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. 2016 Mar 1;7(3):2229-2238.
doi: 10.1039/c5sc03905c. Epub 2015 Dec 3.

A diversity-oriented synthesis of bioactive benzanilides via a regioselective C(sp2)-H hydroxylation strategy

Yong-Hui Sun  1 , Tian-Yu Sun  2 , Yun-Dong Wu  2   3 , Xinhao Zhang  2 , Yu Rao  1
Affiliations

A diversity-oriented synthesis of bioactive benzanilides via a regioselective C(sp2)-H hydroxylation strategy

Yong-Hui Sun et al. Chem Sci. .

Abstract

A diversity-oriented synthesis of bioactive benzanilides via C(sp2)-H hydroxylation has been studied. Different regioselectivity was observed with Ru(ii) and Pd(ii) catalysts. The reaction demonstrates excellent regioselectivity, good tolerance of functional groups, and high yields. A wide range of ortho-hydroxylated-benzanilides can be readily synthesized with excellent regioselectivity via this new synthetic strategy. Computational investigations revealed that the regioselectivity was controlled mainly by both steric and electronic factors. Steric effects determine the regioselective outcomes in the Ru-catalyzed reaction, while electronic effects are dominant in the Pd-catalyzed reaction.

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Figures

Fig. 1
Fig. 1. Biologically important molecules containing hydroxylated benzanilides.
Scheme 1
Scheme 1. A diversity-oriented synthesis for accessing hydroxylated benzanilides via C(sp2)–H functionalization.
Fig. 2
Fig. 2. Substrate scope of Ru(ii) in C(sp2)–H hydroxylation (isolated yield).
Fig. 3
Fig. 3. Substrate scope of Pd(ii) in C(sp2)–H hydroxylation (isolated yield).
Scheme 2
Scheme 2. Deprotection of ortho-hydroxylated N-benzyl-benzanilides.
Scheme 3
Scheme 3. Gram-scale synthesis of ortho-hydroxylated N-methyl-benzanilides.
Scheme 4
Scheme 4. A useful compound analogue library prepared via diversity-oriented synthesis (with [Ru] as a catalyst).
Scheme 5
Scheme 5. A useful compound analogue library prepared via diversity-oriented synthesis (with [Pd] as a catalyst).
Scheme 6
Scheme 6. Kinetic isotope effect.
Scheme 7
Scheme 7. Two types of DGs of N-methyl-benzanilide.
Fig. 4
Fig. 4. The structures and free energies of activation of the Ru- and Pd-catalyzed C–H activations on Ar1 and Ar2 sides for N-methyl-benzanilide; electronic activation energies (in kcal mol–1) are in parentheses (L = N-methyl-benzanilides).
Fig. 5
Fig. 5. The structures and free energies of activation of Ru catalyzed C–H activation on Ar1 and Ar2 sides for N–H-benzanilide; electronic activation energies (in kcal mol–1) are in parentheses.
Scheme 8
Scheme 8. Ortho-hydroxylation of N–H-benzanilides.a
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