The use of anhydrous CeCl3 as a recyclable and selective catalyst for the acetalization of aldehydes and ketones

SHORT REPORT

The use of anhydrous CeCl₃ as a recyclable and selective catalyst for the acetalization of aldehydes and ketones

Claudio C. SilveiraI, ^*; Samuel R. Mendes^I; Francieli I. Ziembowicz^I; Eder J. Lenardão^II; Gelson Perin^II

^IDepartamento de Química, Universidade Federal de Santa Maria, CP 5001, 97105-970 Santa Maria-RS, Brazil

^IIInstituto de Química e Geociências, LASOL, Universidade Federal de Pelotas, CP 354, 96010-900 Pelotas-RS, Brazil

ABSTRACT

An efficient, clean, chemoselective and solvent-free method for the synthesis of ketone and aldehyde dimethyl acetals was developed using trimethyl orthoformate and commercially available anhydrous CeCl₃ as a recyclable catalyst. The method is general and affords the protected carbonyl compounds in good yields and under mild conditions, including aryl and alkyl ketones and activated aldehydes. The catalyst could be utilised directly for 3 cycles, without significant loss of activity.

Keywords: cerium(III) chloride, acetals, trimethyl orthoformate, aldehydes, ketones

RESUMO

Um método eficiente, limpo, quimiosseletivo e sem a utilização de solventes para a síntese de dimetil acetais de aldeídos e cetonas foi desenvolvido usando ortoformiato de trimetila e CeCl₃ anidro como catalisador. O método é geral e, sob condições reacionais brandas, fornece compostos carbonílicos protegidos em bons rendimentos, incluindo aril e alquil cetonas e aldeídos. O catalisador pode ser reutilizado diretamente, três vezes, sem perda significativa da atividade.

Introduction

Acetalization of aldehydes and ketones is the most frequently used strategy for protection of carbonyl groups against nucleophilic reagents.¹ Besides being very useful derivatives in total synthesis, acetals can be easily transformed into several utile functional groups.² Because of the versatility and usefulness of acetals in organic synthesis, several methods for the protection^3-20 and the selective, mild deprotection²¹ of aldehydes and ketones have been described. The classical procedure for protection involves the Lewis^3-15 or protic acid-catalyzed^16-20 reaction of a carbonyl compound with a large excess of an alcohol in the presence of a water scavenger. Among the employed Lewis acids are metal triflates,^3-8 lanthanoid chlorides,^9,10 SnCl₄,¹¹ FeCl₃,¹² LiBF₄,¹³ ZnCl₂¹⁴ and pyridinium ions¹⁵ while HCl,¹⁶p-TsOH,¹⁷ HBF₄,¹⁸ 2,6-pyridinedicarboxylic acid¹⁹ and silica-supported HClO₄²⁰ have been used as protic acids. Despite the advocated advantages of several recently described methods for the acetalization reaction, they have some drawbacks, such as the use of toxic, strong and corrosive acids, non-recyclable catalysts, volatile organic solvents (VOCs) and, in some cases, non-commercially available catalysts. A greener, atom efficient approach to acetals is the use of trialkyl orthoesters instead of alcohols, because they provide both alkoxy groups while scavenging the water produced in the reaction.^{3,4,9,10,13,14}

In view of our interest in the development of new, cleaner methods for classical reactions²² and new applications of cerium(III) in organic synthesis,²³ we decide to study the reaction of carbonyl compounds 1 with trimethyl orthoformate to obtain dimethyl acetals 2 (Tables 1 and 2).²⁴

Results and Discussion

Initially, we chose benzaldehyde 1a (2.0 mmol) and trimethyl orthoformate (2.2 mmol) as standard starting materials to establish the best conditions for the reaction under solvent-free media. We examined the temperature, amount of anhydrous CeCl₃²⁵ and the reaction time (Table 1).

It was found that using 10 mol% of dry CeCl₃ the acetal 2a was obtained in 83% yield after stirring at room temperature for 6 h (Table 1, entry 1). The reaction time was reduced to 1 h when the mixture was stirred at 0 °C, affording the same result (Table 1, entry 2). By stirring at lower temperatures, such as -20 and -78 °C, the product was obtained only in modest yields (entries 3 and 4). The effect of the amount of the catalyst was also evaluated. When 5 mol% of CeCl₃ was used, 2a was obtained in excellent yield (95%) after stirring at 0 °C for 1 h (Table 1, entry 5). The use of lower amounts of CeCl₃ did not presented satisfactory results (entries 6 and 7). We also tested the effect of the solvent in the reaction, such as CH₃CN, CH₃NO₂ and CH₃OH (entries 8-11). When CH₃OH (2 mL) was used, 2a was obtained in 75% yield after stirring for 6 h at room temperature (entry 10) and in 65% yield after 5 h at 0 °C (entry 11). The lower yields observed in these cases are probably due to the reduction of the catalytic activity of CeCl₃ in view of a competition between the heteroatom of the solvent and the carbonyl group of the aldehyde for the cerium metal centre.³

Since the best conditions were established, the protocol was extended to other aromatic and aliphatic aldehydes and ketones (Table 2).

The dimethyl acetals 2 were obtained in good to excellent yields under solvent-free conditions after stirring at 0 °C for 1-4 h in all but three tested examples. In the case of solid p-chlorobenzaldehyde (entry 4) and the less reactive ketones acetophenone and heptan-2-one (entries 11 and 12), it was necessary the use of methanol (2 mL) as solvent under reflux. Besides, a longer reaction time (8-10 h) was required to obtain satisfactory yields from ketones. The chemoselectivity of the reaction was also investigated. Thus, when an equimolar mixture of benzaldehyde 1a, cyclohexanone 1h and trimethylorthoformate was subjected to acetalization reaction in presence of CeCl₃, only the acetal of benzaldehyde 2a was isolated after stirring for 4 h, while the cyclohexanone was completely recovered, along with a small amount of 1a. This result shows the high selectivity of our method. In addition, citral 1g, which is a mixture of trans- and cis-3,7-dimethylocta-2,6-dienal (Z:E = 40:60), was selectively converted to the respective dimethyl acetal in 78% yield after 4 h without any isomerization of the double bonds (Z:E = 40:60; entry 7). To extend the scope of CeCl₃-catalyzed acetalization of carbonyl compounds we sought to explore the use of triethyl orthoformate for the synthesis of diethyl acetals, under the same conditions employed to methyl acetals. In this way, the reaction was performed with benzaldehyde and cyclohexanone, and the corresponding diethyl acetals were obtained in 93 and 86% isolated yield, respectively.

It was observed that the CeCl₃ can be successfully reused up to 2 times without any treatment, with good results. Thus, for example, after the completion of the acetalization of benzaldehyde 1a (in 10.0 mmol scale), the crude product 2a was simply separated by decantation from the insoluble catalyst and a small amount of CeCl₃ (0.05 mmol; 0.5 mol % each time) was added each time before repeating the reaction. Under these conditions, 2a was obtained with similar yield (2 runs, 93 and 94% yield after 1 h reaction). Without adding this extra amount of CeCl₃, the yield was reduced to 89 and 75% on runs 2 and 3, respectively.

Conclusions

In summary, anhydrous CeCl₃ has proved to be an effective, robust and recyclable catalyst for the acetalization of aryl and alkyl carbonyl compounds. The method is simple, clean and general and the catalyst can be reused directly for 2 times without loss of activity. For almost all the examples studied, this new, green methodology eliminates completely the necessity of using organic solvents in the reaction.

Acknowledgments

This project is funded by MCT/CNPq, CAPES and FAPERGS.

References

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24. Typical procedure for the synthesis of dimethyl acetals 2. To a mixture of trimethyl orthoformate (0.254 g, 2.2 mmol) and anhydrous CeCl₃ (0.025 g, 0.1 mmol) at 0 °C under argon, was added benzaldehyde 1a (0.212 g, 2.0 mmol). The reaction progress was followed by TLC, and after stirring at 0 °C for 1.0 h (see Table 2) the starting materials were completely consumed. The resulting reaction mixture was quenched with saturated aqueous sodium bicarbonate solution followed by extraction with ethyl acetate (3 × 5 mL). After drying the organic phase over anhydrous MgSO₄, the solvent was removed under reduced pressure to give the pure acetal 2a as a colorless oil (0.323g, 95%). ¹H NMR (200 MHz, CDCl₃): δ 7.45-7.43 (m, 2H), 7.36-7.29 (m, 3H), 5.38 (s, 1H), 3.31 (s, 6H).^{3l 13}C NMR (50 MHz, CDCl₃): δ 52.56, 103.09, 126.60, 128.08, 128.34, 137.99. When necessary, the residue was purified by column chromatography (ethyl acetate/hexanes 5/95).

25. Cerium chloride was dried according to: Dimitrov, V.; Kostova, K.; Genov, M.; Tetrahedron Lett. 1996, 37, 6787.

Received: July 3, 2009

Web Release Date: November 26, 2009

Publication Dates

• Publication in this collection
  17 Mar 2010
• Date of issue
  2010

History

• Received
  03 July 2009