A Convenient Preparation of Muconaldehyde Using a One-Pot Acid-to-Aldehyde Reduction Protocol

Abstract

(E, E)-Muconaldehyde (1, Figure 1) (muconic dialdehyde, (2E,4E)-hexa-2,4-dienedial), an open-ring metabolite of benzene, has become the subject of numerous investigations into the toxic effects of exposure to benzene. The presumed formation of muconaldehyde as a result of tropospheric oxidation of benzene in photochemical smog also has stimulated investigations on its formation in the atmosphere and resultant effects on pollution. Finally, muconaldehyde is of interest to synthetic chemists, particularly as a linking substrate for polyene synthesis and as a diene reactant for inverse electrondemand Diels-Alder reactions. Our interest in the toxicological studies of this widely investigated dialdehyde has led us to examine its synthesis from the corresponding diacid, muconic acid (2). Several syntheses of muconaldehyde have been reported (Figure 2), spanning a wide variety of approaches from the first synthesis in 1949 by Karrer et al. (3 steps, 32% overall yield) to the more recent reports in 2005 by Kurteva and Afonso (4 steps, 27%) and in 2016 by Chen and coworkers (2 steps, 24%). The double Wittig-Horner approach to the title compound by Kossmehl and Bohn appears most expeditious; however, a recent application of this route reports formation of muconaldehyde in only 22% yield. Given that (E,E)-muconic acid is commercially available and that there are multiple options for the reduction of carboxylic acid derivatives to aldehydes, such as the mono-reduction of acid chlorides, derived carboxymethyleniminium salts, or corresponding Weinreb amides, we postulated that the conversion of muconic acid to a bis-activated intermediate might provide an efficient route to 1. Motivated by the reported selective mono-reduction of acyl imidazole intermediates derived from Bocprotected a-amino acids to aldehydes, we opted to prepare analogous bis-acylurea derivatives of muconic acid for selective reduction studies. We found that when diacid 2 was reacted with N,N’-diisopropylcarbodiimide (DIC, Scheme 1), the initially-formed bis-(O-acyl-N, N’-diisopropyl isourea) (3) underwent acyl O⟶N migration to produce bis-acylurea 4. Subsequent slow addition of diisobutylaluminum hydride (Dibal) at low temperature followed by quenching the putative bis(mono-reduced) aluminum chelate [5] by addition of acetic acid afforded muconaldehyde in 71% yield after chromatography. The use of N,N’-dicyclohexyl-carbodiimide or sodium bis(2-