Catalytic direct amidations in tert-butyl acetate using B(OCH2CF3)3

B(OCH2CF3)3-catalysed direct amidations of challenging substrates (polar heteroycles, poorly nucleophilic anilines) work well in tBuOAc under Dean–Stark conditions.


General Methods
All reagents and solvents were purchased and used as supplied unless otherwise stated. All reactions were carried out at atmospheric pressure with stirring and under air atmosphere unless otherwise indicated. Piperidine was distilled before use. Preparation of Tris (2,2,2trifluoroethyl)borate was performed according to literature procedure (Sci. Adv., 2017, 3, e1701028). All resins were pre-washed with EtOAc, Et2O and CH2Cl2 and dried in vacuo prior to use. In vacuo is used to describe evaporation of solvent by Büchi rotary evaporator between 17 ºC and 50 ºC at a pressure of ~ 10 mmHg. All reactions were monitored by TLC or 1 H NMR.
TLC plates used were pre-coated with silica gel 60 F254 on aluminium (Merck KGaA). The spotted TLCs were visualised by UV light (254 nm or 365 nm) or chemically stained (KMnO4, or Ninhydrin). 1 H NMR and 13 C NMR spectra were recorded at 400, 600 or 700 MHz (for 1 H) and 100, 125 or 175 MHz (for 13 C) on a Bruker AMX400, AMX600 or NEO700 at ambient temperature, unless otherwise indicated. Deuterated solvents for NMR detection used were CDCl3, MeOD-d4 or DMSO-d6 as stated in the spectrum. Peaks are assigned as singlet (s), doublet (d), triplet (t), quartet (q), quintet (qn) or multiplet (m). All shifts are reported in parts per million (ppm) and compared against residual solvent signals: CDCl3 (δ = 7.26 ppm, s), DMSO (δ = 2.50 ppm, qn) or MeOD (δ = 3.31, qn) as the internal standard. Coupling constants (J) are quoted in Hertz (Hz) to one decimal place. Mass spectrometry was performed on VG70 SE (ES+, CI, ES-modes). Infra-red spectra were obtained using a Perkin-Elmer Spectrum 100 FTIR Spectrometer operating in ATR mode, all frequencies given in reciprocal centimetres (cm -1 ). Melting points were measured with a Gallenkamp heating block and are uncorrected.

Optimisation of conditions and catalysts
A suspension of cyclohexanmethylamine (652 µL, 5.0 mmol, 1 eq), 2-picolinic acid (615 mg, 5.0 mmol, 1 eq) and B(OCH2CF3)3 in solvent (5-10 mL as below) with a Dean-Stark apparatus (side arm filled with the given solvent) was heated to reflux for 24 hours. The reaction mixture was cooled to room temperature and water (0.5 mL), dimethyl carbonate (5 mL) Amberlite IRA-743 (0.25 g) and A-26(OH) (0.5 g) resins were added and the resulting suspension was stirred for 30 min. MgSO4 (~0.5 g) was added and the mixture filtered and the resins washed with EtOAc (2 × 5 mL). The combined filtrates were concentrated in vacuo to yield the amide.
In cases where the reaction had not gone to full conversion the product was further purified by flash column chromatography (20% EtOAc in petrol).

Catalyst Stability Study
A suspension of cyclohexanmethylamine (652 µL, 5.0 mmol, 1 eq), 2-picolinic acid (615 mg, 5.0 mmol, 1 eq) and B(OCH2CF3)3 (107 l, 0.5 mmol) in solvent (5 mL of either t BuOAc or n BuOAc) with a Dean-Stark apparatus (side arm filled with the given solvent) was heated to reflux for 24 hours then allowed to cool to room temperature. The contents of the Dean-Stark trap were transferred to a flask and fluorobenzene (96 mg, 1 mmol) was added as an internal standard. A sample from this mixture was removed, diluted with CDCl3 and analysed by 19 F NMR. Fluorobenzene (96 mg, 1 mmol) was also added to the reaction flask and a sample from this mixture was also analysed by 19 F NMR. t

BuOAc
The reaction flask contained 49% of the total quantity of CF3CH2OH (green/blue).
The peak indicated with the arrow is the same signal observed in a similar reaction in TAME where 78% of the CF3CH2OH remained in the reaction flask after 24 h (Sci. Adv. 2017, 3, e1701028).

BuOAc
The reaction flask contained 16% of the total quantity of CF3CH2OH (green/blue).
The peak indicated with the arrow is the same signal observed in a similar reaction in TAME where 78% of the CF3CH2OH remained in the reaction flask after 24 h (Sci. Adv. 2017, 3, e1701028). 7
MgSO4 (~0.5 g) was added and the mixture filtered and the resins washed with EtOAc (2 × 5 mL). The combined filtrates were concentrated in vacuo to yield the pure amide.
MgSO4 (10 g) was added and the mixture filtered and the resins washed with EtOAc (3 × 10 mL). The combined filtrates were concentrated in vacuo to yield the amide as a white solid (21.23 g, 97.22 mmol, 97%). The yield in TAME using 20 mol% B(OCH2CF3)3 was 23%.