Copper-mediated oxidative tandem reactions with molecular oxygen: Synthesis of 2-arylbenzoxazinone derivatives from indoles

Article abstract of DOI:10.1016/j.tetlet.2014.03.128

We developed an efficient method for the transformation of indoles by utilizing a copper catalyst and molecular oxygen as the oxidant. The transformation involves a tandem oxidative process of 2-arylindoles. Our reaction afforded a variety of N-benzoyl an

Full text of DOI:10.1016/j.tetlet.2014.03.128

Tetrahedron Letters 55 (2014) 2991–2993
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-mediated oxidative tandem reactions with molecular
oxygen: synthesis of 2-arylbenzoxazinone derivatives from indoles
⇑
Mitsuaki Yamashita , Akira Iida
School of Agriculture, Kinki University, Nakamachi, Nara 631-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed an efficient method for the transformation of indoles by utilizing a copper catalyst and
Received 24 February 2014
Revised 24 March 2014
Accepted 28 March 2014
Available online 4 April 2014
molecular oxygen as the oxidant. The transformation involves
a tandem oxidative process of
2-arylindoles. Our reaction afforded a variety of N-benzoyl anthranilic acids and benzoxazinones. Our
investigation revealed that the choice of solvent and additives is critical in these reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Copper
Oxidation
Rearrangement
Indoles
Anthranilic acid derivatives such as 4H-3,1-benzoxazin-4-ones
are versatile building blocks in organic synthesis and medicinal
chemistry.1 In addition, they are widely found in various biological
compounds and pharmaceutical drugs.2 Therefore, the develop-
ment of efficient methods to synthesize these compounds contin-
ues to be an active research area.3 Among the reported successful
general synthesis methods of benzoxazinones, palladium-
catalyzed reactions, such as carbonylation of ortho-haloanilines,
benzanilides, or aryl urea derivatives, provide versatile routes to
anthranilic acid and its derivatives.4,5 Very recently, Liu’s group
reported palladium-catalyzed carbon–carbon triple-bond cleavage
of 2-azidoalkynylbenzenes for the synthesis of benzoxazinones.6
Guan’s group reported the preparation of 2-arylbenzoxazinone
through the oxone-induced oxidation of 2-arylindole under
metal-free reaction conditions.7
We recently obtained preliminary results when testing the
copper cyanide-catalyzed reaction of 2-substituted indoles. The
reaction of 2-phenylindoles 1a in the presence of CuCN (3.0 equiv)
in DMSO at 50 °C for 12 h under ambient air atmosphere unexpect-
edly resulted in the preparation of 2-phenylbenzoxazinone 2a and
N-benzoyl anthranilic acid 3a in 40% and 47% yields, respectively.
This reaction proceeded without the formation of 3-cyanated prod-
ucts. These results indicate that the efficient oxidative transforma-
tion of indoles to useful motifs is possible through the use of
molecular oxygen, which is considered an ideal oxidant because
of its high abundance, low cost, and lack of toxic byproducts.8,9
In this Letter, we describe methods for the synthesis of 2-aryl-
benzoxazinone derivatives from 2-arylindoles via copper-cata-
lyzed tandem oxidative reactions performed using the
combination of a Cu(I) salt and molecular oxygen (Scheme 1).
Results of our initial studies to optimize the reaction conditions
during our preliminary work are shown in Table 1. The reaction of
1a in DMSO at 80 °C for 24 h with 100 mol % of CuCN resulted in
the moderate conversion to N-benzoyl anthranilic acid 3a in 71%
yield (Table 1, entry 1). Alternatively, the addition of 2 equiv of
Na2CO3 to the reaction mixture improved the yield of 3a (Table 1,
entry 2), whereas a decrease in the amount of CuCN resulted in a
lower chemical yield (Table 1, entry 3). Meanwhile, the chemical
yield improved when the reaction was performed under molecular
oxygen instead of air (Table 1, entry 4). Unfortunately, a CuCN con-
centration of 10 mol % did not result in a high yield, which suggests
that the optimum concentration of the Cu salt is 20 mol %. The
reaction with other copper salts (i.e., CuCl, CuBr, CuI, and CuCl2)
produced results similar to those obtained with CuCN (Table 1, en-
tries 6, 7, 8, and 10). However, the yield of 3a substantially de-
creased when the reaction was performed without Na2CO3,
demonstrating that Na2CO3 is essential for obtaining a high chem-
ical yield of 3a in the presence of a Cu catalyst (Table 1, entries 9
and 11).10 Some other metal catalysts, such as PdCl2 and FeCl2,
were also tested, but no reaction was observed (Table 1, entries
12 and 13). Solvent effects were also investigated; nonpolar and
polar solvents, such as toluene, CH3CN, and DMF, were ineffective
in promoting the reaction, and protic polar solvents, such as EtOH,
afforded a trace amount of 2a along with 80% recovery of 1a (Ta-
ble 1, entries 14–17). The addition of NaOAc instead of Na2CO3
⇑
Corresponding author. Tel./fax: +81 742 43 1770.
E-mail address: yamash@nara.kindai.ac.jp (M. Yamashita).
http://dx.doi.org/10.1016/j.tetlet.2014.03.128
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

2992
M. Yamashita, A. Iida / Tetrahedron Letters 55 (2014) 2991–2993
Guan et al, 2013
O
N
20 mol % CuCl
500 mol %
Ac2O
200 mol % Na2CO3
O
N
O
300 mol %
Oxone
R1
R1
Ph
O
DMSO
80 °C, 12 h
1atm O2
0.5 h
N
H
Ph
Ph
Ph
N
H
CH3NO2
100 °C, 8-10 h
Ph
1
2
1a
2a: 93%
This work
O
O
O
O
O
H3C
MeO
F
Cl
O
20 mol % CuCl
O
O
O
O
Ac2O
OH
NH
Ph
without Ac2O
200 mol % Na2CO3
O
Ph
N
Ph
O
N
Ph
N
Ph
N
N
H
1a
DMSO
80 °C, 12-24 h
O2 (1 atm)
N
Ph
2b, 82%
2c, 71%
2d, 56%
2e, 66%c
O
O
O
N
with Ac2O
2a
Br
F3C
: 74%
3a
: 90%
O
O
c
O
c
N
Ph
H3C
N
Ph
Ph
Ph
Ph
Scheme 1. Synthesis of 2-phenylbenzoxazinone 2a and N-benzoyl anthranilic acid
3a from 2-phenylindole.
2f
2g
2h
, 71%
O
, 12%
O
, 72%
O
O
O
O
N
N
Ph
Ph
MeO
N
CH3
OMe
2i, 70%
2j, 60%
2k, 63%
Table 1
O
Optimization of reaction conditions for the synthesis of anthranilic acids using Cu
O
O
saltsa
MeO
MeO
O
N
O
O
O
O
N
Cu salt
Cl
N
Ph
N
Ph
additives
2l, 45%c
2m, 78%
2n, 55%
OH
NH
Ph
O
Ph
solvent
80 °C
N
H
1a
Ph
Figure 1. Oxidation of 2-phenylindoles 1 in the presence of CuCl for the synthesis
of 2-phenylbenzoxazinones 2a,b aSubstrate 1 (0.2 mmol), CuCl (0.04 mmol), and
3a
O
2 (1 atm)
2a
O
.
Na2CO3 (0.4 mmol) were stirred in DMSO (1.0 mL) at 80 °C under O2 (1 atm). After
Entry
Time (h)
Cu salt (equiv)
Solvent
Additives
Yieldb (%)
3a
12 h, Ac2O (1.0 mmol) was added. bIsolated yields. cCuCl (0.08 mmol) was used.
1c
2c
3c
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19f
36
36
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
CuCN, 1.0
CuCN, 1.0
CuCN, 0.2
CuCN, 0.2
CuCN, 0.1
CuCl, 0.2
CuBr, 0.2
CuI, 0.2
CuCl, 0.2
CuCl2, 0.2
CuCl2, 0.2
PdCl2, 0.2
FeCl2, 0.2
CuCl, 0.2
CuCl, 0.2
CuCl, 0.2
CuCl, 0.2
CuCl, 0.2
CuCl, 0.2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
None
71
96 (72)d
O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
none
20 mol % CuCl
500 mol %
Ac2O
42
94
78
90
89
75
8
90
200 mol % Na2CO3
O
R1
DMSO
80 °C, 12 h
1atm O2
N
H
0.5 h
N
R1
1
2
O
O
O
O
N
O
Na2CO3
None
O
O
O
0 (70)e
No reaction
No reaction
67
N
N
N
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NaOAc
Na2CO3
CH3
OMe
F
Cl
2o
2p
2q
2r
, 80%
, 71%
O
, 68%
, 73%
CH3CN
toluene
EtOH
DMSO
DMSO
42
25
O
O
O
N
O
O
O
N
Trace (80)e
77
O
F
2a, 74g
N
N
CF3
Br
Ph
a
Substrate 1a (0.2 mmol) and Cu salt were stirred in solvent (1.0 mL) at 80 °C
2s, 56%
2t, 57%
2u, 72%
2v, 73%
under O2 (1 atm).
b
1H NMR yields.
c
Figure 2. Oxidation of 2-arylindoles 1 with CuCl for the synthesis of 2-arylbenzox-
azinones 2a,b aSubstrate 1a (0.2 mmol), CuCl (0.04 mmol), and Na2CO3 (0.4 mmol)
Reaction under air.
d
.
The number in parenthesis is the yield after a single recrystallization from
were stirred in DMSO (1.0 mL) at 80 °C under O2 (1 atm). After 12 h, Ac2O
EtOAc.
(1.0 mmol) was added. bIsolated yields.
e
The numbers in parentheses are the yield of recovered 1a.
After 12 h, Ac2O (1.0 mmol) was added.
f
g
Isolated yield.
in modest yields. The only exception was the reaction of 5-trifluo-
romethyl substituted indole 1g, which gave a lower yield of ben-
zoxazinone 2g even when 40 mol % of CuCl was used, because of
the formation of unknown byproducts.11 Both the 6- and 7-substi-
tuted indoles 1h–1n showed reactivity similar to that of the afore-
mentioned 5-substituted indoles, affording the corresponding
benzoxazinones 2h–2n in satisfactory chemical yields.
Next, the effects of the substituents on the aryl ring of 2-arylin-
doles were examined. The results are shown in Figure 2. Notably,
electron-donating and electron-withdrawing functional groups
on the 2-aryl ring were tolerated under the developed reaction
conditions. The reactions of 2-arylindoles 1o–1v gave the corre-
sponding benzoxazinones 2o–2v in modest yields.
did not improve the reaction further (Table 1, entry 18). Anthra-
nilic acid 3a probably forms through the hydrolysis of benzoxazi-
none 2a. Therefore, we also examined the selective synthesis of
2a and 3a by controlling the reaction conditions (e.g., temperature,
time, etc.); however, all such attempts failed. Finally, a one-pot
synthesis of 2a was realized by the addition of Ac2O after the com-
pletion of oxidative reactions (Table 1, entry 19).
We investigated other substrates to evaluate the developed
methods, and the results are shown in Figure 1. Our reaction
proved to be a general methodology for the preparation of 2-phen-
ylbenzoxazinones, and tolerated various functional groups. 5-
Methyl-, methoxy-, fluoro-, chloro-, and bromo-substituted indoles
1b–1f reacted smoothly to give the corresponding products 2b–2f
Further substrate screening revealed that 2-methylindole 1w
was not a suitable substrate;12 in contrast, simple indole 1x was
transformed into Tryptanthrin in 48% yield under the standard

M. Yamashita, A. Iida / Tetrahedron Letters 55 (2014) 2991–2993
2993
O
oxidation of alcohol showed that molecular oxygen reacts with
Cu(I) to afford Cu(II) species;18 however, the exact species respon-
sible for the oxidation of 1a to 2a is still unclear at this stage. Fur-
ther studies are necessary to elucidate the detailed mechanism.
In conclusion, a practical method for the synthesis of 2-aryl-
benzoxazinones and N-benzoyl anthranilic acids via copper-cata-
lyzed tandem oxidative reactions with molecular oxygen has
been developed. Notably, the developed method proceeds under
simple and mild reaction conditions and tolerates various func-
tional groups. Future applications of this strategy for the synthesis
of biologically active compounds are still under investigation and
will be reported in due course.
20 mol % CuCl
200 mol % Na2CO3
OH
NH
CH3
CH3
DMSO
N
H
not detected
80 °C, 12 h
O
2 (1 atm)
O
1w
3w
O
N
20 mol % CuCl
200 mol % Na2CO3
N
DMSO
N
H
80 °C, 12 h
O
O
2 (1 atm)
Tryptanthrin (4): 48%
1x
Scheme 2. Oxidation of other indoles to Tryptanthrin.
Acknowledgement
O
Ph
20 mol % CuCl
200 mol % Na2CO3
OH
NH
O Ph 3a: 69%
O
This work was supported in part by Grants-in-Aid for Young
Scientists (B) (KAKENHI: 24790116) to M.Y.
DMSO
N
H
CF3
80 °C, 24 h
O
2 (1 atm)
5a
Supplementary data
Scheme 3. Oxidation of 2-alkynylaniline 5a to N-benzoyl anthranilic acid 3a.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
03.128.
O
Cu(II)OOH
or H2O2
Cu(I), O2
Ph
Ph
N
H
Baeyer-Villiger
oxidation
N
1a
6a
References and notes
O
O
1. (a) Giri, R.; Lam, J. K.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 686–693; (b) Michael,
J. P. Nat. Prod. Rep. 2008, 25, 166–187.
OH
O
NH
Ph
hydrolysis
Ph
2. (a) Eissa, A. M. F.; El-Sayed, R. J. Heterocycl. Chem. 2006, 43, 1161–1168; (b)
Neumann, U.; Schechter, N. M.; Gütschow, M. Bioorg. Med. Chem. 2001, 9, 947–
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5. Recent examples of palladium-catalyzed synthesis of benzoxazinones, see: (a)
Wu, X.-F.; Neumann, H.; Beller, M. Chem.-Eur. J. 2012, 18, 12599–12602; (b)
Houlden, C. E.; Hutchby, M.; Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne, M. R.;
Lloyd-Jones, G. C.; Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2009, 48, 1830–
1833; (c) Larksarp, C.; Alper, H. Org. Lett. 1999, 1, 1619–1622.
N
2a
3a
O
Scheme 4. Proposed mechanisms for the transformation of 1a to 3a.
reaction conditions (Scheme 2).13 Copper-catalyzed intramolecular
cyclization reactions of o-alkynylanilines for the synthesis of 2-
substituted indoles have been widely reported over the past
decade.14 Therefore, 2-alkynylaniline 5a was applied under the
developed reaction conditions. To our delight, anthranilic acid 3a
was obtained in 65% yield (Scheme 3). Recently, Liu’s group re-
ported the palladium-catalyzed synthesis of benzoxazinones from
2-azidoalkynylbenzenes, which have typically been prepared from
2-alkynylanilines.6 Thus, our methods provide an alternative ap-
proach for the preparation of anthranilic acid derivatives from 2-
alkynylanilines. Further application of our reaction conditions to
various substrates is currently under investigation in our
laboratory.
A proposed mechanism on the basis of previous reports and our
findings for the transformation is shown in Scheme 4. Initially, the
copper-catalyzed aerobic oxidation of 1a to 6a proceeded. The sub-
sequent Baeyer–Villiger reaction of 6a mediated by Cu(II) hydro-
peroxo species or by a peroxide such as H2O2, followed by the
hydrolysis of 2a, gave 3a.15 Oxidation of a substituted 2-methylin-
dole to N-acetyl anthranilic acid by excess H2O2 has been previ-
ously reported.16,17 However, Guan’s group has reported that the
reaction of 1a with 3 equiv of H2O2, which is known to be a good
oxidant in Baeyer–Villiger reactions, afforded only a trace of 2a
(<5%).7 Thus, the oxidation of 1a with H2O2 is unlikely under our
reaction conditions used in the first step. Contrary to the reaction
of 1a with CuCl, the reaction of 1a with CuCl2 in the absence of Na2-
CO3 did not proceed (Table 1, entries 9 and 11).10 These results
indicate that a Cu(I) species is necessary to initiate the reaction.
Studies on the reaction mechanism of the copper-catalyzed aerobic
6. Liu, Q.; Chen, P.; Liu, G. ACS Catal. 2013, 3, 178–181.
7. Lian, X.-L.; Lei, H.; Quan, X.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem.
Commun. 2013, 8196–8198.
8. For review, see: (a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski,
M. C. Chem. Rev. 2013, 113, 6234–6458; (b) Wendlandt, W. A.; Suess, A. M.;
Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062–11087.
9. Recent example of copper-catalyzed aerobic oxidation of 2-arylindoles: Sang,
P.; Xie, Y.; Zou, J.; Zhang, Y. Adv. Synth. Catal. 2012, 354, 1873–1878.
10. 2-Phenylbenzoxazinone 2a and N-benzoyl anthranilic acid 3a were not
detected by TLC or 1H NMR even when 100 mol % of CuCl2 was used.
11. The reaction of 5-nitro substituted indole gave only trace amount of
corresponding benzoxazinone.
12. Yukimasa, H.; Sawai, H.; Takizawa, T. Chem. Pharm. Bull. 1979, 27, 551–553.
13. Copper-catalyzed aerobic oxidation of simple indole to Tryptanthrin was
recently reported: Wang, C.; Zhang, L.; Ren, A.; Lu, P.; Wang, Y. Org. Lett. 2013,
15, 2982–2985.
14. For recent reviews, see: (a) Hirano, K.; Miura, M. Chem. Commun. 2012, 10704–
10714; (b) Krüger, K.; Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153–
2167; (c) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (d) Humphrey,
G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875–2911.
15. 2a and 3a were obtained from 6a, which was synthesized according to the
reported method, by using our reaction conditions.
16. (a) von, J.-M. Adam; Winkle, T. Helv. Chim. Acta 1984, 67, 2186–2191; (b)
Suehiro, T.; Nakagawa, A. Bull. Chem. Soc. Jpn. 1967, 40, 2919–2924.
17. Oxidation of indoles with peroxides was reported: Astolfi, P.; Greci, L.; Rizzoli,
C.; Sgarabotto, P.; Marrosu, G. J. Chem. Soc., Perkin Trans. 2 2001, 1634–1640.
18. Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 2357–2367.