A Multistep Synthesis Featuring Classic Carbonyl Chemistry for the Advanced Organic Chemistry Laboratory

Abstract

A multistep synthesis of 5-isopropyl-1,3-cyclohexanedione is carried out from three commodity chemicals. The sequence involves an aldol condensation, Dieckmann-type annulation, ester hydrolysis, and decarboxylation. No purification is required until after the final step, at which point gravity column chromatography provides the desired product in good overall yield. This synthesis sequence allows students to put into practice many of the fundamental acid- and base-catalyzed transformations of carbonyls presented in the second semester of a traditional introductory organic chemistry sequence. Importantly, this synthesis has been optimized to fit entirely within a series of five 4 h laboratory periods and requires no specialized equipment. Furthermore, the intermediates and product of the synthesis exhibit proton NMR spectra that illustrate many important concepts in introductory spectroscopic analysis.

Aldol Condensation Reaction Rate Demonstrates Steric and Electronic Substituent Effects in the Organic Chemistry Lab

“…The products are generally easy to purify and characterize, and the aldol reaction exhibits canonical mechanistic steps that link the lab exercise back to important concepts students learn in lecture. This Journal has published many Laboratory Experiments involving aldol reactions, including the following: exercises focusing on multistep synthesis; − purification and identification of unknown aldol products; , spectroscopic characterization using NMR, IR, MS, and UV techniques; − chiral catalysis, chiral separations, and optical rotation; − and development of greener lab procedures. − …”

An Efficient Method for the Synthesis of 2′,3′-Nonsubstituted Cycloalkane-1,3-dione-2-spirocyclopropanes Using (2-Bromoethyl)diphenylsulfonium Trifluoromethanesulfonate

“…25) Interestingly, the use of Meldrum's acid (27) afforded the corresponding spirocyclopropane 28 in 80% yield. We speculate that the higher acidity of Meldrum's acid (27: pK a 7.3, in DMSO at 25°C) 26) than that of dimethyl malonate (25: pK a 15.9, in DMSO at 25°C) is the reason for the success of the reaction.…”

“…All reagents such as 1,3-cyclohexanedione (8a) and its derivatives 8b, c, e, and g, 1,3-cyclopentanedione (17), 1,3-cy- (27), and powdered K 2 CO 3 are commercially available and were purchased from suppliers such as Sigma-Aldrich Co., U.S.A., Tokyo Chemical Industry Co., Ltd., Tokyo, Japan, Wako Pure Chemical Industries, Ltd., Osaka, Japan and Nacalai Tesque, Inc. Dehydrated DMSO CH 2 Cl 2 , toluene, DMF, and EtOAc were purchased from Wako Pure Chemical Industries, Ltd. 5-Isopropylcyclohexane-1,3-dione (8d), 27) spiro[2.5] octane-5,7-dione (8f), 28) and 4-methylcyclohexane-1,3-dione (8h) 29) were prepared according to literature procedures.…”

Dehydrogenative Formation of Resorcinol Derivatives Using Pd/C–Ethylene Catalytic System

“…5.04 g, 80% yield. Pale buff-colored solid after recrystallization from a mixture of hexane/ ethyl acetate (5:1); mp 180−184 °C; 1 20 General Procedure for Oxidation of 5-Substituted 1,3-Cyclohexanedione. To a mixture of 1,3-cyclohexanedione derivatives (0.5 g, 1 equiv) and 5% Pd/C methanol (120 equiv) was added followed by trimethyl orthoformate (2 equiv).…”