Multicomponent Cascade Reaction by Metal-Free Aerobic Oxidation for Synthesis of Highly Functionalized 2-Amino-4-coumarinyl-5-arylpyrroles

Article abstract of DOI:10.1021/acs.joc.9b02063

A novel approach has been constructed for the synthesis of two types of 2-amino-4-coumarinyl-5-arylpyrroles (ACAPs, 5 and 6) through a cascade reaction and a metal-free catalyzed aerobic oxidation reaction of arylglyoxal monohydrates 1, 1,1-enediamines (E

Full text of DOI:10.1021/acs.joc.9b02063

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Article
Multicomponent cascade reaction by metal-free aerobic oxidation for
synthesis of highly functionalized 2-amino-4-cumarinyl-5-arylpyrroles
Quan-Xing Zi, Chang-Long Yang, Kun Li, Qin Luo, Jun Lin, and Sheng-Jiao Yan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02063 • Publication Date (Web): 04 Dec 2019
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Multicomponent cascade reaction by metal-free
aerobic oxidation for synthesis of highly
functionalized 2-amino-4-cumarinyl-5-arylpyrroles
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Quan-Xing Zi, Chang-Long Yang, Kun Li, Qin Luo, Jun Lin* and Sheng-Jiao Yan*
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of
Education, School of Chemical Science and Technology, Yunnan University, Kunming, 650091,
P. R. China.
KEYWORDS: 2-Aminopyrroles, cascade reaction, aerobic oxidation, 1,1-enediamines.
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ABSTRACT: A novel approach has been constructed for the synthesis of two types of 2-amino-
4-cumarinyl-5-arylpyrroles (ACAPs, 5−6) through a cascade reaction and a metal-free catalyzed
aerobic oxidation reaction of arylglyoxal monohydrates 1, 1,1-enediamines (EDAMs) 2−3, and
4-hydroxy-2H-chromen-2-ones 4 via multicomponent reactions to produce the target compounds
with good to excellent yields. Specifically, hydroxyl-substituted 2-amino-4-cumarinyl-5-
arylpyrroles, that is, 2-amino-4-cumarinyl-5-aryl-6-hydroxylpyrroles (ACAHPs) 6, were
obtained by metal-free aerobic oxidation in 1,4-dioxane at simple reflux for approximately 10
hours. As a result, ACAHPs 6 have been produced without metal catalysts or traditional
oxidizing agents. This method represents a route to obtain the novel ACAPs in an
environmentally friendly, concise, rapid, and practical manner with potential biological activity
of the product.
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 INTRODUCTION
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2-Aminopyrroles, as a representative heterocyclic skeleton structure, widely exist in numerous
pharmaceuticals and natural products. These types of compounds have a diverse range of
bioactivities including metallo--lactamase (MBL) inhibitor,1 MAPK/ERK kinase (MEK)
inhibitor2 (Fig. 1), tumor necrosis factor (TNF)-α production inhibitor, phosphodiesterase (PDE)
inhibitor,3 and protein kinase casein kinase 2 (CK2) inhibitor, as well as antimalarial,
antibacterial, and cytotoxic activities.4 Furthermore, 2-aminopyrroles have been used as
precursors for the synthesis of purine analogues, including pyrrolopyrimidines, pyrrolotriazines,
and pyrrolopyridines.
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Figure 1. Bioactive 2-aminopyrroles, coumarins and target compounds 5–6.
The methodology for synthesis of pyrrole derivatives has been previously reported, and
various substituted pyrroles have been obtained.5-9 However, only a few protocols have been
used to construct a library of 2-aminopyrroles through classic methods.10-13 The classic synthesis
methods for 2-aminopyrroles include multicomponent reactions based on nitriles or
isocyanides,10-11 and cycloisomerization of alkyne and allene-containing substrates catalyzed by
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transition metal complexes.12-13 Although these methods have laid a solid foundation for the
synthesis of 2-aminopyrroles, they usually have some shortcomings, such as reliance on
expensive transition metals or requiring harsh reaction conditions or tedious workup
procedures.14
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Currently, there is a lack of efficient and practical methods for synthesis of highly
functionalized 2-aminopyrroles, for example, cumarin-substituted 2-aminopyrroles. However,
the functionalized groups usually have important and widespread biological activities. Among
them, the cumarin, as a “privileged” structural motif, is distributed in naturally occurring
compounds with a broad spectrum of significant biological activities including anti-HIV,15 anti-
tumor (Fig. 1, Compounds A−C)16 anti-inflammatory, anti-microbial, and anti-hyperglycemic
activities.17-19 Consequently, there has been great interest in hybrid molecules of functionalized
group with N-containing heterocycles. Here, our goal is to incorporate the chromene skeleton
into 2-aminopyrroles and design and synthesize 2-amino-4-cumarinyl-5-aryl pyrroles (ACAPs).
Additionally, it is extremely desirable to develop an efficient and metal-free approach toward
ACAPs, aiming at achieving diversity in molecular structures from available building blocks and
under mild reaction conditions.
Scheme 1. Methods for the construction of 2-amino-4-cumarinyl-5-arylpyrroles
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1,1-Enediamines (EDAMs) are versatile building blocks that are widely used to construct
various fused heterocycles.20-27 Some of these compounds have broad-spectrum biological
activities such as anti-tumor,22-23 herbicide, pesticide,24 anti-anxiety,25 anti-leishmanial,26 and
anti-bacterial.27 To further synthesize functionalized heterocyclic compounds with
pharmacological activity and from EDAMs, we designed and constructed chromene-substituted
2-aminopyrroles, that is, ACAPs (Scheme 1). Unexpectedly, as cyclic EDAMs are used in this
reaction, we can obtain a 2-amino-4-cumarinyl-5-aryl-6-hydroxylpyrroles library (ACAHPs) 6
by metal-free aerobic oxidation in 1,4-dioxane at simple reflux for approximately 10 hours.
Using this property, various ACAHPs can be regioselectively constructed based on the cyclic
EDAM building blocks. This provides the key information to design new substrates to capture
the free radical intermediate (for examples, see Scheme 2, intermediate 16). However, based on
the mechanism of this cascade reaction, different functionalized groups such as pyridine- and
quinoline-functionalized 2-aminopyrroles will be constructed in the future. Optimal conditions
will result in the production of the dimer of intermediate 16.
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RESULTS AND DISCUSSION
To obtain the optimal reaction conditions for the synthesis of the target compounds, the
reaction of 2,2-dihydroxy-1-(p-tolyl)ethanone (1a), N-(3-methoxyphenethyl)-2-nitroethene-1,1-
diamine (2a), and 4-hydroxy-2H-chromen-2-one (4a) was chosen as the model reaction. First,
the three-component reaction was refluxed in different solvents, which included 1,4-dioxane,
H2O, and acetone (Table 1, entries 1−3). The results showed that the reaction could not proceed
in the prospective solvents (Table 1, entries 1−3). Then, the green solvent EtOH was used under
the same conditions, and the reaction produced the target compound with an excellent yield
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(91%) (Table 1, entry 4). Then, Et3N as a basic additive was added to the mixture in 1,4-dioxane,
H2O, and acetone at the reflux temperature (Table 1, entries 5−7). The results revealed that Et3N
could not promote the reaction and also could not produce the target compound (Table 1, entries
5−7). Next, Et3N as an additive was incorporated in this reaction, which was refluxed in ethanol,
and it was found that the reaction was more complex. The result showed that Et3N is not suitable
for this cascade reaction. Finally, the reaction times were also screened, and it was found that the
optimal reaction time was approximately 6 h (Table 1, entry 9 vs. 4 and 10). Based on the above
results, we determined that the optimal reaction conditions were the use of EtOH as the solvent
and refluxing for approximately 6 hours without any additives. These conditions produced the
target compound with an excellent yield (93%) (Table 1, entry 9).
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Table 1. Optimization of the reaction conditions for the model reactiona
entry
solvent
1,4-dioxane
H2O
Additiveb
−
t (℃)
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
time/min
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Yield c (%)
complex
complex
complex
91
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5
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8
−
12
acetone
EtOH
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12
−
12
1,4-dioxane
H2O
Et3N
Et3N
Et3N
Et3N
12
complex
complex
complex
complex
12
acetone
EtOH
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EtOH
EtOH
−
−
reflux
reflux
6
4
93
89
10
a Reagents and conditions: Arylglyoxal monohydrate 1a (166.1 mg, 1.0 mmol), EDAM 2a
(237.1 mg, 1.0 mmol), 4-hydroxy-2H-chromen-2-one 4a (162.0 mg, 1.0 mmol) and solvent
(10 mL). b Additive (1.0 mmol). c Isolated yield based on 2a.
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After determining the most optimal reaction conditions, we explored the scope and limitations
of the three-component cascade reaction with various arylglyoxal monohydrates 1, EDAMs 2,
and 4-hydroxy-2H-chromen-2-ones 4. The results revealed that in all cases, the reaction
proceeded smoothly in EtOH at reflux conditions for approximately 6 hours (Table 2, entries
1−11). The different substituent groups (R) of arylglyoxal monohydrates 1 and 4-hydroxy-2H-
chromen-2-ones 4 usually had a slight effect on the yields, but the difference was very small, and
we could not ascertain the effect of any specific substituent. However, the substituent group of
EDAMS 2 had an obvious effect on the yield of compounds 5. In general, EDAMs 2a−2e with a
longer chain usually produce the target compounds with higher yields as compared to reactions
using EDAMs (2f−2g) with a shorter chain (Table 2, entry 4 vs. 7). Overall, reactions with
different substituted substrates 1−3 can proceed smoothly and produce compounds 5 with
excellent yields (80%−94%).
The feasibility of the present method was also examined by gram-scale experimentation that
was conducted with a mixture of 2,2-dihydroxy-1-phenylethanone 1b (0.456 g, 3.0 mmol), (Z)-2-
nitro-N-phenethylethene-1,1-diamine 2c (0.622 g, 3.0 mmol), and 4-hydroxy-2H-chromen-2-one
4a (0.486 g, 3.0 mmol), with ethanol (20 mL) as the solvent. The reaction mixture was then
refluxed for 6 hours. The reaction was found to proceed smoothly, producing the desired product
of target compounds 5e with a yield of 87% (1.220 g), which was similar in all respects with the
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1 mmol scale entry (Table 2, entry 5 vs. 12). This result demonstrates that this cascade reaction is
5
6
efficient for gram-scale production as well (Table 2, entry 12).
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Table 2. The synthesis of 2-amino-4-cumarinyl-5-arylpyrroles (ACAPs) 5a–5ka
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Entry
1
1/R/R'
1a/CH3
1a/CH3
1b/H
1b/H
1b/H
1b/H
1b/H
1b/H
1c/F
2/R1
4/R2
4a/H
4b/Br
4a/H
4a/H
4a/H
4a/H
4a/H
4b/Br
4a/H
4a/H
4b/Br
4a/H
Yield (%)
93
5
5a
5b
5c
5d
5e
5f
2a/p-MeOC6H4(CH2)2
2d/p-ClC6H4(CH2)2
2a/p-MeOC6H4(CH2)2
2b /p-MeC6H4(CH2)2
2c/C6H5(CH2)2
2
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93
5
90
6
91
2e/p-FC6H4(CH2)2
2f/p-MeC6H4CH2
2g/p-MeC6H5
7
85
5g
5h
5i
8
80
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90
2a/p-MeOC6H4(CH2)2
2b /p-MeC6H4(CH2)2
2c/C6H5(CH2)2
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1c/F
92
5j
1c/F
94
5k
5e
1b/H
87b
2c/C6H5(CH2)2
a
Unless otherwise mentioned, the reaction conditions are arylglyoxal monohydrates 1 (1.0
mmol), EDAMs 2 (1.0 equiv), 4-hydroxy-2H-chromen-2-ones 4 (1.0 equiv), Ethanol (10 mL). b
Arylglyoxal monohydrates 1 (3.0 mmol), EDAMs 2 (1.0 equiv), 4-hydroxy-2H-chromen-2-
ones 4 (1.0 equiv), Ethanol (20 mL).
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To further explore the scope and limitations of the cascade reaction, we used various 2,2-
dihydroxy-1-phenylethanone 1b and 4-hydroxy-2H-chromen-2-one 4a compounds as substrates
to react with 1-(4-chlorophenyl)-2-(tetrahydropyrimidin-2(1H)-ylidene)ethanone 3h and screen
for the optimal conditions. First, the three-component reaction was refluxed in different solvents
including Triton X-100, propylene carbonate (PC), 3-methyl-1-octylimidazolium
hexafluorophosphate ([MOMIM]PF6), EtOH, H2O, H2O2 and 2-methyl-2-butanol (MBTL) at
reflux conditions (Table 3, entries 1−7). The results showed that the reaction could not proceed
in Triton X-100 or PC or [MOMIM]PF6 (Table 3, entries 1−3). However, when EtOH was used
as the solvent under the same conditions, the reaction produced the target compound with 70%
yield (Table 3, entry 4). When water or H2O2 was used as the solvent under the same conditions,
the reaction produced the target compound with moderate yield (52% vs. 60%) (Table 3, entry 5
vs. 6). Then, MBTL or 1,4-dioxane was screened using the same conditions, and we found that
1,4-dioxane was the optimal solvent and produced compounds 6r with good yield (80%) (Table
3, entry 8 vs. 1−7). Then, basic additives such as Et3N or piperidine were added to the mixture in
1,4-dioxane at the reflux temperature. The results showed that the basic additives could not
advance the reaction at all (Table 3, entry 8 vs. 9−10). Finally, the reaction times were also
screened, and it was determined that the optimal time was approximately 10 hours (Table 3,
entry 8 vs. 11−12). Based on the results, we consequently found that the optimal conditions were
1,4-dioxane as the solvent at reflux for approximately 10 hours without any additives.
Unexpectedly, we found that the target compounds were 2-amino-4-cumarinyl-5-aryl-6-
hydroxylpyrroles (ACAHPs) 6 rather than 2-amino-4-cumarinyl-5-aryl-pyrroles (ACAPs) 7. It is
must be pointed out that the reaction produced two target compounds, ACAHP (6r) and ACAP
(7r), when EtOH was used as the solvent (Table 3, entry 4), although it is easy to oxidize (ACAP)
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7r to ACAHP (6r) during column chromate-graphic separation or reduced pressure
concentration. After our best efforts, we obtained a little of 7r. This is important data that will
contribute to the hypothesis mechanism (Scheme 2).
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Table 3. Optimization of the reaction conditions for the model reactiona
Entry
1
Solvent
Tritonx-100
PC
Additiveb
T(°C) t (h) 6r/Yieldb(%) 7r/Yieldc (%)
−
−
reflux 10
reflux 10
reflux 10
reflux 10
reflux 10
reflux 10
reflux 10
reflux 10
reflux 10
−
−
−
2
−
3
[MOMIM]PF6
EtOH
−
−
−
4
−
70
52
60
50
80
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15
trace
trace
trace
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H2O
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6
H2O2
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MBTL
−
8
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
−
9
Et3N
36
−
10
11
12
Piperidine reflux 10
−
−
reflux
8
76
79
−
reflux 12
−
a Reagents and conditions: Arylglyoxal monohydrate 1b (166.1 mg, 1.0 mmol), HKA 3h (236.1
b
mg, 1.0 mmol), 4-hydroxy-2H-chromen-2-one 4a (162.0 mg, 1.0 mmol), solvent (10 mL).
Additive (1.0 mmol). c Isolated yield based on 3h.
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To further explore the scope and limitations of the cascade reaction, various arylglyoxal
monohydrates 1, EDAMs 3, and 4-hydroxy-2H-chromen-2-ones 4 were tested with the optimal
conditions (Table 4, entries 1−24). The results demonstrated that in all cases except nitro-
substituted EDMA 3k, the reaction proceeded smoothly in 1,4-dioxane at reflux conditions for
approximately 10 hours (Table 4, entries 1−23). The different substituent groups of arylglyoxal
monohydrates and 4-hydroxy-2H-chromen-2-ones usually had a slight effect on the yields, but
the difference was very small, and we could not ascertain the effect of any specific substituent.
However, the ring size of EDAMs affected the yield of the cascade reaction. In general, the six-
numbered EDAMs are usually more favorable to the yield of the target compounds than that of
five-numbered EDAMs. However, after using nitro-substituted EDMA 3k as the substrate to
react with arylglyoxal monohydrates 1b and 4-hydroxy-2H-chromen-2-one 4a, complicated
compounds were produced, and we could not obtain the pure products. Overall, the different
substituted substrates 3 other than 3k reacted with 1 and 4 and produced compound 6 with good
yields (60%−90%).
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Table 4. The synthesis of 2-amino-4-cumarinyl-5-aryl-6-hydroxylpyrroles (ACAHPs) 6a
Entry
1/R/R '
1a/CH3/H
1a/CH3/H
1b/H/H
3/n/EWG
3b/1/PhCO
4/R2
4a/H
4a/H
4c/Cl
Yieldb (%)
6
1
2
3
76
82
78
6a
6b
6c
3d/1/p-ClPhCO
3b/1/PhCO
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4
1b/H/H
1b/H/H
1b/H/H
1b/H/H
1d/F/F
3e/1/p-FPhCO
3e/1/p-FPhCO
3d/1/p-ClPhCO
3c/1/p-BrPhCO
3a/1/p-MePhCO
3d/1/p-ClPhCO
3g/2/PhCO
4a/H
4c/Cl
4a/H
4c/Cl
4a/H
4a/H
4d/CH3
4c/Cl
4a/H
4d/CH3
4a/H
4b/Br
4a/H
4a/H
4a/H
4c/Cl
4c/Cl
4a/H
4a/H
4a/H
4a/H
83
80
6d
6e
6f
5
6
80
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85
6g
6h
6i
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8
73
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1d/F/F
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1a/CH3/H
1a/CH3/H
1a/CH3/H
1a/CH3/H
1b/H/H
1b/H/H
1b/H/H
1b/H/H
1b/H/H
1b/H/H
1c/F/H
88
6j
3g/2/PhCO
89
6k
6l
3i/2/p-FPhCO
3h/2/p-ClPhCO
3f/2/p-MePhCO
3f/2/p-MePhCO
3g/2/PhCO
90
87
6m
6n
6o
6p
6q
6r
6s
85
87
87
3i/2/p-FPhCO
3h/2/p-ClPhCO
3h/2/p-ClPhCO
3g/2/PhCO
87
86
89
86
6t
1c/F/H
3i/2/p-FPhCO
3h/2/p-ClPhCO
3j/1/MeCO
88
6u
6v
6w
6x
1d/F/F
87
1b/H/H
1b/H/H
60
3k/1/NO2
complex
a Reagents and conditions: Arylglyoxal monohydrates 1 (1.0 mmol), HKAs 3 (1.0 equiv), 4-
hydroxy-2H-chromen-2-ones 4 (1.0 equiv), 1,4-dioxane (10 mL). b Isolated yield based on 2.
The chemical structure of all target derivatives (5−6) was fully characterized by infrared (IR)
spectroscopy, proton (1H) nuclear magnetic resonance (NMR), carbon-13 (13C) NMR, and high-
resolution mass spectrometry (HRMS). To further clarify the structure of the target products,
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compounds 6c and 6v were selected as representative compounds to cultivate single crystals, and
were unequivocally confirmed by X-ray diffraction (XRD) analysis (Supporting Information,
Figure S1 and Figure S2, CCDC1916446 and CCDC1916449).
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Based on the above experimental results, we propose a mechanism, which is shown as Scheme
2. First, the α-C of 4-hydroxy-2H-chromen-2-ones 4 attack the hemiacetal group of arylglyoxal
monohydrates 1 and one molecule of water is lost, which subsequently results in the formation of
intermediates 8. Intermediates 8 lose another molecule of water to produce intermediates 9. Then,
the α-C of EDAMs 3 attack the α,β-unsaturated double bond via Michael reaction to give
intermediates 10. Next, compounds 10, via imine-enamine tautomerism followed by a 1,2-
addition reaction, give intermediates 12. Compounds 7 are formed by successively losing one
molecule of H2O and ketone-enol tautomerism. Next, compounds 7 undergo tautomerism and
lose protons to form intermediates 15. Intermediates 15 react with the oxygen in the air to
produce intermediates 16 through single electron transfer (SET). Eventually, intermediates 16
are attacked by water in the mixture to obtain the target compound 6.
To confirm the mechanism used for this cascade reaction, 1-(4-chlorophenyl)-2-(imidazolidin-
2-ylidene)ethanone (3d), 4-hydroxy-2H-chromen-2-one (4a), and 1,4-dioxane were charged in a
round-bottom flask. Then, 2,2-dihydroxy-1-(p-tolyl)ethanone (1a) was added to the mixture, and
the reaction mixture was refluxed for only 3 hours. The reaction mixture was then injected into
the high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS)
system. The molecular ion peaks that appeared in the high-resolution mass spectrum were:
HRMS (TOF ES+): m/z calcd. for C29H24ClN2O5 [M+H]+, 515.1368; found, 515.1364; HRMS
(TOF ES+): m/z calcd. for C29H24ClN2O5 [M+H]+, 515.1368; found, 515.1359; HRMS (TOF
ES+): m/z calcd. for C29H24ClN2O5 [M+H]+, 515.1368; found, 515.1356. There are the HRMS
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Scheme 2. The proposed mechanism for the formation of ACAHPs 6
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spectra of intermediates 10b/11b/12b (supporting information, Figure S97−Figure S99); HRMS
(TOF ES+): m/z calcd. for C29H22ClN2O4 [M+H]+, 497.1263; found, 497.1259, HRMS (TOF ES+):
m/z calcd. for C29H22ClN2O4 [M+H]+, 497.1263; found, 497.1264, HRMS (TOF ES+): m/z calcd.
for C29H22ClN2O4 [M+H]+, 497.1263; found, 497.1257. There are the HRMS spectra of
intermediates 13b/7b/14b (SI, Figure S100−Figure S102); HRMS (TOF ES+): m/z calcd. for
C29H22ClN2O5 [M+H]+, 513.1212; found, 513.1204, which are the HRMS spectra of the target
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compounds 6b (SI, Figure S103). More importantly, intermediate 7b could easily have been
oxidized by oxygen to afford compound 6b.
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To prove that a single electron transfer (SET) occurred within the key intermediate 16f, we
used 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to trap the free radical intermediate 16f.
2,2-Dihydroxy-1-phenylethanone (1b), 3d, 4a and 1,4-dioxane were charged in a round-bottom
flask. Then, TEMPO was added to the mixture, and the reaction mixture was refluxed for only 3
hours. Then, the reaction mixture was injected into the HPLC-HRMS system. The molecular ion
peaks that appeared in the high-resolution mass spectrum were: HRMS (TOF ES+): m/z calcd.
for C37H37ClN3O5 [M+H]+, 638.2416; found, 5638.2430. The HRMS spectra of intermediates
16f-TEMPO is shown in the Supporting Information, Figure S104.
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Based on the above results, the proposed mechanism of the cascade reaction is described in
Scheme 2.
CONCLUSIONS
We have developed a green and practical strategy for the preparation of highly functionalized
ACAPs through a cascade reaction and a metal-free catalyzed aerobic oxidation reaction of
arylglyoxal monohydrates 1, EDAMs 2−3, and 4-hydroxy-2H-chromen-2-ones 4 via
multicomponent reactions. Interestingly, ACAHPs 6 were unexpectedly obtained by metal-free
aerobic oxidation in 1,4-dioxane at simple reflux for approximately 10 hours. Based on this
protocol, ACAHP 6 was constructed without metal catalysts or traditional oxidizing agents. This
method represents a route to obtain ACAHPs using an environmentally friendly oxidation
reaction, in a concise, rapid, and practical manner and with potential biological activity of the
product. Moreover, testing of this series of highly functionalized ACAHPs is underway to
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determine if any possess potential anti-inflammatory activity and then to test further to determine
which candidates possess good anti-inflammatory activity. Their biological activity, including
anti-inflammatory activity, will be reported in the future.
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 EXPERIMENTAL SECTION
General Methods. All compounds were fully characterised by spectroscopic data. The NMR
spectra were recorded on a Bruker DRX500 & DRX600. Chemical shifts (δ) are expressed in
ppm, J values are given in Hz, and deuterated DMSO-d6 ＆ CDCl3 were used as solvent. IR
spectra were recorded on a FT-IR Thermo Nicolet Avatar 360 using a KBr pellet. The reactions
were monitored by thin layer chromatography (TLC) using silica gel GF254. The melting points
were determined on a XT-4A melting point apparatus and are uncorrected. HRMs were
performed on an Agilent LC/Msd TOF instrument. Column chromatography was performed on
silica gel (200–300 mesh).
EDAMs 2–3 were synthesized by known literature procedures.28-29 All the other chemicals
used in the experiment were purchased from commercial sources and were used without further
purification.
General procedure for the synthesis of ACAPs 5. Arylglyoxal monohydrates 1 (1.0 mmol),
4-hydroxy-2H-chromen-2-ones 4 (1.0 mmol), and ethanol (10 mL) were placed into a 25-mL
round-bottom flask. Then, 1,1-enediamines (EDAMs) 2 (1.0 mmol) was added to this mixture,
and the mixture was refluxed until the completion of the reaction (approximately 6 hours), which
was monitored by thin-layer chromatography (TLC). The reaction mixture was cooled to room
temperature. Finally, the crystals were collected using a Buchner funnel and were washed with a
few milliliters of ethanol to obtain the target compounds 5 with good to excellent yield of
80%−94%.
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4-Hydroxy-3-(5-((4-methoxyphenethyl)amino)-4-nitro-2-(p-tolyl)-1H-pyrrol-3-yl)-2H-chrom-
en-2-one (5a). Yellow solid (475.4 mg, 93%); Mp: 275.6–276.0 °C; IR (KBr): 3300.1, 1618.6,
1642.5, 1433.7, 963.2, 825.9 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 2.25 (s, 3H, CH3), 2.93–
3.77 (m, 2H, CH2), 3.73–3.77 (m, 2H, NHCH2), 3.75 (s, 3H, OCH3), 6.92–6.93 (m, 2H, ArH),
7.13–7.15 (m, 2H, ArH), 7.26–7.41 (m, 6H, ArH), 7.62–7.65 (m, 1H, ArH), 7.82–7.84 (m, 1H,
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ArH), 8.14–8.16 (m, 1H, CH2NH), 11.11 (br, 1H, NH), 11.13 (s, 1H, OH); C{1H} NMR (150
MHz, DMSO-d6): δ = 21.2, 34.7, 44.6, 55.5, 99.7, 103.0, 114.3, 116.5, 116.6, 118.2, 124.0,
124.4, 127.0, 127.3, 128.6, 129.4, 130.3, 132.6, 137.4, 147.4, 152.9, 158.4, 161.4, 162.3; HRMS
(TOF ES+): m/z calcd for C29H25N3NaO6 [M+Na]+, 534.1636; found, 534.1634.
6-Bromo-3-(5-((4-chlorophenethyl)amino)-4-nitro-2-(p-tolyl)-1H-pyrrol-3-yl)-4-hydroxy-2H-
chromen-2-one (5b). Red solid (545.6 mg, 92%); Mp: 280.1–280.5 °C; IR (KBr): 3455.7, 1694.9,
1644.9, 1428.4, 111.8, 820.4 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 2.25 (s, 3H, CH3), 2.98–
3.01 (m, 2H, CH2), 3.73–3.77 (m, 2H, NHCH2), 7.14–7.15 (m, 2H, ArH), 7.24–7.26 (m, 2H,
ArH), 7.38–7.42 (m, 5H, ArH), 7.79–7.80 (m, 1H,ArH), 7.92–7.93 (m, 1H, ArH), 8.20–8.22 (m,
1H, CH2NH), 11.18 (br, 1H, NH), 11.48 (s, 1H, OH); 13C NMR (150 MHz, DMSO-d6): δ = 21.2,
34.9, 44.2, 100.6, 102.7, 116.3, 118.2, 118.5, 119.1, 126.2, 127.0, 127.3, 128.5, 128.8, 129.4,
131.2, 131.5, 135.1, 137.5, 138.3, 147.3, 151.9, 160.2, 161.8; HRMS (TOF ES+): m/z calcd for
C28H21BrClN3O5 [M+H]+, 594.0668; found, 594.0666.
4-Hydroxy-3-(5-((4-methoxyphenethyl)amino)-4-nitro-2-phen-yl-1H-pyrrol-3-yl)-2H-chromen-
2-one (5c). Yellow solid (467.3 mg, 94%); Mp: 269.9–270.3 °C ; IR (KBr): 3244.6, 1681.7,
1643.9, 1434.2, 827.4, 768.5 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 2.94–2.96 (m, 2H, CH2),
3.73–3.78 (m, 2H, NCH2), 3.75 (s, 3H, OCH3), 6.92–6.93 (m, 2H, ArH), 7.24–7.41 (m, 9H, ArH),
7.63–7.65 (m, 1H,ArH), 7.83–7.84 (m, 1H, ArH), 8.16–8.18 (m, 1H, CH2NH), 11.19 (br, 1H,
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NH), 11.19 (s, 1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ = 34.7, 44.6, 55.5, 99.6, 103.6,
114.3, 116.5, 116.7, 118.3, 124.1, 124.4, 126.8, 127.4, 128.0, 128.8, 130.3, 131.0, 131.5, 158.4,
161.6, 162.3; HRMS (TOF ES+): m/z calcd for C28H23N3O6 [M+H]+, 498.1660; found, 498.1660.
4-Hydroxy-3-(5-((4-methylphenethyl)amino)-4-nitro-2-phenyl-1H-pyrrol-3-yl)-2H-chromen-2-
one (5d). Yellow solid (447.5 mg, 93%); Mp: 268.0–268.4 °C; IR (KBr): 3301.9, 1684.3, 1641.5,
1434.0, 808.8, 696.7 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 2.29 (s, 3H, CH3), 2.95–2.97 (m,
2H, CH2), 3.73–3.74 (m, 2H, NHCH2), 7.15–7.25 (m, 6H, ArH), 7.33–7.41 (m, 6H, ArH), 7.62–
7.65 (m, 1H,ArH), 7.82–7.83 (m, 1H, ArH), 8.15–8.18 (m, 1H, CH2NH), 11.20 (br, 1H, NH),
11.20 (s, 1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ = 21.2, 35.2, 44.5, 99.6, 103.6, 116.5,
116.7, 118.3, 124.0, 124.4, 126.8, 127.4, 128.0, 128.8, 129.2, 129.5, 131.5, 132.6, 135.8, 136.1,
147.4, 152.9, 161.5, 162.3; HRMS (TOF ES+): m/z calcd for C28H23NaN3O5 [M+Na]+, 504.1530;
found,504.1532.
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4-Hydroxy-3-(4-nitro-5-(phenethylamino)-2-phenyl-1H-pyrrol -3-yl)-2H-chromen-2-one (5e).
Yellow solid (1.220 g, 87%); Mp: 271.7–272.1 °C ; IR (KBr): 3067.9, 1643.1, 1560.7, 1430.3,
762.1, 696.7 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 3.00–3.02 (m, 2H, NCH2), 3.77–3.78 (m,
2H, NCH2), 7.23–7.26 (m, 2H, ArH), 7.32–7.41 (m, 10H, ArH), 7.62–7.65 (m, 1H,ArH), 7.82–
7.83 (m, 1H, ArH), 8.19–8.21 (m, 1H, CH2NH), 11.20 (br, 1H, NH), 11.21 (s, 1H, OH); 13C
NMR (150 MHz, DMSO-d6): δ = 35.6, 44.4, 99.6, 103.6, 116.5, 116.7, 118.3, 124.0, 124.4,
126.8, 127.4, 128.0, 128.8, 128.9, 129.3, 131.5, 132.6, 139.3, 147.1, 152.9, 161.5, 162.3; HRMS
(TOF ES+): m/z calcd for C27H21N3NaO5 [M+Na]+, 490.1373; found, 490.1374.
3-(5-((4-Fluorophenethyl)amino)-4-nitro-2-phenyl-1H-pyrrol-3-yl)-4-hydroxy-2H-chromen-2-
one (5f). Yellow solid (441.5 mg, 91%); Mp: 267.8–268.2 °C; IR (KBr): 3296.9, 1679.5, 1643.0,
1
1433.3, 767.2, 697.3 cm-1; H NMR (600MHz, DMSO-d6): δ =3.03–3.07 (m, 2H, CH2), 3.78–
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3.82 (m, 2H, NCH2), 7.10–7.40 (m, 11H, ArH), 7.83–7.85 (m, 1H, ArH), 7.89–7.93 (m, 1H,ArH),
5
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8.22– 8.26 (m, 1H, CH2NH), 11.21 (br, 1H, NH), 11.21 (s, 1H, OH); C{1H} NMR (150 MHz,
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DMSO-d6): δ =35.5, 44.0, 99.6, 103.6, 113.6, 113.7, 116.0 (d, J = 21.0 Hz), 116.7, 118.3, 124.1,
124.4, 125.5, 126.8, 127.4, 128.0, 128.9, 130.8 (d, J = 7.5 Hz), 131.5, 132.6, 142.3, 147.3, 152.9,
161.6, 162.3, 162.8 (d, J = 234 Hz); HRMS (TOF ES+): m/z calcd for C27H20FN3NaO5 [M+Na]+,
508.1279; found, 508.1280.
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4-Hydroxy-3-(5-((4-methylbenzyl)amino)-4-nitro-2-phenyl-1H
-pyrrol-3-yl)-2H-chromen-2-
one (5g). Yellow solid (397.1 mg, 85%); Mp: 244.5–244.9 °C; IR (KBr): 3175.6, 1685.8, 1636.9,
1434.7, 761.1, 695.9 cm-1; 1H NMR (600MHz, DMSO-d6): δ = 2.30 (s, 3H, CH3), 4.73–4.74 (m,
2H, CH2), 7.21–7.24 (m, 3H, ArH), 7.32–7.41 (m, 8H, ArH), 7.62–7.65 (m, 1H,ArH), 7.82–7.83
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(m, 1H, ArH), 8.59–8.61 (m, 1H, CH2NH), 11.19 (br, 1H, NH), 11.25 (s, 1H, OH); C NMR
(150 MHz, DMSO-d6): δ = 21.2, 45.9, 99.6, 103.7, 116.6, 118.4, 124.1, 124.4, 126.6, 127.3,
127.9, 128.1, 128.8, 129.6, 129.8, 131.4, 132.6, 137.0, 147.4, 152.9, 161.6, 162.3; HRMS (TOF
ES+): m/z calcd for C27H21N3NaO5 [M+Na]+,490.1372; found, 490.1371.
6-Bromo-4-hydroxy-3-(4-nitro-2-phenyl-5-(p-tolylamino)-1H-pyrrol-3-yl)-2H-chromen-2-one
(5h). Yellow solid (424.8 mg, 80%); Mp: 293.8–294.2 °C ; IR (KBr): 3379.9, 1696.0, 1637.8,
1
1436.4, 1113.5, 974.1 cm-1; H NMR (600MHz, DMSO-d6): δ = 2.13 (s, 3H, CH3), 7.21– 7.42
(m, 10H, ArH), 7.80–7.81 (m, 1H, ArH), 7.92–7.96 (m, 1H,ArH), 9.52–9.56 (m, 1H, CH2NH),
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11.57 (br, 1H, NH), 11.66 (s, 1H, OH); C{1H} NMR (150 MHz, DMSO-d6): δ = 21.0, 100.3,
103.6, 116.4, 118.4, 119.2, 120.3, 121.8, 126.2, 127.1, 127.5, 128.0, 128.7, 130.4, 131.2, 133.9,
135.2, 136.7, 142.6, 151.9, 160.5, 161.9; HRMS (TOF ES+): m/z calcd for C26H18BrN3NaO5
[M+Na]+, 554.0322; found, 554. 0322.
3-(2-(4-Fluorophenyl)-5-((4-methoxyphenethyl)amino)-4-nitro-1H-pyrrol-3-yl)-4-hydroxy-2H-
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chromen-2-one (5i). Yellow solid (463.6 mg, 90%);; Mp: 279.7–280.1 °C ; IR (KBr): 3236.9,
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6
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1681.1, 1616.2, 1432.0, 1247.7, 825.7 cm-1; H NMR (600MHz, DMSO-d6): δ = 2.93–2.95 (m,
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2H, CH2), 3.71–3.74 (m, 2H, NCH2), 3.73 (s, 3H, OCH3), 6.91–6.93 (m, 2H, ArH), 7.21–7.22 (m,
2H, ArH), 7.27–7.29 (m, 2H,ArH), 7.33–7.41 (m, 4H, ArH), 7.63–7.65 (m, 1H, ArH), 7.82–7.85
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(m, 1H, ArH), 8.16–8.17 (m, 1H, CH2NH), 11.20 (br, 1H, NH), 11.20 (s, 1H, OH); C{1H}
NMR (150 MHz, DMSO-d6): δ = 34.7, 44.6, 55.5, 99.4, 103.6, 114.3, 115.9 (d, J = 22.5 Hz),
116.5, 116.7, 118.1, 124.1, 124.4, 125.9, 128.0, 129.5, 130.3, 131.1, 132.7, 147.4, 152.9, 158.4,
161.1, 161.66, 162.3, 162.9 (d, J = 244.5 Hz); HRMS (TOF ES+): m/z calcd for C28H22FN3NaO6
[M+Na]+, 538.1385; 538.1384.
3-(2-(4-Fluorophenyl)-5-((4-methylphenethyl)amino)-4-nitro-1H-pyrrol-3-yl)-4-hydroxy-2H-
chromen-2-one (5j). Yellow solid (459.2 mg, 92%);; Mp: 263.8–264.2 °C; IR (KBr): 3304.7,
1683.6, 1642.3, 1435.5, 1111.5, 695.4 cm-1; H NMR (600MHz, DMSO-d6): δ =2.29 (s, 3H,
1
CH3), 2.95–2.97 (m, 2H, CH2), 3.73–3.74 (m, 2H, NCH2), 7.15–7.25 (m, 6H, ArH), 7.33–7.41
(m, 4H, ArH), 7.62–7.65 (m, 1H,ArH), 7.82–7.83 (m, 1H, ArH), 8.15–8.17 (m, 1H, CH2NH),
11.20 (br, 1H, NH), 11.20 (s, 1H, OH); C{1H} NMR (150 MHz, DMSO-d6): δ = 21.1, 35.1,
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44.5, 99.4, 103.6, 115.9 (d, J = 21.0 Hz ), 116.5, 116.7, 118.1, 124.1, 124.4, 125.9, 127.9, 129.2,
129.5, 129.5, 132.7, 135.8, 136.1, 147.4, 152.9, 161.1, 161.6, 162.3, 161.9 (d, J = 244.5 Hz);
HRMS (TOF ES+): m/z calcd for C28H22FN3NaO5 [M+Na]+, 522.1436; found, 522.1436.
6-Bromo-3-(2-(4-fluorophenyl)-4-nitro-5-(phenethylamino)-1H-pyrrol-3-yl)-4-hydroxy-2H-
chromen-2-one (5k). Yellow solid (529.3 mg, 94%);; Mp: 294.6–295.0 °C; IR (KBr): 3311.3,
1694.4, 1647.0, 1423.6, 1116.8, 840.4 cm-1; H NMR (600MHz, DMSO-d6): δ = 2.99–3.03 (m,
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2H, CH2), 3.73–3.78 (m, 2H, NCH2), 7.10–7.14 (m, 11H, ArH), 7.21–7.37 (m, 2H, ArH), 8.18–
8.22 (m, 1H, CH2NH), 11.24 (br, 1H, NH), 11.55 (s, 1H, OH); 13C{1H} NMR (150 MHz,
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DMSO-d6): δ = 35.6, 44.4, 100.3, 103.3, 115.9 (d, J = 21.0 Hz), 116.3, 118.1, 118.4, 119.1,
126.0, 126.2, 126.9, 127.8, 128.9, 129.3, 129.6, 135.2, 139.2, 147.3, 151.9, 160.4, 161.1 (d, J =
213.0 Hz), 161.1; HRMS (TOF ES+): m/z calcd for C27H19BrFN3NaO5 [M+Na]+, 586.0384;
found, 586.0384.
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General procedure for the synthesis of ACAHPs 6. Arylglyoxal monohydrates 1 (1.0 mmol),
4-hydroxy-2H-chromen-2-ones 4 (1.0 mmol), and 1,4-dioxane (10 mL) were placed into a 25-
mL round-bottom flask. Then, 1,1-enediamines (EDAMs) 3 (1.0 mmol) was added to this
mixture, and the mixture was refluxed until the completion of the reaction (approximately 10
hours), which was monitored by TLC. Then, the mixture was cooled to room temperature and
added to 50 mL of water, followed by extraction with an appropriate amount of ethyl acetate.
The organic phases were combined and dried over anhydrous Na2SO4, concentrated under
reduced pressure, and then purified by fast column chromatography (with the appropriate
proportion of petroleum ether and ethyl acetate). Eventually, the target compounds 6 were
obtained with yields of 73−90%.
(E)-3-(7-Benzoyl-5-hydroxy-5-(p-tolyl)-2,3-dihydro-1H-pyrro-lo[1,2-a]imidazol-6(5H)-ylid-
ene)chromane-2,4-dione (6a). Yellow solid (363.4 mg, 76%);; Mp: 233.8–234.2 °C; IR (KBr):
3411.5, 1667.8, 1606.9, 1405.2, 1286.5, 1119.2, 765.7 cm-1; 1H NMR (600MHz, DMSO-d6): δ =
2.13 (s, 3H, CH3), 3.21–3.24 (m, 1H, NCH2), 3.70–3.75 (m, 1H, NCH2), 4.10–4.14 (m, 2H,
NHCH2), 6.88–6.94 (m, 1H, ArH), 7.03–7.06 (m, 3H, ArH), 7.15–7.17 (m, 2H,ArH), 7.26–7.28
(m, 2H, ArH), 7.33–7.36 (m, 2H, ArH), 7.63–7.66 (m, 3H, ArH), 10.11 (br, 1H, NH), 10.94 (s,
1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ = 21.14, 41.4, 50.6, 93.1, 98.1, 113.9, 116.3,
120.6, 123.7, 125.7, 126.0, 128.2, 128.6, 129.4, 133.1, 133.5, 136.0, 137.6, 138.5, 153.3, 162.5,
169.3, 172.8, 175.6, 188.2; HRMS (TOF ES+): m/z calcd for C29H23N2O5 [M+H]+, 479.1601;
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found, 479.1603.
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(E)-3-(7-(4-Chlorobenzoyl)-5-hydroxy-5-(p-tolyl)-2,3-dihydro-1H-pyrrolo[1,2-a]imidazol-6-
(5H)-ylidene)chromane-2,4-dione (6b). Yellow solid (419.9 mg, 82%); Mp: 225.6–226.0 °C; IR
(KBr): 3450.3, 1637.5, 1464.8, 1290.4, 1120.1, 766.2 cm-1; 1H NMR (500 MHz, DMSO-d6): δ =
2.21 (s, 3H, CH3), 3.29–3.30 (d, 1H, NCH2, J = 27.0 Hz), 3.76–3.82 (m, 1H, NCH2), 4.17–4.22
(m, 2H, NHCH2), 7.00–7.02 (m, 1H, ArH), 7.12–7.14 (m, 3H, ArH), 7.22–7.24 (m, 2H, ArH),
7.44–7.46 (m, 3H, ArH), 7.71–7.75 (m, 3H, ArH), 10.18 (br, 1H, NH), 10.88 (s, 1H, OH);
13C{1H} NMR (125 MHz, DMSO-d6): δ = 21.1, 41.4, 50.1, 93.0, 98.1,113.3, 116.4, 120.5, 123.9,
125.7, 126.1, 128.8, 129.4, 130.0, 133.6, 135.9, 136.4, 137.8, 138.5, 153.3, 162.6, 169.1, 172.7,
175.7, 187.0; HRMS (TOF ES+): m/z calcd for C29H22ClN2O5 [M+H]+, 513.1212; found,
513.1209.
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(E)-3-(7-Benzoyl-5-hydroxy-5-phenyl-2,3-dihydro-1H-pyrrolo-[1,2-a]imidazol-6(5H)-ylidene)
-6-chlorochromane-2,4-dione (6c). Yellow solid (388.5 mg, 78%); Mp: 202.2–202.6 °C; IR
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(KBr): 3432.3, 1655.0, 1438.5, 1289.2, 1125.4, 820.4, 755.6 cm-1; H NMR (500MHz, DMSO-
d6): δ = 3.33–3.34 (m, 1H, NCH2), 3.38–3.84 (m, 1H, NCH2), 4.22–4.23 (m, 2H, NHCH2), 7.03–
7.05 (m, 1H, ArH), 7.29–7.30 (m, 1H, ArH), 7.30–7.38 (m, 6H, ArH), 7.44–7.48 (m, 2H, ArH),
7.63–7.64 (m, 1H, ArH), 7.73–7.74 (m, 2H, ArH),10.31 (br, 1H, NH), 10.80 (s, 1H, OH); 13C{1H}
NMR (125 MHz, DMSO-d6): δ = 41.4, 50.2, 93.1, 97.9, 114.8, 118.6, 121.9, 124.9, 125.7, 128.1,
128.3, 128.6, 128.9, 129.2, 133.1, 133.2, 137.3, 138.7, 151.8, 162.0, 169.3, 172.1, 174.0, 188.1;
HRMS (TOF ES+): m/z calcd for C28H20ClN2O5 [M+H]+, 499.1055; found, 499.1055.
(E)-3-(7-(4-Fluorobenzoyl)-5-hydroxy-5-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]imidazol-6-(5H)
-ylidene)chromane-2,4-dione (6d). Yellow solid (398.5 mg, 83%); Mp: 216.1–216.5 °C; IR
(KBr): 3449.3, 1633.2, 1413.5, 1289.4, 1118.9, 755.9, 606.9 cm-1; 19F NMR (470 MHz, DMSO-
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d6): δ = -106.6; H NMR (500 MHz, DMSO-d6): δ = 3.30 (t, 1H, NCH2), 3.79–3.84 (m, 1H,
NCH2), 4.16–4.25 (m, 1H, NHCH2), 6.99–7.00 (m, 1H, ArH), 7.12–7.15(m, 1H, ArH), 7.19–7.23
(m, 2H, ArH), 7.26–7.28 (m, 1H, ArH), 7.32–7.37 (m, 4H, ArH), 7.43–7.46 (m, 1H, ArH), 7.71–
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7.73 (m, 1H, ArH), 7.80–7.83 (m, 1H, ArH), 10.22 (br, 1H, NH), 10.97 (s, 1H, OH); C{1H}
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NMR (125 MHz, DMSO-d6): δ = 41.4, 50.1, 93.0, 98.0, 113.8, 115.7 (d, J = 22.5 Hz), 116.3,
120.5, 123.8, 125.7, 126.0, 128.8, 129.2, 131.0, 131.1, 133.6, 134.3, 138.9, 153.3, 163.2 (d, J =
225.0 Hz), 166.0, 169.3, 175.7, 186.8; HRMS (TOF ES+): m/z calcd for C28H19FN2NaO5
[M+Na]+, 505.1170; found, 505.1166.
(E)-6-Chloro-3-(7-(4-fluorobenzoyl)-5-hydroxy-5-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]imid-
azol-6(5H)-ylidene)chromane-2,4-dione (6e). Yellow solid (412.9 mg, 80%); Mp: 199.6–
200.0 °C; IR (KBr): 3414.6, 1638.5, 1437.2, 1229.7, 1124.6, 791.8, 607.5 cm-1; 1H NMR (600
MHz, DMSO-d6): δ = 3.32–3.34 (m, 1H, NCH2), 3.81–3.83 (m, 1H, NCH2), 4.20–4.24 (m, 2H,
NHCH2), 7.06–7.07 (m, 1H, ArH), 7.20–7.23 (m, 2H, ArH), 7.28–7.29 (m, 1H, ArH), 7.33–7.36
(m, 4H, ArH), 7.47–7.49 (m, 1H, ArH), 7.64–7.64 (m, 1H, ArH),7.79–7.82 (M, 2H, ArH), 10.29
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(br, 1H, NH), 10.74 (s, 1H, OH); C{1H} NMR (150 MHz, DMSO-d6): δ = 41.4, 50.2, 93.1,
97.8, 114.6, 115.7 (d, J = 21.0 Hz), 118.7, 121.9, 125.0, 125.7, 128.1, 129.0, 129.2, 131.1 ( d, J
= 9.0 Hz ), 133.2, 134.1, 138.6, 151.9, 162.1, 165.1 (d, J = 250.5 Hz), 169.2, 172.0, 174.1, 186.7;
HRMS (TOF ES+): m/z calcd for C28H19ClFN2O5 [M+H]+, 517.0961; found, 517.0961.
(E)-3-(7-(4-Chlorobenzoyl)-5-hydroxy-5-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]imidazol-6 (5H)
-ylidene)chromane-2,4-dione (6f). Yellow solid (398.5 mg, 80%); Mp: 222.2–222.6 °C; IR
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(KBr): 3438.3, 1652.0, 1338.5, 1269.2, 1117.4, 830.4, 765.6 cm-1; H NMR (600MHz, DMSO-
d6): δ = 3.293–3.31 (m, 1H, NCH2), 3.79–3.81(m, 1H, NCH2), 4.19–4.20 (m, 2H, NHCH2),
7.00–7.01 (m, 1H, ArH), 7.14–7.15 (m, 1H, ArH), 7.27–7.28 (m, 1H, ArH), 7.32–7.36 (m, 4H,
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ArH), 7.44–7.47 (m, 3H, ArH), 7.70–7.75 (m, 3H, ArH), 10.21 (br, 1H, NH),10.86 (s, 1H, OH);
13C{1H} NMR (150MHz, DMSO-d6): δ = 41.4, 50.1, 93.0, 98.1, 113.4, 116.4, 120.5, 123.9,
125.7, 126.0, 126.3, 128.8, 128.8, 129.2, 130.0,133.7, 136.4, 137.8, 138.8, 153.3, 169.2, 176.9,
186.9; HRMS (TOF ES+): m/z calcd for C28H20ClN2O5 [M+H]+, 499.1055; found, 499.1055.
(E)-3-(7-(4-Bromobenzoyl)-5-hydroxy-5-phenyl-2,3-dihydro-1H-pyrrolo[1,2-a]imidazol-6-(5H)
-ylidene)-6-chlorochromane-2,4-dione (6g). Yellow solid (489.6 mg, 85%); Mp: 225.5–225.9 °C;
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IR (KBr): 3442.6, 1655.7, 1431.1, 1296.2, 1208.9, 788.8, 744.5 cm-1; H NMR (500 MHz,
DMSO-d6): δ = 3.30–3.32 (m, 1H, NCH2), 3.80–3.82 (m, 1H, NCH2), 4.21–4.22 (m, 2H,
NHCH2), 7.07–7.09 (m, 1H, ArH), 7.28–7.29 (m, 5H, ArH), 7.48–7.50 (m, 1H, ArH), 7.59–7.67
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(m, 5H, ArH), 10.28 (br, 1H, NH), 10.66 (s, 1H, OH); C{1H} NMR (125 MHz, DMSO-d6): δ
= 41.4, 50.2, 93.1, 97.9, 114.2, 118.7, 121.9, 125.0, 125.7, 127.1, 128.2, 128.9, 129.2, 130.2,
131.8, 133.3, 136.6, 138.6, 151.8, 162.2, 169.1, 172.0, 174.2, 187.1; HRMS (TOF ES+): m/z
calcd for C28H19BrClN2O5 [M+H]+, 577.0160; found, 577.0160.
(E)-3-(5-(3,4-Difluorophenyl)-5-hydroxy-7-(4-methylbenzoyl)-2,3-dihydro-1H-pyrrolo[1,2-a]-
imidazol-6(5H)-ylidene)chromane -2,4-dione (6h). Yellow solid (375.3 mg, 73%); Mp: 197.6–
198.0 °C; IR (KBr): 3440.3, 1650.9, 1438.4, 1280.1, 1125.3, 820.4, 755.6 cm-1; 19F NMR (470
MHz, DMSO-d6): δ = 137.7 (t, 1F, ArF), 138.3 (d, 1F, ArF); 1H NMR (600MHz, DMSO-d6): δ =
2.23 (s, 3H, CH3), 3.37–3.42 (m, 1H, NCH2), 3.80–3.82 (d, J = 10.0 Hz, 1H, NCH2), 4.19–4.24
(m, 2H, NHCH2), 7.00–7.01 (m, 1H, ArH), 7.12–7.18 (m, 4H, ArH), 7.38–7.46 (m, 3H, ArH),
7.66–7.68 (m, 2H, ArH), 7.75–7.76 (m, 1H, ArH), 10.35 (br, 1H, NH), 11.24 (br, 1H, OH);
13C{1H} NMR (150 MHz, DMSO-d6): δ = 21.5, 41.4, 50.3, 92.3, 97.8, 114.4, 115.4, 116.4, 118.2,
120.5, 122.9, 123.8, 126.0, 128.4, 129.3, 133.6, 134.9, 137.0, 143.6, 143.6, 149.5 (d, J = 244.5
Hz), 149.9 (d, J = 246.0 Hz),153.4,162.3, 169.6, 171.3, 175.7, 187.5; HRMS (TOF ES+): m/z
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calcd for C29H20F2N2NaO5 [M+Na]+, 537.1232; found, 537.1227.
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(E)-3-(7-(4-Chlorobenzoyl)-5-(3,4-difluorophenyl)-5-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]-
imidazol-6(5H)-ylidene)chromane -2,4-dione (6i). Yellow solid (411.2, 77%); Mp: 217.5–
217.9 °C; IR (KBr): 3299.0, 1610.9, 1409.1, 1281.2, 1117.5, 997.4, 765.0 cm-1; 1H NMR (600
MHz, DMSO-d6): δ = 3.34–3.42 (m, 1H, NCH2 ), 3.78–3.83 (m, 1H, NHCH2), 4.17–4.26 (m, 1H,
NHCH2),7.02–7.04 (m, 1H, ArH), 7.14–7.17 (m, 2H, ArH),7.39–7.49 (m, 5H, ArH), 7.34–7.78
(m, 3H, ArH), 10.32 (br, 1H, NH), 10.99 (s, 1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ =
41.3, 50.3, 92.2, 97.9, 113.6, 115.4, 116.4, 118.1, 120.4, 122.9, 124.0, 126.0, 128.8, 130.0, 133.8,
136.6, 136.9, 137.9, 149.7 (d, J = 244.5 Hz), 149.9 (d, J = 244.5 Hz), 153.4, 162.5, 169.3, 171.6,
175.8, 186.8; HRMS (TOF ES+): m/z calcd for C28H17ClF2N2NaO5 [M+H]+, 557.0686; found,
557.0684.
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(E)-3-(8-Benzoyl-6-hydroxy-6-(p-tolyl)-1,2,3,4-tetrahydropyr-rolo[1,2-a]pyrimidin-7(6H)-ylid
-ene)-6-methylchromane-2,4-di-one (6j). Yellow solid (445.4 mg, 88%); Mp: 225.6–226.0 °C;
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IR (KBr): 3415.8, 1671.7, 1396.8, 1182.4, 1001.2, 912.3, 767.4 cm-1; H NMR (500 MHz,
DMSO-d6): δ = 1.86–1.88 (m, 1H, CH2 ), 1.96–1.98 (m, 1H, CH2), 2.21 (s, 3H, CH3), 2.25 (s, 3H,
CH3), 2.90–2.94 (m, 1H, NCH2), 3.43–3.52 (m, 3H, NHCH2, NCH2), 6.81–6.83 (m, 1H, ArH),
7.11–7.12 (m, 2H, ArH), 7.20–7.22 (m, 3H, ArH), 7.31–7.34 (m, 2H, ArH), 7.40–7.43 (m, 1H,
ArH), 7.52–7.53 (m, 1H, ArH), 7.72–7.74 (m, 2H, ArH), 9.27 (br, 1H, NH), 11.56 (s, 1H, OH);
13C{1H} NMR (125 MHz, DMSO-d6): δ = 19.1, 20.7, 21.1, 37.1, 39.1, 96.5, 96.8, 116.0, 116.6,
120.3, 125.5, 125.8, 128.4, 128.5, 129.4, 132.7, 133.1, 133.9, 135.9, 137.6, 138.5, 151.4, 158.5,
160.0, 162.7, 175.2, 189.2; HRMS (TOF ES+): m/z calcd for C31H26N2NaO5[M+Na]+, 529.1734;
found, 529.1736.
(E)-3-(8-Benzoyl-6-hydroxy-6-(p-tolyl)-1,2,3,4-tetrahydropyr-rolo[1,2-a]pyrimidin-7(6H)-ylid
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-ene)-6-chlorochromane-2,4-di-one (6k). Yellow solid (468.3 mg, 89%); Mp: 210.4–210.8 °C;
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IR (KBr): 3414.9, 1678.9, 1471.5, 1199.3, 1125.3, 992.9, 766.8 cm-1; H NMR (600 MHz,
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DMSO-d6): δ = 1.78–1.81(m, 2H, CH2), 1.89 (t, 3H, CH3), 2.85–2.88 (m, 1H, NCH2 ), 3.34–3.45
(m, 3H, NCH2, NHCH2), 6.91–6.92 (m, 1H, ArH), 7.03–7.05 (m, 2H, ArH), 7.13–7.14 (m, 2H,
ArH), 7.24–7.26 (m, 2H, ArH), 7.32–7.36 (m, 2H, ArH), 7.54–7.57 (m, 1H, ArH),7 .64–7.65 (m,
2H, ArH), 9.27 (br, 1H, NH), 11.15 (s, 1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ = 19.0,
21.1, 37.2, 39.2, 96.3, 96.8, 117.7, 118.5, 122.0, 124.8, 125.8, 127.9, 128.4, 128.6, 129.5, 132.8,
132.2, 135.6, 135.6, 137.4, 138.6, 151.8, 158.4, 162.2, 164.1, 173.6, 189.2; HRMS (TOF ES+):
m/z calcd for C30H24ClN2O5 [M+H]+,527.1368; found, 527.1368.
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(E)-3-(8-(4-Fluorobenzoyl)-6-hydroxy-6-(p-tolyl)-1,2,3,4-tetra-hydropyrrolo[1,2-a]pyrimidin-
7(6H)-ylidene)chromane-2,4-di-one (6l). Yellow solid (459.1 mg, 90%); Mp: 242.6–243.0 °C;
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IR (KBr): 3417.5, 1673.4, 1401.6, 1198.0, 1124.6, 782.2, 621.9 cm-1; H NMR (500 MHz,
DMSO-d6): δ = 1.78–1.79 (m, 2H, CH2), 2.13 (s, 3H, CH3), 2.84 (t, 1H, NHCH2), 3.35–3.44 (m,
3H, NHCH2,NCH2), 6.88–6.90 (m, 1H, ArH), 7.03–7.15 (m, 7H, ArH), 7.32–7.35 (m, 1H, ArH),
7.65–7.73 (m, 3H, ArH), 9.20 (br, 1H, NH), 11.32 (s, 1H, OH); 13C{1H} NMR (125 MHz,
DMSO-d6): δ = 19.0, 21.1, 37.2, 39.1, 96.3, 96.8, 115.5 (d, J = 21.3 Hz), 116.2, 116.7, 120.6,
123.6, 125.8, 125.9, 131.3, 133.2, 134.3, 135.8, 138.6, 153.3, 158.3, 164.0, 163.6 (d, J = 242.5
Hz), 166.0, 175.2, 187.8; HRMS (TOF ES+): m/z calcd for C30H24FN2O5 [M+H]+, 511.1664;
found, 511.1664.
(E)-3-(8-(4-Chlorobenzoyl)-6-hydroxy-6-(p-tolyl)-1,2,3,4-tetra-hydropyrrolo[1,2-a]pyrimidin-
7(6H)-ylidene)-6-methylchromane -2,4-dione (6m). Yellow solid (469.9 mg, 87%); Mp: 219.8–
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220.2 °C; IR (KBr): 3415.1, 1637.6, 1617.5, 1522.3, 1181.8, 997.8, 815.6 cm-1; H NMR (500
MHz, DMSO-d6): δ = 1.80–1.97 (m, 2H, CH2, ), 2.21 (s, 3H, CH3), 2.26 (s, 2H,CH3), 2.92–2.93
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(m, 1H, NCH2), 3.47–3.51(m, 3H, NCH2, NHCH2, NHCH2), 6.86–6.87 (m, 1H, ArH), 7.11–7.12
(m, 2H, ArH), 7.20–7.24 (m, 3H, ArH), 7.42–7.44 (m, 2H, ArH), 7.52 (m, 1H, ArH), 7.71–7,73
(m, 2H, ArH), 9.26 (br, 1H, NH), 11.41 (s, 1H, OH); 13C NMR (150 MHz, DMSO-d6): δ = 19.1,
20.7, 21.1, 37.1, 39.6, 96.5, 96.8, 116.0, 116.2, 120.2, 125.6, 125.7, 128.6, 129.4, 130.2, 132.8,
134.1, 135.8, 136.5, 137.7, 138.5, 151.4, 158.3, 162.8, 165.0, 175.4, 188.0; HRMS (TOF ES+):
m/z calcd for C31H25ClN2NaO5 [M+Na]+,563.1344; found, 563.1343.
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(E)-3-(6-Hydroxy-8-(4-methylbenzoyl)-6-phenyl-1,2,3,4-tetra-hydropyrrolo[1,2-a]pyrimidin-
7(6H)-ylidene)chromane-2,4-di-one (6n). Yellow solid (418.3 mg, 85%); Mp: 214.5–214.9 °C;
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IR (KBr): 3367.9, 1676.1, 1604.4, 1448.3, 1412.2, 1200.3, 775.0, 760.5 cm-1; H NMR (500
MHz, DMSO-d6): δ = 1.87–1.96 (m, 2H, CH2,), 2.22 (s, 3H, CH3), 2.90–2.93 (m, 1H, NCH2),
3.40–3.41(m, 1H, NCH2), 3.50–3.53 (m, 2H, NHCH2), 6.94–6.95 (m, 1H, ArH), 7.10–7.15(m,
3H, ArH), 7.26–7.35 (m, 5H, ArH), 7.40–7.42 (m, 1H, ArH), 7.65–7.67 (m, 2H, ArH), 7.73–7.74
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(m, 1H, ArH), 9.28 (br, 1H, NH), 11.59 (s, 1H, OH); C{1H}NMR (125 MHz, DMSO-d6): δ =
19.1, 21.5, 37.2, 39.1, 96.3, 96.8, 116.2, 117.3, 120.6, 123.6, 125.8, 125.9, 128.6, 128.8, 129.1,
129.2, 133.1, 135.1, 138.8, 143.5, 153.3, 158.6, 162.5, 164.0, 175.2, 188.7; HRMS (TOF ES+):
m/z calcd for C30H25N2O5 [M+H]+, 493.1758, found, 493.1762.
(E)-6-Bromo-3-(6-hydroxy-8-(4-methylbenzoyl)-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyr
-imidin-7(6H)-ylidene)chromane -2,4-dione (6o). Yellow solid (495.9 mg, 87%); Mp: 234.0–
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234.4 °C ; IR (KBr): 3414.7, 1678.4, 1440.7, 1198.4, 1177.2, 832.8, 786.0 cm-1; H NMR (600
MHz, DMSO-d6): δ = 1.90–1.97 (m, 2H, CH2),2.22 (s, 3H, CH3), 2.93 (t, 1H, NCH2), 3.44–3.54
(m, 3H, NCH2, NHCH2), 6.94–6.96 (m, 1H, ArH), 7.14–7.16 (m, 2H, ArH), 7.27–7.27 (m, 5H,
ArH), 7.54–7.55 (m, 1H, ArH), 7.65–7.67 (m, 2H, ArH), 7.80–7.80 (m, 1H, ArH), 9.36 (br, 1H,
NH), 11.32 (s, 1H, OH); 13C{1H} NMR (150 MHz, DMSO-d6): δ =19.0, 21.5, 37.2, 39.1,
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96.1,96.8, 115.6, 118.0, 118.8, 122.5, 125.8, 127.9, 128.7,128.9, 129.1, 129.2, 134.9, 135.5,
138.6, 143.7, 151.8, 158.5, 162.1, 163.5, 173.7, 188.6; HRMS (TOF ES+): m/z calcd for
C30H24BrN2O3 [M+H]+, 571.0863; found, 571.0864.
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(E)-3-(8-Benzoyl-6-hydroxy-6-phenyl-1,2,3,4-tetrahydropyrr-olo[1,2-a]pyrimidin-7(6H)-ylid-
ene)chromane-2,4-dione (6p). Yellow solid (415.9 mg, 87%); Mp: 252.9–253.3 °C; IR (KBr):
3354.3, 1670.9, 1408.6, 1199.9, 1123.3, 906.6, 763.8 cm-1; 1H NMR (500 MHz, DMSO-d6): δ =
1.88–1.99 (m, 2H, CH2), 2.91–2.94 (m, 1H, NCH2), 3.44–3.55 (m, 3H, NCH2,NHCH2), 6.92–
6.93 (m, 1H, ArH), 7.10–7.12 (m, 1H, ArH), 7.25–7.43 (m, 9H, ArH), 7.72–7.75 (m, 3H, ArH),
9.31 (br, 1H, NH), 11.54 (s, 1H, OH); 13C{1H} NMR (125MHz, DMSO-d6): δ = 19.1, 37.2, 39.1,
96.4, 96.8, 116.1, 117.0, 120.6, 123.6, 125.8, 125.8, 128.4, 128.5, 128.8, 129.2, 133.1, 133.1,
137.6, 138.8, 153.3, 158.5, 162.6, 164.5, 175.2, 189.2; HRMS (TOF ES+): m/z calcd for
C29H23N2O5 [M+H]+, 479.1601; found, 479.1600.
(E)-3-(8-(4-Fluorobenzoyl)-6-hydroxy-6-phenyl-1,2,3,4-tetrahy -dropyrrolo[1,2-a]pyrimidin-
7(6H)-ylidene)chromane-2,4-dione (6q). Yellow solid (431.6 mg, 87%); Mp: 267.8–268.2 °C;
IR (KBr): 3414.0, 1682.5, 1540.8, 1404.7, 1198.2, 1122.5, 608.8 cm-1; 1H NMR (500 MHz,
DMSO-d6): δ = 1.88–1.99 (m, 2H, CH2), 2.91–2.93 (m, 1H, NHCH2), 3.51–3.54 (m, 1H,
NHCH2), 3.51–3.54 (m, 2H, NCH2), 6.95–6.97 (m, 1H, ArH), 7.10–7.20 (m,3H, ArH), 7.25–7.43
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(m, 6H,ArH), 7.73–7.82 (m, 3H, ArH), 9.30 (br, 1H, NH), 11.47 (s, 1H, OH); C{1H} NMR
(125 MHz, DMSO-d6): δ = 19.1, 37.2, 39.1, 96.3, 96.8, 115.6 (d, J = 22.5 Hz), 116.2, 116.8,
120.6, 123.7, 125.8, 125.8 (d, J = 5.0 Hz), 128.8, 129.2, 131.3 (d, J = 10.0 Hz), 133.2, 134.3,
138.8, 153.3, 158.4, 163.5 (d, J = 227.5 HZ), 164.0, 166.0, 175.3, 187.8; HRMS (TOF ES+): m/z
calcd for C29H22FN2O5 [M+H], 497.1507; found, 497.1507.
(E)-3-(8-(4-chlorobenzoyl)-6-hydroxy-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidin-7-
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(6H)-ylidene)chromane-2,4-dione (6r).Yellow solid; Mp: 170–172 °C; IR (KBr): 3361.5, 1680.0,
1413.0, 1205.9, 1123.4, 906.9, 769.4 cm-1; 1H NMR (600 MHz, DMSO-d6): δ = 1.77–1.90 (m,
2H, CH2), 2.81–2.85 (m, 1H, NCH2 ), 3.33–3.46 (m, 3H, NCH2, NHCH2), 6.88–6.90 (m, 1H,
ArH), 7.03–7.06 (m, 1H, ArH), 7.13–7.15 (m, 1H, ArH), 7.17–7.39 (m, 4H, ArH), 7.55–7.67 (m,
3H, ArH), 7 .91–7.92 (m, 3H, ArH), 9.23 (br, 1H, NH); 13C{1H} NMR (150 MHz, DMSO-d6): δ
= 19.1, 37.2, 39.1, 96.3, 96.7, 116.2, 116.5, 120.5, 123.7, 125.2, 125.8, 125.9, 128.7, 128.8,
129.3, 130.2, 133.3, 136.5, 137.8, 138.7, 153.2, 158.4, 162.7, 175.3, 188.0; HRMS (TOF ES+):
m/z calcd for C29H21ClN2NaO5 [M+Na]+, 535.1031; found, 535.1034.
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(E)-6-Chloro-3-(8-(4-chlorobenzoyl)-6-hydroxy-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]-
pyrimidin-7(6H)-ylidene)chromane-2,4-dione (6s). Yellow solid (486.0 mg, 89%); Mp: 247.0–
247.4 °C ; IR (KBr): 3415.2, 1679.0, 1438.6, 1223.2, 1013.2, 841.0, 786.0 cm-1; 1H NMR (600
MHz, DMSO-d6): δ =1.89–1.98 (m, 2H, CH2), 2.91–2.94 (m, 1H, NCH2), 3.43–3.53(m,3 H,
NCH2, NHCH2), 7.03–7.04 (m, 1H, ArH),7.27–7.9 (m, 1H, ArH), 7.31–7.33 (m, 4H, ArH), 7.43–
7.46 (m, 3H, ArH), 7.65–7.65 (m, 2H, ArH), 7.74 (m, 1H, ArH), 9.37 (br, 1H, NH), 11.16 (s, 1H,
OH); 13C{1H} NMR (150MHz, DMSO-d6): δ = 19.0, 37.2, 39.2, 96.2, 96.8, 117.3, 118.6, 121.9,
124.9, 128.0, 125.8, 128.7, 128.9, 129.3, 130.3, 132.9, 136.3, 138.0, 138.4, 151.8, 158.4, 162.3,
164.0, 173.8, 188.0; HRMS (TOF ES+): m/z calcd for C29H20Cl2N2NaO5 [M+Na]+, 569.0641;
found, 569.0643.
(E)-3-(8-Benzoyl-6-(4-fluorophenyl)-6-hydroxy-1,2,3,4-tetra-hydropyrrolo[1,2-a]pyrimidin-7-
(6H)-ylidene)-6-chlorochrom-ane-2,4-dione (6t). Yellow solid (455.9 mg, 86%); Mp: 270.4–
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270.8 °C ; IR (KBr): 3346.2, 1675.9, 1440.3, 1243.3, 1047.9, 907.6, 823.8 cm-1; H NMR (600
MHz, DMSO-d6): δ = 1.90–1.99 (m, 2H, CH2),2.94–2.98 (m, 1H, NCH2), 3.44–3.55 (m, 3H,
NCH2, NHCH2), 7.00–7.01 (m, 1H, ArH ), 7.15–7.18 (m, 2H, ArH), 7.32–7.39 (m, 4H, ArH),
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