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Protection of benzaldehydes as cyclic acetals; 2-(2,5-dimethoxyphenyl)-1,3-dioxane

SyntheticPage 775
DOI: 10.1039/SP775
Submitted Feb 24, 2015, published Feb 24, 2015
Chris Donner (cdonner@unimelb.edu.au)
A contribution from Chris Donner, The University of Melbourne
Reaction Scheme: <IMG src="/images/empty.gif"><IMG src="/images/empty.gif">Protection of benzaldehydes as cyclic acetals<IMG src="/images/empty.gif"><IMG src="/images/empty.gif">

Chemicals Used

2,5-Dimethoxybenzaldehyde (Aldrich)

1,3-Propanediol (Aldrich)

Trimethylorthoformate (Aldrich)

Tetrabutylammonium tribromide (Aldrich)

Procedure

To 2,5-dimethoxybenzaldehyde (1.0 g, 6.02 mmol) in 1,3-propanediol (1.75 mL, 24.2 mmol, 4 eq.) were added (MeO)3CH (0.75 mL, 6.86 mmol, 1.1 eq.) and Bu4N.Br3 (26 mg, 0.05 mmol, 0.01 eq.). After stirring at room temperature for 45 min the reaction was quenched with saturated NaHCO3 (5 mL) and H2O (20 mL). The mixture was then extracted with EtOAc (3 × 10 mL) and the combined organic fractions washed sequentially with 10% NaHCO3 (20 mL), H2O (4 × 20 mL) then dried (MgSO4) and concentrated in vacuo to give 2-(2,5-dimethoxyphenyl)-1,3-dioxane (1.35 g, 100%) as a colourless oil suitable for further use.

Author's Comments

Amongst the variety of reaction conditions available for the protection of aldehydes as cyclic acetals [Other References 1], the above procedure is a mild, efficient and rapid method for the protection of benzaldehydes [see Lead Reference].

Note 1. The procedure described here [Other References 2] has been undertaken on larger scales using up to 10 g of the benzaldehyde with similarly efficient yields (97%) of the cyclic acetal product after 1 h reaction time.

Note 2. Thorough washing with water is sufficient to remove all traces of excess 1,3-propanediol.

Note 3. The isomeric 3,4-dimethoxybenzaldehyde undergoes cyclic acetal formation using these conditions with similar efficiency [Other References 3] to give 2-(3,4-dimethoxyphenyl)-1,3-dioxane.

Data

2-(2,5-dimethoxyphenyl)-1,3-dioxane:

1H NMR (500 MHz, CDCl3): δ = 1.41-1.45 (m, 1H), 2.21-2.28 (m, 1H), 3.79 (s, 3H), 3.80 (s, 3H), 3.98-4.04 (m, 2H), 4.24-4.27 (m, 2H), 5.85 (s, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.85 (dd, J = 8.9 and 3.1 Hz, 1H), 7.20 (d, J = 3.1 Hz, 1H).

13C NMR (125 MHz, CDCl3): δ = 25.9, 55.8, 56.4, 67.6, 96.8, 111.9, 112.3, 115.9, 127.7, 150.6, 153.9.

2-(3,4-dimethoxyphenyl)-1,3-dioxane:

1H NMR (500 MHz, CDCl3): δ = 1.43-1.46 (m, 1H), 2.19-2.27 (m, 1H), 3.87 (s, 3H), 3.91 (s, 3H), 3.96-4.01 (m, 2H), 4.25-4.28 (m, 2H), 5.46 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.0 and 2.0 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H).

 

Lead Reference

Gopinath, R.; Haque, S. J.; Patel, B. K. J. Org. Chem., 2002, 67, 5842-5845. DOI: 10.1021/jo025701o

Other References

1. Wuts P. G. M.; Greene, T. W. "Greene's protective groups in organic synthesis", 4th Edition, 2007, John Wiley & Sons, Inc.

2. Donner, C. D. Synthesis, 2010, 415-420. DOI: 10.1055/s-0029-1217118

3. Tan, N. P. H.; Donner, C. D. Tetrahedron Lett., 2008, 49, 4160-4162. DOI: 10.1016/j.tetlet.2008.04.112

Supplementary Information

e.g. Actual NMR spectra (as images or jdx files for interactive spectra), photographs of apparatus, TLC’s or crystals or videos. Please contact the ChemSpider team (ChemSpider-at-rsc.org) for help with this.

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Keywords: 1, 3-dioxane, 3-propanediol, aldehydes, benzaldehyde, cyclic acetal, protecting group, tetrabutylammonium tribromide