Catalytic Access to 4-(sec-Alkyl)Anilines via 1,6-Conjugate Addition of Grignard Reagents to in Situ Generated aza-p-Quinone Methides

The synthesis of aniline derivatives, common building blocks in many pharmaceuticals, agrochemicals, dyes or polymers, has been limited to reactions based on benzene-toluene-xylene derivatives (BTX) due to their ample availability. Despite the large number of existing methodologies, the synthesis of chiral 4-(sec-alkyl)anilines has not been accomplished so far. In this work, a tandem strategy based on the generation of a reactive aza-p-quinone methide (aza-p-QM) intermediate followed by Cu(I)-catalyzed addition of Grignard reagents has been developed.


4.
Enantioselective Catalytic reaction for the Synthesis of chiral anilines 4.1.

General procedure
To a previously dried Schlenk flask under nitrogen, CuBr•SMe2 (5.0 mol%) and ligand (6.0 mol%) were added and dissolved in dry DCM (2 mL). After 15 min stirring at room temperature the solution was cooled down to -50 °C and the substrate (0.2 mmol, 1.0 equiv.) was added in 1mL of DCM. After stirring for an additional 10 min, EtMgBr (Aldrich, 3.0M solution in Et2O, (3.0 equiv.) was added. The reaction mixture was stirred overnight (16-20h). The reaction was quenched with NaHCO3 sat. sol., and extracted with DCM (3 x 5 mL), dried over Na2SO4. filtered and removed under vaccum. The resulting residue was purified by flash column chromatography using the appropriate eluent (generally DCM). The enantiomeric ratio was determined by analytical HPLC using a chiral column.

Synthesis of chiral 4-(sec alkyl)anilines
General procedure for the catalytic reaction To a previously dried Schlenk flask under nitrogen, CuBr (5.0 mol%) and ligand (6.0 mol%) were added and dissolved in dry DCM (1 mL) and Et2O (1 mL). After 15 min stirring at room temperature the solution was cooled down to -50 °C and the substrate (0.2 mmol, 1.0 equiv.) was added in 1mL of DCM. After stirring for an additional 10 min, EtMgBr (Aldrich, 3.0 M solution in Et2O, (3.0 equiv.) was added. The reaction mixture was stirred overnight (16-20h). The reaction was quenched with NaHCO3 sat. sol., and extracted with DCM (3 x 5 mL), dried over Na2SO4 anh. filtered and removed under vacuum. The resulting residue was purified by flash column chromatography using DCM. The enantiomeric ratio was determined by analytical HPLC.

General procedure for the synthesis of the racemic product (HPLC separation)
To a previously dried Schlenk flask under nitrogen, CuBr (5.0 mol%) was added and dissolved in dry DCM (1 mL) and Et2O (1 mL). The solution was cooled down and the substrate (0.2 mmol, 1.0 equiv.) was added in 1mL of solvent. After stirring for an additional 10 min, EtMgBr (Aldrich, 3.0 M solution in Et2O, (3.0 equiv.) was added. The reaction mixture was stirred overnight (16-20h). The reaction was quenched with NaHCO3 sat. sol., and extracted with DCM (3 x 5 mL), dried over Na2SO4 anh. filtered and removed under vacuum. The resulting residue was purified by flash column chromatography using DCM.

Derivatizations (R)-N-(4-(sec-butyl)phenyl)-4-methylbenzenesulfonamide (3)
p-Toluenesulfonyl chloride (165.8 mg, 0.870 mmol, 1.1 equiv) is added to a solution of aniline (118.0 mg, 0.791 mmol, 1.0 equiv) in pyridine (3.2 mL, 39.534 mmol, 50.0 equiv) at 0 °C. The resulting solution is stirred at 25 °C overnight (24h). The solvent is removed in vacuo in order to remove the pyridine. The residue is dissolved in water and it is extracted with DCM (3x). The collected organic phases are dried over MgSO4, filtered and the resulting residue is purified by silica gel column chromatography with pentane: ethyl acetate (7/3) as the eluent affording the desired sulfonamide 3 as a white solid (232.0 mg, 0.767 mmol, 97%). The enantiomeric ratio was found to be 87:13 e.r. by analytical HPLC in OD-H column 98:2 Heptane: iPrOH, 1 mL/min, λ= 227 nm, tr (minor): 40.6 min, tr (major): 43.1 min. General procedure: To a solution of 4-bromobenzaldehyde (1.0 equiv) in anhydrous THF (0.5 M) was added a solution of Grignard reagent (2.1 equiv) dropwise at room temperature. The resulting solution was stirred overnight, and the reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with diethyl ether (x3). The combined organic layers were dried over anhydrous Na2SO4, then concentrated under vacuum to afford a crude, which was purified by column chromatography.

S38
The product was synthesized following general procedure and it was obtained after flash column chromatography in silica gel (Pentane: EtOAc, 9:1) to afford the alcohol as a colourless liquid (1.01 g, 41%). The spectroscopic data matched with those reported in the literature.

General procedure
Step 1: A 20 mL-screw capped vial was charged with aryl bromide 1' (1.0 equiv), CuI (0.1 equiv) and DMEDA (1.5 equiv) in NH3 (25 equiv. or completely full vial) and DMSO (2.5 mL). The vial was flushed with nitrogen and capped. The solution was stirred overnight at 130 °C. The resulting intense blue suspension was cooled down to room temperature, extracted with EtOAc (× 3). The organic layers were separated, and the organic layer is dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (Hexane/EtOAc =7/3-1/1) affording an aniline substrate 1'' which was directly employed in the next step (decomposes easily).
Step 2: To a Schlenk under nitrogen, it was added a mixture of sodium p-toluensulfinate (1.0 equiv) and p-toluenesulfonic acid monohydrate (1.5 equiv) and dry DCM (0.5 M). Then, the aniline substrate 1'' was added to the mixture, and a precipitate was formed immediately. The resulting suspension was stirred either 2h or overnight, then quenched by adjusting to pH 8 with saturated Na2CO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted with DCM (× 3). The combined organic layers were dried over anhydrous Na2SO4, concentrated under vacuum to afford the corresponding sulfone 1. The solid was purified by trituration with diethyl ether and hexane.
Step 1: The product was synthesized following general procedure and it was obtained after flash column chromatography (hexane/EtOAc =7/3-1/1), to afford the corresponding aniline 1''o (1.05 g, 88%). Step 2: The product was synthesized following general procedure to afford a solid that was purified by trituration with pentane and diethyl ether afforded a pure sulfone as a pale yellow solid 1o (0.06 g, 5%). 1

4-(2-phenyl-1-tosylethyl)aniline (1p)
Step 1: The product was synthesized following general procedure and it was obtained after flash column chromatography (hexane/EtOAc =7/3-1/1) to yield the aniline 1''p (0.39 g, 51%) To a previously dried Schlenk flask, it is added the corresponding ketone (1.0 equiv) and it is dissolved in EtOH (0.2 M). Next, NaBH4 (2.0 equiv) was added and the schlenk is open for 15 minutes, to release the overpressure due to the formation hydrogen gas and then closed with a septum. The resulting mixture was stirred at r.t. overnight. Then, the solvent was removed in vacuo, dissolved in EtOAc and water. extracted with EtOAc (3 x) and the collected organic phases were dried over Na2SO4, filtered affording the alcohol 1''.

1-(4-aminophenyl)ethan-1-ol (1''a)
The product was synthesized following general procedure to afford the alcohol 1''a as a white solid (7.0 g, 98%). The spectroscopic data matched with those reported in the literature.

S44
The product was synthesized following general procedure to afford the alcohol as a grey solid 1''t (2.46 g, 97%). To a Schlenk under nitrogen, it was added a mixture of sodium sulfinate (1.0 equiv) and ptoluenesulfonic acid monohydrate (1.5 equiv) and dry DCM (0.5 M). Then, the aniline substrate 1' was added to the mixture, and a precipitate was formed immediately. The resulting suspension was stirred either 2h or overnight, then quenched by adjusting to pH 8 with saturated Na2CO3 aqueous solution.
The organic layer was separated, and the aqueous layer was extracted with DCM (× 3). The combined organic layers were dried over anhydrous Na2SO4, concentrated under vacuum to afford the corresponding sulfone 1. The solid was purified by trituration with diethyl ether and hexane.

4-(1-tosylethyl)aniline (1a)
The product was synthesized following general procedure to afford a solid that was purified by trituration with diethyl ether and pentane to afford a white solid 1a (1.2 g, 40%). The spectroscopic data matched with those reported in the literature.

4-(1-(mesitylsulfonyl)ethyl)aniline (1aa)
The product was synthesized following general procedure to afford a solid that was washed with pentane to afford the corresponding sulfone 1aa as a white solid (1.61 g, 82%).

4-(1-(methylsulfonyl)ethyl)aniline (1ab)
The product was synthesized following general procedure to afford the corresponding sulfone 1ab as a white solid after trituration with diethyl ether (2.58 g, 89%). 1  The product was synthesized following general procedure to afford the corresponding sulfone 1t after trituration with diethyl ether and pentane (2.54 g, 76%) as a white-grey solid.
S46 component present, which was refined using the BASF/TWIN commands, where the BASF refined to 0.005. Crystal data and details on data collection and refinement are presented in Table S1.