Solvent free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type Compounds from L-tryptophan: DFT-B3LYP calculations for the reaction mechanism and 3H-pyrrol-3-one?1H-pyrrol-3-ol tautomeric equilibrium

Article abstract of DOI:10.3390/molecules25194402

In this paper, we describe the solvent-free three-component synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds from L-tryptophan. The first step of the synthetic methodology involved the esterification of L-tryptophan in excellent yields (93–98%). Equimolar mixtures of alkyl 2-aminoesters, 1,3-dicarbonyl compounds, and potassium hydroxide (0.1 eq.) were heated under solvent-free conditions. The title compounds were obtained in moderate to good yields (45%–81%). Density functional theory using “Becke, 3-parameter, Lee–Yang–Parr” correlational functional (DFT-B3LYP) calculations were performed to understand the molecular stability of the synthesized compounds and the tautomeric equilibrium from 3H-pyrrol-3-one type intermediates to 1H-pyrrol-3-ol type aromatized rings.

Full text of DOI:10.3390/molecules25194402

molecules
Article
Solvent Free Three-Component Synthesis of 2,4,5-
trisubstituted-1H-pyrrol-3-ol-type Compounds from
L-tryptophan: DFT-B3LYP Calculations for the Reaction
Mechanism and 3H-pyrrol-3-one↔1H-pyrrol-3-ol
Tautomeric Equilibrium
Diego Quiroga * , Lili Dahiana Becerra and Ericsson Coy-Barrera
Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Universidad Militar Nueva
Granada, Campus Nueva Granada, Cajicá 250247, Colombia; lilidahiana18@gmail.com (L.D.B.);
ericsson.coy@unimilitar.edu.co (E.C.-B.)
*
Correspondence: diego.quiroga@unimilitar.edu.co
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 2 September 2020; Accepted: 24 September 2020; Published: 25 September 2020
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: In this paper, we describe the solvent-free three-component synthesis of 2,4,5-trisubstituted-
H-pyrrol-3-ol-type compounds from L-tryptophan. The first step of the synthetic methodology
1
involved the esterification of L-tryptophan in excellent yields (93–98%). Equimolar mixtures of
alkyl 2-aminoesters, 1,3-dicarbonyl compounds, and potassium hydroxide (0.1 eq.) were heated
under solvent-free conditions. The title compounds were obtained in moderate to good yields
(45%–81%). Density functional theory using “Becke, 3-parameter, Lee–Yang–Parr” correlational
functional (DFT-B3LYP) calculations were performed to understand the molecular stability of the
synthesized compounds and the tautomeric equilibrium from 3H-pyrrol-3-one type intermediates to
1
H-pyrrol-3-ol type aromatized rings.
Keywords: 1H-pyrrol-3-ol; enamines; L-tryptophan; indole phytoalexin; hybrid heterocycles
1
. Introduction
The five-membered heterocyclic systems occur in a large number of natural secondary (currently
called specialized) metabolites. These compounds usually exhibit a wide variety of biological and
biomedical properties [ ]. Within this type of compounds, 1H-pyrrole is representative since it is
well-known as a fundamental structural subunit in many of the naturally-occurring biological agents [ ].
1
2
From this fact, many synthetic pyrrole derivatives have been obtained on the basis of biomimetic exercises,
and have shown promissory behavior as antipsychotics, adrenergic antagonists, anxiolytics, anticancer,
antibacterial and antifungal agents [3–5]. For example, synthetic 1,5-diphenylpyrrole-type compounds
have shown high activity against a panel of Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae,
Acinetobacter baumannii, Pseudomonas aeruginosa y Enterobacter cloacae (ESKAPE) bacteria, similar to or
even better than levofloxacin, a widely known antibiotic [
H-pyrrole-2-carboxylic acid and derivatives have been reported. Such a compound was identified
as a secondary metabolite of Streptomyces griseus, considered the main bioactive compound
against the oomycete Phytophthora capsici [ ]. On the other hand, a series of 2-alkyl-4-bromo-5-
trifluoromethyl)pyrrole-3-carbonitriles was obtained having excellent fungicidal activities against
6]. In addition, the antimicrobial activity of
1
7
(
Alternaria solani and Fusarium oxysporum [8]. Substituted 3,4-dimethyl-1H-pyrrole-2-carboxamides
and carbohydrazide analogues could be considered potential antifungal and antimicrobial agents,
especially against the pathogen Aspergillus niger [9].
Molecules 2020, 25, 4402; doi:10.3390/molecules25194402
www.mdpi.com/journal/molecules

Molecules 2020, 25, 4402
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Several studies employing hybrid heterocyclic systems have led to a synergistic effect, expanding
the scope on their biological activities [10 13]. Novel derivatives of pyrano[2,3-b] pyridine
–
and pyrrolo[2,3-b]pyrano[2,3-d]pyridine proved to be active against Candida sp., Aspergillus multi,
Aspergillus niger, Escherichia coli and Staphylococcus aureus. Ethyl 4-methyl-1,7,8,9-tetrahydropyrano
[2,3-b]pyrrolo[2,3-d]pyridine-3-carboxylate was found as the most active compound against all
the mentioned microorganisms [14]. Other hybrid heterocyclic systems, such as pyrazole-furan
carboxamide and pyrazole-pyrrole carboxamide-type compounds, have shown activities against
three destructive fungi, including Sclerotinia sclerotiorum, Rhizoctonia solani, and Pyricularia grisea [15].
These studies suggested that this kind of heterocyclic systems can be considered phytoalexin-like
analogues with promising bioactivity.
According to this background, the Bioorganic Laboratory at Universidad Militar Nueva Granada
(UMNG) has deepened the synthesis and antifungal activity against the phytopathogenic fungus
Fusarium oxysporum of novel 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds . To establish a
1
high yielding and novel methodology, a comprehensive literature survey was then performed. Such a
review ruled that the pyrrole nucleus can be obtained employing cycloaddition, cyclocondensation and
carbon-carbon coupling reactions by metalorganic-catalyzed reactions [16]. All the described synthetic
methods are diverse in terms of the employed reactants as well as the variation in the reaction conditions,
comprising several representatives, such as Knorr, Hantzsch and Feist methodologies [16
Some advantages have been achieved, primarily establishing more efficient and greener synthetic
protocols [19 21]. Thus, the preparation of 3-substituted-4-(3-chloro-4-fluorophenyl)-1H-pyrrole
–18].
–
derivatives based on the Van Leusen pyrrole synthesis was performed through a metal-free synthetic
method, involving a C-N bond cleavage under mild reaction conditions [22]. The synthesis of
1
1
,3,4-trisubstituted pyrroles via three-component domino reactions between (E)-3-(dimethylamino)-
-arylprop-2-en-1-ones, anilines and 2-nitrostyrenes was also reported. These reactions proceeded via
addition–elimination/Michael addition/intramolecular annulation/elimination domino sequential
reactions, with one C-C and two C-N bonds formation in a single synthetic operation [23].
Phenylpyrrole-substituted tetramic acid derivatives bearing carbonates were designed and synthesized
from 4-(2,4-dioxopyrrolidin3-ylidene)-4-(phenylamino)butanoic acids [24]. An efficient, one-pot
synthetic procedure for [4-(tert-butyl)-1H-pyrrol-3-yl](phenyl)methanone was proposed using
acetophenone and trimethylacetaldehyde in the presence of toluenesulfonylmethyl isocyanide
(TosMIC) and mild base [25].
On the other hand, an efficient, environmentally benign
and molecular iodine-promoted protocol was recently described for the cascade synthesis of
dihydro-1H-pyrrol derivatives. This methodology employed a four-component reaction between
diethyl acetylenedicarboxylate (DEAD), aromatic amines and phenylglyoxal monohydrate catalyzed
by 10 mol% iodine in ethanol at room temperature. The proposed reaction mechanism involved
transformations through an imine intermediate followed by iodine-induced Mannich reaction and
subsequent intramolecular cyclization sequences. Moreover, this protocol involved the formation
of C-N, C-C and O-H bonds [26]. Trying to explore this methodology varying the starting reagents
but taking into advantage the one-pot protocol benefits, the study of the three-component reaction
of alkyl 2-aminoesters derived from L-tryptophan (
solvent-free conditions towards the synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds
1) is presented herein.
2) and 1,3-dicarbonyl compounds (3) under
(
2
. Results and Discussion
Esterification reactions of L-tryptophan were carried out employing Li and Sha methodology [27
]
with some modifications [28]. Mixtures of L-tryptophan (1 eq.), chlorotrimethylsilane (8 eq.) and
aliphatic alcohols in excess (R = Me, Et, i-Pr, n-Bu) were heated under reflux conditions during
1
4
h. Alkyl 2-aminoesteres 2a
yields. Then, neutralization with sodium bicarbonate solution and subsequent extractions using
isopropyl acetate were performed to obtain compounds 2a as the free-base form in a quantitative
–d were obtained in the hydrochloride form as white crystals in high
–d

Molecules 2020, 25, 4402
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yield. Several experiments based on 2a
–
d
and 1,3-dicarbonyl compounds 3a
–d
mixtures were carried
out to establish the optimal conditions to afford compounds 1a–d. Thus, several inorganic bases
in equimolar ratio regarding compounds 2a were initially essayed employing different solvent
–
d
conditions. Thus, experiments using sodium carbonate in polar solvents under reflux conditions
during 24 h afforded polymeric resins, whose chemical characterization attempts were unsuccessful.
Similar results were obtained employing potassium hydroxide. However, compounds 1a–d and
L-tryptophan were detected in low yields (>5%) in all cases. These results suggested that long reaction
times, high temperatures and strong basic media favor polymeric and hydrolysis reactions. In this
regard, catalytic amount of a strong base could enhance the yield of compound series 1.
Solvent-free reactions are widely known in literature for their advantages, such as the absence of
a reaction medium to collect, purify and recycle high-purity products, the reduction of additional and
extensive purification steps, higher yields, low supply of energy, reduction of protection-deprotection
steps of functional groups and especially, rapid reaching of substantial reaction completion in few
minutes as compared to organic solvent-mediated protocols, among other advantageous features [16].
According to these facts, a solvent-free synthesis under conventional heating conditions was then
employed to synthesize the desired products 1a
–d, using several essays to explore the performance of
the present synthetic protocol. Results are showed in Table 1.
Table 1. Yields for obtained product (1) afforded via Scheme 1, employing solvent-free optimized
conditions (time and temperature reaction) under conventional heating, considering different reaction
mixtures stated as each entry.
c,d
Time
RT
Entry
AAE a
R1
DC b
R2
R3
Product e
1a
Yield (%)
◦
(min)
( C)
1
2
3
4
2a
2b
2c
Me
Et
i-Pr
n-Bu
Me
Me
Me
Me
Me
Me
Me
Me
30
30
30
30
100
100
100
100
81
24
22
15
3a
2d
5
6
7
8
2a
2b
2c
Me
Et
i-Pr
n-Bu
Me
Me
Me
Me
OEt
OEt
OEt
OEt
30
30
30
30
120
120
120
120
54
27
25
19
3
b
1b
1c
2d
9
2a
2b
2c
Me
Et
i-Pr
n-Bu
OH
OH
OH
OH
OH
OH
OH
OH
30
30
30
30
170
170
170
170
45
24
17
15
1
1
1
0
1
2
3
c
2d
13
14
15
16
2a
2b
2c
Me
Et
i-Pr
n-Bu
-(CH ) -
30
30
30
30
100
100
100
100
59
27
19
17
2
3
-(CH ) -
2
3
3d
1d
-(CH ) -
2 3
2d
-(CH ) -
2 3
a
2 3
); b DC = 1,3-dicarbonyl compound ( ); c RT = reaction temperature; d RT was
AAE = alkyl 2-aminoester (
established by HPLC-MS in preliminary experiments for each reaction mixture on exploring heating at 100,
20 and 170 C during 5 min, in order to evidence product formation and reactant consumption; respective
,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds (1) (Scheme 1) as product for each reaction mixture.
◦
e
1
2
Scheme 1. Solvent-free synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol-type compounds.

Molecules 2020, 25, 4402
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Compound 1a was obtained from acetylacetone 3a, which has the highest electrophilic character in
comparison with the remaining 1,3-dicarbonyl compounds 3b , affording the highest yield (i.e., 81%)
–
d
when reacted with methyl L-tryptophanate 2a as starting reagent. Aliphatic chain extension of the
alkoxy moiety at ester group conduced to a yield reduction, especially using n-butyl L-tryptophanate
2d. These results can be explained considering a long-distance inductive effect, which tends to reduce
the nucleophilic character of the amine group, affecting the required condition to carry out the first
step within the mechanistic pathway. Moreover, these results led us to conclude that the steric
implications of the ester fragment are not relevant for the reaction completion, so the low yields were
more related to the stability of longer-chain bearing alkoxy moiety, since they degraded more easily
and faster (within 5–20 min) and do not lead to the desired cyclization. Similar results were obtained
for compounds 1b and 1d, i.e., involving low yields, but an identical alkoxy moiety-related trend was
also evidenced. Compound 1c was obtained from malonic acid 3c used as 1,3-dicarboxylic compound.
This reaction series showed yields between 15–45%. To ensure the completion of such reaction series,
basic conditions were not employed within the first 5 min and reaction mixtures were submitted to a
higher temperature. Therefore, this reaction was performed in two stages: the first one corresponds to
the formation of the intermediate amide from malonic acid 3c and alkyl 2-aminoesters during the first
5
min, and a second stage where a catalytic amount of KOH was added to promote the cyclization
reaction towards compound 1c.
According to these results, a reaction mechanism for the formation 1a
–
d
2
was proposed (Scheme 2).
to one of the carbonyl or
towards the formation of (Z)-enamine-type intermediate through a nucleophilic
addition-elimination mechanism. Presumably, this first step is the slowest in the mechanistic pathway.
Then, hydroxyl ion removes an acidic hydrogen of the intermediate increasing its electronic
density to facilitate a 5-exo-trig intramolecular cyclization, affording 2,4-dihydro-3H-pyrrol-3-ones
Such formation is assisted by the alkoxide release, which abstracts one proton from the formed water
molecule in order to restitute the catalytic hydroxyl ion. Finally, intermediate suffers a tautomeric
conversion towards , which could be favored by the intramolecular hydrogen bonding formation
between hydroxyl group at C3 and the carbonyl group of the substituent at C4 of the pyrrole ring
Figure 1).
The first step corresponds to the nucleophilic attack by the amine group in
carboxylic groups in
3
4
4
5
.
5
1
(
Figure 1. Optimized molecular structure of compound 1a using DFT-B3LYP calculations at the
-31G(d,p) level.
6
Scheme 2. A plausible mechanism for the synthesis of 2,4,5-trisubstituted-1H-pyrrol-3-ol type
compounds 1.

Molecules 2020, 25, 4402
5 of 9
Computational calculations were carried out using the DFT-B3LYP method at the 6-31G(d,p) level
of theory. Solvation model comprised the isodensity polarizable continuum model (IPCM), which uses
a static isodensity surface for the solute cavity [29]. Several authors in the literature have used the
Highest Occupied Molecular Orbital (HOMO) Lowest Occupied Molecular Orbital (LUMO) energy
gap as a computational descriptor to understand kinetic stability. In general, a large energy gap
corresponds to a high energy required for electron excitation [30] and it could be correlated with the
nucleophile and electrophile character of reactants in organic reactions. To perform a comparison
between the molecular stability of compounds
1 and 5, computational calculations of HOMO-LUMO
were performed. In addition, we presented a description of the hybridization of the HOMO and LUMO
orbitals using Natural Bond Orbital (NBO) analysis [31], understanding that a high contribution of
p orbitals within the molecular orbitals, as a linear combination of atomic orbitals (LCAO), involves
a greater planar character and, therefore, a higher tendency to aromaticity of the five-membered
heterocyclic ring can be deduced. Frontier molecular orbitals HOMO and LUMO of intermediates 5a
and compounds 1a are presented in Figure 2. HOMO of intermediate 5a showed an occupancy of
.88226, and a predominant p character (s(0.03%), p 99.99(99.78%), d 6.18(0.19%)), being only localized
–d
–d
1
in two carbon atoms of the benzenoid ring in the indole fragment. Similar results are presented
for compound 1a whose HOMO showed occupancy of 1.89607, but a higher p character (s (0.23%),
p 99.99(99.68%), d 0.40(0.09%) was observed due to the extended highly-conjugated
on the aromatic indole system. Relatedly, LUMOs for 5a and 1a showed appreciable differences: LUMO
of intermediate 1a showed high p character (p 99.99(97.56%)), being especially located in the C=O
bond, whereas LUMO of compound 5a had a lesser p character but higher conjugation at pyrrole ring
p 9.47(83.13%)). The calculated gap HOMO-LUMO for intermediate 5a was 0.19893 Hartree; however,
π system localized
π
*
(
compound 1a afforded 0.14731 Hartree. This difference evidenced a decrease in the LUMO energy once
the tautomeric conversion occurred, whose driving force could be based on the aromatic stabilization
of the five-membered heterocyclic system.
Figure 2. Frontier HOMO and LUMO representations for 2,4,5-trisubstituted-1H-pyrrol-3-ol-type
compounds 1a–d and 2,4-dihydro-3H-pyrrol-3-ones 5a–d.
In order to evaluate the incidence of ester fragment on pyrrole ring stability, HOMO and LUMO
analysis was also performed for 1b and 5b structures. Intermediate 5b showed a HOMO with occupancy
of 1.93004 and a prevailing p character (s (10.30%), p 8.70 (89.64%), d 0.01 (0.06%)). In contrast, HOMO
for compound 1b exhibited an occupancy of 1.84916 and a higher p character (s (1.13%), p 87.69 (98.81%),
d 0.06 (0.06%), whose HOMO representation showed the conjugated
towards the pyrrole ring. The LUMO of 5b showed a higher p character (p 99.99(97.40%)), and it was
located on both C=O ketone and C=O ester * bonds, whereas LUMO of 1b was similar to that of 1a
π system to be also extended
π

Molecules 2020, 25, 4402
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(p 10.52 (84.28%)). The calculated HOMO-LUMO gaps of 5b and 1b were 0.10324 and 0.16090 Hartree,
respectively. In this case, there was no LUMO stabilization for 1b due to the presence of the ester
3
group. Additionally, the incidence of the hydroxyl group as R substituent was also examined through
a HOMO-LUMO gap analysis. Such an analysis provided gap values for 5c and 1c of 0.07948 and
0.12878 Hartree, respectively. The above-mentioned differences between 5b–1b and 5c–1c could be
explained due a strong inductive and mesomeric effect generated by the presence of polar groups at
C2 and C3 of the pyrrole ring. Finally, intermediate 1d and compound 5d showed similar DFT-derived
results in comparison to the observed outcome for 1a and 5a structures.
In order to explain the reaction mechanism, some thermodynamic features were also calculated
◦
using DFT-B3LYP methodology. Calculated
∆
G for the conversion of 5→1 is presented in Table 2.
The conversion of
of exergonic processes (
5
towards
1
is thermodynamically favored in all the studied cases, being a series
◦
∆
G
< 0). The formation of compound 1b is presumably a more
calculated
spontaneous process, while formation of 1a
the discussed hypothesis regarding the formation of intramolecular hydrogen bonding in compounds
Figure 1), whose strength resulted higher when the substituent of the pyrrole ring at C4 is an aliphatic
, 1c and 1d are lesser spontaneous. These results supported
1
(
ketone. The inductive effect caused on C=O by the OR group in the alkoxy carbonyl substituent
reduces the electronic density of this hydrogen bond acceptor, leading to a decrease of the interaction
strength and, consequently, the stability of the aromatic form. In addition, the steric effect of the
cyclohexane-type ring fused to the pyrrole system presumably reduces the strength of the hydrogen
bonding interaction, affecting the reaction spontaneity.
◦
Table 2. Calculated ∆G for tautomeric conversion 5→1.
◦
Conversion
Calculated ∆G /kcal/mol
5
a→1a
−2.53
−13.50
−2.36
−2.64
5
5
b→1b
c→1c
5
d→1d
3
. Materials and Methods
3
.1. General Information
All chemicals were purchased from Sigma-Aldrich (Saint Louis, MO, USA) and Merck KGaA
Darmstadt, Germany) and used without further purification. Dry solvents were purchased in sufficient
(
purity. Thin layer chromatography (TLC) was done on TLC silica gel 60 F254 (Merck KGaA), and
compounds were detected at 254 nm. Column chromatography was conducted manually on silica gel
6
0 (0.040–0.063 mm) from Merck KGaA. Nuclear magnetic resonance (NMR) spectra were recorded
on a Bruker Avance AV-400 MHz spectrometer (Billerica, MA, USA). All shifts are given below in
(ppm) using the signal of tetramethylsilane (TMS) as a reference. All coupling constants (J) are
δ
given in Hz. Splitting patterns are typically described as follows: s: singlet, d: doublet, t: triplet,
q: quartet and m: multiplet. Liquid chromatography-mass spectrometry (LC/MS) experiments were
performed on a LCMS 2020 spectrometer (Shimadzu, Columbia, MD, USA), comprising a Prominence®
high-performance liquid chromatography (HPLC) system coupled to a quadrupole single analyzer
with an electrospray ionization (ESI). A Synergi® column (150
×
4.6 mm, 4.0 µm) was used for analysis
at 0.6 mL/min using mixtures of acetonitrile (A) and 1% formic acid (B) in gradient elution. ESI was
operated simultaneously in positive and negative ion modes (scan 100–2000 m/z), desolvation line
◦
temperature at 250 C, nitrogen as nebulizer gas at 1.5 L/min, drying gas at 8 L/min, and detector
voltage at 1.4 kV. Accurate mass data were recorded by high-resolution MS (HRMS) on a micrOTOF-Q
II mass spectrometer (Bruker, Billerica, MA, USA). ESI was also operated in positive and negative
◦
ion modes (scan 100–2000 m/z), desolvation line temperature at 250 C, nitrogen as nebulizer gas at
1
.5 L/min, drying gas at 8 L/min, quadrupole energy at 7.0 eV, and collision energy 14 eV.

Molecules 2020, 25, 4402
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3
.2. General Experimental Procedure for the Synthesis of 2,4,5-trisubs-tituted-1H-pyrrol-3-ol Type
Compounds (1a,b,d)
Alkyl 2-aminoesters
2
(1 mmol), 1,3-dicarbonyl compounds
3
(1 mmol), and potassium hydroxide
(0.1 mmol) mixtures were heated in open vessels employing an oil bath with shaking following the
reaction conditions in Table 1. TLC monitored the progress of each reaction. Upon completing the
reaction, 5 mL of saturated ammonium chloride solution was added to each resulting reaction mixture.
Discontinuous liquid-liquid extractions were performed using chloroform (5
pressure was used for concentrating the reaction mixtures. Conventional column chromatography
using silica gel as sorbent and a hexane: ethyl acetate mixtures as mobile phase was employed for
×
10 mL). Reduced
purifying the afforded products 1a–d. The structure of each compound was confirmed by analytical as
well as conventional spectral studies (Supplementary Materials).
Representative Compounds
1
1
2
-(5-((1H-indol-3-yl)methyl)-4-hydroxy-2-methyl-1H-pyrrol-3-yl)ethan-1-one (1a): Yellow oil; yield:
1
5–81%. H NMR (400 MHz, CDCl ):
δ = 9.33 (s, 1H), 7.58 (m, 1H), 7.32 (m, 1H), 7.11 (m, 1H), 7.10 (m,
3
13
H), 3.32 (s, 2H), 2.03 (s, 3H), 1,68 (s, 3H) ppm. C NMR (100 MHz, CDCl3):
δ = 195.6, 162.15, 136.33,
1
27.02, 124.21, 121.68, 121.39, 119.11, 118.14, 117.99, 111.56, 111.08, 108.91, 96.48, 69.36, 29.45, 26.55 ppm.
+
+
ESI-MS in the positive mode m/z: [M + H] , 269.16; [M + CH CN + H] , 310.19. ESI-HRMS m/z: [M +
H] , 269.1677 (calcd. 269.1690).
3
+
Ethyl 5-((1H-indol-3-yl)methyl)-4-hydroxy-2-methyl-1H-pyrrole-3-carboxylate (1b): Yellow oil; yield:
1
1
(
9–54%. H NMR (400 MHz, CDCl ):
δ
= 8.45 (s, 1H), 7.57 (m, 1H), 7.31 (m, 1H), 7.16 (m, 2H), 7.09
3
13
s, 1H), 4.10 (m, 2H), 4.08 (s, 3H), 3.31 (s, 2H), 1.68 (s, 3H), 0.88 (t, J = 6.0 Hz, 3H) ppm. C NMR (100
MHz, CDCl3): = 172.26, 160.38, 136.23, 127.12, 123.72, 122.23, 122.03, 119.66, 119.46, 118.32, 111.45,
09.76, 109.58, 109.50, 65.40, 19.31, 14.64, 13.71 ppm. ESI-MS m/z in the positive mode: [M + H] , 299.12;
δ
+
1
[
+
−
M + CH CN + H] , 339.23. ESI-HRMS m/z: [M − H] , 297.1266 (calcd. 279.1239).
3
2
-((1H-indol-3-yl)methyl)-3-hydroxy-1,5,6,7-tetrahydro-4H-indol-4-one (1d): Yellow oil; yield: 17–59%.
1
H NMR (400 MHz, CDCl ):
δ = 9.34 (s, 1H), 7.46 (m, 1H), 7.33 (m, 1H), 7.11 (m, 1H), 7.05 (m, 1H),
3
6
δ
6
.93 (s, 1H), 3.33 (s, 2H), 2.29 (m, 2H), 2.20 (m, 2H), 1.88 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3):
= 171.01, 163.68, 136.23, 127.72, 123.26, 121.91, 121.91, 119.31, 119.31, 118.23, 111.56, 108.85, 97.44,
+
0.45, 36.33, 21.69, 14.17 ppm. ESI-MS in the positive mode m/z: [M + H] , 281.16. ESI-HRMS m/z: [M +
+
H] , 279.1134 (calcd. 279.1135).
3
3
.3. General Experimental Procedure for the Synthesis of 5-((1H-indol-3-yl)methyl)-2,4-dihydroxy-1H-pyrrole-
-carboxylic Acid (1c)
Alkyl 2-aminoesters
2
(1 mmol) and malonic acid 3c (1 mmol) were heated in open vessels
◦
employing an oil bath at 170 C for 5 min. Potassium hydroxide (0.1 mmol) was added to the reaction
mixture, and the heating was kept at 170 C for 25 min. Then, 5 mL of saturated ammonium chloride
◦
solution was added to each resulting reaction mixture. Discontinuous liquid-liquid extractions were
performed using chloroform (5
mixtures. Conventional column chromatography using silica gel as sorbent and hexane: ethyl acetate
×
10 mL). Reduced pressure was used for concentrating the reaction
mixtures as mobile phase was employed for purifying the afforded product 1c: Yellow oil; yield:
1
1
(
1
[
5–45%. H NMR (400 MHz, CDCl ):
δ
= 8.24 (s, 1H), 7.52 (m, 1H), 7.35 (m, 1H), 7.13 (m, 2H), 6.97
= 172.59, 169.94, 169.94, 136.24, 136.24, 127.89,
19.86, 119.86, 118.66, 111.44, 111.44, 110.21, 110.21, 23.36 ppm. ESI-MS in the positive mode m/z:
3
s, 1H), 3.70 (s, 2H) ppm. 13C NMR (100 MHz, CDCl3):
δ
+
+
M + H] , 273.15; [M + CH CN + H] , 313.11.
3
4
. Conclusions
In conclusion, we developed a conveniently efficient and environmentally benign alternative
protocol for easy access to a series of diverse 2,4,5-trisubstituted-1H-pyrrol-3-ol type compounds

Molecules 2020, 25, 4402
8 of 9
from the one-pot three-component reaction between alkyl 2-aminoesters derived from L-tryptophan,
potassium hydroxide and 1,3-dicarbonyl compounds in solvent-free conditions. The compounds
1a–d were obtained in moderate to good yields in short reaction times, operational simplicity, and
an easy workup. DFT-B3LYP calculations demonstrated the preference of the performed protocol
towards 1H-pyrrol-3-ol aromatized rings, which are formed through the tautomeric equilibrium from
3
H-pyrrol-3-ones.
Supplementary Materials: The following are available online. Figure S1: 1H NMR spectrum of 1a in CDCl ,
3
1
3
1
Figure S2: C NMR spectrum of 1a in CDCl , Figure S3. HR-MS spectrum of compound 1a, Figure S4: H NMR
spectrum of 1b in CDCl , Figure S5: C NMR spectrum of 1b in CDCl , Figure S6. HR-MS spectrum of compound
1b, Figure S7: H NMR spectrum of 1c in CDCl , Figure S8: C NMR spectrum of 1c in CDCl , Figure S9: H
NMR spectrum of 1d in CDCl , Figure S10: C NMR spectrum of 1d in CDCl , Figure S11: HR-MS spectrum of
3
13
3
3
1
13
1
3
3
13
3
3
compound 1d.
Author Contributions: D.Q. and E.C.-B. designed research and revised the manuscript; L.D.B. performed the
synthesis and characterization of the products. D.Q. performed DTF/B3LYP calculations. All authors analyzed the
data and read and approved the final manuscript.
Funding: This research received no external funding.
Acknowledgments: The present work is a product derived from the project IMP-CIAS-2294 funded by Vicerrectoría
de Investigaciones at UMNG—Validity 2017.
Conflicts of Interest: The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
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