A metal-free visible light promoted three-component facile synthesis of 4-oxo-tetrahydroindoles in ethanol–water

Article abstract of DOI:10.1002/jhet.4202

A mild and efficient visible light–mediated one-pot multicomponent tandem approach to construct 4-oxo-tetrahydroindoles in ethanol–water medium at room temperature has been described. The characteristics of reported methodology are the utilization of visi

Full text of DOI:10.1002/jhet.4202

A metal-free visible light promoted three-component facile synthesis of 4-oxo-
tetrahydroindoles in ethanol-water
Khursheed Ansari,a,+ Mohd Nazeef,a,+ Shabir Ali,b Malik A. Waseem,c Wajaht Amin Shah,c Saif
Ansari,a I. R. Siddiqui,a,* and Jagdamba Singh,d
aLaboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad-211002,
India.
E-mail: dr.irsiddiqui@gmail.com
bDepartment of Chemistry, Aligarh Muslim University, Aligarh- 202002, India.
cDepartment of Chemistry, University of Kashmir, Hazaratbal, Srinagar-190006, India.
dDepartment of Chemistry, University of Allahabad, Allahabad-211002, India.
+These authors contributed equally.
Abstract
A mild and efficient visible light mediated one-pot multicomponent tandem approach to
construct 4-oxo-tetrahydroindoles in ethanol-water medium at room temperature has been
described. The characteristics of reported methodology are the utilization of visible light, an
ideal source of energy to generate C—C and C—N bonds from commercially available
substrates namely dimedone, phenacyl bromides and amines. The presented protocol is highly
compatible for developing 4-oxo-tetrahydroindole derivatives with improved selectivity and high
yields. Moreover, metal-free synthesis, environmental friendly solvent, easy workup process,
high atom economy, cost effectiveness, short reaction time and broad substrate scope are the
major advantages of reported protocol.
Keywords
Green chemistry, mild reaction conditions, visible-light, ethanol-water, 4-oxo-tetrahydroindoles
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Introduction
Heterocycles are vital parts of organic compounds with potential applications in medicinal
chemistry and agrochemistry.[1,2] Among them, indoles are privileged scaffold usually found in
various pharmacological drugs and natural products which exhibited numerous biological
potency such as anti-tuberculosis activity, antitumor activity, antiviral agent, antimalarial agent,
anti-depressant agent and progesterone receptor agonist (Figure 1).[3,4] 4-oxo-tetrahydroindoles, a
subclass of indoles, having enormous significances in pharmaceutical industry and organic
synthesis. These molecules also displayed therapeutic potential in treatment of several diseases
including cancer, tuberculosis, malaria and tumor.[5,6]
Figure 1. Some biologically active compounds containing indole core
Over the past years, development of synthetic transformations in the presence of visible light
have been largely exploited from various research groups in the area of synthetic green
chemistry.[7,8] The noticeable features of visible light are nontoxicity, easy handling, as an
infinite source of energy, eco-compatibility and inexpensive nature showing its increasing
demand towards environmentally benign synthesis.[9,10] Moreover visible light is a clean, non-
hazardous and most importantly selective as no side reactions are associated with it. The use of
visible light has in fact solved biggest problem of current energy demand.[11-12] Hence,
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employing visible light to carry out required photochemical organic transformation would serve
as a valuable “green tool” for organic synthesis. Designing attractive framework of potential
drugs using visible light as a main energy source will induce useful and safer tool in organic
synthesis and in drug design. However several organic molecules are inactive towards visible
light and generally do not absorb visible light radiation and hamper to achieve the target, in order
to achieve the required synthesis various photocatalysts and photosensitizers have been used.[13-
14]
In spite of great efficiency of these photocatalysts, they too possess many problems such as
high toxicity, catalyst recyclability, utilization of imperishable catalysts, typical reaction workup
and high cost.[15,16] Thus achieving organic transformations by the application of visible light in
absence of photocatalysts was more challenging that we have successfully achieved (Scheme 1).
Multicomponent reactions (MCRs) are extremely exploited for diversity oriented synthesis of
complex organic molecules in one-pot and single step.[17,18] Multicomponent reactions usually
require less amount of solvent and catalyst for isolation and purification of products.[19]
Moreover, multicomponent reactions gain over many traditional methods because of high
efficiency, short reaction durability, easy reaction workup procedure, waste reduction and highly
atom economic nature.[20,21]
As a consequence, number of synthetic protocols for construction of 4-oxo-tetrahydroindole
derivatives have been reported.[3a,22,23] Very recently, Pal and co-workers reported β-cyclodextrin
mediated synthesis of 4-oxo-4,5,6,7-tetrahydroindoles under neutral conditions.[24] Also, Lambat
and collaborators described a microwave assisted one-pot process for the synthesis of 4-oxo-
tetrahydroindoles using ZnO-β zeolite nanoparticle.[25] Although some of the reported methods
are significant but poor yield, high cost, typical reaction workup procedure, harsh reaction
conditions and prolonged reaction time limit and remained the challenge for their future
development. Therefore, a clean and eco-sustainable method for the synthesis of 4-oxo-
tetrahydroindole derivatives are extremely desirable. A comparative study of proposed protocol
with the previously reported methods is depicted below (Scheme 1). Thus in continuation of our
research program for the synthesis of biologically relevant heterocyclic compounds via green
methods,[26] we herein reported an efficient and eco-compatible one-pot synthetic strategy for the
synthesis of 4-oxo-tetrahydroindole derivatives in the presence of visible light under aqueous
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ethanol at room temperature. Binary solution of ethanol-water (1:1) was found more suitable
solvent system owing to its green credential.[27]
Scheme 1. Comparison of present work with previously reported methods
Results and Discussion
We initially chose dimedone (1, 1 mmol), phenacyl bromide (2a, 1 mmol) and aniline (3a, 1
mmol) as model substrates to synthesize the product. The reaction mixture was placed in a
simple round bottom flask and exposed under the illumination of 22W compact florescent lamp
(CFL) on a magnetic stirrer at room temperature (RT) to optimize reaction conditions (Table 1).
In the initial experiment, we tested the role of solvent for the synthesis of product. The reaction
was investigated in presence of various polar and nonpolar solvents. A poor yield of reaction
clearly revealed that polar solvents facilitated the reaction much faster than nonpolar solvents
(Table 1, entries 1–4). However low yield of reaction was observed in case of THF which
revealed that non-consumption of reactive substances occurred (Table 1, entry 5). In order to find
more suitable reaction medium for present synthesis, we further examined our reaction in
presence of polar solvents such as acetonitrile, DMSO and DCM but there was no improvement
in the product yield. (Table 1, entries 6–7). However good results were obtained with ethanol or
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water and reaction time was also reduced. (Table 1, entries 8-9). Further improvement in the
yield of reaction was observed when binary solution of ethanol/water was introduced. Keeping
the idea of utilization of environmentally benign solvent, we further prepared the mixture of
ethanol/water in different ratio (Table 1, entries 10–12). The result of this study showed that 1:1
ratio of ethanol-water was more favorable reaction medium for the present synthesis (Table 1,
entry 12).
Table 1. Optimization of solvent for the synthesis of compound (4a)a
Entry
Solvent
Benzene
Timeb (h)
Yieldc (%)
Traced
Trace
Trace
Trace
27
1
2
12
10
9
Hexane
3
Diethyl ether
1,4-dioxane
THF
4
10
11
8
4
5
Acetonitrile
DMSO
35
6
8
28
7
DCM
7.5
5
30
8
EtOH
55
9
H2O
5
51
10
11
12
EtOH-H2O (4:1)
EtOH-H2O (2:1)
EtOH-H2O (1:1)
3.5
3.5
3.5
92
91
92
aReaction conditions: dimedone, 1 (1 mmol), phenacyl bromide, 2a (1 mmol) and aniline, 3a (1 mmol)
were stirred in a round bottom flask in the presence of 22W CFL under different solvents at room
temperature (25 oC). bReaction time. cIsolated yield product. dObserved on TLC
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Next, we screened the effect of energy sources for the present reaction. Initially, the reaction was
investigated in the presence of various compact fluorescence lamps (CFLs) by varying their
intensities and the results showed that CFLs below 22W reduced reaction yield however CFLs
above 22W did not affect reaction yield (Table 2, entries 1–4). Therefore 22W CFLs considered
to be more appropriate light source for the synthesis of 4-oxo-tetrahydroindole. The reaction was
also investigated in the presence of light emitting diodes (LEDs) with various intensities but no
significant increment in the yield of product was noticed (Table 2, entries 5–8). Furthermore,
reaction was carried out in daylight, sunlight and dark but very poor yield of product was
o
o
observed (Table 2, entries 9–11). We also performed our reaction in dark at 60 C and 100 C
and again only trace amount of product was detected (Table 2, entries 12–13). These
observations clearly pointed out that temperature has no role for synthesis of titled compound.
Table 2. Optimization of light source for the synthesis of compound (4a)a
Entry
Reaction conditions
18W CFL, RT
Timeb (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
3.5
3.5
3.5
3.5
5
90
92
22W CFL, RT
24W CFL, RT
92
30W CFL, RT
92
White LED (6W), RT
White LED (8W), RT
Green LED (6W), RT
Blue LED (6W), RT
Daylight, RT
78
5
80
4.5
4.5
8
82
81
Trace
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10
11
12
13
Sunlight, RT
Dark, RT
8
Trace
Trace
Trace
Trace
12
10
10
Dark, 60 oC
Dark, 100 oC
aReaction conditions: 1 mmol of each dimedone (1), phenacyl bromide (2a) and aniline (3a) were
b
stirred in a simple round bottom flask under different reaction conditions. Time required for the
completion of reaction. cIsolated yield of purified product.
To investigate the probable mechanistic pathway for the present reaction, an on/off visible light
photo-irradiation experiments was performed using 1 mmol of each dimedone (1), phenacyl
bromide (2a) and aniline (3) in 5 ml aqueous ethanol (1:1) under the illumination of 22W CFL
on a magnetic stirrer at room temperature. The observed results lead us to draw most probable
mechanism of the synthesized products (Figure 2).[26(a),28]
Figure 2. On/off visible light photo-irradiation experiment
To study scope, efficiency and limitation of reported methodology, we explored the synthesis of
4-oxo-tetrahydroindoles by using dimedone (1) and derivatives of phenacyl bromides (2a-d) and
amines (3a-j) (Table 3). It was noticed that the reported methodology is highly tolerable with
variety of substituents on 4-oxo-tetrahydroindole. The observed products in each results were
obtained in high yield and short reaction time (3.5–4 h). It was also observed that electron
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donating substituents on amines proceeded reaction faster while electron withdrawing
substituents slowed down the reaction. Also electron withdrawing substituents on phenacyl
bromide underwent reaction faster than electron donating substituents (Table 3). It is important
to mention that reagents like alkyl / acyl bromides and alkyl amines were not well tolerated with
very low product yield, hence were not further investigated. The functionalized 4-oxo-
tetrahydroindole scaffolds showed numerous biological significances which might be the subject
of future studies. Hence, from these observations it can be concluded that present protocol is
highly promising for diversity oriented synthesis (DOS). Further studies on 4-oxo-
tetrahydroindoles by investigating molecular complexity are in the process.
Table 3. Substrates scope for the synthesis of 4-oxo-tetrahydroindole derivatives (4a-o)a, b, c
aReaction conditions: 1 mmol of each dimedone (1), phenacyl bromides (2a-d) and amines (3a-j) were
b
irradiated using 22W CFL in 5 ml aqueous ethanol (1:1) at room temperature. Time required for the
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completion of reaction. cIsolated yield of purified product.
Additionally, we performed an experiment for deciphering the reaction mechanism (Table 4).
We started our reaction in dark by taking dimedone 1, (1 mmol) and phenacyl bromide, 2a (1
mmol) during step 1 and observed that reaction was not progressed even after 5 h of stirring.
Thus, further addition of aniline, 3a (1 mmol) in step 2 produced only trace amount of product.
We tried the same experiment at 70 oC but there was no progress in the reaction yield. When the
reaction was carried out under visible light (22W CFL) irradiation in N2 atmosphere, pleasingly
it was found that the reaction progressed smoothly in both step 1 & 2 and 92% yield was
obtained. Also in our next repeated experiment we performed step 2 in absence of visible light
and found that the reaction proceeded smoothly and generated good amount product. However,
only trace amount of intermediate (I) was detected when 1 eq. of (2,2,6,6-Tetramethyl-piperidin-
1-yl)oxyl; TEMPO was added in step 1 and therefore negligible amount of product was formed.
Whereas, addition of TEMPO (1 eq.) in step 2 did not affect the reaction yield. These results
concluded that utilization of visible light was necessary to achieve present transformation.
Table 4. Deciphering the reaction mechanisma
Step 1
Step 2
Entry
Overall
yieldc (%)
Reaction
conditions
Reaction
progress
Reaction
conditions
Reaction
progress
1
2
3
Dark, RT, 5 h
Dark, 70 oC, 4 h
Incomplete
Dark, RT, 8 h
Dark, 70 oC, 6 h
Incomplete
Trace
Trace
92
Incomplete
Completeb
Incomplete
Complete
22W CFL, RT,
N2 atm., 1.5 h
22W CFL, RT,
N2 atm., 1.5 h
22W CFL, RT,
TEMPO (1 eq.),
22W CFL, RT,
N2 atm., 2 h
Dark, RT, 2 h
4
5
Complete
Complete
91
Incomplete
22W CFL, RT,
2 h
Incomplete
Trace
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1.5 h
6
22W CFL, RT,
1.5 h
Complete
22W CFL, RT,
TEMPO (1 eq.),
2 h
Complete
90
aReaction conditions: 1 mmol (1a), 1 mmol (2a) and 1 mmol (3) in 5 ml EtOH-H2O (1/1: v/v); 95%
utilization; cYield of product.
b
On the basis of recent literature studies,[28] a probable mechanism for the synthesis of 4-oxo-
tetrahydroindoles derivatives has been illustrated (Scheme 2). The reaction seems to be initiated
by photo excitation of phenacyl bromides (2a-d) to generate radical intermediates via homolytic
cleavage of C—Br bond. The radical intermediate further reacted with excited form of dimedone
(1) and generated stable intermediate (I). Hereafter, nucleophilic addition of amines (3a-j) on
intermediate (I) followed by dehydration resulted intermediate (II). Finally, intermediate (II)
immediately proceeded for cyclization along with dehydration yielded corresponding 4-oxo-
tetrahydroindoles (4a-o).
Scheme 2. Probable mechanism for synthesis of 4-oxo-tetrahydroindoles
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Practicability the above reaction was also tested by conducting an experiment on gram scale by
the reaction of dimedone 1, (10 mmol), phenacyl bromide 2a, (10 mmol) and aniline 3a, (10
mmol) to synthesize the compound (4a). Common laboratory glassware were used to perform
scale-up reaction. The reaction mixture were simply irradiated in the presence of 22W CFL in 50
mL ethanol-water (1:1) solution at room temperature and observed that 91% yield of product was
obtained after 3.5 h of stirring. This led to conclude that the present process is highly tolerable
over large-scale synthesis (Scheme 3).
Scheme 3. Practicability of present reaction
Conclusion
In summary, we have established a highly efficient and compatible one-pot metal-free strategy
for the synthesis of highly functionalized 4-oxo-tetrahydroindoles. The utilization of
biodegradable aqueous ethanol solvent and universally available visible light source make the
present protocol more efficient and environmentally friendly. The reported methodology shows
numerous advantages like highly atom economic nature, functional group tolerating ability,
excellent reaction yield, easy reaction workup and short reaction time are some attributes in the
context of green chemistry design.
Supporting Information Summary
13
1H NMR, C NMR, HRMS, IR spectral data and other experimental details are available in the
supporting information.
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Acknowledgments
We are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, India and
University Grants Commission (UGC), New Delhi, India and DST, New Delhi for financial
support through PURSE Scheme. The authors also grateful to Department of Chemistry,
University of Allahabad, Prayagraj, India for providing basic research facilities. We sincerely
thank to Sophisticated Analytical Instrumentation Facility (SAIF), Punjab University,
Chandigarh, India for providing spectroscopic and analytical data.
Conflict of interest
The authors declare that they have no conflict of interest.
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