Indium Trichloride Mediated Cleavage of Acetonides in the Presence of Acid-Labile Functional Groups - Enhancing the Synthetic Utility of 1,3-Dioxolanyl-Substituted 1,2-Oxazines

Abstract

Indium trichloride in an acetonitrile-water mixture chemoselectively cleaved the isopropylidene acetals of various 1,3-dioxolanyl-substituted 1,2-oxazines as well as carbohydrate derivatives. Deprotection of acetonides can be achieved in substrates susceptible for acid-induced cyclizations. Most importantly, enol ether moieties are not attacked and the presence of glycosidic linkages or acid-sensitive protecting groups such as tert-butyldimethylsilyl, 2-(trimethylsilyl)ethyl, or tert-butoxycarbonyl is also tolerated.

Key words

deprotection - 1,2-oxazines - isopropylidene acetals - Lewis acids - indium trichloride

References and Notes

• 1a Greene TW. Wuts PGM. Protecting Groups in Organic Synthesis   4th ed.:  Wiley; New York: 2006. 
• 1b Kocienski PJ. Protecting Groups   Thieme; New York: 2004. 
• Selected examples:
• 1c Fleet GWJ. Smith PW. Tetrahedron Lett.  1985,  26:  1469 
• 1d Gerspacher M. Rapoport H. J. Org. Chem.  1991,  56:  3700 
• 1e Vijayasaradhi S. Singh J. Aidhan IS. Synlett  2000,  110 
• 1f Swamy NR. Venkateswarlu Y. Tetrahedron Lett.  2002,  43:  7549 
• 1g Xiao X. Bai D. Synlett  2001,  535 
• 2 For a recent report using Er(OTf)₃ (cat.) in H₂O under microwave conditions, see: Procopio A. Gaspari M. Nardi M. Oliverio M. Romeo R. Tetrahedron Lett.  2008,  49:  1961 
• 3a Schade W. Reissig H.-U. Synlett  1999,  632 
• 3b Helms M. Schade W. Pulz R. Watanabe T.
  Al-Harrasi A. Fišera L. Hlobilová I. Zahn G. Reissig H.-U. Eur. J. Org. Chem.  2005,  1003 
• 4 Al-Harrasi A. Reissig H.-U. Angew. Chem. Int. Ed.  2005,  44:  6227 ; Angew. Chem. 2005, 117, 6383
• 5 Bressel B. Egart B. Al-Harrasi A. Pulz R. Reissig H.-U. Brüdgam I. Eur. J. Org. Chem.  2008,  467 
• 6 For SbCl₃-catalyzed deprotection, see: Wu Q. Chen W. Wang Y. Qu Y. Zhang Q. Lett. Org. Chem.  2006,  271 
• 7 Al-Harrasi A. Dissertation   Freie Universität Berlin; Germany: 2005. 
• 8a Indium trichloride in hot MeOH has already been reported as catalyst for the selective hydrolysis of more labile acetonides: Mahalingam SM. Aidhen IS. Z. Naturforsch., B  2005,  60:  962 
• For similar application of indium salts, see:
• 8b Gregg BT. Golden KC. Quinn JF. J. Org. Chem.  2007,  72:  5890 
• 8c Ranu BC. Jana R. Samanta S. Adv. Synth. Catal.  2004,  436:  446 
• 12 Reissig H.-U. Homann K. Hiller F. Zimmer R. Synthesis  2007,  2681 
• 13 Werz DB. Seeberger PH. Angew. Chem. Int. Ed.  2005,  44:  6315 ; Angew. Chem. 2005, 117, 6474
• Reviews:
• 14a Gilchrist TL. Chem. Soc. Rev.  1983,  12:  53 
• 14b Tsoungas PG. Heterocycles  2002,  57:  915 
• 14c Tsoungas PG. Heterocycles  2002,  57:  1149 
• For selected recent publications of our group, see:
• 14d Pulz R. Watanabe T. Schade W. Reissig H.-U. Synlett  2000,  983 
• 14e Pulz R. Al-Harrasi A. Reissig H.-U. Org. Lett.  2002,  4:  2353 
• 14f Pulz R. Cicchi S. Brandi A. Reissig H.-U. Eur. J. Org. Chem.  2003,  1153 
• 14g Schmidt E. Reissig H.-U. Zimmer R. Synthesis  2006,  2074 
• For selected contributions of other groups, see:
• 14h Kibayashi C. Aoyagi S. Synlett  1995,  873 
• 14i Denmark SE. Thorarensen A. Chem. Rev.  1996,  96:  137 
• 14j Streith J. Defoin A. Synlett  1996,  189 
• 14k Young IS. Kerr MA. Angew. Chem. Int. Ed.  2003,  42:  3023 ; Angew. Chem. 2003, 115, 3131
• 14l Cardona F. Goti A. Angew. Chem. Int. Ed.  2005,  44:  7832 ; Angew. Chem. 2005, 117, 8042

9

Typical Procedure for the InCl ₃ -Mediated Hydrolysis of Isopropylidene Acetals - Conversion of syn -1 into syn -4
1,2-Oxazine syn-1 (6.00 g, 15.3 mmol), InCl₃ (6.68 g, 30.6 mmol), and H₂O (1.10 mL, 61.2 mmol) were dissolved in MeCN (230 mL), and the mixture was stirred for 3 h at r.t. After addition of H₂O and CH₂Cl₂ the layers were separated and the aqueous layer was extracted 2 times with CH₂Cl₂. The combined organic layers were dried with MgSO₄, filtered, and concentrated. Column chromatography (silica gel, EtOAc-hexane = 1:4) provided 4.50 g (84%) syn-4 as colorless oil.
Analytical Data for (1′ S ,3 S )-1-{-2-Benzyl-4-(2-trimethyl-silylethoxy)-3,6-dihydro-2 H [1,2]oxazin-3-yl}ethan-1,2-diol [α]_D ^²² +43.6 (c 0.81, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 0.04 (s, 9 H, SiMe₃), 0.96-1.10 (m, 2 H, CH₂Si), 2.84 (s, 1 H, OH), 3.04 (dd, J = 6.6, 1.6 Hz, 1 H, 3-H), 3.59 (s, 1 H, OH), 3.63 (dd, J = 11.8, 4.7 Hz, 1 H, 2′-H), 3.74 (dd, J = 11.8, 3.6 Hz, 1 H, 2′-H), 3.78-3.83 (m, 1 H, OCH₂), 3.86-3.90 (m, 2 H, OCH₂, 1′-H), 3.93 (d, J = 13.2 Hz, 1 H, NCH₂), 4.17 (dd, J = 15.3, 3.6 Hz, 1 H, 6-H), 4.20 (d, J = 13.2 Hz, 1 H, NCH₂), 4.47 (dt, J = 15.3, 1.9 Hz, 1 H,
6-H), 4.81 (dd, J = 3.6, 1.9 Hz, 1 H, 5-H), 7.24-7.37 (m, 5 H, Ph) ppm. ^¹³C NMR (126 MHz, CDCl₃): δ = -1.3 (q, SiMe₃), 17.5 (t, CH₂Si), 56.9 (t, NCH₂), 60.5 (t, C-6), 62.2 (d, C-3), 64.4 (t, C-2′), 64.5 (t, OCH₂), 72.0 (d, C-1′), 91.7 (d, C-5), 127.8, 128.4, 129.0, 136.3 (3 d, s, Ph), 148.4 (s, C-4) ppm. IR (film): 3460 (OH), 3090-2840 (=C-H, C-H), 1680 (C=C) cm^-¹. ESI-TOF: m/z calcd for [M + H]⁺: 352.1939; found: 352.2002. Anal. Calcd for C₁₈H₂₉NO₄Si (351.5): C, 61.50; H, 8.32; N, 3.98. Found: C, 61.37; H, 8.49; N, 4.12.

10

Using catalytic amounts (20 mol%) of InCl₃ gave almost no conversion.

11

Treatment of 1,2-oxazine 11 with SnCl₄ leads to bicyclic oxocanes (ref. 7) whereas protic acids promote cyclization into bicyclic tetrahydropyrans (ref. 5).