Copper-catalyzed intermolecular C(sp3)–H bond functionalization towards the synthesis of tertiary carbamates

We describe the development of an intermolecular unactivated C(sp3)–H bond functionalization towards the direct synthesis of tertiary carbamates.


3-1. Screening of Metal Sources
In a nitrogen-filled glove box, a flame-dried 10 mL screw cap test tube with magnetic stir-bar was charged with a metal salt (0.050 mmol, 10 mol%) and 1,10-phenanthroline (9.0 mg, 0.050 mmol, 10 mol%). The test tube was removed from the glove box, and cyclohexane (1a, 0.54 mL, 5.00 mmol, 10.0 equiv), phenyl isocyanate (2a, 59.6 mg, 54.3 L, 0.500 mmol), di-tert-butylperoxide (3, 146 mg, 0.18 mL, 1.00 mmol, 2.0 equiv), and benzene (1.0 mL) were added under argon atmosphere. The test tube was placed in a preheated oil bath and the mixture was stirred vigorously at 100 C for 36 h. Cooled to room temperature, the reaction mixture was passed through a short pad of silica gel with the aid of dichloromethane, and concentrated. 1 H NMR using 1,1,2,2-tetrachloroethane as an internal standard quantified the yield of 4a.
Neocuproine was proved to be the best ligand for carbamation of cyclohexane.

Entry
Alkane ( Trifluorotoluene was proved to be the best solvent for carbamation of cyclohexane.
2.5 equiv of 3 was proved to be the best amount for carbamation of cyclohexane.

3-6. Screening of Catalyst Loadings
In an nitrogen-filled glove box, a flame-dried 10 mL screw cap test tube with magnetic stir-bar were charged with tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(NCMe)]BF 4 (X mol%) and neocuproine (Y mol%). The test tube was removed from the glove box, and cyclohexane (1a, 0.54 mL, 5.00 mmol, 10.0 equiv), phenyl isocyanate (2a, 59.6 mg, 54.3 L, 0.500 mmol), di-tert-butyl peroxide (183 mg, 0.23 mL, 1.25 mmol, 2.5 equiv), and trifluorotoluene (0.50 mL) were added under argon atmosphere. The test tube was placed in preheated oil bath and the mixture was stirred vigorously at 100 C for 36 h. Cooled to room temperature, the reaction mixture was passed through a short pad of silica gel with the aid of dichloromethane, and concentrated. 1 H NMR using 1,1,2,2tetrachloroethane as an internal standard quantified the yield of 4a.
5.0 mol% of [Cu(NCMe) 4 ]BF 4 and 5.0 mol% of neocuproine were proved to be the best amounts for carbamation of cyclohexane.

3-7. Screening of Concentrations
In an nitrogen-filled glove box, a flame-dried 10 mL screw cap test tube with magnetic stir-bar were charged with tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(NCMe) 4 ]BF 4 (7.9 mg, 0.0250 mmol, 5.0 mol%) and neocuproine (5.0 mg, 0.0250 mmol, 5.0 mol%). The test tube was removed from the glove box, and cyclohexane (1a, 0.54 mL, 5.00 mmol, 10.0 equiv), phenyl isocyanate (2a, 59.6 mg, 54.3 L, 0.500 mmol), di-tert-butyl peroxide (183 mg, 0.23 mL, 1.25 mmol, 2.5 equiv), and trifluorotoluene were added under argon atmosphere. The test tube was placed in preheated oil bath and the mixture was stirred vigorously at 100 C for 36 h. Cooled to room temperature, the reaction mixture was passed through a short pad of silica gel with the aid of dichloromethane, and concentrated. 1 H NMR using 1,1,2,2-tetrachloroethane as an internal standard quantified the yield of 4a. 0.90 M 63 a Yield was determined by 1 H NMR spectrum using 1,1,2,2-tetrachloroethane as an internal standard. b Reaction was performed in neat cyclohexane (10 equiv) without adding trifluorotoluene. 0.50 M was proved to be the best concentration for carbamation of cyclohexane.
(i) Reaction at 100 C gave tertiary carbamate (4a) selectively. (ii) Reaction at 150 C underwent thermal cleavage of a Boc group in product 4a to give N-cyclohexylaniline selectively.

Entry
Time ( 24 h was proved to be the best reaction time for carbamation of cyclohexane.

General Procedure
Procedure A: In a nitrogen-filled glove box, a flame-dried 10 mL screw cap test tube with a magnetic stir-bar was charged with tetrakis (acetonitrile) copper(I) tetrafluoroborate [Cu(NCMe) 4 ]BF 4 (0.0250 mmol, 5.0 mol%) and neocuproine (0.0250 mmol, 5.0 mol%). The test tube was removed from the glove box, an alkane (1, 5.0 mmol, 10 equiv), trifluorotoluene (0.50 mL), and di-tert-butylperoxide (3, 1.25 mmol, 2.5 equiv) were added sequentially under argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. An isocyanate (2, 0.500 mmol) was added to the mixture, and the test tube was placed in a preheated oil bath. Then, the mixture was stirred vigorously at 100 C for 24 h, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel to give the desired tertiary carbamate.

Procedure B:
In a nitrogen-filled glove box, a flame-dried 10 mL screw cap test tube with a magnetic stir-bar was charged with tetrakis(acetonitrile)copper(I) tetrafluoroborate [Cu(NCMe) 4 ]BF 4 (0.0250 mmol, 5.0 mol%) and neocuproine (0.0250 mmol, 5.0 mol%). The test tube was removed from the glove box, an alkane (1, 15.0 mmol, 30 equiv) and di-tert-butylperoxide (3, 1.25 mmol, 2.5 equiv) were added under argon atmosphere and the mixture was stirred at room temperature for 10 minutes. An isocyanate (2, 0.500 mmol) was added to the reaction mixture and the test tube was placed in a preheated oil bath. Then the mixture was stirred vigorously at 100 C for 24 h, cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography on silica gel to give the desired tertiary carbamate.

b) Reaction of n-butyl carbamate (5n) with peroxide (3) and copper(I) complex:
The differences of the induction periods and absorbance intensities of the bands at 1725 cm -1 for both reactions were correlated to the results that n-butyl isocyanate (2n) was more reactive compared with n-butyl carbamate 5n.

(4) Difference of the reactivity between isocyanates and n-butyl carbamates towards carbamation of cyclohexane:
The difference of the reactivity between isocyanates and carbamates is possibly due to the different modes of the formation of [Cu]-carbamate species. The plausible reaction mechanisms are as shown below.

a) Formation of [Cu]-carbamate species from copper(I)-neocuproine complex, isocyanate, and tert-butyl peroxide:
A reaction of cyclohexane (1a) with phenylisocyanate (2a) was almost completely inhibited by 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO, 2 equivalents) under the optimized conditions. This result indicated that the reaction would proceed in a radical pathway, and the active Cu-carbamate intermediate was formed via i) formation of a t BuO radical from ( t BuO) 2 , ii) formation of a carbamate radical by addition of the in situ generated t BuO radical to an isocyanate, and iii) formation of the Cu(II)-carbamate species 6 by addition of the generated carbamate radical to Cu(I) catalyst. Scheme S1. Plausible mechanism for the formation of [Cu]-carbamate species from isocyanates.

b) Formation of [Cu]-carbamate species from copper(I)-neocuproine complex, secondary carbamate, and tert-butyl peroxide:
In the case of carbamates, the yield of the desired product was higher in tert-butyl phenylcarbamate (65%) than in tert-butyl butylcarbamate (11%). The difference of the yields may be due to the difference of acidities (NH proton of phenylcarbamate > NH proton of butylcarbamate).
These results indicate the carbamate reaction proceeds via a Brønsted acid/base pathway, and the active Cu-carbamate intermediate was generated A possible reason for the observed difference in the induction period between the two reactions whether using isocyanates or carbamates might be due to the faster reaction rate in the addition of t BuO radical to isocyanates to generate presumed active copper(II)-carbamate than deprotonation of carbamates by Cu(II)-O t Bu species.

Kinetic Isotopic Effect (KIE) Experiments
In a nitrogen-filled glove box, flame-dried 10 mL screw cap test tubes with a magnetic stir-bar were charged with tetrakis(acetonitrile) copper(I) tetrafluoroborate [Cu(NCMe) 4 ]BF 4 (7.9 mg, 0.0250 mmol, 5.0 mol%) and neocuproine (5.0 mg, 0.0250 mmol, 5.0 mol%). The test tubes were removed from the glove box, cyclohexane (1a, 420 mg, 5.00 mmol, 10 equiv), trifluorotoluene (0.50 mL), di-tert-butyl peroxide (3, 183 mg, 1.25 mmol, 2.5 equiv), and phenyl isocyanate (2a, 59.6 mg, 54.3 L, 0.500 mmol) were added under argon atmosphere. All the test tubes were placed in a preheated oil bath and the mixtures were stirred vigorously at 100 C. The vials were removed at different designated time interval (0, 30, 40, 70, and 90 min). The reaction mixture was cooled to room temperature, and passed through a short pad of silica gel with the aid of dichloromethane. The reaction mixture was concentrated and dodecane (85.2 mg, 0.500 mmol) was added as an internal standard. The desired product was quantified through gas chromatography.
By using above procedure, the similar sets of experiments were conducted using cyclohexane-d 12 instead of cyclohexane. Based on the above results, the KIE value is k H /k D = 2.9, which suggested that C-H bond cleavage was the rate-determining step of the reaction.

Time [min]
Cy-H Cy-D