Regioselective one-pot C-N coupling of substituted naphthoquinones: Selective intramolecular ring fusion of sulfonamides

Article abstract of DOI:10.1016/j.tet.2013.11.041

The first one-pot copper-catalyzed highly regioselective C-N bond formation between aryl/alkyl amines and sulfonamide-substituted naphthoquinones was accomplished. Facile chemoselective routes obtained diverse ring-opening 6-amino/anilino-naphthalen-dione-1-sulfonamides and ring-fused 6-amino/aniline-5H-naphth[1,8-cd]isothiazol-5-one,1,1-dioxides with great functional group tolerance. Regiochemistry was confirmed by 1D- and 2D-NMRs.

Full text of DOI:10.1016/j.tet.2013.11.041

Tetrahedron 70 (2014) 459e464
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective one-pot CeN coupling of substituted
naphthoquinones: selective intramolecular ring fusion
of sulfonamidesq
*
Wenying Yu, Chenglong Li
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 June 2013
Received in revised form 4 November 2013
Accepted 13 November 2013
Available online 20 November 2013
The first one-pot copper-catalyzed highly regioselective CeN bond formation between aryl/alkyl amines
and sulfonamide-substituted naphthoquinones was accomplished. Facile chemoselective routes obtained
diverse ring-opening 6-amino/anilino-naphthalen-dione-1-sulfonamides and ring-fused 6-amino/aniline-
5H-naphth[1,8-cd]isothiazol-5-one,1,1-dioxides with great functional group tolerance. Regiochemistry was
confirmed by 1D- and 2D-NMRs.
Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
Keywords:
Regioselective
Copper-catalyzed
CeN coupling
Ring fusion
Naphthoquinones
1. Introduction
Naphthoquinone is a prevalent scaffold found in a wide variety of
natural products and drug candidates, for example, vitamin K1 and
K2, JNK inhibitors plumbagin, shikonin, and isothiazoloanthrone
(1),1 antitumor agent aminonaphthoquinones (2),2 and antifungal
candidate aminonaphthalene-l,4-diones (3),3 etc. (Fig. 1). The sul-
fonamide chemical moiety is also present in various therapeutic
drugs,4 which contain both hydrogen bond donors (NH2) and ac-
ceptors (O]S]O). One sulfonamide group can form as many as
seven hydrogen bonds, which tends to form strong interactions
with certain protein targets, thus it becomes a commonly used
functional group in drug design and discovery.5 In our study, the
hybridization of naphthoquinone and sulfonamide group especially
provides a novel series of compounds as potential potent anticancer
agents.6
Fig. 1. Structures of naphthalene-1,4-dione derivatives.
Lots of efforts were spent on the synthesis of amines and ani-
lines with unsubstituted 1,4-naphthoquinone to give 2-amino/
anilino-naphthalene-1,4-dione.7e9 Once the 1,4-naphthoquinone is
substituted with groups (eOH, eNH2, eCl, eSO2NH2, eOMe,
etc.), CeN coupling at position 2 or 3 will lead to two different
regio-isomers, which raises the issue of regioselectivity. Two
general strategies for the preparation of regioselective amino-
naphthoquinone derivatives have been reported. First, nucleophilic
substitution reactions; for example, mono-halo (Br) or di-halo (2Cl/
2Br) substituted naphthoquinones react with amines to produce
regio-isomers;4,10e12 however, the methods usually suffer from low
yields and tedious purifications. Extra steps are required to prepare
q
This is an open-access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-No Derivative Works License, which per-
mits non-commercial use, distribution, and reproduction in any medium, provided
the original author and source are credited.
* Corresponding author. Tel.: þ1 614 247 8786; fax: þ1 614 292 2435; e-mail
address: Li.728@osu.edu (C. Li).
0040-4020/$ e see front matter Ó 2013 The Authors. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.041

460
W. Yu, C. Li / Tetrahedron 70 (2014) 459e464
the halo substituted naphthoquinones, which limited the choices of
substituted groups of naphthoquinones. Thus, the approach is not
applicable to sensitive groups, such as sulfonamide-substituted
naphthoquinones, which could not tolerate bromination or chlo-
rination. Second, oxidative coupling reactions; for example, gold
(Ⅲ) salt is used to catalyze the 1,4-nucleophilic addition of amines
to unsubstituted 5,8-quinolinedione.13 To synthesize regioselective
substituted naphthoquinones, more efficient and less costly ap-
proach still needs to be developed. To the best of our knowledge,
the coupling reaction between sulfonamide-substituted naph-
thoquinone derivatives and amines has never been reported so far.
We herein report one-pot reactions with great functional group
tolerance, incorporating highly regioselective coupling between
naphthoquinosulfonamide and aryl/alkyl amines, and chemo-
selective synthesis of ring-fused or ring-opening naphthoquinone
derivatives.
the reaction solutions. From the results (entries 3 and 4), water was
not a favorable solvent for the synthesis of ring-fused compound
2a; however, it did improve the yield of ring-opening compound 3a.
The yield of 3a was increased to 30% in 10% water/AcOH co-solvent,
80 ꢀC. In order to investigate the best solvent for the coupling re-
action, other solvents were tried, including THF and EtOH (entries 5,
6 and 8, 9), it turned out that glacial acetic acid was the best choice.
As Ce(Ⅲ) salt was also reported as an efficient catalyst for oxidative
coupling, we tried to compare the effects of Ce(Ⅲ) salts and Cu(II)
salts. Both catalysts have their own advantages.
A higher yield and less by-products were obtained by Cu(OAc)$
H2O catalysis than that by CeCl3. In the meanwhile, the reaction was
facilitated by catalyst CeCl3 at a relatively lower temperature, such
as room temperature. These provide an opportunity for reactions
with thermo-sensitive reactants/reagents.
2.2. The hydrolysis reaction from the ring-fused compound to
the ring-opening compound
2. Results and discussion
Recent studies on the oxidative coupling reactions of unsub-
stituted aminonaphthoquinone were reported that the use of Ce(Ⅲ)
salts in ethanol3 and Cu(II) salts in AcOH14,15 both in the presence of
oxygen resulted in good yields. These methodologies could avoid
the prehalogenation of the naphthoquinones and provide possible
alternative routes for the coupling reactions between naph-
thoquinosulfonamide and amines.
Since none of the above conditions led to a majority of the de-
sired compound 3a and the reaction temperature did not appear to
be the key reason for the cyclization of the sulfonamide group with
the adjacent ketone group, in order to free the sulfonamide group
from the fused ring, our initial attempts focused on hydrolysis of
the CeN double bond. Two hydrolysis solvent systems, acids and
bases, were tested. Since the pKa value of sulfonamide group is
about 16.1,16 a base solution, Et3N in THF, was first attempted to
hydrolyze the isothiazole ring. Different volume ratios of Et3N and
THF, from 10/90 to 100/0, were screened. However, no good yield of
the desired product was found. Then, the acidic system, trifluoro-
acetic acid (TFA), was chosen to convert 2a to 3a. A co-solvent TFA/
DCM/H2O (v/v/v: 1/8/1) was initially used to hydrolyze the fused
ring, when heated to reflux, resulting in the ring-opening product
3a in 16% yield. A subsequent screening of different solvent com-
binations, TFA/EtOH and TFA/AcOH, was performed. The yield of 3a
was increased to 33% in TFA/EtOH co-solvent at 40 ꢀC. After a fur-
ther systematic screening on reaction temperature, the fused ring
was found to be opened in a refluxed TFA/EtOH co-solvent, with
yield of 67% (Scheme 1).
2.1. Optimization of reaction conditions
To study concise routes on the regioselective coupling of naph-
thalene-5,8-dione-1-sulfonamide with aniline (Table 1), pre-
liminary attempts using either Cu(OAc)2$H2O as catalyst in AcOH at
60 ꢀC (entry 1) or CeCl3 as catalyst in ethanol (entry 9) at room
temperature were performed, resulting in the CeN direct amina-
tion of the desired C6-aminated products 3a and another ring-fused
product 2a, without C7-aminated regio-isomers. Initially, a screen-
ing of reaction temperature was done, and the yield of 2a was in-
creased to 71% at temperature 80 ꢀC (entry 2). Then an effort to
increase the yield of 3a was made. In order to avoid the dehydration
of the sulfonamide group, different ratios of water were added to
Table 1
Optimization of reaction conditions
Scheme 1. Preparation of ring-opening 6-amino/anilino-naphthalene-dione-1-
sulfonamide. Reaction conditions: TFA and EtOH.
Inspired by the hydrolysis reaction of 2a, a modified synthetic
method of 3a was re-built. Compound 1, aniline, and catalyst
Cu(OAc)2$H2O were reacted in a co-solvent system (TFA/AcOH v/v:
1/10) at 60 ꢀC for 3 h, resulting in pure product 3a, with yield 84%
and without the ring-fused byproduct 2a. Therefore, two distinct
reaction conditions were found to chemoselectively synthesize
either the ring-fused or the ring-opening products.
Reaction conditions: naphthalene-5,8-dione-1-sulfonamide
4 (237 mg, 1 mmol), aniline (0.36 mL, 1.2 mmol),
Cu(OAc)2.H2O (40 mg, 0.2 mmol).
Entry
Catalyst
Solvent
S1/S2a
T (ꢀC)
Yieldb (%)
(v/v, %)
(2a/3a)
1
2
3
4
5
6
7
8
9
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
Cu(OAc)2$H2O
CeCl3
AcOH
AcOH
AcOH/H2O
AcOH/H2O
THF
EtOH
AcOH
THF
EtOH
100
100
90/10
50/50
100
100
100
100
100
60
80
80
80
65
77
rt
26/20
71/Trace
27/30
11/15
37/10
41/8
35/13
21/16
32/11
2.3. The synthesis of ring-fused 6-amino/aniline-5H-naphth
[1,8-cd]isothiazol-5-one,1,1-dioxides
According to the established optimized conditions, firstly the
reactions of various alkyl/aryl amines to synthesize the ring-fused
product were explored (Table 2). A range of amines were toler-
ated under these conditions. For hetero-aryl amines, such as pyr-
idin-3-amine, the reaction gave the fused-ring product (2b) with
moderate yield in pure glacial acetic acid solvent condition. For
CeCl3
CeCl3
rt
rt
a
The volume percent of different solvent systems.
The crude products obtained were purified through a flash column of silica gel,
b
then recrystallized from EtOH/H2O(w2/1 v/v) or THF/H2O(w2/1 v/v). The yields
given in the table are for the first crop of crystals.

W. Yu, C. Li / Tetrahedron 70 (2014) 459e464
461
Table 2
Table 3
Scope of ring-fused 6-amino/aniline-5H-naphth[1,8-cd]isothiazol-5-one,1,1-dioxidesa,b
Scope of ring-opening 6-amino/aniline-naphthalene-5,8-dione-1-sulfonamidesa,c
aReaction conditions: naphthalene-5,8-dione-1-sulfonamide
(237 mg, 1 mmol), alkyl/aryl amine (1.2 mmol), Cu(OAc)2.H2O
(30 mg, 0.15 mmol) in co-solvent TFA/glacial acetic acid (0.05-
0.5 mL/5 mL v/v) at certain temperature, air. Reaction was
monitored by TLC detection. b3g was synthesized in co-solvent
water/ glacial acetic acid (0.5 mL/5mL v/v). cIsolated yields.
aReaction conditions: naphthalene-5,8-dione-1-sulfonamide
(237 mg, 1 mmol), alkyl/aryl amine (1.2 mmol), Cu(OAc)2.H2O
°
(40 mg, 0.2 mmol) in glacial acetic acid (5 mL) at 80-100 C, air.
Reaction was monitored by TLC detection. bIsolated yields.
aniline substituted with electron-withdrawing groups, such as 2-
chloro-4-nitroaniline, higher energy was required to cross the
transition state to synthesize 2c. The reaction did not happen until
the temperature was increased to 100 ꢀC. Intriguingly, both zwit-
terions, alkyl and aryl amines substituted with carboxyl group,
could react with naphthalene-5,8-dione-1-sulfonamide to synthe-
size 2e,f with high selectivity. A higher temperature and longer
time were required. It is also noteworthy that protected amine by
an ester bond, for instance, benzyl formate (Cbz) group, could also
smoothly react with naphthalene-5,8-dione-1-sulfonamide to give
corresponding product 2g in pure glacial acetic acid solvent con-
dition. So the tolerance of Cbz protected amines makes it possible to
selectively react with substrates with multiple amines. In all, the
reaction can tolerate different functional groups, including
electron-donating/withdrawing groups, alkyl/aryl amines, carboxyl
groups, and ester bonds, which provides an opportunity to syn-
thesize various coupled products.
did not give corresponding product 3g in the co-solvent TFA/
AcOH condition. Several by-products were observed. Finally, 3g was
synthesized in a co-solvent system of 10% water in glacial acetic
acid at 80 ꢀC.
2.5. The potential reaction mechanisms
Based upon the above results, plausible mechanisms are pro-
posed in Scheme 3. The oxidative coupling reaction initially in-
volves a Michael addition of alkyl/aryl amines to naphthalene-5,8-
dione-1-sulfonamide, catalyzed by Cu(II) salt. Subsequently, the
resulting copper hydroquinone complex might produce free radical
with the aid of the acetic acid and rearrange electrons and double
bonds, and then the desired ring-opening product is formed. The
resulting Cu(I) salt could be rescued by oxygen in air, and then re-
enters the oxidation coupling cycle. An alternative mechanism
could be that the copper hydroquinone complex might be pro-
tonated with the aid of the acetic acid and be oxidized by either
atmospheric oxygen or copper salt to produce the ring-opening
2.4. The synthesis of ring-opening 6-amino/aniline-naphtha-
lene-5,8-dione-1-sulfonamides
Next, the effective conditions were extended to diverse ring-
opening products as illustrated in Table 3 (3aeg). For the TFA/
AcOH co-solvent condition, alkyl and aryl amines with various
substituents could be converted to the desired products in good to
excellent yields. Subsequently, a screening of the ratios of TFA/
AcOH showed that the higher the percentage of TFA, the lower the
yield. To minimize the ring-fused product, but maximize the yield,
a volume ratio of TFA/AcOH, 1/10, is suitable for most of the prod-
ucts. For hetero-aryl amines, such as pyridin-3-amine, the ratio
could be decreased to 1% TFA in AcOH to increase the yield. For
aniline substituted with electron-withdrawing groups, such as 2-
chloro-4-nitroaniline, reaction temperature was increased to
80 ꢀC. For carboxyl group substituted alkyl and aryl amines, the co-
solvent was heated to reflux to completely consume the reagent
naphthalene-5,8-dione-1-sulfonamide. However, the reaction of
Cbz protected amine with naphthalene-5,8-dione-1-sulfonamide
Scheme 2. Control experiments to explore the reaction mechanism. Reaction condi-
tions: (a) Cu(OAc)2$H2O, AcOH, and H2O (v/v: 1/10), under N2 protection, heated to
80 ꢀC, 3 h; (b) AcOH and H2O (v/v: 1/10), under air condition, heated to 80 ꢀC, 3 h; (c)
Cu(OAc)2$H2O, AcOH, and H2O (v/v: 1/10), under air condition, heated to 80 ꢀC, 3 h.

462
W. Yu, C. Li / Tetrahedron 70 (2014) 459e464
4. Experimental section
4.1. General information
Reactions were monitored by thin layer chromatography with
fluorescent silica coated aluminum sheets. Melting points (mp)
were determined on a Thomas Hoover capillary melting point ap-
paratus. 1H NMR and 13C NMR spectra were recorded on Bruker
Avance 300 MHz and 400 MHz NMR spectrometers (Billerica, MA)
at room temperature using DMSO and (CD3)2CO as solvents.
Chemical shifts (
d) were reported in parts per million with the
solvent resonance as an internal standard (DMSO-d6:
d
¼2.49 ppm).
Abbreviations for signal couplings are: s, singlet; d, doublet; t,
triplet; m, multiplet. Chemical shifts of 13C NMR were reported in
ppm with the solvent as the internal standard (DMSO-d6:
d
¼40 ppm, (CD3)2CO-d6:
(ESI) was used as the ion source for high resolution mass mea-
surement. Analytical HPLC was carried out with a Gemini 5 C18
d
¼29.84 ppm). Electron spray ionization
m
110A Column (250ꢁ4.6 mm) supplied by Phenomenex Inc. CA, USA,
eluting with acetonitrile and water. The peaks were detected by UV
light of irradiation (254 nm).
4.2. Materials
All reactions were carried out under air atmosphere. All reagents
and solvents were obtained from commercial suppliers and used
without further purification. The solvents and reagents used in the
present study were purchased from commercial suppliers and were
used as received. Silica gel was purchased from SigmaeAldrich
Chemical Co. (Milwaukee,WI). Catalysts Cu(OAc)2$H2O and CeCl3,
alkyl/aryl amines were commercially available. Naphthalene-5,8-
dione-1-sulfonamide 1 was prepared according to previous litera-
ture6 with modified conditions. Unless otherwise indicated, all
other reagents and solvents were obtained from commercial sup-
pliers and used as received.
Synthetic procedure of naphthalene-5,8-dione-1-sulfonamide:
naphthalenesulfonylchloride (16.8 g, 74.3 mmol) was dissolved in
acetone (100 mL) and was stirred at 0 ꢀC for 5 min. Ammonium
hydroxide (100 mL) was dropped into the above mixture and stir-
red at room temperature for 3 h. Precipitated white crystals were
filtered then acetone was removed at reduced pressure. The residue
was washed in ethyl acetate (3ꢁ10 mL), producing a white solid
powder, which was used without further purification, yielding
naphthalenesulfonamide (15.9 g, 90.2%); mp (147e149 ꢀC). Naph-
thalenesulfonamide (500 mg, 2.41 mmol) was dissolved in slowly
warming glacial acetic acid (5.0 mL). The mixture was heated to
90 ꢀC and chromium trioxide (1.08 g, 10.85 mmol), which was
dissolved in a mixture of water and glacial acetic acid (3 mL, v/v: 1/
1), and added to the mixture solution. The above solution was
stirred under reflux for 18 min and quenched with iced water
(50 mL). The solution was cooled to 0 ꢀC and stirred 1 h at room
temperature. The precipitated yellow powder was filtered and the
remaining solution was extracted with ether (3ꢁ100 mL). The or-
ganic layer was collected, dried, and removed at reduced pressure.
The yellow powder was combined and purified with silica column
chromatography ethyl acetate/hexane (v/v: 2/3) to yield 1 (110 mg,
19%); mp (186e188 ꢀC).
Scheme 3. Plausible mechanisms of the regioselective CeN coupling and C]N double
bond ring fusion.
product. Control experiments were conducted to partially validate
the mechanisms (Scheme 2). When the reaction was protected by
nitrogen, trace amount (yield <5%) of desired products were syn-
thesized, which indicated that the molecular oxygen acts as the
oxidant. When the reaction was set up without catalyst Cu(II) salt,
no desired products were found. So Cu(II) can greatly facilitate the
reaction and assists to cross the transition state energy threshold.
When the reaction was set up without alkyl/aryl amines, no
cyclized products were found. So the condensation is triggered by
the oxidative coupling. It is also possible that the sulfonamide as an
electron-withdrawing group helps to determine the regiose-
lectivity of the reaction. And a stronger acidic medium TFA moves
the equilibrium from the ring fused state to the ring opening state.
2.6. The regiochemistry of the isomers
To identify the regiochemistry of the isomers, several one-
dimensional and two-dimensional NMRs were performed, in-
cluding H NMR, C NMR, DEPT-90, HMBC, HSQC, 1He1HCOSY
(Supplementary data). The amination coupling was identified at
position 6 but not 7.
3. Conclusion
In summary, we have reported a novel regioselective Cu(II)-
catalyzed direct amination of naphthalene-5,8-dione-1-sulfonamide
through CeN bond formation with excellent functional group
tolerance, which successfully avoids the halogenation of the naph-
thoquinone ring and protects the sulfonamide group. This study also
provides a selective method to synthesize both ring-fused 6-amino/
aniline-5H-naphth[1,8-cd]isothiazol-5-one,1,1-dioxides and ring-
opening 6-amino/anilino-naphthalene-5,8-dione-1-sulfonamide
products. This protocol could not only serve as a new avenue for
amination coupling of naphthoquinones with substituted sensitive
function groups, but also afford a facile approach for the synthesis of
various bioactive molecules. The possible mechanistic pathway is
also proposed.
Synthetic procedure of benzyl 4-(2-aminophenyl) piperazine-
1-carboxylate: 2-(piperazin-1-yl) benzenamine (0.56 mmol,
100 mg) was added to 10 mL of dichloromethane, then triethyl-
amine (1.15 mmol, 0.16 mL) was dropped to the reaction mixture
while stirred and cooled to 0 ꢀC. Benzyl chloroformate (0.51 mmol,
0.07 mL) was added dropwise to the reaction mixture and was
allowed to slowly warm to room temperature and stirring was
continued overnight. The reaction was monitored by TLC de-
tection, Rf¼0.3 (EtOAc/Hexane¼1/2, v/v). Reaction mixture was

W. Yu, C. Li / Tetrahedron 70 (2014) 459e464
463
then diluted with more DCM, washed twice with 1 M HCl and
twice with brine, dried with sodium sulfate, and then concentrated
at reduced pressure. The residue was purified with silica column
chromatography eluting with ethyl acetate/hexane (v/v: 1/4),
yellow oil (116 mg, 73%).
7.71e7.47 (m, 3H), 6.33 (s, 1H). 13C NMR (75 MHz, DMSO):
d
¼181.9,
161.9,144.8,137.3,136.4,136.2,134.2,131.7,130.1,129.8,129.4,128.5,
128.4, 128.4, 127.7, 126.0, 124.0, 123.9, 121.7, 107.6 ppm. HRMS (ESI)
of C20H12N2O3SNa [MþNa]þ calcd, 383.0466; found, 383.0453.
4.4.5. 6-(Cyclohexanecarboxylic acid-3-amino)-5H-naphth[1,8-cd]
isothiazol-5-one,1,1-dioxide (2e). The reactant amine is 3-
aminocyclohexanecarboxylic acid (172 mg, 1.2 mmol). The product
was purified bysilica gel column chromatographyeluting with DCM,
followed by DCM/EtOAc (v/v: 4/1), and then further purified by re-
crystallization. Red crystals (166 mg, yield: 46%); Rf¼0.3 (EtOAc/
Hexane/AcOH¼1/2/0.02, v/v/v); mp (>260 ꢀC). 1H NMR (300 MHz,
4.3. GeneralprocedureofCeNcouplingreactionofring-fused6-
amino/aniline-5H-naphth[1,8-cd]isothiazol-5-one,1,1-dioxides
Compound 1 (237 mg, 1 mmol), amine (1.2 mmol), and
Cu(OAc)2$H2O (40 mg, 0.2 mmol) were solubilized by gently
warming glacial acetic acid (5 mL) at 80e100 ꢀC for about 3e5 h,
monitored by TLC. After 1 was completely reacted, all the volatiles
were removed under reduced pressure. The resulting crude product
was applied to a flash column of silica gel, which was eluted with
DCM or other solvents as indicated in the description of each
product, then recrystallized in EtOH/H2O (v/v: 1/2) or THF/H2O (v/
v: 1/2) to give the ring-fused products (2aeg).
DMSO)
J¼7.6 Hz, 1H), 7.93 (t, J¼7.5 Hz, 1H), 6.30 (s, 1H), 2.12e1.76 (m, 4H),
1.58e1.17 (m, 6H). 13C NMR (100 MHz, (CD3)2CO):
d
12.16 (s, 1H), 8.59 (s, 1H), 8.27 (d, J¼7.5 Hz, 1H), 8.15 (d,
d
¼191.2, 176.1,
160.8, 151.5, 139.9, 134.4, 129.7, 102.5, 52.5, 42.3, 31.8, 24.7, 21.0,
14.7 ppm. HRMS (ESI) of C17H16N2O5SNa [MþNa]þ calcd, 383.0672;
found, 383.0648.
4.4. Characterization data of the ring-fused compounds
4.4.6. 6-(30-Phenylpropanoic acid-3-amino)-5H-naphth[1,8-cd]iso-
thiazol-5-one,1,1-dioxide (2f). The reactant amine is 3-(3-
aminophenyl) propanoic acid (198 mg, 1.2 mmol). The product
was purified by silica gel column chromatography eluting with
DCM, followed by DCM/EtOAc (v/v: 4/1), and then further purified
by recrystallization. Red crystals (214 mg, yield: 56%); Rf¼0.3
(EtOAc/Hexane/AcOH¼1/2/0.02, v/v/v); mp (>260 ꢀC). 1H NMR
4.4.1. 6-(Phenylamino)-5H-naphth[1,8-cd]isothiazol-5-one,1,1-
dioxide (2a). The reactant amine is aniline (0.11 mL, 1.2 mmol). The
product was purified by silica gel column chromatography eluting
with DCM, and then further purified by recrystallization. Red
crystals (220 mg, yield: 71%); Rf¼0.5 (EtOAc/Hexane¼1/2, v/v); mp
(>260 ꢀC). 1H NMR (300 MHz, DMSO)
d
9.78 (s, 1H), 8.39 (d,
(300 MHz, DMSO)
d
12.12 (s, 1H), 9.74 (s, 1H), 8.41 (d, J¼7.1 Hz, 1H),
J¼7.1 Hz, 1H), 8.04 (q, J¼7.3 Hz, 2H), 7.55e7.33 (m, 4H), 7.25 (t,
8.16e7.96 (m, 2H), 7.45e7.08 (m, 4H), 6.16 (s, 1H), 2.87 (t, J¼7.6 Hz,
J¼6.9 Hz,1H), 6.14 (s,1H). 13C NMR (75 MHz, DMSO):
d
¼181.4, 161.5,
2H), 2.57 (t, J¼7.3 Hz, 2H). 13C NMR (75 MHz, DMSO):
¼181.5,
d
144.6, 138.3, 136.8, 135.7, 129.9, 129.4, 129.0, 127.9, 126.2, 125.6,
124.4, 106.8 ppm. HRMS (ESI) of C16H10N2O3SNa [MþNa]þ calcd,
333.0304; found, 333.0329.
174.2, 162.9, 150.9, 144.7, 142.8, 138.1, 136.8, 135.9, 129.9, 129.3,
127.9, 127.5, 125.5, 124.4, 112.4, 36.3, 31.4 ppm. HRMS (ESI) of
C
19H14N2O5SNa [MþNa]þ calcd, 405.0516; found, 405.0520.
4.4.2. 6-(Pyridin-3-ylamino)-5H-naphth[1,8-cd]isothiazol-5-one,1,1-
dioxide (2b). The reactant amine is 3-amine-pyridine (113 mg,
1.2 mmol). The product was purified by silica gel column chroma-
tography eluting with DCM, followed by DCM/EtOAc (v/v: 8/1), and
then further purified by recrystallization. Bright red crystals
(96.5 mg, yield: 31%); Rf¼0.5 (EtOAc/Hexane¼1/1, v/v); mp
4.4.7. 6-(Benzyl carboxylate piperazine-40-phenyl-3-amino)-5H-
naphth[1,8-cd] isothiazol-5-one,1,1-dioxide (2g). The reactant amine
is benzyl 4-(2-aminophenyl) piperazine-1-carboxylate (373 mg,
1.2 mmol). The product was purified by silica gel column chroma-
tography eluting with Hexane/DCM (v/v: 1/4), followed by DCM, and
then further purified by recrystallization. Red crystals (396 mg,
yield: 75%); Rf¼0.3 (EtOAc/Hexane¼1/4, v/v); mp (>260 ꢀC). 1H NMR
(>260 ꢀC). 1H NMR (300 MHz, DMSO)
d 10.39 (s, 1H), 8.53 (s, 1H),
8.36 (d, J¼7.9 Hz, 1H), 8.26 (d, J¼7.9 Hz, 1H), 8.17e8.09 (m, 2H), 8.03
(300 MHz, DMSO)
d
9.16 (s, 1H), 8.42 (d, J¼7.1 Hz, 1H), 8.06 (dt,
(d,1H), 7.68 (t, J¼7.5 Hz,1H), 6.35 (s,1H). 13C NMR (75 MHz, DMSO):
J¼14.8, 7.3 Hz, 2H), 7.50e7.10 (m, 9H), 5.91 (s, 1H), 5.07 (s, 2H),
d
¼183.6, 166.8, 147.0, 146.4, 146.1, 143.2, 135.1, 133.8, 133.8, 131.6,
3.54e3.41 (m, 4H), 2.90e2.83 (m, 4H). 13C NMR (75 MHz, DMSO):
131.4, 130.9, 125.0, 108.4 ppm. HRMS (ESI) of C15H9N3O3SNa
d
¼181.3, 162.9, 161.8, 154.9, 154.7, 146.2, 142.5, 137.2, 136.8, 135.8,
[MþNa]þ calcd, 334.0257; found, 334.0261.
131.3,129.5,128.9,128.3,128.0,128.0,127.4,125.6,125.0,124.5,121.0,
107.9, 66.8, 51.1, 36.3, 31.3 ppm. HRMS (ESI) of C28H24N4O5SNa
[MþNa]þ calcd, 551.1360; found, 551.1294.
4.4.3. 6-(1-Chloro-3-nitrophenylamino)-5H-naphth[1,8-cd]iso-
thiazol-5-one,1,1-dioxide (2c). The reactant amine is 2-chloro-4-
nitroaniline (206 mg, 1.2 mmol). The product was purified by sil-
ica gel column chromatography eluting with DCM, followed by
4.5. General procedure of CeN coupling reaction of ring-
opening 6-amino/aniline-naphthalene-5,8-dione-1-
sulfonamides
a
DCM/EtOAc (v/v: 8/1), and then further purified by re-
crystallization. Orange crystals (346 mg, yield: 89%); Rf¼0.5
(EtOAc/Hexane¼1/1, v/v); mp (>260 ꢀC). 1H NMR (300 MHz,
Compound 1 (237 mg, 1 mmol), amine (1.2 mmol), and
Cu(OAc)2$H2O (40 mg, 0.2 mmol) were solubilized by gently
warming TFA and AcOH co-solvent (0.5 mL/5 mL, v/v), at 50 ꢀC to
reflux, monitored by TLC. After compound 1 was completely con-
sumed, all the volatiles were removed in vacuo to give crude
products, which were purified by flash chromatography on silica gel
and recrystallized in EtOH/H2O (v/v: 1/2) or THF/H2O (1/2 v/v) to
afford the ring-opening derivatives 3aeg.
DMSO)
d
10.19 (s, 1H), 8.51 (d, J¼2.0 Hz, 1H), 8.45e7.93 (m, 4H),
7.83 (d, J¼8.8 Hz, 1H), 6.15 (s, 1H). 13C NMR (75 MHz, DMSO):
d
¼177.6, 161.2, 149.9, 146.5, 141.2, 137.7, 134.8, 130.8, 129.9, 128.8,
127.0, 126.3, 124.2, 96.5 ppm. HRMS (ESI) of C16H8ClN3O5SNa
[MþNa]þ calcd, 411.9765; found, 411.9764.
4.4.4. 6-(Naphthyl-2-amino)-5H-naphth[1,8-cd]isothiazol-5-one,1,1-
dioxide (2d). The reactant amine is 2-naphthylamine (172 mg,
1.2 mmol). The product was purified by silica gel column chroma-
tography eluting with Hexane/DCM (v/v: 1/4), followed by DCM,
and then further purified by recrystallization. Red crystals (277 mg,
yield: 77%); Rf¼0.3 (DCM); mp (>260 ꢀC). 1H NMR (300 MHz,
4.6. Characterization data of the ring-opening compounds
(3aeg)
4.6.1. 5,8-Dioxo-6-(phenylamino)-5,8-dihydronaphthalene-1-
sulfonamide (3a). The reactant amine is aniline (0.11 mL, 1.2 mmol).
DMSO)
d
9.99 (s, 1H), 8.44 (dd, J¼7.2, 1.3 Hz, 1H), 8.17e7.90 (m, 6H),

464
W. Yu, C. Li / Tetrahedron 70 (2014) 459e464
The product was purified by silica gel column chromatography
eluting with DCM, followed by DCM/EtOAc (v/v: 8/1). Red crystals
(275 mg, yield: 84%); Rf¼0.6 (EtOAc/Hexane¼1/1, v/v); mp
was purified by silica gel column chromatography eluting with
DCM, followed by DCM/EtOAc (v/v: 4/1), and then further purified
by recrystallization. Red crystals (180 mg, yield: 45%); Rf¼0.3
(EtOAc/Hexane/AcOH¼1/1/0.02, v/v/v); mp (>260 ꢀC). 1H NMR
(>260 ꢀC). 1H NMR (300 MHz, DMSO)
d 9.46 (s, 1H), 8.48e8.31 (m,
2H), 7.95 (t, J¼6.9 Hz, 1H), 7.61e7.21 (m, 7H), 6.14 (s, 1H). 13C NMR
(300 MHz, DMSO) d 12.17 (s, 1H), 9.46 (s, 1H), 8.43e7.98 (m, 3H),
(75 MHz, DMSO):
d
¼181.7, 179.3, 144.9, 138.6, 137.2, 136.1, 130.3,
7.41e7.07 (m, 6H), 6.13 (s, 1H), 2.88e2.83 (t, J¼7.6 Hz, 2H),
129.9, 129.7, 129.5, 128.3, 126.5, 125.9, 124.8, 104.4 ppm. HRMS (ESI)
2.59e2.54 (t, J¼7.3 Hz, 2H). 13C NMR (75 MHz, DMSO):
¼181.9,
d
of C16H12N2O4SNa [MþNa]þ calcd, 351.0415; found, 351.0423.
174.6,143.3,138.7,136.1,130.2,128.4,126.6,125.7,124.7,122.5,107.0,
35.8, 31.5 ppm. HRMS (ESI) of C19H16N2O6SNa [MþNa]þ calcd,
423.0621; found, 423.0625.
4.6.2. 5,8-Dioxo-6-(pyridin-3-ylamino)-5,8-dihydronaphthalene-1-
sulfonamide (3b). The reactant amine is 3-amine-pyridine (113 mg,
1.2 mmol). The product was purified by silica gel column chroma-
tography eluting with DCM/EtOAc (v/v: 8/1), followed by DCM/
EtOAc (v/v: 2/1), then further purified by recrystallization. Bright
red crystals (286 mg, yield: 87%); Rf¼0.3 (EtOAc/Hexane¼2/1, v/v);
4.6.7. Benzyl 4-(3-(1,4-dioxo-5-sulfamoyl-1,4-dihydronaphthalen-2-
ylamino)phenyl) piperazine-1-carboxylate (3g). The reactant amine
is 4-(2-aminophenyl) piperazine-1-carboxylate (373 mg,1.2 mmol).
The product was purified by silica gel column chromatography
eluting with Hexane/DCM (v/v: 1/4), followed by DCM, and then
further purified by recrystallization. Red crystals (186 mg, yield:
34%); Rf¼0.3 (EtOAc/Hexane¼1/2, v/v); mp (>260 ꢀC). 1H NMR
mp (>260 ꢀC). 1H NMR (300 MHz, DMSO)
d 9.52 (s, 1H), 8.63 (s, 1H),
8.44 (d, J¼7.9 Hz, 2H), 8.35 (d, J¼7.5 Hz, 1H), 7.96 (t, J¼7.7 Hz, 1H),
7.84 (d, J¼7.7 Hz, 1H), 7.48 (s, 1H), 7.35 (s, 2H), 6.13 (s, 1H). 13C NMR
(75 MHz, DMSO):
d
¼183.1, 180.8, 145.9, 142.7, 134.6, 133.3, 133.3,
(300 MHz)
d
8.86 (s, 1H), 8.41 (dd, J¼26.3, 7.6 Hz, 2H), 7.97 (t,
131.1, 130.9, 130.4, 104.6 ppm. HRMS (ESI) of C15H11N3O4SNa
J¼7.9 Hz, 1H), 7.56e7.44 (m, 1H), 7.45e7.20 (m, 10H), 6.20 (s, 1H),
[MþNa]þ calcd, 352.0362; found, 352.0358.
5.11 (s, 2H), 3.62e3.48 (m, 4H), 2.87e2.74 (m, 4H). 13C NMR
(75 MHz, DMSO):
d
¼183.2, 181.0, 162.8, 157.9, 154.9, 146.3, 145.4,
4.6.3. 6-(1-Chloro-3-nitrophenylamino)-5H-naphth[1,8-cd]
iso-
143.5,142.7, 137.2,133.3, 131.7,130.8,128.9,127.1,126.4,124.9,123.2,
122.5, 104.6, 67.2, 51.5, 36.3, 31.2 ppm. HRMS (ESI) of
thiazol-5-one,1,1-dioxide (3c). The reactant amine is 2-chloro-4-
nitroaniline (206 mg, 1.2 mmol). The product was purified by sil-
ica gel column chromatography eluting with DCM, followed by
a DCM/EtOAc (v/v: 4/1), then further purified by recrystallization.
Orange crystals (313 mg, yield: 77%); Rf¼0.6 (EtOAc/Hexane¼2/1, v/
C
28H26N4O6SNa [MþNa]þ calcd, 569.1465; found, 569.1460.
Acknowledgements
v); mp (>260 ꢀC). 1H NMR (300 MHz, DMSO)
d 9.37 (s, 1H), 8.47 (d,
We are grateful to Dr. Sihui Long and Ryan Pavlovicz for paper
editing and mechanism discussion. We are grateful to Dr. Werner
Tjarks and Dr. Kinghorn for HPLC tests.
J¼2.5 Hz, 1H), 8.42 (d, J¼7.9 Hz, 1H), 8.27 (dd, J¼8.9, 2.7 Hz, 2H),
8.07 (s, 1H), 7.78 (d, J¼9.0 Hz, 1H), 7.40 (s, 2H), 6.02 (s, 1H). 13C NMR
(75 MHz, DMSO):
d
¼182.2, 180.2, 169.2, 146.2, 145.2, 143.2, 141.6,
136.1, 134.9, 133.3, 129.0, 127.8 ppm. HRMS (ESI) of
Supplementary data
C
16H10ClN3O6SNa [MþNa]þ calcd, 429.9871; found, 429.9866.
These data include 1H and 13C NMR and 2DNMR spectra of all
the final compounds described in this article. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.11.041.
4 . 6 . 4 . 6 - ( N a p h t h a l e n - 2 - y l a m i n o ) - 5 , 8 - d i o x o - 5 , 8 -
dihydronaphthalene-1-sulfonamide (3d). The reactant amine is 2-
naphthylamine (172 mg, 1.2 mmol). The product was purified by
silica gel column chromatography eluting with DCM, followed by
DCM/EtOAc (v/v: 8/1), and then further purified by re-
crystallization. Red crystals (238 mg, yield: 63%); Rf¼0.4 (EtOAc/
References and notes
Hexane¼1/1, v/v); mp (>260 ꢀC). 1H NMR (400 MHz, DMSO)
d 9.69
1. For examples of recent work, see: (a) Gong, K.; Li, W. Free radical Biol. Med. 2011,
51, 2259e2271; (b) Hsu, Y. L.; Cho, C. Y.; Kuo, P. L.; Huang, Y. T.; Lin, C. C. J.
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(s, 1H), 8.43e8.27 (m, 2H), 8.10e7.89 (m, 5H), 7.64e7.48 (m, 3H),
7.39 (s, 2H), 6.32 (s, 1H). 13C NMR (75 MHz, DMSO):
d
¼182.0, 181.7,
148.0, 143.6, 136.5, 135.7, 134.2, 133.1, 131.6, 130.3, 130.0, 128.6,
128.5, 128.4, 127.6, 126.7, 123.9, 121.4, 102.2 ppm. HRMS (ESI) of
2. For aminonaphthoquinones as antitumor agents, see: (a) Benites, J.; Valder-
rama, J. A.; Bettega, K.; Pedrosa, R. C.; Calderon, P. B.; Verrax, J. Eur. J. Med. Chem.
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8. Mosby, W. L.; Silva, M. L. J. Chem. Soc. (Resumed) 1964, 3990e3994.
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1317e1320.
10. Miguel del Corral, J. M.; Castro, M. A.; Gordaliza, M.; Martın, M. L.; Gualberto, S.
A.; Gamito, A. M.; Cuevas, C.; Feliciano, A. S. Bioorg. Med. Chem. 2005, 13,
631e644.
C
20H14N2O4SNa [MþNa]þ calcd, 401.0566; found, 401.0576.
4.6.5. 3-(1,4-Dioxo-5-sulfamoyl-1,4-dihydronaphthalen-2-ylamino)
cyclohexanecarboxylic acid (3e). The reactant amine is 3-
aminocyclohexanecarboxylic acid (172 mg, 1.2 mmol). The prod-
uct was purified by silica gel column chromatography eluting with
DCM, followed by DCM/EtOAc (v/v: 2/1), and then further purified
by recrystallization. Red crystals (223 mg, yield: 59%); Rf¼0.3
(EtOAc/Hexane/AcOH¼1/1/0.02, v/v/v); mp (>260 ꢀC). 1H NMR
(300 MHz, DMSO)
(m, 5H), 5.97 (s, 1H), 2.12e1.72 (m, 6H), 1.54e1.25 (m, 4H). 13C NMR
(75 MHz, (CD3)2CO):
d
12.10 (s, 1H),
d
8.33 (d, J¼7.1 Hz, 1H), 8.08e7.78
11. Thomson, R. H. J. Org. Chem. 1951, 16, 1082e1090.
12. Thomson, R. H. J. Org. Chem. 1947, 371e376.
13. Wang, S.; Jiang, C. Synlett 2009, 1099e1102.
14. Lisboa Cda, S.; Santos, V. G.; Vaz, B. G.; Lucas, N. C.; Eberlin, M. N.; Garden, S. J. J.
d
¼191.2, 179.1, 176.1, 150.9, 139.9, 134.5, 129.7,
127.8, 126.3, 92.6, 52.5, 42.4, 31.8, 24.8, 21.0, 14.7 ppm. HRMS (ESI)
of C17H18N2O6SNa [MþNa]þ calcd, 401.0778; found, 401.0796.
Org. Chem. 2011, 76, 5264e5273.
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4.6.6. 3-(3-(1,4-Dioxo-5-sulfamoyl-1,4-dihydronaphthalen-2-
ylamino)phenyl)propanoic acid (3f). The reactant amine is 3-(3-
aminophenyl)propanoic acid (198 mg, 1.2 mmol). The product