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Basic anion-exchange resin catalyzed aldol condensation of aromatic ketones with aldehydes in continuous flow Benjamin Laroche, Yuki Saito, Haruro Ishitani, and Shu Kobayashi Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 26 Mar 2019 Downloaded from http://pubs.acs.org on March 26, 2019
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Organic Process Research & Development
Basic anion-exchange resin catalyzed aldol condensation of aromatic ketones with aldehydes in continuous flow Benjamin Larochea, Yuki Saitoa, Haruro Ishitanib, Shū Kobayashi*a,b
a. Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) b. Green & Sustainaible Chemistry Cooperation Laboratory, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan) KEYWORDS: flow chemistry; aldol condensation; heterogeneous catalysis; C-C bond formation; flow fine synthesis.
ABSTRACT: A general method for the aldol condensation of aromatic ketones with aldehydes was developed under continuousflow conditions using a commercially available, strongly basic anion-exchange resin (A26) as catalyst. This procedure, in addition to exhibiting a wide substrate scope, promoted carbon–carbon bond formation under mild conditions using a quasi-stoichiometric ratio of starting reagents with good to excellent yields, thereby forming a limited amount of waste and allowing the process to be applied to sequential-flow systems. A proof of concept was developed in the first fully heterogeneously catalyzed two-step flow synthesis of donepezil, which is a blockbuster commercial anti-Alzheimer drug.
INTRODUCTION The combination of heterogeneous catalysis with continuousflow chemistry is one of the most efficient strategies to promote expeditious access to bioactive molecules in a sustainable way.1 First of all, heterogeneous catalysis allows easy and inexpensive recovery of thermally stable catalysts while avoiding the need for tedious separations and purifications of intermediates or products from reaction mixtures.2 Then, flow systems afford safe, scalable, and continuous production of chemical entities.3 When coupled with atom-economical transformations such as additions, hydrogenations, condensations, or rearrangements, these combined strategies are ideal from a green organic synthesis point of view towards sustainable society, and they have recently attracted much attention for the construction of multistep continuous-flow systems.4 The base-catalyzed aldol condensation reaction between enolates of carbonyl compounds and aldehydes or ketones, also called Claisen–Schmidt condensation, is one of the most fundamental and highly atom-economic C–C bond-forming reactions.5 Brønsted bases such as NaOH, KOH, EtONa, or quaternary ammonium bases are conventionally used as catalysts for this transformation, allowing access to ,unsaturated carbonyl compounds, which are versatile building blocks for synthetic methodologies, natural products, and drug design.6 Despite the relatively straightforward nature of these methods, issues associated with catalyst recovery and waste treatment remain. As an alternative, heterogeneous catalysts such as alumina,7 barium hydroxide,8 zeolite,9 hydrotalcites,10 or, more recently, metal-organic frameworks,11 have been developed for aldol condensation reactions. Despite these efforts, solid-base catalysts still have very limited industrial
applications compared with solid-acid catalysts because of their low stability and sensitivity to moisture, and because they often require harsh conditions and the use of excess amounts of reagents or catalysts. In parallel, anion-exchange resins have been utilized as environmentally friendly and water-tolerant heterogeneous base catalysts for various kinds of transformations, including aldol condensation reactions.12 However, few examples of the application of heterogeneous catalysis in industrially viable continuous-flow systems have been reported.13 Recently, our group has demonstrated the application of strongly basic ammonium hydroxide anionexchange resins for the flow synthesis of venlaflaxine,14 and for the Knoevenagel condensation of aldehydes and ketones with alkyl nitriles under continuous-flow conditions.15 Schütz and colleagues also utilized a strongly basic anion-exchange resin, A26, to catalyze the flow synthesis of -ionone through aldol condensation, but an excess of acetone (9 equiv.) was required and catalyst deactivation was observed after a 16 h operation.13a Herein, we report a general basic anion-exchange resin catalyzed aldol condensation method with a quasistoichiometric ratio of starting reagents in continuous-flow. This method allowed the continuous formation in good to excellent yields of a large panel of ,-unsaturated carbonyl compounds with a limited amount of chemical waste by implementing a key solvent system that enabled the catalyst activity to be maintained for more than 5 days without any deactivation. The method’s application to the heterogeneously catalyzed two-step flow synthesis of donepezil, an antiAlzheimer drug, is also described.
RESULTS AND DISCUSSION Our investigations began with the screening of heterogeneous base catalysts for the aldol condensation between -tetralone 1a
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Organic Process Research & Development and benzaldehyde 2a as model substrates under batch conditions (Table 1). Table 1. Preliminary investigations under batch conditions O
O
O
O
OH
Catalyst (50 mg)
1a 0.3 mmol
Solvent (1 mL) 3 h, 25 °C
2a 1.2 equiv.
3aa
4aa
THF
Yield 3aa [%]a 0
Yield 4aa (dr)[%]a 0
SiO2-DNH
THF
0
0
3
MgO
THF
5 days application to Donepezil
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MeO
O
MeO Donepezil Anti-Alzheimer 92-95% yield for 30 h Productivity: 7.7 g/day
N Ph
