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. 2024 Jan 8;15(7):2593-2600.
doi: 10.1039/d3sc05797f. eCollection 2024 Feb 14.

Enantioselective nickel-catalyzed Mizoroki-Heck cyclizations of amide electrophiles

Ana S Bulger  1 , Daniel J Nasrallah  1 , Arismel Tena Meza  1 , Neil K Garg  1
Affiliations

Enantioselective nickel-catalyzed Mizoroki-Heck cyclizations of amide electrophiles

Ana S Bulger et al. Chem Sci. .

Abstract

Amide cross-couplings that rely on C-N bond activation by transition metal catalysts have emerged as valuable synthetic tools. Despite numerous discoveries in this field, no catalytic asymmetric variants have been disclosed to date. Herein, we demonstrate the first such transformation, which is the Mizoroki-Heck cyclization of amide substrates using asymmetric nickel catalysis. This proof-of-concept study provides an entryway to complex enantioenriched polycyclic scaffolds and advances the field of amide C-N bond activation chemistry.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) Asymmetric metal-catalyzed reactions of acyl electrophiles and current limitations. (B) Current state-of-the-art of amide cross-coupling reactions.
Fig. 2
Fig. 2. Overview of the reaction design and proposed mechanism.
Fig. 3
Fig. 3. Survey of chiral NHC salts with in situ free-basing. aConditions: Ni(cod)2 (15 mol%), NHC Salt (30 mol%), NaOt-Bu (33 mol%), PhMe (0.5 M), 100 °C; 24 h in a sealed vial. bConditions: Ni(cod)2 (15 mol%), NHC Salt (30 mol%), NaOt-Bu (33 mol%), t-amyl alcohol (3.0 equiv.), PhMe (0.5 M), 60 °C; 24 h in a sealed vial. a,bYields determined by 1H NMR using hexamethylbenzene as an external standard. ND is defined as not determined.
Fig. 4
Fig. 4. Results using select chiral NHC ligand salts with amide 6. aYields determined by 1H NMR using hexamethylbenzene as an external standard.
Fig. 5
Fig. 5. Generation of free carbene 10.
Fig. 6
Fig. 6. Survey of alcohol and amine additives in the transformation. aConversions and yields determined by 1H NMR using hexamethylbenzene as an external standard. bMorpholine (1.0 equiv.).
Fig. 7
Fig. 7. Examples of methodology. Yields shown reflect the average of two isolation experiments.
Fig. 8
Fig. 8. Elaboration of (+)-9 to enantioenriched compounds. (i) N-Brosyl hydrazine (5.0 equiv.), acetyl chloride (10 equiv.), EtOH (0.07 M), 0 → 60 °C; 72 h, 47% yield. (ii) (a) Fe(acac)3 (40 mol%), PhSH (40 mol%), PhSiH3 (4.0 equiv.), EtOH (0.1 M), 23 °C, 25 h. (b) TBAF (25 equiv.), 16 h, 87% yield over two steps (c) urea hydrogen peroxide (43 equiv.), TFA (19 equiv.), BF3·OEt3 (73 equiv.), CH2Cl2 (0.1 M), 0 → 23 °C, 16 h, 60% yield, 1.8 : 1 rr. (iii) LiAlH4 (1.5 equiv.), Et2O (0.03 M), 0 → 23 °C, 0.5 h, quant. yield. (iv) PPh3 (1.5 equiv.), DBAD (1.5 equiv.), CH2Cl2 (0.07 M), 10 °C, 3 h, quant. yield. (v) PPh3MeBr (2.4 equiv.), n-BuLi (1.7 equiv.), THF (0.2 M), 23 °C, 2 h, 97% yield. (vi) 2-(Methoxy)benzohydroximinoyl chloride (2.0 equiv.), NEt3 (2.0 equiv.), MeCN (0.1 M), 23 °C, 25 h, 79% yield, 5.3 : 1 dr. (vii) BF3·OEt2 (3.0 equiv.), allylMgCl (15 equiv.), toluene (0.05 M), −78 °C, 2 h, 63% yield, 1.6 : 1 dr. (viii) m-CPBA (1.5 equiv.), NaHCO3 (3.0 equiv.), CH2Cl2 (0.07 M), 0 °C, 2 h, 83% yield, 2.2 : 1 dr.
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