Redox-neutral manganese-catalyzed synthesis of 1-pyrrolines

This report describes a manganese-catalyzed radical [3 + 2] cyclization of cyclopropanols and oxime ethers, leading to valuable multi-functional 1-pyrrolines. In this redox-neutral process, the oxime ethers function as internal oxidants and H-donors. The reaction involves sequential rupture of C–C, C–H and N–O bonds and proceeds under mild conditions. This intermolecular protocol provides an efficient approach for the synthesis of structurally diverse 1-pyrrolines.

General procedure for synthesis of cyclopropanols S2 3. General procedure for synthesis of oxime ethers S3 4. General procedure for synthesis of pyrroline products S5 5. Gram-scale reaction S15 6. Transformation of compound 3a S15 7. Mechanistic studies S18 8. References S21 9. 1 H, 13 C, and 19 F NMR Spectra S22 Electronic Supplementary Material (ESI) for Chemical Science. This journal is © The Royal Society of Chemistry 2022

General experimental details
All reactions were maintained under a nitrogen atmosphere unless otherwise stated. Commercially available reagents were used without further purification. Infrared (FT-IR) spectra were recorded on a BRUKER VERTEX 70, νmax in cm -1 . 1 H-NMR spectra were recorded on a BRUKER AVANCE III HD (400 MHz) spectrometer. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as internal standard (CDCl3: δ 7.26). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quadruplet, br = broad, m = multiplet), coupling constants (Hz) and integration. 13 C-NMR spectra were recorded on a BRUKER AVANCE III HD (100 MHz) spectrometer with complete proton decoupling. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3: δ 77.16). 19

General procedure for synthesis of cyclopropanols
The starting material cyclopropanols were prepared according to the reported procedure 1 . Cyclopropanols 1a-n, 1p, 1q, 1s, and 1u-1v are known compounds. The spectrum data of cyclopropanols 1a-b, 1f-h, 1l, 1n, 1p-1q, 1s, and 1v can be found in Ref. 1a Other cyclopropanols were prepared according to the following procedures: Step one: Ketone (5 mmol, 1.0 equiv.) was added to a 100 mL flame-dried round-bottomed flask at 0 o C under nitrogen. Anhydrous DCM (20 mL) was added to the flask, followed by adding Et3N (7.5 mmol, 1.5 equiv.). Then TMSOTf (6 mmol, 1.2 equiv.) was added dropwise via syringe over 10 min. The reaction was stirred overnight, which was monitored by TLC. Upon completion, the reaction was quenched with sat. NaHCO3, diluted with DCM. The aqueous layer was extracted with DCM (3 x 15 ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuum. The enol ether was used in the next step without further purification.
Step two: The enol ether was transferred to a 100 mL flame-dried round-bottomed flask under nitrogen. The flask was charged with anhydrous DCM (30 mL) and diiodomethane (7.5 mmol, 1.5 equiv.). The mixture was cooled to 0 º C, then neat diethyl zinc (7.5 mmol, 1M in toluene, 1.5 equiv.) was added dropwise to the reaction solution via syringe. The mixture was warmed to room temperature and stirred for 16 h. The reaction was quenched with a sat. NH4Cl at 0 º C. The layers were separated and the aqueous layer was extracted with DCM (3 x 15 ml). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuum. The crude TMS ether was also used in the next step without further purification.
Step three: The crude TMS ether was transferred to a 100 mL flame-dried round-bottomed flask under nitrogen. The flask was charged with methanol (30 mL). A single drop of chlorotrimethylsilane was added via syringe at 0 º C, and the reaction was monitored by TLC. The reaction was completed in about 1 h, then the mixture was concentrated to dryness in vacuum and the residue was purified by flash column chromatography on silica gel. The following cyclopropanol products were synthesized using the procedure described above:

General procedure for synthesis of oxime ethers Method A
O-Benzylhydroxylamine hydrochloride (1.0 equiv.) was dissolved in toluene, glyoxylic acid ester (1.0 equiv.) was then added. The mixture was heated at refluxing temperature, until the material was consumed. The crude mixture was quenched by sat. NaHCO3. The resulting aqueous phase was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography on silica gel.

Method B
First step: O-Benzylhydroxylamine hydrochloride (1.0 equiv.) and NaOH (1.0 equiv.) was dissolved in EtOAc, glyoxylic acid (1.0 equiv.) was then added. The solution was allowed to warm to room temperature over 3 h. The reaction progress was monitored by TLC. The crude mixture was washed with brine, dried over MgSO4, filtered, and concentrated in vacuum. The residue was used in the next step without further purification.

Second step:
To a stirred solution of trans-2-((benzyloxy)imino)acetic acid (2.4 equiv.) and DCC (dicyclohexylcarbodiimide) (2 equiv.) in DCM (15 mL) were added DMAP (4-dimethylaminepyridine) (0.15 equiv.) and phenol (1.0 equiv.). The reaction mixture was stirred at 40 o C until the material was consumed. After filtration, the filtrate was concentrated in vacuum and the residue was purified by flash column chromatography on silica gel to afford the product. Oxime

General procedure for synthesis of products
Cyclopropanol 1 (0.3 mmol, 1.5 equiv.), oxime ether 2 (0.2 mmol, 1.0 equiv.), and MnCl2 (0.04 mmol, 20 mol %) were loaded in a flame-dried reaction vial, which was subjected to evacuation/ flushing with nitrogen three times. HFIP (3.0 mL) was added to the mixture via syringe. Then acetylacetone (acac, 0.2 mmol, 1.0 equiv.) and AcOH (0.2 mmol, 1.0 equiv.) were added to the mixture, which was stirred at room temperature until the starting material had been consumed as determined by TLC. The mixture was quenched with H2O. The aqueous layer was extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuum, and purified by flash column chromatography on silica gel (eluent: EtOAc/Petroleum ether) to give the corresponding products.     -1 ) 2973, 2931, 2159, 2029, 1737, 1670, 1638, 1559, 1507   A screw-cap vial under N2 was charged with 3a (0.15 mmol, 1.0 equiv.) and dry THF (2.0 mL). At 0 °C, the solution of LiAlH4 (0.45 mmol, 3.0 equiv.) in dry THF (2.0 mL) was added to the vial in small portions and the mixture was allowed to react at refluxing temperature. After stirring for 4 h, the reaction mixture was cooled to r.t. and quenched by saturated aq. NH4Cl, the mixture was extracted with EtOAc for three times. Then the organic phase was combined and dried over anhydrous MgSO4. The solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel to provide the product 5. 5: 23.6 mg, 90% yield, brown oil. Purification by flash column chromatography on silica gel (eluent: EtOAc/Petroleum ether = 1/1). 1  Triethylamine (0.18 mmol, 18.2 mg, 25.0 μl, 1.5 equiv.) was added to the solution of 3a (29.3 mg, 0.12 mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ, 54.9 mg, 0.24 mmol, 2.0 equiv.) in CH2Cl2 (2 mL) under N2, the reaction mixture was stirred at r.t. After stirring for 3 h, the solvent was removed under vacuum and the residue was purified by flash column chromatography on silica gel to provide the product 6.

Verification of Radical mechanism
When ethene-1,1-diyldibenzene (2.0 equiv.) was introduced into the model reaction, only trace products were detected according to TLC analysis.
Following the standard procedures, additional 2.0 equiv. TEMPO