An intramolecular cascade cyclization of 2-aryl indoles: Efficient methods for the construction of 2,3-functionalized indolines and 3-indolinones

Article abstract of DOI:10.1039/c4ob00511b

Efficient intramolecular N/O-nucleophilic cyclization of 2-aryl indoles has been developed to afford the corresponding 2-aza-3-oxaindolines and 3-indolinones in 80-95% yield. The methods provided convenient access to fused imidazo[1,2-c]oxazolidinone, oxa

Full text of DOI:10.1039/c4ob00511b

Volume 12 Number 22 14 June 2014 Pages 3515–3756
Organic &
Biomolecular
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Arun K. Ghosh and Zhi-Hua Chen
An intramolecular cascade cyclization of 2-aryl indoles: efficient methods
for the construction of 2,3-functionalized indolines and 3-indolinones

Organic &
Biomolecular Chemistry
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An intramolecular cascade cyclization of 2-aryl
indoles: efficient methods for the construction of
2,3-functionalized indolines and 3-indolinones†
Cite this: Org. Biomol. Chem., 2014,
12, 3567
Received 6th March 2014,
Accepted 9th April 2014
Arun K. Ghosh* and Zhi-Hua Chen
DOI: 10.1039/c4ob00511b
www.rsc.org/obc
Efficient intramolecular N/O-nucleophilic cyclization of 2-aryl
indoles has been developed to afford the corresponding 2-aza-3-
oxaindolines and 3-indolinones in 80–95% yield. The methods
provided convenient access to fused imidazo[1,2-c]oxazolidinone,
oxazolidine, or tetrahydro-1,3-oxazine cores under mild con-
ditions.
Functionalized indole rings are one of the most abundant and
important heterocycles that occur ubiquitously in bioactive
natural products, pharmaceuticals and agrochemicals.1,2 Con-
sequently, practical and atom-economical modifications of the
indole structure have long been a subject of immense interest
in organic and medicinal chemistry.3–5 Among them, intramo-
lecular C2-functionalization of indoles such as C-,6 N-,7 O-,8
and S-nucleophilic cyclizations9 have received much attention
since they provide straightforward access to indolines with a
fused-ring substructure (Scheme 1a). However, to date, these
transformations have mainly focused on indole-based sub-
strates with a pendant nucleophile tethered at the C3 position.
Scheme 1 Intramolecular nucleophilic cyclization of indoles.
As indicated in Table 1, our studies commenced with the
halogenation/cyclization of 5a,13 a model substrate that pos-
sesses an NHBoc group as the pendant nucleophile. We
envisagated that the potential reactivity of indoles toward electro-
philic halogenating reagents, such as N-bromosuccinimide (NBS)
and N-chlorosuccinimide (NCS), might offer a starting point to
identify suitable reaction conditions. Disappointingly, the reac-
tions of 5a with NBS in CCl4 at 0 °C or 23 °C under argon both
gave complex mixtures (entry 1), and no desired cyclization
product was obtained. However, the hypothesized halogenation/
cyclization can be carried out employing NCS as an electrophilic
reagent, producing an unprecedented polycyclic indoline 6a in
41% yield. As shown, the indoline derivative contains the
expected imidazolidine ring along with an unexpected fused
oxazolidinone functionality (entry 2). The structure of 6a
was unambiguously established using 1H, 13C, and 2D NMR
spectra. Optimization of the reaction was next investigated by
varying the solvent. The reaction yield increased to 53% when
CH2Cl2 was used in comparison with CCl4, toluene, or Et2O
(entries 2–5). Subsequently, reaction temperature, time and
the amount of NCS were screened to improve the reaction
efficiency (entries 6–9). The best result was obtained (91%
yield) when the reaction was performed with 3 equiv. of NCS at
Intramolecular cyclization of indole with
a nucleophile
attached to the nitrogen atom to construct an N-fused indoline
has rarely been reported.10 Moreover, N-fused indolines exist
widely throughout nature and have considerable biological
and pharmaceutical importance.11,12 Therefore, development
of efficient synthetic methods toward the formation of N-fused
indolines is important for their utilization in medicinal and
biological chemistry. In connection with our work on the
design and synthesis of ligands to probe enzyme active sites,
we became interested in functionalized indole derivatives.
Herein, we present our studies on the cascade halogenation/
intramolecular nucleophilic cyclization of 2-aryl indoles
to
construct 2-aza-3-oxaindolines
and 3-indolinones
(Scheme 1b).
Department of Chemistry and Department of Medicinal Chemistry, Purdue
University, West Lafayette, IN 47907, USA. E-mail: akghosh@purdue.edu
†Electronic supplementary information (ESI) available: Experimental procedure
and characterization data of new compounds. See DOI: 10.1039/c4ob00511b
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Table 1 Validation and optimization of the N-nucleophilic cyclizationa
Entry
Halogenating reagent
Solvent
Temp (°C)
Time (h)
Base
Yieldb (%)
1
2
3
4
5
6
7
8
NBS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (3 eq.)
NCS (3 eq.)
NCS (4 eq.)
NCS (3 eq.)
NCS (3 eq.)
NCS (3 eq.)
NCS (3 eq.)
CCl4
CCl4
Toluene
CH2Cl2
Et2O
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0/23
23
23
23
23
0
0
−10
0
0
0
0
0
1
2
2
2
24
7
3.5
24
2
3.5
3.5
3.5
3.5
—
—
—
—
—
—
—
—
—
41
46
53
10
73
91
85
65
90
88
91
71
9
—
10c
11c,d
12c
13d
NaHCO3
KHCO3
K2CO3
—
a All reactions were performed with 0.2 mmol of 5a in 2 mL of solvent under argon. b Isolated yield. c 3 equiv. of base. d Reaction performed under
air. NBS = N-bromosuccinimide, NCS = N-chlorosuccinimide.
0 °C under argon for 3.5 h (entry 7). It should be noted that
only 3-chloroindole was observed upon treatment of 5a with
1 equiv. of NCS.14 This observation showed that excess NCS was
critical to initiate the cascade cyclization and hydrogen chlor-
ide might be generated in this process (pH = 2–3). Accordingly,
we attempted to add bases such as NaHCO3, KHCO3, or K2CO3
to neutralize the presumed acid. However, no obvious improve-
ment was obtained (entries 10–12), indicating that acidic or
basic conditions had no apparent influence on the reaction.
Additionally, we found that when the reaction was carried out
in the presence of air, the yield of 6a was substantially reduced
(entries 11 and 13). Reactions described above with different
conditions all gave polycyclic indoline 6a as a single cis diaster-
eoisomer (entries 2–13), demonstrating the high diastereo-
selectivity of this cascade reaction. Presumably, the reaction of
5a with NCS first proceeded with the formation of 3-chloroin-
dole 7. It then underwent an NCS-promoted intramolecular
cyclization as shown in intermediate 8 with the extrusion of
isobutene to provide the cyclization product 6a (Scheme 2).
Table 2 Substrate scope of the N-nucleophilic cyclizationa
a Substrate
5
(0.2 mmol) was dissolved in freshly distilled
CH2Cl2 (2 mL) at 0 °C under argon followed by addition of NCS
(0.6 mmol). b The ratio of diastereoisomers was determined by
1H NMR. NCS = N-chlorosuccinimide.
Scheme 2 Intramolecular cascade cyclization of 2-aryl indole 5a.
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air (Table 3, entry 1). Interestingly, the cyclization proceeded
smoothly to afford 3-indolinone 10a in 50% yield instead of
the anticipated C3 monochlorinated indole. The structure of
1
10a was confirmed using H, 13C, and 2D NMR spectra. Con-
sidering that the oxygen of the newly formed carbonyl group
in 10a might be originating from H2O in air, we added 3 equiv.
of H2O in the reaction and obtained 10a in 55% yield (entry 2).
We then turned our attention to screening of the solvent and
the reaction temperature (entries 3–5). Performing the reaction
in CH2Cl2 at 23 °C reduced the reaction time and increased
the yield to 81% (entry 5). Furthermore, a survey of the base
additive along with H2O was found to accelerate the reaction
and improve the yield up to 94% (entries 6–8). This obser-
vation is in contrast to the N-nucleophilic cyclization described
above in which a base additive was not essential.
We further examined a range of indoles with different sub-
stitutions. As it turned out, the substrates also underwent the
O-nucleophilic cyclization under our optimized conditions
(Table 4).17 Indoles bearing electron-donating substituents
(5-Me, 4-Me, 7-Me, 5,7-dimethyl, and 5-OMe) on the benzenoid
ring worked well, leading to the formation of the cyclization
products 10b–10f in excellent yields (91–95%). When 7-methyl-
substituted indole 9d was used, product 10d was obtained
under standard conditions. Interestingly, chlorination of the
indole ring also occurred by increasing the amount of NCS
(5 equiv.) and prolonging the reaction time (24 h), affording
10d′ in 93% yield. The electronic nature of the substrate has a
slight influence on the reactivity, as indoles 9g and 9h with an
electron-withdrawing group (5-Cl and 5-NO2) required longer
reaction times and provided relatively lower yields (83% and
80%). The reaction of indoles 9i–9k with different aryl groups
at the C2 position including p-MeC6H4, p-MeOC6H4, and
1-naphthyl also proceeded effectively to furnish the desired
products 10i–10k in 82–93% yield. Furthermore, formation of
a tetrahydro-1,3-oxazine instead of an oxazolidine in this
O-nucleophilic cyclization was examined. Indole 9l with an
expanded nucleophile was well-tolerated for this reaction,
Fig. 1 X-ray structure of 6e.
Under the optimized reaction conditions, the scope of this
cascade chlorination/cyclization has been explored using
different substitutions. As summarized in Table 2, indole
scaffolds possessing electron-donating (5-Me, 4-Me, 5,7-
dimethyl, and 5-MeO) or halogen (5-Cl) substituents on the
benzenoid ring were well-tolerated and excellent yields were
obtained (81–95%, 6b–6f). In contrast, highly deactivated
indole bearing a strong electron-withdrawing group (5-NO2)
failed to afford the desired cyclization product. Furthermore,
indoles incorporating various methyl-substituted pendant
nucleophiles (5g and 5h) underwent the reaction to give pro-
ducts 6g and 6h in 86% and 84% yields, respectively. Substi-
tution of the 2-phenyl ring with p-methyl or p-methoxy
substituents (5i and 5j) was also found to give suitable sub-
strates for cyclization, delivering products 6i and 6j in 95%
and 93% yields, respectively.
A single-crystal X-ray analysis of compound 6e further con-
firmed the structure of the halogenation/cyclization product
(Fig. 1).15 Of particular interest, the highly functionalized indo-
line products 6a–6j, which possess a new and interesting fused
heterocyclic skeleton in common, might have potential appli-
cations in biological and material studies.
We have also investigated the development of a parallel
halogenation/cyclization of the indole substrates bearing an
O-nucleophile at the N-1 position. Our initial attempt was the
reaction of 2-phenylindole 9a16 and NCS in CCl4 at 0 °C under
Table 3 Validation and optimization of the O-nucleophilic cyclizationa
Entry
Halogenating reagent
Solvent
Temp (°C)
Time (h)
Additiveb
Yieldc (%)
1
2
3
4
5
6
7
8
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
NCS (2 eq.)
CCl4
CCl4
0
0
0
15
15
17
12
7
5
5
—
H2O
H2O
H2O
50
55
48
65
81
85
90
94
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
23
23
23
23
H2O
H2O/K2CO3
H2O/KHCO3
H2O/NaHCO3
5
a All reactions were performed with 0.2 mmol of 9a in 2 mL of solvent under air. b 3 equiv. of H2O and base. c Isolated yield. NCS =
N-chlorosuccinimide.
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Table 4 Substrate scope of the O-nucleophilic cyclizationa
Fig. 2 X-ray structure of 10e.
by this process that simultaneously generates a fused imidazo-
[1,2-c]oxazolidinone skeleton and incorporates two adjacent
hetero-quaternary stereocenters. Furthermore, we developed
an O-nucleophilic cyclization in which a number of tricyclic
tetrahydrooxazolo[3,2-a]indoles and tetrahydro-1,3-oxazino[3,2-a]-
indoles were effectively assembled in 80–95% yield. The mild
conditions and practical convenience of both reactions make
these methods valuable synthetic tools. Further studies includ-
ing mechanistic investigations on the potential bioactivity
of these novel compounds are currently ongoing in our
laboratory.
Acknowledgements
Financial support by the National Institutes of Health is grate-
fully acknowledged.
a Substrate 9 (0.2 mmol) was dissolved in freshly distilled CH2Cl2
(2 mL) at 23 °C under air followed by addition of NaHCO3 (0.6 mmol),
H2O (0.6 mmol), and NCS (0.4 mmol). b Treatment of 9d (0.2 mmol)
with NaHCO3 (1.5 mmol), H2O (1.5 mmol), and NCS (1.0 mmol) in
freshly distilled CH2Cl2 (3 mL) at 23 °C under air for 24 h. NCS =
N-chlorosuccinimide.
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producing the expected product 10l in 80% yield. Other
indoles 9m–9o with different substituents (5-Me, 5,7-dimethyl,
and 5-OMe) on the benzenoid ring were also suitable for
cyclization. In contrast to the formation of oxazolidine
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tethers was slightly less favored, as 10l–10o were obtained in
relatively lower yields (80–87%). Single-crystal X-ray analysis of
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This journal is © The Royal Society of Chemistry 2014
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