Sequential multicomponent catalytic synthesis of pyrrole-3-carboxaldehydes: Evaluation of antibacterial and antifungal activities along with docking studies

Article abstract of DOI:10.1039/d0nj03575k

A sequential multicomponent synthesis of highly substituted pyrrole-3-carboxaldehydes has been developed under metal-free conditions. This one-pot protocol involves proline-catalyzed direct chemoselective Mannich reaction-cyclization between 1,4-ketoaldehyde and in situ generated Ar/HetAr-imines followed by aerobic oxidative-aromatization at room temperature. A series of fully substituted pyrrole-3-carboxaldehydes and other diverse fused heterocycles have been synthesized. These compounds were tested for in vitro antibacterial and antifungal activities, and the selected ones display significant activity against the tested bacterial strains with a MIC value of 16 μg mL-1, which is close to that of the standard drug chloramphenicol. The bioactivity outcome was further analyzed using docking studies.

Full text of DOI:10.1039/d0nj03575k

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Sequential multicomponent catalytic synthesis of pyrrole-3-
carboxaldehydes: Evaluation for antibacterial and antifungal
activities along with docking studies
Nisar A. Mir,a Panduga Ramaraju,a Satheeshvarma Vanaparthi,a Sachin Choudhary,a Rajnish P.
Singh,b Preetika Sharma,c Rajni Kant,c Rajpal Singh,d Murugesan Sankaranarayanan,e and Indresh
Kumar*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A sequential multicomponent synthesis of highly substituted pyrrole-3-carboxaldehydes has been developed under metal-
free conditions. This one-pot protocol involves proline-catalyzed direct chemoselective Mannich reaction-cyclization
between 1,4-ketoaldehyde and in situ generated Ar/HetAr-imines followed by aerobic oxidative-aromatization at room
temperature. A series of fully substituted pyrrole-3-carboxaldehydes and other diverse fused heterocycles have been
synthesized. These compounds were tested for in vitro antibacterial and antifungal activities, and selected ones display
significant activity against the tested bacterial strains with MIC value of 16 µg/mL, which is close to the standard drug
Chloramphenicol. The bioactivity outcome was further analyzed using docking studies.
Despite extensive efforts, the synthesis of pyrrole using 1,4-
dicarbonyls (aldehyde or ketone) and a primary amine under
the acidic conditions, as Paal-Knorr method is the most
Introduction
Multicomponent reactions (MCRs) have attracted significant
attention of chemists because of their high efficiency in the
construction of complex molecular framework from readily
available reagents. MCRs not only had the advantages of atom
economy, more straightforward procedures, lower costs, and
high variability but also often accompanied by significant
selectivity and impressive molecular diversity.1 Among the class
of medium-sized nitrogen heterocycles,2 pyrroles are crucial
heterocycles due to their occurrence in many natural
compounds, as well as essential components of living organisms
such as porphyrin, chlorin.3 Pyrrole containing molecules exhibit
distinct biological activities,4 along with extensive applications
in agrochemicals and functionalized materials (Figure 1).5 Much
attention has devoted to the development of efficient and
practical methods for accessing these pyrrole ring systems over
past few decades. These methods mainly include
cycloadditions,6 olefin cross-metathesis,7 multicomponent,8
metal-catalyzed reactions,9 along with classical ones.10
appealing method (eq 1, Scheme 1).11 Recently, an alternative
protocol to access functionalized pyrroles from 1,4-dicarbonyls
and imines under amine-catalysis was developed by Kumar and
co-workers,12 particularly direct access to compactly
substituted pyrrole-3-carboxaldehydes from 1,4-ketoaldehydes
and various preformed imines (eq. 2, Scheme 1).12b Notably,
pyrrole-3-carboxaldehydes were earlier accessed through a
complicated multistep process.13 This method resulted in rapid
and direct synthesis of pyrrole-3-carboxaldehydes, though, it
required the use of preformed imines. The clear synthetic
potential of this method to functionalized pyrroles from 1,4-
ketoaldehydes prompted us to explore similar transformation
in a sequential multicomponent fashion. The development of a
more sustainable way to access the library of such
pharmaceutically important compounds is quite exciting.
Br
Cl
OH
Cl
Br
Br
Cl
O2N
Br
Cl
N
Br
Pentabromopseudiline
HO
Pioluteorine
OH
N
H
O
N
a. Department of Chemistry, Birla Institute of Technology and Science, Pilani 333
031, (Rajasthan) India
O
H
H
Pyrrolnitrin antibiotic
E-mail: indresh.chemistry@gmail.com, indresh.kumar@pilani.bits-pilani.ac.in
b. Department of Biological Science, Birla Institute of Technology & Science, Pilani
c. Post-Graduate Department of Physics & Electronics, University of Jammu, Jammu,
India
CO2H
NC
Br
HO2C
O
CF3
N
d.
Research & Development Centre in Pharmaceutical Sci. and Applied Chemistry,
N
H
Cl
Bharati Vidyapeeth Deemed University, Erandawane, Pune, India
e. Department of Pharmacy, Birla Institute of Technology & Science, Pilani
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
N
H2N
O
H
Chlorfenapyl
pesticide against insects
Porphobilinogen
Verrrucarin E
Figure 1. Biologically active compounds having pyrrole as core skeleton
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Table 1. Optimization of reaction conditionsa
Paal-Knorr reaction
R-NH2 and acid (LA/BA)
LA = Lewis acid, BA = Bronsted acid
View ArticlCe OHnlOine
O
DOI: 10.1039/D0NJ03575K
Ph
Ar
Ar
(1)
(2)
R CHO
N
R
O
2b
CHO
4a
solvent
rt, 2 h
Ph
R
CHO
R
Ar
N
+
H2N PMP
3
PMP
(imine)
N
CHO
1
proline (cat)
rt
PMP
proline (cat.)
N
R
H
1,4-ketoaldehyde
5b
R = 4-NO2C6H4
solvent
PMP
our previous work
R = Ar, HetAr
yield (%)b
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entry
time (h)
Present work:
sequential multicomponent protocol
Ar NH2
proline
(20 mol%)
R2
CHO
R
CHO
steps
DMSO
DMF
48
48
30
24
24
36
51
35
26
68
64
60
1
O
+
(3)
DMSO, rt
O
2
R1
R1
R
R1
CHO
N
N
R = Ar, HetAr
R1 = Ar
CH3CN
DMSO
DMSO
DMSO
3
H
R
Ar
Ar
4c
5d
6e
Scheme 1. Utilization of 1,4-dicarbonyls for the synthesis of pyrroles; (1) Paal-
Knorr method, (2) Our earlier protocol for pyrrole synthesis from 1,4-dicarbonyls
and imine, (3) Present work on sequential multicomponent reaction to access
highly and fully substituted pyrroles.
aUnless otherwise indicated, the reaction was carried with 4-nitrobenzaldehyde
2b (0.3 mmol, 1.0 equiv), p-anisidine 3 (0.3 mmol, 1.0 equiv), keto-aldehyde 4a
(0.9 mmol, 3.0 equiv), proline 1 (20 mol %, 0.2 equiv), solvent (3.0 mL). bIsolated
yield of 5a. cWith addition of H2O (100 µL). dWith the addition of water (200 µL).
eReaction was carried out using proline (10 mol%).
On the other hand, bacterial and fungal infection has become a
global challenge for human health due to the lack of availability
of sufficient and effective drug. The demand for the
development of new antimicrobial agents is increasing.14 In this
context, pyrrole derivatives have emerged as original structures
for such activities.15 Herein, we wish to report a sequential
multicomponent protocol for the synthesis of substituted
pyrrole-3-carbaldehydes via amine-catalyzed chemoselective
direct Mannich reaction-cyclization between a series of 1,4-
ketoaldehydes and imines, in situ generated from Ar/HetAr-
aldehydes and primary aromatic amine, followed by aerobic
oxidative-aromatization in the same-pot (eq. 3, Scheme 1) along
with their biological evaluation. Moreover, easy access to fully
substituted pyrrole-3-carboxaldehydes and variously fused aza-
heterocycles such as pyrrolo-acrylates, and pyrrolo-oxadiazole,
which have great importance in medicinal chemistry, have been
discussed.
this one-pot sequential transformation with the optimized
conditions (entry 4, Table 1).
Next, the scope of this reaction was examined by employing
various Ar/HetAr-aldehyde 2, and aromatic amines 3 with 1,4-
ketoaldehydes 4a-4g under optimized conditions, and the
results are shown in Table 2. The reaction worked well when
1,4-ketoaldehydes 4a was reacted with imines, in situ
generated from a wide range of Ar/HetAr-aldehyde 2 decorated
with various groups (e.g., −NO2, −CN, and –CH3) and p-anisidine
3, to furnished pyrroles (5a-5g) in 51-68% yields (Table 2).
Naphthyl-group decorated 1,4-ketoaldehyde 4b also furnished
pyrroles 5h in 50% yields (Table 2). Similarly, 1,4-ketoaldehydes
4c-4f having an electron-donating group on aryl-rings also
provided corresponding pyrroles 5i, 5j-5m, 5n, 5o-5q with good
yields. Moreover, 1,4-ketoaldehydes 4g having para-fluoro
substitution as the electron-withdrawing group also supplied
pyrroles 5r and 5s with 66% and 58% yields, respectively.
Notably, the generality was tested using aromatic amines such
as p-toluidine, p-chloroaniline, p-bromoaniline, also furnished
corresponding the corresponding pyrroles 5t, 5u, and 5v with
moderate yields. Based on our previous studies, a tentative
reaction mechanism is proposed in Scheme S1 (see the
Supporting Information).
Results and Discussion
The quest of finding one-pot domino sequential
multicomponent reaction to pyrrole was initiated by adopting
the conditions from our previous study and choosing proline 1
(20 mol%) as a catalyst, p-nitrobenzaldehyde 2b as model
substrates, along with p-anisidine 3, and 1,4-ketoaldehyde 4a
and the results are shown in Table 1. Our initial experiment in
DMSO as the choice of solvent along the subsequent addition of
substrates gave 5b with 51% yield (entry 1, Table 1). Other
solvents, like- DMF (entry 2, Table 1) and CH3CN (entry 3, Table
1) were found less suitable. Gratifyingly, the addition of H2O
(100 µL) improves the yield (68%) in DMSO (entry 4, Table 1).
Similar observation on the role of H2O facilitating the rate of
amine catalyzed Mannich reactions was made earlier.16 Further
increment in the amount of H2O (200 µL) as an additive (entry
CHO
2a
(1.0 g)
NO2
(i) DMSO, rt, 2 h
N
+
(ii) proline 1 (cat)
PMP
(3.0 equiv), rt, 24 h
H2N PMP 4a
5a
3
(1.66 g, 63% yield)
1400573
(CCDC No.
)
5, Table 1) and reducing the catalyst loading (entry 6, Table 1), Scheme 2. Gram-scale synthesis and X-ray structure of 5a.
did not improve the reaction yield. Thus, we prefer to perform
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Table 2. Sequential multicomponent reaction scope concerning various aldehydes 2, amine 3, and 1,4-ketoaldehydes 4a,b
6
7
O
CHO
R
8
9
Ar
CHO
4a-g
DMSO
rt, 2 h
Ar
Ar NH2
N
R CHO
+
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1
proline (cat)
rt, 24 h
3
Ar
2
5
CHO
CHO
CHO
CHO
R
R
N
N
N
N
R
N
H3CO
PMP
PMP
PMP
PMP
5h
(50%)
5o
5p
5q
, R = 4-ClC6H4 (66%)
, R = 4-BrC6H4 (65%)
, R = 4-pyridyl (60%)
5j
5k
5l
5m
, R = 4-FC6H4 (65%)
, R = 4-ClC6H4 (64%)
, R = 4-CNC6H4 (70%)
, R = 4-pyridyl (63%)
5a
5b
5c
5d
5e
, R = 3-NO2C6H4 (67%)
, R = 4-NO2C6H4 (68%)
, R = 3-CNC6H4 (65%)
, R = 4-CH3C6H4 (51%)
, R = 3-pyridyl (57%)
, R = 4-pyridyl (63%)
CHO
CHO
N
CHO
N
H3C
5f
5g
R
PMP
H3CO
N
, R = 2-thiophene (55%)
F
5i
(58%)
PMP
N
N
5r
, R = 4-CNC6H4 (66%)
5s
PMP
, R = 4-pyridyl (58%)
5n
(61%)
CHO
CHO
CHO
N
N
N
NO2
NO2
NO2
5t
5u
(58%)
5v
(52%)
(55%)
CH3
Cl
Br
aUnless otherwise indicated the reaction was carried out at (i) aldehyde 2 (0.3 mmol), amine 3 (0.3 mmol), ketoaldehyde 4 (0.9 mmol), proline 1 (20 mol%), DMSO
(3.0 mL), H2O (100 µL). bIsolated yield of 5. (PMP = p-OCH3C6H4) (4a, Ar= Ph; 4b, Ar = naphthyl; 4c, Ar = 4-MePh; 4d, Ar = 4-tert-butyl-Ph; 4e, Ar = 3-OMePh; 4f, Ar
= 4-OMePh; 4g, Ar = 4-FPh).
The feasibility of improved protocol was examined at a gram protocol (eq (1), Scheme 3), while the integration of pyrrolo-
scale of 2a (1.0 g) to furnished 5a (1.66 g, 63%), and a single- hydrazone 9 with 90% yields (eq (2), Scheme 3) was obtained
crystal X-ray analysis confirms the structure (Scheme 2).
with the condensation between 5b and 2,4-dinitrophenyl
These suitably functionalized pyrroles are useful synthetic hydrazine 8. Moreover, pyrrole-3-methanol 10 was prepared
intermediates and can be easily converted to important and with 92% yield through the NaBH4-reduction (eq (3), Scheme 3),
fully substituted pyrroles or fused aza-heterocycles that may similarly corresponding α,β-unsaturated ester 12 was achieved
have exciting applications in medicinal and material science. For with 83% yields through Horner-Emmons reaction (eq (4),
this purpose,
a series of fully substituted pyrrole-3- Scheme 3) from 5b, respectively. Next, the pyrrolo-oxadiazole
carboxaldehydes 6 were quickly prepared through a two-step fused product 14 was prepared with 76% yields, through two-
protocol, and the results are shown in Table 3. For this purpose, steps procedure from 5c under standardized conditions in the
pyrroles 5 were initially converted to corresponding bromo- same flask (eq (5), Scheme 3).17
derivatives with NBS and utilized further without purification Evaluation of Biological Activities
for Pd(OAc)2 (10 mol%) catalyzed Suzuki-coupling reaction with Next, we studied the antibacterial and antifungal activities of
PhB(OH)2 under standardized conditions to access fully synthesized compounds. Muller-Hilton agar and Potato
substituted pyrroles 6. A series of fully substituted pyrroles 6a- dextrose agar were used for the antibacterial and antifungal
6f were prepared with 64-71% yields after two steps (Table 3). assay, respectively (For details, see Supporting information).
Results have been organized in Table 4, and 5, which reveals the
potent antibacterial and antifungal activity of selected
compounds while comparing with reference antibiotics. The
antibacterial activity results demonstrated that most of the
synthesized compounds showed varying degrees of bactericidal
Synthetic Applications
Next, the synthetic applications were explored for the synthesis
of fully substituted pyrrole 7 in 72% yield (eq (1), Scheme 3)
through Sonagashira coupling protocol on 5b using two-steps
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Table 3. Access to fully substituted pyrrolesa
having 4-tolyl-unit at C2-position showed half the antifungal
activity than the standard drug. The exact mechanism of action
of the pyrrole-based drug vary, it can exert antimicrobial effect
by damaging cell membranes, inhibiting reverse transcriptase
activities, and protein kinases of the cellular system.14,15
View Article Online
DOI: 10.1039/D0NJ03575K
Ph
CHO
R
CHO
(i) NBS, CH3CN
80 oC, 4 h
Ar
Ar
R
N
N
(ii) PhB(OH)2, K2CO3
Pd(OAc)2 (cat)
PMP
PMP
6
DMF, heat, 4 h
(% yield)b
5
9
Ph
CHO
CHO
Ph
Ph
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(i) NBS, CH3CN
0 oC-rt
CHO
N
N
N
N
CN
H3C
H3C
PMP
PMP
(1)
Ph
(ii)
PhC CH, CuI, Et3N
Pd(OAc)2,DMF
N
6b
6d
(71%)
NO2
6a
(68%)
PMP
7
(72% yield)
Ph
CHO
CHO
Ph
O2N
O2N
NO2
N
N
HN
N
NO2
Cl
NHNH2
PMP
PMP
(69%)
8
(2)
CH3OH, 70 o
C
6c
(66%)
Ph
N
NO2
PMP
Ph
CHO
Ph
CHO
9
5b
(90% yield)
N
N
CN
F
CH2OH
Br
F
PMP
PMP
6f
(65%)
6e
(64%)
NaBH4
MeOH, 0 oC-rt
Ph
(3)
(4)
(5)
N
NO2
PMP
10
(88% yield)
a(i) Compound 5 (0.3 mmol, 1.0 equiv), NBS (0.3 mmol, 1.0 equiv), CH3CN (3.0
mL); (ii) DMF (3.0 mL), PhB(OH)2 (0.3 mmol, 1.0 equiv), K2CO3, Pd(OAc)2 (10 mol
%), heat, 4 h. bIsolated yields of product 6.
CO2Et
O
O
P
OEt
OEt
EtO
11
activity against both Gram-positive and Gram-negative bacteria
(see Table S1, Supporting information). As seen in Table 4(a),
compounds 5e, 5f, and 5g displayed valuable activity against the
tested bacterial strains with MIC value of 16 µg/mL against the
gram-positive and gram-negative bacteria, which is comparable
to standard drug Chloramphenicol. Similarly, compounds 5f and
5g exert the highest inhibitory activity against P. putida with
MIC value of 16 µg/mL, near to that of positive control. The
compound also showed significant inhibition against the other
three tested bacterial strains. Compound 5m also registered the
same inhibitory potential against the tested bacterial strains.
Similarly, compounds 5i and 9 showed antibacterial activity
against the tested strains in the range of 32-64 µg/mL. In
comparison, compound 5d was active at the concentration of
32 µg/mL against both gram-positive and gram-negative
bacterial strains. The synthesized compounds 5d and 5g showed
significant activity against the tested fungal strains, which is
comparable to standard drug Amphotericin B. Notably,
compound 5g displayed higher activity against F. oxysporum
and F. graminearum as compared to A. flavus (Table 5). To study
the structure activity relationship (SAR) pattern of the titled
compounds, 3-formylpyrroles substituted at C2-position with
pyridine (5e, 5f) and thiophene 5g exhibited significant
antibacterial activity. Moreover, compounds 5i and 5m having
4-pyridyl-moiety at C2-position of pyrrole showed weak
antibacterial activity as compared to the standard drug.
Similarly, the 3-formylpyrroles 5g decorated with 2-thiophene
at C2-position exhibited comparable antifungal activity and 5d
Ph
N
NaH, THF, 0 oC-rt
NO2
PMP
12
(83% yield)
N
N
(i) C6H5CONHNH2, MeOH
80 oC, 3 h
O
5c
CN
13
(ii)
(IBD) , CH3CN, rt, 3 h
(76% yield)
Ph
N
PMP
14
Scheme 3. Synthetic applications on aldehyde group of pyrroles 5b and 5c; (1)
Sonagashira coupling for fully substituted pyrrole, (2) pyrrolo-hydrazone
preparation, (3) NaBH4 reduction, (4) the Horner-Emmons reaction to access α,β-
9
unsaturated ester, (5) Synthesis of fused pyrrolo-oxadiazole.
Table 4. Antibacterial activity in terms of; (a) Minimum inhibitory
concentration (MIC, µg/ml), (b) Zone of Inhibition (ZIC, mm)
(a)
E. coli
P. putida
B. subtilis
S. aureus
100
50
0
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co-crystal ligand (Figure-2b), which played an essential role in
View Article Online
E. coli
P. putida
the stable conformation of the co-crystalDlOigIa: 1n0d.10w3i9t/hD0aNdJo0c3k57in5Kg
score of 9.50 kcal/mol and energy of 66.12 kcal/mol (see
Table-S5, Supporting information). The amino-acid residues
GLY-101, ASP-73, and ARG-136 secure their role in the hydrogen
bond interactions. Apart from hydrogen bond interaction, GLY-
101 also exhibits one aromatic bond interaction. ARG-76
displayed a significant role in synergy with the co-crystal ligands
with one π-cationic interaction with LYS-103 and two salt-bridge
interactions with amino-acid residue ARG-136. The 3D docked
pose of significantly active compound 5e exhibited reduced
bond interaction with the surrounded amino-acid residues and
water molecules (Figure-3a). The pyridine-nitrogen of 5e was
actively participating in the hydrogen bond formation (2D pose
of the compound). At the same time, the pyridine ring was
involved in the π-cationic interaction with amino-acid residue
AGR-76 (Figure-3b). The docking score (2.4 kcal/mol) is less
when compared with the co-crystal ligand, and docking energy
is 28.09 kcal/mol (see Table-S5, Supporting information).
Besides, methoxyphenyl and phenyl rings attached to the
pyrrole moiety also contributed to the aromatic bond
interaction with the amino-acid residue-GLY-101. Thus, the in-
vitro and in-silico studies were correlated for compound 5e and
displayed measured zone of inhibition with a maximum
inhibition of 19, 18, 18, and 18 mm at 16 µg/mL against the
gram-positive and gram-negative bacterial strains, that is
comparable to standard drug Chloramphenicol.
20
10
0
9
10
11
12
13
14
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Table 5. Antifungal activities in terms of; (a) Minimum inhibitory concentration
(MIC, µg/ml), and (b) Zone of Inhibition (ZIC, mm)
(a)
FO
FG
20
10
0
5d
5g
Amphotericin B
(b)
FO
FG
AF
80
60
40
20
0
(a)
5d
5g
Amphotericin B
Molecular-docking study to support the bioassay
Having seen the impressive antibacterial and antifungal
activities of selected compounds, we carried out molecular-
docking and other studies to support the generated bioassay of
these compounds. Initially, the physicochemical parameters like
molecular weight, volume, hydrogen bond acceptors and
donors, and polar surface area, were predicted in-silico by using
Qik-prop Module in Schrödinger and found in the acceptable
range similar to that of the approved drugs (Table S2, and S3,
see Supporting information). In the same study, toxicity profile
prediction was carried out by using the ProTox-II18 online server
and various toxicity endpoints, such as hepatotoxicity,
carcinogenicity, immunotoxicity, mutagenicity and cytotoxicity
were predicted. All the screened compounds did not show
cytotoxicity, mutagenicity, and immunotoxicity. At the same
time, low probability (average probability 0.5) of carcinogenicity
was revealed by all the compounds along with hepatotoxicity
(see, Table S4, Supporting information).
The docking studies were performed to find the putative
binding mode related to the significantly active compound 5e in
the active site of the target using Schrödinger software. The
study with the native pose of the ligand (co-crystal ligand, 3D
pose) showed functional interactions with the surrounded
amino-acid residues and water molecules (Figure-2a). The 2D
docked pose showed six hydrogen bond interactions with the
(b)
Figure 2. (a) 3D docked pose of co-crystallized ligand (green color); (b) 2D
representation of the docked pose of the co-crystallized ligand and its interactions
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in the active site of the protein-4DUH (rest of the protein was suppressed for the
clarity) [Color interpretation Yellow- Hydrogen bond, Blue- Aromatic bond, Red-
Pi cationic interaction and Magenta- salt bridge]
Chloramphenicol. Moreover, selected compounds (5d and 5g)
View Article Online
showed a good level of antifungal actiDviOtyI: 1a0g.1a0i3n9s/tD0FNuJs0a3r5iu75mK
oxysporum, Fusarium graminearum, and Aspergillus flavus
fungal strains. Finally, the molecular-docking study of the most
promising compound 5e was also performed. Further
investigation to determine the exact mode of action for the
bioactivity is underway.
(a)
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Experimental
General remarks
All reactions under standard conditions were monitored by
thin-layer chromatography (TLC) on SiO2 gel F-254 plates.
Unless otherwise noted, all reactions have been carried out
with distilled and dried solvents. Oven-dried glassware was
used. All work up, and purification was carried out with reagent
grade distilled solvents. The column chromatography was
performed on silica gel (100-200 mesh) using the mixture of
Hexane-EtOAc as the eluting solvent. All reagents were of
1
analytical grade and used without further purification. H (400
(b)
MHz) and 13C-NMR (100 MHz) spectra were recorded on a
BRUKER-AV400, and spectral data were reported in ppm
referenced to the solvent peak of CDCl3. High-resolution mass
spectra were recorded on Agilent 6545 Q-TOF LC/MS. Infrared
(FT-IR) spectra were recorded on an ABB Bomen MB 3000 FTIR
Spectrophotometer system using KBr pellets. Melting points
were recorded in open glass capillary tubes on an MPA 120-
automated melting point apparatus and are uncorrected. The
Gram-negative bacterial strain Escherichia coli (MTCC 1652),
Pseudomonas putida (MTCC 102) and gram-positive bacteria
Bacillus subtilis (MTCC 121) and Staphylococcus aureus (MTCC
96) were procured from Microbial Type Culture Collection and
Gene Bank (MTCC), Chandigarh, India. The fungal strains,
namely Fusarium oxysporum (MTCC 284), Fusarium
graminearum (1893) and Aspergillus flavus (MTCC 2798)
procured from MTCC, were maintained on potato dextrose agar
(PDA, Himedia, India) plate and used for the antifungal assay.
The docking studies were carried out using Schrodinger
software (Version 2019-1, Schrodinger) installed on Intel Xenon
W 3565 processor and Ubuntu enterprise version 14.04 as the
operating system. The details of the biological activities and
docking study are given in the Supporting information.
Figure 3. (a) 3D docked pose of the significantly active compound 5e (green
color); (b) 2D representation of the docked pose of the significantly active
compound 5e exhibited various interactions in the active site of the protein (4DUH)
(rest of the protein was suppressed for the clarity)[Color interpretation Yellow-
Hydrogen bond, Blue- Aromatic bond, Red- Pi cationic interaction and Magenta-
salt bridge]
Conclusions
In summary, we have developed an improved sequential
multicomponent procedure for the direct catalytic synthesis of
pyrrole-3-carboxaldehydes under mild conditions. The
straightforward protocol proceeds through proline-catalyzed
direct Mannich reaction-cyclization sequence between 1,4-
ketoaldehydes and imines, in situ generated from primary
aromatic amines and Ar/HetAr-aldehydes, followed aerobic
oxidative-aromatization in the same pot. The practical utility of
this procedure is shown; (i) at the gram scale, (ii) synthesis of
fully substituted pyrrole-3-carboxaldehydes using coupling
protocol, (iii) integration of other diverse pyrrole-fused
heterocycles. The synthesized compounds were tested for in
vitro antibacterial and antifungal activities. Among all the tested
compounds, selected compounds (5e, 5f, and 5g) exhibited
significant activity against the tested bacterial strains with MIC
value of 16 µg/mL, which is comparable to standard drug
A typical procedure for the synthesis of 2, 5-diaryl pyrrole-3-
carboxaldehydes (5)
To a stirred solution of Ar/HetAr-aldehydes 2 (0.3 mmol) and p-
anisidine 3 (0.3 mmol) in DMSO (3.0 mL) for 2 h at room
temperature was added 4-Oxo-4-phenyl butanal 4 (0.9 mmol),
H2O (100 µL) and L-proline 1 (0.06 mmol, 20 mol %) and stirred
additionally for 24 h. The reaction was quench with cold water
(5.0 mL) and extracted with ethyl acetate (3 × 5.0 mL). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, concentrated under reduced pressure, and
purification through silica gel column chromatography by
eluting with EtOAc/Hexane to furnished 2, 5-diaryl pyrrole 3-
carboxaldehydes (5) (up to 70% yields).
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1-(4-methoxyphenyl)-2-(3-nitrophenyl)-5-phenyl-1H-pyrrole-
6.88 (d, J = 8.9 Hz, 2H), 6.97 (s, 1H), 7.07-7.09 (m, 4H), 7.18.7.23
View Article Online
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DOI: 10.1039/D0NJ03575K
3-carbaldehyde (5a). Reddish brown solid (80 mg, 67% yield); (m, 3H), 8.53 (s, 2H), 9.75 (s, 1H); C NMR (100 MHz, CDCl3) δ
o
1
(mp = 154-155 C); H NMR (400) MHz, CDCl3) δ 3.75 (s, 3H), 55.3, 108.0, 114.2 (2C), 124.4, 125.4, 127.5 (2C), 128.1 (2C),
6.74 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.98 (s, 1H), 7.10- 128.7 (2C), 129.2, 129.3 (2C), 131.0, 137.5, 137.8, 139.8, 149.3
7.12 (m, 2H), 7.21-7.24 ( m, 3H) 7.39-7.46 (m, 2H) 8.08 (t, J = 1.7 (2C), 159.1, 186.0; IR (KBr)/cm-1 2931, 1674, 1250, 1173, 1026;
Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 9.73 (s, 1H); 13C NMR (100 MHz, HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H19N2O2 355.1447;
CDCl3) δ 55.3, 107.9, 114.3 (2C), 114.5, 123.2, 124.3, 125.7, Found 355.1444.
125.9, 127.5, 128.2 (2C), 128.7 (2C), 129.5 (2C), 131.1, 131.3, 1-(4-methoxyphenyl)-5-phenyl-2-(thiophen-2-yl)-1H-pyrrole-
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136.8, 137.6, 140.2, 147.6, 159.2, 185.9 ; IR (KBr)/cm-1 2932, 3-carbaldehyde (5g). Yellow semi-solid (59 mg, 55% yield); H
1
2854, 1666,1512, 1342, 1172; HRMS (ESI-TOF) m/z: [M + H]+ NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 6.78 (d, J = 8.9 Hz, 2H),
Calcd for C24H19N2O4 399.1345; Found 399.1342.
1-(4-methoxyphenyl)-2-(4-nitrophenyl)-5-phenyl-1H-pyrrole-
6.96-7.00 (m, 5H),7.11-7.13 (m, 2H), 7.21 (t, J = 3.7 Hz, 4H), 9.86
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3, 107.4, 114.0 (2C),
3-carbaldehyde (5b). Yellow solid (81 mg, 68% yield) (mp = 163- 121.8, 125.3 (2C), 126.8, 127.3, 127.8 (2C), 128.1 (2C), 128.5,
1
164 oC); H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 6.75 (d, J = 8.9 128.7 (2C), 129.8 (2C), 130.8, 142.9, 159.3, 186.9; IR (KBr)/cm-1
Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.09-7.11 (m, 2H), 7.23 (t, J = 3.5 2924, 2854, 1666, 1242, 1173 1034; HRMS (ESI-TOF) m/z: [M +
Hz, 3H), 7.37 (d, J = 8.6 Hz, 2H), 8.15 (d, J = 8.7 Hz, 2H), 9.75 (s, H]+ Calcd for C22H18NO2S 360.1058; Found 360.1064.
1H); 13C NMR (100 MHz, CDCl3) δ 55.3, 108.3, 114.3 (2C), 123.1 1-(4-methoxyphenyl)-5-(naphthalen-1-yl)-2-(pyridin-4-yl)-1H-
(2C), 124.5, 127.5, 127.9 , 128.2 (2C), 128.7 (2C), 129.4 (2C), pyrrole-3-carbaldehyde (5h). Yellow viscous liquid (60 mg, 50%
131.8 (2C), 133.0, 133.2, 137.9, 140.1, 147.2, 159.2, 186.0; IR yield); 1H NMR (400 MHz, CDCl3) δ 3.61 (s, 3H), 6.751 (d,
(KBr)/cm-1 2924, 2854, 1674, 1596, 1342, 1172; HRMS (ESI-TOF) J=8.5Hz, 2H), 6.76 (d, J = 8.1 Hz, 2H), 7.01 (s, 1H), 7.15 (d, J = 5.9
m/z: [M + H]+ Calcd for C24H19N2O4 399.1345; Found 399.1338. Hz, 2H), 7.19 (d, J = 7.1 Hz, 1H), 7.31 (t, J = 7.3Hz, 8.0 Hz, 1H),
3-(3-formyl-1-(4-methoxyphenyl)-5-phenyl-1H-pyrrol-2-yl)
7.43-7.47 (m, 2H), 7.76-7.82 (m, 2H), 7.88-7.90 (m, 1H), 8.55 (d,
benzonitrile (5c). Yellow semi-solid (74 mg, 65% yield); 1H NMR J = 5.6 Hz, 2H), 9.85 (s, 1H); 13C NMR (100 MHz, CDCl3) 55.2,
(400 MHz, CDCl3) δ 3.77 (s,3H), 6.74 (d, J = 8.9 Hz, 2H), 6.87 (d, 110.2, 113.9 (2C), 124.3, 124.7, 125.3 (2C), 125.7, 126.0, 126.5,
J = 8.9 Hz, 2H), 6.96 (s, 1H), 7.10 (dt, J = 5.2, 3.1 Hz, 2H), 7.19- 128.2, 128.8 (2C), 128.9 (2C), 129.2, 129.5, 132.8, 133.3, 135.8,
7.25 (m, 3H), 7.39-7.49 (m, 3H), 7.60 (dt, J = 7.3, 1.7 Hz, 1H), 137.7, 139.3, 149.5 (2C), 158.9, 186.2. IR (KBr)/cm-1 2956, 1672,
9.69 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3, 107.8, 112.4, 1510, 1433, 1247; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
114.3 (2C), 118.0, 124.4, 127.5, 128.2 (2C), 128.7 (2C), 128.9, C27H21N2O2 405.1603; Found 405.1612.
129.2, 129.5 (2C), 131.1, 131.2, 131.8, 134.2, 135.3, 137.5, 1-(4-methoxyphenyl)-2-(pyridin-4-yl)-5-p-tolyl-1H-pyrrole-3-
140.4, 159.2, 185.9; IR (KBr)/cm-1 2932, 2230, 1659, 1512, 1443, carbaldehyde (5i). Red semi-solid (64 mg, 58% yield); H NMR
1
1250; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H19N2O2 (400 MHz, CDCl3) δ 2.29 (s, 3H), 3.77 (s, 3H), 6.75 (d, J= 8.8 Hz,
379.1446; Found 379.1473.
2H), 6.89 (d, J = 8.8 Hz, 2H), 6.94 (s, 1H), 6.97 (d, J = 8.1 Hz, 2H),
7.03 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 5.9 Hz, 2H), 8.52 (d, J = 5.8
1-(4-methoxyphenyl)-5-phenyl-2-(p-tolyl)-1H-pyrrole-3-
1
carbaldehyde (5d). Brown semi-solid (56 mg, 51% yield); H Hz, 2H), 9.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.1, 55.3,
NMR (400 MHz, CDCl3) δ 2.33 (s, 3H), 3.76 (s, 3H), 6.72 (d, J = 107.7, 114.3 (2C), 124.4 (2C), 125.4, 128.2, 128.6 (2C), 128.9
8.5 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 6.95 (s, 1H), 7.08 (bs, 5H), (2C), 129.3, 129.4 (2C), 137.4, 137.7, 138.0, 139.8, 149.4 (2C),
7.20 (bs, 2H), 7.35 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 9.69 159.2, 186.1; IR (KBr)/cm-1 2960, 1658, 1597, 1435, 1298, 1251,
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 22.7, 55.3, 107.1, 113.9 1190; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H21N2O2
(2C), 123.8, 125.3, 126.4, 127.1, 127.8, 128.0, 128.5, 128.7 (2C), 369.1603; Found 369.1607.
129.6, 130.1, 131.0 (2C), 131.8, 136.69, 138.3, 143.0, 144.7, 5-(4-tert-butylphenyl)-2-(4-fluorophenyl)-1-(4-methoxy
158.8, 187.1; IR (KBr)/cm-1 2914, 1668, 1248, 1178; HRMS (ESI- phenyl)-1H-pyrrole-3-carbaldehyde (5j). White solid ( M.P =
TOF) m/z: [M + H]+ Calcd for C25H22NO2 368.1650; Found 152-153 oC, 83 mg, 65% yield); H NMR (400 MHz, CDCl3) δ 1.27
1
368.1648.
(s, 9H), 3.77 (s, 3H), 6.74 (d, J= 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz,
2H), 6.93 (s, 1H), 6.94-7.04 (m, 4H), 7.17 (d, J = 8.7, 5.4 Hz, 2H),
1-(4-methoxyphenyl)-5-phenyl-2-(pyridin-3-yl)-1H-pyrrole-3-
carbaldehyde (5e). Reddish brown semi-solid (60 mg, 57% 7.22 (d, J = 8.4 Hz, 2H), 9.67 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
yield); 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 6.73 (d, J = 8.9 31.2 (3C), 34.4, 55.3, 106.8, 114.0 (2C), 115.2 (2C, d, J = 21.7 Hz),
Hz, 2H), 6.90 (d, J = 9.0 Hz, 2H), 6.99 (s, 1H), 7.10-7.12 (m, 2H), 124.0, 125.1 (2C), 125.5 (J = 3.5 Hz), 128.2 (2C), 128.6, 129.6
7.22 (t, J = 3.3 Hz, 4H),7.49-7.52 (m, 1H), 8.49 (s, 1H),8.55 (d, J = (2C), 130.0, 132.9 (2C, d, J = 8.3 Hz), 136.9, 143.1, 150.2, 158.9,
3.9 Hz, 1H), 9.71 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3, 162.6 (d, J = 249.4 Hz), 186.7; IR (KBr)/cm-1 2958, 1672, 1512,
107.8, 114.3 (2C), 122.9, 124.6, 126.0, 127.4, 128.1 (2C), 128.7 1363, 1253, 1172; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
(2C), 129.3, 129.6 (2C), 131.3, 137.7, 138.3, 139.7, 149.0, 150.9, C28H27FNO2 428.2026; Found 428.2032.
159.2, 186.1; IR (KBr)/cm-1 2932, 1666, 1250, 1180, 1026; HRMS 5-(4-tert-butylphenyl)-2-(4-chlorophenyl)-1-(4-methoxy
(ESI-TOF) m/z: [M + H]+ Calcd for C23H19N2O2 355.1446; Found phenyl)-1H-pyrrole-3-carbaldehyde (5k). Yellow solid (mp =
355.1448.
172-173 oC, 85 mg, 64% yield); 1H NMR (400 MHz, CDCl3) δ 1.26
(s, 9H), 3.77 (s, 3H), 6.74 (d, J= 8.8Hz, 2H), 6.88 (d, J = 8.9 Hz,
1-(4-methoxyphenyl)-5-phenyl-2-(pyridin-4-yl)-1H-pyrrole-3-
1
carbaldehyde (5f). Yellow semi-solid ( 67 mg, 63% yield); H 2H), 6.92 (s, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H),
NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 6.74 (d, J = 8.9 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.5 Hz, 3H, includes CDCl3),
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9.67 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.2 (3C), 34.5, 55.4, 130.3, 131.3 (2C), 132.6 (2C), 137.0, 158.9 (2VCie)w, A1r8tic6le.6O;nliInRe
107.1, 114.1 (2C), 124.1, 125.1 (2C), 128.1, 128.2 (2C), 128.3 (KBr)/cm-1 2951, 1668, 1506, 1456, 1220,D1O16I:110;.H10R3M9/DS0(NESJ0I-3T5O75FK)
(2C), 128.5, 129.6 (2C), 129.9, 132.4 (2C), 134.6, 137.1, 142.6, m/z: [M + H]+ Calcd for C25H21BrNO3 462.0705; Found 462.0710.
150.3, 159.0, 186.6; IR (KBr)/cm-1 2960, 1672, 1512, 1406, 1296, 5-(4-methoxyphenyl)-1-(4-methoxyphenyl)-2-(pyridin-4-yl)-
1172; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H27ClNO2 1H-pyrrole-3-carbaldehyde (5q). Yellow semi-solid (69 mg, 60%
444.1733; Found 444.1736.
4-(5-(4-tert-butylphenyl)-3-formyl-1-(4-methoxyphenyl)-1H-
yield); 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 3.77 (s, 3H), 6.74-
6.76 (m, 4H), 6.88 (d, J = 8.9 Hz, 2H), 6.91 (s, 1H), 7.01 (d, J = 8.7
pyrrol-2-yl)benzonitrile (5l). Yellow solid (mp = 160-161 oC, 91 Hz, 2H), 7.08 (d, J = 6.0 Hz, 2H), 8.53 (d, J = 5.8 Hz, 2H), 9.75 (s,
mg, 70% yield); 1 H NMR (400 MHz, CDCl3) δ 1.27 (s, 9H), 3.79 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.2, 55.3, 107.3, 107.4, 113.7
3H), 6.75 (d, J= 8.9 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), (2C), 114.3 (2C), 123.6, 124.5, 125.4, 125.5, 129.4, 129.5, 130.1,
7.01 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.3 130.2, 137.8, 137.9, 139.6, 149.3, 149.4, 159.1, 159.2, 187.2; IR
Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 9.71 (s, 1H); 13C NMR (75 MHz, (KBr)/cm-1 2924, 1680, 1508, 1456, 1249, 1178; HRMS (ESI-TOF)
CDCl3) δ 31.2 (3C), 34.5, 55.4, 107.9 (2C), 122.0, 114.2 (2C), m/z: [M + H]+ Calcd for C24H21N2O3 385.1552; Found 385.1557.
118.3, 124.4, 125.2 (2C), 128.2, 128.3 (2C), 129.5 (2C), 131.65 4-(5-(4-fluorophenyl)-3-formyl-1-(4-methoxyphenyl)-1H-
(2C), 131.68 (2C), 134.4, 137.8, 140.7, 150.6, 159.2, 186.1; IR pyrrol-2-yl)benzonitrile (5r). Red semi-solid (78 mg, 66% yield);
(KBr)/cm-1 2954, 2225, 1682, 1514, 1433, 1249, 1178; HRMS 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H), 6.75 (d, J = 8.9Hz, 2H),
(ESI-TOF) m/z: [M + H]+ Calcd for C29H27N2O2 435.2072; Found 6.85 (d, J = 8.9 Hz, 2H), 6.90-6.95 (m, 3H), 7.06 (dd, J = 8.8, 5.3
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435.2079.
Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz 2H), 9.71 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 55.4, 108.1, 112.1, 114.3 (2C),
5-(4-tert-butylphenyl)-1-(4-methoxyphenyl)-2-(pyridin-4-yl)-
1H-pyrrole-3carbaldehyde (5m). Yellow semi-solid (77 mg, 63% 115.3 (2C, d, J= 21.6 Hz) , 118.2, 124.3, 127.3, 129.1, 129.5 (2C),
yield); 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 9H), 3.77 (s, 3H), 6.75 130.5 (2C, d, J = 8.0 Hz), 131.6 (2C), 131.8 (2C), 134.1, 136.7,
(d, J = 8.9 Hz, 2H), 6.91 (d, J = 8.9 Hz, 2H), 6.95 (s, 1H), 7.00 (d, J 140.8, 159.33, 162.1 (d, J = 248.1 Hz) 186.1; IR (KBr)/cm-1 2956,
= 8.4 Hz, 2H), 7.08 (d, J = 6.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 8.51 2227, 1666, 1598, 1514, 1226, 1157; HRMS (ESI-TOF) m/z: [M +
(d, J = 5.5 Hz, 2H), 9.73 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.1 H]+ Calcd for C25H18FN2O2 397.1352; Found 397.1359.
(3C), 34.4, 55.3, 107.8 (2C), 114.3 (2C), 124.5, 125.1 (2C), 125.4 5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-
(2C), 128.1, 128.3 (2C), 129.5 (2C), 137.7, 137.9, 139.8, 149.3 pyrrole-3-carbaldehyde (5s). Yellowish viscous liquid (65 mg,
1
(2C), 150.5, 159.2, 186.0; IR (KBr)/cm-1 2960, 1658, 1597, 1512, 58% yield); H NMR (400 MHz, CDCl3) 3.77 (s, 3H), 6.75 (d, J =
1435, 1296, 1251, 1190; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for 8.9Hz, 2H), 6.85-6.95 (m, 5H), 7.03-7.10 (m, 4H), 8.53 (d, J = 5.9
C27H27N2O2 411.2072; Found 411.2077.
5-(3-methoxyphenyl)-1-(4-methoxyphenyl)-2-(pyridin-4-yl)-
Hz, 2H), 9.75 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.4, 108.0,
114.4 (2C), 115.3 (2C, d, J = 21.6 Hz), 124.4, 125.4 (2C), 127.3 (d,
1H-pyrrole-3carbaldehyde (5n). Greenish semi-solid (70 mg, J = 3.5 Hz), 129.1, 129.4 (2C), 130.5 (2C, d, J = 8.1 Hz), 136.9,
61% yield); 1H NMR (400 MHz, CDCl3) δ 3.64 (s, 3H), 3.77 (s, 3H), 137.5, 139.9, 149.4 (2C), 159.3, 162.1 (d, J = 248.3 Hz), 186.0; IR
6.62-6.65 (m, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.73-6.80 (m, 3H), (KBr)/cm-12970, 1674, 1514, 1436, 1298, 1257, 1155; HRMS
6.91 (d, J = 8.9 Hz, 2H), 6.99 (s, 1H), 7.09 (d, J = 6.1 Hz, 1H), 7.13 (ESI-TOF) m/z: [M + H]+ Calcd for C23H18FN2O2 373.1352; Found
(t, J = 8.0 Hz, 1H), 8.54 (d, J = 5.4 Hz, 2H), 9.76 (s, 1H); 13C NMR 373.1349.
(100 MHz, CDCl3) 55.0, 55.4, 108.2, 113.6, 114.0, 114.3 (2C), 2-(4-nitrophenyl)-5-phenyl-1-(p-tolyl)-1H-pyrrole-3-
121.2, 124.4, 125.4, 129.2, 129.3, 129.4 (3C), 132.4, 137.6, carbaldehyde (5t). Yellow Solid (82 mg, 55% yield); 1H NMR (400
137.7, 140.0, 149.4 (2C), 159.2, 159.3, 186.1; IR (KBr)/cm-1 2924, MHz, CDCl3) δ 2.34 (s, 3H), 6.85–6.88 (m,2H), 7.02 (s, 1H), 7.04–
1680, 1506, 1456, 1249, 1178; HRMS (ESI-TOF) m/z: [M + H]+ 7.07 (m, 2H), 7.10–7.13 (m, 2H), 7.23–7.27 (m, 3H), 7.37–7.41
Calcd for C24H21N2O3 385.1552; Found 385.1559.
(m, 2H), 8.34–8.38 (m, 2H) 9.78 (s, 1H); 13C NMR (100 MHz,
2-(4-chlorophenyl)-1,5-bis(4-methoxyphenyl)-1H-pyrrole-3-
CDCl3) δ 21.1, 108.5, 123.2 (2C), 124.7, 125.3, 127.6, 128.2 (2C),
1
carbaldehyde (5o). Yellow semi-solid (82 mg, 66% yield); H 128.2 (2C), 128.8 (2C), 129.9 (2C), 131.2, 131.9 (2C), 134.1,
NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 3.77 (s, 3H), 6.71-6.77 (m, 136.3, 137.9, 138.7, 147.4, 186.0; m/z: [M+H]+ Calcd for
4H), 6.87 (d, J = 9.2 Hz, 3H), 7.01 (d, J = 8.8 Hz, 2H), 7.12 (d, J = C24H19N2O3, 383.1395; Found 383.1387.
8.5 Hz, 2H), 7.25 (m, 2H, includes CDCl3 peak), 9.68 (s, 1H); 13
C
1-(4-chlorophenyl)-2-(4-nitrophenyl)-5-phenyl-1H-pyrrole-3-
1
NMR (100 MHz, CDCl3) δ 55.2, 55.3, 106.7, 113.6 (2C), 114.1 carbaldehyde (5u). Yellow solid (70 mg, 58% yield); H NMR
(2C), 124.1, 1128.3 (2C), 129.1, 129.6 (2C), 130.1 (2C), 130.3, (400 MHz, CDCl3) δ 6.89–6.97 (m, 2H), 7.01 (s, 1H), 7.04–7.14
130.4, 130.7, 132.3 (2C), 134.6, 137.0, 158.9, 159.0, 186.5; IR (m, 2H), 7.21–7.34 (m, 5H), 7.32–7.43 (m, 2H), 8.14–8.24 (m,
(KBr)/cm-12954, 1668, 1514, 1251, 1176; HRMS (ESI-TOF) m/z: 2H), 9.77 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 108.8, 123.4 (2C),
[M + H]+ Calcd for C25H21ClNO3 418.1210; Found 418.1217.
2-(4-bromophenyl)-1,5-bis(4-methoxyphenyl)-1H-pyrrole-3-
carbaldehyde (5p). Brown pasty liqui semi-solid (90 mg, 65% 185.9; HRMS (ESI-TOF) m/z: [M+ H]+ Calcd for
yield); 1H NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 3.78 (s,3H), C23H16ClN2O3,403.0149; Found 403.0153.
125.0, 128.0, 128.4 (2C), 128.9 (2C), 129.6 (2C), 129.6 (2C),
130.8, 131.9 (2C), 134.7, 135.2, 135.8, 137.8, 139.8, 147.6,
6.73-6.76 (m, 4H), 6.87 (d, J = 9.2 Hz, 3H), 7.01 (d, J = 8.8 Hz, 1-(4-bromophenyl)-2-(4-nitrophenyl)-5-phenyl-1H-pyrrole-3-
2H), 7.05 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 9.68 (s, 1H); carbaldehyd (5v). Yellow Solid (70 mg, 52% yield); 1H NMR (400
13C NMR (100 MHz, CDCl3) δ 55.2, 55.4, 106.7, 113.6 (2C), 113.7, MHz, CDCl3) δ 6.85–6.87 (d, J = 8.6 Hz, 2H), 7.01 (s, 1H), 7.09–
114.1 (2C), 122.9, 123.9, 124.0, 128.5, 129.6 (2C), 130.1 (2C), 7.11 (m, 2H), 7.26–7.29 (m, 2H), 7.34–7.43 (m, 4H), 8.18–8.21
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(d, J = 8.2 Hz, 2H), 9.76 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 5-(4-tert-butylphenyl)-1-(4-methoxyphenyl)-4-phVeienwyAl-rt2ic-le Online
DOI: 10.1039/D0NJ03575K
108.9, 122.6, 123.4 (2C), 125.0, 127.9, 128.4 (2C), 128.9 (2C), (pyridin-4-yl)-1H-pyrrole-3-carbaldehyde (6d). Yellow semi-
129.9 (2C), 130.7, 131.8 (2C), 132.5 (2C), 135.7, 135.8, 137..8, solid (100 mg, 69% yield); 1H NMR (400 MHz, CDCl3) δ 1.29 (s,
139.7, 147.5, 185.8; HRMS (ESI-TOF) m/z: [M + H]+Calcd for 9H), 3.70 (s, 3H), 6.66 (d, 7.4 Hz, 2H), 6.78 (d, J = 7.4 Hz, 2H),
C23H16BrN2O3447.0344; Found 447.0349.
7.09 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 4.9 Hz, 2H), 7.29 (d, J = 7.1
General procedure for the synthesis of fully substituted 2, 4, 5- Hz, 2H), 7.39 (s, 5H), 8.67 (d, J = 4.8 Hz, 2H), 9.93 (s, 1H); 13C
tri-aryl pyrrole-3-carboxaldehydes (6). To a stirred solution of NMR (100 MHz, CDCl3) δ 31.1 (3C), 34.5, 55.3, 99.7, 114.2 (2C),
5 (0.3 mmol) in CH3CN (4.0 mL) was added N-bromo- 120.3, 124.9, 125.0, 125.6, 126.1, 126.2, 127.4 (2C), 128.6,
succinimide (NBS) (0.3 mmol) and further heated at 80 °C for 4 129.2 (2C), 129.4, 130.2, 130.3, 133.5 (3C), 135.8, 136.0, 139.4,
h. The reaction was cooled to room temperature and solvent 146.4, 146.4, 151.4, 159.3, 185.8; HRMS (ESI-TOF) m/z: [M + H]+
were evaporated under reduced pressure. The crude material Calcd for C33H31N2O2 487.2385; Found 487.2392.
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was taken in saturated NaHCO3 solution (5.0 mL) and extracted 2-(4-bromophenyl)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-
with EtOAc (2 × 5.0 mL) the combined organic layer was washed 4-phenyl-1H-pyrrole-3-carbaldehyde (6e). Yellow liquid (100
with brine and dried over Na2SO4 and concentrated under mg, 64% yield); 1H NMR (400 MHz, CDCl3) δ 3.73 (s, 3H), 6.68 (d,
vacuum. This intermediate bromo-compound was taken in DMF J = 8.9 Hz, 2H), 6.74-6.83 (m, 2H), 6.88 (d, J = 8.9 Hz, 2H), 7.29
(3.0 mL) and added PhB(OH)2 (1.0 equiv.), Pd(PPh3)4 (10 mol%), (dd, J = 16.6, 6.0 Hz, 4H), 7.34-7.38 (m, 1H), 7.43 (t, J = 7.5 Hz,
and K2CO3 (2M solution, 78 μL, 0.15 mmol) under an inert 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 9.87 (s, 1H);
atmosphere. The reaction was further heated to 110 °C for 4 h 13C NMR (100 MHz, CDCl3) δ 55.3, 113.9 (2C), 114.0, 114.8,
and progress monitor by TLC. After completion, reaction was 115.0, 124.3, 126.4 (2C), 126.6, 127.3, 127.7 (2C), 128.6, 128.8
cooled and filtered through celite and crude material was (2C), 129.5, 129.8 (2C), 130.8 (2C), 131.7 (2C), 132.9, 133.0,
chromatographically purified using Hexane: EtOAc (20:1) gave 133.5, 140.1, 140.9, 158.8, 187.1; HRMS (ESI-TOF) m/z: [M + H]+
fully substituted pyrroles 6 in good yields (64-71%).
Calcd for C30H22BrFNO2 526.0818; Found 526.0868.
4-(3-formyl-1-(4-methoxyphenyl)-4-phenyl-5-p-tolyl-1H-
4-(5-(4-fluorophenyl)-3-formyl-1-(4-methoxyphenyl)-4-
pyrrol-2-yl)benzonitrile (6a). Brownish solid (mp = 179-181 °C, phenyl-1H-pyrrol-2-yl)benzonitrile (6f). Brownish semi-solid
95 mg, 68% yield); 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H), 3.69 (92 mg, 65% yield); 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 6.77
(s, 3H), 6.62 (d, J = 8.6 Hz, 2H), 6.72 (d, J = 12.4 Hz, 2H), 6.78(t, (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 6.88-6.93 (m, 2H), 6.98
J = 8.5 Hz, 2H), 6.83 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 3.4 Hz, 1H), (t, J = 8.7 Hz, 2H), 7.15-7.18 (m, 1H), 7.27-7.32 (m, 6H), 7.37 (d,
7.21 (s, 5H), 7.31 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.9 Hz, 2H), 9.78 J = 8.5 Hz, 2H), 9.83 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3,
(s, 1H) ; 13C NMR (100 MHz, CDCl3) δ 21.1, 55.2, 111.6, 113.9 111.9, 114.1 (2C), 114.9, 118.4, 125.5, 127.0, 128.0 (2C), 128.6,
(2C), 115.5, 118.5, 120.5, 126.7, 128.2, 128.5, 128.5 (2C), 128.7, 129.1, 129.4 (2C), 129.6 (2C), 130.8 (2C), 131.5 (2C), 131.8 (2C),
128.8, 128.9, 129.1, 129.3, 129.5, 129.6 (2C), 129.7, 130.6, 132.6 (2C), 132.7, 132.9, 133.7, 134.9,.159.1, 159.3, 186.9;
130.9 (2C), 131.4, 131.5, 131.7, 131.8, 137.1, 158.9, 187.0; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C31H22FN2O2 473.1665;
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H25N2O2 469.1916; Found 473.1671.
Found 469.1922.
1-(4-methoxyphenyl)-2-(4-nitrophenyl)-5-phenyl-4-
1-(4-methoxyphenyl)-4-phenyl-2-(pyridin-4-yl)-5-(p-tolyl)-1H- (phenylethynyl)-1H-pyrrole-3 carbaldehyde (7). To the stirred
pyrrole-3-carbaldehyde (6b). Yellow semi-solid (95 mg, 71% solution of pyrrole 5b (119 mg, 0.3 mmol) in CH3CN (4.0 mL) was
yield); 1H NMR (400 MHz, CDCl3) δ 2.32 (s, 3H), 3.73 (s, 3H), 6.66 added N- Bromosuccinimide (NBS, 0.3 mmol) at rt and heated
(d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.9 Hz, 2H), 7.07 (d, J = 3.0 Hz, at 80 oC for 4 h. The reaction was cooled to rt and solvent was
3H), 7.10 (d, J = 6.0 Hz, 2H), 7.38-7.41 (m, 1H), 7.44-7.49 (m, evaporated under reduced pressure. The crude material was
2H), 7.53-7.57 (m, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.4 taken in saturated NaHCO3 solution (5.0 mL) and extracted with
Hz, 1H), 8.54 (d, J = 6.1 Hz, 2H), 9.90 (s, 1H); 13C NMR (100 MHz, EtOAc (2 × 5.0 mL) the combined organic layer was washed with
CDCl3) δ 21.3, 55.3, 114.2 (2C), 120.1, 125.6, 126.0, 128.4 (2C), brine and dried over Na2SO4 and concentrated under vacuum.
128.5 (2C), 128.8 (2C), 128.9, 129.4 (2C), 130.6 (2C), 131.9 (2C), This intermediate bromo-compound was taken in dry DMF (3.0
132.0 (2C), 132.1 (2C), 133.6, 133.4, 149.0 (2C), 159.3, 185.7; mL) and added Et3N (0.6 mmol, 2.0 equiv.), phenyl acetylene
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C30H25N2O2 445.1916; (0.45 mmol, 1.5 equiv.), CuI (10 mol%), Pd(PPh3)4 (10 mol%),
o
Found. 445.1922.
5-(4-tert-butylphenyl)-2-(4-chlorophenyl)-1-(4-methoxy
and further purged with N2 before heating to 110 C for 5 h.
After completion, reaction was cooled and filtered through
phenyl)-4-phenyl-1H-pyrrole-3-carbaldehyde (6c). Reddish celite and crude material was chromatographically purified
semi-solid (103 mg, 66% yield); 1H NMR (400 MHz, CDCl3) δ 1.23 using Hexane:EtOAc (20:1) gave fully substituted pyrroles 7 as
(s, 9H), 3.76 (s, 3H), 6.68 (d, J = 8.9 Hz, 2H), 6.85 (t, J = 8.8 Hz, red-oily liquid (106 mg, 72% after two steps). 1H NMR (400 MHz,
4H), 7.08 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 7.28 (s, 7H), CDCl3) δ 3.75 (s, 3H), 6.71 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz,
9.83 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 31.1 (3C), 34.4, 55.3, 2H), 7.28-7.32 (m, 8H), 7.38 (d, J = 8.7 Hz, 2H), 7.46-7.43 (m, 2H),
113.7 (2C), 120.5, 124.6 (2C), 126.5, 127.4, 127.6 (2C), 128.1 8.12 (d, J = 8.7 Hz, 2H), 10.12 (s, 1H); 13C NMR (100 MHz, CDCl3)
(2C), 128.3, 129.5, 129.7 (2C), 130.4, 130.7 (2C), 130.9 (2C), δ 55.3, 81.9, 93.6, 114.3 (2C), 122.9 (2C), 127.9 (2C), 128.0,
132.5 (2C), 133.5, 134.0, 134.3, 140.4, 150.1, 158.7, 187.0; 128.1, 128.2 (2C), 128.5, 128.6, 128.8 (2C), 129.4 (2C), 130.0
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C34H31ClNO2 520.2043; (2C), 131.3 (2C), 131.8, 132.0 (2C), 136.1, 136.9, 139.8, 147.4,
Found 520.2049.
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159.4, 185.9; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H23N2O4 158.9, 167.6; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C28H25N2O5
View Article Online
DOI: 10.1039/D0NJ03575K
499.1658; Found 499.1662.
469.1763; Found 469.1769.
(E)-2-(4-bromophenyl)-3-((2-(2,4-dinitrophenyl)hydrazono)
3-(1-(4-methoxyphenyl)-5-phenyl-3-(5-phenyl-1,3,4-
methyl)-1-(4-methoxyphenyl)-5-phenyl-1H-pyrrole (9). To a oxadiazol-2-yl)-1H-pyrrol-2-yl) benzonitrile (14). To a stirred
stirred solution of 5b (92 mg, 0.23 mmol) in EtOH (3.0 mL) was solution of 5c (90 mg, 0.24 mmol) in MeOH (3.0 mL) was added
added 2, 4-dinitro-phenylhydrazine 8 (46 mg, 0.23 mmol) and 4-nitrobenzohydrazide (44.0 mg, 0.24 mmol) at stirred at 80 oC
CH3CO2H (100 mol %) and heated to 80 °C for 3 h. After for 2 h. Next, IBD 13 (Iodobenzene diacetate) (80 mg, 0.24
complete, reaction was cooled, and solid material was filtered mmol) in CH3CN (3.0 mL) was added in the same reaction vessel
and washed with EtOH (5.0 mL). The crude dried sloid material and stirred at rt for 1 h. The reaction was quenched with
was further recrystallized with MeOH gave pure product 9 as a saturated NaHCO3 solution (5.0 mL) and extracted with EtOAc
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red-amorphous solid (165 mg, 90% yield). H NMR (400 MHz, (2 × 5 mL). The combined organic extracts were washed with
CDCl3) δ 3.78 (s, 3H), 6.74 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, brine, dried over anhydrous Na2SO4, and concentrated under
2H), 7.01 (d, J = 8.1 Hz, 3H), 7.15 (dd, J = 6.9, 2.4 Hz, 2H), 7.21 – reduced pressure. The crude material was just passed through
7.25 (m, 3H), 7.46 (d, J = 8.3 Hz, 2H), 7.94 (s, 1H), 8.01 (d, J = 9.6 the small pad of silica gel column using EtOAc/hexane (1:2) gave
1
Hz, 1H), 8.30 (dd, J = 9.6, 2.2 Hz, 1H), 9.12 (d, J = 2.4 Hz, 1H), 14 (90 mg, 76% yield) as yellow semi-solid solid. H NMR (400
11.16 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 55.3, 106.6, 114.1 MHz, CDCl3) δ 3.77 (s, 3H), 6.74 (d, J = 8.9 Hz, 2H), 6.91 (d, J =
(2C), 116.6, 117.8, 122.6, 123.6, 127.2, 128.1 (2C), 128.5, 128.6 8.9 Hz, 2H), 7.12 (s, 1H), 7.13-7.17 (m, 2H), 7.24 (dd, J = 5.2, 1.9
(2C), 129.2, 129.5 (2C), 129.8, 130.2, 131.5 (2C), 131.7, 132.3 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.47 (dt, J = 5.8, 3.7 Hz, 3H), 7.53-
(2C), 137.2, 137.3, 137.7, 143.7, 144.6, 158.8; HRMS (ESI-TOF) 7.57 (m, 1H), 7.58-7.62 (m, 1H), 7.65-7.62 (m, 1H), 7.85 (dd, J =
m/z: [M + H]+ Calcd for C30H22N6O7 579.1628; Found 579.1654. 7.9, 1.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.3, 107.8, 108.9,
(1-(4-methoxyphenyl)-2-(4-nitrophenyl)-5-phenyl-1H-pyrrol-
111.9, 114.1 (2C), 118.3, 123.8, 126.4 (2C), 127.3, 128.1 (2C),
3-yl) methanol (10). To a stirred solution of 5b (64 mg, 0.16 128.6 (2C), 128.9 (2C), 129.6 (2C), 129.7, 130.0, 131.3, 131.4,
mmol) in MeOH (2.0 mL) at 0 °C was added NaBH4 (1.0 equiv.) 131.5, 132.5, 133.4, 134.7, 135.8, 137.0, 159.0, 161.6, 163.2;
slowly and stirred for 3 h at the same temperature. The reaction HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C32H23N4O2 [M + H]+
was quenched with saturated NaHCO3 solution (2.0 mL) and 495.1821; Found 495.1826.
extracted with ethyl acetate (5.0 mL). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The crude material
Conflicts of interest
was passed through a small pad of silica gel column by eluting
the mixture of EtOAc/hexane gave 10 (56 mg, 88% yield) as
yellow semi-solid liquid. 1H NMR (400 MHz, CDCl3) δ 3.78 (s, 3H),
4.61( s, 2H), 6.59 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 7.07-
7.09 (m, 2H), 7.19 (bs, 3H), 7.29 (d, J = 8.7 Hz, 2H), 8.06 (d, J =
8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 55.3, 57.8, 110.8, 114.1
(2C), 123.1 (2C), 123.9, 126.8, 128.0 (2C), 128.6 (2C), 129.6 (2C),
130.5 (2C), 130.9, 131.4, 132.3, 136.5, 138.4, 145.9, 158.7; IR
(KBr)/cm-1 3430, 2933, 1724, 1249, 1174; HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C24H21N2O4 401.1501; Found 401.1510.
(E)-ethyl 3-(1-(4-methoxyphenyl)-2-(4-nitrophenyl)-5-phenyl-
1H-pyrrol-3-yl) acrylate (12). To a stirred solution of 5b (64 mg,
0.16 mmol) in dry THF (3.0 mL) at 0 oC was added
diethylphosphanoacetate 11 (0.19 mmol, 1.2 equiv), followed
by NaH (2.5 equiv.,) under inert atmosphere and stirred further
for 3 h. The reaction was quenched with saturated NaHCO3
solution (5.0 mL) and extracted with EtOAc (2 × 5 mL). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The crude material was just passed through the small pad of
silica gel column by eluting the mixture of EtOAc/hexane gave
12 (62 mg, 83% yield) as yellow solid. 1H NMR (400 MHz, CDCl3)
δ 1.30 (t, J = 7.1 Hz, 3H), 3.76 (s, 3H), 4.22 (q, J = 7.1 Hz, 2H), 6.31
(d, J = 15.6 Hz, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.76 (s, 1H), 6.86 (d,
J = 9.0 Hz, 2H), 7.10 (m, 2H), 7.22 (d, J = 2.7 Hz, 2H), 7.24 (d, J =
8.9 Hz, 3H), 7.60-7.51 (m, 1H), 8.12 (d, J = 8.9 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 14.3, 55.3, 60.1, 107.2, 114.2 (2C), 115.7,
120.2, 123.2 (2C), 127.2, 128.1 (2C), 128.7 (2C), 129.4 (2C),
130.2, 131.4 (2C), 131.6, 135.2, 137.1, 137.4, 137.8, 146.7,
There are no conflicts to declare.
Acknowledgements
This work was supported by DST-SERB and BITS Pilani. Authors
also grateful for generous support from the DST-FIST
(SR/FST/CSI-270/2015) for HRMS facility to the Department of
Chemistry at BITS-Pilani.
Notes and references
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DOI: 10.1039/D0NJ03575K
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Graphical Abstract:
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A sequential multicomponent method is developed to access highly substituted N-Arylpyrrole-3-
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carbaldehydes and tested for antibacterial and antifungal activities against the bacterial strains.
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CO2Et
R
R1
N
Ar
N
NH2
Ar
H
R'
CHO
R
N
proline
O
(20 mol%)
O
O
+
R1
R1
CHO
N
DMSO, rt
R
R1
R
N
Ar
R = Ar, HetAr
R1 = Ar
Ar
one-pot sequential multicomponent protocol
28 examples (up to 70% yield)
R2
CHO
access to related fused heterocycles
antibacterial, antifungal activites with docking study
R1
R
N
Ar