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. 2024 May 6;63(19):e202319930.
doi: 10.1002/anie.202319930. Epub 2024 Mar 28.

Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing SF5-Cyclobutanes

Yannick Kraemer  1 , Jón Atiba Buldt  1 , Wang-Yeuk Kong  1 , Alexander M Stephens  1 , Abbey N Ragan  1 , Soojun Park  1 , Zane C Haidar  1 , Ansh Hiten Patel  1 , Rachel Shey  1 , Roee Dagan  1 , Connor P McLoughlin  1 , James C Fettinger  1 , Dean J Tantillo  1 , Cody Ross Pitts  1
Affiliations

Overcoming a Radical Polarity Mismatch in Strain-Release Pentafluorosulfanylation of [1.1.0]Bicyclobutanes: An Entryway to Sulfone- and Carbonyl-Containing SF5-Cyclobutanes

Yannick Kraemer et al. Angew Chem Int Ed Engl. .

Abstract

The first assortment of achiral pentafluorosulfanylated cyclobutanes (SF5-CBs) are now synthetically accessible through strain-release functionalization of [1.1.0]bicyclobutanes (BCBs) using SF5Cl. Methods for both chloropentafluorosulfanylation and hydropentafluorosulfanylation of sulfone-based BCBs are detailed herein, as well as proof-of-concept that the logic extends to tetrafluoro(aryl)sulfanylation, tetrafluoro(trifluoromethyl)sulfanylation, and three-component pentafluorosulfanylation reactions. The methods presented enable isolation of both syn and anti isomers of SF5-CBs, but we also demonstrate that this innate selectivity can be overridden in chloropentafluorosulfanylation; that is, an anti-stereoselective variant of SF5Cl addition across sulfone-based BCBs can be achieved by using inexpensive copper salt additives. Considering the SF5 group and CBs have been employed individually as nonclassical bioisosteres, structural aspects of these unique SF5-CB "hybrid isosteres" were then contextualized using SC-XRD. From a mechanistic standpoint, chloropentafluorosulfanylation ostensibly proceeds through a curious polarity mismatch addition of electrophilic SF5 radicals to the electrophilic sites of the BCBs. Upon examining carbonyl-containing BCBs, we also observed rare instances whereby radical addition to the 1-position of a BCB occurs. The nature of the key C(sp3)-SF5 bond formation step - among other mechanistic features of the methods we disclose - was investigated experimentally and with DFT calculations. Lastly, we demonstrate compatibility of SF5-CBs with various downstream functionalizations.

Keywords: cyclobutanes; hybrid isosteres; pentafluorosulfanylation; radical reactions; strain-release functionalization.

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Figures

Figure 1.
Figure 1.
Select structural comparisons. Crystal structures for 44, 45, trans-17, syn-1, and cis-17 determined by SC-XRD (displacement ellipsoids depicted at 50% probability level). The unit cell for 44 contains two symmetry-independent moieties (only one shown)
Figure 2.
Figure 2.
(Top) Computed free energy profile for SF5 radical addition to a model BCB (35) computed at the PWPB95-D4/def2-QZVPP//PCM(Et2O)-ωB97X-D/def2-SVP level of theory. (Bottom-Left) Intermolecular competitive isotope effect experiment probing the first product-determining step. (Bottom-Right) Solvent isotope effect experiment probing the second product-determining step.
Figure 3.
Figure 3.
Free energy profiles at the PWPB95-D4/def2-QZVPP//PCM(Et2O)-ωB97X-D/def2-SVP level of theory comparing SF5 radical addition across an analogously substituted BCB (35), housane (52), and alkene (47).
Figure 4.
Figure 4.
Fukui functions comparing site-susceptibilities to radical attack.
Figure 5.
Figure 5.
Free energy profiles showing comparison of SF5 radical addition at 1-position and 3-position of 56 at PWPB95-D4/def2-QZVPP//PCM(Et2O)-ωB97X-D/def2-TZVP level of theory.
Scheme 1.
Scheme 1.
(Top) Strain-release pentafluorosulfanylation of [1.1.1]propellane (previous work) and [1.1.0]bicyclobutane (this work) to access hybrid isosteres. (Bottom) Strain-release SF5-functionalization overrides a radical polarity mismatch that has hindered related transformations.
Scheme 2.
Scheme 2.
(Top) Reductive dechlorinations using pure syn and pure anti isomers of 1 result in epimerization. (Middle) Reduction of anti-3 with deuterium-labelled reagents suggests difference in mechanisms in aryl- vs. α-halide reduction. (Bottom) Highlighting selectivity for reduction of α-chloro-sulfones. Isolated yield is reported.
Scheme 3.
Scheme 3.
(Top) Extension of logic to tetrafluoro(aryl)sulfanylation. (Bottom) Extension of logic to tetrafluoro(trifluoromethyl)sulfanylation. 19F NMR yields are reported with isolated yields in parentheses.
Scheme 4.
Scheme 4.
(Top) Proof-of-concept for a three-component reaction (3CR), i.e., iodopentafluorosulfanylation. (Bottom) Extension of 3CR logic to achieve formal pentafluorosulfanylation-allylation. 19F NMR yields are reported.
Scheme 5.
Scheme 5.
(Top) Proposed radical chain initiation mechanism for pentafluorosulfanylation of [1.1.0]bicyclobutane substrates. (Bottom) Fluorine-labelled standard independently synthesized and used to confirm by-product formation in reaction mixture.
Scheme 6.
Scheme 6.
(Top) BCB reactivity vs. an analogously substituted alkene (Method A). (Bottom) BCB reactivity vs. an analogously substituted housane (Method A). 19F NMR yields are reported with isomeric ratios in parentheses.
Scheme 7.
Scheme 7.
Proof-of-concept (POC) transformations of (top) sulfone- and (bottom) carbonyl-containing SF5-CBs synthesized during this study. Isolated yields reported.
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