C-H bonds as ubiquitous functionality: a general approach to complex arylated imidazoles via regioselective sequential arylation of all three C-H bonds and regioselective N-alkylation enabled by SEM-group transposition

Abstract

Imidazoles are an important group of the azole family of heterocycles frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials. Owing to their wide application in academia and industry, new methods and strategies for the generation of functionalized imidazole derivatives are in demand. We here describe a general and comprehensive approach for the synthesis of complex aryl imidazoles, where all three C-H bonds of the imidazole core can be arylated in a regioselective and sequential manner. We report new catalytic methods for selective C5- and C2-arylation of SEM-imidazoles and provide a mechanistic hypothesis for the observed positional selectivity based on electronic properties of C-H bonds and the heterocyclic ring. Importantly, aryl bromides and low-cost aryl chlorides can be used as arene donors under practical laboratory conditions. To circumvent the low reactivity of the C-4 position, we developed the SEM-switch that transfers the SEM-group from N-1 to N-3 nitrogen and thus enables preparation of 4-arylimidazoles and sequential C4-C5-arylation of the imidazole core. Furthermore, selective N3-alkylation followed by the SEM-group deprotection (trans-N-alkylation) allows for regioselective N-alkylation of complex imidazoles. The sequential C-arylation enabled by the SEM-switch allowed us to produce a variety of mono-, di-, and triarylimidazoles using diverse bromo- and chloroarenes. Using our approach, the synthesis of individual compounds or libraries of analogues can begin from either the parent imidazole or a substituted imidazole, providing rapid access to complex imidazole structures.

Figure 1

Rapid access to complex imidazoles via direct C–H arylation.

Figure 2

C2- and C5-arylation methods, together with the SEM-switch, provide rapid access to complex arylimidazoles with complete control of regioselectivity. The SEM group also allows for regioselective N-alkylation (trans-N-alkylation). (A) An example of sequential elaboration of SEM-imidazole to furnish 1-alkyl-2,4-diarylimidazoles and 1-alkyl-2,4,5-triarylimidazoles. (B) Advanced intermediates (accessed for example by condensation methods) may also be arylated and alkylated in a regioselective manner via the strategy based on the SEM group.

Figure 3

(A) General reactivity trends of imidazole. (B) Two methods for palladium-catalyzed C–H arylation of SEM-imidazoles were developed with complementary regioselectivity (C5 and C2). The C2- and C5-arylation protocols enable the use of both aryl bromides and aryl chlorides, providing a practical method for synthesis of arylimidazoles. (C) The SEM-group transposition (SEM-switch) leads to 4-arylimidazoles and allows for subsequent arylation and preparation of complex arylimidazoles. Similarly, the SEM group enables regioselective N-alkylation (trans-N-alkylation) to afford 1-alkyl-4-arylimidazoles.

Figure 4

Mechanistic rationales for the observed regioselectivity of the imidazole arylation. (A) In the presence of carbonate or carboxylate base (R″ = alkyl or alkoxide), the C–H activation occurs via ligand-assisted palladation (via either EMD or CMD mechanism). The C-5 position is preferred over the C-2 and C-4 due to stabilization of the C–Pd bond by the inductive effect of N-1 nitrogen. (B) In contrast, palladation at the C-4 position is disfavored by electronic repulsion between the nitrogen e⁻ pair and the polarized C–Pd bond. (C) In the presence of a strong base, deprotonation occurs at the C-2 position, presumably facilitated by complexation of the palladium complex to N-3. The same rationale applies to other azoles including oxazoles, thiazoles, and triazoles.

Scheme 1

C2-Arylation of SEM-Imidazoles

Scheme 2. Synthesis of 4,5-Diarylimidazoles^a

^aReaction conditions: (a) 5.0 mol % Pd(OAc)₂, 7.5 mol % P(n-Bu)Ad₂, 1.2 equiv of 4-bromoanisole, 2.0 equiv of K₂CO₃, DMA (0.5 M), 120 °C, 17 h, 63% yield; (b) 5.0 mol % SEM Cl, CH₃CN, 80 °C, 22 h, 88% yield; (c) 5.0 mol % Pd(OAc)₂, 7.5 mol % P(n-Bu)Ad₂, 1.2 equiv of 3-bromopyridine, 2.0 equiv of K₂CO₃, DMA(0.5 M), 120 °C, 20 h, 46% yield. Recovered starting material and 2,5-diarylation product were isolated in 17% and 11% yields, respectively. Yields are an average of two separate isolated yields.

Scheme 3

Synthesis of 1-Alkyl-4-arylimidazoles

Scheme 4. Synthesis of 1-Methyl-2,4,5-triarylimidazoles via Sequential C-Arylation and N-Methylation^a

^aReaction conditions: (a) 5.0 mol % Pd(OAc)₂, 7.5 mol % P(n-Bu)Ad₂, 1.2 equiv of 1-bromo-3,5-dimethoxybenzene, 2.0 equiv of K₂CO₃, DMA(0.5 M), 120 °C, 18 h (68% yield). (b) 5.0 mol % Pd(OAc)₂, 7.5 mol % P(n-Bu)Ad₂, 1.5 equiv of 4-bromobenzotrifluoride, 2.0 equiv of NaOt-Bu, toluene (1.0 M), 100 °C, 24 h (65% yield). (c) 1.5 equiv of Me₃O·BF₄, CH₂Cl₂, rt, 1 h; 1 N HCl, H₂O, 80 °C, 2 h (55% yield over 2 steps). (d) 5.0 mol % Pd(OAc)₂, 7.5 mol % P(n-Bu)Ad₂, 1.2 equiv of 2-bromonaphthalene, 2.0 equiv of K₂CO₃, DMA (0.5 M), 120 °C, 18 h (82% yield). Yields are an average of two separate isolated yields.