Borate esters: Simple catalysts for the sustainable synthesis of complex amides

A commercially available borate ester catalyzes amide formation from carboxylic acids and amines with very high efficiency.


1b. Optimisation for unprotected amino acid amidation
Reaction conditions: Phenylalanine (0.330 g, 2 mmol), benzylamine (0.662 mL, 6 mmol), 10 mol% B(OCH2CF3)3, cyclopentyl methyl ether (4 mL), reflux, 15 h. 1,4-dimethoxybenzene was used as an internal standard      Procedure for entry 1: Under argon atmosphere phenylacetic acid (0.55 mmol, 75.0 mg, 1.1 equiv.), the borinic acid (12 mg, 0.05 mmol, 10 mol%) and 1 g of powdered of activated 5Å molecular sieves were introduced. Dry CH2Cl2 (7 mL) was added, and the suspension was vigorously stirred for 15 min. Then, benzylamine (0.50 mmol, 54.6 µL, 1 equiv.) was added and the resulting mixture was further stirred for 48 h at room temperature. The suspension was filtered through a pad of celite and washed with CH2Cl2 (3 x 5 mL). The filtrate was extracted twice with an aqueous solution of HCl (1M, 10 mL), twice with an aqueous solution of NaOH (1M, 10 mL) and brine (10 mL). The organic layer was collected, dried over anhydrous MgSO4, filtered and evaporated under reduced pressure to yield the title amide as pure product. Procedure for entry 2: Carboxylic acid (38 mg, 0.5 mmol), molecular sieves 4Å (0.75 g) and Hf(Cp)2Cl2 (5-10 mol%) were added to a 20 mL MW-vial equipped with a magnetic stirring bar and a cap with septum was crimped on. The atmosphere was evacuated and replaced with nitrogen gas. The vial was placed in an oil bath at 26 °C and dry diethylether (5 mL) was added. The amine (1 mmol) was added with a syringe and the reaction was stirred at constant temperature for the time indicated in the article. Thereafter, the mixture was filtered through a plug of silica (4 x 3.5 cm) with 100 mL of an EtOAc:Et3N (200:1) eluent. The solvent was removed under reduced pressure affording analytically pure product unless otherwise noted.
3 Solvent (1M), 4 Å MS (1g/mmol), catalyst (10 mol%), Acid (1.1 eq), Amine (1.0 eq), 50 °C, 18h PhMe (29 g), 4 Å MS (33 g), MIBA (0.92 g), Phenyl acetic acid (4.90 g), Benzylamine (3.56 g), total = 71.4 g CH2Cl2 (67 g) 1M HCl (200 g) 1M NaOH (200 g) Brine (50 g) CH2Cl2 (266 g) total = 783 g 89% yield, 6.693 g Procedure for entry 3: Into a 250 ml round bottom flask equipped with a stir bar was added phenylacetic acid (4.90 g, 36 mmol, 1.1 equiv.), 5-methoxy-2-iodophenylboronic acid (0.92 g, 3.3 mmol, 10 mol%) and 33 g (1 g per mmol of amine substrate) of activated 4A molecular sieves. Toluene was added to maintain a concentration at 1 M and the mixture was stirred. After 10 minutes, the amine (3.56 g, 33 mmol, 1.0 equiv.) was added. The resulting mixture was stirred for 18 h at 50 °C. The reaction mixture was filtered through a pad of Celite 545, which was rinsed with  19 F NMR analysis (using PhF as an internal standard) of the Dean-Stark trap and crude reaction mixture, of a reaction to prepare amide 2, suggested that less than one equivalent of trifluoroethanol was removed from the reaction mixture over the course of the amidation reaction. Procedure: The reaction was run according to general procedure A using benzoic acid (610 mg, 5.0 mmol) and benzylamine (545 µL, 5.0 mmol) and 10 mol% B(OCH2CCF3)3 for 24 h, at which point the reaction was brought to RT. The contents of the Dean-Stark were transferred to a 10 mL vial, to which Fluorobenzene (the internal standard, 47 L, 0.50 mmol) was added. Fluorobenzene (the internal standard, 47 L, 0.50 mmol) was then added to the reaction mixture. Aliquots taken from the reaction mixture and the material from the Dean Stark trap were diluted with CDCl3 (50% v/v) and analysed by 19 F NMR (300 mHz). For improved quantification the 19 F NMR were run without proton decoupling and with an increased relaxation time of 20s.

Results & Discussion:
Run 1: 23% of the trifluoroethanol was in the Dean-Stark, and 77% in the reaction flask.
Run 2: 21% of the trifluoroethanol was in the Dean-Stark, and 79% in the reaction flask.
The signal for the trifluoroethanol present in the reaction mixture was broadened (top spectrum, figure SI 11). This could be interpreted as exchange between free trifluoroethanol and trifluoroethoxy groups coordinated to boron.

B NMR studies
Analysis of the crude reaction mixture by 11 B NMR for the synthesis of amide 2, only shows the presence of a tetrahedral boron species.

Procedure:
The reaction was run according to general procedure A using benzoic acid (610 mg, 5.0 mmol) and benzylamine (545 µL, 5.0 mmol) and 10 mol% B(OCH2CCF3)3 for 24 h, at which point the reaction was brought to RT. 0.3 mL of the reaction was transferred to an NMR tube and topped up with 0.3 mL of CDCl3. Spectra for B(OCH2CF3)3 and the crude reaction mixture at 4 h and 24 h intervals are shown below. This method is based on a procedure described by Watson et al. 45 Benzoyl chloride 3.4 mL, 30 mmol) was added dropwise to trifluoroethanol (1.4 mL, 20 mmol) and triethylamine (3.4 mL, 24 mmol) in CH2Cl2 (30 mL). The reaction mixture was heated to reflux for 15 h, at which point it was concentrated in vacuo. The resulting residue was dissolved in EtOAc (40 mL), washed with saturated NaHCO3 (40 mL) and brine (40 mL), dried over anhydrous MgSO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Pet.

Kinetic Analysis
The graphical method developed by Burés was used to determine the reaction orders from concentration profiles. This method uses a variable normalization of the time scale to enable the visual comparison of entire concentration profiles, allowing for the order in each component of the reaction to be determined.

Raw data for determination of order of Catalyst
For determination of the order in catalyst, the reaction was run with 5 mol%, 10 mol% and 15 mol% B(OCH2CF3)3. A plot of the concentration of product vs. time is shown below: Graph S1: Effects of catalyst loading

Raw data for determination of order of Amine
For determination of the order in amine, the reaction was run with 1.0 eq, 1.6 eq and 2.0 eq of (S)-(−)-α-Methylbenzylamine. A plot of the concentration of product vs. time is shown below: Graph S2: Effects of excess amine

Raw data for determination of order of Acid
For determination of the order in carboxylic acid, the reaction was run with 1.0 eq, 1.2 eq, 1.4 eq of phenylacetic acid. A plot of the concentration of product vs. time is shown below: Graph S3: Effects of excess acid: Data set 1 Due to the graphical nature of the kinetic analysis, it was difficult to unambiguously determine the order of reaction with respect to acid concentration. For this reason, the reaction was repeated with 1.0 eq and 1.6 eq of phenylacetic acid to obtain further data. A plot of the concentration of product vs. time is shown below: Graph S4: Effects of excess acid: Data set 2

Reproducibility of data:
Two experiments were run with varying times for collection of aliquots. The two reactions displayed excellent reproducibility.
For determination of order in catalyst, the reaction was run with 5 mol%, 10 mol% and 15 mol% B(OCH2CF3)3. For determination of order in amine, the reaction was run with 1.0 eq, 1.6 eq and 2.0 eq of (S)-(−)α-Methylbenzylamine.

Raw data for determination of order of Acid
For determination of order in carboxylic acid, the reaction was run with 1.0 eq (above), 1.2 eq, 1.4 eq of phenylacetic acid. Note: The reaction should be conducted on a scale >25 g to facilitate purification by distillation.

N-Benzylbenzamide (2)
Prepared according to general procedure A from benzoic acid (610 mg, 5.0 mmol) and benzylamine (545 µL, 5.0 mmol) for 28 h, and purified using the standard resin workup procedure to yield 1 a white solid (
Data in agreement with the literature. 28

N-Benzyl-N-methyl-2-phenylacetamide (18)
Prepared according to general procedure A from phenylacetic acid (681 mg, 5.0 mmol) and methylbenzylamine (644 µL, 5.0 mmol) for 24 h, and purified using the standard resin workup procedure to yield 18 as a pale yellow oil (1.12 g, 94%). Note on purity of amine: 3-(trifluoromethyl)-5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazine is described as a colourless oil or yellow oil in literature. The purchased material was a dark brown solid, and resulted in the formation of a dense layer of insoluble oil at the bottom of the reaction flask. Liquid-liquid extraction with EtOAc/NaHCO3 resulted in a pale yellow oil as described in literature and successful amidation reaction. Alternatively, the commercially available HCl salt of the amine can also be washed with EtOAc/NaHCO3 to give free amine as a colourless oil.
Compound was also prepared according to general procedure A using B(OMe)3 as the catalyst from, Boc-alanine (0.945 g, 5.0 mmol) and benzylamine (0.546 mL, 5.0 mmol) in both TAME and PhMe for 24 h, and purified using the standard resin workup procedure to yield 37 as a white solid (0.64 g, 46% in TAME and 85% in PhMe). Spectroscopic data and chiral purity was identical.
Data in agreement with literature. 28