A redox-enabled strategy for intramolecular hydroamination

Metal- or acid-catalyzed intramolecular hydroamination and Cope-type intramolecular hydroamination, a distinct concerted approach using hydroxylamines, typically suffer from significant synthetic limitations. Herein we report a process for intramolecular hydroamination that uses a redox-enabled strategy relying on efficient in situ generation of hydroxylamines by oxidation, followed by Cope-type hydroamination, then reduction of the resulting pyrrolidine N-oxide. The steps are performed sequentially in a single pot, no catalyst is required, the conditions are mild, the process is highly functional group tolerant, and no chromatography is generally required for isolation. A robustness screen and a gram-scale example further support the practicality of this approach.


Boron reductants
) were determined to be optimal reductants and were not evaluated within the following entries.

Entry Solvent (M) Oxidant (equiv) Temp (°C) Yield 3a (%) b
General procedure B: Redox-enabled hydroamination sequence To a clean dry microwave vial was added the corresponding secondary amine 1 (1.0 equiv) followed by dilution with TFE (0.1 M). UHP was then added (1.2 equiv). The vial was sealed then stirred at 50 °C for 16 h. The reaction vessel was opened and B2(OH)4 (1.2 equiv for alkylsubstituted amines or 2.2 equiv for Lewis -base -substituted amines) was added. The vial was resealed then stirred at 50 °C for 1 h. The crude reaction mixture was concentrated via rotary evaporation, then diluted with DCM (50 mL) and water (50 mL). 10 mL of 1M HCl was added, and the phases were separated. 15 mL of 1M KOH was added to the aqueous phase, which was then extracted with DCM twice (50 mL each). The combined organic phases were washed with brine, dried over Na2SO4, then filtered before concentration via rotary evaporation. The crude product did not require any further purification.
General procedure C: Robustness screen 1 To a clean dry microwave vial was added additive (0.1 mmol, 1.0 equiv), followed by amine 1a (17.5 mg, 0.1 mmol) in a solution of TFE (0.1 M). UHP was then added (11.3 mg, 0.12 mmol). The vial was sealed then stirred at 50 °C for 16 h. The reaction vessel was opened and B2(OH)4 (10.8 mg, 0.12 mmol) was added. The vial was resealed then stirred at 50 °C for 1 h. The crude reaction mixture was concentrated via rotary evaporation, then 1,3,5-trimethoxybenzene (16.8 mg, 0.1 mmol) in a solution of CDCl3 (0.2 M) was added to the crude reaction mixture. 1 H NMR spectra were obtained and the integration of diagnostic signals for the additive and for pyrrolidine 4a were attained to find the amount (%) of both species. When the additive was volatile and no signals for this species could be observed, no amount remaining is reported. However, when the additive was somewhat volatile and signals for this species could be observed, likely in reduced quantities due to evaporation, the amount remaining is reported.

N-Benzylhex-5-en-2-amine 1h
To a vial was added a solution of hex-5-en-2-one (1.0 mL, 8.6 mmol) and TFE (17 mL), which was stirred at rt for 18 h. Then, benzylamine (1.0 mL, 9.5 mmol) was added and the mixture vigorously stirred overnight. Then, NaBH4 (0.39 g, 10 mmol) was added. After completion of the reaction, as monitored by TLC, the reaction mixture was filtered, washing with TFE (17 mL). The filtrate was concentrated via rotary evaporation, and the crude product was purified using silicagel flash column chromatography (20% EtOAc/petroleum ether + 1% NEt3) to yield the title compound as a yellow oil (0.90 g, 55% over 2 steps). Characterization data is in good agreement with previously reported data. 3

N-Benzyl-4-methylpent-4-en-1-amine 1i
Ethyl 4-methylpent-4-enoate was prepared using a literature procedure. The obtained crude product (2.10 g, 98%) was used next step without further purification. 4 To a vial was added benzylamine (0.60 mL, 5.50 mmol) and 1M DIBAL in THF solution (1.0 mL, 1.0 mmol), which was stirred at rt. After 5 minutes, ethyl 4-methylpent-4-enoate (0.711 g, 5 mmol) was added and the mixture was vigorously stirred at 80 °C for 24 h. Upon completion by TLC, the mixture was transferred to a 100 mL round bottomed flask and the vial was rinsed with additional THF (15 mL) and cooled to 0 °C. LiAlH4 was added slowly to the flask. The reaction mixture was allowed to warm to room temperature, then was and stirred overnight at 60 °C. The reaction was quenched by cooling to 0 °C and adding sequentially water (1 mL per g LiAlH4), then 15% aqueous NaOH (1 mL per g LiAlH4), then water (3 mL per g LiAlH4), then saturated Rochelle's solution (50 mL). The solution was allowed to stir for 1 h then filtered, washing with EtOAc. The filtrate was added into an extraction funnel and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, then dried over Na2SO4, and concentrated via rotary evaporation. The crude product was purified by alumina column chromatography (20% EtOAc/hexanes + 1% NEt3) to yield the title compound as a yellow oil (0.53 g, 56% over 3 steps). Characterization data is in good agreement with previously reported data. 5

(Z)-N-Benzylhex-4-en-1-amine 1j'
The title compound was synthesized according to a two-step procedure. To a round bottom flask was added (Z)-hex-4-en-1-ol (1.00 g, 10.0 mmol) followed by dilution in THF (0.2 M). PPh3 (3.15 g, 12.0 mmol), then imidazole (2.04 g, 30.0 mmol) were added, and the mixture was cooled to 0 °C. Iodine (2.79 g, 11.0 mmol) was then added. The reaction mixture was stirred at 0 °C for 30 min then rt for 30 min. Upon completion, the reaction was concentrated via rotary evaporation. The reaction mixture was diluted with EtOAc and was extracted using water (x1) and then brine (x1). The organic phase was dried with Na2SO4 and filtered. The filtrate was concentrated via rotary evaporation and OPPh3 was removed from the mixture via precipitation using Et2O/hexanes. The filtrate was concentrated, and this product was used without further purification. Then, the amine was alkylated according to a modified general procedure A using the crude 6-iodohex-2-ene, N-benzylamine (5.50 mL, 50.0 mmol) in EtOH (2.5 M). The product was purified using silica-gel flash column chromatography (20% EtOAc/Hexanes + 1% NEt3) to yield the title compound as a yellow oil (0.397 g, 21% over two steps).

(E)-N-Benzylhex-4-en-1-amine 1j''
The title compound was synthesized according to a two-step procedure. To a round bottom flask was added (E)-hex-4-en-1-ol (1.50 g, 15.0 mmol) followed by dilution in THF (0.2 M). PPh3 (4.72 g, 18.0 mmol), then imidazole (3.06 g, 45.0 mmol) were added, and the mixture was cooled to 0 °C. Iodine (4.18 g, 16.5 mmol) was then added. The reaction mixture was stirred at 0 °C for 30 min then rt for 30 min. Upon completion, the reaction was concentrated via rotary evaporation. The reaction mixture was diluted with EtOAc and was extracted using water (x1) and then brine (x1). The organic phase was dried with Na2SO4 and filtered. The filtrate was concentrated via rotary evaporation and OPPh3 was removed from the mixture via recrystallization using Et2O/hexanes. The filtrate was concentrated, and this product was used without further purification. Then, the amine was alkylated according to a modified general procedure A using the crude 6-iodohex-2-ene, N-benzylamine (8.20 mL, 75.0 mmol) in EtOH (2.5 M). The product was purified using silica-gel flash column chromatography (20% EtOAc/Hexanes + 1% NEt3) to yield the title compound as a yellow oil (1.17 g, 41% over two steps).

2-Allyl-N-benzylaniline 1m
To a clean dry microwave vial was added a solution of benzaldehyde (0.3 mL, 3 mmol) and TFE (6 mL) and was magnetically stirred at RT. After 5 minutes, the respective o-allylanline (3 mmol) was added and the mixture vigorously stirred. After stirring for overnight, NaBH4 (0.14 g, 3.6 mmol) was added. After completion of the reaction, as monitored by TLC, the mixture was filtered, washing with TFE (6 mL). The filtrate was concentrated via rotary evaporation and the crude product was purified using silica-gel flash column chromatography (30% toluene/petroleum ether) to yield the title compound as a yellow oil (0.30 g, 44% over 2 steps). Characterization data is in good agreement with previously reported data. 7

N-(Thiophen-2-ylmethyl)pent-4-en-1-amine 1o
To a round bottom flask was added 5-bromopent-1-ene (1.01 g, 6.8 mmol) followed by dilution in DMSO (1 M). NaN3 (0.771 g, 11.9 mmol) was added and the mixture was stirred at room temperature for 3 h until the solution gets cloudy. Upon completion, the reaction mixture was poured into water (50 mL) and extracted with Et2O (50 mL x 2), then the organic layer was dried through Na2SO4. PPh3 (3.56 g, 13.6 mmol) and thiophene -2 -carbaldehyde (0.76 g, 6.8 mmol) were added to the ether solution and the mixture was stirred over night at room temperature. The reaction mixture was concentrated via rotary evaporation and added MeOH (20 mL) followed by NaBH4 (0.308 g, 8.13 mmol). The mixture was stirred at room temperature for 1h. Upon completion, HCl 1 M (20 mL) and H2O (30 mL) were added, the slurry mixture was filtered to remove phosphine-based by-products. The acidic solution was extracted with Et2O (50 mL) to remove other impurities and then basified by NaOH 1M (25 mL). The basic solution was extracted by DCM (50 mL x 2), then the DCM layer was rinsed with water (x1), and then brine (x1). The organic phase was dried with Na2SO4 and filtered. The filtrate was concentrated via rotary evaporation. The product was purified using silica-gel flash column chromatography (20% EtOAc/Hexanes + 1% Et3N) to yield the title compound as a yellow oil (0.43 g, 37%).

2-Allylaniline 1v
The title compound was prepared using a modified literature procedure to yield the title compound as a yellow oil (0.57 g, 57%). Characterization data is in good agreement with previously reported data. 8

2-Methyl-1-(4-methylbenzyl)pyrrolidine 4b
The title compound was synthesized according to general procedure B using urea hydrogen peroxide (0.0677 g, 0.72 mmol), amine 1b (0.114 g, 0.60 mmol), B2(OH)4 (0.118 g, 1.32 mmol) in TFE (0.1 M). The crude reaction mixture was concentrated via rotary evaporation, then diluted with DCM (50 mL) and water (50 mL). 10 mL of 1 M HCl was added, and the phases were separated. Additional 20 mL of water was added into DCM layer, the aqueous phases were separated and combined. The product was isolated after basic extraction to yield the title compound as a yellow oil (0.076 g, 67%).

1-(Cyclohexylmethyl)-2-methylpyrrolidine 4e
The title compound was synthesized according to general procedure B using urea hydrogen peroxide (0.0677 g, 0.72 mmol), amine 1e (0.109 g, 0.60 mmol), B2(OH)4 (0.118 g, 1.32 mmol) in TFE (0.1 M). The crude reaction mixture was concentrated via rotary evaporation, then diluted with DCM (50 mL) and water (50 mL). 10 mL of 1M HCl was added, and the phases were separated. Additional 20 mL of water was added into DCM layer, the aqueous phases were separated and combined. The product was isolated after basic extraction to yield the title compound as a yellow oil (0.070 g, 64%).

1-Benzyl-2,2-dimethylpyrrolidine 4i
The title compound was synthesized according to general procedure B using urea hydrogen peroxide (0.068 g, 0.72 mmol), amine 1i (0.114 g, 0.60 mmol), B2(OH)4 (0.065 g, 0.72 mmol) in TFE (0.1 M). The crude reaction mixture was concentrated via rotary evaporation, then diluted with DCM (50 mL) and water (50 mL). 10 mL of 1 M HCl was added, and the phases were N N + separated. The product was isolated after basic extraction to yield the title compound as a yellow oil (0.077 g, 68%). Characterization data is in good agreement with previously reported data. 10

2-Methyl-1-phenylpyrrolidine 4k
The title compound was synthesized according to a modified general procedure B using urea hydrogen peroxide (0.068 g, 0.72 mmol), amine 1k (0.097 g, 0.60 mmol), B2(OH)4 (0.645 g, 0.72 mmol) in TFE (0.1 M). The product was isolated after aqueous extraction to yield the title compound as a brown oil (0.049 g, 51%). Characterization data is in good agreement with previously reported data. 11

1-Benzyl-2-methylindoline 4m
The title compound was synthesized according to a modified general procedure B using urea hydrogen peroxide (0.068 g, 0.72 mmol), amine 1m (0.134 g, 0.60 mmol), B2(OH)4 (0.065 g, 0.72 mmol) in TFE (0.1 M). The crude reaction mixture was concentrated via rotary evaporation, and it was purified by column chromatography (20% toluene/petroleum ether) to yield the title compound as a yellow oil (0.043 g, 32%). Characterization data is in good agreement with previously reported data. 13

3-(2-Methylpyrrolidin-1-yl)propan-1-ol 4s
The title compound was synthesized according to general procedure B using urea hydrogen peroxide (0.0677 g, 0.72 mmol), amine 1s (0.086 g, 0.60 mmol), B2(OH)4 (0.118 g, 1.32 mmol) in TFE (0.1 M). The crude reaction mixture was concentrated via rotary evaporation, then diluted with DCM (50 mL) and water (50 mL). 10 mL of 1M HCl was added, and the phases were separated. 15 mL of 1M KOH and excessive amount of NaCl were added to saturate the acidic solution. The product was isolated after aqueous extraction to yield the title compound as a yellow oil (0.053 g, 62%).