ItOct (ItOctyl) – pushing the limits of ItBu: highly hindered electron-rich N-aliphatic N-heterocyclic carbenes

ItBu (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) represents the most important and most versatile N-alkyl N-heterocyclic carbene available in organic synthesis and catalysis. Herein, we report the synthesis, structural characterization and catalytic activity of ItOct (ItOctyl), C2-symmetric, higher homologues of ItBu. The new ligand class, including saturated imidazolin-2-ylidene analogues has been commercialized in collaboration with MilliporeSigma: ItOct, 929 298; SItOct, 929 492 to enable broad access of the academic and industrial researchers within the field of organic and inorganic synthesis. We demonstrate that replacement of the t-Bu side chain with t-Oct results in the highest steric volume of N-alkyl N-heterocyclic carbenes reported to date, while retaining the electronic properties inherent to N-aliphatic ligands, such as extremely strong σ-donation crucial to the reactivity of N-alkyl N-heterocyclic carbenes. An efficient large-scale synthesis of imidazolium ItOct and imidazolinium SItOct carbene precursors is presented. Coordination chemistry to Au(i), Cu(i), Ag(i) and Pd(ii) as well as beneficial effects on catalysis using Au(i), Cu(i), Ag(i) and Pd(ii) complexes are described. Considering the tremendous importance of ItBu in catalysis, synthesis and metal stabilization, we anticipate that the new class of ItOct ligands will find wide application in pushing the boundaries of new and existing approaches in organic and inorganic synthesis.

SI-6 room temperature. After the indicated time, the reaction mixture was diluted with diethyl ether (50 mL), washed with saturated NH4Cl (aq., 50 mL), and the aqueous layer was extracted with diethyl ether (3 x 20 mL). The combined organic layers were dried under vacuum to afford the title product. Yield 91% (5.16 g, 18.1 mmol). (

SI-11
reaction mixture was diluted with CH2Cl2 (10 mL) and filtered. The solution was collected and concentrated. The title product was obtained by trituration from hexanes as a white solid.

SI-12
LiHMDS (1.0 M in THF, 0.11 mL, 0.11 mmol, 1.1 equiv) were added and the resulting reaction mixture was stirred at room temperature for 2 h. After the indicated time, [{Pd(allyl)Cl}2] (29.5 mg, 0.1 mmol, 1.0 equiv) in THF (0.5 mL) was added and the reaction mixture was stirred at room temperature for 15 h. After the indicated time, the reaction mixture was diluted with CH2Cl2 (10 mL) and filtered. The solution was collected and concentrated. The title product was obtained by trituration from hexanes as a yellow solid.

General Procedure for [Au-NHC]-Catalyzed Hydration of Alkynes.
General procedure. An oven-dried vial equipped with a stir bar was charged with an alkyne substrate (1.0 mmol), [Au-NHC] catalyst (0.5 mol%), AgSbF6 (covering the tip of a spatula), 1,4-dioxane (1.0 mL) and stirred for 1 min. Distilled water (0.1 mL) was added and the reaction mixture was stirred at 80 °C for 15 h. After the indicated time, the reaction mixture was diluted with water (5 mL), extracted with CH2Cl2 (3 x 5 mL), dried and concentrated.
The sample was analyzed by 1 HNMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, selectivity and yield using internal standard and comparison with authentic samples.
Purification by chromatography on silica gel (EtOAc/hexanes) afforded the title product.

General Procedure for [Pd-NHC]-Catalyzed Suzuki Cross-Coupling.
General procedure. An oven dried vial equipped with a stir bar was charged with an aryl bromide substrate (0. Purification by chromatography on silica gel (EtOAc/hexanes) afforded the title product.          Cu-Cl  The striking difference in the steric environment between ItOct and ItBu should be noted.
There are two major steric effects of the ItBu to ItOct replacement: (1) increased percent buried volume, resulting in a more sterically-demanding ligand; (2) non-equivalent quadrant distribution in steric maps. The same differnce is observed in the comparison between SItOct and SItBu. Overall, these studies strongly support ItOct as a unique class of N-alkyl ligands with sterically-defined C2-symmetric environment and strong -donation enabled by N-alkyl wingtip substitution. Further studies on the development of NHC ligands are underway in our laboratory and these findings will be reported in due course.