Regiochemistry of the Condensation of 2-Aroyl-cyclohexanones and 2-Cyanoacetamide: ¹³C-Labeling Studies and Semiempirical MO Calculations

Abstract

Hydroxy-aryl-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles represent interesting chemical scaffolds, but synthetic access to these compounds is limited. The reaction of 2-aroyl-cyclohexanones with 2-cyanoacetamide and base in ethanol has been reported to lead to the formation of the tetrahydroisoquinoline isomer. We show that depending on the electronic nature of the para-substituent on the aryl ring, formation of the regioisomeric tetrahydroquinoline isomer can significantly compete. The electron-donating or -withdrawing properties of the para-substituent of the aryl ring determines the ratio of product isomers. A series of 2-aroyl-cyclohexanones, with para-substituents ranging from electron-donating to electron-withdrawing, were reacted with [2-(13)C]-cyanoacetamide. The product ratio and absolute regiochemistry were directly determined by quantitative (13)C, HMBC, and NOESY NMR spectroscopy on the reaction mixtures. A clear relationship between the regioisomeric product ratio and the Hammett sigma values of the substituents is demonstrated. This is explained by the separate in situ yields, which reveal that the pathway leading to the tetrahydroquinoline regioisomer is significantly more sensitive toward the electronic nature of the para-substituent than the pathway leading to the tetrahydroisoquinoline. Semiempirical AM1 molecular orbital calculations on the starting electrophile 2-aroyl-cyclohexanone support a correlation between the energy of the LUMOs and the regioisomeric product ratio. Our results facilitate synthetic access to a range of these interesting synthetic intermediates.

Alkali Carbonates Improve β,β-Diaryl Serine-Catalyzed Enantioselective α-Fluorination of β-Dicarbonyl Compounds

“…If the purity is not enough, subsequent recrystallization was conducted from hexane to afford the desired product. The data of cyclic β-diketones 1a – 1g were identical to the previously reported data …”

“…General Procedure for the Preparation of Cyclic β-Diketones. Cyclic β-diketones 1 were prepared by the modified procedure of de Esch's method: 25 A solution of diisopropylamine (5.5 mmol, 1.1 equiv) in anhydrous tetrahydrofuran (THF) (16.6 mL, 0.3 M) was carefully treated with n-BuLi (6.6 mmol, 1.32 equiv) at 0 °C under an argon atmosphere, and the resulting solution was stirred for 30 min at 0 °C to prepare for lithium diisopropylamide (LDA). Cyclohexanone (5.0 mmol, 1.0 equiv) was added to a prepared LDA solution at −78 °C.…”

“…The data of cyclic β-diketones 1a−1g were identical to the previously reported data. 25 2-(3-Methylbenzoyl)cyclohexanone (1h). The reaction was conducted using 9.4 mmol of cyclohexanone.…”

Solubility Determination, Solvent Effect, Thermodynamic Modeling, and Preferential Solvation of 2-Cyanoacetamide in Four Aqueous Binary Mixtures of Alcohols

“…As the fractional molar volumes of 2-CA in these combinations are not in the literature, this study assumes them to be like the pristine compound, which is considered a reasonable approximation. 14,35,36,42 Consequently, the molar volume of 2-CA is calculated based on its molar mass (84.08 g• mol −1 ) and density (1.136 g•cm −3 ), 29 resulting in a value of 72.296 cm 3 •mol −1 . The V 1 and V 2 values for MeOH (1) + water (2), EtOH (1) + water (2), and 1-PrOH (1) + water (2) mixtures are presented in Tables S12−S15, respectively.…”

“…7,8 2-Cyanoacetamide may be employed in the spectrofluorimetric technique to measure antihistaminic H1 receptor antagonist medications, including fexofenadine hydrochloride, cetirizine dihydrochloride, and ebastine. 1,3,9,10 A fundamental understanding of solid−liquid phase equilibrium and critical thermodynamic data, especially solubility, is crucial to improve the design and control of the crystallization process. As a physiochemical characteristic, solubility is essential to determining how active pharmaceutical ingredients (APIs) balance out in solid−liquid combinations.…”