Efficient domino synthesis of pyrrole-fused isocoumarins with microwave heating

Article abstract of DOI:10.1002/ejoc.201402164

A new three-component approach to polyfunctionalized isochromeno[4,3-b] pyrroles has been developed with excellent regioselectivity. During these domino reactions, two ring-opening and three cyclization reactions were readily achieved through carbon-carbon bond cleavage under transition-metal-free conditions. The advantages of atom and step economy, and scope make this reaction a powerful tool for assembling tri-heterocyclic scaffolds of general chemical and biomedical interest. Copyright

Full text of DOI:10.1002/ejoc.201402164

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FULL PAPER
DOI: 10.1002/ejoc.201402164
Efficient Domino Synthesis of Pyrrole-Fused Isocoumarins with Microwave
Heating
Mu-Yan Sun,[a][‡] Xiao-Yan Meng,[a][‡] Fu-Jie Zhao,[a][‡] Yi-Jing Dang,[a][‡] Fei Jiang,[a][‡]
Kai Liu,[a][‡] Cong-Shuai Wang,[a][‡] Bo Jiang,*[a] and Shu-Jiang Tu*[a]
Keywords: Synthetic methods / Domino reactions / Oxygen heterocycles / Nitrogen heterocycles / Regioselectivity /
Microwave chemistry
A new three-component approach to polyfunctionalized
isochromeno[4,3-b]pyrroles has been developed with excel-
lent regioselectivity. During these domino reactions, two
ring-opening and three cyclization reactions were readily
achieved through carbon–carbon bond cleavage under tran-
sition-metal-free conditions. The advantages of atom and
step economy, and scope make this reaction a powerful tool
for assembling tri-heterocyclic scaffolds of general chemical
and biomedical interest.
Introduction
The development of highly efficient syntheses of multi-
heterocyclic scaffolds, particularly of those containing iso-
coumarin rings, is of chemical and biomedical importance
and has been actively pursued in organic and medicinal re-
search for several decades.[1,2] The structurally diverse and
intriguing isocoumarin family has been found to exist in
many natural products, for example cytogenin, bergenin, fu-
sarentin, monocerin and cephalosol (Figure 1), and exhibit
significant biological activities, such as antiallergenic, anti-
microbial,[1,2] immunomodulatory,[3] cytotoxic,[4] antifun-
gal,[5] antiinflammatory,[6] antiangiogenic,[7] and antimalar-
ial.[8] There are a few methods to synthesize isocoumarin
derivatives by using transition-metal complexes, such as
Rh,[9] Pd,[10] Ru[11] and Cu[12] as the catalysts. Despite these
limited isocoumarin syntheses, the development of a facile
protocol for the direct formation of fused isocoumarin de-
rivatives would be highly favorable.
In addition, multicomponent reactions (MCRs) have
emerged as effective methods for the assembly of complex
cyclic structures through the combination of two or more
distinct reactions into a one-pot transformation.[13] MCRs
can enhance annulation efficiency and also avoid time-con-
suming isolation of intermediates and minimize the genera-
Figure 1. Some naturally occurring bioactive isocoumarins.
tion of waste. In recent years, enormous efforts have been the formation of various heterocycles.[14] However, to the
made to conduct multicomponent domino reactions toward best of our knowledge, the use of multicomponent reactions
combined with insertion for the construction of a tricyclic
pyrrole-fused isocoumarin skeleton through carbon–carbon
bond cleavage has not been documented.
[a] School of Chemistry and Chemical Engineering, and Jiangsu
Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University,
Recently, we have established several multicomponent
domino reactions for a series of heterocycles.[15] In continu-
ation of this project, we now report the challenging ring
expansion and annulation of 2,2-dihydroxyindene-1,3-dione
(1) with aromatic amines 2 and symmetrical dimethyl but-
Xuzhou 211116, P. R. China
E-mail: jiangchem@jsnu.edu.cn
laotu@jsnu.edu.cn
[‡] These authors contributed equally to this work
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402164.
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FULL PAPER
2-ynedioates 3 to yield multifunctionalized pyrrole-fused as formic acid (HCOOH) and CF3COOH, at 80 °C under
isocoumarin derivatives (Scheme 1). The advantage of the microwave irradiation (Table 1, Entries 1 and 2). An incom-
present multicomponent domino reactions is the formation plete reaction was observed when acetic acid was used as
of two new rings (pyran-2-one and pyrrole rings) and four the acidic media (Table 1, Entry 3). Gratifyingly, this reac-
sigma bonds that were readily achieved through a metal- tion worked more efficiently in acetic anhydride, which af-
free ring-expansion reaction in a one-pot operation; and the forded corresponding product 4a in 59% yield (Table 1, En-
cyclopentenedione ring was converted into the correspond- try 4). Next, the influence of reaction temperature was also
ing pyran-2-one unit by insertion of oxygen into the sp2–sp3 optimized, and the same reaction in Ac2O was performed
C–C bond of the 2,2-dihydroxyindene-1,3-dione ring under and repeated many times at different temperatures in a
transition-metal-free conditions. The present work repre- sealed vessel under microwave irradiation for 24 min. The
sents a special example for construction of tricyclic hetero- yield of product 4a was increased from 59 to 73% as the
cycles containing and isocoumarin unit with high regiose- temperature increased from 80 to 100 °C, respectively
lectivity.
(Table 1, Entry 5). Further increase in the reaction tempera-
ture failed to improve the yield of desired product 4a
(Table 1, Entry 6). Subsequently, the identical reaction was
investigated under conventional heating at 100 °C for
60 min to provide desired product 4a in 65% yield (Table 1,
Entry 7).
With acceptable conditions in hand, we proceeded to
probe the substrate diversity of the three-component dom-
ino reaction by using readily available starting materials.
Pleasingly, all the reactions proceeded efficiently and af-
forded the desired products in good to excellent yields. The
results are presented in Table 2. The substituents on the
arylamine ring did not hamper the reaction. Reactions of
fluoro-, chloro-, bromo-, methyl-, or methoxy-substituted
arylamine ring 2 with 1 and 3 all worked well to provide
Scheme 1. The synthesis of polysubstituted fused isocoumarins 4.
Results and Discussion
2,2-Dihydroxyindene-1,3-dione, which possesses three
electrophilic centers, has proven to be an important build-
ing block for the construction of important cyclic skel-
etons.[16] Our strategy for the synthesis of highly function-
alized tricyclic isocoumarins started from the reaction of
2,2-dihydroxyindene-1,3-dione with aromatic amines 2 and
dimethyl but-2-ynedioate 3, based on the fact that: (1) di-
methyl but-2-ynedioate would undergo nucleophilic ad-
dition with amines, generating a β-enamino ester with 1,3-
bisnucleophilic centers;[17] (2) 2,2-dihydroxyindene-1,3-di-
one was subjected to appropriate 1,3-bisnucleophiles to give
dihydroxyindenes, which were converted into isocoumarin
derivatives in acidic media.[18]
Table 2. The domino synthesis of compounds 4.[a]
Entry
4
R (2)
R
Time[b] Yield [%][c]
Based on the above analysis, the reaction of 2,2-di-
hydroxyindene-1,3-dione 1 with aniline 2a and dimethyl
but-2-ynedioate 3a was tested under a variety of conditions.
Representative data are summarized in Table 1. The reac-
tion did not give desired product 4 in acidic solvents, such
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph (2a)
3,5-F2Ph (2b)
3-FPh (2c)
4-ClPh (2d)
3,4-Cl2Ph (2e)
3,5-Cl2Ph (2f)
4-BrPh (2g)
3-BrPh (2h)
4-MePh (2i)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
24
21
25
25
26
22
24
23
21
26
23
24
21
30
28
21
25
28
25
23
22
25
28
73
68
76
72
75
74
77
78
88
86
71
75
79
53
64
81
66
77
79
72
82
85
60
Table 1. Optimization of reaction conditions.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4j
4k
4l
3-Br-4-MePh (2j) Me (3a)
2-MePh (2k)
3-MePh (2l)
4-MeOPh (2m)
Me (2n)
Cyclopropyl (2o) Me (3a)
Ph (2a)
3,5-F2Ph (2b)
4-ClPh (2d)
3,4-Cl2Ph (2a)
3,5-Cl2Ph (2f)
3-Br-4-MePh (2j) Et (3b)
4-MePh (2i) Et (3b)
Cyclopropyl (2o) Et (3b)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
4m
4n
4o
4p
4q
4r
4s
4t
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Entry
Solvent
T [°C]
Time [min]
Yield [%]
1
2
3
4
5
6
7
CF3COOH
HCOOH
HOAc
Ac2O
Ac2O
Ac2O
80
80
80
24
24
24
24
24
–
–
21
59
73
61
65
80
4u
4v
4w
100
120
100[a]
24
Ac2O
60[a]
[a] Reagents and conditions: 100 °C, Ac2O (1.5 mL), microwave
heating. [b] Time [min]. [c] Isolated yield.
[a] Conventional heating.
2
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Efficient Domino Synthesis of Pyrrole-Fused Isocoumarins
the desired products in good yields (Table 2, Entries 1–13). as chloro and bromo in this protocol provides the opportu-
Bulky o-substituted arylamine 2k was converted into corre- nity for further chemical manipulations of the products. It
sponding isochromeno[4,3-b]pyrroles 4k in 71% yield. Simi- is worth mentioning that the protocol provides a straight-
larly, methylamine 2n and cyclopropanamine 2o still dis- forward pathway to synthesize poly-substituted iso-
played high reactivity and a clean reaction under these con- chromeno[4,3-b]pyrroles, which are generally prepared
ditions (Table 2, Entries 14 and 15). Furthermore, diethyl through multi-step reactions.[19]
but-2-ynedioate 3b was suitable for this transformation.
In all cases the reaction was very fast and complete
Next, amino alcohols were employed to replace aromatic within 21–30 min. Water is nearly the sole by-product,
amines to test the scope of this three-component domino which makes work-up convenient. In most cases, the prod-
reaction. As anticipated, 2-aminoethanol (2p), 1-amino- ucts precipitate when a dilute basic solution is poured into
propan-2-ol (2q), and 2-amino-1-phenylethanol (2r) were all the reaction mixture. The structural elucidation was
transformed into corresponding tetracyclic isocoumarin de-
rivatives 4x–4z in 59–71% yields (Scheme 2). These results
display the scope and generality of the three-component cy-
clization reaction with regard to a wide range of amine
components, including amino alcohols, aromatic, aliphatic,
and alicyclic amines. The tolerance of functionalities, such
Scheme 2. Domino synthesis of tetracyclic isocoumarins.
Figure 2. The ORTEP drawing of 4m.[20]
Scheme 3. Proposed mechanism for formation of products 4.
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FULL PAPER
were added. The reaction vial was capped and stirred in an oil bath
at 100 °C for 60 min. The work-up was as described for the above
reaction to give a white solid; m.p. 265–266 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.26–8.24 (m, 1 H, Ar-H), 7.73–7.69
(m, 1 H, Ar-H), 7.68–7.64 (m, 2 H, Ar-H), 7.61–7.55 (m, 3 H, Ar-
H), 7.52–7.48 (m, 1 H, Ar-H), 6.39 (d, J = 7.6 Hz, 1 H, Ar-H),
3.87 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 162.1, 161.1, 160.5, 138.7, 137.0,
135.6, 131.8, 131.0, 130.4, 129.6, 129.5 (6), 128.6, 128.2, 119.7,
unequivocally determined by NMR spectroscopic analysis
and single-crystal X-ray diffraction of 4m (Figure 2).
On the basis of literature reports[18c] and observations
from the above results, a possible mechanism for this new
reaction is proposed and is depicted in Scheme 3. Firstly, an
addition reaction between dimethyl but-2-ynedioate 3 and
arylamines 1 occurs to generate β-enamino ester A, which
reacts with protonated 2 providing intermediate B. Interme-
diate B undergoes intramolecular two continuous cycliza-
119.3, 116.0, 105.9, 53.2, 52.6 ppm. IR (KBr): ν = 3062, 1728, 1720,
˜
tions to give three-membered ring-intermediate G, followed 1614, 1584, 1556, 1513, 1439, 1407 cm–1. HRMS (ESI): calcd. for
C21H16NO6 378.0978 [M + H]+; found 378.0999.
by ring-opening and deprotonation to yield isochro-
meno[4,3-b]pyrroles 4. Isochromeno[4,3-b]pyrroles 4x–4z
are obtained through a third cyclization (intramolecular es-
terification).
Dimethyl
1-(3,5-Difluorophenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4b): A white solid; m.p. Ͼ 300 °C.
1H NMR (400 MHz, [D6]DMSO): δ = 8.29–8.27 (m, 1 H, Ar-H),
7.73–7.67 (m, 2 H, Ar-H), 7.61–7.54 (m, 3 H, Ar-H), 6.56 (d, J =
8.0 Hz, 1 H, Ar-H), 3.88 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 161.7, 161.1 (JCF
=
1
Conclusions
216.5 Hz), 160.8, 139.5, 138.6, 136.0, 131.9, 129.2, 128.8, 128.7
3
4
(JCF = 8.2 Hz), 126.8 (JCF = 4.4 Hz), 120.0, 119.4, 116.6, 113.5
In summary, we have described a new three-component
domino reaction involving a ring-opening and cyclization
process, which provides a general and efficient strategy for
the synthesis of isochromeno[4,3-b]pyrrole derivatives with
good yields in a one-pot manner. The bond-forming effi-
ciency, structural accessibility and reaction generality make
the present method a highly attractive approach to pyrrole-
fused isocoumarin scaffolds of chemical and biomedical im-
portance. Advantages of this strategy include the relatively
mild conditions, convenient one-pot operation, and short
reaction times. Efforts toward the extension of this method-
ology to natural products and drug synthesis are underway.
(JCF2 = 28.0 Hz), 107.7, 107.2, 53.2, 52.9 ppm. IR (KBr): ν = 3084,
˜
1737, 1720, 1616, 1585, 1557, 1512, 1479 cm–1. HRMS (ESI): calcd.
for C21H14F2NO6 414.0789 [M + H]+; found 414.0799.
Dimethyl 1-(3-Fluorophenyl)-5-oxo-1,5-dihydroisochromeno[4,3-b]-
1
pyrrole-2,3-dicarboxylate (4c): A white solid; m.p. 177–178 °C. H
NMR (400 MHz, [D6]DMSO): δ = 8.26 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.74–7.58 (m, 4 H, Ar-H), 7.55–7.48 (m, 2 H, Ar-H), 6.45 (d,
J = 8.0 Hz, 1 H, Ar-H), 3.86 (d, J = 11.2 Hz, 3 H, OCH3), 3.68 (d,
J = 10.4 Hz, 3 H, OCH ) ppm. IR (KBr): ν = 3049, 1734, 1721,
˜
3
1610, 1556, 1496, 1455, 1408 cm–1. HRMS (ESI): calcd. for
C21H15FNO6 396.0883 [M + H]+; found 396.0877.
Dimethyl 1-(4-Chlorophenyl)-5-oxo-1,5-dihydroisochromeno[4,3-b]-
1
pyrrole-2,3-dicarboxylate (4d): A white solid; m.p. 224–225 °C. H
NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m, 1 H, Ar-H), 7.75–
7.71 (m, 2 H, Ar-H), 7.67–7.63 (m, 3 H, Ar-H), 7.55–7.51 (m, 1 H,
Ar-H), 6.50 (d, J = 8.0 Hz, 1 H, Ar-H), 3.87 (s, 3 H, OCH3), 3.66
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.1,
161.0, 160.35, 138.7, 136.1, 135.8, 135.6, 131.9, 130.6, 130.5, 129.4,
128.4, 127.9, 119.8, 119.4, 116.3, 106.7, 53.2, 52.7 ppm. IR (KBr):
Experimental Section
General: Microwave irradiation was carried out with Initiator 2.5
Microwave Synthesizers from Biotage, Uppsala, Sweden. The reac-
tion temperatures were measured with an infrared detector during
microwave heating.
ν = 3072, 1727, 1710, 1612, 1556, 1517, 1494, 1461 cm–1. HRMS
˜
(ESI): calcd. for C21H15ClNO6 412.0588 [M + H]+; found 412.0594.
General Procedure for the Synthesis of Compounds 4a–4w
Dimethyl 5-Oxo-1-phenyl-1,5-dihydroisochromeno[4,3-b]pyrrole-2,3-
dicarboxylate (4a): Microwave Heating: Dimethyl but-2-ynedioate
(3a; 1.0 mmol, 0.142 g) was introduced into a 10-mL Initiator reac-
tion vial, and aniline (2a; 1.0 mmol, 0.093 g) was slowly added. The
mixture was stirred at room temperature for 6 min. Subsequently,
2,2-dihydroxyindene-1,3-dione (1; 1.0 mmol, 0.178 g) and Ac2O
(1.5 mL) were added. The reaction vial was capped and stirred for
20 s. The mixture was irradiated (time: 24 min, temperature:
100 °C; absorption level: high; fixed hold time) until TLC (petro-
leum ether/acetone, 3:1) revealed that conversion of starting mate-
rial 1 was complete. The reaction mixture was cooled to room tem-
perature. The diluted basic solution was poured into the reaction
mixture until Ac2O was neutralized, and then cold water (30 mL)
was added. The solid product was filtered and washed with water
and EtOH (95%), and subsequently dried and recrystallized from
EtOH (95%) to give pure product 4a.
Dimethyl
1-(3,4-Dichlorophenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4e): A white solid; m.p. 231–
232 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.27 (d, J = 7.6 Hz,
1 H, Ar-H), 8.10–8.09 (m, 1 H, Ar-H), 7.94 (d, J = 8.8 Hz, 1 H,
Ar-H), 7.71–7.67 (m, 2 H, Ar-H), 7.55 (t, J = 7.6 Hz, 1 H, Ar-H),
6.57 (d, J = 8.0 Hz, 1 H, Ar-H), 3.88 (s, 3 H, OCH3), 3.68 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.2, 160.9,
160.1, 138.6, 137.1, 136.0, 133.9, 132.6, 132.2, 131.9, 131.0, 129.3,
129.2 (7), 128.6, 126.9, 120.0, 119.4, 116.7, 107.6, 53.2, 52.9 ppm.
IR (KBr): ν = 3064, 1727, 1720, 1614, 1585, 1557, 1509, 1474,
˜
1409 cm–1. HRMS (ESI): calcd. for C21H14Cl2NO6 446.0198 [M +
H]+; found 446.0188.
Dimethyl
1-(3,5-Dichlorophenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4f): A white solid; m.p. 249–
1
250 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.29–8.27 (m, 1 H,
Ar-H), 8.03 (t, J = 2.0 Hz, 1 H, Ar-H), 7.91 (d, J = 1.6 Hz, 2 H,
Ar-H), 7.73–7.69 (m, 1 H, Ar-H), 7.59–7.55 (m, 1 H, Ar-H), 6.53
(d, J = 8.0 Hz, 1 H, Ar-H), 3.89 (s, 3 H, OCH3), 3.69 (s, 3 H,
OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.2, 160.8,
160.0, 139.5, 138.6, 136.1, 135.3, 132.0, 131.0, 129.2, 128.7, 128.2,
Conventional Heating: Dimethyl but-2-ynedioate (3a; 1.0 mmol,
0.142 g) was introduced into a 10-mL Initiator reaction vial, and
aniline (2a; 1.0 mmol, 0.093 g) was slowly added. The mixture was
stirred at room temperature for 6 min. Subsequently, 2,2-dihy-
droxyindene-1,3-dione (1; 1.0 mmol, 0.178 g) and Ac2O (1.5 mL)
126.4, 120.0, 119.4, 116.9, 108.0, 53.2, 52.9 ppm. IR (KBr): ν =
˜
4
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Efficient Domino Synthesis of Pyrrole-Fused Isocoumarins
3066, 1731, 1722, 1612, 1573, 1555, 1508, 1439 cm–1. HRMS (ESI):
calcd. for C21H14Cl2NO6 446.0198 [M + H]+; found 446.0185.
(m, 4 H, Ar-H), 7.40–7.37 (m, 2 H, Ar-H), 6.43 (d, J = 8.0 Hz, 1
H, Ar-H), 3.87 (s, 3 H, OCH3), 3.64 (s, 3 H, OCH3), 2.41 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.1, 161.1,
160.6, 140.2, 138.7, 136.9, 135.6, 131.8, 131.6, 130.1, 129.6, 128.8,
128.7, 128.2, 125.6, 119.8, 119.3, 115.9, 105.7, 53.2, 52.6, 21.2 ppm.
Dimethyl 1-(4-Bromophenyl)-5-oxo-1,5-dihydroisochromeno[4,3-b]-
1
pyrrole-2,3-dicarboxylate (4 g): A white solid; m.p. 230–231 °C. H
NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m, 1 H, Ar-H), 7.89–
7.85 (m, 2 H, Ar-H), 7.68–7.64 (m, 1 H, Ar-H), 7.61–7.57 (m, 2 H,
Ar-H), 7.55–7.51 (m, 1 H, Ar-H), 6.50 (d, J = 8.0 Hz, 1 H, Ar-H),
3.87 (s, 3 H, OCH3), 3.66 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 162.1, 161.0, 160.4, 138.7, 136.5,
135.8, 133.4, 131.9, 130.8, 129.4, 128.4, 127.9, 124.2, 119.8, 119.4,
IR (KBr): ν = 3074, 1729, 1711, 1613, 1583, 1556, 1511, 1489,
˜
1402 cm–1. HRMS (ESI): calcd. for C22H18NO6 392.1134 [M + H]+;
found 392.1122.
Dimethyl
1-(4-Methoxyphenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4m): A white solid; m.p. 223–
1
116.3, 106.7, 53.2, 52.7 ppm. IR (KBr): ν = 3070, 1733, 1724, 1611,
˜
224 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.26–8.23 (m, 1 H,
1556, 1518, 1493, 1460 cm–1. HRMS (ESI): calcd. for
C21H15BrNO6 456.0083 [M + H]+; found 456.0087.
Ar-H), 7.64–7.60 (m, 1 H, Ar-H), 7.52–7.48 (m, 3 H, Ar-H), 7.19–
7.15 (m, 2 H, Ar-H), 6.51 (d, J = 8.0 Hz, 1 H, Ar-H), 3.89 (s, 3 H,
OCH3), 3.88 (s, 3 H, OCH3), 3.65 (s, 3 H, OCH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 162.1, 161.1, 160.8, 160.7, 138.6,
135.7, 131.8, 129.8, 129.7, 129.3, 129.2, 128.1, 119.7, 119.2, 116.0,
Dimethyl 1-(3-Bromophenyl)-5-oxo-1,5-dihydroisochromeno[4,3-b]-
1
pyrrole-2,3-dicarboxylate (4h): A white solid; m.p. 236–237 °C. H
NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m, 1 H, Ar-H), 7.96–
7.91 (m, 2 H, Ar-H), 7.68–7.60 (m, 3 H, Ar-H), 7.55–7.51 (m, 1 H,
Ar-H), 6.44 (d, J = 7.6 Hz, 1 H, Ar-H), 3.88 (s, 3 H, OCH3), 3.66
(s, 3 H, OCH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.1,
160.9, 160.25, 138.6, 138.5 (7), 135.8, 134.0, 132.1, 131.9, 131.6,
129.4, 128.4, 128.0, 127.5, 122.5, 119.8, 119.4, 116.5, 107.0, 53.2,
115.4, 105.4, 56.1, 53.2, 52.6 ppm. IR (KBr): ν = 3075, 1745, 1719,
˜
1613, 1584, 1556, 1513, 1459, 1441 cm–1. HRMS (ESI): calcd. for
C22H18NO7 408.1083 [M + H]+; found 408.1078.
Dimethyl 1-Methyl-5-oxo-1,5-dihydroisochromeno[4,3-b]pyrrole-2,3-
dicarboxylate (4n): A white solid; m.p. 238–239 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.31 (d, J = 8.0 Hz, 1 H, Ar-H), 8.20
(d, J = 8.0 Hz, 1 H Ar-H), 7.96 (t, J = 7.6 Hz, 1 H, Ar-H), 7.64 (t,
J = 7.6 Hz, 1 H, Ar-H), 4.16 (s, 3 H, CH3), 3.90 (s, 3 H, CH3),
3.83 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
162.2, 161.5, 161.2, 138.6, 136.0, 131.8, 130.0, 128.1, 127.6, 121.6,
52.8 ppm. IR (KBr): ν = 3060, 1732, 1720, 1614, 1557, 1509, 1476,
˜
1439 cm–1. HRMS (ESI): calcd. for C21H15BrNO6 456.0083 [M +
H]+; found 456.0097.
Dimethyl 5-Oxo-1-(p-tolyl)-1,5-dihydroisochromeno[4,3-b]pyrrole-
2,3-dicarboxylate (4i): A white solid; m.p. 190–191 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.25–8.23 (m, 1 H, Ar-H), 7.61–7.57
(m, 1 H, Ar-H), 7.52–7.48 (m, 1 H, Ar-H), 7.46 (s, 4 H, Ar-H),
6.46 (d, J = 8.0 Hz, 1 H, Ar-H), 3.86 (s, 3 H, OCH3), 3.64 (s, 3 H,
OCH3), 2.48 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]
DMSO): δ = 162.0, 161.1, 160.6, 140.7, 138.7, 135.6, 134.4, 131.8,
130.8, 129.6, 129.0, 128.3, 128.2, 119.7, 119.2, 115.9, 105.6, 53.2,
119.1, 115.7, 104.9, 53.5, 52.5, 36.2 ppm. IR (KBr): ν = 3058, 1743,
˜
1691, 1636, 1563, 1474 cm–1. HRMS (ESI): calcd. for
C16H13NO6Na 338.0635 [M + Na]+; found 338.0633.
Dimethyl1-cyclopropyl-5-oxo-1,5-dihydroisochromeno[4,3-b]pyrrole-
2,3-dicarboxylate(4o): A white solid; m.p. 232–234 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.45 (d, J = 8.4 Hz, 1 H, Ar-H), 8.28
(d, J = 8.0 Hz, 1 H, Ar-H), 7.96 (t, J = 8.0 Hz, 1 H, Ar-H), 7.62
(t, J = 7.6 Hz, 1 H, Ar-H), 3.93 (s, 3 H, CH3), 3.91–3.88 (m, 1 H,
CH), 3.81 (s, 3 H, CH3), 1.32–1.28 (m, 2 H, CH2), 0.99–0.95 (m, 2
H, CH2) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 161.8, 161.7,
161.3, 138.3, 135.7, 131.5, 130.8, 130.0, 127.9, 122.3, 118.9, 116.1,
52.6, 21.4 ppm. IR (KBr): ν = 3074, 1734, 1726, 1613, 1555, 1511,
˜
1461, 1434 cm–1. HRMS (ESI): calcd. for C22H18NO6 392.1134 [M
+ H]+; found 392.1166.
Dimethyl 1-(3-Bromo-4-methylphenyl)-5-oxo-1,5-dihydroisochrom-
eno[4,3-b]pyrrole-2,3-dicarboxylate (4j): A white solid; m.p. 232–
1
103.6, 53.6, 52.3, 31.0, 10.3 ppm. IR (KBr): ν = 3068, 1733, 1690,
˜
233 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m, 1 H,
1633, 1559, 1478 cm–1. HRMS (ESI): calcd. for C18H15NO6Na
364.0792 [M + Na]+; found 364.0798.
Ar-H), 7.92 (d, J = 2.0 Hz, 1 H, Ar-H), 7.67–7.62 (m, 2 H, Ar-H),
7.57–7.51 (m, 2 H, Ar-H), 6.51 (d, J = 8.0 Hz, 1 H, Ar-H), 3.87 (s,
3 H, OCH3), 3.67 (s, 3 H, OCH3), 2.50–2.49 (m, 3 H, CH3) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 162.1, 161.0, 160.4, 140.6,
138.6, 135.9, 135.8, 132.4, 132.0, 131.9, 129.5, 128.4, 127.9 (4),
127.9 (1), 124.7, 119.8, 119.3, 116.4, 106.7, 53.2, 52.7, 22.8 ppm.
Diethyl 5-Oxo-1-phenyl-1,5-dihydroisochromeno[4,3-b]pyrrole-2,3-
dicarboxylate (4p): A white solid; m.p. 127–128 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.26–8.23 (m, 1 H, Ar-H), 7.73–7.64
(m, 3 H, Ar-H), 7.61–7.55 (m, 3 H, Ar-H), 7.52–7.48 (m, 1 H, Ar-
H), 6.40 (d, J = 8.0 Hz, 1 H, Ar-H), 4.35–4.30 (m, 2 H, CH2), 4.09–
4.04 (m, 2 H, CH2), 1.30 (t, J = 7.2 Hz, 3 H, CH3), 1.00 (t, J =
7.2 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
161.0, 160.5, 159.3, 138.2, 136.7, 135.0, 132.1, 131.3, 130.4, 129.8,
129.1, 128.1, 127.6, 119.1, 118.8, 115.3, 105.6, 61.4, 60.7, 14.0,
IR (KBr): ν = 3080, 1733, 1724, 1614, 1557, 1509, 1491, 1438,
˜
1407 cm–1. HRMS (ESI): calcd. for C22H17BrNO6 470.0239 [M +
H]+; found 470.0235.
Dimethyl 5-Oxo-1-(o-tolyl)-1,5-dihydroisochromeno[4,3-b]pyrrole-
2,3-dicarboxylate (4k): A white solid; m.p. 224–225 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.27–8.24 (m, 1 H, Ar-H), 7.63–7.51
(m, 4 H, Ar-H), 7.49–7.47 (m, 2 H, Ar-H), 6.28 (d, J = 7.6 Hz, 1
H, Ar-H), 3.88 (s, 3 H, OCH3), 3.63 (s, 3 H, OCH3), 1.98 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 162.1, 161.1,
160.5, 138.8, 136.7, 136.3, 135.9, 131.9, 131.7, 131.3, 129.5, 128.7,
128.3, 128.1, 127.8, 119.4, 118.8, 115.4, 106.0, 53.2, 52.6, 17.1 ppm.
13.4 ppm. IR (KBr): ν = 3058, 1726, 1719, 1615, 1557, 1498, 1444,
˜
1402 cm–1. HRMS (ESI): calcd. for C23H20NO6, 406.1291 [M +
H]+; found 406.1289.
Diethyl 1-(3,5-Difluorophenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4q): A white solid; m.p. 220–
1
221 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.29–8.27 (m, 1 H,
IR (KBr): ν = 3060, 1723, 1710, 1611, 1552, 1504, 1439, 1402 cm–1.
˜
Ar-H), 7.72–7.67 (m, 2 H, Ar-H), 7.64–7.54 (m, 3 H, Ar-H), 6.57
(d, J = 8.0 Hz, 1 H, Ar-H), 4.37–4.31 (m, 2 H, CH2), 4.15–4.10 (m,
2 H, CH2), 1.31 (t, J = 6.8 Hz, 3 H, CH3), 1.08 (t, J = 7.2 Hz, 3
HRMS (ESI): calcd. for C22H18NO6 392.1134 [M + H]+; found
392.1153.
Dimethyl 5-Oxo-1-(m-tolyl)-1,5-dihydroisochromeno[4,3-b]pyrrole-
2,3-dicarboxylate (4l): A white solid; m.p. 224–225 °C. 1H NMR
H, CH ) ppm. IR (KBr): ν = 3070, 1737, 1708, 1616, 1557, 1509,
˜
3
1474, 1402 cm–1. HRMS (ESI): calcd. for C23H18F2NO6 442.1102
(400 MHz, [D6]DMSO): δ = 8.26–8.24 (m, 1 H, Ar-H), 7.61–7.48 [M + H]+; found 442.1084.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O42164
/KAP1
Date: 17-04-14 18:14:37
Pages: 8
B. Jiang, S.-J. Tu et al.
FULL PAPER
Diethyl 1-(4-Chlorophenyl)-5-oxo-1,5-dihydroisochromeno[4,3-b]pyr-
role-2,3-dicarboxylate (4r): A white solid; m.p. 156–157 °C. 1H
NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m, 1 H, Ar-H), 7.76–
7.72 (m, 2 H, Ar-H), 7.68–7.63 (m, 3 H, Ar-H), 7.55–7.51 (m, 1 H,
Ar-H), 6.50 (d, J = 8.0 Hz, 1 H, Ar-H), 4.35–4.30 (m, 2 H, CH2),
4.12–4.06 (m, 2 H, CH2), 1.31 (t, J = 7.2 Hz, 3 H, CH3), 1.05 (t, J
= 6.8 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
161.6, 161.0, 159.7, 138.7, 136.3, 135.8, 135.5, 131.9, 130.7, 130.4,
129.5, 128.3, 127.8, 119.8, 119.4, 116.2, 107.1, 62.0, 61.4, 14.5,
1613, 1554, 1514, 1465, 1401 cm–1. HRMS (ESI): calcd. for
C24H22NO6 420.1447 [M + H]+; found 420.1454.
Diethyl 1-Cyclopropyl-5-oxo-1,5-dihydroisochromeno[4,3-b]pyrrole-
2,3-dicarboxylate (5w): A white solid; m.p. 199–200 °C. 1H NMR
(400 MHz, [D6]DMSO): δ = 8.45 (d, J = 8.0 Hz, 1 H, Ar-H), 8.28
(d, J = 8.0 Hz, 1 H, Ar-H), 7.96 (t, J = 8.0 Hz, 1 H, Ar-H), 7.62
(t, J = 8.0 Hz, 1 H, Ar-H), 4.41–4.36 (m, 2 H, CH2), 4.29–4.24 (m,
2 H, CH2), 3.93–3.88 (m, 1 H, CH), 1.35 (t, J = 8.0 Hz, 3 H, CH3),
1.31–1.26 (m, 5 H, CH3 and CH2), 1.00–0.96 (m, 2 H, CH2) ppm.
13C NMR (100 MHz, [D6]DMSO): δ = 161.3, 161.2, 138.4, 135.7,
31.5, 130.9, 130.0, 127.9, 122.3, 118.9, 116.0, 103.8, 62.6, 60.9, 30.9,
14.0 ppm. IR (KBr): ν = 3097, 1737, 1720, 1611, 1556, 1496, 1455,
˜
1437, 1409 cm–1. HRMS (ESI): calcd. for C23H19ClNO6 440.0901
[M + H]+; found 440.0919.
14.6, 14.2, 10.5 ppm. IR (KBr): ν = 3065, 1721, 1695, 1630, 1559,
˜
1473 cm–1. HRMS (ESI): calcd. for C20H19NO6Na 392.1105 [M +
Na]+; found 392.1106.
Diethyl 1-(3,4-Dichlorophenyl)-5-oxo-1,5-dihydroisochromeno-
[4,3-b]pyrrole-2,3-dicarboxylate (4s): A white solid; m.p. 194–
195 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.27 (d, J = 8.0 Hz,
1 H, Ar-H), 8.11–8.10 (m, 1 H, Ar-H), 7.94 (d, J = 8.8 Hz, 1 H,
Ar-H), 7.71–7.68 (m, 2 H, Ar-H), 7.55 (t, J = 7.6 Hz, 1 H, Ar-H),
6.58 (d, J = 8.0 Hz, 1 H, Ar-H), 4.36–4.31 (m, 2 H, CH2), 4.14–
4.08 (m, 2 H, CH2), 1.31 (t, J = 7.2 Hz, 3 H, CH3), 1.06 (t, J =
7.2 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
161.7, 160.9, 159.5, 138.6, 137.3, 136.0, 133.9, 132.6, 132.1, 132.0,
131.1, 129.4, 129.3, 128.5, 126.8, 120.0, 119.4, 116.6, 108.0, 62.0,
Methyl 5,8-Dioxo-5,8,10,11-tetrahydroisochromeno[3Ј,4Ј:4,5]-
pyrrolo[2,1-c][1,4]oxazine-7-Carboxylate (4x): A gray solid; m.p.
299–300 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.25 (d, J =
8.0 Hz, 1 H, Ar-H), 7.90 (t, J = 8.0 Hz, 1 H, Ar-H), 7.81 (d, J =
8.0 Hz, 1 H, Ar-H), 7.57 (t, J = 8.0 Hz, 1 H, Ar-H), 4.70 (t, J =
5.2 Hz, 2 H, CH2), 4.36 (t, J = 5.6 Hz, 2 H, CH2), 3.93 (s, 3 H,
CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 165.4, 159.7,
157.3, 141.4, 136.6, 133.3, 131.7, 127.8, 122.7, 118.3, 115.9, 112.6,
61.6, 14.5, 14.0 ppm. IR (KBr): ν = 3068, 1733, 1726, 1614, 1557,
˜
99.7, 66.4,53.3 ppm. IR (KBr): ν = 3053, 1720, 1705, 1687, 1567,
˜
1475, 1439, 1411 cm–1. HRMS (ESI): calcd. for C23H18Cl2NO6
474.0511 [M + H]+; found 474.0523.
1483 cm–1. HRMS (ESI): calcd. for C16H11NO6 313.0586 [M –
H]–; found 313.0595.
Diethyl 1-(3,5-Dichlorophenyl)-5-oxo-1,5-dihydroisochromeno-
Methyl 10-Methyl-5,8-dioxo-5,8,10,11-tetrahydroisochromeno-
[3Ј,4Ј:4,5]pyrrolo[2,1-c][1,4]oxazine-7-carboxylate (4y): A red solid;
m.p. Ͼ 300 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.24 (d, J =
8.0 Hz, 1 H, Ar-H), 7.90 (t, J = 7.6 Hz, 1 H, Ar H), 7.81 (d, J =
[4,3-b]pyrrole-2,3-dicarboxylate (4t): A white solid; m.p. 188–
1
189 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.29–8.27 (m, 1 H,
Ar-H), 8.02 (t, J = 2.0 Hz, 1 H, Ar-H), 7.91 (d, J = 1.6 Hz, 2 H,
Ar-H), 7.73–7.68 (m, 1 H, Ar-H), 7.58–7.54 (m, 1 H, Ar-H), 6.56 8.0 Hz, 1 H, Ar-H), 7.57 (t, J = 7.6 Hz, 1 H, Ar-H), 7.97–7.92 (m,
(d, J = 8.0 Hz, 1 H, Ar-H), 4.37–4.31 (m, 2 H, CH2), 4.15–4.10 (m, 1 H, CH2), 4.58–4.40 (m, 1 H, CH2), 4.04–4.00 (m, 1 H, CH), 3.94
2 H, CH2), 1.31 (t, J = 7.2 Hz, 3 H, CH3), 1.07 (t, J = 7.2 Hz, 3
(s, 3 H, CH3), 1.46 (d, J = 6.4 Hz, 3 H, CH3) ppm. 13C NMR
H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 161.7, 160.9, (100 MHz, [D6]DMSO): δ = 165.4, 164.7, 159.7, 141.3, 136.6,
159.3, 139.7, 138.6, 136.0, 135.2, 132.0, 130.9, 129.2, 128.6, 128.3,
126.4, 120.0, 119.4, 116.7, 108.4, 62.0, 61.6, 14.5, 14.0 ppm. IR
133.3, 131.7, 127.8, 122.7, 118.3, 115.7, 112.2, 99.8, 74.3, 53.3, 44.6,
17.9 ppm. IR (KBr): ν = 3058, 1753, 1674, 1628, 1550, 1467 cm–1.
˜
(KBr): ν = 3067, 1736, 1721, 1614, 1583, 1510, 1446, 1407 cm–1.
HRMS (ESI): calcd. for C17H13NO6Na 326.0635 [M + Na]+; found
˜
HRMS (ESI): calcd. for C23H18Cl2NO6 474.0511 [M + H]+; found 362.0645.
474.0522.
Ethyl 5,8-Dioxo-10-phenyl-5,8,10,11-tetrahydroisochromeno-
[3Ј,4Ј:4,5]pyrrolo[2,1-c][1,4] oxazine-7-carboxylate (4z): A white so-
lid; m.p. 262–263 °C. 1H NMR (400 MHz, [D6]DMSO): δ = 8.32
(d, J = 8.0 Hz, 1 H, Ar-H), 7.19 (d, J = 8.0 Hz, 1 H, Ar-H),7.92
(t, J = 8.0 Hz, 1 H, Ar-H), 7.70–7.61 (m, 3 H, Ar-H), 7.51 (t, J =
4.0 Hz, 3 H, Ar-H),6.09–6.05 (m, 1 H, CH), 5.17–5.13 (m, 1 H,
CH), 4.84 (t, J = 12.0 Hz, 1 H, CH), 4.50 (s, 2 H, CH2), 4.38–
4.31 (m, 2 H, CH2),1.33 (t, J = 8.0 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 161.5, 160.8, 156.6, 135.6, 131.8,
129.8, 129.1, 127.9, 127.6, 122.6, 119.8, 118.6, 115.6, 108.6, 97.2,
Diethyl 1-(3-Bromo-4-methylphenyl)-5-oxo-1,5-dihydroiso-
chromeno[4,3-b]pyrrole-2,3-dicarboxylate (4u): A white solid; m.p.
1
161–162 °C. H NMR (400 MHz, [D6]DMSO): δ = 8.27–8.25 (m,
1 H, Ar-H), 7.93 (d, J = 2.0 Hz, 1 H, Ar-H), 7.67–7.62 (m, 2 H,
Ar-H), 7.57–7.50 (m, 2 H, Ar-H), 6.53 (d, J = 8.0 Hz, 1 H, Ar-H),
4.35–4.30 (m, 2 H, CH2), 4.13–4.07 (m, 2 H, CH2), 1.30 (t, J =
7.2 Hz, 3 H, CH3), 1.05 (t, J = 6.8 Hz, 3 H, CH3) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 161.6, 161.0, 159.7, 140.5, 138.7,
136.1, 135.8, 132.3, 132.1, 131.9, 129.5, 128.3, 128.0, 127.8, 124.7,
119.8, 119.3, 116.2, 107.0, 62.0, 61.4, 22.8, 14.5, 14.0 ppm. IR
78.2, 61.5, 54.9, 48.3, 31.2, 14.5 ppm. IR (KBr): ν = 3065, 1738,
˜
1646, 1632, 1551, 1478 cm–1. HRMS (ESI): calcd. For C23H17NO6
403.1056 [M – H]–; found 403.1066.
(KBr): ν = 3083, 1750, 1716, 1613, 1554, 1515, 1494, 1412 cm–1.
˜
HRMS (ESI): calcd. for C24H21BrNO6 498.0552 [M + H]+; found
498.0552.
General Procedure for the Synthesis of Compounds 4x–4z
Diethyl 5-Oxo-1-(p-tolyl)-1,5-dihydroisochromeno[4,3-b]pyrrole-2,3- Methyl 5,8-Dioxo-5,8,10,11-tetrahydroisochromeno[3Ј,4Ј:4,5]-
dicarboxylate (4v): A white solid; m.p. 160–161 °C. 1H NMR pyrrolo[2,1-c][1,4]oxazine-7-carboxylate (4x): Dimethyl but-2-
(400 MHz, [D6]DMSO): δ = 8.26–8.24 (m, 1 H, Ar-H), 7.61–7.57 ynedioate (3a; 1.0 mmol, 0.142 g) was introduced into a 10-mL Ini-
(m, 1 H, Ar-H), 7.52–7.50 (m, 1 H, Ar-H), 7.48–7.45 (m, 4 H, Ar- tiator reaction vial, and 2-aminoethanol (2p; 1.0 mmol, 0.061 g)
H), 6.48 (d, J = 8.0 Hz, 1 H, Ar-H), 4.34–4.29 (m, 2 H, CH2), 4.10–
4.05 (m, 2 H, CH2), 2.47 (s, 3 H, CH3), 1.30 (t, J = 7.2 Hz, 3 H,
CH3), 1.03 (t, J = 7.2 Hz, 3 H, CH3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 161.6, 161.1, 160.0, 140.7, 138.7, 135.6, 134.6,
131.8, 130.8, 129.7, 128.9, 128.4, 128.1, 119.7, 119.3, 115.7, 105.8,
was slowly added at 0 °C. The mixture was stirred at room tempera-
ture for 8 min. Subsequently, 2,2-dihydroxyindene-1,3-dione (1;
1.0 mmol, 0.178 g) and Ac2O (1.5 mL) were added. The reaction
vial was capped and stirred for 20 s. The mixture was irradiated
(time: 25 min, temperature: 110 °C; absorption level: high; fixed
hold time) until TLC (petroleum ether/acetone, 3:1) revealed that
62.0, 61.2, 21.4, 14.5, 14.0 ppm. IR (KBr): ν = 3072, 1744, 1727,
˜
6
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42164
/KAP1
Date: 17-04-14 18:14:37
Pages: 8
Efficient Domino Synthesis of Pyrrole-Fused Isocoumarins
2007, 9, 1407; c) K. Ueura, T. Satoh, M. Miura, J. Org. Chem.
conversion of starting material 1 was complete. The reaction mix-
ture was cooled to room temperature. The diluted basic solution
was poured into the reaction mixture until Ac2O was neutralized,
and then cold water (30 mL) was added. The solid product was
filtered and washed with water and EtOH (80%), and subsequently
dried and recrystallized from EtOH (80%) to give pure product 4x
as a gray solid; m.p. 299–300 °C. 1H NMR (400 MHz, [D6]DMSO):
δ = 8.25 (d, J = 8.0 Hz, 1 H, Ar-H), 7.90 (t, J = 8.0 Hz, 1 H, Ar-
H), 7.81 (d, J = 8.0 Hz, 1 H, Ar-H), 7.57 (t, J = 8.0 Hz, 1 H, Ar-
H), 4.70 (t, J = 5.2 Hz, 2 H, CH2), 4.36 (t, J = 5.6 Hz, 2 H, CH2),
3.93 (s, 3 H, CH3) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
165.4, 159.7, 157.3, 141.4, 136.6, 133.3, 131.7, 127.8, 122.7, 118.3,
2007, 72, 5362.
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra of products 4a–4x.
Acknowledgments
The authors are grateful for financial support from the National
Natural Science Foundation of China (NSFC) (grant numbers
21272095 and 21102124), Jiangsu Science and Technology Support
Program (grant number SBE2011045), the Qing Lan Project (grant
number 12QLG006), and National Students’ Innovative Training
Program (grant number 201310320020Z). Mr Wei Fan is thanked
for his generous assistance.
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Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42164
/KAP1
Date: 17-04-14 18:14:37
Pages: 8
B. Jiang, S.-J. Tu et al.
FULL PAPER
Domino Reactions
M.-Y. Sun, X.-Y. Meng, F.-J. Zhao,
Y.-J. Dang, F. Jiang, K. Liu, C.-S. Wang,
B. Jiang,* S.-J. Tu* .......................... 1–8
A new three-component approach to poly-
functionalized isochromeno[4,3-b]pyrroles
has been developed with excellent regiose-
lectivity.
Efficient Domino Synthesis of Pyrrole-
Fused Isocoumarins with Microwave Heat-
ing
Keywords: Synthetic methods / Domino re-
actions / Oxygen heterocycles / Nitrogen
heterocycles / Regioselectivity /
Microwave chemistry
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0