Solvent Free Synthesis of N-Substituted Pyrroles Catalyzed by Calcium Nitrate

Article abstract of DOI:10.1002/jhet.3507

Moderated and mild way for synthesizing N-substituted pyrrole has been demonstrated herein. No solvents need to be used for this reaction, and instead, reactants themselves acted as a reaction medium. In fact, the reaction is carried out using catalytic amount of Ca(NO₃)₂.4H₂O. The reaction conditions are selective and mild that helped to tolerate a wide variety of functional groups to give the desired products in good chemical yields.

Full text of DOI:10.1002/jhet.3507

Month 2019
Solvent Free Synthesis of N-Substituted Pyrroles Catalyzed by Calcium
Nitrate
a
a
Rucha R. Wani, Hemchandra K. Chaudhari
and Balaram S. Takaleb
*
aDepartment of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga (E), Mumbai,
Maharashtra 400 019, India
bDepartment of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA
*E-mail: hk.chaudhari@ictmumbai.edu.in
Received September 12, 2018
DOI 10.1002/jhet.3507
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Moderated and mild way for synthesizing N-substituted pyrrole has been demonstrated herein. No sol-
vents need to be used for this reaction, and instead, reactants themselves acted as a reaction medium. In fact,
the reaction is carried out using catalytic amount of Ca(NO3)2.4H2O. The reaction conditions are selective
and mild that helped to tolerate a wide variety of functional groups to give the desired products in good
chemical yields.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
chemistry [6]. Calcium nitrate being a salt of strong acid
and weak base possesses acidic property (pH = 6). We
proposed that mild Lewis acidity of calcium nitrate could
be useful for Clauson–Kaas reaction [7]. In the event, we
tried heating 2,5-dimethoxytetrahydrofuran (DMTHF) with
aniline and catalytic amount of Ca(NO3)2•4H2O in water.
N-Substituted pyrroles are emerging class of
heterocycles in bioactive molecules. Perhaps, their
presence is strongly anticipated in well-known drugs—
atorvastatin, isamoltane, aloracetam Figure 1 [1], etc.
Apart from those, the ongoing medicinal chemistry
research has highlighted several potential hits possessing
N-substituted pyrrole. The most traditional and widely
used way to prepare pyrrole from synthetic chemists is
the Paal–Knorr synthesis [2,3]. Hence, it is not surprising
to see extensive research happening on this reaction [4].
Generally, the Paal–Knorr synthesis of pyrrole can be
achieved in two different ways where the nature of the
product is completely depend on the electrophiles used.
For example, one method could lead to di-, tri-, tetra-
carbon substituted products, and other could led to only
N-substituted product, leaving wide scope for late stage
derivatization. However, this method where only N-
substituted pyrroles could be obtained is not studied
widely due to necessity of special reaction conditions
such as transition metals, ultrasounds, and microwave.
Removing trace transition metals from biologically active
products including heterocycles is a great challenge.
Scientists are concerned to use transition metals due to
their human toxicity at parts per million (ppm) level and
strict recent pharma regulations [5].
RESULTS AND DISCUSSION
It is noteworthy to mention that this preliminary research
work resulted in the formation of the desired product
although in low yield (Table 1, entry 1).
Further, an optimization study was carried out to find out
the best reaction condition (Table 1). Different polar
solvents were screened, and DMF was found to be the
best of all (entry 4). Surprisingly, without solvent, the
reaction was even faster and led to comparatively good
yield of the desired product (70%) (entry 7). It should be
mentioned that the reaction yield was decreased when
catalyst loading was decreased to 20 mol% (entry 7, yield
in parentheses). Other metal catalyzed reported reaction
is cited in the table showing good chemical yield;
however, the reaction conditions were not satisfactory
to be used in large scale due to the use of ultrasound
(entry 8) [8]. Another reaction using bismuth as a
catalyst was also reported for the synthesis of N-
substituted pyrrole. However, the reaction scope was
not extended by using DMTHF, but instead, 2,5-
Hence, the use of alternative metals such as alkaline earth
metals in chemical reactions could be promising due to their
low toxicity. We are continuously exploring the ability of
Ca(NO3)2•4H2O as a catalyst and/reagent in heterocyclic
diketone
(Scheme
1;
upper
equation
where
R2 = R3 = H, R1 = R4 = CH3, and R5 = Ph) was used
© 2019 Wiley Periodicals, Inc.

R. R. Wani, H. K. Chaudhari, and B. S. Takale
Vol 000
Table 2
Substrate scope for N-substituted pyrroles catalyzed by calcium nitrate.
Figure 1. Few important drugs containing N-substituted pyrrole motifs.
[Color figure can be viewed at wileyonlinelibrary.com]
Table 1
2a; 70%
2b; 65%
2c; 72%
2d; 75%
2e; 62%
Optimization of reaction conditiona.
Entry
Catalysts
Solvent
t (h) Yieldb (%)
1
2
3
4
5
6
7
8
9
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
Ca(NO3)2·4H2O
UO2(NO3)2.6H2O
Bi(NO3)2.5H2O
Water
Acetonitrile
DMSO
DMF
Ethanol
12
6
8
40
50
20
55
40
2h; 72%
2i; 70%
2j; 73%
2f; 55%
2g; 71%
2l; 69%
8
12
12
4.5
0.5
10
Water
40
Solvent free
Methanol
CH2Cl2
70 (30)c
90[8]
96[9]
2m; 74%
2n; 76%
aReaction conditions: Aniline (2.0 mmol), 2,5-dimethoxytetrahydrofuran
(3.0 mmol), refluxed.
2k; 68%
2p; 70%
2o; 85%
bIsolated yield.
cReaction was carried out using 20 mol% catalyst for 6 h.
Scheme 1. Paal–Knorr and Clauson–Kaas synthesis of pyrroles using two
approaches.
amines showed no difference in normal reactivity (entries
2g–2l). Aliphatic amines were found give better chemical
yields compared with aryl amines (entries 2n and 2o).
Heterocyclic amine such as 1p gave good yield of the
desired product 2p.
One of the importance of this type of reaction is that the
late stage functionalization of the product could be carried
out. Scheme 2 represents few important fundamental
reactions that could be carried out on pyrrole ring of N-
phenylpyrrole. Bromination using N-bromosuccinimide
[11], chlorination using N-chlorosuccinimide [12], nitration
using nitric acid [13], and formylation using Vilsemier–
Hack reaction [14] could be performed.
To investigate the possible reaction pathway, we carried
out several control experiments as summarized in Figure 2.
Initially, only DMTHF in the absence and presence of
calcium nitrate was refluxed, and the nuclear magnetic
resonance (NMR) of crude reaction mixture of both
conditions was recorded. As shown in the figure, only in
the presence of calcium nitrate, succinaldehyde was formed
(Fig. 2, reaction 2), while in the absence of catalyst, no
succinaldehyde was formed (Fig. 2, reaction 1). To check
the role of catalyst in the next step, a separate reaction on
that resulted in the formation of 2,5-disubstituted product
(entry 9) [9]. Also, dichloromethane, which is used as a
solvent, is a known carcinogen.
Optimized conditions in hand, a variety of aliphatic,
aromatic, heteroaromatic amines were used as
a
nucleophiles, and results are summarized in Table 2 [10].
Electron donating groups on amines helped to give good
yields compared with strong electron withdrawing groups
(entries 2a–2d vs 2e and 2f). Sterically, bulky amines
were also found to give satisfactory yield of the desired
product (entries 2d, 2e, 2h, 2i). Halo-substituted aryl
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Solvent Free Synthesis of N-Substituted Pyrroles Catalyzed by Calcium Nitrate
Scheme 2. Literature procedures to derivatize N-substituted pyrroles.
[Color figure can be viewed at wileyonlinelibrary.com]
Scheme 3. Plausible reaction pathway for the synthesis of N-substituted
pyrroles.
this path, calcium nitrate could transform to calcium
oxide or even hydroxide. The actual catalytic active
species is difficult to predict here and requires additional
studies. However, when either CaO or Ca(OH)2 was used
as a catalyst instead of Ca(NO3)2, no reaction was
occurred, hence the possibility of these two species in
reaction mechanism could be eliminated.
CONCLUSION
In summary, we have shown that alkaline earth metal-
based catalyst could be used for the synthesis of pyrroles
in good chemical yields. Reactions were carried out
without organic solvents which is an additional advantage
for minimizing organic waste. With the help of nuclear
magnetic resonance studies, it was clear that Ca(NO3)2 is
necessary for both the steps and hence for the reaction to
occur. With this important info in hand, this inexpensive
catalyst could open path for interesting chemical
reactions in future.
Figure 2. The importance of the catalyst in both reaction steps has been
confirmed in this nuclear magnetic resonance study. [Color figure can be
viewed at wileyonlinelibrary.com]
succinaldehyde with aniline in the absence and presence of
the catalyst was performed. It was interesting to know that
only the trace amount of product was formed in the
absence of catalyst (Fig. 2, reaction 3). On the other hand,
reaction in the presence of catalyst resulted in excellent
conversion to N-phenylpyrrole (Fig. 2, reaction 4).
Based on these facts, a possible reaction pathway is
proposed in Scheme 3. Calcium nitrates activate
degradation of DMTHF a to succinaldehyde b, which
then undergoes nucleophilic addition to give
corresponding imine c. Intramolecular nucleophilic attack
by enamine d onto carbonyl (which is in small
equilibrium with imine c) resulted in the formation of
cyclic hemiaminal intermediate e. Further, dehydration
and aromatization resulted in the formation of product 2
along with the regeneration of catalyst. While following
Acknowledgments. R. R. W. and H. K. C. are grateful to
University Grants Commission UGC-SAP for financial support.
REFERENCES AND NOTES
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DOI 10.1002/jhet

R. R. Wani, H. K. Chaudhari, and B. S. Takale
Vol 000
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All products are known compounds and were identified by their melting
point, 1H NMR spectra according to the literature. For example, 2a; White
solid, Mp 59–60°C, 1H NMR (400 MHz, CDCl3) δ 7.50–7.38 (m, 4H),
7.28–7.25 (m, 1H), 7.13–7.10 (m, 2H), 6.47–6.29 (m, 2H); 13C NMR
(75MHz, CDCl3): δ = 140.74, 129.51, 125.59, 120.51, 119.29, 110.35;
C10H9N; MS m/z143 (M+) 2e; Yellow Solid, Mp 43–46°C, 1H NMR,
(400 MHz, CDCl3) δ 8.14 (d, J = 36.8 Hz, 1H), 7.30 (d, J = 47.5 Hz,
2H), 6.83 (d, J = 1.9 Hz, 2H), 6.37 (d, J = 1.9 Hz, 2H), 2.38 (s, 3H);
13C NMR (75 MHz, CDCl3): δ = 146.12, 145.70, 134.46, 126.79,
126.58, 122.07, 121.72, 110.24, 77.34, 76.71, 18.63; C11H1N2O2, MS
m/z 202(M+).
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[10] For Experimental procedure and characterization data of se-
lected compounds, follow; General procedure for the synthesis of N-
Substituted Pyrroles: To the reaction mixture of primary amines (2 mmol)
and 2, 5-dimethoxy tetrahydrofuran (1.5 equiv.) was added calcium nitrate
(40 mol%). The reaction was stirred at reflux (100 oC). The progress of the
reaction was monitored by TLC. After completion of reaction 10 mL ethyl
acetate added. The reaction mixture is filtered, and filtrate was evaporated
using rota evaporator under vacuum to get crude product. Crude product is
purified by column chromatography using silica as stationary phase and
hexane: ethyl acetate (10:0 to 8:2) as mobile phase to afford pure product.
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet