Substituents Effect on the Erlenmeyer−Plöchl Reaction: Understanding an Observed Process Reaction Time

Abstract

A systematic study on hippuric acid substituents was performed in order to better understand the influence of stereoelectronic factors on the Erlenmeyer reaction rate. In addition, two reaction systems were evaluated: Hünig’s base solvent free conditions and catalytic sodium acetate in 2-methyl-THF. The effect on reaction rate of electron withdrawing and electron donating groups are reported. Specifically, the study led to the conclusion that stereoelectronic factors have significant influence in one of our key Erlenmeyer reaction by affecting its reaction rate.

Utilization of Stable Isotope Labeling to Facilitate the Identification of Polar Metabolites of KAF156, an Antimalarial Agent

“…This conclusion was supported by mass spectrometric analysis (Fig. 8) and comparison of observed NMR chemical shifts to those reported for 4-fluoro-hippuric acid (Chavez et al, 2010).…”

Catalyzing the Erlenmeyer Plöchl reaction: organic bases versus sodium acetate

“…This could be explained by the presence of substituents on the hippuric acid aromatic ring, as reported previously by our group. 22 Re-evaluation of sodium acetate as base: The original Erlenmeyer reaction conditions involve the reaction of an appropriate hippuric acid with an aromatic aldehyde, sodium acetate as the base, and acetic anhydride as the dehydrating agent. Typically, this reaction is performed at a high temperature.…”

“…As in the DIPEA process, these forcing reaction conditions lead to unfavorable results, especially with substituted hippuric acids. 22 To attenuate the concentration effect, the use of a solvent was introduced. Various solvents were screened for the formation of oxazolones 1 and 4 under various amounts of sodium acetate (Table 4).…”

“…On the other hand, cleaner reactions with fewer by-products were observed if the reaction was carried out in Me-THF (method C). Therefore, method C reaction conditions would result in a more robust process, 22 especially for gram/kilogram scale up. Independent to the reaction conditions, EWG-aldehydes observed faster reaction and good isolated yield as compared with those having EDG.…”

The Zwitterionic Imidazolium Salt: First Used for Synthesis of 4-Arylidene-2-phenyl-5(4H)-oxazolones under Solvent-Free Conditions

“…Since the �rst report on the synthesis of azlactones published in 1883, a number of catalysts have been developed in recent years. For example, lead acetate [10], SO 3 in dimethylformamide [11], perchloric acid [12], polyphosphoric acid [13], carbodiimides [14], anhydrous zinc chloride [15], Bi(OAc) 3 [16], Bi(OTf) 3 [17], Ca(OAc) 2 [18], KF-alumina [19], Yb(OTf) 3 [20], POCl 3 [21], H 3 PW 12 O 40 [22], Sm [22], RuCl 3 [22], Al 2 O 3 [23], organic bases [1,24], K 3 PO 4 [25], and organic-inorganic hybrid polyoxometalates [26] have been used to perform this condensation. However, some of these procedures have important drawbacks, such as the use of water-sensitive catalyst [11,15,19], the use of noble metal/or salts as catalysts [16,20,22], rigorous conditions [12,21,25], and the use of toxic reagents [1,10,12,21,25].…”