Synthesis of Biologically Active Indenoisoquinoline Derivatives via a One-Pot Copper(II)-Catalyzed Tandem Reaction

Article abstract of DOI:10.1021/acs.joc.6b02814

A concise route for the synthesis of indenoisoquinoline derivatives from 2-iodobenzamide and 1,3-indanedione derivatives in the presence of copper(II) chloride and cesium carbonate in acetonitrile solvent is reported. A wide variety of 2-iodobenzamide derivatives and indandiones could be used to synthesize indenoisoquinoline derivatives and other fused indenoisoquinoline in moderate to good yields. This methodology was adapted for the one-step synthesis of a series of clinically active topoisomerase I inhibitors such as NSC 314622, LMP-400, LMP-776.

Full text of DOI:10.1021/acs.joc.6b02814

Article
pubs.acs.org/joc
Synthesis of Biologically Active Indenoisoquinoline Derivatives via a
One-Pot Copper(II)-Catalyzed Tandem Reaction
Chia-Yu Huang,† Veerababurao Kavala,† Chun-Wei Kuo, Ashok Konala, Tang-Hao Yang,
and Ching-Fa Yao*
Department of Chemistry, National Taiwan Normal University, 88, Sec. 4, Ting-Chow Road, Taipei 116, Taiwan R.O.C
S
* Supporting Information
ABSTRACT: A concise route for the synthesis of inden-
oisoquinoline derivatives from 2-iodobenzamide and 1,3-
indanedione derivatives in the presence of copper(II) chloride
and cesium carbonate in acetonitrile solvent is reported. A
wide variety of 2-iodobenzamide derivatives and indandiones
could be used to synthesize indenoisoquinoline derivatives and
other fused indenoisoquinoline in moderate to good yields.
This methodology was adapted for the one-step synthesis of a series of clinically active topoisomerase I inhibitors such as NSC
314622, LMP-400, LMP-776.
synthesis of nitidine chloride.6 Later, the same group developed
effecient procedures for the synthesis of indeno[1,2-c]-
INTRODUCTION
■
Indeno[1,2-c]isoquinoline derivatives have been reported to
isoquinoline derivatives, such as by the condensation of
have potential inhibition activities against topoisomerase I
indeno[1,2-c]isochromene-5,11-diones7 and amines, homo-
(Top1).1 In fact, camptothecin (CPT) derivatives appear to be
phthalic anhydrides, and arylmethanimines.8 Other groups
best Top1 inhibitors that are currently available.2 However,
have also used Cushman group strategies for the construction
extensive research by Cushman and co-workers from the NIH
revealed that indenoisoquinoline derivatives are novel Top1
of indenoisoquinoline derivatives.9
Other alternative procedures developed in recent years
inhibitors with better pharmacokinetic features than CPT and
include the intramolecular cyclization reaction of 2-((4-
that they have good chemical stability and resistance to reversal
after the drug is removed.3 Some of the indeno[1,2-
c]isoquinoline derivatives that are reported to have anticancer
methoxybenzyl)oxy)benzonitrile and N,2-dimethylbenzamide,
the ring-closing metathesis reaction of polyenic benzamides.10
Very recently, Hsieh and co-workers reported on the cobalt-
activities are shown in Figure 1.
catalyzed annulation of 2-halobenzaldimines with terminal
alkynes followed by oxidation to furnish indenoisoquinolines.11
Some other methods have also been developed for the
synthesis of indeno[1,2-c]isoquinoline derivatives.12 Known
synthetic strategies for accessing indeno[1,2-c]isoquinoline
derivatives are summarized in Figure 2.
Most of the reported methods have one or more short-
comings such as the need for multiple steps, limited substrate
scope, unavailable starting materials, and other stereochemistry
problems. Hence, the concise synthesis of bioactive indeno[1,2-
c]isoquinoline derivatives from readily available starting
materials would be useful, given the present status of the
process. In 2012, we published the copper-catalyzed synthesis
of isocoumarin derivatives from acyclic 1,3-diketones and 2-
halobenzamide derivatives.13 Further, when the acyclic 1,3-
Figure 1. Some important indenoisoquinoline derivatives having Top1
inhibitors activity.
diketones were replaced with 1,3-hexadione in this reaction, the
isoquinoline derivative was produced in poor yield. On the
other hand, Liang et al. also showed similar results when similar
materials were reacted in the absence of a metal catalyst.14
Based on previous reports15 and our prior experience with 2-
In addition, indenoisoquinoline derivatives showed potential
activity for treating visceral leishmaniasis.4 Indeno[1,2-c]-
isoquinoline derivatives such as LMP-400 and LMP-776 have
also been used as multitumor treatment drugs.5 The first
indenoisoquinoline derivative was synthesized accidentally by
Cushman et al. as a byproduct that was produced during the
Received: November 24, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.6b02814
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Table 1. Optimization of Reaction Conditions
temp.
(°C)
time
(h)
yield
b
a
entry
additve base (equiv) solvent
(%)
1
2
3
4
5
6
7
8
9
−
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
MeCN
MeCN
DMF
90
90
2
NR
CuI
CuI
CuI
CuI
CuI
4
51
mixture
mixture
48
80
5
DMSO
dioxane
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
80
2
100
110
90
2.5
2
NR
CuSO4 K2CO3 (2)
4
35
CuCl
CuCl2
CuCl
CuCl2
CuCl2
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
Cs2CO3 (2)
90
4
64
Figure 2. Synthetic strategies of indenoisoquinolines.
90
2.5
4
61
c
10
90
53
iodobenzamide derivatives under conditions of copper
catalysis,16 we envisioned that indeno[1,2-c]isoquinoline
derivatives could be synthesized in a concise manner from 2-
iodobenzamide derivatives and 1,3-indandiones as starting
materials, which are commercially available materials (Scheme
1).
11
12
90
3
67
Cs2CO3
(1.2)
90
3
72
d
13
CuCl2
Cs2CO3
(1.2)
MeCN
90
4
56
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol), additive (5
mmol %), base, solvent (0.5 mL). Isolated yields. Under Ar.
Microwave.
b
c
d
Scheme 1. Copper-Catalyzed Tandem Reactions
catalytic role in our reactions. Moreover, when the base K2CO3
was replaced with Cs2CO3, the yield of the desired product was
slightly higher (entry 11). It is notable that the reaction
furnished good yields of the desired product when the amount
of base was decreased from 2 equiv to 1.2 equiv (entry 12).
Finally, when the reaction was performed under microwave
conditions, it took a longer time to reach completion (entry
13).
After establishing the optimized reaction conditions, we
explored the substrate scope and limitations of the method-
ology. We initially examined the reaction of various N-
substituted 2-iodobenzamides and indane-1,3-dione (Table
2). When 2-iodobenzamide substrates having different N-
substitutions such as methyl, ethyl, allyl, benzyl, phenyl, 3-
morphinoethyl, and methoxyethyl groups were used, the
reaction proceeded smoothly to afford the corresponding
indenoisoquinoline derivatives in good yields (3a−3g). Even
the reaction of N-unprotected 2-iodobenzamide and indan-
dione worked well to afford the desired indenoisoquinoline
(3a′). Further, compounds with electron-withdrawing sub-
stituents such as nitro, chloro, and bromo groups on the
iodobenzamide moiety also worked well in affording the
desired products (3h−3j). The X-ray structure of 3j is
presented as Figure 3. It is noteworthy that the yield of the
desired product obtained in the case of a nitro substituent was
superior to any other substituent. On the other hand, electron-
donating groups such as methoxy, methylene dioxy furnished
the desired indeno[1,2-c]isoquinoline derivatives in good to
moderate yields (3k−3o).
RESULTS AND DISCUSSION
■
To execute our plan, we used 2-iodo-N-methylbenzamide 1a
and indandione 2a as model substrates. To initiate the reaction,
we treated 2-iodo-N-methylbenzamide 1a with 1,3-indandione
in the presence of 2 equiv of K2CO3 in acetonitrile at 90 °C
(Table 1, entry 1). No indenoisoquinoline derivative was
produced in the reaction. Even when the reaction was
conducted in DMSO in the presence of cesium carbonate,
the desired product was not produced. Next, the reaction was
conducted in the presence of CuI and K2CO3 in acetonitrile at
90 °C. In this case, the desired indeno[1,2-c]isoquinoline
derivative was produced in 51% yield.
Encouraged by this finding, we next optimized the reaction
conditions. We examined the use of a variety of solvents. An
inseparable mixture of products was produced in polar aprotic
solvents such as DMSO and DMF (entries 3 and 4), while a
moderate yield of the product was obtained when dioxane was
used as the solvent (entry 5). Moreover, no reaction occurred
when toluene was used (entry 6). We also examined different
copper catalysts such as CuSO4, CuCl, and CuCl2 (entries 7−
9). Among the copper salts used for our transformation, CuCl
and CuCl2 seemed to be equally efficient, however, the yield
dropped as the reaction was conducted with CuCl under argon
(entry 10), meaning that copper(II) did play an important
A literature survey indicated that most of the bioactive
compounds possess a dimethoxy or a methylendioxy group on
the indenone moiety. Hence, we examined the reactions of
dimethoxy and methylenedioxy-substituted indandiones with
various 2-iodobenzamide derivatives (Table 3).
When 2-iodobenzamides bearing electron-withdrawing sub-
strates such as nitro or bromo groups (3r, 3s, and 3z) were
B
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Table 2. Scope of the Reaction of Various
Indenoisoquinoline Derivatives
Table 3. Synthesis of Various Indenoisoquinolines from
Various 2-Iodobenzamide Derivatives and 3,4-
Dimethoxyindan-1,3-diones/3,4-methylenedioxy-1,3-diones
a
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), CuCl2 (5 mol %),
b
Cs2CO3 (1.2 mmol), MeCN (10−15 mL), 90 °C. Isolated yields.
a
Reaction conditions: 1 (1 mmol), 2a (1.5 mmol), CuCl2 (5 mol %),
b
Cs2CO3 (1.2 mmol), MeCN (10−15 mL), 90 °C. Isolated yields.
obtain high-quality 1H spectra. However, the solubility could be
greatly improved by adding few drops of trifluoroacetic acid-d
in the tube sample, making it a convenient way for recording
13C spectra of these compounds.
As shown in Scheme 2, we introduced a heterocycle
containing ortho halo amide derivatives such as 2-chloro-8-
Scheme 2. Synthesis of Heterocyclic Fused Indenopyridone
Derivatives
Figure 3. X-ray structure of 3j.
used, the reactions proceeded faster than when unsubstituted
benzamides (3p, 3q, 3v, and 3w) were used, but longer reaction
times were needed for benzamides with electron-donating
groups like methoxy, dimethoxy, and methylenedioxy groups
(3t, 3u, and 3aa−3ad). Moreover, the yields of the desired
products were more or less similar in almost all substrates
containing N-methyl and N-benzyl substitutions, irrespective of
the eletronic effect on benzamide rings. However, when
benzamide substrates having an N-morphinopropyl or N-
imidazopropyl group were used, the desired product was
produced in 54% and 49% yields, respectively (3ac and 3ad).
Using the above developed methodology, we were able to
synthesize a series of clinically tested anticancer agents such as
NSC 314622 (3ab), LMP-400 (3ac), and LMP-776 (3ad) in
moderate yields. The solubility of some compounds (3h, 3r, 3s,
3y, 3z, 3aa, 3ac, and 3ad) were extremely poor in deuterated
solvents such as CDCl3, D2O, acetonitrile-d3, acetone-d6, acetic
acid-d4, MeOD, and DMSO-d6, which made it difficult to
methyl-N-phenylquinoline-3-carboxamide and N-benzyl-2-io-
dothiophene-3-carboxamide in the present protocol instead of
an benzamide component. It is interesting that under optimized
reaction conditions, the former substrate provided the
corresponding pentacyclic multi heterocyclic compound 11-
methyl-5-phenyl-5H-benzo[b]indeno[1,2-h][1,6]naphthy-rid-
C
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ine-6,13-dione (3ae) in high yield. The latter substrate N-
benzyl-2-iodothiophene-3-carboxamide afforded the tetracyclic
compound 5-benzyl-4H-indeno[1,2-b]thieno[2,3-d]pyridine-
4,10(5H)-dione (3af) in moderate yield.
To further extend the scope of this methodology for the
synthesis of fused indenoisoquinoline derivatives, we examined
the reaction of 2-iodo-N-(2-iodobenzyl)benzamide and 1,3-
indandione using the developed reaction conditions, with 6-(2-
iodobenzyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
(3ag) being produced, which was further converted into the
corresponding azepine-fused indenoisoqunoline derivative 1H-
6a-azabenzo[a]benzo[5,6]-cyclohepta[1,2,3,4-def ]fluorene-
1,6(7H)-dione (4a) through a Heck reaction, as shown in
Scheme 3 (the X-ray structure is shown as Figure 4). Finally,
CONCLUSION
■
In summary, we report the successful development of a short
and efficient route for the synthesis of bioactive indenoisoqui-
noline derivatives by using a copper(II)-catalyzed tandem
reaction under mild conditions. A wide variety of benzamide
derivatives and indandiones were used to furnish indenoiso-
quinoline derivatives in moderate to good yields. In addition,
using the developed procedures, we were able to synthesize
clinically active Top1 inhibitors such as NSC 314622, LMP-400
and LMP-776 in a single step. Further, the current protocol was
successfully extended to the synthesis of other fused
indenoisoquinoline cores, thus making them available for use
in additional SAR studies.
EXPERIMENTAL SECTION
■
Scheme 3. Synthesis of Fused Indenoisoquinoline
Derivatives
General Information. Reagents and solvents were purchased from
various commercial sources and were used directly without any further
purification, unless otherwise stated. Column chromatography was
performed using 63−200 mesh silica gel. H and 13C NMR spectra
1
were recorded at 400/500/600 and 100/125/150 MHz, respectively.
Chemical shifts are reported in parts per million (δ) using TMS and
chloroform as internal standards, and coupling constants are expressed
in hertz. Melting points were recorded using an electrothermal
capillary melting point apparatus and are uncorrected. HRMS spectra
were recorded using ESI-TOF or EI+ mode. The starting 2-
iodobenzamide derivatives 1 and indandione derivatives 2 were all
synthesized following previously reported methods from 2-iodoben-
zoyl chlorides17 and benzaldehydes,18 respectively.
General Procedure for Indenoisoquinoline 3. 2-Iodobenzamide 1
(1 mmol), indandione 2 (1.5 mmol), and Cs2CO3 (0.39 g, 1.2 mmol)
were added to a 50 mL round-bottom flask equipped with a magnetic
stir bar, and 10−15 mL of acetonitrile was added. The mixture was
heated to 90 °C for 5 min, and then CuCl2 (0.0085 g, 0.05 mmol) was
added and reacted for the time indicated. The progress of the reaction
was monitored by TLC for disappearance of 1. After the reaction was
completed, it was brought back to r.t., 1−2 mL of brine was added, and
the acetonitrile was removed under reduced pressure. More iced brine
was added, and the indenoisoquinoline was solidified. If the crude was
sticky oil, adding a moderate amount of acetone or EA was acceptable
to assist solidification. The precipitation (fine power) was then filtered
by gravity filtration, and the resulting solid was washed thoroughly
with iced water and then dried in 60−100 °C ovens to yield the
desired product. In a few cases, the solids were mixtures of the
products and unconsumed amides. In such cases, the crude products
were washed with EA/hexane or acetone to yield the pure products.
General Procedure for 1H-6a-Azabenzo[a]benzo[5,6]-
cyclohepta[1,2,3,4-def ]fluorene-1,6(7H)-dione 4a. Indenoisoquino-
line 3ag (0.116 g, 0.25 mmol), PdCl2(PPh3)2 (0.009 g, 0.0125 μmol),
and NaOAc (0.041 g, 0.5 mmol) were added to a 10 mL round-
bottom flask under N2 atmosphere, and then 4 mL of DMA was added
and heated to 120 °C for 16 h. After the reaction was completed, the
mixture was purified by column chromatography using EA/hexane as
the eluent to yield the pure product 4a as a red solid (0.035 g, 42%).
General Procedure for 10H-Benzo[4,5]imidazo[2,1-a]-indeno[1,2-
c]isoquinolin-10-one 5a. A mixture of indenoisoquinoline 3ah (0.092
g, 0.25 mmol), Fe power (0.07 g, 1.25 mmol), and AcOH (4 mL) were
heated to 80 °C for 2 h. After the reaction was completed, the mixture
was filtered through a Celite pad and washed with EA. The eluent was
evaporated, and the solid collected was then washed with EA to yield
the desired product 5a as a red solid (0.066 g, 83%).
Figure 4. X-ray structure of 4a.
we carried out the reaction of the 2-iodobenzamide substrate
derived from 2-nitroaniline and 1,3-indandione under opti-
mized reaction conditions, with 6-(2-nitrophenyl)-5H-indeno-
[1,2-c]isoquinoline-5,11(6H)-dione (3ah) being obtained in
good yield. Further, this compound was subjected to the
reductive cyclization in the presence of iron/acetic acid to
afford 10H-benzo[4,5]imidazo[2,1-a]indeno[1,2-c]isoquinolin-
10-one (5a) in high yield.
Spectral Data. 6-Methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
dione (3a).11 Yield: 199 mg, 76%. Red solid. Mp: 240−242 °C. H
1
NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.0 Hz, 1H), 8.36 (d, J = 8.2
Hz, 1H), 7.75−7.71 (m, 1H), 7.68−7.63 (m, 2H), 7.49−7.41 (m, 3H),
4.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 190.7, 163.7, 156.3,
137.9, 135.4, 134.1, 133.3, 132.4, 131.3, 128.8, 127.4, 123.7, 123.6,
123.5, 123.0, 108.6, 32.5; HRMS (ESI) m/z calcd for C17H12NO2 (M+
+ H) 262.0868, found 262.0869.
D
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5H-Indeno[1,2-c]isoquinoline-5,11(6H)-dione (3a′). Yield: 138
mg, 56%. Orange solid. Mp: >350 °C. 1H NMR (400 MHz,
(CD3)2SO) δ 8.39 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.87−
7.73 (m, 2H), 7.54−7.41 (m, 4H); 13C NMR (100 MHz, (CD3)2SO)
δ 190.2, 164.6, 157.7, 137.6, 135.1, 134.1, 133.6, 131.8, 128.3, 126.7,
124.5, 122.9, 122.5, 121.2, 105.9; HRMS (ESI) m/z calcd for
C16H10NO2 (M+ + H) 248.0706, found 248.0705.
3-Bromo-6-methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
(3i).20 Yield: 201 mg, 59%. Orange solid. Mp: 272−274 °C. 1H NMR
(400 MHz, CDCl3) δ 8.56 (d, J = 8.7 Hz, 1H), 8.50 (s, 1H), 7.80 (d, J
= 8.6 Hz, 1H), 7.68−7.64 (m, 2H), 7.46−7.40 (m, 2H), 4.07 (s, 3H);
13C NMR (150 MHz, CDCl3 + CF3CO2D) δ 191.7, 163.7, 156.4,
138.1, 137.3, 134.7, 134.3, 132.1, 131.3, 131.1, 125.4, 124.5, 124.4,
123.7, 122.0, 109.4, 33.4; HRMS (ESI) m/z calcd for C17H11BrNO2
(M+ + H) 339.9973, found 339.9970.
6-Ethyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (3b).1b
1
Yield: 177 mg, 64%. Brown solid. Mp: 184−186 °C. H NMR (400
6-Benzyl-3-chloro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
1
(3j). Yield: 249 mg, 67%. Orange solid. Mp: 261−263 °C. H NMR
MHz, CDCl3) δ 8.70 (d, J = 8.1 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H),
7.74−7.70 (m, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H),
7.48−7.38 (m, 3H), 4.60 (q, J = 7.1 Hz, 2H), 1.55 (t, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 190.7, 163.5, 155.7, 137.3, 135.5,
134.0, 133.4, 132.5, 131.2, 128.6, 127.4, 123.8, 123.7, 123.5, 122.7,
108.8, 40.2, 14.7; HRMS (ESI) m/z calcd for C18H14NO2 (M+ + H)
276.1025, found 276.1026.
(400 MHz, CDCl3) δ 8.70 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H), 7.69 (d, J
= 8.3 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.37−7.21 (m, 8H), 5.79 (s,
2H); 13C NMR (100 MHz, CDCl3) δ 190.5, 162.7, 156.3, 137.1,
135.3, 135.1, 134.8, 133.6, 131.3. 131.0, 129.4, 128.4, 128.0, 125.9,
125.5, 124.9, 123.6, 123.2, 108.6, 48.5; HRMS (ESI) m/z calcd for
C23H15ClNO2 (M+ + H) 372.0791, found 372.0789.
6-Allyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (3c).8d Yield:
3-Methoxy-6-methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
1
1
dione (3k). Yield: 187 mg, 64%. Brown solid. Mp: 228−230 °C. H
187 mg, 65%. Red solid. Mp: 160−162 °C. H NMR (600 MHz,
NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H),
7.64−7.55 (m, 2H), 7.41−7.33 (m, 3H), 4.06 (s, 3H), 3.93 (s, 3H);
13C NMR (150 MHz, CDCl3) δ 190.8, 163.4, 159.2, 154.0, 138.3,
135.3, 133.3, 130.8, 126.5, 125.4, 125.1, 124.4, 123.5, 122.5, 109.0,
108.8, 55.8, 32.6; HRMS (ESI) m/z calcd for C18H14NO3 (M+ + H)
292.0974, found 292.0973.
CDCl3) δ 8.68 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.73−7.70
(m, 1H), 7.58 (d, J = 6.2 Hz, 1H), 7.47−7.44 (m, 2H), 7.40−7.33 (m,
2H), 6.14−6.08 (m, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.20−5.16 (m,
3H); 13C NMR (150 MHz, CDCl3) δ 190.7, 163.3, 156.0, 137.1,
135.3, 134.1, 133.3, 132.5, 131.6, 131.1, 128.8, 127.4, 123.7, 123.6,
123.3, 123.1, 117.6, 108.8, 46.6; HRMS (ESI) m/z calcd for
C19H14NO2 (M+ + H) 288.1025, found 288.1024.
2,3-Dimethoxy-6-methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
dione (3l).10 Yield: 171 mg, 53%. Red solid. Mp: 281−283 °C. H
1
6-Benzyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (3d).12b
1
NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.70 (s, 1H), 7.62−7.58 (m,
2H), 7.43−7.34 (m, 2H), 4.07 (s, 3H), 4.05 (s, 3H), 4.00 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 190.9, 162.8, 155.1, 154.8, 149.7, 138.2,
135.4, 133.3, 130.9, 128.1, 123.4, 122.7, 117.9, 108.5, 103.7, 56.5, 56.3,
32.5; HRMS (ESI) m/z calcd for C19H16NO4 (M+ + H) 322.1079,
found 322.1079.
Yield: 202 mg, 61%. Orange solid. Mp: 208−210 °C. H NMR (400
MHz, CDCl3) δ 8.76 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 8.2 Hz, 1H),
7.79−7.75 (m, 1H), 7.62−7.60 (d, J = 6.8 Hz, 1H), 7.51−7.48 (m,
1H), 7.37−7.23 (m, 8H), 5.80 (s, 2H); 13C NMR (125 MHz, CDCl3 +
CF3CO2D) δ 191.5, 164.7, 156.3, 137.0, 135.0, 134.9, 133.9, 132.8,
131.5, 129.4, 128.9, 128.1, 128.1, 125.9, 123.9, 123.4, 109.9, 48.9;
HRMS (ESI) m/z calcd for C23H16NO2 (M+ + H) 338.1181, found
338.1183.
6-Benzyl-2,3-dimethoxy-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
dione (3m).12b Yield: 243 mg, 61%. Brown solid. Mp: 289−290 °C.
1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 7.73 (s, 1H), 7.56 (d, J =
6.6 Hz, 1H), 7.37−7.33 (m, 2H), 7.28−7.22 (m, 6H), 5.79 (s, 2H),
4.09 (s, 3H), 3.99 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 191.1,
162.9, 155.3, 154.9, 149.8, 137.6, 135.8, 135.3, 133.4, 130.7, 129.3,
128.4, 127.8, 126.0, 123.2, 122.7, 118.0, 108.9, 108.7, 103.8, 56.6, 56.3,
48.3; HRMS (ESI) m/z calcd for C25H20NO4 (M+ + H) 398.1392,
found 398.1390.
6-Methyl-5H-[1,3]dioxolo[4,5-g]indeno[1,2-c]isoquinoline-
5,11(6H)-dione (3n). Yield: 220 mg, 72%. Red solid. Mp: 327−329
°C. 1H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.69 (s, 1H), 7.63−
7.60 (m, 2H), 7.44−7.35 (m, 2H), 6.10 (s, 2H), 4.04 (s, 3H); 13C
NMR (150 MHz, CDCl3 + CF3CO2D) δ 192.1, 165.4, 154.6, 154.5,
149.0, 137.5, 134.7, 134.2, 131.6, 130.7, 124.4, 123.3, 118.9, 110.3,
106.1, 102.6, 101.6, 33.4; HRMS (ESI) m/z calcd for C18H12NO4 (M+
+ H) 306.0766, found 306.0765.
6-Benzyl-5H-[1,3]dioxolo[4,5-g]indeno[1,2-c]isoquinoline-
5,11(6H)-dione (3o). Yield: 256 mg, 67%. Brown solid. Mp: 302−304
°C. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.70 (s, 1H), 7.57 (d,
J = 6.4 Hz, 1H), 7.35−7.33 (m, 2H), 7.26−7.21 (m, 6H), 6.11 (s, 2H),
5.76 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 190.8, 162.8, 154.9,
153.7, 148.3, 137.3, 135.7, 135.2, 133.5, 130.8, 130.2, 129.3, 128.3,
127.9, 125.9, 123.4, 122.8, 119.6, 109.1, 106.8, 102.2, 102.0, 48.3;
HRMS (ESI) m/z calcd for C24H16NO4 (M+ + H) 382.1079, found
382.1079.
6-Phenyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (3e).
1
Yield: 220 mg, 68%. Red solid. Mp: 242−244 °C. H NMR (400
MHz, CDCl3) δ 8.74 (d, J = 7.9 Hz, 1H), 8.37 (d, J = 8.1 Hz, 1H),
7.80 (m, 1H), 7.65−7.64 (m, 3H), 7.56−7.44 (m, 4H), 7.26−7.21 (m,
1H), 7.01−6.98 (m, 1H), 5.49 (d, J = 7.5 Hz, 1H); 13C NMR (150
MHz, CDCl3) δ 190.8, 163.8, 155.5, 137.7, 137.3, 135.0, 134.4, 132.9,
132.9, 130.9, 130.3, 128.9, 128.9, 127.5, 124.2, 123.9, 123.0, 122.6,
108.4; HRMS (ESI) m/z calcd for C22H14NO2 (M+ + H) 324.1025,
found 324.1027.
6-(2-Morpholinoethyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
dione (3f).19 Yield: 224 mg, 62%. Pale brown solid. Mp: 192−194 °C.
1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 8.2 Hz, 1H), 8.33 (d, J =
8.0 Hz, 1H), 7.75−7.68 (m, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.49−7.44
(m, 2H), 7.42−7.39 (m, 1H), 4.69 (t, J = 7.6 Hz, 2H), 3.74 (t, J = 4.6
Hz, 4H), 2.82 (t, J = 7.6 Hz, 2H), 2.62 (t, J = 4.6 Hz, 4H); 13C NMR
(150 MHz, CDCl3) δ 190.6, 163.5, 155.8, 137.4, 135.4, 134.1, 133.5,
132.5, 131.2, 128.6, 127.5, 123.7, 123.6, 123.5, 122.6, 108.9, 67.2, 56.9,
54.2, 42.6; HRMS (ESI) m/z calcd for C22H21N2O3 (M+ + H)
361.1552, found 361.1553.
6-(2-Methoxyethyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
(3g).8d Yield: 199 mg, 65%. Red solid. Mp: 184−186 °C. H NMR
1
(600 MHz, CDCl3) δ 8.70 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 8.3 Hz,
1H), 7.73−7.70 (m, 2H), 7.61 (d, J = 7.0 Hz, 1H), 7.47−7.42 (m,
2H), 7.38−7.36 (m, 1H), 4.71 (t, J = 6.4 Hz, 2H), 3.85 (t, J = 6.4 Hz,
2H), 3.38 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 190.8, 163.8,
156.4, 137.7, 135.3, 134.1, 133.3, 132.6, 131.1, 128.6, 127.4, 123.8,
123.6, 123.5, 123.3, 108.9, 70.1, 59.5, 44.8; HRMS (ESI) m/z calcd for
C19H16NO3 (M+ + H) 306.1130, found 306.1130.
8,9-Dimethoxy-6-methyl-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
1
dione (3p). Yield: 206 mg, 64%. Brown solid. Mp: 326−328 °C. H
NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 8.4
Hz, 1H), 7.70−7.66 (m, 1H), 7.42−7.39 (m, 1H), 7.22 (s, 1H), 7.18
(s, 1H), 4.03 (s, 3H), 4.00 (s, 3H), 3.97 (s, 3H); 13C NMR (125 MHz,
CDCl3 + CF3CO2D) δ 192.7, 156.1, 152.6, 151.2, 135.2, 132.8, 131.4,
128.6, 128.4, 127.8, 123.3, 122.5, 108.9, 108.8, 57.0, 56.7, 33.2; HRMS
(ESI) m/z calcd for C19H16NO4 (M+ + H) 322.1079, found 322.1078.
6-Benzyl-8,9-dimethoxy-5H-indeno[1,2-c]isoquinoline-5,11(6H)-
dione (3q).12b Yield: 274 mg, 69%. Brown solid. Mp: 272−274 °C. 1H
NMR (400 MHz, CDCl3) δ 8.68 (d, J = 8.1 Hz, 1H), 8.38 (d, J = 8.1
Hz, 1H), 7.77−7.73 (m, 1H), 7.49−7.45 (m, 1H), 7.40−7.36 (m, 2H),
6-Methyl-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
(3h).20 Yield: 261 mg, 85%. Red solid. Mp: >350 °C. H NMR (400
1
MHz, CDCl3 + CF3CO2D) δ 9.21 (s, 1H), 8.86 (d, J = 8.9 Hz, 1H),
8.58 (d, J = 8.9 Hz, 1H), 7.80 (d, J = 7.1 Hz, 1H), 7.76 (d, J = 7.1 Hz,
1H), 7.62−7.54 (m, 2H), 4.19 (s, 3H); 13C NMR (150 MHz, CDCl3 +
CF3CO2D) δ 191.2, 163.9, 146.3, 137.0, 136.8, 135.0, 134.5, 133.0,
128.6, 125.3, 125.2, 124.8, 124.5, 123.0, 108.5, 33.5; HRMS (ESI) m/z
calcd for C17H11N2O4 (M+ + H) 307.0719, found 307.0716.
E
DOI: 10.1021/acs.joc.6b02814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.31 (d, J = 7.1 Hz, 1H), 7.25 (d, J = 7.5 Hz, 2H), 7.17 (s, 1H), 6.78
(s, 1H), 5.81 (s, 1H), 3.93 (s, 3H), 3.61 (s, 3H); 13C NMR (150 MHz,
CDCl3) δ 190.6, 163.8, 156.3, 151.9, 150.6, 135.9, 134.1, 132.9, 130.3,
129.4, 128.9, 128.5, 127.9, 126.8, 125.5, 123.2, 123.0, 108.4, 108.0,
107.4, 56.5, 56.4, 48.2; HRMS (ESI) m/z calcd for C25H20NO4 (M+ +
H) 398.1392, found 398.1391.
7.46−7.42 (m, 1H), 7.35 (s, 1H), 7.14 (s, 1H), 6.13 (s, 2H), 4.66 (t, J
= 5.9 Hz, 2H), 3.87 (t, J = 6.2 Hz, 2H), 3.40 (s, 3H); 13C NMR (125
MHz, CDCl3 + CF3CO2D) δ 190.9, 155.4, 152.3, 149.7, 135.2, 132.8,
132.8, 130.1, 128.4, 127.7, 123.4, 109.8, 106.4, 106.1, 103.2, 70.0, 60.0,
45.0; HRMS (ESI) m/z calcd for C20H16NO5 (M+ + H) 350.1028,
found 350.1026.
8,9-Dimethoxy-6-methyl-3-nitro-5H-indeno[1,2-c]isoquinoline-
5,11(6H)-dione (3r). Yield: 268 mg, 73%. Brown solid. Mp: 345−347
°C (decompose). 1H NMR (500 MHz, CDCl3 + CF3CO2D) δ 9.11 (s,
1H), 8.69 (d, J = 9.0 Hz, 1H), 8.46 (d, J = 9.0 Hz, 1H), 7.33 (s, 1H),
7.24 (s, 1H), 4.09 (s, 3H), 4.03 (s, 3H), 4.00 (s, 3H); 13C NMR (125
MHz, CDCl3 + CF3CO2D) δ ;190.7, 163.7, 159.5, 152.8, 152.3, 145.7,
137.0, 130.1, 129.0, 128.5, 125.4, 124.6, 122.0, 109.2, 108.6, 107.6,
57.0, 56.8, 33.2; HRMS (ESI) m/z calcd for C19H15N2O6 (M+ + H)
367.0930, found 367.0926.
3-Bromo-8,9-dimethoxy-6-methyl-5H-indeno[1,2-c]isoquinoline-
5,11(6H)-dione (3s). Yield: 251 mg, 63%. Brown solid. Mp: >350 °C.
1H NMR (400 MHz, CDCl3) δ 8.47−8.44 (m, 2H), 7.75 (d, J = 8.3
Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 4.02 (s, 3H), 4.00 (s, 3H), 3.97 (s,
3H); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ 190.7, 163.0, 156.2,
152.4, 151.3, 137.5, 131.1, 128.4, 124.8, 123.7, 120.8, 108.5, 108.1,
107.8, 56.9, 56.6, 32.8; HRMS (ESI) m/z calcd for C19H14BrNO4 (M+
+ H) 399.0106, found 399.0109.
3-Bromo-6-methyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]-
isoquinoline-5,12(6H)-dione (3z). Yield: 238 mg, 62%. Brown solid.
Mp: 322−324 °C (decompose). 1H NMR (400 MHz, CDCl3) δ
8.48−8.45 (m, 2H), 7.76 (d, J = 9.8 Hz, 1H); 7.19 (s, 1H), 7.13 (s,
1H), 6.11 (s, 2H), 4.00 (s, 3H); 13C NMR (125 MHz, CDCl3 +
CF3CO2D) δ 190.6, 163.9, 155.7, 152.4, 150.0, 138.1, 132.8, 131.2,
131.1, 130.0, 124.9, 123.7, 121.4, 108.8, 106.6, 106.2, 103.3, 33.2;
HRMS (ESI) m/z calcd for C18H11BrNO4 (M+ + H) 383.9871, found
383.9866.
3-Methoxy-6-methyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]-
isoquinoline-5,12(6H)-dione (3aa). Yield: 218 mg, 65%. Brown solid.
Mp: 286−288 °C. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J = 8.8 Hz,
1H); 7.7 (s, 1H), 7.31−7.26 (m, 2H), 7.13 (s, 1H), 7.09 (s, 1H), 6.08
(s, 2H), 3.99 (s, 3H), 3.91 (s, 1H); 13C NMR (100 MHz, CDCl3 +
CF3CO2D) δ 192.2, 159.3, 153.2, 152.7, 149.6, 133.6, 129.4, 127.3,
126.4, 125.1, 108.2, 106.9, 106.1, 103.3, 55.9, 33.4; HRMS (ESI) m/z
calcd for C19H14NO5 (M+ + H) 336.0872, found 336.0868.
2,3-Dimethoxy-6-methyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]-
isoquinoline-5,12(6H)-dione (3ab).6,21 Yield: 201 mg, 55%. Brown
solid. Mp: 298−300 °C (decompose). 1H NMR (400 MHz, CDCl3) δ
8.00 (s, 1H), 7.66 (s, 1H), 7.14 (s, 1H), 7.08 (s, 1H), 6.09 (s, 2H),
4.05 (s, 3H), 3.99 (s, 3H), 3.99 (s, 3H); 13C NMR (150 MHz, CDCl3
+ CF3CO2D) δ 191.2, 156.0, 153.8, 152.4, 149.8, 149.6, 133.3, 129.8,
129.2, 116.8, 109.6, 108.0, 106.5, 105.9, 103.2, 103.0, 56.6, 56.3, 33.2;
HRMS (ESI) m/z calcd for C20H16NO6 (M+ + H) 366.0978, found
366.0978.
8,9-Dimethoxy-6-methyl-5H-[1,3]dioxolo[4,5-g]indeno[1,2-c]-
isoquinoline-5,11(6H)-dione (3t). Yield: 223 mg, 61%. Brown solid.
1
Mp: 321−323 °C. H NMR (500 MHz, CDCl3) δ 8.03 (s, 1H), 7.66
(s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 6.08 (s, 2H), 4.01 (s, 3H), 3.99 (s,
3H), 3.96 (s, 3H); 13C NMR (150 MHz, CDCl3 + CF3CO2D) δ
193.1, 155.2, 153.8, 152.8, 150.8, 149.2, 131.8, 131.4, 128.2, 125.2,
109.4, 108.9, 105.6, 102.8, 101.2, 56.9, 56.7, 33.5; HRMS (ESI) m/z
calcd for C20H16NO6 (M+ + H) 366.0978, found 366.0976.
6-Benzyl-8,9-dimethoxy-5H-[1,3]dioxolo[4,5-g]indeno[1,2-c]-
isoquinoline-5,11(6H)-dione (3u). Yield: 287 mg, 65%. Brown solid.
Mp: 315−317 °C. (500 MHz, CDCl3 + CF3CO2D) δ 8.03 (s, 1H),
7.63 (s, 1H), 7.39−7.36 (m, 2H), 7.33−7.30 (m, 1H), 7.24 (s, 1H),
7.17(d, J = 7.4 Hz, 2H), 6.73 (s, 1H), 6.15 (s, 2H), 5.82 (s, 2H), 3.91
(s, 3H), 3.59 (s, 3H); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ
192.9, 164.4, 155.1, 154.7, 152.7, 150.5, 149.0, 134.6, 131.5, 130.8,
129.7, 128.5, 127.9, 125.3, 118.3, 110.3, 108.9, 106.2, 102.7, 101.3,
56.6, 56.5, 49.3; HRMS (ESI) m/z calcd for C26H20NO6 (M+ + H)
442.1291, found 442.1292.
6-Methyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-
5,1(6H)-dione (3v).1a Yield: 202 mg, 66%. Brown solid. Mp: 308−310
°C. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 7.8 Hz, 1H), 8.32 (d, J
= 8.2 Hz, 1H), 7.71−7.67 (m, 1H), 7.43−7.39 (m, 1H), 7.19 (s, 1H),
7.13 (s, 1H), 6.10 (s, 2H), 4.00 (s, 3H); 13C NMR (150 MHz, CDCl3
+ CF3CO2D) δ 191.1, 155.5, 152.3, 149.9, 135.1, 132.9, 132.6, 129.9,
128.6, 127.8, 123.3, 122.3, 109.5, 106.5, 106.2, 103.3, 33.1; HRMS
(ESI) m/z calcd for C18H12NO4 (M+ + H) 306.0766, found 306.0763.
6-Benzyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-
5,12(6H)-dione (3w). Yield: 229 mg, 60%. Brown solid. Mp: 297−299
°C. 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.5 Hz, 1H), 8.34 (d, J
= 8.0 Hz, 1H), 7.75−7.71 (m, 1H), 7.46−7.42 (m, 1H), 7.38−7.34 (m,
2H), 7.30−7.20 (m, 3H), 7.09 (s, 1H), 6.80 (s, 1H), 6.00 (s, 2H), 5.73
(s, 2H); 13C NMR(125 MHz, CDCl3 + CF3CO2D) δ 191.0, 155.3,
152.3, 149.8, 135.2, 132.8, 132.3, 130.7, 130.0, 128.7, 127.8, 123.4,
122.5, 118.1, 109.6, 106.3, 106.2, 103.1, 47.2; HRMS (ESI) m/z calcd
for C24H16NO4 (M+ + H) 382.1079, found 382.1079.
2,3-Dimethoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo-
[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione (3ac).3a,22 Yield:
1
259 mg, 54%. Brown solid. Mp: 293−295 °C. H NMR (400 MHz,
CDCl3) δ 8.05 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 7.09 (s, 1H), 6.10
(s, 1H), 4.55−4.48 (m, 2H), 4.05 (s, 3H), 3.99 (s, 3H), 3.79−3.92 (m,
4H), 2.60−2.48 (m, 6H), 2.06−1.97 (m, 2H); 13C NMR (100 MHz,
CDCl3 + CF3CO2D) δ 191.2, 152.9, 152.5, 150.1, 150.0, 131.9, 129.6,
129.4, 116.3, 110.4, 107.5, 106.7, 104.8, 103.5, 103.2, 64.2, 56.7, 56.2,
55.5, 52.9, 42.0, 24.3; HRMS (ESI) m/z calcd for C26H27N2O7 (M+ +
H) 479.1818, found 479.1820.
6-(3-(1H-Imidazol-1-yl)propyl)-2,3-dimethoxy-5H-[1,3]dioxolo-
[4′,5′:5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione (3ad).3a,22 Yield:
1
225 mg, 49%. Brown solid. Mp: 320−322 °C. H NMR (400 MHz,
CDCl3) δ 8.05 (s, 1H), 7.66 (s, 1H), 7.64−7.59 (m, 1H), 7.19−7.13
(m, 1H), 7.08 (s, 1H), 7.07−7.03 (m, 1H), 6.43 (s, 1H), 6.09 (s, 2H),
4.47 (t, J = 6.8 Hz, 2H), 4.22 (t, J = 6.8 Hz, 2H), 4.05 (s, 3H), 4.00 (s,
3H), 2.39−2.32 (m, 2H); 13C NMR (100 MHz, CDCl3 + CF3CO2D)
δ 191.8, 156.5, 153.1, 152.8, 150.1, 135.3, 132.2, 129.8, 129.6, 121.9,
121.0, 116.4, 110.5, 107.7, 107.1, 104.9, 103.6, 103.3, 56.7, 56.3, 47.5,
42.1, 30.3; HRMS (ESI) m/z calcd for C25H22N3O6 (M+ + H)
460.1509, found 460.1507.
11-Methyl-5-phenyl-5H-benzo[b]indeno[1,2-h][1,6]-
naphthyridine-6,13-dione (3ae). Yield: 311 mg, 80%. Pale brown
solid. Mp: >350 °C. 1H NMR (400 MHz, CDCl3) δ 9.16 (s, 1H), 7.82
(d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.69−7.64 (m, 4H),
7.53−7.47 (m, 3H), 7.32−7.28 (m, 1H), 7.06−7.02 (m, 1H), 5.56 (d, J
6-Allyl-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]isoquinoline-
5,12(6H)-dione (3x). Yield: 249 mg, 75%. Brown solid. Mp: 242−244
°C. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.5 Hz, 1H), 8.32 (d, J
= 8.0 Hz, 1H), 7.72−7.69 (m, 1H), 7.44−7.41 (m, 1H), 7.11 (s, 1H),
7.00 (s, 1H), 6.18−6.03 (m, 3H), 5.33 (d, J = 10.4 Hz, 1H), 5.20−5.11
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 189.5, 163.3, 151.5, 149.3,
134.1, 132.7, 132.3, 131.5, 130.7, 128.8, 126.9, 123.3, 123.0, 117.6,
105.8, 105.6, 103.9, 102.8, 46.3; HRMS (ESI) m/z calcd for
C20H14NO4 (M+ + H) 322.0923, found 332.0923.
= 7.6 Hz, 1H), 3.01 (s, 3H); 13C NMR (125 MHz, CDCl3
+
CF3CO2D) δ 189.8, 166.0, 160.7, 151.3, 143.0, 141.0, 138.1, 135.8,
135.6, 135.2, 135.1, 134.8, 132.1, 131.3, 130.5, 129.9, 128.0, 127.7,
127.0, 126.2, 125.3, 118.2, 99.7, 16.0; HRMS (ESI) m/z calcd for
C26H17N2O2 (M+ + H) 389.1290, found 389.1288.
5-Benzyl-4H-indeno[1,2-b]thieno[2,3-d]pyridine-4,10(5H)-dione
1
(3af). Yield: 172 mg, 50%. Orange solid. Mp: 232−234 °C. H NMR
(400 MHz, CDCl3) δ 7.94 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 5.2 Hz,
1H), 7.37−7.22 (m, 7H), 5.81 (s, 2H); 13C NMR (100 MHz, CDCl3)
δ 189.1, 159.5, 156.6, 140.3, 137.7, 136.8, 135.4, 134.9, 133.6, 131.1,
129.4, 128.8, 128.0, 126.0, 123.8, 123.2, 123.0, 110.2, 47.9; HRMS
6-(2-Methoxyethyl)-5H-[1,3]dioxolo[4′,5′:5,6]indeno[1,2-c]-
isoquinoline-5,12(6H)-dione (3y). Yield: 186 mg, 53%. Brown solid.
1
Mp: 205−207 °C (decompose). H NMR (400 MHz, CDCl3) δ 8.66
(d, J = 8.4 Hz, 1H), 8.32 (d, J = 7.7 Hz, 1H), 7.73−7.70 (m, 1H),
F
DOI: 10.1021/acs.joc.6b02814
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(ESI) m/z calcd for C21H14NO2S (M+ + H) 344.0745, found
344.0745.
providing HRMS, NMR spectral, and crystallographic data,
respectively.
6-(2-Iodobenzyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
(3ag). Yield: 445 mg, 96%. Orange solid. Mp: 236−238 °C. 1H NMR
(500 MHz, CDCl3 + CF3CO2D) δ 8.74 (d, J = 8.1 Hz, 1H), 8.37 (d, J
= 8.1 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.83−7.80 (m, 1H), 7.59−
7.53 (m, 2H), 7.32−7.21 (m, 3H), 7.03−7.00 (m, 1H), 6.96 (d, J = 7.4
Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.65 (s, 2H); 13C NMR (125 MHz,
CDCl3 + CF3CO2D) δ 191.5, 164.4, 156.0, 140.2, 136.6, 135.1, 134.7,
134.1, 132.8, 131.5, 129.8, 129.3, 129.0, 128.2, 125.9, 124.0, 123.3,
123.0, 116.0, 113.7, 110.0, 96.7, 54.4; HRMS (ESI) m/z calcd for
C23H15INO2 (M+ + H) 464.0147, found 464.0151.
REFERENCES
■
(1) (a) Kohlhagen, G.; Paull, K.; Cushman, M.; Nagafuji, P.;
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Cushman, M. J. Med. Chem. 2012, 55, 1682. (e) Nguyen, T. X.;
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4890.
6-(2-Nitrophenyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
1
(3ah). Yield: 258 mg, 70%. Pale brown solid. Mp: 286−288 °C. H
NMR (400 MHz, CDCl3) δ 8.75 (d, J = 8.1 Hz, 1H), 8.40 (d, J = 7.8
Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.94−7.86 (m, 3H), 7.82−7.79 (m,
1H), 7.61−7.58 (m, 2H), 7.53−7.49 (m, 1H), 7.04−7.00 (m, 1H),
5.57 (d, J = 7.1 Hz, 1H); 13C NMR (125 MHz, CDCl3 + CF3CO2D) δ
191.5, 154.6, 146.4, 137.7, 136.7, 135.6, 135.4, 134.4, 133.6, 133.1,
132.1, 131.8, 131.6, 131.2, 129.1, 128.3, 126.8, 124.5, 124.1, 124.0,
123.5, 121.2, 110.2; HRMS (ESI) m/z calcd for C22H13N2O4 (M+ +
H) 369.0875, found 369.0876.
1H-6a-Azabenzo[a]benzo[5,6]cyclohepta[1,2,3,4-def ]fluorene-
1,6(7H)-dione (4a). Yield: 141 mg, 42%. Red solid. Mp: 276−278 °C.
1H NMR (400 MHz, CDCl3 + (CD3)2SO) δ 8.46 (d, J = 8.1 Hz, 1H),
8.13 (d, J = 7.9 Hz, 1H), 7.57−7.53 (m, 1H), 7.30−7.27 (m, 2H),
7.08−7.00 (m, 4H), 6.88−6.85 (m, 2H), 5.55 (d, J = 7.4 Hz, 1H); 13
C
NMR (100 MHz, CDCl3 + (CD3)2SO) δ 190.4, 162.6, 155.9, 141.0,
136.6, 134.1, 133.8, 132.9, 132.5, 130.9, 130.5, 129.0, 128.3, 126.8,
124.2, 123.8, 123.1, 122.2, 121.9, 120.7, 118.7, 108.2; HRMS (ESI) m/
z calcd for C23H14NO2 (M+) 336.1025, found 336.1026.
(4) Balana-Fouce, R.; Prada, C. F.; Requena, J. M.; Cushman, M.;
̃
́
Pommier, Y.; Alvarez-Velilla, R.; Escudero-Martínez, J. M.; Calvo-
́
10H-Benzo[4,5]imidazo[2,1-a]indeno[1,2-c]isoquinolin-10-one
(5a). Yield: 267 mg, 83%. Red solid. Mp: 286−288 °C. 1H NMR (400
MHz, CDCl3) δ 8.56 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 7.5 Hz, 1H),
7.86 (d, J = 8.1 Hz, 1H), 7.76−7.71 (m, 3H), 7.64 (d, J = 7.0 Hz, 1H),
7.56−7.52 (m, 2H), 7.50−7.46 (m, 2H), 5.46 (s, 2H); 13C NMR (100
MHz, CDCl3) δ 189.5, 163.0, 137.2, 136.3, 135.7, 135.5, 134.1, 134.0,
132.9, 132.6, 132.2, 131.7, 131.6, 129.9, 129.5, 129.2, 128.6, 127.1,
124.7, 123.8, 122.8, 107.5, 47.9; HRMS (ESI) m/z calcd for
C22H13N2O (M+) 321.1028, found 321.1028.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02814.
■
S
1H and 13C NMR spectra for all products (PDF)
X-ray crystallography data for 3j (CIF)
X-ray crystallography data for 4a(CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: cheyaocf@ntnu.edu.tw.
ORCID
■
Ching-Fa Yao: 0000-0002-8692-5156
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Ministry of Science and Technology of
the Republic of China (MOST 103-2113-M-003-008-MY3),
National Taiwan Normal University (103-07-C), and Instru-
mentation Centre at National Taiwan Normal University is
gratefully acknowledged. The authors are grateful to Ms. Hsiu-
Ni Huang, Ms. Chiu-Hui He, and Mr. Ting-Shen Kuo for
(10) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P.
Tetrahedron Lett. 2011, 52, 1481−1484.
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DOI: 10.1021/acs.joc.6b02814
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