Photochemical Synthesis of Substituted Indan-1-ones Related to Donepezil

POSPÍŠIL, Tomáš, Aneesh TAZHE VEETIL, Lovely ANGEL P. A and Petr KLÁN. Photochemical Synthesis of Substituted Indan-1-ones Related to Donepezil. Photochemical & Photobiological Sciences. Cambridge, UK: Royal Society of Chemistry, 2008, vol. 7, No 5, p. 625–632. ISSN 1474-905X.

Basic information

• Original name: Photochemical Synthesis of Substituted Indan-1-ones Related to Donepezil
• Name in Czech: Fotochemická syntéza substituovaných indan-1-onů jako derivátů donepezilu
• Authors: POSPÍŠIL, Tomáš (203 Czech Republic), Aneesh TAZHE VEETIL (356 India, belonging to the institution), Lovely ANGEL P. A (356 India, belonging to the institution) and Petr KLÁN (203 Czech Republic, guarantor, belonging to the institution).
• Edition: Photochemical & Photobiological Sciences, Cambridge, UK, Royal Society of Chemistry, 2008, 1474-905X.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 10401 Organic chemistry
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• Impact factor: Impact factor: 2.144
• RIV identification code: RIV/00216224:14310/08:00026021
• Organization unit: Faculty of Science
• UT WoS: 000255743700015
• Keywords in English: Photochemistry; donepezil; photoenolization
• Tags: donepezil, Photochemistry, photoenolization
• Tags: International impact, Reviewed

Abstract

A photoenolization reaction is shown to be the key reaction step in the preparation of substituted indan-1-ones as convenient precursors for the synthesis of donepezil, a well known acetylcholinesterase inhibitor. Model 2,5-dialkylphenacyl chlorides, differently substituted in the alpha carbon position, were found to produce indan-1-ones upon irradiation in non-nucleophilic solvents in high chemical yields via hydrogen chloride release. While direct excitation of 4,5-dimethoxy-2-methylphenacyl chloride led to a complex mixture of photoproducts, photolysis of the corresponding benzoate was found to form 5,6-dimethoxyindan-1-one in 62-72% chemical yields and a relatively low quantum efficiency (F = 0.02). This compound can then be easily converted to donepezil by standard synthetic steps described in the literature. Isotopic exchange and quenching experiments revealed that the product is obtained by the photoenolization process via the triplet excited state, while minor side-photoproducts originate from the singlet excited state. Irradiation of the reactant in neat acetone, used both as a triplet sensitizer and solvent at the same time, was found to form 5,6-dimethoxyindan-1-one exclusively in high (90%)chemical yield.

Abstract (in Czech)

A photoenolization reaction is shown to be the key reaction step in the preparation of substituted indan-1-ones as convenient precursors for the synthesis of donepezil, a well known acetylcholinesterase inhibitor. Model 2,5-dialkylphenacyl chlorides, differently substituted in the alpha carbon position, were found to produce indan-1-ones upon irradiation in non-nucleophilic solvents in high chemical yields via hydrogen chloride release. While direct excitation of 4,5-dimethoxy-2-methylphenacyl chloride led to a complex mixture of photoproducts, photolysis of the corresponding benzoate was found to form 5,6-dimethoxyindan-1-one in 62-72% chemical yields and a relatively low quantum efficiency (F = 0.02). This compound can then be easily converted to donepezil by standard synthetic steps described in the literature. Isotopic exchange and quenching experiments revealed that the product is obtained by the photoenolization process via the triplet excited state, while minor side-photoproducts originate from the singlet excited state. Irradiation of the reactant in neat acetone, used both as a triplet sensitizer and solvent at the same time, was found to form 5,6-dimethoxyindan-1-one exclusively in high (90%)chemical yield.

Links

• GA203/05/0641, research and development project: Name: Vývoj a aplikace fotolabilních chránících skupin

Investor: Czech Science Foundation, Design and Applications of Photoremovable Protecting Groups

• MSM0021622413, plan (intention): Name: Proteiny v metabolismu a při interakci organismů s prostředím

Investor: Ministry of Education, Youth and Sports of the CR, Proteins in metabolism and interaction of organisms with the environment