Br?nsted acid-promoted multicomponent reaction for the construction of pyrrolocoumarin derivatives

Article abstract of DOI:10.3987/COM-18-13867

An efficient one-pot synthesis of functionalized indole-containing pyrrolocoumarin derivatives via a three-component reaction of 4-aminocoumarins, arylglyoxal monohydrates and indoles promoted by p-TSA in ethanol is described. The attractive features of t

Full text of DOI:10.3987/COM-18-13867

HETEROCYCLES, Vol. 96, No. 3, 2018
501
HETEROCYCLES, Vol. 96, No. 3, 2018, pp. 501 - 508. © 2018 The Japan Institute of Heterocyclic Chemistry
Received, 11th January, 2018, Accepted, 19th February, 2018, Published online, 2nd March, 2018
DOI: 10.3987/COM-18-13867
BRØNSTED ACID-PROMOTED MULTICOMPONENT REACTION FOR
THE CONSTRUCTION OF PYRROLOCOUMARIN DERIVATIVES
Zhiwei Chen,* Sunjia Ye, and Xiongfei Zhang
Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, P. R.
China. E-mail: chenzhiwei@zjut.edu.cn
Abstract – An efficient one-pot synthesis of functionalized indole-containing
pyrrolocoumarin derivatives via a three-component reaction of 4-aminocoumarins,
arylglyoxal monohydrates and indoles promoted by p-TSA in ethanol is described.
The attractive features of this protocol are simple starting materials, operational
simplicity, short reaction time and moderate to good yields.
Heterocycles are common structural units in natural compounds and many of them exhibit significant
pharmacological activities.1 It is well known that the selective and environment amiability synthesis of
highly functionalized compound libraries of medicinal motifs is a constant challenge in chemical
sciences.2 Among a number of methods available for the construction of heterocyclic frameworks,
multicomponent reactions (MCRs) are particularly important.3 Such reactions provide the advantages of
high atom economy, simplicity and good synthesis efficiency.
Coumarin derivatives have latent ability to exert noncovalent interactions with the various active sites in
organisms and display a wide range of biological activities.4 The pyrrolocoumarins, in particular, are
involved in various natural products, such as marine alkaloids ningalin A, ningalin B and lamellarin D
which are likely to exhibit interesting biological properties.5 On the other hand, indole nucleus is one of
the most common heterocycles found in nature.6 Amongst them, 3-substituted indole is an unique one
with significant biological activities and has a venerable value in medical applications.7 Furthermore,
indoles are important building blocks that can be used in the synthesis of drug-like compounds.8 Thus, a
combination of pyrrolocoumarin and 3-substituted indole could potentially lead to a series of compounds
that possess structural and biological interests.
Recently, we have developed a series of new MCRs that provided easy access to heterocycles.9 In this
regard, Tu10 and co-workers have developed an efficient protocol for the synthesis of bis-indole
derivatives through a one-pot reaction using N-aryl enaminones, arylglyoxal monohydrates and indoles.

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HETEROCYCLES, Vol. 96, No. 3, 2018
Lin11 and co-workers have reported another three-component reaction for the synthesis of highly
functionalized bicyclic pyrrole derivatives in 72-95% yields. Choudhury12 and co-workers described a
microwave-assisted MCR of arylglyoxal monohydrates, 4-hydroxycoumarins, and various cyclic
1,3-C,N-binucleophiles in acetic acid providing access to fused five- or six-membered N-heterocycles.
Based on the previous works and our continuous interests in the development of functionalized
heterocycle libraries, we would like to report another new synthetic method for the synthesis of
indole-containing chromeno[4,3-b]pyrrole unit by simple heating 4-aminocoumarins, arylglyoxal
monohydrates, and indoles promoted by p-TSA in EtOH.
The initial reaction was conducted by subjecting 4-aminocoumarin (1a) to phenylglyoxal monohydrate
(2a) and 2-methylindole (3a) in EtOH at reflux without catalyst for 3 h (entry 1, Table 1). As expected,
no desired product was obtained. Fortunately, the reaction was able to produce the targeted product 4a in
30% yield when using FeCl3 as catalyst (entry 2, Table 1). After a set of Brønsted and Lewis acids were
explored as potential catalysts, p-TSA was identified as the optimal catalyst to enable facilitate this
procedure (entries 3-6, Table 1). Next, the reaction temperature was examined. It was found that an
Table 1. Optimization of the reaction condition for the synthesis of compound 4a
OH
NH2
O
OH
conditions
HN
O
+
+
N
H
O
O
NH
O
1a (1 mmol)
2a (1.1 mmol)
3a (1.1 mmol)
4a
Loading
(mol%)
-
Temperature
Time
(h)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Yield
(%)
n.r.
30
41
56
45
63
trace
45
74
72
68
73
67
trace
51
Entry
Catalyst
Solvent
(oC)
reflux
reflux
reflux
reflux
reflux
reflux
rt
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
-
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
FeCl3
Y(OTf)3
20
20
20
20
20
20
20
20
20
10
40
20
20
20
MeSO3H
AcOH
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
60
100
120
100
100
100
reflux
100
EtOH
EtOH
MeOH
toluene
[bmim]BF4

HETEROCYCLES, Vol. 96, No. 3, 2018
503
increase in yield was observed under higher temperature, while the reaction got less effectively under
lower temperature (entries 6-10, Table 1). In addition, switching the catalyst loading from 10 mol% to 40
mol% had less influence on the reaction yield (entries 11, 12, Table 1). Finally, the reaction solvent was
explored, such as [bmim]BF4, toluene and MeOH, however, no improved yield was afforded (entries
13-15, Table 1). It should be mentioned that protic solvents were proved to be better than aprotic solvents
according to the reaction outcomes as shown in Table 1.
After identifying the optimum reaction conditions, various reactions were examined with a wide variety
of starting materials in order to explore the synthetic scope and the generality of the present protocol.
Upon experimentation, it was found that this protocol had a broad substrate scope and functional group
tolerance, delivering the corresponding products in moderate to good yields (Table 2). The scope of this
reaction was initially explored with a range of indole derivatives 3, 4-aminocoumarin (1a) and
phenylglyoxal monohydrate (2a). It was found that the 2-substituted indole with electron-donating group
showed better reactivity (entry 1, Table 2) and resulted in higher yields than the one with
electron-withdrawing group (entry 2, Table 2). Furthermore, the substitution pattern of the aryl moieties
had a slight effect on the efficiency of the reaction as well as the N-substituted indoles, producing the
desired products in 47-58% yield (entries 3-6, Table 2). It should be mentioned that indole with methyl at
C3 position was employed in this process, but no desired product was obtained due to the
C-nucleophilicity at the C2 position is weaker than that of the C3 position.13
Next, the substrate scope with arylglyoxal monohydrates 2 was examined, and the results was shown in
Table 2. The electronic nature of the substituents on the phenyl ring of arylglyoxal monohydrates had
some influence on the reaction yields. Arylglyoxal monohydrates substituted with electron-withdrawing
groups (4h-m) offered a little bit higher yields than those with electron-donating groups (4n-r) 2-Me,
3-Me, 4-Me, 4-OH 4-OMe, and 3,4-(OCH2O) (entries 8-19, Table 2). It was noteworthy that the
arylglyoxal monohydrates with 2-Cl gave rise to 4g in relatively low yield due to the steric hindrance
(entry 7, Table 2). To our delight, 1-naphthylglyoxal monohydrates and 2-thienylglyoxal monohydrates
also performed smoothly to give the corresponding products 4t and 4u in 67% and 64% yields,
respectively (entries 20, 21, Table 2).
To further investigate the scope of 4-aminocoumarin (1a), 6-substituted and N-substituted
4-aminocoumarins were examined as a replacement for 4-aminocoumarin to synthesize the target
products. The electronic nature of the substituents on the phenyl ring of 4-aminocoumarin had no
significant influence on the reaction yield (entries 22, 23, Table 2). However, both
N-ethyl-4-aminocoumarin and N-phenyl-4-aminocoumarin were carried out in poor performances
towards the generation of final products with little yields and hard to separate. It could be assumed that
steric effects play the major role when there was a nitrogen substituent at 4-aminocoumarin.

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HETEROCYCLES, Vol. 96, No. 3, 2018
Table 2. Synthesis of substituted pyrrolocoumarin derivatives 4
R5
NH2
OH
R2
R5
R1
O
p-TSA
EtOH, 100 oC
HN
O
R4
OH
+
+
R1
R2
N
R3
O
O
N
R3
R4
O
1
2
3
4
Yield
Entry
R1
R2
R3
R4
R5
4
(%)
74
51
57
57
58
47
56
74
82
81
83
81
83
65
72
71
68
66
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
Bn
H
H
H
H
H
H
H
H
H
H
H
H
Me
C6H5
H
H
H
H
H
H
Me
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
H
2-ClC6H4
3-ClC6H4
4-Cl C6H4
4-FC6H4
4-BrC6H4
4-NO2C6H4
4-CNC6H4
2-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeOC6H4
4-HOC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3,4-(OCH2O)
C6H3
19
H
H
Me
H
69
4s
20
21
22
23
H
H
Cl
1-naphthyl
2-thienyl
C6H5
H
H
H
H
Me
Me
Me
Me
H
H
H
H
67
64
72
77
4t
4u
4v
4w
t-Bu
C6H5
To propose a plausible reaction mechanism, we began our investigation by testing the reaction of
phenylglyoxal monohydrate (2a) and 2-methylindole (3a) initially. However, none of the expected
intermediate was observed during the reaction, instead the compound 5 was afforded (Scheme 1). It was
found that the intermediate A could be detected when we lowered the reaction temperature, suggesting
that intermediate A might immediately react with nucleophiles at high temperature, making it difficult to
detect. We next added 4-aminocoumarin (1a) to the resulting mixture and the target product 4a was
obtained fortunately (Scheme 1). If necessary, intermediate A can be separated and then react with 1a in
the same condition to afford the target product 4a in 86% yields.

HETEROCYCLES, Vol. 96, No. 3, 2018
505
O
O
H
N
O
NH
OH
p-TSA
NH
+
+
OH
EtOH, 100 oC
0.5 h
OH
2a
3a
5
A
NH
not observed
NH2
O
O
O
H
N
O
HN
O
OH
p-TSA
1a
NH
+
p-TSA, EtOH, 100 oC
OH
EtOH, 0 oC
1 h
NH
OH
2 h
O
2a
3a
A
4a
Scheme 1. Verification of reaction mechanism
O
O
O
NH
NH
p-TSA
H
OH
+
N
-H2O
OH
OH2
OH
H
O
2a
3a
A
B
O
-H2O
NH2
1a
NH
NH
NH
H
O
HN
O
HO
O
OH2
NH
-H2O, -H+
H
O
O
H2N
O
H2N
NH
O
O
4a
E
D
C
Scheme 2. Proposed mechanism for the synthesis of compound 4a
Based on the above observation and previous reports,10,14 a plausible pathway for the formation of
3-(2-methyl-1H-indol-3-yl)-2-phenylchromeno[4,3-b]pyrrol-4(1H)-one (4a) is proposed in Scheme 2.
Initially, intermediate A is formed by the condensation of phenylglyoxal monohydrate (2a) and
2-methylindole (3a) promoted by p-TSA. Next, nucleophilic attack upon the protonated form of
intermediate A by 4-aminocoumarin (1a) gives intermediate C, which was subsequently converted into
intermediate D. Moreover, intermediate D undergoes intramolecular cyclization followed by dehydration
to afford the target product 4a.

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HETEROCYCLES, Vol. 96, No. 3, 2018
In conclusion, we have described a Brønsted acid-promoted multicomponent reaction for the construction
of indole-containing pyrrolocoumarin derivatives from easily accessible starting materials. The reaction is
operationally simple and offers moderate to good yields of the target products. Further investigation on
biological activity studies of these compounds is in progress at our lab.
EXPERIMENTAL
Melting points were determined using a Büchi B-540 capillary melting point apparatus. IR spectra were
1
13
recorded with a Thermo Nicolet AVATAR 370 spectrophotometer in KBr. H NMR and C NMR were
recorded with Varian instrument at 600 and 150 MHz, respectively, and TMS was used as internal
standard. Mass spectra were measured with Thermo Finnigan LCQ-Advantage. High resolution mass
spectral (HRMS) analyze were measured on a Bruker micrOTOF-Q II instrument using ESI techniques.
The preparation of 4-aminocoumarins 1 and arylglyoxal monohydrates 2 were according to the literature
procedure.15 All other chemicals used in this study were commercially available.
General procedure for the synthesis of indole-containing pyrrolocoumarin derivatives 4: In a 10 mL
reaction tube, 4-aminocoumarins 1 (1 mmol), arylglyoxal monohydrates 2 (1.1 mmol) and indoles 3 (1.1
mmol), p-TSA (34 mg, 0.2 mmol), and EtOH (3 mL) were mixed and then capped. The mixture was
o
heated for 3 h at 100 C (oil bath). Upon completion of the reaction, monitored by TLC, the reaction
solution was transferred to a 100 mL single-necked flask. Water (30 mL) was add to it. After being stirred
for 3 h, the solution was filtered. The residue was purified by column chromatography (CH2Cl2/MeOH,
180:1 v/v) to afford target product 4. Spectral data for 4a and 4e were as follows:
3-(2-Methyl-1H-indol-3-yl)-2-phenylchromeno[4,3-b]pyrrol-4(1H)-one (4a): Pale yellow powder. mp
189-191 oC. IR (KBr): 3421, 1695, 1507 cm-1. 1H NMR (600 MHz, DMSO-d6): δ = 12.74 (s, 1H), 11.00
(s, 1H), 8.34 (d, J = 7.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (m, 4H), 7.33–7.25 (m, 3H), 7.22 (t, J =
13
7.2 Hz, 1H), 6.97 (t, J = 8.4 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H), 2.09 (s, 3H). C NMR (150 MHz,
DMSO-d6): δ = 157.7, 151.8, 136.0, 136.0, 134.3, 134.3, 132.5, 129.1, 128.8, 127.7, 127.4, 124.4, 122.2,
120.4, 119.0, 118.8, 117.1, 114.3, 113.8, 110.9, 109.2, 104.6, 12.6. MS (ESI): m/z = 391 [M + H]+.
HRMS-ESI: calcd for C26H18N2NaO2 [M + Na]+: 413.1266; found 413.1250.
3-(5-Bromo-1H-indol-3-yl)-2-phenylchromeno[4,3-b]pyrrol-4(1H)-one (4e): Off-white powder. mp
272-274 oC. IR (KBr): 3439, 1667, 1507 cm-1. 1H NMR (600 MHz, DMSO-d6): δ = 12.80 (s, 1H), 11.41
(d, J = 1.8 Hz, 1H), 8.33 (dd, J = 7.8, 1.4 Hz, 1H), 7.51–7.38 (m, 7H), 7.36–7.31 (m, 2H), 7.31–7.27 (m,
1H), 7.16 (dd, J = 8.4, 1.8 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H). 13C NMR (150 MHz, DMSO-d6): δ = 157.9,
151.8, 136.0, 135.1, 134.2, 132.2, 129.3, 129.2, 128.9, 128.3, 128.0, 127.9, 124.5, 123.7, 122.3, 122.2,
117.1, 114.2, 113.9, 113.4, 111.7, 108.5, 106.9. MS (ESI): m/z = 455 [M + H]+. HRMS-ESI: calcd for
C25H15BrN2NaO2 [M + Na]+: 477.0215; found 477.0213.

HETEROCYCLES, Vol. 96, No. 3, 2018
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ACKNOWLEDGEMENTS
We are grateful for the National Natural Science Foundation of China (No. 21676253 and 21276238) for
financial support. Cooperation from the colleague's analytical research and development is highly
appreciated.
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