Chiral Aniline Synthesis via Stereospecific C(sp3)–C(sp2) Coupling of Boronic Esters with Aryl Hydrazines

An enantiospecific coupling between alkylboronic esters and lithiated aryl hydrazines is described. The reaction proceeds under transition-metal-free conditions and is promoted by acylation of a hydrazinyl arylboronate complex, which triggers a N–N bond cleavage with concomitant 1,2-metalate rearrangement. Judicious choice of the acylating agent enabled the synthesis of ortho- and para-substituted anilines with essentially complete enantiospecificity from a wide range of boronic ester substrates.

S3 dm) -1 . Chiral HPLC was performed on an HP Agilent 1100 with Chiralpak columns and monitored by DAD (Diode Array Detector). Chiral SFC was performed on a Waters TharSFC system using a Diacel Chiralpak columns (4.6 m × 250 mm × 5 μm) and monitored by DAD (Diode Array Detector). GC-MS was performed on an Agilent 7820A using an HP-5MS UI column (30 m x 0.25 mm x 0.25 μm).

The naming of compounds:
Compound names are those generated by ChemDraw Pro 16.0 software (PerkinElmer), following the IUPAC nomenclature.

Boronic ester substrates:
All boronic ester substrates are either commercially available or were synthesized according to literature procedures. 1

Bromophenyl Hydrazines I. General Procedure for the Synthesis of ortho-and para-bromophenyl hydrazines
To a stirred solution of o-/p-bromoaniline (1.74 mmol) in concentrated aq. HCl (3.4

ml) and
H2O (1.2 ml) at 0 °C a solution of sodium nitrite (120 mg, 1.74 mmol) in H2O (1.2 ml) was added over a period of 30 minutes. The reaction mixture was stirred for a further 30 minutes then added dropwise to a solution of tin chloride hydrate (1.97 g, 8.71 mmol) in concentrated aq. HCl (3 ml) at 0 °C. After the addition is complete, the reaction was stirred at room temperature for 5 hours. Then the reaction was basified with 40% aqueous NaOH at 0 °C until the pH was 13. The mixture was then extracted with DCM (25 mL x 3) and water (30 mL). The organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The crude product was further purified by column chromatography with silica gel using pentane/EtOAc as eluents.
After the addition was complete, the reaction was stirred at room temperature for 5 hours.
Then the reaction mixture was basified with 40% aqueous NaOH at 0 °C until the pH was 13.
The mixture was then extracted with DCM (25 mL x 3) and water (30 mL). The organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The success of the permethylation was judged by crude 1 H NMR. The crude product was then purified by column chromatography with silica gel using pentane/EtOAc as eluents.
After the addition was complete, the reaction was stirred at room temperature for 5 hours.
Then the reaction mixture was basified with 40% aqueous NaOH at 0 °C until the pH was 13.
The mixture was then extracted with DCM (25 mL x 3) and water (30 mL). The organic phase S8 was separated and dried over Na2SO4 and concentrated in vacuo. The success of the permethylation was judged by crude 1 H NMR. If the permethylation was not complete, the dimethylation product was purified by column chromatography with silica gel using pentane/EtOAc as eluents. Methylation of Dimethylated Hydrazine: To a stirred solution of dimethyl-o-/p-bromohydrazine (1 mmol, 1 equiv.) in DMF (10 mL) at 0 °C was added 40% sodium hydride in mineral oil (1.5 mmol, 1.5 equiv.). The reaction mixture was allowed to stir for 20 min and then methyl iodide (1.05 mmol, 1.05 equiv.) was added dropwise at 0 °C. After the addition is complete, the reaction was warmed to room temperature and stirred for 1 hour after which excess NaH was quenched by the addition of water at 0 °C. The mixture was then extracted with DCM (25 mL x 2) and water (30 mL). The organic phase was separated and dried over Na2SO4 and concentrated in vacuo. The crude product was then purified by column chromatography with silica gel using pentane/EtOAc as eluents.

5-Bromo-N,N-dimethylindolin-1-amine (4d)
Following the literature procedure, 5-bromoindoline (620 mg) was converted to 5bromoindolin-1-amine. 12 To a stirred solution of 5-bromoindoline (620 mg, 3.15 mmol, 1 S10 equiv.) in EtOH (3 mL) at 0 °C Conc. HCl (0.33 mL) was added. A freshly prepared solution of aqueous sodium nitrite solution (0.26 g, 3.78 mmol, 1.2 equiv.) in 2mL of water was added dropwise. After the addition is complete, the reaction mixture was allowed to stir for 1 h at 0 °C. After checking complete consumption of substrate material by TLC analysis, a solution of NaOH (2 g, 50 mmol) in H2O (4 mL) and Na2S2O4 (75%, 1.64 g, 9.45 mmol, 3 equiv.) was added at 0 °C. The suspension was refluxed at 80 °C for 2 h, and then the reaction mixture was cooled to room temperature. After addition of H2O (25 mL) to the reaction mixture followed by extraction with DCM (25 mL x 2), the organic layer was dried over anhydrous Na2SO4 and concentrated to give crude material. The crude product of 5-bromoindolin-

S15
The synthesis of product 7a was also performed on a 1.2 mmol scale: A solution of p-bromophenyl hydrazine (300 mg, 1.31 mmol, 1.10 equiv.) in THF (6.5 mL, 0.20 M) was cooled to -78 °C and n-BuLi (0.818 mL, 1.31 mmol, 1.10 equiv., 1.6 M in hexanes) was added dropwise over 30 min using a syringe pump. The solution was stirred at -78 °C for 1 h before the boronic ester (250 mg, 1.19 mmol, 1.0 equiv.) was added as a solution in THF (0.4 mL x 3) dropwise over 5 min. The mixture was stirred at -78 °C for 1 h before a solution of trifluoroacetic anhydride (0.347 mL, 2.50 mmol, 2.10 equiv.) in THF (0.5 mL) was added dropwise over 5 min. The reaction was allowed to warm slowly to rt overnight (12 h). The reaction mixture was then quenched with sat. aqueous NaHCO3 solution (7 mL) and diluted with DCM (30 mL) and water (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 30 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography (silica gel, 5% EtOAc/pet. ether) to give compound 7a (268 mg; 79%) as a gummy oil.