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. 2013 Aug 14;135(32):12122-34.
doi: 10.1021/ja406223k. Epub 2013 Jul 30.

Radical-based regioselective C-H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability

Fionn O'Hara  1 , Donna G Blackmond, Phil S Baran
Affiliations

Radical-based regioselective C-H functionalization of electron-deficient heteroarenes: scope, tunability, and predictability

Fionn O'Hara et al. J Am Chem Soc. .

Abstract

Radical addition processes can be ideally suited for the direct functionalization of heteroaromatic bases, yet these processes are only sparsely used due to the perception of poor or unreliable control of regiochemistry. A systematic investigation of factors affecting the regiochemistry of radical functionalization of heterocycles using alkylsulfinate salts revealed that certain types of substituents exert consistent and additive effects on the regioselectivity of substitution. This allowed us to establish guidelines for predicting regioselectivity on complex π-deficient heteroarenes, including pyridines, pyrimidines, pyridazines, and pyrazines. Since the relative contribution from opposing directing factors was dependent on solvent and pH, it was sometimes possible to tune the regiochemistry to a desired result by modifying reaction conditions. This methodology was applied to the direct, regioselective introduction of isopropyl groups into complex, biologically active molecules, such as diflufenican (44) and nevirapine (45).

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Figures

Figure 1
Figure 1
Regioselective radical functionalization of heteroarenes.
Figure 2
Figure 2
Factors influencing regioselectivity in reports of homolytic substitution reactions of heteroarenes (Refs. 10-18).
Figure 3
Figure 3
1H NMR analysis of the crude reaction mixture allowed ratios of regioisomeric products and starting material to be quantified (A) and tracked as the reaction progressed (B). The regioisomeric ratio remained constant throughout the reaction (C).
Figure 4
Figure 4
Factors controlling the regiochemistry of radical addition to pyridines. Reagent and conditions: pyridine (0.125 mmol), zinc sulfinate reagent (1 eq.), TBHP (1.5 eq.), 50 °C, 1.5-2 h. See Supporting Information for more details.
Figure 5
Figure 5
Three major factors controlling regiochemistry of homolytic aromatic substitution of pyridines. Green circles highlight positions activated to attack by nucleophilic radicals; blue circles highlight positions activated to attack by electrophilic radicals.
Figure 6
Figure 6
Regioselectivity modifying effect of solvent and radical electrophilicity. Green circles highlight positions activated to attack by nucleophilic radicals; blue circles highlight positions activated to attack by electrophilic radicals. The size of the circle represents relative degree of activation within the same molecule.
Figure 7
Figure 7
Regioselectivity-modifying effects of functional groups. Green circles highlight sites activated to nucleophilic attack, red circles represent a site with a functional group induced deactivating effect. The size of the circle represents relative degree of activation/deactivation within the same molecule.
Figure 8
Figure 8
Flowchart for the prediction of regioselectivity of alkylsulfinate-derived radical functionalization of pyridines. Color code: green circles, sites activated to nucleophilic attack; red circles, sites subject to a functional group induced deactivating influence; yellow circles, otherwise activated sites that have reduced or negligible activity due to substituent-induced deactivation. The size of the circle represents relative degree of activation within the same molecule. Further examples of regioselectivity prediction are in the Supporting Information.
Figure 9
Figure 9
Substrates tested to assess combined directing effects on complex pyridines. (For key to highlighting circles see Figures 6 and 7.) Reagents and conditions: pyridine (0.125 mmol), zinc sulfinate reagent (TFMS or IPS) (2 eq.), TBHP (3 eq.), 50 °C, 12–16 h. See Supporting Information for more details.
Figure 10
Figure 10
Tuning regioselectivity with solvent choice. (For key to highlighting circles see Figures 6 and 7.) Reagents and conditions: standard conditions as previously described. Forcing conditions for compound 30. See Supporting Information for details.
Figure 11
Figure 11
Extension of regioselectivity study to diazines: the same general principles apply, although the innate preference of the parent heterocycle is harder to overcome. (For key to highlighting circles, see Figures 6 and 7.) Reagents and conditions: heterocycle (0.125 mmol), IPS (2 eq.), TBHP (3 eq.), DMSO, 50 °C, 12–16 h. See Supporting Information for more details.
Figure 12
Figure 12
Regioselectivity remains predictable on complex substrates. (For key to highlighting circles see Figures 6-8.) Reagents and conditions: standard conditions as previously described. All examples gave >9:1 selectivity for the regioisomer shown. aD-MSO solvent. bCHCl3/H2O solvent mixture.
Figure 13
Figure 13
Extension of regioselectivity prediction to “borono-Minisci” direct arylation. Reagents and conditions: heterocycle (0.125 mmol), p-tolylboronic acid (1.5 eq.), AgNO3 (20 mol%), K2S2O8 (3 eq.), 50 °C, 3–16 h.
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References

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