Palladium-catalyzed benzylic C(sp3)–H carbonylative arylation of azaarylmethyl amines with aryl bromides

A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp3)–H bonds of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence of a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines to undergo efficient reactions with aryl bromides and CO to provide α-amino aryl-azaarylmethyl ketones in moderate to high yields with a broad substrate scope and good tolerance of functional groups. This reaction proceeds via in situ reversible deprotonation of the benzylic C–H bonds to give the active carbanions, thereby avoiding prefunctionalized organometallic reagents and generation of additional waste. Importantly, the operational simplicity, scalability and diversity of the products highlight the potential applicability of this protocol.


Optimization of the reaction conditions a) HTE (High Throughput Experimentation) micro-scale (0.01 mmol) screen
. Base and solvent screening.

General Procedure for DCCC of Azaarylmethyl Amines
(a) General procedure under 1 atm CO.
An oven-dried 8 mL vial equipped with a stir bar was charged with Pd(dba)2 (5 mol %) and NIXANTPHOS (6 mol %) under a nitrogen atmosphere in glove box. Next, 0.1M of 1,4dioxane was taken up by syringe and added to the vail. The resulting solution stirred for 15 min at room temperature, during which time the mixture became red. This solution was used as the stock solution for this procedure. To an oven-dried 10 mL Schlenk tube with stir bar was added LiN(SiMe3)2 (100.5 mg, 0.6 mmol, 3 equiv). A pipette was used to take 2 mL of the Pd/NIXANTPHOS stock solution and add it to the Schlenk tube. The resulting (dark green) solution was then stirred for 10 min at room temperature. Azaarylmethyl amine 1 (0.2 mmol, 1 equiv) and aryl bromide 2 (0.3 mmol, 1.5 equiv) were added to the reaction mixture, sequentially. The Schlenk tube was capped with rubber stopper and removed from the glove box. The reaction mixture was then degassed with CO by using Schlenk line, and connected with a CO balloon, placed in an 80 °C oil bath and stirred for 16 h. After this time, the flask was rem and stirred for 16 h at 80 °C. After this time, the tube was removed from the oil bath, allowed to cool to room temperature, uncapped carefully in a fumehood and the reaction quenched with two drops of H2O. After quench the color of the reaction mixture changed from brown to red. It was next diluted with 3.0 mL of ethyl acetate and filtered over a pad of MgSO4 and Celite. The pad was rinsed with additional ethyl acetate (5.0 mL) and the resulting solution evaporated under vacuum to remove the volatile materials. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexanes to give the pureified product.
(b) General procedure at high CO pressure.
An oven-dried 8 mL vial equipped with a stir bar was sequentially added Pd(dba)2 (5.8 mg, 0.01 mmol, 5 mol %) and NIXANTPHOS (6.6 mg, 0.012 mmol, 6 mol %) under a nitrogen atmosphere inside a glove box. Next, 2 mL of 1,4-dioxane was taken up by syringe and added to the flask at room temperature. The reaction mixture was stirred for 15 min at room temperature, until the mixture became red. Then LiN(SiMe3)2 (100.5 mg, 0.6 mmol, 3 equiv) was added and the reaction mixture was stirred for 10 min at room temperature. Azaarylmethyl amine 1 (0.2 mmol, 1 equiv) and aryl bromide 2 (0.3 mmol, 1.5 equiv) were added to the reaction mixture, sequentially. The solution was then transferred to a 30 mL Parr Instruments 5000 Multiple Reactor system vessel. The reactor was then sealed, removed from the glovebox. The reaction vessel was then pressurized with CO at 8.6 atm. Reaction was run for 16 hours at S6 80 °C. After this time, reactor was cooled room temperature. The CO pressure was slowly released in a fume hood. Then the reactor was uncapped, and the reaction mixture was quenched with two drops of H2O. The color of the reaction mixture changed from brown to red. It was next diluted with 3.0 mL of ethyl acetate and filtered over a pad of MgSO4 and Celite. The pad was rinsed with additional ethyl acetate (5.0 mL) and the resulting solution evaporated under vacuum to remove the volatile materials. The assay yield was determined based on 1 H NMR analysis by integration (4% AY).

The general procedure for synthetic applications a) Gram-scale synthesis
To an oven-dried 100 mL Schlenk flask with a stir bar were sequentially added Pd(dba)2 (143.8 mg, 0.25 mmol, 5 mol %) and NIXANTPHOS (165.5 mg, 0.3 mmol, 6 mol %) under a nitrogen atmosphere inside a glove box. Next, 50 mL of 1,4-dioxane was taken up by syringe and added to the flask at room temperature. The reaction mixture was stirred for 30 min at room temperature, until the mixture became red. Then added LiN(SiMe3)2 (2.5 g, 15 mmol, 3 equiv) and stirred for 20 min at room temperature. Pro-nucleophile 1a (891.0 mg, 5 mmol, 1 equiv) and 4-tert-butyl-bromobenzen 2a (1.6 g, 7.5 mmol, 1.5 equiv) were added to the reaction mixture sequentially. The Schlenk flask was capped, removed from the glove box, the reaction mixture was degassed with CO by using Schlenk line (the Schlenk flask was evacuated by Schlenk line and then refiled with CO gas), then connected with a CO balloon, and placed in an 80 °C oil bath and stirred for 16 h. After this time, the flask was removed from the oil bath, allowed to cool to room temperature, then the cap was carefully removed in the fume hood, exposing the solution to the atmosphere, and the reaction quenched with H2O (1 mL). The color of the reaction mixture changed from dark brown to red. It was next diluted with 30 mL of ethyl acetate and filtered over a pad of MgSO4 and celite. The pad was rinsed with additional ethyl acetate (50 mL) and evaporated under vacuum to remove the volatile materials. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate/hexanes (1/2, v/v) to give the pure product 3aa (1.20 g, 71%) as yellow oil.

b) Oxidation of 3aa
i) Conditions 1. When m-CPBA was employed as an oxidant. 3 A 20 mL reaction vial was charged with a stir bar and solution of 1-(4-(tert-butyl)phenyl)-2-morpholino-2-(pyridin-2-yl)ethan-1-one 3aa (67.7 mg, 0.2 mmol) in 3 mL CHCl3. To the S7 resulting clear solution was added m-CPBA as a solid (138.1 mg, 4 equiv) at room temperature with stirring, resulting in a brown suspension. The reaction mixture was heated to 50 °C in an oil bath and stirred for 16 h at this temperature. The reaction mixture was then allowed to cool to room temperature, quenched with 3 mL a solution of K2CO3 (10%w/w) and extracted with CH2Cl2 (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to remove the volatile materials. The resulting brown crude oil was purified by flash chromatography on silica gel (eluted with hexanes/ethyl acetate = 1/1) to give the product 4 in 91% yield as a light-yellow oil. Characterization of 4 is given below.
ii) Conditions 2. When placing 3aa directly under air atmosphere.
A 20 mL reaction vial was charged with a stir bar and a solution of 1-(4-(tertbutyl)phenyl)-2-morpholino-2-(pyridin-2-yl)ethan-1-one 3aa (67.7 mg, 0.2 mmol) in 3 mL CHCl3. The open vial was stirred under air atmosphere for 48 h at room temperature. The reaction mixture was concentrated under reduced pressure. The brown crude oil was purified by flash chromatography on silica gel (eluted with hexanes/ethyl acetate = 1/1) to give the product 4 in 86% yield (33.1 mg) as a light-yellow oil.

Reaction studies a) Detection of the enolate: i) Deprotonatation of 3aa:
An oven-dried 20 mL vial equipped with a stir bar was charged with 3aa (67.7 mg, 0.2 mmol) under a nitrogen atmosphere in the glove box. A solution of LiN(SiMe3)2 (100.5 mg, 0.6 mmol) in 2.0 mL of dry THF was added with stirring at room temperature. After stirring for 3 h at room temperature, the color had changed from colorless to yellow. The resulting solution was evaporated under vacuum to remove the volatile materials. The resulting oil was taken up in 0.5 mL dry d 8 -THF. The suspension formed was filtered through dry celite and the filtrate was carefully transferred to J-Young NMR tube that was then sealed. NMR data was then collected and the 1 H NMR and 13 C{ 1 H} NMR spectrum are shown below.
ii) Reaction monitoring: An oven-dried 8 mL vial equipped with a stir bar under a nitrogen atmosphere in glove box was charged with Pd(dba)2 (5 mol %), NIXANTPHOS (6 mol %) and 0.1 M of 1,4-dioxane was taken up by syringe and added to the vail. The resulting solution was stirred for 15 min at room temperature during which time the mixture became red. This solution was used as the stock solution. To an oven-dried 10 mL Schlenk tube in the glove box with stir bar was added LiN(SiMe3)2 (50.3 mg, 0.3 mmol, 3 equiv). Next, 1 mL of the stock solution was added by pipette and the resulting solution stirred for 10 min at room temperature. 2-Pyridylmethylmorpholine 1a (17.8 mg, 0.1 mmol, 1 equiv) and aryl bromide 2a (32 mg, 0.15 mmol, 1.5 equiv) were sequentially added to the reaction mixture. The Schlenk tube was capped, removed from the glove box and the reaction mixture was degassed with CO by using Schlenk line, and connected with a CO balloon stirred for 16 h at 80 °C. After this time, the tube was removed from the oil bath, allowed to cool to room temperature, connected to a Schlenk line and evaporated under reduced pressure. While under vacuum, the tube was brought back into the glove box, the cap was carefully removed, and 0.5 mL dry d 8 -THF was added to the crude reaction mixture. The suspension was filtered through dry celite and the filtrate was carefully transferred to J-Young tube and NMR spectra acquired. Figure S1: 1 H NMR comparison of standard carbonylation product before aqueous workup, deprotonated 3aa, and product 3aa in d 8 -THF. These spectra support the contention that the product formed in the carbonylation reaction before workup is the enolate. S10 Supplementary Figure S2: 13 C{ 1 H} NMR comparison of standard carbonylation product before aqueous workup, deprotonated 3aa, and product 3aa in d 8 -THF. These spectra support the contention that the product formed in the carbonylation reaction before workup is the enolate. S11