Sulfamic acid promoted one-pot multicomponent reaction: A facile synthesis of 4-oxo-tetrahydroindoles under ball milling conditions

Article abstract of DOI:10.1039/c9ra08478a

We report an efficient and facile one-pot synthesis of 4-oxo-tetrahydroindoles using sulfamic acid under ball milling conditions. The present protocol for preparation of biologically important 4-oxo-tetrahydroindoles offers several advantages such as mild

Full text of DOI:10.1039/c9ra08478a

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Sulfamic acid promoted one-pot multicomponent
reaction: a facile synthesis of 4-oxo-
Cite this: RSC Adv., 2019, 9, 39735
tetrahydroindoles under ball milling conditions†
a
b
c
d
Trimurti L. Lambat, * Ahmed A. Abdala, Sami Mahmood,
Ratiram G. Chaudhary
Pankaj V. Ledade,
e
f
and Subhash Banerjee*
We report an efficient and facile one-pot synthesis of 4-oxo-tetrahydroindoles using sulfamic acid under
ball milling conditions. The present protocol for preparation of biologically important 4-oxo-
tetrahydroindoles offers several advantages such as mild reaction conditions, improved selectivity and
higher isolated yields. Moreover, solvent-free reaction conditions and the use of ball milling make the
present protocol environmentally friendly in nature.
Received 16th October 2019
Accepted 19th November 2019
DOI: 10.1039/c9ra08478a
rsc.li/rsc-advances
simplicity to perform relative to the conventional multistep
reactions. Further, the MCR is performed in a single step
Introduction
2c
Ball milling is a mechanochemical procedure that is mainly which does not require isolation of the intermediates, leading
used to grind minerals and prepare and modify inorganic to a favourable reduction of the reaction time and energy.
1a
compounds. Nowadays, its application in synthetic organic Additionally, solvent-free reaction is a promising approach in
2
d
chemistry has become an emerging eld of research. Examples organic synthesis it does not produce unwanted solvent waste.
1
b
of the recent applications of ball milling in organic synthesis
Conventionally, solvent-free reactions have been performed via
include C–C bond forming reactions, metal-catalyzed C–N, C–C a mortar and pestle, but recently high-energy ball milling
organo-catalyzed C–C bond (HEBM) was realized as a more attractive alternative. Although
formation, cycloaddition reactions, synthesis of hetero- ball milling is a technique that works according to the same
1
c,d
and C–F bond development,
1e
1f
1g
1h
1i
cycles, protecting group chemistry, redox processes, reac- principles as traditional mortar and pestle, its mechanical
2e
1j
tions with fullerenes and bromination reactions. Compared to energy is usually high enough to facilitate a chemical reaction.
conventional solution phase reactions, ball milling conditions Many reports have demonstrated the effectiveness of HEBM for
commonly yield increased selectivity and reactivity, and thus organic transformations and development of environmentally
2f
there should be further exploration of applications of ball benign synthetic processes. Due to the aforementioned
1
k
2g
milling in organic synthesis.
advantages, MCRs found numerous applications in the
2
a
On the other hand, multicomponent reactions (MCRs)
provide attractive synthetic approach in the elds of organic organic scaffolds.
synthesis of drugs and new biologically important active
2
h
2b
and medicinal chemistry due to their higher atom economy,
Heterocyclic motifs are critical in drug discovery because of
structural variability, selective bond formation ability and their vast array of applications in the agrochemicals, pharma-
Among others, tetrahy-
droindole and indole related moieties impart distinct and
Department of Chemistry, Manoharbhai Patel College of Arts, Commerce & Science, interesting structural features with various biological charac-
3
a
ceuticals and veterinary elds.
3b
3c
a
Deori, Dist-Gondia 441901, Maharashtra, India. E-mail: lambatges@gmail.com; Tel:
3d
teristics such as progesterone receptor agonist, inhibitor at
vanilloid receptor-1, MDM2-p53 interaction inhibitor, anti-
malarial, antituberculotic, CR TH2 receptor antagonist and
Satavaptan. Representative bioactive molecular structures are
provided in (Fig. 1).
+
917972047470
3e
b
Chemical Engineering Program, Texas A & M University at Qatar, POB 23784, Doha,
Qatar
3f
c
Department of Physics, The University of Jordan, Amman 11942, Jordan
d
Department of Chemistry, Yashwantrao Chawhan Arts, Commerce & Science College,
Lakhandur, Bhandara 441803, Maharashtra, India
e
Because of these important applications of heterocyclic
Post Graduate Department of Chemistry, S. K. Porwal College of Arts, Commerce & compounds, different synthetic methods were developed for
Science, Kamptee-441001, India
4a–d
their production.
However, most the methods are metal
f
Department of Chemistry, Guru Ghasidas Vishwavidyalaya, Bilaspur, 495009,
4e
catalysed and have several limitations such as harsh reaction
conditions, employment of toxic and expensive metals as cata-
lysts, longer reaction time, non-reusability of catalysts etc.
Chhattisgarh, India. E-mail: ocsb2006@gmail.com; Fax: +917752260148; Tel:
+
†
1
917587401979
4f,g
Electronic supplementary information (ESI) available. See DOI:
0.1039/c9ra08478a
The dimedone reacts with a-chloroacetaldehyde in sodium
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Fig. 1 Biologically important compounds possessing 2-oxoindole and indole scaffolds.
carbonate to produced 4-oxo tetrahydrofuran which reacts with
In contribution to development of environmentally benign
ammonium hydroxide to gives 4-oxo tetrahydroindole in protocols for bioactive heterocyclic compounds synthesis, we
4e,f
another route depicted in (Scheme 1).
report a facile, low-cost and green approach to synthesize 4-oxo-
Therefore, the design of effective and facile approaches for tetrahydroindoles using sulfamic acid under ball milling
5a
creation of these derivatives is of utmost importance. More- condition following (Scheme 2).
over, heterogeneous acidic catalysts are more successful than
their homogeneous counterparts because of their ease of
separation and retrieval for cyclic use making the process more Result & discussion
5b
2 3
economical. On the other hand, sulfamic acid (H NSO H,
5
c
To begin the study, the reaction of dimedone (1), phenacyl
bromide (2), and aniline (3) was chosen as a model substrate in
the ball mill. In our rst attempt the reaction was conducted in
the absence of catalyst by milling for 60 min at a milling rota-
tional speed of 600 rpm, the product, 6-dimethyl-1,2-diphenyl-
sulfamic acid) has been recently proven as very effective in
promoting acid-catalyzed reactions due to its low cost, higher
stability, resistance to corrosion, non-hygroscopic, and non-
5
d,e
volatile nature.
In addition, miscibility of sulfamic acid
with water makes it easily recyclable. Sulfamic acid is used as
promoter for protection of aliphatic substrate, Beckmann
1
,5,6,7-tetrahydro-4H-indol-4-one (4a) was isolated with 10%
yield (entry 1, Table 1). Then different types of catalysts like
SiO , PMA–SiO , Amberlite, Montmorillonite K10, Indion resin,
and Wang sulfonic acid were incorporated and milled for
0 min at 600 rpm. The isolated product revealed a yield
5
f
5g
5h
rearrangement, Hantzsch reaction,
Biginelli reaction,
5i
5j
2
2
Pechmann condensation, Michael addition and Mannich
5k
reactions.
6
Scheme 1 Conventional approach for the synthesis of tetrahydroindole derivatives.
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Scheme 2 General reaction scheme of sulfamic acid catalyzed for
synthesis of 4-oxo-tetrahydroindoles scaffolds under ball milling
conditions.
increase up to 24–62% (entry 2–7, Table 1). However, the
product yield using sulfamic acid was signicantly higher (entry
8, Table 1). A mixture of model substrate and sulfamic acid
(15 mol%) milled for 60 min at rotation speed of 600 rpm
yielded 92% (4a) without column chromatography.
Fig. 2 Effect of sulfamic acid loading and reaction conditions on the
yield of (4a).
In order to study the effect of ball milling conditions and
amount of sulfamic acid on the yield, sulfamic acid loading was
varied between 5 to 25 mol% and the ball milling speed was
varied between 400–600 rpm and the reaction time was either 60
or 90 minutes. Therefore, following the experimental procedure –Br, –cyclopropyl, –n-butyl etc.) increase the reaction rate as well
ESI† for detail experimental procedure) and the aforemen- as the product yields. The ndings were depicted in (Table 2).
(
tioned conditions, the yield of (4a) using sulfamic acid varied The synthesized 4-oxo-tetrahydroindoles were puried by
between 88–98% with the optimum conditions at loading of recrystallization from hot ethanol and thus, column chroma-
2
0 mol% (Fig. 2).
tography is not required in the present protocol. Their structure
ꢀ
With the optimal conditions, we investigated possible scopes was conrmed by measuring the melting points (MP C) fol-
of reactants as revealed in (Table 2). All of these 4-oxo- lowed by spectroscopic characterization using nuclear magnetic
1
13
tetrahydroindoles are identied motifs and were simply recog- resonance ( H NMR, C NMR and mass spectra); spectra were
nized by assessment of their spectroscopic information with provided in (ESI for copies of spectra; S3†).
4g
those previously reported (ESI for spectroscopic data; S2†).
The phenacyl bromide consists of both electron withdrawing one-pot reaction is revealed in (Scheme 3). In the rst step,
e.g. –CN group) and electron donating (e.g. –Cl, –OCH etc.) dimedone (1) containing active methylene group undergoes
The plausible mechanistic pathway for this three-component
(
3
groups participated prociently in the reaction not together alkylation with the phenacyl bromide (2) to produced tri-
with a few electronic effects. The aromatic amine having pres- carbonyl compound (A). In the existence of the sulfamic acid,
ence of electron donating groups (e.g. –Me, –naphthyl, –F, –Cl, primary amine (3) can react with one of the keto groups of
Table 1 Optimization of reaction conditions for the synthesis of (4a) using ball milling
a
Entry
Catalysts or additive
No catalyst
Catalyst (mol%)
Rotation (rpm)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
—
20
20
20
20
20
20
20
600
600
600
600
600
600
600
600
60
60
60
60
60
60
60
60
10
33
55
41
40
24
62
98
SiO
PMA–SiO
2
2
Amberlite
MMT K-10 clay
Indion resin
Wang-OSO
Sulfamic acid
3
H
b
a
Isolated yield; model reaction (4a): dimedone (140.18 mg, 1.0 mmol), phenacyl bromide (199.04 mg, 1.0 mmol), and aniline (93.13 mg, 1.0 mmol)
b
under ball milling. Present work.
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Table 2 Sulfamic acid catalyzed synthesis of 4-oxo-tetrahydroindoles derivatives
4
g
dimedone to produced an intermediate (B) followed by loss of supported sulfonic acid in terms of reaction time, product
water molecule giving N-alkylenamine (C). The amino group of yield and catalyst recyclability.
N-alkylenamine (C) can attack on the carbonyl group of phe-
Next, we have investigated the reusability of sulfamic acid for
nacyl bromide specically to generate an intermediate (D). In the synthesis of (4a) as a model reaction in 2 mmol scale. Aer
the presence of sulfamic acid undergo cyclization to produced reaction, sulfamic acid was retrieved from the reaction mixture
(
(
E) and followed by loss of water molecule furnishes the product by simple ltration, consequently washed with aqueous
4a). ethanol, dried and reused for the next cycle. We conrmed that
In order to assess the effect of various Brønsted acids, we sulfamic acid can be effectively recycled for ve cycles without
carried out the reaction between dimedone (140.18 mg, 1.0 appreciable loss of catalytic activity. However, a little (ꢁ12%)
mmol), phenacyl bromide (199.04 mg, 1.0 mmol), and aniline loss in the yield of the product was observed. The results were
(93.13 mg, 1.0 mmol) at reuxing conditions in EtOH, catalyzed presented in (Fig. 3). The decrease of the yield could be due to
by using 20 mol% of various additives (Table 3). The reaction loss of sulfamic acid (ꢁ8.5%) during reaction and recycling.
afforded the product (4a) although the yield was low as
compared with ball milling condition (compare with entry 8 in
Table 1).
Experimental
General
To signify the advantage of the current methodology,
a comparative study of current and earlier known methods is
provided in (Table 4) which claries the effectiveness of the
sulfamic acid promoter compared with the known Wang resin
The chemicals were procured from S. D. Fine, India and Merck
Ltd. without additional purication. The sulfamic acid was
purchased from Merck Ltd. (catalogue no. 242780). The
39738 | RSC Adv., 2019, 9, 39735–39742
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Scheme 3 Plausible mechanism for the synthesis of 4-oxo-tetrahydroindole (4a) using sulfamic acid.
reactions were monitored by thin-layer chromatography (TLC) uncorrected. HRMS was determined using waters LCT premier
on silica gel plates (60 F254), visualizing with ultraviolet light or XETOF ARE-047 apparatus.
iodine spray. Flash chromatography was performed on silica gel
(
100–200 mesh) using distilled hexane, ethyl acetate, and
dichloromethane. A Retsch 01.462.0220 Agate Grinding Jar
250 mL capacity) was used for the Planetary Ball Mill 100. All
General procedure for synthesis of 4-oxo-tetrahydroindoles
derivatives using ball milling technique: representative
experimental procedure for the synthesis of 6,6-dimethyl-1,2-
diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one (4a)
(
the products were identied compounds and their physical
information, FT-IR, mass spectra and H NMR was basically the
same as those of the genuine samples. Melting points were
determined using melting point B-540 apparatus and are
1
The mixture of dimedone (140.18 mg; 1 mmol), phenacyl
bromide (199.04 mg; 1 mmol), and aniline (93.13 mg; 1 mmol)
and catalytic amount of sulfamic acid (19.50 mg; 20 mol%) was
Table 3 Comparison of Brønsted acids catalyzed conventional methods for synthesis of (4a)
a
Entry
Additives
TFA
(mol%)
Reaction conditions
Time (min)
Yield (%)
1
2
3
4
5
6
20
20
20
20
20
20
Reux/EtOH
Reux/EtOH
Reux/EtOH
Reux/EtOH
Reux/EtOH
Reux/EtOH
180
240
180
180
480
360
69
61
78
71
45
84
C
C
6
H
H
5
CO
2
H
H
6
5
SO
3
p-CH
AcOH
Sulfamic acid
3 6 4 3
C H SO H
b
a
Isolated yield; model reaction (4a): dimedone (140.18 mg, 1.0 mmol), phenacyl bromide (199.04 mg, 1.0 mmol), and aniline (93.13 mg, 1.0 mmol)
b
under conventional reux. Present work.
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Table 4 Comparative study of the present and reported methods for synthesis of (4a)
Sr. no.
Catalyst
Reaction conditions
Yield (%)
Time
Reusable?
4
g
ꢀ
1
2
Wang resin
Water/80–85 C
80–90
88–98
4–5 h
60 min
Up to 4 cycles
Up to 5 cycles
a
Sulfamic acid
Room temperature
a
Present work.
(
7
s, 2H), 6.78 (s, 1H), 7.05–7.07 (m, 2H), 7.12–7.17 (m, 5H), 7.39–
1
3
.41 (m, 3H); C NMR (CDCl
3
, 100 MHz) d: 28.6 (2C), 35.5, 37.0,
52.1, 105.6, 120.0, 122.5, 126.8, 127.7 (2C), 128.1 (2C), 128.1
(2C), 128.2, 129.3 (2C), 136.3, 137.7, 144.7, 194.0; HRMS (ESI) [M
+
1] calcd for C22
H22NO: 316.1702, found: 316.1691.
1
-(4-Bromophenyl)-6,6-dimethyl-2-phenyl-1,5,6,7-tetrahydro-
1
4
2
7
6
5
1
+
H-indol-4-one (4b). H NMR (CDCl , 400 MHz) d: 1.10 (s, 6H),
3
.41 (s, 2H), 2.50 (s, 2H), 6.77 (s, 1H), 7.00–7.03 (m, 2H), 7.04–
.07 (m, 2H), 7.18–7.20 (m, 3H), 7.52 (dd, J 1,2 ¼ 2.0 Hz, J 1,3 ¼
1
3
3
.8 Hz, 2H); C NMR (CDCl , 100 MHz) d: 28.6 (2C), 35.5, 37.0,
2.0, 105.9, 120.2, 122.1, 127.1, 128.2 (2C), 128.3, 129.2 (2C),
31.5 (2C), 132.5 (2C), 136.2, 136.6, 144.4, 193.8; HRMS (ESI) [M
Fig. 3 Recyclability of sulfamic acid for the synthesis (4a) as a model
reaction.
1] calcd for C22
H21NOBr: 394.0808, found: 394.0811.
6
,6-Dimethyl-2-phenyl-1-(o-tolyl)-1,5,6,7-tetrahydro-4H-
1
indol-4-one (4c). H NMR (CDCl , 400 MHz) d: 1.05 (d, J ¼
3
9
3
.6 Hz, 6H), 1.86 (s, 3H), 2.15 (d, J ¼ 16 Hz, 1H), 2.36–2.50 (m,
taken in one pot under solvent/additives free under ball-milling
at 600 rpm with six balls (d ¼ 10 mm) of the equivalent
substance using 25 mL stainless steel beaker for 60 min. The
ball-milling was carried out at inverted rotation directions, for
time durations of 10 min separated by intervals of 30 s. The
extraction of the reaction residue was accomplished by elution
with ethanol (5 mL), acetone (2.5 mL) followed by solvent
evaporation and recrystallization to provide 6,6-dimethyl-1,2-
diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one as yellow solid in
13
H), 6.83 (s, 1H), 7.08–7.14 (m, 5H), 7.2–7.36 (m, 4H); C NMR
3
(CDCl , 100 MHz) d: 17.4, 27.9, 29.2, 35.5, 36.5, 52.1, 104.9,
1
1
19.7, 126.9 (2C), 127.4 (2C), 128.1 (2C), 128.6, 129.1, 131.2,
32.0, 136.1, 136.4, 136.9, 144.8, 193.9; HRMS (ESI) [M + 1] calcd
for C23
H24NO: 330.1859, found: 330.1847.
1
-(2,3-Dimethylphenyl)-6,6-dimethyl-2-phenyl-1,5,6,7-tetra-
1
hydro-4H-indol-4-one (4d). H NMR (CDCl , 400 MHz) d: 1.07 (s,
3
3
2
3
H), 1.10 (s, 3H), 1.74 (s, 3H), 2.15 (d, J ¼ 16 Hz, 1H), 2.26 (s, 3H),
.40–2.47 (m, 3H), 6.82 (s, 1H), 7.06–7.09 (m, 3H), 7.12–7.14 (m,
98% yield. This experimental procedure was followed for the
13
3
H), 7.18–7.19 (m, 1H), 7.22–7.23 (m, 1H); C NMR (CDCl , 100
synthesis of all products listed in (Table 2).
MHz) d: 13.9, 20.3, 27.9, 29.1, 35.5, 36.5, 52.1, 104.8, 119.5,
1
1
26.1, 126.8, 127.4 (2C), 128.1 (2C), 130.1, 130.4, 132.0, 133.4,
36.6, 136.8, 138.6, 145.1, 194.0; HRMS (ESI) [M + 1] calcd for
General procedure for recycling of sulfamic acid
The reusability of the sulfamic acid was investigated for the C H NO: 344.2014, found: 344.2012.
2
4
26
synthesis of 6,6-dimethyl-1,2-diphenyl-1,5,6,7-tetrahydro-4H-
indol-4-one (4a) as a model reaction in 2 mmol scale. Sulfamic tetrahydro-4H-indol-4-one (4e). H NMR (CDCl , 400 MHz) d:
1-(3-Chloro-2-methylphenyl)-6,6-dimethyl-2-phenyl-1,5,6,7-
1
3
acid was separated from the reaction mixture through ltration, 1.52 (s, 3H), 1.55 (s, 3H), 2.34 (s, 3H), 2.60 (d, J ¼ 16.4 Hz, 1H),
washed thoroughly with ethanol (2 ꢂ 1 mL) followed by acetone 2.85–2.87 (m, 2H), 2.90 (d, J ¼ 2.8 Hz, 1H), 7.26 (s, 1H), 7.49 (d, J
(
2 ꢂ 1 mL), dried under oven and reused for the subsequent ¼ 2.0 Hz, 2H), 7.50–7.60 (m, 3H), 7.61–7.67 (m, 1H), 7.88–7.93
1
3
cycle. We have observed that aer ve consecutive cycles there (m, 2H); C NMR (CDCl , 100 MHz) d: 15.0, 27.9, 29.1, 35.6,
3
was 8.5% loss of sulfamic acid during reactions and recycling 36.5, 52.0, 105.2, 119.9, 127.3 (2C), 128.3 (2C), 129.3 (2C), 130.1,
process.
131.6, 133.6, 135.0, 135.8, 136.7, 138.1, 144.8, 194.0; HRMS (ESI)
M + 1] calcd for C H NO: 364.1468, found: 364.1455.
[
2
3
23
Analytical dada for all synthesized products
6,6-Dimethyl-1-(naphthalen-1-yl)-2-phenyl-1,5,6,7-tetrahy-
dro-4H-indol-4-one (4f). H NMR (CDCl , 400 MHz) d: 1.02 (s,
3
6H), 2.13 (d, J ¼ 16.4 Hz, 1H), 2.32–2.42 (m, 3H), 6.91 (s, 1H),
1
6
,6-Dimethyl-1,2-diphenyl-1,5,6,7-tetrahydro-4H-indol-4-one
1
(
3
4a). H NMR (CDCl , 400 MHz) d: 1.10 (s, 6H), 2.42 (s, 2H), 2.51
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7
7
5
1
1
.01–7.36 (m, 5H), 7.46–7.49 (m, 2H), 7.50–7.56 (m, 3H), 7.92–
4-(1-(2,3-Dimethylphenyl)-6,6-dimethyl-4-oxo-4,5,6,7-tetrahy-
1
3
1
.95 (m, 2H); C NMR (CDCl , 100 MHz) d: 28.0, 28.8, 35.5, 36.3, dro-1H-indol-2-yl)benzonitrile (4m). H NMR (CDCl , 400 MHz)
3
3
2.1, 105.1, 119.8, 122.5, 125.2, 126.5, 126.8 (2C), 127.5 (2C), d: 1.36 (s, 3H), 1.40 (s, 3H), 2.02 (s, 3H), 2.46 (d, J ¼ 16.8 Hz, 1H),
27.7 (2C), 128.3 (2C), 129.3, 130.9, 131.8, 134.0, 134.2, 137.5, 2.59 (s, 3H), 2.70–2.77 (m, 3H), 7.36 (s, 1H), 7.38–7.44 (m, 2H),
46.1, 194.0; HRMS (ESI) [M + 1] calcd for C26H24NO: 366.1858, 7.50–7.52 (m, 1H), 7.54–7.55 (m, 1H), 7.57–7.59 (m, 1H) 7.69–
1
3
found: 366.1850.
7.72 (m, 2H); C NMR (CDCl , 100 MHz) d: 13.8, 20.3, 27.9, 29.0,
3
1
-Cyclopropyl-6,6-dimethyl-2-phenyl-1,5,6,7-tetrahydro-4H-
35.5, 36.4, 52.0, 107.0, 109.9, 118.7, 120.0, 125.9, 126.5, 127.0
1
3
indol-4-one (4g). H NMR (CDCl , 400 MHz) d: 0.55–0.60 (m, (2C), 131.0, 132.0 (2C), 134.3, 134.5, 136.3, 136.4, 139.1, 146.3,
2
H), 0.85–0.95 (m, 2H), 1.17 (s, 6H), 2.37 (s, 2H), 2.80 (s, 2H), 193.8; HRMS (ESI) [M + 1] calcd for C H N O: 369.1967, found:
25 25 2
3
.20–3.24 (m, 1H), 6.54 (s, 1H), 7.31–7.33 (m, 1H), 7.36–7.40 (m, 369.1951.
1
3
2H), 7.45–7.47 (m, 2H); C NMR (CDCl , 100 MHz) d: 9.2 (2C),
2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-1,5,6,7-tetrahydro-
3
1
27.0, 28.7 (2C), 35.5, 37.2, 51.9, 104.6, 119.0, 127.0, 128.1 (2C), 4H-indol-4-one (4n). H NMR (CDCl , 400 MHz) d: 1.09 (s, 6H),
3
1
28.3 (2C), 132.8, 137.0, 146.0, 193.6; HRMS (ESI) [M + 1] calcd 2.41 (s, 2H), 2.50 (s, 2H), 6.77 (s, 1H), 6.96–6.98 (d, J ¼ 8.4 Hz,
1
3
for C19
H
22NO: 280.1701, found: 280.1707.
2H), 7.11–7.14 (m, 4H), 7.41–7.42 (m, 3H); C NMR (CDCl , 100
3
1
-Butyl-6,6-dimethyl-2-phenyl-1,5,6,7-tetrahydro-4H-indol-4- MHz) d: 28.6 (2C), 35.5, 37.0, 52.0, 105.9, 120.2, 122.1, 127.1,
1
one (4h). H NMR (CDCl
3
, 400 MHz) d: 0.77 (t, J ¼ 7.6 Hz, 3H), 128.2 (2C), 128.3, 129.2 (2C), 131.5 (2C), 132.5 (2C), 136.2, 136.6,
1
2
3
.10–1.19 (m, 2H), 1.25 (s, 6H), 1.46–1.52 (m, 2H), 2.36 (s, 2H), 144.4, 193.8; HRMS (ESI) [M + 1] calcd for C H NOCl:
2
2
21
.67 (s, 2H), 3.83 (t, J ¼ 7.6 Hz, 2H), 6.53 (s, 1H), 7.34–7.42 (m, 350.1312, found: 350.1300.
1
3
H), 7.42–7.49 (m, 1H), 7.58–7.62 (m, 1H); C NMR (CDCl , 100
3
MHz) d: 13.5, 19.6, 28.8 (2C), 35.5, 36.5, 40.8, 44.2, 51.9, 105.4,
Conclusion
119.2, 127.7, 128.4 (2C), 129.2 (2C), 130.1, 133.6, 143.3, 193.7;
HRMS (ESI) [M + 1] calcd for C20
H
26NO: 296.2014, found: In conclusion, we presented a facile and effective protocol for
296.2000.
the synthesis of 4-oxo-tetrahydroindole moieties using sulfamic
1
-(4-Fluorophenyl)-6,6-dimethyl-2-phenyl-1,5,6,7-tetrahydro- acid. The entire reactions described in (Table 2) are very clean
1
4
2
7
2
H-indol-4-one (4i). H NMR (CDCl
3
, 400 MHz) d: 1.10 (s, 6H), and provide high yield (88–98%) under ball milling conditions.
.42 (s, 2H), 2.49 (s, 2H), 6.77 (s, 1H), 7.04–7.07 (m, 2H), 7.09– Moreover, a very short reaction time of 60 min was possible for
1
3
.12 (m, 4H), 7.17–7.19 (m, 3H); C NMR (CDCl , 100 MHz) d: the synthesis of 4-oxo-tetrahydroindoles derivatives (4a–n)
3
2
8.6 (2C), 35.5, 37.0, 52.0, 105.6, 116.2 & 116.4 (d, J ¼ 23.0 compared to the very lengthy procedures reported for other
C,F
3
Hz) (2C), 119.9, 127.0 (2C), 128.2 (3C), 129.3 &129.4 (d, JC,F
¼
¼
methods. The relative results of current and earlier reported
method for the synthesis presented in (Table 4) have demon-
21NOF: strated a signicant development in terms of reaction yields,
1
9
2
3
.0 Hz) (2C), 131.6, 133.6, 136.3, 144.6, 160.7 & 163 (d, JC,F
47.0 Hz), 193.9; HRMS (ESI) [M + 1] calcd for C22
34.1607, found: 334.1600.
H
time and green protocol. Moreover, under ball milling condi-
2
-(4-Methoxyphenyl)-6,6-dimethyl-1-phenyl-1,5,6,7-tetrahy-
tions, solvent free, simple isolation and purication without
1
dro-4H-indol-4-one (4j). Brown gum; H NMR (CDCl , 400 MHz) column chromatography, mild sulfamic acid as recyclable
3
d: 1.10 (s, 6H), 2.42 (s, 2H), 2.49 (s, 2H), 3.69 (s, 3H), 6.77 (s, 1H), promoter make the current synthetic approach environmentally
1
3
7.04–7.07 (m, 2H), 7.09–7.12 (m, 3H), 7.17–7.19 (m, 3H);
C
benign and more attractive.
3
NMR (CDCl , 100 MHz) d: 28.4, 28.7, 35.4, 36.4, 52.1, 55.5, 104.8,
1
1
12.1, 119.6, 120.8, 126.4, 126.7, 127.7 (2C), 127.9 (2C), 129.6,
Conflicts of interest
30.1, 132.2, 136.7, 145.8, 155.1, 194.0; HRMS (ESI) [M + 1] calcd
: 346.1807, found: 346.1812.
-(6,6-Dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indol-
for C23
H
24NO
2
There are no conicts to declare.
4
1
2
2
7
5
-yl)benzonitrile (4k). H NMR (CDCl , 400 MHz) d: 1.10 (s, 6H),
3
Acknowledgements
.43 9 (s, 2H), 2.51 (s, 2H), 6.91 (s, 1H), 7.11–7.15 (m, 4H), 7.42–
1
3
.46 (m, 5H); C NMR (CDCl , 100 MHz) d: 28.5 (2C), 35.5, 36.9, The author T. L. Lambat would like to acknowledge the nan-
1.9, 107.7, 118.6, 120.2, 127.5 (2C), 127.9 (2C), 128.8, 129.7 cial support through INSPIRE Fellowship [IF120418] research
3
(
(
2C), 131.9 (2C), 132.2, 134.1, 136.2, 137.1, 146.1, 194.0; HRMS grant awarded from DST, New Delhi.
ESI) [M + 1] calcd for C23 O: 341.1654, found: 341.1644.
-(6,6-Dimethyl-4-oxo-1-(o-tolyl)-4,5,6,7-tetrahydro-1H-indol-
21 2
H N
4
Notes and references
1
2
1
3
-yl)benzonitrile (4l). H NMR (CDCl
3
, 400 MHz) d: 1.07 (s, 3H),
.11 (s, 3H), 1.85 (s, 3H), 2.16 (d, J ¼ 16.8 Hz, 1H), 2.41–2.50 (m, 1 (a) H. K. Choi and W. S. Cho, Korean J. Chem. Eng., 2003, 20(4),
H), 6.96 (s, 1H), 7.13–7.16 (m, 2H), 7.23 (d, J ¼ 1.2 Hz, 1H), 7.28
783–789; (b) T. L. Lambat, R. G. Chaudhary, A. Abdala,
R. Mishra, S. Mahmood and S. Banerjee, RSC Adv., 2019, 9,
31683–31690; (c) H. Sharma, N. Singh and D. O. Jang, Green
Chem., 2014, 16, 4922–4930; (d) B. C. Ranu and
K. Chattopadhyay, in Eco-Friendly Synthesis of Fine
Chemicals, ed, R. Ballini, Royal Society of Chemistry,
Cambridge, UK, 2009, ch. 5; (e) A. Stolle, T. Szuppa,
(
d, J ¼ 0.8 Hz, 1H), 7.30–7.37 (m, 1H), 7.39 (d, J ¼ 1.6 Hz, 1H),
13
7
3
1
1
3
3
.40–7.43 (m, 2H); C NMR (CDCl , 100 MHz) d: 17.2, 27.8, 29.1,
5.5, 36.5, 52.05, 107.1, 110.0, 118.7, 120.1, 127.0 (2C), 127.3,
28.3, 129.7, 131.5, 132.1 (2C), 134.2, 134.2, 135.8, 136.4, 146.1,
93.7; HRMS (ESI) [M + 1] calcd for C24
55.1805.
23 2
H N O: 355.1810, found:
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