Electrophilic Etherification of α-Heteroaryl Carbanions with Monoperoxyacetals as a Route to Ketene O,O- and N,O-Acetals

Abstract

Alkyl ketene acetals are useful reactants in a variety of synthetic processes, and yet, there are limited routes to their formation as isolable products. We now report the successful synthesis and isolation of heteroaryl ketene acetals through intermolecular transfer of alkoxyl (δ + OR) from electrophilic peroxides to lithiated benzofurans, indoles, and pyridines. Primary and secondary peroxyacetals enable selective transfer of the nonanomeric alkoxy group in moderate to high yield; substrates bearing an electron-donating substituent show enhanced reactivity toward electrophilic oxygen. Heteroaryl ketene acetals are remarkably stable throughout traditional purification techniques; the superior stability of ketene N,O-acetals compared to ketene O,O-acetals is presumably due to increased aromaticity of the indole and pyridine structures. The presented method overcomes typical problems associated with alkyl ketene acetal synthesis as reported products withstood workup and flash column chromatography procedures.

Rapid, One-Step Synthesis of α-Ketoacetals via Electrophilic Etherification

“…The following procedures differ only slightly; specifically, reaction temperatures, times, and reagents are the only modifications to the previously reported acid-catalyzed acetalization procedure implemented herein. , …”

“…From dihydrooxacycles, tetrahydropyranyl ( 3 , “THP”) and methyl tetrahydrofuranyl ( 4 , “MTHF”) monoperoxyacetal hydroperoxides were synthesized in good yields via acid-catalyzed acetalization (Scheme ). Base-promoted methylation of anionic hydroperoxides ( 2b , 3 , and 5 ) provided simple electrophiles in moderate to excellent yields ( 7 – 9 ; Table , entries 1–3); acid-catalyzed acetalization efficiently converted monoperoxyacetal hydroperoxides to bisperoxyacetals ( 10a , 10b , and 11 ; Table , entries 4–6). , Lastly, from freshly prepared alkyl trifluoromethanesulfonates (“triflates”, 12 – 16 ), MTHP monoperoxyacetals ( 17a , 18a , and 20a ), THP monoperoxyacetals ( 17b , 18b , and 20b ), an MTHF monoperoxyacetal ( 19 ), and tert -butyl peroxides ( 21 and 22 ) were synthesized with reliable success (Table ). ,, As illustrated, primary electrophiles were isolated in moderate to excellent yields, while secondary substrates were provided in slightly lower yields.…”

“… Base-promoted methylation of anionic hydroperoxides ( 2b , 3 , and 5 ) provided simple electrophiles in moderate to excellent yields ( 7 – 9 ; Table , entries 1–3); acid-catalyzed acetalization efficiently converted monoperoxyacetal hydroperoxides to bisperoxyacetals ( 10a , 10b , and 11 ; Table , entries 4–6). , Lastly, from freshly prepared alkyl trifluoromethanesulfonates (“triflates”, 12 – 16 ), MTHP monoperoxyacetals ( 17a , 18a , and 20a ), THP monoperoxyacetals ( 17b , 18b , and 20b ), an MTHF monoperoxyacetal ( 19 ), and tert -butyl peroxides ( 21 and 22 ) were synthesized with reliable success (Table ). ,, As illustrated, primary electrophiles were isolated in moderate to excellent yields, while secondary substrates were provided in slightly lower yields. Nevertheless, the application of the peroxide-generating technology to the synthesis of sterically hindered products ( 20a and 20b ) should be noted as the formation of “β-branched” electrophiles, via S N 2 displacement of the triflate anion, is known to be quite challenging …”

“…Over the past 10 years, the use of monoperoxyacetals, as a source of electrophilic oxygen for reactions with nucleophilic carbanions, has emerged as a facile means of adding C–O bonds to a variety of carbon skeletons . We recently described the synthesis of ketene O , O - and N , O -acetals via intermolecular etherification of electrophilic monoperoxyacetals and unstabilized α-heteroaryl carbanions …”

Modern Synthesis and Chemistry of Stabilized Ketene N,O-Acetals

“…In 2021, our group reported a method of ketene N,O-acetal synthesis via intermolecular etherification of -heteroaryl carbanions and monoperoxyacetals (Table 6). 72 Therein, indole-or pyridine-based nucleophiles 38 or 39, respectively, reacted with primary and secondary electrophiles in moderate to excellent yields; peroxide/carbanion technology, as a means of obtaining N-stabilized, ketene N,O-acetals (indole-based products: 40a-h; pyridine-based products: 41a-k), is efficient and shows reasonable functional group compatibility. In summary, the synthesis of synthetically useful, stable ketene N,O-acetals is often achieved with either -or N-stabilization; importantly, throughout these stabilization techniques, ketene N,O-acetals clearly retain their reactivity.…”