Presentation Title

Gold-Catalyzed Arylation of Benzylic Alcohols to Afford Bioactive 1,2,3-Benzotriazole Derivatives

Faculty Mentor

Robert Iafe

Start Date

17-11-2018 1:30 PM

End Date

17-11-2018 1:45 PM

Location

C335

Session

Oral 3

Type of Presentation

Oral Talk

Subject Area

physical_mathematical_sciences

Abstract

In the past few decades, 1,2,3-benzotriazole derivatives have been commonly used for anti-fungal, anti-cancer, and even anti-parasitic medications. Triazoles are the second major chemical class of antifungal derivatives due to their wider range of activity and lower toxicity levels when compared to other antifungal drugs. 1,2,3-Triazole antifungals act by inhibiting the conversion of lanosterol 14-alpha-demethylase (CYP51) into ergosterol, the primary sterol in fungal cell membranes. During our previous study using gold(I) salts to catalyze etherification reactions, we discovered that 1,2,3-benzotriazoles have nucleophilic reactivity in preference to the etherification pathway. We were able to successfully achieve N-alkylated products using microwave conditions. From this, our lab has developed the first microwave-assisted, gold(I)-catalyzed substitution reaction of 1,2,3-benzotriazole with benzylic alcohols to afford N-substituted 1,2,3-benzotriazole derivatives. To our knowledge, while examples of base-catalyzed and phase transfer catalysis displacement reactions are well-known, a microwave assisted, gold(I)-catalyzed substitution reaction is currently unprecedented in the literature. Herein, we present the synthesis of 1-[(4-chlorophenyl) phenylmethyl]-1H-benzotriazole, an antifungal medication to treat candida, with our gold(I) reaction methodology. Candida is a fungus with over 20 species and cause infections. In the literature, this antifungal medication has been synthesized with a 48% yield by a displacement reaction. Using our gold(I) protocol, this compound was prepared in 92% yield in only 6 hours. The product was validated with spectroscopic techniques, such as 1H-NMR. Knowledge gained from this project will be applied to the synthesis of other bioactive natural products and building blocks useful in the synthesis of these molecules.

Summary of research results to be presented

The synthesis of 1-[(4-chlorophenyl) phenylmethyl]-1H-benzotriazole, a potent anti fungal medication, was prepared in high yield starting from p-chlorobenzaldehyde. To prepare the benzylic alcohol, p-chlorobenzaldehyde underwent a Grignard reaction with phenyl magnesiumbromide to afford 4-chloro-α-phenyl-benzenemethanol in 95% yield. With the benzylic alcohol in hand, our novel gold(I) methodology was used to react the alcohol with 1,2,3-benzotriazole in the presence of PPh3AuCl (5 mol %), AgSbF6 (5 mol %), and acetonitrile as the solvent. After isolation and purification, the target compound was obtained in 92% yield (87% overall yield). With small catalyst loading and low equivalents of nucleophile required, the gold(I) salt catalyst demonstrated to be very effective in yielding the desired benzotriazole derivative.

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Nov 17th, 1:30 PM Nov 17th, 1:45 PM

Gold-Catalyzed Arylation of Benzylic Alcohols to Afford Bioactive 1,2,3-Benzotriazole Derivatives

C335

In the past few decades, 1,2,3-benzotriazole derivatives have been commonly used for anti-fungal, anti-cancer, and even anti-parasitic medications. Triazoles are the second major chemical class of antifungal derivatives due to their wider range of activity and lower toxicity levels when compared to other antifungal drugs. 1,2,3-Triazole antifungals act by inhibiting the conversion of lanosterol 14-alpha-demethylase (CYP51) into ergosterol, the primary sterol in fungal cell membranes. During our previous study using gold(I) salts to catalyze etherification reactions, we discovered that 1,2,3-benzotriazoles have nucleophilic reactivity in preference to the etherification pathway. We were able to successfully achieve N-alkylated products using microwave conditions. From this, our lab has developed the first microwave-assisted, gold(I)-catalyzed substitution reaction of 1,2,3-benzotriazole with benzylic alcohols to afford N-substituted 1,2,3-benzotriazole derivatives. To our knowledge, while examples of base-catalyzed and phase transfer catalysis displacement reactions are well-known, a microwave assisted, gold(I)-catalyzed substitution reaction is currently unprecedented in the literature. Herein, we present the synthesis of 1-[(4-chlorophenyl) phenylmethyl]-1H-benzotriazole, an antifungal medication to treat candida, with our gold(I) reaction methodology. Candida is a fungus with over 20 species and cause infections. In the literature, this antifungal medication has been synthesized with a 48% yield by a displacement reaction. Using our gold(I) protocol, this compound was prepared in 92% yield in only 6 hours. The product was validated with spectroscopic techniques, such as 1H-NMR. Knowledge gained from this project will be applied to the synthesis of other bioactive natural products and building blocks useful in the synthesis of these molecules.