Wang
Zhou
*a,
Youqing
Yang
a,
Yong
Liu
b and
Guo-Jun
Deng
b
aCollege of Chemical Engineering, Xiangtan University, Xiangtan 411105, China. E-mail: wzhou@xtu.edu.cn
bCollege of Chemistry, Xiangtan University, Xiangtan 411105, China
First published on 23rd October 2012
A copper-catalyzed approach for the synthesis of acridones via C–C bond cleavage and intramolecular cyclization using air as the oxidant under neutral conditions is described. This transformation offers an alternative method to prepare medicinally important acridones and a new strategy for C–C bond cleavage.
Scheme 1 New route to synthesize acridones. |
Our initial studies focused on identifying the optimal conditions. 1-(2-(Phenylamino)phenyl)ethanone (1a) could be smoothly converted to the desired acridone 2a in 80% yield with 20 mol% CuI in dimethyl sulfoxide (DMSO) under O2 (1 atm) at 140 °C for 12 h (Table 1, entry 1). Carrying out the reaction under N2 or without CuI led to almost quantitative recovery of 1a, suggesting that the presence of oxygen and CuI are essential (Table 1, entries 2 and 3). Then, we began to screen solvents under O2, finding that polar solvents, such as N-methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA), and N,N-dimethylformamide (DMF), gave products in lower yields (entries 4–6). Notably, none of 2a but unreacted 1a was detected in the presence of p-xylene as a solvent (entry 7). Gratifyingly, the desired acridone could be obtained in 85% yield under air by prolonging the reaction time (36 h, entry 8). Lower temperature or catalyst loading has a significant effect on the yield (entries 9–11). Other copper catalysts, such as CuBr, CuCl, CuBr2, Cu(OAc)2 and Cu(NO3)2·3H2O, showed sluggish catalytic activity (entries 12–16). Moreover, Pd(OAc)2 was not a suitable catalyst for this transformation (entry 17). On the basis of these observations, we tried to investigate the substrate scope under the reaction conditions as entry 8 listed (Table 1). However, the unsatisfying results spurred us to explore more conditions (ESI, Tables S1 and S2†). Finally, a mixed solvent furnished the best result unexpectedly (entry 18).
Entry | Cat. (20 mol%) | Oxidant (1 atm) | Solvent | 1 (h) | Yieldb (%) |
---|---|---|---|---|---|
a Reaction conditions: 1a (0.3 mmol), catalyst, and solvent (1.6 mL) were stirred at 140 °C. b Isolated yield. c The reaction was carried out under N2. d The reaction was carried out at 100 °C. e The reaction was carried out at 120 °C. f CuI (10 mol%) was used. g Mixed solvent (vDMSO/vPhCl = 1:1) was used. | |||||
1 | CuI | O2 | DMSO | 12 | 80 |
2c | CuI | None | DMSO | 12 | Trace |
3 | None | O2 | DMSO | 12 | Trace |
4 | CuI | O2 | NMP | 12 | 79 |
5 | CuI | O2 | DMA | 12 | 58 |
6 | CuI | O2 | DMF | 12 | 55 |
7 | CuI | O2 | p-Xylene | 12 | 0 |
8 | CuI | Air | DMSO | 36 | 85 |
9d | CuI | Air | DMSO | 36 | 17 |
10e | CuI | Air | DMSO | 36 | 75 |
11f | CuI | Air | DMSO | 36 | 17 |
12 | CuBr | Air | DMSO | 36 | 58 |
13 | CuBr2 | Air | DMSO | 36 | 70 |
14 | CuCl | Air | DMSO | 36 | 48 |
15 | Cu(OAc)2 | Air | DMSO | 36 | 17 |
16 | Cu(NO3)23H2O | Air | DMSO | 36 | 19 |
17 | Pd(OAc)2 | Air | DMSO | 36 | 58 |
18g | CuI | Air | DMSO/PhCl | 48 | 90 |
Based on the optimized conditions, the substrate scope was observed. The effect of different substituents on the aromatic rings A and B is listed in Table 2. Substrates bearing electron-donating substituents on the aromatic ring A could be successfully transformed into the desired products in high yields, such as 4′-Me (entry 2), 4′-OMe (entry 4) and 4′-NHAc (entry 5), but on the aromatic ring B in relatively low yields, such as 5-Me (entry 12) and 5-OMe (entry 13). The product with the phenyl substituent could be obtained in high yield (entry 6). It is worth noting that 3′-Me substituted substrate 1j led to a mixture of 3′-Me and 5′-Me products in 84% yield with the ratio of 1:4 (2j/2j′, entry 10). Electron-withdrawing functional groups, such as 4′-COOEt (entry 7) and 4′-F (entry 8), on the aromatic ring A or 5-OCF3 (entry 14) and 5-F (entry 15) on the aromatic ring B could be well-tolerated, giving products in good to excellent yields. Moreover, the reaction scope could be expanded to the substrates with substituents on both rings A and B at the same time (Table 2, entries 17–19).
Entry | Substrate | Product | Yieldb (%) | ||||
---|---|---|---|---|---|---|---|
a Reaction conditions: 1 (0.30 mmol), CuI (20 mol%) in solvent (vDMSO/vPhCl = 1/1, 1.6 mL) were stirred at 140 °C under air (1 atm) for 48 h. b Isolated yield. c CuI (40 mol%) was used. d Determined by 1H NMR. | |||||||
R1 | R2 | ||||||
1 | H | H | 1a | 2a | 90 | ||
2 | 4′-Me | H | 1b | 2b | 91 | ||
3c | 6′-Me | H | 1c | 2c | 56 | ||
4 | 4′-OMe | H | 1d | 2d | 89 | ||
5 | 4′-NHAc | H | 1e | 2e | 86 | ||
6 | 4′-Ph | H | 1f | 2f | 85 | ||
7 | 4′-COOEt | H | 1g | 2g | 90 | ||
8 | 4′-F | H | 1h | 2h | 92 | ||
9 | 4′-Cl | H | 1i | 2i | 50 | ||
10d | 3′-Me(1j) | H | 84 | ||||
11 | H | 3-Me | 1k | 2c | 38 | ||
12 | H | 5-Me | 1l | 2b | 65 | ||
13 | H | 5-OMe | 1m | 2d | 65 | ||
14 | H | 5-OCF3 | 1n | 2k | 84 | ||
15 | H | 5-F | 1o | 2h | 83 | ||
16 | H | 5-Cl | 1p | 2i | 84 | ||
17 | 4′-F | 5-F | 1q | 2l | 69 | ||
18 | 4′-Me | 5-OCF3 | 1r | 2m | 70 | ||
19 | 4′-OMe | 5-Cl | 1s | 2n | 53 |
In addition, a series of substrates with different substituents on both the nitrogen atom and the ketone were examined (Table 3). The substituting group R3 could be phenyl (Table 3, entry 1). R4 could be alkyl (entries 2–5) or alkenyl (entry 6). Notably, the substrate with tert-butyl only gave the product in 7% yield (entry 3). Moreover, we could detect p-methyl and p-methoxyl benzaldehydes as by-products when 1w and 1x were employed respectively (Table 3, entries 4 and 5).
Entry | Substrate | Product | Yieldb (%) | |||
---|---|---|---|---|---|---|
a Reaction conditions: 1 (0.30 mmol), CuI (20 mol%) in solvent (vDMSO/vPhCl = 1/1, 1.6 mL) were stirred at 140 °C under air (1 atm) for 48 h. b Isolated yield. | ||||||
R3 | R4 | |||||
1 | Ph | Me | 1t | 2o | 82 | |
2 | H | Et | 1u | 2a | 80 | |
3 | H | t Bu | 1v | 2a | 7 | |
4 | H | 4-Methylbenzyl | 1w | 2a | 60 | |
5 | H | 4-Methoxybenzyl | 1x | 2a | 65 | |
6 | H | Styryl | 1y | 2a | 19 |
When 1-(2-(benzylamino)phenyl)ethanone (1z) was employed, we could only observe N-benzyl-indoline-2,3-dione (3z) as the product (Table 4, entry 1). Meanwhile, similar species could be detected by GC-MS analysis when 1a was used (ESI, Fig. S1†). To probe the reaction mechanism, indoline-2,3-dione 3a was synthesized and subjected to control experiments, giving 2a in 79% yield under the optimized conditions (Table 4, entry 3). When CuI or CuBr2 was used as the catalyst under N2, acridone 2a was obtained in 17% and 65% yields respectively (Table 4, entries 4 and 5). Furthermore, other possible intermediates also have been investigated (Table 4, entries 6–10). Although N-arylanthranilic aldehyde 7 could be successfully converted into the desired product in excellent yield (Table 4, entry 9), further studies ruled out the possibility of compound 7 working as a key intermediate in this transformation (see ESI, Table S3† for details). Moreover, radical mechanism studies indicate that a radical pathway may be not involved in this reaction (see ESI, Table S4† for details).
Entry | Substrate | Productb (%) | Othersb (%) | ||
---|---|---|---|---|---|
a Reaction conditions: substrate (0.15 mmol), CuI (20 mol%) in solvent (vDMSO/vPhCl = 1/1, 0.8 mL) stirred at 140 °C under air (1 atm) for 48 h. b Isolated yield. c The reaction was carried out without CuI. d The reaction was carried out under N2. e CuBr2 was used instead of CuI. | |||||
1 | |||||
2c | 2a | Trace | 3a | 66 | |
3 | 2a | 79 | 3a | 0 | |
4d | 2a | 17 | 3a | 60 | |
5d,e | 2a | 65 | 3a | 35 | |
6 | 2a | Trace | |||
7 | 2a | 17 | |||
8 | 2a | Trace | |||
9 | 2a | 92 | |||
10 | 2a | 0 |
Intermolecular kinetic isotope effects (kH/kD = 1.23) and intramolecular kinetic isotope effects (kH/kD = 1.69) indicate that aromatic C–H bond cleavage may be not turnover-limiting and does not occur via a chelation-assisted, SEAr or a free radical mechanism (see ESI† for details).14,15 Interestingly, 13C labeling experiments unveil that only about 86% of carbonyl carbon in the product originate from the carbonyl carbon of the substrate (Scheme 2).
Scheme 2 13C labeling experiments. |
On the basis of these preliminary results, we still can not speculate on a reasonable mechanistic pathway.16 Multiple pathways may be involved in this transformation. A thorough mechanistic study is needed to unravel the mechanistic intricacies of this process.
In conclusion, we have demonstrated a copper-catalyzed approach for the synthesis of acridones via C–C bond cleavage and intramolecular cyclization using air as the oxidant under neutral conditions. This reaction not only provides an efficient method for constructing medicinally important acridones, but also offers a new strategy for C–C bond cleavage.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2gc36502b |
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