Direct dehydrogenative alkyl Heck-couplings of vinylarenes with umpolung aldehydes catalyzed by nickel

Abstract

Alkenes are fundamental functionalities in nature and highly useful intermediates in organic synthesis, medicinal chemistry and material sciences. Transition-metal-catalyzed Heck couplings with organic halides as electrophiles have been established as a powerful protocol for the synthesis of this valuable building block. However, the requirement of organic halides and the generation of stoichiometric hazardous halide wastes may cause significant sustainable concerns. The halide-free oxidative Heck alkenylations involving organometallics or arenes as the coupling partners provide a facile and alternative pathway. Nonetheless, stoichiometric amounts of extra oxidant are essential in most cases. Herein, we present a direct dehydrogenative alkyl Heck-coupling reaction under oxidant-free conditions, liberating hydrogen, nitrogen and water as the side products. Excellent regioselectivity is achieved via neighboring oxygen atom coordination. Broad substrate scope, great functional group (ketone, ester, phenol, free amine, amide etc) tolerance and modification of pharmaceutical candidates and biological molecules exemplified its generality and practicability.

Fig. 1

Strategies in the Heck coupling reaction. a Traditional Mizoroki-Heck coupling with hazardous organic halide; b Oxidative Heck coupling with pre-synthesized organometallic reagent; c Stoichiometric oxidant mediated Heck coupling via C–H bond activation; d Oxidant-free direct dehydrogenative alkyl Heck-coupling

Fig. 2

Scope of substrates. Reaction conditions: 3 (0.2 mmol), 1 (0.6 mmol), N₂H₄•H₂O (0.72 mmol), Ni(cod)₂ (10 mol%), dcype (10 mol%), DIPEA (0.4 mmol), NaI (0.1 mmol), THF (1.0 mL), 100 °C, 12 h under N₂. Reported yields are the isolated ones (the ratio of allylic isomerization was in parentheses), the E:Z ratio was more than 20:1 unless otherwise noted. ^aThe Z:E ratio in parenthesis

Fig. 3

Functionalization of naturally and pharmaceutically important derivatives. a Regioselective Heck coupling of L-Menthol derivative; b Regioselective Heck coupling of Theobromine derivative; c Regioselective Heck coupling of Theophylline derivative; d Regioselective Heck coupling of vinyl Estrone derivative; e Regioselective Heck coupling of Estrone derivative; f Regioselective Heck coupling of Tyrosine derivative; g Regioselective Heck coupling of α-Tocopherol derivative; h Regioselective Heck coupling of Cholesterol derivative

Fig. 4

Mechanistic studies. a Reaction of styrene with phenyldiazomethane did not give the desired product; b Reaction of 1,2-diphenylcyclopropane under the standard conditions did not give the desired product; c Reaction of 1-methoxy-4-(3-phenylpropyl)benzene under the standard conditions did not give the desired product; d Radical scavenger, 2,6-di-tert-butyl-4-methylphenol (BHT) added and the reaction was almost unaffected; e N-Ts hydrazone used instead of simple hydrazone did not give the desired product; f H/D exchanges occurred in the isotope experiment

Fig. 5

Reaction mechanism. Proposed pathway for the oxidant-free Heck-type reaction