Grignard-mediated rearrangement of trifluoroacetyl from dihydroisoquinoline enamides to afford tertiary trifluoromethylcarbinols

Abstract

Treatment of the trifluoroacetyl enamides of dihydroisoquinolines 2 with diverse Grignard reagents afforded tertiary trifluoromethyl-carbinols 4 by facilitating the addition of tertiary carbinols to the β-carbon of enamides 2. Based on the confirmed formation of vinylogous amides 3, the transformation likely proceeds via unique acyl group rearrangement to the β-carbon of the enamide and subsequent nucleophilic addition of the Grignard reagent. Given the synthetic utility and novelty of this reaction, this work may open new avenues for the synthesis of pharmaceutically important tertiary trifluoromethylcarbinols on cyclic enamide systems.

Synthetic Studies on the Initially Proposed Structure of Protoaculeine B: Discovery of Neuronally Active Heterotricyclic Amino Acids

“…As shown in Entry 3, the first attempt (TFAA, TFA, Fe), [28] wherein the conditions identical to Entry 2 were employed, was unsuccessful. However, the reaction with Lewis acid (TMSCl) [29] provided the desired TFA enamide 27 b in 23 % yield (Entry 4). The yield was improved to 63 % by using TESCl (Entry 5).…”

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…Energy dispersive X‐ray spectrometer (EDS) data were obtained using Bruker Quantax 200 EDS. DHIQs 1a‐e were prepared with reported methods …”

“…DHIQs 1a-e were prepared with reported methods. 35 General Procedure for the Preparation of 3. To a solution of DHIQ 1a (100 mg, 0.571 mmol, 1.0 equiv) in Table 4.…”

“…Allylation at the C1‐methyl of DHIQ was accomplished using allyl iodide and a strong base, such as n ‐butyllithium . Lately, we also reported a novel approach for the C1‐methyl alkylation on DHIQ‐enamides using Grignard reagents . In this study, we describe double alkylation of DHIQ 1a under mild and metal‐free conditions to afford compound 3 through creating two covalent bonds at both the nitrogen of DHIQ and the C1‐methyl group in a one‐pot manner (Scheme (b)).…”

A one-pot diastereoselective synthesis of 1,3-diols and 1,3,5-triols via cascade reactions of arylalkynyl Grignard reagents with enol esters

“…In recent years, significant advances in cascade reactions involving Grignard reagent-mediated rearrangements have been reported. [22][23][24][25][26] In addition, nucleophilic addition of Grignard reagents to esters is one of the methods for the synthesis of tertiary alcohols. Initially, Zwahlen et al 27 reported a nucleophilic/rearrangement/nucleophilic addition cascade between a Grignard reagent and an enol lactone to afford a 1,3-diol compound.…”