Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

Abstract

Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf 2 NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening of the oxetane. High regio- and diastereoselectivity are achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.

Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

“…TIPS-protected phenol was deprotected under the reaction conditions to give free phenol 7a . Importantly, and in contrast to our previous strategies generating oxetane carbocations, electron-neutral phenyl oxetane acid was a successful substrate and provided 3,3-disubstituted oxetane 8a in 49% yield. A comparison of the reaction profiles for the formation of 2a and 8a indicated the rate of reaction was faster to form 2a , which could be correlated with the lower oxidation potential of the carboxylate from 1 (see Supporting Tables S14–S15 and Figure S11).…”

“…Following our interest in 3-aryloxetane and azetidine derivatives involving carbocation intermediates, we envisaged that benzylic oxetane radicals would broaden the range of options for oxetane incorporation and provide access to valuable, unexplored, and medicinally relevant chemical space under mild photoredox conditions. However, tertiary benzylic radicals remain underinvestigated in photoredox catalysis and might be expected to display low reactivity in their addition reactions due to their relatively stabilized nature .…”

Synthesis of oxetane and azetidine ethers as ester isosteres by Brønsted acid catalysed alkylation of alcohols with 3-aryl-oxetanols and 3-aryl-azetidinols

“…Propargylic alcohol could be employed ( 2g ), introducing a potential click handle. Whereas ethylene glycol under these reaction conditions gives a dioxane product, 16 NCbz-amino ethanol gave oxetane ether 2h in 42% yield. 1,3-Dihydroxy propane provided oxetane ether 2i as the major product in 38% yield without ring-opening of oxetane.…”

“…14 f , g 3,3-Disubstituted oxetane ethers have also been exploited as intermediates in the synthesis of heterocycles through intramolecular oxetane opening. 15,16 In these cases, the ethers are typically prepared from oxetanols with strong bases and halide alkylating agents. We have recently developed catalytic approaches to use benzylic oxetanols and azetidinols as alkylating agents for the preparation of 3-aryl-3-functionalised-oxetanes and azetidines via carbocation intermediates (Fig.…”

Oxetanes in Drug Discovery Campaigns

“…Oxetanes substituted with electron-donating groups at C2 are likely to be unstable. Internal nucleophiles can also lead to cyclization processes, which can be synthetically productive. , …”