Direct Conversion of Nitriles into Alkene “Isonitriles”

Abstract

The sequenced addition of RLi to nitriles, trapping with isopropylformate, and dehydration with phosphoryl chloride provides an efficient, direct synthesis of alkeneisocyanides. The one-pot sequence involves a series of carefully orchestrated steps: addition, formylation, tautomerization, and dehydration, with CuCN catalyzing a key equilibration of a formyl imine to an N-formyl enamine. The resulting aromatic alkeneisocyanides, that are otherwise challenging to synthesize, engage in an unusual [4+2] type cycloaddition-1,3-H shift-decyanation sequence to afford substituted naphthalenes.

Copper-Catalyzed Conjugate Additions to Isocyanoalkenes

“…Isocyanoalkenes were prepared following a modification of the published procedure . A solution of alkyllithium (1.2 equiv) was added to a −60 °C THF (0.08 M) solution of the nitrile (1.0 equiv) and CuCN (0.02 equiv).…”

“…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), NaH (8.8 mg, 365 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 3-bromopropane-1-thiol (24.9 mg, 161 μmol) for 30 min at −78 °C to afford, after purification (dry-loaded with Celite onto a C-2 silica gel, eluent of 10% EtOAc/hexanes), 40.1 mg (76%) of isocyanosulfanyl bromide 14f as a colorless oil: IR (ATR) 3030, 2921, 2137 cm –1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.67–7.56 (m, 4H), 7.50–7.42 (m, 4H), 7.41–7.35 (m, 1H), 4.87 (dd, J = 7.6, 5.8 Hz, 1H), 3.49 (t, J = 6.3 Hz, 2H), 3.07 (dd, J = 14.0, 7.6 Hz, 1H), 3.01 (dd, J = 14.0, 5.8 Hz, 1H), 2.69 (t, J = 7.0 Hz, 2H), 2.14–2.04 (m, 2H); 13 C­{ 1 H} NMR (100 MHz, CDCl 3 ) δ 158.7, 142.0, 140.1, 134.8, 128.9, 127.8, 127.7, 127.1, 126.7, 58.9, 40.41, 32.2, 31.8, 31.2; HRMS (+APCI) m / z [M – NC] calcd for C 17 H 18 BrS 333.0313, found 333.0307.…”

“…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 isocyanoalkene conjugate addition procedure with 4-(1-isocyanovinyl)-1,1′-biphenyl ( 13a ) (30.0 mg, 146 μmol), NaH (7.0 mg, 292 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 phthamilidine (53.8 mg, 365 μmol) for 97 h at 50 °C to afford, after purification (dry-loaded with Celite onto a 4g silica gel cartridge, eluent gradient from 0% to 5% MeOH/CH 2 Cl 2 ), 38.0 mg (75%) of isocyanophthamilidine 14l as a yellow solid: mp 138.4–139.4 °C; IR (ATR) 3031, 2947, 2139, 1776, 1714 cm –1 ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.93–7.88 (m, 2H), 7.80–7.74 (m, 2H), 7.67–7.62 (m, 2H), 7.61–7.56 (m, 2H), 7.56–7.51 (m, 2H), 7.48–7.42 (m, 2H), 7.40–7.35 (m, 1H), 5.28 (dd, J = 9.7, 5.4 Hz, 1H), 4.28 (dd, J = 13.9, 9.7 Hz, 1H), 3.91 (dd, J = 13.9, 5.4 Hz, 1H); 13 C­{ 1 H} NMR (100 MHz, CDCl 3 ) δ 167.7, 159.8, 142.2, 140.1, 134.4, 132.7, 131.7, 128.9, 127.9, 127.8, 127.1, 126.8, 123.8, 56.3, 44.1; HRMS (+APCI) m / z [M – NC] calcd for C 22 H 16 O 2 N 326.1181, found 326.1179.…”

“…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.…”