Domino reaction of 2,2-dihydroxyindene-1,3-dione with aromatic amines: Efficient synthesis of isochromeno[4,3- b ]indol-5(11 H)-one derivatives

Article abstract of DOI:10.1055/s-0034-1378617

An efficient approach to 16 examples of polyfunctionalized isochromeno[4,3-b]indol-5(1H)-one derivatives, obtained in 60-85% yield and with excellent regioselectivity, has been developed through a domino reaction of 2,2-dihydroxyindene-1,3-dione with aromatic amines under microwave irradiation. The atom- and step-economy and scope make this reaction a powerful tool for assembling polyheterocyclic scaffolds of general chemical and biomedical interest.

Full text of DOI:10.1055/s-0034-1378617

PAPER
▌3207
Paper
Domino Reaction of 2,2-Dihydroxyindene-1,3-dione with Aromatic Amines:
Efficient Synthesis of Isochromeno[4,3-b]indol-5(11H)-one Derivatives
Reaction of 2,2-Dihydroxyindene-1,3-dione with Aromatic Amines
Xiao-Yan Meng,1 Mu-Yan Sun,1 Fu-Jie Zhao,1 Yi-Jing Dang,1 Bo Jiang,* Shu-Jiang Tu*
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu
Normal University, Xuzhou, 221116, Jiangsu, P. R. or China
Fax +86(516)83500065; E-mail: jiangchem@jsnu.edu.cn; E-mail: laotu@jsnu.edu.cn
Received: 15.04.2014; Accepted after revision: 17.07.2014
thetic methods, metal-catalyzed domino cyclization has
Abstract: An efficient approach to 16 examples of polyfunctional-
taken a dominant position, and various transition-metal
ized isochromeno[4,3-b]indol-5(1H)-one derivatives, obtained in
complexes, such as rhodium,9 palladium,10 ruthenium,11
60–85% yield and with excellent regioselectivity, has been devel-
oped through a domino reaction of 2,2-dihydroxyindene-1,3-dione
and copper,12 have been utilized. Bullington and co-work-
with aromatic amines under microwave irradiation. The atom- and ers reported the reaction between 2,2-dihydroxyindene-
step-economy and scope make this reaction a powerful tool for as-
sembling polyheterocyclic scaffolds of general chemical and bio-
medical interest.
1,3-dione and electron-donating aromatic amines for the
formation of tetrahydroindeno[l,2-b]indolones, which
was subsequently rearranged to three examples of iso-
chromeno[4,3-b]indol-5(11H)-ones.13 However, the sub-
Key words: domino reactions, heterocycles, cyclizations, regiose-
lectivity, isochromeno[4,3-b]indol-5(11H)-one, 2,2-dihydroxyin-
dene-1,3-dione, aromatic amines
strate scope was limited, and a multistep route was used,
leading to low total yields of the products. Therefore, de-
veloping a facile and efficient protocol for the direct for-
mation
of
isochromeno[4,3-b]indol-5(11H)-one
Functional heterocycles of chemical and biomedical im-
portance, particularly those containing the isocoumarin
ring, have played a pivotal role in organic and medicinal
research for several decades.2 The structurally diverse and
intriguing isocoumarin derivatives are widespread in
many natural products, remarkably represented by
monocerin, bergenin, cephalosol, cytogenin, and fusaren-
tin (Figure 1). They show significant biological activities
such as antiallergic, antimicrobial,2 immunomodulatory,3
cytotoxicity,4 antifungal,5 antiinflammatory,6 antiangio-
genic,7 and antimalarial8 properties. Much effort has been
devoted to the synthesis of isocoumarin derivatives, to
make it more powerful and applicable. Among the syn-
derivatives would be highly beneficial.
Domino reactions have emerged as an effective tool for
the assembly of complex cyclic structures by the combi-
nation of two or more distinct reactions into a one-pot
transformation.14 Recently, we have developed several
domino reactions toward the construction of diverse het-
erocyclic structures.15 In continuation of this project, we
now report an improved one-pot reaction of 2,2-dihy-
droxyindene-1,3-dione (1) with various aromatic amines
2, providing indole-fused isocoumarin derivatives with
different structural patterns in good yields (Scheme 1).
The present work demonstrates broad substrate scope and
O
OH
O
O
OH
HO
O
O
MeO
MeO
O
H
OH
OH
O
MeO
MeO
H
O
OH
O
O
CO2Me
OH
OH
monocerin
cephalosol
bergenin
OH
O
O
O
O
OH
O
R
MeO
O
OH
N
H
MeO
MeO
OH
cytogenin
this work
fusarentin
Figure 1 Some naturally occurring bioactive isocoumarins
SYNTHESIS 2014, 46, 3207–3212
Advanced online publication: 20.08.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0034-1378617; Art ID: SS-2014-H0243-OP
© Georg Thieme Verlag Stuttgart · New York

3208
X.-Y. Meng et al.
PAPER
generality of this domino reaction for the rapid formation With these acceptable conditions in hand, we then pro-
of the isochromeno[4,3-b]indole framework, avoiding te- ceeded to probe the substrate diversity of this domino re-
dious isolation and purification of the tetrahydroinde- action by using readily available starting materials. 2,2-
no[l,2-b]indolone intermediate.
Dihydroxyindene-1,3-dione (1) was subjected to the reac-
tion with various fused aromatic amines 2a–d including
naphthalen-2-amine (2a), anthracen-2-amine (2b), quino-
lin-6-amine (2c), and indol-5-amine (2d), leading to the
formation of 3a–d, four examples of new polycyclic
indole-fused isocoumarins, in good yields as listed in
Scheme 2. To further evaluate the scope of this protocol,
simple aromatic amines 2 were also employed. We were
pleased to find that the substituents on the arylamine ring
did not hamper the reaction process. Aromatic amines
bearing either electron-donating or electron-withdrawing
functional groups such as fluoro (2e and 2f), chloro (2g,
2h and 2i), bromo (2j and 2k), methyl (2l, and 2m), and
methoxy (2n) all provided the desired products in good
yields. The bulky 2-iodoaniline (2o) was converted into
the corresponding isochromeno[4,3-b]indole 3o in 70%
yield. 4-Nitroaniline (1p) and 4-aminobenzonitrile (1q)
were also suitable for this domino reaction, giving the cor-
responding nitro- and cyano-substituted isochrome-
no[4,3-b]indoles 3p and 3q in 60 and 65% yield,
respectively, due to the strong electron-withdrawing ef-
fect. The resulting functionalities of these fused isocou-
marins offer great flexibility for further structural
modifications. This protocol thus provides a straightfor-
ward pathway to polysubstituted indole-fused isocouma-
rins, which are generally prepared via multistep
reactions.16
O
OH
OH
O
O
O
1
HCO2H
Het
+
100 °C
MW
R
N
H
Het
3
H2N
R
2
Scheme 1 Domino formation of indole-fused isocoumarin deriva-
tives
In an initial study, the reaction of 2,2-dihydroxyindene-
1,3-dione (1) with naphthalen-2-amine (2a) was tested un-
der a variety of different conditions using microwave
heating. The representative data are summarized in Table
1. It was found that the reaction did not give the desired
product 3a in trifluoroacetic acid as solvent at 100 °C un-
der microwave irradiation (entry 1). An incomplete reac-
tion was observed when acetic acid or acetic anhydride
was used as acidic media (entries 2 and 3). Gratifyingly,
this reaction worked more efficiently in formic acid,
which afforded the corresponding product 3a in 85% yield
(entry 4). Thus, formic acid was chosen for the substrate
scope investigation. The identical reaction was also inves-
tigated under classical heating conditions at 100 °C for 80
minutes, providing the desired product 3a in 62% yield
(entry 5).
In all cases, the reaction occurred very fast. Water is al-
most the sole byproduct, which makes workup conve-
nient. In most cases, the products can precipitate out after
diluted basic solution is poured into the reaction mixture.
The structures were elucidated unequivocally by NMR
spectroscopic analysis. Furthermore, the structure of com-
pound 3m was confirmed by single-crystal X-ray diffrac-
tion (Figure 2).17
Table 1 Optimization of the Reaction Conditions To Prepare Prod-
uct 3aa
O
O
O
MW
OH
OH
+
H2N
N
H
2a
O
1
3a
Entry
Solvent
Temp (°C) Time (min) Yield (%)b
1
2
3
4
5
TFA
100
100
100
100
100
20
20
20
20
80c
trace
48
AcOH
Ac2O
53
HCO2H
HCO2H
85
Figure 2 ORTEP drawing of 3m
62
a Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), solvent (1.0 mL),
On the basis of literature reports13 and observations of the
above results, a possible mechanism for this new reaction
is proposed and depicted in Scheme 3. Firstly, protonated
1 reacts with aromatic amines to generate intermediate
B.18 The intermediate B undergoes two subsequent intra-
100 °C.
b Isolated yield.
c Conventional heating.
Synthesis 2014, 46, 3207–3212
© Georg Thieme Verlag Stuttgart · New York

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Reaction of 2,2-Dihydroxyindene-1,3-dione with Aromatic Amines
3209
O
O
O
Het
R
HCO2H
Het
OH
OH
H2N
+
100 °C
MW
R
N
2
H
O
O
1
3
NH
O
O
O
N
O
O
O
O
O
O
F
N
N
N
N
HN
H
H
H
H
F
3a (85%)
3b (71%)
3c (76%)
3d (74%)
3e (71%)
F
Cl
Cl
O
Br
O
O
O
O
O
O
O
O
O
F
Cl
Cl
N
H
N
H
N
H
N
H
N
H
Cl
3j (74%)
3g (75%)
3f (69%)
3h (73%)
3i (70%)
Me
OMe
O
O
O
O
O
Me
O
O
O
O
O
Br
OMe
Br
N
H
N
H
N
H
N
H
N
H
I
3l (78%)
3k (68%)
3o (70%)
3m (79%)
3n (76%)
O
O
NO2
CN
O
O
N
H
N
H
3p (60%)
3q (65%)
Scheme 2 Domino synthesis of polycyclic isocoumarins 3. Reagents and conditions: 1 (1.0 mmol), 2 (1.0 mmol), HCO2H (1.0 mL), 100 °C,
MW heating. (Isolated yields are provided.)
molecular cyclizations to give three-membered-ring inter- make the present method a highly attractive approach to a
mediate E; ring-opening19 and deprotonation follow, to polycyclic fused isocoumarin scaffold of chemical and
yield the final fused isocoumarins 3.
biomedical importance. Features of this strategy include
the relatively mild conditions, convenient one-pot opera-
tion, and short reaction times. Efforts are currently direct-
ed toward the extension of this methodology to natural
products and drug synthesis.
In summary, we have developed a general and efficient
strategy for the synthesis of multifunctionalized iso-
chromeno[4,3-b]indol-5(11H)-ones with different struc-
tural patterns in a one-pot manner. The bond-forming
efficiency, structural accessibility, and reaction generality
+
OH
O
O
O
O
OH
OH
R
OH
R
OH
OH
OH
H+
H+
H2N
OH2
+
– H+
R
N
H
N
H
R
HO
OH
HO
O
O
+
H2N
1
A
B
C
D
OH
+HO
O
OH
O
O
O
O
H+
– H2O
R
– H+
R
R
N
H
N
N
+
R
HO
N
H
H
H
E
F
G
3
Scheme 3 Proposed mechanism of the reaction
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3207–3212

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X.-Y. Meng et al.
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Microwave irradiation was carried out with an initiator from the
Biotage Company, Sweden. Melting points were determined in open
capillaries and are uncorrected. IR spectra were taken on an FT-IR-
13C NMR (100 MHz, DMSO-d6): δ = 163.5, 161.9, 148.0, 145.3,
136.1, 131.9, 131.7, 131.5, 130.9, 127.9, 126.6, 124.4, 122.1, 121.9,
121.0, 118.7, 117.8, 117.0.
ESI-HRMS: m/z calcd for C18H9N2O2: 285.0664 [M – H]–; found:
285.0644.
1
Tensor 27 spectrometer of samples prepared as KBr pellets. H
NMR spectra were measured on a Bruker DPX 400 MHz spectrom-
eter of samples in DMSO-d6; the chemical shifts are given in ppm
relative to TMS as internal standard. ESI-HRMS was determined by
using a microTOF-Q II HRMS/MS instrument (Bruker). X-ray
crystallographic analysis was performed with a Siemens SMART
CCD and a Siemens P4 diffractometer. ESI-MS was determined on
an Agilent Technologies 1260 Infinity HPLC-Chip/MS System.
ESI-MS: m/z calcd for C18H11N2O2: 287.1 [M + H]+; found: 287.1.
3H-Isochromeno[4,3-b]pyrrolo[3,2-e]indol-11(6H)-one (3d)
Yield: 0.203 g (74%); yellow solid; mp >300 °C.
IR (KBr): 3445, 2950, 1687, 1569, 1429, 1366 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 13.30 (s, 1 H, NH), 12.29 (s, 1
H, NH), 8.28 (t, J = 8.0 Hz, 2 H, Ar-H), 8.07 (d, J = 8.0 Hz, 1 H, Ar-
H), 7.96 (t, J = 7.6 Hz, 1 H, Ar-H), 7.56 (t, J = 7.2 Hz, 2 H, Ar-H),
7.50 (d, J = 8.8 Hz, 1 H, CH), 3.48–3.41 (m, 1 H, CH).
13C NMR (100 MHz, DMSO-d6): δ = 162.1, 135.9, 134.7, 131.5,
131.1, 130.4, 127.4, 120.8, 118.7, 116.4, 113.5, 113.0, 108.8, 105.9,
56.5, 19.0.
ESI-HRMS: m/z calcd for C17H9N2O2: 273.0664 [M – H]–; found:
273.0656.
ESI-MS: m/z calcd for C17H11N2O2: 276.0 [M + H]+; found: 276.0.
Benzo[e]isochromeno[4,3-b]indol-5(13H)-one (3a); Typical Mi-
crowave Heating Procedure
2,2-Dihydroxyindene-1,3-dione (1; 0.178 g, 1.0 mmol) was intro-
duced into a 10 mL Initiator reaction vial. Naphthalen-2-amine (2a;
0.143 g, 1.0 mmol) and HCO2H (1.0 mL) were subsequently added
to the reaction system. The reaction vial was capped and the mixture
was stirred for 10 min. The mixture was irradiated (time: 20 min,
temperature: 100 °C; absorption level: high; fixed hold time) until
TLC (PE–acetone, 3:1) revealed that conversion of the starting ma-
terial 1 was complete. The mixture was cooled to r.t. A diluted basic
solution was poured into the mixture until the HCO2H was neutral-
ized, and then cold H2O (30 mL) was added into the mixture. The
solid product was collected by Büchner filtration and washed with
H2O and EtOH (95%), and subsequently dried and recrystallized
from EtOH (95%) to give the pure product 3a.
9,10-Difluoroisochromeno[4,3-b]indol-5(11H)-one (3e)
Yield: 0.192 g (71%); yellow solid; mp >300 °C.
IR (KBr): 3448, 2968, 1671, 1589, 1576, 1470 cm–1.
Yield: 0.242 g (85%); yellow solid; mp >300 °C.
IR (KBr): 3458, 2954, 1677, 1564, 1450, 1378 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.45 (s, 1 H, NH), 8.55 (d, J =
8.0 Hz, 1 H, Ar-H), 8.30 (d, J = 8.0 Hz, 1 H, Ar-H), 8.09 (d, J = 8.0
Hz, 1 H, Ar-H), 8.02–7.95 (m, 2 H, Ar-H), 7.77 (d, J = 9.2 Hz, 1 H,
Ar-H), 7.71–7.67 (m, 2 H, Ar-H), 7.60 (t, J = 7.6 Hz, 1 H, Ar-H),
7.50 (t, J = 7.6 Hz, 1 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 162.1, 136.5, 136.0, 132.6,
131.4, 131.1, 129.3, 129.1, 127.4, 127.2, 126.8, 125.9, 124.4, 123.8,
120.8, 118.4, 116.0, 114.3, 109.5.
1H NMR (400 MHz, DMSO-d6): δ = 12.26 (s, 1 H, NH), 8.27 (d, J =
8.0 Hz, 1 H, Ar-H), 8.07 (d, J = 8.0 Hz, 1 H, Ar-H), 7.98 (t, J = 7.6
Hz, 1 H, Ar-H), 7.82–7.78 (m, 1 H, Ar-H), 7.63–7.58 (m, 2 H, Ar-
H).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 148.8 (dd, J1CF = 240.5
Hz, J2CF = 16.0 Hz), 146.2 (dd, J1′CF = 236.2 Hz, J2′CF = 15.2 Hz),
136.1, 133.9 (JCF = 2.0 Hz), 131.4, 130.8 (JCF = 10.8 Hz), 130.5,
128.3, 121.2, 119.3, 119.1 (JCF = 3.5 Hz), 111.6 (JCF = 9.0 Hz),
104.6 (JCF = 20.4 Hz), 101.0 (JCF = 21.7 Hz).
ESI-HRMS: m/z calcd for C15H6F2NO2: 270.0367 [M – H]–; found:
270.0357.
ESI-MS: m/z calcd for C15H8F2NO2: 272.0 [M + H]+; found: 272.0.
ESI-HRMS: m/z calcd for C19H10NO2: 284.0712 [M – H]–; found:
284.0721.
ESI-MS: m/z calcd for C19H12NO2: 286.1 [M + H]+; found: 286.1.
7,9-Difluoroisochromeno[4,3-b]indol-5(11H)-one (3f)
Yield: 0.187 g (69%); yellow solid; mp >300 °C.
Isochromeno[4,3-b]naphtho[2,3-e]indol-15(5H)-one (3b)
Yield: 0.238 g (71%); yellow solid; mp >300 °C.
IR (KBr): 3392, 2934, 1667, 1574, 1455, 1371 cm–1.
IR (KBr): 3448, 2967, 1679, 1588, 1459, 1382 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.25 (s, 1 H, NH), 8.27 (d, J =
8.0 Hz, 1 H, Ar-H), 8.06 (d, J = 7.6 Hz, 1 H, Ar-H), 7.98 (t, J = 7.6
Hz, 1 H, Ar-H), 7.81–7.64 (m, 1 H, Ar-H), 7.63–7.57 (m, 2 H, Ar-
H).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 148.9 (dd, J1CF = 241.0
Hz, J2CF = 16.0 Hz), 146.2 (dd, J1′CF = 235.7 Hz, J2′CF = 15.3 Hz),
136.1, 133.9 (JCF = 1.2 Hz), 131.4, 130.8 (JCF = 10.9 Hz), 130.5,
128.3, 121.2, 119.3, 119.1 (JCF = 3.6 Hz), 111.6 (JCF = 9.0 Hz),
104.6 (JCF = 20.3 Hz), 101.0 (JCF = 21.8 Hz).
1H NMR (400 MHz, DMSO-d6): δ = 12.67 (s, 1 H, NH), 9.03 (s, 1
H, Ar-H), 8.65 (s, 1 H, Ar-H), 8.32 (d, J = 8.0 Hz, 1 H, Ar-H), 8.23
(d, J = 8.4 Hz, 1 H, Ar-H), 8.14–8.09 (m, 2 H, Ar-H), 7.98 (t, J =
7.6 Hz, 1 H, Ar-H), 7.91 (d, J = 9.2 Hz, 1 H, Ar-H), 7.72 (d, J = 9.2
Hz, 1 H, Ar-H), 7.62–7.53 (m, 3 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 162.2, 137.4, 136.1, 136.1,
132.1, 131.9, 131.5, 130.3, 128.8, 128.6, 128.1, 127.9, 127.2, 126.5,
126.5, 125.6, 125.4, 121.4, 120.7, 118.1, 115.7, 115.4, 108.1.
ESI-HRMS: m/z calcd for C23H12NO2: 334.0868 [M – H]–; found:
334.0866.
ESI-MS: m/z calcd for C23H14NO2: 336.0 [M + H]+; found: 336.0.
ESI-HRMS: m/z calcd for C15H6F2NO2: 270.0367 [M – H]–; found:
270.0353.
ESI-MS: m/z calcd for C15H8F2NO2: 272.0 [M + H]+; found: 272.0.
8-Chloroisochromeno[4,3-b]indol-5(11H)-one (3g)
Isochromeno[3′,4′:4,5]pyrrolo[3,2-f]quinolin-12(7H)-one (3c)
Yield: 0.202 g (75%); white solid; mp >300 °C.
Yield: 0.217 g (76%); yellow solid; mp >300 °C.
IR (KBr): 3444, 2966, 1673, 1589, 1459, 1384 cm–1.
IR (KBr): 3432, 2964, 1659, 1570, 1456, 1377 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.21 (s, 1 H, NH), 8.27 (d, J =
8.0 Hz, 1 H, Ar-H), 8.06 (d, J = 7.6 Hz, 1 H, Ar-H), 8.00–7.96 (m,
1 H, Ar-H), 7.15 (d, J = 2.0 Hz, 1 H, Ar-H), 7.64–7.60 (m, 1 H, Ar-
H), 7.55 (d, J = 8.8 Hz, 1 H, Ar-H), 7.31–7.28 (m, 1 H, Ar-H).
1H NMR (400 MHz, DMSO-d6): δ = 12.71 (s, 1 H, NH), 8.85 (d, J =
8.0 Hz, 2 H, Ar-H), 8.31 (d, J = 7.6 Hz, 1 H, Ar-H), 8.13 (t, J = 6.4
Hz, 1 H, Ar-H), 8.02–7.94 (m, 2 H, Ar-H), 7.86 (d, J = 9.2 Hz, 1 H,
Ar-H), 7.70–7.67 (m, 1 H, Ar-H), 7.61 (t, J = 7.6 Hz, 1 H, Ar-H).
Synthesis 2014, 46, 3207–3212
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Reaction of 2,2-Dihydroxyindene-1,3-dione with Aromatic Amines
3211
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 136.0, 133.9, 133.2,
131.4, 130.5, 128.5, 125.0, 124.8, 121.4, 119.7, 119.0, 117.1, 116.7,
114.5.
ESI-HRMS: m/z calcd for C15H7ClNO2: 268.0166 [M – H]–; found:
268.0160.
9-Bromo-8-methylisochromeno[4,3-b]indol-5(11H)-one (3l)
Yield: 0.255 g (78%); yellow solid; mp >300 °C.
IR (KBr): 3443, 2967, 1673, 1588, 1449, 1372 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.02 (s, 1 H, NH), 8.26 (d, J =
8.0 Hz, 1 H, Ar-H), 8.05 (d, J = 8.0 Hz, 1 H, Ar-H), 7.97 (t, J = 7.2
Hz, 1 H, Ar-H), 7.75 (s, 1 H, Ar-H), 7.71 (s, 1 H, Ar-H), 7.61 (t, J =
7.6 Hz, 1 H, Ar-H), 2.45 (s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 136.0, 134.8, 133.4,
131.4, 130.7, 128.8, 128.2, 121.3, 120.9, 119.5, 118.6, 118.3, 115.9,
115.8, 23.2.
ESI-MS: m/z calcd for C15H9ClNO2: 270.0 [M + H]+; found: 270.0.
9,10-Dichloroisochromeno[4,3-b]indol-5(11H)-one (3h)
Yield: 0.221 g (73%); pale yellow solid; mp >300 °C.
IR (KBr): 3438, 2980, 1670, 1568, 1455, 1382 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.34 (s, 1 H, NH), 8.27 (d, J =
7.6 Hz, 1 H, Ar-H), 8.08 (d, J = 8.0 Hz, 1 H, Ar-H), 8.01–7.97 (m,
2 H, Ar-H), 7.78 (s, 1 H, Ar-H), 7.66–7.62 (m, 1 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 161.5, 136.1, 134.1, 132.9,
131.5, 130.2, 128.8, 123.0, 123.2, 121.5, 119.8, 119.7, 118.7, 116.0,
114.4.
ESI-HRMS: m/z calcd for C16H9BrNO2: 325.9817 [M – H]–; found:
325.9806.
ESI-MS: m/z calcd for C16H11BrNO2: 328.0 [M + H]+; found: 328.0.
8-Methylisochromeno[4,3-b]indol-5(11H)-one (3m)
Yield: 0.197 g (79%); green solid; mp >300 °C.
IR (KBr): 3445, 2963, 1679, 1588, 1465, 1367 cm–1.
ESI-HRMS: m/z calcd for C15H6Cl2NO2: 301.9776 [M – H]–; found:
1H NMR (400 MHz, DMSO-d6): δ = 11.86 (s, 1 H, NH), 8.27 (d, J =
8.0 Hz, 1 H, Ar-H), 8.05 (d, J = 8.0 Hz, 1 H, Ar-H), 7.96 (t, J = 7.6
Hz, 1 H, Ar-H), 7.58 (t, J = 8.0 Hz, 1 H, Ar-H), 7.51 (s, 1 H, Ar-H),
7.43 (d, J = 7.6 Hz, 1 H, Ar-H), 7.14 (d, J = 8.4 Hz, 1 H, Ar-H), 2.43
(s, 3 H, CH3).
13C NMR (100 MHz, DMSO-d6): δ = 162.0, 135.9, 134.1, 133.7,
131.4, 131.0, 129.3, 127.8, 126.6, 121.1, 119.3, 117.5, 116.8, 116.4,
112.6, 21.6.
301.9772.
ESI-MS: m/z calcd for C15H8Cl2NO2: 304.0 [M + H]+; found: 304.0.
7,9-Dichloroisochromeno[4,3-b]indol-5(11H)-one (3i)
Yield: 0.212 g (70%); yellow solid; mp >300 °C.
IR (KBr): 3448, 2966, 1674, 1588, 1453, 1381 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.48 (s, 1 H, NH), 8.24 (d, J =
8.0 Hz, 1 H, Ar-H), 8.05 (d, J = 8.0 Hz, 1 H, Ar-H), 7.99–7.95 (m,
1 H, Ar-H), 7.64–7.60 (m, 1 H, Ar-H), 7.52 (d, J = 2.0 Hz, 1 H, Ar-
H), 7.22 (d, J = 2.0 Hz, 1 H, Ar-H).
ESI-HRMS: m/z calcd for C16H10NO2: 248.0712 [M – H]–; found:
248.0702.
13C NMR (100 MHz, DMSO-d6): δ = 161.4, 136.3, 136.0, 132.8,
131.4, 130.0, 128.9, 128.8, 124.4, 121.5, 120.8, 119.6, 119.4, 113.2,
111.5.
ESI-HRMS: m/z calcd for C15H6Cl2NO2: 301.9776 [M – H]–; found:
301.9768.
ESI-MS: m/z calcd for C16H12NO2: 250.1 [M + H]+; found: 250.1.
8,9-Dimethoxyisochromeno[4,3-b]indol-5(11H)-one (3n)
Yield: 0.224 g (76%); yellow solid; mp 268–270 °C.
IR (KBr): 3448, 2966, 1670, 1576, 1459, 1378 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 11.67 (s, 1 H, NH), 8.23 (d, J =
8.0 Hz, 1 H, Ar-H), 7.98 (d, J = 7.6 Hz, 1 H, Ar-H), 7.92 (t, J = 7.2
Hz, 1 H, Ar-H), 7.50 (t, J = 8.0 Hz, 1 H, Ar-H), 7.19 (s, 1 H, Ar-H),
6.99 (s, 1 H, Ar-H), 3.86 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3).
13C NMR (100 MHz, DMSO-d6): δ = 162.1, 149.4, 145.8, 135.9,
134.6, 131.4, 130.8, 126.9, 120.6, 118.2, 115.9, 108.9, 98.9, 95.6,
56.2, 56.1.
ESI-HRMS: m/z calcd for C17H12NO4: 294.0767 [M – H]–; found:
294.0761.
ESI-MS: m/z calcd for C17H14NO4: 296.1 [M + H]+; found: 296.1.
ESI-MS: m/z calcd for C15H8Cl2NO2: 304.0 [M + H]+; found: 304.0.
8-Bromoisochromeno[4,3-b]indol-5(11H)-one (3j)
Yield: 0.232 g (74%); yellow solid; mp >300 °C.
IR (KBr): 3431, 2961, 1676, 1584, 1459, 1388 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.22 (s, 1 H, NH), 8.26 (d, J =
8.0 Hz, 1 H, Ar-H), 8.06 (d, J = 8.0 Hz, 1 H, Ar-H), 7.98 (t, J = 7.6
Hz, 1 H, Ar-H), 7.74 (s, 1 H, Ar-H), 7.62 (t, J = 7.6 Hz, 1 H, Ar-H),
7.55 (t, J = 8.8 Hz, 1 H, Ar-H), 7.29 (d, J = 8.8 Hz, 1 H, Ar-H).
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 136.1, 134.1, 133.0,
131.5, 130.5, 128.5, 127.3, 121.4, 119.7, 118.8, 117.7, 114.9, 112.8.
10-Iodoisochromeno[4,3-b]indol-5(11H)-one (3o)
ESI-HRMS: m/z calcd for C15H7BrNO2: 311.9660 [M – H]–; found:
311.9655.
ESI-MS: m/z calcd for C15H9BrNO2: 314.0 [M + H]+; found: 314.0.
Yield: 0.253 g (70%); white solid; mp 195–197 °C.
IR (KBr): 3522, 3440, 2975, 1664, 1553, 1454, 1355 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.61 (s, 1 H, NH), 8.33 (s, 1 H,
Ar-H), 8.17–8.10 (m, 3 H, Ar-H), 7.80 (d, J = 8.4 Hz, 1 H, Ar-H),
7.58 (s, 1 H, Ar-H), 7.17 (dd, J = 8.8, 1.6 Hz, 1 H, Ar-H).
9-Bromoisochromeno[4,3-b]indol-5(11H)-one (3k)
Yield: 0.213 g (68%); yellow solid; mp >300 °C.
IR (KBr): 3445, 2963, 1673, 1588, 1456, 1384 cm–1.
13C NMR (100 MHz, DMSO-d6): δ = 164.2, 160.9, 141.0, 140.2,
1H NMR (400 MHz, DMSO-d6): δ = 12.18 (s, 1 H, NH), 8.27 (d, J =
8.0 Hz, 1 H, Ar-H), 8.07 (d, J = 8.0 Hz, 1 H, Ar-H), 8.00–7.96 (m,
1 H, Ar-H), 7.72 (d, J = 1.2 Hz, 1 H, Ar-H), 7.70 (d, J = 7.2 Hz, 1
H, Ar-H), 7.64–7.60 (m, 1 H, Ar-H), 7.29 (dd, J = 8.4, 2.0 Hz, 1 H,
Ar-H).
138.9, 138.0, 135.8, 129.3, 124.9, 124.8, 93.3.
ESI-HRMS: m/z calcd for C15H7INO2: 359.9521 [M – H]–; found:
359.9511.
ESI-MS: m/z calcd for C15H9INO2: 362.0 [M + H]+; found: 362.0.
13C NMR (100 MHz, DMSO-d6): δ = 161.7, 136.1, 136.0, 133.8,
131.5, 130.6, 128.4, 123.6, 121.4, 119.6, 119.4, 118.3, 117.5, 115.3,
115.3.
ESI-HRMS: m/z calcd for C15H7BrNO2: 311.9660 [M – H]–; found:
311.9665.
8-Nitroisochromeno[4,3-b]indol-5(11H)-one (3p)
Yield: 0.169 g (60%); yellow solid; mp >300 °C.
IR (KBr): 3445, 2976, 1675, 1589, 1437, 1366 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.83 (s, 1 H, NH), 8.64 (d, J =
2.0 Hz, 1 H, Ar-H), 8.32 (d, J = 8.0 Hz, 1 H, Ar-H), 8.17–8.11 (m,
2 H, Ar-H), 8.03 (t, 1 H, Ar-H), 7.74–7.67 (m, 2 H, Ar-H).
ESI-MS: m/z calcd for C15H9BrNO2: 314.0 [M + H]+; found: 314.0.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 3207–3212

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X.-Y. Meng et al.
PAPER
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13C NMR (100 MHz, DMSO-d6): δ = 161.4, 141.6, 137.9, 136.2,
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113.5.
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ESI-HRMS: m/z calcd for C15H7N2O4: 279.0406 [M – H]–; found:
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ESI-MS: m/z calcd for C15H9N2O4: 281.1 [M + H]+; found: 281.1.
5-Oxo-5,11-dihydroisochromeno[4,3-b]indole-8-carbonitrile
(3q)
Yield: 0.169 g (65%); yellow solid; mp >300 °C.
IR (KBr): 3402, 3014, 2219, 1692, 1460, 1306 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 12.64 (s, 1 H, NH), 8.31 (d, J =
8.8 Hz, 2 H, Ar-H), 8.11 (d, J = 7.6 Hz, 1 H, Ar-H), 8.02 (t, J = 8.4
Hz, 1 H, Ar-H), 7.71 (d, J = 8.4 Hz, 1 H, Ar-H), 7.69–7.63 (m, 2 H,
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13C NMR (100 MHz, DMSO-d6): δ = 168.6, 136.9, 136.1, 134.6,
131.5, 130.7, 128.3, 126.8, 126.3, 124.6, 121.3, 119.6, 118.6, 117.6,
115.8, 112.4.
ESI-HRMS: m/z calcd for C16H7N2O2: 259.0508 [M – H]–; found:
259.0521.
ESI-MS: m/z calcd for C16H9N2O2: 261.1 [M + H]+; found: 261.1.
Acknowledgment
We are grateful for the financial support from the National Science
Foundation of China (21232004, 21272095, and 21102124), PAPD
of Jiangsu Higher Education Institutions, Jiangsu Science and Tech-
nology Support Program (No. BE2011045), the Qing Lan Project
(12QLG006), and Students’ Innovative Training Program of
Jiangsu Normal University. Thanks to Dr. Wei Fan for his generous
assistance.
(16) Bihel, F.; Quéléver, G.; Lelouard, H.; Petit, A.; Alvès da
Costa, C.; Pourquié, O.; Checler, F.; Thellend, A.; Pierree,
P.; Krausa, J.-L. Bioorg. Med. Chem. 2003, 11, 3141.
(17) The single crystal growth was obtained from EtOH–DMF at
room temperature. Crystal data for 3m: C16H11NO2, crystal
dimension 0.25 × 0.09 × 0.06 mm, monoclinic, space group
P2(1)/c, a = 8.6422(7) Å, b = 7.4618(5) Å, c = 18.7810(16)
Å, β = 92.3390(10)°, V = 1210.11(16) Å3, Mr = 249.26, Z =
4, λ = 0.71073 Å, μ (Mo Kα) = 0.736 mm–1, F(000) = 520,
R1 = 0.0877, wR2 = 0.2254. CCDC 1019219 contains the
supplementary crystallographic data for 3m. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Supporting Information for this article is available online
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10.1055/s-00000084.SunpfgIpi
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Synthesis 2014, 46, 3207–3212
© Georg Thieme Verlag Stuttgart · New York