A Tandem Sulfonylation and Knoevenagel Condensation for the Preparation of Sulfocoumarin-3-carboxylates

Article abstract of DOI:10.1055/s-0037-1611703

Sulfocoumarins are key structural motifs in several bioactive molecules. Herein, we describe a simple, one-pot procedure for the synthesis of structurally diverse sulfonocoumarin-3-carboxylates by heating 2-hydroxyaryl aldehydes with an active sulfonyl chloride in the presence of pyridine. The process tolerates numerous functional groups including alkoxy, alkyl, halogen, nitro, and even nucleophilic phenolic hydroxy. Additionally, reactions of 2-hydroxyaryl ketones and 2-methylaminoaryl aldehydes give 4-substituted sulfocoumarins and 1-aza-2-sulfocoumarins, respectively. A gram-scale synthesis and further derivatizations are also reported. The ester group is easily removed via apper's decarboxylation.

Full text of DOI:10.1055/s-0037-1611703

SYNTHESIS
0
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1
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
Z. Dong et al.
Paper
Synthesis
A Tandem Sulfonylation and Knoevenagel Condensation for the
Preparation of Sulfocoumarin-3-carboxylates
Ziyang Dong ‡a
R2
O
Yang Chen ‡a
Zhiheng Yangb
Zhanhui Yang*a
Jiaxi Xu*a
Pyridine, DCE
85 °C, 1 h
CO2Et
O
R2
EtO2C
SO2Cl
R1
R1
+
S
0
0
0
0-
0
0
0
1-7
0
5
0-8
7
8
0
OH
O
O
R
1 = MeO
R2 = H
LiI, DMF
reflux
♠ Tandem reactions
♠ Mild conditions
♠ Excellent functional
group tolerance
Cl
a State Key Laboratory of Chemical Resource Engineering, Department of
Organic Chemistry, College of Science, Beijing University of Chemical
Technology, Beijing 100029, P. R. of China
zhyang@mail.buct.edu.cn
jxxu@mail.buct.edu.cn
b Department of Pharmacy, The First Affiliated Hospital, Zhengzhou
University, Zhengzhou 450052, P. R. of China
H
O
S
O
O
♠ Up to 90% yields
MeO
O
hCA II inhibitor
‡ These authors contributed equally to this work.
Received: 20.09.2018
Accepted after revision: 27.11.2018
Published online: 24.01.2019
N
N
N
N
DOI: 10.1055/s-0037-1611703; Art ID: ss-2018-h0636-op
O
S
O
S
MeO
O
Ar
O
O
O
O
S
I
II
Ar = 4-ClC6H4
III
Abstract Sulfocoumarins are key structural motifs in several bioactive
molecules. Herein, we describe a simple, one-pot procedure for the syn-
thesis of structurally diverse sulfonocoumarin-3-carboxylates by heat-
ing 2-hydroxyaryl aldehydes with an active sulfonyl chloride in the pres-
ence of pyridine. The process tolerates numerous functional groups
including alkoxy, alkyl, halogen, nitro, and even nucleophilic phenolic
hydroxy. Additionally, reactions of 2-hydroxyaryl ketones and 2-methyl-
aminoaryl aldehydes give 4-substituted sulfocoumarins and 1-aza-2-
sulfocoumarins, respectively. A gram-scale synthesis and further deri-
vatizations are also reported. The ester group is easily removed via
Happer’s decarboxylation.
O
O
hCA II inhibitor
Ki = 1.5 nM
ref. 1
hCA IX inhibitor, Ki = 8.8 nM
hCA XII inhibitor, Ki = 4.3 nM
hCA IX inhibitor, Ki = 9.1 nM
hCA XII inhibitor, Ki = 6.8 nM
ref. 2b
ref. 3
H
N
N
O
HO
O
S
O
S
O
V
O
O
O
O
IV
hCA IX inhibitor, Ki = 7.7 nM
hCA XII inhibitor, Ki = 2.1 nM
hCA VA inhibitor
Ki = 60 nM
ref. 4
ref. 5
Figure 1 Representative bioactive sulfocoumarins reported by Supuran’s
group
Key words sulfocoumarin-3-carboxylates, tandem reactions, sulfo-
nylation, Knoevenagel condensation, salicylaldehyde
Sulfocoumarins, the sulfonyl analogues of coumarins,
have been demonstrated as potent and selective inhibitors
of human carbonic anhydrases (hCA)1–6 and metalloen-
zymes.2 Recent work from the group of Zalubovskis and Su-
puran disclosed that 7-alkoxy- or 7-acyloxy-substituted
sulfocoumarins were inhibitors against the most abundant
and cytosolic hCA II,1 while 6-triazolyl-,2 6-tetrazolyl,3 6-
aryl-,4 6-amidyl-,5 and 6-alkoxy-substituted examples6
were inhibitors against tumor-associated hCA IX and XII.
Representative bioactive sulfocoumarins reported by
Supuran’s group are listed in Figure 1. 7-(2-Hydroxyethyl)-
substituted sulfocoumarin V also showed good inhibition
against the mitochondrial hCA VA.6 In organic chemistry,
sulfocoumarins also act as important building blocks for the
construction of valuable structures.7
Despite their importance, synthetic approaches toward
sulfocoumarins are very limited. In 1975, Hoogenboom and
co-workers synthesized 3-substituted sulfocoumarin deriv-
atives from different salicylaldehydes and α-substituted
methanesulfonates via a transesterification and condensa-
tion sequence (Scheme 1a).8 The conditions were depen-
dent on the substituent effect of not only the sulfonates, but
also the salicylaldehydes. In 2011, Ghandi’s group reported
the stepwise synthesis of 3-substituted sulfocoumarins
from salicylaldehydes and alkenesulfonyl chlorides
(Scheme 1b).9 These two methods are mainly restricted by
the inconvenient routes to access the sulfonyl reagents. In
2012, in response to the irreproducibility of literature pro-
cedures,10 Zalubovskis et al. developed an efficient proce-
dure to prepare 3,4-unsubstituted sulfocoumarins, which
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

B
Z. Dong et al.
Paper
Synthesis
featured the mesylation of salicylaldehydes, a DBU-cata-
lyzed aldol-type condensation, and POCl3-mediated dehy-
dration (Scheme 1c).11 This method was widely used in the
studies by Supuran and co-workers on the bioactivities of
structurally diverse sulfocoumarins.1–6 Despite these syn-
thetic advances, new methods to conveniently construct
structurally diverse sulfocoumarins are still in high de-
mand.
(a) Hoogenboom's syntheses in 1975
O
X
O
O
R1
Ph
S
X
H
O
R1
O
S
+
O
O
OH
30–82% yields
Conditions: (A) PhH, piperidine, reflux, 4–8 h;
(B) pyridine, steam heat, 24 h;
(C) acetone, K2CO3, anionic exchange resin, r.t.
X = PhCO, (A) or (B); X = PhNHCO, (A) or (C); X = 4-O2NC6H4, (A) or (B)
(b) Ghandi's syntheses in 2011
Over the past five years, our group has investigated the
chemistry of the sulfonyl moiety. We improved the synthet-
ic methods for the preparation of alkanesulfonyl chlo-
rides,12 and used them in mechanistic and stereochemical
studies on sulfa-Staudinger (sulfene-imine) cycloaddi-
tions.13 Our work on sulfonyl chlorides has also supported
our studies on the selectivity of C–H functionalizations of
diazosulfonamides.14 During these studies, we found that
the active sulfonyl chlorides could react with 2-hydroxy- or
2-aminobenzaldehydes to give the corresponding six-mem-
bered products in a one-pot fashion (Scheme 1d). The reac-
tion can be used to prepare not only 3- or 4-substituted sul-
focoumarins (X = O), but benzoazacycles (X = NR). Herein,
we present our synthetic studies on sulfocoumarin-3-car-
boxylates and their nitrogen analogues. The introduction of
the ester group significantly improves the electrophilicity
of the sp2 C4 carbon, and will allow potential transforma-
tions at the ester group, enabling future structural modifi-
cations.
O
O
O
O
Acetone, K2CO3
O
H
O
S
R1
R1
+
Cl
S
Ar
O
Ar
OH
Ar
DBU, MeOH
OMe
O
R1
O
S
O
O
(c) Zalubovskis's syntheses in 2012
OH
O
O
H
MsCl, base
DBU, DCM
R1
O
O
R1
R1
O
S
S
O
O
OH
R1
POCl3, pyridine
O
S
O
O
(d) This work: One-pot procedure, wide substrate scope
further transformation
R2
O
more electrophilic
CO2Et
R2
Pyridine
R1
R1
EtO2C
SO2Cl
+
O
S
O
DCE, 85 °C, 1 h
X
XH
X = O, R2 = H or alkyl
X = NR, R2 = H
The reaction between salicylaldehyde (1a) and ethyl
chlorosulfonylacetate (2) was used to perform the optimi-
zation (Table 1). Solvent screening with Et3N (2.4 equiv) as
the base revealed 1,2-dichloroethane (DCE) as the optimum
(entries 1–9). Nucleophilic solvents such as ethanol and
water gave no or a trace amount of the desired product, re-
spectively (entries 8 and 9), because they reacted with the
sulfonyl chloride. When 1.2 equivalents of Et3N was used,
only a trace amount of product was observed by TLC. Opti-
mization of the base was performed next. Inorganic bases
such as potassium carbonate and cesium carbonate gave
only trace and 5% yields, respectively, probably due to their
poor solubility in 1,2-dichloroethane (entries 10 and 11).
Scheme 1 Previous synthetic approaches toward sulfocoumarins and
this work
base. Furthermore, heating at 85 °C for 1 hour gave the
highest yield of 79% (entry 29). Prolonging the heating time
gave almost the same yields (75–78%) (entries 30–32).
Table 1 Optimization of the Reaction Conditions
O
CO2Et
Base (2.4 equiv)
H
EtO2C
SO2Cl
+
O
i
S
Strong organic bases, for example, DMAP, Pr2NEt, DABCO,
solvent, Temp, 12 h
O
OH
1a, 0.25 mmol
O
2
imidazole (Imid), N-methylimidazole (N-Me-Imid), and
1,1,3,3-tetramethylguanidine (TMG) gave yields ranging
from trace to 25% (entries 12–18). However, the weak or-
ganic bases quinoline and pyridine gave 54% and 56% yields,
respectively (entries 19 and 20). Different substituted pyri-
dines were also tested. 4-Methylpyridine (4-Me-Py) and
2,6-dimethylpyridine (2,6-diMe-Py) gave moderate yields
of 39% and 48% (entries 21 and 22), while 2,6-di-tert-bu-
tylpyridine (2,6-ditBu-Py) gave only a poor 6% yield (entry
23). The presence of fluorine or chlorine atoms at the 2-po-
sition of the pyridine ring completely inhibited the reac-
tions (entries 24–28). Thus, pyridine was the most suitable
1.2 equiv
3a
Entry
Solventa
Base (pKa)b
Temp (°C) Yield (%)c
1
2
3
4
5
6
7
8
9
PhMe
THF
Et3N (10.68)15
Et3N
25
25
25
25
25
25
25
25
25
17
22
MeCN
DCM
DCE
Et3N
12
Et3N
12
Et3N
25
EtOAc
CHCl3
H2O
Et3N
16
Et3N
19
Et3N
traced
trace
EtOH
Et3N
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Z. Dong et al.
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Synthesis
salicylaldehyde (1a) (pKa = 7.95)22 to the sulfene (see
Scheme S1 in the Supporting Information).
Table 1 (continued)
Entry
Solventa
Base (pKa)b
Temp (°C) Yield (%)c
With optimized conditions in hand, different 2-hy-
droxybenzaldehydes were reacted with sulfonyl chloride 2
to deliver sulfocoumarin-3-carboxylates 3 (Table 2). 4-Me-
thoxy- (1b) and 5-methoxysalicylaldehyde (1c) were con-
verted into the corresponding sulfocoumarins 3b and 3c in
77% and 66% yields, respectively (entries 2 and 3). However,
the reaction of 3,5-di-tert-butylsalicylaldehyde (1d) only
gave a 31% yield of the desired product 3d (entry 4), possi-
bly due to the large steric hindrance of the 3-tert-butyl
groups. The sulfonylation of 3-hydroxy-2-naphthaldehyde
(1e) and subsequent condensation occurred readily, deliv-
ering sulfocoumarin-3-carboxylate 3e in 75% yield (entry
5). 5-Fluoro- (1f), 3-fluoro- (1g), and 6-fluoro- (1h) salicyl-
aldehydes were converted into sulfocoumarins 3f, 3g, and
3h in 90%, 70%, and 53% yields, respectively (entries 6–8). 6-
Chloro- and 6-bromo-sulfocoumarins 3i and 3j were isolat-
ed in 61% and 66% yields, respectively, from the correspond-
ing salicylaldehydes 1i and 1j (entries 9 and 10). 3,5-Dibro-
mosalicylaldehyde (1k) and its iodo counterpart 1l readily
underwent the tandem reaction to produce sulfocoumarins
3k and 3l in 50% and 51% yields, respectively (entries 11
and 12). The presence of a nitro group para to the hydroxy
group of the aldehyde facilitated the formation of sulfocou-
marins, as demonstrated by the reactions of 1m and 1n (en-
tries 13 and 14). In these two cases, 84% and 85% yields
were obtained. 2,4-Dihydroxybenzaldehyde, with two free
hydroxy groups, selectively underwent the 2-sulfonylation
and subsequent condensation to give 7-hydroxysulfocou-
marin-3-carboxylate 3o in 61% yield (entry 15), even
though the amount of sulfonyl chloride and pyridine had
been doubled. Sulfonylation of the 4-hydroxy group also oc-
curred to give the 4-sulfonylated aldehyde in 8% yield. Our
present method provides a direct access to 7-hydroxysulfo-
coumarins, without protection and deprotection manipula-
tions. In Supuran’s report on the synthesis of 7-hydroxysul-
focoumarin using the method of Zalubovskis, tedious pro-
tection and deprotection manipulations were required.6
Generally, in the reactions of different 2-hydroxybenzal-
dehydes, sterically large substituents ortho to the hydroxy
or formyl group of 1 resulted in decreased yields of the sul-
focoumarins (entries 4, 11 and 12), because they to some
extent inhibit either the sulfonylation or Knoevenagel con-
densation step. However, the presence of electron-with-
drawing substituents at C-5 gave rise to high yields of the
corresponding sulfocoumarins (entries 6, 13 and 14), possi-
bly because of the increased acidity of the hydroxy group
and facile deprotonation to form nucleophilic phenoxide
anions.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29e
30f
31g
32h
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
K2CO3
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
85
85
85
85
trace
5
Cs2CO3
DMAP (9.87)15
iPr2NEt (10.75)16
DBU (11.6)15
DABCO (8.72)15
Imid (7.03)15
N-Me-Imid (7.12)15
TMG (13.6)17
quinoline (4.85)18
Py (5.37)15
6
10
25
25
20
trace
13
54
56
4-Me-Py (6.02)18
2,6-diMe-Py (6.70)17
2,6-ditBu-Py (3.58)18
4-Me-2-F-Py
6-Me-2-F-Py
2-F-5-Cl-Py
2-Cl-Py (0.49)19
2,6-diCl-Py
Py
39
48
6
trace
trace
trace
trace
trace
79
Py
78
Py
75
Py
75
a With the exception of water, all solvents were anhydrous.
b The pKa of the base (B) was recorded by measuring its conjugate acid
(BH+), see the cited references for details.
c Yield of isolated product.
d TLC indicated no product.
e Reaction time = 1 h.
f Reaction time = 2 h.
g Reaction time = 4 h.
h Reaction time = 8 h.
As shown in Table 1 (entries 5 and 12–28), the basicity
and nucleophilicity of the organic bases affected the yield of
sulfocoumarin 3a. The best yield was obtained at pKa = 5.37,
with greater or smaller values leading to decreased yields of
3a to different degrees (see Figure S1 in the Supporting In-
formation). An irregular yield–MCA (methyl cation affini-
ty)20 correlation was observed (see Figure S2 and Table S1 in
the Supporting Information). Probably, the yield of sulfo-
coumarin 3a was controlled by both the basicity and nucle-
ophilicity of the added organic base. The basicity should be
strong enough to dehydrochlorinate sulfonyl chloride 2 to
generate sulfene B,21 while the nucleophilicity should be
weak enough to not interrupt the nucleophilic addition of
Other sulfonyl chlorides, for example, ethanesulfonyl
chloride and phenylmethanesulfonyl chloride, did not un-
dergo the tandem reaction under the standard conditions
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

D
Z. Dong et al.
Paper
Synthesis
to afford the corresponding sulfocoumarin derivatives.
Switching to stronger bases such as triethylamine also
failed.
This process was not limited to 2-hydroxybenzalde-
hydes, as 2-hydroxyacetophenone (1p) also underwent the
cyclization to afford 4-methylsulfocoumarin-3-carboxylate
3p in 39% yield under the standard conditions (Scheme 2,
a). The low reaction rate was probably due to the slow con-
Table 2 Synthesis of Structurally Diverse Sulfocoumarin-3-carboxylates from 2-Hydroxy Aryl Aldehydesa
O
CO2Et
O
Pyridine (2.4 equiv)
DCE, 85 °C, 1 h
H
R1
R1
EtO2C
SO2Cl
+
S
O
OH
1, 0.5 mmol
O
2
1.2 equiv
3
Entry
1
Substrate
Product
Entry
9
Substrate
Product
O
O
CO2Et
O
Cl
CO2Et
O
Cl
H
H
S
S
S
S
O
O
O
O
OH
OH
3i, 61%
3a, 71%
1a
1i
O
O
CO2Et
O
Br
Br
CO2Et
O
Br
Br
H
H
H
S
S
2
3
10
11
MeO
MeO
O
O
O
O
MeO
OH
OH
O
3j, 66%
3b, 77%
1j
1b
O
CO2Et
O
CO2Et
O
MeO
H
O
O
O
O
OH
1k
OH
Br
3c, 66%
3k, 50%
1c
Br
O
O
tBu
CO2Et
O
I
CO2Et
O
tBu
I
H
H
S
S
4
5
6
12
13
14
15b
O
O
O
O
OH
OH
tBu
I
3l, 51%
tBu
3d, 31%
I
1l
1d
O
O
CO2Et
O2N
CO2Et
O
O2N
H
O
H
H
S
S
O
O
O
O
OH
OH
3m, 84%
3e, 75%
1m
1e
O
O2N
CO2Et
O
O
F
CO2Et
O
O2N
F
S
H
S
O
O
O
O
OH
Br
OH
3f, 90%
1f
3n, 85%
Br
1n
O
O
CO2Et
O
CO2Et
O
H
H
S
7
8
S
O
O
HO
O
O
OH
HO
OH
F
F
3o, 61%
3g, 70%
1o
1g
F
F
O
CO2Et
H
O
S
OH
3h, 53%
O
O
1h
a Yields of isolated products after column chromatography on silica gel.
b The amounts of sulfonyl chloride 2 and pyridine were doubled.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Z. Dong et al.
Paper
Synthesis
a)
O
CO2Et
O
Pyridine (2.4 equiv)
DCE, 85 °C, 1 h
EtO2C
SO2Cl
+
S
O
OH
O
2, 0.6 mmol
1p, 0.5 mmol
3p, 39%
b)
O
H
HO
H
HN
NH2
N
Pyridine
(2.4 equiv)
O
N
+
4a, 0.5 mmol
N
N
+
DCE,
N
85 °C, 1 h
N
EtO2C
SO2Cl
S
(
)-6
(
)-5
O
S
O
28%
CO2Et
O
15%
2, 0.6 mmol
CO2Et
O
O
c)
Pyridine (2.4 equiv)
DCE, 85 °C, 1 h
O
H
Hydrogen
bonding
+
EtO2C
SO2Cl
N
NH2
2, 0.6 mmol
O
CO2Et
S
4b, 0.5 mmol
O
7, 32%
H
d)
O
H
CO2Et
Pyridine (2.4 equiv)
DCE, 85 °C, 1 h
EtO2C
SO2Cl
+
O
O
S
N
N
H
2, 0.6 mmol
4c, 0.5 mmol
8, 74%
Scheme 2 Reactions of 2-hydroxyacetophenone (1p), 2-aminobenzaldehyde (4a), 2-aminoacetophenone (4b), and 2-methylaminobenzaldehyde (4c)
densation between the active methylene and the ketone
moiety. To our surprise, the reaction of 2-aminobenzalde-
hyde (4a) delivered tetramer 5 and trimer 6 in 15% and 28%
yield, respectively (Scheme 2, b). Such types of products
had been occasionally observed by several groups.23 The re-
action of 2-aminoacetophenone (4b) stopped at the sulfo-
nylation step, giving the corresponding sulfonamide 7 in
32% yield (Scheme 2, c). Most likely, it was either the intra-
molecular hydrogen bonding between the N–H and C=O
groups or the electronic and steric factors of the ketone
moiety that prevented the condensation. Gratifyingly, when
2-methylaminobenzaldehyde (4c) was submitted to the
standard conditions, the desired ring-closed product, cyclic
alkenesulfonamide 8, was isolated in 74% yield (Scheme 2, d).
In a gram-scale preparation, sulfocoumarin 3a was ob-
tained in 72% yield (1.37 g) (Scheme 3, a). Palladium-cata-
lyzed Suzuki coupling of 3j with phenylboronic acid gave 9
in 59% yield (Scheme 3, b), while reduction of the nitro
group in 3m delivered amine 10 in 84% yield (Scheme 3, c).
The ester groups were tolerated in the two derivations de-
scribed above. Reduction of the ester group in 3j with
NaBH4 or LiAlH4 failed. No reaction occurred with NaBH4,
while LiAlH4 gave unidentifiable mixtures. However, the re-
action of 3j with PhMgBr delivered the 1,4-addition prod-
uct 11 in 74% yield (Scheme 3, d). Decarboxylation of 3b by
refluxing in aqueous NaOH solution24 or by reflux in aque-
ous AcOH/HCl solution failed.25 Finally, using Happer’s de-
carboxylation procedure,26 3b was directly converted into
hCA II inhibitor 12 in 66% yield in only one step (Scheme 3, e).
In conclusion, a one-pot procedure for the synthesis of
sulfonocoumarin-3-carboxylates has been established by
heating 2-hydroxyaryl aldehydes with ethyl chlorosulfony-
lacetate in the presence of pyridine. The procedure consists
of two reactions, namely sulfonylation of phenolic hydroxy
groups and subsequent intramolecular Knoevenagel con-
densation. A number of structurally diverse products are
easily prepared. Functional groups such as alkoxy, alkyl,
halogen, nitro, and even nucleophilically active phenolic
hydroxy, are well tolerated. In addition, 2-hydroxyaryl ke-
tones and 2-(alkylamino)aryl aldehydes also serve as good
materials for the synthesis of 4-substituted sulfocoumarin
and 1-aza-2-sulfocoumarin derivatives, respectively. In
combination with Happer’s decarboxylation procedure, our
report also provides an efficient route to bioactive sulfocou-
marins.
Toluene and tetrahydrofuran were dried by refluxing over sodium
with diphenyl ketone as an indicator. Acetonitrile, dichloromethane,
1,2-dichloroethane, and ethyl acetate were dried by refluxing over
calcium hydride. Chloroform was dried over MgSO4 overnight. Etha-
nol was dried by refluxing over magnesium powder. All the solvents
were freshly distilled prior to use. Ethyl chlorosulfonylacetate (2) was
prepared according to our published procedures.13b–e,14a The other
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

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Z. Dong et al.
Paper
Synthesis
IR (film): 1716, 1567, 1449, 1376, 1332, 1179, 1013, 970, 755, 720
H
O
O
a)
cm–1
.
CO2Et
O
Pyridine (2.4 equiv)
H
1H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.62–7.31 (m, 4 H, ArH),
4.45 (q, J = 8.0 Hz, 2 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.8, 152.5, 142.2, 134.5, 131.1,
EtO2C
SO2Cl
+
DCE, 85 °C, 1 h
S
OH
O
2, 9 mmol
1a, 7.5 mmol
3a, 1.37 g, 72%
127.6, 126.34, 118.9, 118.9, 63.1, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H11O5S: 255.0322; found:
255.0326.
b)
H
H
Pd(PPh3)4 (20 mol%)
PhB(OH)2 (1.5 equiv)
K3PO4 (2 equiv)
Ph
CO2Et
Br
CO2Et
O
O
S
S
S
S
S
PhMe, N2, 100 °C, 20 h
O
O
H
O
O
Ethyl 7-Methoxybenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3b)
3j
9, 59%
H
c)
d)
Yield: 109 mg (77%); white solid; mp 167–169 °C; Rf = 0.35 (PE/EtOAc
= 5:1, v/v).
Fe, AcOH
O2N
CO2Et
O
H2N
CO2Et
O
H2O/EtOH, 75 °C, 1 h
IR (film): 1715, 1596, 1446, 1368, 1324, 1277, 1180, 1102, 826, 750
O
H
O
O
O
cm–1
.
3m
10, 84%
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.47–6.79 (m, 3 H, ArH),
4.42 (q, J = 8.0 Hz, 2 H), 3.90 (s, 3 H), 1.41 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 164.8, 160.1, 154.4, 142.5, 132.5,
123.8, 113.5, 111.9, 103.8, 62.8, 56.2, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H13O6S: 285.0427; found:
Ph
CO2Et
O
CO2Et
O
PhMgBr (3 equiv)
THF, r.t.
S
O
O
H
O
O
3j
trans-11, 74%, d.r. > 20:1
H
e)
285.0429.
H
CO2Et
O
LiI (2 equiv)
DMF, reflux
O
Ethyl 6-Methoxybenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3c)
S
S
MeO
O
MeO
O
O
O
3b
12, 66%, hCA II inhibitor
Yield: 94 mg (66%); light yellow solid; mp 118–120 °C; Rf = 0.15
(PE/EtOAc = 5:1, v/v).
IR (film): 1719, 1615, 1491, 1375, 1275, 1127, 856, 751 cm–1
Scheme 3 A gram-scale synthesis of 3a and further derivatizations of
sulfocoumarin-3-carboxylates 3b,j,m
.
1H NMR (400 MHz, CDCl3): δ = 8.02 (s, 1 H), 7.26–7.00 (m, 3 H, ArH),
4.45 (q, J = 8.0 Hz, 2 H), 3.85 (s, 3 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.8, 157.3, 146.3, 142.2, 128.0,
120.7, 119.9, 119.4, 114.2, 63.1, 56.0, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H13O6S: 285.0427; found:
chemicals used are commercially available. TLC analyses were per-
formed on Yantai Chemical Co., Ltd. silica gel GF254 plates with combi-
nations of petroleum ether (PE) and ethyl acetate (EA) as the eluent,
and the plates were visualized with UV light. Products were purified
by column chromatography using Qingdao Ocean Chemical Co., Ltd.
silica gel (200–300 mesh). Melting points were obtained on a Yanaco
MP-500 melting point apparatus and are uncorrected. IR spectra were
recorded on a Bruker FT-IR spectrometer on KBr pellets. 1H and 13C
NMR spectra were recorded on a Bruker 400 MHz spectrometer as
CDCl3 solutions with TMS as an internal standard. HRMS data were
obtained using a Agilent LC/MS TOF mass spectrometer.
285.0428.
Ethyl 6,8-Di-tert-butylbenzo[e][1,2]oxathiine-3-carboxylate 2,2-
Dioxide (3d)
Yield: 57 mg (31%); white solids; mp 110–112 °C; Rf = 0.60 (PE/EtOAc
= 5:1, v/v).
IR (film): 1726, 1614, 1583, 1468, 1383, 1252, 855, 756, 732 cm–1
1H NMR (400 MHz, CDCl3): δ = 8.05 (s, 1 H), 7.63–7.37 (m, 2 H, ArH),
.
Sulfocoumarin-3-carboxylates; General Procedure
To a heavy-walled reaction tube containing a magnetic stir bar were
sequentially added 2-hydroxyaryl aldehyde 1 (0.5 mmol), 1,2-dichlo-
roethane (3 mL), pyridine (98 μL, 1.2 mmol), and sulfonyl chloride 2
(112 mg, 0.6 mmol, dropwise addition). The resulting solution quickly
turned brown in color. The tube was quickly sealed with a screw cap
and placed in a preheated (85 °C) oil bath. After stirring for 1 h, the
mixture was cooled to room temperature and washed with 2 M HCl (8
mL) to remove the pyridine. The aqueous phase was washed with di-
chloromethane (5 mL). The combined organic phase was washed with
saturated NaHCO3 solution (15 mL), dried over Na2SO4, and concen-
trated under vacuum. The residue was submitted to column chroma-
tography over silica gel with PE/EtOAc as eluent to afford the pure
products 3.
4.44 (q, J = 8.0 Hz, 2 H), 1.48 (s, 9 H), 1.42 (t, J = 8.0 Hz, 3 H), 1.34 (s, 9
H).
13C NMR (101 MHz, CDCl3): δ = 160.0, 149.6, 148.9, 143.8, 139.9,
129.8, 126.5, 126.1, 119.3, 62.9, 35.2, 34.8, 31.2, 30.0, 29.3, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C19H27O5S: 367.1574; found:
367.1577.
Ethyl Naphtho[2,3-e][1,2]oxathiine-3-carboxylate 2,2-Dioxide (3e)
Yield: 114 mg (75%); yellow solid; mp 169–171 °C; Rf = 0.50 (PE/EtOAc
= 3:1, v/v).
IR (film): 1716, 1622, 1567, 1516, 1454, 1379, 1273, 819, 749 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.86 (s, 1 H), 8.24–7.42 (m, 6 H, ArH),
4.50 (q, J = 8.0 Hz, 2 H), 1.46 (t, J = 8.0 Hz, 3 H).
Ethyl Benzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide (3a)
13C NMR (101 MHz, CDCl3): δ = 160.2, 152.8, 138.4, 136.2, 131.0,
130.2, 129.5, 129.4, 125.0, 126.1, 121.9, 117.6, 113.2, 63.2, 14.2.
Yield: 85 mg (71%); white solid; mp 111–113 °C; Rf = 0.40 (PE/EtOAc =
3:1, v/v).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

G
Z. Dong et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C15H13O5S: 305.0478; found:
Ethyl 6-Bromobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
305.0471.
(3j)
Yield: 110 mg (66%); light brown solid; mp 170–171 °C; Rf = 0.45
Ethyl 6-Fluorobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(PE/EtOAc = 5:1, v/v).
(3f)
IR (film): 1718, 1598, 1486, 1378, 1276, 1180, 750 cm–1
.
Yield: 122 mg (90%); white solid; mp 112–114 °C; Rf = 0.50 (PE/EtOAc
= 5:1, v/v).
1H NMR (400 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.69–7.20 (m, 3 H, ArH),
4.46 (q, J = 8.0 Hz, 2 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.4, 151.3, 140.7, 137.0, 133.2,
128.7, 120.6, 120.4, 119.1, 63.4, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H10BrO5S: 332.9427; found:
IR (film): 1720, 1619, 1579, 1480, 1381, 1261, 751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.00 (s, 1 H), 7.32–7.28 (m, 3 H, ArH),
4.46 (q, J = 8.0 Hz, 2 H), 1.43 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.6 (d, JC–F = 247.8 Hz), 159.5, 148.4
(d, JC–F = 2.7 Hz), 141.0 (d, JC–F = 2.6 Hz), 128.8, 121.3 (d, JC–F = 24.2 Hz),
120.7 (d, JC–F = 8.4 Hz), 119.9 (d, JC–F = 8.9 Hz), 116.8 (d, JC–F = 24.6 Hz),
63.3, 14.1.
332.9428.
Ethyl 6,8-Dibromobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Diox-
ide (3k)
HRMS (ESI): m/z [M + H]+ calcd for C11H10FO5S: 273.0227; found:
273.0232.
Yield: 104 mg (50%); white solid; mp 149–151 °C; Rf = 0.50 (PE/EtOAc
= 5:1, v/v).
IR (film): 1715, 1612, 1549, 1442, 1381, 1276, 1172, 865, 755 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.93 (s, 1 H), 7.65 (s, 1 H),
4.46 (q, J = 8.0 Hz, 2 H), 1.43 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.0, 148.6, 140.3, 139.7, 132.2,
129.4, 121.3, 119.1, 113.9, 63.6, 14.1.
.
Ethyl 8-Fluorobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3g)
Yield: 95 mg (70%); white solid; mp 138–140 °C; Rf = 0.35 (PE/EtOAc =
5:1, v/v).
IR (film): 1721, 1608, 1476, 1385, 1365, 1265, 765 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H9Br2O5S: 410.8532; found:
410.8531.
1H NMR (400 MHz, CDCl3): δ = 8.07 (s, 1 H), 7.43–7.30 (m, 3 H, ArH),
4.46 (q, J = 8.0 Hz, 2 H), 1.43 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.4, 150.9 (d, JC–F = 254.9 Hz), 141.5
(d, JC–F = 3.2 Hz), 140.3 (d, JC–F = 13.2 Hz), 128.6, 126.5 (d, JC–F = 6.8 Hz),
126.0 (d, JC–F = 3.8 Hz), 121.5 (d, JC–F = 17.7 Hz), 120.7, 63.4, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H10FO5S: 273.0227; found:
273.0226.
Ethyl 6,8-Diiodobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3l)
Yield: 129 mg (51%); white solid; mp 190–192 °C; Rf = 0.50 (PE/EtOAc
= 5:1, v/v).
IR (film): 1716, 1613, 1387, 1276, 1173, 750 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.89 (s, 1 H), 7.82 (s, 1 H),
4.46 (q, J = 8.0 Hz, 2 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.1, 152.1, 150.9, 140.3, 139.1,
129.2, 121.1, 89.9, 87.4, 63.5, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H9I2O5S: 506.8255; found:
Ethyl 5-Fluorobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3h)
Yield: 72 mg (53%); white solid; mp 108–110 °C; Rf = 0.30 (PE/EtOAc =
5:1, v/v).
IR (film): 1724, 1614, 1472, 1385, 1275, 1184, 1068, 750 cm–1
.
506.8253.
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.61–7.08 (m, 3 H, ArH),
4.46 (q, J = 8.0 Hz, 2 H), 1.43 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.11 (d, JC–F = 260.8 Hz), 159.4,
152.6 (d, JC–F = 4.1 Hz), 135.3 (d, JC–F = 10.3 Hz), 135.0 (d, JC–F = 4.9 Hz),
127.9 (d, JC–F = 2.0 Hz), 114.7 (d, JC–F = 3.8 Hz), 112.9 (d, JC–F = 20.4 Hz),
109.1 (d, JC–F = 17.3 Hz), 63.3, 14.1.
Ethyl 6-Nitrobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3m)
Yield: 125 mg (84%); yellow solid; mp 193–195 °C; Rf = 0.45 (PE/EtOAc
= 5:1, v/v).
IR (film): 1716, 1614, 1575, 1384, 1347, 1265, 750 cm–1
.
HRMS (ESI): m/z [M + H]+ calcd for C11H10FO5S: 273.0227; found:
273.0222.
1H NMR (400 MHz, CDCl3): δ = 8.51–8.46 (m, 2 H, ArH), 8.14 (s, 1 H),
7.51–7.48 (m, 1 H, ArH), 4.49 (q, J = 8.0 Hz, 2 H), 1.44 (t, J = 8.0 Hz, 3
H).
Ethyl 6-Chlorobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
13C NMR (101 MHz, CDCl3): δ = 158.9, 155.9, 145.3, 140.1, 129.7,
(3i)
128.9, 126.7, 120.2, 119.1, 63.8, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H10NO7S: 300.0172; found:
Yield: 88 mg (61%); white solid; mp 159–160 °C; Rf = 0.40 (PE/EtOAc =
5:1, v/v).
300.0174.
IR (film): 1722, 1616, 1563, 1383, 1277, 1218, 1183, 751 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.55–7.29 (m, 3 H, ArH),
4.46 (q, J = 8.0 Hz, 2 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.4, 150.1, 140.8, 134.1, 131.8,
130.2, 128.7, 120.3, 120.0, 63.3, 14.0.
HRMS (ESI): m/z [M + H]+ calcd for C11H10ClO5S: 288.9932; found:
Ethyl 8-Bromo-6-nitrobenzo[e][1,2]oxathiine-3-carboxylate 2,2-
Dioxide (3n)
Yield: 161 mg (85%); light brown solid; mp 185–186 °C; Rf = 0.35
(PE/EtOAc = 5:1, v/v).
IR (film): 1724, 1609, 1543, 1391, 1275, 1212, 749 cm–1
.
288.9933.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

H
Z. Dong et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = = 8.67 (d, J = 1.6 Hz, 1 H), 8.46 (d, J = 1.6
Hz, 1 H), 8.13 (s, 1 H), 4.50 (q, J = 8.0 Hz, 2 H), 1.45 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 158.6, 153.3, 145.0, 139.9, 132.1,
130.1, 124.9, 112.0, 113.9, 64.0, 14.1.
HRMS (ESI): m/z [M + H]+ calcd for C11H9BrNO7S: 377.9278; found:
1H NMR (400 MHz, CDCl3): δ = 7.71 (d, J = 7.9 Hz, 1 H), 7.52–6.95 (m,
11 H), 6.36 (s, 1 H), 5.77 (s, 1 H), 5.71 (s, 1 H), 4.57 (d, J = 13.8 Hz, 1 H),
4.24–4.15 (m, 2 H), 4.10 (d, J = 13.8 Hz, 1 H), 3.26 (s, 1 H), 1.29 (t, J =
7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.5, 143.0, 141.8, 133.9, 129.9,
129.8, 129.6, 129.5, 129.0, 127.9, 127.3, 126.6, 125.3, 125.0, 124.7,
124.4, 124.1, 85.8, 72.6, 63.0, 62.5, 56.7, 14.0.
377.9283.
HRMS (ESI): m/z [M + H]+ calcd for C25H24N3O5S: 478.1431; found:
478.1435.
Ethyl 7-Hydroxybenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3o)
Yield: 83 mg (61%); light brown solid; mp 196–198 °C; Rf = 0.60
(PE/EtOAc = 1:1, v/v).
Ethyl 2-[N-(2-Acetylphenyl)sulfamoyl]acetate (7)
Yield: 43 mg (32%); brownish oil; Rf = 0.20 (PE/EtOAc = 5:1, v/v).
IR (film): 1741 (br), 1652, 1603, 1578, 1396, 1276, 1154, 750 cm–1
1H NMR (400 MHz, CDCl3): δ = 11.64 (s, 1 H), 7.97–7.18 (m, 4 H, ArH),
IR (film): 1719, 1598, 1508, 1447, 1371, 1214, 750 cm–1
1H NMR (400 MHz, acetone-d6): δ = 10.00 (s, 1 H), 8.12 (s, 1 H), 7.64–
6.71 (m, 3 H, ArH), 4.44 (q, J = 8.0 Hz, 2 H), 1.22 (t, J = 8.0 Hz, 3 H).
.
.
4.15 (q, J = 8.0 Hz, 2 H), 4.08 (s, 2 H), 2.69 (s, 3 H), 1.24 (t, J = 8.0 Hz, 3
H).
13C NMR (101 MHz, CDCl3): δ = 202.4, 162.4, 139.8, 135.3, 132.3,
123.2, 122.3, 117.9, 62.5, 55.6, 28.2, 13.9.
13C NMR (101 MHz, acetone-d6): δ = 164.6, 160.7, 155.3, 143.8, 134.6,
124.1, 115.3, 115.2, 112.2, 106.2, 106.1, 63.0, 14.4.
HRMS (ESI): m/z [M + H]+ calcd for C11H11O6S: 271.0271; found:
271.0276.
HRMS (ESI): m/z [M + H]+ calcd for C12H16NO5S: 286.0744; found:
286.0747.
Ethyl 4-Methylbenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(3p)
Ethyl 1-Methyl-1H-benzo[c][1,2]thiazine-3-carboxylate 2,2-Diox-
ide (8)
Yield: 52 mg (39%); white solid; mp 87–88 °C; Rf = 0.35 (PE/EtOAc =
5:1, v/v).
Yield: 99 mg (74%); yellow solid; mp 96–98 °C; Rf = 0.20 (PE/EtOAc =
5:1, v/v).
IR (film): 1719, 1596, 1561, 1449, 1377, 1241, 1178, 762 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.71–7.29 (m, 4 H, ArH), 4.44 (q, J = 8.0
Hz, 2 H), 2.64 (s, 3 H), 1.42 (t, J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.5, 150.4, 149.5, 133.5, 127.6,
127.1, 126.3, 121.8, 119.5, 62.9, 16.7, 14.1.
.
IR (film): 1719, 1613, 1562, 1455, 1368, 1335, 1211, 1151, 762 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.11 (s, 1 H), 7.61-7.54 (m, 2 H, ArH),
7.24-7.17 (m, 2 H, ArH), 4.44 (q, J = 8.0 Hz, 2 H), 3.54 (s, 3 H), 1.42 (t,
J = 8.0 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.4, 142.3, 142.2, 133.8, 132.0,
126.2, 123.1, 119.6, 116.3, 62.6, 30.7, 14.2.
HRMS (ESI): m/z [M + H]+ calcd for C12H13O5S: 269.0478; found:
269.0469.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO4S: 268.0638; found:
268.0647.
Ethyl 2-({13-[(2-Formylphenyl)amino]-6H,13H-6,12-[1,2]ben-
zenoquinazolino[3,4-a]quinazolin-7(11bH)-yl}sulfonyl)acetate (5)
Yield: 11 mg (15%); yellow solid; mp 138–140 °C; Rf = 0.7 (PE/EtOAc =
3:1, v/v).
Ethyl 6-Phenylbenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(9)
IR (film): 2930, 2826, 1717, 1698, 1653, 1521, 1508, 1374, 1275,
To a dry reaction tube were sequentially added 3j (31 mg, 0.1 mmol),
phenylboronic acid (18 mg, 0.15 mmol), K3PO4 (43 mg, 0.2 mmol),
and Pd(PPh3)4 (7 mg, 0.02 mmol). The tube was evacuated and back
filled with nitrogen (3 times). Next, dry toluene (1.5 ml) was added
and the mixture was heated at 100 °C for 20 h. After cooling, the mix-
ture was filtered through a pad of Celite, the solvent removed and the
residue purified by column chromatography over silica gel to give the
title product.
1030, 750 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.97 (s, 1 H), 9.05 (d, J = 4.6 Hz, 1 H),
7.87–7.63 (m, 4 H), 7.45–6.93 (m, 12 H), 6.39 (s, 1 H), 5.80 (d, J = 4.7
Hz, 1 H), 5.75 (s, 1 H), 4.60 (d, J = 13.8 Hz, 1 H), 4.27–4.14 (m, 2 H),
4.09 (d, J = 13.8 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 194.7, 162.5, 148.7, 143.5, 143.0,
136.8, 136.0, 133.8, 130.0, 129.8, 129.3, 129.2, 129.1, 128.2, 126.9,
126.6, 125.7, 124.7, 124.5, 123.1, 119.8, 117.6, 113.4, 73.2, 73.1, 62.9,
62.5, 56.7, 29.7, 14.0.
Yield: 18 mg (59%); yellow solid; mp 134–136 °C; Rf = 0.4 (PE/EtOAc =
1:1, v/v).
HRMS (ESI): m/z [M + H]+ calcd for C32H29N4O5S: 581.1854; found:
581.1862.
IR (film): 1719, 1613, 1576, 1479, 1380, 1251, 1174, 834, 764, 719
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.79 (dd, J = 8.5, 2.2 Hz, 1
H), 7.73 (d, J = 2.2 Hz, 1 H), 7.57–7.52 (m, 2 H), 7.52–7.46 (m, 2 H),
7.45–7.36 (m, 2 H), 4.46 (q, J = 7.1 Hz, 2 H), 1.43 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 159.8, 151.7, 142.3, 140.0, 138.5,
133.2, 129.3, 129.2, 128.4, 127.9, 127.1, 119.3, 115.3, 63.2, 14.1.
Ethyl 2-[(13-Hydroxy-6H,13H-6,12-[1,2]benzenoquinazolino[3,4-
a]quinazolin-7(11bH)-yl)sulfonyl]acetate (6)
Yield: 22 mg (28%); yellow solid; mp 175–178 °C; Rf = 0.2 (PE/EtOAc =
3:1, v/v).
IR (film): 1740, 1605, 1484, 1455, 1366, 1275, 1156, 1053, 1029, 762
HRMS (ESI): m/z [M + H]+ calcd for C17H15O5S: 331.0635; found:
331.0640.
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–J

I
Z. Dong et al.
Paper
Synthesis
Ethyl 6-Aminobenzo[e][1,2]oxathiine-3-carboxylate 2,2-Dioxide
(10)
1H NMR (400 MHz, CDCl3): δ = 7.32 (d, J = 8.6 Hz, 1 H), 7.19 (d, J = 10.2
Hz, 1 H), 6.83 (dd, J = 8.5, 2.3 Hz, 1 H), 6.78 (d, J = 2.3 Hz, 1 H), 6.62 (d,
J = 10.2 Hz, 1 H), 3.87 (s, 3 H).
13C NMR (101 MHz, CDCl3): δ = 162.8, 153.1, 135.9, 130.4, 118.8,
112.8, 112.1, 104.0, 55.9.
To a reaction tube were sequentially added 3m (8 mg, 0.027 mmol)
and Fe powder (9 mg, 0.16 mmol). The tube was evacuated and back-
filled with nitrogen (3 times). H2O (67 μL), AcOH (1 μL) and EtOH (44
μL) were added and the resulting mixture was stirred at 75 °C for 1 h.
Following extraction with EtOAc, the organic phase was washed with
saturated NaHCO3 solution and dried over Na2SO4. Removal of the sol-
vent and subsequent purification of the residue by column chroma-
tography over silica gel gave the title product.
Funding Information
This work is financially supported by the National Natural Science
Foundation of China (No. 21602010 to Z.Y., and No. 21572017 to J.X.),
the BUCT Fund for Discipline Construction and Development (Project
No. XK1533, to Z.Y.), the China Postdoctoral Science Foundation (No.
2016M600900, to Z.Y.), and the Fundamental Research Funds for the
Yield: 6 mg (84%); yellow solid; mp 159–161 °C; Rf = 0.4 (PE/EtOAc =
1:1, v/v).
IR (film): 3384, 2918, 1716, 1161, 1576, 1491, 1368, 1244, 1167, 859,
823, 770 cm–1
.
Central Universities (XK1802-6, to Z.Y. and J.X.).
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1H NMR (400 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.10 (d, J = 8.8 Hz, 1 H),
6.85 (dd, J = 8.8, 2.8 Hz, 1 H), 6.76 (d, J = 2.8 Hz, 1 H), 4.43 (q, J = 7.1 Hz,
2 H), 3.83 (br s, 2 H), 1.41 (t, J = 7.1 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 160.1, 144.9, 144.7, 142.5, 127.8,
120.7, 119.7, 119.4, 115.1, 63.0, 14.1.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611703.
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HRMS (ESI): m/z [M + H]+ calcd for C11H12NO5S: 270.0431; found:
270.0434.
References
Ethyl (3,4-trans)-4-Phenyl-3,4-dihydronaphtho[2,3-e][1,2]oxathi-
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ine-3-carboxylate 2,2-Dioxide (11)
To a dry reaction tube was added 3j (30 mg, 0.1 mmol) and the tube
was evacuated and backfilled with nitrogen (3 times). Dry THF (1.5
mL) was added via a syringe, followed by the slow addition of PhMgBr
(0.3 mmol, 0.3 mL, 1 mol/L) at room temperature. The mixture was
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