DMSO–Superbase Route to Dioxabicyclooctanes from Simple Ketones and Acetylenes

The number of self-assembly reactions involving acetylenes under KOt-Bu– and KOH–DMSO superbase conditions continues to grow.¹ The Trofimov group has shown that simple ketones and acetylene can self-assemble in a one-pot KOH–DMSO reaction to provide 6,8-dioxabicyclo[3.2.1]octanes (DOBCOs) (1), which, upon treatment with acid, isomerize to the corresponding acetyl-substituted dihydropyrans 2 (Scheme 1).² There is interest in species like compound 1 as this structural motif is abundant in many natural product compounds.

Scheme 1: KOH–DMSO superbase synthesis of an acetyl-substituted dihydropyran 2.

Recently, further elaboration by DMSO–superbase-promoted C-vinylation of the acetyl group of compound 2 by reaction with an aromatic alkyne has also been demonstrated by the Trofimov group (Table 1).³ This reaction appears to be only mildly affected by the electronic character of the aromatic alkyne, with all akynes in Table 1 resulting in similar yields. Of note, if R¹ is a large aromatic group (i.e., PhC₆H₅ or 2-naphthyl), the C-vinylation reaction fails, and only deacetylation of the dihydropyran ring occurs.

Table 1: KOt-Bu–DMSO superbase C-vinylation of acetyl-substituted dihydropyran 2.

The Trofimov group also developed a cyclization method whereby compound 3 is converted into the dienyl DOBCO 4 (Scheme 2).³ In other words, following a self-assembly reaction between acetylene and a simple ketone (Scheme 1), subsequent C-vinylation  with another alkyne (Table 1), and then cyclization (Scheme 2), functionalized DOBCOs like compound 4 can be readily synthesized through the two highlighted DMSO superbase reactions.

Scheme 2: Cyclization of dihydropyran 3 to DOBCO 4.

This route is transition-metal-free, requires only readily-available starting materials, and proceeds through simple conditions and protocols.

Debra D. Dolliver, Ph.D.

¹ Trofimov, B. A.; Schmidt, E. Y. Accounts of Chemical Research 2018, 51, 1117.

² Trofimov, B. A.; Schmidt, E. Y.; Ushakov, I. A.; Mikhaleva, A. I.; Zorina, N. V.; Protsuk, N. I.; Senotrusova, E. Y.; Skital’tseva, E. V.; Kazheva, O. N.; Alexandrov, G. G.; Dyachenko, O. A. European Journal of Organic Chemistry 2009, 2009, 5142.

³ Schmidt, E. Y.; Tatarinova, I. V.; Semenova, N. V.; Protsuk, N. I.; Ushakov, I. A.; Trofimov, B. A. The Journal of Organic Chemistry 2018, 83, 10272.