Synthesis of α-Cyano and α-Sulfonyl Cyclic Ethers via Intramolecular Reactions of Peroxides with Sulfone- and Nitrile-Stabilized Carbanions

Abstract

The intramolecular reaction of carbon nucleophiles with oxygen-centered electrophiles has been little explored outside of nucleophilic epoxidation. We now report the synthesis of sulfonyl-and cyano-substituted oxacycles via intramolecular reaction of sulfone-and nitrile-stabilized carbanions with dialkyl peroxides, triethylsilyl/alkyl peroxides, and monoperoxyacetals. The cyclizations are successfully applied to synthesize oxetanes, tetrahydrofurans, and tetrahydropyrans but fail for oxepanes. Cyclizations involving the relatively stabilized anion derived from a benzylic nitrile proceed in high yields for a variety of peroxides, including those in which the electrophilic oxygen is formally isobutyl or neopentyl. Corresponding cyclizations of an alkanenitrile are successful with both dialkyl and alkyl silyl peroxides but demonstrate much greater variability in yields. Reactions of sulfone-containing substrates are successful only with dialkyl peroxides. The success of reactions appears to be strongly influenced by the rate of peroxide decomposition, which appears to be highest for reactions involving poorly stabilized anions. The significant variation in diastereoselectivity observed for different classes of peroxide on a common framework suggests the possibility of substrate-dependent reaction mechanisms.

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

“…Therefore, we turned our attention to the use of carbon nucleophiles and electrophilic peroxides for intermolecular etherification, as demonstrated by several groups throughout the last century (eqs and 2). − Furthermore, we were encouraged by reports of successful alkoxy transfer to sp 2 -hybridized organometallics , and were optimistic that the same chemistry could be applied to the production of stable, heteroaryl ketene acetals. …”

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

“…The potassium counterion proved to be essential for etherification; when applied to a previously reported reaction, nitrogen and phosphate “superbases”, albeit strong enough according to the p K a value, failed to facilitate even trace amounts of C–O bond formation (Table S1). This finding lends support to the carbanion/peroxide metal insertion mechanism, which was hypothesized before, as the potassium counterion clearly plays an essential role in the electrophilic etherification. , Substituted dioxolanone enolates ( 23a and 23b ) failed to react with peroxides despite the encouraging precedents (Table ); regardless of the temperature, base, or stoichiometric equivalencies, desired alkoxylation products, derived from dioxolanone substrates, were not successfully produced. Commercial 2-methoxyacetophenone ( 25 ), however, quickly provided adequate reactivity toward electrophilic oxygen (Table ).…”

A click-based modular approach to introduction of peroxides onto molecules and nanostructures

“…The basis for inhibition of azide reactivity at a four-carbon distance from a peroxide remains unclear; however, we should note that we have observed a dampening inuence of peroxides on S N 2 reactions across a similar span. 42 The use of CuI in organic solvents gives more consistent and oen superior results compared to the use of CuSO 4 /ascorbate in biphasic media. The alkynyl peroxides and alkynyl peroxyacetal substrates, although stable towards Cu(I), are both prone to decomposition reactions in the presence of the reaction intermediates (Scheme 5).…”