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.

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

References

<A NAME="RU13805ST-1A">1a</A> 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 

<A NAME="RU13805ST-1B">1b</A> Part 27: Kumamoto K. Fukada I. Kotsuki H. Angew. Chem. Int. Ed.  2004,  43:  2015 

<A NAME="RU13805ST-2">2</A> Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   Wiley; New York: 1999. 

Reviews:

<A NAME="RU13805ST-3A">3a</A> Kotsuki H. Kumamoto K. Yuki Gosei Kagaku Kyokaishi  2005,  in press 

<A NAME="RU13805ST-3B">3b</A> Jenner G. Tetrahedron  2005,  61:  3621 

<A NAME="RU13805ST-3C">3c</A> High Pressure Chemistry   van Eldik R. Klärner F.-G. Wiley-VCH; Weinheim: 2002. 

<A NAME="RU13805ST-3D">3d</A> Jenner G. Tetrahedron  2002,  58:  5185 

<A NAME="RU13805ST-3E">3e</A> Klärner F.-G. Wurche F. J. Prakt. Chem.  2000,  342:  609 

<A NAME="RU13805ST-4">4</A> 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 

<A NAME="RU13805ST-5">5</A> Dauben WG. Gerdes JM. Look GC. J. Org. Chem.  1986,  51:  4964 

<A NAME="RU13805ST-6">6</A> Hamann SD. Physico-Chemical Effects of Pressure   Butterworths; London: 1957.  p.155 

<A NAME="RU13805ST-7">7</A>

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.

<A NAME="RU13805ST-8">8</A>

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

<A NAME="RU13805ST-9">9</A> 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:

<A NAME="RU13805ST-10A">10a</A> Leonard NM. Oswald MC. Freiberg DA. Nattier BA. Smith RC. Mohan RS. J. Org. Chem.  2002,  67:  5202 

<A NAME="RU13805ST-10B">10b</A> Thurkauf A. Jacobson AE. Rice KC. Synthesis  1988,  233 

<A NAME="RU13805ST-11">11</A>

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

<A NAME="RU13805ST-12">12</A> See for example: Ley SV. Osborn HMI. Priepke HWM. Warriner SL. Org. Synth., Coll. Vol. 10   Wiley; New York: 2004.  p.523 

<A NAME="RU13805ST-13">13</A>

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

<A NAME="RU13805ST-14">14</A>

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

The acid- or base-catalyzed conjugate addition reaction of alcohols to enones under high pressure is known:

<A NAME="RU13805ST-15A">15a</A> H₂SO₄: Scott JJ. Brower KR. J. Am. Chem. Soc.  1967,  89:  2682 

<A NAME="RU13805ST-15B">15b</A> DMAP/LiClO₄: Hayashi Y. Nishimura K. Chem. Lett.  2002,  296 

See also:

<A NAME="RU13805ST-15C">15c</A> Jenner G. Tetrahedron  2002,  58:  4311 

<A NAME="RU13805ST-15D">15d</A> Jenner G. Tetrahedron Lett.  2001,  42:  4807