Synthesis of α-Arylated Cycloalkanones from Congested Trisubstituted Spiro-epoxides: Application of the House–Meinwald Rearrangement for Ring Expansion

Abstract

A three-step sequence for the synthesis of α-arylated cyclohexanones and the most challenging cycloheptanones is reported. First, an efficient one-pot synthesis of β,β'-disubstituted benzylidene cycloalkanes (styrenes) using the palladium-catalyzed Barluenga reaction from readily available feedstock chemicals is described. Furthermore, an epoxidation followed by the House-Meinwald rearrangement (HMR) of spiro-epoxides is reported to produce a number of α-arylated cycloalkanones upon ring expansion. Reactions catalyzed by bismuth triflate underwent quasi-exclusively ring expansion for all substrates (electronically poor and rich), with yields ranging from 15% to 95%, thus demonstrating the difficulty of achieving ring enlargement for electron-deficient spiro-epoxides. On the other hand, by means of catalysis with aluminum trichloride, the rearrangement of spiro-epoxides proceeded typically in high yields and with remarkable regioselectivity on a broader substrate scope. In this case, a switch of regioselectivity was achieved for spiro-epoxides with electron-withdrawing substituents which enable the method to be successfully extended to some chemospecific arene shifts and the synthesis of aldehydes bearing a α-quaternary carbon. While the HMR has been extensively studied for smaller ring enlargement, we are pleased to report herein that larger cyclohexanones and cycloheptanones can be obtained efficiently from more sterically demanding trisubstituted spiro-epoxides bearing electron-releasing and electron-neutral arene substituents.

Nucleophilic Organic Base DABCO-Mediated Chemospecific Meinwald Rearrangement of Terminal Epoxides into Methyl Ketones

“…3 The isomerization of epoxides into carbonyl compounds is well-known as the Meinwald rearrangement or Meinwald reaction. 4 The acid-catalyzed, including various protonic and Lewis acids, Meinwald rearrangements of epoxides have been widely investigated, 5 in which terminal epoxides generate the corresponding aldehydes as sole or major products (Scheme 1a), 6 accompanied by methyl ketones as byproducts in some cases, 6d,e while internal epoxides generally afford the corresponding ketones with aldehydes as side products in certain reactions, 7 especially for aryl epoxides. 8 Occasionally, aldehydes are obtained as major products.…”

Late-Stage Lead Diversification Coupled with Quantitative Nuclear Magnetic Resonance Spectroscopy to Identify New Structure–Activity Relationship Vectors at Nanomole-Scale Synthesis: Application to Loratadine, a Human Histamine H1 Receptor Inverse Agonist

“…The ring-expanded ketone 25 is novel and most likely the result of the House–Meinwald type rearrangement from epoxide 24 ; unfortunately, analogue 25 is not active against the H 1 receptor (Scheme ). Nevertheless, serendipitous products such as 25 provide valuable SAR to medicinal chemistry teams and generate new chemical matter in a single step that would be challenging to synthesize using conventional methods.…”

Studies on the Origin of the Stabilizing Effects of Fluorinated Alcohols and Weakly Coordinated Fluorine-Containing Anions on Cationic Reaction Intermediates

“…Compounds 7a and 7b were prepared from anisole (324 mg, 3 mmol) and 4-bromostyrene oxide (199 mg, 1 mmol) according to the general procedure. Purification by column chromatography (EtOAc/PE = 1/10) afforded 7a (49 mg, 16%) and 7b (138 mg, 45%) as a colorless oil.…”