Pospísil Tomás, Veetil Aneesh Tazhe, Antony Lovely Angel Panamparambil, Klán Petr
Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A8, 62500 Brno, Czech Republic.
Photochem Photobiol Sci. 2008 May;7(5):625-32. doi: 10.1039/b719760h. Epub 2008 Mar 4.
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 (Phi approximately 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.
光烯醇化反应被证明是制备取代茚满-1-酮的关键反应步骤，茚满-1-酮是合成多奈哌齐（一种著名的乙酰胆碱酯酶抑制剂）的便利前体。发现2,5-二烷基苯甲酰氯模型在α-碳位置有不同取代，在非亲核溶剂中辐照时通过释放氯化氢以高化学产率生成茚满-1-酮。虽然4,5-二甲氧基-2-甲基苯甲酰氯的直接激发导致光产物的复杂混合物，但发现相应苯甲酸酯的光解以62-72%的化学产率和相对较低的量子效率（Φ约为0.02）形成5,6-二甲氧基茚满-1-酮。然后，该化合物可以通过文献中描述的标准合成步骤轻松转化为多奈哌齐。同位素交换和猝灭实验表明，产物是通过三重激发态的光烯醇化过程获得的，而少量的副光产物则源自单重激发态。发现同时用作三重敏化剂和溶剂的纯丙酮中反应物的辐照仅以高（90%）化学产率形成5,6-二甲氧基茚满-1-酮。
