High-Pressure-Promoted Uncatalyzed Ketalization of Ketones and Oxy-Michael/Ketalization of Conjugated Enones [1]

Abstract

A new practical method for ketalization or oxy-Michael/ketalization was developed using the high-pressure-promoted condensation of ketones or α,β-unsaturated ketones with alcohols in the presence of trialkyl orthoformates as water scavengers.

Key words

ketalization - ketones - enones - trialkyl orthoformates - high-pressure reaction

References

• 1a High-Pressure Organic Chemistry, Part 29. For Part 28, see: Matsumoto K. Kim JC. Iida H. Hamana H. Kumamoto K. Kotsuki H. Jenner G. Helv. Chim. Acta  2005,  in press 
• 1b Part 27: Kumamoto K. Fukada I. Kotsuki H. Angew. Chem. Int. Ed.  2004,  43:  2015 
• 2 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   Wiley; New York: 1999. 
• Reviews:
• 3a Kotsuki H. Kumamoto K. Yuki Gosei Kagaku Kyokaishi  2005,  in press 
• 3b Jenner G. Tetrahedron  2005,  61:  3621 
• 3c High Pressure Chemistry   van Eldik R. Klärner F.-G. Wiley-VCH; Weinheim: 2002. 
• 3d Jenner G. Tetrahedron  2002,  58:  5185 
• 3e Klärner F.-G. Wurche F. J. Prakt. Chem.  2000,  342:  609 
• 4 For our recent work on a high-pressure-promoted uncatalyzed reaction, see: Kumamoto K. Misawa Y. Tokita S. Kubo Y. Kotsuki H. Tetrahedron Lett.  2002,  43:  1035 
• 5 Dauben WG. Gerdes JM. Look GC. J. Org. Chem.  1986,  51:  4964 
• 6 Hamann SD. Physico-Chemical Effects of Pressure   Butterworths; London: 1957.  p.155 
• 9 Firouzabadi H. Iranpoor N. Karimi B. Synth. Commun.  1999,  29:  2255 ; and references cited therein
• Difficulties were encountered only with highly stabilized ketones such as benzophenone and anthraquinone. See, for example:
• 10a Leonard NM. Oswald MC. Freiberg DA. Nattier BA. Smith RC. Mohan RS. J. Org. Chem.  2002,  67:  5202 
• 10b Thurkauf A. Jacobson AE. Rice KC. Synthesis  1988,  233 
• 12 See for example: Ley SV. Osborn HMI. Priepke HWM. Warriner SL. Org. Synth., Coll. Vol. 10   Wiley; New York: 2004.  p.523 
• The acid- or base-catalyzed conjugate addition reaction of alcohols to enones under high pressure is known:
• 15a H₂SO₄: Scott JJ. Brower KR. J. Am. Chem. Soc.  1967,  89:  2682 
• 15b DMAP/LiClO₄: Hayashi Y. Nishimura K. Chem. Lett.  2002,  296 
• See also:
• 15c Jenner G. Tetrahedron  2002,  58:  4311 
• 15d Jenner G. Tetrahedron Lett.  2001,  42:  4807 

7

General procedure A mixture of ketone and trimethyl orthoformate (2 equiv) in MeOH was placed in a Teflon reaction vessel (2.0 mL volume), and the mixture was allowed to react at 0.8 GPa at the appropriate temperature and for the specified time (Table [1] ). After the mixture was cooled and the pressure was released, the mixture was concentrated in vacuo. The crude product was purified quickly by column chromatography on alumina (elution with hexane-Et₂O) to afford the pure product in good to excellent yields.

8

The use of a stoichiometric amount of this reagent resulted in incomplete conversion.

11

The ease of mono-ketalization of these difunctional substrates can be ascribed to the low electron density at one of the carbonyl groups.

13

Under the normal conditions (1 atm, r.t.) both substrates were recovered unchanged.

14

These reactions were best performed in CH₂Cl₂ using trimethyl orthoformate (2 equiv) and MeOH (2 equiv).