Reaction of Unsymmetrical Enolate Anions with Gold'S Reagent

Scalable synthesis of enaminones utilizing Gold's reagents

“…With a library of novel Gold’s reagents in hand, we turned to optimization of the conditions for enaminone formation (Table 1). Previous conditions described by Gupton and co-workers 16a employed using the newly synthesized Gold’s reagents were ineffective, thus alternative reaction conditions were examined. Optimization efforts focused on variation of the base employed along with modification of solvent and temperature (Table 1).…”

“…When the previously described conditions using NaOMe in MeOH 16a or NaO- i -Pr in i -PrOH 15 were employed for the transformation of 1b to 4c , modest yields up to 29% were observed (Entries 1 and 2). Alteration of the alkoxide base to NaO- t -Bu in t- BuOH did not result in product formation (Entry 3).…”

“…In order to demonstrate the scalability of the newly developed reaction conditions, we applied them in the synthesis of enaminone 4b , which was required for the total synthesis of andirolide N. Reaction of 2-butanone ( 1a ) and 5a on 1-mol scale provided enaminone 4b in 73% yield after vacuum distillation (Scheme 2B), which is a notable improvement over the previously reported yield of 48%. 15 The modified procedure additionally replaced the alcoholic solvent used in reaction workup with diethyl ether to allow for a facile extractive isolation and recovery of product.…”

“…During the course of a total synthesis of andirolide N, 14 we examined these conventional approaches for enaminone synthesis and ultimately found the most scalable approach utilized the aminomethylene electrophile equivalent ( 5 ), known as Gold’s reagent. 15–17 This approach allowed for the direct regio- and diastereoselective functionalization of 2-butanone using Gold’s reagent, a bench stable reagent which can be prepared in a single step and purified by recrystallization. 17 The straightforward preparation of this valuable equivalent to DMF-DMA employs inexpensive cyanuric chloride and DMF.…”