Catalytic β C–H amination via an imidate radical relay† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc05685d

An iodine-catalyzed strategy for β C–H amination of alcohols is enabled by a chemo-, regio-, and stereo-selective H-atom transfer mechanism.

To a round-bottom flask containing a stir bar, alcohol (1 equiv.), and CH2Cl2 (0.1 M) was added trichloroacetonitrile (1.5 equiv.) and DBU (0.1 equiv.). The solution was stirred and monitored by TLC until consumption of alcohol. Upon completion, the solution was concentrated and directly loaded onto silica gel and purified.
Benzimidate Formation -General Procedure (GP2) To a 50 mL round bottom flask was added benzonitrile (1 equiv.), alcohol (12 equiv.), and a stir bar. The solution was cooled to 0 °C, an addition funnel containing acetyl chloride (8 equiv.) was attached, and the apparatus was sealed. The acetyl chloride was added dropwise over a half an hour and then the solution was warmed to room temperature (warning: HCl gas is evolved during this addition, poorly sealed glassware will allow gas to escape). The reaction was stirred at room temperature for 24 hours and then evaporated under reduced pressure to yield the imidate•HCl salt. Free base protocol. The salt was suspended in Et2O and a saturated solution of NaHCO3 was added dropwise until the salt dissolved completely. Upon dissolution, the solution was stirred for five minutes and then diluted with H2O. The organic phase was separated and the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic phase was dried over MgSO4 and concentrated. In most cases, the imidate was analytically pure upon isolation. Alternatively, the crude material could be purified by column chromatography.
Benzimidate Formation -General Procedure (GP3) To a 2-dram vial equipped with a stir bar was added the desired alcohol (1 equiv.) and benzonitrile (1 equiv.) and dry solvent (toluene or dichloroethane, 0.5 M). Triflic acid (1.2 equiv.) was added to the solution, the vial was sealed, and heated to reflux for 24 hours. Upon completion, the vial was cooled to room temperature and evaporated to dryness. The resulting solid was suspended in Et2O and subjected to the free base protocol from GP2. The product was purified by column chromatography.

Transimidation -General Procedure (GP4)
To a 2-dram vial equipped with a stir bar was added the trifluoroethyl benzimidate hydrochloride 1 (1 equiv.), the desired alcohol (1 equiv), and MeCN (0.2 M). The reaction was heated to 50 °C and stirred until consumption of starting imidate (monitored by 1 H NMR). Upon completion, the solution was concentrated and the resulting crude solid was suspended in Et2O and subjected to the free base protocol from GP2. The crude reaction mixture was loaded onto silica gel and purified.

C-H Amination -General Procedure (GP5)
To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added imidate (0.4 mmol, 1 equiv.) and PhI(OAc)2 (154.6 mg, 0.48 mmol, 1.2 equiv.). This vial was evacuated and backfilled with N2 (3x). A degassed stock solution of I2 in dry DMF (2 mL, 0.01 M, 0.05 equiv.) was added to the vial under N2. The reaction was heated to 50°C (by placing vial in an aluminum heating block) and stirred for 4 hours. Upon completion, the reaction was cooled, transferred to a round-bottom flask, and concentrated in vacuo. Hydrolysis and acid/base extraction. To the flask, was added methanol (4 mL) and 2M HCl (0.8 mL). After stirring for 2 hours, 25 mL of CHCl3 and 10 mL of H2O was added. The aqueous layer was washed with CHCl3 (5 x 25 mL). The combined organic fractions were rewashed with H2O (10 mL). The combined aqueous layer was poured into a round bottom, diluted with CHCl3 (25 mL), and finally 6M NaOH (10 mL) was added and stirred for 30 minutes. The aqueous layer was washed with CHCl3 (5 x 25 mL) and the combined organic solution was dried over MgSO4 and concentrated to yield the pure amino alcohol.

Cyclopentyl benzimidate (S20)
Cyclopentanol (86 mg, 0.090 mL, 1 mmol) was subjected to GP4. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the free-base protocol, followed by purification on silica gel (5% Ethyl acetate/hexanes with 1% Et3N) to yield imidate S20 (
The crude mixture was subjected to the free-base protocol, followed by purification on silica gel (5% Ethyl acetate/hexanes with 1% Et3N to yield imidate S22 (

IV. Optimization
Benzimidate 1 was subjected to GP5 with the described modifications. After five hours, the mixture was cooled to room temperature, the solvent was removed in vacuo, and the crude reaction was analyzed via crude 1 H NMR. a Yields were determined by 1 H NMR analysis using 1,2-dichloroethane as an internal standard.

V. Robustness Screen
To determine the tolerance of this reaction in the presence of various functional groups, a robustness screen was conducted. We subjectively chose functional groups that we deemed to be synthetically relevant (alcohols, aldehydes, ketones, alkenes, allyl bromides) or medicinally relevant (heteroarenes, amino acids). 3,4 All additives that were investigated are included below, including those that we were surprised to find were recovered in high yields under both conditions. Only the first five examples are included in the manuscript, since they represent the biggest different between the two conditions. Benzimidate 1 (0.1 mmol) was subjected to GP5 or the stoichiometric amination procedure, 1 with the addition of 1 equivalent of the corresponding additive (0.1 mmol). After two hours, standard was added to the reaction, an aliquot was removed, and diluted with CDCl3 for 1 H NMR analysis. The percent yield of oxazoline and additive remaining were determined with respect to internal standard.
Yields were determined by 1 H NMR analysis using 1,2-dichloroethane as an internal standard.

2-amino-2-(2-(trifluoromethyl)phenyl)ethan-1-ol (8)
Trichloroacetimidate S8 was subjected to GP5. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol 8 (72 mg, 88%) as a white solid.

2-amino-2-(o-tolyl)ethan-1-ol (9)
Trichloroacetimidate S9 was subjected to GP5. Upon reaction completion, the mixture was cooled to room temperature and the solvent was removed in vacuo. The crude mixture was subjected to the hydrolysis protocol to yield amino alcohol 9 (47 mg, 87%) as a white solid.
To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added imidate (0.4 mmol, 1 equiv.) and PhI(OAc)2 (258 mg, 0.8 mmol, 2 equiv.) This vial was evacuated and backfilled with N2 (3x). A degassed stock solution of I2 in dry DMF (2 mL, 0.01 M, 0.05 equiv.) was added to the vial under N2. The reaction was heated to 50°C (by placing vial in an aluminum heating block) and stirred for 4 hours. Hydrolysis and acid/base extraction. Upon completion, the mixture was concentrated in a round-bottom flask, then methanol (4 mL), 2M HCl (0.8 mL), tetrabutylammonium chloride (111 mg, 0.4 mmol) were added. After stirring for 24 hours, the

VI I. Mechanistic Studies a. Time Studies
To study product formation over the course of the reaction, side-by-side reactions of the amination of pentyl benzimidate 1 were quenched at time points and analyzed by 1 H NMR.

Catalytic Amination Procedure:
To obtain this data, pentyl benzimidate 1 was subjected to a modified GP5.
To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added imidate 1 (0.4 mmol, 1 equiv.), PhI(OAc)2 (154.6 mg, 0.48 mmol, 1.2 equiv.). This vial was evacuated and backfilled with N2 (3x). 2 mL of a degassed stock solution of I2 in dry DMF (5 mol%, 10 mol%, or 20 mol%) was added to the vial under N2. The reaction was heated to 50°C (by placing vial in an aluminum heating block). At the indicated time points, the reaction was quenched with 10% aqueous Na2S2O3 (2 mL) and then extracted with Et2O (4 x 4 mL). The crude reaction was concentrated and analyzed by 1 H NMR using an internal standard, dichloroethane (31.6 L, 1 equiv.

b. HAT Selectivity
To probe the selectivity of HAT with various electronic perturbations, we synthesized two benzimidate substrates with -benzylic and -tertiary hydrogen atoms. These substrates were subjected to both the catalytic conditions, and our previously reported stoichiometric conditions. In both cases, more efficient amination was observed in the catalytic system. Using superstiochiometric NaI and PhI(OAc)2 leads to competitive formation of a geminal di-iodide product-suppressing the amination yield.
 vs  competition: secondary vs benzylic C-H Catalytic: Imidate S27 was subjected to GP5. Analysis of the crude 1 H NMR (with 1 equiv. DCE standard) indicates 63% of the desired oxazoline 27a with 36% of the corresponding  aminated product 27b.
Stoichiometric: Imidate S27 was subjected to the stoichiometric reaction conditions. 1 Analysis of the crude 1 H NMR (with 1 equiv. DCE standard) indicates 32% of the desired oxazoline 27a with 15% of the corresponding aminated product 27b and 10% of the di-iodinated imidate 27c.

c. Stereochemical Probe
To probe intermediates in the reaction, cis and trans stereochemical probes were synthesized to understand both the HAT and amination. The catalytic amination results were compared to those previously observed using the stoichiometric conditions. 1 First, subjection of the cis substrate led to material decomposition with none of the desired oxazoline presumably due to the inaccessible benzylic hydrogen. This result mirrors the previous observations. For the trans diastereomer, a notable difference in diastereoselectivity was observed in the isolated oxazoline. Interestingly, in the catalytic system the alkyl iodide intermediate can be observed which was previously not present in the photolytic conditions.
Trichloroacetimidate cis-29 was subjected to GP5 and the stoichiometric reaction conditions. 1 Analysis of the crude 1 H NMR (with 1 equiv. DCE standard) indicates < 5% of the desired oxazoline.

d. Hammett Plot
To determine the stabilization effect of substituents in the transition state of the 1,5-hydrogen atom transfer, a Hammett Plot analysis was conducted. Each data point in Figure S3 is represented as an average of two trials. To identify the pseudo-first order regime, the early reaction time points from Figure S1 were re-examined. Based on the data depicted in Figure S2, a 5-minute time point was selected for Hammett analysis. Figure S2: Expanded kinetic profile for the first ten minutes of a reaction with 5 mol% I2 determined by 1 H NMR.

Catalytic Amination Procedure:
To a 2-dram vial equipped with PTFE septa cap and magnetic stir bar was added imidate (0.4 mmol, 1 equiv.) and PhI(OAc)2 (154.6 mg, 0.48 mmol, 1.2 equiv.). This vial was evacuated and backfilled with N2 (3x). A degassed stock solution of I2 in dry DMF (2 mL, 0.01 M, 0.05 equiv.) was added to the vial under N2. The reaction was heated to 50 °C (by placing vial in an aluminum heating block). After 5 minutes, the reaction was quenched with 10% aqueous Na2S2O3 (2 mL) and then extracted with Et2O (4 x 4 mL). The crude reaction was concentrated and analyzed by 1 H NMR using an internal standard, dichloroethane (31.6 L, 1 equiv.).

e. Intermediate Probe
To probe the mechanism of this reaction, possible intermediates were synthesized. In the event that N-OAc, instead of N-I benzimidate, is formed via AcO-I, N-acetoxybenzimidate S35 was synthesized. The oxime imidate S35 was subjected to our catalytic amination condition, which resulted in full recovery of S35, indicating this is unlikely to be an intermediate. Additionally, S35 is stable in refluxing DMF for 2 hrs.
Oxime Imidate S35 was subjected to GP5. Analysis of the crude 1 H NMR (with 1 equiv. DCE standard) indicates no oxazoline and full recovery of oxime imidate starting material.
Oxime Imidate S35 was heated in DMF at 100 °C for 2 hrs. Analysis of the crude 1 H NMR (with 1 equiv. DCE standard) indicates no oxazoline and full recovery of oxime imidate starting material.