Ferric(III) chloride catalyzed intramolecular cyclization of N-alkyl-2-oxo-acetanilides: A facile access to isatins

Article abstract of DOI:10.1016/j.tetlet.2015.11.054

A facile strategy for the synthesis of isatins in high yield from N-alkyl-2-oxo-acetanilides has been developed via Friedel-Crafts alkylation using FeCl₃ as catalyst under air. This reaction proceeds through direct intramolecular addition and oxidation in one pot. Also this methodology is operationally simple, atom economical, and environment friendly.

Full text of DOI:10.1016/j.tetlet.2015.11.054

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ferric(III) chloride catalyzed intramolecular cyclization of N-alkyl-2-
oxo-acetanilides: a facile access to isatins
⇑
Yang Zheng, Jue Li, Xinling Yu, Songyang Lv, Li Hai, Yong Wu
Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610041, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile strategy for the synthesis of isatins in high yield from N-alkyl-2-oxo-acetanilides has been
developed via Friedel–Crafts alkylation using FeCl3 as catalyst under air. This reaction proceeds through
direct intramolecular addition and oxidation in one pot. Also this methodology is operationally simple,
atom economical, and environment friendly.
Received 14 October 2015
Revised 16 November 2015
Accepted 19 November 2015
Available online xxxx
Ó 2015 Published by Elsevier Ltd.
Keywords:
Isatin
FeCl3-catalyzed
Intramolecular cyclization
Friedel–Crafts alkylation
Atom economy
Indoline-2,3-dione, commonly known as isatin, is a ubiquitous
unit in a wide range of natural products and synthetic organic
compounds. Isatin and its derivatives exhibit a board array of
biological and pharmacological activities, and have been used as
antiviral,1 antimalarial,2 antiplatelet,3 antiasthmatic,4 and anal-
gesic5 agents (Fig. 1). The isatin motifs are also considered as the
privileged synthetic intermediates that can be found in applica-
tions of organic reactions, such as the nucleophilic addition to
the C-3 ketone carbonyl6 and the electrophilic substitution at C-5
and C-7 of the aromatic ring.7 Giving such importance of isatins,
much effort have been put into the preparation of this compound.
Classically, the Sandmeyer procedure is used in the synthesis of
isatins. This procedure involves a treatment of aniline with chloral
hydrate, hydroxylamine hydrochloride in an aqueous sodium sul-
fate medium.8 The Stollé procedure9 and Martinet procedure,10
which involve the condensation of aniline with oxalyl chloride or
diethyl ketomalonate, are another two common strategies to
synthesize isatins. However, these methods suffer from harsh con-
ditions, poor yields, and limited diversification. This prompts the
development of better methods on the construction of isatins to
overcome these limitations. Gratifyingly, a number of new meth-
ods have been proved efficient in building this useful framework,
such as the I2-mediated11 or Cu-catalyzed12 intramolecular
cyclic amidation from substituted anilines, the ylide-mediated
carbonyl homologation of anthranilic acids,13 the metal complexes
mediated oxidation of indoles,14 and the base-promoted oxidation
of indolin-2-one.15 However, there are some drawbacks in these
methods too, such as the employment of noble metals and/or
expensive ligands, the hazardous reagent, the not readily available
intermediates or pre-functionalized aromatic substrates, high
temperature, and low yield. Moreover, some methods are also
not atom economical. Therefore, considering the importance of
isatins in medicinal chemistry and organic synthesis, improved
methods are still highly desirable.
Recently, Li and co-workers have reported copper-catalyzed
intramolecular C–H oxidation/acylation to isatin derivatives
(Scheme 1a).16 That is a quite attractive work. Firstly, the starting
material formyl-N-arylformamides can be easily prepared, and
secondly isatins can be smoothly obtained in the presence of CuCl2
and O2 in THF at 100 °C for 12 h. However, problems of the compli-
cated operation (reacting in Schlenk tube and charging with O2),
long reaction time, and no large-scaled application make the work
undesirable. This motivates the development of an operationally
simple and cost-effective method in our study. Herein we present
a
FeCl3-catalyzed intramolecular Friedel–Crafts alkylation to
synthesize isatin derivatives under air within short time
a
(Scheme 1b). This protocol is simple, environment friendly and
atom economical. Also, it obtains isatin units in high-yield without
the preparation of ortho-substituted anilides or other complicated
intermediates.
Due to our interest in isatins and their inherent importance, we
envisioned that finding an efficient protocol for the synthesis of
isatins would be interesting. During our previous research, we
⇑
Corresponding author. Tel.: +86 028 85503235; fax: +86 028 85506666.
E-mail addresses: smile@scu.edu.cn (L. Hai), wyong@scu.edu.cn (Y. Wu).
http://dx.doi.org/10.1016/j.tetlet.2015.11.054
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Zheng, Y.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.054

2
Y. Zheng et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
Cl
Optimization of the reaction conditionsa
N
H
N
N
CHO
F
NH
O
N
Cat., Solvent
O
F
N
O
O
N
O
Oxidant,100oC
12h
N
H
NH
H
Cl
O
Cl
2a
1a
Cl
NH
Antiviral
Entry
Catalyst
Oxidant
Temp (°C)
Solvent
Yieldb (%)
AntImalarial
O
F
O
N
1
2
3
4
5
6
7
8
AlCl3
SnCl2
TiCl4
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
K2S2O8
TBHP
Cu(OAc)2
PhI(OAc)2
—
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
84
41
72
Trace
66
O
O
Cl
O
O
HO
N
O
MnCl2
CoCl2
NiCl2
Hg2SO4
CuSO4
AgNO3
IrCl3
N
O
N
nPent
HN
O
S
O
O
O
21
Trace
Trace
Trace
60
86
68
90
0
63
86
74
83
Trace
90
83
88
90
75
83
37
31
65
93
76
92
56
87
OH
Analgesic
Antiplatelet
Antiasthmatic
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29c
30c
31c
32
33c
Figure 1. Selected biological and pharmacological activities containing isatin
CeCl3
RhCl3
FeCl3
—
motifs.
had synthesized N-methyl-2-oxo-acetanilide 1a.17 Thus, our inves-
tigation started with 1a as prototypical substrate in toluene. Firstly
a series of metal salts were screened for this reaction under O2
(Table 1, entries 1–13). To our delight, FeCl3 had excellent reaction
efficiency (Table 1, entry 13). It was found that this transformation
would not be a success without the presence of any metal salts
(Table 1, entry 14). Further optimization of the reaction conditions
was needed in order to improve the yield. When O2 was replaced
by other oxidants, including K2S2O8, tert-butyl hydroperoxide
(TBHP), Cu(OAc)2 and PhI(OAc)2, the yield of N-methyl-indoline-
2,3-dione 2a was not increased (Table 1, entries 15–18). Notably
no corresponding product was detected when replacing O2 with
argon, which revealed that an oxidant was necessary (Table 1,
entry 19). Surprisingly, we observed that the reaction still pro-
ceeded smoothly under air. This observation was quite interesting
as employing air as an oxidant is quite easy, and a reaction which
could run under air system is obviously simple to operate (Table 1,
entry 20). Thus, air was chosen as oxidant for further optimization.
Additionally, the examination of other iron complexes was set. Out
of cost concerns, FeCl3 was chosen as the most suitable iron cata-
lyst (Table 1, entries 21–23). Furthermore, the choice of various
solvents was evaluated. Dimethyl sulfoxide (DMSO) was more
effective among all the solvents such as dimethylformamide
(DMF), acetonitrile (MeCN), ethanol (EtOH), tetrahydrofuran
(THF) and 1,4-dioxane (Table 1, entries 24–29). It was notable that
in DMSO, conversion of 1a could be completed in 1.5 h (Table 1,
entry 29). The use of 10 mol % of FeCl3 was necessary to achieve
a satisfactory yield. When 5 mol % of FeCl3 was used, the reaction
yield decreased to 76%, whereas the yield was not enhanced when
FeCl3 loading was up to 20 mol % (Table 1, entries 30–31). More-
over, further investigation on evaluating reaction temperature
suggested that 100 °C was the best choice as increasing or
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
KFe(CN)3
FeBr3
Fe(TFA)3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
Dioxane
MeCN
EtOH
THF
DMSO
DMSO
DMSO
DMSO
d
FeCl3
FeCl3
FeCl3
FeCl3
e
Air
Air
120
DMSO
a
Reaction conditions: 1a (0.4 mmol), catalyst (10 mol %), solvent (2.0 mL), oxi-
dant (0.6 mmol or 1 atm) were heated at 100 °C for 12 h. TFA = trifluoroacetate;
TBHP = tert-butyl hydroperoxide.
b
Isolated yield.
c
Reaction for 1.5 h.
d
5 mol % FeCl3.
20 mol % FeCl3.
e
decreasing the temperature from 100 °C only led to a decrease in
yield (Table 1, entries 32–33). Accordingly, the reaction conditions
are optimized as follows: 10 mol % FeCl3 under air atmosphere in
DMSO at 100 °C for 1.5 h.
With the optimum reaction conditions in hand, we investigated
the substrate scope as following trials. Results are shown in
Figure 2. Methyl, ethyl, n-butyl, allyl, and 4-methoxyl phenyl
groups that attached to amine gave a high yield of corresponding
(a) Previous work: CuCl2 catalyzed intramolecular acylation
O
• Complicated operation
• Long time reaction
• No gram-scaled
application
CuCl2, O2
O
R1
R1
O
N
CHO
N
R2
THF, 100oC, 12h
R2
• Moderate yield
(b) This work
R1
O
H
• Operationally simple
• Cost-effective
• Gram-scaled application
• Non-toxic catalyst
• High yield
O
FeCl3, air
R1
O
N
R2
CHO
N
R2
DMSO, 100oC, 1.5h
Scheme 1. Typical pathway for the synthesis of isatins.
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Y. Zheng et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
R2
R2
N
FeCl3, air
N
CHO
R1
O
R1
DMSO,100oC
O
H
O
2
1
O
O
O
N
O
O
O
O
O
N
N
N
2a
2b
2c
2d
,78% yield
, 93% yield
, 90% yield
, 86% yield
O
O
O
O
N
MeO
X
O
N
O
O
O
N
N
OMe
2g
X=Cl, , 81% yield
2f
, 94% yield
2e
, 86% yield
2i, 88% yield
X=Br, 2h, 85% yield
O
O
O
O
O
O
O
O
+
N
N
N
N
2l
2l 2l'
2l'
= 1:1.5)
2k, 90% yield
2j
, 87% yield
2l 2l'
/
+
85% yield(
F
O
O
O
NC
O
O
O
N
N
N
2m
, 79% yield
2o
, 72% yield
2n
, 75% yield
Cl
O
O
S
Cl
O
O
N
N
2q
2p
, 76% yield
, 70% yield
Figure 2. Substrate scope of substituted aldehydes uses air as oxidant in DMSO. Reaction conditions: aldehydes 1 (0.4 mmol), FeCl3 (10 mol %), DMSO (2.0 mL) were heated at
100 °C for 1.5 h under air.
products (Fig. 2, 2a–2e). Additionally, it was observed that
para-substituted N-methyl-2-oxo-acetanilides bearing either
electron-donating substituents such as methyl and methoxyl, or
electron-withdrawing groups such as chloro and bromo were well
tolerated during the reaction (Fig. 2, 2f–2l).
Notably, a mixture of 4-Me and 6-Me products were achieved
from meta-methyl acetanilide in 85% yield with the ratio of 1:1.5
(2l/2l0). Gratifyingly other functional groups, such as cyano, substi-
tuted phenyl, and heterocycles, were also compatible with the
optimal condition (Fig. 2, 2m–2q). Moreover, to show the synthetic
utility of this FeCl3-catalyzed transformation, the gram-scale
reaction was carried out by employing 1a as prototypical substrate.
When 6.1 mmol of 1a (1.0 g) is used, this reaction proceeded with
similar efficiency under optimal condition (89%). Overall, this
method had been proved to be versatile for the synthesis of isatin
derivatives.
In order to explore the mechanism of this reaction, some control
experiments were performed (Scheme 2). When N-methyl-2-oxo-
N-phenylacetamide 1a was treated with 10 mol % FeCl3 in DMSO
under argon heating for 0.5 h, the amount of 2a was observed with
33% yield and 3-hydroxy-1-methylindolin-2-one 5a was also
detected in 17% yield (Scheme 2a). Without the presence of
FeCl3 and O2, 5a can be converted to 2a by DMSO with 20% yield
(Scheme 2b). Additionally, when 5a was added to the solvent of
1,4-dioxane at 100 °C under air, the target product isatin 2a was
obtained in 60% yield after 0.5 h of heating (Scheme 2b). According
N
N
N
CHO
FeCl3, DMSO
O
(a)
O
+
100oC, argon, 0.5h
O
O
OH
5a
1a
2a
33% yield
1a
17% yield(46%of
was recovered)
DMSO, argon
100oC, 0.5h,20%yield
N
N
O
O
(b)
1,4-dioxane,air
O
OH
5a
2a
o
100 C, 0.5h, 60% yield
Scheme 2. Control experiments.
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4
Y. Zheng et al. / Tetrahedron Letters xxx (2015) xxx–xxx
H
N
O
FeCl3
N
O
OH
O
5a
DMSO and air(O2
)
1a
N
O
O
2a
N
O
O
N
O
O
H
H
H
FeCl3
FeCl3
4a
Scheme 3. Proposed mechanism.
3a
to the previous Letters18 and the control experiment, we proposed
that Friedel–Crafts alkylation would be the most likely mechanism.
As shown in Scheme 3, coordination of FeCl3 with substrate 1a
formed the intermediate 3a, which subsequently was transformed
to the cyclization intermediate 4a through Friedel–Crafts
alkylation. Then 3-hydroxy-1-methylindolin-2-one 5a was formed
after FeCl3 leaving. Finally, compound 5a was converted into
N-methylindoline-2,3-dione 2a with the assistance of DMSO
and O2.
In summary, we have found a FeCl3-catalyzed intramolecular
cyclization to isatin derivatives under air in DMSO. This cost-effec-
tive strategy that involves Friedel–Crafts procedures is really
attractive. Its efficiency on generating isatin structures in high
yield through directed intramolecular addition to aldehyde car-
bonyl has also been demonstrated. Besides the advantages such
as atom economy and gram-scaled application, this transformation
is also fascinating in other aspects. For example, using air as an
oxidant is lucrative and makes this reaction easier to operate.
Additionally, this protocol avoids the complicated preparation of
ortho-substituted acetanilides, which are the starting materials in
previous methods.11–15 Most importantly, iron compounds as cat-
alysts are interesting not only for their abundance in the earth’s
crust, but also for their non-toxicity, environmentally benign nat-
ure, and economy. Applications of this method to other substrates
are in progress in our group.
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Supplementary data
Supplementary data associated with this article can be found, in
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