N-(2,6-diisopropylphenyl)imidazole can be synthesized on multigram scales via the four-step sequence below, which is adapted from a literature procedure:[1]
Synthesis of N-(2,6-diisopropylphenyl)isothiocyanate.[2] To a suspension of 2,6-diisopropylaniline (18.3 g, 0.103 mol), K2CO3 (28.2 g, 0.204 mol), and dimethylformamide (10 mL) in water (70 mL), was added CS2 (10.0 g, 0.131 mol) dropwise under vigorous stirring. The mixture was stirred overnight at room temperature. Next day, the orange mixture was cooled to 0ºC, and a solution of cyanuric chloride (9.40 g, 0.051 mol) in dichloromethane (70 mL) was added dropwise (c.a. one drop per second) via dropping funnel. The reaction was stirred at room temperature for four hours and subsequently basified to a pH > 11 with 7M aqueous NaOH. After addition of dichloromethane (150 mL) and water (150 mL) to partition the layers, the organic fraction was extracted, washed with water (2 x 100 mL), dried with MgSO4, and solvents removed in vacuo. The resulting brown oil was purified via short path distillation to yield the product as a colorless oil (16.2 g, 0.074 mol, 72 %).
Synthesis of N-(2,6-diisopropylphenyl)-2-mercaptoimidazole.[1] N-(2,6-diisopropylphenyl)isothiocyanate (16.2 g, 0.074 mol) was added dropwise to a stirred solution of aminoacetaldehyde diethyl acetal (9.81 g, 0.074 mol) in ethanol (30 mL). The resulting solution was heated to reflux for 1.5 h, cooled to room temperature, and the solvent removed in vacuo. The residue was suspended in 10% aqueous HCl (150 mL) and heated to reflux for one hour, resulting in formation of a white precipitate. Reaction mixture was brought to room temperature and, after cooling in ice for 30 minutes, the product was isolated by vacuum filtration as a white solid (18.2 g, 0.070 mol, 95 %).
Synthesis of N-(2,6-diisopropylphenyl)imidazole.[1] In a 1 L round-bottom flask with a large magnetic stir bar, N-(2,6-diisopropylphenyl)-2-mercaptoimidazole (18.2 g, 0.070 mol) was suspended in 20% aqueous nitric acid. The mixture was heated to reflux until the evolution of brown fumes had stopped (c.a. 30 minutes). After cooling the mixture to room temperature, water (150 mL) was added, and the product was extracted with ethyl acetate (2 x 150 mL). Combined organic layers were dried with MgSO4 and the solvent removed in vacuo to yield the product as a light-yellow solid (14.6 g, 0.064 mol, 91 %). Spectral data matched literature.[1]
Notes
- Due to the biphasic nature of the reaction, DMF usage is essential in the first (isothiocyanate synthesis) step. Yields are dramatically lower if omitted.
- Removal of mercapto group (last step) produces considerable amounts of NO2 fumes. Care should be taken to use a large enough flask and a well-ventilated fumehood. If unsure about whether the fuming has stopped, heat the reaction for 1h instead of the 30min.
- Despite being slightly cumbersome, I have found this four-step procedure to be the most reliable method for synthesizing Dipp-imidazole on multigram scales. Although the widely cited 2003 Synthesis paper[3] describes a one-pot synthesis, it always proved either unreliable or low-yielding in my hands so I gave up on it.
[1] Benson, S.; Payne, B.; Waymouth, R. Synthesis and reactivity of allyl nickel(II) N-heterocyclic carbene enolate complexes. J. Polym. Sci. A Polym Chem. 2007, 45, 16, 3637-3647.
[2] Vass, V.; Dehmel, M.; Lehni, F.; Kretschmer, R. A Facile One-Pot Synthesis of 1,2,3-Tri- and 1,1,2,3-Tetrasubstituted Bis(guanidine)s from Bis(thiourea)s. Eur. J. Org. Chem. 2017, 5066-5073.
[3] Liu, J.; Chen, J.; Zhao, J.; Zhao, Y.; Li, L.; Zhang, H. A Modified Procedure for the Synthesis of 1-Arylimidazoles. Synthesis 2003, 17, 2661-2666.