Synthesis of new functionalized indoles based on ethyl indol-2-carboxylate

Article abstract of DOI:10.3390/molecules21030333

Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid. Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis.

Full text of DOI:10.3390/molecules21030333

molecules
Article
Synthesis of New Functionalized Indoles Based on
Ethyl Indol-2-carboxylate
Ahmed T. A. Boraei 1,*,†, El Sayed H. El Ashry 3,†, Assem Barakat 2,3,† and
Hazem A. Ghabbour 4,5,†
1
Chemistry Department, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
Chemistry Department, College of Science, King Saud University, P. O. BOX 2455, Riyadh 11451,
2
Saudi Arabia; ambarakat@ksu.edu.sa
Chemistry Department, Faculty of Science, Alexandria University, P. O. Box 426, Ibrahimia,
3
Alexandria 21321, Egypt; eelashry60@hotmail.com
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457,
4
Riyadh 11451, Saudi Arabia; ghabbourh@yahoo.com
Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
5
*
†
Correspondance: ahmed_tawfeek83@yahoo.com; Tel.: +20-102-7330-822
These authors contributed equally to this work.
Academic Editor: Roman Dembinski
Received: 24 December 2015 ; Accepted: 26 February 2016 ; Published: 10 March 2016
Abstract: Successful alkylations of the nitrogen of ethyl indol-2-carboxylate were carried out using
aq. KOH in acetone. The respective N-alkylated acids could be obtained without separating the
N-alkylated esters by increasing the amount of KOH and water. The use of NaOMe in methanol
led to transesterification instead of the alkylation, while the use of NaOEt led to low yields of
the N-alkylated acids. Hydrazinolysis of the ester gave indol-2-carbohydrazide which then was
allowed to react with different aromatic aldehydes and ketones in ethanol catalyzed by acetic acid.
Indol-2-thiosemicarbazide was used in a heterocyclization reaction to form thiazoles. The new
structures were confirmed using NMR, mass spectrometry and X-ray single crystal analysis.
Keywords: ethyl indol-2-carboxylate; alkylation; hydrazinolysis; single-crystal X-ray diffraction
1. Introduction
Indole derivatives have been a topic of substantial research interest and continue to be one
of the most active areas of heterocyclic chemistry, particularly due to their natural occurrence and
pharmacological activities [1]. Indole derivatives also occur widely in many natural products such as
those obtained from plants [
2
], fungi [ ], and marine organisms [ ]. The isolation, biological evaluation,
3
4
and chemical properties of natural products have attracted the attention of organic chemists, medicinal
chemists, biologists and pharmacists as well as led to optimization of highly efficient and economical
synthetic routes.
At present there are several thousand indole alkaloids described, including simple and more
complex functionalized indole compounds [5]. The growing importance of substituted indoles
(Figure 1) in the field of medicinal chemistry as potential chemotherapeutic agents and their implication
for pro-drug design have been previously reported [6–15].
The indazoline
disease [16]. The indole derivative eletriptan (
synthesis of eletriptan published by Pfizer starts from a preformed bromoindole [17]. Fluvastatin (
A
is an indole derivative inhibitor of acetylcholinesterase used to treat Alzheimer’s
) is an anti-migraine drug. A process route for the
) is
B
C
a member of the statin drug class, used to treat hypercholesterolemia and to prevent cardiovascular
diseases. It has also been shown to exhibit antiviral activity against hepatitis C [18]. Ondansetron
Molecules 2016, 21, 333; doi:10.3390/molecules21030333
www.mdpi.com/journal/molecules

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(D
) is a indole derivative used mainly as an antiemetic [19]. It is indicated for the prevention of acute
nausea and vomiting associated with cancer chemotherapy [20].
Figure 1. Biologically active compounds incorporating an indole scaffold.
Bis-indole alkaloids are an important structural class due to their high degree of biological activity.
For example, the nortopsentins Ei-iii exhibit in vitro cytotoxicity against P388 cells with IC50 (inhibitory
concentration) values of 7.6, 7.8, and 1.7 µg/mL, respectively [21–23].
Given the significant pharmacological activities associated with these heterocycles, and in order
to contribute to the development of the chemistry of indole [24–32], we were interested in the synthesis
of new heterocyclic polyfunctional indole derivative systems using alkylation reactions.
2. Results
Alkylation of the nitrogen of the indole ring in indole-containing compounds requires strong
bases to generate the indole anion [33]. Protecting the nitrogen of the indole ring in ethyl
1H-indol-2-carboxylate requires special care to avoid the ester hydrolysis before the alkylation. KOH
in anhydrous DMSO was used for the alkylation of nitrogen of the indole esters [34]. Herein, we
describe the alkylation of the indole nitrogen using aq. KOH in acetone. In this method we can control
the reaction to give the alkylated esters or the alkylated acids in the same reaction process, with the
additional benefit of the ease of solvent removal after reaction completion.
Reaction of ethyl indol-2-carboxylate (
of aq. KOH (3.0 mmol/0.1 mL H2O/10 mL acetone) and stirring for two hours at 20 C afforded
ethyl 1-allyl-1H-indole-2-carboxylate ( ) and ethyl 1-benzyl-1H-indole-2-carboxylate ( ) in excellent
yields. The corresponding alkylated carboxylic acids 1-allyl-1H-indol-2-carboxylic acid ( ) and
1-benzyl-1H-indol-2-carboxylic acid ( ) were obtained in high yields directly without separating the
1) with allyl bromide and benzyl bromide in the presence
˝
2
3
5
6
alkylated esters by increasing the amount of aq. KOH and refluxing for one hour. Alkylation with amyl
bromide seems to be slow, since it took about eight hours to give ethyl 1-pentyl-1H-indole-2-carboxylate
(
4
) under the same conditions. Moreover, a considerable amount of 1H-indol-2-carboxylic acid (
detected. The alkylated acids were also obtained in excellent yields from the hydrolysis of
the respective esters using aqueous KOH in acetone The use of NaOMe in methanol led to
transesterification to afford methyl indol-2-carboxylate ( ) instead of NH alkylation, whereas using
NaOEt in ethanol gave the acids and in low to moderate yields in the case of the of with allyl
was
9) was
5–7
2–
4
.
8
5
6
1
and benzyl bromides whereas, in case of amyl bromide a high yield of 1H-indol-carboxylic acid
9
obtained (Scheme 1, Table 1).
Hydrazinolysis of either ethyl or methyl esters 1 or 8 afforded indol-2-carbohydrazide (10). The
hydrazide 10 was reacted with D-glucose, indol-3-carboxyaldehyde, pyridine-3-carboxyaldehyde
and 21-aminoacetophenone in ethanol and drops of acetic acid to yield N1-
β
-D-glucopyranosyl-
1H-indole-2-carbohydrazide (11), N1-((1H-indol-3-yl)methylene)-1H-indole-2-carbohydrazide (12),

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N1-(pyridin-3-ylmethylene)-1H-indole-2-carbohydrazide (13) and N1-(1-(2-aminophenyl)ethylidene)-
1H-indole-2-carbohydrazide (14), respectively (Scheme 2).
Scheme 1. Alkylation of indole nitrogen, transesterification and ester hydrolysis.
Table 1. Conditions of indole nitrogen alkylation and ester hydrolysis.
Entry
Reactant
R-Br
Base
T (˝C)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
2
3
4
1
1
1
Allyl-Br
Benzyl-Br
Amyl-Br
-
KOH (3.0 mmol/0.1 mL¨ H2O)
KOH (3.0 mmol/0.1 mL¨ H2O)
KOH (3.0 mmol/0.1 mL¨ H2O)
KOH (6.0 mmol/1.0 mL¨ H2O)
KOH (6.0 mmol/1.0 mL¨ H2O)
KOH (6.0 mmol/1.0 mL¨ H2O)
NaOEt (6.0 mmol)/EtOH
20
20
20
60
60
60
60
60
60
2.0
2.0
8.0
1.0
1.0
1.0
2
2
3
4/9
5
6
7
5
6
9
85
94
60/30
95
97
90
35
40
90
-
-
Allyl-Br
Benzyl-Br
Amyl-Br
NaOEt (6.0 mmol)/EtOH
NaOEt (6.0 mmol)/EtOH
2
2
Scheme 2. Reaction of indol-2-carbohydrazide 10 with aldehydes and ketones.
Moreover, hydrazide 10 was reacted with terephthalaldehyde under the same conditions to give
the bis-indolyl product 15. A thiosemicarbazide 16 was obtained from the hydrazide 10 and served as
adduct for cyclization with two phenacyl bromides to afford indolylcarbonylhydrazino-thiazoles 17
and 18 (Scheme 3).

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Scheme 3. Synthesis of thiazoles 17 and 18.
2.1. Structural Analysis
All NMR spectra showed the indole CH protons between
δ
7.00 and 7.70 ppm and all indole
carbons from δ 103.0 to 138.0 ppm.
2.2. Alkylated Ester Analysis
The formation of ethyl N-alkylated indol-2-carboxylates
of the indole NH proton signal from the 1H-NMR of these compounds, the presence of ethoxy group
signals (-OCH2CH3) at 15.0 and
1.30 and 4.30 ppm and the respective carbons in 13C-NMR at
46.7 ppm in addition to the ester carbonyl group around 162.0 ppm. Moreover, new signals appeared
in the NMR spectra which are characteristic for the new groups and can be summarized as follows: in
compound the signals of the allyl group appeared as two doublets at 4.81 and 5.06 ppm for the
olefinic CH2 with coupling constants 16.8 and 10.2 Hz, respectively, the NCH2 appeared at 5.23 ppm
and the corresponding carbon (NCH2) appeared at 46.7 ppm, whereas, the remaining olefinic CH
appeared as multiplet at 5.97–6.07 ppm. The benzylated ester showed the NCH2 protons as a
singlet at 5.87 ppm and the respective carbon at 47.6 ppm in addition to the phenyl protons and
carbons. The pentylated ester showed characteristic signals for the pentyl group protons at 0.83,
14.3, 22.3, 28.8, 30.4
2–4 was confirmed by the disappearance
δ
δ
δ
2
δ
δ
δ
δ
3
δ
δ
4
δ
1.23–1.29, 1.68–1.70 and 4.55 ppm and the corresponding carbons appeared at
and 44.4 ppm.
δ
2.3. Hydrolyzed Ester Data Analysis
Hydrolysis of the esters with time was deduced from the disappearance of the signals of the
ethoxy group in the NMR of and instead a new broad signal appeared around 12.90 ppm for
COOH, in addition to characteristic allyl, benzyl and pentyl signals.
Transesterification and formation of the methyl ester
was confirmed by 1H-NMR by observing
a singlet signal at 3.88 ppm for the ester methyl group and the indole NH at 11.91 ppm. The
respective methyl carbon appeared in 13C-NMR at
52.2 ppm and the ester carbonyl appeared at
162.3 ppm. The acid lacked any alkyl signals and showed the C=O at 163.0 ppm, in addition to the
5–
7
δ
8
δ
δ
δ
δ
9
δ
remaining expected protons and carbons.
2.4. Hydrazinolysis of the Esters and the Related Products Analysis
Hydrazinolysis of either indol-2-carboxylate
acid hydrazide (10). The structure of 10 was confirmed by NMR which showed only two signals at
4.52 and 9.78 ppm for the -NH-NH2 group, whereas the carbonyl group appeared at 161.7 ppm.
The 1H-NMR (DMSO-d6 + D2O) of 11 showed the anomeric proton as a doublet at 3.87 ppm with a
coupling constant value of 8.7 Hz which confirms the -configuration. The corresponding anomeric
carbon appeared in 13C-NMR at 90.9 ppm and the carbonyl carbon signal appeared at 161.3 ppm.
1 or 2 led to the formation of indol-2-carboxylic
δ
δ
β

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The NMR spectra of 12
,
13 showed the -CH=N- proton around
δ
8.60 ppm whereas, the NMR of
14 showed the methyl protons at 2.43 ppm and the respective methyl carbon at 15.5 ppm in addition to
the remaining aromatic signals. The NMR spectra of 15 showed a singlet signal at 8.51 ppm for the
two –CH=N- protons and two signals at 11.86 and 12.02 ppm for indole and hydrazide NHs, besides
δ
δ
all aromatic protons and carbons signals.
2.5. Thiazole Structural Analysis
The 1H-NMR spectra of thiazoles 17 and 18 showed all aromatic CH protons of thiazole, indole
and phenyl in the range of
δ
7.07–7.83 ppm, while the three NH protons appeared as broad signals at
δ
9.69, 10.87 and 11.76 ppm. In addition, the 13C-NMR of 17 and 18 showed the carbonyl carbons at
δ
161.42 and 161.35 ppm, respectively.
2.6. X-ray Diffraction Analysis
The structure of 13 was confirmed by X-ray crystal structural analysis. The crystallographic data,
conditions retained for the intensity data collection and some features of the structure refinements are
listed in Table 2. Selected interatomic distances and bond angles are given in Table 3. The unit cell of
the titled compound contains one molecule. All of the bond lengths and bond angles in the phenyl
˝
rings are in the normal range. The indole ring (C1—C8/N1) forms a dihedral angle of 28.05 with the
pyridine-3-yl ring (C11-C14/N4/C15). The title compound exists in trans configuration with respect to
the C10=N3 bond [1.2805 (15) Å] as shown in Figure 2. In the crystal structure (Figure 3), molecules are
linked via three intermolecular N1—H1N1¨ ¨ ¨ N4, N2—H1N2¨ ¨ ¨ O1 and C10—H10A¨ ¨ ¨ O1 hydrogen
bonds in b axis (Table 4).
Table 2. The crystal structure and refinement data of compound 13.
Crystal Data
Chemical formula
C15H12N4O
Mr
Crystal system, space group
Temperature (K)
a, b, c (Å)
264.29
Orthorhombic, Pbca
100
7.8503 (2), 10.1780 (3), 31.9226 (9)
V (Å3)
2550.63 (12)
Z
8
Mo Kα
0.09
Radiation type
µ (mm´1
)
Crystal size (mm)
0.47 ˆ 0.35 ˆ 0.23
Data Collection
Diffractometer
Absorption correction
Tmin, Tmax
Bruker APEX-II D8 venture diffractometer
Multi-scan, SADABS Bruker 2014
0.844, 0.881
No. of measured, independent and observed
[I > 2σ(I)] reflections
Rint
17978, 2927, 2645
0.032
Refinement
R[F2 > 2σ(F2)], wR(F2), S
No. of reflections
0.037, 0.104, 1.04
2927
No. of parameters
No. of restraints
190
0
H atoms treated by a mixture of independent and
constrained refinement
H-atom treatment
∆ρmax, ∆ρmin (e¨ Å´3
)
0.36, ´0.22

Molecules 2016, 21, 333
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Table 3. Selected bond lengths and bond angles in compound 13.
Å, ˝
Å, ˝
Atoms
Atoms
O1—C9
N1—C1
N1—C8
1.2301 (14)
1.3700 (14)
1.3773 (15)
1.3771 (14)
108.34 (9)
119.20 (9)
115.30 (10)
117.59 (10)
108.28 (9)
129.58 (11)
110.20 (9)
N2—C9
N3—C10
N4—C14
1.3594 (15)
1.2805 (15)
1.3430 (16)
1.3376 (14)
117.81 (10)
121.67 (10)
114.68 (10)
123.62 (10)
119.51 (10)
122.99 (12)
123.74 (10)
N2—N3
N4—C15
C1—N1—C8
N3—N2—C9
N2—N3—C10
C14—N4—C15
N1—C1—C6
N1—C1—C2
N1—C8—C7
N1—C8—C9
O1—C9—C8
N2—C9—C8
O1—C9—N2
N3—C10—C11
N4—C14—C13
N4—C15—C11
Figure 2. ORTEP diagram of the titled compound 11 drawn at 50% ellipsoids for non-hydrogen atoms.
Figure 3. A view of the crystal packing down the b axis for the title compound. Dotted lines indicates
the intermolecular interaction.
Table 4. Hydrogen-bond geometry (Å, ˝) in compound 13.
D—H¨ ¨ ¨ A
D—H
H¨ ¨ ¨ A
1.975(17)
2.135(17)
2.4300
D¨ ¨ ¨ A
2.8856(14)
2.9909(13)
3.2266(14)
D—H¨ ¨ ¨ A
173.4(14)
155.4(14)
144.00
N1—H1N1¨ ¨ ¨ N4i
N2—H1N2¨ ¨ ¨ O1ii
C10—H10A¨ ¨ ¨ O1ii
0.915(17)
0.915(17)
0.9300
Symmetry codes: (i) x ´ 1/2, ´y + 3/2, ´z + 1; (ii) –x + 3/2, y + 1/2, z.
3. Experimental Section
3.1. General Details
Melting points were measured with a Stuart melting-point apparatus (SMP10, Bibby Scientific
Ltd., Staffordshire, UK) in open capillaries and are uncorrected. Flash chromatography was done

Molecules 2016, 21, 333
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on silica gel 60 (230–400 mesh ASTM). TLC was performed on silica gel 60 F254 (Merck Millipore,
Darmstadt, Germany) and spots were detected by absorption of UV light. 1H-NMR spectra were
recorded on Advanced NMR spectrometers (Bruker Biospin, Fallanden, Switzerland) at 300–600 MHz
whereas 13C-NMR spectra were recorded on the same instruments at 75–150 MHz, with TMS as
internal standard. Mass spectra were obtained using MAT312 (ThermoFinnigan GmbH, Tokyo,
Japan) and a JMS.600H (Jeol, Tokyo, Japan) instruments for EIMS; HRMS spectra were recorded on a
Thermo Finnigan MAT 95XP and Jeol JMS HX110 and ESI on an Ion Trap 6320 mass detector (Agilent
Technologies, Wilmington, DE, USA). IR spectra were recorded using KBr discs on a Bruker FT-IR IFS
48 spectrophotometer (Bruker Optics, Ettlingen, Germany).
3.2. General Procedure for the Alkylation of Ethyl Indol-2-carboxylate (1)
A solution of ethyl indol-2-carboxylate (
was stirred at 20 ˝C for half hour, then the appropriate alkylating agent (1.1 mmol) was added and
stirring was continued for 2 h to give and and for eight hours to give . The solvent was removed,
1, 1.0 mmol) and aq. KOH (3.0 mmol) in acetone (10 mL)
2
3
4
water was added and organic layer was extracted using ethyl acetate. The products were purified
using column chromatography (ethyl acetate/hexane 1:9).
3.3. Hydolysis of the Ester and Formation of Acids 5–7
Method a: the above procedure was followed until the alkylation was complete, then KOH
(6.0 mmol in 1.0 mL H2O) was added and the reaction mixture refluxed one hour, the solvent removed,
¨
cold water added, and acidified. The ppt was collected and purified by crystallization from ethanol in
the case of 5 and 6 and from hexane in the case of 7.
Method b: a solution of the appropriate ester
2
–
4
and KOH (6.0 mmol in 1.0 mL H2O) and acetone
¨
(10 mL) was refluxed for one hour, then the above purification process was followed.
Method c: A mixture of ethyl indol-2-carboxylate (1, 1.0 mmol) and NaOEt (3.0 mmol) in ethanol
(10 mL) was stirred for half an hour then, alkylating agent was added and the mixture heated under
reflux for two hours and the above purification process followed.
Ethyl 1-allyl-1H-indole-2-carboxylate (
(DMSO-d6, 600 MHz) 1.33 (t, 3H, J 6.3 Hz, CH3), 4.32 (q, 2H, OCH2CH3), 4.81 (d, 1H, Jtrans 16.8 Hz,
-NCH2-CH=C H), 5.06 (d, 1H, Jcis 10.2 Hz, -NCH2-CH=CH ), 5.23 (s, 2H, -NC 2-CH=CH2), 5.97–6.07
(m, 1H, -NCH2-C =CHH), 7.15 (dd, 1H, J4,5 7.8, J5,6 7.2 Hz, H-5Indol), 7.32–7.34 (m, 2H, H-3Indol
H-6Indol), 7.56 (d, 1H, J6,7 8.4 Hz, H-7Indol), 7.71 (d, 1H, J4,5 7.8 Hz, H-4Indol); 13C-NMR (DMSO-d6,
150 MHz) 14.7 (CH3), 46.7 (-N H2-CH=CH2), 60.9 (OCH2CH3), 110.7 (C-3Indol), 111.6 (C-7Indol), 116.2
(-NCH2-CH= H2), 121.1 (C-5Indol), 122.9 (C-4Indol), 125.5 (C-6Indol), 125.9 (C-2Indol), 127.6 (C-3aIndol),
135.0 (-NCH2-
H=CH2), 139.2 (C-7aIndol), 161.6 (C=O); LRMS-ESI+ m/z (int. %): 58.7 (6), 79.3 (55),
101.1 (11), 142.1 (100), 182.0 (10), 216.9 (31), 230 (18 for M + H).
2
): Colorless oil, Rf 0.65 (ethyl acetate/n-hexane 1:9); 1H-NMR
δ
H
H
H
H
,
δ
C
C
C
Ethyl 1-benzyl-1H-indole-2-carboxylate (
acetate/n-hexane 1:9); H-NMR (DMSO-d6, 600 MHz)
3
): White ppt, m.p. 52–53 ˝C (lit. [26] 55–56 ˝C), Rf 0.61 (ethyl
1.28 (t, 3H, J 7.2 Hz, CH3), 4.27 (q, 2H,
2-Ph), 7.05 (d, 2H, J 7.8 Hz, 2 HPh), 7.14–7.33 (m, 5H, H-5Indol, H-6Indol
3 HPh), 7.40 (s, 1H, H-3Indol), 7.57 (d, 1H, J6,7 8.4 Hz, H-7Indol), 7.74 (d, 1H, J4,5 7.8 Hz, H-4Indol);
13C-NMR (DMSO-d6, 150 MHz)
14.5 (OCH2 H3), 47.6 (N H2-Ph), 60.9 (O H2CH3), 111.1, 111.8
1
δ
OC
H
2CH3), 5.87 (s, 2H, -NC
H
,
δ
C
C
C
(C-3Indol, C-7Indol), 121.3 (C-5Indol), 123.0 (C-4Indol), 125.7 (C-6Indol), 126.1 (C-2Indol), 126.7 (2 CHPh),
127.5 (CHPh) 127.7 (C-3aIndol), 128.9 (2 CHPh), 138.9, 139.6 (CPh, C-7aIndol), 161.7 (C=O).
Ethyl 1-pentyl-1H-indole-2-carboxylate (
(DMSO-d6, 600 MHz) 0.83 (t, 3H, J 6.3 Hz, CH3), 1.23–1.29 (m, 4H, 2 CH2), 1.34 (t, 3H, J 6.6 Hz,
OCH2C 3), 1.68–1.70 (m, 2H, CH2), 4.33 (q, 2H, OC 2CH3), 4.55 (t, 2H, J 6.6 Hz, -NC 2-), 7.13 (dd,
1H, J4,5 7.8, J5,6 7.2 Hz, H-5Indol), 7.28 (s, 1H, H-3Indol), 7.34 (dd, 1H, J5,6 7.2, J6,7 8.4 Hz, H-6Indol), 7.59
(d, 1H, J6,7 8.4 Hz, H-7Indol), 7.68 (d, 1H, J4,5 7.8 Hz, H-4Indol); 13C-NMR (DMSO-d6, 150 MHz)
14.3,
14.6 (2 CH3), 22.3, 28.8, 30.4 (3 CH2), 44.4 (N H2-), 60.8 (O H2CH3), 110.1, 111.4 (C-3Indol, C-7Indol),
4
): Colorless oil, Rf 0.75 (ethyl acetate/n-hexane 1:9); 1H-NMR
δ
H
H
H
δ
C
C

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120.9 (C-5Indol), 122.8 (C-4Indol), 125.4 (C-6Indol), 125.8 (C-2Indol), 127.5 (C-3aIndol), 139.2 (C-7aIndol),
161.7 (C=O).
˝
1-Allyl-1H-indole-2-carboxylic acid (
1H-NMR (DMSO-d6, 600 MHz)
4.81 (d, 1H, Jtrans 17.4 Hz, -NCH2-CH=C
-NCH2-CH=CH ), 5.24 (d, 2H, J 1.2 Hz, -NC 2-CH=CH2), 5.96–6.00 (m, 1H, -NCH2-CH
5
): White solid, m.p. 178–179 C, Rf 0.51 (ethyl acetate/n-hexane 3:7);
H), 5.05 (d, 1H, Jcis 10.2 Hz,
=CHH),
δ
H
H
H
7.13 (dd, 1H, J4,5 7.8, J5,6 7.2 Hz, H-5Indol), 7.27 (s, 1H, H-3Indol), 7.32 (dd, 1H, J5,6 7.2, J6,7 8.4 Hz,
H-6Indol), 7.53 (d, 1H, J6,7 8.4 Hz, H-7Indol), 7.69 (d, 1H, J4,5 7.8 Hz, H-4Indol), 12.92 (br.s, 1H, -COOH);
13C-NMR (DMSO-d6, 150 MHz)
(-NCH2-CH=
135.2 (-NCH2-
δ
46.5 (-N
CH2-CH=CH2), 110.5, 111.5 (C-3Indol, C-7Indol), 116.1
C
C
H2), 120.9 (C-5Indol), 122.9 (C-4Indol), 125.2 (C-6Indol), 126.0 (C-2Indol), 128.4 (C-3aIndol),
´
H=CH2), 139.2 (C-7aIndol), 163.2 (C=O); LRMS-ESI m/z (int. %): 116.0 (20), 155.9 (50),
199.9 (100 for M ´ H).
1-Benzyl-1H-indole-2-carboxylic acid (
(ethyl acetate/n-hexane 3:7); 1H-NMR (DMSO-d6, 600 MHz)
˝
˝
6
): White solid, m.p. 190–191 C (lit. [26] 194–196 C), Rf 0.50
δ
5.89 (s, 2H, -NC 2-Ph), 7.04 (d, 2H,
H
J 6.6 Hz, 2 HPh), 7.12–7.29 (m, 5H, H-5Indol, H-6Indol, 3 HPh), 7.34 (s, 1H, H-3Indol), 7.54 (d, 1H, J6,7
8.4 Hz, H-7Indol), 7.72 (d, 1H, J4,5 7.8 Hz, H-4Indol), 12.99 (br.s, 1H, -COOH); 13C-NMR (DMSO-d6,
150 MHz)
δ 47.4 (NCH2-Ph), 110.9, 111.7 (C-3Indol, C-7Indol), 121.1 (C-5Indol), 122.8 (C-4ndol), 125.4
(C-6Indol), 126.1 (C-2Indol), 126.7 (2 CHPh), 127.4 (CHPh) 128.7 (C-3aIndol), 128.9 (2 CHPh), 139.1, 139.4
(CPh, C-7aIndol), 163.4 (C=O); LRMS-ESI+ m/z (int. %): 142.1 (10), 156.9 (30), 169.9 (11), 178.8 (13), 252.0
(100 for M + H).
1-Pentyl-1H-indole-2-carboxylic acid (
3:7); 1H-NMR (CDCl3, 400 MHz)
0.93 (t, 3H, J 6.9 Hz, CH3), 1.28–1.42 (m, 4H, 2 CH2), 1.82–1.89 (m,
7
): White solid, m.p. 91–92 ˝C, Rf 0.43 (ethyl acetate/n-hexane
δ
2H, CH2), 4.61 (t, 2H, J 7.5 Hz, NCH2), 7.19 (dd, 1H, J5,6 7.4, J4,5 8.0 Hz, H-5Indol), 7.40 (dd, 1H, J5,6 7.4,
J6,7 8.1 Hz, H-6Indol), 7.45 (d, 1H, J6,7 8.1 Hz, H-7Indol), 7.51 (s, 1H, H-3Indol), 7.74 (d, 1H, J4,5 8.0 Hz,
H-4Indol); IR (KBr): νmax/cm´1 2500–3500 (OH acid), 1684.1 (C=O acid).
3.4. Transesterification Procedures
A mixture of ethyl indol-2-carboxylate
1 (1.0 mmol) with or without the alkylating agents and
NaOMe (4.0 mmol) in methanol (10 mL) was stirred for one hour. The mixture was acidified and the
precipitate was collected, dried and crystallized from ethanol or purified by sublimation.
Methyl 1H-indole-2-carboxylate (
(ethyl acetate/n-hexane 1:9); H-NMR (DMSO-d6, 600 MHz)
8
): Yield: 89% as colorless needle crystals, m.p. 149–150 ˝C, Rf 0.28
1
δ 3.88 (s, 3H, CH3), 7.09 (dd, 1H, J4,5
7.8, J5,6 7.2 Hz, H-5Indol), 7.18 (s, 1H, H-3Indol), 7.27 (dd, 1H, J5,6 7.2, J6,7 8.4 Hz, H-6Indol), 7.49 (d, 1 H,
J6,7 8.4 Hz, H-7Indol), 7.66 (d, 1H, J4,5 7.8 Hz, H-4Indol), 11.91 (s, 1H, NHIndol); 13C-NMR (DMSO-d6,
150 MHz) δ 52.2 (CH3), 108.3 (C-3Indol), 113.1 (C-7Indol), 120.7 (C-5Indol), 122.5 (C-4Indol), 125.1 (C-6Indol),
127.2, 127.5 (C-2Indol, C-3aIndol), 137.9 (C-7aIndol), 162.3 (C=O); LRMS-ESI´ m/z (int. %): 89.0 (6),
113.1 (7), 145.9 (5), 158.9 (10), 173.9 (100 for M ´ H).
3.5. Synthesis of 9 Following Methods b: Starting with 1 or 8
1H-Indole-2-carboxylic acid (
acetate/n-hexane 3:7); H-NMR (DMSO-d6, 600 MHz)
9
): Yield: 55% as yellow solid, m.p. 203–204 ˝C, Rf 0.30 (ethyl
7.06 (dd, 1H, J4,5 7.8, J5,6 7.2 Hz, H-5Indol),
1
δ
7.11 (s, 1H, H-3Indol), 7.24 (dd, 1H, J5,6 7.2, J6,7 8.4 Hz, H-6Indol), 7.46 (d, 1H, J6,7 8.4 Hz, H-7Indol), 7.65
(d, 1H, J4,5 7.8 Hz, H-4Indol), 11.74 (s, 1H, NHIndol); 13C-NMR (DMSO-d6, 150 MHz)
δ
107.79, 112.96
(C-3Indol, C-7Indol), 120.4 (C-5Indol), 122.4 (C-4ndol), 124.7 (C-6Indol), 127.3, 128.9 (C-2Indol, C-3aIndol),
´
137.7 (C-7aIndol), 163.3 (C=O); LRMS-ESI m/z (int. %): 115.9 (25), 159.8 (100 for M + H).
3.6. Hydrazide Formation
Either ethyl indol-2-carboxylate
1 or methyl indol-2-carboxylate 8 was refluxed with hydrazine
hydrate in ethanol (4 h), the formed ppt was collected and crystalized from 95% ethanol.

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1H-Indole-2-carbohydrazide (10): Yield: 90% as colorless crystals, m.p. 247–248 ˝C (lit. [17
,
18]), Rf 0.43
1
(9:1 CH2Cl2/MeOH); H-NMR (DMSO-d6, 600 MHz):
δ 4.52 (s, 2H, NH2), 7.03 (dd, 1H, J5,6 7.2,
J
4,5 7.8 Hz, H-5Indol), 7.10 (s, 1H, H-3Indol), 7.18 (dd, 1H, J5,6 7.2, J6,7 7.8 Hz, H-6Indol), 7.45 (d, 1H, J6,7
7.8 Hz, H-7Indol), 7.60 (d, 1H, J4,5 7.8 Hz, H-4Indol), 9.78 (s, 1H, NH), 11.60 (s, 1H, NHIndol); 13C-NMR
(DMSO-d6, 150 MHz): 102.3 (C-3Indol), 112.7 (C-7Indol), 120.2 (C-5Indol), 121.9 (C-4Indol), 123.6 (C-6Indol),
δ
´
127.6, 131.0, 136.8 (C-2Indol, C-3aIndol, C-7aIndol), 161.7 (C=O). LRMS-ESI m/z (Int. %): 115.9 (6), 173.9
(100 for M ´ H).
N1- -D-Glucopyranosyl-1H-indole-2-carbohydrazide (11): Yield: 60% as white solid, m.p. 208–210 ˝C, Rf
β
0.10 (MeOH/DCM 1.5:8.5); 1H-NMR (DMSO-d6 + D2O, 300 MHz)
δ 3.02–3.24 (m, 4H, H-5Glc, H-6Glc,
H-3Glc, H-4Glc), 3.44 (dd, 1H, J5,6 6, J6,61 17.7 Hz, H-61Glc), 3.66 (dd, 1H, J 9.9 Hz, H-2Glc), 3.87 (d, 1H,
J 8.7 Hz, H-1Glc), 7.02 (dd, 1H, J4,5 8.1, J5,6 7.2 Hz, H-5Indol), 7.16–7.23 (m, 2H, H-3Indol, H-6Indol), 7.42
(d, 1H, J6,7 8.1 Hz, H-7Indol), 7.59 (d, 1H, J4,5 8.1 Hz, H-4Indol); 13C-NMR (DMSO-d6 + D2O, 150 MHz)
δ
61.3, 70.3, 71.2, 76.6, 78.1, 90.9 (6 CGlc), δ 103.3 (C-3Indol), 112.25 (C-7Indol), 119.8 (C-2Indol), 121.5
(C-5Indol), 123.4 (C-4ndol), 126.9, 129.7, 136.5 (C-6Indol, C-3aIndol, C-7aIndol), 161.3 (C=O); HRMS (+ESI)
calcd for C15H20N3O6 [M+]: 338.1352. Found: 338.1348.
3.7. Condensation of Hydrazide with Aromatic Aldehydes and Ketones
A mixture of hydrazide 10 (1.0 mmol) and the appropriate aldehyde or ketone (1.1 mmol) in
ethanol (5.0 mL) containing acetic acid (0.5 mL) was refluxed until the ppt appeared. The ppt was
filtered and crystalized from DMF or DMF/EtOH mixture.
N'-((1H-Indol-3-yl)methylene)-1H-indole-2-carbohydrazide (12): Yield: 82% as yellowish white needle-like
˝
1
crystals, m.p. 277–278 C, Rf 0.49 (ethyl acetate/n-hexane 6:4); H-NMR (DMSO-d6, 600 MHz):
δ
7.08–7.23 (m, 5H), 7.30–7.49 (m, 2H), 7.68 (d, 1H, J 6.6 Hz), 7.86 (s, 1H), 8.32 (d, 1H, J 6.0 Hz), 8.65 (s, 1H),
11.56, 11.61, 11.70 (3s, 1H, 3 NH); 13C-NMR (DMSO-d6, 150 MHz):
δ 103.3, 112.2, 112.3, 112.8, 120.3,
120.9, 122.06, 122.4, 123.1, 123.9, 124.8, 127.6, 130.7, 131.2, 137.2, 137.5, 145.0, 157.6 (C=O); LRMS-ESI+
m/z (Int. %): 79.4 (6), 303.1 (100 for M + H).
1
N -(Pyridin-3-ylmethylene)-1H-indole-2-carbohydrazide (13): Yield: 71% as colorless needle crystals, m.p.
˝
250–251 C, Rf 0.35 (ethyl acetate/n-hexane 6:4); 1H-NMR (DMSO-d6, 600 MHz):
δ 7.07–7.70 (m, 6H),
8.18 (d, 1H, J 4.8 Hz), 8.52 (s, 1H), 8.63 (s, 1H), 8.90 (s, 1H), 11.83, 12.07 (2 s, 2H, NH, NHIndol); 13C-NMR
(DMSO-d6, 150 MHz):
δ
104.3 (C-3Indol), 112.9 (C-7Indol), 120.5 (C-5Indol), 122.3 (C-4Indol), 124.5 (C-6Indol
,
,
CHPyridin), 127.4, 130.5, 130.8, 133.9, 137.4, 144.8, 151.1, 158.2 (C-2Indol, C-3aIndol, C-7aIndol, 3 CHPyridin
´
2 CPyridin), 160.8 (C=O). LRMS-ESI m/z (Int. %): 79.3 (8), 265.0 (100 for M + H).
-(1-(2-Aminophenyl)ethylidene)-1H-indole-2-carbohydrazide (14): Yield: 60% as colorless scale crystals,
m.p. 207–209 ˝C, Rf 0.82 (ethyl acetate/n-hexane 6:4); 1H-NMR (DMSO-d6, 600 MHz):
2.43 (s, 3H,
N'
δ
CH3), 6.56 (t, 1H, J 7.2 Hz), 6.77 (d, 1H, J 7.8 Hz), 7.07–7.09 (m, 2H), 7.23–7.26 (m, 2H), 7.41 (s, 1H), 7.48
(d, 1H, J 7.8 Hz), 7.50 (d, 1H, J 8.4 Hz), 7.69 (d, 1H, J 7.8 Hz), 10.84 (s, H, NH), 11.79 (s, H, NHIndol);
13C-NMR (DMSO-d6, 150 MHz):
δ 15.5 (CH3), 104.9, 112.8, 115.0, 116.6, 118.1, 120.4, 122.2, 124.3, 127.5,
129.6, 130.1, 130.6, 148.5, 157.3, 158.7 (2 C=O).
N1,N11-(1,4-Phenylenebis(methan-1-yl-1-ylidene))bis(1H-indole-2-carbohydrazide) (15): Yield: 90% as
˝
1
yellowish white solid, m.p. 332–333 C, Rf 0.77 (ethyl acetate); H-NMR (DMSO-d6, 600 MHz):
7.09 (dd, 2H, J5,6 7.2, J4,5 7.8 Hz, 2 H-5Indol), 7.25 (dd, 2H, J5,6 7.2, J6,7 6.6 Hz, 2 H-6Indol), 7.25 (s,
2H, 2 H-3Indol), 7.50 (d, 2H, J6,7 7.8 Hz, 2 H-7Indol), 7.70 (br, 2H, 2 H-4Indol), 7.87 (s, 4H, 4 HPh), 8.51
(s, 2H, -N=CH), 11.86 (s, 2H, 2 NHIndol), 12.02 (s, 2H, 2 NH); 13C-NMR (DMSO-d6, 150 MHz):
δ
δ
104.30 (2 C-3Indol), 112.9 (2 C-7Indol), 120.5 (2 C-5Indol), 122.3 (2 C-4Indol), 124.4 (2 C-6Indol), 127.5, 128.0,
130.5 (2 C-2Indol, 2 C-3aIndol, 4 CHPh), 136.2, 137.4 (2 CPh, 2 C-7aIndol), 146.9, 158.2 (2 CH=N, 2 C=O).
LRMS-ESI+ m/z (Int. %): 79.3 (100), 101.0 (20), 142.1 (62), 237.0 (66), 280.0 (30), 341.9 (12), 448.8
(10 for M + H).

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1
3.8. Synthesis of N -(4-Aryl-1,3-thiazol-2-yl)-1H-indole-2-carbohydrazides 17, 18
A mixture of 1-[(1H-Indol-2-yl)-carbonyl]-thiosemicarbazide (16 29], 1.0 mmol) and the respective
[
phenacyl bromide (1.1 mmol) in ethanol (10 mL) was stirred at room temperature for 25 min. A
precipitate was formed, filtered, and then recrystallized from ethanol.
N1-(4-Ph˝enyl-1,3-thiazol-2-yl)-1H-indole-2-carbohydrazide (17): Yield: 68% as pink shiny crystals, m.p.
245–247 C, Rf 0.68 (ethyl acetate/n-hexane 6:4); 1H-NMR (DMSO-d6, 400 MHz)
δ 7.07 (dd, 1H, J4,5 8.0,
J5,6 7.6 Hz, H-5Indol), 7.19–7.29 (m, 4H, H-3Indol, H-6Indol, H-4Thiazol, CHPh), 7.38 (dd, 2H, J 7.2, J 8.0 Hz,
2HPh), 7.45 (d, 1H, J6,7 8.0 Hz, H-7Indol), 7.66 (d, 1H, J4,5 8.0 Hz, H-4Indol), 7.83 (d, 2H, J 7.6 Hz, 2HPh),
9.69 (br. s, 1H, NH), 10.87 (br. s, 1H, NH), 11.76 (br. s, 1H, NHIndol); 13C-NMR (DMSO-d6, 100 MHz)
δ
103.16, 103.69 (C-3Indol, CHThiazol), 112.43 (C-7Indol), 120.06 (C-5Indol), 121.83 (C-4Indol), 123.93 (C-6Indol),
125.60 (2 CHPh), 126.98 (C-3aIndol), 127.53 (CHPh), 128.60 (2 CHPh), 129.19 (C-2Indol), 134.69 (CPh), 136.8
(C-7aIndol), 150.71 (C-4Thiazol), 161.42 (C=O), 172.71 (C-2Thiazol)); HRMS (EI) calcd for C18H14N4OS
[M+.]: 334.0888. Found: 334.0890.
1
N -(4-(3-Bromophenyl)-1,3-thiazol-2-yl)-1H-indole-2-carbohydrazide (18): Yield: 60% as pink shiny crystals,
˝
1
m.p. 250–251 C, Rf 0.73 (ethyl acetate/n-hexane 6:4); H-NMR (DMSO-d6, 300 MHz)
δ 7.07 (dd,
1H, J4,5 7.8, J5,6 7.5 Hz, H-5Indol), 7.19–7.27 (m, 2H, H-3Indol, H-6Indol), 7.35 (dd, 1H, J 7.8, J 8.1 Hz,
CHPh), 7.42–7.48 (m, 3H, H-7Indol, H-4Thiazol, CHPh), 7.66 (d, 1H, J4,5 7.8 Hz, H-4Indol), 7.84 (d, 1H,
J 7.5 Hz, 2HPh), 8.02 (s, 1H, CHPh), 9.75 (br. s, 1H, NH), 10.89 (br. s, 1H, NH), 11.77 (br. s, 1H, NHIndol);
13C-NMR (DMSO-d6, 100 MHz)
δ 103.67, 104.71 (C-3Indol, CHThiazol), 112.37 (C-7Indol), 120.00 (C-5Indol),
121.78 (C-4Indol), 122.02 (CPh), 123.90 (C-6Indol), 124.42 (CHPh), 126.90 (C-3aIndol), 128.09 (CHPh), 129.05
(C-2Indol), 130.30, 130.76 (2 CHPh), 134.75, 136.84 (C-7aIndol, CPh), 148.87 (C-4Thiazol), 161.35 (C=O),
172.81 (C-2Thiazol); HRMS (EI) calcd for C18H13N4OSBr [M+]: 411.9993. Found: 411.9954.
3.9. X-ray Crystallography
Compound 13 was obtained as single crystals by slow evaporation of ethanol. Data
were collected on a Bruker APEX-II D8 Venture area diffractometer (Bruker AXS GmbH,
Karlsruhe, Germany), equipped with graphite monochromatic Mo K
Cell refinement and data reduction were carried out by Bruker SAINT. SHELXS-97 [33
α
radiation at 100(2) K.
36
–
]
was used to solve structure. The final refinement was carried out by full-matrix least-squares
techniques with anisotropic thermal data for nonhydrogen atoms on F2. CCDC 1438576 contains
the supplementary crystallographic data for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
4. Conclusions
In summary, using NaOMe did not catalyze the alkylation of the ethyl indole-2-carboxylate
(NH), and instead led to transesterification. The alkylation succeeded by the use of aq. KOH in
acetone and is time dependent. Hydrazinolysis of ethyl or methyl indol-2-carboxylate afforded
indol-2-carbohydrazide, which reacted with some aromatic aldehydes and ketones to form hydrazones.
Indol-2-thiosemicarbazide was used for the synthesis of thiazoles. Further biological evaluations of
the synthesized compounds 2–18 are underway.
Acknowledgments: The authors would like to extend their sincere appreciation to the Deanship of Scientific
Research at King Saud University for funding this Research group NO (RGP-1436-038).
Author Contributions: A.T.A.B and E-S.H.E.-A conceived and designed the experiments; A.T.A.B
performed the experiments; A.T.A.B, and E-S.H.E.-A. Analyzed the data; A.B., and H.A.G. contributed
reagents/materials/analysis tools; A.B., and H.A.G. carried out the X-ray single crystal; A.T.A.B and A.B. wrote
the paper.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 2–18 are available from the authors.
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