A Practical Route to Cyclobutanols and Fluorocyclobutanes

Abstract

1‐[(Ethoxycarbonothioyl)sulfanyl]cyclobutyl acetate (xanthate 7) was found to add to electronically unbiased alkenes and to certain heteroarenes. In the latter case, this corresponds to a variant of the Minisci reaction and allows the late‐stage modification of biologically active substances. Saponification of the acetate furnishes the corresponding cyclobutanols, which, in the case of the nicotine adduct, can be converted into fluorocyclobutanes by the action of DAST. Fluorocyclobutyl substituted aromatics and heteroaromatics are increasingly present in drug candidates. Heating of the acetoxycyclobutyl derivative of caffeine with TFA gives rise to the cyclobutene analogue. Finally, O‐ethyl S‐[1‐(2,2,2‐trifluoroethoxy)cyclobutyl] carbonodithioate, obtained unexpectedly while optimizing the synthesis of xanthate 7, is a very promising reagent for the introduction of the very rare 2,2,2‐trifluoroethoxycyclobutyl motif.

Some Aspects of α-(Acyloxy)alkyl Radicals in Organic Synthesis

“…The chlorides (5, X = Cl) are most common and are prepared from aldehydes and, but to a lesser extent, ketones by reaction with an acid chloride under catalysis by a Lewis acid, most commonly zinc chloride [1,2]. Xanthates made by this route are assembled in Scheme 3 [4,[11][12][13][14] (note that the same numbers 3, 5, and 13 for the generic structures in Schemes 1-3 are used are for both aldehydes and ketone derived compounds). Examples 24 and 25 are taken from a study by Lee and Kim (but no yields are given) [4].…”

“…This Scheme 9. Further examples of addition of α-(acyloxy)alkyl xanthates to various alkenes [12,39,41,42].…”

“…In the case of symmetrical pyrazine 198, successive reactions with xanthates 199 and 58 furnish unsymmetrical pyrazine 201 [31]. Examples of additions of cyclobutyl xanthate 26 (Scheme 3) to a variety of heteraromatics are also assembled in Scheme 16 [12]. The yields are variable, and basic heteroaromatics required activation by addition of camphorsulfonic acid; nevertheless, a collection of otherwise difficultly accessible series of compounds could be rapidly prepared for an eventual biological screening.…”