Air-Stable Secondary Phosphine Oxides for Nickel-Catalyzed Cross-Couplings of Aryl Ethers by C–O Activation

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

Air- and moisture-stable secondary phosphine oxides (SPOs) enabled nickel-catalyzed Kumada–Corriu cross-couplings of various arylmethyl ethers at room temperature by challenging C–O activation.

Key words

C–O activation - arylation - cross-coupling - secondary phosphine oxide - nickel

Transition-metal-catalyzed cross-coupling reactions have emerged as a uniquely powerful tool for the assembly of substituted biaryl motifs.[1] Thus far, these cross-couplings have heavily relied on aryl halides as electrophilic coupling reagents. In contrast, easily accessible phenol-based electrophiles have recently undergone a renaissance as attractive alternatives.[2] On the basis of Wenkert’s early studies from 1979,[3] the considerable potential of phenol-derived substrates has only recently been fully recognized. Thus, versatile cross-couplings have been realized with challenging carbamates, carbonates, sulfamates, silyloxyarenes, esters and ethers, among others, prominently featuring nickel catalysis.[4] Generally, these nickel catalysts largely require electron-rich tertiary phosphines as stabilizing ligands to guarantee efficacy in the key C–O bond scission.[4] Unfortunately, these electron-rich tertiary phosphines are usually highly air-sensitive, with a documented half-life for the aerobic oxidation of tri-t-butyl-phosphine of a few minutes.[5]

The (heteroatom-substituted) secondary phosphine oxides (HA)SPOs represent uniquely powerful ancillary preligands for metal catalysis because of their unique features, including the air- and moisture-stable nature, among others.[6] Notably, air-stable SPOs undergo a self-assembly process in the presence of transition metals to generate a monoanionic bidentate chelate coordination environment (Scheme [1, a]).[6] While Ackermann and others have unraveled the considerable potential of SPO complexes towards a wealth of efficient cross-coupling reactions with various aryl halides,[7] the possibility of employing air-stable SPO preligands for more challenging C–O activations with aryl ethers has thus far proven elusive. Within our program on sustainable transition-metal-catalyzed transformations[8] and selective C–O activation,[9] we hence became attracted to probing the unprecedented use of air-stable SPOs preligands for cross-couplings with easily available aryl ethers, the result of which we report herein. Notable features of our findings include (i) air- and moisture-stable SPOs for efficient C–O activations, (ii) earth-abundant nickel catalysis, and (iii) exceedingly mild reaction conditions at room temperature (Scheme [1, b]).

Scheme 1 (a) Self-assembly with SPOs, (b) nickel/SPO-catalyzed C–O activation

We initiated our studies by probing reaction conditions for the envisioned cross-coupling of ether 1a with Ni(acac)₂ and Ph₂P(O)H (L1) in toluene at a room temperature of 23 °C (Table [1], entry 1). Among a variety of preligands and solvents, the electron-rich HASPO L7 as well as (n-Bu)₂P(O)H (L8) and THF gave optimal results, respectively (entries 2–13). NiCl₂(DME) proved to be most effective (entries 14–17). It is noteworthy that under otherwise identical reaction conditions, the bidentate ligand dppp featured a significantly inferior performance (entry 18). A control experiment verified the essential role of the nickel catalyst (entry 19).

Table 1 Optimization of the Nickel/SPO-Catalyzed C–O Activation of Ether 1a ^a

Entry	Ni Catalyst	SPO	Solvent	Yield (%)
1	Ni(acac)2	L1	toluene	10
2	Ni(acac)2	L2	toluene	12
3	Ni(acac)2	L3	toluene	25
4	Ni(acac)2	L4	toluene	35
5	Ni(acac)2	L5	toluene	23
6	Ni(acac)2	L6	toluene	50
7	Ni(acac)2	L6	THF	64
8	Ni(acac)2	L1	THF	15
9	Ni(acac)2	L5	THF	21
10	Ni(acac)2	L3	THF	60
11	Ni(acac)2	L4	THF	48
12	Ni(acac)2	L7	THF	69
13	Ni(acac)2	L8	THF	83
14	Ni(OTf)2	L8	THF	53
15	NiBr2	L8	THF	n.r.
16	NiCl2(DME)	L8	THF	90
17	NiCl2(DME)	L8	THF	68b
18	NiCl2(DME)	dppp	THF	39c
19	–	L8	THF	n.r.

^a Reaction conditions: 1a (0.50 mmol), p-TolMgBr (0.75 mmol), [Ni] (5.0 mol%), (HA)SPO (10 mol%), solvent (1.5 mL), 23 °C, 16 h; yield of isolated product given; n.r. = no reaction.

^b SPO L8 (5.0 mol%).

^c dppp (5.0 mol%).

Having the optimized reaction conditions for the nickel/SPO-catalyzed C–O activation in hand, we tested its versatility with a representative set of ethers 1 (Scheme [2]). Thus, a variety of naphthyl ethers 1 were identified as viable substrates for the Kumada–Corriu cross-coupling to deliver the desired products 2 with high catalytic efficacy. Notably, the nickel catalyst derived from the air-stable SPO L8 even proved amenable to the chemoselective synthesis of biaryl 2b and the sterically congested mesityl nucleophiles with comparable levels of activity (2d and 2i).

Scheme 2 Scope of SPO/nickel-catalyzed C–O activation; ^a with NiCl₂(DME) (10 mol%) and L8 (20 mol%)

Based on our previous literature reports,[6c] [d] [10] the working mode of the air-stable SPO-enabled C–O activation is suggested to initially involve the formation of complex 3 through self-assembly, along with the subsequent C–O activation by the key hetero-bimetallic intermediate 4 (Scheme [3]).

Scheme 3 Plausible working mode of SPOs for C–O activation

In summary, we have reported on the first use of air-stable secondary phosphine oxides (SPOs) for challenging cross-couplings of aryl ethers by C–O activation.[11] Thus, in situ generated nickel catalysts enabled efficient Kumada–Corriu arylations of naphthyl ethers at room temperature, even when using sterically hindered aryl nucleophiles.

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• 11 Representative Experimental Procedure and Characterization DataA mixture of 2-methoxynaphthalene (1a) (79 mg, 0.5 mmol), [NiCl₂(DME)] (6.0 mg, 0.025 mmol, 5.0 mol%), and L8 (8.0 mg, 0.05 mmol, 10.0 mol%) was stirred in THF (1.5 mL) for 2 min at ambient temperature under N₂. Then, p-TolMgBr (1.0 m in THF, 0.75 mL, 0.75 mmol) was added, and the resulting solution was stirred for 16 h at ambient temperature. To the reaction was added aqueous HCl (1 m, 5 mL) and then EtOAc (5 mL), and the separated aqueous phase was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried with anhydrous Na₂SO₄ and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane) to yield 2a (98 mg, 90%) as a colorless solid. Mp 93–95 °C. IR (ATR): 3054, 3024, 1501, 1351, 893, 856, 811, 748 cm⁻¹. ¹H NMR (300 MHz, CDCl₃): δ = 8.14 (d, J = 1.4 Hz, 1 H), 8.03–7.93 (m, 3 H), 7.85 (dd, J = 8.5, 1.9 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 2 H), 7.64–7.54 (m, 2 H), 7.40 (dd, J = 8.5, 0.6 Hz, 2 H), 2.53 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 138.5 (C_q), 138.3 (C_q), 137.2 (C_q), 133.8 (C_q), 132.5 (C_q), 129.6 (CH), 128.4 (CH), 128.2 (CH), 127.7 (CH), 127.3 (CH), 126.3 (CH), 125.8 (CH), 125.6 (CH), 125.5 (CH), 21.2 (CH₃). MS (EI): m/z (relative intensity) = 218 [M]⁺ (100), 217 (41), 202 (35). HRMS (EI): m/z [M]⁺ calcd for [C₁₇H₁₄]⁺: 218.1096; found: 218.1094.