Hydrogen Peroxide Promoted Metal-Free Oxidation/Cyclization of α-Hydroxy N-Arylamides: A Facile One-Pot Synthesis of Isatins

Article abstract of DOI:10.1055/s-0035-1562517

A novel, efficient, and environmentally friendly method was developed for converting α-hydroxy N-arylamides into isatins (1H-indole-2,3-diones) by using hydrogen peroxide as oxidant. The reactions proceeded smoothly under metal-free conditions and generated the corresponding products in good to excellent yields. This method has advantages of a broad substrate scope and simple operations.

Full text of DOI:10.1055/s-0035-1562517

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
J. Li et al.
Letter
Synlett
Hydrogen Peroxide Promoted Metal-Free Oxidation/Cyclization of
α-Hydroxy N-Arylamides: A Facile One-Pot Synthesis of Isatins
Jie Lia
Xu Chenga
R2
N
Metal-free
R2
Non polluting
Xiaojun Maa
Guanghui Lva
Zhen Zhana
Mei Guan*b
Yong Wu*a
N
H2O2
OH
R1
O
R1
Easily available starting materials
DMSO, 100 °C
O
Broad substrate scope
Good to excellent yields
H
O
R1 = alkyl, aryl, halo, OMe, NO2
23 examples
up to 89% yield
R2 = Me, Et, n-Bu, allyl, PMB
a Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University, Chengdu 610041, P. R. of China
b West China Hospital, Sichuan University, No. 37. GuoXue
road, Chengdu, Chengdu 610041, P. R. of China
meiguan92@163.com
wyong@scu.edu.cn
Received: 27.05.2016
Accepted after revision: 23.06.2016
Published online: 25.07.2016
domino synthesis of isatins from easily accessible (2-amin-
ophenyl)acetylenes.17 However, all these reported methods
suffer from one or more drawbacks, such as the use of ex-
pensive or toxic catalysts, prolonged reaction times, tedious
synthetic procedures, or low yields of product. Therefore,
there is still a need to develop milder, more convenient, and
more environmentally benign processes to access isatins.
DOI: 10.1055/s-0035-1562517; Art ID: st-2016-w0367-l
Abstract A novel, efficient, and environmentally friendly method was
developed for converting α-hydroxy N-arylamides into isatins (1H-in-
dole-2,3-diones) by using hydrogen peroxide as oxidant. The reactions
proceeded smoothly under metal-free conditions and generated the
corresponding products in good to excellent yields. This method has
advantages of a broad substrate scope and simple operations.
N
O
O
O
N
S
Key words hydrogen peroxide, hydroxy amides, isatins, cyclization,
indoles
O
O
N
O
Isatins (1H-indole-2,3-diones) are common building
blocks in organic synthesis. They are also frequently found
in natural products that display a variety of important
pharmacological and material-like properties.1 For exam-
ple, they have been developed as caspase 7 inhibitors,2 on-
colytic drugs,3 antiparkinsonian drugs,4 and antiepileptic
drugs5 (Figure 1). Furthermore, isatins are versatile building
blocks for the synthesis of various heterocyclic com-
pounds,6 such as isatoic anhydrides, indoles, quinolines, or
spiro-fused frameworks.7 As a result, continual attention
has been paid to the preparation of this valuable structural
unit since 1840.6–8 There are two practical approaches to
their synthesis. The first is the condensation of aniline with
diethyl oxomalonate (the Martinet procedure),9 oxalyl chlo-
ride (the Stollé procedure),10 or chloral hydrate (the Sand-
meyer procedure),11 mediated by a strong acid (often
H2SO4) or a base. The other involves the introduction of
substituents onto an existing aromatic ring.8a,b Several im-
proved protocols for the construction of isatins have been
reported, such as aryne-based methods,12 Sandmeyer mod-
ifications,13 metal-catalyzed oxidations,14 sulfur ylide medi-
ated carbonyl homologation,15 and C–H amination.16 Ilango-
van and co-workers reported a molecular iodine-promoted
caspase 7 inhibitor
O
O
Br
O
F3C
O
O
H
N
N
N
Br
NO2
O
N
oncolytic drug
antiparkinsonian drug
O
H
H
H
N
N
N
O
S
O
N
O
antiepileptic drug
Figure 1 Biologically active molecules containing an isatin moiety
We recently reported the synthesis of isatins from α-
formyl N-arylamides by a PCC-catalyzed intramolecular
Friedel–Crafts acylation.18 Because α-formyl N-arylamides
are the oxidation products of α-hydroxy N-arylamides, we
were interested in realizing the conversion of α-hydroxy N-
arylamides into isatins in one pot. Also, hydrogen peroxide
is an attractive oxidant that is widely used in laboratory-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
J. Li et al.
Letter
Synlett
R2
N
O
30% H2O2
DMSO, 100 °C
OH
R1
O
R1
O
N
R2
H
1
2
O
O
O
O
O
R1
O
O
O
O
O
N
N
N
N
N
R2
2b–e
2 = Et: 2b, 84%
R2 = n-Bu: 2c, 78%
2 = allyl: 2d, 66%
R2 = 4-MeOC6H4CH2: 2e, 76%
2f–j
R1 = Me: 2f, 77%
R
2k, 85%
2l, 86%
2m, 89%
R
R
1 = OMe: 2g, 79%
1 = Cl: 2h, 80%
R
R1 = Br: 2i, 78%
R
1 = NO2: 2j, 77%
R1
O
O
O
O
R3
S
and
O
O
N
O
O
R1
N
N
N
2n–p
2n'–p'
2q–v
3 = H: 2q, 79%
R3 = 4-F: 2r,81%
R3 = 4-Cl: 2s, 75%
R3 = 3-Cl: 2t, 73%
R3 = 3,5-Cl2: 2u, 77%
R3 = 3-CN: 2v,72%
2w, 56%
R
1 = Cl: 2n + 2n', total yield 78% (2n/2n' = 1.1:1)
R1 = Br: 2o + 2o', total yield 76% (2o/2o' = 1.4:1)
R1 = Me: 2p + 2p', total yield 78% (2p/2p' = 2.0:1)
R
Scheme 1 Transformation of α-hydroxy N-arylamides 1 into isatins 2. Reaction conditions: α-hydroxy amide 1 (1.0 mmol), 30% H2O2 (6.0 mmol) in
DMSO (2 mL) at 100 °C for 3 h under air.
scale and industrial syntheses. It is a mild oxidant and is
comparatively inexpensive. From the perspective of green
chemistry, the use of H2O2 as an oxidant is promising be-
cause water is formed as the sole byproduct.
In this study, we examined an efficient and metal-free
synthesis of isatins by a H2O2-promoted intramolecular oxi-
dation/cyclization reaction of α-hydroxy N-arylamides. To
the best of our knowledge, the use of H2O2 in the synthesis
of isatins has not been reported before.
At the beginning of our investigations, we focused on
the optimization of the conditions for the oxidative cycliza-
tion reaction of 2-hydroxy-N-methyl-N-phenylacetamide
(1a) as a model substrate (Table 1). A series of peroxides
promoted this reaction to give N-methylisatin (2a) in mod-
erate to high yields (Table 1, entries 1–6), whereas
PhI(OAc)2, SeO2, CrO3, OsO4, or PCC gave 2a in 0–59% yield
(entries 7–11). Six equivalents of H2O2 gave the best yield in
the model reaction (entries 12 and 13). Further investiga-
tions indicated that temperature is important for this trans-
formation, and 100 °C emerged as the best reaction tem-
perature, whereas reactions at 50, 80, or 120 °C were less
effective (entries 14–16). When the reaction was per-
formed in various solvents, an optimal yield of 87% was ob-
tained in DMSO (entries 12 and 17–19). The yield fell to 83%
when the reaction was conducted in a sealed tube (entry
20). Therefore, H2O2 and DMSO, as dual oxidants, are im-
portant for the present reaction system (entries 17–19 and
21–22). The optimal reaction conditions therefore involve
the α-hydroxy amide (1.0 mmol) and 30% H2O2 (6.0 mmol)
in DMSO at 100 °C.
To evaluate the versatility of this novel method, we ap-
plied the procedure to the oxidation of a wide range of α-
hydroxy N-arylamides (Scheme 1). Amides with electron-
donating or electron-withdrawing substituents on the
phenyl ring gave good to excellent yields of the desired
products, indicating that the reaction is not sensitive to
electronic effects. Notably, substrates with meta-methyl or
-halo groups on the N-aryl ring provided mixtures of 4- and
6-substituted isatins; the 6-substituted isomers 2n, 2o, and
2p were the major products in this transformation, which
indicated that steric hindrance had a significant effect on
this reaction. Furthermore, synthetically useful biphenyl,
thienyl, and allyl substituents were tolerated in this trans-
formation, giving 2d and 2q–w in good yields. Furthermore,
a variety of functional groups such as ether, nitro, halo, cya-
no, and vinyl were well tolerated under the optimized reac-
tion conditions.
Finally, in relation to the general application of this
transformation, we demonstrated a gram-scale reaction of
hydroxy amide 1a that gave a good (82%) yield of the prod-
uct 2a (Scheme 2).
A series of control experiments were performed to ex-
plore the mechanism of this reaction (Scheme 3). When the
radical scavenger TEMPO was added to the reaction mix-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
J. Li et al.
Letter
Synlett
Table 1 Optimization Studies for the Synthesis of Isatinsa
perature and sunlight play important roles in the radical
process. Moreover, under the optimal conditions, isatin 2a
was obtained in excellent yield from the formyl amide 3a
(Scheme 3, d); this reaction also failed in the presence of
TEMPO (Scheme 3, e). These results suggest that an α-
formyl amide such as 3a is an important intermediate in
the synthesis of the corresponding isatin.
O
N
oxidant
OH
O
O
N
1a
2a
Entry
Oxidantb (equiv)
Solvent
Temp (°C)
Yieldc (%)
1
2
H2O2 (2.0)
TBHP (2.0)
CHP (2.0)
BPO (2.0)
DTBP (2.0)
TBPB (2.0)
IBD (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
50
72
67
64
51
57
53
27
30
0
a)
b)
c)
N
N
30% H2O2 (6 equiv), TEMPO (4 equiv)
DMSO, 100 °C, air, 5 h
O
OH
O
3
2a, 0%
O
1a
4
N
30% H2O2 (6 equiv)
5
OH
OH
n.r.
DMSO, 25 °C, air, 20 h
O
O
6
1a
N
7
N
30% H2O2 (6 equiv), in darkness
DMSO, 100 °C, air, 12 h
O
8
SeO2 (1.0)
CrO3 (1.0)
OsO4 (1.0)
PCC (1.0)
H2O2 (4.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
H2O2 (6.0)
–
2a, 11%
O
9
1a
O
O
10
11
12
13
14
15
16
17
18
19
20d
21
22f
11
59
81
89
41
74
51
53
34
47
83
NRe
88
N
d)
e)
N
30% H2O2 (6 equiv)
O
O
H
H
DMSO, 100 °C, air, 5 h
O
O
3a
2a, 90%
2a, 0%
O
N
N
30% H2O2 (6 equiv), TEMPO (4 equiv)
DMSO, 100 °C, air, 5 h
80
3a
O
120
100
100
100
100
100
100
Scheme 3 Control experiments for the reaction mechanism
1,4-dioxane
toluene
DMSO
DMSO
DMSO
On the basis of our preliminary mechanistic investiga-
tions and some relevant publications,19 we propose the
mechanism shown in Scheme 4. Initially, α-hydroxy amide
1a is oxidized to the α-formyl amide 3a in the presence of
H2O2 and DMSO. Meanwhile, hydrogen peroxide is trans-
formed into a hydroxyl radical by the effects of heat and
sunlight. The hydroxyl radical then traps the formyl hydro-
gen of 3a to produce the acyl radical 4, which is trans-
formed into intermediate 5 by a radical aromatic substitu-
H2O2 (6.0)
a Reaction conditions: 1a (1 mmol), oxidant, solvent (2 mL), air, 3 h.
b TBHP = tert-butyl hydroperoxide; CHP = cumyl hydroperoxide; BPO = ben-
zoyl peroxide; DTBP = di-tert-butyl peroxide; TBPB = tert-butyl peroxyben-
zoate; IBD = PhI(OAc)2.
c Isolated yield.
d Sealed tube.
e No reaction.
f Under argon.
N
N
O
OH
O
O
2a
30% H2O2
H2O
N
1a
O
OH
O
DMSO, 100 °C
N
O
HO
H2O2, DMSO
1a, 1.0 g
2a, 82%
N
Scheme 2 Large-scale reaction
O
O
N
H
H
O
5
O
3a
ture, no product 2a was obtained, suggesting that the trans-
formation might involve a radical pathway (Scheme 3, a).
Also, no reaction occurred when the temperature was re-
duced to 25 °C (Scheme 3, b). When the reaction was con-
ducted in darkness, only an 11% yield of 2a was obtained
(Scheme 3, c). These results imply that both a high tem-
O
and/or
hv
N
H2O2
2 HO
O
H2O
4
Scheme 4 A proposed mechanism for the formation of 2a
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
J. Li et al.
Letter
Synlett
tion reaction. Finally, the isatin 2a is generated efficiently
from intermediate 5 with the assistance of the hydroxyl
radical.
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In summary, a novel and efficient method for the oxida-
tion of α-hydroxy N-arylamides to give isatins in the pres-
ence of H2O2 has been developed.20 The utilization of cheap
aqueous hydrogen peroxide as the oxidant provides a clean
synthetic route, with water as the sole byproduct. In view
of the wide functional-group tolerance and the mild reac-
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Acknowledgment
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (NSFC) (grant numbers 81373259 and
81573286).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562517.
S
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(20) N-Methylisatin (2a); Typical Procedure
A mixture of α-hydroxy amide 1a (152.2 mg, 1.0 mmol) and
30% aq H2O2 (0.68 g, 6.0 mmol, 0.61 mL) was added to DMSO (2
mL), and the mixture was stirred under air at 100 °C for 3 h.
When the reaction was complete (TLC), the mixture was cooled
to r.t., diluted with H2O, and extracted with EtOAc (3 × 10 mL).
The organic layer was washed with sat. brine, dried (Na2SO4),
and evaporated to dryness. The crude residue was purified by
flash chromatography [silica gel, PE–EtOAc (10:1)] to give a red
solid; yield: 143.3 mg (0.89 mmol, 89%); mp 130–133 °C. 1H
NMR (400 MHz, CDCl3): δ = 7.64–7.58 (m, 2 H), 7.15–7.11 (m, 1
H), 6.92 (d, J = 8.0 Hz, 1 H), 3.26 (s, 3 H). 13C NMR (150 MHz,
CDCl3): δ = 183.3, 158.1, 151.4, 138.4, 125.1, 123.8, 117.3, 109.9,
26.2. HRMS (ESI): m/z [M + Na+] calcd for C9H7NNaO2: 184.0374;
found: 184.0370.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D