LETTER
Ring Enlargement of Enantiopure 1,2-Oxazines to 1,2-Oxazepine Derivatives
2377
In conclusion, the cyclopropanation–ring enlargement se-
quence of enantiopure 1,2-oxazines leads to homologous
1,2-oxazepine derivatives, which should have a high po-
tential for diversity orientated chemistry.10
MeO OMe O
Br
OMe
O
O
O
a) 54%, dr 70:30
b) 49%
N
N
O
Bn
Bn
O
syn-3
syn-1
Acknowledgment
Scheme 3 Reagents and conditions: a) CHBr3, 50% NaOH (aq),
KF, Et3BnNCl, r.t., 2 d; b) K2CO3, MeOH, reflux, 20 h.
Generous support of this work by the Deutsche Forschungsgemein-
schaft, the Deutscher Akademischer Austauschdienst (fellowship
for A.H.), the Fonds der Chemischen Industrie and the Schering AG
is most gratefully acknowledged. We thank Dr. W. Schade for
preliminary experiments and M. Brasholz for help during the prepa-
ration of this manuscript.
strate that Suzuki couplings6 or Sonogashira reactions7
provide compounds such as anti-4, anti-5, and anti-6, re-
spectively, in excellent yields. Gratifyingly, Stille
reactions8 and Heck couplings9 of 1,2-oxazepine anti-3a
also occurred smoothly delivering 1,3-dienes anti-7 and
anti-8 with very good efficacy. These latter coupling
products should be excellent partners in Diels–Alder reac-
tions, which may lead to interesting enantiopure skeletons
incorporating a 1,2-oxazepine ring.
References
(1) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
(b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-
Harrasi, A.; Fisera, L.; Hlobilová, I.; Zahn, G.; Reissig, H.-
U. Eur. J. Org. Chem. 2005, 1003.
(2) (a) Pulz, R.; Watanabe, T.; Schade, W.; Reissig, H.-U.
Synlett 2000, 983. (b) Pulz, R.; Al-Harrasi, A.; Reissig, H.-
U. Synlett 2002, 817. (c) Pulz, R.; Al-Harrasi, A.; Reissig,
H.-U. Org. Lett. 2002, 4, 2353. (d) Pulz, R.; Schade, W.;
Reissig, H.-U. Synlett 2003, 405. (e) Pulz, R.; Cicchi, S.;
Brandi, A.; Reissig, H.-U. Eur. J. Org. Chem. 2003, 1153.
(f) Helms, M.; Reissig, H.-U. Eur. J. Org. Chem. 2005, 998.
(g) Al-Harrasi, A.; Reissig, H.-U. Synlett 2005, 1152.
(h) Al-Harrasi, A.; Reissig, H.-U. Angew. Chem. Int. Ed.
2005, in press; Angew. Chem. 2005, in press.
MeO OMe O
Ph
O
O
O
O
O
a
N
Bn
80%
O
anti-4
Ph
MeO OMe O
N
(3) (a) Raman, C. V.; Murali, R.; Nagarjan, M. J. Org. Chem.
1997, 62, 7694. For other ring expansions of
b
dibromocyclopropanes, see: (b) Maeda, H.; Hirai, T.;
Sugimoto, A.; Mizuno, K. J. Org. Chem. 2003, 68, 7700.
(c) Miller, T. A.; Bulman, A. L.; Thompson, C. D.; Garst, M.
E.; Macdonald, T. L. J. Med. Chem. 1997, 40, 3836.
(d) Loozen, H. J.; Robben, W. H.; Richter, T. L.; Buck, H.
M. J. Org. Chem. 1976, 41, 384. (e) Banwell, M. G.;
Sydnes, M. O. Aust. J. Chem. 2004, 57, 537.
Bn
O
95%
anti-5
OMe
MeO OMe O
Br
MeO OMe O
N
O
(4) Typical Procedure, conversion of anti-1a into anti-3a.
A solution of NaOH (0.60 g) and KF (4.10 g) in H2O (4.10
mL) was added to a vigorously stirred solution of anti-1a
(0.50 g, 1.64 mmol) in CHBr3 (2.70 mL) containing
benzyltriethylammonium chloride (5.5 mg). The biphasic
mixture was stirred for 2 d at r.t. and then diluted with H2O
(8 mL) and extracted with Et2O. The combined ethereal
extracts were washed with brine, dried (Na2SO4) and
concentrated. The excess CHBr3 was removed in vacuum.
The residue was purified by column chromatography (silica
gel, hexane–EtOAc, 4:1) to give 2a as colorless liquid (511
mg, 65%, dr 68:32).
c
N
Bn
Bn
O
74%
O
anti-3a
anti-6
MeO OMe O
N
d
Bn
O
94%
anti-7
Dibromocyclopropane derivative 2a was refluxed for 20 h in
a solution of anhyd K2CO3 (0.87 g, 6.27 mmol) in MeOH (7
mL) under Ar atmosphere. The mixture was cooled to r.t.,
diluted with H2O and extracted with CH2Cl2. The combined
organic extracts were dried (Na2SO4) and concentrated. The
product was purified by column chromatography (silica gel,
hexane–EtOAc, 9:1) to yield 241 mg (53%) of anti-3a as
colorless oil.
Analytical data for (3R,4¢S)-2-benzyl-5-bromo-3-(2¢,2¢-
dimethyl-1¢,3¢-dioxolan-4¢-yl)-4,4-dimethoxy-2,3,4,7-
tetrahydro-1,2-oxazepine: [a]D22 –84.2 (c 0.45, CHCl3). 1H
NMR (500 MHz, CDCl3): d = 1.33, 1.36 (2 s, 3 H each, Me),
3.19, 3.29 (2 s, 3 H each, OMe), 3.28 (d, J = 5.6 Hz, 1 H, 3-
H), 4.07 (dd, J = 8.4, 8.8 Hz, 1 H, 5¢-H), 4.11 (dd, J = 8.0,
8.4 Hz, 1 H, 5¢-H), 4.29, 4.34 (2 d, J = 14.0 Hz, 1 H each,
MeO OMe O
N
MeO2C
e
Bn
O
82%
anti-8
Scheme 4 Reagents and conditions: a) PhB(OH)2, Pd(OAc)2, PPh3,
K2CO3, DMF, 70 °C, 10 h; b) phenylacetylene, Pd(OAc)2, PPh3, CuI,
i-Pr2NH, DMF, r.t., 10 h; c) 3-methoxypropyne, Pd(OAc)2, PPh3, CuI,
i-Pr2NH, DMF, r.t., 10 h; d) tributylvinylstannane, Pd(OAc)2, PPh3,
DMF, 65 °C, 3 h; e) methyl acrylate, Pd(OAc)2, LiCl, Et3N, DMF,
70 °C, 10 h.
Synlett 2005, No. 15, 2376–2378 © Thieme Stuttgart · New York