Cyclometalated iridium complexes-catalyzed acceptorless dehydrogenative coupling reaction: construction of quinoline derivatives and evaluation of their antimicrobial activities

We started our research with the ADC reaction of 2-aminobenzyl alcohol (1a) with 1-phenylethanol (2a) as model reaction in the presence of various cyclometalated iridium complexes TC-1–TC-6 (Table 1). Encouragingly, employing TC-1 as the catalyst, toluene as the solvent and t-BuOK as the base at 100 °C, quinoline 3aa was obtained in 73% yield accompanied by 27% yield of 1,2-dihydroquinoline 4aa (Table 1, entry 1). Then, several other cyclometalated iridium complexes were studied. The catalysts TC-2 and TC-4 containing electron-donating ligands provided quinoline 3aa in higher chemoselectivity and yield (Table 1, entries 2 and 4). On the contrary, the catalysts TC-3 and TC-5 containing electron-withdrawing ligands offered lower chemoselectivity and yield (Table 1, entries 3 and 5). Further catalyst screening revealed that TC-6 (6-methoxy) is the best catalyst for the ADC reaction affording the product in a yield of 95% (Table 1, entry 6). On the other hand, when no catalyst was added to the reaction system under the above conditions, the reaction also proceeded, but the chemical selectivity and yield were significantly lower (Table 1, entry 7).

Table 1: Optimization of catalyst for ADC reaction of 2-aminobenzyl alcohol and 1-phenylethanol.a

Entry Tang’s catalyst Time (h) 3aa:4aab Yield of 3aab (%) 1 TC-1 24 73:27 73 2 TC-2 24 79:21 79 3 TC-3 24 56:44 56 4 TC-4 24 82:18 82 5 TC-5 24 59:41 59 6 TC-6 24 95:5 95 (93)c 7d – 48 51:49 51

aReaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), t-BuOK (1.0 mmol), dioxane (3 mL) and Tang’s catalyst (0.1 mol %) at 100 °C for 24 h. bDetermined by GC–MS. cYield of isolated product 3aa. dReaction performed without Tang’s catalyst.

In order to obtain optimal conditions, the bases, reaction medium, and temperature were also surveyed (Table 2). First, several bases were examined and the results showed that different bases have different effects on the chemoselectivity and yield of the reaction. The weak bases including HCO2Na, CH3CO2K, and Na2CO3, resulted in decreased yields of quinoline 3aa (Table 2, entries 1–3). Interestingly, the chemoselectivity of the reaction and product yield were significantly improved with strong bases, such as NaOH, KOH, or t-BuOK (Table 2, entries 4–6). To our excitement, a loading of 1.1 equiv of t-BuOK delivered the product 3aa in the yield of 96% with perfect selectivity (Table 2, entries 6–8).

Table 2: Studies of reaction parameters in the iridium-catalyzed ADC reaction.a

Entry Base Solvent Temperature (°C) Time (h) 3aa:4aab Yield of 3aab (%) 1 CH3CO2K 1,4-dioxane 100 24 74:26 74 2 HCO2Na 1,4-dioxane 100 24 69:31 69 3 Na2CO3 1,4-dioxane 100 24 76:24 76 4 NaOH 1,4-dioxane 100 24 82:18 82 5 KOH 1,4-dioxane 100 24 93:7 93 6 t-BuOK 1,4-dioxane 100 24 95:5 95 7c t-BuOK 1,4-dioxane 100 24 >99:1 >99 (96)d 8e t-BuOK 1,4-dioxane 100 24 94:6 94 9c t-BuOK toluene 100 24 90:10 90 10c t-BuOK THF 80 24 81:19 81 11c t-BuOK DMF 100 24 69:31 69 12c t-BuOK H2O 100 24 83:17 83 13c t-BuOK 1,4-dioxane 80 36 87:13 87 14c,f t-BuOK 1,4-dioxane 100 48 >99:1 >99

aReaction conditions: 1a (1.1 mmol), 2a (1.0 mmol), base, solvent (3 mL), and TC-6 (0.1 mol %) at 100 °C for 24 h. bDetermined by GC–MS. c1.1 mmol t-BuOK was used. dYield of isolated product 3aa. e0.8 mmol t-BuOK was used. f0.01 mol % TC-6 was used.

Afterward, we further screened the solvent and catalyst loading (Table 2, entries 7, 9–12, and 14) and the results showed that 1,4-dioxane was the most favorable solvent for the outcome of product 3aa, even when the catalyst loading was decreased to 0.01 mol % (Table 2, entry 14). All other solvents screened resulted in lower product yield (Table 2, entries 9–12). Finally, we examined the effect of temperature on the reaction and found that decreasing the reaction temperature hindered the production of compound 3aa (Table 2, entry 13).

Based on the screening of above reaction conditions, we obtained the optimal catalytic system, with 0.1 mol % TC-6 as the catalyst, 1.1 equiv of t-BuOK as the base, and 1,4-dioxane as reaction solvent. Under the optimal reaction conditions, we investigated the universality of the cyclometalated iridium-catalyzed ADC reaction by expanding the range of substrates (Table 3). It can be seen that quinoline compounds 3 were obtained with excellent yield and chemoselectivity through the cyclometalated iridium-catalyzed ADC reaction of 2-aminobenzyl alcohol and different substituted aromatic secondary alcohols including electron-donating (Me, OMe) and electron-withdrawing substituents (F, Cl, Br) as the substrate (Table 3, entries 1–24). Aromatic secondary alcohols substituted with electron-donating groups led to higher chemoselectivities and yields of the products (Table 3, entries 2–5) than the aryl secondary alcohols and aminobenzyl alcohol with electron-withdrawing groups (Table 3, entries 8, 11, 12, 15, 16, 19, 20, 23, and 24). Meanwhile, the heteroaromatic secondary alcohols 2i–n could also be employed in the cyclometalated iridium-catalyzed system obtaining the products 3ai–an with excellent yield and chemoselectivity (Table 3, entries 26–42). The results showed that the yield and chemoselectivity was higher when the heteroaromatic secondary alcohols and aminobenzyl alcohols have electron-donating groups (Table 3, entries 27, 30, 31, 34, 35, 39, and 42). On the contrary, with the electron-withdrawing group, the yield and chemoselectivity of the reaction were relatively lower (Table 3, entries 28, 29, 32, 33, 36, 37, and 40). It is worth noting that high conversions were also accomplished when 1-cyclohexylethanol and pentan-1-ol were employed in this catalytic system (Table 3, entries 43 and 44).