Domino Synthetic Strategy for Tetrahydrothiopyran Derivatives from Benzaldehydes, 2-Acetylfuran/2-Acetylthiophene, and Sodium Sulfide

Article abstract of DOI:10.1021/acs.joc.0c01006

A novel domino reaction from benzaldehydes and 2-acetylfuran/2-acetylthiophene with sodium sulfide was developed to synthesize a series of tetrahydrothiopyran (THTP) derivatives. The reaction proceeded well to construct a tetrahydrothiopyran ring and five new bonds in one step. A mechanism is proposed, involving a stepwise Aldol/double Michael addition/Aldol (AMMA) reaction cascade. In this transformation, sodium sulfide acts as a nucleophile and base. This method is characterized by transition-metal-free, commercially available starting materials and mild reaction conditions.

Full text of DOI:10.1021/acs.joc.0c01006

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Article
A Domino Synthetic Strategy for Tetrahydrothiopyran Derivatives from
Benzaldehydes, 2-Acetylfuran/2-Acetylthiophene and Sodium Sulfide
Dongdong Chen, Weixia Du, Xufeng Yang, and Tao Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01006 • Publication Date (Web): 12 Jun 2020
Downloaded from pubs.acs.org on June 13, 2020
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A Domino Synthetic Strategy for Tetrahydrothiopyran Derivatives from
Benzaldehydes, 2-Acetylfuran/2-Acetylthiophene and Sodium Sulfide
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Dongdong Chen , Weixia Du, Xufeng Yang, and Tao Liu
Department of Chemistry & Chemical Engineering, Lvliang University, Lishi 033001, P. R. China.
*E-mail: chenddxy@163.com
*E-mail: liutao@llhc.edu.cn
TOC Graphic:
O
X
X
Na2S•9H2O
R
OH
+
O
MeOH
O
S
r.t.
R
R
X
2
7 examples
X = O, S
up to 95% yield


High efficiency
one pot, six new bonds
Mild reaction conditions
Metal-free
ABSTRACT: A novel domino reaction from benzaldehydes and 2-acetylfuran/2-acetylthiophene
with sodium sulfide was developed to synthesize a series of tetrahydrothiopyran (THTP) derivatives.
The reaction proceeded well to construct a tetrahydrothioan ring and five new bonds in one step. A
mechanism is proposed, involving a stepwise of Aldol/double Michael addition/Aldol (AMMA)
reaction cascade. In this transformation, sodium sulfide acts as a nucleophile and base. This method
is characterized by transition-metal free, commercially available starting materials and mild reaction
conditions.
INTRODUCTION
Sulfur-containing compounds are widely applied as pesticides, medicines and synthons playing its
irreplaceable roles in academic and industrial communities.1-3 THTP derivatives have been testified
to exhibit many pharmaceutical properties such as anti-bacterial, anti-cancer, anti-inflammatory and
anti-viral activities.4-7 In the past decades, some convenient methods for the synthesis of THTP
derivatives have been developed. However, most of them suffer from a number of drawbacks such
as the introduction of expensive or toxic metal catalysts, long synthesis routes, limited substrate
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scopes and low yields.8-11 These problems greatly limited its practical applications. The exploration
of a simple and efficient new method for obtaining sulfur-containing heterocyclic compounds
caused huge attention in chemical synthesis. In this context, domino reactions exhibited significant
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potential in the construction of complex molecules from simple precursors . Sodium sulfide, the
simplest inorganic compound bearing both a useful base and a sulfur source often, is often employed
in organic synthesis.13
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Recently, we explored a novel and general tandem AMMA reaction from benzaldehydes and 2-
acetylfuran/2-acetylthiophene with sodium sulfide (acts as nucleophile and base), which is a
convenient and mild method to synthesize THTP derivatives with no catalysts needed. (Scheme 1).
To the best of our knowledge, this new class of THTP derivatives have never been reported.
X
O
X
O
MeOH
r.t.
OH
+
+
•
Na2S 9H2O
R
O
X
S
X = O, S
R
R
Scheme 1. Synthesis of THTP Derivatives.
RESULTS AND DISCUSSION
To begin with, the investigation into the adaptability of a tandem process from benzaldehyde 1a, 2-
acetylfuran 2a, and Na S·9H O was conducted followed by the optimization of reaction conditions
2
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(Table 1). As shown in Table 1, we found that it failed to yield the desired product 3aa in
dichloromethane (DCM) or toluene at 25 °C for 48 h (Table 1, entries 1 and 2). we got the target
compound 3aa with low yields when N,N-dimethylformamide (DMF), acetonitrile (CH CN) and
3
ethanol (EtOH) were selected as the solvent (Table 1, entry 3-5). The yield of 3aa was raised to 72%
within 6 h in methanol (MeOH) (Table 1, entry 6), which means MeOH is the most optimal solvent
for the reaction (Table 1, entry 1-6). In terms of reaction time, yield is increasing when reaction
time is increased from 6 h to 48 h, while the yield decreased when the reaction time was extended
to 72 h (Table 1, entry 6-10). Therefore, the treatment to the reaction solution of benzaldehyde 1a
(
1 equiv, 1 mmol) plus 2-acetylfuran 2a (1.1 equiv, 1.1 mmol) with Na S·9H O (1 equiv, 1 mmol)
2 2
in MeOH (5 mL) at 25 °C for 48 h was selected as the most optimal condition (Table 1, entry 9).
Table 1. Optimization of the Reaction Conditionsa
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O
O
O
O
MeOH
OH
+
+
Na S•9H O
2
2
O
O
r.t.
S
1
a
2a
3
aa
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entry
solvent
DCM
Time (h)
48
temp (°C)
Yield (%)b
1
2
25
25
25
25
25
25
25
25
25
25
50
0
0
toluene
DMF
48
0
4c
3
48
4
CH CN
48
11
14
72
81
85
91
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3
5
EtOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
6
6
6
7
12
8
24
9
48
10
72
1
1
1
2
48
48
aReaction conditions: 1a (1 mmol), 2a (1.1 mmol), Na
b
2
2
S·9H O (1 mmol), solvent (5 mL). Isolated yield based on
c
1a. The reaction generated a complex mixture from which pure product could nevertheless be isolated.
With optimized reaction condition in hand (Table 1, entry 9), it was applied in to a variety of
substituted benzaldehydes 1a and 2-acetylfuran 2a/2-Acetylthiophene 2b to yield the corresponding
THTP derivatives 3 (Scheme 2). It was found that the domino reaction exhibited a wide tolerance
for different substituents in substrates 1. The yields for the compounds 3a and 3b series showed that
an oxygen or sulfur atom in the pent-heterocycle exerted little influence on the yield. The selection
for substituents in the benzene ring of benzaldehydes 1a can significantly influence the yields of
THTP derivatives 3. Compared to the yields from non-substituted benzaldehyde substrates (3aa,
3
ba), benzaldehydes substituted by an alkyl group at the 4-position [methyl (3ad, 3bd), ethyl (3ai,
bj), n-propyl (3ak, 3bk), isopropyl (3ah, 3bh) and tert-butyl (3ai, 3bi)] exhibited excellent yields.
3
In terms of substitution sites of methyl groups in the benzene ring showed no obvious differences
in the yields. The introduction of a weak electron-withdrawing group such as chloro (3ab, 3bb) or
bromo (3ac, 3bc) led to a slightly reduction in the yield. The presence of a strong electron-donating
group such as methoxy (3an) or methylthio (3al, 3bl) led to decreased yields. In the intermediate I
(Scheme 3), the electron-rich β position donated by benzyl group resulted in slow formation rate of
intermediate Ⅱ. While the fairly non-reactive diphenyl group in aldehyde (3am and 3bm)
substantially stabilized intermediate I, which hindered the formation of intermediate Ⅱ.
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Scheme 2. Synthesis of THTP Derivatives 3a
X
X
O
O
MeOH
rt
OH
3
7
4
+
+
Na2S•9H2O
5
O
R
X
6
2
S1
X = O, S
R
R
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X
X
X
X
X
X
X
OH
OH
OH
OH
O
O
O
O
S
S
S
S
Cl
Cl
Br
Br
3aa, X = O, 91%
3ab, X = O, 85%
3bb, X = S, 91%
3ac, X = O, 76%
3bc, X = S, 89%
3ad, X = O, 72%
3bd, X = S, 70%
3ba, X = S, 89%
X
X
X
X
X
X
X
X
OH
O
OH
O
OH
O
OH
O
S
S
S
S
3ae, X = O, 75%
3be, X = S, 80%
3af
,
X = O, 74%
X = S, 82%
3ah, X = O, 95%
3bh, X = S, 94%
3
ag, X = O, 92%
3bf
,
3
bg, X = S, 88%
X
X
X
X
X
X
X
X
OH
O
OH
OH
OH
O
O
O
S
S
S
S
S
S
3ai, X = O, 93%
3bi, X = S, 94%
3aj, X = O, 82%
3bj, X = S, 89%
3
ak, X = O, 76%
3
al, X = O, 43%
3
bk, X = S, 83%
3bl, X = S, 42%
X
X
X
X
OH
OH
O
O
S
S
O
O
3am, X = O, 33%
3an, X = O, 38%
3bm, X = S, 34%
aReaction conditions: 1a (1 mmol), 2a (1.1 mmol) and Na
Isolated yield based on 1.
2
2
S·9H O (1 mmol) in MeOH (5 mL) at room temperature.
The relative stereochemistry of compound 3aa was confirmed by the X-ray single crystal
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analysis (Figure 1) . The THTP ring exists as the stable chair conformation. Two phenyl groups
(
2,6-position) and a 2-furyl group (4-position) on the same side in the equatorial positions, while
the hydroxyl (4-position) group directed to another side in the axial direction.
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OH
H
H
O
O
O
S
H
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aa
CCDC 2006752
Figure 1. The relative stereochemistry and single-crystal X-ray structures of compound 3aa
A plausible reaction mechanism was proposed as shown in scheme 3. The mechanism involves
three steps: (1) A base-promoted intermolecular Aldol reaction of substituted benzaldehyde 1a and
2
-acetylfuran (2a)/2-acetylthiophene (2b) to yield intermediate I (We have captured intermediate I
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of compound 3aa ); (2) Michael addition of sulfide anion takes place with two molecular
equivalence of intermediate I to generate intermediate Ⅱ (we have not captured intermediate Ⅱ
unfortunately); (3) An intramolecular Aldol reaction of II furnishes the THTP derivatives 3. Thus,
the mechanism involvs a stepwise Aldol reaction/double Michael addition/Aldol reaction (AMMA)
is a reaction cascade mechanism.
Scheme 3. Plausible Reaction Mechanism
O
O
O
O
O
R
O
MeOH
MeOH
X
1
X
-H O
2
X
X
Na S•9H O
2
2
R
O
R
2

S2-
X
X
X
X
S
O
MeOH
O O
S
X
OH
X
R
O
R
S
R
R

3
R
R
CONCLUSION
In summary, we have explored a novel and strategic one pot reaction through a sequential Aldol
reaction/double Michael addition/Aldol, which provides straightforward access to THTP derivatives
with high yields from readies available substrates (benzaldehydes, 2-acetylfuran/2-acetylthiophene
and Na S·9H O). This domino strategy features transition-metal free, wide substrate scope and mild
2
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reaction conditions. Further investigations and applications of this protocol are under study in our
laboratory.
EXPERIMENTAL SECTION
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General Information. All starting materials were purchased from commercial suppliers and used
without further purification unless otherwise stated. Melting points (mp) were determined on an
XT-4 micro-melting point apparatus and uncorrected. Nuclear magnetic resonance spectra (NMR)
were recorded on a Bruker AVANCE III operating at 500 or 400 MHz (Bruker, Karlsruhe, Germany)
instrument in CDCl or DMSO-d and using tetramethyl silane (TMS) as an internal standard. All
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chemical shifts (δ values) are given in ppm and coupling constants (J values) are given in Hz. High
resolution mass spectra (HRMS) were obtained using a Bruker micrOTOF-Q II focus spectrometer
(ESI).
General Experimental Procedures for the Synthesis of compounds 3 (with 3aa as an example).
To a solution of benzaldehyde 1a (1.0 mmol) and 2-acetylfuran 2a (1.1 mmol) in MeOH (5 mL)
was added Na S·9H O (1 mmol) at room temperature. The reaction mixture was stirred at room
2
2
temperature until the completion of reaction (checked by TLC). To the resulting mixture was added
DCM (30 mL) and washed with water (30 mL) three times. The organic layer was dried over
anhydrous MgSO and evaporated under vacuum. The residue was purified by silica gel column
4
using petroleum ether/ethyl acetate (5:1, v/v) mixture to afford 3aa (195.8 mg) in 91% yield as a
white solid.
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-diphenyltetrahydro-2H-thiopyran-3-yl)methanone
(3aa). Obtained as a white solid; isolated yield: 195.8 mg (91%); mp 142–143 °C. Eluent: petroleum
1
ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.52–7.50 (m, 2H), 7.45–7.36 (m, 5H),
3
7
.32–7.30 (m, 1H), 7.20–7.17 (m, 3H), 7.13–7.10 (m, 1H), 6.93 (d, 1H, J = 3.6 Hz), 6.31 (dd, 1H,
J = 3.6, 1.6 Hz), 6.23 (dd, 1H, J = 3.3, 0.9 Hz), 6.16 (dd, 1H, J = 3.3, 1.8 Hz), 4.98–4.95 (m, 2H),
4
1
1
4
.88 (dd, 1H, J = 12.2, 2.7 Hz), 4.48 (d, 1H, J = 11.2 Hz), 2.68 (td, 1H, J = 13.0, 2.7 Hz), 2.50 (dd,
1
3
1
H, J = 14.0, 2.7 Hz); C{ H} NMR (125 MHz, CDCl ) δ 192.8, 158.3, 152.5, 147.3, 141.5, 140.5,
3
37.7, 128.7, 128.5, 128.4, 128.0, 127.8, 127.7, 119.2, 112.3, 110.3, 105.5, 73.8, 56.6, 47.2, 44.6,
+
3.0; HRMS (ESI) m/z: [M+H] calcd for C H O S 431.1312; found 431.1311.
2
6
23
4
(2,6-Bis(4-chlorophenyl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
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yl)methanone (3ab). Obtained as a white solid; isolated yield: 210.9 mg (85%); mp 180–181 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, DMSO-d ) δ 7.71–7.52 (m,
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1
H), 7.52–7.40 (m, 7H), 7.27–7.25 (m, 3H), 6.46 (d, 1H, J = 3.6 Hz), 6.19 (s, 1H), 6.14 (s, 1H),
.56 (s, 1H), 4.98 (d, 1H, J = 11.2 Hz), 4.73 (d, 1H, J = 12.1 Hz), 4.33 (d, 1H, J = 11.2 Hz), 2.79 (t,
5
1
1
1
1
1
1
1
1
1
1
2
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3
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5
5
5
5
5
5
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0
1
2
3
4
5
6
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9
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1
2
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1
2
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0
1
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4
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1
3
1
1
H, J = 12.9 Hz), 2.24 (d, 1H, J = 13.4 Hz); C{ H} NMR (125 MHz, DMSO-d) δ 187.8, 158.2,
1
52.7, 148.2, 142.1, 139.9, 138.2, 132.7, 132.6, 130.8, 130.0, 129.2, 128.8, 119.5, 112.7, 110.6,
-
1
06.1, 72.9, 56.9, 45.3, 44.9, 41.9; HRMS (ESI) m/z: [M+Cl] calcd for C H Cl O S 533.0153;
2
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found 533.0147.
(2,6-Bis(4-bromophenyl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
yl)methanone (3ac). Obtained as a white solid; isolated yield: 224.0 mg (76%); mp 185–186 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, DMSO-d ) δ 7.71–7.58 (m,
6
3
1
H), 7.46–7.26 (m, 8H), 6.46 (d, 1H, J = 3.6 Hz), 6.19-6.14 (m, 2H), 5.56 (s, 1H), 4.97 (d, 1H, J =
1.2), 4.71 (d, 1H, J = 12.1 Hz), 4.32 (d, 1H, J = 11.2 Hz), 2.79 (t, 1H, J = 13.0 Hz), 2.24 (d, 1H, J
= 13.5); 13C{ H} NMR (125 MHz, DMSO-d) δ 187.8, 158.2, 152.7, 148.2, 142.1, 140.4, 138.7,
1
132.2, 131.8, 131.1, 130.3, 121.2, 119.5, 112.7, 110.6, 106.1, 72.9, 56.9, 45.4, 44.8, 42.0; HRMS
+
(ESI) m/z: [M+H] calcd for C H Br O S 586.9522; found 586.9521.
2
6
21
2
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-di-p-tolyltetrahydro-2H-thiopyran-3-yl)methanone
(3ad). Obtained as a white solid; isolated yield: 164.7 mg (72%); mp 183–184 °C. Eluent: petroleum
1
ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.42–7.38 (m, 3H), 7.31–7.30 (m, 2H),
3
7
1
2
2
1
4
.19–7.17 (m, 3H), 7.98 (d, 2H, J = 7.7 Hz), 6.94 (d, 1H, J = 3.6 Hz), 6.33–6.32 (m, 1H), 6.21 (d,
H, J = 3.2 Hz), 6.15-6.14 (m, 1H), 4.92 (d, 1H, J = 11.1 Hz), 4.91 (s, 1H), 4.83 (dd, 1H, J = 12.3,
.6 Hz), 4.45 (d, 1H, J = 11.2 Hz), 2.66 (td, 1H, J = 13.0, 2.7 Hz), 2.45 (dd, 1H, J = 13.9, 2.6 Hz),
1
3
1
.37 (s, 3H), 2.21 (s, 3H); C{ H} NMR (125 MHz, CDCl ) δ 192.9, 158.4, 152.5, 147.3, 141.5,
3
37.6, 137.3, 134.7, 129.4, 129.1, 128.3, 127.6, 119.2, 112.3, 110.3, 105.4, 73.9, 56.7, 46.8, 44.6,
+
2.7, 21.1, 21.0; HRMS (ESI) m/z: [M+Na] calcd for C H O SNa 481.1444; found 481.1438.
2
8
26
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-di-o-tolyltetrahydro-2H-thiopyran-3-yl)methanone
(3ae). Obtained as a white solid; isolated yield: 172.3 mg (75%); mp 139–140 °C. Eluent: petroleum
1
ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.61 (d, 1H, J = 7.4 Hz), 7.54 (d, 1H,
3
J = 7.6 Hz), 7.44 (d, 1H, J = 1.8 Hz), 7.26–7.19 (m, 4H), 7.05–6.99 (m, 4H), 6.35 (dd, 1H, J = 3.7,
1
.6 Hz), 6.22 (d, 1H, J = 3.3 Hz), 6.15 (dd, 1H, J = 3.3, 1.8 Hz), 5.26 (d, 1H, J = 11.1 Hz), 5.08 (dd,
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H, J = 12.1, 2.5 Hz), 4.84 (d, 1H, J = 2.5 Hz), 4.56 (d, 1H, J = 11.2 Hz), 2.75 (td, 1H, J = 13.0, 2.6
1
3
1
Hz), 2.57 (s, 3H), 2.48 (s, 3H), 2.42 (dd, 1H, J = 14.0, 2.6 Hz); C{ H} NMR (125 MHz, CDCl )
3
δ 192.8, 158.3, 152.4, 147.4, 141.5, 138.4, 136.3, 135.9, 130.7, 130.6, 127.7, 127.6, 127.4, 126.6,
1
26.4, 125.9, 119.2, 112.3, 110.3, 105.5, 74.0, 56.3, 43.9, 41.7, 39.0, 19.7, 19.3; HRMS (ESI) m/z:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
[M+Na] calcd for C H O SNa 481.1444; found 481.1432.
2
8
26
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-di-m-tolyltetrahydro-2H-thiopyran-3-yl)methanone
(3af). Obtained as a white solid; isolated yield: 170.0 mg (74%); mp 125–127 °C. Eluent: petroleum
1
ether/ethyl acetate = 5/1, v/v. H NMR (400 MHz, CDCl ) δ 7.38 (dd, 1H, J = 1.7, 0.7 Hz), 7.27–
3
7
.25 (m, 1H), 7.24–7.14 (m, 5H), 7.08–6.99 (m, 2H), 6.90–6.85 (m, 2H), 6.28 (dd, 1H, J = 3.6, 1.7
Hz), 6.17 (dd, 1H, J = 3.3, 0.9 Hz), 6.11 (dd, 1H, J = 3.6, 1.7 Hz), 4.90 (s, 1H), 4.85 (d, 1H, J = 11.2
Hz), 4.78 (dd, 1H, J = 12.2, 2.6 Hz), 4.43 (d, 1H, J = 11.2 Hz), 2.61 (t, 1H, J = 13.0 Hz), 2.42 (dd,
13
1
1
1
H, J = 13.9, 2.7 Hz), 2.34 (s, 3H), 2.20 (s, 3H); C{ H} NMR (100 MHz, CDCl ) δ 192.9, 158.4,
3
52.6, 147.2, 141.5, 140.4, 138.3, 138.0, 137.5, 129.2, 128.7, 128.6, 128.42, 128.40, 128.2, 125.5,
124.8, 119.0, 112.3, 110.3, 105.4, 73.8, 56.4, 47.1, 44.6, 42.9, 21.4, 21.2; HRMS (ESI) m/z:
+
[M+Na] calcd for C H O SNa 481.1444; found 481.1440.
2
8
26
4
(2,6-Bis(3,5-dimethylphenyl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
yl)methanone (3ag). Obtained as a white solid; isolated yield: 224.1 mg (92%); mp 200–201 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.44 (d, 1H, J = 1.7
3
Hz), 7.20 (d, 1H, J = 1.8 Hz), 7.12 (s, 2H), 7.04 (s, 2H), 6.96 (d, 1H, J = 3.6 Hz), 6.94 (s, 1H), 6.73
(
s, 1H), 6.34 (dd, 1H, J = 3.7, 1.7 Hz), 6.23 (d, 1H, J = 3.3 Hz), 6.16 (dd, 1H, J = 3.3, 1.8 Hz), 4.93
d, 1H, J = 2.6 Hz), 4.87 (d, 1H, J = 11.2 Hz), 4.80 (dd, 1H, J = 12.2, 2.6 Hz), 4.51 (d, 1H, J = 11.2
(
Hz), 2.64 (td, 1H, J = 13.0, 2.6 Hz), 2.50 (dd, 1H, J = 13.9, 2.7 Hz), 2.35 (s, 6H), 2.20 (s, 6H);
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ 193.0, 158.5, 152.7, 147.1, 141.5, 140.4, 138.2, 137.8, 137.3,
3
1
29.5, 129.3, 126.3, 125.5, 118.9, 112.3, 110.3, 105.4, 73.9, 56.3, 47.0, 44.7, 43.0, 21.3, 21.1;
+
HRMS (ESI) m/z: [M+Na] calcd for C H O SNa 509.1757; found 509.1756.
3
0
30
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-bis(4-isopropylphenyl)tetrahydro-2H-thiopyran-3-
yl)methanone (3ah). Obtained as a white solid; isolated yield: 245.0 mg (95%); mp 169–171 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.43–7.39 (m, 3H),
3
7
1
.34–7.31 (m, 2H), 7.24–7.19 (m, 3H), 7.01 (d, 2H, J = 8.0 Hz), 6.90 (d, 1H, J = 3.6 Hz), 6.29 (dd,
H, J = 3.6, 1.7 Hz), 6.22 (d, 1H, J = 3.3 Hz), 6.15 (dd, 1H, J = 3.3, 1.8 Hz), 5.02 (d, 1H, J = 2.6
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Hz), 4.92 (d, 1H, J = 11.1 Hz), 4.85 (dd, 1H, J = 12.2, 2.6 Hz), 4.41 (d, 1H, J = 11.2 Hz), 2.97–2.89
(m, 1H), 2.81–2.72 (m, 1H), 2.64 (td, 1H, J = 13.0, 2.7 Hz), 2.50 (dd, 1H, J = 13.9, 2.7 Hz), 1.28
1
(
d, 6H, J = 6.9 Hz), 1.13 (d, 6H, J = 6.9 Hz); 13C{ H} NMR (125 MHz, CDCl ) δ 193.1, 158.5,
3
1
1
52.5, 148.5, 148.2, 147.2, 141.5, 137.9, 135.0, 128.3, 127.6, 126.7, 126.4, 119.1, 112.2, 110.3,
1
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2
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4
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4
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4
4
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5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
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9
0
1
2
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9
0
1
2
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4
5
6
7
8
9
0
+
05.4, 73.8, 56.8, 47.0, 44.8, 42.6, 33.8, 33.7, 23.82, 23.79; HRMS (ESI) m/z: [M+H] calcd for
C H O S 515.2251; found 515.2232.
3
2
35
4
(2,6-Bis(4-(tert-butyl)phenyl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
yl)methanone (3ai). Obtained as a white solid; isolated yield: 251.6 mg (93%); mp 186–188 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.44–7.39 (m, 5H),
3
7
.34–7.31 (m, 2H), 7.19–7.16 (m, 3H), 6.89 (d, 1H, J = 3.6 Hz), 6.28 (dd, 1H, J = 3.7, 1.7 Hz), 6.23
d, 1H, J = 3.3 Hz), 6.16 (dd, 1H, J = 3.3, 1.8 Hz), 5.04 (d, 1H, J = 2.6 Hz), 4.93 (d, 1H, J = 11.1
Hz), 4.85 (dd, 1H, J = 12.2, 2.6 Hz), 4.41 (d, 1H, J = 11.1 Hz), 2.63 (td, 1H, J = 13.0, 2.7 Hz), 2.48
(
1
3
1
(
dd, 1H, J = 14.0, 2.7 Hz), 1.35 (s, 9H), 1.21 (s, 9H); C{ H} NMR (125 MHz, CDCl ) δ 193.1,
3
158.5, 152.6, 150.8, 150.5, 147.1, 141.5, 137.6, 134.6, 128.1, 127.4, 125.6, 125.2, 119.1, 112.1,
+
110.3, 105.4, 73.8, 56.8, 46.9, 44.9, 42.5, 34.5, 34.4, 31.4, 31.2; HRMS (ESI) m/z: [M+Na] calcd
for C H O SNa 565.2383; found 565.2387.
3
4
38
4
(2,6-Bis(4-ethylphenyl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
yl)methanone (3aj). Obtained as a white solid; isolated yield: 200.1 mg (82%); mp 177–178 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.42–7.33 (m, 3H),
3
7
1
1
2
.32–7.31 (m, 2H), 7.21–7.19 (m, 3H), 7.00 (d, 2H, J = 7.7 Hz), 6.92 (d, 1H, J = 3.7 Hz), 6.31 (d,
H, J = 3.7, 1.7 Hz), 6.22 (d, 1H, J = 3.3 Hz), 6.15-6.14 (m, 1H), 4.97 (d, 1H, J = 2.6 Hz), 4.92 (d,
H, J = 11.1 Hz), 4.84 (dd, 1H, J = 12.1, 2.7 Hz), 4.43 (d, 1H, J = 11.1 Hz), 2.69–2.62 (m, 3H),
.53–2.48 (m, 3H), 1.26 (t, 3H, J = 7.6 Hz), 1.12 (t, 3H, J = 7.6 Hz); 13C{ H} NMR (125 MHz,
1
CDCl ) δ 193.0, 158.4, 152.5, 147.3, 143.9, 143.6, 141.5, 137.8, 134.9, 128.4, 128.2, 127.9, 127.7,
3
1
19.2, 112.2, 110.3, 105.4, 73.9, 56.7, 46.9, 44.7, 42.6, 28.5, 28.4, 15.5, 15.4; HRMS (ESI) m/z:
+
[
M+Na] calcd for C H O SNa 509.1757; found 509.1746.
3
0
30
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-bis(4-propylphenyl)tetrahydro-2H-thiopyran-3-
yl)methanone (3ak). Obtained as a white solid; Obtained as a white solid; isolated yield: 195.7 mg
1
(
76%); mp 153–154 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl )
3
δ 7.41–7.31 (m, 5H), 7.19–7.17 (m, 3H), 6.97 (d, 2H, J = 7.8 Hz), 6.91 (d, 1H, J = 3.6 Hz), 6.30
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(
dd, 1H, J = 3.7, 1.7 Hz), 6.22 (d, 1H, J = 3.3 Hz), 6.15 (dd, 1H, J = 3.5, 1.8 Hz), 5.00 (d, 1H, J =
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5
.6 Hz), 4.91 (d, 1H, J = 11.1 Hz), 4.84 (dd, 1H, J = 12.2, 2.6 Hz), 4.42 (d, 1H, J = 11.1 Hz), 2.67–
.59 (m, 3H), 2.48–2.43 (m, 3H), 1.69–1.63 (m, 2H), 1.53–1.48 (m, 2H), 0.97 (t, 3H, J = 7.3 Hz),
.81 (t, 3H, J = 7.3 Hz); 13C{ H} NMR (125 MHz, CDCl ) δ 193.0, 158.5, 152.5, 147.2, 142.3,
1
3
0
1
2
3
4
5
6
7
8
9
0
1
2
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7
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42.1, 141.5, 137.8, 134.9, 128.8, 128.5, 128.3, 127.6, 119.2, 112.2, 110.3, 105.4, 73.9, 56.8, 47.0,
+
4.7, 42.6, 37.7, 37.5, 24.5, 24.3, 13.9, 13.5; HRMS (ESI) m/z: [M+Na] calcd for C H O SNa
3
2
34
4
37.2070; found 537.2073.
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-bis(4-(methylthio)phenyl)tetrahydro-2H-thiopyran-3-
yl)methanone (3al). Obtained as a white solid; isolated yield: 111.7 mg (43%); mp 184–185 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.44–7.33 (m, 5H),
3
7
.27–7.19 (m, 3H), 7.07–7.05 (m, 2H), 6.89 (d, 1H, J = 3.6 Hz), 6.35–6.34 (m, 1H), 6.21 (d, 1H, J
3.4 Hz), 6.15 (dd, 1H, J = 3.4, 1.8 Hz), 4.90 (d, 1H, J = 11.2 Hz), 4.88 (d, 1H, J = 2.5 Hz), 4.81
=
(dd, 1H, J = 12.2, 2.6 Hz), 4.43 (d, 1H, J = 11.2 Hz), 2.63 (td, 1H, J = 13.0, 2.6 Hz), 2.51 (s, 3H),
2.48 (dd, 1H, J = 13.9, 2.7 Hz), 2.40 (s, 3H); 13C{ H} NMR (125 MHz, CDCl ) δ 192.6, 158.1,
1
3
152.4, 147.5, 141.5, 138.2, 137.9, 137.2, 134.4, 128.8, 128.2, 126.9, 126.5, 119.3, 112.4, 110.4,
+
105.5, 73.8, 56.5, 46.7, 44.4, 42.5, 15.9, 15.7; HRMS (ESI) m/z: [M+Na] calcd for C H O S Na
2
8
26
4 3
545.0885; found 545.0898.
(2,6-Di([1,1'-biphenyl]-4-yl)-4-(furan-2-yl)-4-hydroxytetrahydro-2H-thiopyran-3-yl)(furan-2-
yl)methanone (3am). Obtained as a white solids; isolated yield: 96.4 mg (33%); mp 171–172 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.64–7.59 (m, 6H),
3
7
.53–7.47 (m, 6H), 7.44–7.39 (m, 6H), 7.38–7.31 (m, 2H), 6.98 (d, 1H, J = 3.6 Hz), 6.32 (d, 1H, J
3.6), 6.26 (d, 1H, J = 3.3), 6.18 (d, 1H, J = 3.3), 5.04 (d, 1H, J = 11.2), 4.99 (d, 1H, J = 2.4), 4.96
=
(dd, 1H, J = 12.2, 2.6 Hz), 4.54 (d, 1H, J = 11.2 Hz), 2.74 (td, 1H, J = 13.0, 2.6 Hz), 2.55 (dd, 1H,
J = 13.9, 2.6 Hz); 13C{ H} NMR (125 MHz, CDCl ) δ 192.8, 158.2, 152.5, 147.4, 141.6, 140.8,
1
3
1
1
40.6, 140.5, 139.5, 136.7, 128.9, 128.8, 128.7, 128.2, 127.5, 127.4, 127.3, 127.2, 127.1, 127.0,
+
19.3, 112.4, 110.4, 105.6, 73.9, 56.6, 46.9, 44.6, 42.7; HRMS (ESI) m/z: [M+Na] calcd for
C H O SNa 605.1757; found 605.1767.
3
8
30
4
Furan-2-yl(4-(furan-2-yl)-4-hydroxy-2,6-bis(4-methoxyphenyl)tetrahydro-2H-thiopyran-3-
yl)methanone (3an). Obtained as a white solid; isolated yield: 92.2 mg (38%); mp 150–151 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.43–7.40 (m, 3H),
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.34 (d, 2H, J = 8.3 Hz), 7.19 (s, 1H), 6.95 (d, 1H, J = 3.6 Hz), 6.90 (d, 2H, J = 8.2 Hz), 6.71 (d,
H, J = 8.2 Hz), 6.31 (dd, 1H, J = 3.7, 1.7 Hz), 6.21 (d, 1H, J = 3.3 Hz), 6.15 (dd, 1H, J = 3.5, 1.8
2
Hz), 4.92–4.89 (m, 2H), 4.81 (dd, 1H, J = 12.2, 2.6 Hz), 4.42 (d, 1H, J = 11.2 Hz), 3.83 (s, 3H),
1
3
1
3
.71 (s, 3H), 2.63 (td, 1H, J = 13.0, 2.7 Hz), 2.44 (dd, 1H, J = 13.9, 2.7 Hz); C{ H} NMR (125
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
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4
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4
4
4
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4
4
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5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MHz, CDCl ) δ 193.0, 159.1, 159.0, 158.4, 152.5, 147.4, 141.5, 132.6, 129.8, 129.5, 128.8, 119.2,
3
1
14.1, 113.8, 112.3, 110.3, 105.4, 73.9, 56.8, 55.3, 55.2, 46.5, 44.6, 42.3; HRMS (ESI) m/z: [M+H]+
calcd for C H O S 491.1523; found 491.1529.
2
8
27
6
(4-Hydroxy-2,6-diphenyl-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-yl)(thiophen-2-
yl)methanone (3ba). Obtained as a white solid; isolated yield: 206.5 mg (89%); mp 173–175 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.52–7.31 (m, 9H),
3
7
.18–6.99 (m, 5H), 6.87–6.79 (m, 2H), 5.72 (s, 1H), 5.50 (d, 1H, J = 10.8 Hz), 4.92 (d, 1H, J = 11.7
13
1
Hz), 4.30 (d, 1H, J = 10.9 Hz), 2.67–2.54 (m, 2H); C{ H} NMR (125 MHz, CDCl ) δ 197.5, 151.9,
3
1
44.7, 140.4, 137.8, 135.3, 133.8, 128.8, 128.6, 128.5, 128.1, 127.8, 127.7, 127.7, 126.8, 124.1,
+
122.9, 75.6, 61.2, 48.7, 48.4, 43.3; HRMS (ESI) m/z: [M+H] calcd for C H O S 463.0855; found
2
6
22
2 3
463.0843.
(2,6-Bis(4-chlorophenyl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bb). Obtained as a white solid; isolated yield: 240.4 mg (91%); mp
1
164–165 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, DMSO-d ) δ
6
7
.82 (d, 1H, J = 3.8), 7.73 (d, 1H, J = 5.0), 7.54–7.46 (m, 6H), 7.24 (d, 3H, J = 7.3), 7.14 (d, 1H, J
5.0), 6.96 (t, 1H, J = 4.3), 6.79 (t, 1H, J = 4.2), 5.86 (s, 1H), 4.99 (d, 1H, J = 11.0), 4.76 (dd, 1H,
J = 12.1, 2.5 Hz), 4.67 (d, 1H, J = 11.1 Hz), 2.81 (t, 1H, J = 12.9 Hz), 2.35 (dd, 1H, J = 13.5, 2.6
=
1
3
1
Hz); C{ H} NMR (125 MHz, DMSO-d) δ 194.5, 152.8, 145.8, 139.9, 138.1, 135.9, 135.1, 132.7,
1
32.6, 130.9, 130.0, 129.3, 128.8, 128.6, 127.4, 124.6, 123.9, 74.9, 59.0, 47.7, 46.7, 42.4; HRMS
-
(ESI) m/z: [M+Cl] calcd for C H Cl O S 564.9696; found 564.9701.
2
6
20
3
2 3
(2,6-Bis(4-bromophenyl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bc). Obtained as a white solid; isolated yield: 275.4 mg (89%); mp
1
1
7
89–190 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, DMSO-d ) δ
6
.81 (d, 1H, J = 4.0), 7.73 (d, 1H, J = 4.0), 7.60 (d, 2H, J = 8.3), 7.47–7.36 (m, 6H), 7.23 (d, 1H, J
=
=
3.6), 7.14 (d, 1H, J = 5.0), 6.96 (t, 1H, J = 4.2), 6.79 (t, 1H, J = 4.0), 5.86 (s, 1H), 4.98 (d, 1H, J
10.9), 4.74 (dd, 1H, J = 11.9, 2.4 Hz), 4.66 (d, 1H, J = 11.1 Hz), 2.81 (t, 1H, J = 12.8 Hz), 2.35
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(
d, 1H, J = 13.1 Hz); C{ H} NMR (125 MHz, DMSO-d) δ 194.4, 152.7, 145.8, 140.4, 138.5, 135.9,
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4
35.0, 132.2, 131.7, 131.2, 130.4, 128.6, 127.4, 124.6, 123.9, 121.21, 121.19, 74.9, 58.9, 47.7, 46.7,
-
2.5; HRMS (ESI) m/z: [M-H] calcd for C H Br O S 616.8919; found 616.8918.
2
6
19
2
2 3
(
4-Hydroxy-4-(thiophen-2-yl)-2,6-di-p-tolyltetrahydro-2H-thiopyran-3-yl)(thiophen-2-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
yl)methanone (3bd). Obtained as a white solid; isolated yield: 171.9 mg (70%); mp 195–196 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (400 MHz, CDCl ) δ 7.38–7.32 (m, 3H),
3
7
.26–7.24 (m, 2H), 7.14–7.12 (m, 3H), 7.93 (d, 2H, J = 7.9 Hz), 6.89 (dd, 1H, J = 3.6, 0.8 Hz), 6.28
dd, 1H, J = 3.6, 1.7 Hz), 6.16 (dd, 1H, J = 3.3, 0.9 Hz), 6.09 (dd, 1H, J = 3.3, 1.7 Hz), 4.86 (d, 2H,
J = 11.2 Hz), 4.77 (dd, 1H, J = 12.3, 2.6 Hz), 4.39 (d, 1H, J = 11.2 Hz), 2.60 (td, 1H, J = 13.0, 2.7
(
13
1
Hz), 2.40 (dd, 1H, J = 13.9, 2.7 Hz), 2.32 (s, 3H), 2.17 (s, 3H); C{ H} NMR (100 MHz, CDCl )
3
δ 192.9, 158.4, 152.5, 147.3, 141.4, 137.5, 137.3, 134.6, 129.3, 129.1, 128.3, 127.6, 119.1, 112.2,
+
1
12.2, 110.3, 105.4, 73.8, 56.6, 46.8, 44.6, 42.6, 21.1, 21.0; HRMS (ESI) m/z: [M+Na] calcd for
C H O S Na 513.0987; found 513.0968.
2
8
26
2 3
(4-Hydroxy-4-(thiophen-2-yl)-2,6-di-o-tolyltetrahydro-2H-thiopyran-3-yl)(thiophen-2-
yl)methanone (3be). Obtained as a white solid; isolated yield: 195.7 mg (80%); mp 149–151 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.67 (d, 1H, J = 7.8
3
Hz), 7.54 (d, 1H, J = 7.6 Hz), 7.46–7.44 (m, 2H), 7.27–7.21 (m, 3H), 7.07–6.95 (m, 5H), 6.90–6.79
(m, 2H), 5.61 (d, 1H, J = 2.4 Hz), 5.31 (d, 1H, J = 10.7 Hz), 5.11 (dd, 1H, J = 11.2, 3.0 Hz), 4.37
1
3
1
(
d, 1H, J = 10.8 Hz), 2.67–2.58 (m, 5H), 2.45 (s, 3H); C{ H} NMR (125 MHz, CDCl ) δ 197.6,
3
1
1
51.8, 144.6, 138.3, 136.4, 136.02, 135.98, 135.1, 133.8, 130.72, 130.70, 128.0, 127.8, 127.7, 127.4,
26.8, 126.5, 126.4, 126.1, 124.0, 123.0, 75.9, 60.8, 47.9, 42.8, 39.5, 19.7, 19.3; HRMS (ESI) m/z:
+
[
M+Na] calcd for C H O S Na 513.0987; found 513.0968.
2
8
26
2 3
(
4-Hydroxy-4-(thiophen-2-yl)-2,6-di-m-tolyltetrahydro-2H-thiopyran-3-yl)(thiophen-2-
yl)methanone (3bf). Obtained as a white solid; isolated yield: 199.9 mg (82%); mp 142–143 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.45 (d, 1H, J = 4.9
3
Hz), 7.40 (d, 1H, J = 3.9 Hz), 7.32–7.21 (m, 5H), 7.13–6.98 (m, 4H), 6.88–6.79 (m, 3H), 5.70 (d,
1
H, J = 2.6 Hz), 4.93 (d, 1H, J = 10.8 Hz), 4.87 (dd, 1H, J = 11.2, 3.0 Hz), 4.30 (d, 1H, J = 10.8
Hz), 2.63 (dd, 1H, J = 13.9, 2.8 Hz), 2.54 (td, 1H, J = 13.0, 2.6 Hz), 2.40 (s, 3H), 2.23 (s, 3H);
13
1
C{ H} NMR (125 MHz, CDCl ) δ 197.6, 152.0, 144.8, 140.3, 138.4, 138.1, 137.6, 135.2, 133.7,
3
1
29.2, 128.7, 128.6, 128.5, 128.4, 127.6, 126.8, 125.5, 124.8, 124.0, 122.9, 75.7, 61.1, 48.7, 48.3,
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+
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3.3, 21.5, 21.2; HRMS (ESI) m/z: [M+Na] calcd for C H O S Na 513.0987; found 513.0982.
2
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2 3
(
2,6-Bis(3,5-dimethylphenyl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bg). Obtained as a white solid; isolated yield: 227.5 mg (88%); mp
1
1
81–182 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.45
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
d, 1H, J = 4.9 Hz), 7.41 (d, 1H, J = 3.8 Hz), 7.12 (s, 2H), 7.06 (d, 1H, J = 5.0 Hz), 7.00 (s, 2H),
6
4
.99 (d, 1H, J = 3.6 Hz), 6.94 (s, 1H), 6.89–6.79 (m, 2H), 6.68 (s, 1H), 5.69 (d, 1H, J = 2.6 Hz),
.88 (d, 1H, J = 10.8 Hz), 4.83 (dd, 1H, J = 11.8, 2.8 Hz), 4.29 (d, 1H, J = 10.7 Hz), 2.61 (dd, 1H,
13
1
J = 13.9, 2.7 Hz), 2.52 (td, 1H, J = 13.0, 2.6 Hz), 2.35 (s, 6H), 2.18 (s, 6H); C{ H} NMR (125
MHz, CDCl ) δ 197.7, 152.2, 144.9, 140.3, 138.2, 137.9, 137.4, 135.0, 133.5, 129.5, 129.3, 127.4,
3
1
26.8, 126.3, 125.5, 124.0, 122.8, 75.7, 61.1, 48.8, 48.3, 43.3, 21.3, 21.1; HRMS (ESI) m/z:
+
[
M+Na] calcd for C H O S Na 541.1300; found 541.1313.
3
0
30
2 3
(
4-Hydroxy-2,6-bis(4-isopropylphenyl)-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bh). Obtained as a white solid; isolated yield: 255.3 mg (94%); mp
1
187–188 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.44–
3
7.40 (m, 3H), 7.34–7.31 (m, 3H), 7.25 (d, 2H, J = 8.0 Hz), 7.06 (dd, 1H, J = 5.0, 1.1 Hz), 6.99–6.97
(m, 3H), 6.84–6.79 (m, 2H), 5.76 (d, 1H, J = 2.5 Hz), 4.96 (d, 1H, J = 10.8 Hz), 4.89 (dd, 1H, J =
11.9, 2.7 Hz), 4.24 (d, 1H, J = 10.7 Hz), 2.96–2.91 (m, 1H), 2.76–2.70 (m, 1H), 2.63 (dd, 1H, J =
14.0, 2.7 Hz), 2.63 (td, 1H, J = 13.0, 2.7 Hz), 1.29 (d, 6H, J = 6.9 Hz), 1.09 (d, 6H, J = 6.9 Hz);
1
3
1
C{ H} NMR (125 MHz, CDCl ) δ 197.9, 152.2, 148.7, 148.3, 144.8, 137.8, 135.2, 134.9, 133.8,
3
1
2
28.4, 127.6, 127.5, 126.8, 126.5, 124.0, 122.8, 75.7, 61.4, 49.0, 48.2, 43.0, 33.8, 33.7, 24.0, 23.83,
+
3.77; HRMS (ESI) m/z: [M+H] calcd for C H O S 547.1794; found 547.1775.
3
2
35
2 3
(
2,6-Bis(4-(tert-butyl)phenyl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bi). Obtained as a white solid; isolated yield: 268.4 mg (94%); mp
1
1
96–197 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.45–
3
7
.34 (m, 5H), 7.33–7.31 (m, 3H), 7.14–7.12 (m, 2H), 7.06 (dd, 1H, J = 3.6, 1.2 Hz), 6.98 (dd, 1H,
J = 3.6, 1.2 Hz), 6.82–6.79 (m, 2H), 5.76 (d, 1H, J = 2.6 Hz), 4.95 (d, 1H, J = 10.8 Hz), 4.89 (dd,
1
1
1
7
H, J = 11.8, 2.6 Hz), 4.23 (d, 1H, J = 10.7 Hz), 2.63 (dd, 1H, J = 14.0, 2.7 Hz), 2.50 (td, 1H, J =
13
1
3.0, 2.7 Hz), 1.36 (s, 9H), 1.17 (s, 9H); C{ H} NMR (125 MHz, CDCl ) δ 197.9, 152.3, 150.9,
3
50.5, 144.9, 137.5, 134.9, 134.8, 133.7, 128.1, 127.44, 127.36, 126.7, 125.6, 125.3, 124.0, 122.7,
+
5.7, 61.5, 49.0, 48.1, 42.8, 34.5, 34.4, 31.3, 31.1; HRMS (ESI) m/z: [M+Na] calcd for
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C H O S Na 597.1926; found 597.1943.
3
4
38
2 3
(2,6-Bis(4-ethylphenyl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-yl)(thiophen-
2
-yl)methanone (3bj). Obtained as a white solid; isolated yield: 229.3 mg (89%); mp 151–152 °C.
1
Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.43–7.35 (m, 4H),
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
7
.33–7.31 (m, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.06–6.97 (m, 4H), 6.86–6.78 (m, 2H), 5.71 (d, 1H, J
2.5 Hz), 4.95 (d, 1H, J = 10.8 Hz), 4.87 (dd, 1H, J = 11.8, 2.7 Hz), 4.26 (d, 1H, J = 10.8 Hz),
=
1
3
1
2
.70–2.55 (m, 3H), 2.53–2.45 (m, 3H), 1.27 (t, 3H, J = 7.6 Hz), 1.07 (t, 3H, J = 7.6 Hz); C{ H}
NMR (125 MHz, CDCl ) δ 197.8, 152.1, 144.8, 144.1, 143.7, 137.7, 135.05, 134.99, 133.8, 128.4,
3
1
28.2, 128.0, 127.7, 127.6, 126.8, 124.0, 122.8, 75.7, 61.3, 48.8, 48.1, 43.0, 28.5, 28.4, 15.52, 15.49;
+
HRMS (ESI) m/z: [M+Na] calcd for C H O S Na 541.1300; found 541.1278.
3
0
30
2 3
(4-Hydroxy-2,6-bis(4-propylphenyl)-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bk). Obtained as a white solid; isolated yield: 225.6 mg (83%); mp
1
1
65–167 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (400 MHz, CDCl ) δ 7.38–
3
7.34 (m, 4H), 7.27–7.24 (m, 2H), 7.14 (d, 2H, J = 8.1 Hz), 7.00 (dd, 1H, J = 5.1, 1.2 Hz), 6.92–6.87
(m, 3H), 6.80–6.73 (m, 2H), 5.67 (s, 1H), 4.89 (d, 1H, J = 10.8 Hz), 4.82 (dd, 1H, J = 11.7, 2.8 Hz),
4.20 (d, 1H, J = 10.8 Hz), 2.59–2.53 (m, 3H), 2.46 (t, 1H, J = 13.0 Hz), 2.37 (t, 2H, J = 7.4 Hz),
1
3
1
1.64–1.59 (m, 2H), 1.43–1.38 (m, 2H), 0.92 (t, 3H, J = 7.3 Hz), 0.70 (t, 3H, J = 7.3 Hz); C{ H}
NMR (100 MHz, CDCl ) δ 197.8, 152.1, 144.7, 142.4, 142.1, 137.7, 135.0, 133.7, 128.8, 128.6,
3
1
28.3, 127.5, 126.7, 123.9,122.8, 75.7, 61.4, 48.8, 48.1, 43.0, 37.7, 37.4, 24.5, 24.3, 13.8, 13.4;
+
HRMS (ESI) m/z: [M+Na] calcd for C H O S Na 569.1613; found 569.1620.
32 35
2 3
(4-Hydroxy-2,6-bis(4-(methylthio)phenyl)-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bl). Obtained as a white solid; isolated yield: 115.3 mg (42%); mp
1
1
51–153 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (500 MHz, CDCl ) δ 7.47
3
(
dd, 1H, J = 4.9 Hz), 7.42–7.38 (m, 3H), 7.34–7.31 (m, 3H), 7.28–7.27 (m, 1H), 7.06–7.03 (m, 3H),
.97 (dd, 1H, J = 3.6, 1.2 Hz), 6.89–6.87 (m, 1H), 6.80–6.78 (m, 1H), 5.62 (d, 1H, J = 2.5 Hz), 4.93
d, 1H, J = 10.9 Hz), 4.85 (dd, 1H, J = 11.9, 2.7 Hz), 4.25 (d, 1H, J = 10.8 Hz), 2.61 (dd, 1H, J =
6
(
1
3
1
1
1
1
5
4.0, 2.7 Hz), 2.53–2.48 (m, 4H), 2.37 (s, 3H); C{ H} NMR (125 MHz, CDCl ) δ 197.4, 151.7,
3
44.6, 138.4, 137.9, 137.1, 135.4, 134.5, 133.8, 12.8.9, 128.2, 127.8, 126.9, 126.8, 126.7, 124.1,
+
23.0, 75.6, 61.1, 48.4, 47.9, 42.9, 15.9, 15.8; HRMS (ESI) m/z: [M+Na] calcd for C H O S Na
2
8
26
2 5
77.0429; found 577.0435.
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(
2,6-Di([1,1'-biphenyl]-4-yl)-4-hydroxy-4-(thiophen-2-yl)tetrahydro-2H-thiopyran-3-
yl)(thiophen-2-yl)methanone (3bm). Obtained as a white solid; isolated yield: 104.3 mg (34%); mp
1
1
7
85–186 °C. Eluent: petroleum ether/ethyl acetate = 5/1, v/v. H NMR (400 MHz, CDCl ) δ 7.59–
3
.53 (m, 6H), 7.47–7.29 (m, 14H), 7.04–6.96 (m, 2H), 6.81–6.75 (m, 2H), 5.68 (s, 1H), 5.01 (d, 1H,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 10.7 Hz), 4.93 (dd, 1H, J = 11.7, 2.6 Hz), 4.29 (d, 1H, J = 10.7 Hz), 2.65 (dd, 1H, J = 14.0, 2.6
Hz), 2.55 (t, 1H, J = 12.7 Hz); 13C{ H} NMR (100 MHz, CDCl ) δ 197.6, 151.8, 144.7, 140.9,
1
3
1
1
70.73, 140.66, 140.5, 139.4,136.8, 135.4, 133.8, 128.9, 128.8, 128.7, 128.2, 127.7, 127.5, 127.3,
27.2, 127.1, 127.0, 126.8, 124.1, 122.9, 75.6, 61.2, 48.6, 48.1, 43.1; HRMS (ESI) m/z: [M+Na]+
calcd for C H O S Na 637.1300; found 637.1315.
3
8
30
2 3
(E)-1-(furan-2-yl)-3-phenylprop-2-en-1-one (intermediate I of compound 3aa). mp 85–86 °C.
1
H NMR (400 MHz, CDCl ) δ: 7.89 (d, 1H, J = 15.8 Hz), 7.64–7.66 (3H, m), 7.45 (d, 1H, J = 15.8),
3
7
.41–7.43 (m, 3H), 7.33 (dd, 1H, J = 3.5, 0.4 Hz), 6.59 (dd, 1H, J = 3.5, 1.6 Hz). The NMR data
were consistent with those in the literature [15].
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website. H, 13C
1
NMR spectra and HRMS for new compounds (PDF).
AUTHOR INFORMATION
Corresponding Authors
*E-mail: chenddxy@163.com
*E-mail: liutao@llhc.edu.cn
ORCID
Dongdong Chen: 0000-0002-5855-0465
Tao Liu: 0000-0002-2192-9447
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The work is financially supported by Scientific and Technological Innovation Programs of Higher
Education Institutions in Shanxi (2019L0941, 2019L0937, 2019L0966).
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