Copper-catalyzed C–C bond cleavage and intramolecular cyclization: an approach toward acridones

Abstract

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.

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Because of its potential applications in organic synthesis and industry, transition-metal-catalyzed C–C and C–H bond cleavage has recently emerged as an active research topic in organic chemistry.^1,2 Although the cleavage of C–C bonds is a challenging task, some elegant methods involved in employing the catalyst of noble metals, such as Rh,³ Ru,⁴ Pd,⁵ Pt,⁶ and others,⁷ have been developed. However, there are a limited number of strategies using the catalyst of cheap metals such as Cu⁸ and Fe.⁹ In the mid-1960s, Brackman and Volger reported the conversion of aliphatic aldehydes to aldehydes of one less carbon atom via a radical process.¹⁰ Later, Sayre and co-workers studied the mechanism of oxygenation α to carbonyl groups.¹¹ To date, there are only a few reports employing the copper/O₂ catalytic system for C–C bond cleavage.¹² Recently, we reported a copper-catalyzed intramolecular direct amination of the sp² C–H bond for the synthesis of N-aryl acridones.¹³ As part of our ongoing research, herein, we disclose an efficient copper-catalyzed approach for the synthesis of acridones via C–C bond cleavage and intramolecular cyclization using air as an oxidant under neutral conditions (Scheme 1).

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).

Table 1 Optimization of reaction conditions^a

Entry	Cat. (20 mol%)	Oxidant (1 atm)	Solvent	1 (h)	Yield^b (%)
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
2^c	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
9^d	CuI	Air	DMSO	36	17
10^e	CuI	Air	DMSO	36	75
11^f	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
18^g	CuI	Air	DMSO/PhCl	48	90

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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).

Table 2 The effect of substituents on the aromatic moiety^a

Entry		Substrate			Product	Yield^b (%)
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.
		R^1	R^2
1		H	H	1a		2a	90
2		4′-Me	H	1b		2b	91
3^c		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
10^d		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

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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).

Table 3 The effect of substituents on the nitrogen and ketone moiety^a

Entry		Substrate			Product	Yield^b (%)
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.
		R^3	R^4
1		Ph	Me	1t	2o	82
2		H	Et	1u	2a	80
3		H	^tBu	1v	2a	7
4		H	4-Methylbenzyl	1w	2a	60
5		H	4-Methoxybenzyl	1x	2a	65
6		H	Styryl	1y	2a	19

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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).

Table 4 Mechanism probing experiments^a

Entry	Substrate	Product^b (%)		Others^b (%)
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
2^c		2a	Trace	3a	66
3		2a	79	3a	0
4^d		2a	17	3a	60
5^d^,^e		2a	65	3a	35
6		2a	Trace
7		2a	17
8		2a	Trace
9		2a	92
10		2a	0

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Intermolecular kinetic isotope effects (k_H/k_D = 1.23) and intramolecular kinetic isotope effects (k_H/k_D = 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.

Acknowledgements

Financial support from National Science Foundation of China (No. 21102123), Hunan Province Department of Education (No. 11C1208) and Xiangtan University (Nos. KZ08018 and KZ03011) is greatly appreciated.

Notes and references

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16. At the beginning, we speculated that oxygenation α to the carbonyl group of 1-(2-(arylamino)phenyl)ethanone 1 gave α-keto aldehyde A, which undergoes a copper-catalyzed intramolecular Friedel–Crafts type reaction to give product 2. However, we disfavor this pathway because (1) the electron-deficient aromatic ring gave good or better results, clearly contradictory to this Friedel–Crafts type pathway. If the reaction does work in this manner, ester 6 should give product 2a under the optimized conditions more likely (Table 4, entry 8); (2) it contradicts with the result of the ¹³C labeling experiment (Scheme 2).
    .

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c2gc36502b

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