Conjugate addition of grignard reagents to thiochromones catalyzed by copper salts: A unified approach to both 2-alkylthiochroman-4-one and thioflavanone

Article abstract of DOI:10.3390/molecules25092128

Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive. The best yields of 1,4-adducts can be attained with CuCN-2LiCl as the copper source. Excellent yields of 2-alkyl-substituted thiochroman-4-ones and thioflavanones (2-aryl substituted) are attained with a broad range of Grignard reagents. This approach works well with both alkyl and aromatic Grignard reagents, thus providing a unified synthetic approach to privileged 2-substituted thiochroman-4-ones and a potential valuable precursor for further synthetic applications towards many pharmaceutically active molecules. The use of commercially available and/or readily prepared Grignard reagents will expedite the synthesis of a large library of both 2-alkyl substituted thiochroman-4-ones and thioflavanones for additional synthetic applications.

Full text of DOI:10.3390/molecules25092128

molecules
Article
Conjugate Addition of Grignard Reagents to
Thiochromones Catalyzed by Copper Salts: A Unified
Approach to Both 2-Alkylthiochroman-4-One
and Thioflavanone
Tania J. Bellinger 1, Teavian Harvin 1, Ti’Bran Pickens-Flynn 1, Nataleigh Austin 1,
Samuel H. Whitaker 1, Mai Ling C. Tang Yuk Tutein 1, Dabria T. Hukins 1, Nichele Deese 1 and
Fenghai Guo 1,2,
*
1
Department of Chemistry, Winston Salem State University, 601 S. Martin Luther King Jr. Dr.,
Winston Salem, NC 27110, USA; tbellinger115@rams.wssu.edu (T.J.B.); tharvin117@rams.wssu.edu (T.H.);
tpickensflynn117@rams.wssu.edu (T.P.-F.); naustin116@rams.wssu.edu (N.A.);
swhitaker118@rams.wssu.edu (S.H.W.); mtangyuktutein118@rams.wssu.edu (M.L.C.T.Y.T.);
dhukins116@rams.wssu.edu (D.T.H.); ndeese119@rams.wssu.edu (N.D.)
Biomedical Research Infrastructure Center, Winston Salem State University, Winston Salem, NC 27110, USA
Correspondence: guof@wssu.edu; Tel.: +01-336-750-3158
2
*
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Roman Dembinski and Igor Alabugin
Received: 8 April 2020; Accepted: 29 April 2020; Published: 1 May 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Grignard reagents undergo conjugate addition to thiochromones catalyzed by copper
salts to afford 2-substituted-thiochroman-4-ones, both 2-alkylthiochroman-4-ones and thioflavanones
(2-arylthiochroman-4-ones), in good yields with trimethylsilyl chloride (TMSCl) as an additive.
The best yields of 1,4-adducts can be attained with CuCN 2LiCl as the copper source. Excellent yields
·
of 2-alkyl-substituted thiochroman-4-ones and thioflavanones (2-aryl substituted) are attained with a
broad range of Grignard reagents. This approach works well with both alkyl and aromatic Grignard
reagents, thus providing a unified synthetic approach to privileged 2-substituted thiochroman-4-ones
and a potential valuable precursor for further synthetic applications towards many pharmaceutically
active molecules. The use of commercially available and/or readily prepared Grignard reagents
will expedite the synthesis of a large library of both 2-alkyl substituted thiochroman-4-ones and
thioflavanones for additional synthetic applications.
Keywords: conjugate addition; thiochroman-4-ones; Grignard reagents; thiochromones;
thioflavanones; 2-alkylthiochroman-4-ones
1. Introduction
The 1,4-conjugate addition reaction of organometallic reagents, including Grignard reagents, is
one of the most reliable carbon–carbon bond formation reaction in organic synthesis. [
the addition of catalysts, such as Cu (I) salts, Grignard reagents usually undergo 1,2-addition to
-unsaturated carbonyl compounds. It has been shown that with the addition of Cu(I) salts, Grignard
reagents undergo exclusive 1,4-conjugate addition to carbonyl compounds to afford 1,4-adducts [ ].
1] Without
α
,
β
1,2
In this investigation, we aimed to develop a unified approach to a broad scope of 2-substituted
thiochroman-4-ones by taking advantage of the ease in preparation and the breadth in the scope of
Grignard reagents. Sulfur-containing heterocycles are widely present in numerous pharmaceutical
active molecules as well as in many bioactive natural products [
areas, such as material science, biology, medicinal chemistry, and food chemistry, in recent years [
Although the isosteric replacement of an oxygen atom by a sulfur atom is expected to improve
3–
6], with widespread applications in
7–
13].
Molecules 2020, 25, 2128; doi:10.3390/molecules25092128
www.mdpi.com/journal/molecules

Molecules 2020, 25, 2128
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the bioavailability and bioactivity [14], sulfur-containing heterocyclic compounds are a much less
studied area compared to oxygen-containing heterocycles. Due to their rich biological activities
and widespread applications, the development towards an efficient synthesis of sulfur-containing
compounds has gradually gained interest. In recent years, sulfur-containing heterocycles have been
found to display rich biological activities, such as cytotoxic effects on tumor cells in vitro
antileishmanial and cytotoxic activities [16], as well as the ability to kill tumor cells by inducing tumor
cell apoptosis. [17] Thioflavonoids, the sulfur analogues of flavonoids [18 21], display many biological
activities, such as antimicrobial, antioxidant, inhibition of nitric oxide production, and antifungal
properties, etc. [22 30]. Many thiochromanone derivatives have been known to be effective bioreductive
[15], the in vitro
–
–
alkylating agents [25]. Thiochromanones, i.e., thiochroman-4-ones, 2-alkylthiochroman-4-ones, and
thioflavanone (2-arylthiochroman-4-ones), have become increasingly valuable synthons and vital
precursors in organic synthesis for bioactive thiochromanone derivatives [31–38].
Although the synthesis of sulfur-containing heterocycles is much less explored than
oxygen-containing counterparts, increasingly more synthetic approaches to thiochroman-4-ones,
thioflavone, thiochromones [39
–50], and 2-substituted thiochroman-4-ones have been reported
in recent years. The enantioselective synthesis of 2-arylsubstituted thiochromanone via
Rh-catalyzed conjugate addition to thiochromones [51] and 2-alkylthiochromanones via the
Cu-phosphoamidite-promoted enantioselective conjugate addition pathway has been reported
recently [52]. A recent synthetic approach of thioflavanones by regioselective cyclization of
1-(2-benzylthio)phenyl-3-phenyl-2-propen-1-ones has also been published [53]. Other synthetic
approaches to 2-substituted thiochroman-4-ones include the hydrogenation of thiochromones [54
–56],
intramolecular thio-Michael addition [57 63], and Friedel–Crafts acylation of thiopropanoic
–
acid [64]. The synthesis of thiochroman-4-ones and thioflavanones via rhodium-catalyzed alkyne
hydroacylation/thio conjugate addition sequence has also been reported [65]. With our interests in
heterocycles, including sulfur-heterocycles, we also reported the synthesis of 2-alkylthiochromanones
via conjugate addition of lithium dialkylcuprates to thiochromones [66] and a rapid entry to
thioflavanones via the conjugate addition of diarylcuprates to thiochromones [67]. While most
of these approaches provided efficient approaches to either thioflavanones (2-arylthiochroman-4-ones)
or 2-alkylthiochromanone, there is a need for a unified approach that works well in introducing both the
aliphatic and aromatic groups to furnish the desired 2-alkylthiochroman-4-ones
(2-arylthiochroman-4-ones ). In pursuit of a unified approach of a broad scope of 2-substituted
thiochroman-4-ones ( , R1 = alkyl and , R1 = Ar; Figure 1) by taking advantage of the readily available
and/or readily prepared Grignard reagents, both alkyl and aryl Grignard reagents, we now report the
conjugate addition of Grignard reagents to thiochromones to afford 2-substituted thiochroman-4-ones
and in good yields using copper salts (Figure 1). This approach will allow access to a broader scope
2 and thioflavanones
3
2
3
1
2
3
of thiochromanones and thioflavanones due to the readily available Grignard reagents compared to
organolithium reagents.
Figure 1. Copper-catalyzed conjugate addition of Grignard reagents to thiochromones.
2. Results and Discussions
Our investigation started with n-BuMgCl to find the optimal reactional condition for 1,4-conjugate
addition to thiochromone with copper salts. Our previous report showed that a Lewis acid activator,

Molecules 2020, 25, 2128
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such as TMSCl, was needed in the conjugate addition of organolithium reagents to thiochromones
using a stoichiometric amount of copper salts as no desired 1,4-adducts were observed in the absence
of a Lewis acid activator [66,67]. A modest yield of 1,4-adduct 2-n-butylthiochroman-4-one 2Aa was
formed with n-BuMgCl and a 0.2 equivalent of CuI or CuCN with TMSCl as the activator (Scheme 1,
entries 1–2). The use of CuCl did not improve the yield (Scheme 1, entry 3). With the addition of
LiCl to CuCN, an excellent yield of 2-n-butylthiochroman-4-one 2Aa was achieved in the presence
of TMSCl (Scheme 1, entry 5, 89%). Other Lewis acids, such as TMSOTf, TMSI, and BF3
activated this reaction but were not better activators than TMSCl as they did not offer better yields
(Scheme 1, entries 6–8). These results show that the use of 0.2 equivalent of CuCN 2LiCl and TMSCl
offered the highest yield. We also found that CuCN 2LiCl can be further reduced to 0.1 equivalent and
·OEt2, also
·
·
a comparable yield of 2Aa could be attained (Scheme 1, entry 9, 85%).
Scheme 1. Optimization of 1,4-conjugate addition of n-butyl magnesium chloride to thiochromone.
a. Reagents were prepared by adding n-BuMgCl to copper salts in THF. b. Yields are based on isolated
products by column chromatography.
With the optimal reaction condition in hand, the scope of the Grignard reagents was explored
(Scheme 2, 64–90%). It was found that a broad range of Grignard reagents underwent conjugate
addition to thiochromone 1A to afford 1,4-adducts 2Aa–Ah and 3Aa–Ai with good reaction yields
(Scheme 2). Simple Grignard reagents, such as methyl, ethyl, n-butyl, and n-hexyl Grignard reagents,
were added to 1A smoothly to afford 1,4-adducts with excellent efficiency (Scheme 2, 75–88%). Steric
bulkier Grignard reagents, such as i-Pr, t-butyl Grignard reagents, gave lower yields (Scheme 2, 2Ae
,
69% and 2Af, 64%). Cyclic Grignard reagents were also tolerated to give good yields of 1,4-adducts
(Scheme 2, 2Ag, 82% and 2Ah, 85%). Aromatic Grignard reagents also reacted very well under these
optimal reaction conditions. PhMgBr was added to thiochromone 1A to offer 1,4-adduct 3Aa in an
89% yield. Grignard reagents with electron-donating groups on the aromatic ring were also found
to work well (Scheme 2, 3Ab–Ad, 80–90%). Grignard reagents with strong electron-withdrawing
groups on the aromatic ring were also tolerated (Scheme 2, 3Ae, 70%). Grignard reagents prepared
from extended aryl bromides, such as 2-bromonaphthalene and 9-bromophenanthrene, were also
added to thiochromone 1A smoothly with high yields (Scheme 2, 3Af, 84%; 3Ag, 78%). To our delight,
Grignard reagents prepared from aromatic heterocycles also worked well. Both (2-furyl)magnesium
bromide and 2-thienylmagnesium bromide were added to thiochromone 1A to afford corresponding
1,4-adducts in good yields (Scheme 2, 3Ah, 79%; 3Ai, 75%).

Molecules 2020, 25, 2128
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Scheme 2. The scope of Grignard reagents in conjugate addition to thiochromone. a. All the reactions
were performed using 1.5 equiv of RMgX in the presence of 2.0 equiv of TMSCI unless noted otherwise.
b. RMgX were commercially available or prepared from corresponding RX in THF and used as a THF
solution. c. Yields are based on isolated products by column chromatography.
With the optimal reaction addition for conjugate addition to thiochromone 1A in hand, we next
investigated the scope of thiochromone substrates for the conjugate addition of Grignard reagents.
A number of substituted thiochromones 1B
chloride readily added to the substituted thiochromones 1B
with good yields (Scheme 3, 73–86%). Thiochromones bearing simple alkyl groups, such as a
methyl group, reacted with n-BuMgCl to afford 2Ba 2Da in good yields under the optimal reaction
–
1O were investigated. It was found that n-butylmagnesium
–
1O to afford 1,4-adducts 2Ba 2Oa
–
–
condition (Scheme 3, 80–84%). The bulky t-butyl group was also tolerated to afford 1,4-adduct 2Ea
with good yield. Thiochromones with halides, such as F, Br, and Cl, also reacted smoothly with
n-BuMgCl (Scheme 3, 74–80%). Thiochromones with two halides on the aromatic ring, such as
6,8-difluorothiochromanone and 6,8-dichlorothiochromone, were also tolerated (Scheme 3, 2Ka, 73%
and 2La, 77%). Electron-donating groups, such as MeO-, also worked well to afford 1,4-adduct 2Ma
and 2Na in higher yields (Scheme 3). Thiochromane 1O with an extended aromatic structure also
underwent conjugate addition with n-BuMgCl to afford 1,4-adduct 2Oa in a 77% yield (Scheme 3).

Molecules 2020, 25, 2128
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Scheme 3. Scope of the substituted thiochromones with n-BuMgCl. a. All the reactions were performed
using 1.5 equiv of BuMgCl in the presence of 2.0 equiv of TMSCI unless noted otherwise. b. RMgX
were commercially available or prepared from corresponding RX in THF and used as a THF solution.
c. Yields are based on isolated products by column chromatography.
The scope of thiochromones was also explored with PhMgBr to synthesize various thioflavanones.
Phenylmagnesium bromide underwent conjugate addition to thiochromones 1B–1P smoothly to
furnish thioflavanones with good yields (Scheme 4). It was found that thiochromones with simple alkyl
groups, such as methyl, on the aromatic ring reacted smoothly with PhMgBr to afford 1,4-adduct in
good yields (Scheme 4, 83–88%). Bulky groups (i-Pr) were also tolerated (Scheme 4, 3Ea, 77%). PhMgBr
also underwent conjugate addition to thiochromones with halides F, Br, and Cl on the aromatic ring
with high efficiency (Scheme 4, 78–82%). Thiochromones with two halides on the aromatic ring, such
as 6,8-diflurothiochromanone and 6,8-dichlorothiochromone, were also tolerated to afford good yields
of 1,4-adduct (Scheme 4, 3Ka, 70% and 3La, 76%). Electron-donating groups, such as MeO-, were also
tolerated to furnish 1,4-adducts in an excellent yield (Scheme 4, 3Ma, 84% and 3Na, 83%). The steric
hindrance was not a problem as PhMgBr adds to 8-substituted thiochromone (8-MeO-, 8-i-Pr) with
high yields (Scheme 4). PhMgBr also underwent conjugate addition to thiochromones with extended
aromatic structures with high efficiency (Scheme 4, 3Oa, 81%; 3Pa, 80%).

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Scheme 4. Reactions of PhMgBr with substituted thiochromones. a. All the reactions were performed
using 1.5 equiv of PhMgBr in the presence of 2.0 equiv of TMSCI unless noted otherwise. b. PhMgBr
were commercially available. c. Yields are based on isolated products by column chromatography.
Thiochromanones, i.e., thiochroman-4-ones, 2-alkyltiochroman-4-ones, and thioflavanones
(2-arylthioflavanones), are valuable synthons and vital precursors in organic synthesis for bioactive
thiochromanone derivatives. [31–38] In our previous investigation, 2-alkylthiochroman-4-ones were
successfully converted into other useful thiochroman-4-one derivatives for additional synthetic
application [66]. The 1,4-adducts-thioflavones can also be utilized for further synthetic applications
towards 2-aryl substituted thiochroman-4-one derivatives (Scheme 5). For example, thioflavanone 3 was

Molecules 2020, 25, 2128
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converted to chlorinated thiochromone
4
upon treatment with excess N-chlorosuccinimide and pyridine
(Scheme 5, 4Aa, 65%; 4Af, 68%). It was also oxidized to sulfone
acid (m-CPBA) in dichloromethane (Scheme 5, 5Ac, 74%; 5Ae, 70%). After treatment with
N-chlorosuccinimide (NCS, 1.0 equivalent), thioflavanone was transformed to thiochromone
5 with excess m-chloroperobenzoic
3
6
with good yields (Scheme 5, 6Aa, 70%; 6Af, 66%). It was also reduced by sodium borohydride to the
corresponding alcohol 7 (Scheme 3, 7Aa, 81%; 7Ab, 85%).
Scheme 5. Synthetic applications of thioflavanones.
3. Materials and Methods
3.1. General Methods
The 1H, 13C, and 19F-NMR spectra were recorded on a BRUKER AscendTM 400 NMR spectrometer
(Bruker Corporation, Billerica, MA, USA), operating at 400 MHz for 1H and 100 MHz for 13C and
376 MHz for 19F. Samples for NMR spectra were dissolved in deuterated chloroform unless otherwise
noted. Analytical thin layer chromatography (TLC) was performed on silica gel plates, 60 mesh, with
an F254 indicator. Visualization was accomplished by UV light (254 nm), and/or a 10% ethanol solution
of phosphomolybdic acid and/or KMnO4 stain prepared by dissolving 1.5 g KMnO4, 10 g potassium
carbonate, and 1.25 mL of 10% sodium hydroxide in 200 mL of water. Flash chromatography was
performed with 230–400 mesh silica gel. Infrared (IR) spectra were recorded on a Nicolet iS10 FT-IR
spectrometer (Thermo Scientific, Waltham, MA, USA) as neat samples (thin films).
3.2. Materials
Solvents and chemicals were obtained from commercial sources and used without further
purification unless stated otherwise. Anhydrous tetrahydrofuran (THF) was purchased from Sigma
Aldrich (Sigma-Aldrich, St. Louis, MO, USA). TMSCl was distilled from CaH2 under a positive N2
atmosphere. Grignard reagents were purchased from Sigma Aldrich or prepared from the corresponding
bromocompounds. All glassware was flamed-dried under high vacuum and purged with argon to
cool to room temperature. Low-temperature baths were prepared using dry ice-isopropanol slush

Molecules 2020, 25, 2128
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bath mixtures. All 1,4-conjugate addition reactions with Grignard reagents were conducted under a
positive dry argon atmosphere in anhydrous solvents in flasks fitted with a rubber septum.
3.3. General Procedure A: Conjugate Addition Reactions of Grignard Reagents (RMgX or ArMgX ; X = Cl or
Br) to Thiochromones Catalyzed by CuCN·2LiCl (0.2 eq)
To flame-dried LiCl (8.5 mg, 0.2 mmol, 0.4 equivalent) under argon, CuCN (9.0 mg, 0.1 mmol,
0.2 equivalent) and THF (1.0 mL) were added. The resultant mixture was stirred for 10 min at room
temperature and then cooled to 0 ◦C followed by the addition of a Grignard reagent (0.75 mmol, 1.5
equivalent). The resultant solution was stirred for an additional 30 min at 0 ◦C under argon and then
thiochromones [0.5 mmol mixed with TMSCl (1.0 mmol) in THF 1.0 mL)] were added. The reaction
mixture was allowed to warm up to room temperature during overnight stirring. Then, the reaction
mixture was quenched with saturated aqueous NH4Cl (10.0 mL) and extracted with ethyl acetate
(3
×
10.0 mL). The combined organic phase was washed with brine (15.0 mL), dried over anhydrous
Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography (silica gel, 0–2%
ethyl acetate in hexane, v/v) to give pure compounds.
3.4. Synthesis
HRMS data for compounds 2Ag
and 7Ab were analyzed by TOF MS. Compounds 2Aa
,
3Ag
,
2Ka
,
2La
,
2Na
2Af
51 67], 3Ga
,
3Ea
,
3Fa
,
3Ka
[
-
3Ma
65], 2Ba
51 67], 3Ma
,
3Pa
,
4Af
66], 2Ma
51], 3Na[58]
,
5Ac
,
5Ae
,
–
[
[
66], 2Ah
–
2Ia
[
[
66],
2Oa
3Oa
[
66], 3Aa
–
3Af
[
51,
67], 3Ah
–
3Ai
[
51,
59], 3Ba
–
3Da
,
–
3Ja
[
,
[
,
[
51,67], 4Aa
[
68], 6Aa
[
69], 6Af
[
70], and 7Aa
[
59] have been fully characterized and reported.
(Supplementary materials)
3.4.1. Synthesis of 2-Cyclopropylthiochroman-4-one (2Ag)
Employing General Procedure A, using cyclopropylmagnesium bromide (1.0 M, 1.0 mL, 1.0 mmol)
and thiochromone (81 mg, 0.5 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow solid 2Ag (84 mg, 82%): mp 83–84 ◦C; IR (neat)
3056 (w), 3001 (w), 2921 (w), 1671 (s), 1590 (s), 1456 (w), 1434 (s), 1394 (w), 1284 (s), 1229 (m), 1154 (w),
1068 (w), 1023 (w), 954 (w), 759 (s) cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.22–0.29 (m, 1 H), 0.29–0.35 (m,
1 H), 0.55–0.65 (m, 2 H), 0.95–1.07 (m, 1 H), 2.70 (ddd, J = 2.80, 9.60, 11.6 Hz, 1 H), 2.88 (dd, J = 11.6,
16.4 Hz, 1 H), 3.08 (dd, J = 2.8, 16.4 Hz, 1 H), 7.09 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H), 7.20 (ddd, J = 0.4, 1.2,
8.0 Hz, 1H), 7.31 (ddd, J = 1.6, 7.2, 8.0 Hz, 1H), 8.01 (ddd, J = 0.4, 1.6, 8.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
δ 4.7, 5.0, 15.4, 46.4, 47.2, 124.8, 127.5, 129.0, 130.6, 133.5, 142.1, 194.7; HRMS (EI-ion trap) m/z:
[M + 1]+ calcd for C12H13OS, 205.0687; found 205.0679.
3.4.2. Synthesis of 2-(9-Phenanthryl)thiochroman-4-one (3Ag)
Employing General Procedure A, using 9-phenanthrenylmagnesium bromide (1.0 M, 1.0 mL,
1.0 mmol) and thiochromone (81 mg, 0.50 mmol), after purification by flash column chromatography
(silica gel, 0–2% ethyl acetate: hexanes, v/v), gave a yellow solid 3Ag (133 mg, 78%): mp 180–181 ◦C; IR
(neat) 3062 (w), 2922 (w), 1668 (s), 1582 (m), 1450 (w), 1439 (w), 1295 (m), 1089 (w), 892 (w), 760 (w),
746 (m), 722 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 3.38 (dd, J = 2.8, 16.4 Hz, 1 H), 3.56 (dd, J = 12.8,
16.4 Hz, 1 H), 5.44 (dd, J = 2.8, 12.8 Hz, 1 H), 7.19 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H), 7.37 (ddd, J = 1.2, 7.2,
8.0 Hz, 1H), 7.54 (ddd, J = 0.8, 7.2, 8.0 Hz, 1H), 7.57–7.65 (m, 3H), 7.80-7.85 (m, 2H), 8.13–8.19 (m, 2H),
8.60 (d, J = 8.0 Hz, 1H), 8.69 (dd, J = 1.2, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 41.2, 46.2, 122.5,
123.6, 123.7, 125.4, 126.0, 126.9, 127.1, 127.4, 127.5, 129.0, 129.4, 129.5, 130.3, 130.5, 131.0, 131.04, 132.3,
133.7, 142.2, 194.9; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C23H17OS, 341.1000; found 341.1014.
3.4.3. Synthesis of 6,8-Difluoro-2-n-butylthiochroman-4-one (2Ka)
Employing General Procedure A, using n-butylmagnesium chloride (1.71 M, 0.44 mL, 0.75 mmol)
and thiochromone (99 mg, 0.50 mmol), after purification by flash column chromatography (silica gel,

Molecules 2020, 25, 2128
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0–2% ethyl acetate: hexanes, v/v), gave a light-yellow oil 2Ka (93 mg, 73%): IR (neat) 3083 (w), 2958
(s), 2929 (s), 2858 (s), 1686 (s), 1611 (m), 1571 (m), 1437 (m), 1571 (m), 1437 (s), 1326 (s), 1281 (s), 1217
(w), 1112 (m), 997 (m) 878 (w), 856 (w), 641 (w), 620 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.85 (t,
J = 7.2 Hz, 3 H), 1.22–1.33 (m, 2H), 1.34–1.47 (m, 2H), 1.67 (q, J = 7.8 Hz, 2 H), 2.75 (dd, J = 11.2, 16.4 Hz,
1 H), 2.99 (dd, J = 2.8, 16.4 Hz, 1 H), 3.36-3.46 (m, 1H), 6.93 (ddd, J = 2.8, 8.0, 9.2 Hz, 1H), 7.57 (ddd,
J = 1.2, 2.8, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.7, 34.1, 41.1, 45.9, 108.7 (t, J = 26 Hz),
110.9 (dd, J = 3.0, 22 Hz), 125.4 (dd, J = 3.0, 18 Hz), 132.6 (dd, J = 3.0, 7.0 Hz), 158.6 (dd, J = 11, 246 Hz),
159.7 (dd, J = 11, 246 Hz), 192.6; 19F NMR (376 MHz, CDCl3) δ −107.4 (dd, J = 6.4, 8.7 Hz),
−
114.1 (dt,
J = 6.3, 8.3 Hz); HRMS (EI-ion trap) m/z: [M + Na]+ calcd for C13H14ONaSF2, 279.0631; found 279.0642.
3.4.4. Synthesis of 6,8-Dichloro-2-n-butylthiochroman-4-one (2La)
Employing General Procedure A, using n-butylmagnesium chloride (1.71 M, 0.32 mL, 0.54 mmol)
and thiochromone (83 mg, 0.36 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow oil 2La (80 mg, 77%): IR (neat) 3067 (w), 2956 (m),
2928 (m), 2858 (m), 1686 (s), 1571 (m), 1538 (w), 1465 (w), 1426 (w), 1397 (s), 1285 (w), 1244 (m), 1120
(w), 1053 (w), 873 (w), 812 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.85 (t, J = 7.2 Hz, 3 H), 1.23–1.33
(m, 2H), 1.35–1.46 (m, 2H), 1.68 (q, J = 7.2 Hz, 2 H), 2.72 (dd, J = 11.2, 16.4 Hz, 1 H), 2.96 (dd, J = 3.2,
16.4 Hz, 1 H), 3.34–3.43 (m, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3)
δ 13.9, 22.3, 28.6, 34.1, 40.8, 44.8, 127.2, 130.6, 132.4, 132.7, 133.5, 139.7, 192.9; HRMS (EI-ion
trap) m/z: [M − 1]+ calcd for C13H13OSCl2, 287.0064; found 287.0067.
3.4.5. Synthesis of 6,7-Dimethoxyl-2-n-butylthiochroman-4-one (2Na)
Employing General Procedure A, using n-butylmagnesium chloride (1.71 M, 0.27 mL, 0.47 mmol)
and thiochromone (69 mg, 0.31 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow oil 2Na (74 mg, 85%): IR (neat) 3077 (w), 3000 (w),
2954 (s), 2927 (s), 2853 (s), 1660 (s), 1591 (s), 1498 (s), 1462 (m), 1436 (m), 1388 (s), 1352 (m), 1258 (s), 1210
(s), 1177 (m), 1146 (m), 1098 (w), 1033 (s), 872 (w), 796 (w) cm−1; 1H NMR (400 MHz, CDCl3)
δ 0.84 (t,
J = 7.2 Hz, 3 H), 1.22–1.31 (m, 2H), 1.32–1.43 (m, 2H), 1.64 (q, J = 7.2 Hz, 2 H), 2.66 (dd, J = 11.2, 16.4 Hz,
1 H), 2.92 (dd, J = 3.2, 16.4 Hz, 1 H), 3.35–3.46 (m, 1H), 3.82 (s, 3H), 3.84 (s, 3H), 6.61 (s, 1H), 7.51 (s, 1H);
13C NMR (100 MHz, CDCl3)
δ 13.9, 22.3, 28.9, 34.1, 42.3, 46.0, 56.0, 56.2, 109.0, 110.2, 123.9, 135.6, 147.1,
153.8, 193.6; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C15H21O3S, 281.1211; found 281.1210.
3.4.6. Synthesis of 6-Isopropyl-2-phenylthiochroman-4-one (3Ea)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.25 mL, 0.71 mmol)
and thiochromone (95 mg, 0.47 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a yellow solid 3Ea (102 mg, 77%): mp 78–79 ◦C; IR (neat) 3056
(w), 2965 (s), 2927 (m), 1673 (s), 1576 (m), 1489 (w), 1451 (w), 1411 (m), 1286 (w), 1262 (s), 1147 (w), 1973
(w), 1042 (w), 780 (w), 766 (w), 731 (w), 698 (w) cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.24 (d, J = 6.8
Hz, 3 H), 1.31 (d, J = 6.8 Hz, 3 H), 3.23 (dd, J = 2.8, 16.4 Hz, 1 H), 3.26–3.34 (m, 1H), 3.35 (dd, J = 13.6,
16.4 Hz, 1 H), 4.66 (dd, J = 2.8, 13.6 Hz, 1 H), 7.25 (dd, J = 7.6, 15.2 Hz, 1H), 7.34–7.51 (m, 6H), 8.09 (dd,
J = 1.6, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 22.7, 23.1, 30.3, 44.9, 46.3, 124.8, 127.2, 127.5, 128.5,
129.0, 130.3, 130.9, 138.7, 140.4„ 145.8, 195.1; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C18H19OS,
283.1157; found 283.1147.
3.4.7. Synthesis of 6,8-Dimethyl-2-phenylthiochroman-4-one (3Fa)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.13 mL, 0.35 mmol)
and thiochromone (42.8 mg, 0.23 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a white solid 3Fa (52.5 mg, 85%): mp 123–124 ◦C; IR (neat) 3041
(w), 2977 (w), 2922 (m), 2852 (w), 1670 (s), 1600 (m), 1456 (m), 1421 (w), 1371 (w), 1310 (m), 1280 (m),
1250 (m), 1125 (w), 871 (m), 781 (m), 706 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.09 (s, 3 H), 2.14 (s, 3

Molecules 2020, 25, 2128
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H), 2.98 (dd, J = 3.2, 16.4 Hz, 1 H), 3.11 (dd, J = 13.2, 16.4 Hz, 1 H), 4.45 (dd, J = 2.8, 13.2 Hz, 1 H), 6.98
(dd, J = 0.8, 1.6 Hz, 1 H), 7.12–7.23 (m, 3 H), 7.24–7.28 (m, 2 H), 7.68 (dd, J = 0.8, 1.6 Hz, 1 H); 13C NMR
(100 MHz, CDCl3)
δ 19.9, 20.7, 44.9, 46.3, 127.1, 127.5, 128.5, 129.0, 130.4, 134.1, 135.0, 136.1, 138.3, 138.8,
195.1; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C17H17OS, 269.1000; found 269.0999.
3.4.8. Synthesis of 6,8-Difluoro-2-phenylthiochroman-4-one (3Ka)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.16 mL, 0.44 mmol)
and thiochromone (58 mg, 0.293 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow solid 3Ka (57 mg, 70%): mp 70–71 ◦C; IR (neat)
3076 (s), 3031 (w), 2959 (w), 2892 (w), 1685 (s), 1609 (m), 1571 (m), 1438 (m), 1322 (m), 1282 (m), 1130
(w), 995 (m), 879 (w), 772 (w), 697 (w) cm−1; 1H NMR (400 MHz, CDCl3)
H), 3.14 (dd, J = 13.2, 16.4 Hz, 1 H), 4.48 (dd, J = 3.2, 13.2 Hz, 1 H), 6.83 (ddd, J = 2.8, 8.0, 8.8 Hz, 1H),
7.13–7.26 (m, 5H), 7.51 (ddd, J = 1.6, 2.8, 8.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
45.0, 46.3, 108.9
δ 3.01 (dd, J = 0.4, 3.2 Hz, 1
δ
(dd, J = 2.5, 2.6 Hz), 111.2 (dd, J = 3, 23 Hz), 125.8 (dd, J = 4, 19 Hz), 127.5, 128.9, 129.1, 132.4 (dd, J =
3.0, 7.0 Hz), 137.7, 158.3 (dd, J = 11, 247 Hz), 159.91 (dd, J = 11, 247 Hz), 192.3 (t, J = 3.0 Hz); 19F NMR
(376 MHz, CDCl3) δ −107.2 (dd, J = 6.8, 8.3 Hz),
−
113.5 (dt, J = 7.5, 8.3 Hz); HRMS (EI-ion trap) m/z:
[M − 1]+ calcd for C15H9OSF2, 275.0342; found 275.0345.
3.4.9. Synthesis of 6,8-Dichloro-2-phenylthiochroman-4-one (3La)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.08 mL, 0.225 mmol)
and thiochromone (33.6 mg, 0.15 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow solid 3La (35 mg, 76%): mp 112–113 ◦C; IR (neat)
3067 (w), 2921 (s), 1682 (s), 1571 (m), 1539 (w), 1453 (w), 1397 (s), 1283 (w), 1241 (m), 1177 (w), 1121 (w),
1051 (w), 808 (w), 767 (w), 697 (m) cm−1; 1H NMR (400 MHz, CDCl3)
H), 3.10 (dd, J = 13.2, 16.4 Hz, 1 H), 4.45 (dd, J = 3.2, 13.2 Hz, 1 H), 7.15–7.45 (m, 5 H), 7.32 (d, J = 2.4
Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
44.8, 45.3, 127.51, 127.53, 128.9, 129.2,
δ 3.00 (dd, J = 3.2, 16.4 Hz, 1
δ
131.0, 132.1, 132.5, 133.7, 137.5, 140.0, 192.6; HRMS (EI-ion trap) m/z: [M
306.9751; found 306.9765.
−
1]+ calcd for C15H9OSCl2,
3.4.10. Synthesis of 8-Methoxy-2-phenylthiochroman-4-one (3Ma)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.16 mL, 0.44 mmol)
and thiochromone (55 mg, 0.29 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow solid 3Ma (66 mg, 84%): mp 147–148 ◦C; IR (neat)
3017 (w), 2972 (W), 2936 (w), 1673 (s), 1579 (m), 1559 (m), 1451 (m), 1420 (m), 1316 (m), 1254 (s), 1155
(w), 1055 (w), 1031 (s), 789 (m), 770 (m), 712 (w), 697 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 3.08 (dd,
J = 2.8, 16.0 Hz, 1 H), 3.21 (dd, J = 13.6, 16 Hz, 1 H), 3.82 (s, 3 H), 4.54 (dd, J = 2.8, 13.6 Hz, 1 H), 6.91 (dd,
J = 1.2, 8.0 Hz, 1 H), 7.09 (t, J = 8.0 Hz, 1 H), 7.22–7.32 (m, 3H), 7.33–7.38 (m, 2H), 7.71 (dd, J = 1.2, 8.0 Hz,
1 H); 13C NMR (100 MHz, CDCl3)
δ 44.4, 46.0, 56.3, 114.2, 121.1, 124.8, 127.5, 128.5, 129.0, 131.3, 131.9,
138.7, 155.1, 194.6; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C16H15O2S, 271.0793; found 271.0794.
3.4.11. Synthesis of 2,3-Dihydro-2-phenyl-4H-naphtho[1,2-b]thiopyran-4-one (3Pa)
Employing General Procedure A, using phenylmagnesium bromide (2.8 M, 0.19 mL, 0.53 mmol)
and thiochromone (75 mg, 0.354 mmol), after purification by flash column chromatography (silica gel,
0–2% ethyl acetate: hexanes, v/v), gave a light-yellow solid 3Pa (82 mg, 80%): mp 144.0–145.0 ◦C; IR
(neat) 3057 (w), 3031 (w), 2020 (w), 1668 (w), 1594 (m), 1552 (w), 1450 (w), 1326 (m), 1310 (m), 1267 (m),
1245 (m), 1165 (w), 1076 (w), 810 (m), 771 (m), 746 (m) cm−1; 1H NMR (400 MHz, CDCl3)
J = 2.8, 16.4 Hz, 1 H), 4.35 (dd, J = 13.6, 16.4 Hz, 1 H), 4.74 (dd, J = 3.2, 13.6 Hz, 1 H), 7.28–7.39 (m,
3H), 7.41–7.46 (m, 1H), 7.46–7.51 (m, 1H), 7.52–7.58 (m, 1H), 7.73–7.78 (m, 1H), 8.10–8.17 (m, 2H); 13
NMR (100 MHz, CDCl3) 45.4, 45.8, 124.1, 125.1, 125.4, 126.8, 127.6, 127.7, 128.6, 128.7, 129.1, 129.2,
δ 3.21 (dd,
C
δ

Molecules 2020, 25, 2128
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130.1, 135.5, 138.4, 142.9, 194.6; HRMS (EI-ion trap) m/z: [M + 1]+ calcd for C19H15OS, 291.0844; found
291.0847.
3.4.12. Synthesis of 3-Chloro-2-(2-naphthyl)-4H-thiochromen-4-one (4Af)
To a dichloromethane (DCM) solution of 2-(2-naphthyl)thiochroman-4-one (1.0 equivalent, 0.542
mmol, 157.2 mg), NCS (N-chlorosuccinimide) (3.0 equivalent, 1.63 mmol, 217 mg) was added. The
reaction mixture was stirred at room temperature overnight (12 h). It was then quenched with water
(10 mL) and extracted with DCM (3
×
10 mL). The organic layers were combined and dried over
anhydrous Na2SO4. It was filtered and concentrated in vacuum. The crude product was purified by
flash column chromatography (silica gel, 5 % ethyl acetate: hexanes, v/v) to give 4Af as a white solid
(119 mg, 68%): mp 161.0–162.0 ◦C; IR (neat) 3052 (w), 2922 (w), 1621 (s), 1586 (s) 1562 (m), 1500 (w),
1462 (w), 1435 (w), 1320 (w), 1305 (w), 1272 (w), 1135 (w), 1112 (w), 851 (m), 839 (m), 735 (m) cm−1; 1H
NMR (400 MHz, CDCl3)
δ
7.48–7.63 (m, 6 H), 7.82–7.88 (m, 2 H), 7.90 (d, J = 8.4 Hz, 1 H), 7.96 (t, J = 0.8
125.6, 125.9, 126.5, 127.0,
Hz, 1 H), 8.57 (ddd, J = 0.8, 1.6, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ
127.7, 127.9, 128.1, 128.5, 128.6, 128.7, 129.8, 130.5, 131.9, 132.6, 132.8, 133.7, 136.6, 148.4, 174.8; HRMS
(EI-ion trap) m/z: [M + 1]+ calcd for C19H12OSCl, 323.0297; found 323.0296.
3.4.13. Synthesis of 2-(4-Methoxyphenyl)thiochroman-4-one 1,1-dioxide (5Ac)
To a dry DCM solution of 2-(4-methoxyphenyl)thiochroman-4-one (94 mg, 0.348 mmol) under Ar
atmosphere in a 50-mL RB flask, excess 3-meta-chloroperoxybenzoic acid (m-CPBA, 3.0 equivalent,
180 mg, 1.04 mmol) was added. The resultant mixture was stirred at room temperature until the
reaction was complete by TLC monitoring (4–5 h). Then the reaction mixture was quenched with
NaHCO3 (10 mL) and diluted with DCM (10 mL). The organic layers were separated and the aqueous
layer was extracted with DCM (2
×
10 mL). The organic layers were combined and washed with brine
and dried over anhydrous Na2SO4. It was filtered and concentrated in vacuum. The crude product
was purified by flash column chromatography (silica gel, 20% ethyl acetate: hexanes, v/v) to give a
white solid 5Ac (78 mg, 74%): mp 163–164 ◦C; IR (neat) 3100 (w), 2902 (w), 1690 (s), 1587 (w), 1376 (m),
1312 (m), 1273 (s), 1150 (m), 1115 (s), 934 (m), 904 (m), 759 (m) cm−1; 1H NMR (400 MHz, CDCl3)
δ 3.41
(dd, J = 3.2, 17.6 1 H), 3.85 (s, 3 H), 3.95 (dd, J = 12.8, 17.6 Hz, 1 H), 4.85 (dd, J = 3.2, 12.8 Hz, 1 H), 7.00
(dd, J = 2, 6.8 Hz 1 H), 7.42 (dd, J = 2, 6.8 Hz, 2 H), 7.78 (td, J = 1.2, 8 Hz, 1 H), 7.85 (td, J = 1.2, 8.0 Hz, 1
H), 8.10 (dd, J = 1.2, 8.0 Hz, 1 H), 8.19 (dd, J = 1.2, 8 Hz, 1 H); 13C NMR (100 MHz, CDCl3)
δ 43.2, 55.4,
63.5, 114.6, 119.7, 124.5, 128.7, 130.6, 131.1, 133.3, 135.1, 141.5, 160.9, 191.1; HRMS (EI-ion trap) m/z:
[M + 1]+ calcd for C16H15O4S, 303.0691; found 303.0699.
3.4.14. Synthesis of 2-[3,5-(Trifluoromethyl)phenyl]thiochroman-4-one 1,1-dioxide (5Ae)
To a dry DCM solution of 2-[3,5-(trifluoromethyl)phenyl]thiochroman-4-one (116 mg, 0.308 mmol)
under Ar atmosphere in a 50-mL RB flask, excess 3-meta-chloroperoxybenzoic acid (mCPBA, 3.0
equivalent, 0.924 mmol, 159 mg, mCPBA was 70–75%) was added. The resultant mixture was stirred
at room temperature until the reaction was complete by TLC monitoring (4–5 h). Then, the reaction
mixture was quenched with NaHCO3 (10 mL) and diluted with DCM (10 mL). The organic layers
were separated and the aqueous layer was extracted with DCM (2
×
10 mL). The organic layers were
combined and washed with brine and dried over anhydrous Na2SO4. It was filtered and concentrated
in vacuum. The crude product was purified by flash column chromatography (silica gel, 20% ethyl
acetate: hexanes, v/v) to give a white solid 5Ae (88 mg, 70%): mp 162–163 ◦C; IR (neat) 3100 (w), 2902
(w), 1690 (s), 1627 (w), 1587 (w), 1469 (w), 1376 (m), 1313 (s), 1273 (s), 1199 (m), 1115 (s), 1038 (w), 934
(m), 904 (m), 844 (w), 780 (w), 759 (s), 706 (w), 679 (w) cm−1; 1H NMR (400 MHz, CDCl3)
δ 3.36 (dd,
J = 3.2, 17.6 1 H), 3.92 (dd, J = 13.2, 17.6 Hz, 1 H), 4.94 (dd, J = 3.2, 12.8 Hz, 1 H), 7.74 (dt, J = 1.6, 7.6 Hz,
1 H), 7.89 (s, 1 H), 7.93 (s, 1 H), 8.01 (dd, J = 1.2, 8.0 Hz, 1 H), 8.13 (dd, J = 1.2, 8.0 Hz, 1 H); 13C NMR
(100 MHz, CDCl3)
δ 42.6, 63.1, 121.5, 122.8 (q, J = 258 Hz), 124.2, 124.5, 129.1, 130.0, (d, J = 3 Hz), 130.3,

Molecules 2020, 25, 2128
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130.7, 132.6 (q, J = 34 Hz), 133.9, 135.4, 140.7, 189.4; 19F NMR (376 MHz, CDCl3) δ −62.9; HRMS (EI-ion
trap) m/z: [M + 1]+ calcd for C17H11O3SF6, 409.0333; found 409.0333.
3.4.15. Synthesis of 2-(2-Methylphenyl)thiochroman-4-ol (7Ab)
To a dry ethanol solution (3.0 mL) of 2-(2-methylphenyl)thiochroman-4-one (50 mg, 1.0 eq,
0.197 mmol, 50 mg) under argon, sodium borohydride (5 mg, 0.6 eq, 0.12 mmol, 10 mg) was added
portion-wise. The resultant mixture was stirred at room temperature for 2 h when TLC monitoring
showed that all the starting material was gone. Then solvent was evaporated, ice water (10 mL) was
added, and the mixture was acidified with 10% HCl to pH = 1–2. It was then extracted with ethyl
acetate (3
×
10 mL) and organic layers were combined, and washed with brine (15 mL). The organic
layer was dried (Na2SO4), filtered, and evaporated under vacuum to give the crude product. The crude
product was then purified by flash column chromatography (silica gel, 10% ethyl acetate: hexanes, v/v)
to give 2-(2-methylphenyl)thiochroman-4-ol 7Ab as a white solid (41 mg, 81%): mp 146–147 ◦C; IR
(neat) 3269 (sb), 3064 (w), 3021 (w), 2918 (s), 1953 (w), 1916 (w), 1590 (w), 1565 (w), 1487 (m), 1486 (s),
1435 (m), 1244 (w0, 1220 (w), 1063 (m), 1021 (m), 753 (s) cm−1; 1H NMR (400 MHz, CDCl3)
δ 2.0 (s,
1H), 2.47 (s, 3H), 2.48–2.53 (m, 1H), 2.67 (ddd, J = 2.8, 5.2, 12.8 Hz, 1 H), 4.86 (dd, J = 3.2, 12 Hz, 1 H),
5.0–5.10 (m, 1 H), 7.11–7.28 (m, 6H), 7.49–7.55 (m, 1 H), 7.65–7.73 (m, 6H); 13C NMR (100 MHz, CDCl3)
δ
19.3, 40.0, 40.3, 70.0, 124.8, 125.9, 126.7, 126.79, 126.80, 127.7, 127.8, 130.7, 134.1, 135.9, 136.6, 138.4;
HRMS (EI-ion trap) m/z: [M + Na]+ calcd for C16H16ONaS, 279.0820; found 279.0826.
4. Conclusions
In conclusion, we successfully developed the conjugate addition of Grignard reagents to
thiochromones catalyzed by CuCN 2LiCl in the presence of chlorotrimethylsilane (TMSCl) as
·
an activator to afford 2-alkylthiochroman-4-ones and thioflavanones (2-arylthiochromon-4-ones)
in good yields. This reaction was shown to work well with a broad range of Grignard
reagents, both alkyl and aromatic Grignard reagents. This synthetic approach will allow
access to a broader scope of thiochromanones and thioflavanones due to the readily available
Grignard reagents compared to organolithium reagents. Very interesting compounds, such as
6,8-difluorosubstituted thiochroman-4-ones, were synthesized for further studies. The 1,4-adducts,
both 2-alkylthiochroman-4-ones and thioflavanones, can be utilized for additional synthetic applications
and provide quick access that privileges sulfur-heterocycles.
Supplementary Materials: The following are available online.
Author Contributions: T.J.B., T.H., T.P.-F., N.A., S.H.W., M.L.C.T.Y.T., D.T.H., and N.D. performed the experiments.
F.G. conceived and designed the experiments; F.G. wrote the paper. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by NSF HBCU-UP RIA, grant number 1600987 and NSF EiR, grant number
1831339. Part of this research was funded NIH RISE, and grant number R25GM113774. Tania J. Bellinger, Nataleigh
Austin, Mai Ling Yuk Tutein, and Nichele Deese are NIH RISE scholars. We like to thank NSF CUR-TP team
(NSF, grant 1625354) for supporting the re-design of CH3236 (I&R) and the undergraduate transformation project.
The APC was funded by NSF HBCU-UP RIA, grant number 1600987. We also like to thank Dr. Marcus Wright
from Chemistry Department, Wake Forest University, Winston Salem for access to NMR facility and assistance in
attaining NMR spectra. We thank WSSU Provost’s Office for supporting the re-design of CH3236 (I&R). This is
also part of the project that Mai Ling Tang Yuk Tutein, Ti’Bran Pickens-Flynn and Nataleigh Austin are working
on for CH3236 (I&R) and CH4244 (Directed Research) courses, backward redesigned I&R and directed research,
part of the NSF Council of Undergraduate Research Transformation Project.
Conflicts of Interest: The authors declare no conflict of interest.

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References
1.
Ortiz, P.; Lanza, F.; Harutyunyan, S.R. 1,2- Versus 1,4-Asymmetric Addition of Grignard Reagents to
Carbonyl Compounds. In Progress in Enantioselective Cu(I)-catalyzed Formation of Stereogenic Centers;
Harutyunyan, S.R., Ed.; Springer Press: Basel, Switzerland, 2016; pp. 99–134.
2.
Kharasch, M.S.; Tawney, P.O. Factors Determining the Course and Mechanisms of Grignard Reactions.
II. The Effect of Metallic Compounds on the Reaction between Isophorone and Methylmagenisum Bromide.
J. Am. Chem. Soc. 1941, 63, 2308–2316. [CrossRef]
3.
4.
Damani, L.A. (Ed.) Sulphur-Containing Drugs and Related Organic Compounds; Wiley: New York, NY, USA, 1989.
Clayden, J.; MacLellan, P. Asymmetric synthesis of tertiary thiols and thioethers. Beilstein J. Org. Chem.
2011, 7, 582–595. [CrossRef] [PubMed]
5.
6.
7.
8.
Ingall, A.H. Thiopyrans and Fused Thiopyrans. In Comprehensive Heterocyclic Chemistry; Katritzky, A.R.,
Rees, C.W., Eds.; Pergamon Press: Oxford, UK, 1984; Volume 3, p. 885.
Schneller, S.W. Thiochromanones and Related Compounds. In Advances in Heterocyclic Chemistry;
Katritzky, A.R., Boulton, A.J., Eds.; Academic Press: New York, USA, 1975; Volume 18, p. 59.
Acton, A.Q. (Ed.) Sulfur Compounds: Advances in Research and Application; Scholarly Editions:
Atlanta, GA, USA, 2012.
Nielsen, S.F.E.; Nielsen, O.; Olsen, G.M.; Liljefors, T.; Peters, D. Novel Potent Novel Potent Ligands for the
Central Nicotinic Acetylcholine Receptor: Synthesis, Receptor Binding, and 3D-QSAR Analysis. J. Med. Chem.
2000, 43, 2217–2226. [CrossRef] [PubMed]
9.
Smith, B.R.; Eastman, C.M.; Njardarson, J.T. Beyond C, H, O and N! Analysis of the Elemental Composition
of U.S. FDA Approved Drug Architectures. J. Med. Chem. 2014, 57, 9764–9773. [CrossRef] [PubMed]
10. Takimiya, K.;
Osaka, I.;
Mori, T.;
Nakano, M. Organic Semiconductors Based on
[1]Benzothieno[3,2-b][1]benzothiophene Substructure. Acc. Chem. Res. 2014, 47, 1493–1502. [CrossRef]
[PubMed]
11. Joyce, N.I.; Eady, C.C.; Silcock, P.; Perry, N.B.; Van Klink, J.W. Fast Phenotyping of LFS-Silenced (Tearless)
Onions by Desorption Electrospray Ionization Mass Spectrometry (DESI-MS). J. Agric. Food Chem.
2013, 61, 1449–1456. [CrossRef] [PubMed]
12. Mishra, A.; Ma, C.Q.; Bauerle, P. Functional Oligothiophenes: Molecular Design for Multidimensional
Nanoarchitectures and Their Applications. Chem. Rev. 2009, 109, 1141–1276. [CrossRef]
13. Lin, D.Y.; Zhang, S.Z.; Block, E.; Katz, L.C. Encoding social signals in the mouse main olfactory bulb. Nature
2005, 434, 470–477. [CrossRef]
14. Wermuch, C.G. Molecular variations based on isosteric replacements. In The Practice of Medicinal Chemistry;
Wermuth, C.G., Ed.; Academic Press: San Diego, CA, USA, 1996; pp. 203–237.
15. Choi, E.J.; Lee, J.I.; Kim, G.-H. Evaluation of the anticancer activities of thioflavanone and thioflavone in
human breast cancer cell lines. Int. J. Mol. Med. 2012, 29, 252–256.
16. Vargas, E.; Echeverri, F.; Vélez, I.D.; Robledo, S.M.; Quinˇones, W. Synthesis and Evaluation of
Thiochroman-4-one Derivatives as Potential Leishmanicidal Agents. Molecules 2017, 22, 2041. [CrossRef]
17. Zhao, J.; Li, H.-Z.; Suo, H.; Wang, Y.; Yang, C.; Ma, Z.; Liu, Y. Cytoxic effect of three novel thiochromanone
derivatives on tumor cell in vitro and underlying mechanism. Glob. Adv. Res. J. Med. Sci. 2014, 3, 240–250.
18. Harborne, J.B. The Flavonoids: Advances in Research Since 1980; Chapman and Hall: New York, NY, USA, 1988.
19. Harborne, J.B.; Williams, C.A. Anthocyanins and other flavonoids. Nat. Prod. Rep. 1995, 12, 639–657.
[CrossRef]
20. Pietta, P.G. Flavonoids as antioxidants. J. Nat. Prod. 2000, 63, 1035–1042. [CrossRef] [PubMed]
21. Andersen, O.M.; Markham, K.R. (Eds.) Flavonoids: Chemistry, Biochemistry and Applications; Taylor & Francis:
London, UK, 2006.
22. Philipp, A.; Jirkovsky, I.; Martel, R.R. Synthesis and antiallergic properties of some
4H,
5H-pyrano[3,2-c][1]benzopyran-4-one,
4H,5H-[1]benzothiopyrano[4,3-b]pyran-4-one,
and
1,4-dihydro-5H-[1]benzothiopyrano[4,3-b]pyridine-4-one derivatives. J. Med. Chem. 1980, 23, 1372–1376.
[CrossRef]
23. Ramalingam, K.; Thyvelikakath, G.X.; Berlin, K.D.; Chesnut, R.W.; Brown, R.A.; Durham, N.N.; Ealick, S.E.;
Van der Helm, D. Synthesis and biological activity of some derivatives of thiochroman-4-one and
tetrahydrothiapyran-4-one. J. Med. Chem. 1977, 20, 847–850. [CrossRef]

Molecules 2020, 25, 2128
14 of 16
24. Wang, H.K.; Bastow, K.F.; Cosentino, L.M.; Lee, K.H. Antitumor Agents. 166. Synthesis and Biological
Evaluation of 5,6,7,8-Substituted-2-phenylthiochromen-4-ones. J. Med. Chem. 1996, 39, 1975–1980. [CrossRef]
25. Holshouser, M.H.; Loeffler, L.J.; Hall, I.H. Synthesis of peptides by the solid-phase method. 6. Neurotensin,
fragments, and analogs. J. Med. Chem. 1981, 24, 853–858. [CrossRef]
26. Dhanak, D.; Keenan, R.M.; Burton, G.; Kaura, A.; Darcy, M.G.; Shah, D.H.; Ridgers, L.H.; Breen, A.; Lavery, P.;
Tew, D.G.; et al. Benzothiopyran-4-one based reversible inhibitors of the human cytomegalovirus (HCMV)
protease. Bioorg. Med. Chem. Lett. 1998, 8, 3677–3682. [CrossRef]
27. Nussbaumer, P.; Lehr, P.; Billich, A. 2-Substituted 4-(Thio)chromenone 6-O-Sulfamates: Potent Inhibitors of
Human Steroid Sulfatase. J. Med. Chem. 2002, 45, 4310–4320. [CrossRef]
28. Kataoka, T.; Watanabe, S.; Mori, E.; Kadomoto, R.; Tanimura, S.; Kohno, M. Synthesis and structure-activity
relationships of thioflavone derivative as specific inhibitors of the ERK-MAP kinase signaling pathway.
Bioorg. Med. Chem. 2004, 12, 2397–2407. [CrossRef]
29. Soni, D.V.; Jacobberger, J.W. Gene modulation by Cox-1 and Cox-2 specific inhibitors in human colorectal
carcinoma cancer cells. Cell Cycle 2004, 3, 349–357. [PubMed]
30. Bondock, S.; Metwally, M.A. Thiochroman-4-ones: Synthesis and reactions. J. Sulfur Chem. 2008, 29, 623–653.
[CrossRef]
31. Dalla Via, L.; Marciani Magno, S.; Gia, O.; Marini, A.M.; Da Settimo, F.; Salerno, S.; La Motta, C.; Simorini, F.;
Taliani, S.; Lavecchia, A.; et al. Benzothiopyranoindole-Based Antiproliferative Agents: Synthesis, Cytoxicity,
Nucleic Acids Interaction, and Topoisomerases Inbibition Properties. J. Med. Chem. 2009, 52, 5429–5441.
[CrossRef] [PubMed]
32. Bates, D.K.; Li, K. Stannous Chloride-Mediated Reductive Cyclization-Rearrangement of Nitroarenyl Ketones.
J. Org. Chem. 2002, 67, 8662–8665. [CrossRef]
33. Aramaki, Y.; Seto, M.; Okawa, T.; Oda, T.; Kanzaki, N.; Shiraishi, M. Synthesis of 1-Benzothiepine and
1-Benzazepine Derivatives as Orally Active CCR5 Antagonists. Chem. Pharm. Bull. 2004, 52, 254–258.
[CrossRef]
34. Dike, S.Y.; Ner, D.H.; Kumar, A. A New Enantioselective Chemoenzymatic Synthesis of R-( )Thiazesim
−
Hydrochloride. Bioorg. Med. Chem. Lett. 1991, 1, 383–386. [CrossRef]
35. Phippen, C.B.W.; McErlean, C.S.P. A 1,5-Benzothiazepine Synthesis. Tetrahedron Lett. 2011, 52, 1490–1492.
[CrossRef]
36. Li, W.; Schlepphorst, C.; Daniliuc, C.; Glorius, F. Asymmetric Hydrogenation of Vinylthioethers: Access to
Optically Active 1,5-Benzothiazepine Derivatives. Angew. Chem. Int. Ed. 2016, 55, 3300–3303. [CrossRef]
37. Fang, X.; Li, J.; Wang, C.J. Organocatalytic Asymmetric Sulfa-Michael Addition of Thiols to α,β-Unsaturated
Hexafluoroisopropyl Esters: Expeditious Access to (R)-Thiazesim. Org. Lett. 2013, 15, 3448–3451. [CrossRef]
38. Fukata, Y.; Asano, K.; Matsubara, S. Facile Net Cycloaddition Approach to Optically Active
1,5-Benzothiazepines. J. Am. Chem. Soc. 2015, 137, 5320–5323. [CrossRef]
39. Qi, X.; Xiang, H.; Yang, C. Synthesis of Functionalized Chromeno[2,3-b]pyrrol-4(1H)-ones by Silver-Catalyzed
Cascade Reactions of Chromones/Thiochromones and Isocyanoacetates. Org. Lett. 2015, 17, 5590–5593.
[CrossRef] [PubMed]
40. Ali, A.; Ahmad, V.U.; Liebscher, J. Stereoselective Synthesis of Thiochroman-4-ones by Ring Transformation of
Chiral 5-Ylidene-1,3-dioxan-4-ones with 2-Bromothiophenol via Bromo-Lithium Exchange. Eur. J. Org. Chem.
2001, 2001, 529–535. [CrossRef]
41. Vaghoo, H.; Prakash, G.K.; Narayanan, A.; Choudhary, R.; Paknia, F.; Mathew, T.; Olah, G.A. Superelectrophilic
Activation of Crotonic/Methacrylic Acids: Direct Access to Thiochroman-4-ones from Benzenethiols by
Microwave-Assisted One-Pot Alkylation/Cyclic Acylation. Org. Lett. 2015, 17, 6170–6173. [CrossRef]
[PubMed]
42. Cui, D.-M.; Kawamura, M.; Shimada, S.; Hayashi, T.; Tanaka, M. Synthesis of 1-Tetralones by
Intramolecular Friedel-Crafts Reaction of 4-Arylbutyric Acids Using Lewis Acid Catalysts. Tetrahedron Lett.
2003, 44, 4007–4010. [CrossRef]
43. Hoettecke, N.; Rotzoll, S.; Albrecht, U.; Lalk, M.; Fischer, C.; Langer, P. Synthesis and Antimicrobial Activity
of 2-Alkenylchroman-4-ones, 2-Alkenylthiochroman-4-ones and 2-Alkenylquinol-4-ones. Bioorg. Med. Chem.
2008, 16, 10319–10325. [CrossRef]
44. Dong, X.Q.; Fang, X.; Wang, C.J. Organocatalytic Asymmetric Sulfa-Michael Addition of Thiols to
4,4,4-Trifluorocrotonates. Org. Lett. 2011, 13, 4426–4429. [CrossRef]

Molecules 2020, 25, 2128
15 of 16
45. Xiao, W.-J.; Alper, H. Regioselective Carbonylative Heteroannulation of o-Iodothiophenols with Allenes and
Carbon Monoxide Catalyzed by a Palladium Complex: A Novel and Efficient Access to Thiochroman-4-one
Derivatives. J. Org. Chem. 1999, 64, 9646–9652. [CrossRef]
46. Dawood, K.M.; Ishii, H.; Fuchigami, T. Electrolytic Partial Fluorination of Organic Compound. 54.1 Anodic
Mono- and Trifluorination of Thiochroman-4-one Derivatives and the Factors Affecting Product Selectivity.
J. Org. Chem. 2001, 66, 7030–7034. [CrossRef]
47. Palani, T.; Park, K.; Song, K.H.; Lee, S. Palladium-Catalyzed Synthesis of (Z)-3-Arylthioacrylic Acids and
Thiochromenones. Adv. Synth. Catal. 2013, 355, 1160–1168. [CrossRef]
48. Han, X.; Yue, Z.; Zhang, X.; He, Q.; Yang, C. Copper-Mediated, Palladium-Catalyzed Cross-Coupling
of 3-Iodochromones, Thiochromones, and Quinolones with Ethyl Bromodifluoroacetate. J. Org. Chem.
2013, 78, 4850–4856. [CrossRef]
49. Inami, T.; Kurahashi, T.; Matsubara, S. Nickel-Catalyzed Reaction of Thioisatins and Alkynes: A Facile
Synthesis of Thiochromones. Org. Lett. 2014, 16, 5660–5662. [CrossRef] [PubMed]
50. Muthupandi, P.; Sundaravelu, N.; Sekar, G. Domino Synthesis of Thiochromenes through Cu-Catalyzed
Incorporation of Sulfur Using Xanthate Surrogate. J. Org. Chem. 2017, 82, 1936–1942. [CrossRef] [PubMed]
51. Meng, L.; Jin, M.; Wang, J. Rh-Catalyzed Conjugate Addition of Arylzinc Chlorides to Thiochromones:
A Highly Enantioselective Pathway for Accessing Chiral Thioflavanones. Org. Lett. 2016, 18, 4986–4989.
[CrossRef] [PubMed]
52. Xiong, D.; Zhou, W.; Lu, Z.; Zeng, S.; Wang, J. A highly enantioselective access to chiral chromanones and
thiochromanones via copper-catalyzed asymmetric conjugated reduction of chromones and thiochromones.
Chem. Comm. 2017, 53, 6844–6847. [CrossRef]
53. Lee, J.I. New Synthesis of Thioflavanones by the Regioselective Cyclization of
1-(2-Benzylthio)phenyl-3-phenyl-2-propen-1-ones with Hydrobromic Acid. Bull. Korean Chem. Soc.
2020, 41, 484–487. [CrossRef]
54. Lemke, M.K.; Schwab, P.; Fischer, P.; Tischer, S.; Witt, M.; Noehringer, L.; Rogachev, V.; Jager, A.; Kataeva, O.;
Frohlich, R.; et al. A Practical Access to Highly Enantiomerically Pure Flavanones by Catalytic Asymmetric
Transfer Hydrogenation. Angew. Chem. Int. Ed. 2013, 52, 11651–11655. [CrossRef]
55. Zhao, D.-B.; Beiring, B.; Glorius, F. Ruthenium-NHC-catalyzed Asymmetric Hydrogenation of Flavones
and Chromones: General Access to Enantiomerically Enriched Flavanones, Flavanols, Chromanones, and
Chromanols. Angew. Chem. Int. Ed. 2013, 52, 8454–8458. [CrossRef]
56. Kumar, P.; Rao, A.T.; Pandey, B. Chemoselective Reduction of Vinylogous Thioesters of Thiochromones.
Synth. Commun. 1994, 24, 3297–3306. [CrossRef]
57. Sakirolla, R.; Yaeghoobi, M.; Abd Rahman, N. Synthesis of Flavanones, Azaflavanones, and Thioflavanones
Catalyzed by PMA-SiO2 as a Mild, Efficient, and Reusable Catalyst. Monatsh. Chem. 2012, 143, 797–800.
[CrossRef]
58. Kobayashi, K.; Kobayashi, A.; Tanmatsu, M. A Facile Synthesis of 2-Arylthiochroman-4-ones by the Reaction
of 3-Aryl-1-(2-halophenyl)prop-2-en-1-ones with Sodium Hydrogensulfide. Heterocycles 2012, 85, 919–925.
[CrossRef]
59. Sangeetha, S.; Muthupandi, P.; Sekar, G. Copper-Catalyzed Domino Synthesis of 2-Arylthiochromanones
through Concomitant C–S Bond Formations Using Xanthate as Sulfur Source. Org. Lett. 2015, 17, 6006–6009.
[CrossRef] [PubMed]
60. Konieczny, W.; Konieczny, M. Synthesis of Thioflavanone and Flavanone Derivatives by Cyclization of
Chalcones. Synthesis 2009, 1811–1814. [CrossRef]
61. Lee, J.I. A New Synthesis of Thioflavanones from Thiosalicylic Acid. Bull. Korean Chem. Soc.
2008, 29, 1263–1265.
62. Zu, L.; Wang, J.; Li, H.; Xie, H.; Jiang, W.; Wang, W. Cascade Michael-Aldol Reactions Promoted by Hydrogen
Bonding Mediated Catalysis. J. Am. Chem. Soc. 2007, 129, 1036–1037. [CrossRef]
63. Konieczny, M.T.; Horowska, B.; Kunikowski, A.; Konopa, J.; Wierzba, K.; Yamada, Y.; Asao, T. Synthesis and
Reactivity of 5,8-Dihydroxythioflavanone Derivatives. J. Org. Chem. 1999, 64, 359–364. [CrossRef]
64. Kaye, P.T.; Mphahlele, M.J. Benzodiazepine Analogues. Part 8.1 Trimethylsilyl Azide Mediated Schmidt
Rearrangement of Thioflavanone and Thiochromanone Precursors. Synth. Commun. 1995, 25, 1495–1509.
[CrossRef]

Molecules 2020, 25, 2128
16 of 16
65. Bouisseau, A.; Glancy, J.; Willis, M.C. Two-Component Assembly of Thiochroman-4-ones and
Tetrahydrothiopyran-4-ones Using Rhodium-Catalyzed Alkyne Hydroacylation/Thio-Conjugate-Addition
Sequence. Org. Lett. 2016, 18, 5676–5679. [CrossRef]
66. Bass, S.A.; Parker, D.M.; Bellinger, T.J.; Eaton, A.S.; Dibble, A.S.; Koroma, K.L.; Sekyi, S.A.; Pollard, D.A.;
Guo, F. Development of Conjugate Addition of Lithium Dialkylcuprates to Thiochromones: Synthesis of
2-Alkylthiochroman-4-ones and Additional Synthetic Applications. Molecules 2018, 23, 1728. [CrossRef]
67. Guo, F.; Jeffries, M.C.; Graves, B.N.; Graham, S.A.; Pollard, D.A.; Pang, G.; Chen, H.Y. A Rapid Entry Into
Thioflavanones via Conjugate Additions of Diarylcuprates to Thiochromones. Tetrahedron 2017, 73, 5745–5750.
[CrossRef]
68. Dike, S.Y.; Mahalingam, M. Efficient and Improved Procedure for the Synthesis of 3-Chloro Derivatives of
Flavones, Chromones and their Sulfur Analogues. Synthetic Communications 1989, 19, 3443–3451. [CrossRef]
69. Sangeetha, S.; Sekar, G. Copper-Catalyzed One-pot Synthesis of 2-Arylthiochromenones: An in situ Recycle
of Waste Byproduct as Useful Reagent. Org. Lett. 2019, 21, 75–79. [CrossRef] [PubMed]
70. French, K.L.; Angel, A.J.; Williams, A.R.; Hurst, D.R.; Beam, C.F. A new preparation of substituted
4H-1-benzothiopyran-4-ones from c(
α)N-benzoylbydrazones or c(α)N-carboalkoxyhydrazones and methyl
thiosalicylate. J. Heterocycl. Chem. 1998, 35, 45–48. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
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