Iodine-catalyzed tandem oxidative coupling reaction: A one-pot strategy for the synthesis of new coumarin-fused pyrroles

Article abstract of DOI:10.1016/j.tetlet.2017.11.055

The simple and facile strategy for the synthesis of 2,3-disubstituted-chromeno[4,3-b]pyrrole-4(1H)-ones has been established. This method describes the Kornblum oxidation reaction of acetophenones, followed by the Knoevenagle treatment of the resulted (he

Full text of DOI:10.1016/j.tetlet.2017.11.055

Accepted Manuscript
Iodine-catalyzed tandem oxidative coupling reaction: a one-pot strategy for the
synthesis of new coumarin-fused pyrroles
Hoda Yahyavi, Majid M. Heravi, Mohammad Mahdavi, Alireza Foroumadi
PII:
S0040-4039(17)31489-2
https://doi.org/10.1016/j.tetlet.2017.11.055
TETL 49498
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 October 2017
27 November 2017
28 November 2017
Please cite this article as: Yahyavi, H., Heravi, M.M., Mahdavi, M., Foroumadi, A., Iodine-catalyzed tandem
oxidative coupling reaction: a one-pot strategy for the synthesis of new coumarin-fused pyrroles, Tetrahedron
Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.11.055
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Iodine-catalyzed tandem oxidative coupling reaction: a one-pot strategy for the synthesis of new
coumarin-fused pyrroles
a
a
b
c,d
Hoda Yahyavi, Majid M. Heravi,* Mohammad Mahdavi, Alireza Foroumadi*
a
Faculty of Chemistry and Physics, Department of Chemistry, Alzahra University, Tehran, Iran
Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences
b
Institute, Tehran University of Medical Sciences, Tehran, Iran
c
Department of Medicinal Chemistry, Faculty of Pharmacy and pharmaceutical Sciences Research
Center, Tehran University of Medical Sciences, Tehran, Iran
d
Department of Medicinal Chemistry, Faculty of Pharmacy and Neuroscience Research Center,
Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
Corresponding authors. Tel.: +98-21-66954708; fax: +98-21-66461178; e-mail:
aforoumadi@yahoo.com (A. Foroumadi); Tel.: +98-21-88041344; e-mail: mmh1331@yahoo.com
(M. M. Heravi)
Abstract. The simple and facile strategy for the synthesis of 2,3-disubstituted-chromeno[4,3-
b]pyrrole-4(1H)-ones has been established. This method describes the Kornblum oxidation reaction of
acetophenones, followed by the Knoevenagle treatment of the resulted (het)arylglyoxals with active
methylene compounds and consequently iodine-activated Michael type reaction with 4-amino
coumarin in a one-pot manner to afford disubstituted chromeno[4,3-b]pyrrole-4(1H)-one derivatives.
Key words: 2,3-Disubstituted chromeno[4,3-b]pyrrole-4(1H)-ones; Kornblum oxidation reaction;
Iodine; Michael type reaction.

Introduction
Chromene and pyrrole are important heterocyclic motifs in biomolecules and setting these rings in one
compound creates important systems, which are found as the basic building block in several bioactive
1-3
compounds including marine alkaloids ningalin B and lamellarin D. Many synthetic protocols have
been reported for the synthesis of chromeno[4,3-b]pyrrole-4(1H)-ones, an important fused
heterocyclic core consisting chromene and pyrrole, including the reaction of β-nitroalkenes and 4-
4
phenylamino coumarins under solvent–free condition and the reaction of amine, glyoxal
5
4
6
monohydrate and 4-amino coumarin in the presence of nanocrystalline CuFe
2
O
and KHSO . 4-
4
7
Chloro coumarin was reported as starting material in literature and reacted with α-amino ketones and
8
α-amino acid derivatives to produce N-(α)-(2-oxo-2H-1-benzopyran-4-yl)Weinreb-α-aminoamides.
In addition, the reaction of 4-N-(4´-aryloxybut-2-ynyl)-N-methylaminocoumarins with 3-
9
chloroperoxybenzoic acid afforded the desired pyrrolo[3,2-c]coumarin derivatives.
The assembly of N-heterocycles by designing new catalytic systems has attracted the chemists’
attention. Since the first application of molecular iodine as a catalytic system in the conversion of
10
diacetone alcohol into mesityl oxide in 1915, the catalytic applications of iodine in organic synthesis
and in chemical technology have become the focus of organic chemists in functional group
11
transformation. Two modes of activation have been proposed for iodine-catalyzed reactions,
1
2
meaning iodine-bond activation and hidden Brønsted acid catalysis.
Among these
1
3-16
approaches,
the first one has been favored in catalytic reactions over another pathway,
especially in Michael type reactions. By combining the advantageous features of tandem reactions
and iodine as a catalyst, a powerful synthetic strategy has been presented in this report for the
construction of complex structure, chromeno[4,3-b]pyrrole-4(1H)-ones, from simple substrates. In
continuation of our efforts to introduce economic and environmentally benign methods for the
17
synthesis of heterocyclic compounds, herein, we report a novel I -catalyzed, four-component
2
approach towards chromeno[4,3-b]pyrrole-4(1H)-ones. The reaction entails the in situ synthesis of 2-
oxo-2-arylacetaldehyde via the Kornblum oxidation reaction from the corresponding acetophenone
18
derivatives in the presence of molecular iodine and DMSO.
We started our quest for the in situ synthesis of 2-oxo-2-phenylacetaldehyde (phenylglyoxal), by the
18
Kornblum oxidation reaction of acetophenone, according to previously reported procedure. After
purification, we performed the one-pot reaction between phenyl glyoxal, 4-amino coumarin and
o
dimedone in DMSO at 100 C. To find a suitable catalyst, the reaction was screened by utilizing

different acidic catalysts such as TsOH-H
2
O, HOAc, ZnCl2, FeCl
3
and I (Table 1, entries 1-5). It
2
was found that iodine afforded the desired product 5a in better yields. Since iodine was also effective
in the preparation of compound 2a, we decided to attempt the reaction in a one-pot manner. Relied on
similar isolated yields (Table 1, entry 6) and advantageous features of one-pot reaction, allowing easy
purification and preparation, we chose this condition for further optimization and derivatization.
Subsequently, with the intention of finding optimized temperature and iodine amount, the model
o
reaction was evaluated at different temperatures (80, 90 and 110 C) (Table 1, entries 7-9) and iodine
amount (1.2 equiv.) (Table 1, entry 10). The best condition for this reaction was determined heating
o
the starting materials at 100 C by utilizing 1.1 equiv. iodine.
a
Table 1. Optimization of reaction condition
O
O
1
)
HO
O
O
HN
O
O
CH3
3a
H
NH2
O
O
O
1
a
2a
5a
2
)
O
4
Entry
T (ºC)
Catalyst
TsOH-H
HOAc
Yield (%)
a
b
1
2
3
4
5
6
100
100
100
100
100
100
80
90
110
100
2
O
60
a
55
35
32
79
86
41
65
85
85
a
ZnCl
2
a
FeCl
3
a
I
I
I
I
I
I
2
2
2
2
2
2
c
7
8
9
d
1
0
a
Reaction conditions: phenyl glyoxal (1 mmol), dimedone (1 mmol), 4-amino coumarin (1 mmol) and acidic
o
b
c
catalyst (1.1 equiv.) were heated in DMSO at 100 C for 7 h. Isolated yields. Acetophenone (1 mmol) and
o
iodine (1.1 equiv.) were heated in DMSO at 100 C for 2 h, then dimedone (1 mmol) and 4-amino coumarin
d
(
1 mmol) were added and the reaction was continued for 7 h. 1.2 equiv. of iodine was used.
Encouraged by this success, we extended this reaction to a series of (het)aryl methyl ketones 1a-
g and 1,3-dicarbonyl compounds 3a-d under optimized condition and corresponding

2
0
chromeno[4,3-b]pyrroles 5a-o were obtained in high yields. The results are summarized in Table
2
.
Table 2. Substrate scope for the one-pot synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones 5a-o
Ar
HO
HN
O
O
O
OH
1)
or
3a-d
O
O
O
5
O
O
a-j
I2 (1.1 eqiuv.)
O
Ar
CH3
a-g
Ar
or
DMSO, 100 °C
NH2
H
2
h
1
2a-g
2)
, 7 h
O
Ar
O
O
HN
1
a-g: Ar = Ph, 4-CH OC H , 4-CH C H ,
3 6 4 3 6 4
4
-FC H , 4-ClC H , 4-BrC H , 2-thienyl
4
6
4
6
4
6 4
3
a-d: dimedone, 2-hydroxy-1,4-naphtoquinone
O
barbituric acid, 1,3 dimethyl barbituric acid
O
O
5
k-o
a
a
Product
Structure
Yield (%) Product
Structure
Yield (%)
Me
HO
HN
HO
5
a
86
5b
78
HN
O
O
O
O
O
O
Cl
Br
HO
HO
5
5
c
e
89
80
5d
82
76
HN
O
HN
O
O
O
O
O
S
HO
HO
O
HN
O
HN
O
5f
O
O
O
O

OMe
F
HO
HO
5
g
O
81
79
5h
O
73
76
HN
O
HN
O
O
O
O
O
Cl
Br
HO
5
i
HO
O
5j
O
HN
O
HN
O
O
O O
O
O
O
HN
O
HN
O
5
k
NH
73
86
5l
N
N
85
88
O
O
N
O
H
O
O O
Cl
Cl
O
O
5
m
5n
HN
O
HN
O
NH
N
O
O
N
N
O
H
O
O
O
Me
O
5
o
77
HN
O
NH
O
N
O
H
O
a
Isolated yields.
1
13
The structures of the isolated products were deduced by IR, H, C NMR spectroscopy, mass
1
9
spectrometry and elemental analyses. For example, the IR spectrum of 5a showed the
–
1
stretching bands for N−H, and C=O bonds at 3339 (sharp), 1721 and 1613 cm , respectively.
1
The H NMR spectrum of 5a exhibited two singlets at 1.06 and 1.17 ppm related to methyl
groups. The methylene groups of dimedone appeared at 2.42 and 2.50 ppm as two singlets as
well as the characteristic signals with appropriate chemical shifts and coupling constants at 7.30-

8
.24 ppm related to the nine aromatic H-atoms. In addition, the sharp singlet at 10.14 and 12.49
1
13
ppm are related to the NH of pyrrole ring and enolic OH, respectively. The H-decoupled C
NMR spectrum of 5a showed characteristic signals at 27.9, 28.2, 31.6, 42.9 and 50.5 ppm for the
dimedone moiety. Also, 18 distinguishing signals were observed in 107-195 ppm, arising from
the aromatic and carbonyl groups of the desired product.
The proposed mechanism for this reaction is provided in Scheme 2. Mechanistically, it is conceivable
20
that the reaction involves the initial formation of phenylglyoxal 2a, followed by the Knoevenagle
condensation reaction with dimedone 3a and formation of adduct 6, which was assisted by molecular
iodine via the activation of aldehyde group. Then, Michael type addition of 4-aminocoumarin to
intermediate 6, imine-enamine rearrangement, annulation and elimination of H
intermediate 9. The latter undergoes proton shift to afford 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-
-en-1-yl)-2-phenylchromeno[4,3-b]pyrrole-4(1H)-one 5a.
2
O furnished
1
Ph
O
Ph
NH
O
HO
O
HO
H N
2
H
O
O
O
H
O
3a
-H O
2
O
O
O
O O
6
Ph
2
7
a
4
Ph
O
HO
Ph
HO
Ph
HO
NH2
N
HN
O
1
,3-H shift
-
H O
2
H
O
O
O
O
O
O
O
O
5a
8
9
Scheme 2. The proposed mechanism for the synthesis of 3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-2-phenylchromeno[4,3-
b]pyrrole-4(1H)-one.
In conclusion, we have developed an efficient, I -catalyzed approach for the synthesis of 3-
2
substituted-2-(het)arylchromeno[4,3-b]pyrrole-4(1H)-ones. Considering the availability of the starting
materials, nontoxic and nonmetallic characteristics of iodine, easy work-up and high yields of the
desired products, this approach provides a straightforward route to construct novel chromeno[4,3-
b]pyrrole derivatives. The synthesized compounds in the present study may find useful applications in
synthetic organic and medicinal chemistry.
Acknowledgments
This study was funded and supported by Iran National Science Foundation (INSF).

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1
1
1
1
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1
9. General Procedure for the Preparation of 5a: A mixture of acetophenone (0.120 g, 1
mmol) and molecular iodine (0.140 g, 1.1 mmol) in DMSO (10 mL) was stirred at 100 °C for 2
h. Upon completion, as indicated by TLC analysis, dimedone (0.140 g, 1 mmol) and 4-amino
coumarin (0.168 g, 1 mmol) were added to the mixture, respectively and the mixture was
allowed to stir for another 7 h at 100 °C. After this time, the reaction mixture was cooled and
poured into the ice/water mixture (50 mL). The resulting precipitate was filtered, washed with
hot EtOH and dried to afford the pure product 5a.
3
4
-(2-Hydroxy-4,4-dimethyl-6-oxocyclohex-1-en-1-yl)-2-phenylchromeno[4,3-b]pyrrole-
(1H)-one (5a):
–
1
Yield: (0.34 g, 86%); White powder, mp >300 C, IR (KBr) (νmax/cm ): 3339 (NH), 3053, 2963,
1
2
865, 1721 (broad, C=O), 1613, 1508, 1465, 1368, 1203, 1116, 1030, 954, 754, 684. H NMR
(
500 MHz, DMSO-d
6
): δ 1.06 and 1.17 (2s, 6H, 2CH
3
), 2.42 and 2.50 (2s, 4H, 2CH ), 7.31 (t, J
2
=
7.0 Hz, 1H), 7.36-7.46 (m, 5H), 7.55 (d, J = 7.5 Hz, 2H), 8.24 (d, J = 7.5 Hz, 1H), 10.14 (s,
1
3
1
H, NH), 12.50 (s, 1H, OH). C NMR (125 MHz, DMSO-d
6
): δ 27.9 and 28.2 (2CH ), 31.6
3
(
C(CH ), 42.9 and 50.4 (2CH ), 107.2, 109.2 (−C=C−OH), 113.8, 116.4, 116.7, 121.3, 123.7,
3
)
2
2
1
1
26.6, 126.8, 128.2, 128.4, 131.9, 134.3, 134.9, 151.1 (O−C=O), 157.1 (C−O), 171.4 (C−OH),
+
95.9 (C=O). EI-MS m/z (%): 399 (M , 100), 384 (78), 301 (47), 286 (11), 274 (31), 245 (9), 172
(
90), 216 (14), 126 (6), 55 (11). Anal. Calcd. for C25
H
21NO : C, 75.17; H, 5.30; N, 3.51. Found:
4
C, 75.39; H, 5.42; N, 3.68.
2
-Hydroxy-3-(4-oxo-2-phenyl-1,4-dihydrochromeno[4,3-b]pyrrol-3-yl)naphthalene-1,4-
dione (5f):
–
1
Yield 0.33 g, (76%); Red powder, mp >300 ˚C, IR (KBr) (νmax/cm ): 3345 (NH), 3253, 3224,
1
1
678 (broad, C=O), 1590, 1506, 1461, 1358, 1203, 1158, 1130, 1040, 752, 721. H NMR (500
MHz, DMSO-d
6
): 7.31 (s, 1H, CH), 7.39-7.47 (m, 4H, 4CH), 7.49 (t, J = 7.5 Hz, 1H, CH), 7.61
(
d, J = 7.5 Hz, 2H, 2CH), 7.84-7.90 (m, 2H, 2CH), 7.99 (d, J = 7.5 Hz, 1H, CH), 8.10 (d, J = 7
1
3
Hz, 1H, CH), 8.30 (d, J = 7.5 Hz, 1H, CH), 11.14 (s, 1H, pyrrole NH), 12.82 (s, 1H, OH). C
NMR (125 MHz, DMSO-d ): 109.4 (−C=C−OH), 110.2 (C pyrrole), 114.0 (C), 117.3 (CH),
18.0 (C pyrrole), 122.2 (CH), 124.7 (CH), 126.6 (CH), 127.1 (2CH), 128.3 (CH), 129.2 (2CH),
6
1
1
30.7 (C), 131.8 and 132.6 (2C of pyrrole), 133.8 (CH), 135.3 (CH), 136.0 (C), 151.8 (C), 157.7
+
(
O−C=O), 181.4 (C=O), 183.7 (C=O). EI-MS, m/z (%): 433 (M , 100), 405 (79), 388 (5), 376

(
9), 360 (8), 348 (23), 320 (7), 301 (6), 272 (5), 216 (6), 104 (19), 76 (17). Anal. Calcd. for
: C, 74.82; H, 3.49; N, 3.23. Found: C, 74.65; H, 3.67; N, 3.01.
C
27
H15NO
5
2
0. (a) Yin G, Wang Z, Chen A, Gao M, Wu A, Pan Y. J Org Chem. 2008;73:3377-3383.
(
b) Yin G, Zhou B, Meng X, Wu A, Pan Y. Org Lett. 2006;8:2245-2248.

Graphical Abstract:
Ar
OH
HN
O
O
I2, DMSO,100 °C
O
O
O
Ar
CH3
O
NH2
O
Ar
O
HN
,
or
O
O
OH
O
O
O
15 Examples

Highlights
The new method for the synthesis of chromeno[4,3-b]pyrrol-4(1H)-ones is reported.
In this method, iodine is utilized as nontoxic and nonmetallic catalyst.
Iodine conducted Kornblum oxidation and Michael type reaction in one-pot manner.