Copper(I)-catalyzed asymmetric decarboxylative Mannich reaction enabled by acidic activation of 2H-azirines

Chiral aziridines are structure units found in many biologically active compounds and are important building blocks in organic synthesis. Herein, by merging nucleophilic generation through copper(I)-catalyzed decarboxylation and activation of poorly electrophilic 2H-azirines through protonation with carboxylic acids, an asymmetric decarboxylative Mannich reaction between α,α-disubstituted cyanoacetic acids and 2H-azirines is uncovered, which leads to generation of chiral aziridines containing vicinal tetrasubstituted and acyclic quaternary stereogenic carbon centers in good to excellent diastereo- and enantioselectivities. At last, transformations of the produced chiral aziridine are successfully carried out to deliver synthetically useful compounds.


General information
Nuclear Magnetic Resonance (NMR) spectra were acquired on an Agilent 400 or Agilent 500 or Bruker 400 spectrometer. For 1 H NMR, chemical shifts were reported in δ ppm referenced to an internal SiMe4 standard. For 19 F NMR, CFCl3 was used as the reference with chemical shift at 0 ppm. For 13 C NMR, chemical shifts were reported in the scale relative to NMR solvent (CDCl3:  77.0 ppm; DMSO-d6: δ 39.52 ppm) as an internal reference. Multiplicities are reported using the following abbreviations: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. High-resolution mass spectra (ESI) were measured on Agilent 6200 Series TOF/6500 Series. Highresolution mass spectra (DART) were measured on Thermo Fisher Scienticfic LTQ FTICR-MS. Infrared (IR) spectra were recorded on Thermo Scientific Nicolet iS5 FT-IR. Optical rotation was measured on an Anton Paar Mcp 5500 polarimeter. HPLC analysis was conducted on a Shimadzu HPLC system equipped with Daicel chiral-stationary-phase columns (4.6 mm × 250 mm).
Cyanoacetic acids were synthesized according to the literature method. 1 All other reagents were obtained commercially unless otherwise noted.

Preparation of 2H-azirines Preparation of 2a-2q
To a solution of alkene (5 mmol) in DCM (10 mL) cooled to 0 °C was added bromine (1.0 M DCM solution) dropwise until the solution turned orange. The resulting solution was stirred at room temperature for 5 minutes. Upon completion as indicated by TLC, the reaction was quenched with saturated aqueous Na2SO3 and stirred vigorously until the orange color disappeared. The organic phase was separated and the aqueous phase was extracted with DCM (20 mL × 2). The organic extracts were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give the crude product which was used in next step without further purification.
To a solution of dibromide in DMF (10 mL) was added NaN3 (3.0 equiv). The mixture was stirred overnight at room temperature, then diluted with water and extracted with diethyl ether (20 mL × 3). The combined organic layers were washed for three times with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product which was used in next step without further purification.
The crude vinyl azide was refluxed in toluene (0.1 M) for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether /ethyl acetate) to afford 2H-azirine.

Preparation of 2r-2v
To a stirring suspension of acid (10 mmol), K2CO3 (1.5 equiv) and KI (1.5 equiv) in DMF (20 mL) was added 4-vinylbenzyl chloride (1.1 equiv). The mixture was stirred for 24 h at room temperature, then diluted with water and extracted with diethyl ether (20 mL × 3). The combined organic layers were washed for three times with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether /ethyl acetate) to afford alkene.
To a solution of alkene (5 mmol) in DCM (10 mL) cooled to 0 °C was added bromine (1.0 M DCM solution) dropwise until the solution turned orange. The resulting solution was stirred at room temperature for 5 minutes. Upon completion as indicated by TLC, the reaction was quenched with saturated aqueous Na2SO3 and stirred vigorously until the orange color disappeared. The organic phase was separated and the aqueous phase was extracted with DCM (20 mL × 2). The organic extracts were dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure to give the crude product which was used in next step without further purification.
To a solution of dibromide in DMF (10 mL) was added NaN3 (3.0 equiv). The mixture was stirred overnight at room temperature, then diluted with water and extracted with diethyl ether (20 mL × 3). The combined organic layers were washed for three times with water, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product which was used in next step without further purification.
The crude vinyl azide was refluxed in toluene (0.1 M) for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (petroleum ether /ethyl acetate) to afford 2H-azirine.

Preparation of 4a-4c and 4i-4k
To a solution of alkyne (2.0 mmol), TMSN3 (2.0 equiv) and H2O (2.0 equiv) in DMSO (4 mL) at 80 o C, Ag2CO3 (0.1 equiv) was added. The mixture was stirred for 1-2 h. Upon completion as indicated by TLC, the reaction was quenched with water and extracted with diethyl ether (10 mL × 3). The combined organic layers were washed for three times with water, dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to give the crude product which was used in next step without further purification. 4 The crude vinyl azide was heated in toluene (0.1 M) in sealed tube at 150 o C for 20 minutes. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give the crude product, which was purified by flash silica gel column chromatography (petroleum ether /ethyl acetate) to afford 2H-azirine.
To a stirred solution of indometacin (10 mmol, 1.0 equiv) and hept-6-yn-1-ol (1.1 equiv) in DCM (20 mL) were added DCC (1.5 equiv) and DMAP (0.01 equiv) at room temperature. The reaction mixture was stirred overnight. The precipitate was filtered off and washed with CH2Cl2. After removal of solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the alkyne. Following the above method, alkyne can be transformed to corresponding 2H-azirine. To a stirred solution of hept-6-ynoic acid (10 mmol, 1.0 equiv) and dehydroepiandrosterone (1.1 equiv) in DCM (20 mL) were added DCC (1.5 equiv) and DMAP (0.01 equiv) at room temperature. The reaction mixture was stirred overnight. The precipitate was filtered off and washed with CH2Cl2. After removal of solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to afford the alkyne. Following the above method, alkyne can be transformed to corresponding 2H-azirine. To a stirred solution of diacetone-D-glucose (15 mmol, 1.0 equiv) in DMF (20 mL) at 0 o C was added NaH (1.2 equiv, 60% in mineral oil). After 30 minutes, hept-6-yn-1-yl 4methylbenzenesulfonate (1.5 equiv) was added and the mixture was stirred overnight. The reaction was quenched with water and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed for three times with water, and dried over anhydrous Na2SO4. After removal of solvent under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether/acetone) to afford the alkyne. Following the above method, alkyne can be transformed to corresponding 2H-azirine.

Screening of copper(I) source
Supplementary

DIPA-MeO-BIPHEP in the decarboxylative Mannich reaction of aliphatic 2Hazirine 4a and 1a
Datafile Name  A dried 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with aromatic 2H-azirines 2 (0.2 mmol, 1.0 equiv). The catalyst solution (1.0 mL) containing copper(I) complex (0.006 mmol, 0.03 equiv) was added via a syringe. The reaction mixture was then cooled to -60 °C and cyanoacetic acid 1a (0.3 M in THF, 1.0 mL, 0.3 mmol, 1.5 equiv) was added dropwise over 2 minutes. The resulting reaction mixture was stirred at -60 °C for indicated time (36-90 h). The reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the product.

Procedure B:
A dried 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with CuOAc (1.5 mg, 0.012 mmol, 0.06 equiv) and (R)-DIPA-MeO-BIPHEP (13.1 mg, 0.012 mmol, 0.06 equiv) in a glove box under Ar atmosphere. Anhydrous THF (1 mL) was added via a syringe. The mixture was stirred for 15 minutes to give a clear catalyst solution. Then aromatic 2H-azirines 2 (0.2 mmol, 1.0 equiv) was added. The reaction mixture was then cooled to -60 °C and cyanoacetic acid 1a (0.6 M in THF, 1.0 mL, 0.6 mmol, 3.0 equiv) was added dropwise over 2 minutes. The resulting reaction mixture was stirred at -60 °C for 80 h. The reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the product.

General procedure for Copper(I)-catalyzed asymmetric decarboxylative Mannich reaction of aliphatic 2H-azirines and cyanoacetic acids
Procedure C: Preparation of catalyst solution: A dried 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with CuOAc (1.5 mg, 0.012 mmol) and (R)-DTBM-SEGPHOS (14.2 mg, 0.012 mmol) in a glove box under Ar atmosphere. Anhydrous THF (2 mL) was added via a syringe. The mixture was stirred for 15 minutes to give a clear catalyst solution.
A dried 25 mL Schlenk tube equipped with a magnetic stirring bar was charged with aliphatic 2H-azirines 4 (0.2 mmol, 1.0 equiv). The catalyst solution (1.0 mL) containing copper(I) complex (0.006 mmol, 0.03 equiv) was added via a syringe. The reaction mixture was then cooled to -20 °C and cyanoacetic acid 1a (0.25 M in THF, 2.0 mL, 0.5 mmol, 2.5 equiv) was added over 12 h with a syringe pump. The reaction mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the product.

DIBAL-H reduction and protection of the free amine
To a stirred solution of 3a (74.5 mg, 0.3 mmol, 1.0 equiv) in anhydrous DCM (3 mL) was added dropwise DIBAL-H (1.5 M in toluene, 1.0 mL, 1.5 mmol, 5.0 equiv) under N2 atmosphere at -78 °C. After being stirred overnight at -78 °C, the mixture was allowed to warm up to room temperature and the reaction was quenched by 60 μL water. After addition of 60 μL 15% aqueous solution of sodium hydroxide and 150 μL water, the resulting mixture was stirred for 15 minutes and dried over anhydrous MgSO4. The mixture was filtered through a pack of Celite and washed with DCM. The solvent was removed under reduced pressure to give the crude product which was used in next step without further purification.
The crude was dissolved in 3 mL anhydrous DCM under N2 atmosphere. Et3N (60.7 mg, 0.6 mmol, 2.0 equiv) and Boc2O (131.0 mg, 0.6 mmol, 2.0 equiv) were added sequentially at 0 o C. The reaction mixture was then allowed to warm up to room temperature and stirred for additional 6 h. After removal of solvent under reduced pressure, the crude was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3.5/1) to afford 7 (63.5 mg, 60% yield, >20/1 dr, 98% ee) as a white foam.    A diethyl ether solution of 8 (>20/1 dr, 99% ee) was allowed to grow crystals at room temperature, which led to the determination of the absolute configuration of stereocenters in 8 through X-ray analysis. CCDC number 1891666 contains the supplementary crystallographic data for this report. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.