Ru(II)-catalyzed selective C-H amination of xanthones and chromones with sulfonyl azides: Synthesis and anticancer evaluation

Article abstract of DOI:10.1021/jo501709f

A ketone-assisted ruthenium-catalyzed selective amination of xanthones and chromones C-H bonds with sulfonyl azides is described. The reactions proceed efficiently with a broad range of substrates with excellent functional group compatibility. This protoc

Full text of DOI:10.1021/jo501709f

Article
pubs.acs.org/joc
Ru(II)-Catalyzed Selective C−H Amination of Xanthones and
Chromones with Sulfonyl Azides: Synthesis and Anticancer
Evaluation
Youngmi Shin,† Sangil Han,† Umasankar De,† Jihye Park,† Satyasheel Sharma,† Neeraj Kumar Mishra,†
Eui-Kyung Lee,† Youngil Lee,‡ Hyung Sik Kim,† and In Su Kim*,†
†School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea
‡Department of Chemistry, University of Ulsan, Ulsan 680-749, Republic of Korea
S
* Supporting Information
ABSTRACT: A ketone-assisted ruthenium-catalyzed selective
amination of xanthones and chromones C−H bonds with
sulfonyl azides is described. The reactions proceed efficiently
with a broad range of substrates with excellent functional
group compatibility. This protocol provides direct access to 1-
aminoxanthones, 5-aminochromones, and 5-aminoflavonoid
derivatives known to exhibit potent anticancer activity.
reaction via C−H bond activation has played a pivotal role for
carbon−carbon and carbon−heteroatom bond formation
reactions due to the minimization of stoichiometric metallic
waste and of the costs associated with substrate preactiva-
tion.13 Catalytic direct C−N bond formation via C−H bond
activation is one of the most important research topics
because of the prevalence of nitrogen-containing bioactive
molecules.14 Although great advances in catalytic C−H
amination or amidation reactions have been made, stoichio-
metric byproducts generated from external oxidants, bases,
and halide salts lead to the development of truly green
transformation.15,16 Chang and co-workers have made a
significant breakthrough for direct N-arylation via Rh(III)-
catalyzed amination reactions of sp2 C−H bonds using
sulfonyl, aryl, and alkyl azides as new amine equivalents
without external oxidants and bases.17 Recently, the Ir(III)-
catalyzed C−H amidation using sulfonyl and acyl azides has
been reported to give access to the corresponding amides.18
Since the pioneering report by Murai,19 ruthenium catalysts
have tremendously contributed to the discovery of cheaper
and efficient catalytic systems in C−H bond activation.20 In
this context, there has been a great deal of effort in the area of
Mirozoki−Heck-type reactions, redox-neutral biaryl synthesis,
hydroalkenylation, acylation, hydroxylation, and oxidative
annulations. Despite these achievements, however, the
ruthenium-catalyzed selective C−H amination reaction of
xanthones and chromones containing a weakly coordinating
ketone group still remains unexplored.21 Our continued efforts
INTRODUCTION
■
Xanthones (9H-xanthen-9-ones) and chromones (4H-chro-
men-4-ones) are among the most interesting discoveries in
the field of natural products and have attracted considerable
attention by virtue of their interesting biological properties.1
In fact, this class of compounds is known to have diverse
biological profiles, including antioxidant activity,2 topoisomer-
ase II inhibitory activity,3 antitumor activity,4 α-glucosidase
inhibitory activity,5 cholesterol acyltransferase inhibitory
activity,6 and antibacterial/antifungal activity.7 The biological
activities of these compounds are associated with their tri- and
bicyclic scaffolds but vary depending on the nature and/or
position of the different substituents. As a consequence, a
variety of synthetic analogues of xanthones and chromones
have been prepared and evaluated for clinical applications.1a,e,8
In particular, 1-aminoxanthones and 5-aminochromones have
shown promising antitumor properties against several cancer
cell lines. For example, 1-aminopyranoxanthone 1 and its
pyrazole-fused counterpart 2, respectively, displayed potent
antiproliferative activity toward the leukemia L1210 cell line
and solid tumor cell lines (Figure 1).9,10 The xantheno-
imidazole 3 showed significant inhibitory effect against the
human breast MDA-MB-231 cell line.11 In addition, amino-
flavone (NSC686288, 4) is a new anticancer drug that has
recently entered phase II clinical trials and exhibits potent
antitumor activity against MCF-7 human breast cancer cells
and neoplastic cells of renal origin.12
Organic chemists continue to strive toward the develop-
ment of atom and step economical processes for the synthesis
of complex molecular structures from simple precursors. In
this regard, transition-metal-catalyzed selective cross-coupling
Received: July 28, 2014
© XXXX American Chemical Society
A
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Figure 1. Structure of biologically active 1-aminoxanthones and 5-aminochromones.
a
Table 1. Selected Optimization of Reaction Conditions
b
yield (%)
entry
catalyst (mol %)
additive (mol %)
solvent
3a
12
3aa
1
2
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5)
DCE
trace
DCE
N.R.
N.R.
50
3
AgSbF6 (10)
DCE
4
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgNTf2 (10)
[Ru(p-cymene)Cl2]2 (2.5)
NaOAc (30)
DCE
trace
trace
3
5
CsOAc (30)
DCE
64
6
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (100)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
Cu(OAc)2 (30)
DCE
68
7
DCE
62
6
8
DCE
N.R.
75
9
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
[Ru(p-cymene)Cl2]2 (2.5), AgSbF6 (10)
DCE
14
2
10
11
12
13
THF
4
MeCN
DMSO
CH2Cl2
N.R.
N.R.
75
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), AgSbF6 or AgNTf2 (10 mol %), additive (quantity noted),
b
and solvent (1 mL) in pressure tubes. Isolated yield by flash column chromatography.
in transition-metal-catalyzed C−H bond activation and cross-
coupling reactions22 prompted us to explore the ruthenium-
catalyzed coupling reaction of xanthones and chromones with
sulfonyl azides and to evaluate the cytotoxic effect of
amination products against the human breast adenocarcinoma
MCF-7 cell line.
Ru catalysts generated from [Ru(p-cymene)Cl2]2 and silver
salts are unique in their ability to facilitate high levels of
conversion (Table 1, entries 7 and 8). Further study showed
that the increased loading of Cu additive displayed the
improved catalytic activity to afford monoaminated compound
3a and bisaminated compound 3aa in 89% combined yield,
albeit resulting in a low level of monoselectivity (5.4:1), as
shown in entry 9. After further optimization, we found that a
treatment of 2.5 mol % of [Ru(p-cymene)Cl2]2 and 10 mol %
of AgSbF6, in the presence of 30 mol % of Cu(OAc)2 in
CH2Cl2 solvent at 100 °C for 15 h provided the desired 1-
aminoxanthone 3a in high yield (75%) (Table 1, entries 10−
13).
Having established the optimized reaction conditions, the
substrate scope was examined with respect to xanthones and
their structural analogues (Table 2). The amidation reaction
of unsymmetrical xanthones 1b−1d with tosyl azide (2a)
occurred exclusively at the less sterically hindered position to
afford the corresponding products 3b−3d in moderate to
good yields. However, 2-fluoro-substituted xanthone 1e
furnished a separable mixture of 3e and 3ee, albeit providing
the regioisomers at C8 and C1 with a 3:1 ratio. These data
suggest that the steric effect of the substrates strongly
interferes with either the formation of the cycloruthenated
intermediate or the proximity of tosyl azide into the
RESULTS AND DISCUSSION
■
In our initial study, 9H-xanthen-9-ones (1a) and p-
toluenesulfonyl azide (2a) were chosen as model substrates
for optimizing the reaction conditions, and selected results are
summarized in Table 1. To our delight, the combination of
[Ru(p-cymene)Cl2]2 and AgSbF6 in DCE solvent promoted
the coupling of 1a and 2a to provide monoaminated
compound 3a in 12% isolated yield (Table 1, entry 1). In
the absence of either [Ru(p-cymene)Cl2]2 or AgSbF6, no
formation of product was detected, indicating that both
catalysts are required in the coupling reaction (Table 1,
entries 2 and 3). After screening of acetate additives under
otherwise identical conditions, Cu(OAc)2 was found to be
most effective in this coupling reaction, affording exclusively
monoaminated product 3a in 68% yield with a mono-
selectivity of 23:1, whereas other additives such as NaOAc
and CsOAc were less effective in the coupling reaction (Table
1, entries 4−6). Further investigations revealed that cationic
B
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ab c d
, , ,
Table 2. Scope of Xanthones
a
Reaction conditions: 1a−1j (0.3 mmol), 2a (0.45 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (30 mol %), CH2Cl2
b
c
d
(1 mL) in pressure tubes. Isolated yield by flash column chromatography. DCE was used as a solvent. 40 h.
cyclometalated intermediate. As expected, xanthone 1f with a
methoxy group at the C3 position exhibited poor
regioselectivity to afford an inseparable mixture of 3f and
3ff in 73% combined yield with a 1:1 ratio. The 2-substituted
xanthone 1g was found to be less reactive in this catalyst
system. Finally, xanthone analogues such as thioxanthone
(1h), acridinone (1i), and anthraquinone (1j) also smoothly
underwent amidation reaction to generate the corresponding
products 3h−3j, respectively.
To further examine the substrate scope of this process, a
broad range of azides was screened to couple with xanthone
(1a), as shown in Table 3. The reaction between 1a and
sulfonyl azides 2b−2j with either electron-rich or electron-
deficient groups, regardless of the substituent position on the
arene ring, was found to be favored in the amidation reaction
to afford the corresponding products 4b−4j in high yields.
Particulary, this transformation was compatible with acetani-
lide or bromo groups as versatile functionalities for further
cross-coupling reaction. It should be noted that the reaction
exclusively provided the monoaminated product in all cases,
and a trace amount (<5%) of bisaminated product was
observed by 1H NMR or GC-MS analysis. In contrast,
benzoyl azide (2k) and phenyl azide (2l) were unreactive
under the present reaction conditions.
fashion to that for ruthenium-catalyzed amination reaction of
xanthones. This reaction condition was also compatible with
C3- or C2-substituted chromones, furnishing the correspond-
ing products 6b and 6c. This protocol was also successfully
applied to highly substituted isoflavones 5d and 5e and
flavone 5f. In addition, C5-amidation reaction of 5a with a
wide range of sulfonyl azides proceeded smoothly to give the
corresponding products 6g−6l in moderate to good yields.
To demonstrate the further transformation of sufonyl amide
substituted xanthones and chromones, a N-sulfonyl group of
3a was removed under hydrolysis conditions to give 1-
aminoxanthone (7a) in 84% yield (Scheme 1).
Scheme 1. Deprotection of an N-Sulfonyl Group
After successful exploration of direct amidation of
xanthones with sulfonyl azides, we turned our attention to
C5-selective amidation of chromones due to structural
similarities between xanthones and chromones as well as
potent anticancer activity of 5-aminochromones (Table 4).
To our pleasure, chromone (5a) was efficiently coupled
with tosyl azide (2a) to produce our desired C5-aminated
product 6a in 61% yield under ruthenium catalysis. The
optimal reaction condition was obtained in a very similar
To obtain the mechanistic insight, we carried out an
intramolecular competition experiment of deuterio-1a with
tosyl azide (2a) under standard reaction conditions for 30
min, which results in a kinetic isotope effect (kH/kD) of 2.1
(Scheme 2), thus indicating that C−H bond cleavage might
be involved in the rate-determining step.23
A possible mechanistic pathway of the Ru-catalyzed
amidation reaction is proposed in Scheme 3. Initially, the
C
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a b
,
Table 3. Scope of Azides
a
Reaction conditions: 1a (0.3 mmol), 2b−2l (0.45 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (30 mol %), CH2Cl2
b
(1 mL) in pressure tubes. Isolated yield by flash column chromatography.
Scheme 2. Intramolecular Kinetic Isotope Experiment
removal of a chloride ligand by a Ag salt from the [RuCl2(p-
cymene)]2 complex initiates the catalytic reaction. Though the
exact role of Cu(OAc)2 is not clear, we believe that it
provides an OAc source to the active ruthenium species in
order to accelerate the ortho-metalation. The coordination of
the carbonyl oxygen in 1b with the active Ru(II) catalyst
delivers the metallacycle intermediate I.20 Subsequently, tosyl
azide coordinates with intermediate I to form the ruthenacycle
II, followed by migratory insertion of the sulfonamido moiety
with the evolution of N2 gas leads to the intermediate III.21e,h
Finally, the active ruthenium complex is generated by
protonolysis, and the amidation product 3b is obtained.
All the synthesized 1-aminoxanthones and 5-aminochro-
mones were screened for growth inhibition activity against
human breast cancer MCF-7 cells, and the results of
inhibitory activity are summarized in Table 5. Cancer cells
were exposed to increasing concentrations of compounds 3a−
3j, 4b−4j, and 6a−6l for 24 h, and cell survival was
determined using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide) assay.24 Several of the synthetic
1-aminoxanthones, e.g., 3e, 3ee, 3g, and 4j, showed promising
growth inhibition of MCF-7 cells. In particular, compounds
3ee and 3g displayed the most potent activities (IC50 = 5.26
μM for 3ee and IC50 = 5.12 μM for 3g) among the tested
compounds. The antiproliferative activities of 3ee and 3g were
about 1.5-fold stronger than that of the well-known anticancer
agent doxorubicin (IC50 = 7.57 μM) as a positive control.25
On the other hand, synthetic 5-aminochromones 6a−6i were
relatively less effective than 1-aminoxanthone derivatives for
MCF-7 cell growth inhibition. These results show that 1-
D
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a b
,
Table 4. Scope of Chromones
a
Reaction conditions: 5a−5f (0.3 mmol), sulfonyl azide (0.45 mmol), [Ru(p-cymene)Cl2]2 (2.5 mol %), AgSbF6 (10 mol %), Cu(OAc)2 (50 mol
b
%), DCE (1 mL) in pressure tubes. Isolated yield by flash column chromatography.
%) in CH2Cl2 (1 mL) was added tosyl azide (2a) (88.7 mg, 0.45
mmol, 150 mol %). The reaction mixture was allowed to stir at 100
°C for 15 h. After cooling at room temperature, the reaction mixture
was evaporated onto silica gel. Purification of the product by flash
column chromatography (SiO2: n-hexanes/EtOAc = 10:1) provided
3a (81.7 mg, 0.224 mmol, 75% yield) and 3aa (3.3 mg, 0.006 mmol,
2% yield), respectively.
4-Methyl-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (3a).
81.7 mg (75%); pale yellow solid; mp = 159−165 °C; 1H NMR
(700 MHz, CDCl3) δ 12.50 (s, 1H), 8.20 (dd, J = 8.1, 1.5 Hz, 1H),
7.81 (d, J = 8.4 Hz, 2H), 7.70−7.67 (m, 1H), 7.51 (t, J = 8.3 Hz,
1H), 7.46 (dd, J = 8.2, 1.0 Hz, 1H), 7.37 (dd, J = 8.4, 0.5 Hz, 1H),
7.34−7.32 (m, 1H), 7.20 (d, J = 8.1 Hz, 2H), 7.01 (dd, J = 8.3, 1.1
Hz, 1H), 2.30 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 180.5, 156.9,
155.3, 143.9, 140.9, 136.5, 135.7, 135.5, 129.7, 127.3, 126.4, 124.3,
121.0, 117.6, 111.4, 111.2, 109.3, 21.5; IR (KBr) υ 3032, 2920, 2169,
2005, 1627, 1604, 1568, 1467, 1382, 1296, 1232, 1152, 1047, 930,
883, 734 cm−1; HRMS (quadrupole, EI) m/z calcd for C20H15NO4S
[M]+ 365.0722, found 365.0718.
amidated xanthone derivatives represent a new class of strong
inhibitors against human breast cancer cells.
CONCLUSION
■
In conclusion, we described the ruthenium-catalyzed direct
C−H amination of xanthones and chromones with sulfonyl
azides. These transformations have been applied to a wide
range of substrates and typically proceed with an excellent
level of regio- and chemoselectivity as well as with high
functional group tolerance. Furthermore, synthetic 1-amino-
xanthones and 5-aminochromones were evaluated for in vitro
anticancer activity. Compounds 3ee and 3g proved to be
highly cytotoxic, with an activity competitive with anticancer
doxorubicin. Further detailed studies to determine the
biological mechanism of these compounds are currently
under investigation.
EXPERIMENTAL SECTION
N,N′-(9-Oxo-9H-xanthene-1,8-diyl)bis(4-methylbenzene-
■
sulfonamide) (3aa). 3.3 mg (2%); pale yellow solid; mp = 230−249
Typical Procedure for the Amidation of Xanthones (1a−1j)
with Sulfonyl Azides (2a−2l). To an oven-dried sealed tube with
9H-xanthen-9-one (1a) (58.9 mg, 0.3 mmol, 100 mol %), [Ru(p-
cymene)Cl2]2 (4.6 mg, 0.075 mmol, 2.5 mol %), AgSbF6 (10.3 mg,
0.03 mmol, 10 mol %), and Cu(OAc)2 (16.3 mg, 0.09 mmol, 30 mol
1
°C; H NMR (700 MHz, CDCl3) δ 11.98 (s, 2H), 7.84 (dd, J = 6.6,
1.7 Hz, 4H), 7.53 (t, J = 8.3 Hz, 2H), 7.48 (dd, J = 8.3, 1.1 Hz, 2H),
7.25 (dd, J = 8.5, 0.5 Hz, 4H), 6.97 (dd, J = 8.3, 1.0 Hz, 2H), 2.35
(s, 6H); 13C NMR (175 MHz, CDCl3) δ 184.0, 156.5, 144.5, 141.1,
E
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Scheme 3. Proposed Mechanistic Pathway
a
Table 5. Cytotoxicity of 1-Aminoxanthones and 5-Aminochromones with Human Breast Cancer Cells
compounds
IC50 (μM)
compounds
IC50 (μM)
compounds
IC50 (μM)
3a
>50
4b
4c
4d
4e
4f
20.53
>50
6c
>50
3b
3c
22.57
21.34
>50
6d
>50
>50
6e
>50
3d
3e
>50
6f
42.24
25.81
>50
9.26
>50
6g
3ee
3f/3ff
3g
5.26
4g
4h
4i
30.11
>50
6h
>50
6i
>50
5.12
>50
6j
>50
3h
3i
40.38
45.38
32.51
4j
5.44
26.68
24.77
6k
>50
6a
6b
6l
20.61
7.57
3j
doxorubicin
a
IC50 value: substance concentration necessary for 50% inhibition of cell viability.
136.7, 136.6, 130.0, 127.6, 111.8, 111.2, 109.0, 21.8; IR (KBr) υ
3355, 3259, 3054, 2923, 2167, 2025, 1600, 1475, 1385, 1299, 1155,
1092, 1037, 900, 815 cm−1; HRMS (quadrupole, EI) m/z calcd for
C27H22N2O6S2 [M]+ 534.0919, found 534.0919.
917, 810, 777 cm−1; HRMS (quadrupole, EI) m/z calcd for
C22H19NO4S [M]+ 393.1035, found 393.1045.
4-Methyl-N-(4,6,7-trimethyl-9-oxo-9H-xanthen-1-yl)benzene-
sulfonamide (3d). 58.7 mg (48%); pale yellow solid; mp = 222−231
1
°C; H NMR (700 MHz, CDCl3) δ 12.50 (s, 1H), 7.91 (s, 1H), 7.78
4-Methyl-N-(7-methyl-9-oxo-9H-xanthen-1-yl)benzene-
sulfonamide (3b). 79.7 mg (70%); light yellow solid; mp = 199−218
(d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.3 Hz, 1H), 7.34 (d, J = 8.4 Hz,
1H), 7.19 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 2.36 (s, 3H), 2.35 (s,
3H), 2.32 (s, 3H), 2.29 (s, 3H); 13C NMR (175 MHz, CDCl3) δ
180.6, 154.8, 153.8, 146.4, 143.6, 138.6, 136.7, 136.2, 133.5, 129.6,
127.4, 125.8, 120.5, 118.8, 117.8, 110.9, 109.4, 21.5, 20.6, 19.3, 15.5;
IR (KBr) υ 3027, 2920, 2156, 1982, 1625, 1595, 1487, 1466, 1367,
1282, 1232, 1157, 1089, 1071, 959, 889, 812 cm−1; HRMS
(quadrupole, EI) m/z calcd for C23H21NO4S [M]+ 407.1191, found
407.1194.
1
°C; H NMR (700 MHz, CDCl3) δ 12.55 (s, 1H), 8.01 (s, 1H), 7.82
(d, J = 8.3 Hz, 2H), 7.52−7.46 (m, 3H), 7.30 (d, J = 8.5 Hz, 1H),
7.20 (d, J = 8.1 Hz, 2H), 7.02 (dd, J = 8.3, 1.1 Hz, 1H), 2.44 (s,
3H), 2.31 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 180.6, 157.0,
153.6, 143.9, 141.0, 136.9, 136.6, 135.6, 134.2, 129.7, 127.4, 125.7,
120.8, 117.4, 111.4, 111.1, 109.4, 21.5, 20.9; IR (KBr) υ 3032, 2923,
2169, 2018, 1623, 1604, 1468, 1291, 1156, 1088, 1048, 965, 885,
806, 737 cm−1; HRMS (quadrupole, EI) m/z calcd for C21H17NO4S
[M]+ 379.0878, found 379.0878.
N-(7-Fluoro-9-oxo-9H-xanthen-1-yl)-4-methylbenzene-
sulfonamide (3e). 35.7 mg (31%); pale yellow solid; mp = 224−238
N-(6,7-Dimethyl-9-oxo-9H-xanthen-1-yl)-4-methylbenzene-
1
sulfonamide (3c). 51.9 mg (44%); light yellow solid; mp = 233−244
°C; H NMR (700 MHz, CDCl3) δ 11.85 (s, 1H), 8.22 (dd, J = 7.9,
1
°C; H NMR (700 MHz, CDCl3) δ 12.63 (s, 1H), 7.92 (s, 1H), 7.81
1.4 Hz, 1H), 7.44−7.37 (m, 3H), 7.26−7.24 (m, 2H), 7.16 (dd, J =
9.1, 3.6 Hz, 1H), 2.36 (s, 3H); 13C NMR (175 MHz, CDCl3) δ
180.3, 155.5, 152.8, 149.4 (d, JC−F = 245.5 Hz), 143.6, 137.7 (d, JC−F
= 23.9 Hz), 135.8, 129.2, 127.6 (d, JC−F = 13.7 Hz), 127.3, 126.5,
124.5, 123.8 (d, JC−F = 22.5 Hz), 120.6, 117.6, 113.4 (d, JC−F = 7.4
Hz), 112.4 (d, JC−F = 2.8 Hz), 21.5; IR (KBr) υ 3076, 2920, 2157,
2029, 1638, 1610, 1471, 1391, 1303, 1234, 1155, 1090, 886, 810, 753
(d, J = 8.3 Hz, 2H), 7.49−7.46 (m, 2H), 7.19 (d, J = 8.2 Hz, 2H),
7.15 (s, 1H), 6.99 (dd, J = 8.1, 1.1 Hz, 1H), 2.36 (s, 3H), 2.32 (s,
3H), 2.31 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 180.4, 156.9,
153.9, 146.5, 143.8, 140.9, 136.7, 135.3, 133.6, 129.7, 127.4, 125.9,
118.9, 117.7, 111.4, 111.0, 109.3, 21.5, 20.6, 19.3; IR (KBr) υ 3027,
2922, 2166, 2018, 1605, 1566, 1467, 1332, 1249, 1157, 1089, 1053,
F
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cm−1; HRMS (quadrupole, EI) m/z calcd for C20H14FNO4S [M]+
383.0628, found 383.0629.
8.21−8.20 (m, 1H), 8.00 (dd, J = 8.4, 1.1 Hz, 1H), 7.94 (dd, J = 7.6,
1.1 Hz, 1H), 7.81−7.76 (m, 4H), 7.63 (t, J = 8.0 Hz, 1H), 7.23 (d, J
= 8.1 Hz, 2H), 2.33 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 186.9,
182.3, 144.4, 141.3, 136.4, 135.5, 134.6, 134.4, 134.3, 132.8, 129.9,
127.5, 127.3, 127.1, 123.4, 122.4, 117.7, 21.5; IR (KBr) υ 3077, 3032,
2922, 2157, 2028, 1666, 1638, 1588, 1466, 1376, 1335, 1275, 1154,
1088, 1022, 912, 805, 707 cm−1; HRMS (quadrupole, EI) m/z calcd
for C21H15NO4S [M]+ 377.0722, found 377.0720.
N-(2-Fluoro-9-oxo-9H-xanthen-1-yl)-4-methylbenzene-
sulfonamide (3ee). 11.5 mg (10%); pale yellow solid; mp = 215−
1
221 °C; H NMR (700 MHz, CDCl3) δ 12.34 (s, 1H), 7.87 (dd, J =
8.2, 2.7 Hz, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.55 (t, J = 8.2 Hz, 1H),
7.49 (dd, J = 8.2, 0.9 Hz, 1H), 7.44−7.42 (m, 2H), 7.21 (d, J = 8.0
Hz, 2H), 7.05 (dd, J = 8.2, 0.9 Hz, 1H), 2.32 (s, 3H); 13C NMR
(175 MHz, CDCl3) δ 179.8, 158.8 (d, JC−F = 244.4 Hz), 156.9,
151.6, 144.0, 140.9, 136.5, 136.0, 129.7, 127.4, 123.8 (d, JC−F = 25.3
Hz), 122.0 (d, JC−F = 7.4 Hz), 119.7 (d, JC−F = 3.0 Hz), 111.4,
111.3, 111.2, 108.7, 21.5; IR (KBr) υ 3054, 2921, 2157, 2039, 1628,
1605, 1571, 1471, 1388, 1285, 1227, 1158, 1090, 1048, 881, 819
cm−1; HRMS (quadrupole, EI) m/z calcd for C20H14FNO4S [M]+
383.0628, found 383.0629.
N-(9-Oxo-9H-xanthen-1-yl)benzenesulfonamide (4b). 82.2 mg
1
(78%); pale yellow solid; mp = 168−170 °C; H NMR (700 MHz,
DMSO-d6) δ 12.58 (s, 1H), 8.19 (dd, J = 7.9, 1.6 Hz, 1H), 7.95−
7.94 (m, 2H), 7.89 (dt, J = 7.7, 1.6 Hz, 1H), 7.75 (t, J = 8.3 Hz,
1H), 7.64−7.61 (m, 2H), 7.58−7.56 (m, 2H), 7.51−7.49 (m, 1H),
7.37 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H); 13C NMR (175
MHz, DMSO-d6) δ 180.2, 156.4, 154.9, 139.8, 138.3, 136.6, 136.4,
133.7, 129.6, 127.0, 125.8, 124.7, 120.4, 117.8, 111.8, 110.6, 108.6;
IR (KBr) υ 3066, 2925, 2156, 2016, 1625, 1601, 1568, 1470, 1387,
1293, 1238, 1156, 1089, 929, 883, 753 cm−1; HRMS (quadrupole,
EI) m/z calcd for C19H13NO4S [M]+ 351.0565, found 351.0562.
4-Methoxy-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (4c).
90.4 mg (79%); pale yellow solid; mp = 163−168 °C; 1H NMR
(700 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.19 (dd, J = 7.9, 1.5 Hz,
1H), 7.90−7.87 (m, 3H), 7.47 (t, J = 8.3 Hz, 1H), 7.62 (d, J = 8.1
Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.24 (d,
J = 8.4 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 3.77 (s, 3H); 13C NMR
(175 MHz, DMSO-d6) δ 180.2, 163.0, 156.4, 154.9, 140.1, 136.6,
136.4, 129.8, 129.4, 125.8, 124.7, 120.4, 117.8, 114.7, 111.6, 110.5,
108.5, 55.7; IR (KBr) υ 3065, 2925, 1633, 1605, 1572, 1471, 1385,
1297, 1261, 1239, 1158, 1093, 1048, 930, 882, 783, 759 cm−1;
HRMS (quadrupole, EI) m/z calcd for C20H15NO5S [M]+ 381.0671,
found 381.0665.
N-(6-Methoxy-9-oxo-9H-xanthen-1-yl)-4-methylbenzene-
sulfonamide (3f) and N-(3-methoxy-9-oxo-9H-xanthen-1-yl)-4-
methylbenzenesulfonamide (3ff). 86.6 mg (73%); light yellow
1
solid; mp = 166−169 °C; H NMR (700 MHz, CDCl3) δ 12.67 (s,
1H), 12.65 (s, 1H), 8.20 (dd, J = 7.9, 1.4 Hz, 1H), 8.11 (d, J = 8.8
Hz, 1H), 7.81 (t, J = 8.4 Hz, 4H), 7.65 (dt, J = 7.7, 1.6 Hz, 1H),
6.98 (dd, J = 7.7, 1.6 Hz, 1H), 6.90 (dd, J = 8.9, 2.3 Hz, 1H), 6.76
(d, J = 2.3 Hz, 1H), 6.46 (s, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 2.32 (s,
3H), 2.31 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 179.5, 179.2,
165.6, 165.3, 158.6, 157.3, 156.9, 155.2, 143.9, 143.8, 142.4, 140.9,
136.6, 136.5, 135.1, 134.9, 129.7, 129.6, 127.9, 127.4, 127.3, 126.3,
124.1, 121.1, 117.3, 114.9, 113.8, 111.3, 111.1, 109.1, 103.9, 99.7,
99.2, 95.2, 55.9, 55.8, 21.6, 21.5; IR (KBr) υ 3058, 2932, 2180, 2028,
1601, 1566, 1466, 1440, 1319, 1232, 1148, 1088, 1049, 963, 883,
804, 769 cm−1; HRMS (quadrupole, EI) m/z calcd for C21H17NO5S
[M]+ 395.0827, found 395.0825.
4-Methyl-N-(12-oxo-12H-benzo[a]xanthen-11-yl)benzene-
N-(4-(N-(9-Oxo-9H-xanthen-1-yl)sulfamoyl)phenyl)acetamide
(4d). 84.5 mg (69%); light yellow solid; mp = 199−204 °C; 1H
NMR (700 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.32 (s, 1H), 8.20
(dd, J = 7.9, 1.6 Hz, 1H), 7.91−7.87 (m, 3H), 7.76−7.71 (m, 3H),
7.64 (d, J = 8.1 Hz, 1H), 7.52−7.49 (m, 1H), 7.34 (d, J = 8.2 Hz,
1H), 7.25 (d, J = 8.4 Hz, 1H), 2.02 (s, 3H); 13C NMR (175 MHz,
DMSO-d6) δ 180.2, 169.0, 156.4, 154.9, 143.8, 140.0, 136.6, 136.3,
131.6, 128.5, 125.9, 124.7, 120.4, 118.8, 117.9, 111.6, 110.4, 108.5,
24.0; IR (KBr) υ 3056, 2922, 2144, 2026, 1703, 1630, 1604, 1591,
1529, 1474, 1401, 1295, 1239, 1157, 1092, 1048, 930, 885, 736
cm−1; HRMS (quadrupole, EI) m/z calcd for C21H16N2O5S [M]+
408.0780, found 408.0780.
sulfonamide (3g). 32.4 mg (26%); light yellow solid; mp = 225−236
1
°C; H NMR (700 MHz, CDCl3) δ 12.89 (s, 1H), 9.92 (d, J = 8.6
Hz, 1H), 8.11 (d, J = 8.9 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.85 (d,
J = 8.4 Hz, 2H), 7.79−7.77 (m, 1H), 7.61−7.59 (m, 1H), 7.53−7.52
(m, 2H), 7.45 (d, J = 8.9 Hz, 1H), 7.19 (d, J = 8.2 Hz, 2H), 7.19
(dd, J = 7.0, 2.2 Hz, 1H), 2.29 (s, 3H); 13C NMR (175 MHz,
CDCl3) δ 182.3, 157.1, 155.6, 143.9, 140.7, 137.7, 136.7, 134.8,
130.6, 130.3, 130.0, 129.7, 128.7, 127.4, 126.8, 126.5, 117.4, 114.1,
111.9, 111.1, 110.9, 21.5; IR (KBr) υ 3021, 2920, 2157, 1981, 1626,
1590, 1485, 1468, 1336, 1244, 1152, 1090, 1037, 999, 891, 818, 751
cm−1; HRMS (quadrupole, EI) m/z calcd for C24H17NO4S [M]+
415.0878, found 415.0881.
4-Nitro-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (4e).
1
4-Methyl-N-(9-oxo-9H-thioxanthen-1-yl)benzenesulfonamide
88.0 mg (74%); yellow solid; mp = 210−213 °C; H NMR (700
1
(3h). 70.9 mg (62%); yellow solid; mp = 183−189 °C; H NMR
MHz, DMSO-d6) δ 12.80 (s, 1H), 8.36−8.34 (m, 2H), 8.23−8.19
(m, 3H), 7.93 (t, J = 8.5 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.63 (d,
J = 8.3 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H),
7.31 (d, J = 7.8 Hz, 1H); 13C NMR (175 MHz, DMSO-d6) δ 180.2,
156.5, 154.9, 150.2, 143.7, 139.2, 136.7, 136.5, 128.7, 125.8, 124.9,
124.8, 120.4, 117.8, 112.5, 110.9, 108.9; IR (KBr) υ 3098, 2922,
2186, 2015, 1628, 1606, 1529, 1467, 1348, 1299, 1231, 1161, 1089,
1046, 892, 849, 779, 734 cm−1; HRMS (quadrupole, EI) m/z calcd
for C19H12N2O6S [M]+ 396.0416, found 396.0415.
(700 MHz, CDCl3) δ 13.18 (s, 1H), 8.51 (dd, J = 8.1, 1.0 Hz, 1H),
7.80 (d, J = 8.3 Hz, 2H), 7.61−7.58 (m, 2H), 7.48−7.45 (m, 2H),
7.41 (t, J = 8.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 7.14 (dd, J = 8.0,
1.0 Hz, 1H), 2.30 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 183.9,
143.9, 143.4, 139.8, 136.6, 136.5, 133.2, 132.8, 130.0, 129.7, 129.3,
127.4, 126.6, 125.3, 120.0, 116.0, 114.9, 21.5; IR (KBr) υ 3071, 2922,
2156, 2004, 1582, 1443, 1340, 1285, 1219, 1157, 1086, 973, 916,
828, 744 cm−1; HRMS (quadrupole, EI) m/z calcd for C20H15NO3S2
[M]+ 381.0493, found 381.0490.
N-(9-Oxo-9H-xanthen-1-yl)-4-(trifluoromethyl)benzene-
4-Methyl-N-(10-methyl-9-oxo-9,10-dihydroacridin-1-yl)benzene-
sulfonamide (3i). 52.2 mg (44%); yellow solid; mp = 220−225 °C;
1H NMR (700 MHz, CDCl3) δ 13.98 (s, 1H), 8.39 (dd, J = 8.1, 1.5
sulfonamide (4f). 93.1 mg (74%); light yellow solid; mp = 144−147
1
°C; H NMR (700 MHz, DMSO-d6) δ 12.73 (s, 1H), 8.18−8.16 (m,
3H), 7.65 (d, J = 8.4 Hz, 2H), 7.89 (td, J = 7.7, 1.6 Hz, 1H), 7.75 (t,
J = 8.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H),
7.37 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H); 13C NMR (175
MHz, DMSO-d6) δ 180.2, 156.4, 154.9, 142.3, 139.3, 136.7, 136.5,
133.2 (q, JC−F = 32.5 Hz), 128.1, 126.9, 125.8, 124.7, 123.2 (q, JC−F
= 270.9 Hz), 120.3, 117.8, 112.3, 110.7, 108.7; IR (KBr) υ 3060,
2924, 2185, 2035, 1632, 1606, 1568, 1475, 1321, 1300, 1232, 1164,
1131, 1061, 931, 892, 850, 708 cm−1; HRMS (quadrupole, EI) m/z
calcd for C20H12F3NO4S [M]+ 419.0439, found 419.0439.
Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.68−7.67 (m, 1H), 7.45−7.44
(m, 2H), 7.32 (dd, J = 8.1, 0.6 Hz, 1H), 7.25−7.23 (m, 1H), 7.16
(d, J = 8.1 Hz, 2H), 6.99 (d, J = 8.5 Hz, 1H), 3.78 (s, 3H), 2.28 (s,
3H); 13C NMR (175 MHz, CDCl3) δ 180.8, 143.8, 143.5, 142.1,
141.8, 137.0, 134.6, 134.4, 129.5, 127.4, 127.3, 122.0, 121.8, 114.7,
109.9, 108.5, 108.3, 34.6, 21.5; IR (KBr) υ 3356, 3259, 2921, 2157,
2029, 1596, 1499, 1465, 1304, 1258, 1156, 1089, 1017, 930, 888, 812
cm−1; HRMS (quadrupole, EI) m/z calcd for C21H18N2O3S [M]+
378.1038, found 378.1045.
4-Bromo-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (4g).
1
114.9 mg (89%); yellow solid; mp = 177−180 °C; H NMR (700
N-(9,10-Dioxo-9,10-dihydroanthracen-1-yl)-4-methylbenzene-
sulfonamide (3j). 50.9 mg (45%); yellow solid; mp = 214−228 °C;
1H NMR (700 MHz, CDCl3) δ 12.16 (s, 1H), 8.27−8.25 (m, 1H),
MHz, DMSO-d6) δ 12.63 (s, 1H), 8.18 (dd, J = 7.9, 1.4 Hz, 1H),
7.90−7.87 (m, 3H), 7.84−7.74 (m, 3H), 7.62 (d, J = 8.4 Hz, 1H),
G
dx.doi.org/10.1021/jo501709f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.49 (t, J = 7.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.4
Hz, 1H); 13C NMR (175 MHz, DMSO-d6) δ 180.2, 156.4, 154.9,
139.5, 137.6, 136.6, 136.4, 132.7, 129.0, 127.7, 125.8, 124.7, 120.4,
117.8, 112.1, 110.7, 108.7; IR (KBr) υ 3087, 2917, 1633, 1605, 1569,
1471, 1385, 1300, 1239, 1159, 1087, 1048, 1006, 889, 756, 735
cm−1; HRMS (quadrupole, EI) m/z calcd for C19H12BrNO4S [M]+
428.9670, found 428.9677.
N-(9-Oxo-9H-xanthen-1-yl)naphthalene-2-sulfonamide (4h).
74.7 mg (62%); pale yellow solid; mp = 154−158 °C; 1H NMR
(700 MHz, CDCl3) δ 12.67 (s, 1H), 8.53 (s, 1H), 8.24 (dd, J = 7.9,
1.4 Hz, 1H), 7.92−7.89 (m, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.79 (d, J
= 7.9 Hz, 1H), 7.69 (dt, J = 7.6, 1.6 Hz, 1H), 7.56−7.49 (m, 4H),
7.38−7.34 (m, 2H), 7.01 (dd, J = 8.3, 1.1 Hz, 1H); 13C NMR (175
MHz, CDCl3) δ 180.8, 157.1, 155.5, 141.0, 136.5, 136.0, 135.7,
135.1, 132.1, 129.7, 129.5, 129.2, 129.1, 128.0, 127.7, 126.6, 124.5,
122.5, 121.3, 117.8, 111.7, 111.4, 109.5; IR (KBr) υ 3055, 2923,
2145, 2044, 1569, 1628, 1604, 1474, 1456, 1330, 1237, 1158, 1046,
930, 882, 733 cm−1; HRMS (quadrupole, EI) m/z calcd for
C23H15NO4S [M]+ 401.0722, found 401.0719.
3H); 13C NMR (175 MHz, CDCl3) δ 175.7, 156.9, 153.8, 144.1,
140.1, 136.3, 135.1, 129.7, 127.4, 112.9, 111.4, 110.9, 109.8, 21.5; IR
(KBr) υ 3088, 2924, 2208, 2035, 1628, 1603, 1569, 1480, 1346,
1279, 1158, 1091, 1025, 879, 804, 738 cm−1; HRMS (quadrupole,
EI) m/z calcd for C16H12BrNO4S [M]+ 392.9670, found 392.9669.
Benzyl 5-(4-Methylphenylsulfonamido)-4-oxo-4H-chromene-2-
carboxylate (6c). 68.8 mg (51%); light yellow solid; mp = 115−
1
118 °C; H NMR (700 MHz, CDCl3) δ 12.01 (s, 1H), 7.77 (d, J =
8.4 Hz, 2H), 7.54−7.53 (m, 2H), 7.41−7.36 (m, 5H), 7.20 (d, J =
8.5 Hz, 2H), 7.14−7.12 (m, 1H), 6.99 (s, 1H), 5.37 (s, 2H), 2.32 (s,
3H); 13C NMR (175 MHz, CDCl3) δ 181.8, 159.6, 156.7, 151.7,
144.1, 140.0, 136.3, 135.6, 134.2, 129.7, 129.0, 128.8, 128.6, 127.3,
114.8, 113.1, 112.2, 112.0, 68.6, 21.5; IR (KBr) υ 3054, 2922, 2851,
2194, 2021, 1745, 1640, 1607, 1486, 1466, 1334, 1253, 1153, 1120,
1089, 986, 808, 732 cm−1; HRMS (quadrupole, EI) m/z calcd for
C24H19NO6S [M]+ 449.0933, found 449.0939.
Benzyl 3-Methyl-5-(4-methylphenylsulfonamido)-4-oxo-2-phe-
nyl-4H-chromene-8-carboxylate (6d). 123.0 mg (76%); light yellow
1
solid; mp = 181−185 °C; H NMR (700 MHz, CDCl3) δ 13.23 (s,
1H), 8.07 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.3 Hz, 2H), 7.62 (d, J =
7.1 Hz, 2H), 7.41 (t, J = 8.8 Hz, 2H), 7.35 (d, J = 7.8 Hz, 2H),
7.25−7.23 (m, 5H), 7.17 (d, J = 8.0 Hz, 2H), 5.23 (s, 2H), 2.28 (s,
3H), 2.10 (s, 3H); 13C NMR (175 MHz, CDCl3) δ 181.9, 163.6,
161.1, 155.9, 143.3, 144.2, 137.6, 136.3, 135.5, 131.9, 130.8, 129.7,
129.3, 128.5, 128.4, 128.3, 128.2, 127.3, 117.4, 112.7, 110.1, 109.7,
67.0, 21.5, 11.3; IR (KBr) υ 3032, 2921, 2851, 2113, 2022, 1715,
1627, 1591, 1489, 1367, 1258, 1151, 1130, 1087, 1021, 981, 869,
804, 752 cm−1; HRMS (quadrupole, EI) m/z calcd for C31H25NO6S
[M]+ 539.1403, found 539.1398.
3-Chloro-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (4i).
92.6 mg (80%); pale yellow solid; mp = 139−142 °C; 1H NMR
(700 MHz, DMSO-d6) δ 12.62 (s, 1H), 8.16 (dd, J = 7.9, 1.4 Hz,
1H), 7.98 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.60 (t, J = 7.9 Hz, 2H),
7.49 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.4
Hz, 1H); 13C NMR (175 MHz, DMSO-d6) δ 180.1, 156.4, 154.8,
140.3, 139.4, 136.6, 136.4, 134.1, 133.8, 131.7, 126.6, 125.8, 125.7,
124.7, 120.3, 117.8, 112.2, 110.8, 108.7; IR (KBr) υ 3071, 2923,
1633, 1605, 1570, 1470, 1386, 1297, 1240, 1165, 1049, 930, 888,
784, 759 cm−1; HRMS (quadrupole, EI) m/z calcd for C19H12-
ClNO4S [M]+ 385.0176, found 385.0179.
N-(3-Methoxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen-5-yl)-4-
methylbenzenesulfonamide (6e). 46.1 mg (34%); light yellow solid;
2-Fluoro-N-(9-oxo-9H-xanthen-1-yl)benzenesulfonamide (4j).
1
1
mp = 173−192 °C; H NMR (700 MHz, CDCl3) δ 12.48 (s, 1H),
100.8 mg (91%); yellow solid; mp = 176−179 °C; H NMR (700
8.04 (d, J = 9.1 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.50−7.45 (m,
2H), 7.20 (d, J = 8.2 Hz, 2H), 7.07 (dd, J = 8.1, 1.2 Hz, 1H), 6.99
(d, J = 9.1 Hz, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 2.32 (s, 3H); 13C
NMR (175 MHz, CDCl3) δ 178.0, 161.9, 155.8, 155.6, 143.8, 140.0,
139.9, 136.6, 134.1, 130.2, 129.6, 127.3, 122.3, 114.1, 111.9, 111.7,
111.4, 59.9, 55.4, 21.5; IR (KBr) υ 3000, 2925, 2851, 2035, 1596,
1481, 1438, 1342, 1259, 1182, 1153, 1086, 993, 847, 807, 732 cm−1;
HRMS (quadrupole, EI) m/z calcd for C24H21NO6S [M]+ 451.1090,
found 451.1086.
MHz, DMSO-d6) δ 12.91 (s, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.06 (t,
J = 6.8 Hz, 1H), 7.90 (t, J = 8.4 Hz, 1H), 7.74−7.71 (m, 2H), 7.67−
7.62 (m, 2H), 7.51 (t, J = 7.4 Hz, 1H), 7.44−7.40 (m, 2H), 7.31 (d,
J = 8.1 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H); 13C NMR (175 MHz,
DMSO-d6) δ 180.2, 158.0 (d, JC−F = 252.5 Hz), 156.5, 156.4, 139.3,
136.9 (d, JC−F = 8.7 Hz), 136.5 (d, JC−F = 24.3 Hz), 134.5 (d, JC−F
7.7 Hz), 130.9, 128.3, 125.8, 124.8, 120.3, 117.8, 117.5 (d, JC−F
=
=
19.9 Hz), 116.9 (d, JC−F = 20.6 Hz), 112.0, 109.9, 108.4; IR (KBr) υ
2919, 2851, 2187, 2015, 1628, 1607, 1569, 1468, 1334, 1299, 1156,
1074, 891, 824, 759, 714 cm−1; HRMS (quadrupole, EI) m/z calcd
for C19H12FNO4S [M]+ 369.0471, found 369.0473.
N-(7-Methoxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-5-yl)-4-
methylbenzenesulfonamide (6f). 77.2 mg (57%); light yellow solid;
1
mp = 178−181 °C; H NMR (700 MHz, CDCl3) δ 12.66 (s, 1H),
Typical Procedure for the Amidation of Chromomes (5a−
5f) with Sulfonyl Azides (2a−2c, 2e, 2g, 2i, and 2j). To an
oven-dried sealed tube with 4H-chromen-4-ones (5a) (43.8 mg, 0.3
mmol, 100 mol %), [Ru(p-cymene)Cl2]2 (4.6 mg, 0.075 mmol, 2.5
mol %), AgSbF6 (10.3 mg, 0.03 mmol, 10 mol %), and Cu(OAc)2
(27.2 mg, 0.15 mmol, 50 mol %) in DCE (1 mL) was added tosyl
azide (2a) (88.7 mg, 0.45 mmol, 150 mol %). The reaction mixture
was allowed to stir at 100 °C for 6 h. After cooling at room
temperature, the reaction mixture was evaporated onto silica gel.
Purification of the product by flash column chromatography (SiO2:
n-hexanes/EtOAc = 2:1) provided 6a (57.7 mg, 0.183 mmol) in 61%
yield.
4-Methyl-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide (6a).
71.1 mg (72%); white solid; mp = 163−172 °C; 1H NMR (700
MHz, CDCl3) δ 12.31 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.74 (d, J =
5.9 Hz, 1H), 7.49−7.45 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.00 (dd,
J = 7.9, 1.4 Hz, 1H), 6.24 (d, J = 5.8 Hz, 1H), 2.32 (s, 3H); 13C
NMR (175 MHz, CDCl3) δ 181.4, 157.4, 155.3, 144.1, 140.3, 136.7,
134.8, 129.8, 127.5, 113.0, 112.7, 112.6, 111.8, 21.7; IR (KBr) υ
3354, 3258, 3054, 2921, 1631, 1480, 1380, 1285, 1153, 1089, 1004,
883 cm−1; HRMS (quadrupole, EI) m/z calcd for C16H13NO4S [M]+
315.0565, found 315.0573.
7.80 (d, J = 8.3 Hz, 2H), 7.77 (s, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.21
(d, J = 8.4 Hz, 2H), 7.10 (s, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.44 (s,
1H), 3.82 (s, 6H), 2.33 (s, 3H); 13C NMR (175 MHz, CDCl3) δ
179.2, 164.2, 159.8, 158.7, 151.7, 143.8, 141.8, 136.5, 130.2, 129.6,
127.4, 124.7, 123.0, 114.0, 106.4, 100.3. 95.0, 55.8, 55.3, 21.5; IR
(KBr) υ 3065, 2927, 2840, 2165, 2035, 1635, 1612, 1510, 1446,
1315, 1245, 1141, 1087, 963, 884, 814, 735 cm−1; HRMS
(quadrupole, EI) m/z calcd for C24H21NO6S [M]+ 451.1090, found
451.1088.
N-(4-Oxo-4H-chromen-5-yl)benzenesulfonamide (6g). 55.1 mg
(61%); white solid; mp = 150−153 °C; 1H NMR (700 MHz,
CDCl3) δ 12.36 (s, 1H), 7.90 (dd, J = 8.4, 1.1 Hz, 2H), 7.74 (d, J =
5.9 Hz, 1H), 7.51−7.46 (m, 3H), 7.41 (t, J = 8.1 Hz, 2H), 7.01 (d, J
= 7.4 Hz, 1H), 6.23 (d, J = 5.9 Hz, 1H); 13C NMR (175 MHz,
CDCl3) δ 181.2, 157.2, 155.2, 140.0, 139.4, 134.6, 133.0, 129.0,
127.2, 112.8, 112.6, 112.4, 111.8; IR (KBr) υ 3087, 2923, 2851,
2160, 2029, 1633, 1609, 1573, 1480, 1335, 1282, 1159, 1090, 1007,
883, 831, 760 cm−1; HRMS (quadrupole, EI) m/z calcd for
C15H11NO4S [M]+ 301.0409, found 301.0407.
4-Methoxy-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide
(6h). 53.7 mg (54%); light yellow solid; mp = 140−144 °C; 1H
NMR (700 MHz, CDCl3) δ 12.25 (s, 1H), 7.81 (d, J = 9.0 Hz, 2H),
7.73 (d, J = 5.8 Hz, 1H), 7.47−7.46 (m, 2H), 7.00−6.98 (m, 1H),
6.86 (d, J = 9.0 Hz, 2H), 6.22 (d, J = 5.8 Hz, 1H), 3.77 (s, 3H); 13C
NMR (175 MHz, CDCl3) δ 181.1, 163.1, 157.2, 155.1, 140.1, 134.5,
130.9, 129.4, 114.2, 112.8, 112.5, 112.4, 111.5, 55.5; IR (KBr) υ
N-(3-Bromo-4-oxo-4H-chromen-5-yl)-4-methylbenzene-
sulfonamide (6b). 49.7 mg (42%); light yellow solid; mp = 183−187
1
°C; H NMR (700 MHz, CDCl3) δ 11.99 (s, 1H), 8.12 (s, 1H), 7.79
(d, J = 8.4 Hz, 2H), 7.59 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.3 Hz,
1H), 7.21 (d, J = 7.9 Hz, 2H), 7.02 (d, J = 7.9 Hz, 1H), 2.33 (s,
H
dx.doi.org/10.1021/jo501709f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3055, 2927, 2928, 2158, 2011, 1641, 1596, 1482, 1337, 1261, 1156,
1092, 1003, 835, 730 cm−1; HRMS (quadrupole, EI) m/z calcd for
C16H13NO5S [M]+ 331.0514, found 331.0521.
of growth medium for 24 h. After medium removal, 100 μL of fresh
medium containing individual analogue compounds at different
concentrations was added to each well and incubated at 37 °C for 72
h. After 24 h of culture, the cells were supplemented with 10 μL of
test compounds dissolved in DMSO (less than 0.25% in each
preparation). After 24 h of incubation, 15 μL of the MTT reagent
was added to each well. After 4 h incubation at 37 °C, the
supernatant was aspirated, and the formazan crystals were dissolved
in 100 μL of DMSO at 37 °C for 10 min with gentle agitation. The
absorbance per well was measured at 540 nm using a VERSA max
Microplate Reader (Molecular Devices Corp., USA). The IC50 was
defined as the compound concentration required inhibiting cell
proliferation by 50% in comparison with cells treated with the
maximum amount of DMSO (0.25%) and considered as 100%
viability.
4-Nitro-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide (6i).
1
60.3 mg (58%); yellow solid; mp = 164−173 °C; H NMR (700
MHz, CDCl3) δ 12.56 (s, 1H), 8.24 (d, J = 8.9 Hz, 2H), 8.06 (d, J =
9.0 Hz, 2H), 7.78 (d, J = 5.8 Hz, 1H), 7.54−7.53 (m, 2H), 7.09 (dd,
J = 7.0, 2.4 Hz, 1H), 6.26 (d, J = 5.8 Hz, 1H); 13C NMR (175 MHz,
CDCl3) δ 181.2, 157.3, 155.5, 150.2, 145.1, 139.1, 134.8, 128.5,
124.3, 113.0, 112.8, 112.6; IR (KBr) υ 3013, 2923, 2853, 2169, 2015,
1637, 1609, 1572, 1532, 1482, 1347, 1281, 1162, 1085, 1003, 836,
737 cm−1; HRMS (quadrupole, EI) m/z calcd for C15H10N2O6S
[M]+ 346.0260, found 346.0264.
4-Bromo-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide (6j).
65.0 mg (57%); white solid; mp = 154−156 °C; 1H NMR (700
MHz, CDCl3) δ 12.40 (s, 1H), 7.76 (d, J = 5.8 Hz, 1H), 7.74 (d, J =
8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.50−7.49 (m, 2H), 7.05−
7.03 (m, 1H), 6.24 (d, J = 5.8 Hz, 1H); 13C NMR (175 MHz,
CDCl3) δ 181.2, 157.2, 155.3, 139.6, 138.4, 134.7, 132.3, 128.7,
128.1, 112.8, 112.7, 112.5, 112.2; IR (KBr) υ 3080, 2928, 2851,
2130, 2009, 1633, 1571, 1461, 1342, 1283, 1162, 1004, 829, 768, 731
cm−1; HRMS (quadrupole, EI) m/z calcd for C15H10BrNO4S [M]+
378.9514, found 378.9512.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all products, the selected
optimization of reaction conditions for chromone (5a), and
an intramolecular kinetic isotope experiment. This material is
available free of charge via the Internet at http://pubs.acs.org.
3-Chloro-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide (6k).
48.3 mg (48%); light yellow solid; mp = 164−173 °C; 1H NMR
(700 MHz, CDCl3) δ 12.46 (s, 1H), 7.86 (t, J = 7.8 Hz, 1H), 7.76
(d, J = 5.8 Hz, 2H), 7.52−7.44 (m, 3H), 7.36 (t, J = 7.9 Hz, 1H),
7.05 (dd, J = 8.1, 1.1 Hz, 1H), 6.25 (d, J = 5.8 Hz, 1H); 13C NMR
(175 MHz, CDCl3) δ 181.2, 157.2, 155.3, 141.2, 139.5, 135.2, 134.7,
133.2, 130.4, 127.3, 125.3, 112.8, 112.6, 112.4, 112.2; IR (KBr) υ
3263, 3080, 2921, 2852, 2223, 2009, 1638, 1613, 1574, 1482, 1342,
1284, 1161, 1112, 1078, 1005, 886, 836, 790 cm−1; HRMS
(quadrupole, EI) m/z calcd for C15H10ClNO4S [M]+ 335.0019,
found 335.0018.
AUTHOR INFORMATION
Corresponding Author
*Tel: +82-31-290-7788. Fax: +82-31-292-8800. E-mail:
insukim@skku.edu (I.S.K.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
2-Fluoro-N-(4-oxo-4H-chromen-5-yl)benzenesulfonamide (6l).
This research was supported by the Basic Science Research
Program through the National Research Foundation of Korea
(Nos. 2013R1A2A2A01005249 and 2013R1A1A2058800).
1
51.7 mg (54%); yellow solid; mp = 160−168 °C; H NMR (700
MHz, CDCl3) δ 12.71 (s, 1H), 7.97 (t, J = 7.3 Hz, 1H), 7.77 (d, J =
5.8 Hz, 1H), 7.52−7.49 (m, 1H), 7.45−7.41 (m, 2H), 7.24−7.21 (m,
1H), 7.08 (t, J = 9.1 Hz, 1H), 7.01 (dd, J = 7.4, 1.9 Hz, 1H), 6.27
(d, J = 5.9 Hz, 1H); 13C NMR (175 MHz, CDCl3) δ 181.0, 158.9
(d, JC−F = 256.1 Hz), 157.2, 155.2, 139.5, 135.5 (d, JC−F = 8.8 Hz),
134.5, 130.8, 127.2 (d, JC−F = 13.3 Hz), 124.2 (d, JC−F = 41.4 Hz),
117.3 (d, JC−F = 20.8 Hz), 112.8, 112.2, 111.8, 111.7; IR (KBr) υ
3324, 3236, 2922, 2851, 2225, 2011, 1636, 1474, 1343, 1263, 1167,
1125, 1005, 835, 735 cm−1; HRMS (quadrupole, EI) m/z calcd for
C15H10FNO4S [M]+ 319.0315, found 319.0309.
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dx.doi.org/10.1021/jo501709f | J. Org. Chem. XXXX, XXX, XXX−XXX

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