Primary α-tertiary amine synthesis via α-C–H functionalization

A reactive ketimine intermediate was demonstrated to be intercepted by a variety of nucleophiles including organometallics and TMSCN.


1: General information:
All reagents bought from commercial sources were used as received. Organic solvents were evaporated under reduced pressure using a Büchi rotary evaporator. All solvents were commercially supplied or dried by filtration through activated alumina (powder ~150 mesh, pore size 58 Å, basic, Sigma-Aldrich) columns. Petrol ether (PE) refers to distilled light petroleum of fraction 30 -40 °C.
Toluene was distilled twice over calcium hydride.
All reactions were followed by thin-layer chromatography (TLC) when practical, using Merck Kieselgel 60 F254 fluorescent treated silica. Visualization was accomplished under UV light (λ max = 254 nm) and by staining with potassium permanganate staining dip. Chromatographic purification was performed on VWR 60 silica gel 40-63 μm using HPLC grade solvents that were used as supplied.
NMR spectra were recorded on Bruker spectrometers operating at 400 or 500 MHz ( 1 H resonance).
Proton chemical shifts () are given in parts per million (ppm) relative to tetramethylsilane (TMS) with the solvent resonance as internal standard: CDCl 3 , δ = 7.26 ppm; CD 2 Cl 2 , δ = 5.32 ppm; CD 3 CN, δ = 2.13 ppm; CD 3 OD, δ = 3.31 ppm. The following abbreviations are used to describe spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, ddt = doublet of doublet of triplets, m = multiplet, br s = broad signal. Coupling constants (J) are given in Hertz (Hz). 13 C NMR spectra were recorded with complete proton decoupling. Carbon chemical shifts are reported in ppm (δ) relative to TMS with the solvent resonance as internal standard: CDCl 3 , δ = 77.16 ppm; CD 2 Cl 2 , δ = 53.84 ppm; CD 3 CN, δ = 1.32 ppm. CD 3 OD, δ = 49.00 ppm. Two-dimensional NMR spectroscopy experiments (COSY, HSQC and HMBC) were used where appropriate to assist in the assignment of signals in 1 H and 13 C spectra and data are not reported. High-resolution mass spectra (HRMS) were recorded on Bruker Daltonics MicroTOF mass spectrometer equipped with an ESI source. Infrared spectra (IR) were recorded on a Bruker Tensor 27 FT-IR spectrometer from a thin film on a diamond ATR module. Only selected maximum absorbances are reported. All other commercial reagents were used without further purification, unless otherwise indicated. S4 2: Optimization studies: 2.1: Optimization for organometallic addition: Table S1: Protocol optimization for organometallic addition We began our investigation by screening various quinones against 1-(4methoxyphenyl)ethan-1-amine with commercially available allylmagnesium bromide and the results are summarised in Table S1. Further screening in solvents reveal that toluene (entry 5) is superior to chlorinated (entry 6) or ethereal solvents (entries 7-9) under these standard conditions. DCE is superior to other solvents for p-quinones E and F, due to its poor solubility. No hemiaminal formation occurred with both p-quinones E and F (entries [10][11] with DCE at either 25 ˚C or 80 ˚C which suggest that are not suitable reagents for this transformation.

2.2: Optimization for cyanation:
After several attempts, we were delighted to found that the careful selection of solvents along with the nucleophile source (TMSCN), can play a crucial role in the incorporation of nitriles to the ketimines (Table S2). The reaction is unsuccessful with toluene alone but successful with the combination of toluene and MeOH in 2:1 ratio (0.1 M), suggesting that MeOH is crucial for the S5 generation of HCN from TMSCN. Pleasingly, almost comparable results were observed (Table S2,   entries 2-3) with MeOH (0.1 M) alone. For the sake of convenience and homogeneity, we decided to use MeOH (0.1 M) as solvent for the subsequent transformations. The initial oxidative conditions (I 2 /NaOH) were unsuccessful and gave only the undesired imine 49'' (Table S3, entry 1). Further hydrolysis of 49'' with either aqueous NaOH or aqueous HCl gave complex mixture of products. After numerous attempts by screening a variety of oxidants, we were pleased to find that orthoperiodic acid (H 5 IO 6 ) proved to be more efficient and cleaved the phenolic unit completely from the cyanoaddition product (entry 8).

Synthesis of 3,5-diisopropyl-o-benzoquinone (C):
The compound C was synthesised using the known literature method with slight modifications. 3,5diisopropylcatechol S5 (0.50 g, 2.57 mmol) was dissolved in a 100 mL round bottom flask using 49 mL of EtOAc and 2.5 mL of water (20:1, 0.05 M) and the resulting biphasic solution was cooled to 0 ˚C before the addition of bleach (NaOCl·5H 2 O) (3.02 mL, 2.57 mmol, 6-14% active Cl 2 ). The resulting heterogeneous green solution was stirred for exactly 30 minutes at 0 ˚C. After this time, the crude product was taken into separating funnel and organic phase was separated, washed with brine and dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The crude product was recrystallized using pentane gave a deep brown solid of compound C (380 mg, 1.98 mmol, 77%  8, 180.4, 161.8, 149.1, 134.6, 122.2, 34.9, 27.5, 21.7, 20.6. The remaining data was consistent with the literature. 2

Synthesis of 3,5-di-tert-butyl-o-benzoquinone (D):
The compound D was synthesised using the known literature method with slight modifications. 3,5di-tert-butylcatechol S6 (12.5 g, 56.3 mmol) was dissolved in a 2 L round bottom flask using 1.07 L of EtOAc and 53.6 mL of water (20:1, 0.05 M) and the resulting biphasic solution was cooled to 0 ˚C before the addition of bleach (NaOCl·5H 2 O) (66.0 mL, 56.2 mmol, 6-14% active Cl 2 ). The resulting heterogeneous green solution was stirred for exactly 30 minutes at 0 ˚C. After this time, the crude product was taken into separating funnel and organic phase was separated, washed with brine and dried (Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The crude product was recrystallized using pentane gave a deep red crystals of compound D (11.9 g, 53.97 mmol, 96% 3, 180.2, 163.4, 150.1, 133.6, 122.2, 36.2, 35.6, 29.3, 28.0. The remaining data was consistent with the literature. 2

3.2: General Procedure A for α-C-H Functionalization of primary amines with Grignard reagent:
The synthesis of 2-(4-methoxyphenyl)pent-4-en-2-amine 1 is representative. To a stirred solution of 3,5-di-tert-butyl-o-benzoquinone D (0.29 g, 1.32 mmol, 1.0 equiv) in toluene (6.0 mL), was added a solution of 1-(4-methoxyphenyl)ethan-1-amine S1 (0.20 g, 1.32 mmol, 1.0 equiv) in toluene (7.2 mL) dropwise over 5 min under argon atmosphere. The deep green coloured solution was stirred at room temperature for 2 h. After completion as indicated by TLC (Note: colour changes from deep green to dark violet), the reaction mixture was cooled to 0 ˚C, and was added TMEDA (0.19 mL, 1.32 mmol, 1.0 equiv) and allylmagnesium bromide (1.0 M in Et 2 O, 7.94 mL, 7.94 mmol, 6.0 equiv) and maintained at 0˚C for 1 h. During the Grignard addition, the colour of the reaction mixture changes from dark violet to yellowish brown. The reaction temperature was gradually allowed to return to 25 ˚C and allowed to stir until TLC analysis (A small aliquot of the reaction mixture was worked up in NH 4 Cl-EtOAc to check TLC (Pentane:EtOAc 9.5:0.5)) showed complete conversion. After completion of the reaction as indicated by TLC, the reaction mixture was again cooled to 0 ˚C and aqueous NaOH (1 M) (6.62 mL, 6.62 mmol, 5.0 equiv) was carefully added dropwise to quench the remaining Grignard reagent. To the resulting heterogeneous mixture were added 26 mL of CH 3 CN (0.05 M) and iodine granules (0.40 g, 1.59 mmol, 1.2 equiv) and stirred vigorously for 10 min under argon S9 atmosphere. The o-quinone reappeared gradually during basic oxidation. After completion, reaction mixture was extracted with CH 3 CN (3 x 20 mL). The combined organic layers were washed with aqueous saturated sodium thiosulfate (1 x 10 mL) and brine (2 x 10 mL), respectively, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel eluting with Pentane:EtOAc (80:20 v:v) to EtOAc:MeOH:Et 3 N (70:20:10 v:v) to afford compound 1 (205 mg, 1.07 mmol, 81%) as a yellow oil.

3.3: General Procedure B
for α-C-H Functionalization of primary amines with Grignard reagent: The synthesis of 4-allyltetrahydro-2H-pyran-4-amine hydrochloride 27 is representative. For volatile, low boiling point amines, a modified work-up was employed. After oxidative cleavage of the oquinone, the reaction mixture was extracted with CH 3 CN (3 x 20 mL). The combined organic layers were washed with saturated sodium thiosulfate (1 x 10 mL), brine (2 x 10 mL) respectively. The organic layer was acidified with aqueous 2 M HCl and extracted two times (2 x 20 mL) with aqueous 2 M HCl. The combined aqueous phases were washed with hexane and concentrated in vacuo (Bath temp: 60 ˚C, 72 mbar) to afford the crude yellow solid, which was dissolved in warm CHCl 3 , dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give 4-allyltetrahydro-2H-pyran-4-amine hydrochloride 27 (139 mg, 0.78 mmol, 79%) as off-white powder.

General Procedure D for oxidative cyanation of primary amines:
The synthesis of 4-aminotetrahydro-2H-pyran-4-carbonitrile 54 is representative. 7 To a stirred solution of 3,5-di-tert-butyl-o-benzoquinone D (0.22 g, 0.99 mmol, 1.0 equiv) in MeOH (5.0 mL), was added slowly a solution of 4-aminotetrahydropyran S7 (0.10 g, 0.99 mmol, 1.0 equiv) in MeOH (5 mL) dropwise over 5 min and the resulting mixture was stirred for 1 h at 25 ˚C. After S11 completion as indicated by TLC, the reaction mixture was then cooled to 0˚C and trimethylsilyl cyanide (0.74 mL, 5.93 mmol, 6.0 equiv) was added. The resulting mixture was gradually allowed to return to 25 ˚C and allowed to stir until TLC analysis showed complete conversion. After completion as indicated by TLC, solvent and excess trimethylsilyl cyanide were removed on a rotary evaporator using bath temperature below 25 ˚C (Caution: high bath temperature causes decomposition of addition product). The resulting grey solid was dissolved in CH 3 CN:H 2 O (1:1) (14.1 mL), and cooled to 0 ˚C. To the resulting mixture was added orthoperiodic acid (H 5 IO 6 ) (0.24 g, 1.04 mmol, 1.05 equiv) and stirred vigorously for 10 min (appearance of brown colour denotes reformation of quinone).

3.6: General Procedure E for the photocatalytic reverse polarity α-allylation:
To a mass spec vial under a stream of N 2 was equipped a micro-stirrer charged 3,5-di-tert-butyl-obenzoquinone D (55.0 mg, 0.25 mmol), anhydrous MeOH (0.50 mL), and relevant benzylamine structure (0.25 mmol). The nitrogen line was removed and the reaction mixture allowed to stir for 2 S12 h. The solvent was then removed under a nitrogen stream. To the residue was added anhydrous DMSO (0.25 mL), followed by (Ir[(dFCF 3 ppy) 2 (dtbbpy)]PF 6 ([Ir], 2.8 mg, 0.0025 mmol), diethyl 1,4dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (HE, 95.0 mg, 0.375 mmol) and tert-butyl 2-((phenylsulfonyl)methyl)acrylate (282 mg, 1.00 mmol). The reaction mixture was then degassed with N 2 for 10 min. The flask was sealed and allowed to stir for 20 h under blue light irradiation. After this time the reaction mixture was cooled to 0 °C, and MeCN (0.50 mL), water (0.25 mL) and periodic acid (63.0 mg, 0.28 mmol) were added. The resulting mixture went instantly deep brown to signal reformation of 3,5-di-tert-butyl-o-benzoquinone and was then allowed to stir at 0 °C for 30 min. The reaction mixture was poured into a separating funnel containing water (5 mL) and Et 2 O (10 mL). The aqueous phase was extracted, and the organic phase re-extracted with water (4 x 5 mL). To the combined aqueous phases was added NaOH (1M, 10 mL). The aqueous phase was then extracted with EtOAc:MeCN (1:1, 5 x 10 mL). The combined organics were then washed with NaOH (1M, 5 x 5 mL) and the organics were dried over MgSO 4 and concentrated in vacuo. The crude residue was then purified via silica gel column chromatography to give the desired primary amine product.

3.7: Photoreactor details and photochemistry synthetic procedures:
Hepatochem PhotoRedOx Box, equipped with an EvoluChem LED 18 W light source supplied by Hepatochem. A cardboard cover was also placed over the reactor during reactions. Capable of carrying out up to 8 reactions at one time. Accurate and reproducible results, high throughput.

Synthesis of tert-butyl 2-((phenylsulfonyl)methyl)acrylate:
To a 1 L round-bottomed flask containing tert-butyl acrylate (11.7 mL, 80.0 mmol) and formaldehyde (3.60 g, 120 mmol) in 1,4-dioxane (80 mL) and water (80 mL) was added 1,4diazabicyclo[2.2.2]octane (11.6 g, 104 mmol) portionwise. The reaction mixture was allowed to stir at room temperature for 16 h. The resulting mixture was partitioned between EtOAc (200 mL) and water (200 mL). The organic layer was extracted and then washed with brine (300 mL). The organics were then dried over MgSO 4 and concentrated in vacuo. The crude residue was then dispersed in anhydrous Et 2 O (300 mL) and the flask cooled to -10 °C. To the resulting mixture was added phosphorus tribromide (4.05 mL, 43.0 mmol) dropwise. The flask was allowed to warm to room temperature and stirred for 4 h. The flask was quenched by dropwise addition of water (200 mL).
The resulting suspension was poured into a separating funnel and organic layer extracted. The aqueous phase was then re-extracted with pentane (2 x 200 mL). The combined organics were washed with brine, dried over MgSO 4 and concentrated in vacuo. The crude residue was dissolved in MeOH (300 mL) and was added sodium benzenesulfinate (5.50 g, 33.5 mmol) and the reaction mixture was heated to reflux for 16 h. The flask was allowed to cool for rt and then the MeOH was removed in vacuo. The crude residue was partitioned between EtOAc (200 mL) and water (200 mL).

Synthesis of ethyl 2-((phenylsulfonyl)methyl)acrylate:
To a 1 L round-bottomed flask containing ethyl acrylate (21.8 mL, 200 mmol) and formaldehyde (9.00 g, 300 mmol) in 1,4-dioxane (200 mL) and water (200 mL) was added 1,4diazabicyclo[2.2.2]octane (29.1 g, 260 mmol) portionwise. The reaction mixture was allowed to stir S14 at room temperature for 16 h. The resulting mixture was partitioned between EtOAc (300 mL) and water (300 mL). The organic layer was extracted and then washed with brine (300 mL). The organics were then dried over MgSO 4 and concentrated in vacuo. The crude residue was then dispersed in anhydrous Et 2 O (300 mL) and the flask cooled to -10 °C. To the resulting mixture was added phosphorus tribromide (13.8 mL, 134 mmol) dropwise. The flask was allowed to warm to room temperature and stirred for 4 h. The flask was quenched by dropwise addition of water (300 mL).
The resulting suspension was poured into a separating funnel and organic layer extracted. The aqueous phase was then re-extracted with pentane (2 x 300 mL). The combined organics were washed with brine, dried over MgSO 4 and concentrated in vacuo. The crude residue was dissolved in MeOH (300 mL) and was added sodium benzenesulfinate (19.4 g, 119 mmol) and the reaction mixture was heated to reflux for 16 h. The flask was allowed to cool for rt and then the MeOH was removed in vacuo. The crude residue was partitioned between EtOAc (300 mL) and water (300 mL).

Synthesis of [Ir(dF(CF 3 )ppy) 2 Cl] 2 :
To a three-necked 100 mL round bottomed flask was charged iridium(III) chloride hydrate (448 mg, 1.50 mmol) and 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine (856 mg, 3.30 mmol). The flask was equipped with a condenser, then evacuated and refilled with nitrogen three times. Rigorously degassed 2-ethoxyehtanol (18 mL) and water (6 mL) were added via syringe. The reaction mixture was heated 150 °C for 16 h. After this time the reaction mixture was allowed to return to room temperature and the bright yellow precipitate formed was filtered under a blanket of N 2 , washing with water (150 mL) and then hexane (60 mL
After this time the flask was allowed to return to room temperature. The mixture was diluted in water (300 mL) and hexane (300 mL). The aqueous phase was then separated and then re-extracted with hexane (2 x 300 mL). The aqueous phase was then decanted into a 500 mL conical flask and equipped with a stirrer bar. The flask was heated at 80 °C for 1 hour to remove residual hexane. The flask was allowed to return to room temperature, and an aqueous solution of potassium hexafluorophosphate (7 g in 70 mL water) was added with stirring, and a vibrant yellow precipitate was formed. The mixture was then allowed to stand at 5 °C for 1 hour, before the precipitate was collected via vacuum filtration washing with water (150 mL) and hexane (100 mL o-quinone (6.60 g, 30.0 mmol) was placed in a 3 neck round bottom flask (1000 ml), which was connected to a reflux condenser and argon. The evacuate/refill cycle was repeated 2-3 times before the addition of dry toluene and the whole setup was maintained under argon. Washed with brine twice (2 x 50 mL) to remove TMEDA and any residual iodinated species.

S28
Organic layer was acidified directly with 2 M HCl (General Procedure B). For General Procedure A and C; the resulting organic layer was dried and condensed via vacuo, followed by column chromatography.
Dispersion of aqueous acidic phase from organic phase; and conformation of its acidity using pH paper.
Partitioned between aqueous and organic layers Separation of aqueous acidic phase from organic phase and followed by further extraction twice with 2M aqueous HCl (2 x 250 mL).

S30
The aqueous acidic phase was washed with pentane to remove any I 2 impurity.

Synthesis of 2-(4-methoxyphenyl)pent-4-en-2-amine (1)
The title compound was prepared using General Procedure A. The cleavage of phenol unit was performed by using 3 equiv of I 2 and 5 equiv NaOH (1 M

Synthesis of 1-allylcyclooctan-1-amine hydrochloride (25)
The title compound was prepared using General Procedure A. The free amine was protected as HCl salt using 4 M HCl in dioxane. The cleavage of phenol unit was performed by using 2 equiv of I 2 and 5 S40

Synthesis of tert-butyl 4-allyl-4-aminopiperidine-1-carboxylate hydrochloride (30)
The title compound was prepared using General Procedure B. The cleavage of phenol unit was performed by adding 1.2 equiv of pyrrolidine along with I 2 (1.2 equiv) and NaOH (1 M

Synthesis of 2-(4-methoxyphenyl)but-3-en-2-amine hydrochloride (36)
The title compound was prepared using General Procedure C. Vinyl lithium was generated using the known literature method 6 in brief, in a Schlenk tube under an argon atmosphere, n-butyllithium (3.17, 7.94 mmol. 2.5 M in hexanes) was added dropwise to the neat tetravinyl stannane (0.72 mL, 3.97 mmol) over the course of 5 min at 25 ˚C. A white precipitate has formed during the addition of n-butyllithium. After letting it settle, the supernatant solution was collected through syringe and added to the ketimine/hemiaminal and TMEDA mixture at 0 ˚C. The reaction was gradually warmed to 25 ˚C and continued the stirring for 24 h. The remaining procedure is same as General Procedure C. 10 equiv of NaOH (1.0 M) was used during oxidation. The free amine was protected as HCl salt using 4 M HCl (0.5 mL) in dioxane. Yellow solid (107 mg, 0.50 mmol, 76%). FT-IR (thin film) ν max (cm -