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. 2016 Jul 1;7(7):4105-4109.
doi: 10.1039/c6sc00702c. Epub 2016 Mar 8.

Nickel-catalyzed enantioselective arylation of pyridine

J Patrick Lutz  1 , Stephen T Chau  1 , Abigail G Doyle  1
Affiliations

Nickel-catalyzed enantioselective arylation of pyridine

J Patrick Lutz et al. Chem Sci. .

Abstract

We report an enantioselective Ni-catalyzed cross coupling of arylzinc reagents with pyridiniumions formed in situ from pyridine and a chloroformate. This reaction provides enantioenriched 2-aryl-1,2-dihydropyridine products that can be elaborated to numerous piperidine derivatives with little or no loss in ee. This method is notable for its use of pyridine, a feedstock chemical, to build a versatile, chiral heterocycle in a single synthetic step.

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Figures

Scheme 1
Scheme 1. (A) Classes of 1,2-dihydropyridine and piperidinone accessible by asymmetric addition of a nucleophile to a pyridinium salt. (B) Asymmetric arylation of pyridine.
Scheme 2
Scheme 2. Proposed mechanism for the Ni-catalyzed arylation of 4-methoxypyridinium ions.
Scheme 3
Scheme 3. Derivatization of dihydropyridine 5a. Ar = 4-fluorophenyl. Reagents and conditions: (a) Et3SiH (1.05 equiv.), trifluoroacetic acid (20 equiv.), CH2Cl2, −10 °C, 45 s; (b) H2 (1 atm), Lindlar catalyst (3 mol%), MeOH, rt, overnight; (c) N-iodosuccinimide (3 equiv.), DMF, rt, 2 h; (d) Buchwald precatalyst (2 mol%), XPhos (4 mol%), K3PO4 (2 equiv.), 4-MeO-PhB(OH)2 (1.5 equiv.), THF, 80 °C, overnight; (e) OsO4 (4 mol%), N-methylmorpholine-N-oxide (1.2 equiv.), THF : H2O (2 : 1), rt, 3 h; (f) H2 (100 psi), Pd/C (5 mol%), MeOH, rt, overnight; (g) n-BuLi (1.2 equiv.), THF, −50 °C, 30 min, then MeI (3 equiv.), THF, −78 °C, 2 h; (h) nitrosobenzene (2 equiv.), CH2Cl2, rt, 2 h; (i) CuCl (20 mol%), MeOH, rt, overnight; (j) LiAlH4 (4 equiv.), THF, 50 °C, overnight, then HCl in Et2O.
Scheme 4
Scheme 4. Hydrogenation/deprotection of Cbz-protected dihydropyridine. aDetermined after Boc protection.
See this image and copyright information in PMC

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