Gram-Scale Synthesis of 3-Sulfonyl Flavanones

Article abstract of DOI:10.1021/acs.joc.9b02980

In this paper, an easy-operational, high-yielding method for the gram-scale synthesis of 3-sulfonyl flavanones is described by a one-pot straightforward POCl₃ mediated intermolecular (5 + 1) annulation of the β-ketosulfones with an o-hydroxyaryl group (dual nucleophile) and arylaldehydes (dual electrophile) in refluxing toluene for 3 h. 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:10.1021/acs.joc.9b02980

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Article
Gram-Scale Synthesis of 3-Sulfonyl Flavanones
Meng-Yang Chang, Yu-Lin Tsai, and Yu-Lun Chang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02980 • Publication Date (Web): 05 Dec 2019
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Gram-Scale Synthesis of 3-Sulfonyl Flavanones
Meng-Yang Chang,*a,b Yu-Lin Tsaia and Yu-Lun Changa
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aDepartment of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan bDepartment of
Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
*Email: mychang@kmu.edu.tw
O
S
O
O
S
O
O
Gram-scale synthesis
sole stereoisomers
74%-93% yields
O
POCl
3
3
2
R
R
+
O
Ar
O
Ar'
Ar'
Ar
toluene
reflux, 3 h
OH
30 examples
ABSTRACT: In this paper, an easy-operational, high-yielding method for the gram-scale synthesis of 3-sulfonyl flavanones is
described by one-pot straightforward POCl3 mediated intermolecular (5+1) annulation of β-ketosulfones with an o-hydroxyaryl
group (dual nucleophile) and arylaldehydes (dual electrophile) in refluxing toluene for 3 h. 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.
Introduction
According to our long-standing interest in synthetic applica-
tions of β-ketosulfones4 and this duplicate addition protocol,
β-(o-hydroxyaryl)ketosulfone (a β-arylketosulfone analog)
was chosen as the starting material to develop the synthesis of
3-sulfonyl flavanones. Flavonoids (2-aryl dihydrobenzopyran-
4-ones) are found in plant metabolites having biological activi-
ties such as anticancer antitumor, antioxidant, and
antiproliferative properties.5-6 Due to their potential applica-
tions, the development of a concise synthetic route has attract-
ed significant attention, and many attempts have been reported.
The general approach toward flavanone could be achieved
from promoters mediating the ring-closure of 2’-
hydroxychalcone.7 The typical organocatalyst-promoted for-
mation of flavanone is investigated.8
Traditionally, many synthetic routes, such as A3-type cou-
pling1, the Pictet-Spengler reaction,2 and double Michael addi-
tion3 exhibit a one-pot twice reaction of two nucleophile
synthons and a dual electrophilic equivalent bearing a carbon-
yl unit or Michael acceptor (alkenyl or alkynyl), and these
could construct diversified frameworks by a tandem intermo-
lecular and/or intramolecular double-addition characteristic
process (Scheme 1). In this reaction of two nucleophilic atoms
attacking one-carbonyl or Michael acceptor carbon, water is
released as the only by-product, or atom-economic pathways
are exhibited. Moreover, these generated targets represent
useful key intermediates, building blocks, bioactive com-
pounds, natural products and functionalized materials based on
transition-metal catalyzed cross-coupling, organocatalysis
promoted annulation, Lewis acid-mediated cyclization and
other diversified approaches.
Scheme 2. Transition Metal Mediated Routes of Flavanones
O
O
O
O
S
Tol
Br Ar
BF K
Ar'
Ar'
Ar'
Scheme 1. One-pot Route for Double Addition
O
O
Ar
O
3
BrMg Ar
flavanone (1)
A3 coupling
Pictet-Spengler reaction
[Cu], Solladie (ref 8g)
O
[Ni], Molander (ref 8a)
NR
2
O
H O
+
N
R
+
2
t
CO Bu
2
H O
2
O
NaBAr
Ar
4
Ar'
Ar'
Ar
or
(HO) B Ar
N
R'
OH Ar
O
H
2
H
Ar'
2
R NH
2
ref 1a
ref 2a
O
O
NHR
[Pd], Stoltz (ref 8d)
[Rh], Liao (ref 8e)
[Rh], Korenaga (ref 8f)
[Ni], Feng (ref 8b)
O
Ar
+




R'
Ar
Ar
N
[Ru], Glorius (ref 8c)
H
dual electrophilic equivalent
Results and Discussion
NHTs
NHTs
N
N
EWG
EWG
Recently, transition metals promoting the pioneering meth-
ods have been explored as main strategies (Scheme 2).9 For
example, Molander and co-worker reported that the


ref 3b
Ts
ref 3a


H
N
N
N
EWG
Ts
photoredox Ni(II) complex mediated
a
direct α-
N
arylation/heteroarylation of 2-BF3K chromanones with
bromoarenes.9a Feng et al. developed a Ni(II) complex medi-
ated intramolecular oxa-Michael addition of t-butyl ester acti-
double Michael addition
EWG
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vated 2’-hydroxy-α,β-unsaturated ketones followed by decar-
the yield (43%) of 4a (entry 6). Then, to elevate the reaction
boxylation.9b Glorius et al. demonstrated a Ru(II)-NHC cata-
lyzed hydrogenation of flavones.9c Stoltz et al. explored the
Pd(II) mediated conjugated addition of flavones with
ArB(OH)2.9d Both Liao and Korenaga groups described an
Rh(I) catalyzed 1,4-addition of flavones with NaBAr4 or
ArB(OH)2.9e-f The Solladie group also reported a similar trans-
formation on a Cu(II) catalyzed Michael addition of flavones
with ArMgBr.9g While flavanones have been successfully em-
ployed in many routes, to the best of our knowledge, no
sulfonyl flavanones skeleton has been reported.10 In spite of
these advancements, some problems exist, such as expensive
reagents, complicated catalytic systems, lack of broad general-
ity, and prefunctionalized fragments. Therefore, further inves-
tigation into an efficient, easy-operational, high-yielding
method for the gram-scale synthesis of 3-sulfonyl flavanones 4
is still highly desired. Herein, we present a one-pot intermo-
lecular Knoevenagel condensation of β-ketosulfones 2 with an
o-hydroxyaryl group and arylaldehydes 3, followed by an
intramolecular oxa-Michael ring-closure of the resulting
sulfonyl (E)-chalcone via a (5+1) annulation mode (Scheme 3).
temperature (25  reflux), the yield of 4a was enhanced to
76% (entry 7) in 3 h. But, an elongated time (30 h) at reflux
temperature (102oC) decreased the yield (57%) of 4a (entry 8).
From the experiments, we found that a reflux temperature and
a shorter time (3 h) were key factors affecting the POCl3 (1.3
equiv) mediated reaction of 2a and 3a. To achieve better
yields of 4a, other solvents (toluene, benzene, DMF) were
tested. When MeNO2 was changed to toluene and benzene,
higher yields (87% and 86%) were obtained (entries 9-10).
3
4
5
6
7
8
9
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Table 1. Synthesis of 4aa
O
S
O
O
O
O
3
2
S
reagent
OMe
OMe
Tol
Tol
+
O
O
OMe
OMe
solvent
condition
OH
2a
O
3a
4a
entry reagent (equiv) solvents temp (oC) time (h) 4a(%)b-c
1
2
3
4
5
6
7
8
9
POCl3 (0.3)
POCl3 (0.3)
POCl3 (1.0)
POCl3 (1.3)
POCl3 (2.0)
POCl3 (1.3)
POCl3 (1.3)
POCl3 (1.3)
POCl3 (1.3)
MeNO2 25
3
16
15
45
50
44
43
76
57
87
85
16
72
9
MeNO2 25
30
3
MeNO2 25
Scheme 3. Route of Sulfonyl Flavanones 4
MeNO2 25
3
Knoevenagel condensation
oxa-Michael ring-closure
O
O
MeNO2 25
3
O
S
O
O
S
O
O
S
MeNO2 25
30
3
R
R
R
+
O
Ar
O
Ar'
O
Ar'
Ar'
Ar
MeNO2 reflux
MeNO2 reflux
toluene reflux
benzene reflux
OH
2
O
4
OH
Ar
3
30
3
After searching related literature on Knoevenagel condensa-
tion,11 we found that several metal chlorides have been chosen
as promoters to trigger dehydration of active methylene with
carbonyl compounds and also to play the key acidic source to
initiate diversified reaction types.12-27 The initial studies com-
menced with the treatment of model substrates 2a (Ar’ = Ph, R
= Tol, 3.0 mmol) and 3a (Ar = 3,4-(MeO)2C6H3, 3.0 mmol) in
the presence of a 0.3 equivalent of metal chlorides (InCl3,
BiCl3, CuCl2, FeCl3, ZnCl2, MgCl2, SnCl2, PdCl2 and AlCl3) in
MeNO2 (5 mL).12-20 However, no reaction occurred at 25oC
after 3 h. Especially when the reaction mixture was heated to
reflux in MeNO2 for 3 h, only InCl3 and BiCl3 produced better
yields (31% and 20%) than the other eight metal chlorides in
the formation of 4a. After controlling InCl3 and BiCl3 as the
promoters, the stoichiometric amount (1.0 equiv) provided
slightly higher yields of 4a (40% and 31%) under refluxing
MeNO2 conditions. Furthermore, after elongating the reaction
time from 3 h to 30 h under the above-mentioned conditions
(boiling MeNO2, 1.0 equiv.), only trace amounts of 4a were
isolated, and a major complex mixture was observed. The
results showed that metal chlorides would be inappropriate for
the generation of 4a. Under the consideration of economic
issues, cheaper non-metal chlorides were used as the promoter
to investigate the substrate’s scope. With this idea in mind and
changing the promoters from metal chlorides to metal-free
promoters, POCl3 was examined first and the reaction condi-
tions were screened, as shown in Table 1. Initially, a 0.3
equivalent of POCl3 only provided a 15% yield of 4a in Me-
NO2 at 25oC after 3 h (entry 1). However, an elongated time
(30 h) did not enhance the yield of 4a (entry 2). By using 1.0,
1.3, and 2.0 equivalents of POCl3, similar yields (45%, 50%,
44%) of 4a were shown in entries 3-5. Furthermore, control-
ling POCl3 as the 1.3 equivalent, adding an elongated time (30
h), and using room temperature (25oC) still did not increase
10 POCl3 (1.3)
11 POCl3 (1.3)
12 SOCl2 (1.3)
3
DMF
reflux
3
toluene reflux
3
13 (COCl)2 (1.3) toluene reflux
3
d
14 BCl3 (1.3)
toluene reflux
toluene reflux
3
─
e
15 TCCA (1.3)
3
─
aThe reactions were run on a 3.0 mmol scale with 2a, 3a (1.0
equiv), solvent (5 mL). bIsolated yields. cdr ratio >20:1.
dComplex mixture. eNo reaction.
However, after changing to DMF, only a 16% yield of 4a
was isolated (entry 11). On the other hand, adjusting POCl3 to
SOCl2, (COCl)2, BCl3, and trichloroisocyanurate (TCCA), was
studied. However, the conversion yields were not enhanced
(entries 12-15). Entry 12 shows that SOCl2 afforded a poorer
yield (72%) than entry 9 (87%). In entry 13, (COCl)2 provided
trace amounts (9%) of 4a along with a complex mixture.
When BCl3 was treated with the reaction conditions, only a
complex mixture was produced (entry 14). In particular, no
reaction was observed for the TCCA mediated annulation of
2a and 3a (entry 15). When POCl3 served as a promoter, it
would prefer to coordinate with the carbonyl group. We be-
lieved that in-situ formed HCl in the medium was responsible
for the reaction which protonated the aldehydic carbonyl
group of 3a. On the other hand, SOCl2 was giving decent yield
(72%) due to the releasing HCl. However, COCl2 having a bis
electrophilic species might be reacting with the substrate as it
had two nucleophilic sites giving some unidentified products
thereby reducing the yield (9%). From our observations, we
concluded that POCl3 (1.3 equiv) refluxing toluene and 3 h
would be optimal conditions for the one-pot cascade
Knoevenagel condensation/oxa-Michael ring-closure proce-
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dure. The expeditious synthetic route sets up sulfonyl
not only the electron-neutral phenyl group but also the elec-
2
flavanones, including the bond formation of the one C-O and
the one C-C bonds via a formal (5+1) cycloaddition. The rela-
tive stereochemical structure of 4a was determined by single-
crystal X-ray crystallography.28
tron-withdrawing 4-halophenyl group and electron-donating 5-
methoxyphenyl group were suitable. After a naphthyl (Ar’, for
2n) group was applied to the reaction conditions, 4n was iso-
lated in an 82% yield (entry 14). For sulfonyl substituents (R)
of 2a-2o, both the aliphatic (Me, nBu) groups and aromatic
(Tol, Ph, 4-FC6H4, 4-MeOC6H4, 3-MeC6H4, 4-EtC6H4, 4-
iPrC6H4, 4-nBuC6H4, 4-tBuC6H4) groups were well-tolerated.
Different aryl groups (Ar) on 3a-3p were also suitable to form
4a-4ad. However, entry 29 shows that lower yields (74%) of
4ab were observed due to the steric hindrance of the ortho-
bromo group on the aryl (Ar’) ring. Furthermore, the relative
stereochemical structures of 4a, 4e, and 4ab were determined
by Single-crystal X-ray crystallography.28
3
4
5
6
7
8
9
Table 2. Synthesis of 4a-4ada
O
S
O
O
O
4
2
POCl (1.3 equiv)
3
O
S
R
R
+
O
Ar
O
Ar'
Ar'
Ar
3a-3p
toluene
reflux, 3 h
5
1
OH
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
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53
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59
60
2a-2o
4a-4ad
entry 2a-2o, Ar’ =, R =
3a-3p, Ar =
4a-4ad (%)b-c
1
2
3
4
5
6
7
8
9
2a, Ph, Tol
2b, Ph, Ph
3a, 3,4-(MeO)2C6H3 4a, 87
3a, 3,4-(MeO)2C6H3 4b, 90
3a, 3,4-(MeO)2C6H3 4c, 92
3a, 3,4-(MeO)2C6H3 4d, 86
3a, 3,4-(MeO)2C6H3 4e, 83
Scheme 4. Plausible Mechanism
2c, Ph, Me
O
O
O
S
O
S
O
POCl
2
3
2d, Ph, nBu
2e, Ph, 4-FC6H4
Cl
Cl
P
3
2
R
O
O
R
O
O
Ar
Ar'
Ar'
Ar
Ar
O
4
Cl
+
OH
Ar
2f, Ph, 4-MeOC6H4 3a, 3,4-(MeO)2C6H3 4f, 84
3
A
B
PO Cl
2
H PO
3
4
POCl + H O
+
+
3
2
2g, Ph, 3-MeC6H4
2h, Ph, 4-EtC6H4
2i, Ph, 4-iPrC6H4
3a, 3,4-(MeO)2C6H3 4g, 87
3a, 3,4-(MeO)2C6H3 4h, 92
3a, 3,4-(MeO)2C6H3 4i, 93
2 HCl
HCl
On the basis of the experimental results, a plausible mecha-
nism for the formation of 4 is illustrated in Scheme 4. Initially,
an oxygen atom of the carbonyl group on 3 attacked POCl3 to
yield A and released a chloride anion via an O-P bond for-
mation. By the involvement of 2, the chloride anion should
deprotonate the α-proton of 2 to generate an enolate ion. Fol-
lowing the intermolecular Knoevenagel condensation of A
with the resulting enolate ion of 2, B could be generated along
with the in-situ formed PO2Cl and 2.0 equivalents of HCl.
After the reaction equilibrium was achieved, we found that the
reaction equation “PO2Cl + 2 HCl POCl3 + H2O” occurred
easily.29 Furthermore, the mixture of POCl3 and H2O convert-
ed into Brønsted acids, H3PO4, and HCl. According to the
previous experiment, B possessed an (E)-configurated orienta-
tion due to the effect of steric hindrance between the aryl (Ar)
and sulfonyl (SO2R) groups.30 Finally, the ortho-hydroxy on
aryl substituent (Ar’) promoted a subsequent intramolecular
oxa-Michael ring-closure of B to provide 4 via a C-O bond
formation under acidic conditions. On the basis of B with an
(E)-form regioisomer, two stereochemical centers (C2 and C3)
on 4 were orientated as a trans-conformation. The ratio of the
10 2j, Ph, 4-nBuC6H4 3a, 3,4-(MeO)2C6H3 4j, 86
11 2k, Ph, 4-tBuC6H4 3a, 3,4-(MeO)2C6H3 4k, 87
12 2l, 4-BrC6H3, Tol
3a, 3,4-(MeO)2C6H3 4l, 84
13 2m, 4-ClC6H3, Tol 3a, 3,4-(MeO)2C6H3 4m, 85
14 2n, naphthyl, Tol
15 2a, Ph, Tol
16 2a, Ph, Tol
17 2a, Ph, Tol
18 2a, Ph, Tol
19 2a, Ph, Tol
20 2a, Ph, Tol
21 2a, Ph, Tol
22 2a, Ph, Tol
23 2a, Ph, Tol
24 2a, Ph, Tol
25 2a, Ph, Tol
26 2a, Ph, Tol
27 2a, Ph, Tol
28 2a, Ph, Tol
3a, 3,4-(MeO)2C6H3 4n, 82
3b, Ph
4o, 88
4p, 84
4q, 82
4r, 86
4s, 89
4t, 80
4u, 78
4v, 85
4w, 80
3c, 4-MeOC6H4
3d, 3-MeOC6H4
3e, 4-FC6H4
3f, 4-MeC6H4
3g, 4-PhC6H4
3h, 2-naphthyl
3i, 3,4-CH2O2C6H3
3j, 3,4-Cl2C6H3
3k, 3,4,5-(MeO)3C6H2 4x, 86
1
3l, 2-furyl
4y, 92
diastereomers 4 was >20:1 by the determination of H-NMR
3m, 2-thienyl
3n, 3-pyridyl
3o, 2-BrC6H4
4z, 88
spectra. Products 4 were obtained as racemates.
4aa, 90
4ab, 74
4ac, 80
To explore this POCl3 mediated annulation route, a one-pot
synthesis of 3-sulfonyl chromanones was undertaken, as
shown in Table 3. By changing the aryl (Ar) group to an ali-
phatic (R’ = CF3, fluoral) group on aldehyde skeleton 3, we
found that this one-pot route still allowed a direct (5+1) annu-
lation mode and provided 3-sulfonyl chromanones 4ae-4aj
with a 2-trifluoromethyl group in moderate yields (55%-69%,
entries 1-6) under easy-operational reaction conditions under
the above-mentioned conditions. 4ah and 4aj with tetrafluoro
atoms were also prepared (entries 4 and 6). For the polyfluoro
chromanone skeleton, potential bioactive properties were re-
ported.31 In entries 7-11, Et, Me, (CH2)2Ph, and nC7H15 (R’)
groups showed lower yields (22%-38%) than the Ar group in
the generation of 4ak-4ao. A possible reason could be that
POCl3 could make the enolization of 3r-3u easier such that the
Knoevenagel reaction of 2 could be initiated with some diffi-
culty. Furthermore, the relative stereochemical structures of
29 2m, 4-ClC6H3, Tol 3p, 4-ClC6H4
30 2o, 5-MeOC6H3, Tol 3k, 3,4,5-(MeO)3C6H2 4ad, 86
aThe reactions were run on a 3.0 mmol scale with 2a-2o, 3a-
3p (1.0 equiv), POCl3 (1.3 equiv), toluene (5 mL), reflux, 3 h.
bIsolated yields. cdr ratio >20:1.
To study the scope and limitations of this one-pot approach,
2a-2o and 3a-3p were reacted with POCl3 to afford diversified
4a4ad, as shown in Table 2. With optimal conditions estab-
lished (Table 1, entry 9), we found that this route allowed a
direct (5+1) annulation under easy-operational conditions with
moderate to good yields (74%-93%). Among entries 1-30, the
efficient formation of 4a-4ad showed that these substituents
(for 2a-2o, Ar’ and R; for 3a-3p, Ar) did not affect the yields.
For the electronic nature of aryl substituents (Ar’) of 2a-2o,
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3
4
5
6
7
8
4af and 4aj were determined by Single-crystal X-ray crystal-
forward pathway for one carbon-oxygen and one carbon-
1
lography.28 By the determination of H-NMR spectra on 4ae-
carbon bond formations. The substrate scope and limitations
are investigated for facile and efficient transformation. Related
plausible mechanisms have been proposed. The structures of
the key products were confirmed by X-ray crystallography.
Further investigations regarding the synthetic application of β-
ketosulfones will be conducted and published in due course.
4ao, only the diastereomeric ratio (dr) of 4am was 9:1, and
others
were
>20:1.
In
Scheme
5,
3-sulfonyl
flindersiachromanone 4an could be synthesized by one-pot
route. Flindersiachromanone was isolated from extracts of the
bark of Flindersia laevicarpa, and it was synthesized by dif-
ferent routes.8a,9c,32
Experimental Section
9
Table 3. Synthesis of 4ae-4aoa
General. All reagents and solvents were obtained from
commercial sources and used without further purification.
Reactions were routinely carried out under an atmosphere of
dry air with magnetic stirring. The heating mantle is used to
provide a stable heat source. Products in organic solvents were
dried with anhydrous magnesium sulfate before concentration
in vacuo. Melting points were determined with a SMP3 melt-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
S
O
O
O
O
4
2
POCl (1.3 equiv)
3
O
S
R
R
+
O
R'
O
Ar'
Ar'
R'
3q-3u
toluene
reflux, 3 h
5
1
OH
2a-2c, 2e, 2o-2p
4ae-4ao
entry 2a-2c, 2e, 2o-2p, Ar’ =, R = 3q-3u, R’ = 4ae-4ao, (%)b-c
1
2
3
4
5
6
7
8
9
2c, Ph, Me
3q, CF3
3q, CF3
3q, CF3
3q, CF3
3q, CF3
3q, CF3
3r, Et
4ae, 62
4af, 55
4ag, 68
4ah, 69
4ai, 56
4aj, 65
4ak, 30
4al, 22
4am, 31d
1
ing apparatus. H and 13C NMR spectra were recorded on a
2b, Ph, Ph
Varian INOVA-400 spectrometer operating at 400 and at 100
MHz, respectively. Chemical shifts (δ) are reported in parts
per million (ppm) and the coupling constants (J) are given in
Hertz. High resolution mass spectra (HRMS) were measured
with a mass spectrometer Finnigan/Thermo Quest MAT 95XL.
X-ray crystal structures were obtained with an Enraf-Nonius
FR-590 diffractometer (CAD4, Kappa CCD).
2a, Ph, Tol
2p, 4-FC6H3, Tol
2o, 5-MeOC6H3, Tol
2e, Ph, 4-FC6H4
2a, Ph, Tol
2e, Ph, 4-FC6H4
2a, Ph, Tol
3s, Me
3s, Me
For the starting compounds 2a-2p, the general synthetic
procedure has been described in our previous reports.4a For the
starting compounds 3a-3u, these reagents were obtained from
commercial sources and used without further purification.
10 2a, Ph, Tol
11 2a, Ph, Tol
3t, (CH2)2Ph 4an, 35
3u, nC7H15 4ao, 38
aThe reactions were run on a 3.0 mmol scale with 2a-2c and
2o-2p, 3q-3u (1.0 equiv), POCl3 (1.3 equiv), toluene (5 mL),
reflux, 3 h. bIsolated yields. cdr ratio >20:1. ddr ratio = 9:1.
General synthetic procedure of skeleton 4 is as follows:
phosphorus oxychloride (POCl3, 600 mg, 3.9 mmol) was add-
ed to a solution of 3 (3.0 mmol) in dry toluene (3 mL) at 25 oC.
The reaction mixture was stirred for 10 min at reflux. Then, 2
(3.0 mmol) in dry toluene (2 mL) was added to the reaction
mixture. The reaction mixture was stirred at reflux for 3 h,
cooled to 25 oC and the solvent was concentrated. The residue
was diluted with water (10 mL) and the mixture was extracted
with CH2Cl2 (3 x 20 mL). The combined organic layers were
washed with brine, dried, filtered and evaporated to afford
crude product under reduced pressure. Purification on silica
gel (hexanes/EtOAc = 10/1~4/1) afforded 4 as racemates.
Scheme 5. Structures of 4an and Flindersiachromanone
O
O
O
S
Tol
Ph
O
O
O
Ph
flindersiachromanone
4an
Scheme 6. Reaction of 2q with 3a
O
O
O
S
O
O
S
O
O N
2
4
O N
2
OMe
OMe
POCl (1.3 equiv)
3
Tol
Tol
O
O
+
OMe
OMe
toluene
reflux, 3 h
OH
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4a). 4a was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 87% (1.14 g); Colorless solid; mp = 156-
158 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C24H23O6S 439.1215, found
2q
3a
4ap (ND)
By adjusting the Ar’ as the electron-withdrawing 4-
nitrophenyl group, 2q was involved in the above condition
(Scheme 6). When 2q was reacted with 3a, however, no de-
sired 4ap was detected. And, only starting material 2q was
recovered (82%) along with 65% of 3a. One possible reason
could be that C4-nitro group of 2q could not promote the elec-
tron density efficiently to the para-hydroxy position such that
POCl3-mediated Knoevenagel condensation occurred more
difficultly. Although substrate 2 was inappropriate to the elec-
tron-withdrawing group, the present route still provided novel
and efficient synthesis of the sulfonyl flavanones.
1
439.1216; H NMR (400 MHz, CDCl3): δ 7.72-7.68 (m, 3H),
7.42 (dt, J = 1.6, 8.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.92
(dt, J = 0.8, 8.0 Hz, 1H), 6.85 (d, J = 0.8, 8.0 Hz, 1H), 6.77 (s,
1H), 6.68 (br s, 2H), 6.49 (s, 1H), 4.40 (d, J = 1.2 Hz, 1H),
3.77 (s, 3H), 3.75 (s, 3H), 2.36 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 182.3, 158.8, 149.3, 145.6, 137.2, 134.2,
129.5 (2x), 129.4 (3x), 128.4, 126.8, 121.6, 120.8, 118.6,
118.2, 110.9, 109.6, 76.1, 72.7, 55.78, 55.77, 21.6. Single-
crystal X-Ray diagram: crystal of compound 4a was grown by
slow diffusion of EtOAc into a solution of compound 4a in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the monoclinic crystal system, space group P 21/c, a =
21.002(3) Å , b = 11.9195(15) Å , c = 8.3067(11) Å , V =
In summary, we have developed an easy-operational, high-
yielding method for gram-scale synthesis of 3-sulfonyl
flavanones
via
POCl3
mediated
with
β-(o-
hydroxyaryl)ketosulfones and arylaldehydes in refluxing tolu-
ene for 3 h in moderate to good yields. The synthesis of 3-
sulfonyl chromanones was accomplished by the one-pot pro-
tocol. The formal (5+1) annulation process provides a straight-
ACS Paragon Plus Environment

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The Journal of Organic Chemistry
2062.6(5) Å 3, Z = 4, dcalcd = 1.412 g/cm3, F(000) = 920, 2θ
0.8 Hz, 1H), 6.71-6.66 (m, 2H), 6.49 (s, 1H), 4.43 (d, J = 1.2
2
3
4
range 0.977 to 26.475o, R indices (all data) R1 = 0.0488, wR2
= 0.1084.
Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 182.0, 166.2 (d, J = 257.0 Hz), 158.6, 149.4, 149.3,
137.5, 133.2 (d, J = 3.1 Hz), 132.4 (d, J = 9.9 Hz, 2x), 128.1,
126.8, 121.9, 120.7, 118.7, 118.2, 116.1 (d, J = 22.7 Hz, 2x),
111.0, 109.7, 76.3, 72.9, 55.81, 55.79. Single-crystal X-Ray
diagram: crystal of compound 4e was grown by slow diffusion
of EtOAc into a solution of compound 4e in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21/c, a = 20.5754(16) Å , b =
11.9457(8) Å , c = 8.2774(6) Å , V = 2031.3(3) Å 3, Z = 4, dcalcd
= 1.447 g/cm3, F(000) = 920, 2θ range 0.991 to 26.478o, R
indices (all data) R1 = 0.0489, wR2 = 0.0997.
5
6
7
8
(2S*,3S*)-3-Benzenesulfonyl-2-(3,4-
dimethoxyphenyl)chroman-4-one (4b). 4b was synthesized
according to general synthetic procedure from 2b (828 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 90% (1.14 g); Colorless solid;
9
o
mp = 157-159 C (recrystallized from hexanes and EtOAc);
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H21O6S
1
425.1059, found 425.1060; H NMR (400 MHz, CDCl3): δ
7.84-7.82 (m, 2H), 7.71 (dd, J = 1.6, 8.0 Hz, 1H), 7.58-7.54
(m, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.42-7.38 (m, 1H), 6.91 (dt,
J = 0.8, 8.0 Hz, 1H), 6.84 (d, J = 0.8, 8.0 Hz, 1H), 6.77 (s, 1H),
6.69 (br s, 2H), 6.50 (s, 1H), 4.43 (d, J = 1.2 Hz, 1H), 3.78 (s,
3H), 3.75 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.1,
158.7, 149.3 (2x), 137.4, 137.2, 134.4, 129.4 (2x), 128.9 (2x),
128.3, 126.8, 121.7, 120.8, 118.7, 118.2, 111.0, 109.7, 76.2,
72.8, 55.8 (2x).
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(4-
methoxybenzenesulfonyl)chroman-4-one (4f). 4f was synthe-
sized according to general synthetic procedure from 2f (918
mg, 3.0 mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5
mL). The ratio of dr was >20:1; Yield = 84% (1.14 g); Color-
o
less solid; mp = 152-154 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C24H23O7S 455.1165, found 455.1168; H NMR (400 MHz,
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-
1
methanesulfonylchroman-4-one (4c). 4c was synthesized ac-
cording to general synthetic procedure from 2c (642 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 92% (1.00 g); Colorless solid;
CDCl3): δ 7.70 (d, J = 9.2 Hz, 2H), 7.69 (dt, J = 1.6, 8.0 Hz,
1H), 7.37 (dt, J = 1.6, 8.8 Hz, 1H), 6.87 (dt, J = 1.2, 8.0 Hz,
1H), 6.84-6.82 (m, 1H), 6.82 (d, J = 8.8 Hz, 2H), 6.75 (d, J =
1.2 Hz, 1H), 6.66-6.63 (m, 2H), 6.44 (s, 1H), 4.41 (d, J = 1.2
Hz, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.71 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 182.2, 164.1, 158.6, 149.08,
149.05, 137.1, 131.5 (2x), 128.3, 128.2, 126.6, 121.5, 120.7,
118.5, 118.0, 113.9 (2x), 110.8, 109.5, 76.2, 72.7, 55.62, 55.59,
55.5.
o
mp = 144-146 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H19O6S
1
363.0902, found 363.0903; H NMR (400 MHz, CDCl3): δ
7.87 (dd, J = 1.6, 8.0 Hz, 1H), 7.55 (dt, J = 2.0, 8.4 Hz, 1H),
7.06 (dd, J = 0.8, 8.4 Hz, 1H), 7.01 (dt, J = 0.8, 8.0 Hz, 1H),
6.82 (s, 1H), 6.73 (br s, 2H), 6.45 (d, J = 0.8 Hz, 1H), 4.32 (d,
J = 0.8 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.12 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 183.1, 159.3, 149.39,
149.36, 138.0, 128.4, 127.2, 122.1, 120.5, 118.72, 118.65,
111.0, 109.8, 74.7, 70.6, 55.83, 55.81, 41.3.
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(toluene-3-
sulfonyl)chroman-4-one (4g). 4g was synthesized according to
general synthetic procedure from 2g (870 mg, 3.0 mmol) and
3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 87% (1.14 g); Colorless solid; mp = 176-
178 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C24H23O6S 439.1215, found
(2S*,3S*)-3-(n-Butane-1-sulfonyl)-2-(3,4-
dimethoxyphenyl)chroman-4-one (4d). 4d was synthesized
according to general synthetic procedure from 2d (768 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 86% (1.04 g); Colorless oil;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H25O6S
1
439.1216; H NMR (400 MHz, CDCl3): δ 7.71 (dd, J = 1.6,
8.0 Hz, 1H), 7.64-7.61 (m, 2H), 7.40 (dt, J = 1.6, 8.8 Hz, 1H),
7.35-7.29 (m, 2H), 6.91 (dt, J = 1.2, 8.0 Hz, 1H), 6.84 (dd, J =
0.8, 8.4 Hz, 1H), 6.77 (s, 1H), 6.69-6.68 (m, 2H), 6.48 (s, 1H),
4.42 (d, J = 0.8 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 2.33 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.1, 158.7, 149.3
(2x), 139.2, 137.3, 136.9, 135.2, 129.6, 128.7, 128.3, 126.8,
126.6, 121.7, 120.8, 118.7, 118.1, 111.0, 109.6, 76.2, 72.8,
55.79, 55.78, 21.1.
1
405.1372, found 405.1374; H NMR (400 MHz, CDCl3): δ
7.85 (dd, J = 1.6, 8.4 Hz, 1H), 7.53 (dt, J = 1.6, 8.4 Hz, 1H),
7.04 (dd, J = 0.4, 8.4 Hz, 1H), 7.00 (dt, J = 0.8, 8.0 Hz, 1H),
6.81 (s, 1H), 6.72 (br s, 2H), 6.44 (d, J = 1.2 Hz, 1H), 4.29 (d,
J = 1.6 Hz, 1H), 3.79 (s, 3H), 3.77 (s, 3H), 3.27-3.22 (m, 2H),
1.91-1.83 (m, 2H), 1.52-1.44 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 183.4, 159.3, 149.32,
149.28, 137.8, 128.6, 127.0, 121.9, 120.6, 118.7, 118.6, 110.9,
109.8, 74.6, 68.6, 55.8, 53.1, 23.3 (2x), 21.5, 13.4.
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(4-
ethylbenzenesulfonyl)chroman-4-one (4h). 4h was synthesized
according to general synthetic procedure from 2h (912 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 92% (1.25 g); Colorless oil;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25O6S
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(4-
fluorobenzenesulfonyl)chroman-4-one (4e). 4e was synthe-
sized according to general synthetic procedure from 2e (882
mg, 3.0 mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5
mL). The ratio of dr was >20:1; Yield = 83% (1.10 g); Color-
1
453.1372, found 453.1375; H NMR (400 MHz, CDCl3): δ
7.72 (d, J = 8.4 Hz, 2H), 7.71 (dt, J = 1.6, 8.0 Hz, 1H), 7.39
(dt, J = 1.6, 8.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 6.91 (dt, J =
0.8, 8.0 Hz, 1H), 6.82 (dd, J = 0.8, 8.0 Hz, 1H), 6.77 (s, 1H),
6.69 (br s, 2H), 6.49 (s, 1H), 4.41 (d, J = 1.2 Hz, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 2.65 (q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.3, 158.7, 151.7,
149.32, 149.30, 137.3, 134.3, 129.6 (2x), 128.4, 128.3 (2x),
o
less solid; mp = 159-161 C (recrystallized from hexanes and
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
1
C23H20FO6S 443.0965, found 443.0964; H NMR (400 MHz,
CDCl3): δ 7.86-7.81 (m, 2H), 7.70 (dt, J = 1.6, 8.0 Hz, 1H),
7.43 (dt, J = 1.6, 8.8 Hz, 1H), 7.11-7.05 (m, 2H), 6.93 (dt, J =
0.8, 8.0 Hz, 1H), 6.84 (dd, J = 0.4, 8.4 Hz, 1H), 6.77 (d, J =
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 13
1
2
3
4
5
6
7
8
126.9, 121.7, 120.8, 118.7, 118.2, 111.0, 109.7, 76.3, 72.9,
55.8 (2x), 28.9, 15.0.
1H), 7.69 (d, J = 8.4 Hz, 2H), 7.50 (dd, J = 2.0, 8.8 Hz, 1H),
7.27 (d, J = 8.0 Hz, 2H), 6.80 (d, J = 8.8 Hz, 1H), 6.75 (d, J =
2.0 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.4 Hz,
1H), 6.50 (s, 1H), 4.40 (d, J = 0.8 Hz, 1H), 3.78 (s, 3H), 3.77
(s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
181.4, 157.7, 149.5, 149.4, 145.9, 139.7, 134.1, 129.6 (2x),
129.3 (2x), 129.1, 127.8, 121.9, 120.3, 118.7, 114.3, 110.9,
109.7, 76.2, 72.1, 55.84, 55.78, 21.6.
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(4-
isopropylbenzenesulfonyl)chroman-4-one (4i). 4i was synthe-
sized according to general synthetic procedure from 2i (954
mg, 3.0 mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5
mL). The ratio of dr was >20:1; Yield = 93% (1.30 g); Color-
o
less solid; mp = 153-155 C (recrystallized from hexanes and
9
EtOAc); HRMS (ESI-TOF) m/z: [M + H]+ calcd for
(2S*,3S*)-6-Chloro-2-(3,4-dimethoxyphenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4m). 4m was synthesized according
to general synthetic procedure from 2m (972 mg, 3.0 mmol)
and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of
dr was >20:1; Yield = 85% (1.20 g); Colorless solid; mp =
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
C26H27O6S 467.1528, found 467.1530; H NMR (400 MHz,
CDCl3): δ 7.72 (d, J = 8.4 Hz, 2H), 7.69 (dt, J = 1.6, 8.0 Hz,
1H), 7.37 (dt, J = 1.6, 8.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H),
6.89 (dt, J = 0.8, 8.0 Hz, 1H), 6.79 (dd, J = 0.8, 8.4 Hz, 1H),
6.77 (s, 1H), 6.69 (br s, 2H), 6.49 (s, 1H), 4.42 (d, J = 0.8 Hz,
1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.93-2.86 (m, 1H), 1.19 (d, J =
6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.2, 158.7,
156.2, 149.3, 137.2, 134.3, 129.7 (2x), 128.4, 126.9 (2x),
126.8 (2x), 121.6, 120.8, 118.7, 118.1, 111.0, 109.6, 76.5, 73.0,
55.8 (2x), 34.2, 23.5, 23.4.
o
154-156 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H22ClO6S 473.0826,
found 473.0827; 1H NMR (400 MHz, CDCl3): δ 7.70-7.67 (m,
3H), 7.37 (dd, J = 2.8, 8.8 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H),
6.86 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 6.69 (d, J =
8.4 Hz, 1H), 6.64 (dd, J = 2.0, 8.4 Hz, 1H), 6.50 (s, 1H), 4.40
(d, J = 0.8 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.40 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 181.6, 157.2, 149.5,
149.4, 145.9, 137.0, 134.2, 129.7 (2x), 129.3 (2x), 127.8,
127.2, 126.1, 121.4, 120.0, 118.7, 110.9, 109.7, 76.2, 72.1,
55.85, 55.78, 21.6.
(2S*,3S*)-3-(4-n-Butylbenzenesulfonyl)-2-(3,4-
dimethoxyphenyl)chroman-4-one (4j). 4j was synthesized ac-
cording to general synthetic procedure from 2j (996 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 80% (1.15 g); Colorless solid;
o
mp = 123-125 C (recrystallized from hexanes and EtOAc);
(2S*,3S*)-2-(3,4-Dimethoxyphenyl)-3-(toluene-4-sulfonyl)-
2,3-dihydrobenzo[h]chromen-4-one (4n). 4n was synthesized
according to general synthetic procedure from 2n (1.02 g, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 82% (1.20 g); Colorless solid;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H29O6S
1
481.1685, found 481.1687; H NMR (400 MHz, CDCl3): δ
7.72-7.68 (m, 3H), 7.37 (dt, J = 2.0, 8.4 Hz, 1H), 7.19 (d, J =
8.4 Hz, 2H), 6.89 (dt, J = 0.8, 8.0 Hz, 1H), 6.80 (dd, J = 0.8,
8.4 Hz, 1H), 6.77 (s, 1H), 6.68 (br d, J = 0.8 Hz, 2H), 6.48 (s,
1H), 4.42 (d, J = 1.2 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.59
(t, J = 7.6 Hz, Hz, 2H), 1.55-1.48 (m, 2H), 1.33-1.24 (m, 2H),
0.91 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
182.2, 158.7, 150.4, 149.3, 149.2, 137.2, 134.3, 129.4 (2x),
128.8 (2x), 128.4, 126.8, 121.6, 120.8, 118.6, 118.1, 110.9,
109.6, 76.4, 72.9, 55.77, 55.75, 35.5, 32.9, 22.1, 13.8.
o
mp = 175-177 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C28H25O6S
1
489.1372, found 489.1372; H NMR (400 MHz, CDCl3): δ
8.25 (dd, J = 0.8, 8.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d,
J = 8.4 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.60 (dt, J = 1.6, 8.4
Hz, 1H), 7.51 (dt, J = 1.2, 8.4 Hz, 2H), 7.30 (d, J = 8.8 Hz,
1H), 7.04 (d, J = 8.4 Hz, 2H), 6.82 (d, J = 2.0 Hz, 1H), 6.73
(dd, J = 2.4, 8.0 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 4.48 (d, J =
0.8 Hz, 1H), 3.75 (s, 3H), 3.69 (s, 3H), 2.12 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 181.5, 157.0, 149.4, 149.3, 145.6,
137.9, 133.9, 130.1, 129.3 (4x), 128.2, 127.8, 126.4, 124.4,
123.5, 121.5, 121.0, 118.4, 115.6, 111.0, 109.3, 77.0, 72.8,
55.78, 55.76, 21.3.
(2S*,3S*)-3-(4-t-Butylbenzenesulfonyl)-2-(3,4-
dimethoxyphenyl)chroman-4-one (4k). 4k was synthesized
according to general synthetic procedure from 2k (996 mg, 3.0
mmol) and 3a (500 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 87% (1.25 g); Colorless solid;
o
mp = 181-183 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C27H29O6S
(2S*,3S*)-2-Phenyl-3-(toluene-4-sulfonyl)chroman-4-one
(4o). 4o was synthesized according to general synthetic proce-
dure from 2a (870 mg, 3.0 mmol) and 3b (318 mg, 3.0 mmol)
in dry toluene (5 mL). The ratio of dr was >20:1; Yield = 88%
1
481.1685, found 481.1684; H NMR (400 MHz, CDCl3): δ
7.72 (d, J = 8.8 Hz, 2H), 7.70 (dt, J = 1.6, 8.0 Hz, 1H), 7.38 (d,
J = 8.8 Hz, 2H), 7.35 (dt, J = 1.6, 8.8 Hz, 1H), 6.88 (dt, J = 0.8,
8.0 Hz, 1H), 6.78 (dt, J = 0.8, 8.0 Hz, 1H), 6.78 (s, 1H), 6.68
(br s, 2H), 6.48 (s, 1H), 4.43 (d, J = 1.2 Hz, 1H), 3.77 (s, 3H),
3.75 (s, 3H), 1.25 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3):
δ 182.2, 158.6, 158.4, 149.3, 149.2, 137.2, 133.9, 129.4 (2x),
128.3, 126.8, 125.7 (2x), 121.6, 120.8, 118.6, 118.0, 110.9,
109.6, 76.5, 72.9, 55.78, 55.76, 35.2, 30.8 (3x).
o
(1.00 g); Colorless solid; mp = 131-133 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H19O4S 379.1004, found 379.1006; 1H NMR (400
MHz, CDCl3): δ 7.72-7.70 (m, 3H), 7.46 (dt, J = 1.6, 8.4 Hz,
1H), 7.27-7.19 (m, 7H), 6.95 (dd, J = 0.8, 7.6 Hz, 1H), 6.91
(dd, J = 0.8, 8.4 Hz, 1H), 6.57 (s, 1H), 4.39 (d, J = 1.6 Hz, 1H),
2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.0,
159.0, 145.7, 137.4, 136.2, 134.2, 129.6 (2x), 129.4 (2x),
129.0 (2x), 128.7, 126.9, 126.1 (2x), 121.7, 120.8, 118.2, 76.2,
73.0, 21.6.
(2S*,3S*)-6-Bromo-2-(3,4-dimethoxyphenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4l). 4l was synthesized according to
general synthetic procedure from 2l (1.1 g, 3.0 mmol) and 3a
(500 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr was
>20:1; Yield = 84% (1.30 g); Colorless solid; mp = 155-157
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C24H22BrO6S 517.0321, found
(2S*,3S*)-2-(4-Methoxyphenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4p). 4p was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3c (408 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
1
517.0320; H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 2.8 Hz,
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o
was >20:1; Yield = 84% (1.03 g); Colorless solid; mp = 121-
= 80% (1.09 g); Colorless solid; mp = 123-125 C (recrystal-
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123 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
lized from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M +
TOF) m/z: [M + H]+ calcd for C23H21O5S 409.1110, found
H]+ calcd for C28H23O4S 455.1317, found 455.1318; H NMR
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409.1112; H NMR (400 MHz, CDCl3): δ 7.72-7.68 (m, 3H),
(400 MHz, CDCl3): δ 7.41-7.38 (m, 3H), 7.15-7.11 (m, 5H),
7.08-7.04 (m, 2H), 7.01-6.99 (m, 1H), 6.97-6.90 (m, 4H),
6.64-6.59 (m, 2H), 6.28 (s, 1H), 4.10 (d, J = 1.2 Hz, 1H), 2.05
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.1, 159.0,
145.7, 141.6, 139.9, 137.4, 135.1, 134.2, 129.6 (2x), 129.4
(2x), 128.8 (2x), 127.6 (2x), 127.0 (3x), 126.9 (2x), 126.6 (2x),
121.7, 118.3, 76.1, 72.9, 21.6.
7.42 (dt, J = 1.6, 8.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.13 (d,
J = 8.4 Hz, 2H), 6.92 (dt, J = 0.8, 8.0 Hz, 1H), 6.85 (dd, J =
0.8, 8.4 Hz, 1H), 6.77 (d, J = 8.8 Hz, 2H), 6.50 (s, 1H), 4.38 (d,
J = 0.8 Hz, 1H), 3.71 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 182.3, 159.7, 158.8, 145.6, 137.2, 134.3,
129.5 (2x), 129.3 (2x), 128.0, 127.6 (2x), 126.8, 121.6, 120.7,
118.3, 114.3 (2x), 76.0, 72.8, 55.2, 21.6.
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(2S*,3S*)-2-Naphthalen-2-yl-3-(toluene-4-
(2S*,3S*)-2-(3-Methoxyphenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4u). 4u was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3h (468 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 78% (1.00 g); Colorless solid; mp = 141-
143 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C26H21O4S 429.1161, found
sulfonyl)chroman-4-one (4q). 4q was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3d (408 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 82% (1.00 g); Colorless solid; mp = 148-
150 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C23H21O5S 409.1110, found
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429.1160; H NMR (400 MHz, CDCl3): δ 7.79-7.68 (m, 6H),
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409.1108; H NMR (400 MHz, CDCl3): δ 7.72-7.69 (m, 3H),
7.58 (br s, 1H), 7.48-7.39 (m, 4H), 7.26 (d, J = 8.8 Hz, 2H),
6.96-6.91 (m, 2H), 6.73 (s, 1H), 4.57 (d, J = 1.2 Hz, 1H), 2.39
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.1, 158.9,
145.7, 137.4, 134.3, 133.4, 132.9, 132.7, 129.6 (2x), 129.4
(2x), 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.
7.45 (dt, J = 1.6, 8.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.16 (t,
J = 8.4 Hz, 1H), 6.93 (dt, J = 0.8, 8.0 Hz, 1H), 6.91 (dd, J =
0.8, 8.4 Hz, 1H), 6.77-6.74 (m, 3H), 6.53 (s, 1H), 4.38 (d, J =
1.2 Hz, 1H), 3.69 (s, 3H), 2.37 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 181.9, 159.9, 159.0, 145.7, 137.7, 137.3,
134.2, 130.0, 129.5 (2x), 129.3 (2x), 126.9, 121.7, 120.7,
118.1, 118.0, 113.8, 112.1, 76.1, 73.0, 55.1, 21.6.
(2S*,3S*)-2-Benzo[1,3]dioxol-5-yl-3-(toluene-4-
sulfonyl)chroman-4-one (4v). 4v was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3i (450 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 85% (1.08 g); Colorless solid; mp = 198-
200 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C23H19O6S 423.0902, found
(2S*,3S*)-2-(4-Fluorophenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4r). 4r was synthesized according to
general synthetic procedure from 2a (870 mg, 3.0 mmol) and
3e (372 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr
was >20:1; Yield = 86% (1.02 g); Colorless solid; mp = 156-
158 oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H18FO4S 397.0910, found
1
423.0902; H NMR (400 MHz, CDCl3): δ 7.72 (dd, J = 1.6,
8.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.44 (dt, J = 2.0, 8.4 Hz,
1H), 7.23 (d, J = 8.0 Hz, 2H), 6.94 (dd, J = 1.2, 8.0 Hz, 1H),
6.87 (dd, J = 0.8, 8.4 Hz, 1H), 6.71 (d, J = 1.6 Hz, 1H), 6.66 (d,
J = 8.0 Hz, 1H), 6.63 (dd, J = 1.6, 8.0 Hz, 1H), 6.45 (s, 1H),
5.90 (d, J = 1.2 Hz, 1H), 5.89 (d, J = 1.2 Hz, 1H), 4.33 (d, J =
1.2 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
182.1, 158.7, 148.3, 147.9, 145.7, 137.3, 134.2, 129.9, 129.5
(2x), 129.4 (2x), 126.9, 121.7, 120.7, 119.9, 118.3, 108.4,
106.8, 101.4, 76.0, 72.8, 21.6.
1
397.0912; H NMR (400 MHz, CDCl3): δ 7.72-7.68 (m, 3H),
7.45 (dt, J = 1.6, 8.4 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.22-
7.18 (m, 2H), 6.97-6.93 (m, 3H), 6.89 (dd, J = 0.8, 8.4 Hz, 1H),
6.53 (s, 1H), 4.37 (d, J = 0.8 Hz, 1H), 2.37 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 181.9, 162.6 (d, J = 247.1 Hz),
158.7, 145.8, 137.4, 134.1, 132.0 (d, J = 3.5 Hz), 129.5 (2x),
129.3 (2x), 128.06 (d, J = 8.4 Hz, 2x), 126.9, 121.8, 120.7,
118.2, 116.0 (d, J = 21.2 Hz, 2x), 75.7, 72.8, 21.6.
(2S*,3S*)-3-(Toluene-4-sulfonyl)-2-p-tolylchroman-4-one
(4s). 4s was synthesized according to general synthetic proce-
dure from 2a (870 mg, 3.0 mmol) and 3f (360 mg, 3.0 mmol)
in dry toluene (5 mL). The ratio of dr was >20:1; Yield = 89%
(2S*,3S*)-2-(3,4-Dichlorophenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4w). 4w was synthesized according
to general synthetic procedure from 2a (870 mg, 3.0 mmol)
and 3j (522 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of
dr was >20:1; Yield = 80% (1.07 g); Colorless solid; mp =
o
(1.05 g); Colorless solid; mp = 157-159 C (recrystallized
from hexanes and EtOAc); HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H21O4S 393.1161, found 393.1162; 1H NMR (400
MHz, CDCl3): δ 7.72-7.70 (m, 3H), 7.43 (dt, J = 1.6, 8.4 Hz,
1H), 7.23 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 7.05 (d,
J = 8.0 Hz, 2H), 6.92 (dt, J = 0.8, 8.0 Hz, 1H), 6.88 (dd, J =
0.8, 8.8 Hz, 1H), 6.53 (s, 1H), 4.40 (d, J = 1.2 Hz, 1H), 2.37 (s,
3H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 182.1,
158.9, 145.6, 138.5, 137.2, 134.2, 133.0, 129.6 (2x), 129.5
(2x), 129.3 (2x), 126.8, 126.0 (2x), 121.6, 120.7, 118.2, 76.1,
72.8, 21.5, 20.9.
159-161 C (recrystallized from hexanes and EtOAc); HRMS
o
(ESI-TOF) m/z: [M + H]+ calcd for C22H17Cl2O4S 447.0225,
1
found 447.0224; H NMR (400 MHz, CDCl3): δ 7.71 (dd, J =
1.6, 8.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.49 (dt, J = 2.0, 8.4
Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H),
7.25 (d, J = 8.4 Hz, 2H), 7.05 (dd, J = 2.0, 8.4 Hz, 1H), 6.98
(dd, J = 0.8, 8.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H),
4.33 (d, J = 1.2 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 181.5, 158.4, 146.0, 137.7, 136.4, 134.0,
133.4, 131.0, 129.7 (2x), 129.43, 129.37 (2x), 128.3, 127.1,
125.3, 122.2, 120.6, 118.2, 75.1, 72.4, 21.7.
(2S*,3S*)-2-Biphenyl-4-yl-3-(toluene-4-sulfonyl)chroman-
4-one (4t). 4t was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3g (546 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
(2S*,3S*)-3-(Toluene-4-sulfonyl)-2-(3,4,5-
trimethoxyphenyl)chroman-4-one (4x). 4x was synthesized
according to general synthetic procedure from 2a (870 mg, 3.0
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mmol) and 3k (588 mg, 3.0 mmol) in dry toluene (5 mL). The
(2S*,3S*)-2-(2-Bromophenyl)-3-(toluene-4-
ratio of dr was >20:1; Yield = 86% (1.21 g); Colorless solid;
sulfonyl)chroman-4-one (4ab). 4ab was synthesized according
to general synthetic procedure from 2a (870 mg, 3.0 mmol)
and 3o (552 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of
dr was >20:1; Yield = 74% (1.01 g); Colorless solid; mp =
o
mp = 190-192 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H25O7S
1
469.1321, found 469.1322; H NMR (400 MHz, CDCl3): δ
o
7.70 (dd, J = 1.6, 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.43
(dt, J = 2.0, 8.4 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 6.93 (dt, J =
0.8, 8.4 Hz, 1H), 6.87 (dd, J = 0.8, 8.4 Hz, 1H), 6.47 (d, J =
0.4 Hz, 1H), 6.38 (d, J = 0.8 Hz, 2H), 4.39 (d, J = 1.2 Hz, 1H),
3.73 (s, 3H), 3.68 (s, 6H), 2.34 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 182.0, 158.8, 153.4 (2x), 145.7, 138.0, 137.3,
134.0, 131.5, 129.4 (2x), 129.3 (2x), 126.8, 121.7, 120.7,
117.9, 103.4 (2x), 76.3, 72.9, 60.6, 55.9 (2x), 21.5.
158-160 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C22H18BrO4S 457.0109,
1
found 457.0110; H NMR (400 MHz, CDCl3): δ 7.70 (dd, J =
9
1.6, 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.57 (dt, J = 2.0, 8.4
Hz, 1H), 7.56 (dd, J = 2.0, 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz,
2H), 7.15-7.08 (m, 2H), 7.08-7.00 (m, 3H), 6.80 (s, 1H), 4.47
(d, J = 1.2 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 181.8, 159.9, 145.7, 137.7, 134.9, 134.5, 134.0,
130.2, 129.7 (2x), 129.3 (2x), 127.7, 127.1, 127.0, 121.9,
121.5, 120.6, 117.7, 76.1, 71.3, 21.7. Single-crystal X-Ray
diagram: crystal of compound 4ab was grown by slow diffu-
sion of EtOAc into a solution of compound 4ab in CH2Cl2 to
yield colorless prisms. The compound crystallizes in the ortho-
rhombic crystal system, space group P 21 21 21, a = 8.6975(7)
Å , b = 11.1079(9) Å , c = 19.6779(17) Å , V = 1901.1(3) Å 3, Z
= 4, dcalcd = 1.598 g/cm3, F(000) = 928, 2θ range 2.070 to
26.508o, R indices (all data) R1 = 0.0342, wR2 = 0.0561.
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(2S*,3S*)-2-Furan-2-yl-3-(toluene-4-sulfonyl)chroman-4-
one (4y). 4y was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3l (288 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 92% (1.02 g); Colorless solid; mp = 151-153 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H17O5S 369.0797, found 369.0798;
1H NMR (400 MHz, CDCl3): δ 7.76 (dd, J = 2.0, 8.0 Hz, 1H),
7.69 (d, J = 8.4 Hz, 2H), 7.41 (dt, J = 2.0, 8.4 Hz, 1H), 7.28 (t,
J = 1.2 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 6.95 (dt, J = 0.8, 8.4
Hz, 1H), 6.81 (dd, J = 0.8, 8.4 Hz, 1H), 6.48 (d, J = 1.2 Hz,
1H), 6.24 (br s, 1H), 6.23 (br s, 1H), 4.33 (d, J = 1.2 Hz, 1H),
2.36 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 181.9,
158.3, 149.0, 145.7, 143.6, 137.0, 134.1, 129.5 (2x), 129.3
(2x), 126.8, 121.9, 120.4, 118.3, 110.5, 110.1, 70.9, 70.8, 21.6.
(2S*,3S*)-6-Chloro-2-(4-chlorophenyl)-3-(toluene-4-
sulfonyl)chroman-4-one (4ac). 4ac was synthesized according
to general synthetic procedure from 2m (972 mg, 3.0 mmol)
and 3p (420 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of
dr was >20:1; Yield = 80% (1.07 g); Colorless solid; mp =
o
172-174 C (recrystallized from hexanes and EtOAc); HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C22H17Cl2O4S 447.0225,
(2R*,3S*)-2-Thiophen-2-yl-3-(toluene-4-sulfonyl)chroman-
4-one (4z). 4z was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3m (336 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 88% (1.01 g); Colorless solid; mp = 139-141 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C20H17O4S2 385.0568, found 385.0566;
1H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 1.6, 8.0 Hz, 1H),
7.71 (d, J = 8.8 Hz, 2H), 7.43 (dt, J = 1.6, 8.8 Hz, 1H), 7.23 (d,
J = 8.4 Hz, 2H), 7.20 (dd, J = 1.2, 8.0 Hz, 1H), 6.95 (dt, J =
0.8, 8.4 Hz, 1H), 6.90 (dt, J = 1.2, 8.4 Hz, 1H), 6.46-6.84 (m,
2H), 6.70 (br d, J = 1.2 Hz, 1H), 4.39 (d, J = 1.2 Hz, 1H), 2.37
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 181.9, 158.1,
145.8, 139.0, 137.2, 134.1, 129.5 (2x), 129.4 (2x), 127.1,
126.9 (2x), 126.8, 122.1, 120.6, 118.7, 73.4, 72.7, 21.6.
1
found 447.0225; H NMR (400 MHz, CDCl3): δ 7.66 (d, J =
8.4 Hz, 2H), 7.64 (dd, J = 2.8, 8.8 Hz, 1H), 7.38 (dd, J = 2.8,
8.8 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H),
7.09 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 9.2 Hz, 1H), 6.51 (s, 1H),
4.31 (d, J = 1.2 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 181.1, 157.1, 146.1, 137.3, 135.0, 134.1,
134.0, 129.8 (2x), 129.33 (2x), 129.30 (2x), 127.6, 127.5 (2x),
126.2, 121.3, 120.0, 75.8, 72.1, 21.7.
(2S*,3S*)-7-Methoxy-3-(toluene-4-sulfonyl)-2-(3,4,5-
trimethoxyphenyl)chroman-4-one (4ad). 4ad was synthesized
according to general synthetic procedure from 2o (960 mg, 3.0
mmol) and 3k (588 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 86% (1.28 g); Colorless solid;
o
mp = 195-197 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H27O8S
(2S*,3S*)-3-Pyridin-2-yl-3-(toluene-4-sulfonyl)chroman-4-
one (4aa). 4aa was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3n (321 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 90% (1.02 g); Colorless solid; mp = 136-138 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C21H18NO4S 380.0957, found
1
499.1427, found 499.1428; H NMR (400 MHz, CDCl3): δ
7.69 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.24 (d, J =
8.4 Hz, 2H), 6.51 (dd, J = 2.4, 8.8 Hz, 1H), 6.43 (s, 1H), 6.40
(s, 2H), 6.32 (d, J = 2.4 Hz, 1H), 4.30 (d, J = 0.8 Hz, 1H), 3.79
(s, 3H), 3.75 (s, 3H), 3.70 (s, 6H), 2.38 (s, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 180.3, 167.3, 161.0, 153.4 (2x), 145.6,
138.1, 134.2, 131.8, 129.5 (2x), 129.3 (2x), 128.7, 114.7,
110.5, 103.5 (2x), 100.8, 76.5, 72.6, 60.7, 56.0 (2x), 55.7, 21.6.
1
380.0957; H NMR (400 MHz, CDCl3): δ 8.54 (d, J = 2.4 Hz,
1H), 8.51 (dd, J = 1.2, 4.8 Hz, 1H), 7.71 (dt, J = 1.6, 8.8 Hz,
1H), 7.68 (d, J = 8.8 Hz, 2H), 7.54-7.51 (m, 1H), 7.47 (dt, J =
2.0, 8.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 3.2,
8.0 Hz, 1H), 6.97 (dt, J = 1.2, 8.4 Hz, 1H), 6.92 (dd, J = 0.8,
8.4 Hz, 1H), 6.61 (s, 1H), 4.36 (d, J = 1.2 Hz, 1H), 2.38 (s,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 181.5, 158.5, 150.0,
147.8, 145.9, 137.7, 134.1, 133.8, 132.1, 129.6 (2x), 129.4
(2x), 127.0, 123.6, 122.2, 120.7, 118.3, 74.6, 72.4, 21.6.
(2S*,3S*)-3-Methanesulfonyl-2-trifluoromethylchroman-4-
one (4ae). 4ae was synthesized according to general synthetic
procedure from 2c (642 mg, 3.0 mmol) and 3q (294 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 62% (547 mg); Colorless solid; mp = 138-140 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C11H10F3O4S 295.0252, found
1
295.0253; H NMR (400 MHz, CDCl3): δ 7.93 (dd, J = 2.0,
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8.0 Hz, 1H), 7.63 (t, J = 5.6 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H),
mmol) and 3q (294 mg, 3.0 mmol) in dry toluene (5 mL). The
2
3
4
5
7.10 (d, J = 8.4 Hz, 1H), 5.70 (q, J = 8.0 Hz, 1H), 4.11 (s, 1H),
3.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 180.6,
158.2, 138.4, 127.1, 123.23, 123.18 (q, J = 283.5 Hz), 118.1
(2x), 71.2 (q, J = 33.4 Hz), 64.6, 41.2.
ratio of dr was >20:1; Yield = 56% (672 mg); Colorless solid;
o
mp = 123-125 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16F3O5S
1
401.0671, found 401.0670; H NMR (400 MHz, CDCl3): δ
6
7.71 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.29 (d, J =
8.4 Hz, 2H), 6.61 (dd, J = 2.4, 8.8 Hz, 1H), 6.40 (d, J = 2.4 Hz,
1H), 5.74 (q, J = 8.0 Hz, 1H), 4.12 (d, J = 0.8 Hz, 1H), 3.84 (s,
3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 177.8,
167.4, 159.9, 146.3, 133.4, 129.8 (2x), 129.4 (2x), 128.7,
123.1 (d, J = 284.3 Hz), 113.6, 111.5, 100.7, 73.1 (q, J = 32.6
Hz), 66.6, 55.9, 21.7.
(2S*,3S*)-3-Benzenesulfonyl-2-trifluoromethylchroman-4-
one (4af). 4af was synthesized according to general synthetic
procedure from 2b (828 mg, 3.0 mmol) and 3q (294 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 55% (587 mg); Colorless solid; mp = 123-125 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H12F3O4S 357.0408, found
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
357.0409; H NMR (400 MHz, CDCl3): δ 7.81-7.79 (m, 2H),
(2S*,3S*)-3-(4-Fluoro-benzenesulfonyl)-2-trifluoromethyl-
chroman-4-one (4aj). 4aj was synthesized according to gen-
eral synthetic procedure from 2e (882 mg, 3.0 mmol) and 3q
(294 mg, 3.0 mmol) in dry toluene (5 mL). The ratio of dr was
>20:1; Yield = 65% (729 mg); Colorless solid; mp = 151-153
oC (recrystallized from hexanes and EtOAc); HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C16H11F4O4S 375.0314, found
7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.53-7.46
(m, 3H), 7.07-7.03 (m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.77 (q,
J = 8.4 Hz, 1H), 4.22 (d, J = 0.8 Hz, 1H); 13C{1H} NMR (100
MHz, CDCl3): δ 179.5, 157.7, 137.7, 136.2, 135.0, 129.4 (2x),
129.2 (2x), 126.8, 123.7 (d, J = 284.3 Hz), 122.9, 119.7, 117.7,
73.0 (q, J = 32.6 Hz), 66.9. Single-crystal X-Ray diagram:
crystal of compound 4af was grown by slow diffusion of
EtOAc into a solution of compound 4af in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the orthorhom-
bic crystal system, space group P n a 21, a = 24.1977(12) Å , b
= 9.9696(5) Å , c = 12.6028(6) Å , V = 3040.3(3) Å 3, Z = 4,
dcalcd = 1.557 g/cm3, F(000) = 1456, 2θ range 1.683~26.419o,
R indices (all data) R1 = 0.0574, wR2 = 0.1359.
1
375.0315; H NMR (400 MHz, CDCl3): δ 7.83-7.80 (m, 2H),
7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.56-7.52 (m, 1H), 7.18-7.13
(m, 2H), 7.09-7.05 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.77 (q,
J = 7.6 Hz, 1H), 4.20 (s, 1H); 13C{1H} NMR (100 MHz,
CDCl3): δ 179.5, 166.6 (d, J = 257.7 Hz), 157.7, 137.9, 132.6
(d, J = 9.9 Hz, 2x), 132.2 (d, J = 3.0 Hz), 126.8, 123.08,
123.06 (d, J = 284.3 Hz), 121.6, 117.8, 116.6 (d, J = 22.7 Hz,
2x), 73.0 (q, J = 33.4 Hz), 67.0. Single-crystal X-Ray diagram:
crystal of compound 4aj was grown by slow diffusion of
EtOAc into a solution of compound 4aj in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the triclinic
crystal system, space group P-1, a = 8.3801(12) Å , b =
9.4312(12) Å , c = 11.0839(15) Å , V = 745.01(18) Å 3, Z = 2,
dcalcd = 1.669 g/cm3, F(000) = 380, 2θ range 1.976~26.815o, R
indices (all data) R1 = 0.0489, wR2 = 0.1165.
(2S*,3S*)-3-(Toluene-4-sulfonyl)-2-
trifluoromethylchroman-4-one (4ag). 4ag was synthesized
according to general synthetic procedure from 2a (870 mg, 3.0
mmol) and 3q (294 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 68% (755 mg); Colorless solid;
o
mp = 139-141 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H14F3O4S
1
371.0565, found 371.0566; H NMR (400 MHz, CDCl3): δ
7.76 (dd, J = 1.6, 8.0 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.53-
7.49 (m, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.07-7.03 (m, 1H), 6.94
(d, J = 8.4 Hz, 1H), 5.76 (q, J = 7.6 Hz, 1H), 4.18 (s, 1H), 2.39
(s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 179.7, 157.8,
146.4 (2x), 137.6, 133.2, 129.8 (2x), 129.4 (2x), 126.8, 123.1
(q, J = 284.8 Hz), 122.8, 117.7, 73.0 (q, J = 33.3 Hz), 66.9,
21.7.
(2S*,3S*)-2-Ethyl-3-(toluene-4-sulfonyl)chroman-4-one
(4ak). 4ak was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3r (174 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 30% (298 mg); Colorless solid; mp = 131-133 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C18H19O4S 331.1004, found 331.1003;
1H NMR (400 MHz, CDCl3): δ 7.75 (dd, J = 1.6, 8.0 Hz, 1H),
7.64 (d, J = 8.4 Hz, 2H), 7.43 (dt, J = 1.6, 8.4 Hz, 1H), 7.21 (d,
J = 8.4 Hz, 2H), 6.95 (dt, J = 1.2, 8.0 Hz, 1H), 6.80 (dd, J =
1.4, 8.4 Hz, 1H), 5.31 (ddd, J = 0.8, 5.2, 10.0 Hz, 1H), 3.85 (d,
J = 1.2 Hz, 1H), 2.36 (s, 3H), 1.91-1.83 (m, 1H), 1.60-1.49 (m,
1H), 1.01 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 182.6, 158.2, 145.5, 137.1, 134.4, 129.4 (2x), 129.3
(2x), 126.9, 121.5, 120.2, 118.5, 77.0, 72.7, 25.3, 21.6, 10.0.
(2S*,3S*)-6-Fluoro-3-(toluene-4-sulfonyl)-2-
trifluoromethylchroman-4-one (4ah). 4ah was synthesized
according to general synthetic procedure from 2p (924 mg, 3.0
mmol) and 3q (294 mg, 3.0 mmol) in dry toluene (5 mL). The
ratio of dr was >20:1; Yield = 69% (803 mg); Colorless solid;
o
mp = 122-124 C (recrystallized from hexanes and EtOAc);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13F4O4S
1
389.0471, found 389.0472; H NMR (400 MHz, CDCl3): δ
7.67 (d, J = 8.4 Hz, 2H), 7.43 (dd, J = 3.2, 8.0 Hz, 1H), 7.31 (d,
J = 8.8 Hz, 1H), 7.28-7.23 (m, 2H), 6.97 (dd, J = 4.0, 9.2 Hz,
1H), 5.76 (q, J = 6.4 Hz, 1H), 4.17 (s, 1H), 2.43 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 179.2, 159.0, 156.6,
154.0 (d, J = 2.3 Hz), 146.7, 133.2, 130.0 (2x), 129.5 (2x),
125.1 (d, J = 24.2 Hz), 123.1 (d, J = 284.3 Hz), 119.6 (d, J =
6.9 Hz), 112.0 (d, J = 24.2 Hz), 73.1 (q, J = 33.3 Hz), 66.5,
21.7.
(2S*,3S*)-3-(4-Fluorobenzenesulfonyl)-2-methylchroman-
4-one (4al). 4al was synthesized according to general synthet-
ic procedure from 2e (882 mg, 3.0 mmol) and 3s (132 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 22% (210 mg); Colorless solid; mp = 130-132 oC
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C16H14FO4S 321.0597, found
1
321.0598; H NMR (400 MHz, CDCl3): δ 7.80-7.74 (m, 3H),
7.46-7.42 (m, 1H), 7.09-7.03 (m, 2H), 6.96 (dt, J = 0.2, 8.4 Hz,
1H), 6.77 (dd, J = 0.4, 8.4 Hz, 1H), 5.62 (dq, J = 0.8, 6.8 Hz,
1H), 3.85 (d, J = 0.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H); 13C{1H}
(2S*,3S*)-7-Methoxy-3-(toluene-4-sulfonyl)-2-
trifluoromethyl-chroman-4-one (4ai). 4ai was synthesized
according to general synthetic procedure from 2o (960 mg, 3.0
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ORCID
NMR (100 MHz, CDCl3): δ 182.3, 166.2 (d, J = 256.2 Hz),
158.1, 137.5, 132.38, 132.33 (d, J = 9.9 Hz, 2x), 126.9, 121.7,
119.7, 118. 6, 116.1 (d, J = 22.7 Hz, 2x), 73.7, 72.1, 18.4.
Meng-Yang Chang: 0000-0002-1983-8570
Notes
(2S*,3S*)-2-Methyl-3-(toluene-4-sulfonyl)chroman-4-one
(4am). 4am was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3s (132 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >9:1; Yield
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors would like to thank the Ministry of Science and
Technology of the Republic of China for financial support
(MOST 106-2628-M-037-001-MY3).
=
31% (294 mg); Colorless solid; mp = 59-61 oC
9
(recrystallized from hexanes and EtOAc); HRMS (ESI-TOF)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
m/z: [M + H]+ calcd for C17H17O4S 317.0848, found 317.0846;
1
Two isomers, ratio > 10:1; For major isomer: H NMR (400
REFERENCES
MHz, CDCl3): δ 7.76 (ddd, J = 0.4, 1.6, 8.0 Hz, 1H), 7.63 (d, J
= 8.4 Hz, 2H), 7.43 (ddd, J = 1.6, 7.2, 8.8 Hz, 1H), 7.19 (d, J =
8.0 Hz, 2H), 6.94 (dt, J = 1.2, 8.4 Hz, 1H), 6.79 (dd, J = 0.4,
8.4 Hz, 1H), 5.61 (dq, J = 1.2, 6.8 Hz, 1H), 3.82 (d, J = 1.6 Hz,
1H), 2.35 (s, 3H), 1.44 (d, J = 6.8 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3): δ 182.6, 158.2, 145.5, 137.2, 134.3, 129.4
(2x), 129.2 (2x), 126.8, 121.5, 119.8, 118.5, 73.6, 71.9, 21.6,
18.4.
(1) Selected examples on A3-coupling, see: (a) Seidel, D. The redox-
A3 reaction. Org. Chem. Front. 2014, 1, 426-429. (b) Cheng, H.;
Wen, J.; Bolm, C. Synthesis of N-Propargylsulfoximines by
Copper-Catalyzed A3-Couplings. Chem. Eur. J. 2017, 23,
12100-12103. For a review, see: (c) Peshkov, V. A.; Pereshivko,
O. P.; van der Eycken, E. V. A Walk around the A3-Coupling.
Chem. Soc. Rev. 2012, 41, 3790-3807.
(2) Recent example on Pictet-Spengler reaction, see: (a) Li, L.;
Aibibula, P.; Jia, Q.; Jia, Y. Total Syntheses of Naucleamides
A–C and E, Geissoschizine, Geissoschizol, (E)-Isositsirikine,
and 16-epi-(E)-Isositsirikine. Org. Lett. 2017, 19, 2642-2645.
For reviews, see: (b) Larghi, E. L.; Kaufman, T. S. The Oxa-
Pictet-Spengler Cyclization. Synthesis of Isochromanes and Re-
lated Pyran-Type Heterocycles. Synthesis 2006, 187-210. (c)
Cox, E. D.; Cook, J. M. The Pictet-Spengler Condensation: a
New Direction for an Old Reaction. Chem Rev. 1995, 95, 1797-
1842.
(3) Examples on double Michael addition, see: (a) Selvaraju, M.;
Wang, Y.-L.; Sun, C.-M. Ruthenium(II)-Catalyzed C–H
Alkenylation/Annulation Cascade for the Rapid Synthesis of
Benzoimidazoisoindoles. Org. Chem. Front. 2017, 4, 1358-1362.
(b) Sriramurthy, V.; Kwon, O. Diphosphine-Catalyzed Mixed
Double-Michael Reaction: A Unified Synthesis of Indolines,
(2S*,3S*)-2-Phenethyl-3-(toluene-4-sulfonyl)chroman-4-
one (4an). 4an was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3t (402 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 35% (426 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C24H23O4S 407.1317, found 407.1318; H NMR
(400 MHz, CDCl3): δ 7.77 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 (d, J
= 8.4 Hz, 2H), 7.46 (ddd, J = 1.6, 7.2, 8.8 Hz, 1H), 7.29-7.17
(m, 5H), 7.13-7.11 (m, 2H), 6.98 (dt, J = 1.2, 8.4 Hz, 1H),
6.85 (dd, J = 0.4, 8.4 Hz, 1H), 5.44-5.40 (m, 1H), 3.84 (d, J =
1.2 Hz, 1H), 2.78-2.74 (m, 2H), 2.36 (s, 3H), 2.23-2.14 (m,
1H), 1.83-1.74 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
182.5, 158.0, 145.5, 139.7, 137.2, 134.3, 129.4 (2x), 129.2
(2x), 128.6 (2x), 128.3 (2x), 126.9, 126.3, 121.6, 120.2, 118.5,
74.8, 72.7, 33.4, 31.5, 21.6.
Dihydropyrrolopyridines,
Benzimidazolines,
Tetrahydroquinolines, Tetrahydroisoquinolines, Dihydrobenzo-
1,4-oxazines, and Dihydrobenzo-3,1-oxazines. Org. Lett. 2010,
12, 1084-1087. (c) Sobenina, L. N.; Tomilin, D. N.; Sagitova, E.
F.; Ushakov, I. A.; Trofimov, B. A. Transition-Metal-Free, At-
om- and Step-Economic Synthesis of Aminoketopyrrolizines
from Benzylamine, Acylethynylpyrroles, and Acylacetylenes.
Org. Lett. 2017, 19, 1586-1589. (d) Sonehara, T.; Murakami, S.;
Yamazaki, S.; Kawatsura, M. Iron-Catalyzed Intermolecular
Hydrothiolation of Internal Alkynes with Thiosalicylic Acids,
and Sequential Intramolecular Cyclization Reaction. Org. Lett.
2017, 19, 4299-4302. (e) Holeman, D. S.; Rasne, R. M.;
Grossman, R. B. Trimethylsilylethynyl Ketones as Surrogates
for Ethynyl Ketones in the Double Michael Reaction. J. Org.
Chem. 2002, 67, 3149-3151. (f) Kang, T.; Zhao, P.; Yang, J.; Lin,
L.; Feng, X.; Liu, X. Asymmetric Catalytic Double Michael Ad-
ditions for the Synthesis of Spirooxindoles. Chem. Eur J. 2018,
24, 3703-3706.
(2S*,3S*)-2-n-Heptyl-3-(toluene-4-sulfonyl)chroman-4-one
(4ao). 4ao was synthesized according to general synthetic
procedure from 2a (870 mg, 3.0 mmol) and 3u (384 mg, 3.0
mmol) in dry toluene (5 mL). The ratio of dr was >20:1; Yield
= 38% (456 mg); Colorless gum; HRMS (ESI-TOF) m/z: [M +
1
H]+ calcd for C23H29O4S 401.1787, found 401.1788; H NMR
(400 MHz, CDCl3): δ 7.75 (dd, J = 1.6, 8.0 Hz, 1H), 7.63 (d, J
= 8.4 Hz, 2H), 7.43 (dt, J = 2.0, 8.8 Hz, 1H), 7.19 (d, J = 8.0
Hz, 2H), 6.94 (dt, J = 1.2, 8.4 Hz, 1H), 6.79 (dd, J = 0.8, 8.4
Hz, 1H), 5.41-5.38 (m, 1H), 3.83 (d, J = 1.2 Hz, 1H), 2.35 (s,
3H), 1.89-1.80 (m, 1H), 1.51-1.40 (m, 3H), 1.35-1.21 (m, 8H),
0.85 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
182.6, 158.2, 145.4, 137.1, 134.4, 129.4 (2x), 129.3 (2x),
126.8, 121.4, 120.1, 118.5, 75.6, 72.8, 31.8, 31.5, 28.9, 28.7,
25.3, 22.5, 21.6, 14.0.
(4) Recent examples on synthetic applications of β-ketosulfones by
the authors, see: (a) Chang, M.-Y.; Chen, H.-Y.; Tsai, Y.-L.
Temperature-Controlled Desulfonylative Condensation of α-
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ASSOCIATED CONTENT
Supporting Information
Scanned photocopies of NMR spectral data for all compounds and
X-ray analysis data of 4a, 4e, 4ab, 4af and 4aj. This information
is available free of charge via the Internet at http: //pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: mychang@kmu.edu.tw
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