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. 2023 Jul 8;14(1):4044.
doi: 10.1038/s41467-023-39707-8.

Ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/palladium catalysis

Hai-Ying Wang  1   2 , Xin-Han Wang  1   2 , Bang-An Zhou  1   2 , Chun-Lin Zhang  3 , Song Ye  4   5
Affiliations

Ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/palladium catalysis

Hai-Ying Wang et al. Nat Commun. .

Abstract

Direct synthesis of ketones from aldehydes features high atom- and step-economy. Yet, the coupling of aldehydes with unactivated alkyl C(sp3)-H remains challenging. Herein, we develop the synthesis of ketones from aldehydes via alkyl C(sp3)-H functionalization under photoredox cooperative NHC/Pd catalysis. The two-component reaction of iodomethylsilyl alkyl ether with aldehydes gave a variety of β-, γ- and δ-silyloxylketones via 1,n-HAT (n = 5, 6, 7) of silylmethyl radicals to generate secondary or tertiary alkyl radicals and following coupling with ketyl radicals from aldehydes under photoredox NHC catalysis. The three-component reaction with the addition of styrenes gave the corresponding ε-hydroxylketones via the generation of benzylic radicals by the addition of alkyl radicals to styrenes and following coupling with ketyl radicals. This work demonstrates the generation of ketyl radical and alkyl radical under the photoredox cooperative NHC/Pd catalysis, and provides two and three component reactions for the synthesis of ketones from aldehydes with alkyl C(sp3)-H functionalization. The synthetic potential of this protocol was also further illustrated by the late-stage functionalization of natural products.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Ketone synthesis.
a Classical ketone synthesis from alcohols and acyl electrophiles. b Ketone synthesis via TM-catalyzed coupling with aldehydes. c Ketone synthesis via NHC-catalyzed acylation of activated alkylation reagents. d This work: ketone synthesis via photoredox NHC/Pd-catalyzed acylation of alkyl C(sp3)-H. X = halide. TM = transition metal. NHC = N-heterocyclic carbene. NHPI = N-hydroxyphthalimide. hv = photoirradiation. RN = reaction.
Fig. 2
Fig. 2. Two-component reaction.
Conditions: 1 (0.3 mmol), 2 (1.5 equiv.), Pd(OAc)2 (10 mol%), PCy3 (20 mol%), N2 (20 mol%), Cs2CO3 (2.0 equiv.), 3.0 mL PhCF3, 36 W Blue LEDs, r.t., under N2, 16 h; awith 5-(trifluoromethyl)pyridin-2-ol (20 mol%); bwith 4-methylpyridin-2-ol (20 mol%); cdr = 1:1; dAfter treating with TBAF (2.0 equiv.), 2 h.
Fig. 3
Fig. 3. Three-component reaction.
Conditions: 1 (0.3 mmol), 5 (2.0 equiv.), 2 (1.5 equiv.), Pd(OAc)2 (10 mol%), PCy3 (20 mol%), N2 (20 mol%), Cs2CO3 (2.0 equiv.), 3.0 mL PhCF3, 36 W Blue LEDs, r.t., under N2, 16 h; then TBAF (2.0 equiv.); aWithout TBAF; bdr = 5:1.
Fig. 4
Fig. 4. Gram-scale synthesis and further chemical transformations.
a Si reagent (1.5 equiv.), imidazole (2.0 equiv.), THF, r.t. b Picolinaldehyde (1.5 equiv.), Pd(OAc)2 (10 mol%), PCy3 (20 mol%), N2 (20 mol%), Cs2CO3 (2.0 equiv.), PhCF3, 36 W Blue LEDs, r.t. c TBAF (2.0 equiv.), THF, r.t. d LiAlH4 (2.0 equiv.), Et2O, 0 °C. e TMSCN (3.0 equiv.), KF (3.0 equiv.), DMF, 80 °C. f (1) Si reagent (1.5 equiv.), imidazole (2.0 equiv.), THF, r.t.; (2) Styrene (2.0 equiv.), picolinaldehyde (1.5 equiv.), Pd(OAc)2 (10 mol%), PCy3 (20 mol%), N2 (20 mol%), Cs2CO3 (2.0 equiv.), PhCF3, 36 W Blue LEDs, r.t.; (3) TBAF (2.0 equiv.), THF, r.t. g Dess-Martin periodinane (2.0 equiv.), CH2Cl2, r.t.
Fig. 5
Fig. 5. Mechanistic experiments.
a Radical trapping experiment with diphenyl diselenide. b Crossover experiment with the addition of (iodomethyl)trimethylsilane. c Cation and anion trapping experiment with the addition of deuterium oxide or methanol. N.D. not detected.
Fig. 6
Fig. 6. Proposed mechanism.
The plausible mechanism for cooperative NHC/Pd-catalyzed functionalization of remote C(sp3)-H bond of alcohols.
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