Isocyanide Purification: C-2 Silica Cleans Up a Dirty Little Secret

Abstract

EtSiCl3-treated silica gel, ‘C-2 silica,’ proved exceptionally effective for purifying isocyanides that are otherwise irreversibly adsorbed during silica gel chromatography. Purification of a prototypical isocyanide on several chromatographic matrices provided valuable insight into the requirements for purifying silica-sensitive isocyanides. EtSiCl3-modified silica proved optimal as the solid phase, providing up to 90% recovery of pure isocyanides that otherwise fail to elute during silica gel purification.

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes

“… a Ligand L1 (5 mol %) was used unless stated otherwise. b Isolated yield after chromatography on C-2 silica …”

“…TLC plates were visualized by being exposed to short wavelength UV light (254 nm). Flash chromatography was performed using the Buchi Reveleris X2 Automated Flash Chromatography System with commercial or self-prepared cartridges filled with SilicaFlash silica gel P60 (30–400 mesh) purchased from Silicycle or with “C-2 silica” prepared as previously described …”

“…The title compound was prepared following the general isocyanoalkene conjugate addition procedure with 4-(1-isocyanovinyl)-1,1′-biphenyl ( 13a ) (30.0 mg, 146 μmol), Cs 2 CO 3 (14.3 mg, 43.9 μmol), Cu­(I)I (0.7 mg, 4 μmol), ( S )-4-( tert -butyl)-2-[5-(trifluoromethyl)­pyridin-2-yl]-4,5-dihydrooxazole (1.0 mg, 4 μmol), and diethyl 2-methylmalonate (38.2 mg, 219 μmol) for 29 h at rt to afford, after purification (dry-loaded with Celite onto a C-2 silica gel column, eluent of 5% EtOAc/hexanes), 30 mg (55%) of isocyano ester 14g as a yellow oil: IR (ATR) 2982, 2136, 1726 cm –1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.64–7.56 (m, 4H), 7.51–7.42 (m, 4H), 7.39–7.34 (m, 1H), 5.00 (dd, J = 9.2, 3.5 Hz, 1H), 4.30–4.16 (m, 2H), 4.24 (q, J = 7.1 Hz, 2H), 2.51 (dd, J = 14.9, 9.2 Hz, 1H), 2.44 (dd, J = 14.9, 3.5 Hz, 1H), 1.60 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13 C­{ 1 H} NMR (100 MHz, CDCl 3 ) δ 171.3, 171.1, 158.6, 141.5, 140.3, 137.0, 128.9, 127.7, 127.6, 127.1, 126.3, 61.9, 61.8, 54.8, 52.5, 44.6, 20.6, 14.0, 13.9; HRMS (+APCI) m / z [M – NC] calcd for C 22 H 25 O 4 353.1753, found 353.1751.…”

“…The title compound was prepared following the general isocyanocyclopropane synthesis procedure with 4-(1-isocyanovinyl)-1,1′-biphenyl ( 13a ) (30.0 mg, 150 μmol), Cs 2 CO 3 (57.1 mg, 175 μmol), Cu­(I)I (0.7 mg, 3.7 μmol), ( S )-4-( tert -butyl)-2-[5-(trifluoromethyl)­pyridin-2-yl]-4,5-dihydrooxazole (1.0 mg, 3.7 μmol), and dimethyl bromomalonate (33.9 mg, 161 μmol) for 4 h at rt to afford, after purification (dry-loaded with Celite onto C-2 silica gel, eluent of 5% EtOAc/hexanes), 36.2 mg (74%) of isocyanocyclopropane 16b as a yellow solid: mp 114.8–115.8 °C; IR (ATR) 2953, 2130, 1740 cm –1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.64–7.56 (m, 4H), 7.52–7.34 (m, 5H), 3.94 (s, 1H), 3.42 (s, 1H), 2.53 (ABq, Δν = 34.1 Hz, J = 6.8 Hz, 2H); 13 C­{ 1 H} NMR (400 MHz, CDCl 3 ) δ 165.2, 164.8, 158.9, 142.5, 139.9, 130.5, 128.9, 128.5, 127.9, 127.3, 127.2, 53.8, 53.1, 46.8, 43.3, 23.7; HRMS (+APCI) m / z [M + H] + calcd for C 20 H 18 O 4 N 336.1236, found 336.1231; HPLC (Daicel Chiral Technologies Inc. CHIRALPAK IE, 10/90 ethyl acetate/hexanes, flow rate of 2.0 mL/min, λ = 238 nm) t R = 8.9 min (major), 10.5 min (minor) indicated er of 1.05:1.00.…”

Isocyanide 2.0

“…35 Recently, the purification of isocyanides on reversed-phase silica was introduced as an innovation. 36 However, all improvements still suffer from one or another issue such as lengthy laborious procedures, exotic and expensive reagents, massive waste generation, and long exposure of the chemist to potentially hazardous fumes and often show a narrow scope of functionalization. Phosphorus oxychloride (POCl 3 ) is the most used dehydrating agent and yields inorganic phosphate as a side product and is therefore preferable over p-TsCl yielding additional organic waste.…”