Palladium-Catalyzed Multicomponent Synthesis of 2 ‑ Aryl-2-imidazolines from Aryl Halides and Diamines

: An e ﬃ cient palladium-catalyzed three-compo-nent reaction that combines aryl halides, isocyanides, and diamines provides access to 2-aryl-2-imidazolines in yields up to 96%. Through variation of the diamine component, the reaction can be extended to the synthesis of 2-aryl-1 H benzimidazoles and 2-aryl-1,4,5,6-tetrahydropyrimidines. 2-Imidazolines are an important class of heterocyclic compound which target numerous pharmaceutically relevant binding sites and receptors and which act as ligands in homogeneous catalysis. 1 Of these, 2-aryl-2-imidazolines have demonstrated anticancer 2 and appetite stimulant activity 3 and have been used as ligands in polymer 4 and asymmetric synthesis. 5 A range of methods have been developed for the preparation of 2-aryl-2-imidazolines, but most commonly they have been made by reacting a 1,2-diamine with a carboxylic acid or its equivalent (usually an imidate or orthoester) or with an aldehyde in the presence of an oxidant. 1

2-Imidazolines are an important class of heterocyclic compound which target numerous pharmaceutically relevant binding sites and receptors and which act as ligands in homogeneous catalysis. 1 Of these, 2-aryl-2-imidazolines have demonstrated anticancer 2 and appetite stimulant activity 3 and have been used as ligands in polymer 4 and asymmetric synthesis. 5 A range of methods have been developed for the preparation of 2-aryl-2imidazolines, but most commonly they have been made by reacting a 1,2-diamine with a carboxylic acid or its equivalent (usually an imidate or orthoester) or with an aldehyde in the presence of an oxidant. 1 In the search for a general, catalytic route to 2-aryl-2imidazolines, we were attracted to the report by Whitby et al. concerning the preparation of amidines by palladium-catalyzed coupling of an aryl halide, isocyanide, and amine. 6 Since this initial report, 6 palladium-catalyzed isocyanide insertion has been utilized in the preparation of various nitrogen heterocycles including cyclic amidines and imidates, 7 oxazolines and benzoxazoles, 8 quinazoline[3,2-a]quinazolines, 9 4-aminoquinazolines, 10 quinazolin-4(3H)-imines, 11 4-aminophthalazin-1(2H)-ones, 12 2-substituted 1H-indole-3-carboxamides, 13 6aminoindolo[3,2-c]quinolines, 14 4-amine-benzo[b] [1,4]oxazepines, 15 4-imino-3,4-dihydroquinazolin-2-ylphosphonates, 16 and guanidine-containing heterocycles. 17 By replacement of the amine component with a diamine, we imagined that this chemistry could provide a simple and general entry into imidazolines such as 2 through initial formation of amidine 1 and subsequent cyclization with loss of tertbutylamine (Scheme 1).
Reaction of iodobenzene, tert-butyl isocyanide and ethylenediamine in toluene using PdCl 2 ·dppf·CH 2 Cl 2 as catalyst provided 2-phenyl-2-imidazoline (3) in a very encouraging 79% yield ( Table 1, entry 1). Additional catalyst and ligand combinations were screened (entries 2−9), and PdCl 2 in combination with the dppp ligand led to further improvement to 94% yield (Table 1, entry 7). The reaction proceeds in excellent yield using 5 equiv of ethylenediamine, but lower yields are seen when the stoichiometry is reduced (Table 1, entries 10 and 11). The reaction proceeds well in toluene, 1,4dioxane, and THF (entries 7, 12, and 13), but the yield is reduced when acetonitrile is used as the solvent (entry 14). Commercially available tert-butyl isocyanide proved to be the most convenient isocyanide source for this reaction. Alternative isocyanide sources (BnNC, 4-MeOC 6 H 4 NC, CyNC, PhMe 2 CNC, and Ph 3 CNC) all proved inferior. For example, when cumyl isocyanide (PhMe 2 CNC) was used, 2-phenyl-2imidazoline (3) was produced in just 43% yield under the conditions employed in Table 1, entry 7. When studying amidine synthesis, Whitby made similar observations. 6 When the experiment detailed in entry 7 was performed without dppp, or separately without cesium carbonate, the yield of 3 reduced to 26% and 71%, respectively. These results indicate the importance of both the phosphine ligand and the inorganic base to achieving high yields.
Having optimized the reaction conditions, we then explored variation in the aryl halide component. A broad range of aryl halides and heteroaromatic halides, and an aryl triflate, were screened with our best two catalyst/ligand combinations (Table  2). Most substrates were found to give the desired imidazolines in good yield, with eight examples furnishing the product in greater than 90% yield (entries 1, 3, 6−7, 9, and 11−13). Initial attempts to extend the reaction to nonaromatic halides have not been fruitful. 18 PdCl 2 in combination with dppp was found to give better yields with most aryl halides (Table 2, entries 1−4, 6, and 11− 14), while PdCl 2 ·dppf·CH 2 Cl 2 was the superior catalyst with electron-rich aryl bromides and triflates (entries 7−9). Both ligands gave a low yield of 6 (entry 5) which may be attributed to the sterically hindered nature of 2-iodotoluene. Satisfyingly, 2,6-dibromopyridine was found to give bis-imidazoline 11 in an excellent yield of 94% via a 5-component reaction. The structure of this bis-imidazoline was unambiguously established by X-ray crystallography (see the Supporting Information). While no imidazoline formation was observed using chlorobenzene, 4-chloroanisole, and 3-chloropyridine, a 96% yield of 10 was achieved from 2-chloropyridine (entry 12). To our knowledge, this is the first example of a high-yielding, palladium-catalyzed iminocarbonylative cross-coupling of an aryl chloride. It is not clear why 10 is formed from 2-bromo-or 2-chloropyridine in much higher yield with dppp than dppf (entries 11 and 12), while 3-bromopyridine, which is not activated toward oxidative addition, gives 9 in a higher yield with dppf (entry 10).
To extend the usefulness of this reaction we then investigated the reaction of alternative diamines (Table 3). 1,3-Diaminopropane was found to give tetrahydropyrimidine 13 in 95% yield (entry 1), and N-alkylated ethylenediamines were also found to react successfully (entries 2 and 3). Simultaneous substitution of both carbons of the ethylenediamine unit was well tolerated (entries 4 and 5), and 1,2diaminobenzenes were found to give benzimidazoles, albeit in lower yields (entries 6 and 7).
The successful formation of 11 (Table 2, entry 13) and 17 (Table 3, entry 5) encouraged us to attempt the one-pot synthesis of the chiral pybim ligand 20, which has found applications in ruthenium-catalyzed asymmetric transfer hydro-genation 5a and epoxidation reactions 5b,c (Scheme 2). This 5component reaction successfully yielded 20 in 51% yield (after purification by recrystallization) via the formation of 2 × C−C and 4 × C−N bonds. The relatively modest yield reflects difficulties associated with product purification rather than low chemical conversion (see the Experimental Section).
In conclusion, a structurally diverse range of 2-aryl-2imidazolines, 2-aryl-1H-benzimidazoles, and a 2-aryl-1,4,5,6tetrahydropyrimidine have been prepared from aryl halides in one step in up to 96% yield by a novel palladium-catalyzed 3component reaction. Good variation in the aryl halide and the diamine components has been demonstrated, which will enable the rapid preparation of libraries of compounds with potential as pharmaceuticals, agrochemicals, or ligands in homogeneous catalysis.

■ EXPERIMENTAL SECTION
HRMS analyses were performed on a time-of-flight mass spectrometer equipped with an ESI source.

Notes
The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS
We thank the EPSRC, the University of Warwick, and the Daphne Jackson Trust for financial support. We are grateful to Dr. Guy Clarkson for the X-ray crystallographic analysis of compound 11. ■ REFERENCES