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Oxidative Aliphatic C-H Fluorination with Fluoride Ion Catalyzed by a Manganese
| Content Provider | Semantic Scholar |
|---|---|
| Author | Porphryin |
| Copyright Year | 2012 |
| Abstract | Carolyn L. Ladd November 13, 2012 recently reported (24), suggesting that a similar reactive oxoor dioxo-manganese(V) intermediate (29) is responsible for the H abstraction step in both reactions. Likewise, sclareolide, a plant-derived terpenoid with antifungal and cytotoxic activities, afforded C2 and C3 methylene-fluorinated products in an overall 58% yield (Fig. 1B). C2-fluorination was favored by nearly 3:1, probably because of the steric hindrance of the gem-dimethyl groups at C4. The products could be separated chromatographically. C2 selectivity has been observed for this substrate by Baran and Eschenmoser for a Rh-catalyzed amination (30, 31) and by White and Chen in a Fe(pdp)/H2O2-mediated oxidation (32). In contrast, reaction of this molecule using Selectfluor (17) afforded an intractable mixture. F-substituted steroids, such as dexamethasone and fluasterone, have been found to be beneficial in blocking metabolic pathways (33–35), and F-fluorodihydrotestosterone has shown promise as a radiotracer for imaging prostate cancer in men (36). Because a direct, late-stage steroid fluorination protocol could greatly facilitate such applications, we sought to apply this manganesecatalyzed fluorination reaction to simple steroids. We examined the fluorination of 5a-androstan17-one, which contains 28 unactivated sp C-H bonds (Fig. 1C). Analysis of this molecule suggested that the carbonyl group would electronically deactivate ring D. Rings B and C are sterically hindered, leaving the methylene groups of the A ring as the most likely sites for H abstraction. Consistent with this analysis, and despite the complexity of the molecule, only the C2 and C3 positions in the A ring were fluorinated in an overall yield of 55% (78% of the product distribution at 70% conversion, withminor amounts of oxygenated products). The products of the reaction could be readily separated by column chromatography and structurally assigned by the diagnostic F–nuclear magnetic resonance (NMR) spectrum and the characteristic proton J-couplings (figs. S19 to S22). A 5:1 a/b diastereoselectivity was observed for both the C2 and C3 positions, probably reflecting the steric effect of the axial methyl group at C10. The reaction of bornyl acetate afforded a 55% yield of a single product, exo-5-fluoro-bornyl acetate (Fig. 1D). The characterization of this product was based on C-H correlation NMR and F-NMR spectroscopy (figs. S27 to S30) (37). We anticipated that the C5 position of camphor would also be accessible, in analogy to the selectivity of P450cam (CYP101) (38). However, treating camphor under the standard fluorination conditions resulted in 95% recovered starting material. We attribute the low reactivity in this case to the electron-withdrawing carbonyl group, which apparently deactivates the entire molecule toward fluorination, as with the monofluoride products. These results highlight the subtle electronic effects on both the reactivity and selectivity of the fluorination reaction. We suggest the catalytic cycle shown in Fig. 2A for this manganese porphyrin–catalyzed fluorination, although there are numerous aspects of these transformations that will require further elucidation. Oxidation of the resting Mn(TMP)F catalyst, formed in situ, would afford a reactive oxomanganese(V) species (29), O=Mn(TMP)F, which then abstracts a substrate H atom to produce a C-centered radical and a HO-Mn-F rebound intermediate. Fluoride binding to separately prepared Mn(O)(TMP) was indicated by anultraviolet (UV) spectral shift (423 to427nm) that we assign to the formation of [Mn(O)(F)(TMP)], in analogy to the well-characterized coordination of hydroxide to Mn(O) (39). The key step in forming the fluorinated products is capture of the incipient substrate radicals either by HO-Mn-F or a trans-difluoro-manganese(IV) species. There is no precedent for such a F atom transfer. In this important regard, the fluorination reaction differs from the manganese/ hypochlorite chlorinating system we have described (24). Chloride ion is rapidly and reversibly oxidized to hypochlorite by oxoMn porphyrins (40). Although HOF is known (15), there is no evidence that fluoride is oxidized in that way under these conditions. The importance of the hypochlorite in the Mn/OCl case is illustrated by the observation of C-H bromination in the presence of hypobromite, even with a large excess of chloride ion present. We attribute the unusual methylene selectivity observed in both the fluorination and chlorination reactions to stereoelectronically enforced steric clashes between the substrate and the approaching oxoMn catalyst Table 1. Manganese porphyrin–catalyzed fluorination of simple molecules. Reactions were run for 6 to 8 hours at 50°C under N2 in 3:1 CH3CN/CH2Cl2 solvent, 1.5 mmol substrate, 4.5 mmol silver fluoride, 6 to 8 mole % catalyst, 0.3 equivalent of t trabutylammonium fluoride (TBAF) trihydrate, and 6 to 8 equivalents of iodosylbenzene. Yields were determined by integration of gas chromatography traces using naphthalene as the internal standard. Typical conversions were 70%. Unless otherwise noted, all major fluorination products were isolated as single compounds. |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://charette.corg.umontreal.ca/literature/20121113-CL.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
