Base‐Mediated Syntheses of Di‐ and Trisubstituted Imidazoles from Amidine Hydrochlorides and Bromoacetylenes

Abstract

A new transition metal-free method for the preparation of substituted imidazoles from easy-to-handle amidine hydrochlorides and bromoacetylenes has been developed. The reactions proceed in air and use inexpensive K2 CO3 as base. Additions of 2,2'-bipyridine and water have beneficial effects on the product yields. Various di- and trisubstituted imidazoles have been prepared in good yields (up to 88 %).

Modular Synthesis of Di- and Trisubstituted Imidazoles from Ketones and Aldehydes: A Route to Kinase Inhibitors

“…The title compound was prepared according to general procedure B, using acetophenone (46.0 mg, 0.375 mmol, 1.25 equiv) and 3-hydroxybenzaldehyde (37.0 mg, 0.30 mmol, 1.00 equiv). Purification by silica gel chromatography, eluting with EtOAc in hexanes (19 cm × 20 mm, gradient elution, 0% → 30%, 5% increases, 50 mL runs, 5–10 mL fractions), yielded 16 as a white yellow solid (85% yield, 60.0 mg, 0.25 mmol): R f = 0.30 (30% EtOAc/hexane, UV, Dragendorff stain); 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.76 (dd, J = 1.1, 8.3 Hz, 2H), 7.44 (s, 1H), 7.41–7.36 (m, 4H), 7.30–7.23 (m, 2H), 6.83 (ddd, J = 1.1, 2.4, 8.0 Hz, 1H); 13 C{ 1 H} NMR (126 MHz, MeOD- d 4 ) δ 159.1, 149.0, 132.7, 131.0, 129.7, 128.0, 126.1, 117.9, 116.9, 113.7 (note that, due to slow relaxation, some 13 C{ 1 H} NMR signals were difficult to identify; 28 concerning this compound, three signals are missing); HRMS (ESI+/TOF) m / z [M + H] + calcd for C 15 H 13 N 2 O 237.1028, found 237.1011.…”

“…Purification by silica gel chromatography, eluting with EtOH/EtOAc/NH 4 OH/hexane (11:34:5:50) (18 cm × 40 mm, isocratic elution, (11:34:5:50) EtOH/EtOAc/NH 4 OH/hexane, 1 L run, 20 mL fractions), yielded 36 as a white solid (82% yield, 793 mg, 2.40 mmol): R f = 0.40 (EtOH/EtOAc/NH 4 OH/hexane (11:34:5:50), UV, Dragendorff stain); 1 H NMR (500 MHz, DMSO- d 6 ) δ 12.10 (br s, 1H), 8.46 (d, J = 6.0 Hz, 2H), 7.77 (br s, 1H), 7.66 (d, J = 6.0 Hz, 2H), 3.99 (d, J = 12.4 Hz, 2H), 2.96–2.78 (m, 3H), 1.90 (dd, J = 13.0, 2.3 Hz, 2H), 1.59 (dq, J = 12.3, 3.9 Hz, 2H), 1.41 (s, 9H). 13 C{ 1 H} NMR (126 MHz, DMSO- d 6 ) δ 153.9, 152.1, 149.7, 118.5, 78.6, 43.2, 35.2, 30.4, 28.1 (note that, due to slow relaxation, some 13 C{ 1 H} NMR signals were not identified in the spectra; 28 specifically, the 13 C{ 1 H} NMR data for compound 36 lacks three of the 12 expected signals); ν max (cm –1 , thin film, ATR) 2867 (br), 1690 (s), 1603 (s), 1553 (w), 1429 (m), 1363 (w), 1285 (w), 1248 (w), 1230 (w), 1212 (w), 1173 (s), 1151 (m), 1126 (m), 1038 (w), 1004 (m), 942 (w), 876 (w), 766 (s), 720 (w), 686 (m); HRMS (ESI+/TOF) m / z [M + H] + calcd for C 18 H 25 N 4 O 2 329.1978, found 329.1964; mp 215.0 °C (dec)…”

Base-Promoted Annulation of Amidoximes with Alkynes: Simple Access to 2,4-Disubstituted Imidazoles

“…One of the known procedures is the annulation of amidines with terminal alkynes catalyzed by CuCl 2 •2H 2 O in pyridine in the presence of Na 2 CO 3 under atmospheric oxygen to afford 1,2,4-trisubstituted imidazoles in modest to good yields (Equation 2) [25]. The other involves the cyclocondensation of amidine hydrochlorides with bromoacetylenes promoted by K 2 CO 3 under air in the presence of 2,2 -bipyridine and water affording various 2,5-disubstituted imidazoles in good yields (Equation 3) [26]. It is readily apparent to find that, in addition to the requirement of CuCl 2 •2H 2 O and/or ligand (pyridine and 2,2 -bipyridine), in both cases, inorganic bases were used as the additives, indicating that base is the key promoter to realize the formation of imidazoles.…”

“…2H2O in pyridine in the presence of Na2CO3 under atmospheric oxygen to afford 1,2,4-trisubstituted imidazoles in modest to good yields (Equation 2) [25]. The other involves the cyclocondensation of amidine hydrochlorides with bromoacetylenes promoted by K2CO3 under air in the presence of 2,2′bipyridine and water affording various 2,5-disubstituted imidazoles in good yields (Equation 3) [26]. It is readily apparent to find that, in addition to the requirement of CuCl2 .…”

Catalyst-Free Synthesis of 2,4-Disubstituted-1H-imidazoles through [3 + 2] Cyclization of Vinyl Azides with Amidines

“…5 Consequently, many efforts have been made in the past decade on the synthesis of those privileged scaffolds. The reported methods include reaction of amidines with halo (nitro)alkenes, 6 haloketones, 7 alkyne/haloakynes, 8 and other methods. 9 Although these methods are elegant and appear to be developed specifically for obtaining multisubstituted imidazole derivatives, in organic synthesis, the site-selective synthesis of the desired products is still an attractive and challenging task.…”