A nitroalkane-based approach to one-pot three-component synthesis of isocryptolepine and its analogs with potent anti-cancer activities

Article abstract of DOI:10.1039/C8RA08155G

A second generation polyphosphoric acid-mediated one-pot three-component synthesis of indoloquinoline scaffold is developed. This improved version of the process involves electrophilically activated nitroalkanes for the installation of strategic C-C and C-N bonds and ring C assembly. This modification allows the elimination of unnecessary solvent change operations and all steps are carried out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.

Full text of DOI:10.1039/C8RA08155G

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A nitroalkane-based approach to one-pot three-
component synthesis of isocryptolepine and its
analogs with potent anti-cancer activities†
Cite this: RSC Adv., 2018, 8, 36980
a
a
b
*
Nicolai A. Aksenov,
Alexander V. Aksenov,
Alexander Kornienko,
Annelise De Carvalho,cd Veronique Mathieu,cd Dmitrii A. Aksenov,a
´
Sergei N. Ovcharov,a Georgii D. Griaznove and Michael Rubin
ae
*
A
second generation polyphosphoric acid-mediated one-pot three-component synthesis of
indoloquinoline scaffold is developed. This improved version of the process involves electrophilically
activated nitroalkanes for the installation of strategic C–C and C–N bonds and ring C assembly. This
modification allows the elimination of unnecessary solvent change operations and all steps are carried
out in a true, uninterrupted one-pot manner. A further improvement involves the possibility to install an
ortho-amino group in situ. A synthetic application of this method is showcased by the concise synthesis
of an isocryptolepine alkaloid and its synthetic analogs with potent anticancer activities.
Received 1st October 2018
Accepted 23rd October 2018
DOI: 10.1039/c8ra08155g
rsc.li/rsc-advances
carbonyl compound equivalent (carboxylic acid, nitrile or
triazine) afforded species 6, that underwent intramolecular
Introduction
Vilsmeier reaction (step D) to provide the indoloquinoline core
of the alkaloid (Scheme 1).4 Remarkably, this transformation is
carried out in a one-pot fashion requiring a single isolation
operation at the end of the sequence, leading to an efficient
synthesis of an anticancer drug candidate library for SAR
studies. However, this synthetic protocol depended on the
Isocryptolepine (cryptosanguinolentine, 1), one of the four types
of indoloquinoline alkaloids isolated from West African plant
Cryptolepis sanguinolenta,1 has been investigated as a promising
antimalarial and anticancer agent (Fig. 1),2 and has been the
target of numerous synthetic efforts.3 All these synthetic routes
required multistep linear sequences with the isolation and
purication of intermediates. Recently, we disclosed a highly
efficient metal-free three-component synthesis of iso-
cryptolepine and its bioactive analogs involving a sequential
assembly of the indoloquinoline core in one-pot with a single
isolation operation.4 This synthetic approach was inspired by
the 2009 Kundu total synthesis, featuring Fischer indolization
followed by an oxidative Pictet–Spengler type reaction to
assemble ring C.5 Our featured protocol (Generation 1) involved
the formation of hydrazones 4 from hydrazines 2 and ortho-
aminoacetophenones 3 (step A), followed by polyphosphoric
acid (PPA)-assisted Fischer indolization (step B) to furnish
indole 5 (Scheme 1).4 Subsequent acid-mediated acylation of
ortho-aniline substituent at C-2 (step C) with an appropriate
availability of ortho-aminoacetophenones
3 and carbonyl
compound equivalents (acylating agents used in step C:
carboxylic acids, nitriles or 1,3,5-triazines). We also discovered
an alternative protocol involving unusual cyclization with
nitroalkenes accompanied by extrusion of HCN (Scheme 2).6
Still, these previously developed methods did not provide any
synthetically meaningful results in reactions of acylating agents
bearing functional group as substituent R5. In certain cases,
aDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation. E-mail: naksenov@ncfu.ru
bDepartment of Chemistry and Biochemistry, Texas State University, San Marcos,
Texas 78666, USA
cDepartment of Pharmacotherapy and Pharmaceutics, Faculte de Pharmacie,
´
´
Universite Libre de Bruxelles, Brussels, Belgium
d
´
ULB Cancer Research Center, Universite Libre de Bruxelles, Brussels, Belgium
eDepartment of Chemistry, University of Kansas, 1251 Wescoe Hall Dr., Lawrence, KS
66045-7582, USA. E-mail: mrubin@ku.edu; Tel: +1-785-864-5071
† Electronic supplementary information (ESI) available: Spectral data. See DOI:
10.1039/c8ra08155g
Fig. 1 Natural indoloquinoline alkaloids isolated from Cryptolepis
sanguinolenta.
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situ generated intermediate 5 into indoloquinoline species 1.
Indeed, a nucleophilic attack of indole 5 across the C]N bond
of the phosphorylated nitronate 10 would afford (azanediylbi-
s(oxy))bis(phosphonic) species 11, which aer 1,2-elimination
of ortho-phosphoric acid would produce O-phosphorylated
oxime 12 (Scheme 3). Intramolecular nucleophilic attack of
aniline moiety would produce cyclic aminal 13, which aer 1,2-
elimination of hydroxylamine O-phosphonate would aromatize
into product 1 (Scheme 3). Alternatively, nitronate 10 can be
attacked by the nucleophilic aniline moiety in 5 to form an O-
phosphorylated N0-hydroxyacetimidamide species that can be
viewed as a direct analog of intermediate 6 (with X ¼
NOPO(OH)2). This intermediate can undergo a subsequent
Vilsmeier-type intramolecular attack involving the nucleophilic
C-3 center of indole moiety to produce indoloquinoline 1 in
a way similar to the one described in Scheme 1.
To test this idea, we subjected 2-phenyl-1H-indole (5aa) to
the reaction with excess nitromethane (9a) (ca. 5 equiv.) in PPA
(80% P2O5). Gratifyingly, the reaction proceeded smoothly at
ꢀ
100 C forming the desired indoloquinoline 1aaa as the sole
product, which was isolated in 92% yield (Scheme 4). Large
excess of nitromethane was used in this case to offset its high
volatility at high temperature, and probably its amount could
be reduced upon scale up or in the case when the process is
carried out in a closed pressurized reactor. For this study,
however, to simplify the set up and reduce the reagent cost, we
preferred to use an open vessel and excess of nitromethane.
Reactions with nitroethane (9b, ca. 3 equiv.) and 1-nitrohexane
(9c, 1.2 equiv.) also proceeded uneventfully at 110 ꢀC affording
the corresponding tetracyclic products 1aab and 1aac in 91
and 88% yields, respectively (Scheme 4). Expectedly, lower
Scheme 1
Scheme 2
these issues rendered synthesis of some types of compounds for
our SAR studies impossible or cost prohibitive. Herein, we
disclose a further modied synthetic protocol (Generation 2)
addressing these problems, and results of our second series of
screening for antiproliferative activities that allowed to identify
highly potent lead structures.
Results and discussion
It should be pointed out that cyclization of intermediate 8
shown in Scheme 2 involves an unusual electrophilic compo-
nent formed via phosphorylation of a nitroalkane in nitronate
form. Mechanistically, this process is related to the classical Nef
reaction,7 employing nucleophilic amine species instead of
water. We have discovered a number of innovative one-pot
transformations involving nitrogen8 or carbon9 nucleophile-
based versions of the Nef reaction and wondered if nitro-
alkane species 9, electrophilically activated by PPA, could serve
as an alternative acylating agent to trigger cyclization of the in
Scheme 3
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Scheme 4
volatility of nitroalkane 9c allowed a nearly stoichiometric assembly of indole moiety 5 via Fischer indolization of readily
amount of this reagent to be used. available arylhydrazines 2 and ortho-aminoacetophenones 3. To
Also, we tested if the featured method is compatible with the this end, phenylhydrazine 2a was rst heated with an equimolar
ester functionality. To this end, reaction of 5aa in PPA was amount of acetophenone 3a for a short period of time without
carried at 130 ꢀC in the presence of nitroacetic ester (9e, 1.2 solvent to assemble hydrazine 12. The addition of PPA and
equiv.). We were pleased to nd that the corresponding func- heating at 70 ꢀC triggers the Fischer indolization, which pro-
tionalized indoloquinoline 1aae was obtained smoothly in high ceeded within 3 h to afford indole 5aa. Nitroalkanes could be
yield (Scheme 4).
then added directly to this mixtures and the temperature of the
With this reaction protocol in hand, we proceeded with the mixture should be raised (100 ꢀC for nitromethane (9a), 110 ꢀC
development of a one-pot method allowing for an in situ for longer linear nitroalkanes (9b, c), 130 ꢀC for ethyl
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nitroacetate (9e), 140 ꢀC for a-nitrotoluene (9d)). The optimal a mixture of 9- and 7-substituted indoloquinolines. The
excess amounts of the nitroalkanes are shown in Scheme 4. We problem was solved by carrying out the indolization at lower
ꢀ
were pleased to nd that via this one-pot protocol indoloqui- temperatures (below 70 C), which led to 6-substituted indoles
noline products were obtained in high yields, which were only predominantly (the typical product ratio was about 9 : 1 for both
slightly lower than those obtained from indole precursor 5a hydrazines 2c and 2d). The subsequent reaction with nitro-
(Scheme 4).
alkanes resulted in the formation of 9-methyl- (1cea, 1cfa) or 9-
Next, we evaluated the possibility of employing N-methyl chloro- (1daa, 1dda, 1dea) substituted indoloquinolines along
protected aminoacetophenone 3b as one of the key reactants. If with minor amounts of 7-substituted isomers. This impurity
successful, the application of this starting material would was removed by preparative column chromatography, which
provide access to derivatives of 5H-indolo[3,2-c]quinoline, lowered the yields of puried materials (Scheme 4).
including the natural alkaloid isocryptolepine. To our delight,
In continuation of our studies of isocryptolepine and its
a three component one-pot reaction between hydrazine 2a, analogs as potential anticancer agents, we evaluated the
acetophenone 3b, and nitromethane (9a) afforded iso- synthesized compounds against a panel of six cancer cell lines
cryptolepine (1aba) in high yield (Scheme 4). The replacement that included the human A549 non-small cell lung cancer
of nitromethane with nitroethane (9b) or 1-nitrohexane (9c) (NSCLC), MCF-7 breast carcinoma, U373 glioblastoma, HS683
allowed for the efficient preparation of homologs 1abb and oligodendroglioma, SKMEL-28 melanoma as well as murine
1acc, respectively (Scheme 4). To further elaborate on the newly B16F10 melanoma using cryptolepine as control (Table 1). The
developed method we decided to synthesize a small library of A549, U373 and SKMEL-28 cell lines represent in vitro cell
isocryptolepine analogs by varying hydrazine and acetophenone models of the corresponding aggressive cancer types, i.e.
reagents, capitalizing mostly on the use of nitromethane to take NSCLCs, glioma and melanoma because they have been shown
advantage of its low cost. Also, taking into account the results of to display various degrees of resistance to pro-apoptotic
our preliminary SAR studies, we concentrated on the prepara- insults.10 It was found that methylated compounds,
tion of structures bearing alkoxy substituents in ring D, as they including isocryptolepine (1aba) itself, in general had higher
demonstrated the highest antiproliferative potency. Reactions activities than their demethylated counterparts. A number of
involving p-tolylhydrazine 2b proceeded smoothly affording the such compounds were equally or more potent than the parent
corresponding indoloquinolines 1bba, 1bbb, and 1bbd in good alkaloid itself. These included 1abb, 1aea, 1bbb, 1cea, 1dea. It
yields. It is important to mention that straight aer aqueous also appeared that alkoxy groups in the quinoline part of the
work up of the reaction mixtures all of these products were molecule, such as in compounds 1aea, 1cea, 1cfa, 1dea were
sufficiently pure for all practical purposes.
benecial for activity. Of note however, demethylated analog
The employment of meta-substituted arylhydrazines 2c and 1cfa, which contains bridged alkoxy groups in the quinoline
2d proved to be more challenging as the Fischer indolization part of the molecule showed nanomolar antiproliferative
reaction in this case suffered from the lack of regioselectivity. activity, more than two orders of magnitude more potent than
When carried out at elevated temperatures (above 90 ꢀC) it that of isocryptolepine (1aba). Synthesis of a methylated
afforded nearly equimolar mixtures of 4- and 6-substituted analogue of 1cfa, which is expected to have even higher
indole intermediates, which were further converted into potency is underway.
Table 1 50% in vitro growth inhibitory concentration (IC50, mMa) determined by the colorimetric MTT assay
Carcinoma
A549
Glioma
U373n
Melanoma
SKMEL-28
Mean +
SEM
Compound
MCF-7
27
4
27
5
HS638
B16F10
1aaab
1aab
1aac
1aae
1abab
1abb
1aeab
1bba
1bbb
1bbd
1cea
1cfa
8
3
17
16
4
3
11
24
7
3
4
3
14 ꢁ 4
4.0 ꢁ 0.5
17 ꢁ 4
6
24
5
6
22
4
4
4
4.0 ꢁ 0.3
0.8 ꢁ 0.1
1.2 ꢁ 0.4
0.4 ꢁ 0.05
3.0 ꢁ 0.4
0.6 ꢁ 0.1
4.1 ꢁ 0.4
0.7 ꢁ 0.2
0.06 ꢁ 0.04
4.0 ꢁ 0.7
2.0 ꢁ 0.4
0.2 ꢁ 0.1
0.6
0.5
0.4
3
0.4
4
0.4
0.008
5
1.0
1.3
0.4
0.5
0.3
1
0.4
4
0.4
0.01
4
0.9
0.7
0.7
0.3
2
0.3
3
0.4
0.008
3
0.6
0.21
1.3
0.5
4
0.6
6
0.7
0.05
6
3.3
0.6
4
1.2
4
1.6
0.27
2
1.0
0.4
4
0.7
4
0.5
0.007
6
1daa
1dda
1dea
2
0.04
3
0.18
3
0.24
1
0.06
2
0.65
a
Mean concentration required to reduce the cell viability by 50% aer a 72 h treatment relative to a control as determined by MTT assay. Each
experiment was performed once in sextuplicate. These data were previously reported in ref. 4.
b
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mixture acetone/benzene (1 : 3) doped with aqueous ammonia
(1 drop of per 10 mL of eluent).
Conclusion
In conclusion, we designed and developed an improved one-pot
assembly of 5H- and 11H-indolo[3,2-c]quinoline skeleton. The
method involved an in situ formation of hydrazones, followed by
a PPA-assisted Fischer indolization reaction and intramolecular
cycloaddition of electrophilically activated nitroalkanes. Using
this protocol, we synthesized the natural alkaloid iso-
cryptolepine and a small library of its analogs, which were
evaluated for anti-proliferative activity against six cancer cell
lines. Several analogs demonstrated activity higher than that of
the natural alkaloid, with one compound (1cfa) having signi-
cant activity at nanomolar concentrations.
Preparation of indoloquinolines from indole (general procedure B)
The reaction vessel was charged with 2-phenyl-1H-indole (5aa)
(193 mg, 1.0 mmol) and polyphosphoric acid (80% PPA, 1.5 g).
The mixture was stirred at 70 ꢀC, and nitroalkane was added
according to the specications described in general procedure
A. Temperature regimen, post-reaction work up, isolation and
purication of the products was performed in the same manner
as described in general procedure A.
Ethyl 11H-indolo[3,2-c]quinoline-6-carboxylate (1aae)
Yield 78% (general procedure A), 89% (general procedure B).
Light-yellow crystalline solid, mp 91–92 ꢀC (acetone–hexane), Rf
0.46 (Hex/EtOAc/EtOH 7 : 2 : 1). 1H NMR (400 MHz, CDCl3)
d 11.39 (s, 1H), 8.63 (d, J ¼ 7.8 Hz, 1H), 8.37 (d, J ¼ 8.1 Hz, 1H),
8.25 (d, J ¼ 8.4 Hz, 1H), 7.63 (d, J ¼ 8.0 Hz, 1H), 7.58 (t, J ¼
7.6 Hz, 1H), 7.50–7.42 (m, J ¼ 15.6, 7.8 Hz, 2H), 7.36 (t, J ¼
Experimental part
General information
1H and 13C NMR spectra were recorded on a Bruker Avance-III
spectrometer (400 or 100 MHz, respectively) equipped with
a BBO probe in CDCl3 or DMSO-d6, using TMS as internal
standard. High-resolution mass spectra were registered with
7.6 Hz, 1H), 4.61 (q, J ¼ 7.1 Hz, 2H), 1.39 (t, J ¼ 7.1 Hz, 3H); 13
C
NMR (101 MHz, CDCl3) d 166.6, 144.0, 143.4, 142.6, 139.6, 129.4,
a Bruker Maxis spectrometer (electrospray ionization, in MeCN 129.3, 127.6, 126.8, 124.2, 121.8, 121.6, 121.5, 117.4, 113.5,
solution, using HCO2Na–HCO2H for calibration). Melting 111.8, 62.7, 14.4; IR (KBr, lm, cmꢂ1): 2930, 2855, 2368, 1730,
points were measured with a Stuart smp30 apparatus. All 1565, 1501, 1460, 1355, 1310, 1238, 1193, 1081, 1017, 744;
HRMS (ES TOF) calcd for C18H15N2O2 (M + H)+ 291.1128, found
reactions were performed in oven-dried 5 mL round-bottomed
291.1127 (0.4 ppm).
asks open to the atmosphere, employing overhead stirring.
The reaction progress and purity of isolated compounds were
controlled by TLC on Silufol UV-254 plates, with EtOAc as
eluent. All reagents and solvents were purchased from
commercial vendors and used as received. Indoloquinoline
products 1aaa,11 1aab,12 1aac,4 1aba,10 1abb,11 1abc,4 1aca,13
1ada,3g 1aea,3g 1bba,4 1bbb,12 1bbd6 are known compounds and
their physical and spectral properties matched those previously
reported in literature.
2,3-Dimethoxy-5,9-dimethyl-5H-indolo[3,2-c]quinoline (1cea)
Yield 58% (via general procedure A). Yellow crystalline solid, Rf
0.20 (acetone/benzene/ammonia 8 : 8 : 1), mp 252–253 ꢀC
(CH2Cl2–benzene–hexane), Lit mp 252–253 C.3g 1H NMR (400
ꢀ
MHz, DMSO) d 9.14 (s, 1H), 7.95–7.88 (m, 2H), 7.48 (s, 1H), 7.25
(s, 1H), 7.05 (d, J ¼ 7.8 Hz, 1H), 4.19 (s, 3H), 3.98 (s, 3H), 3.96 (s,
3H); 13C NMR (101 MHz, DMSO) d 151.5, 149.9, 148.2, 136.5,
135.4, 131.1 (2C), 121.9, 121.4, 119.4, 116.5, 114.9, 113.6, 103.0,
99.2, 56.1, 55.8, 42.8, 21.9; HRMS (ES TOF) calcd for C19H19N2O2
(M + H)+ 307.1441, found 307.1443 (0.8 ppm).
Preparation of indoloquinolines via three-component one-pot
protocol (general procedure A)
Reaction vessel was charged with arylhydrazine 2 (1.0 mmol)
and o-aminoacetophenone 3 (1.0 mmol), and the mixture was
heated at 120 ꢀC for 10 min. Then, the mixture was cooled down
to ca. 70 ꢀC, and polyphosphoric acid (80% PPA, 2.0 g) was
added. The mixture was stirred at the same temperature for 3 h,
then the nitroalkane of choice was added in the listed excess
(5.0 mmol (305 mg, 368 mL) of nitromethane (9a), 3.0 mmol
(225 mg, 214 mL) of nitroethane (9b), 1.2 mmol (157 mg, 167 mL)
of 1-nitrohexane (9c), 1.4 mmol (192 mg, 160 mL) of a-nitro-
toluene (9d), or 1.2 mmol (160 mg, 133 mL) of ethyl a-nitro-
acetate (9e)). The reaction mixture was stirred at the appropriate
temperature (100 ꢀC for reactions with 9a, 110 ꢀC for 9b, c,
130 ꢀC for 9e, and 140 ꢀC for 9d) for 5 h, then poured into water
(50 mL) and neutralized with 25% aqueous ammonia. The
formed precipitate was ltered out and dried on air. Usually
10-Methyl-2,3-dihydro-12H-[1,4]dioxino[2,3-g]indolo[3,2-c]
quinoline (1cfa)
Yield 51% (via general procedure A). Colorless crystalline solid,
Rf 0.60 (acetone/benzene/ammonia 8 : 8 : 1). Decomposed
without melting at 380 ꢀC (DMF–dioxane). Lit decomp. 380 ꢀC.3g
1H NMR (400 MHz, DMSO) d 12.29 (s, 1H), 9.33 (s, 1H), 8.09 (d, J
¼ 8.0 Hz, 1H), 7.90 (s, 1H), 7.50 (c, 1H), 7.47 (c, 1H), 7.12 (dd, J ¼
8.0, 0.7 Hz, 1H), 4.39–4.41 (m, 4H), 2.51 (s, 3H); 13C NMR (101
MHz, DMSO) d 145.2, 143.4, 142.8, 141.3, 139.3, 139.0, 134.8,
122.0, 119.9, 119.6, 114.4, 113.2, 112.3, 111.6, 106.9, 64.4, 64.2,
21.7; HRMS (ES TOF) calcd for C18H15N2O2 (M + H)+ 291.1128,
found 291.1126 (0.7 ppm).
9-Chloro-11H-indolo[3,2-c]quinoline (1daa)
such material was sufficiently pure for all practical application, Yield 63% (via general procedure A). Colorless crystalline solid,
but for analytical purposes it could be additionally puried by Rf 0.60 (acetone/benzene/ammonia 8 : 8 : 1), mp 325 ꢀC with
ash column chromatography on silica gel, eluting with sublimation (dioxane), Lit mp 325 ꢀC.3g 1H NMR (400 MHz,
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DMSO) d 12.89 (br. s, 1H), 9.61 (s, 1H), 8.52 (dd, J ¼ 8.0, 1.2 Hz, yl)-2,5-diphenyl tetrazolium bromide) (Sigma, Bornem, Bel-
1H), 8.35 (d, J ¼ 8.4 Hz, 1H), 8.15 (dd, J ¼ 8.3, 0.6 Hz, 1H), 7.70– gium) mitochondrial reduction into formazan by living cells.
7.79 (m, 3H), 7.38 (dd, J ¼ 8.4, 1.9 Hz, 1H); 13C NMR (101 MHz, The optical density of the untreated control aer 72 h was
DMSO) d 145.6, 144.9, 140.4, 139.4, 130.0, 129.7, 128.4, 126.0, normalized as 100% of viable cells allowing determination of
122.2, 121.6, 121.0, 120.8, 117.0, 113.9, 111.6; HRMS (ES TOF) the concentration that reduced their global growth by 50% aer
calcd for C15H10ClN2 (M + H)+ 253.0527, found 253.0528 (0.6 72 h of treatment.
ppm).
Conflicts of interest
9-Chloro-2,3-dimethoxy-5-methyl-5H-indolo[3,2-c]quinoline
(1dea)
There are no conicts to declare.
Yield 61% (via general procedure A). Yellow crystalline solid, Rf
0.39 (acetone/benzene/ammonia 8 : 8 : 1), mp 270–271 ꢀC Acknowledgements
(dioxane–EtOH), Lit mp 270–271 ꢀC.3g 1H NMR (400 MHz,
DMSO) d 9.17 (s, 1H), 8.04–7.98 (m, 2H), 7.70 (d, J ¼ 1.8 Hz, 1H),
7.31 (s, 1H), 7.16 (dd, J ¼ 8.2, 1.9 Hz, 1H), 4.20 (s, 3H), 4.00 (s,
2H), 3.99 (s, 3H); 13C NMR (101 MHz, DMSO) d 155.5, 153.7,
This work was nanced by the Russian Science Foundation
(grant #17-73-10301).
151.2, 148.0, 136.8, 131.0, 129.5, 124.3, 120.6, 118.7, 117.3, Notes and references
115.1, 115.0, 103.3, 99.5, 56.0, 55.9, 42.5; HRMS (ES TOF) calcd
for C18H16ClN2O2 (M + H)+ 327.0895, found 327.0886 (2.8 ppm).
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9-Chloro-2,3-dimethoxy-11H-indolo[3,2-c]quinoline (1dda)
Yield 54% (viꢀa general procedure A). Off-white crystalline solid,
mp 309–310 C (acetone/hexane), Lit mp 309–310 C.3g Rf 0.55
ꢀ
(acetone/benzene/ammonia 8 : 8 : 1). 1H NMR (400 MHz,
DMSO) d 12.53 (s, 1H), 9.39 (s, 1H), 8.26 (d, J ¼ 8.4 Hz, 1H), 7.91
(s, 1H), 7.71 (d, J ¼ 1.6 Hz, 1H), 7.53 (s, 1H), 7.32 (dd, J ¼ 8.4,
1.5 Hz, 1H), 3.99 (s, 3H), 3.95 (s, 3H); 13C NMR (101 MHz,
DMSO) d 150.9, 148.8, 142.2, 142.2, 140.3, 139.3, 129.6, 121.3,
121.0, 120.5, 113.1, 111.3, 111.0, 109.2, 101.2, 55.8, 55.6; HRMS
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