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O-Stannyl Ketyl Radical Cyclization

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DOI: 

Submitted: March 28, 2014, published: April 22, 2014

Authors

Chris Donner (cdonner@unimelb.edu.au)

A contribution from 

Reaction Scheme

Chemicals

Benzaldehyde (Prepared in-house)

Tributyltin hydride (Prepared in-house according to procedure in Other References 1)

Azobis(isobutyronitrile) (AIBN)

Benzene (Distilled from sodium-benzophenone ketyl)

Procedure

To a solution of the benzaldehyde (250 mg, 0.89 mmol, 1 equiv.) in dry benzene (23 mL) were added Bu3SnH (338 mg, 1.16 mmol, 1.3 equiv.) and AIBN (15 mg, 0.09 mmol, 0.1 equiv.) (Note 1). The solution was sparged by bubbling argon through the solution for 30 minutes after which the solution was maintained under an atmosphere of argon whilst being heated at reflux for 2 hours. After cooling and removal of the solvent in vacuo the remaining residue was dissolved in CHCl3 (Note 2) and filtered through a short column of 10% KF/silica gel (KF 1.5 g, silica gel 12 g) eluting with EtOAc-CHCl3 (1 : 9) (Note 3). The fractions containing material between Rf 0.15-0.40 were combined (240 mg recovered material) and subjected to further chromatography (3.5 x 22 cm column of silica gel, graded solvent system of EtOAc-CHCl3, 1 : 9 to 1 : 4) to give the lactone (150 mg, 71%, Rf = 0.38 in EtOAc-CHCl3, 1 : 9) as a colourless solid (m.p. 181-183 °C) and the alcohol (64 mg, 25%, Rf = 0.18 in EtOAc-CHCl3, 1 : 9) as a colourless oil.

Author Comments

O-Stannyl ketyl radical cyclization provides a mild and generally high yielding method for the synthesis of benzopyrans and benzofurans (see Lead Reference and Other References 2). Whilst the reaction is a reductive process, the use of an aldehyde as a radical precursor results in formation of an alcohol and two new adjacent asymmetric centres and can thus be used to effectively increase both structural and stereochemical complexity.

Note 1: The concentration of Bu3SnH in this reaction is 0.05 M. For the corresponding 6-exo cyclization to form benzopyrans (isochromans), competitive reduction takes place and a lower concentration of Bu3SnH is required. However, the isomeric chromans can be formed efficiently using this strategy (see Lead Reference).

Note 2: Approximately 10 mL of CHCl3 is required to dissolve the crude product mixture.

Note 3: We have found that a most effective method for removal of the tin-based by-products from O-stannyl ketyl radical reactions involves pre-filtration through a short column of potassium fluoride (KF) mixed with silica gel (10% w/w) before a subsequent purification through silica gel. This procedure is based on the method described in Other References 3. We have used this procedure for compounds that contain silyl ether (TBS) protecting groups and found no evidence that the TBS group is removed using this procedure.

Data

Lactone product:

1H NMR (500 MHz, CDCl3): δ = 3.01-3.09 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 5.40-5.43 (m, 1H), 6.09 (d, J = 6.1 Hz, 1H), 6.39 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ = 35.2, 55.9, 56.7, 82.1, 82.4, 103.4, 112.6, 115.9, 139.0, 150.6, 151.5, 174.4

GC-MS: (EI) 236 (M+, 100%), 221 (44), 191 (25), 177 (37)

 

Alcohol product:

1H NMR (500 MHz, CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3H), 2.53 (brs, 1H), 2.68 (dd, J = 16.2, 8.0 Hz, 1H), 2.87 (dd, J = 16.2, 6.1 Hz, 1H), 3.83 (s, 6H), 4.18 (q, J = 7.2 Hz, 2H), 4.97-5.00 (m, 1H), 5.36-5.37 (m, 1H), 6.34 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H)

13C NMR (125 MHz, CDCl3): δ = 14.1, 38.1, 55.6, 56.7, 60.9, 75.9, 87.4, 102.4, 114.6, 116.1, 139.4, 149.3, 151.2, 170.1

GC-MS: (EI) 264 ([M – 18]+, 100%), 249 (75), 191 (55), 176 (34), 161 (24)

Lead Reference

Santoso, H.; Casana, M. I.; Donner, C. D. Org. Biomol. Chem., 2014, 12, 171-176

Other References

1. Trépanier, V. É.; Fillion, E. Organometallics, 2007, 26, 30–32.

2. Enholm, E. J.; Prasad, G. Tetrahedron Lett., 1989, 30, 4939-4942.

3. Harrowven, D. C.; Guy, I. L. Chem. Commun., 2004, 1968-1969.

Keywords

AIBN, benzaldehyde, dihydrobenzofuran, heterocyclic compounds, O-Stannyl ketyl, radical cyclization, tributyltin hydride