A rapid entry into thioflavanones via conjugate additions of diarylcuprates to thiochromones

Article abstract of DOI:10.1016/j.tet.2017.08.012

Thiochromone undergo conjugate addition reactions with arylcuprates to afford 2-substituted thioflavanones, providing an efficient synthetic approach to privileged sulfur-containing structural motifs and valuable precursor for many pharmaceuticals. Excellent yields of substituted thioflavanones are achieved with lithium diarylcuprates, lithium arylcyanocuprates and Grignard reagents with copper catalysis. This method provides a rapid entry to a variety of thioflavanones in excellent yields (up to 92%). The use of commercially available or easily prepared organometallic reagents will expedite the synthesis of a large library of thioflavanones for further synthetic applications and biological studies.

Full text of DOI:10.1016/j.tet.2017.08.012

Accepted Manuscript
A rapid entry into thioflavanones via conjugate additions of diarylcuprates to
thiochromones
Fenghai Guo, Malcolm C. Jeffries, Briana N. Graves, Shekinah A. Graham, David A.
Pollard, Gehao Pang, Henry Y. Chen
PII:
S0040-4020(17)30832-3
10.1016/j.tet.2017.08.012
TET 28906
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 June 2017
Revised Date: 4 August 2017
Accepted Date: 9 August 2017
Please cite this article as: Guo F, Jeffries MC, Graves BN, Graham SA, Pollard DA, Pang G, Chen HY,
A rapid entry into thioflavanones via conjugate additions of diarylcuprates to thiochromones, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.08.012.
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A rapid entry into thioflavanones via conjugate
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a,b
a
a
a
a
a
Fenghai Guo *, Malcolm C. Jeffries , Briana N. Graves , Shekinah A. Graham , David A. Pollard , Gehao Pang ,
a
and Henry Y. Chen
a
b
Department of Chemistry
Biomedical Research Infrastructure Center, Winston Salem State University, Winston Salem, NC 27110, USA

1
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Tetrahedron
journal homepage: www.elsevier.com
A rapid entry into thioflavanones via conjugate additions of diarylcuprates to
thiochromones
a,b
a
a
a
a
Fenghai Guo *, Malcolm C. Jeffries , Briana N. Graves , Shekinah A. Graham , David A. Pollard , Gehao
a
a
Pang , and Henry Y. Chen
a
Department of Chemistry, Winston Salem State University, 601 S. Martin Luther King Jr. Dr., Winston Salem, NC 27110, USA
Biomedical Research Infrastructure Center, Winston Salem State University, Winston Salem, NC 27110, USA
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Thiochromone undergo conjugate addition reactions with arylcuprates to afford 2-substituted
thioflavanones, providing an efficient synthetic approach to privileged sulfur-containing
structural motifs and valuable precursor for many pharmaceuticals. Excellent yields of
substituted thioflavanones are achieved with lithium diarylcuprates, lithium arylcyanocuprates
and Grignard reagents with copper catalysis. This method provides a rapid entry to a variety of
thioflavanones in excellent yields (up to 92%). The use of commercially available or easily
prepared organometallic reagents will expedite the synthesis of a large library of thioflavanones
for further synthetic applications and biological studies.
Available online
Keywords:
Thioflavanones
Conjugate Addition
Organocuprates
Thiochromones
Organometallic
2
017 Elsevier Ltd. All rights reserved.
7
1c,d
1
. Introduction
production. Known as an important class of heterocycles,
thioflavanones are vital precursors of bioactive thiochhroman-4-
Sulfur-containing heterocycles/subunits are widely present in
4c,d,
8
one 1,1-dioxanes as well as benzothiazepins.
Unlike
many pharmaceutical active molecules and bioactive natural
products. There has been increasing interest in the development
of efficient synthetic approaches to sulfur-containing compounds
due to their widespread applications in medicinal chemistry,
biology, food chemistry and material science. Compared to the
oxygen-containing analog, the sulfur-containing compounds are
much less studied area. For example, flavonoids, especially
flavanones are important class of oxygen-containing heterocycles
and are widely present in numerous pharmaceutical active
molecules as well as bioactive natural products. Flavonoids and
substituted flavonoids have been well studied and found to
exhibit many biological activities including antioxidant,
flavanones, which are abundant in citrus fruits and widely present
in many plants in nature, thiofavanones are not found in nature.
Thus, development of efficient synthetic routes to structurally
diverse thioflavanones is critical in studying and improving their
bioavailability and bioactivity.
1
1,2
Scheme 1. Structures of Thiochromone, Thiochromanone,
Thioflavone, and Thioflavanones
3
antitumor, and anti-inflammatory properties. Thioflavonoids
(Scheme 1), the sulfur analogues of flavonoids, also display
many biological activities such as antimicrobial, antioxidant,
4
inhibiting nitric oxide production, and antifungal . For example,
thioflavanones have been reported to significantly inhibit cellular
proliferation with weak cytotoxicity and induce apoptosis in
Although many synthetic approaches to thiochroman-4-ones,
thioflavone and thiochromones have been reported in literature,
9
-
5
.6
11
human breast cancer cells.
It has been reported that
reports on efficient synthesis of thioflavanones are scarce.
Previous synthetic approaches to thioflavanones generally
revolve around four strategic approaches: (A) hydrogenation of
modification of the functional groups on aromatic ring of
thioflavanones resulted in the significantly increased antioxidant
activities and inhibitory activities against nitric oxide
12
thiochromones; (B) Friedel-Crafts acylation of thiopropanoic
1
3
14
acid; (C) intramolecular thio-Michael addition;
and more
addition to
alkyne
recently,
thiochromones.
(D)
Rh-catalyzed
A
conjugate
1
5
rhodium-catalyzed
*
Corresponding author
hydroacylation/thio-conjugate addition sequence in synthesis of
E-mail: guof@wssu.edu

2
Tetrahedron
thio-4-chromanones including thioflavanones has also been
Table 1. Optimization of 1,4-Conjugate Addition of
ACCEPTED MANUSCRIPT
16
reported recently. Among these approaches, methods A and B
are not particularly suitable for synthesis of 2-aryl substituted
thioflavanones. To the best of our knowledge, conjugate addition
of organocuprates to thiochromones has not been reported despite
the fact that conjugate addition reaction of organocuprates to
Michael-acceptors is one of the most reliable carbon carbon bond
forming strategies. We now report the first conjugate addition
of organocuprates to thiochromones 1 to afford 1,4-adducts
thioflavanones 2 in excellent yields (Figure 1).
Organocuprates to Thiochromone
17
c
Entries
PhM
Copper (I) salt/reagent
TMSCl
equiv)
Yield
(%)
(
1
2
3
4
5
6
7
8
9
PhLi
CuI (0.3 equiv)
PhCuCNLi
0
0
Figure 1. Conjugate Addition of Organocopper Reagents to
Thiochromones
PhLi
0
0
PhLi
Ph
2
CuLi
0
trace
70
PhLi
CuI (0.3 equiv)
CuI (0.3 equiv)
CuI (0.3 equiv)
CuI (1.5 equiv)
CuCN (0.3 equiv)
CuCN (0.3 equiv)
CuCN (1.5 equiv)
2.0
2.0
2.0
2.0
2.0
2.0
2.0
d
PhLi
75
e
PhLi
73
2
. Results and discussions
d
PhLi
77
We commenced our study with PhLi, copper (I) salt and
PhLi
69
thiochromone to optimize the reaction condition. When 0.3
equivalent of CuI was added as catalyst to effect 1,4-conjugate
addition of PhLi to thiochromone 3A in THF, no 1,4-adduct 4Aa
was formed (Table 1, entry 1, 0%). Cyanocuprate (i.e.,
PhCuCNLi) also fail to add to thiochromone with recovery of
unreacted thiochromone (Table 1, entry 2, 0%) under this
reaction condition. Under similar reaction condition, more
d
PhLi
72
1
1
1
0
1
2
PhLi
71
78
82
90
80
88
PhLi
CuCN•2LiCl (0.3 equiv) 2.0
PhLi
PhCuCNLi
2.0
2.0
2.0
2.0
13
PhLi
2
Ph CuLi
reactive Gilman reagents (i.e., Ph CuLi) offered only trace
2
1
4
PhMgBr
PhMgBr
PhCuCNMgBr
amount of 1,4-adduct 4Aa (Table 1, entry 3). These results
demonstrated that thiochromone are very sluggish towards the
addition of organocopper reagents.
15
2
Ph CuMgBr
a
Trimethylsilyl chloride (TMSCl) has been reported to
accelerate 1,4-conjugate additions of both stoichiometric cuprates
Reagents were prepared by adding PhLi or PhMgBr to CuCN or CuI. All the
reactions were performed in the presence of 2.0 equiv of TMSCl unless noted
otherwise.
18
and catalytic amount of copper (I) salts. It is generally thought
that TMSCl stabilized the Cu π-complex intermediate by
converting it to a reactive tetravalent copper species that is
b
PhLi and PhMgBr are commercially available.
c
Yields are based on isolated products by column chromatography.
d
Organocopper reagents were prepared at 0 °C, then cooled to – 78 °C.
18g
e
capable of a rapid reductive elimination to form 1,4-adduct.
The reaction was run at 0 °C.
We decided to investigate the effect of TMSCl on this reaction.
With the addition of TMSCl, the yield of desired 1,4-adduct 4Aa
can be increased to 70% (Table 1, entry 4). A slightly higher
yields can be achieved when the amount of CuI was increased to
With the optimal reaction condition in hand, we next examined
the scope of diarylcuprates (i.e., Ar CuLi or Ar CuMgBr)
conjugate addition to thiochromone 3A (Table 2, entries 1-14). In
general, a broad range of diarylcuprates underwent smooth
conjugate addition to thiochromone 3A to afford 1,4-adducts
2
2
1
.5 equivalent (Table 1, entry 7). Similarly, CuCN also promoted
conjugate addition of PhLi to thiochromone 3A in the presence of
TMSCl (Table 1, entries 8-10). The chemical yield of 1,4-adduct
4
Aa can be improved to 78% with 0.3 equiv of CuCN and
4
Aa-Am with good to excellent chemical yields (Table 2).
addition of LiCl as additive in the present of TMSCl (Table 1,
entry 11). With the addition of TMSCl, lithium cyanocuprate
reagent underwent smooth conjugate addition to thichromone 3A
with 82% yield (Table 1, entry 12). Lithium diphenylcuprate
gave the highest yield of 1,4-adduct 4Aa at 90% (Table 1, entry
Simple diarylcuprates such as diphenylcuprates and
dinaphthylcuprates add to 3A with excellent chemical yields
table 2, entries 1, 5). The diarylcuprates with electron donating
(
substituents on aromatic ring usually add to thiochromone
smoothly (table 2, entries 3, 4, 6, 7, 9, 10). The ortho-substituted
arylreagents gave lower yields presumably due to steric
hindrance (entries 2, 8). The diarylcuprate reagents with strong
electron withdrawing groups such as fluoro, trifluoromethyl,
bistrifluoromethyl groups on aryl ring also underwent conjugate
addition but with lower chemical yields (entries 11-13). The yield
of 1,4-adduct can be significantly improved when large excess of
diarylcuprates with strong electron withdrawing groups on aryl
ring was used. For example, with bistrifluoromethyl groups on
1
3) and it is consistent with the reactivity pattern that Gilman
reagents (Ph CuLi) are generally more reactive than the
2
cyanocuprate reagents (PhCuCNLi). Comparable chemical yields
of 4Aa can be achieved when the organocuprates are prepared
from the Grignard reagent PhMgBr (Table 1, entries 14, 15).
The control experiment showed that PhLi failed to afford any
1
,4-adduct 4Aa without any copper(I) salt in the presence of 2.0
equiv TMSCl in THF. With Cu(OTf) added (1.0 equiv), only
2
trace amount of 1,4-adduct 4Aa were attained (3%) as over 90%
starting material 3A was recovered.
phenyl
ring,
when
2.4
equivalent
of
di(3,5-
bistryfluoromethyl)phenylcuprate was used and the yield of 1,4-
adduct 4Am can be improved to 88% (Table 2, entry 14).

3
ACCEPTED MANUSCRIPT
Table 2. Reactions of Diarylcuprates with Thiochromone
c
Entries
Ar
M
equiv
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.4
Product Yield
1
2
3
4
5
6
7
8
9
C
6
H
5
Li
4Aa
4Ab
4Ac
4Ad
4Ae
4Af
90%
81%
88%
91%
86%
89%
92%
83%
86%
87%
65%
69%
76%
88%
2-MeC
4-MeC
6
6
H
4
4
Li
H
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
MgBr
4-PhC
2-Naphthyl
3,5-Me
6
H
4
2
C
6
H
3
4-MeOC
2-MeOC
6
6
H
4
4
4Ag
4Ah
4Ai
H
3-Me-4-MeOC
3-MeOC
4-FC
4-CF
3,5-(CF
3,5-(CF
6 3
H
1
1
1
1
1
0
1
2
3
4
6
H
4
4Aj
6
H
4
4Ak
4Al
3
6 4
C H
3
)
2
2
C
C
6
6
H
3
4Am
4Am
3
)
H
3
a
All reactions were performed using 1.2 equiv of Ar
.0 equiv of TMSCl unless noted otherwise. ArLi or ArMgBr are either
2
CuM in the presence of
b
2
commercially available or prepared from corresponding ArBr and used in situ
c
as a THF solution. Yields are based on isolated products by column
chromatography.
To explore the scope of thiochromones, a number of substituted
thiochromones 3B-H were also investigated. Diarylcuprates with
both electron-withdrawing and electron-donating substituents on
aryl ring were investigated (Scheme 2). Diphenylcuprates (i.e.,
Ph CuLi) add to substituted thiochromones 3B-H smoothly to
2
afford 1,4-adducts 4 with good yields (72-90%). With an
electron-donating group on the aromatic ring (4-MeO-), (4-
MeOPh) CuMgBr is more reactive than Ph CuLi or Ph CuMgBr
Conclusion
In conclusion, we have successfully developed the first
conjugate addition of diarylcuprates to thiochromone and
substituted
2
2
2
with all the substituted thiochromones investigated (Scheme 2,
6-89%). Diarylcuprates with strong electron-donating groups on
8
thiochromones
in
the
presence
of
aromatic ring are generally less reactive and gave slightly lower
yields (Scheme 2, 68-82%).
chlorotrimethylsilane (TMSCl). TMSCl showed remarkable
accelerating effects on 1,4-conjugate addition of diarylcuprates to
thiochromones. This reaction is compatible with a broad scope of
diarylcuprates with both electron-donating and electron-
withdrawing substituents on aromatic rings to afford a variety of
thioflavanones with excellent chemical yields. Further studies on
synthetic applications using these thioflavanones as key
intermediates are ongoing in our lab.
Scheme 2. Reactions of Diarylcuprates with Substitututed
Thiochromones
Experimental section
1
13
19
General Methods. The H, C, and F-NMR spectra were
recorded on a BRUKER Ascend
TM
400 NMR spectrometer,
1
13
operating at 400 MHz for H and 100 MHz for C and 376 MHz
19
for F. Some samples were recorded on a BRUKER 300 NMR
1
13
spectrometer, operating at 300 MHz for H and 75 MHz for
C
19
and 282 MHz for F. Samples for NMR spectra were dissolved

4
Tetrahedron
in deuterated chloroform (with TMS). Infrared (IR) spectra
purified by flash column chromatography (silica, 0-5% ethyl
ACCEPTED MANUSCRIPT
were recorded on a Nicolet iS10 FT-IR spectrometer as neat
samples (thin films). Analytical thin layer chromatography (TLC)
was performed on silica gel plates, 60 µ mesh with F254 indicator.
Visualization was accomplished by UV light (254 nm), and/or a
acetate in hexane, v/v) to give pure compounds.
General Procedure C: Conjugate addition reactions of aryl
Lithium with thiochromones in the presence of catalytic
amount of CuI. The reaction was run at about 0.12 M
concentration and was worked up after 18 hrs To a CuCN (0.30
equivalent) in THF (1.5 mL) under argon at 0 °C, was added aryl
lithium (1.2 equivalent). The resultant mixture was stirred for 30
mins at 0 °C and then cooled to a – 78 °C followed by addition of
thiochromone [0.5 mmol mixed with TMSCl (1.0 mmol) in THF
(2.0 mL)]. The reaction mixture was allowed to warm up to room
temperature during over night stirring. Then the reaction mixture
1
0% ethanol solution of phosphomolybdic acid and/or KMnO4
stain prepared by dissolving 1.5 g KMnO , 10 g potassium
carbonate, and 1.25 mL 10% sodium hydroxide in 200 mL water.
Flash chromatography was performed with 200–400 µ silica gel.
4
Materials. Unless stated otherwise, solvents and chemicals were
obtained from commercial sources and used without further
purification. Anhydrous tetrahydrofuran (THF) was purchased
from Sigma Aldrich. TMSCl was distilled from CaH under a
was quenched with saturated aqueous NH Cl (10.0 mL) and
2
4
positive N2 atmosphere. Phenyllithium was purchased from
Sigma Aldrich. Aryllithium reagents were prepared from the
corresponding arylhalides and t-BuLi (1.70 M in pentane) and
used in situ. t-BuLi (1.70 M in pentane) were commercially
available and titrated using 2,6-di-tert-butyl-4-methylphenol and
fluorene in THF. All glassware was flamed-dried under high
vacuum and purged with argon and then cooled under a dry
nitrogen atmosphere. Low temperature baths were prepared using
dry ice-isopropanol slush bath mixtures. All organocuprate 1,4-
conjugate addition reactions were conducted under a positive, dry
argon atmosphere in anhydrous solvents in flasks fitted with a
rubber septum.
extracted with ethyl acetate (3 × 10.0 mL). The combined organic
phase was washed with brine (15.0 mL), dried over anhydrous
Na SO , filtered, concentrated in vacuo, and purified by flash
column chromatography (silica, 0-5% ethyl acetate in hexane,
v/v) to give pure compounds.
2
4
General Procedure D: Conjugate addition reactions of phenyl
lithium to thiochromones in the presence of 0.3 equivalent of
2LiCl•CuCN and TMSCl. The reaction was run at about 0.12 M
concentration and was worked up after 18 hrs To a flame-dried
LiCl (12 mg, 0.3 mmol, 0.6 equivalent) under argon was added
CuCN (13 mg, 0.15 mmol, 0.3 equivalent) and THF (1.5 mL).
The resultant mixture was stirred for 10 mins at room
temperature and then cooled to a – 78 °C followed by addition of
phenyl lithium (0.6 mmol, 1.2 equivalent). The resultant solution
was stirred for additional 30 mins at – 78 °C under argon,
followed by addition of thiochromones [0.5 mmol mixed with
TMSCl (1.0 mmol) in THF (2.0 mL)] at – 78 °C. The reaction
mixture was allowed to warm up to room temperature during
over night stirring. Then the reaction mixture was quenched with
General Procedure A: Conjugate addition reactions of
lithium diarylcuprates or Magnesiumbromide diarylcuprates
(
Ar CuLi or Ar CuMgBr) with thiochromones. The reaction
2 2
was run at about 0.11 M concentration and was worked up after
8 hrs. To a flame-dried LiCl (51 mg, 1.2 mmol, 2.4 equivalent)
1
under argon was added CuCN (54 mg, 0.6 mmol, 1.2 equivalent)
and THF (1.5 mL).The resultant mixture was stirred for 10 mins
at room temperature and then cooled to a – 78 °C followed by
addition of aryl lithium or aryl magnesium bromide(1.2 mmol,
saturated aqueous NH Cl (10.0 mL) and extracted with ethyl
4
acetate (3 × 10.0 mL). The combined organic phase was washed
with brine (15.0 mL), dried over anhydrous Na SO , filtered,
2
3
.4 equivalent). The resultant solution was stirred for additional
0 mins at – 78 °C under argon, followed by addition of
2
4
concentrated in vacuo, and purified by flash column
chromatography (silica, 0-5% ethyl acetate in hexane, v/v) to
give pure compounds.
thiochromones [0.5 mmol mixed with TMSCl (1.0 mmol) in THF
2.0 mL)] at – 78 °C. The reaction mixture was allowed to warm
(
up to room temperature during over night stirring. Then the
HRMS data for compounds 4Ad, 4Ai, 4Am, 4Bg, 4Bk,
reaction mixture was quenched with saturated aqueous NH Cl
4
4
Bm, 4Cg, 4Cm, 4Em, and 4Fm were analyzed by TOF MS.
(10.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The
Compounds 4Aa–Ac, 4Ae-Ah, 4Aj-Am, 4Ba, 4Ca, 4Da, 4Ea,
combined organic phase was washed with brine (15.0 mL), dried
over anhydrous Na SO , filtered, concentrated in vacuo, and
4
Fa, 4Ga, and 4Ha have been fully characterized and
2
4
14d, 14g, 15, 16, 19
purified by flash column chromatography (silica, 0-5% ethyl
acetate in hexane, v/v) to give pure compounds.
reported.
2
-phenylthiochroman-4-one (4Aa): Employing General
General Procedure B: Conjugate addition reactions of
lithium arylcyanocuprates (ArCuCNLi) with thiochromones.
The reaction was run at about 0.12 M concentration and was
worked up after 18 hrs. To a flame-dried LiCl (51 mg, 1.2 mmol,
Procedure B, using PhLi (1.9 M, 0.32 mL, 0.6 mmol) and
thiochromone (81 mg, 0.5 mmol), after purification by flash
column chromatography (silica, 0-5% Ethyl acetate : hexanes,
v/v) gave light yellow solid 4Aa (98 mg, 82%): mp 55.9 – 56.2
°C; IR (neat) 3060 (w), 1674 (s), 1580 (s), 1489 (w), 1452 (m),
1431 (s), 1279 (s), 1237 (m), 1153 (w), 1082 (m), 752 (m), 706
2
1
.4 equivalent) under argon was added CuCN (53 mg, 0.6 mmol,
.2 equivalent) and THF (1.5 mL).The resultant mixture was
-
1
1
stirred for 10 mins at room temperature and then cooled to a – 78
C followed by addition of aryl lithium (0.6 mmol, 1.2
(m) cm ; H NMR (400 MHz, CDCl ) δ 3.14 (dd, J = 3.2,
3
°
16.4Hz, 1 H), 3.25 (dd, J = 13.2, 16.4Hz, 1 H), 4.66 (dd, J = 3.2,
13.2 Hz, 1 H), 7.14 (ddd, J = 1.2, 7.2, 8.0 Hz, 1H), 7.22 (dd, J =
0.8, 8.0 Hz, 1H), 7.24-7.38 (m, 6H), 8.08 (dd, J = 1.2, 8.0 Hz, 1
equivalent). The resultant solution was stirred for additional 30
mins at – 78 °C under argon, followed by addition of
thiochromone [0.5 mmol mixed with TMSCl (1.0 mmol) in THF
1
3
H); C NMR (100 MHz, CDCl
127.4, 128.5, 129.0, 129.3, 130.4, 133.7, 138.5, 142.1, 194.4; The
) δ 45.5, 46.7, 125.3, 127.3,
3
(2.0 mL)] at – 78 °C. The reaction mixture was allowed to warm
1
4d, 14g, 15
up to room temperature during over night stirring. Then the
data matches with literature.
reaction mixture was quenched with saturated aqueous NH Cl
4
(10.0 mL) and extracted with ethyl acetate (3 × 10.0 mL). The
2-(4-phenylbenzene)thiochroman-4-one (4Ad): Employing
General Procedure A, using 4-biphenylmagnesium bromide (1.0
M, 2.4 mL, 2.4 mmol) and thiochromone (162 mg, 1.0 mmol),
after purification by flash column chromatography (silica, 0-5%
combined organic phase was washed with brine (15.0 mL), dried
over anhydrous Na SO , filtered, concentrated in vacuo, and
2
4

5
Ethyl acetate : hexanes, v/v) gave light yellow solid 4Ad (287
mg, 91%): mp 117.6– 118.5 °C; IR (neat) 3031 (w), 2894 (w),
6-chloro-2-(4-fluorophenyl)thiochroman-4-one
(4Bk):
using 6-
ACCEPTED MANUSCRIPT
Employing
General
Procedure
A
and
1
1
679 (s), 1589 (w), 1486 (w), 1433 (w), 1281 (m), 1235 (w),
085 (w), 840 (w), 759 (m), 717 (m) cm ; H NMR (300 MHz,
chlorothiochromone (95 mg, 0.5 mmol) and 4-FPhMgBr (1.2 mL
of 1.0 M, 1.20 mmol), after purification by flash column
chromatography (silica, 0-5% Ethyl acetate : hexanes, v/v) gave
light yellow solid 4Bk (99 mg, 68%): mp 76.5 – 77.3 °C; IR
(neat) 3040 (w) 3045 (w), 2981 (w), 1677 (s), 1603 (w), 1577
(w), 1507 (s), 1451 (m), 1389 (m), 1271 (w), 1229 (m), 1159 (w),
-
1 1
CDCl ) δ 3.29 (dd, J = 3.6, 16.5 Hz, 1 H), 3.41 (dd, J = 12.6,
1
9
3
6.5 Hz, 1 H), 4.82 (dd, J = 3.3, 12.6 Hz, 1 H), 7.23-7.58 (m,
13
H), 7.61-7.69 (m, 3 H), 8.22 (dd, J = 1.5, 7.8 Hz, 1 H);
C
NMR (75 MHz, CDCl ) δ 45.2, 46.7, 125.3, 127.1, 127.3, 127.6,
3
-
1
1
1
1
3
27.7, 127.9, 128.9, 129.3, 130.5, 133.7, 137.4, 140.4, 141.5,
1094 (w), 898 (w), 862 (w), 820 (m), 792 (m) cm ; H NMR
+
42.1, 194.4; HRMS (EI-ion trap) m/z: [M] calcd for C H OS,
(300 MHz, CDCl ) δ 3.22 (dd, J = 3.9, 16.5 Hz, 1 H), 3.31 (dd, J
21
16
3
16.0922; found 316.0918.
= 12.0, 16.5 Hz, 1 H), 4.72 (dd, J = 4.2, 12.0 Hz, 1 H), 7.06-7.15
(
m, 2H), 7.26 (d, J = 8.7 Hz, 1 H), 7.37-7.47 (m, 3 H), 8.14 (d, J
13
2
-(3-methyl-4-methoxyphenyl)thiochroman-4-one
(4Ai):
= 2.4 Hz, 1 H); C NMR (75 MHz, CDCl ) δ 44.8, 46.4, 116.1
3
Employing General Procedure A and using thiochromone (162
mg, 1.0 mmol) and 3-Me-4-MeOPhMgBr (2.4 mL of 1.0 M, 2.40
mmol), after purification by flash column chromatography
(d, JC-F = 21.8 Hz), 128.6, 128.9, 129.2 (d, JC-F = 7.5 Hz), 131.4,
131.6, 133.7, 133.9 (d, J = 3.0 Hz), 140.1, 162.6 (d, JC-F = 247
C-F
19
Hz), 193.0; F NMR (282 MHz, CDCl ) δ - 112.7 (septet, J =
3
+
(silica, 0-5% Ethyl acetate : hexanes, v/v) gave light yellow solid
5.64 Hz); HRMS (EI-ion trap) m/z: [M] calcd for C H OSFCl,
15
10
4
Ai (243 mg, 85%): mp 67.3 – 68.1 °C; IR (neat) 3067 (w), 3004
292.0125; found 292.0123.
(
(
(
w), 2918 (w), 2839 (w0, 1671 (s), 1608 (m), 1581 (m), 1503
m), 1455 (w), 1435 (m), 1284 (m), 1254 (m), 1227 (m), 1132
6-Chloro-2-[3,5-(trifluoromethyl)phenyl]thiochroman-4-one
(4Bm): Employing General Procedure and using 6-
-
1
1
m), 1227 (m), 1132 (m), 1027 (m), 827 (m), 758 (m) cm ; H
A
NMR (300 MHz, CDCl ) δ 2.27 (s, 3H), 3.21 (dd, J = 3.3,
chlorothiochromone (70 mg, 0.36 mmol) and 3,5-
(trifluoromethyl)PhMgBr (3.46 mL of 0.5 M, 1.73 mmol), after
purification by flash column chromatography (silica, 0-5% Ethyl
acetate : hexanes, v/v) gave light yellow solid 4Bm (105 mg,
71%): mp 97.1 – 98.0 °C; IR (neat) 3090 (w), 2922 (m), 2851
(w), 1679 (s), 1582 (w), 1455 (w), 1378 (m), 1278 (s), 1169 (s),
1120 (s), 1053 (m), 938 (w), 901 (m), 846 (w), 823 (w), 704 (w),
3
1
6.5Hz, 1 H), 3.34 (dd, J = 13.2, 16.5 Hz, 1 H), 3.88 (s, 3H), 4.69
(dd, J = 3.0, 13.2 Hz, 1 H), 6.85 (d, J = 9.0 Hz, 1 H), 7.16-7.35
(
m, 4H), 7.45 (ddd, J = 1.5, 7.2, 7.8 Hz, 1H), 8.19 (dd, J = 1.5,
13
7
5
1
.8 Hz, 1 H); C NMR (75 MHz, CDCl ) δ 16.4, 45.1, 47.0,
3
5.4, 110.1, 125.1, 125.8, 127.2, 127.3, 129.2, 129.7, 129.9+,
30.4, 133.6, 142.5, 157.8, 194.8; HRMS (EI-ion trap) m/z: [M]
-
1
1
calcd for C H O S, 284.0871; found 284.0867.
682 (m) cm ; H NMR (400 MHz, CDCl ) δ 3.29 (dd, J = 3.6,
17
16
2
3
1
6.4 Hz, 1 H), 3.37 (dd, J = 12.0, 16.4 Hz, 1H), 4.86 (dd, J = 3.6,
2
-[3,5-(trifluoromethyl)phenyl]thiochroman-4-one
(4Am):
12.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.4, 8.4 Hz,
13
Employing General Procedure A and using thiochromone (162
mg, 1.0 mmol) and 3,5-(trifluoromethyl)PhMgBr (4.80 mL of 1.0
M, 4.80 mmol), after purification by flash column
chromatography (silica, 0-5% Ethyl acetate : hexanes, v/v) gave
light yellow solid 4Am (330 mg, 88%): mp 125 – 127 °C; IR
1H), 7.92 (s, 3H), 8.16 (d, J = 2.4 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 44.6, 45.7, 122.8 (p, J = 3.7 Hz), 122.9 (q, JC-F = 271
3
C-F
Hz, CF ), 127.8 (d, J = 12.5 Hz), 128.7, 129.1, 131.3, 132.2,
3
C-F
1
9
132.6 (q, JC-F = 34 Hz), 134.0, 138.8, 140.6, 191.7; F NMR
(376 MHz, CDCl ) δ - 62.9; HRMS (EI-ion trap) m/z: [M] calcd
+
3
(neat) 3056 (w), 2848 (w), 1677 (s), 1584 (w), 1438 (w), 1378
for C H OSF Cl, 409.9967; found 409.9962.
17
9
6
(
w), 1278 (s), 1174 (m), 1123 (s), 1054 (w), 939 (w), 901 (m),
-
1
1
7
3
4
1
8
64 (w), 744 (w), 681 (w) cm ; H NMR (400 MHz, CDCl ) δ
6-Bromo-2-(4-methoxyphenyl)thiochroman-4-one
Employing General Procedure and
(4Cg):
using 6-
3
.26 (dd, J = 3.2, 16.4 Hz, 1 H), 3.35 (dd, J = 12.4, 16.4 Hz, 1H),
.86 (dd, J = 3.2, 12.4 Hz, 1H), 7.23-7.34 (m, 2H), 7.47 (ddd, J =
.6, 7.2, 8.0 Hz, 1H), 7.90 (s, 1H), 7.93 (s, 2H), 8.17 (dd, J = 1.6,
A
bromothiochromone (73 mg, 0.3 mmol) and 4-MeOPhMgBr
(0.72 mL of 1.0M, 0.72 mmol), after purification by flash column
chromatography (silica, 0-5% Ethyl acetate : hexanes, v/v) gave
light yellow solid 4Cg (92 mg, 88%): mp 101.0– 102.1 °C; IR
(neat) 3052 (w), 2925 (w), 2831 (w), 1676 (s), 1609 (m), 1573
(m), 1509 (m), 1453 (w), 1417 (w), 1305 (w), 1248 (m), 1176
13
.0 Hz, 1H); C NMR (100 MHz, CDCl ) δ 44.6, 46.1, 122.5 (p,
3
JC-F = 4.0 Hz), 123.0 (q, JC-F = 272 Hz, CF ), 125.9, 127.5, 127.8
3
(
1
d, JC-F = 12 Hz), 129.4, 130.3, 132.4 (q, J = 34.0 Hz), 134.0,
C-F
19
40.5, 141.1, 192.8;
F NMR (376 MHz, CDCl ) δ - 62.9;
3
+
-1
1
HRMS (EI-ion trap) m/z: [M] calcd for C H OSF , 376.0356;
(w), 1111 (w), 1090 (w), 1022 (w), 832 (w), 820 (w) cm ; H
17
10
6
16
found 376.0360. The data matches with literature.
NMR (300 MHz, CDCl ) δ 3.18 (dd, J = 3.6, 16.5 Hz, 1 H), 3.28
3
(dd, J = 12.6, 16.5 Hz, 1 H), 3.82 (s, 3H), 4.67 (dd, J = 3.6, 12.6
6
-chloro-2-(4-methoxyphenyl)thiochroman-4-one
(4Bg):
using 6-
Hz, 1 H), 6.91 (dd, J = 1.8, 6.9 Hz, 1 H), 7.16 (d, J = 8.7 Hz, 1
H), 7.34 (dd, J = 1.8, 6.9 Hz, 1 H), 7.51 (dd, J = 2.4, 8.4 Hz, 1
Employing General Procedure and
A
13
chlorothiochromone (98 mg, 0.5 mol) and 4-MeOPhMgBr (2.4
mL of 1.0 M, 2.40 mmol), after purification by flash column
chromatography (silica, 0-5% Ethyl acetate : hexanes, v/v) gave
light yellow solid 4Bg (131 mg, 86%): mp 95.5 – 96.7 °C; IR
H), 8.26 (d, J = 2.4 Hz, 1 H); C NMR (75 MHz, CDCl ) δ 44.9,
3
46.5, 55.4, 114.4, 118.9, 128.6, 128.8, 130.0, 131.7, 131.8, 136.4,
+
141.2, 159.7, 193.3; HRMS (EI-ion trap) m/z: [M] calcd for
C H O SBr, 347.9820; found 347.9818.
16
13
2
(
(
(
neat) 3057 (w), 2951 (w), 2924 (w), 2832 (w), 1676 (s), 1608
m), 1580 (m), 1509 (m), 1450 (m), 1418 (w), 1297 (w), 1249
m), 1177 (w), 1093 (w), 1023 (m), 889 (w), 820 (m), 779 (w)
6-Bromo-2-[3,5-(trifluoromethyl)phenyl]thiochroman-4-one
(4Cm): Employing General Procedure and using 6-
A
-
1 1
cm ; H NMR (300 MHz, CDCl ) δ 3.22 (dd, J = 3.6, 16.5 Hz, 1
H), 3.32 (dd, J = 12.3, 16.5 Hz, 1 H), 3.86 (s, 3H), 4.70 (dd, J =
3
7
CDCl ) δ 45.0, 46.5, 55.4, 114.0, 128.6, 128.6, 128.8, 130.0,
1
m/z: [M] calcd for C H O SCl, 304.0325; found 304.0328.
bromothiochromone (100 mg, 0.41 mmol) and 3,5-
(trifluoromethyl)PhMgBr (1.96 mL of 0.5 M, 0.98 mmol), after
purification by flash column chromatography (silica, 0-5% Ethyl
acetate : hexanes, v/v) gave light yellow solid 4Cm (165 mg,
82%): mp 101.2 – 102.5 °C; IR (neat) 3079 (w), 2923 (w), 2853
(w), 1679 (s), 1572 (w), 1454 (w), 1379 (m), 1343 (w), 1276 (s),
1227 (m), 1166 (s), 1121 (s), 1110 (s), 1048 (w), 914 (w), 845
3
.6, 12.6 Hz, 1 H), 6.91-6.98 (m, 2H), 7.26 (d, J = 8.7 Hz, 1 H),
13
.33-7.43 (m, 3 H), 8.14 (d, J = 2.4 Hz, 1 H); C NMR (75 MHz,
3
31.4, 131.5, 133.6, 140.6, 160.0, 193.5; HRMS (EI-ion trap)
+
16
13
2
-
1
1
(
w), 702 (w) 683 (m) cm ; H NMR (300 MHz, CDCl ) δ 3.17
3

6
Tetrahedron
ACCEPTED MANUSCRIPT
(
dd, J = 4.2, 16.5 Hz, 1 H), 3.26 (dd, J = 11.7, 16.5 Hz, 1H),
3.
(a) Harborne, J. B., Ed. The Flavonoids: Advances in Research
Since 1980; Chapman and Hall: New York, 1988. (b) Harborne, J.
B.; Williams, C. A. Nat. Prod. Rep. 1995, 12, 639-657. (c) Le
Bail, J. C.; Varnat, F.; Nicolas, J. C.; Habrioux, G. Cancer Lett.
1998, 130, 209-216. (d) Bracke, M. E.; Depypere, H. T.;
Boterberg, T.; Van Marck, V. L.; Vennekens, K. M.; Vanluchene,
E.; Nuytinck, M.; Serreyn, R.; Mareel, M. M. J. Natl. Cancer Inst.
4
.75 (dd, J = 3.9, 12.0 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 7.49
dd, J = 2.1, 8.4 Hz, 1H), 7.82 (s, 3H), 8.19 (d, J = 2.1 Hz, 1H);
3
(
1
=
3
C NMR (75 MHz, CDCl ) δ 44.5, 45.7, 119.8, 122.8 (p, JC-F
3
1
1
.8 Hz), 123.0 (q, JC-F = 271 Hz, CF ), 127.8 (d, J = 3.85 Hz),
28.8, 131.5, 132.1, 132.6 (q, J = 33.8Hz), 136.8, 139.4, 140.6,
91.6; F NMR (282 MHz, CDCl ) δ - 62.9; HRMS (EI-ion
3
C-F
C-F
19
1
999, 91, 354-359. (e) Pietta, P. G. J. Nat. Prod. 2000, 63, 1035-
3
+
1042. (f) Chang, L. C.; Kinghorn, A. D. In Bioactive Compounds
from Natural Sources: Isolation, Characterisation and Biological
Properties; Tringali, C., Ed.; Taylor & Francis: London, 2001. (g)
Flavonoids: Chemistry, Biochemistry and Applications; Andersen,
Ø. M., Markham, K. R., Eds.; Taylor & Francis: London, 2006.
(a) Schneller, S. W. Thiochromanones and Related Compounds. In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Boulton,
A. J., Eds.; Academic Press: New York, 1975; Vol. 18. (b)
Ramalingam, K.; Thyvelikakath, G. X.; Berlin, K. D.; Chesnut, R.
W.; Brown, R. A.; Durham, N. N.; Ealick, S. E.; Van der Helm, D.
J. Med. Chem. 1977, 20, 847-850. (c) Philipp, A.; Jirkovsky, I.;
Martel, R. R. J. Med. Chem. 1980, 23, 1372-1376. (d) Holshouser,
M. H.; Loeffler, L. J.; Hall, I. H. J. Med. Chem. 1981, 24,
trap) m/z: [M] calcd for C H OSF Br, 453.9462; found
17
9
6
4
53.9459.
6
-Methyl-2-[3,5-(trifluoromethyl)phenyl]thiochroman-4-one
and using 6-
methylthiochromone (95 mg, 0.5 mmol) and 3,5-
trifluoromethyl)PhMgBr (4.80 mL of 0.5 M, 2.40 mmol), after
4
.
(4Em): Employing General Procedure A
(
purification by flash column chromatography (silica, 0-5% Ethyl
acetate : hexanes, v/v) gave light yellow solid 4Em (163 mg,
8
4%): mp 106.1 – 107.2 °C; IR (neat) 3040 (w), 2956 (m), 2928
(m), 2870 (w), 1676 (s), 1600 (w), 1464 (w), 1376 (s), 1349 (w),
8
53−858. (e) Wang, H. K.; Bastow, K. F.; Cosentino, L. M.; Lee,
1
8
2
1
1
2
275 (s), 1239 (w), 1166 (s), 1123 (s), 939 (w), 900 (m), 845 (w),
17 (w), 703 (m), 680 (m) cm ; H NMR (400 MHz, CDCl ) δ
.29 (s, 3H), 3.16 (dd, J = 3.6, 16.4 Hz, 1 H), 3.25 (dd, J = 12.4,
6.4 Hz, 1H), 4.73 (dd, J = 3.2, 12.4 Hz, 1H), 7.12 (d, J = 8.0 Hz,
H), 7.21 (ddd, J = 0.4, 2.0, 8.0 Hz, 1 H), 7.79 (s, 1H), 7.82 (s,
K. H. J. Med. Chem. 1996, 39, 1975-1980. (f) 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.; West, A.
Bioorg. Med. Chem. Lett. 1998, 8, 3677-3682. (g) Nussbaumer, P.;
Lehr, P.; Billich, A. J. Med. Chem. 2002, 45, 4310-4320. (h) Soni,
D. V.; Jacobberger, J. W. Cell Cycle 2004, 3, 349-357. (i)
Kataoka, T.; Watanabe, S.; Mori, E.; Kadomoto, R.; Tanimura, S.;
Kohno, M. Bioorg. Med. Chem. 2004, 12, 2397−2407. (j)
Bondock, S.; Metwally, M. A. J. Sulfur Chem. 2008, 29, 623−653.
-
1 1
3
13
H), 7.90 (dd, J = 0.4, 1.6 Hz, 1H); C NMR (100 MHz, CDCl3)
δ 20.8, 44.6, 46.2, 122.5 (p, JC-F = 4.0 Hz), 123.0 (q, JC-F = 271
Hz, CF ), 127.2, 127.8 (d, J = 2.6 Hz), 129.5, 130.1, 132.4 (q,
JC-F = 32.0 Hz), 135.2, 135.9, 137.1, 141.2, 193.1; F NMR (376
MHz, CDCl ) δ - 62.9; HRMS (EI-ion trap) m/z: [M] calcd for
C H OSF , 390.0513; found 390.0518.
3
C-F
19
5. Choi, E. J.; Lee, J. I.; Kim, G. H. Int. J. Mol. Med. 2012, 29,
52−256.
6
+
2
3
.
Song, Y.-L.; Wu, F.; Zhang, C.-C.; Liang, G.-C.; Zhou, G.; Yu, J.-
J. Bioorg. Med. Chem. Lett. 2015, 25, 259−261.
1
8
12
6
7
8
.
.
Lee, J. I.; Lee, J.-H. Food Sci. Biotechnol. 2014, 23, 957-963.
(a) Dike, S. Y.; Ner, D. H.; Kumar, A. Bioorg. Med. Chem. Lett.
1991, 1, 383−386. (b) Bates, D. K.; Li, K. J. Org. Chem. 2002, 67,
8662−8665. (c) Aramaki, Y.; Seto, M.; Okawa, T.; Oda, T.;
Kanzaki, N.; Shiraishi, M. Chem. Pharm. Bull. 2004, 52,
6
,7-dimethyl-2-[3,5-(trifluoromethyl)phenyl]thiochroman-4-
one (4Fm): Employing General Procedure A and using 6,7-
dimethylthiochromone (95 mg, 0.5 mmol) and 3,5-
(trifluoromethyl)PhMgBr (4.80 mL of 0.5 M, 2.40 mmol), after
2
54−258. (d) Phippen, C. B. W.; McErlean, C. S. P. Tetrahedron
purification by flash column chromatography (silica, 0-5% Ethyl
acetate : hexanes, v/v) gave light yellow solid 4Fm (165 mg,
8
Lett. 2011, 52, 1490−1492. (e) Fang, X.; Li, J.; Wang, C. J. Org.
Lett. 2013, 15, 3448−3451. (f) Fukata, Y.; Asano, K.; Matsubara,
S. J. Am. Chem. Soc. 2015, 137, 5320−5323. (g) Li, W.;
2%): mp 111.5-112.6 °C; IR (neat) 3035 (w), 2954 (m) 2923
(
m), 2854 (m), 1672 (s), 1599 (s), 1474 (m), 1463 (m), 1337 (w),
Schlepphorst, C.; Daniliuc, C.; Glorius, F. Angew. Chem., Int. Ed.
2
016, 55, 3300−3303.
9. (a) Ali, A.; Ahmad, V. U.; Liebscher, J. Eur. J. Org. Chem. 2001,
001, 529−535. (b) Cui, D.-M.; Kawamura, M.; Shimada, S.;
1
7
3
1
7
275 (s), 1169 (s), 1123 (s), 1050 (w), 938 (w), 899 (s), 861 (w)
-
1
1
02 (m), 682 (m) cm ; H NMR (300 MHz, CDCl ) δ 2.19 (s,
3
2
H), 2.20 (s, 1H), 3.11 (dd, J = 3.6, 16.5 Hz, 1 H), 3.22 (dd, J =
2.0, 16.5 Hz, 1H), 4.71 (dd, J = 3.6, 12.0 Hz, 1H), 6.98 (s, 1H),
Hayashi, T.; Tanaka, M. Tetrahedron Lett. 2003, 44, 4007−4010.
(c) Hoettecke, N.; Rotzoll, S.; Albrecht, U.; Lalk, M.; Fischer, C.;
Langer, P. Bioorg. Med. Chem. 2008, 16, 10319−10325. (d) Dong,
X. Q.; Fang, X.; Wang, C. J. Org. Lett. 2011, 13, 4426−4429. (e)
Vaghoo, H.; Prakash, G. K.; Narayanan, A.; Choudhary, R.;
Paknia, F.; Mathew, T.; Olah, G. A. Org. Lett. 2015, 17,
13
.78 (s, 1H), 7.81 (s, 2H), 7.84 (s, 1H); C NMR (75 MHz,
CDCl ) δ 19.3, 20.1, 44.7, 46.1, 122.4 (p, J = 3.8 Hz), 123.0 (q,
JC-F = 271 Hz, CF ), 127.8 (d, J = 3.8 Hz), 128.2, 128.5, 130.0,
1
3
C-F
3
C-F
19
32.4 (q, JC-F = 33.8 Hz), 135.0, 137.4, 141.4, 144.5, 192.9;
F
6
170−6173. (f) Qi, X.; Xiang, H.; Yang, C. Org. Lett. 2015, 17,
+
NMR (282 MHz, CDCl ) δ - 62.9; HRMS (EI-ion trap) m/z: [M]
3
5590−5593.
calcd for C H OSF , 404.0669; found 404.0666.
10. (a) Taylor, A. W.; Dean, D. K. Tetrahedron Lett. 1988, 29,
19
14
6
1
1
9
845−1848. (b) Beifuss, U.; Tietze, M.; Gehm, H. Synlett 1996,
82−184. (c) Xiao, W.-J.; Alper, H. J. Org. Chem. 1999, 64,
646−9652. (d) Dawood, K. M.; Ishii, H.; Fuchigami, T. J. Org.
References and notes
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1
2
.
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1
493.

7
1
1
3. Kaye, P. T.; Mphahlele, M. J. Synth. Commun. 1995, 25,
18. (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-
ACCEPTED MANUSCRIPT
1
495−1509.
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