Copper(II) Acetate Mediated Synthesis of 3-Sulfonyl-2-aryl-2 H -chromenes

Article abstract of DOI:10.1055/s-0039-1689973

This paper describes a concise, easy-operation, high-yielding method for the synthesis of 3-sulfonyl-2-aryl-2 H -chromenes by a one-pot, straightforward two-step synthetic route, which includes (i) Cu(OAc) ₂ /PyBOP-mediated intermolecular [4+2] annulation of substituted salicylic acids with β-sulfonylstyrenes in the presence of DMAP in refluxing DMF, and (ii) sequential O -alkylation of the resulting sulfonylflavanones with n -butyl bromide. A plausible mechanism is proposed and discussed. This protocol provides a highly effective annulation via one carbon-oxygen (C-O) and one carbon-carbon (C-C) bond formations.

Full text of DOI:10.1055/s-0039-1689973

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–L
paper
A
en
M.-Y. Chang et al.
Paper
Synthesis
Copper(II) Acetate Mediated Synthesis of 3-Sulfonyl-2-aryl-2H-
chromenes
Meng-Yang Chang*a,b
Yu-Hsin Chena
Han-Yu Chena
0
0
0
0-
0
0
0
2-1
9
8
3-8
5
7
0
nBu
O
O
O
O
O
O
O
O
R
R
R
S
S
S
Cu(OAc)2
nBuBr
OH
OH
+
O
O
O
Ar'
Ar'
Ar'
PyBOP
DMAP
Ar
Ar
Ar
a Department of Medicinal and Applied Chemistry, Kaohsiung
Medical University, Kaohsiung 807, Taiwan, ROC
b Department of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan, ROC
easy operation
inexpensive copper salt
high yield
37 examples
one-pot two-step route
mychang@kmu.edu.tw
Received: 13.04.2019
Accepted after revision: 20.05.2019
Published online: 12.06.2019
coupling of chromene acetals with arylboronic acids.6d
Yadav and co-workers explored the Ga(III)-mediated multi-
component reaction of phenols, alkynes, and arylalde-
hydes.6e Cossy and co-workers described an Fe(III)-cata-
lyzed intramolecular cyclization of o-(1-hydroxy-
cinnamyl)phenols.6f The Scheidt group also reported a
similar transformation with the Pd(II)-catalyzed facile an-
nulation of o-(1-hydroxycinnamyl)phenol diacetates.6g Hou
and co-workers examined the Pd(II)-catalyzed redox-relay
Heck coupling of 4H-chromenes with arylboronic acids.6h
Wang and co-workers studied the Pd(II)-catalyzed cross-
coupling of salicyl N-tosylhydrazones with -bromosty-
renes.6i Environmentally benign synthetic methods have
been developed by the Qu7a and Gois groups.7b
DOI: 10.1055/s-0039-1689973; Art ID: ss-2019-h0221-op
Abstract This paper describes a concise, easy-operation, high-yielding
method for the synthesis of 3-sulfonyl-2-aryl-2H-chromenes by a one-
pot, straightforward two-step synthetic route, which includes (i)
Cu(OAc)2/PyBOP-mediated intermolecular [4+2] annulation of substi-
tuted salicylic acids with -sulfonylstyrenes in the presence of DMAP in
refluxing DMF, and (ii) sequential O-alkylation of the resulting sulfonyl-
flavanones with n-butyl bromide. A plausible mechanism is proposed
and discussed. This protocol provides a highly effective annulation via
one carbon–oxygen (C–O) and one carbon–carbon (C–C) bond forma-
tions.
Key words copper(II) acetate, 2-aryl-2H-chromenes, salicylic acids, -
sulfonylstyrenes, intermolecular [4+2] annulation
(de Bruin, ref 6a)
(Wang, ref 6i)
H
N
H
N
2-Aryl-2H-chromene 1 is an important substructure1 in
a wide range of natural products2a,b (candenatenin E, hilgar-
tene), bioactive molecules2c (acolbifene), and photochromic
materials.3 Due to the potential applications, the develop-
ment of a one-pot synthetic route to access this motif has
attracted significant attention and many attempts have
been reported. The general approach toward 2-aryl-2H-
chromenes 1 is based on a domino process by aldol conden-
sation/oxa-Michael addition/reduction of substituted o-hy-
droxyacetophenones and benzaldehydes under basic condi-
tions.4 Typical organocatalyst-assisted formation of 2-aryl-
2H-chromenes 1 has been investigated.5 Recently, transi-
tion metals promoting the pioneering methods have been
explored as the main strategies (Scheme 1).6
N
Ts
N
Ts
Br
Ar'
Ar'
+
+
(Doris, ref 6b)
(You, ref 6c)
OH
OH
(Hou, ref 6h)
Ar
Ar
Pd(II)
Co(II)
Ar'
O
Ar'
O
Ar
Pd(II)
Pd(II)
Ru(II)
Ni(0)
Ar'
Ar B(OH)2
O
Ar
2-aryl-2H-chromenes 1
(Scheidt, ref 6g)
OAc
(Doyle, ref 6d)
Ar'
Fe(III)
Ga(III)
Ar'
(Cossy, ref 6f)
OH
(Yadav, ref 6e)
O
OEt
O
Ac
Ar
Ar B(OH)2
+
Ar'
CHO
Ar
Ar'
OH
OH Ar
For example, de Bruin and co-workers reported that
Co(II) complexes of porphyrins catalyze the metalloradical
cyclization of salicyl N-tosylhydrazones with arylacety-
lenes.6a Both the Doris and You groups developed a Ru(II)-
mediated ring-closing metathesis of o-O-allylstyrenes.6b,c
Graham and Doyle demonstrated a Ni(0)-catalyzed cross-
Scheme 1 Transition-metal-mediated synthetic routes to 2-aryl-2H-
chromenes
Despite these advancements, some problems exist, such
as multistep reactions, complicated catalytic systems, lack
of broad substrate generality, and prefunctionalized frag-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M.-Y. Chang et al.
Paper
Synthesis
ments. Therefore, further investigation of efficient synthet-
ic methods toward 2-aryl-2H-chromenes 1 is still highly de-
sired. Synthetic transformations from 2-aryl-2H-
chromenes 1 to useful structural frameworks have been in-
vestigated, including dimerized chromenes, dihydrochal-
cones, flavones, and cyclopropylchromanes.8
Table 1 Optimization of the Reaction Conditionsa
nBu
O
O
O
O
O
O
O
Tol
Tol
Tol
S
S
S
copper complex
OH
O
O
O
+
activator, DMAP
then nBuBr (5a)
OH
Ar
O
Ar
Ar
Ar = 3,4-(MeO)2C6H3
2a
3a
6a
4a
Continuing our research on the synthetic applications of
-sulfonylstyrenes,9a we herein present a one-pot, cop-
per(II) complex mediated synthesis of 3-sulfonyl-2-aryl-
2H-chromenes 6 in the presence of an activator and a base
via intermolecular [4+2] annulation of substituted salicylic
acids 2 with -sulfonylstyrenes 3, followed by O-alkylation
of the resulting sulfonylflavanones 4 with n-butyl bromide
(5a), as shown in Scheme 2.
Entry Cu complex Activator Solvent Temp
Time (h) Yield (%) of 6ab
c
1
2
3
4e
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
CuF2
BOP
MeNO2 25 °C
5
25
5
–
–
c
BOP
MeNO2 25 °C
MeNO2 reflux
MeNO2 reflux
BOP
11d
72d
65d
74d
71d
80
BOP
5
BOP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
100 °C
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
5
nBu
BOP
5
O
O
O
O
O
O
R
R
R
S
S
S
Cu(II)
nBuBr (5a)
BOP
10
5
OH
+
O
O
O
Ar'
Ar'
Ar'
activator
base
PyBOP
PyBOP
PyBOP
PyBOP
PyBOP
PyBOP
PyBOP
PyBOP
OH
Ar
O
Ar
O
Ar
5
70
2
3
4
6
10
5
32f
Scheme 2 Route to 3-sulfonyl-2-aryl-2H-chromenes 6
c
11
CuO
5
–
c
12
CuSO4
5
–
In particular, so far there are no reports on the synthesis
of 3-sulfonyl-2-aryl-2H-chromenes 6 with a pull–push na-
ture.10 In contrast to the literature on transition-metal-me-
diated reactions, we chose inexpensive copper complexes
as the promoters to screen for the optimal reaction condi-
tions. According to previous synthetic work,9b the initial
study examining the formation of the 3-sulfonyl-2-aryl-2H-
chromene skeleton commenced with the treatment of mod-
el substrates salicylic acid (2a, 0.3 mmol) and 3a (Ar = 3,4-
(MeO)2C6H3, 0.33 mmol) using a combination of Cu(OAc)2
(1.1 equiv), BOP (1.1 equiv), DMAP (1.1 equiv), and nBuBr
(5a, 3.0 equiv) in MeNO2 (3 mL). However, no reaction oc-
curred at 25 °C for 5 or 25 hours (Table 1, entries 1, 2). In
particular, when the reaction mixture was heated to reflux
in MeNO2 for 5 hours, two products, 4a (78%) and 6a (11%),
were isolated (entry 3). With the aim of improving the yield
of 6a, the equivalents of 5a were increased (3.0 → 10.0)
during the process (entry 4). However, the ratio of 4a and
6a (1:7) was not enhanced. A reasonable hypothesis is that
excess 5a could be trapped by MeNO2 (pKa ~10) such that
the transformation from 4a to 6a cannot be performed effi-
ciently in the presence of DMAP.
13g
14h
15i
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
5
–
c,d
5
30
41
5
a Reaction conditions: 2a (0.3 mmol), 3a (1.1 equiv), Cu complex (1.1
equiv), activator (1.1 equiv), DMAP (40 mg, 0.33 mmol), nBuBr (5a, 140
mg, 1.0 mmol), solvent (3 mL).
b Isolated yields.
c Not detected.
d 4a (entry 3, 78%; entry 4, 10%; entry 5, 16%; entries 6, 7, ~5%; entry 13,
89%).
e 5a (10 equiv) used.
f 2a and 3a were recovered as major compounds.
g Without 5a.
h Cu(OAc)2 (0.3 equiv) used.
i Cu(OAc)2 (0.5 equiv) used.
yield of 6a (70%, entry 9) was slightly poorer than for
Cu(OAc)2. Using CuF2, only 32% of 6a was yielded along with
the major recovery of starting materials 2a and 3a (entry
10). For CuO and CuSO4, however, no desired 6a (or 4a) was
detected (entries 11, 12). When 5a was removed, only 4a
was isolated, in 89% yield (entry 13). Furthermore, catalytic
amounts of Cu(OAc)2 (0.3 and 0.5 equiv) were tested. How-
ever, 6a was obtained in 30% and 41% yield, respectively
(entries 14, 15).
From these observations, we concluded that the combi-
nation of Cu(OAc)2 and PyBOP provided the optimal condi-
tions (reflux, 5 h) in the presence of DMAP for a one-pot
[4+2] annulation/O-n-butylation procedure. This expedi-
tious synthetic route sets up a 3-sulfonyl-2-aryl-2H-
chromene skeleton, including the formation of one C–O and
one C–C bond via a formal [4+2] cycloaddition, under mild
conditions.
When the reaction solvent was changed (MeNO2
→
DMF), the ratio of 4a and 6a was increased to 1:4 (16% and
65%) after 5 hours at 100 °C (entry 5). By elevating the reac-
tion temperature to reflux, the ratio of 4a and 6a was en-
hanced to 1:15 (entry 6). However, an elongated time (10 h)
did not alter the ratio (entry 7). Subsequently, another acti-
vator, PyBOP (a less toxic analogue of BOP), was examined
(entry 8). An almost quantitative conversion from 4a into
6a was achieved. With DMAP and PyBOP controlled as base
and activator, other copper(II) complexes were screened.
For Cu(OTf)2-mediated reaction conditions, the isolated
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

C
M.-Y. Chang et al.
Paper
Synthesis
To study the substrate scope and limitations of this one-
pot route, 2 and 3 were reacted with the combination of
Cu(OAc)2/PyBOP/DMAP and 5a to afford diversified 6, as
shown in Table 2. With the optimal conditions established
(Table 1, entry 8), we found that this route allowed a direct
intermolecular Baylis–Hillman-type annulation of phenox-
ide donor 2 with Michael acceptors 3 under easy-operation
and open-vessel conditions in moderate to good yields (73–
88%). Among entries 1–30, the efficient formation of 6a–
6ad showed that these substituents (Ar′ for 2a–2e; Ar, R for
3a–3z) did not affect the yield. Regarding the electronic na-
ture of the aryl substituents of 2 and 3, not only electron-
neutral groups but also the electron-withdrawing 4-fluoro-
phenyl group and electron-donating oxygenated groups
were suitable. For sulfonyl aliphatic substituents (R) of 3,
both the methyl and n-butyl group were well-tolerated.
Compounds 6ac and 6ad with a -alkoxysulfonyl motif (en-
tries 29 and 30) are the analogues of two bioactive com-
pounds with potent antiviral (BW683C)11a and anti-inflam-
matory activities (TNF- inhibitor),11b as shown in Figure 1.
Furthermore, the molecular structures of 6b, 6q, 6x–6z and
6ab were determined by single-crystal X-ray crystallogra-
phy.12
TLC), we find that there are a number of suspended brown-
ish black particles generated in the product mixture. Fur-
thermore, by the addition of 6 N H2SO4(aq), the collected sol-
ids could be dissolved to form a blue solution. Therefore, we
believe that CuO is produced. From the possible mecha-
nism, we found that the stoichiometric amounts of
Cu(OAc)2, PyBOP, and DMAP required are at least 1 equiva-
lent, such that a one-pot reaction provided a better yield of 6.
Cu(OAc)2 + DMAP
O
O
O
O
3
N
N
PyBOP
N
P
OH
O
O
Ar'
Ar'
Ar'
PF6
Cu
Cu
OH
O
O
H
H
N
A
B
2
N
N
N
N
+ 2 OAc
O
O
N
N
N
AcO
S
PF6
R
O
P
+
O
Ar'
nBu
nBuBr 5a
O
O
O
O
O
S
R
O
Cu
O
Ar
O
Ar'
S
S
PF6
O
R
R
O
Cu
O
O
O
Ar'
Ar'
β
O
Ar
O
Ar
Ar
O
N
CuO
+
BTA-OAc
C
D
4
6
P
N
N
N
N
N
N
N
OAc
N
Cl
Scheme 3 Plausible mechanism
OMe
O
MeO
O
By replacing the aromatic (Ar) group with an aliphatic
(R′) group as the -substituent of 3, the synthesis of sulfo-
nylchromenes 6ae–6ag was examined, as shown in Scheme
4. Under the optimal reactions conditions, the Cu(OAc)2/Py-
BOP/DMAP-mediated cyclization of 2a with 3aa–3ac (R′ =
Me, (CH2)2Ph, nC7H15) provided 6ae, 6af, and 6ag in 66%,
72%, and 63% yield, respectively.
Cl
OMe
BW683C
OMe
TNF-α inhibitor
Me
Me
Me
Cl
O
O
S
Me
O
O
S
O
O
OMe
OMe
O
MeO
O
Cl
6ac
6ad
OMe
nBu
O
O
O
O
Tol
Figure 1 Structures of BW683C, a TNF- inhibitor, 6ac, and 6ad
Tol
S
S
Cu(OAc)2
OH
OH
O
O
+
PyBOP, DMAP
then nBuBr (5a)
O
R'
R'
On the basis of the experimental results, a plausible
mechanism for the formation of 6 is illustrated in Scheme 3.
Initially, the DMAP-mediated complexation of Cu(OAc)2
with the hydroxyl and carboxylic acid groups of 2 yields
A.13 By intermolecular cross-coupling of A with PyBOP, B
should be afforded via O–P bond cleavage of PyBOP. Follow-
ing the introduction of 3, the oxy–copper arm of in situ gen-
erated C attacks the -position of 3 via O–C bond formation.
Subsequently, the corresponding formed -anion promotes
intramolecular C–C bond formation and the release of tri-
pyrrolidinylphosphine oxide to produce D. Then, the con-
struction of 4, furnished via the acetate anion, mediates the
removal of benzotriazoyl acetate (BTA-OAc) and copper ox-
ide (CuO). Finally, the expeditious construction of 6 is fur-
nished via another releasing acetate ion deprotonation of 4
followed by O-butylation of the resulting enolate of 4 with
nBuBr (5a). After the reaction is complete (monitored by
2a
3aa, R' = Me
3ab, R' = CH2CH2Ph
3ac, R' = nC7H15
6ae (66%)
6af (72%)
6ag (63%)
Scheme 4 Synthesis of 6ae–6ag
Furthermore, when n-butyl bromide (5a) was changed
to benzyl bromide (5b) (Scheme 5), the desired 6ah was
produced in 70% yield, along with the formation of 6ah-1
(11%), via one-pot annulation of 2a with 3c. For the genera-
tion of isomer 6ah-1, we envision that the methyl group
(for R) provides less steric hindrance to promotion of the
occurrence of C-benzylation. Comparing the two alkyl bro-
mides (butylation and benzylation), 5b is more reactive
than 5a such that the opportunity for the selectivity of C-
benzylation increases. Under similar conditions, however,
treatment of 2a with 3a and 3e provided the sole products
6ai and 6aj in 76% and 74% yield, respectively. Also, 1-naph-
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

D
M.-Y. Chang et al.
Paper
Synthesis
Table 2 Synthesis of 6a
nBu
O
O
O
O
R
R
S
S
Cu(OAc)2
5
OH
OH
O
O
Ar'
+
Ar'
PyBOP, DMAP
then nBuBr (5a)
4
2
Ar
O
Ar
2
3
6
Entry
2, Ar′
3, Ar, R
Yield (%) of 6b
1
2
2a, C6H4
3a, 3,4-(MeO)2C6H3, Tol
3b, 3,4-(MeO)2C6H3, Ph
3c, 3,4-(MeO)2C6H3, Me
3d, 3,4-(MeO)2C6H3, nBu
3e, 3,4-(MeO)2C6H3, 4-FC6H4
6a, 80
6b, 84
6c, 78
6d, 78
6e, 83
6f, 86
2a, C6H4
3
2a, C6H4
4
2a, C6H4
5
2a, C6H4
6
2a, C6H4
3f, 3,4-(MeO)2C6H3, 4-MeOC6H4
3g, 3,4-(MeO)2C6H3, 3-MeC6H4
3h, 3,4-(MeO)2C6H3, 4-EtC6H4
3i, 3,4-(MeO)2C6H3, 4-iPrC6H4
3j, 3,4-(MeO)2C6H3, 4-nBuC6H4
3k, 3,4-(MeO)2C6H3, 4-tBuC6H4
3a, 3,4-(MeO)2C6H3, Tol
3a, 3,4-(MeO)2C6H3, Tol
3a, 3,4-(MeO)2C6H3, Tol
3l, Ph, Tol
7
2a, C6H4
6g, 80
6h, 81
6i, 78
8
2a, C6H4
9
2a, C6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2a, C6H4
6j, 76
2a, C6H4
6k, 77
6l, 73
2b, 5-BrC6H3
2c, 5-ClC6H3
2d, C10H6 (2-naphthylc)
2a, C6H4
6m, 74
6n, 76
6o, 84
6p, 86
6q, 88
6r, 76
6s, 84
6t, 73
6u, 78
6v, 82
6w, 80
6x, 84
6y, 82
6z, 83
6aa, 80
6ab, 73
6ac, 79
6ad, 84
2a, C6H4
3m, 4-MeOC6H4, Tol
3n, 3-MeOC6H4, Tol
2a, C6H4
2a, C6H4
3o, 4-FC6H4, Tol
2a, C6H4
3p, Tol, Tol
2a, C6H4
3q, 4-PhC6H4, Tol
2a, C6H4
3r, 2-naphthyl, Tol
2a, C6H4
3s, 3,4-OCH2OC6H3, Tol
3t, 3,4-Cl2C6H3, Tol
2a, C6H4
2a, C6H4
3u, 3,4,5-(MeO)3C6H2, Tol
3v, 2-furyl, Tol
2a, C6H4
2a, C6H4
3w, 2-thienyl, Tol
2a, C6H4
3x, 3-pyridyl, Tol
2a, C6H4
3y, 2-BrC6H4, Tol
2c, 5-ClC6H3
2e, 4-MeOC6H3
3z, 4-ClC6H4, Tol
3u, 3,4,5-(MeO)3C6H2, Tol
a Reaction conditions: 2a–2e (0.3 mmol), 3a–3z (1.1 equiv), Cu(OAc)2 (60 mg, 0.33 mmol), PyBOP (172 mg, 0.33 mmol), DMAP (40 mg, 0.33 mmol), nBuBr (5a,
140 mg, 1.0 mmol), DMF (3 mL), 5 h, reflux.
b Isolated yields.
c 2d = 1-hydroxy-2-naphthoic acid.
thylmethyl bromide (5c) afforded 6ak in 68% yield (Scheme
5). The molecular structure of 6aj was determined by sin-
gle-crystal X-ray analysis.12
(DMAP, equation 2). These two control experiments point-
ed out that PyBOP and DMAP are the key factors in effecting
the tandem Michael addition–intramolecular cyclization.
When the activator (PyBOP) was removed, no reaction
was observed (Scheme 6, equation 1). On the other hand,
the reaction could not be triggered in the absence of base
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

E
M.-Y. Chang et al.
Paper
Synthesis
substituted salicylic acids 2 with -sulfonylstyrenes 3. The
process provides a straightforward pathway for one car-
bon–oxygen and one carbon–carbon bond formations. The
substrate scope and limitations were investigated for this
facile and efficient transformation. Mechanistic investiga-
tions were undertaken and a plausible mechanism has been
proposed. The molecular structures of key products were
determined by X-ray crystal structure analysis. Further in-
vestigations regarding the synthetic application of -sulfo-
nylstyrenes are underway in our laboratory.
Bn
O
O
O
S
O
O
O
O
O
Bn
R
R
R
Cu(OAc)2
S
S
OH
+
+
O
O
O
PyBOP, DMAP
then BnBr (5b)
Ar
OH
Ar
Ar
Ar = 3,4-(MeO)2C6H3
3c, R = Me
3a, R = Tol
2a
6ah (70%)
6ai (76%)
6aj (74%)
6ah-1 (11%)
6ai-1 (ND)
6aj-1 (ND)
3e, R = 4-FC6H4
1-NA
O
O
O
1-NA
O
O
O
Tol
Tol
Tol
Cu(OAc)2
S
S
S
OH
OH
+
+
O
O
O
PyBOP, DMAP
then 1-NACH2Br (5c)
O
Ar
Ar
O
Ar
3a
Ar = 3,4-(MeO)2C6H3
Na = naphthyl
2a
6ak (68%)
6ak-1 (ND)
All reagents and solvents were commercial grade and were used
without further purification. All reactions were routinely performed
under a dry nitrogen atmosphere, with magnetic stirring. A heating
mantle was used to provide a stable heat source. All products in or-
ganic solvents were dried with anhydrous MgSO4 before concentra-
tion in vacuo. Melting points were obtained with an SMP3 melting
point apparatus. 1H (400 MHz) and 13C NMR (100 MHz) spectra were
recorded on a Varian INOVA-400 spectrometer. Chemical shifts () are
reported in ppm and coupling constants (J) are given in hertz (Hz).
High-resolution mass spectra were measured with a Bruker micrO-
TOF-Q double-focusing mass spectrometer by ESI using a hybrid ion
trap. X-ray crystal structures were determined with a Bruker Enraf-
Nonius single-crystal diffractometer (CAD4, Kappa CCD).
Scheme 5 Synthesis of 6ah–6ak and 6ah-1 (ND = not detected)
nBu
O
O
O
O
O
Tol
Tol
S
S
Cu(OAc)2
DMAP
OH
(eq 1)
O
+
O
X
OH
Ar
Ar
then nBuBr (5a)
Ar = 3,4-(MeO)2C6H3
2a
3a
6a (ND)
nBu
O
O
O
O
O
Tol
Tol
S
S
Cu(OAc)2
OH
OH
(eq 2)
O
O
+
X
PyBOP
then nBuBr (5a)
Ar
Ar
Ar = 3,4-(MeO)2C6H3
Skeleton 3; General Procedure9a
2a
3a
6a (ND)
Ac2O (510 mg, 5.0 mmol) was added to a stirred solution of arylacet-
aldehyde (5.0 mmol) at 25 °C. The mixture was stirred at 25 °C for 2
min. Polyphosphoric acid (490 mg, 5.0 mmol) was added slowly to
the mixture at 25 °C for 3 min. The reaction mixture was stirred at
25 °C for 5 min. Then, sodium sulfonate (RSO2Na, 10.0 mmol) was
added to the mixture at 25 °C. The reaction mixture was stirred at
25 °C for 4 h. The residue was diluted with water (20 mL) and the
mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layers were washed with NaHCO3 (3 × 10 mL) and brine, dried, fil-
tered, and concentrated under reduced pressure to afford crude prod-
uct. Purification on silica gel (hexanes/EtOAc, 8:1 to 4:1) afforded 3.
These materials are known compounds and their analytical data were
consistent with the literature.9a
Scheme 6 Control experiments (ND = not detected)
Under the optimal reaction conditions, this study exam-
ined replacement of the -sulfonylstyrene with an ,-un-
saturated ethyl ester, as shown in Scheme 7. For the one-pot
intermolecular [4+2] annulation of 2a by treatment with 7,
however, the predicted O-n-butylated 8 could not be ob-
tained. Interestingly, only 8a was produced, in 65% yield,
due to the reflux temperature triggering decarboxylation of
the ethyl ester group. In the reaction process, there was no
isolation of an n-butyl product. For the difference between
-sulfonylstyrene and ,-unsaturated ethyl ester, we un-
derstand that the sulfonyl group could serve as a fastening
substituent to stabilize O-butylation of the resulting sulfo-
nylflavanones with n-butyl bromide under refluxing condi-
tions. According to our results, the sulfonyl group plays a
key electronic withdrawing role for constructing the frame-
work of sulfonylchromenes.
Skeleton 6 and Compound 4a; General Procedure
(Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos-
phate (PyBOP; 172 mg, 0.33 mmol) was added to a solution of salicyl-
ic acid 2 (0.3 mmol) and Cu(OAc)2 (60 mg, 0.33 mmol) in DMF (2 mL)
at 25 °C. The reaction mixture was stirred at 25 °C for 5 min. DMAP
(40 mg, 0.33 mmol) was added and the reaction mixture was stirred
at reflux for 2 h, then cooled to 25 °C. -Sulfonylstyrene 3 (0.33
mmol) in DMF (1 mL) was added at 25 °C and the reaction mixture
was stirred at reflux for an additional 1 h, then cooled to 25 °C. Then,
bromide 5 (1.0 mmol) was added at 25 °C and the reaction mixture
was stirred at reflux for an additional 2 h (monitored by TLC), then
cooled to 25 °C and concentrated. The residue was diluted with water
(10 mL) and the mixture was extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were washed with brine, dried, filtered, and
concentrated under reduced pressure to afford crude product. Purifi-
cation on silica gel (hexanes/EtOAc, 8:1 to 4:1) afforded 6 and 4a.
nBu
O
O
O
O
O
Cu(OAc)2
OH
OEt
OEt
+
PyBOP, DMAP
then nBuBr (5a)
OH
O
Ph
O
Ph
Ph
2a
7
8a (65%)
8 (ND)
Scheme 7 Reaction of 2a and 7 (ND = not detected)
In summary, we have developed a Cu(OAc)2/PyBOP/
DMAP-mediated synthesis of sulfonylchromenes 6 in mod-
erate to good yields via intermolecular [4+2] annulation of
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

F
M.-Y. Chang et al.
Paper
Synthesis
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-(4-tolylsulfonyl)-2H-
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-(methylsulfonyl)-2H-
chromene (6a)
chromene (6c)
Yield: 119 mg (80%); colorless solid; mp 142–144 °C (recrystallized
from hexanes/EtOAc).
Yield: 98 mg (78%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.39 (dd, J = 2.0, 8.0 Hz, 1 H), 7.26 (dt,
J = 1.6, 8.0 Hz, 1 H), 6.98 (dt, J = 0.8, 7.6 Hz, 1 H), 6.93 (d, J = 1.6 Hz, 1
H), 6.89 (dd, J = 2.0, 8.4 Hz, 1 H), 6.81 (dd, J = 0.4, 8.4 Hz, 1 H), 6.72 (d,
J = 8.4 Hz, 1 H), 6.29 (s, 1 H), 4.18–4.04 (m, 2 H), 3.81 (s, 3 H), 3.80 (s, 3
H), 3.06 (s, 3 H), 1.93–1.86 (m, 2 H), 1.60–1.52 (m, 2 H), 1.02 (t, J = 7.2
Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.5, 155.7, 149.7, 149.1, 133.1,
129.9, 124.0, 121.6, 120.1, 119.7, 118.1, 117.9, 110.9, 110.7, 75.5, 75.2,
55.80, 55.76, 44.2, 32.0, 19.1, 13.9.
1H NMR (400 MHz, CDCl3):  = 7.59 (d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 1.6,
7.6 Hz, 1 H), 7.21–7.17 (m, 3 H), 6.90 (dt, J = 0.8, 8.4 Hz, 1 H), 6.79–
6.75 (m, 2 H), 6.72 (d, J = 2.0 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H), 6.45 (s, 1
H), 4.06–4.01 (m, 1 H), 3.92–3.86 (m, 1 H), 3.80 (s, 3 H), 3.62 (s, 3 H),
2.37 (s, 3 H), 1.93–1.85 (m, 2 H), 1.55–1.48 (m, 2 H), 1.02 (t, J = 7.2 Hz,
3 H).
13C NMR (100 MHz, CDCl3):  = 157.0, 155.5, 149.4, 148.6, 143.9,
139.2, 132.8, 129.4, 129.0 (2 ×), 128.0 (2 ×), 124.0, 121.5, 120.82,
120.75, 118.1, 118.0, 111.0, 110.5, 76.1, 74.8, 55.7, 55.5, 32.0, 21.5,
19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H27O6S: 419.1528; found:
419.1529.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H31O6S: 495.1841; found:
495.1842.
4-n-Butoxy-3-(n-butylsulfonyl)-2-(3,4-dimethoxyphenyl)-2H-
chromene (6d)
2-(3,4-Dimethoxyphenyl)-3-(4-tolylsulfonyl)chroman-4-one (4a;
For Table 1, Entry 5)
Yield: 108 mg (78%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.38 (dd, J = 1.6, 8.0 Hz, 1 H), 7.24 (dt,
J = 1.6, 8.0 Hz, 1 H), 6.96 (dt, J = 1.2, 8.0 Hz, 1 H), 6.91–6.89 (m, 2 H),
6.80 (dd, J = 1.2, 8.4 Hz, 1 H), 6.71 (d, J = 8.8 Hz, 1 H), 6.26 (s, 1 H),
4.17–4.12 (m, 1 H), 4.07–4.01 (m, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H),
3.30–3.23 (m, 1 H), 3.07–2.99 (m, 1 H), 1.90–1.83 (m, 2 H), 1.68–1.60
(m, 2 H), 1.58–1.48 (m, 2 H), 1.40–1.30 (m, 2 H), 1.00 (t, J = 7.2 Hz, 3
H), 0.84 (t, J = 7.2 Hz, 3 H).
Yield: 21 mg (16%); colorless solid; mp 156–158 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.72–7.68 (m, 3 H), 7.42 (dt, J = 1.6, 8.0
Hz, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.92 (dt, J = 0.8, 8.0 Hz, 1 H), 6.85 (dd,
J = 0.8, 8.0 Hz, 1 H), 6.77 (s, 1 H), 6.68 (br s, 2 H), 6.49 (s, 1 H), 4.40 (d,
J = 1.2 Hz, 1 H), 3.77 (s, 3 H), 3.75 (s, 3 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 182.3, 158.8, 149.3, 145.6, 137.2,
134.2, 129.5 (2 ×), 129.4 (3 ×), 128.4, 126.8, 121.6, 120.8, 118.6, 118.2,
110.9, 109.6, 76.1, 72.7, 55.8, 55.8, 21.6.
13C NMR (100 MHz, CDCl3):  = 157.2, 155.6, 149.5, 148.8, 133.0,
130.1, 124.0, 121.5, 119.8, 119.4, 117.9 (2 ×), 110.7, 110.6, 75.6, 75.0,
55.73, 55.65, 55.62, 31.8, 23.4, 21.5, 18.9, 13.7, 13.4.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H23O6S: 439.1215; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H33O6S: 461.1998; found:
439.1216.
461.1999.
Single-crystal X-ray analysis: crystals of 4a were grown by slow diffu-
sion of EtOAc into a solution of 4a in CH2Cl2, which yielded colorless
prisms. Compound 4a crystallized in the monoclinic crystal system,
space group P21/c, a = 21.002(3) Å, b = 11.9195(15) Å, c = 8.3067(11)
Å, V = 2062.6(5) Å3, Z = 4, dcalcd = 1.412 g/cm3, F(000) = 920, 2θ range
0.977–26.475°, R indices (all data) R1 = 0.0488, wR2 = 0.1084.
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-[(4-fluorophenyl)sulfo-
nyl]-2H-chromene (6e)
Yield: 124 mg (83%); colorless solid; mp 137–139 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.70–7.65 (m, 2 H), 7.29 (dd, J = 1.6, 7.6
Hz, 1 H), 7.20 (dt, J = 1.6, 8.0 Hz, 1 H), 7.08–7.00 (m, 2 H), 6.91 (dt, J =
0.8, 8.4 Hz, 1 H), 6.77–6.74 (m, 2 H), 6.68 (dd, J = 2.0, 8.0 Hz, 1 H), 6.59
(d, J = 8.4 Hz, 1 H), 6.42 (s, 1 H), 4.10–4.05 (m, 1 H), 4.00–3.91 (m, 1
H), 3.79 (s, 3 H), 3.65 (s, 3 H), 1.95–1.87 (m, 2 H), 1.58–1.48 (m, 2 H),
1.03 (t, J = 7.2 Hz, 3 H).
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-(phenylsulfonyl)-2H-
chromene (6b)
Yield: 121 mg (84%); colorless solid; mp 101–103 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.73–7.70 (m, 2 H), 7.53–7.49 (m, 1 H),
7.40–7.36 (m, 2 H), 7.28 (dd, J = 1.6, 8.0 Hz, 1 H), 7.20 (ddt, J = 0.4, 1.6,
7.6 Hz, 1 H), 6.90 (dt, J = 0.4, 7.6 Hz, 1 H), 6.78–6.74 (m, 2 H), 6.72 (d,
J = 2.0 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 6.46 (s, 1 H), 4.07–4.02 (m, 1
H), 3.91–3.85 (m, 1 H), 3.79 (s, 3 H), 3.61 (s, 3 H), 1.93–1.85 (m, 2 H),
1.57–1.46 (m, 2 H), 1.01 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.3, 155.6, 149.5, 148.6, 142.1,
133.0, 132.9, 129.3, 128.4 (2 ×), 127.9 (2 ×), 124.1, 121.5, 120.8, 120.4,
118.1 (2 ×), 111.0, 110.5, 76.1, 74.9, 55.7, 55.5, 31.9, 19.0, 13.9.
13C NMR (100 MHz, CDCl3):  = 165.3 (d, J = 253.9 Hz), 157.4, 155.6,
149.6, 148.7, 138.1 (d, J = 3.1 Hz), 133.0, 130.7 (d, J = 9.1 Hz, 2 ×),
129.1, 124.0, 121.6, 120.7, 120.3, 118.1, 117.9, 115.5 (d, J = 21.9 Hz,
2 ×), 111.1, 110.4, 76.1, 75.1, 55.7, 55.6, 32.0, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H28FO6S: 499.1591; found:
499.1593.
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-[(4-methoxyphenyl)sul-
fonyl]-2H-chromene (6f)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H29O6S: 481.1685; found:
Yield: 132 mg (86%); colorless gum.
481.1685.
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 8.8 Hz, 2 H), 7.28 (dd, J = 1.6,
7.6 Hz, 1 H), 7.19 (dt, J = 1.6, 8.0 Hz, 1 H), 6.90 (dt, J = 0.8, 8.4 Hz, 1 H),
6.84 (d, J = 8.8 Hz, 2 H), 6.77–6.73 (m, 3 H), 6.62 (d, J = 9.2 Hz, 1 H),
6.43 (s, 1 H), 4.07–4.01 (m, 1 H), 3.97–3.90 (m, 1 H), 3.82 (s, 3 H), 3.80
(s, 3 H), 3.65 (s, 3 H), 1.95–1.87 (m, 2 H), 1.56–1.49 (m, 2 H), 1.03 (t,
J = 7.2 Hz, 3 H).
Single-crystal X-ray analysis: crystals of 6b were grown by slow diffu-
sion of EtOAc into a solution of 6b in CH2Cl2, which yielded colorless
prisms. Compound 6b crystallized in the monoclinic crystal system,
space group P21/c, a = 12.1123(7) Å, b = 23.2762(17) Å, c = 8.6774(7)
Å, V = 391.1(3) Å3, Z = 4, dcalcd = 1.335 g/cm3, F(000) = 1016, 2θ range
1.930–26.531°, R indices (all data) R1 = 0.0489, wR2 = 0.1181.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

G
M.-Y. Chang et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3):  = 163.2, 156.6, 155.5, 149.5, 148.6,
133.8, 132.7, 130.2 (2 ×), 129.4, 124.0, 121.5, 121.2, 120.8, 118.2,
118.0, 113.6 (2 ×), 111.1, 110.5, 76.2, 74.9, 55.8, 55.6 (2 ×), 32.0, 19.0,
14.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H31O7S: 511.1791; found:
511.1792.
4-n-Butoxy-3-[(4-n-butylphenyl)sulfonyl]-2-(3,4-dimethoxyphe-
nyl)-2H-chromene (6j)
Yield: 122 mg (76%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 1.6,
7.6 Hz, 1 H), 7.20 (dt, J = 0.8, 7.6 Hz, 1 H), 7.18 (d, J = 8.4 Hz, 2 H), 6.90
(t, J = 7.6 Hz, 1 H), 6.77–6.73 (m, 3 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.45 (s,
1 H), 4.06–4.00 (m, 1 H), 3.88–3.83 (m, 1 H), 3.79 (s, 3 H), 3.61 (s, 3 H),
2.62 (t, J = 7.6 Hz, 2 H), 1.92–1.84 (m, 2 H), 1.60–1.46 (m, 4 H), 1.37–
1.25 (m, 2 H), 1.01 (t, J = 7.6 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H).
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-(3-tolylsulfonyl)-2H-
chromene (6g)
13C NMR (100 MHz, CDCl3):  = 157.0, 155.5, 149.4, 148.7, 148.6,
139.4, 132.8, 129.4, 128.4 (2 ×), 128.0 (2 ×), 124.0, 121.5, 120.8, 120.7,
118.2, 118.0, 111.0, 110.5, 76.1, 74.8, 55.7, 55.5, 35.5, 33.1, 32.0, 22.2,
19.0, 13.9, 13.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C31H37O6S: 537.2311; found:
537.2310.
Yield: 119 mg (80%); colorless solid; mp 121–123 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.57–7.54 (m, 1 H), 7.37 (br s, 1 H),
7.33–7.26 (m, 3 H), 7.20 (dt, J = 1.6, 8.0 Hz, 1 H), 6.91 (dt, J = 1.2, 7.6
Hz, 1 H), 6.78 (dd, J = 2.0, 8.0 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 2 H), 6.74 (d,
J = 8.4 Hz, 1 H), 6.45 (s, 1 H), 4.07–4.01 (m, 1 H), 3.95–3.86 (m, 1 H),
3.80 (s, 3 H), 3.62 (s, 3 H), 2.27 (s, 3 H), 1.93–1.85 (m, 2 H), 1.58–1.49
(m, 2 H), 1.02 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.1, 155.6, 149.5, 148.7, 141.9,
138.5, 133.7, 132.9, 129.4, 128.5, 128.3, 125.1, 124.0, 121.5, 120.9,
120.8, 118.09, 118.06, 111.1, 110.5, 76.2, 74.8, 55.8, 55.6, 32.0, 21.1,
19.0, 13.9.
4-n-Butoxy-3-[(4-tert-butylphenyl)sulfonyl]-2-(3,4-dimethoxy-
phenyl)-2H-chromene (6k)
Yield: 124 mg (77%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.64 (d, J = 8.8 Hz, 2 H), 7.37 (d, J = 8.4
Hz, 2 H), 7.29 (dd, J = 1.6, 7.6 Hz, 1 H), 7.17 (dt, J = 1.6, 7.6 Hz, 1 H),
6.89 (dt, J = 1.2, 7.6 Hz, 1 H), 6.78–6.74 (m, 2 H), 6.69 (d, J = 2.0 Hz, 1
H), 6.60 (d, J = 8.4 Hz, 1 H), 6.45 (s, 1 H), 4.06–4.00 (m, 1 H), 3.89–3.82
(m, 1 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 1.92–1.84 (m, 2 H), 1.54–1.47 (m,
2 H), 1.28 (s, 9 H), 1.01 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.9, 156.7, 155.4, 149.3, 148.5,
139.1, 132.7, 129.3, 127.7 (2 ×), 125.3 (2 ×), 124.0, 121.4, 120.8, 120.6,
118.1, 117.9, 110.9, 110.4, 76.1, 74.8, 55.6, 55.4, 35.0, 31.9, 30.9 (3 ×),
18.9, 13.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H31O6S: 495.1841; found:
495.1840.
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-[(4-ethylphenyl)sulfo-
nyl]-2H-chromene (6h)
Yield: 123 mg (81%); colorless solid; mp 114–116 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 8.0 Hz, 2 H), 7.28 (dd, J = 1.6,
7.6 Hz, 1 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.89 (dt, J = 0.8, 7.6 Hz, 1 H), 6.77
(dt, J = 2.0, 8.4 Hz, 1 H), 6.79–6.75 (m, 2 H), 6.71 (d, J = 2.0 Hz, 1 H),
6.62 (d, J = 8.4 Hz, 1 H), 6.45 (s, 1 H), 4.06–4.00 (m, 1 H), 3.92–3.84 (m,
1 H), 3.78 (s, 3 H), 3.59 (s, 3 H), 2.66 (q, J = 7.6 Hz, 2 H), 1.92–1.84 (m,
2 H), 1.56–1.46 (m, 2 H), 1.21 (t, J = 7.6 Hz, 3 H), 1.01 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3):  = 156.9, 155.5, 150.0, 149.4, 148.5,
139.4, 132.8, 129.3, 128.0 (2 ×), 127.8 (2 ×), 124.0, 121.4, 120.8, 120.7,
118.1, 118.0, 111.0, 110.5, 76.1, 74.8, 55.7, 55.5, 31.9, 28.7, 19.0, 15.1,
13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C31H37O6S: 537.2311; found:
537.2311.
6-Bromo-4-n-butoxy-2-(3,4-dimethoxyphenyl)-3-(4-tolylsulfo-
nyl)-2H-chromene (6l)
Yield: 125 mg (73%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.55 (d, J = 8.4 Hz, 2 H), 7.38 (d, J = 2.0
Hz, 1 H), 7.26 (dd, J = 2.4, 8.8 Hz, 1 H), 7.17 (d, J = 7.6 Hz, 2 H), 6.70 (dt,
J = 2.0, 8.0 Hz, 1 H), 6.69 (s, 1 H), 6.64 (d, J = 8.4 Hz, 1 H), 6.62 (d, J = 8.0
Hz, 1 H), 6.44 (s, 1 H), 4.05–3.94 (m, 2 H), 3.81 (s, 3 H), 3.64 (s, 3 H),
2.38 (s, 3 H), 1.95–1.86 (m, 2 H), 1.58–1.51 (m, 2 H), 1.04 (t, J = 7.2 Hz,
3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H33O6S: 509.1998; found:
509.1997.
13C NMR (100 MHz, CDCl3):  = 155.5, 154.4, 149.6, 148.7, 144.1,
138.8, 135.3, 129.0 (2 ×), 128.7, 128.1 (2 ×), 126.5, 122.0, 120.8, 120.0,
119.8, 113.7, 111.1, 110.5, 76.4, 75.1, 55.8, 55.5, 31.9, 21.5, 18.9, 13.9.
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-[(4-isopropylphenyl)sul-
fonyl]-2H-chromene (6i)
Yield: 122 mg (78%); colorless gum.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H30BrO6S: 573.0947;
1H NMR (400 MHz, CDCl3):  = 7.63 (d, J = 8.4 Hz, 2 H), 7.29 (dd, J = 1.6,
7.6 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.18 (dt, J = 0.8, 7.6 Hz, 1 H), 6.89
(dt, J = 1.2, 7.6 Hz, 1 H), 6.78–6.74 (m, 2 H), 6.69 (d, J = 2.0 Hz, 1 H),
6.61 (d, J = 8.0 Hz, 1 H), 6.45 (s, 1 H), 4.06–4.00 (m, 1 H), 3.92–3.83 (m,
1 H), 3.78 (s, 3 H), 3.58 (s, 3 H), 2.95–2.88 (m, 1 H), 1.92–1.84 (m, 2 H),
1.54–1.47 (m, 2 H), 1.21 (d, J = 6.8 Hz, 6 H), 1.01 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.9, 155.5, 154.5, 149.3, 148.5,
139.5, 132.7, 129.3, 128.1 (2 ×), 126.5 (2 ×), 124.0, 121.4, 120.8, 120.6,
118.1, 118.0, 110.9, 110.5, 76.1, 74.8, 55.7, 55.4, 34.1, 31.9, 23.6, 23.5,
18.9, 13.9.
found: 573.0948.
4-n-Butoxy-6-chloro-2-(3,4-dimethoxyphenyl)-3-(4-tolylsulfo-
nyl)-2H-chromene (6m)
Yield: 117 mg (74%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.53 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 2.4
Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.12 (dd, J = 2.8, 8.8 Hz, 1 H), 6.72–
6.68 (m, 3 H), 6.62 (d, J = 8.4 Hz, 1 H), 6.43 (s, 1 H), 4.06–3.93 (m, 2 H),
3.80 (s, 3 H), 3.63 (s, 3 H), 2.37 (s, 3 H), 1.95–1.86 (m, 2 H), 1.58–1.50
(m, 2 H), 1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 155.7, 153.9, 149.7, 148.7, 144.1,
138.8, 132.4, 129.0 (2 ×), 128.8, 128.1 (2 ×), 126.6, 123.6, 122.1, 120.9,
119.6, 119.4, 111.1, 110.5, 76.4, 75.1, 55.8, 55.5, 31.9, 21.5, 18.9, 13.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H35O6S: 523.2154; found:
523.2155.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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M.-Y. Chang et al.
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Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H30ClO6S: 529.1452; found:
529.1451.
13C NMR (100 MHz, CDCl3):  = 159.4, 157.1, 155.6, 143.9, 139.1,
138.4, 132.8, 130.2, 129.3, 129.0 (2 ×), 128.9, 128.0 (2 ×), 124.2, 121.5,
120.3, 117.9, 114.7, 113.3, 76.1, 74.8, 54.9, 31.9, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H29O5S: 465.1736; found:
465.1735.
4-n-Butoxy-2-(3,4-dimethoxyphenyl)-3-(4-tolylsulfonyl)-2H-ben-
zo[h]chromene (6n)
Yield: 124 mg (76%); colorless solid; mp 156–158 °C (recrystallized
from hexanes/EtOAc).
Single-crystal X-ray analysis: crystals of 6q were grown by slow diffu-
sion of EtOAc into a solution of 6q in CH2Cl2, which yielded colorless
prisms. Compound 6q crystallized in the monoclinic crystal system,
space group P21/n, a = 6.727(3) Å, b = 12.012(5) Å, c = 28.621(14) Å,
V = 2312.6(19) Å3, Z = 4, dcalcd = 1.334 g/cm3, F(000) = 984, 2θ range
1.423–27.009°, R indices (all data) R1 = 0.1112, wR2 = 0.1804.
1H NMR (400 MHz, CDCl3):  = 8.17 (dd, J = 1.2, 7.6 Hz, 1 H), 7.73 (d, J =
8.4 Hz, 2 H), 7.69 (dd, J = 1.2, 7.2 Hz, 1 H), 7.50–7.41 (m, 2 H), 7.35 (d,
J = 8.8 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 6.89
(dd, J = 2.0, 8.0 Hz, 1 H), 6.85 (d, J = 2.0 Hz, 1 H), 6.73 (s, 1 H), 6.59 (d,
J = 8.0 Hz, 1 H), 4.09–4.03 (m, 1 H), 3.85–3.80 (m, 1 H), 3.74 (s, 3 H),
3.60 (s, 3 H), 2.40 (s, 3 H), 1.94–1.86 (m, 2 H), 1.59–1.43 (m, 2 H), 1.02
(t, J = 7.2 Hz, 3 H).
4-n-Butoxy-2-(4-fluorophenyl)-3-(4-tolylsulfonyl)-2H-chromene
(6r)
13C NMR (100 MHz, CDCl3):  = 158.1, 152.9, 149.4, 148.5, 143.8,
139.6, 135.7, 129.7, 129.1 (2 ×), 128.3, 128.0 (2 ×), 127.6, 126.2, 125.1,
122.6, 121.0, 120.5, 120.0, 118.0, 112.6, 110.7, 110.5, 76.5, 74.8, 55.7,
55.4, 32.0, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C32H33O6S: 545.1998; found:
545.1996.
Yield: 103 mg (76%); colorless solid; mp 153–155 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.58 (d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 1.6,
8.0 Hz, 1 H), 7.25–7.18 (m, 5 H), 6.92 (dt, J = 1.2, 8.4 Hz, 1 H), 6.90–
6.84 (m, 2 H), 6.77 (dt, J = 0.8, 8.4 Hz, 1 H), 6.48 (s, 1 H), 4.07–4.01 (m,
1 H), 3.90–3.84 (m, 1 H), 2.39 (s, 3 H), 1.92–1.84 (m, 2 H), 1.55–1.46
(m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.0 (d, J = 246.4 Hz), 157.1, 155.4,
144.1, 139.1, 133.1 (d, J = 3.1 Hz), 133.0, 130.0 (d, J = 8.4 Hz, 2 ×),
129.1 (2 ×), 128.0 (2 ×), 124.3, 121.6, 120.6, 118.02, 117.99, 115.3 (d,
J = 22.0 Hz, 2 ×), 75.5, 74.8, 32.0, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H26FO4S: 453.1536; found:
453.1536.
4-n-Butoxy-2-phenyl-3-(4-tolylsulfonyl)-2H-chromene (6o)
Yield: 109 mg (84%); colorless solid; mp 119–121 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.55 (d, J = 8.4 Hz, 2 H), 7.30–7.15 (m, 9
H), 6.90 (dt, J = 1.2, 7.6 Hz, 1 H), 6.77 (dd, J = 1.2, 8.4 Hz, 1 H), 6.51 (s, 1
H), 4.08–4.03 (m, 1 H), 3.93–3.88 (m, 1 H), 2.38 (s, 3 H), 1.94–1.85 (m,
2 H), 1.56–1.49 (m, 2 H), 1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.0, 155.6, 143.9, 139.1, 137.1,
132.8, 129.0 (2 ×), 128.9, 128.3 (2 ×), 128.02 (2 ×), 127.99 (2 ×), 124.2,
121.5, 120.7, 118.0, 117.9, 76.3, 74.7, 32.0, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H27O4S: 435.1630; found:
435.1632.
4-n-Butoxy-2-(4-tolyl)-3-(4-tolylsulfonyl)-2H-chromene (6s)
Yield: 113 mg (84%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.56 (d, J = 8.4 Hz, 2 H), 7.27 (dd, J = 1.6,
8.0 Hz, 1 H), 7.21–7.12 (m, 5 H), 6.98 (d, J = 7.6 Hz, 2 H), 6.89 (dt, J =
1.2, 7.6 Hz, 1 H), 6.76 (dt, J = 0.8, 8.4 Hz, 1 H), 6.47 (s, 1 H), 4.07–4.01
(m, 1 H), 3.92–3.86 (m, 1 H), 2.39 (s, 3 H), 2.27 (s, 3 H), 1.92–1.84 (m,
2 H), 1.57–1.49 (m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
4-n-Butoxy-2-(4-methoxyphenyl)-3-(4-tolylsulfonyl)-2H-
13C NMR (100 MHz, CDCl3):  = 157.0, 155.7, 143.8, 139.2, 138.8,
134.1, 132.8, 129.0 (4 ×), 128.1 (2 ×), 128.0 (2 ×), 124.2, 121.4, 120.8,
118.2, 118.0, 76.1, 74.7, 32.0, 21.6, 21.1, 19.0, 13.9.
chromene (6p)
Yield: 120 mg (86%); colorless solid; mp 118–120 °C (recrystallized
from hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H29O4S: 449.1787; found:
449.1785.
1H NMR (400 MHz, CDCl3):  = 7.55 (d, J = 8.0 Hz, 2 H), 7.28 (dd, J = 1.2,
8.0 Hz, 1 H), 7.21–7.15 (m, 5 H), 6.90 (dt, J = 1.2, 8.4 Hz, 1 H), 6.75 (dt,
J = 0.8, 8.4 Hz, 1 H), 6.69 (d, J = 8.8 Hz, 2 H), 6.46 (s, 1 H), 4.07–4.01 (m,
1 H), 3.93–3.88 (m, 1 H), 3.73 (s, 3 H), 2.38 (s, 3 H), 1.93–1.85 (m, 2 H),
1.56–1.49 (m, 2 H), 1.03 (t, J = 7.2 Hz, 3 H).
2-(1,1′-Biphenyl-4-yl)-4-n-butoxy-3-(4-tolylsulfonyl)-2H-
chromene (6t)
13C NMR (100 MHz, CDCl3):  = 160.0, 156.8, 155.5, 143.8, 139.1,
132.7, 129.5 (2 ×), 129.2, 129.0 (2 ×), 128.0 (2 ×), 124.1, 121.4, 120.8,
118.01, 117.96, 113.6 (2 ×), 75.8, 74.7, 55.1, 31.9, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H29O5S: 465.1736; found:
465.1734.
Yield: 112 mg (73%); colorless solid; mp 145–147 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.61 (d, J = 8.4 Hz, 2 H), 7.53–7.50 (m, 2
H), 7.44–7.40 (m, 4 H), 7.36–7.31 (m, 4 H), 7.25–7.11 (m, 3 H), 6.93
(dt, J = 1.2, 8.0 Hz, 1 H), 6.82 (dd, J = 0.8, 8.4 Hz, 1 H), 6.57 (s, 1 H),
4.11–4.05 (m, 1 H), 3.95–3.90 (m, 1 H), 2.38 (s, 3 H), 1.95–1.87 (m, 2
H), 1.60–1.49 (m, 2 H), 1.04 (t, J = 7.6 Hz, 3 H).
4-n-Butoxy-2-(3-methoxyphenyl)-3-(4-tolylsulfonyl)-2H-
13C NMR (100 MHz, CDCl3):  = 157.0, 155.6, 143.9, 141.8, 140.4,
139.2, 136.1, 132.9, 129.0 (2 ×), 128.7 (2 ×), 128.5 (2 ×), 128.0 (2 ×),
127.5, 127.04 (2 ×), 126.99 (2 ×), 124.3, 121.5, 120.7, 118.1, 118.0,
76.1, 74.8, 32.0, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C32H31O4S: 511.1943; found:
511.1943.
chromene (6q)
Yield: 122 mg (88%); colorless solid; mp 133–135 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.59 (d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 1.2,
8.4 Hz, 1 H), 7.21–7.16 (m, 3 H), 7.08 (dt, J = 1.2, 7.6 Hz, 1 H), 6.90 (dt,
J = 1.2, 8.4 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.79–6.77 (m, 3 H), 6.49 (s,
1 H), 4.08–4.02 (m, 1 H), 3.92–3.86 (m, 1 H), 3.63 (s, 3 H), 2.37 (s, 3 H),
1.93–1.85 (m, 2 H), 1.57–1.46 (m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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M.-Y. Chang et al.
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Synthesis
4-n-Butoxy-2-(naphthalen-2-yl)-3-(4-tolylsulfonyl)-2H-chromene
(6u)
13C NMR (100 MHz, CDCl3):  = 157.2, 155.5, 152.9 (2 ×), 144.0, 139.2,
138.2, 132.9, 132.3 (2 ×), 129.0 (2 ×), 128.0 (2 ×), 124.0, 121.6, 120.5,
118.0, 105.1 (2 ×), 76.3, 75.0, 60.7, 55.7 (2 ×), 31.9, 21.5, 19.0, 13.9.
Yield: 113 mg (78%); colorless solid; mp 157–159 °C (recrystallized
from hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C29H33O7S: 525.1947; found:
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 7.6 Hz, 1 H), 7.70 (d, J = 8.4
Hz, 1 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.54–7.38 (m, 5 H), 7.32 (dd, J = 1.6,
8.0 Hz, 1 H), 7.17 (dt, J = 1.6, 8.8 Hz, 1 H), 7.11 (d, J = 8.0 Hz, 2 H), 6.89
(dt, J = 0.8, 7.6 Hz, 1 H), 6.78 (dd, J = 0.8, 8.0 Hz, 1 H), 6.69 (s, 1 H),
4.11–4.06 (m, 1 H), 3.99–3.93 (m, 1 H), 2.36 (s, 3 H), 1.98–1.90 (m, 2
H), 1.63–1.53 (m, 2 H), 1.05 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.5, 155.6, 144.0, 139.1, 134.2,
133.4, 132.9, 132.6, 129.1 (2 ×), 128.30, 128.26, 128.1 (2 ×), 127.6,
127.4, 126.4, 126.0, 125.7, 124.3, 121.6, 120.4, 118.2, 118.0, 76.2, 74.9,
32.0, 21.5, 19.0, 13.9.
525.1948.
Single-crystal X-ray analysis: crystals of 6x were grown by slow diffu-
sion of EtOAc into a solution of 6x in CH2Cl2, which yielded colorless
prisms. Compound 6x crystallized in the monoclinic crystal system,
space group P21/c, a = 8.5862(10) Å, b = 11.7120(13) Å, c = 26.193(3)
Å, V = 2631.5(5) Å3, Z = 4, dcalcd = 1.324 g/cm3, F(000) = 1112, 2θ range
1.905–26.501°, R indices (all data) R1 = 0.0458, wR2 = 0.1176.
4-n-Butoxy-2-(furan-2-yl)-3-(4-tolylsulfonyl)-2H-chromene (6y)
Yield: 104 mg (82%); colorless solid; mp 155–157 °C (recrystallized
from hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H29O4S: 485.1787; found:
1H NMR (400 MHz, CDCl3):  = 7.65 (d, J = 8.0 Hz, 2 H), 7.30 (dd, J = 1.6,
7.6 Hz, 1 H), 7.25–7.21 (m, 4 H), 6.93 (dt, J = 1.2, 8.0 Hz, 1 H), 6.84 (dd,
J = 0.8, 8.4 Hz, 1 H), 6.51 (s, 1 H), 6.15 (dd, J =1.6, 3.2 Hz, 1 H), 6.07 (d,
J = 3.2 Hz, 1 H), 4.06–4.02 (m, 1 H), 3.94–3.89 (m, 1 H), 2.40 (s, 3 H),
1.91–1.84 (m, 2 H), 1.55–1.48 (m, 2 H), 1.02 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.5, 155.6, 150.6, 144.0, 143.5,
139.1, 132.8, 129.1 (2 ×), 127.9 (2 ×), 124.3, 121.7, 118.9, 117.9, 117.8,
111.1, 110.1, 74.9, 69.1, 31.9, 21.5, 19.0, 13.9.
485.1788.
2-(Benzo[1,3]dioxol-5-yl)-4-n-butoxy-3-(4-tolylsulfonyl)-2H-
chromene (6v)
Yield: 118 mg (82%); colorless solid; mp 159–161 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.61 (d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 1.6,
7.6 Hz, 1 H), 7.22–7.18 (m, 3 H), 6.90 (dt, J = 0.8, 7.6 Hz, 1 H), 6.77 (dt,
J = 0.8, 8.0 Hz, 1 H), 6.72 (dd, J = 2.0, 8.0 Hz, 1 H), 6.71 (s, 1 H), 6.59 (d,
J = 8.0 Hz, 1 H), 6.41 (s, 1 H), 5.87 (d, J = 1.2 Hz, 1 H), 5.86 (d, J = 1.6 Hz,
1 H), 4.06–4.01 (m, 1 H), 3.90–3.85 (m, 1 H), 2.38 (s, 3 H), 1.92–1.84
(m, 2 H), 1.55–1.48 (m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.9, 155.4, 148.1, 147.6, 143.9,
139.1, 132.8, 131.0, 129.0 (3 ×), 128.0 (2 ×), 124.2, 122.1, 121.5, 120.6,
117.9, 108.4, 107.8, 101.1, 76.0, 74.7, 31.9, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H25O5S: 425.1423; found:
425.1423.
Single-crystal X-ray analysis: crystals of 6y were grown by slow diffu-
sion of EtOAc into a solution of 6y in CH2Cl2, which yielded colorless
prisms. Compound 6y crystallized in the monoclinic crystal system,
space group C2/c, a = 26.290(2) Å, b = 8.3391(7) Å, c = 19.8288(16) Å,
V = 4128.0(6) Å3, Z = 8, dcalcd = 1.366 g/cm3, F(000) = 1792, 2θ range
1.631–26.445°, R indices (all data) R1 = 0.1300, wR2 = 0.2920.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H27O6S: 479.1528; found:
479.1530.
4-n-Butoxy-2-(thiophen-2-yl)-3-(4-tolylsulfonyl)-2H-chromene
(6z)
4-n-Butoxy-2-(3,4-dichlorophenyl)-3-(4-tolylsulfonyl)-2H-
chromene (6w)
Yield: 110 mg (83%); colorless solid; mp 156–158 °C (recrystallized
from hexanes/EtOAc).
Yield: 120 mg (80%); colorless solid; mp 118–120 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.61 (d, J = 8.4 Hz, 2 H), 7.32 (dd, J = 1.6,
7.6 Hz, 1 H), 7.25 (dt, J = 1.6, 7.6 Hz, 1 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.13
(dd, J = 1.2, 8.8 Hz, 1 H), 6.96 (dd, J = 1.2, 7.6 Hz, 1 H), 6.96–6.92 (m, 1
H), 6.85 (dd, J = 0.8, 8.0 Hz, 1 H), 6.79 (dd, J = 3.6, 5.2 Hz, 1 H), 6.72 (d,
J = 0.4 Hz, 1 H), 4.08–4.02 (m, 1 H), 3.94–3.89 (m, 1 H), 2.38 (s, 3 H),
1.93–1.85 (m, 2 H), 1.57–1.46 (m, 2 H), 1.02 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.66 (d, J = 8.4 Hz, 2 H), 7.30 (dd, J = 1.6,
7.6 Hz, 1 H), 7.29–7.20 (m, 5 H), 7.13 (dd, J = 2.0, 8.4 Hz, 1 H), 6.94 (dt,
J = 0.8, 8.4 Hz, 1 H), 6.79 (d, J = 8.0 Hz, 1 H), 6.45 (s, 1 H), 4.07–4.01 (m,
1 H), 3.88–3.83 (m, 1 H), 2.41 (s, 3 H), 1.92–1.84 (m, 2 H), 1.55–1.48
(m, 2 H), 1.02 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.7, 155.2, 143.9, 140.6, 139.1,
132.9, 129.0 (2 ×), 128.0, 127.9 (2 ×), 126.8, 126.2, 124.3, 121.8, 121.4,
118.3, 118.1, 74.9, 71.5, 31.9, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C24H25O4S2: 441.1194; found:
441.1196.
13C NMR (100 MHz, CDCl3):  = 157.6, 155.1, 144.4, 138.8, 137.3,
133.2, 133.0, 132.5, 130.4, 130.0, 129.3 (2 ×), 127.9 (2 ×), 127.4, 124.5,
122.0, 119.7, 118.0, 117.8, 75.1, 74.8, 31.9, 21.6, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H25Cl2O4S: 503.0851;
found: 503.0852.
Single-crystal X-ray analysis: crystals of 6z were grown by slow diffu-
sion of EtOAc into a solution of 6z in CH2Cl2, which yielded colorless
prisms. Compound 6z crystallized in the monoclinic crystal system,
space group P21/n, a = 12.2582(7) Å, b = 8.5061(4) Å, c = 21.0937(11)
Å, V = 2185.5(2) Å3, Z = 4, dcalcd = 1.339 g/cm3, F(000) = 928, 2θ range
1.837–26.519°, R indices (all data) R1 = 0.0517, wR2 = 0.1010.
4-n-Butoxy-3-(4-tolylsulfonyl)-2-(3,4,5-trimethoxyphenyl)-2H-
chromene (6x)
Yield: 132 mg (84%); colorless solid; mp 125–127 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 8.4 Hz, 2 H), 7.29 (dd, J = 1.6,
7.6 Hz, 1 H), 7.24–7.20 (m, 1 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.91 (dt, J =
1.2, 8.0 Hz, 1 H), 6.80 (dd, J = 0.8, 8.4 Hz, 1 H), 6.43 (d, J = 0.4 Hz, 1 H),
6.42 (s, 2 H), 4.06–4.01 (m, 1 H), 3.89–3.82 (m, 1 H), 3.77 (s, 3 H), 3.57
(s, 6 H), 2.37 (s, 3 H), 1.92–1.85 (m, 2 H), 1.54–1.47 (m, 2 H), 1.01 (t,
J = 7.6 Hz, 3 H).
3-[4-n-Butoxy-3-(4-tolylsulfonyl)-2H-chromen-2-yl]pyridine
(6aa)
Yield: 104 mg (80%); colorless gum.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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M.-Y. Chang et al.
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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.52 (d, J = 2.4 Hz, 1 H), 8.47 (dd, J = 1.6,
8.8 Hz, 1 H), 7.60 (d, J = 8.4 Hz, 2 H), 7.52 (dt, J = 2.0, 8.0 Hz, 1 H), 7.29
(dd, J = 1.6, 8.0 Hz, 1 H), 7.21 (dt, J = 2.0, 8.0 Hz, 1 H), 7.19 (d, J = 8.0 Hz,
2 H), 7.10 (dd, J = 0.4, 8.0 Hz, 1 H), 6.92 (dt, J = 1.2, 7.6 Hz, 1 H), 6.78
(dd, J = 0.8, 8.0 Hz, 1 H), 6.54 (s, 1 H), 4.07–4.02 (m, 1 H), 3.88–3.82
(m, 1 H), 2.38 (s, 3 H), 1.91–1.82 (m, 2 H), 1.55–1.45 (m, 2 H), 1.00 (t,
J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 163.7, 157.8, 157.5, 152.9 (2 ×), 143.7,
139.6, 132.6, 129.0 (2 ×), 127.93, 127.87 (2 ×), 125.4, 117.2, 111.0,
108.6, 105.1 (2 ×), 102.9, 76.9, 75.1, 60.7, 55.7 (2 ×), 55.4, 32.0, 21.5,
19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H35O8S: 555.2053; found:
555.2053.
13C NMR (100 MHz, CDCl3):  = 157.5, 155.1, 150.1, 149.4, 144.3,
138.9, 135.4, 133.2, 132.7, 129.3 (2 ×), 127.8 (2 ×), 124.4, 123.2, 122.0,
119.6, 118.0, 117.9, 75.0, 74.1, 31.9, 21.5, 19.0, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H26NO4S: 436.1583; found:
436.1584.
4-n-Butoxy-2-methyl-3-(4-tolylsulfonyl)-2H-chromene (6ae)
Yield: 74 mg (66%); colorless solid; mp 75–77 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.90 (d, J = 8.4 Hz, 2 H), 7.30 (dd, J = 0.8,
8.8 Hz, 2 H), 7.29–7.24 (m, 2 H), 6.93 (dt, J = 1.2, 7.6 Hz, 1 H), 6.88 (dd,
J = 1.2, 8.8 Hz, 1 H), 5.59 (q, J = 6.4 Hz, 1 H), 3.97–3.91 (m, 1 H), 3.73–
3.67 (m, 1 H), 2.40 (s, 3 H), 1.83–1.74 (m, 3 H), 1.47–1.40 (m, 1 H),
1.36 (d, J = 6.4 Hz, 3 H), 0.96 (t, J = 7.2 Hz, 3 H).
2-(2-Bromophenyl)-4-n-butoxy-3-(4-tolylsulfonyl)-2H-chromene
(6ab)
Yield: 112 mg (73%); colorless solid; mp 162–164 °C (recrystallized
from hexanes/EtOAc).
13C NMR (100 MHz, CDCl3):  = 155.6, 155.2, 143.9, 139.8, 132.6,
129.3 (2 ×), 127.5 (2 ×), 124.3, 122.6, 121.3, 117.8, 117.5, 74.3, 71.4,
31.8, 21.4, 19.6, 18.8, 13.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H25O4S: 373.1474; found:
373.1474.
1H NMR (400 MHz, CDCl3):  = 7.62–7.58 (m, 3 H), 7.30 (dd, J = 1.6, 7.6
Hz, 1 H), 7.20–7.16 (m, 3 H), 7.12–7.07 (m, 1 H), 6.94 (s, 1 H), 6.93–
6.88 (m, 3 H), 6.76 (dd, J = 0.4, 8.0 Hz, 1 H), 4.09–4.04 (m, 1 H), 3.95–
3.89 (m, 1 H), 2.39 (s, 3 H), 1.95–1.86 (m, 2 H), 1.59–1.48 (m, 2 H),
1.03 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 157.8, 155.2, 144.1, 138.8, 134.9,
133.6, 132.9, 130.6, 129.6, 129.1 (2 ×), 128.1 (2 ×), 126.9, 124.8, 124.1,
121.7, 119.8, 118.1, 118.0, 74.9, 74.7, 32.0, 21.5, 19.0, 13.9.
4-n-Butoxy-2-phenethyl-3-(4-tolylsulfonyl)-2H-chromene (6af)
Yield: 100 mg (72%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.91 (d, J = 8.0 Hz, 2 H), 7.35–7.13 (m, 9
H), 6.99 (dt, J = 1.2, 8.0 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 5.49 (dd, J =
3.2, 10.4 Hz, 1 H), 4.02–3.96 (m, 1 H), 3.72–3.63 (m, 1 H), 2.88–2.73
(m, 2 H), 2.43 (s, 3 H), 2.18–2.08 (m, 1 H), 2.01–1.92 (m, 1 H), 1.85–
1.77 (m, 2 H), 1.52–1.39 (m, 2 H), 1.00 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 155.9, 155.1, 143.9, 140.8, 139.7,
132.7, 129.3 (2 ×), 128.24 (2 ×), 128.22 (2 ×), 127.6 (2 ×), 125.8, 124.4,
121.7, 121.5, 118.0, 117.7, 74.44, 74.39, 34.9, 31.8, 31.6, 21.4, 18.8,
13.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H26BrO4S: 513.0735;
found: 513.0733.
Single-crystal X-ray analysis: crystals of 6ab were grown by slow dif-
fusion of EtOAc into a solution of 6ab in CH2Cl2, which yielded color-
less prisms. Compound 6ab crystallized in the monoclinic crystal sys-
tem, space group P21/n, a = 12.2442(6) Å, b = 8.7485(4) Å, c =
21.6094(11) Å, V = 2288.57(19) Å3, Z = 4, dcalcd = 1.490 g/cm3, F(000) =
1056, 2θ range 1.805–26.405°, R indices (all data) R1 = 0.0299, wR2 =
0.0634.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H31O4S: 463.1943; found:
463.1942.
4-n-Butoxy-6-chloro-2-(4-chlorophenyl)-3-(4-tolylsulfonyl)-2H-
chromene (6ac)
4-n-Butoxy-2-heptyl-3-(4-tolylsulfonyl)-2H-chromene (6ag)
Yield: 86 mg (63%); colorless solid; mp 77–79 °C (recrystallized from
hexanes/EtOAc).
Yield: 119 mg (79%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.56 (d, J = 8.4 Hz, 2 H), 7.23 (d, J = 2.0
Hz, 1 H), 7.20 (d, J = 8.4 Hz, 2 H), 7.17–7.12 (m, 5 H), 6.71 (d, J = 8.4 Hz,
1 H), 6.46 (s, 1 H), 4.06–4.00 (m, 1 H), 3.95–3.89 (m, 1 H), 2.40 (s, 3 H),
1.94–1.85 (m, 2 H), 1.56–1.48 (m, 2 H), 1.04 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.0, 153.8, 144.4, 138.7, 135.2,
135.1, 132.7, 129.5 (2 ×), 129.2 (2 ×), 128.7 (2 ×), 128.0 (2 ×), 127.0,
124.0, 121.8, 119.5, 119.4, 75.8, 75.2, 32.0, 21.6, 19.0, 13.9.
1H NMR (400 MHz, CDCl3):  = 7.91 (d, J = 8.4 Hz, 2 H), 7.32 (dd, J = 0.8,
8.8 Hz, 2 H), 7.26 (dt, J = 1.6, 8.0 Hz, 2 H), 6.94 (dt, J = 1.2, 7.6 Hz, 1 H),
6.91 (dd, J = 1.2, 8.8 Hz, 1 H), 5.41 (dd, J = 3.2, 10.0 Hz, 1 H), 3.97–3.91
(m, 1 H), 3.67–3.61 (m, 1 H), 2.43 (s, 3 H), 1.82–1.73 (m, 3 H), 1.59–
1.51 (m, 1 H), 1.47–1.38 (m, 4 H), 1.28–1.22 (m, 8 H), 0.97 (t, J = 7.2
Hz, 3 H), 0.86 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 155.8, 155.5, 144.0, 140.0, 132.7,
129.4 (2 ×), 127.8 (2 ×), 124.4, 122.3, 121.4, 118.2, 117.9, 75.2, 74.4,
33.5, 31.9, 31.7, 29.1, 28.9, 25.4, 22.6, 21.6, 19.0, 14.1, 13.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H25Cl2O4S: 503.0851;
found: 503.0853.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C27H37O4S: 457.2413; found:
457.2412.
4-n-Butoxy-7-methoxy-3-(4-tolylsulfonyl)-2-(3,4,5-trimethoxy-
phenyl)-2H-chromene (6ad)
Yield: 140 mg (84%); colorless solid; mp 146–148 °C (recrystallized
from hexanes/EtOAc).
4-Benzyloxy-2-(3,4-dimethoxyphenyl)-3-(methylsulfonyl)-2H-
chromene (6ah)
1H NMR (400 MHz, CDCl3):  = 7.61 (d, J = 8.0 Hz, 2 H), 7.21–7.17 (m, 3
H), 6.46 (dd, J = 2.4, 8.8 Hz, 1 H), 6.43 (s, 2 H), 6.41 (s, 1 H), 6.33 (d, J =
2.4 Hz, 1 H), 4.06–4.00 (m, 1 H), 3.92–3.86 (m, 1 H), 3.78 (s, 3 H), 3.73
(s, 3 H), 3.58 (s, 6 H), 2.37 (s, 3 H), 1.91–1.84 (m, 2 H), 1.55–1.47 (m, 2
H), 1.01 (t, J = 7.2 Hz, 3 H).
Yield: 95 mg (70%); colorless solid; mp 154–156 °C (recrystallized
from hexanes/EtOAc).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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1H NMR (400 MHz, CDCl3):  = 7.60–7.58 (m, 2 H), 7.50–7.39 (m, 4 H),
7.29 (dt, J = 1.6, 8.0 Hz, 1 H), 7.00 (dt, J = 0.8, 8.0 Hz, 1 H), 6.96 (d, J =
2.0 Hz, 1 H), 6.93 (dd, J = 2.0, 8.0 Hz, 1 H), 6.85 (dd, J = 0.8, 8.0 Hz, 1 H),
6.73 (d, J = 8.0 Hz, 1 H), 6.35 (s, 1 H), 5.17 (d, J = 10.4 Hz, 1 H), 5.08 (d,
J = 10.0 Hz, 1 H), 3.80 (s, 3 H), 3.79 (s, 3 H), 3.03 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.8, 155.6, 149.7, 149.0, 135.6,
133.2, 129.7, 128.7 (3 ×), 128.5 (2 ×), 123.9, 121.7, 120.9, 119.7, 118.1,
117.5, 110.8, 110.7, 76.6, 75.5, 55.7, 55.6, 44.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C30H26FO6S: 533.1434; found:
533.1432.
Single-crystal X-ray analysis: crystals of 6aj were grown by slow dif-
fusion of EtOAc into a solution of 6aj in CH2Cl2, which yielded color-
less prisms. Compound 6aj crystallized in the monoclinic crystal sys-
tem, space group P21/c, a = 12.1195(4) Å, b = 16.7902(5) Å, c =
13.7432(5) Å, V = 2567.39(15) Å3, Z = 4, dcalcd = 1.378 g/cm3, F(000) =
1112, 2θ range 1.830–26.396°, R indices (all data) R1 = 0.0773, wR2 =
0.1101.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H25O6S: 453.1372; found:
453.1372.
2-(3,4-Dimethoxyphenyl)-4-(naphthalen-1-ylmethoxy)-3-(4-tolyl-
sulfonyl)-2H-chromene (6ak)
3-Benzyl-2-(3,4-dimethoxyphenyl)-3-(methylsulfonyl)chroman-
4-one (6ah-1)
Yield: 118 mg (68%); colorless solid; mp 150–152 °C (recrystallized
from hexanes/EtOAc).
Yield: 15 mg (11%); colorless solid; mp 205–207 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.26–8.24 (m, 1 H), 7.96–7.93 (m, 2 H),
7.76 (d, J = 6.8 Hz, 1 H), 7.62–7.55 (m, 3 H), 7.53 (d, J = 8.8 Hz, 2 H),
7.32 (dd, J = 1.2, 7.6 Hz, 1 H), 7.23 (dt, J = 1.6, 7.6 Hz, 1 H), 6.99 (d, J =
8.4 Hz, 2 H), 6.86 (dt, J = 0.8, 8.4 Hz, 1 H), 6.83 (dt, J = 0.8, 8.4 Hz, 1 H),
6.80 (dd, J = 2.0, 8.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1 H), 6.63 (d, J = 8.0 Hz,
1 H), 6.54 (s, 1 H), 5.63 (d, J = 11.6 Hz, 1 H), 5.40 (d, J = 11.6 Hz, 1 H),
3.81 (s, 3 H), 3.60 (s, 3 H), 2.27 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.9, 155.7, 149.6, 148.7, 143.9,
138.9, 133.6, 133.1, 132.2, 131.1, 129.3, 129.1, 129.0 (2 ×), 128.7,
128.1 (3 ×), 126.6, 126.1, 126.0, 125.4, 124.3, 123.8, 121.8, 121.6,
120.9, 118.1, 111.1, 110.6, 76.3, 74.3, 55.8, 55.5, 21.4.
1H NMR (400 MHz, CDCl3):  = 8.01 (dd, J = 1.6, 8.0 Hz, 1 H), 7.59 (dt,
J = 2.0, 8.4 Hz, 1 H), 7.35–7.27 (m, 5 H), 7.13 (dt, J = 0.8, 8.0 Hz, 1 H),
7.05 (dd, J = 0.8, 8.0 Hz, 1 H), 6.92 (d, J = 2.4 Hz, 1 H), 6.88 (dd, J = 2.4,
8.4 Hz, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 5.68 (s, 1 H), 3.85 (s, 3 H), 3.85 (d,
J = 14.8 Hz, 1 H), 3.72 (s, 3 H), 3.60 (d, J = 14.4 Hz, 1 H), 2.52 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 188.5, 160.7, 150.0, 148.4, 137.5,
133.1, 131.2 (2 ×), 128.4 (2 ×), 127.7, 127.6, 126.6, 122.2, 121.8, 120.4,
118.4, 113.0, 110.5, 82.1, 75.9, 55.82, 55.78, 41.1, 36.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C25H25O6S: 453.1372; found:
453.1374.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C35H31O6S: 579.1841; found:
579.1842.
4-Benzyloxy-2-(3,4-dimethoxyphenyl)-3-(4-tolylsulfonyl)-2H-
chromene (6ai)
2-Phenylchroman-4-one (8a)14
Yield: 120 mg (76%); colorless solid; mp 143–145 °C (recrystallized
from hexanes/EtOAc).
PyBOP (172 mg, 0.33 mmol) was added to a solution of 2a (41 mg, 0.3
mmol) and Cu(OAc)2 (60 mg, 0.33 mmol) in DMF (2 mL) at 25 °C. The
reaction mixture was stirred at 25 °C for 5 min. DMAP (40 mg, 0.33
mmol) was added and the reaction mixture was stirred at reflux for 2
h, then cooled to 25 °C. Ethyl ester 7 (58 mg, 0.33 mmol) in DMF (1
mL) was added at 25 °C and the reaction mixture was stirred at reflux
for an additional 1 h, then cooled to 25 °C. Then, 5a (138 mg, 1.0
mmol) was added at 25 °C and the reaction mixture was stirred at re-
flux for an additional 2 h (monitored by TLC), then cooled to 25 °C
and concentrated. The residue was diluted with water (10 mL) and the
mixture was extracted with CH2Cl2 (3 × 20 mL). The combined organ-
ic layers were washed with brine, dried, filtered, and concentrated
under reduced pressure to afford crude product. Purification on silica
gel (hexanes/EtOAc, 8:1 to 4:1) afforded 8a.
1H NMR (400 MHz, CDCl3):  = 7.60–7.58 (m, 2 H), 7.50–7.43 (m, 5 H),
7.34 (dd, J = 1.2, 8.0 Hz, 1 H), 7.24–7.20 (m, 1 H), 7.06 (d, J = 8.0 Hz, 2
H), 6.91 (dd, J = 1.2, 8.0 Hz, 1 H), 6.81–6.77 (m, 2 H), 6.73 (d, J = 2.0 Hz,
1 H), 6.63 (d, J = 8.0 Hz, 1 H), 6.50 (s, 1 H), 5.09 (d, J = 10.4 Hz, 1 H),
5.04 (d, J = 10.8 Hz, 1 H), 3.81 (s, 3 H), 3.60 (s, 3 H), 2.33 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 156.4, 155.6, 149.5, 148.6, 143.9,
138.9, 136.0, 133.0, 130.6, 130.4, 129.3, 129.0 (2 ×), 128.7 (2 ×), 128.5,
128.2 (2 ×), 128.1 (2 ×), 124.0, 121.6, 120.9, 118.1, 111.0, 110.5, 76.3,
76.2, 55.8, 55.5, 21.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C31H29O6S: 529.1685; found:
529.1688.
Yield: 44 mg (65%); colorless solid; mp 77–79 °C (recrystallized from
hexanes/EtOAc).
4-Benzyloxy-2-(3,4-dimethoxyphenyl)-3-[(4-fluorophenyl)sulfo-
nyl]-2H-chromene (6aj)
Yield: 118 mg (74%); colorless solid; mp 160–162 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.94 (dd, J = 1.6, 8.0 Hz, 1 H), 7.54–7.39
(m, 6 H), 7.08–7.04 (m, 2 H), 5.49 (dd, J = 2.8, 13.2 Hz, 1 H), 3.10 (dd,
J = 13.2, 16.8 Hz, 1 H), 2.90 (dd, J = 2.8, 16.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 192.0, 161.5, 138.7, 136.2, 128.84
(2 ×), 128.76, 127.0, 126.1 (2 ×), 121.6, 120.9, 118.1, 79.6, 44.6.
1H NMR (400 MHz, CDCl3):  = 7.61–7.55 (m, 4 H), 7.52–7.45 (m, 3 H),
7.37 (dd, J = 1.6, 8.0 Hz, 1 H), 7.26–7.22 (m, 1 H), 6.95–6.89 (m, 3 H),
6.80 (dd, J = 0.8, 8.0 Hz, 1 H), 6.77 (d, J = 2.0 Hz, 1 H), 6.70 (dd, J = 2.0,
8.4 Hz, 1 H), 6.61 (d, J = 8.4 Hz, 1 H), 6.48 (s, 1 H), 5.13 (d, J = 10.4 Hz, 1
H), 5.08 (d, J = 10.4 Hz, 1 H), 3.81 (s, 3 H), 3.66 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13O2: 225.0916; found:
225.0918.
13C NMR (100 MHz, CDCl3):  = 165.3 (d, J = 253.9 Hz), 156.8, 155.6,
149.7, 148.8, 137.8 (d, J = 3.1 Hz), 135.8, 133.3, 130.9 (d, J = 9.1 Hz,
2 ×), 129.1, 128.74 (2 ×), 128.68, 128.3 (2 ×), 124.0, 121.7, 121.4,
120.7, 118.2, 117.6, 115.5 (d, J = 21.9 Hz, 2 ×), 111.1, 110.5, 76.5, 76.2,
55.8, 55.6.
Funding Information
The authors would like to thank the Ministry of Science and Technol-
ogy of the People’s Republic of China for financial support (MOST
106-2628-M-037-001-MY3).
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L

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Supporting Information
(d) Graham, T. J. A.; Doyle, A. G. Org. Lett. 2012, 14, 1616. For
Ga(III), see: (e) Yadav, J. S.; Reddy, B. V. S.; Biswas, S. K.;
Sengupta, S. Tetrahedron Lett. 2009, 50, 5798. For Fe(III), see:
(f) Calmus, L.; Corbu, A.; Cossy, J. Adv. Synth. Catal. 2015, 357,
1381. For Pd(II), see: (g) Zeng, B.-S.; Yu, X.; Siu, P. W.; Scheidt, K.
A. Chem. Sci. 2014, 5, 2277. (h) Jiang, Z.-Z.; Gao, A.; Li, H.; Chen,
D.; Ding, C.-H.; Xu, B.; Hou, X.-L. Chem. Asian J. 2017, 12, 3119.
(i) Xia, Y.; Xia, Y.; Zhang, Y.; Wang, J. Org. Biomol. Chem. 2014,
12, 9333.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1689973.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–L