Synthesis and Evaluation of Antimicrobial Activities of Novel N-Substituted Indole Derivatives

Article abstract of DOI:10.1155/2020/4358453

Indole motifs are one of the most significant scaffolds in the discovery of new drugs. We have described a synthesis of new N-substituted indole derivatives (1-3), and their in vitro antimicrobial activities were investigated. The synthesis of titled compounds has been demonstrated by utilizing commercially available starting materials. The antibacterial and antifungal activities were performed using new strains of bacteria Staphylococcus aureus, Escherichia coli, and Candida albicans using the disc diffusion method. Notably, the compound 4-(1-(2-(1H-indol-1-yl) ethoxy) pentyl)-N,N-dimethyl aniline (1) was found to be most potent than the other analogues (2 and 3), which has shown higher inhibition than the standard drug chloramphenicol.

Full text of DOI:10.1155/2020/4358453

Hindawi
Journal of Chemistry
Volume 2020, Article ID 4358453, 9 pages
https://doi.org/10.1155/2020/4358453
Research Article
Synthesis and Evaluation of Antimicrobial Activities of Novel
N-Substituted Indole Derivatives
Tanveer MahamadAlli Shaikh and Habtamu Debebe
Department of Chemistry, College of Natural and Computational Sciences, Mekelle University, Mekelle, Ethiopia
Correspondence should be addressed to Tanveer MahamadAlli Shaikh; tanveerchem1@gmail.com
Received 28 June 2019; Accepted 20 March 2020; Published 14 April 2020
Guest Editor: Maria Grazia Bonomo
Copyright © 2020 Tanveer MahamadAlli Shaikh and Habtamu Debebe. ,is is an open access article distributed under the
Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
Indole motifs are one of the most significant scaffolds in the discovery of new drugs. We have described a synthesis of new
N-substituted indole derivatives (1-3), and their in vitro antimicrobial activities were investigated. ,e synthesis of titled
compounds has been demonstrated by utilizing commercially available starting materials. ,e antibacterial and antifungal
activities were performed using new strains of bacteria Staphylococcus aureus, Escherichia coli, and Candida albicans using the
disc diffusion method. Notably, the compound 4-(1-(2-(1H-indol-1-yl) ethoxy) pentyl)-N,N-dimethyl aniline (1) was found
to be most potent than the other analogues (2 and 3), which has shown higher inhibition than the standard
drug chloramphenicol.
A literature survey reveals that the infections caused by
bacteria, fungi, or microorganisms in tropical and sub-
tropical regions could be controlled by designing new an-
timicrobial agents [62, 63]. In an attempt to design and
synthesize new antimicrobial agents, herein, we reported the
synthesis of N1-alkylated indole derivatives and investiga-
tion of their antimicrobial activity against Staphylococcus
aureus, Escherichia coli, and Candida albicans (Figure 2).
1. Introduction
,e versatility of heterocycles has been known from the
century since their direct involvement in natural products
[1–4]. Particularly, the nitrogen-containing heterocycles (N-
heterocycles) have proven ubiquitous structural features and
pivotal role in medicinal chemistry [5–11]. Amongst the
various N-heterocycles, indole motifs have received signif-
icant attention due to their presence in proteins, amino
acids, bioactive alkaloids, and drugs (Figure 1) [12–23]. In
this context, a large number of indole moieties have been
investigated in the development of new efficient bioactive
molecules with diverse pharmacological properties, such as
antimicrobial, antiviral, anticancer, anti-inflammatory, in-
hibitors, and antioxidant [24–47]. Generally, indoles
substituted at 2nd or 3rd position [48–50], are known to
exhibit certain bioactivity. On the other hand, the impor-
tance of N1-substituted indole derivatives in marketed drug
molecules, natural products, and marine organisms are at
great extent [51–53]. Despite the structural novelties and
valuable biological activities of N1-substituted indoles [54],
it remains challenging due to the inertness of the nitrogen
atom (-NH-) towards electrophilic reagents [55–61].
2. Results and Discussion
As part of our studies to design new bioactive N-substituted
indole derivatives, we envisaged that the utilization of
commercially available 4-N,N-dimethylamino benzaldehyde
might be suitable for the syntheses of target compounds 1–3.
,e retrosynthetic analyses of N-substituted indoles (1-3)
are outlined in Scheme 1. In order to find suitable synthons,
firstly, the cleavage of C-O bond resulted to N-alkylated
indole 7 and the corresponding benzylic alcohols 4-6, which
could be envisaged to form desired compounds (1–3) via
O-alkylation reaction. Furthermore, a common intermedi-
ate 7 could be synthesized via N-alkylation reaction of
commercially available indole (9) and 1,2-dibromoethane

2
Journal of Chemistry
Cl
O
N
H
N
N
O
OH
HO
O
OH
O
N
N
N
H
H
O
O
CH3
N
H
(a)
(b)
(c)
(d)
Figure 1: Representative examples of drugs with indole. (a) Roxindole schizophrenia. (b) Oxypertine antipsychotic drug. (c) Pindolol
antihypertensive drug. (d) Indometacin anti-inflammatory drug.
N
N
N
O
O
O
CH3
CH3
H3C
H3C
H3C
N
N
N
CH3
CH3
CH3
1
2
3
Figure 2: New bioactive indole derivatives.
Br
Br
N
H
10
9
N
N
O
OH
Br
7
H
R
R-MgX
O
H3C
H3C
N
CH3
N
CH3
R
H3C
N
8
CH3
1, R =
2, R =
4, R =
5, R =
CH3
CH3
CH3
CH3
3, R =
6, R =
Scheme 1: Retrosynthesis of compounds 1–3.
(10). Finally, the benzylic alcohols 4-6 could be obtained by
performing Grignard reaction of 4-N,N-dimethylamino
benzaldehyde (8) with the corresponding alkyl or aryl halide.
To validate our outlined approach, we have commenced
our synthesis by performing Grignard reaction of 4-N,N-
dimethylamino benzaldehyde (8) with n-BuMgBr, which
was prepared by in situ reaction of n-BuBr (10) and Mg in
diethyl ether solvent resulting in benzylic alcohol 4 at an
excellent yield (Scheme 2). Similarly, the other benzylic
alcohols 5 and 6 were successfully obtained by subjecting
“Grignard reaction” of 4-N,N-dimethylamino benzaldehyde
(8) with EtMgBr and PhMgBr, respectively. Next, we in-
vestigated the synthesis of N-alkyl indole (7) via
N-alkylation, employing commercially available indole (9)
with 1,2-dibromoethane (13) in the presence of potassium
hydroxide as base and DMF as a solvent (Scheme 3) [64]. In

Journal of Chemistry
3
N
N
OH
O
CH3
7
Br
CH3
H3C
N
CH3
K2CO3, TBAF,
CH3CN, 50°C
H3C
N
CH3
5
2
Mg, diethyl ether
0°C to 25°C
H3C
I
N
then sat. NH4Cl
11
OH
N
O
O
CH3
H3C
Br
7
Br
10
H
H3C
Mg, diethyl ether
0°C to 25°C
N
CH3
H3C
K2CO3, TBAF, H3C
CH3CN, 50°C
CH3
N
N
CH3
CH3
1
then sat. NH4Cl
4
8
Mg, diethyl ether
0°C to 25°C
then sat. NH4Cl
Br
N
12
OH
N
O
7
Br
H3C
K2CO3, TBAF,
CH3CN, 50°C
N
CH3
H3C
N
CH3
6
3
Scheme 2: Synthesis of target compounds 1–3.
Br
Br
13
N
N
H
KOH, CH3CN,
50°C, 90min
7
Br
9
Scheme 3: Synthesis of N-alkylated indole 7.
order to accomplish the synthesis of desired compounds
1–3, we decided to facilitate O-alkylation of benzylic alcohol
(4) with readily synthesized N-alkylated indole (7). To our
surprise, the O-alkylation reactions reduced the yield and
prolonged the reaction time. To overcome this problem, we
began to optimize O-alkylation reaction under different
conditions, and the results are presented in Table 1.
TBAF (1 mmol), and acetonitrile (10 mL) heated at 50°C.
Under the optimized conditions, we then explored O-al-
kylation of 1-(4-(dimethylamino)phenyl)propan-1-ol (5)
and (4-(dimethylamino)phenyl) (phenyl)methanol (6) with
N-alkyl indole (7) to provide the desired compounds 2 and
3 with good yields, respectively.
,e O-alkylation between 1-(4-(dimethylamino)phe-
nyl)pentan-1-ol (4) and N-alkylated indole (7) employing
KOH as base under neat conditions resulted traces of
O-alkylated product (1) along with the domination of
unidentified side reactions (Table 1, entry 1). Screening of
various solvents such as pyridine, acetonitrile, and dimethyl
formamide provided slightly improved yields of O-alky-
lated product (1) (entries 3–6). However, substantial
amount of starting material was recovered during the
course of reaction. Subsequently, it was found that Chi and
Kazemi exploited ionic-liquids and phase transfer catalyst
in alkylation reaction [65, 66]. ,e situation improved
dramatically, when we utilized the combination of K2CO3/
TBAF in acetonitrile to provide the corresponding
O-alkylated product (1) with 72% yield (entry 7). ,us, the
optimized reaction conditions involved benzylic alcohol (4)
(1.5 mmol), N-alkyl indole (7) (1 mmol), K2CO3 (1 mmol),
2.1. In Vitro Antimicrobial Activity. In vitro antifungal ac-
tivities of the synthesized compounds 1–3 were evaluated
utilizing Staphylococcus aureus and Escherichia coli and
antifungal activity against Candida albicans using disc dif-
fusion method (Table 2). ,e inhibition zone was measured
in diameter. Bavistin and chloramphenicol were used as the
standard drug to compare antifungal activity. In order to
investigate antifungal activity, the inhibition against the test
organisms and ethanol as positive control, and the effec-
tiveness of the target compounds (1–3) was measured by
calculating inhibition zone against the tested organisms. ,e
zone of inhibition was compared with the standard drug
after 72 h. Organisms Staphylococcus aureus (Gram-posi-
tive) and Escherichia coli (Gram-negative) were subcultured
into sterile nutrient broth. ,en, aliquots of 50% and 100%
of the sample solutions of target compounds, 1–3, were

4
Journal of Chemistry
Table 1: Optimization of O-alkylation reactiona.
N
OH
O
base, additives
solvent, temp.
CH3
N
CH3
H3C
N
H3C
N
CH3
Br
CH3
4
7
1
Entry
Base (mol%)
Additives (equiv.)
Solvent (mL)
Temperature (°C)
Yield of 1b,c (%)
1
2
3
4
5
6
7
KOH
Pyridine
—
—
Neat
Pyridine
CH3CN
DMF
25
80
Traces
nr
K2CO3
—
80
25
K2CO3
—
100
80
50
50
20
K2CO3 (50)
K2CO3 (50)
K2CO3 (100)
TBAF
TBAF (1)
TBAF (1)
DMF
35
CH3CN
CH3CN
50
72d
aReaction conditions: alcohol (1.5 mmol), indole-alkyl bromide (1 mmol), base, and solvent; bisolated yield; ccharacterized by IR and NMR; dfurther yield did
not improve even when the 1.5 equiv. of base was utilized.
Table 2: Antimicrobial activities of target compound 1–3.
Zone of inhibitions (mm)
Sr.No
Compounds
Escherichia coli
Staphylococcus aureus
Candida albicans
50%
100%
50%
100%
50%
100%
1
2
1
—
—
—
—
25
18
15
18
—
—
27
20
20
20
—
—
—
—
—
—
2
3
3
4
5
Chloramphenicol
Bavistin
2
—
—
3
—
—
—
20
—
—
30
—
Negative control
100
90
80
70
60
50
40
30
20
10
0
inhibition zone diameter was measured to the nearest mm.
All the tests were performed in triplicate. Obtained bioac-
tivity results were compared with commercially available
drugs, chloramphenicol and bavistin, and the results are
presented in Figure 3.
3. Conclusion
We have reported the synthesis of indole derivatives using
commercially available starting materials, and their anti-
microbial activity was also investigated. ,e in vitro bio-
activity was performed using Staphylococcus aureus,
Escherichia coli, and Candida albicans as antibacterial and
antifungal, respectively, using the disc diffusion method. ,e
mean inhibition zone of commercially available drug
chloramphenicol and bavistin was used as standard, and
inhibition zone was calculated in mm. Compounds 1–3
tested for antifungal and antibacterial activity showed poor
inhibition against Gram-negative bacteria Escherichia coli.
On the other hand, compounds 1–3 showed good bioactivity
towards pathogen Staphylococcus aureus, Gram-positive
bacteria. Interestingly, it was observed that compound 1,
which incorporates butyl substitue nts, exhibited enhanced
selectivity compared with analogues 2 and 3. Further
Chloramphenicol Compound 1
Compound 2
Compound 3
50%
100%
Figure 3: Comparison of % of bioactivity: chloramphenicol drug
with compounds 1–3.
pipetted to the discs in three replications each. ,e discs
were impregnated with the sample solutions and then
transferred to nutrient agar (NA) plate seeded with bacteria
and incubated at 37°C for 24 h. Subsequently, the plates were
examined for microbial growth of inhibition, and the

Journal of Chemistry
5
extension of designing new indole derivatives is currently
under development.
1H,Ar-H), 6.76 (d, 1H,Ar-H), 7.25 (d, 1H,Ar-H); 13C-NMR
(CDCl3/TMS) δ 76-78 (CdCl3), δ 14.09, 22.69, 28.19, 38.47,
40.78, 74.47, 112.45, 126.97, 132.99, 150.19.
4. Experimental
4.3. Synthesis of 1-(4-(dimethylamino)phenyl)propan-1-ol (5)
via Grignard Reaction. ,e synthesis 1-(4-(dimethylamino)
phenyl)propan-1-ol (5) was also achieved by Grignard re-
action. ,is reaction was carried out similar to the afore-
mentioned process. A 500 mL oven-dried round bottom
flask was charged with Mg (1.25 g, 51.42 mmol) and iodine
crystal (0.2 g) followed by the addition of anhydrous diethyl
ether (100 mL) and stirred for 5 min. To this solution, ethyl
iodide (6) (3.23 mL, 40.17 mmol) was added slowly with the
help of a syringe. Upon addition of ethyl iodide, the reaction
mixture color was changed from brown to grey color, which
indicates the formation of Grignard reagent. To this
Grignard reagent, 4-N,N-dimethylamino benzaldehyde (8)
(5 g, 33.51 mmol) dissolved in anhydrous DEE was added
with the help of the addition funnel. ,e resulting reaction
mixture was stirred at room temperature for 2 h. ,e re-
action was monitored by TLC 20% of ethyl acetate in pe-
troleum ether. After completion of the reaction, saturated
NH4Cl (15 mL) was added to the reaction mixture. ,e
combined organic layers was separated, washed, and dried
over anhydrous Na2SO4. ,e crude product was obtained by
removing organic solvent evaporated using the rotatory
evaporator. Furthermore, the purification of crude product
was performed using column chromatography: silica gel
(100–200 mesh) and 30% ethyl acetate in petroleum ether as
eluents to obtain pure 1-(4-(dimethylamino)phenyl)propan-
1-ol (5).
4.1. General Experimental Procedure. FTIR spectra of the
synthesized compounds were recorded on a Shimadzu 4000
instrument using KBr pellet within the range of 400 10 to
4000 10 cm−1. 1H-NMR, 13C-NMR, and DEPT-135 spectra
of compounds were recorded on Bruker Avance II-400 MHz
NMR spectrometer in deuterated CDCl3, MeOD and DMSO
solvents using TMS as internal standard. Chemical shift
values are expressed in δ (ppm).
4.1.1. Pharmacological Reagents. Reagents for biochemical
assays such as potato dextrose agar (PDA, Micro master
laboratories, India), nutrient agar (NA, Aldrich chemical
company, Germany), bavistin (Domina Pharmaceuticals,
India), chloramphenicol (Addis Pharmaceuticals S.C.,
Adigrat, Ethiopia) were used for the antimicrobial studies.
4.2. Synthesis of 1-(4-(dimethylamino)phenyl)pentan-1-ol (4).
To an oven-dried three necked round bottom flask, Mg
turnings (1.25 g, 5.14 mmol) was charged followed by the
addition of iodine crystals (3 piece) and covered the flask
with a CaCl2 dry tube. To this, anhydrous diethyl ether
(100 mL) was added using addition funnel. ,e whole re-
action mixture was allowed to stir for 10 minutes. ,en,
bromobutane (10) (4.4 mL, 4.0 mmol) was introduced
dropwise with the help of syringe. In order to initiate the
reaction, the flask was warmed using hot water, and the
addition of bromobutane was continued. It was observed
that vigorous reaction between magnesium and bromobu-
tane leads to the formation of Grignard reagent. ,e
Grignard reagent in the flask appears grey in color. To the
formed Grignard reagent (BuMgBr), 4-dimethylamino
benzaldehyde (8) (5 g, 3.35 mmol) dissolved in 50 mL an-
hydrous DEE was introduced with the help of an addition
funnel (dropwise). After the completion of the reaction (1 h),
which was monitored by TLC, the mixture was quenched
with saturated solutions of NH4Cl (20 mL). ,e resulting
mixture was transferred to a separatory funnel followed by
the addition of ethyl acetate (50 mL), and the aqueous layer
was removed, and the organic layer was dried with sodium
sulphate. ,e solvent was removed using rotary evaporator,
and compound 4 was obtained as the crude product. ,en,
further purification of the residue was performed using
column chromatography using 20% ethyl acetate in petro-
leum ether as an eluent to give the pure 1-(4-(dimethyla-
mino)phenyl)pentan-1-ol (4).
Yield (80%), FR-IR (KBr) stretch(str) cm−1: 1522.83,
1615.41 (str, C�C-Ar), 2873.98 (str, -CH3), 2930.89 (str,
-CH2), 2959.82 (str, N(CH3)2), 3075.55(str, C-H), 3096.77,
3141.13 (str C-H-Ar), 3357.16 (str, O-H)1H-NMR
(400 MHz, CDCl3, ppm): δ �1.01 (t, 3H, CH3), 1.62–1.96 (m,
2H, CH2), 2.2 (brs, 1H, OH), 2.84 (s, 6H, N(CH3)2), 4.63 (t,
1H, -CH), 6.52 (d, 2H, Ar-H), 6.97 (d, 2H, Ar-H); 13C-NMR
(100 MHz, CDCl3, ppm): δ � 07.87 (1C, -CH3), 31.18 (1C,-
CH2), 40.67 (2C, N(CH3)2), 79.32 (1C, -C-OH), 114.87 (2C,
Ar-C), 128.11 (2C, Ar-C), 129.17 (1C,Ar-C), 146.12 (1C, Ar-
C).
4.4. Synthesis of (4-(dimethyl Amino) Phenyl) (Phenyl)
Methanol (6). To a three-necked round bottom flask, oven-
dried Mg 1.17 g (4.87 mmol) and few crystals of iodine were
taken and maintained inert atmosphere. To this flask, an-
hydrous diethyl ether (100 mL) was added with continuous
stirring. ,e solution turned into brown color, and the flask
was warmed using hot water. ,en, bromobenzene (12)
(6.5 mL, 6.2 mmol) was added dropwise maintaining the
flask in ice cold water while the addition of bromobenzene
was continued. ,e color of the reaction mixture turned to
grey due to the formation of Grignard reagent phenyl
magnesium bromide (PhMgBr). To this reaction mixture, 4-
dimethylamino benzaldehyde (8) (5 g, 3.35 mmol) dissolved
in 40 mL of anhydrous DEE was added drop wise. After
completion of reaction, which was monitored by TLC, the
4.2.1. Appearance. Pale yellow oil yield � 72% (4.9 g); FT-IR
(KBr, cm−1). 3311(O-H str), 3072(C-H str, ring/cyclic),
1
2927(C-H str, acyclic), 1615(C�C str), 1464(C-C str); H-
NMR (CDCl3/TMS) δ 0.92 (t, 3H, -CH2CH3), 1.21-1.29 (m,
2H,-CH2CH2CH3), 1.40 (q, 2H, -CH2-CH-OH), 3.06 (s, 6H,
N-CH3), 4.0 (t, 1H, OH), 4.58 (t, 1H, Ar-CH-OH), 6.76 (d,

6
Journal of Chemistry
reaction mixture was quenched with saturated solution of
ammonium chloride (20 mL). ,e resulting organic layer
was then transferred to the separatory funnel, and the
collected organic layer was dried over sodium sulphate. ,e
solvent was removed using rotary evaporator, and the crude
residue was further purified by column chromatography.
,e column chromatography was performed using 20%
ethyl acetate in petroleum ether as the eluent to give pure (4-
(dimethyl amino) phenyl) (phenyl) methanol in 67% yield
(5.15 g) as a pale yellow solid.
progress of the reaction was monitored by TLC. After
cooling the reaction mixture at room temperature, the re-
action mixture was poured in 30 mL water and then
extracted with 50 mL ethyl acetate. ,e combined organic
layers were dried over anhydrous Na2SO4, and the solvent
was removed using rotary evaporator.
,e residue was purified by column chromatography
and air pressure using a 1 :12 (v/v) mixture of ethyl acetate
and petroleum ether as eluting solution to afford 4-(1-(2-
(1H-indol-1-yl) ethoxy) pentyl)-N, N-dimethyl aniline (1) in
72% yield (0.28 g) as yellow color oil.
FT-IR (KBr, cm−1): 3454(O-H str), 2923–2955(C-H str),
1615(C�C str); 1H-NMR (CDCl3/TMS): δ 2.90 (s, 6H,
N-CH3), 5.72 (s, 1H, (Ar)2-CH-OH), 6.67 (d, 1H, OH),
7.16–7.38 (d, Ar-H); 13C-NMR (CDCl3/TMS): δ 40.12, 79.67,
114.22, 125.87, 129.12, 129.82, 130.11, 130.80, 131.13, 140.06,
146.67.
1H-NMR (DMSO/TMS): δ 1.30 (t, 3H, -CH2CH3),
1.65–1.81 (m, 4H, -CH3CH2CH2-), 2.50 (t, 2H, O-CH-CH2-
), 3.14 (s, 6H, -N-(CH3)2), 4.76 (t, 2H, O-CH2-), 4.94 (t, 2H,
N-CH2-), 5.36 (t, 1H, -O-CH-Ar), 6.37 (d, 1H,,pyrrole), 6.62
(d, 1, 1H, Ph.-H), 6.62 (d, 1H, Ar-H), 6.95, (t, 1H, Ar-H),
7.39 (d, 1H, Ph - H), 7.46 (d, 1H, pyrrole), 7.54 (t, 1H, Ar-H),
7.62 (d, Ar-H, 1H), 7.89 (d, 1H, Ar-H); 13C-NMR (DMSO/
TMS): δ 14.19, 23.27, 28.59, 35.62, 39.03, 40.80, 74.53, 77.68,
96.38, 105.29, 109.80, 113.01, 121.08, 121.43, 122.99, 127.15,
129.86, 130.22, 133.61, 149.93.
4.5. Synthesis of 1-(2-bromoethyl)-1H-indole (7). A 100 mL
round bottom flask was charged with potassium hydroxide
(3.83 g, 68.3 mmol) and tetrabutylammonium fluoride
(0.14 g, 0.54 mmol). ,en, indole (9) (2 g, 17.1 mmol), which
was dissolved in anhydrous DMF (25 mL), was added slowly
to the above mixture with stirring. ,en, the reaction
mixture was heated at 50 C for 1.5 h and then cooled to 0 C.
To this cooled reaction mixture 1,2-dibromoethane (10)
(1.5 mL, 17.1 mmol) was added slowly with the help of sy-
ringe. Furthermore, the reaction mixture was allowed to stir
for 30 min at 0 C and again heated at 50 C for 2 h. ,e re-
action was monitored by TLC. After completion of reaction,
the reaction mixture was poured in 70 mL water and
extracted with dichloromethane (3 × 50 mL). ,e combined
organic layers were washed with brine, and collected organic
layers were dried over sodium sulphate. ,e solvent was
removed using rotary evaporator, and the crude residue was
subjected to column chromatography. ,e column chro-
matography was performed using silica gel and eluent
combinations of petroleum ether/ethyl acetate (9 :1) to
obtain pure 1-(2-bromoethyl)-1H-indole in 54% yield (2.3 g)
as pale yellow oil.
4.7. Synthesis of 4-((2-(1H-indol-1-yl) Ethoxy) (Phenyl)
methyl)-N,N-dimethyl Aniline (2). ,e synthesis of target
compound 2 was carried out by using the same procedure
and conditions, which was described for the synthesis of
compound 1. To a round bottom flask Grignard product,
secondary alcohol 6 (0.34 g, 1.5 mmol) was charged followed
by the addition of phase transfer catalyst TBAF (0.316,
1.0 mmol) and acetonitrile (10 mL). ,e reaction mixture
was stirred at room temperature, and then K2CO3 (0.14 g,
1 mmol) was added slowly and allowed whole reaction
mixture to heat at 50°C. To this hot reaction mixture,
N-alkylated product 1-(2-bromoethyl)-1H-indole (7)
(0.224 g, 1.0 mmol) was added slowly. ,e reaction mixture
was stirred further, and the progress of the reaction was
monitored by TLC. After cooling the reaction mixture at
room temperature, the reaction mixture was poured in
30 mL water and then extracted with 50 mL ethyl acetate.
,e combined organic layers were dried over anhydrous
Na2SO4, and the solvent was removed using rotary evapo-
rator. ,e residue was purified by column chromatography
with air pressure using a 1 :12 (v/v) mixture of ethyl acetate
and petroleum ether as eluent to afford 4-((2-(1H-indol-1-
yl) ethoxy) (phenyl) methyl)-N, N-dimethyl aniline (2) in
64% yield (0.25 g).
1H-NMR (CDCl3 + MeOD)/TMS): δ 3.33 (t, 2H, -CH2-
Br), 4.31 (t, 2H, N-CH2-), 6.61 (d, 1H, pyrrole - H), 7.12 (d,
1H, benzene - H), 7.23 (d, 1H, pyrrole - H), 7.45 (t, 1H,
benzene - H), 7.60 (d, 1H, benzene - H); 13C-NMR
(CDCl3 + MeOD)/TMS): δ 80.9 (CDCl3), 52.6 (MeOD), 25.4,
100.2, 108.7, 113.4, 124.5, 126.5, 127.2, 133.5, 139.4, 139.6.
1H-NMR (DMSO/TMS): δ 2.95 (d, 6H, -N-(CH3)2), 4.63
(t, 2H, -O-CH2-), 5.07 (t, 2H, -N-CH2), 5.66 (s, 1H, -O-CH-),
6.54 (d, 1H, Ar-H), 7.13 (t, 1H, Ar-H), 7.28 (d, 1H, Ar-H),
7.32 (d, 1H, pyrrole), 7.60 (t, 1H, Ar-H),7.68 (d, 1H, Ar-H);
13C-NMR (DMSO/TMS): δ 40.59, 58.21, 96.48, 109.54,
110.52, 112.41, 120.71, 121.05, 123.42, 126.54, 127.73, 128.04,
129.30, 131.20, 132.66, 135.38, 139.23, 145.71, 149.73, 153.36.
4.6. Synthesis of 4-(1-(2-(1H-indol-1-yl) Ethoxy) pentyl)-N,N-
dimethyl Aniline (1). A compound 1 was synthesized using
O-alkylation reaction by combining intermediate 4 with 7.
To a round bottom flask Grignard product, secondary al-
cohol (4) (0.31 g, 1.5 mmol) was charged followed by the
addition of phase transfer catalyst TBAF (0.31, 1.0 mmol)
and acetonitrile (10 mL). ,is reaction mixture was stirred at
room temperature, and then K2CO3 (0.14 g, 1 mmol) was
added slowly and allowed whole reaction mixture to heat at
50 C. To this hot reaction mixture, N-alkylated product 1-(2-
bromoethyl)-1H-indole (7) (0.224 g, 1 mmol) was added
slowly. ,e reaction mixture was stirred further, and the
4.8. Synthesis of 4-((2-(1H-indol-1-yl) Ethoxy) (Phenyl)
methyl)-N,N-dimethyl Aniline (3). ,e synthesis of target
compound 3 was carried out by using same procedure and

Journal of Chemistry
7
conditions, which was described for the synthesis of com-
pound 1.
((2-(1H-indol-1-yl)ethoxy) (phenyl) methyl)-N,N-dimethyl
aniline (3). (Supplementary Materials)
,e synthesis of target compound 2 was carried out by
using same procedure and conditions, which was described
for the synthesis of compound 1. To a round bottom flask
Grignard product, secondary alcohol 5 (0.34 g, 1.5 mmol)
was charged followed by the addition of phase transfer
catalyst TBAF (0.316, 1.0 mmol) and acetonitrile (10 mL).
,e reaction mixture was stirred at room temperature, and
then K2CO3 (0.14 g, 1 mmol) was added slowly and allowed
whole reaction mixture to heat at 50°C. To this hot reaction
mixture, N-alkylated product 1-(2-bromoethyl)-1H-in-
dole (3) (0.224 g, 1.0 mmol) was added slowly. ,e reaction
mixture was stirred further, and the progress of the re-
action was monitored by TLC. After cooling the reaction
mixture at room temperature, the reaction mixture was
poured in 30 mL water and then extracted with 50 mL ethyl
acetate. ,e combined organic layers were dried over
anhydrous Na2SO4, and the solvent was removed using
rotary evaporator. ,e residue was purified by column
chromatography with air pressure using a 1 :12 (v/v)
mixture of ethyl acetate and petroleum ether as eluent to
afford 4-((2-(1H-indol-1-yl) ethoxy) (phenyl) methyl)-N,
N-dimethyl aniline (2) in 64% yield (0.25 g).
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,is section includes FT-IR spectrum, 1H-NMR spectrum,
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