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. 2019 Feb 18;58(8):2454-2458.
doi: 10.1002/anie.201814524. Epub 2019 Jan 30.

Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents

Tie-Gen Chen  1 , Haolin Zhang  1 , Pavel K Mykhailiuk  1   2   3 , Rohan R Merchant  1 , Courtney A Smith  1 , Tian Qin  1 , Phil S Baran  1
Affiliations

Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents

Tie-Gen Chen et al. Angew Chem Int Ed Engl. .

Abstract

This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.

Keywords: decarboxylative radical coupling; nickel catalysis; quaternary centers; redox-active esters; tertiary acids.

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Figures

Figure 1.
Figure 1.
(A) Access to quaternary centers via cross coupling: Prior art. (B) Optimization on Ni-catalyzed cross coupling of tertiary RAEs with arylzinc reagents. a0.1 mmol. bYield determined by 1H NMR with CH2Br2 as an internal standard. cIsolated yield. See Supporting Information for details. DMI = 1,3-dimethyl-2-imidazolidinone, ND = not detected. dpm = 2,2,6,6-tetramethylheptane-3,5-dione, acac = acetylacetone, dibm = iPrCOCH2COiPr, hfac = hexafluoroacetylacetone, fdh = 1,1,1-trifluoro-5,5-dimethyl-2,4-hexanedione, btfa = 3-benzoyl-1,1,-trifluoroacetone, dbm = dibenzoylmethane Ts = tosyl, TCNHPI = N-hydroxytetrachlorophthalimide, NHPI = N-hydroxyphthalimide.
Scheme 1.
Scheme 1.
Scope of the Ni-catalyzed arylation of tertiary RAEs. Reaction conditions: Redox-active ester (1 equiv), Ni(dpm)2•xH2O (20 mol%), Ar2Zn (1.5 equiv), ZnBr2 (1 equiv) in THF/DMI (4:3) at rt for 12 h. [Isolated] refers to yields from the isolated redox-active ester, and [in situ] refers to yields from the carboxylic acid. a With Ni(dpm)2•xH2O (40 mol%) and Ar2Zn (2.5 equiv). b With Ni(dpm)2•xH2O (40 mol%) and Ar2Zn (2.5 equiv) at 60 °C. c With Ni(dpm)2•xH2O (40 mol%) and Ar2Zn (2.5 equiv) in THF/DMF at 60°C. d With Ni(dpm)2•xH2O (20 mol%) and Ar2Zn (2.5 equiv). e In situ from carboxylic acid (1.0 equiv.), TCNHPI (1.1 equiv.), DIC (1.1 equiv.) and DMAP (0.1 equiv.). Ts: tosyl; TBS: tert-butyldimethylsilyl; Boc: tert-butyloxycarbonyl; Phth: phthalimido; DIC: N/,N’-diisopropylcarbodiimide.
Scheme 2.
Scheme 2.
Radical retrosynthesis simplifies the synthesis of bioactive compounds from the patent literature.
Scheme 3.
Scheme 3.
Gram-scale synthesis of compound 4.
See this image and copyright information in PMC

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