Lewis Acid Promoted Rearrangements of 1,3-Dioxolanyl-Substituted 1,2-Oxazines into Novel Products with 1,3,6-Trioxa-7-azacyclopenta[cd]indene Skeletons

Abstract

Lewis acid promoted rearrangements of 4-methoxy- and 4-benzyloxy-substituted 1,2-oxazines syn-1b and syn-1c furnished novel tricyclic products 5 and 6. A mechanistic rationale is suggested for the different rearrangement pathways depending on the configuration and the nature of the 4-alkoxy groups of the precursor 1,2-oxazines. Short period hydrogenolyses of these rearrangement products afforded tetrahydrofuranyl-annulated 5,6-dihydro-4H-1,2-oxazines 10 and 11, whereas longer reduction times led to formation of tetrahydrofuran derivatives 14, 15 and 16, 17 in good yields.

heterocycles - 1,2-oxazines - furans - Lewis acids - rearrangements - 1,2-alkyl shifts - hydrogenations

References and Notes

1 Al-Harrasi A. Reissig H.-U. Angew. Chem. Int. Ed.  2005,  44:  6227 ; Angew. Chem. 2005, 117, 6383

2a Schade W. Reissig H.-U. Synlett  1999,  632 

2b 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 

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Brüdgam, I.; Hartl, H., Institut für Chemie und Biochemie, Freie Universität Berlin, unpublished results.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.
Analytical Data for (4a R ,7a S ,7b S )-7-Benzyl-7b-methoxy-4,4-dimethylhexahydro-2 H ,4 H -1,3,6-trioxa-7-azacyclopenta[ cd ]indene.
[α]_D ²² +4.8 (c 0.42, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 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): ν = 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.

Review concerning 1,2-sigmatropic shifts of alkyl groups:

5a Shubin VG. Top. Curr. Chem.  1984,  116-117:  267 ; the rearrangement described here has some similarities to the pinacol rearrangement

5b For Prins-pinacol tandem reactions, see: Lavigne RMA. Riou M. Girardin M. Morency L. Barriault L. Org. Lett.  2005,  7:  5921 

5c Also see: Overman LE. Pennington LD. J. Org. Chem.  2003,  68:  7143 

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. 

Reviews:

8a Gilchrist TL. Chem. Soc. Rev.  1983,  12:  53 

8b Tsoungas PG. Heterocycles  2002,  57:  915 

8c Tsoungas PG. Heterocycles  2002,  57:  1149 

For selected recent publications of our group, see:

8d Pulz R. Watanabe T. Schade W. Reissig H.-U. Synlett  2000,  983 

8e Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 

8f Pulz R. Cicchi S. Brandi A. Reissig H.-U. Eur. J. Org. Chem.  2003,  1153 

8g Schmidt E. Reissig H.-U. Zimmer R. Synthesis  2006,  2074 

Selected contributions of other groups, see:

8h Kibayashi C. Aoyagi S. Synlett  1995,  873 

8i Denmark SE. Thorarensen A. Chem. Rev.  1996,  96:  137 

8j Streith J. Defoin A. Synlett  1996,  189 

8k Young IS. Kerr MA. Angew. Chem. Int. Ed.  2003,  42:  3023 ; Angew. Chem. 2003, 115, 3131

8l Cardona F. Goti A. Angew. Chem. Int. Ed.  2005,  44:  7832 ; Angew. Chem. 2005, 117, 8042