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F. Pfrengle et al.
LETTER
Analytical Data for (4aR,7aS,7bS)-7-Benzyl-7b-
methoxy-4,4-dimethylhexahydro-2H,4H-1,3,6-trioxa-7-
azacyclopenta[cd]indene.
then in situ protected to generate the NHBoc moiety. In
the case of 4-benzyloxy-substituted 1,2-oxazine 6 the ben-
zyl group was also reductively removed giving com-
pounds 16, 17 with a free tertiary hydroxyl group.
[a]D22 +4.8 (c 0.42, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 1.35, 1.41 (2 s, 3 H each, Me), 2.15 (dd, J = 1.1, 5.1 Hz,
1 H, 4a-H), 3.42 (s, 3 H, OMe), 3.85 (dd, J = 4.6, 10.4 Hz, 1
H, 2-H), 3.99 (dd, J = 1.1, 12.3 Hz, 1 H, 5-H), 4.00 (dd,
J = 1.0, 10.4 Hz, 1 H, 2-H), 4.01 (d, J = 14.2 Hz, 1 H,
NCH2), 4.08 (dd, J = 5.1, 12.3 Hz, 1 H, 5-H), 4.22 (d,
J = 14.2 Hz, 1 H, NCH2), 4.49 (dd, J = 1.0, 4.6 Hz, 1 H, 2a-
H), 4.50 (s, 1 H, 7a-H), 7.24–7.40 (m, 5 H, Ph) ppm. IR
(film): n = 3055–3030 cm–1 (=C–H), 2970–2870 (C–H),
1605 (C=C). MS (EI, 80 eV, 150 °C): m/z (%) = 305 (44)
[M]+, 244 (100) [M – OCH3 – CH2O]+, 214 (3) [M – C7H7]+,
91 (57) [C7H7]+. Anal. Calcd for C17H23NO4 (305.4): C,
66.86; H, 7.59; N, 4.59. Found: C, 66.51; H, 7.27; N, 4.54.
HRMS (EI, 80 eV, 150 °C): m/z calcd for C17H23NO4:
305.16272; found: 305.16366.
In summary, a novel stereoselective Lewis acid promoted
rearrangement of 1,3-dioxolanyl-substituted 1,2-oxazines
was discovered, which led to enantiopure heterocyclic
compounds with a complex skeleton. The resulting tricy-
clic products 5 and 6 are suitable precursors for further
transformations as demonstrated by their reductive trans-
formations into compounds such as 10, 11 and 14–17.
Easily accessible intermediates such as 5,6-dihydro-4H-
1,2-oxazines 10 and 11 should be excellent starting mate-
rials for addition reactions to the C=N double bond, thus
leading to new enantiopure heterocycles. All these options
will enhance the synthetic utility of 1,2-oxazines, which
has already been demonstrated in several reports.8
(5) Review concerning 1,2-sigmatropic shifts of alkyl groups:
(a) Shubin, V. G. Top. Curr. Chem. 1984, 116-117, 267; the
rearrangement described here has some similarities to the
pinacol rearrangement. (b) For Prins–pinacol tandem
reactions, see: Lavigne, R. M. A.; Riou, M.; Girardin, M.;
Morency, L.; Barriault, L. Org. Lett. 2005, 7, 5921. (c)
Also see: Overman, L. E.; Pennington, L. D. J. Org. Chem.
2003, 68, 7143.
Acknowledgment
Support by the Deutsche Forschungsgemeinschaft, the Fonds der
Chemischen Industrie and the Schering AG is most gratefully ack-
nowledged. We thank Prof. Dr. H. Hartl and I. Brüdgam for the X-
ray crystallographic analyses.
(6) In case of a p-methoxybenzyloxy substituent fragmentation
leading to bicyclic ketone 4 was observed (Pfrengle, F.;
Reissig, H.-U. unpublished results).
(7) Helms, M. Dissertation; Freie Universität Berlin: Germany,
2005.
(8) Reviews: (a) Gilchrist, T. L. Chem. Soc. Rev. 1983, 12, 53.
(b) Tsoungas, P. G. Heterocycles 2002, 57, 915.
References and Notes
(1) Al-Harrasi, A.; Reissig, H.-U. Angew. Chem. Int. Ed. 2005,
44, 6227; Angew. Chem. 2005, 117, 6383.
(2) (a) Schade, W.; Reissig, H.-U. Synlett 1999, 632.
(b) Helms, M.; Schade, W.; Pulz, R.; Watanabe, T.; Al-
Harrasi, A.; Fisera, L.; Hlobilova, I.; Zahn, G.; Reissig, H.-
U. Eur. J. Org. Chem. 2005, 1003.
(c) Tsoungas, P. G. Heterocycles 2002, 57, 1149. For
selected recent publications of our group, see: (d) Pulz, R.;
Watanabe, T.; Schade, W.; Reissig, H.-U. Synlett 2000, 983.
(e) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002,
4, 2353. (f) Pulz, R.; Cicchi, S.; Brandi, A.; Reissig, H.-U.
Eur. J. Org. Chem. 2003, 1153. (g) Schmidt, E.; Reissig,
H.-U.; Zimmer, R. Synthesis 2006, 2074. Selected
contributions of other groups, see: (h) Kibayashi, C.;
Aoyagi, S. Synlett 1995, 873. (i) Denmark, S. E.;
Thorarensen, A. Chem. Rev. 1996, 96, 137. (j) Streith, J.;
Defoin, A. Synlett 1996, 189. (k) Young, I. S.; Kerr, M. A.
Angew. Chem. Int. Ed. 2003, 42, 3023; Angew. Chem. 2003,
115, 3131. (l) Cardona, F.; Goti, A. Angew. Chem. Int. Ed.
2005, 44, 7832; Angew. Chem. 2005, 117, 8042.
(3) Brüdgam, I.; Hartl, H., Institut für Chemie und Biochemie,
Freie Universität Berlin, unpublished results.
(4) Typical Procedure, Conversion of syn-1b into 5.
SnCl4 (0.78 mL) was added to a solution of syn-1b (0.65 g,
2.13 mmol) in MeCN (18 mL) at –30 °C. The mixture was
allowed to warm up to 0 °C within 3 h, then stirred for an
additional 5 h at r.t., H2O (32 mL) was added and the mixture
was extracted with CH2Cl2. The combined organic extracts
were dried (Na2SO4) and concentrated. The residue was
purified by column chromatography (silica gel, hexane–
EtOAc, 2:1) to give 5 (0.44 g, 68%) as a colorless oil.
Synlett 2006, No. 20, 3498–3500 © Thieme Stuttgart · New York