MeONH 2·hCl-Mediated α-Methylenation/Conjugate Addition of α-Sulfonylo-Hydroxyacetophenones with Methyl Sulfoxides: Route to 3-Sulfonylchroman-4-ones

Article abstract of DOI:10.1055/s-0040-1707245

A novel and efficient route for the synthesis of 3-sulfonylchroman-4-ones from α-sulfonyl o -hydroxyacetophenones with methyl sulfoxides via a MeONH ₂·HCl-mediated sequential methylenation/ conjugate addition is described. Plausible reaction mechanisms are proposed and discussed. Various reaction conditions for this novel, one-pot, environmentally friendly conversion were investigated.

Full text of DOI:10.1055/s-0040-1707245

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–K
paper
A
en
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
MeONH2·HCl-Mediated -Methylenation/Conjugate Addition of
-Sulfonyl o-Hydroxyacetophenones with Methyl Sulfoxides:
Route to 3-Sulfonylchroman-4-ones
Meng-Yang Chang*a,b
Kuan-Ting Chena
0
0
0
0-
0
0
0
2-1
9
8
3-8
5
7
0
O
O
O
O
O
O
MeONH2·HCl
(2.0 equiv)
S
S
R1
R
R
S
+
Ar
Ar
CH2
O
OH
O
a Department of Medicinal and Applied Chemistry, Kaohsiung
Medical University, Kaohsiung 807, Taiwan
mychang@kmu.edu.tw
b Department of Medical Research, Kaohsiung Medical University
Hospital, Kaohsiung 807, Taiwan
DMSO as dual role
>30 examples
up to 93% yield
Received: 06.07.2020
Accepted after revision: 13.07.2020
Published online: 19.08.2020
the best of our knowledge, no examples have been reported
for the tandem -methylenation/conjugate addition process
to establish the core skeleton of sulfonylchroman-4-ones.
Substituted chroman-4-ones are versatile skeletons
common in useful synthetic intermediates10 and bioactive
molecules.11 Representative synthetic routes toward 3-sul-
fonylchroman-4-ones are shown in Scheme 1, including our
previous reports on (i) double conjugated addition of -sul-
fonyl o-hydroxyacetophenones with alkynones12a and (ii)
Dean–Stark dehydration of -sulfonyl o-hydroxyacetophe-
nones with aryl aldehydes.12b Two common and classic ex-
amples have been described, namely (i) H2O2-mediated oxi-
dation of -sulfenylchroman-4-ones12c and (ii) nucleophilic
substitution of -bromochroman-4-ones with sodium sul-
finates (RSO2Na).12d As a result of recent finding,12 new
methods for the preparation of 3-sulfonylchroman-4-ones
are needed. For their preparation, no routes using Umpol-
ung bond formation have been studied.13,14
DOI: 10.1055/s-0040-1707245; Art ID: ss-2020-g0366-op
Abstract A novel and efficient route for the synthesis of 3-sulfonyl-
chroman-4-ones from -sulfonyl o-hydroxyacetophenones with methyl
sulfoxides via
a MeONH2·HCl-mediated sequential methylenation/
conjugate addition is described. Plausible reaction mechanisms are pro-
posed and discussed. Various reaction conditions for this novel, one-
pot, environmentally friendly conversion were investigated.
Key words chroman-4-ones, o-hydroxyacetophenones, methylena-
tion, methyl sulfoxides, sulfonyl compounds
In the field of organic synthesis, solvents as reactants or
reagents for the efficient installation of a methylene moiety
have attracted the continuous attention of many chemists
on the basis of cost and easy availability perspectives.1
Therefore, the development of diversified reaction systems
involving a ‘CH2 synthon’ in the construction of functional-
ized molecules from purchased solvents would be highly
valuable. Generally, CH2Cl2 is one of the most common
methylene bridges for carbon–heteroatom bond formation.2
By using DMF and DMA, transition-metal-catalyzed oxida-
tive methylene-linked dimerizations of bicyclic het-
eroarenes have been performed.3 The bridging methylena-
tion of two aromatics has been described by choosing
DMSO as a one-carbon (CH2) source to afford symmetric or
asymmetric products.4 Other solvents, such as toluene,
MeCN and MeNO2, have been employed as conjugated CH2
units to insert into the desired target blocks.5–7 Among
these solvents, DMSO exhibits high polarity, low toxicity
and relative stability, resulting in a number of synthetic ap-
plications.8 Compared with these reported synthetic varia-
tions of different methods, there has been little focus on
DMSO-mediated, one-pot methylene bond formations.9 To
Dean–Stark
dehydration (ref. 12b)
O
O
O
oxidation (ref. 12c)
conjugated
addition (ref. 12a)
S
R
O
H2O2
O
Ar
O
O
O
O
H
S
S
Ar'
R
R
Ar
Ar
HOAc
O
O
H
piperidine
O
CuI
K2CO3
HOAc
Ar'
O
O
O
S
R
Ar
nucleophilic
substitution (ref. 12d)
Umpolung bond
formation (this work)
O
MeONH2·HCl
3-sulfonylchroman-4-ones
O
O
O
O
Br
S
R
δ−
Ar
Ar
O
H2
R1
O
O
δ−
H
C
S
δ−
S
H
O
R
O
Scheme 1 Synthetic routes toward 3-sulfonylchroman-4-ones
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
Very recently, we reported the synthesis of ,-bis-sul-
fonyl aryl ketones 3 via NH2OH·HCl-mediated Umpolung -
methylsulfonylation of -sulfonyl ketones 1 (X = H) with
methyl sulfoxides 2, as shown in Scheme 2.15 Continuing
our research on -sulfonyl o-hydroxyacetophenones 1 (X =
OH),12a,b herein we present the synthesis of 3-sulfonylchro-
man-4-ones 4 via a MeONH2·HCl (2.0 equiv) mediated, one-
pot (5+1) annulation process. These results highlight that
DMSO with the dual role of reagent and solvent plays a key
role in effecting different kinds of products.
15% yield of 4a (entry 13). When the small methyl group of
MeONH2·HCl was changed to a bulkier benzyl group,
BnONH2·HCl, a lower yield of 4a was provided (78%, entry
14). To check other methylene sources, four reported sol-
vents were chosen as reagents to screen the reaction condi-
tions (entries 15–18). By replacing DMSO with DMF, DMA,
MeNO2 or toluene, however, 4a could not be generated.
With the removal of HCl, only an oxime product was isolat-
ed, in 88% yield (entry 19). Free MeONH2 did not promote
the Umpolung reaction successfully, so the desired 4a was
not produced. From these observations, we conclude that
alkoxy-linked primary amine (MeONH2 or BnONH2), protic
acid (HCl) and DMSO are the three key factors that effect
the formation of 3-sulfonylchroman-4-ones. The molecular
structure of 4a was determined by single-crystal X-ray
analysis.16
1,2-bis-sulfones
(previous work)
chroman-4-ones
(this work)
O
X
X = H
X = OH
O
O
O
O
S
O
O
O
O
R
NH2OH-HCl
MeONH2-HCl
S
S
Ar
R
R1
R
+
Ar
H2
C
Ar
R1
CH2
H2C
O
S
S
H
O
O
3
1
2
O
4
Table 1 Investigation of the Reaction Conditionsa
Scheme 2 DMSO-mediated reactions
MeO
O
O
N
O
O
O
O
O
O
S
S
S
promoters
conditions
Tol
Tol
Tol
S
+
On the basis of our previous NH2OH·HCl/DMSO combi-
nation conditions, the investigation commenced with treat-
ing model substrate 1a (Ar = C6H4, R = Tol, X = OH; 1.0
mmol), NH2OH·HCl (1.1 equiv) and DMSO (2a, 2 mL) at
100 °C for 10 hours.15 In the initial concept, the desired
product 3a (Ar = Ph, R = Tol, R1 = Me) was anticipated in a
modest yield. Unexpectedly, only a complex mixture was
produced. Then, after changing the promoter from
NH2OH·HCl to MeONH2·HCl, 4a was isolated in 52% yield
under the reported conditions (Table 1, entry 1). By adjust-
ing the temperature from 100 °C to 25, 80 and 150 °C, for 10
hours, 4a was isolated in 0%, 42% and 50% yield, respectively
(entries 2–4). Under room temperature conditions, the re-
action could not be initiated, and starting material 1a was
recovered as the major material. Controlling the tempera-
ture at 100 °C, extended reaction times (15 and 20 h) en-
hanced the isolated yield of 4a (63%, 60%; entries 5, 6). Ac-
cordingly, 15 hours and 100 °C should be the optimal reac-
tion time and temperature, and could be applied to
switching the loading of MeONH2·HCl for the (5+1) annula-
tion process. Fortunately, higher yields of 4a (92% and 89%)
were observed with both 2.0 and 3.0 equivalents of
MeONH2·HCl (entries 7, 8). Thus, 2.0 equivalents of
MeONH2·HCl could provide a better yield of 4a (92%). Fur-
thermore, the reaction concentration was studied. When
the volume of DMSO was changed from 2 mL to 1 or 4 mL,
the isolated yields of 4a (88%, 85%; entries 9, 10) were simi-
lar to entry 7 (92%). These results demonstrated that the re-
action concentration (1.0, 0.5 and 0.25 M) has little influ-
ence on the formation of 4a. Then, three alternative pro-
moters (Et3N·HCl, C5H5N·HCl, DMPU·HCl; 2 equiv) were
used in our investigation of the reaction conditions. In two
cases, however, only 1a was recovered, and no expected 4a
was observed (entries 11, 12). DMPU·HCl provided only a
CH2
O
OH
O
OH
1a
2a
4a
A
Entry Promoter
Solvent
Time (h) Temp (°C) Yield (%) of 4ab
1
2
MeONH2·HCl
MeONH2·HCl
MeONH2·HCl
MeONH2·HCl
MeONH2·HCl
MeONH2·HCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSOf
DMSOg
DMSO
DMSO
DMSO
DMSO
DMF
10
10
10
10
15
20
15
15
15
15
15
15
15
15
15
15
15
15
15
100
25
52
c
–
3
80
42
50
63
60
92
89
88
85
4
150
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
5
6
7
MeONH2·HCld
MeONH2·HCle
MeONH2·HCld
MeONH2·HCld
Et3N·HCld
8
9
10
11
12
13
14
15
16
17
18
19
c
–
C5H5N·HCld
–
c
DMPU·HCld
15
78
BnONH2·HCld
MeONH2·HCld
MeONH2·HCld
MeONH2·HCld
MeONH2·HCld
c
c
c
c
h
–
–
–
–
–
DMA
MeNO2
toluene
DMSO
d
MeONH2
a Reaction conditions: 1a (1.0 mmol), promoter (1.1 equiv), solvent (2 mL);
reactions were monitored by TLC.
b Isolated yields.
c No reaction.
d 2.0 equivalents.
e 3.0 equivalents.
f 1 mL.
g 4 mL.
h Oxime product A (88%) was isolated.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

C
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
Based on the above experimental results (Table 1), a
plausible mechanism for the formation of 4a is proposed, as
illustrated in Scheme 3. Initially, intermolecular condensa-
tion of 1a with 1 equivalent of MeONH2·HCl yields oxime A
and H2O. After tautomerization of oxime A, enamine B with
Z- and E-isomers is generated, and DMSO (2a) can trap the
released 2 equivalents of HCl (formed in situ from
MeONH2·HCl) to produce methylsulfonium methylide salt D
by the removal of HCl and H2O.4a Following the intermolec-
ular conjugation of B and D, the oxygen atom on the phenol
attacks the methylide moiety of D to achieve E. Further-
more, proton exchange between the oxonium ion and sulfo-
nium ion triggers the transformation from E to F. After the
resulting chloride ion mediated deprotonation of F, the
enamine forces the elimination of methyl mercaptan
(MeSH) such that G with a six-membered ring is provided
via a sequential intramolecular annulation. With the releas-
ing of H2O and HCl, subsequent hydrolysis of G sponta-
neously forms 4a. Finally, MeONH2 can be regenerated for
the next cycle. From the above reaction pathways, basically,
catalytic amounts of MeONH2·HCl are enough to promote
the overall reaction, but the reaction efficiency is poor com-
pared with stoichiometric amounts of MeONH2·HCl.
electron-neutral, electron-donating oxygenated or elec-
tron-withdrawing groups. The yields of the provided 4l–4y
(73–87%, entries 12–25) were slightly lower than for 4a–4k.
From these results, we understood that good yields of 4a–
4y can be maintained with different Ar and R groups, which
have little influence on the yield outcome. Next, by chang-
ing the R1 group from Me to Ph, the MeONH2·HCl-mediated
reaction of 1a with 2b was studied (entry 26). However,
only an 11% yield of 4a was isolated along with generation
of the major product, oxime A (70%). On elongating the time
Table 2 Synthesis of 4a–4ya
O
O
O
O
O
O
3
Ar
6
S
S
MeONH2-HCl
R1
4
5
R
R
+
S
Ar
CH2
(2.0 equiv)
15 h, 100 °C
O
OH
O
1
2
4
Entry
1, Ar, R
2, R1
Yield (%) of 4b
1
2
1a, C6H4, Tol
1b, C6H4, Ph
2a, Me
4a, 92
4b, 90
4c, 86
4d, 87
4e, 87
4f, 90
4g, 93
4h, 86
4i, 84
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2b, Ph
2c, tBu
3
1c, C6H4, 4-FC6H4
4
1d, C6H4, 4-MeOC6H4
1e, C6H4, 3-MeC6H4
1f, C6H4, 4-EtC6H4
1g, C6H4, 4-iPrC6H4
1h, C6H4, 4-tBuC6H4
1i, C6H4, 4-nBuC6H4
1j, C6H4, Me
MeO
MeO
N
NH
O
S
O
O
5
S
MeONH2-HCl
(2 equiv)
DMSO (2a)
Tol
Tol
1a
O
6
– H2O
– MeONH2·HCl
– HCl
OH
OH
7
A
B
8
2 HCl
S
S
MeO
S
– H2O
– HCl
2 Cl
9
NH
O
S
O
O
H
H
Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
4j, 84
4k, 90
4l, 87
Tol
2a
C
D
O
1k, C6H4, nBu
O
H
E
S
Cl
1l, 4-FC6H3, Tol
H
MeO
MeO
N
Cl
N
O
S
O
O
1m, 4-ClC6H3, Tol
1n, 4-BrC6H3, Tol
1o, 4-MeC6H3, Tol
1p, 4-MeOC6H3, Tol
1q, 3-MeOC6H3, Tol
1r, 5-MeOC6H3, Tol
1s, 5-nBuOC6H3, Tol
1t, 4-PhC6H3, Tol
4m, 84
4n, 87
4o, 86
4p, 87
4q, 80
4r, 83
4s, 82
4t, 78
4u, 76
4v, 75
4w, 74
4x, 73
4y, 80
4a, 11c
4a, 6c
H2O, HCl
S
Tol
4a
Tol
O
S
– MeONH2
– MeSH
– HCl
CH2
H
O
O
G
F
Scheme 3 Plausible mechanism
To study the scope and limitations of this approach, 1a–1y
were reacted with MeONH2·HCl in methyl sulfoxides 2a–2c
to afford products 4a–4y, as shown in Table 2, entries 1–27.
With optimal conditions established (Table 1, entry 7) and a
plausible mechanism proposed (Scheme 3), we found that
this route allowed direct, one-pot Umpolung cross-cou-
plings under mild conditions in good to excellent yields. By
maintaining the Ar group as phenyl (Ar = C6H4, entries 1–
11) in the reaction of 1a–1k with DMSO (2a, R1 = Me), sul-
fonyl group variation showed that R substituents with ali-
phatic (Me, nBu) or electron-neutral, electron-donating ox-
ygenated or electron-withdrawing aromatic groups were
tolerated, and 4a–4k were obtained in 84–93% yield. Fur-
thermore, by controlling the sulfonyl group as tosyl (R =
Tol), the Ar group was changed to other aromatic rings with
1u, 4-(4-MeOC6H4)C6H3, Tol
1v, 4-(4-FC6H4)C6H3, Tol
1w, 4,6-F2C6H2, Tol
1x, C10H6 (2-naphthyl), Tol
1y, 4,6-Cl2C6H2, Tol
1a, C6H4, Tol
1a, C6H4, Tol
a Reaction conditions: 1a–1y (1.0 mmol), 2a–2c (2 mL), MeONH2·HCl (167
mg, 2 equiv), 15 h, 100 °C.
b Isolated yields.
c Oxime product A (entry 26, 70%; entry 27, 75%) was isolated.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

D
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
to 30 hours, the yield of the desired product 4a was de-
creased to trace amounts (<5%). On the other hand, treat-
ment of 1a with tert-butyl methyl sulfoxide (2c, R1 = tBu)
produced trace amounts of 4a (6%, entry 27). These results
show that a phenyl or tert-butyl group on methyl sulfoxide
2 possesses bulkier steric hindrance than the methyl group
such that the poor reactivity provides a low yield of 4a. All
products 4a–4y were obtained as racemates. The molecular
structures of 4f and 4x were determined by single-crystal
X-ray analysis.16
O
O
O
O
O
O
Cu(OAc)2
(2.2 equiv)
S
S
4
5
R
Me
Ar
Ar
+
S
15 h, 100 °C
O
6
2a
4a, Ar = C6H4, R = Tol
4j, Ar = C6H4, R = Me
4l, Ar = 4-FC6H3, R = Tol
4m, Ar = 4-ClC6H3, R = Tol
4w, Ar = 4,6-F2C6H2, R = Tol
4y, Ar = 4,6-Cl2C6H2, R = Tol
5a (90%)
5a (86%)
5b (87%)
5c (80%)
5d (75%)
5e (78%)
Cu
Cu(OAc)2
DMSO
DMSO
Me
O
S
OAc
H
S
S
S
Me
H
O
Me
With these results in hand, the synthetic application of
4 with 2a in the presence of Cu(OAc)2 was screened next
(Scheme 4). Initially, the Cu(OAc)2-mediated reaction of
starting material 4a with 2a provided 3-sulfanylchromen-
4-one 5a in 90% yield via an -sulfanylative desulfonylation
process. Based on the literature,17 we understood that the
combination of Cu(OAc)2 and DMSO could trigger the gen-
eration of three components, namely methyl mercaptan
(MeSH), formaldehyde (HCHO) and methylsulfonium me-
thylide ion II, via the six-membered-ring transition states I
and III. By the involvement of DMSO, the regenerated II
could be converted into III for the overall reaction cycle. Un-
der a Pummerer-type pathway, suspended brownish-black
copper oxide (CuO) particles were observed. Subsequently,
the in situ formed MeSH could be oxidized to dimethyl di-
sulfide (Me2S2) by molecular oxygen mediated dimeriza-
tion.18 Jain and co-workers have reported a similar phe-
nomenon for the formation of Me2S2 via Cu(OAc)2-mediated
thermal decomposition of DMSO.19 Then, -sulfanylation of
4a with the resulting Me2S2 provides IV. Subsequent re-
moval of RSO2H generates 5a. For the in situ desulfonyla-
tion,20 similar results have been reported for the introduc-
tion of an unsaturated conjugation system in the synthesis
of the quinoxaline skeleton.5a After changing the R group
from Tol to Me, 4j was also converted into 5a (86% yield)
based on this synthetic route.21 Furthermore, by controlling
R as the tolyl group, different Ar groups were tested. Treat-
ment of 4l, 4m, 4w and 4y under the Cu(OAc)2-mediated
conditions produced 5b–5e in 75–87% yield (Scheme 4).
The molecular structures of 5a and 5b were determined by
single-crystal X-ray analysis.16
Encouraged by the above results, we chose to replace
methyl sulfoxides 2a–2c by the symmetrical diethyl or
dibenzyl sulfoxides 2d–2g (R2 = Me, Ph, 4-MeOC6H4, 2-
naphthyl) as the carbon source, as shown in Scheme 5, eq 1.
Because sulfoxides 2d–2g with high boiling points are hard
to remove, we used 1.4 equivalents of 2d–2g to examine the
reaction in refluxing dioxane (101 °C). The temperature
was similar to the above-mentioned conditions (100 °C).
Under the optimal conditions, the expected 3-sulfonylfla-
van-4-ones 6a–6d with major trans-isomers were afforded
in 70–80% yield. By changing the substituents of sulfoxides
2, chroman-4-ones can be converted into flavan-4-ones. As
an extension of the MeONH2·HCl-mediated reaction of 1a
CuO
+ HOAc
OAc
I
II
III
H
Me
S
S
Pummerer-type pathway
Me
+
II
Cu(II)
Cu(I)
O2
O
H2C
O
O
O
O
S
S
4
Me
RSO2H
R
Me
S S
Me
Ar
Ar
Me
S
OAc
O
O
5
IV
Scheme 4 Synthesis of 5a–5e
with DMSO, ethyl formate (a carbonyl synthon) was exam-
ined next (eq 2). Using 1a, 1b as model substrates, two
Knoevenagel cycloadducts 7a, 7b with a chromen-4-one
skeleton were isolated in 80% and 74% yield, respective-
ly.22,23 In a subsequent reaction with 1a, when DMSO (2a)
was changed to DMSO-d6 (2h, eq 3), 8 was isolated in 86%
yield. This important result confirms the proposed reaction
mechanism.
In summary, we have developed a facile, one-pot route for
synthesizing 3-sulfonylchroman-4-ones via MeONH2·HCl-
mediated intermolecular Umpolung -methylenation and
sequential intramolecular conjugate addition of -sulfonyl
o-hydroxyacetophenones with methyl sulfoxides. Related
plausible reaction mechanisms have been proposed. The
structures of the key products were confirmed by X-ray
crystallography. The effects of various reaction conditions
were investigated to optimize this environmentally friendly
O
O
O
O
O
O
MeONH2-HCl
(2.0 equiv)
S
S
Tol
R2
Tol
(1)
S
R2
+
dioxane (2 mL)
15 h, 101 °C
R2
O
OH
O
1a
2d, R2 = Me
2e, R2 = Ph
6a (76%)
6b (80%)
6c (71%)
6d (70%)
2f, R2 = 4-MeOC6H4
2g, R2 = 2-naphthyl
O
O
O
O
O
O
MeONH2-HCl
(2.0 equiv)
S
S
H
OEt
R
R
(2)
(3)
+
15 h, 54 °C
O
OH
O
H
1a, R = Tol
1b, R = Ph
7a (80%)
7b (74%)
O
O
O
O
O
O
MeONH2-HCl
(2.0 equiv)
S
D
S
D3C
CD3
Tol
Tol
S
+
15 h, 100 °C
O
OH
O
D
1a
2h
8 (86%)
Scheme 5 Synthesis of 6a–6d, 7a, 7b and 8
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

E
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
transformation. Further investigations regarding synthetic
applications of -sulfonyl o-hydroxyacetophenones will be
conducted and the results reported in due course.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H18NO4S: 320.0957; found:
320.0960.
3-(Toluene-4-sulfonyl)chroman-4-one (4a)
Synthesized from 1a (290 mg, 1.0 mmol).
Yield: 278 mg (92%); white solid; mp 184–185 °C (recrystallized from
hexanes/EtOAc).
All reagents and solvents were obtained from commercial sources
and used without further purification. Reactions were routinely car-
ried out under an atmosphere of dry air, with magnetic stirring. A
heating mantle was used to provide a stable heat source. Products in
organic solvents were dried with anhydrous MgSO4 before concentra-
tion in vacuo. Melting points were determined with an SMP3 melting
1H NMR (400 MHz, CDCl3):  = 7.80 (dd, J = 1.6, 8.0 Hz, 1 H), 7.70 (d, J =
8.4 Hz, 2 H), 7.45 (dt, J = 1.6, 8.4 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 6.99
(dt, J = 1.2, 8.4 Hz, 1 H), 6.87 (dd, J = 1.2, 8.4 Hz, 1 H), 5.26 (dd, J = 2.8,
12.8 Hz, 1 H), 4.70 (dd, J = 4.0, 13.2 Hz, 1 H), 4.00 (dd, J = 2.8, 4.0 Hz, 1
H), 2.37 (s, 3 H).
1
point apparatus. H and 13C NMR spectra were recorded on a Varian
INOVA-400 spectrometer operating at 400 and at 100 MHz, respec-
tively. Chemical shifts () are reported in parts per million (ppm) and
coupling constants (J) are given in hertz. High-resolution mass spec-
tra were measured with a Finnigan/ThermoQuest MAT 95XL mass
spectrometer. X-ray crystal structures were obtained with an Enraf-
Nonius FR-590 diffractometer (CAD4, Kappa CCD).
13C{1H} NMR (100 MHz, CDCl3):  = 182.7, 160.8, 145.6, 136.9, 134.8,
129.5 (2 ×), 129.2 (2 ×), 127.4, 122.0, 120.4, 118.0, 68.6, 65.9, 21.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15O4S: 303.0691; found:
303.0697.
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 = 10.8297(6) Å, b = 6.8348(4) Å, c = 19.1877(10)
Å, V = 1372.38(13) Å3, Z = 4, dcalcd = 1.463 g/cm3, F(000) = 632, 2θ range
1.946–26.423°, R indices (all data) R1 = 0.0333, wR2 = 0.0756.
Skeleton 1; General Procedure12b
CuBr2 (450 mg, 2.0 mmol) was added to a solution of commercially
available, substituted o-hydroxyacetophenone (1.0 mmol) in EtOAc
(30 mL) at 25 °C. The reaction mixture was stirred at reflux for 10 h.
Then, the reaction mixture was cooled to 25 °C, filtered, neutralized
with saturated aq NaHCO3 (30 mL) and extracted with EtOAc (3 × 30
mL). The combined organic layers were washed with brine, dried, fil-
tered and evaporated under reduced pressure to afford crude product.
Without further purification, substituted sodium sulfinate (2.1
mmol) was added to the resulting substituted -bromo-o-hydroxy-
acetophenone in a cosolvent of dioxane and water [20 mL, 1:1 (v/v)]
at 25 °C. The reaction mixture was stirred at reflux for 3 h. Then, the
reaction mixture was cooled to 25 °C and extracted with CH2Cl2
(3 × 30 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated under reduced pressure to afford crude
product. Purification on silica gel (hexanes/EtOAc, 10:1–2:1) afforded
skeleton 1, known compounds whose analytical data are consistent
with the literature.12b
3-(Benzenesulfonyl)chroman-4-one (4b)
Synthesized from 1b (276 mg, 1.0 mmol).
Yield: 259 mg (90%); white solid; mp 141–142 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.85–7.79 (m, 3 H), 7.57 (dt, J = 1.2, 8.4
Hz, 1 H), 7.47–7.45 (m, 3 H), 6.99 (dt, J = 1.2, 8.4 Hz, 1 H), 6.86 (dd, J =
0.8, 8.4 Hz, 1 H), 5.28 (dd, J = 2.8, 12.8 Hz, 1 H), 4.71 (dd, J = 4.0, 12.8
Hz, 1 H), 4.04 (dd, J = 2.8, 4.0 Hz, 1 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.5, 160.8, 137.8, 137.0, 134.4,
129.3 (2 ×), 128.9 (2 ×), 127.4, 122.1, 120.4, 118.0, 68.7, 65.9.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H13O4S: 289.0535; found:
289.0539.
Oxime A and Compounds 4a–4y; General Procedure
3-(4-Fluorobenzenesulfonyl)chroman-4-one (4c)
MeONH2·HCl (167 mg, 2 mmol) was added to a solution of 1a–1y (1.0
mmol) in 2a–2c (2 mL) at 25 °C. The reaction mixture was stirred at
25 °C for 10 min, then at 100 °C for 15 h. The reaction mixture was
cooled to 25 °C, diluted with water (10 mL) and extracted with CH2Cl2
(3 × 20 mL). The combined organic layers were washed with brine,
dried, filtered and evaporated under reduced pressure to afford crude
product. Purification on silica gel (hexanes/EtOAc, 20:1–10:1) afford-
ed A and 4a–4y.
Synthesized from 1c (294 mg, 1.0 mmol).
Yield: 263 mg (86%); white solid; mp 149–150 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.87–7.83 (m, 2 H), 7.81 (dd, J = 1.6, 8.0
Hz, 1 H), 7.46 (dt, J = 2.0, 8.8 Hz, 1 H), 7.14–7.08 (m, 2 H), 7.01 (dt, J =
1.2, 8.0 Hz, 1 H), 6.87 (dd, J = 0.4, 8.4 Hz, 1 H), 5.29 (dd, J = 2.8, 12.8 Hz,
1 H), 4.72 (dd, J = 4.0, 12.8 Hz, 1 H), 4.03 (dd, J = 2.8, 4.0 Hz, 1 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.5, 166.2 (d, J = 257.0 Hz),
160.7, 137.2, 133.8, 132.3 (d, J = 9.8 Hz, 2 ×), 127.5, 122.3, 120.4,
118.1, 116.2 (d, J = 22.7 Hz, 2 ×), 68.8, 66.0.
1-(2-Hydroxyphenyl)-2-(toluene-4-sulfonyl)ethanone O-Methyl-
oxime (A)
19F NMR (376 MHz, CDCl3):  = –105.32 (s, 1 F).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C15H12FO4S: 307.0440; found:
Synthesized from 1a (290 mg, 1.0 mmol) using MeONH2 (Table 1, en-
try 19).
Yield: 281 mg (88%); white solid; mp 136–137 °C (recrystallized from
hexanes/EtOAc).
307.0449.
1H NMR (400 MHz, CDCl3):  = 10.5 (br s, 1 H), 7.71 (d, J = 8.4 Hz, 2 H),
7.54 (dd, J = 1.6, 8.0 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.27 (dt, J = 1.2,
7.6 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H), 4.73 (s, 2
H), 3.61 (s, 3 H), 2.43 (s, 3 H).
3-(4-Methoxybenzenesulfonyl)chroman-4-one (4d)
Synthesized from 1d (306 mg, 1.0 mmol).
Yield: 277 mg (87%); white solid; mp 117–118 °C (recrystallized from
hexanes/EtOAc).
13C{1H} NMR (100 MHz, CDCl3):  = 157.7, 149.9, 145.1, 136.2, 131.5,
129.3 (2 ×), 128.7, 128.6 (2 ×), 119.4, 117.4, 116.1, 62.5, 52.3, 21.6.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

F
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 7.81 (dd, J = 1.6, 8.0 Hz, 1 H), 7.79 (d, J =
8.8 Hz, 2 H), 7.45 (dt, J = 2.0, 8.8 Hz, 1 H), 6.99 (dt, J = 1.2, 8.0 Hz, 1 H),
6.89 (d, J = 8.8 Hz, 2 H), 6.87 (dd, J = 2.0, 8.4 Hz, 1 H), 5.26 (dd, J = 2.8,
12.8 Hz, 1 H), 4.70 (dd, J = 4.0, 12.8 Hz, 1 H), 3.99 (dd, J = 2.8, 4.0 Hz, 1
H), 3.82 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.8, 164.3, 160.8, 136.9, 131.6
(2 ×), 129.2, 127.4, 122.0, 120.5, 118.0, 114.1 (2 ×), 68.8, 66.1, 55.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H19O4S: 331.1004; found:
331.1015.
3-(4-tert-Butylbenzenesulfonyl)chroman-4-one (4h)
Synthesized from 1h (332 mg, 1.0 mmol).
Yield: 296 mg (86%); white solid; mp 158–159 °C (recrystallized from
hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15O5S: 319.0640; found:
319.0648.
1H NMR (400 MHz, CDCl3):  = 7.77 (dd, J = 1.6, 8.0 Hz, 1 H), 7.72 (d, J =
8.8 Hz, 2 H), 7.39 (d, J = 8.8 Hz, 2 H), 7.37 (dt, J = 2.0, 8.4 Hz, 1 H), 6.94
(dt, J = 0.8, 7.6 Hz, 1 H), 6.78 (dd, J = 0.8, 8.4 Hz, 1 H), 5.25 (dd, J = 2.4,
12.8 Hz, 1 H), 4.67 (dd, J = 4.0, 12.8 Hz, 1 H), 4.02 (dd, J = 2.4, 4.0 Hz, 1
H), 1.25 (s, 9 H).
3-(Toluene-3-sulfonyl)chroman-4-one (4e)
Synthesized from 1e (290 mg, 1.0 mmol).
Yield: 263 mg (87%); white solid; mp 117–118 °C (recrystallized from
hexanes/EtOAc).
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 160.6, 158.3, 136.8, 134.5,
129.2 (2 ×), 127.3, 125.8 (2 ×), 121.9, 120.4, 117.9, 68.8, 66.2, 35.1,
30.8 (3 ×).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H21O4S: 345.1161; found:
345.1169.
1H NMR (400 MHz, CDCl3):  = 7.82 (dd, J = 2.0, 8.0 Hz, 1 H), 7.64 (d, J =
6.8 Hz, 1 H), 7.63 (s, 1 H), 7.45 (dt, J = 1.6, 8.4 Hz, 1 H), 7.38–7.31 (m, 2
H), 7.00 (dt, J = 1.2, 8.0 Hz, 1 H), 6.87 (dd, J = 0.4, 8.4 Hz, 1 H), 5.28 (dd,
J = 2.4, 12.8 Hz, 1 H), 4.70 (dd, J = 4.0, 12.8 Hz, 1 H), 4.02 (dd, J = 2.4,
4.0 Hz, 1 H), 2.35 (s, 3 H).
3-(4-n-Butylbenzenesulfonyl)chroman-4-one (4i)
Synthesized from 1i (332 mg, 1.0 mmol).
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 160.8, 139.3, 137.6, 137.0,
135.1, 129.5, 128.8, 127.4, 126.5, 122.1, 120.5, 118.0, 68.7, 66.0, 21.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H15O4S: 303.0691; found:
Yield: 289 mg (84%); white solid; mp 136–137 °C (recrystallized from
hexanes/EtOAc).
303.0698.
1H NMR (400 MHz, CDCl3):  = 7.80 (dd, J = 1.6, 8.0 Hz, 1 H), 7.72 (d, J =
8.8 Hz, 2 H), 7.42 (dt, J = 1.6, 8.4 Hz, 1 H), 7.22 (d, J = 8.8 Hz, 2 H), 6.98
(dt, J = 0.8, 8.0 Hz, 1 H), 6.84 (dd, J = 0.4, 8.4 Hz, 1 H), 5.28 (dd, J = 2.8,
12.8 Hz, 1 H), 4.69 (dd, J = 4.0, 13.2 Hz, 1 H), 4.02 (dd, J = 2.8, 4.0 Hz, 1
H), 2.63–2.59 (m, 2 H), 1.57–1.49 (m, 2 H), 1.33–1.24 (m, 2 H), 0.91 (t,
J = 7.2 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 160.7, 150.4, 136.9, 134.9,
129.4 (2 ×), 128.9 (2 ×), 127.4, 122.0, 120.5, 118.0, 68.8, 66.1, 35.6,
33.0, 22.1, 13.8.
3-(4-Ethylbenzenesulfonyl)chroman-4-one (4f)
Synthesized from 1f (304 mg, 1.0 mmol).
Yield: 284 mg (90%); white solid; mp 142–143 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.79 (dd, J = 2.0, 8.0 Hz, 1 H), 7.73–7.71
(m, 2 H), 7.42 (dt, J = 2.0, 8.8 Hz, 1 H), 7.24 (d, J = 8.4 Hz, 2 H), 6.97 (dt,
J = 1.2, 8.0 Hz, 1 H), 6.84 (dd, J = 0.8, 8.4 Hz, 1 H), 5.26 (dd, J = 2.4, 12.8
Hz, 1 H), 4.69 (dd, J = 4.0, 12.8 Hz, 1 H), 4.01 (dd, J = 2.4, 4.0 Hz, 1 H),
2.65 (q, J = 7.6 Hz, 2 H), 1.18 (t, J = 7.6 Hz, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H21O4S: 345.1161; found:
345.1164.
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 160.7, 151.6, 136.9, 134.9,
129.4 (2 ×), 129.3 (2 ×), 127.4, 122.0, 120.4, 118.0, 68.7, 66.0, 28.8,
15.0.
3-(Methanesulfonyl)chroman-4-one (4j)
Synthesized from 1j (214 mg, 1.0 mmol).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O4S: 317.0848; found:
317.0855.
Yield: 190 mg (84%); white solid; mp 145–146 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.93 (dd, J = 1.6, 7.6 Hz, 1 H), 7.55 (dt,
J = 1.6, 8.4 Hz, 1 H), 7.09 (dt, J = 0.8, 8.0 Hz, 1 H), 7.03 (dd, J = 0.8, 8.4
Hz, 1 H), 5.20 (dd, J = 4.0, 12.8 Hz, 1 H), 4.77 (dd, J = 4.4, 12.8 Hz, 1 H),
3.98 (t, J = 4.0 Hz, 1 H), 3.12 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 183.5, 161.2, 137.5, 127.7, 122.4,
120.2, 118.4, 66.4, 64.5, 42.0.
Single-crystal X-ray analysis: crystals of 4f were grown by slow diffu-
sion of EtOAc into a solution of 4f in CH2Cl2, which yielded colorless
prisms. Compound 4f crystallized in the triclinic crystal system, space
group P1, a = 8.2604(4) Å, b = 8.4159(4) Å, c = 11.1927(6) Å, V =
723.83(6) Å3, Z = 2, dcalcd = 1.452 g/cm3, F(000) = 332, 2θ range 2.505–
26.432°, R indices (all data) R1 = 0.0721, wR2 = 0.1749.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H11O4S: 227.0378; found:
227.0383.
3-(4-Isopropylbenzenesulfonyl)chroman-4-one (4g)
Synthesized from 1g (318 mg, 1.0 mmol).
Yield: 307 mg (93%); white solid; mp 127–128 °C (recrystallized from
hexanes/EtOAc).
3-(n-Butane-1-sulfonyl)chroman-4-one (4k)
Synthesized from 1k (256 mg, 1.0 mmol).
Yield: 241 mg (90%); colorless gum.
1H NMR (400 MHz, CDCl3):  = 7.93 (dd, J = 1.6, 8.0 Hz, 1 H), 7.55 (dt,
J = 2.0, 7.6 Hz, 1 H), 7.08 (dt, J = 0.8, 8.0 Hz, 1 H), 7.03 (dd, J = 0.8, 8.4
Hz, 1 H), 5.22 (dd, J = 4.0, 12.8 Hz, 1 H), 4.77 (dd, J = 4.4, 12.8 Hz, 1 H),
3.95 (t, J = 4.0 Hz, 1 H), 3.33–3.21 (m, 2 H), 1.93–1.79 (m, 2 H), 1.53–
1.43 (m, 2 H), 0.96 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.79 (dd, J = 1.6, 8.0 Hz, 1 H), 7.73 (d, J =
8.4 Hz, 2 H), 7.41 (dt, J = 2.0, 8.4 Hz, 1 H), 7.26 (d, J = 8.8 Hz, 2 H), 6.97
(dt, J = 0.8, 8.0 Hz, 1 H), 6.82 (dd, J = 0.8, 8.4 Hz, 1 H), 5.28 (dd, J = 2.4,
12.8 Hz, 1 H), 4.69 (dd, J = 4.0, 12.8 Hz, 1 H), 4.01 (dd, J = 2.4, 4.0 Hz, 1
H), 2.94–2.87 (m, 1 H), 1.19 (d, J = 6.8 Hz, 6 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 160.7, 156.1, 136.9, 135.0,
129.5 (2 ×), 127.4, 126.9 (2 ×), 122.0, 120.5, 118.0, 68.8, 66.2, 34.2,
23.5, 23.4.
13C{1H} NMR (100 MHz, CDCl3):  = 183.8, 161.3, 137.4, 127.6, 122.3,
120.4, 118.4, 64.6, 64.5, 53.8, 23.5, 21.6, 13.5.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

G
M.-Y. Chang, K.-T. Chen
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H17O4S: 269.0848; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O4S: 317.0848; found:
269.0852.
317.0853.
6-Fluoro-3-(toluene-4-sulfonyl)chroman-4-one (4l)
6-Methoxy-3-(toluene-4-sulfonyl)chroman-4-one (4p)
Synthesized from 1l (308 mg, 1.0 mmol).
Synthesized from 1p (320 mg, 1.0 mmol).
Yield: 278 mg (87%); white solid; mp 186–187 °C (recrystallized from
hexanes/EtOAc).
Yield: 289 mg (87%); white solid; mp 152–153 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.70 (d, J = 8.4 Hz, 2 H), 7.46 (dd, J = 3.2,
8.0 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 2 H), 7.19 (ddt, J = 3.2, 4.0, 9.2 Hz, 1 H),
6.89 (dd, J = 4.0, 9.2 Hz, 1 H), 5.28 (dd, J = 2.4, 12.8 Hz, 1 H), 4.68 (dd,
J = 4.0, 12.8 Hz, 1 H), 3.99 (dd, J = 2.4, 4.0 Hz, 1 H), 2.40 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.72 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.0
Hz, 2 H), 7.21 (d, J = 3.2 Hz, 1 H), 7.07 (dd, J = 3.2, 8.8 Hz, 1 H), 6.81 (d,
J = 8.8 Hz, 1 H), 5.23 (dd, J = 2.8, 12.8 Hz, 1 H), 4.66 (dd, J = 4.0, 12.8 Hz,
1 H), 3.98 (dd, J = 2.8, 4.0 Hz, 1 H), 3.77 (s, 3 H), 2.39 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.1, 157.4 (d, J = 241.9 Hz),
157.1, 145.8, 130.3, 129.65 (2 ×), 129.3 (2 ×), 124.6 (d, J = 25.1 Hz),
120.8 (d, J = 6.8 Hz), 119.9 (d, J = 7.6 Hz), 112.3 (d, J = 23.5 Hz), 68.3,
66.1, 21.6.
13C{1H} NMR (100 MHz, CDCl3):  = 182.7, 155.7, 154.5, 145.6, 135.0,
129.6 (2 ×), 129.5, 129.3 (2 ×), 126.5, 119.4, 107.3, 68.5, 66.1, 55.8,
21.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O5S: 333.0797; found:
333.0805.
19F NMR (376 MHz, CDCl3):  = –122.12 (s, 1 F).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H14FO4S: 321.0597; found:
321.0602.
5-Methoxy-3-(toluene-4-sulfonyl)chroman-4-one (4q)
Synthesized from 1q (320 mg, 1.0 mmol).
6-Chloro-3-(toluene-4-sulfonyl)chroman-4-one (4m)
Yield: 266 mg (80%); white solid; mp 132–133 °C (recrystallized from
hexanes/EtOAc).
Synthesized from 1m (324 mg, 1.0 mmol).
Yield: 282 mg (84%); white solid; mp 154–155 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.77 (d, J = 2.8 Hz, 1 H), 7.69 (d, J = 8.4
Hz, 2 H), 7.40 (dd, J = 2.8, 9.2 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.88 (d,
J = 8.8 Hz, 1 H), 5.31 (dd, J = 2.8, 12.8 Hz, 1 H), 4.69 (dd, J = 4.0, 12.8 Hz,
1 H), 3.98 (dd, J = 2.4, 4.0 Hz, 1 H), 2.41 (s, 3 H).
1H NMR (400 MHz, CDCl3):  = 7.73 (d, J = 8.4 Hz, 2 H), 7.35 (t, J = 8.4
Hz, 1 H), 7.26–7.23 (m, 2 H), 6.48 (d, J = 8.4 Hz, 2 H), 5.19 (dd, J = 2.8,
12.8 Hz, 1 H), 4.64 (dd, J = 4.0, 12.8 Hz, 1 H), 3.96 (dd, J = 2.8, 4.0 Hz, 1
H), 3.87 (s, 3 H), 2.38 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 190.7, 162.3, 161.2, 145.3, 139.6,
136.9, 135.3, 129.5 (2 ×), 129.2 (2 ×), 109.9, 104.3, 69.7, 65.4, 56.2,
21.6.
13C{1H} NMR (100 MHz, CDCl3):  = 181.8, 159.3, 145.9, 136.8, 134.7,
129.7 (2 ×), 129.2 (2 ×), 127.7, 126.6, 121.1, 119.9, 68.2, 66.0, 21.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O5S: 333.0797; found:
333.0789.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H14ClO4S: 337.0301; found:
337.0308.
7-Methoxy-3-(toluene-4-sulfonyl)chroman-4-one (4r)
Synthesized from 1r (320 mg, 1.0 mmol).
6-Bromo-3-(toluene-4-sulfonyl)chroman-4-one (4n)
Synthesized from 1n (368 mg, 1.0 mmol).
Yield: 276 mg (83%); white solid; mp 133–134 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.76 (d, J = 8.8 Hz, 1 H), 7.71 (d, J = 8.4
Hz, 2 H), 7.27 (d, J = 7.2 Hz, 2 H), 6.57 (dd, J = 2.4, 8.8 Hz, 1 H), 6.32 (d,
J = 2.4 Hz, 1 H), 5.27 (dd, J = 2.8, 12.8 Hz, 1 H), 4.69 (dd, J = 4.0, 12.8 Hz,
1 H), 3.94 (dd, J = 2.8, 4.0 Hz, 1 H), 3.82 (s, 3 H), 2.40 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 181.0, 166.9, 163.0, 145.4, 135.0,
129.6 (2 ×), 129.3, 129.2 (2 ×), 114.4, 111.1, 100.6, 68.4, 66.1, 55.7,
21.6.
Yield: 331 mg (87%); white solid; mp 190–191 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.92 (d, J = 2.4 Hz, 1 H), 7.69 (d, J = 8.0
Hz, 2 H), 7.54 (dd, J = 2.4, 8.8 Hz, 1 H), 7.28 (d, J = 8.0 Hz, 2 H), 6.82 (d,
J = 8.4 Hz, 1 H), 5.30 (dd, J = 2.4, 12.8 Hz, 1 H), 4.68 (dd, J = 4.0, 12.8 Hz,
1 H), 3.98 (dd, J = 2.4, 4.0 Hz, 1 H), 2.41 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 181.7, 159.7, 145.9, 139.5, 134.6,
129.74, 129.71 (2 ×), 129.2 (2 ×), 121.6, 120.2, 114.8, 68.2, 66.0, 21.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H14BrO4S: 380.9796;
found: 380.9805.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O5S: 333.0797; found:
333.0806.
7-n-Butoxy-3-(toluene-4-sulfonyl)chroman-4-one (4s)
Synthesized from 1s (362 mg, 1.0 mmol).
6-Methyl-3-(toluene-4-sulfonyl)chroman-4-one (4o)
Synthesized from 1o (304 mg, 1.0 mmol).
Yield: 307 mg (82%); white solid; mp 63–64 °C (recrystallized from
hexanes/EtOAc).
Yield: 272 mg (86%); white solid; mp 172–173 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.73 (d, J = 9.2 Hz, 1 H), 7.70 (d, J = 8.4
Hz, 2 H), 7.25 (d, J = 8.0 Hz, 2 H), 6.54 (dd, J = 2.4, 8.8 Hz, 1 H), 6.29 (d,
J = 2.4 Hz, 1 H), 5.24 (dd, J = 2.4, 12.8 Hz, 1 H), 4.67 (dd, J = 4.0, 12.4 Hz,
1 H), 3.98–3.92 (m, 3 H), 2.39 (s, 3 H), 1.79–1.72 (m, 2 H), 1.51–1.42
(m, 2 H), 0.97 (t, J = 7.2 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 180.9, 166.4, 162.9, 145.4, 135.0,
129.5 (2 ×), 129.2 (3 ×), 114.2, 111.4, 101.0, 68.4, 68.3, 66.1, 30.8, 21.6,
19.1, 13.7.
1H NMR (400 MHz, CDCl3):  = 7.71 (d, J = 8.4 Hz, 2 H), 7.60 (dd, J = 1.2,
1.6 Hz, 1 H), 7.28–7.25 (m, 3 H), 6.79 (d, J = 8.4 Hz, 1 H), 5.23 (dd, J =
2.4, 12.8 Hz, 1 H), 4.67 (dd, J = 4.0, 12.8 Hz, 1 H), 3.97 (dd, J = 2.8, 4.0
Hz, 1 H), 2.39 (s, 3 H), 2.37 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.8, 159.0, 145.5, 138.1, 135.0,
131.6, 129.6 (2 ×), 129.2 (2 ×), 126.9, 120.1, 117.9, 68.6, 65.9, 21.6,
20.3.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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M.-Y. Chang, K.-T. Chen
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H23O5S: 375.1266; found:
375.1275.
13C{1H} NMR (100 MHz, CDCl3):  = 181.1, 159.1, 156.0 (dd, J = 9.8,
244.8 Hz), 151.4 (dd, J = 11.3, 253.2 Hz), 146.0, 134.5, 129.7 (2 ×),
129.3 (2 ×), 122.0, 111.8 (dd, J = 21.2, 28.0 Hz), 107.6 (dd, J = 3.8, 22.7
Hz), 68.5, 66.8, 21.6.
6-Phenyl-3-(toluene-4-sulfonyl)chroman-4-one (4t)
19F NMR (376 MHz, CDCl3):  = –122.38 (dt, J = 1.5, 8.6 Hz, 1 F),
–124.16 (dt, J = 1.9, 10.9 Hz, 1 F).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H13F2O4S: 339.0503; found:
Synthesized from 1t (366 mg, 1.0 mmol).
Yield: 295 mg (78%); white solid; mp 191–192 °C (recrystallized from
hexanes/EtOAc).
339.0506.
1H NMR (400 MHz, CDCl3):  = 8.03 (d, J = 2.4 Hz, 1 H), 7.74–7.70 (m, 3
H), 7.54–7.52 (m, 2 H), 7.45–7.42 (m, 2 H), 7.37–7.33 (m, 1 H), 7.06 (d,
J = 8.0 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 1 H), 5.33 (dd, J = 2.8, 13.2 Hz, 1 H),
4.74 (dd, J = 4.0, 12.8 Hz, 1 H), 4.03 (dd, J = 2.8, 4.0 Hz, 1 H), 2.38 (s, 3
H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.8, 160.2, 145.6, 139.1, 135.6,
129.6 (2 ×), 129.1 (2 ×), 129.0 (3 ×), 128.9, 127.6, 126.7 (2 ×), 125.4,
120.5, 118.6, 68.7, 66.0, 21.6.
3-(Toluene-4-sulfonyl)benzo[h]chroman-4-one (4x)
Synthesized from 1x (340 mg, 1.0 mmol).
Yield: 257 mg (73%); white solid; mp 185–186 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.18 (dd, J = 0.4, 8.4 Hz, 1 H), 7.75–7.73
(m, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.62 (dt, J = 1.2, 8.0 Hz, 1 H), 7.52 (dt,
J = 1.2, 8.0 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 1 H), 7.09 (d, J = 8.0 Hz, 2 H),
5.54 (dd, J = 2.4, 12.8 Hz, 1 H), 4.89 (dd, J = 4.0, 12.8 Hz, 1 H), 4.08 (dd,
J = 2.4, 4.0 Hz, 1 H), 2.18 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19O4S: 379.1004; found:
379.1015.
13C{1H} NMR (100 MHz, CDCl3):  = 182.0, 159.3, 145.5, 134.6, 130.3,
129.6, 129.4 (2 ×), 129.2 (2 ×), 127.7, 126.5, 124.3, 123.7, 121.8, 121.5,
120.3, 68.4, 66.6, 21.4.
6-(4-Methoxyphenyl)-3-(toluene-4-sulfonyl)chroman-4-one (4u)
Synthesized from 1u (396 mg, 1.0 mmol).
Yield: 310 mg (76%); white solid; mp 115–116 °C (recrystallized from
hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H17O4S: 353.0848; found:
353.0852.
1H NMR (400 MHz, CDCl3):  = 7.97 (d, J = 2.4 Hz, 1 H), 7.73 (d, J = 8.4
Hz, 2 H), 7.66 (dd, J = 2.4, 8.4 Hz, 1 H), 7.44 (d, J = 8.8 Hz, 2 H), 7.27–
7.25 (m, 2 H), 6.99–6.94 (m, 3 H), 5.31 (dd, J = 2.8, 12.8 Hz, 1 H), 4.73
(dd, J = 4.0, 12.8 Hz, 1 H), 4.02 (dd, J = 2.8, 4.0 Hz, 1 H), 3.85 (s, 3 H),
2.38 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.8, 160.0, 159.8, 145.6, 135.3,
135.0, 129.6 (2 ×), 129.5, 129.3 (2 ×), 129.0, 128.2, 127.8 (2 ×), 124.7,
118.5, 114.3 (2 ×), 68.7, 66.0, 55.4, 21.6.
Single-crystal X-ray analysis: crystals of 4x were grown by slow diffu-
sion of EtOAc into a solution of 4x in CH2Cl2, which yielded colorless
prisms. Compound 4x crystallized in the monoclinic crystal system,
space group P21/c, a = 14.1887(5) Å, b = 5.9979(2) Å, c = 19.5252(7) Å,
V = 1626.57(10) Å3, Z = 4, dcalcd = 1.487 g/cm3, F(000) = 758, 2θ range
2.131–26.373°, R indices (all data) R1 = 0.0409, wR2 = 0.0976.
6,8-Dichloro-3-(toluene-4-sulfonyl)chroman-4-one (4y)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H21O5S: 409.1110; found:
409.1118.
Synthesized from 1y (358 mg, 1.0 mmol).
Yield: 296 mg (80%); white solid; mp 120–121 °C (recrystallized from
hexanes/EtOAc).
6-(4-Fluorophenyl)-3-(toluene-4-sulfonyl)chroman-4-one (4v)
1H NMR (400 MHz, CDCl3):  = 7.70–7.68 (m, 3 H), 7.51 (d, J = 2.4 Hz, 1
H), 7.27 (d, J = 7.6 Hz, 2 H), 5.42 (dd, J = 2.4, 12.8 Hz, 1 H), 4.74 (dd, J =
4.0, 12.8 Hz, 1 H), 4.02 (dd, J = 2.4, 4.0 Hz, 1 H), 2.40 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 181.2, 155.0, 146.1, 136.3, 134.4,
129.7 (2 ×), 129.3 (2 ×), 127.3, 125.3, 124.2, 121.9, 68.1, 66.6, 21.7.
Synthesized from 1v (384 mg, 1.0 mmol).
Yield: 297 mg (75%); white solid; mp 164–165 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.98 (d, J = 2.4 Hz, 1 H), 7.73 (d, J = 8.0
Hz, 2 H), 7.66 (dd, J = 2.4, 8.4 Hz, 1 H), 7.50–7.46 (m, 2 H), 7.27 (d, J =
8.0 Hz, 2 H), 7.14–7.10 (m, 2 H), 6.99 (d, J = 8.8 Hz, 1 H), 5.34 (dd, J =
2.8, 12.8 Hz, 1 H), 4.74 (dd, J = 4.0, 12.8 Hz, 1 H), 4.02 (dd, J = 2.8, 4.0
Hz, 1 H), 2.39 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H13Cl2O4S: 370.9912;
found: 370.9921.
13C{1H} NMR (100 MHz, CDCl3):  = 182.8, 162.6 (d, J = 245.6 Hz),
160.2, 145.7, 135.5, 134.9, 134.4, 129.7 (2 ×), 129.5, 129.3 (2 ×), 129.0,
128.3 (d, J = 8.3 Hz, 2 ×), 125.3, 118.7, 115.8 (d, J = 21.9 Hz, 2 ×), 68.6,
66.0, 21.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H18FO4S: 397.0910; found:
397.0917.
Compounds 5a–5e; General Procedure
Cu(OAc)2 (200 mg, 1.1 mmol) was added to a solution of 4a, 4j, 4l, 4m,
4w or 4y (0.5 mmol) in DMSO (2a, 2 mL) at 25 °C. The reaction mix-
ture was stirred at 25 °C for 10 min, then at 100 °C for 15 h. The reac-
tion mixture was cooled to 25 °C, diluted with water (10 mL) and ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated under reduced
pressure to afford crude product. Purification on silica gel (hexanes/
EtOAc, 20:1–10:1) afforded 5a–5e.
6,8-Difluoro-3-(toluene-4-sulfonyl)chroman-4-one (4w)
Synthesized from 1w (326 mg, 1.0 mmol).
Yield: 250 mg (74%); white solid; mp 173–174 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.71 (d, J = 8.4 Hz, 2 H), 7.31–7.28 (m, 3
H), 7.08–7.03 (m, 1 H), 5.37 (dd, J = 2.4, 13.2 Hz, 1 H), 4.74 (dd, J = 4.0,
12.8 Hz, 1 H), 4.03 (dd, J = 2.4, 4.0 Hz, 1 H), 2.40 (s, 3 H).
3-(Methylsulfanyl)chromen-4-one (5a)
Synthesized from 4a (151 mg, 0.5 mmol) or 4j (113 mg, 0.5 mmol).
Yield from 4a: 86 mg (90%); yield from 4j: 83 mg (86%); white solid;
mp 87–88 °C (recrystallized from hexanes/EtOAc).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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M.-Y. Chang, K.-T. Chen
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Synthesis
1H NMR (400 MHz, CDCl3):  = 8.24 (dd, J = 1.6, 8.0 Hz, 1 H), 8.04 (s, 1
H), 7.67 (dt, J = 1.6, 8.8 Hz, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.41 (dt, J =
1.2, 8.0 Hz, 1 H), 2.40 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 175.6, 156.2, 153.9, 133.8, 126.0,
125.4, 123.1, 121.8, 118.0, 16.2.
6,8-Dichloro-3-(methylsulfanyl)chromen-4-one (5e)
Synthesized from 4y (185 mg, 0.5 mmol).
Yield: 101 mg (78%); white solid; mp 121–122 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 2.4 Hz, 1 H), 8.05 (s, 1 H),
7.72 (d, J = 2.4 Hz, 1 H), 2.40 (s, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H9O2S: 193.0323; found:
193.0330.
13C{1H} NMR (100 MHz, CDCl3):  = 173.8, 152.9, 150.6, 133.9, 131.1,
Single-crystal X-ray analysis: crystals of 5a were grown by slow diffu-
sion of EtOAc into a solution of 5a in CH2Cl2, which yielded colorless
prisms. Compound 5a crystallized in the monoclinic crystal system,
space group P21/n, a = 10.3835(5) Å, b = 7.5647(5) Å, c = 12.3143(7) Å,
V = 878.12(9) Å3, Z = 4, dcalcd = 1.454 g/cm3, F(000) = 400, 2θ range
2.165–26.425°, R indices (all data) R1 = 0.0441, wR2 = 0.1018.
124.6, 124.3, 124.2, 123.1, 15.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H7Cl2O2S: 260.9544; found:
260.9550.
Compounds 6a–6d; General Procedure
MeONH2·HCl (84 mg, 1 mmol) was added to a solution of 1a (145 mg,
0.5 mmol) and 2d–2g (0.7 mmol) in dioxane (2 mL) at 25 °C. The reac-
tion mixture was stirred at 25 °C for 10 min, then at reflux (101 °C)
for 15 h. The reaction mixture was cooled to 25 °C, diluted with water
(10 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were washed with brine, dried, filtered and evaporated under
reduced pressure to afford crude product. Purification on silica gel
(hexanes/EtOAc, 20:1–10:1) afforded 6a–6d.
6-Fluoro-3-(methylsulfanyl)chromen-4-one (5b)
Synthesized from 4l (160 mg, 0.5 mmol).
Yield: 91 mg (87%); white solid; mp 135–136 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.05 (s, 1 H), 7.86 (ddd, J = 0.4, 3.2, 8.0
Hz, 1 H), 7.47 (ddd, J = 0.4, 4.4, 9.2 Hz, 1 H), 7.39 (dt, J = 3.2, 9.2 Hz, 1
H), 2.39 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 174.9 (d, J = 2.3 Hz), 159.6 (d, J =
245.6 Hz), 153.9, 152.5, 124.2 (d, J = 7.6 Hz), 122.1 (d, J = 25.0 Hz),
121.4, 120.2 (d, J = 8.3 Hz), 110.8 (d, J = 23.5 Hz), 16.2.
2-Methyl-3-(toluene-4-sulfonyl)chroman-4-one (6a)
Yield: 120 mg (76%); two isomers, ratio >10:1; colorless solid; mp 59–
61 °C (recrystallized from hexanes/EtOAc).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H8FO2S: 211.0229; found:
211.0232.
1H NMR (400 MHz, CDCl3):  (major isomer) = 7.76 (ddd, J = 0.4, 1.6,
8.0 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.43 (ddd, J = 1.6, 7.2, 8.8 Hz, 1 H),
7.19 (d, J = 8.0 Hz, 2 H), 6.94 (dt, J = 1.2, 8.4 Hz, 1 H), 6.79 (dd, J = 0.4,
8.4 Hz, 1 H), 5.61 (dq, J = 1.2, 6.8 Hz, 1 H), 3.82 (d, J = 1.6 Hz, 1 H), 2.35
(s, 3 H), 1.44 (d, J = 6.8 Hz, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.6, 158.2, 145.5, 137.2, 134.3,
129.4 (2 ×), 129.2 (2 ×), 126.8, 121.5, 119.8, 118.5, 73.6, 71.9, 21.6,
18.4.
Single-crystal X-ray analysis: crystals of 5b were grown by slow diffu-
sion of EtOAc into a solution of 5b in CH2Cl2, which yielded colorless
prisms. Compound 5b crystallized in the triclinic crystal system,
space group P1, a = 3.9228(5) Å, b = 5.7519(9) Å, c = 19.400(3) Å, V =
436.52(11) Å3, Z = 2, dcalcd = 1.599 g/cm3, F(000) = 216, 2θ range
1.051–26.516°, R indices (all data) R1 = 0.0956, wR2 = 0.2494.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O4S: 317.0848; found:
317.0840.
6-Chloro-3-(methylsulfanyl)chromen-4-one (5c)
Synthesized from 4m (168 mg, 0.5 mmol).
2-Phenyl-3-(toluene-4-sulfonyl)chroman-4-one (6b)
Yield: 90 mg (80%); white solid; mp 132–133 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.20 (dd, J = 0.4, 2.8 Hz, 1 H), 8.03 (s, 1
H), 7.61 (dd, J = 2.8, 8.8 Hz, 1 H), 7.42 (dd, J = 0.4, 8.8 Hz, 1 H), 2.40 (s,
3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 174.5, 154.6, 153.7, 134.0, 131.4,
125.4, 124.0, 122.2, 119.8, 16.1.
Yield: 151 mg (80%); colorless solid; mp 131–133 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.72–7.70 (m, 3 H), 7.46 (dt, J = 1.6, 8.4
Hz, 1 H), 7.27–7.19 (m, 7 H), 6.95 (dd, J = 0.8, 7.6 Hz, 1 H), 6.91 (dd, J =
0.8, 8.4 Hz, 1 H), 6.57 (s, 1 H), 4.39 (d, J = 1.6 Hz, 1 H), 2.38 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.0, 159.0, 145.7, 137.4, 136.2,
134.2, 129.6 (2 ×), 129.4 (2 ×), 129.0 (2 ×), 128.7, 126.9, 126.1 (2 ×),
121.7, 120.8, 118.2, 76.2, 73.0, 21.6.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H8ClO2S: 226.9934; found:
226.9941.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C22H19O4S: 379.1004; found:
379.1009.
6,8-Difluoro-3-(methylsulfanyl)chromen-4-one (5d)
Synthesized from 4w (169 mg, 0.5 mmol).
2-(4-Methoxyphenyl)-3-(toluene-4-sulfonyl)chroman-4-one (6c)
Yield: 86 mg (75%); white solid; mp 163–164 °C (recrystallized from
hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 8.05 (s, 1 H), 7.70–7.67 (m, 1 H), 7.28–
Yield: 145 mg (71%); colorless solid; mp 121–123 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.72–7.68 (m, 3 H), 7.42 (dt, J = 1.6, 8.4
Hz, 1 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.13 (d, J = 8.4 Hz, 2 H), 6.92 (dt, J =
0.8, 8.0 Hz, 1 H), 6.85 (dd, J = 0.8, 8.4 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 2 H),
6.50 (s, 1 H), 4.38 (d, J = 0.8 Hz, 1 H), 3.71 (s, 3 H), 2.37 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 182.3, 159.7, 158.8, 145.6, 137.2,
134.3, 129.5 (2 ×), 129.3 (2 ×), 128.0, 127.6 (2 ×), 126.8, 121.6, 120.7,
118.3, 114.3 (2 ×), 76.0, 72.8, 55.2, 21.6.
7.22 (m, 1 H), 2.41 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 173.8, 158.4 (dd, J = 9.1, 247.9 Hz),
153.3, 152.9, 151.4 (dd, J = 11.4, 256.2 Hz), 125.1 (d, J = 7.6 Hz), 122.5,
109.3 (dd, J = 19.7, 28.1 Hz), 106.2 (dd, J = 4.5, 23.5 Hz), 16.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H7F2O2S: 229.0135; found:
229.0143.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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M.-Y. Chang, K.-T. Chen
Paper
Synthesis
HRMS (ESI-TOF): m/z [M + H]+ calcd for C23H21O5S: 409.1110; found:
409.1117.
with brine, dried, filtered and evaporated under reduced pressure to
afford crude product. Purification on silica gel (hexanes/EtOAc, 20:1–
10:1) afforded 8.
2-(Naphthalen-2-yl)-3-(toluene-4-sulfonyl)chroman-4-one (6d)
Yield: 261 mg (86%); white solid; mp 181–182 °C (recrystallized from
hexanes/EtOAc).
1H NMR (600 MHz, CDCl3):  = 7.82 (ddd, J = 0.6, 1.8, 7.8 Hz, 1 H), 7.72
(d, J = 8.4 Hz, 2 H), 7.46 (dt, J = 1.8, 8.4 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 2 H),
7.00 (dt, J = 0.6, 7.8 Hz, 1 H), 6.88 (dd, J = 0.6, 8.4 Hz, 1 H), 4.00 (s, 1 H),
2.39 (s, 3 H).
Yield: 150 mg (70%); colorless solid; mp 141–143 °C (recrystallized
from hexanes/EtOAc).
1H NMR (400 MHz, CDCl3):  = 7.79–7.68 (m, 6 H), 7.58 (br s, 1 H),
7.48–7.39 (m, 4 H), 7.26 (d, J = 8.8 Hz, 2 H), 6.96–6.91 (m, 2 H), 6.73 (s,
1 H), 4.57 (d, J = 1.2 Hz, 1 H), 2.39 (s, 3 H).
13C{1H} NMR (125 MHz, CDCl3):  = 182.7, 160.8, 145.6, 136.9, 134.9,
129.6 (2 ×), 129.3 (2 ×), 127.5, 122.1, 120.5, 118.1, 68.5, 65.4 (quintet,
J = 19.0 Hz, CD2), 21.6.
13C{1H} NMR (100 MHz, CDCl3):  = 182.1, 158.9, 145.7, 137.4, 134.3,
133.4, 132.9, 132.7, 129.6 (2 ×), 129.4 (2 ×), 129.2, 128.1, 127.5, 126.9,
126.8, 126.7, 125.5, 123.6, 121.8, 120.8, 118.3, 76.2, 72.6, 21.6.
2H NMR (92 MHz, CH2Cl2):  = 4.89 (d, J = 47.7 Hz, 2 D).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H21O4S: 429.1161; found:
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H13D2O4S: 305.0815;
429.1169.
found: 305.0820.
Compounds 7a, 7b; General Procedure
MeONH2·HCl (84 mg, 1 mmol) was added to a solution of 1a or 1b (0.5
mmol) in HCO2Et (2 mL) at 25 °C. The reaction mixture was stirred at
25 °C for 10 min, then at reflux (54 °C) for 15 h. The reaction mixture
was cooled to 25 °C, diluted with water (10 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were washed with
brine, dried, filtered and evaporated under reduced pressure to afford
crude product. Purification on silica gel (hexanes/EtOAc, 20:1–10:1)
afforded 7a, 7b.
Funding Information
The authors would like to thank the Ministry of Science and Technol-
ogy of the Republic of China, Taiwan for financial support (MOST 109-
2113-M-037-014-MY3).
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Supporting Information
3-(Toluene-4-sulfonyl)chromen-4-one (7a)
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707245. Included are scanned pho-
tocopies of NMR spectra for all compounds and X-ray analysis data of
Synthesized from 1a (145 mg, 0.5 mmol).
Yield: 120 mg (80%); white solid; mp 230–231 °C (recrystallized from
hexanes/EtOAc).
4a, 4f, 4x, 5a and 5b.
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1H NMR (400 MHz, CDCl3):  = 8.89 (s, 1 H), 8.16 (dd, J = 1.6, 8.0 Hz, 1
H), 8.05 (d, J = 8.4 Hz, 2 H), 7.72 (dt, J = 2.0, 8.8 Hz, 1 H), 7.52 (dd, J =
0.8, 8.4 Hz, 1 H), 7.44 (dt, J = 1.2, 8.0 Hz, 1 H), 7.33 (d, J = 8.0 Hz, 2 H),
2.41 (s, 3 H).
13C{1H} NMR (100 MHz, CDCl3):  = 171.5, 160.2, 156.0, 145.0, 136.7,
134.9, 129.5 (2 ×), 129.0 (2 ×), 126.7, 126.6, 126.2, 124.6, 118.4, 21.6.
References
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HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H13O4S: 301.0535; found:
301.0542.
3-(Benzenesulfonyl)chromen-4-one (7b)
Synthesized from 1b (138 mg, 0.5 mmol).
Yield: 106 mg (74%); white solid; mp 211–212 °C (recrystallized from
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1H NMR (400 MHz, CDCl3):  = 8.91 (s, 1 H), 8.20–8.15 (m, 3 H), 7.73
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3-(Toluene-4-sulfonyl)chroman-4-one-2,2-d2 (8)
MeONH2·HCl (167 mg, 2 mmol) was added to a solution of 1a (290
mg, 1.0 mmol) in DMSO-d6 (2h, 2 mL) at 25 °C. The reaction mixture
was stirred at 25 °C for 10 min, then at 100 °C for 15 h. The reaction
mixture was cooled to 25 °C, diluted with water (10 mL) and extract-
ed with CH2Cl2 (3 × 20 mL). The combined organic layers were washed
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K

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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–K