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. 2016 Jun 10;352(6291):1304-8.
doi: 10.1126/science.aaf6635. Epub 2016 Apr 28.

Native functionality in triple catalytic cross-coupling: sp³ C-H bonds as latent nucleophiles

Megan H Shaw  1 , Valerie W Shurtleff  1 , Jack A Terrett  1 , James D Cuthbertson  1 , David W C MacMillan  2
Affiliations

Native functionality in triple catalytic cross-coupling: sp³ C-H bonds as latent nucleophiles

Megan H Shaw et al. Science. .

Abstract

The use of sp(3) C-H bonds--which are ubiquitous in organic molecules--as latent nucleophile equivalents for transition metal-catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp(3) C-H bonds in both cyclic and acyclic systems.

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Figures

Fig. 1
Fig. 1. Photoredox-mediated hydrogen atom transfer and nickel catalysis enables highly selective cross-coupling with sp3 C–H bonds as latent nucleophiles
Fig. 2
Fig. 2. Photoredox, HAT, and nickel-catalyzed cross-coupling: proposed mechanistic pathway and catalyst combination
Ac, acetyl; t-Bu, tert-butyl; Boc, tert-butoxycarbonyl; DMSO, dimethyl sulfoxide; LED, light-emitting diode; SET, single-electron transfer; HAT, hydrogen atom transfer.
Fig. 3
Fig. 3. Photoredox, HAT, and nickel-catalyzed cross-coupling: aryl halide and C–H nucleophile scope
All yields are isolated yields. Reaction conditions as in Fig. 2; see supplementary materials for experimental details. Ac, acetyl; t-Bu, tert-butyl; Boc, tert-butoxycarbonyl; Piv, pivalate; Cbz, benzyloxycarbonyl; Bac, tert-butylaminocarbonyl. *Reaction performed with 4-bromobenzotrifluoride to deliver N-Bac 2-(4-trifluoromethylphenyl)-pyrrolidine.†Minor regioisomer is arylated on Me position.‡Minor regioisomer is arylated on α-amino methylene position. §Yield determined by 1H–nuclear magnetic resonance.
Fig. 4
Fig. 4. Regioselective arylation: Using C–H arylation and decarboxylative arylation delivers differentially arylated pyrrolidine products
All yields are isolated yields. See supplementary materials for experimental details.
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References

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