lett. 1994, 4, 509.
(h) Hallinan, E. A.; Hagen, T. J.; Tsymbalov, S.; Husa, R.
K.; Lee, A. C.; Stapelfeld, A.; Savage, M. A. J. Med. Chem.
1996, 39, 609. (i) Hallinan, E. A.; Hagen, T. J.; Tsymbalov,
S.; Stapelfeld, A.; Savage, M. A. Bioorg. Med. Chem. 2001,
9, 1.
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
H
Cy
Cy
Cy
Cy
Cy
Bn
Bn
Bn
94
92
89
76
86
88
70
90
228–230
248–249
222–224
249–250
268–270
210–212
246–247
NAc
8-Me
7-Me
8-Cl
8-t-Bu
H
5g
5h
8-Ph
8-Cl
a All reactions were carried out in toluene in the presence of 10 mol%
Pd(OAc)2, 10 mol% BINAP, and 2 equiv of K2CO3. The reactions
were heated at 150 °C for 40 min. See footnote ‘a’ in Table 1 for
microwave reaction technique.
(5) For synthesis of indoles, see: (a) Dai, W.-M.; Guo, D.-S.;
Sun, L.-P. Tetrahedron Lett. 2001, 42, 5275. (b) Dai, W.-
M.; Sun, L.-P.; Guo, D.-S. Tetrahedron Lett. 2002, 43,
7699. (c) Dai, W.-M.; Guo, D.-S.; Sun, L.-P.; Huang, X.-H.
Org. Lett. 2003, 5, 2919. (d) Sun, L.-P.; Huang, X.-H.; Dai,
W.-M. Tetrahedron 2004, 60, 10983.
b Recrystallized from EtOAc–hexane.
c Not crystalline.
entries 1–5). All compounds 5a–h display atropisomerism
(6) For synthesis of benzofuranes, see: Dai, W.-M.; Lai, K. W.
Tetrahedron Lett. 2002, 43, 9677.
in solution as evident from both H NMR and 13C NMR
1
spectra taken at ambient temperature and at 80 °C.
(7) For synthesis of 1,4-benzoxazines, see: (a) Dai, W.-M.;
Wang, X.; Ma, C. Tetrahedron 2005, 61, 6879. (b) Feng,
G.; Wu, J.; Dai, W.-M. Tetrahedron 2006, 62, 4635.
(c) Xing, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron
2006, 62, 6774.
(8) (a) Künzle, F.; Schmutz, J. Helv. Chim. Acta 1969, 52, 622.
(b) Nagarajan, K.; Venkateswarlu, A.; Kulkarni, C. L.; Shah,
R. K. Indian J. Chem. 1974, 12, 227. (c) Chakrabarti, J. K.;
Hicks, T. A. Eur. J. Med. Chem. 1987, 22, 161.
In summary, we have established a general and efficient
one-pot synthesis of highly functionalized dibenz-
[b,f][1,4]oxazepines via microwave-assisted one-pot U-
4CR and intramolecular O-arylation. Further post modifi-
cation has also successful by formation of a 2-oxindole
unit via the Pd-catalyzed intramolecular N-arylation
under controlled microwave heating, which afforded
superior results than a recent report15 in terms of both
product yields and substrate scope. In addition to the
relevance of biological activity, the unique structures of
dibenz[b,f][1,4]oxazepines 3, 4, and the conjugates 517
may have potentials for studies in other areas, such as
molecular recognition.
(d) Konstantinova, A. V.; Gerasimova, T. N.; Kozlova, M.
M.; Petrenko, N. I. Chem. Heterocycl. Compd. 1989, 25,
451. (e) Samet, A. V.; Marshalkin, V. N.; Kislyi, K. A.;
Chernysheva, N. B.; Strelenko, Y. A.; Semenov, V. V. J.
Org. Chem. 2005, 70, 9371 . For examples of solid-phase
synthesis, see: (f) Ouyang, X.; Tamayo, N.; Kiselyov, A. S.
Tetrahedron 1999, 55, 2827. (g) Hone, N. D.; Salter, J. I.;
Reader, J. C. Tetrahedron Lett. 2003, 44, 8169; see also ref.
1a.
Acknowledgment
(9) Hagen, T. J.; Rafferty, M. F.; Collins, J. T.; Garland, D. J.;
Li, J. J.; Norton, M. B.; Reitz, D. B.; Tsymbalov, S.; Pitzele,
B. S.; Hallinan, E. A. Heterocycles 1994, 38, 601.
(10) (a) Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.;
Wiley: Weinheim, 2005. (b) Gokel, G.; Lüdke, G.; Ugi, I. In
Isonitrile Chemistry; Ugi, I., Ed.; Academic Press: New
York, 1971.
This work is supported by a research grant provided by Zhejiang
University. W.-M. Dai is the recipient of Cheung Kong Scholars
Award of The Ministry of Education of China.
References and Notes
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For a recent synthesis of annulated 1,4-oxazepines via Ugi
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