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

Article abstract of DOI:10.1039/c2gc36502b

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.

Full text of DOI:10.1039/c2gc36502b

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Copper-catalyzed C–C bond cleavage and
intramolecular cyclization: an approach toward
Cite this: Green Chem., 2013, 15, 76
Received 22nd September 2012,
Accepted 22nd October 2012
acridones†
Wang Zhou,*a Youqing Yang,a Yong Liub and Guo-Jun Dengb
DOI: 10.1039/c2gc36502b
www.rsc.org/greenchem
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 trans-
formation offers an alternative method to prepare medicinally
important acridones and a new strategy for C–C bond
cleavage.
Because of its potential applications in organic synthesis and
industry, transition-metal-catalyzed C–C and C–H bond clea-
vage 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 carbo-
nyl 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 acri-
dones.13 As part of our ongoing research, herein, we disclose
an efficient copper-catalyzed approach for the synthesis of acri-
dones via C–C bond cleavage and intramolecular cyclization
using air as an oxidant under neutral conditions (Scheme 1).
Our initial studies focused on identifying the optimal con-
ditions. 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
Scheme 1 New route to synthesize acridones.
Table 1 Optimization of reaction conditionsa
Cat.
Oxidant
(1 atm)
Yieldb
1 (h) (%)
Entry (20 mol%)
Solvent
1
CuI
O2
DMSO
DMSO
DMSO
NMP
12
12
12
12
12
12
12
36
36
36
36
36
36
36
36
36
36
80
2c
3
CuI
None
O2
Trace
Trace
79
None
CuI
4
O2
5
CuI
O2
DMA
58
6
CuI
O2
DMF
55
7
CuI
O2
p-Xylene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
0
8
CuI
Air
Air
Air
Air
Air
Air
Air
Air
85
9d
10e
11f
12
13
14
15
16
17
18g
CuI
17
CuI
75
CuI
17
CuBr
CuBr2
CuCl
Cu(OAc)2
58
70
48
17
Cu(NO3)23H2O Air
Pd(OAc)2
CuI
19
Air
Air
58
DMSO/PhCl 48
90
aCollege of Chemical Engineering, Xiangtan University, Xiangtan 411105, China.
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.
E-mail: wzhou@xtu.edu.cn
bCollege of Chemistry, Xiangtan University, Xiangtan 411105, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c2gc36502b
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Table 2 The effect of substituents on the aromatic moietya
Entry
Substrate
Product
Yieldb (%)
R1
R2
H
H
H
H
H
H
H
H
H
H
1
H
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
90
91
56
89
86
85
90
92
50
84
2
4′-Me
6′-Me
4′-OMe
4′-NHAc
4′-Ph
4′-COOEt
4′-F
4′-Cl
3′-Me(1j)
3c
4
5
6
7
8
9
10d
11
12
13
14
15
16
17
18
19
H
3-Me
5-Me
5-OMe
5-OCF3
5-F
1k
1l
2c
2b
2d
2k
2h
2i
38
65
65
84
83
84
69
70
53
H
H
1m
1n
1o
1p
1q
1r
H
H
H
5-Cl
4′-F
4′-Me
4′-OMe
5-F
5-OCF3
5-Cl
2l
2m
2n
1s
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.
Table 3 The effect of substituents on the nitrogen and ketone moietya
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). Grat-
ifyingly, 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).
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
Substrate
Yieldb
Product (%)
Entry
R3 R4
Ph Me
1
2
3
4
5
6
1t 2o
1u 2a
1v 2a
1w 2a
82
80
7
60
65
19
H
H
H
H
H
Et
tBu
4-Methylbenzyl
4-Methoxybenzyl 1x 2a
Styryl
1y 2a
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.
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,
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Table 4 Mechanism probing experimentsa
Entry
1
Substrate
Productb (%)
Othersb (%)
2c
2a
2a
2a
2a
Trace
79
3a
3a
3a
3a
66
0
60
35
3
4d
5d,e
17
65
6
7
8
9
2a
2a
2a
2a
Trace
17
Trace
92
10
2a
0
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.
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 reac-
Scheme 2 13C labeling experiments.
tion scope could be expanded to the substrates with substitu- successfully converted into the desired product in excellent
ents on both rings A and B at the same time (Table 2, entries yield (Table 4, entry 9), further studies ruled out the possibility
17–19).
of compound 7 working as a key intermediate in this trans-
In addition, a series of substrates with different substitu- formation (see ESI, Table S3† for details). Moreover, radical
ents on both the nitrogen atom and the ketone were examined mechanism studies indicate that a radical pathway may be not
(Table 3). The substituting group R3 could be phenyl (Table 3, involved in this reaction (see ESI, Table S4† for details).
entry 1). R4 could be alkyl (entries 2–5) or alkenyl (entry 6).
Intermolecular kinetic isotope effects (kH/kD = 1.23) and
Notably, the substrate with tert-butyl only gave the product in intramolecular kinetic isotope effects (kH/kD = 1.69) indicate
7% yield (entry 3). Moreover, we could detect p-methyl and that aromatic C–H bond cleavage may be not turnover-limiting
p-methoxyl benzaldehydes as by-products when 1w and 1x and does not occur via a chelation-assisted, SEAr or a free
were employed respectively (Table 3, entries 4 and 5).
When 1-(2-(benzylamino)phenyl)ethanone (1z)
radical mechanism (see ESI† for details).14,15 Interestingly, 13C
was labeling experiments unveil that only about 86% of carbonyl
employed, we could only observe N-benzyl-indoline-2,3-dione carbon in the product originate from the carbonyl carbon of
(3z) as the product (Table 4, entry 1). Meanwhile, similar the substrate (Scheme 2).
species could be detected by GC-MS analysis when 1a was used
On the basis of these preliminary results, we still can not
(ESI, Fig. S1†). To probe the reaction mechanism, indoline-2,3- speculate on a reasonable mechanistic pathway.16 Multiple
dione 3a was synthesized and subjected to control exper- pathways may be involved in this transformation. A thorough
iments, giving 2a in 79% yield under the optimized conditions mechanistic study is needed to unravel the mechanistic intri-
(Table 4, entry 3). When CuI or CuBr2 was used as the catalyst cacies of this process.
under N2, acridone 2a was obtained in 17% and 65% yields
In conclusion, we have demonstrated a copper-catalyzed
respectively (Table 4, entries 4 and 5). Furthermore, other poss- approach for the synthesis of acridones via C–C bond cleavage
ible intermediates also have been investigated (Table 4, entries and intramolecular cyclization using air as the oxidant under
6–10). Although N-arylanthranilic aldehyde
7
could be neutral conditions. This reaction not only provides an efficient
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method for constructing medicinally important acridones, but
also offers a new strategy for C–C bond cleavage.
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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.
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intramolecular Friedel–Crafts type reaction to give product
2. However, we disfavor this pathway because (1) the elec-
tron-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).
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
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