Mechanism and selectivity in nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides

Abstract

The direct cross-coupling of two different electrophiles, such as an aryl halide with an alkyl halide, offers many advantages over conventional cross-coupling methods that require a carbon nucleophile. Despite its promise as a versatile synthetic strategy, a limited understanding of the mechanism and origin of cross selectivity has hindered progress in reaction development and design. Herein, we shed light on the mechanism for the nickel-catalyzed cross-electrophile coupling of aryl halides with alkyl halides and demonstrate that the selectivity arises from an unusual catalytic cycle that combines both polar and radical steps to form the new C-C bond.

Figure 1

Comparison of the selectivity models of conventional cross-coupling and the studied cross-electrophile cou- pling. L = 1:1 4,4′-di-tert-butyl-2,2′-bipyridine:1,2- bis(diphenylphosphino)benzene, 4,4′-di-MeO-2,2′- bipyridine, or 1,10-phenanthroline.

Figure 2

Potential mechanisms for cross-electrophile coupling: (A) in situ formation of an organometallic reagent (R¹MnI) followed by cross-coupling; (B) transmetalation between two organonickel species; (C) sequential oxidative additions at a single nickel center; (D) radical chain reaction. R¹ and R² could be either alkyl or aryl.

Figure 3

Change of the molar ratio of 3aa/5a (red circles) and 3aa/4a (blue diamonds) with catalyst concentration, suggesting product and dimers arise from different mechanisms. Exponential fits: solid blue line: f(x) = 121.05x^−0.824, R² = 0.94; dashed red line: f(x) = 723.81x^−1.063, R² = 0.92.

Figure 4

Ratio of U (3ad, includes olefin isomers) to R(3ad′) formed in reactions at different catalyst concentrations, showing that the degree of rearrangement, a measure of the radical lifetime, depends upon nickel concentration. The data shown are for 50-100% conversion to avoid fluctuations in active catalyst concentration at the beginning of the reaction. Error bars are SD of the data used for the plot. Linear fit: f(x) = 0.417x + 1.83; R² = 0.984. The same experiment run with unactivated Mn gave the same conclusion, but the reactions had longer induction periods (Figure S2).

Scheme 1. Formation of Biaryl From the Reaction of Arylnickel with Alkylnickel^a

^a Ratio of organic products determined by GC analysis. See Supporting Information for full details. The corresponding reaction with (L)Ni(Et)I could not be run because this intermediate could only be generated at low concentration with an excess of Et-I, vide infra.

Scheme 2. Apparent Reversibility of Oxidative Addition

Scheme 3. Radical Clock Experiments^a

^a ND = none detected. Catalytic reaction as in Table 1, entry 1.

Scheme 4. Proposed Mechanism for Cross-Electrophile Coupling of Aryl Halides with AlkylHal-ides

Scheme 5. Hypothesis for Self Initiation