An Efficient, Scalable and Eco-friendly Synthesis of 4,5-substituted Pyrrole-3-Carbonitriles by Intramolecular Annulation on Pd/C and HZSM-5

Article abstract of DOI:10.1002/cctc.201900154

An efficient and eco-friendly protocol for the synthesis of diverse 4,5-substituted 1H-pyrrole-3-carbonitriles has been developed using commercially available HZSM-5 and Pd/C as recyclable heterogeneous catalysts with more excellent yields (up to 98 %) than traditional liquids acids, and successfully applied in the practical synthesis of vonoprazan. The conspicuous features of this protocol are higher product yield, easy work-up, eco-friendly and reusability of catalysts.

Full text of DOI:10.1002/cctc.201900154

Accepted Article
Title: An efficient, scalable and eco-friendly synthesis of 4,5-substituted
pyrrole-3-carbonitriles by intramolecular annulation on Pd/C and
HZSM-5
Authors: Jianchao Chen, Chengtao Li, Yanan Zhou, Changshan Sun,
and Tiemin Sun
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemCatChem 10.1002/cctc.201900154
Link to VoR: http://dx.doi.org/10.1002/cctc.201900154
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10.1002/cctc.201900154
ChemCatChem
FULL PAPER
An efficient, scalable and eco-friendly synthesis of 4,5-
substituted pyrrole-3-carbonitriles by intramolecular annulation
on Pd/C and HZSM-5
Jianchao Chen, [a] Chengtao Li, [a] Yanan Zhou, [a] Prof. Dr. Changshan Sun*[b] and Prof. Dr. Tiemin
Sun*[a]
Dedication ((optional))
Abstract: An efficient and eco-friendly protocol for the synthesis of
diverse 4,5-substituted 1H-pyrrole-3-carbonitriles has been
developed using commercially available HZSM-5 and Pd/C as
recyclable heterogeneous catalysts with more excellent yields (up to
98%) than traditional liquids acids, and successfully applied in the
practical synthesis of vonoprazan. The conspicuous features of this
protocol are higher product yield, easy work-up, eco-friendly and
reusability of catalysts.
ethyl)malononitriles was disclosed in EP3318551A1, in which the
cyclization performed continuously in the presence of H2 and
acetic acid in a fixed bed reactor filled with Pd/Al2O3 to furnish the
target compounds with yield up to 91%. Unfortunately, all current
methods suffer from one or more major drawbacks such as
inadequate yields, tedious operation, use of toxic and/or corrosive
liquid acid and neutralization of the acid after reaction. Therefore,
it is still highly desired to develop a more efficient and ecofriendly
protocol for the synthesis of diversified 1H-pyrrole-3-carbonitriles
that avoids these drawbacks and could be used both on a
laboratory and industrial scale.
Introduction
Owing to their unique physical and chemical properties, pyrroles
are widely known as biologically active scaffolds in natural
products and pharmaceuticals and show a wide range of
biological properties, [1] such as antimicrobial, [2] anti-tubercular, [3]
anti-malarial, [4] anticancer, [5] anti-inflammatory, [6] antipsychotic,
[7]
hepatoprotective and antihypertension activity, and so on.
Substituted 1H-pyrrole-3-carbonitriles, an important class of
pyrrole derivatives, are basic skeleton and key intermediates of
multiple drugs, such as potassium-competitive acid blocker
vonoprazan, non-systemic fungicide fludioxonil and chlorfenapyr.
[8]
Generally, pyrroles could be formed via following ways: (1)
Hantzsch pyrrole synthesis; (2) Paal-Knorr pyrrole synthesis; (3)
[9]
Barton-Zard reaction; along with other strategies.
Much
improvement has been achieved to promote the synthesis of 1H-
[10]
pyrrole-3-carbonitriles 2 (Scheme 1).
Santo and co-workers
first reported the preparation of 2 using tosylmethylisocyanides
and acrylonitriles as starting materials with 24~60% yields.
Scheme 1. Approaches to the synthesis of 1H-pyrrole-3-carbonitriles
Ikemoto
disclosed
the
cyclization
of
2-(2-oxo-2-
ethyl)malononitriles 1 with HCl or thionocarboxylic acids or
mercaptan, then upon reduction to furnish compounds 2 with
yields 49%~87%, while the usage of liquid acids led to device
corrosion and lots of industrial wastes. Subsequently, to improve
In recent decades, solid acids have gained many organic
chemists’ attention because of their easy availability, mild and
environment friendly nature with high selectivity. [11] Replacement
of liquid acids with reusable heterogeneous solid acids like
zeolites, clays, silicas and resinsis becoming a popular field in the
past decades. [12] Nowadays, the combination of Pd/C and solid
acids such as montmorillonite K-10, zeolites, Amberlyst-15 has
showed their wide applications in organic synthesis. [13] In view of
the above requirement and existing literature reports, we herein
report an ecofriendly and efficient protocol for the synthesis of 1H-
pyrrole-3-carbonitriles using HZSM-5 and Pd/C as heterogeneous
recyclable catalysts with excellent yields and successfully applied
it in the practical synthesis of vonoprazan with simplified operation
and reduced pollution.
these
problems
one-step
cyclization
of
2-(2-oxo-2-
[a]
Key Laboratory of Structure-based Drug Design and Discovery,
Shenyang Pharmaceutical University, Ministry of Education
Shenyang 110016, PR China
E-mail: suntiemin@126.com
[b]
Pharmacy Department, Shenyang Pharmaceutical University,
Shenyang 110016, PR China
E-mail: freescs@163.com
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cctc.201900154
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FULL PAPER
HZSM-5(360[c]
)
60
24
75%
Results and Discussion
18
[a] Reaction conditions: 1a (1.0 g), 10%Pd/C (0.10 g), solid acids (0.6 g),
60 °C, 10 mL THF under 1 atm H2 atmosphere. [b] Isolated yield. [c] the ratio
of SiO2:Al2O3
In the initial investigation, the reaction of 2-(2-(2-fluorophenyl)-2-
oxoethyl)malononitrile (1a) was chosen as the model system to
optimize different reaction parameters. To explore the scope of
homogeneous catalysts and seek for the most appropriate solid
acid, the reaction was carried out in the presence of various
commercially available solid acids under hydrogen atmosphere in
THF at 60 °C (Table 1, entries 1~18), and the obtained results
were present in Table 1. Interestingly, a trace amount of product
2a was obtained in the absence of solid acids, thus confirming the
role of the solid acid in the reaction (Table 1, entry 1). Solid acids
with low acidity such as silico gel and TS-1 (Hammett H0 = +3.3 ~
+4.8) couldn’t provide enough catalytic activity for the conversion
of the product (Table 1, entries 7 and 8). Changing the solid acid
to HZSM-5 (SiO2/Al2O3 = 70) displayed the superior catalytic
Subsequently, further investigation of the solvent effect on the
reaction yield was carried out (Table 2, entries 1~8). With polar
aprotic solvents such as 1,4-dioxane and dimethylformamide
(DMF), the desired product was isolated with good yields 84% and
75% respectively (Table 2, entries 2~3). Obviously, 1,4-dioxane
stands out as the solvent of choice for further reactions with its
high product yield. To explore the role of reaction temperature,
the reaction was carried out in dioxane at various temperatures
and it was obvious that the reaction yield and time were
significantly improved when the reaction temperature raised from
room temperature to 80°C with the yield increased to 91% and the
time shortened to 18 h (Table 2, entries 9~12). The effect of
HZSM-5 amounts on the formation of desire product 2a was
explored by varying the amount from 0.20 to 1.20 g (Table 2,
entries 15~19). As the amount of the catalyst increased from 0.20
to 0.8 g, the formation of desired product increased from 61% to
95%, and no improvement in the yield was observed when the
amount of HZSM-5 increased from 0.8 g to 1.2 g. Apparently, 0.8
g of HZSM-5 displayed the best catalytic effect (Table 2, entry 17).
After extensive screening, we have observed that 2-(2-(2-
fluorophenyl)-2-oxoethyl)malononitrile (1.0 g), HZSM-5(120) (0.8
g) and Pd/C (0.1 g) at 80°C in dioxane under H2 atmosphere is
the optimum condition to get the maximum yield of the desired
product.
activity (Table 1, entry 15). Considering the key role of SiO2-Al2O3
[14]
ratio in catalytic activity of HZSM-5 zeolite,
we then
investigated the effect of different SiO2-Al2O3 ratios (Table 1,
entries 14~18). The results showed that HZSM-5 with a SiO2-
Al2O3 ratio of 120 displayed the best catalytic activity with 80%
yield (Table 1, entry 16). Based on these data, HZSM-5(120) was
selected as the best catalyst for the reaction for further
optimization.
Table 1. Screening of solid acids[a] in the synthesis of 5-(2-fluorophenyl)-1H-
pyrrole-3-carbonitrile
Yield/%[b]
7%
Entry
Solid acid
No solid acid
Nafion-H
Temp./°C
60
Time/h
24
Table 2. Optimization of reaction parameters[a]
1
2
Yield/%[b]
73%
Entry
HZSM-5/wt%
Temp/°C
solvent
Time/h
24
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
12
12
12
12
24
24
24
24
24
24
24
24
24
24
24
24
58%
67%
65%
62%
54%
23%
27%
61%
55%
70%
69%
72%
61%
73%
80%
77%
Acetonitrile
60
60
60
60
60
60
60
60
60
60
60
60
60
60
20
60
60
1
2
3
Amberlyst-15
HND-8
1,4-Dioxane
DMF
24
24
24
24
24
24
24
48
48
24
18
16
12
24
84%
75%
72%
65%
69%
74%
71%
60%
77%
87%
91%
90%
92%
61%
4
60
3
5
HND-520
Ethylacetate
Toluene
60
4
6
Mont. K-10
silico gel
60
5
7
n-Hexane
EtOH
60
6
TS-1
8
60
7
H-Mordenite
HZSM-35 (30[c]
HMCM-41
9
MeOH
60
8
)
10
11
12
13
14
15
16
17
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
r.t.
40
9
10
11
12
13
14
15
H-β (40[c]
)
70
HY
80
HZSM-5(27[c]
HZSM-5(70[c]
)
)
90
reflux
80
HZSM-5(120[c]
HZSM-5(300[c]
)
)
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1,4-Dioxane
16
40
80
80
80
80
80
24
12
12
12
83%
95%
93%
94%
1,4-Dioxane
17
1,4-Dioxane
18
100
120
1,4-Dioxane
19
[a] Reaction conditions: 1a (1.0 g), 10% Pd/C (0.10 g), solvent (10 mL), H2
(1 atm). [b] isolated yield.
HZSM-5 possesses both Brꢀnsted and Lewis acid sites, and its
structural hydroxyl groups connecting a Si and an Al atom
possess strong Bronsted acidic properties, while the three-
coordinated skeleton aluminum furnishes Lewis acidic properties.
[14f, 15]
Thus, it is very important to characterize the acidity of
HZSM-5 qualitatively and quantitatively. NH3-TPD spectrum is
usually ultlised to furnish the information on the amount and
strength distribution of surface acid sites. The NH3-TPD curves of
different Si/Al ratios of HZSM-5 obtained with the heating rate of
10 °C·min-1 are reported in Figure 1. As shown in Fig. 1a, HZSM-
5 (27) exhibits two desorption signals at ca. 180 °C and 260 °C
corresponded to acid sites with weak and medium strength
respectively, and the third desorption signal at 490 °C ascribed to
strong acid site. As the Si/Al ratio increased, the acidity of HZSM-
5 gradually decreased, which was in agreement with literatures.
[14]
Considering HZSM-5 (360) still showed moderate catalytic
activity with only weak acidity site (at ca. 170 °C), we think that
the superior catalysis activity of HZSM-5 is mainly due to
synergistic effects of the Brꢀnsted and Lewis acid sites rather than
the acidic strength. [16] Thus the identification of acid sites types of
HZSM-5 was achieved by pyridine absorbed Fourier transform
infrared. As presented in Figure 1b and 1c, the HZSM-5 samples
that were purged at 150 °C and 350 °C display Lewis, hydrogen-
bonded and Brꢀnsted sites, and the IR adsorption bonds are
usually observed in the region of 1400−1600 cm−1. [17] In HZSM-5,
the weak acidity consists of Lewis and hydrogen-bonded sites,
while the strong acidity mainly contains the Brꢀnsted acid sites.
The band at about 1454 cm−1 originates from the C−C stretch of
pyridine coordinated with Lewis acidic sites. The band at 1490
cm−1 reflects a combination of Brꢀnsted and Lewis acid sites. The
band at 1546 cm−1 originating from C−C stretching vibrational
frequencies of pyridinium ions displays the Brꢀnsted acidic sites.
The related results of acid sites characterization are summarized
in Table S1 and S2.
Figure 1. NH3-TPD and Pyridine-FTIR spectra of HZSM-5: a) the NH3-TPD
profiles of different Si/Al ratios of HZSM-5; b) the Pyridine-FTIR profiles of
different Si/Al ratios of HZSM-5 at 150°C; c) the Pyridine-FTIR profiles of
different Si/Al ratios of HZSM-5 at 350°C
Encouraged by the remarkable results obtained from above
experiments, substrates bearing different substituted benzene
rings were evaluated under the standard conditions (Scheme 2).
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Figure 2. ORTEP diagram of compound 2r as determined by X-ray analysis
The results showed that 2-(2-oxo-2-phenylethyl)malononitriles
bearing different groups (-F, -Cl, -OCH3, -CH3) were well tolerated
for this transformation and the corresponding products 2a-2l were
obtained in more excellent yields (85-97%) compared with the
yields reported in literatures. The structure of 2r was further
confirmed by X-ray single crystal diffraction (Fig. 2). Overall,
substrates with electron-withdrawing substituents performed
better than those bearing electron-donating groups because the
electron-withdrawing effect enhanced the positive charge of the
carbonyl carbon atom which made the attack of the nitrogen atom
on the carbonyl carbon easier (Scheme 2). To our delight, this
protocol could also be applied to substrates with naphthalene,
adamantane groups or heterocyclic group such as furan in high
yields (Scheme 2, 2m~2p). On the basis we further extended the
generality and scope of this new protocol, and some 4,5-
disubstituted 1H-pyrrole-3-carbonitriles (2q~2t) were obtained
although in a little bit lower yields (respectively 85%, 88%, 83%,
84% yields) compared with 5-monosubstituted 1H-pyrrole-3-
carbonitriles.
The recovery and reusability of heterogeneous catalysts are
important features that highly determine their potential industrial
applications and environmental considerations. The recyclability
study was carried out on 5.0 g scale and examined under
standard reaction conditions. After the reaction completed, the
catalysts were easily separated from the reaction mixture by
simple filtration and the collected catalysts were reflux in EtOH to
remove unwanted traces of adhered compounds, then dried
under vacuum at 50°C for 12 h before used for further cycles. The
reused catalysts showed persistent activity and the reaction yield
was up to 92.25% even when the catalysts were reused after four
runs (Fig. 3 and 4). The reused catalysts showed the similar
diffraction patterns with the fresh ones and remained stable in
structure with only a certain loss in intensity of crystallinity which
would result in an increase in reaction time and a decrease in yield.
In the XRD patterns of catalysts, 7.72 and 8.6° characteristic
angles at low 2θ reflections were observed with a small shift from
the reference peaks (i.e., 2θ = 7.9, 8.8, 23.0, 23.2, 23.6, 23.9, 24.4,
and 30.0°) for HZSM-5.[18] The decrease in product yields during
catalysts recycling studies is due to gradual loss and
contamination of the surface acidity of HZSM-5 and deactivation
of palladium carbon. Compound 2a with a high purity is necessary
to control the quality of subsequent reaction intermediates in good
manufacturing practices (GMP) for vonoprazan. Though it is
foreseeable that the catalysts could be reused more times, we
make some compromises on the recycling number because the
cost of purification of 2a is larger than the gain of catalysts when
recycling than 4 times.
97.27%
95.36%
93.06%
92.25%
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Scheme 2. Scope of the intramolecular annulation on Pd/C and HZSM-5. [a]
yields reported in literatures. [a] yields reported in reference 10b
run 1
run 2
Yield of 2a
run 3
run 4
Fig 3. The yields of 2a using catalysts reused different times.
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imines followed by (2) tautomerism of imines and enamines, (3)
acid-catalyzed intramolecular annulation of enamines and finally
(4) an acid-catalyzed dehydration to give the desired product.
Fig. 4 XRD diffraction patterns of recycling catalysts
Scheme 4. The proposed mechanism of intramolecular annulation on Pd/C
and HZSM-5
Owning to the excellent activity and reusability of the catalyst
system, the catalyst system was then used for the practical
synthesis of vonoprazan in which the reaction was scaled up to
200 g (Scheme 3). When the reaction finished with 2a purity
97.30% (Fig. S8), the catalysts were filtered off and the combined
filtrate could be directly transferred to another reactor for further
reaction without additional treatments and compound 3 was
obtained with HPLC purity 99.7% and yield 81% over 2 steps (Fig.
S9). The pilot scale experiment is in progress with economic and
environmental benefits brought by excellent catalytic activities of
the catalyst system.
Conclusions
Using commercially available Pd/C and HZSM-5 as
heterogeneous reusable catalysts, we have successfully
developed an efficient and ecofriendly protocol for the synthesis
of substituted 1H-pyrrole-3-carbonitriles with more excellent
yields (up to 98%) compared with traditional liquid acids. The
product 5-(2-fluorophenyl)-1H-pyrrole-3-carbonitrile,
a
key
intermediate in the synthesis of vonoprazan, proves the
practicality of this protocol. Further studies on the scope and
synthetic applications of this protocol are underway in our
laboratory.
Experimental Section
Malononitriles 1 (1.0 g), HZSM-5 (0.8 g) and 10% Pd/C (0.1 g) in 1,4-
dioxane (10 mL) was placed in a flask and replaced with hydrogen gas.
The mixture was stirred under hydrogen atmosphere at 80°C and the
reaction progress was monitored by TLC (EtOAc: Petroleum =1: 4). After
the reaction finished, the catalysts were filtered off and washed with 1,4-
dioxane (2 mL). The combined filtrate and washings were concentrated
under vacuum at 55°C using rotary evaporator and the crude product was
purified by flash chromatography on silica-gel using EtOAc/Petroleum 1:10
as an eluting system to furnish the desired compounds 2.
Scheme 3. The synthetic route of vonoprazan fumarate
After above experiments, the reaction mechanism attracted our
attention. The intermediates were isolated and characterized by
1H and 13C NMR spectrum. The results revealed that the
intermediates existed as an equilibrium mixture of two isomers
(the same result was also found in TLC) in DMSO resulting from
the Z-E isomerization with populations in a ratio of about 1: 0.17
(Fig. S1). The Z-enamine was considered as the majority
Acknowledgements
Keywords: annulation • heterogeneous catalysis • Hzsm-5 •
green chemistry • pyrroles synthesis
considering it is more stable than the E-enamine in energy. Based
[9,19,20]
on the experimental results and research literatures,
a
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possible mechanism was proposed as shown in Scheme 4. The
accepted mechanism for this reaction is rather complex and
involves (1) an Pd/C-catalyzed hydrogenation of malononitriles to
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10.1002/cctc.201900154
ChemCatChem
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Jianchao Chen, Chengtao Li, Yanan Zhou,
Changshan Sun* and Tiemin Sun*
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An efficient, scalable and eco-friendly synthesis
of 4,5-substituted pyrrole-3-carbonitriles by
intramolecular annulation on Pd/C and HZSM-5
HZSM-5 and Pd/C as recyclable heterogeneous catalysts were used in
the efficient and eco-friendly synthesis of diverse 4,5-substituted 1H-
pyrrole-3-carbonitriles with more excellent yields (up to 98.18%) than
traditional liquids acids. The conspicuous features of this protocol are
higher product yield, easy work-up, eco-friendly and reusability of
catalysts. This protocol was successfully applied in the practical synthesis
of potassium-competitive acid blocker vonoprazan
This article is protected by copyright. All rights reserved.