Naturally occurring organic acids for organocatalytic synthesis of pyrroles via Paal–Knorr reaction

Article abstract of DOI:10.1007/s11164-020-04260-2

Abstract: In this study, common naturally occurring organic acids, namely oxalic, malonic, succinic, tartaric and citric acid (as safe, inexpensive, and biodegradable organocatalysts), have been employed for Paal–Knorr pyrrole synthesis. The organocatalyzed reaction proved to be effective in ethanol at 60?°C. However, the reaction rate is mainly dominated by the nature and position of functional groups on the aromatic ring of substrate. This metal-free procedure tolerates a series of functional groups and should be considered as an asset to the pharmaceutical industry since no metal contamination could take place during the synthesis of pyrrole scaffolds. Graphic abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s11164-020-04260-2

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-020-04260-2
Naturally occurring organic acids for organocatalytic
synthesis of pyrroles via Paal–Knorr reaction
Farshid Mohsenzadeh1 · Hossein Reza Darabi1 · Mahsa Alivand1 ·
Kioumars Aghapoor1 · Yadollah Balavar1
Received: 16 June 2020 / Accepted: 26 August 2020
© Springer Nature B.V. 2020
Abstract
In this study, common naturally occurring organic acids, namely oxalic, malonic,
succinic, tartaric and citric acid (as safe, inexpensive, and biodegradable organo-
catalysts), have been employed for Paal–Knorr pyrrole synthesis. The organocata-
lyzed reaction proved to be efective in ethanol at 60 °C. However, the reaction rate
is mainly dominated by the nature and position of functional groups on the aromatic
ring of substrate. This metal-free procedure tolerates a series of functional groups
and should be considered as an asset to the pharmaceutical industry since no metal
contamination could take place during the synthesis of pyrrole scafolds.
Graphic abstract
O
NH2
N
[COOH]2·2H2O (20 mol%)
EtOH / 60 °C
+
O
R
R
Keywords Organocatalysis · Paal–knorr reaction · 2,5-dimethylpyrrole · Metal-free
protocol
*
Kioumars Aghapoor
k.aghapoor@yahoo.com; aghapoor@ccerci.ac.ir
1
Applied Chemicals Synthesis Lab., Chemistry & Chemical Engineering Research Center
of Iran, Pajoohesh Blvd., km 17, Karaj Hwy, 14968-13151 Tehran, Iran
Vol.:(0123456789)
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F. Mohsenzadeh et al.
Introduction
Since 2000, organocatalysts have made a valuable contribution to develop eco-
friendly synthetic protocols in organic reactions [1, 2]. These small organic mol-
ecules are usually robust, inexpensive, safe, stable to air and moisture and bio-
degradable without having any detrimental efect on the environment [3, 4]. Due
to these interesting characteristics, metal-free organocatalyzed reactions have
gained a great deal of interest for synthesizing bioactive compounds, since no
metal contamination (with regard to the pharmaceutically relevant product) is
expected [5, 6].
Azaheterocyclic frameworks are present in a variety of biologically active
substances (including natural products and synthetic molecules) [7]. Due to their
high structural diversity, these privileged structures have contributed actively to
the pharmaceutical research and drug synthesis [8]. Pyrrole moieties represent
an important class of azaheterocycles and are widely used as intermediates in the
synthesis of a variety of pharmacophores [9–11]. These moieties are of increas-
ing interest in pharmaceutical industry owing to their appearance in various nat-
ural products and their utility in medicinal chemistry [12–15]. Among various
straightforward methods to construct the pyrrole scafold, Paal–Knorr cyclocon-
densation of 1,4-dicarbonyls with primary amines has gained tremendous popu-
larity among synthetic chemists [16–19]. In general, this reaction is catalyzed by
Lewis acids [20] or heterogeneous solid supports endowed with acidic sites [21,
22]. However, despite a plethora of methodologies reported in the literature for
the Paal–Knorr synthesis of pyrroles, the use of organocatalysts remains scarce
[23–25].
Naturally occurring organic acids constitute a class of inexpensive organocata-
lysts containing usually two or three carboxylic functionalities. In general, ali-
phatic dicarboxylic and tricarboxylic organic acids exhibit better catalytic activity
than monocarboxylic ones presumably due to their lower pKa values. These acids
have proved to be efective for catalyzing various organic reactions, e.g., citric
acid for the synthesis of pyrrolidinones [26], pyrano[2,3-e]pyrimidin-amines
[27], quinolines, spiro[4H-pyran-oxindoles] and xanthenes [28], itaconic acid for
the synthesis of 4H-isoxazol-5-ones [29], malic acid for synthesis of quinolones
via Friedländer reaction [30] and bisindolylmethanes [31], oxalic acid for synthe-
sis of 1-(benzothiazolylamino) methyl-2-naphthols [32], 2,3-dihydroquinazolin-
4(1H)-ones [33], 1,8-dioxodecahydroacridines [34] and 3-aminoisoxazolmethyl-
naphthols [35], succinic acid for the synthesis of α-amino phosphonates [36], and
tartaric acid for the Beckmann rearrangement of ketoximes [37] and synthesis of
dihydropyrrol-2-ones [38].
Taking into account the importance of organocatalysis as a green approach for
chemical transformations [39–42] and our ongoing interest in the development
of practical methodologies for the synthesis of 2,5-dimethylpyrrole derivatives
[20, 23, 25, 43–45], we herein disclose our latest work on the Paal–Knorr pyrrole
cyclocondensation by investigating on a range of common naturally occurring
organic acids (Fig. 1) as eco-friendly catalysts.
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Naturally occurring organic acids for organocatalytic…
OH
O
O
O
OH
O
O
O
O
O
HO
HO
HO
OH
OH
OH
Succinic acid
HO
OH
HO
OH
O
OH
O
O
OH
Citric acid
Malonic acid
Oxalic acid
Tartaric acid
Fig. 1 Naturally occurring organic acids used as organocatalysts in this study
Experimental
General procedure for the preparation of 2,5‑dimethylpyrroles
In a typical reaction, primary aromatic amine (1 mmol), hexane-2,5-dione
(1.2 mmol) and a naturally occurring organic acid (0.2 mmol) were dissolved in
ethanol (2 mL) and stirred at 60 °C for an appropriate reaction time. After comple-
tion of the reaction (monitored by GC), water (2×10 mL) was added to the reac-
tion mixture in order to remove the catalyst. The obtained solution was extracted by
ethyl acetate (2×5 mL), and the organic layer was separated and dried over Na2SO4.
The separated organic phase was evaporated under reduced pressure to give the cor-
responding pyrrole. In cases where the reaction did not proceed to completeness,
crude product was purifed by recrystallization (in ethanol) or by column chroma-
tography [ethyl acetate/petroleum ether (3:7)] to give the pure product 1. All prod-
ucts 1a‒r are known compounds, and their structures were confrmed by melting
point and/or identifed by comparison of their GC and GC/MS with those of authen-
tic samples reported in our previous papers.
N-Phenyl-2,5-dimethylpyrrole (1a): m.p. 50–51 °C [20, 23, 25, 43–45]
N-(4′-Methylphenyl)-2,5-dimethylpyrrole (1b): m.p. 44–45 °C [20, 23, 25, 44,
45]
N-(3′-Methylphenyl)-2,5-dimethylpyrrole (1c): oil [20, 23, 25, 44, 45]
N-(2′-Methylphenyl)-2,5-dimethylpyrrole (1d): oil [20, 23, 25, 44, 45]
N-(2′,4′-Dimethylphenyl)-2,5-dimethylpyrrole (1e): m.p. 87–88 °C [46]
N-(2′,5′-Dimethylphenyl)-2,5-dimethylpyrrole (1f): oil [20, 23, 25, 43–45]
N-(4′-Bromophenyl)-2,5-dimethylpyrrole (1g): m.p. 75–76 °C [20, 23, 25, 43–45]
N-(4′-Chlorophenyl)-2,5-dimethylpyrrole (1h): m.p. 55–57 °C [20, 25, 43, 45]
N-(3′-Chlorophenyl)-2,5-dimethylpyrrole (1i): m.p. 51–52 °C [20, 23]
N-(3′,4′-Dichlorophenyl)-2,5-dimethylpyrrole (1j): m.p. 100–101 °C [20, 23, 25,
43–45]
N-(2′,5′-Dichlorophenyl)-2,5-dimethylpyrrole (1k): m.p. 139–140 °C [20]
N-(4′-Carboxyphenyl)-2,5-dimethylpyrrole (1l): m.p. 204–205 °C [47]
N-(4′-Acetylphenyl)-2,5-dimethylpyrrole (1m): m.p. 110–111 °C [47]
N-(3′-Acetylphenyl)-2,5-dimethylpyrrole (1n): m.p. 69–70 °C [48]
N-(4′-nitrophenyl)-2,5-dimethylpyrrole (1o): m.p. 146–147 °C [20, 23, 25,
43–45]
N-(3′-nitrophenyl)-2,5-dimethylpyrrole (1p): m.p. 84–85 °C [20, 23, 25, 43–45]
N-(2′-Cyanophenyl)-2,5-dimethylpyrrole (1r): m.p. 85–86 °C [20]
N-Benzyl-2,5-dimethylpyrrole (1s): m.p. 44–45 °C [20, 43, 44]
1 3

F. Mohsenzadeh et al.
N-Hexyl-2,5-dimethylpyrrole (1t): oil [20]
Results and discussion
Among various naturally occurring organic acids used in this study, oxalic acid
remains the strongest organic acid having the lowest pKa value (pKa =1.27) mainly
because its C2 structure contains two carboxylic groups joined directly together.
Consequently, initial screening reactions between hexane-2,5-dione (1.2 mmol) and
4-bromoaniline were made in the presence of oxalic acid as the most acidic organo-
catalyst (Table 1). The frst organocatalyzed model reaction was carried out using
microwave heating under solvent-free conditions. While the uncatalyzed reaction
aforded poor yield of 1g (Table 1, entry 1), the same reaction in the presence of
Table 1 Optimization of the reaction conditions for the synthesis of 1g
Entry
Catalyst
Solvent
Conditions
Time
Conversion (%)a
1
2
3
4
5
6
7
8
–
–
–
–
–
–
–
MWIb
MWI
MWI
MWI
MWI
25 °C
25 °C
25 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
60 °C
15 min
15 min
15 min
15 min
10 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
30 min
15 min
15 min
15 min
28
44
50
100
72
40
63
79
84
79
38
100
10
100
95
93
95
Oxalic acid dihydrate (1 mmol)
Oxalic acid dihydrate (0.5 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
–
Hexane
Ethanol
–
9
10
11
12
13
14
15
16
17
Hexane
Water
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.2 mmol)
Oxalic acid dihydrate (0.1 mmol)
Oxalic acid dihydrate (0.5 mmol)
aGas Chromatography assay (%).
bMicrowave irradiation (420 W).
1 3

Naturally occurring organic acids for organocatalytic…
oxalic acid improved the reaction yield (Table 1, entries 2–5). Various amounts
of catalyst were investigated to reveal that 20 mol% of catalyst was the optimum
amount for the quantitative conversion of 1g (Table 1, entry 4).
In the next step of our investigation, the same reaction was carried out under
classical conditions. The optimized catalyst molar ratio (20 mol%) under hexane,
water, ethanol and solvent-free conditions was investigated within 1h. Upon solvent
screening at room temperature, ethanol was found to be the most suitable solvent
for the reaction (79%) (Table 1, entry 8). In order to simulate the results obtained
by microwave heating, the same catalyzed reaction was performed at 60 °C within
1h (Table 1, entries 9–12). Ethanol proved to be the best medium over water, hex-
ane and neat conditions with its quantitative conversion and green nature. In order
to evaluate the need of the catalyst, the uncatalyzed reaction was also performed in
ethanol at 60 °C within 1h. Poor yield of 1g was obtained (10%) to show the neces-
sity of catalyst for the reaction (Table 1, entries 13). Time decrease of the catalyzed
reaction from 60 min to 30 min gave also the same quantitative conversion (Table 1,
entries 12, 14). Besides, reducing the reaction time to 15 min did not lead to quan-
titative conversion even with an increase in the amount of catalyst (Table 1, entries
15–17).
In order to determine the efect of organocatalyst type on the reaction rate, a
range of naturally occurring organic acids (Fig. 1) was also investigated in ethanol at
60 °C within 15, 30 and 60 min (Table 2). While oxalic, malonic, tartaric and citric
acid gave excellent yield of 1g within 30 min (Table 2, entries 2, 3, 5, 6), succinic
acid needed twice that time (60 min) to catalyze the reaction and to produce the
product in excellent yield (Table 2, entry 4).
These fndings show a direct relationship between pKa1 and activity of catalysts
to suggest the strength of acids play the main role in the reaction. As the solubility
Table 2 Screening various naturally occurring organic acids on the synthesis of 1g
Entry
Organocatalyst
pKa1
Conversion (%)
15 min
30 min
60 min
1
2
3
4
5
6
–
10
Oxalic acid dihydrate
Malonic acid
Succinic acid
L-(+)-Tartaric acid
Citric acid monohydrate
1.27
2.86
4.16
3.00
3.13
95
94
63
92
91
100
98
78
98
96
100
100
93
100
100
1 3

F. Mohsenzadeh et al.
of the organocatalysts in ethanol is higher, their activity is improved when compared
with other solvents.
After obtaining the best reaction conditions, a range of primary aryl amines bear-
ing electron-donating and electron-withdrawing substituents with diferent posi-
tions on the aromatic ring was investigated to confrm the generality of the present
method (Table 3). Primary aromatic amine derivatives bearing electron-donating
methyl groups and aniline itself were readily converted to their corresponding pyr-
roles quantitatively (1a−1f). Excellent yields of products 1g−1j were also obtained
with regard to haloaniline derivatives with an exception for 1k (71%) demanding
Table 3 Organocatalyzed synthesis of N-substituted pyrrole derivativesa
1b, 100% (95%)
1a, 100% (96%)
1e, 100% (92%)
1i, 100% (96%)
1c, 100% (95%), oil
1g, 100% (98%)
1d, 100% (95%), oil
1h, 97% (92%)
1f, 100% (93%), oil
1j, 100% (95%)
1l, 100% (90%)
1k, 39% / 84% (71%) b
1m, 71% / 100% (91%) c
1o, 24% / 60% (46%) b
1p, 94% / 100% (94%) d
1t, 100% (90%)
1n, 100% (93%)
1s, 98% (90%)
1q, 4% / 5% b
1r, 33% / 40% (22%) b
aReaction conditions: primary amine (1.0 mmol), hexane-2,5-dione (1.2 mmol), oxalic acid dihydrate
(0.2 mmol), ethanol (2 mL), 60 °C, 30 min; product 1, GC yield (isolated yield)
bThe reaction was carried out for 150 min
cThe reaction was carried out for 90 min
dThe reaction was carried out for 60 min
1 3

Naturally occurring organic acids for organocatalytic…
extended reaction time (150 min) which may be explained mainly by the steric hin-
drance of Cl in ortho position. Interestingly, anilines with electron-withdrawing
functionalities such as carboxylic and acetyl underwent Paal–Knorr cyclocondensa-
tion in excellent yield (1l−1n). Aliphatic amines such as benzylamine and n-hexy-
lamine were also readily converted to their corresponding 2,5-dimethylpyrrole giv-
ing excellent yields of 1s and 1t. However, the trend of the reaction was best shown
with nitro as an electron-withdrawing functional group on aniline where longer reac-
tion time is required. While quantitative conversion was obtained for NO2 in meta
position within 60 min (1p), the para position gave a modest yield of 1o (46%) and
2-nitroaniline as substrate gave trace amount of 1q (even after 150 min) because of
its electron-withdrawing nature as well as steric hindrance in ortho position. Simi-
larly, the same phenomenon was observed in aniline bearing cyano group in ortho
position, which resulted in poor yield of 1r (22%). In general, a decreased product
yield was noticed when a bulky group such as chloro, nitro and cyano was intro-
duced into the ortho position of the substrate, (i.e., 1k, 1q, 1r). Thus, it may be
assumed that the organocatalyzed reaction is governed by electronic (1m, 1o) as
well as steric efects (1k, 1q, 1r) leading to a further decrease in the reaction rate.
Conclusions
In summary, a sustainable methodology has been developed by employing natu-
rally occurring organic acids (oxalic, malonic, succinic, tartaric and citric acid) as
green catalysts for Paal–Knorr pyrrole synthesis in ethanol. It was found the organo-
catalyzed reaction of 4-bromoaniline and hexane-2,5-dione proceeded excellently,
afording the quantitative conversion of product 1g. Nevertheless, the reaction rate
was directly proportional to the acidic strength of the organocatalyst. Therefore,
the reaction scope was extended to other aliphatic and aromatic primary amines by
choosing oxalic acid as catalyst. The efect of various functional groups at diferent
positions on the aromatic ring of substrate was examined. It was observed that steric
and electronic efects are two factors dominating the reaction rate.
The eco-friendly aspects of this work consist in the use of a non-toxic, inexpen-
sive and biodegradable catalyst in a green medium providing a clean reaction pro-
fle with simple purifcation. This metal-free method provides an alternative access
to pharmaceutically relevant pyrrole scafolds and may be considered as a valuable
asset to fne chemical industry.
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