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. 2020 Sep 2;142(35):15027-15037.
doi: 10.1021/jacs.0c06139. Epub 2020 Aug 24.

Development of an Aryl Amination Catalyst with Broad Scope Guided by Consideration of Catalyst Stability

Scott D McCann  1 , Elaine C Reichert  1 , Pedro Luis Arrechea  1 , Stephen L Buchwald  1
Affiliations

Development of an Aryl Amination Catalyst with Broad Scope Guided by Consideration of Catalyst Stability

Scott D McCann et al. J Am Chem Soc. .

Abstract

We have developed a new dialkylbiaryl monophosphine ligand, GPhos, that supports a palladium catalyst capable of promoting carbon-nitrogen cross-coupling reactions between a variety of primary amines and aryl halides; in many cases, these reactions can be carried out at room temperature. The reaction development was guided by the idea that the productivity of catalysts employing BrettPhos-like ligands is limited by their lack of stability at room temperature. Specifically, it was hypothesized that primary amine and N-heteroaromatic substrates can displace the phosphine ligand, leading to the formation of catalytically dormant palladium complexes that reactivate only upon heating. This notion was supported by the synthesis and kinetic study of a putative off-cycle Pd complex. Consideration of this off-cycle species, together with the identification of substrate classes that are not effectively coupled at room temperature using previous catalysts, led to the design of a new dialkylbiaryl monophosphine ligand. An Ot-Bu substituent was added ortho to the dialkylphosphino group of the ligand framework to improve the stability of the most active catalyst conformer. To offset the increased size of this substituent, we also removed the para i-Pr group of the non-phosphorus-containing ring, which allowed the catalyst to accommodate binding of even very large α-tertiary primary amine nucleophiles. In comparison to previous catalysts, the GPhos-supported catalyst exhibits better reactivity both under ambient conditions and at elevated temperatures. Its use allows for the coupling of a range of amine nucleophiles, including (1) unhindered, (2) five-membered-ring N-heterocycle-containing, and (3) α-tertiary primary amines, each of which previously required a different catalyst to achieve optimal results.

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Conflict of interest statement

The authors declare the following competing financial interest(s): MIT has patents on ligands that are described in this manuscript, from which S.L.B and former coworkers receive royalty payments.

Figures

Figure 1.
Figure 1.
(A) Comparison of reaction time courses as measured by reaction calorimetry for the reaction shown with catalysts OA1–OA6 (Ar = 4-(2-(trimethylsilyl)ethyl benzoate)). (B) 31P NMR spectrum of the reaction employing OA1 as the precatalyst after 1 h. Reaction conditions: 1.0 mmol 2-bromo-1,4-dimethylbenzene, 1.4 mmol n-propylamine, 1.4 mmol NaOt-Bu, 0.1 mmol n-dodecane (internal standard), 2.5 or 5.0 μmol OAn in THF (1.0 M [2-bromo-1,4-dimethylbenzene]) maintained at 26.0 °C in OmniCal calorimeter. Note: OA1 refers to precatalyst with L1, OA2 to that with L2, etc. Reaction GC conversions for each catalyst: OA1 = 9%, OA2 = 9%, OA3 = 60%, OA4 = 65%, OA5 = 90%, OA6 = 96%.
Figure 2.
Figure 2.
(A) C,O-isomerism observed in some dialkylbiaryl monophosphine-based OACs. A bulkier R group decreases the relative population of the O-bound isomer. (B) Amine binding mode previously proposed for XPhos-supported OAC. (C) Comparison of the performance of precatalysts (OA5, OA6; Ar = 4-(2-(trimethylsilyl)ethyl benzoate)) for the coupling of α-branched primary amines. Reaction conditions: 0.4 mmol 2-bromo-1,4-dimethylbenzene or 1-(tert-butoxy)-4-chlorobenzene, 0.56 mmol cyclohexylamine or tert-octylamine, 0.56 mmol NaOt-Bu, 0.04 mmol n-dodecane (internal standard), 0.4 or 2.0 μmol OAn in 0.2 mL THF at RT.
Figure 3.
Figure 3.
Common dialkylbiaryl monophosphine ligands used to support Pd catalysts for the arylation of different types of primary amine nucleophiles. Key ligand features are highlighted.
Figure 4.
Figure 4.
Assessment of unheated and heated OA1’-catalyzed aryl amination. Reaction conditions: 0.5 mmol 2-bromo-1,4-dimethylbenzene, 0.7 mmol n-hexylamine, 0.7 mmol NaOt-Bu, 0.05 mmol n-dodecane (internal standard), 2.5 μmol OA1’, 2.5 μmol L1 in 0.5 mL 1,4-dioxane at RT (1 h time point) followed by RT (gray box) or 90 °C (red box). Calibrated GC yields. See Supporting Information for full details.
Figure 5.
Figure 5.
Reaction time course using A as a precatalyst. Reaction conditions: 0.5 mmol 2-bromo-1,4-dimethylbenzene, 0.7 mmol n-hexylamine, 0.7 mmol NaOt-Bu, 0.05 mmol n-dodecane (internal standard), 2.5 μmol A, 5.0 μmol L1 or L6 in 0.5 mL 1,4-dioxane at 90 °C. Calibrated GC yields. See Supporting Information for full details. Dashed lines are intended to guide the eye and do not reflect a kinetic fit.
Figure 6.
Figure 6.. Substrate scope of the room temperature aryl amination protocol.a,b
aIsolated yields are reported as the average of two runs. Standard reaction conditions: aryl halide (1.0 mmol), amine (1.4 mmol), NaOt-Bu (1.4 mmol), [x mol%] OA6, THF (0.5 mL), RT, 1 h. bPrevious conditions refer to previously published conditions for the same or similar coupling reactions. Pd = Pd loading, L = total ligand loading. c1.4 equiv NaOMe, 45 min reaction time. d24 h. e1.4 equiv NaOPh.
Figure 7.
Figure 7.. Scope of the room temperature aryl amination of drug-like substrates.a
aIsolated yields are reported as the average of two runs. Standard reaction conditions: aryl halide (1.0 mmol), amine (1.4 mmol), NaOt-Bu (1.4 mmol), [x mol%] OA6, THF (0.5 mL), RT, 1 h. b1.2 mmol aryl halide, 1.0 mmol amine. cReaction conditions: aryl halide (0.5 mmol), amine (0.7 mmol), NaOt-Bu (0.7 mmol), 0.75 mol% OA6, THF (0.25 mL), RT, 1 h.
Figure 8.
Figure 8.. Scope of the aryl amination with heatinga,b
aIsolated yields are reported as the average of two runs. Standard reaction conditions: aryl halide (1.0 mmol), amine (1.4 mmol), NaOt-Bu (1.4 mmol), [x mol%] OA6, THF (0.5 mL), 90 °C, 1 h. bPrevious conditions refer to previously published conditions for the same or similar coupling reactions. Pd = Pd loading, L = total ligand loading. cRT results from Figure 6. d1.4 equiv NaOPh. e2.4 mmol NaOt-Bu, 2.5 mL THF. f75 °C. gReaction conditions: aryl halide (1.0 mmol), amine (1.2 mmol), NaOPh (1.2 mmol), [x mol%] OA6, 2-MeTHF (4 mL), 100 °C, 3 h.
Figure 9.
Figure 9.. A comparison of reactions employing OA6 and other, commonly employed, Pd sources.a
aYields determined by 1H NMR. Standard reaction conditions: aryl halide (1.0 mmol), amine (1.4 mmol), NaOt-Bu (1.4 mmol), [x mol%] Pd, [x mol%] L6 (Pd:L6 = 1:1), THF (0.5 mL), RT or 90 °C, 1 h. bResults from Figure 6 (3a, 3j) and Figure 8 (3bb). cReaction conditions: aryl halide (0.4 mmol), amine (0.56 mmol), NaOt-Bu (0.56 mmol), [x mol%] Pd(OAc)2, [2x mol%] L6 (Pd:L6 = 1:2), THF (0.2 mL), RT or 90 °C, 1 h. dPd:L6 = 1:2. Using water preactivation protocol.
Scheme 1.
Scheme 1.
Mechanistic Hypothesis and Previous Studies of Elementary Steps.
See this image and copyright information in PMC

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