Cu-Catalyzed Conjugate Addition of Grignard Reagents to Thiochromones: An Enantioselective Pathway for Accessing 2-Alkylthiochromanones

Article abstract of DOI:10.1055/s-0037-1610225

The enantioselective incorporation of alkyl groups in thiochromones was realized for the first time by a Cu/(R, S)-PPF-P ^t Bu ₂ -catalyzed conjugate addition of Grignard reagents to thiochromones. With this method, a series of 2-methylthiochromanones were obtained in good yields (up to 96% yield) with moderate-to-good ee values (up to 87% ee). The established method expedites the synthesis of a large library of chiral thiochromanones for further synthetic applications and biological studies.

Full text of DOI:10.1055/s-0037-1610225

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–E
letter
A
en
S. Luo et al.
Letter
Synlett
Cu-Catalyzed Conjugate Addition of Grignard Reagents to Thio-
chromones: An Enantioselective Pathway for Accessing 2-Alkyl-
thiochromanones
Shihui Luoa
Ling Menga
Qingxiong Yang*b
Jun (Joelle) Wang*a
O
O
Cu(MeCN)4PF6
(R,S)-PPF-PtBu2
alkyl-MgBr
+
R
R
TMSI, –75 °C, DCM
*
S
S
alkyl
R = Me, MeO, F, Cl, Br, CF3
36–99% yield
9–87% ee
a Department of Chemistry, Southern University of Science and
Technology, Shenzhen 518055, P. R. of China
wang.j@sustc.edu.cn
b School of Karst Science, Guizhou Normal University/State En-
gineering Technology Institute for Karst Desertification Con-
trol, Guiyang 550001, P. R. of China
yangqx@gznu.edu.cn
Received: 17.05.2018
Accepted after revision: 02.07.2018
Published online: 02.08.2018
sis in human breast cancer cells.6 However, thiochroma-
nones, rarely found in nature, have not been studied as
thoroughly as chromanones, which are widely present in
many plants. Thus, the development of efficient synthetic
routes to access structurally diverse thiochromanones is
requisite for their further biological studies.
DOI: 10.1055/s-0037-1610225; Art ID: st-2018-w0312-l
Abstract The enantioselective incorporation of alkyl groups in
thiochromones was realized for the first time by a Cu/(R,S)-PPF-PtBu2-
catalyzed conjugate addition of Grignard reagents to thiochromones.
With this method, a series of 2-methylthiochromanones were obtained
in good yields (up to 96% yield) with moderate-to-good ee values (up to
87% ee). The established method expedites the synthesis of a large li-
brary of chiral thiochromanones for further synthetic applications and
biological studies.
O
O
O
O
R
S
R
S
R
R = alkyl, chromanone R = H or alkyl, thiochromanone R = H or alkyl, thiochromone
R = aryl, flavanone
R = aryl, thioflavanone
R = aryl, thioflavone
Key words asymmetric synthesis, Grignard reagents, conjugate addi-
tion, thiochromanones, flavonoids
O
O
O
F
N
Flavonoids are privileged structural motifs in many nat-
ural products and pharmaceutical molecules, which show
many biological activities such as antitumor, antioxidant,
antibacterial, and anti-inflammatory properties.1 Chroma-
nones, belonging to the subgroup of flavonoids, are import-
ant intermediates and interesting building blocks in organic
synthesis and the design of new lead compounds in drug
discovery.2 Thiochromanones, the sulfur analogues of chro-
manones, are as important as these heterocycles and exhib-
it plentiful bioactivities, such as antimicrobial, antioxidant,
inhibition of nitric oxide production, and antifungal.3 2-
Methyl thiochromanones, such as 7-methoxy-2-methyl
thiochromanone and 3-[(dimethylamino)methyl]-6-fluoro-
2-methyl thiochromanone, have shown strong antifungal
ability (Figure 1).4 A number of 2-alkenylthiochromanones
exhibit a considerable antimicrobial activity.5 Thiochroma-
nones have also been reported to significantly inhibit cellu-
lar proliferation with weak cytotoxicity and induce apopto-
O
S
Cl
S
S
antifungal
antifungal
antimicrobial
Figure 1 Representative structures of biologically active thiochroma-
nones
In recent years, there have been reported several effi-
cient routes to construct thiochromanones. Among them,
the intramolecular thio-Michael addition and related cas-
cade reactions are the most common methods to give
thiochromanones.7 The reaction of chiral (Z)-5-ylidene-1,3-
dioxan-4-one and 2-bromothiophenol, followed by bromo–
lithium exchange, provided optically active thiochroma-
nones.7e Intramolecular Friedel–Crafts acylation of thiopro-
panoic acid8 and hydrogenation of thiochromones9 also can
afford thiochromanones. In 2017, our group succeeded in
developing a copper-catalyzed asymmetric conjugated re-
duction of thiochromones to afford chiral thiochromanones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

B
S. Luo et al.
Letter
Synlett
in good yields and excellent ee values (Scheme 1, method a)
9c Actually, the transition-metal-catalyzed asymmetric 1,4-
On the basis of our previous experience, chiral bisphos-
phine ligands always have a better coordination with the
metal to overcome catalyst poisoning.9c,10b Trimethylsilyl
chloride (TMSCl) has been reported to activate the substrate
toward 1,4-addition (as a Lewis acid) and stabilize the
product (by forming a silyl enol ether).13 We embarked on
this investigation using thiochromone 1a and methyl
Grignard reagent 2a as model substrates. Firstly, we
screened different copper salts with ferrocene-based chiral
ligand (R,S)-PPF-PtBu2 (Table 1). In general, most Cu(I) and
Cu(II) salts gave the expected 2-methylthiochromanones in
moderate to good yields and ee values. Among them,
Cu(MeCN)4PF6 was superior to others both regarding the
product yield and enantioselectivity (Table 1, entry 7). Fur-
ther optimizations using Cu(MeCN)4PF6 in combination
with a series of chiral bisphosphine ligands were carried
out, and the results are presented in Scheme 2. The best
product enantioselectivity was still obtained by employing
(R,S)-PPF-PtBu2 as a chiral ligand.
.
addition of organometallic reagents to thiochromone is one
of the most convenient and efficient methods to obtain the
thiochromanone and thioflavanone compounds.10 Recently,
a conjugate addition of diarylcuprates to thiochromones
was reported to give thioflavanones in good yields.10a The
asymmetric conjugate addition to thiochromones was real-
ized by our group through rhodium-catalyzed addition of
arylzinc chlorides to thiochromones, which gave a direct
and general access to chiral thioflavanones in good yields
and excellent ee values (Scheme 1, method b).10b However,
only arylzinc reagents can be directly employed in this
transformation. Thus, the development of asymmetric con-
jugate addition of alkylmetal species to thiochromones,
which targets enantioenriched thiochrmanones, is still
highly needed. In 2005, Hoveyda reported a copper–peptide
complex for the catalytic enantioselective addition of dial-
kylzincs to chromone.11 More recently, Feringa found that
Grignard reagents undergo enantioselective additions to
chromone in the presence of a copper catalyst and Josi-
phos-based ligands.12 Both of these strategies enable the
addition of aliphatic groups to chromones with good yields
and high stereoselectivities. Inspired by their work, we
studied the conjugate addition of methyl Grignard reagent
to thiochromones, which is noted as a more challenging
substrate in metal-catalyzed transformations as the affinity
of sulfur with transition metals invariably makes the cata-
lytic reaction complicated.
Table 1 Effects of Copper Saltsa
O
O
PtBu2
Cu/L1 ligand
PPh2
+
MeMgBr
Fe
TMSCl, DCM
–75 °C, 15 h
S
S
1a
2a
L1
3aa
Entry
Copper salt
Yield (%)b
ee (%)c
1
CuCl
CuBr
CuI
64
64
68
31
52
49
73
57
60
62
48
48
42
49
64
82
79
79
72
69
72
82
83
82
75
58
63
78
80
82
2
(a) Copper-catalyzed asymmetric conjugated reduction of thiochromones
O
O
3
Cu(OAc)2, (R)-DM-Segphos
4
CuOAc
CuCN
DEMS, THF, rt to 60 °C
5
S
R'
S
R'
R
R
6
Cu(MeCN)4BF4
Cu(MeCN)4PF6
CuTc
74–87% yield
up to 97% ee
7
(b) Rh-catalyzed conjugate addition of arylzinc chlorides to thiochromones
8
O
O
9
CuOTf
[Rh(COD)Cl]2
(R)-3,4,5-MeO-BIPHEP
ArZnCl
10
11
12
13
14
15
CuBr·SMe2
CuBr2
TMSCl, THF, rt
*
S
S
Ar
R
R
57–91% yield
up to 97% ee
Cu(OTf)2
(CF3CO2)2Cu
Cu(acac)2
Cu(ClO4)2
(c) This work: Cu-catalyzed conjugate addition of Grignard reagents to thiochromones
O
O
Cu(MeCN)4PF6
(R,S)-PPF-PtBu2
R'MgBr
a Reaction conditions: Unless indicated otherwise, Cu (5 mol%) and L1 ligand
(6 mol%) in DCM (1.0 mL) were stirred at rt for 30 min under Ar. Then, the
reaction was cooled down to –75 °C, and 1a (0.1 mmol), 2a (0.125 mmol),
and TMSCl (0.03 mmol) were added, and the mixture was stirred at –75 °C
for 24 h. CuTc = copper(I)-thiophene-2-carboxylate.
b Isolated yields.
TMSI, DCM, –75 °C
*
S
R
S
R'
R
R' = alkyl
41–99% yield
up to 87% ee
Scheme 1 Asymmetric synthesis of thioflavanones and thiochroma-
c Determined by HPLC analysis.
nones
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

C
S. Luo et al.
Letter
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O
S
O
mined as follows: 5 mol% Cu(MeCN)4PF6 in combination
with 6 mol% (R,S)-PPF-PtBu2 in 4 mL CH2Cl2 at –75 °C, using
TMSI as an additive.
5 mol% Cu(MeCN)4PF6/ligand
TMSCl, DCM, –75 °C, 15 h
MeMgBr
+
S
1a
2a
3aa
Table 2 Optimization of Reaction Conditionsa
O
O
5 mol% Cu(MeCN)4PF6
6 mol% (R,S)-PPF-PtBu2
PPh2
PtBu2
PtBu2
PCy2
P
MeMgBr
+
PPh2
Fe
P
Fe
additive, solvent, –75 °C, 20 h
S
S
PCy2
Fe
2a
3aa
1a
L4
73% yield
82% ee
72% yield
61% ee
64% yield
0% ee
64% yield
0% ee
L1
L2
L3
Entry
Catalyst loading Solvent
(mol% Cu)
Additive
Yield
(%)b
ee (%)c
iPr
1
5
DCM
DCM
DCM
CHCl3
DCE
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCl
TMSCN
TMSOTf
TMSI
73
73
42
38
23
18
17
81
11
82
93
82
25
85
85
30
8
PAr2
N
N
P
P
tBu
2
2.5
10
5
PiPr2
PiPr2
FeH6
MeO
MeO
iPr
iPr
tBu
P
3
P
PCy2
4
iPr
82% yield
47% ee
Ar = 3,5-(CF3)2C6H3
62% yield
0% ee
5
5
L7
L8
69% yield
22% ee
49% yield
2% ee
L5
L6
6
5
C6H5Cl
MeOtBu
DCM
DCM
DCM
DCM
Scheme 2 Ligand screening. Reaction conditions: Unless indicated oth-
erwise, Cu(MeCN)4PF6 (5 mol %) and ligand (6 mol%) in DCM (1.0 mL)
were stirred at rt for 30 min under Ar. Then, the reaction was cooled
down to –75 °C. Compound 1a (0.1 mmol), 2a (0.125 mmol), and
TMSCl (0.03 mmol) were added, and the mixture was stirred at –75 °C
for 24 h. Isolated yields are given. Enantiomeric excess determined by
HPLC analysis
7
5
3
8d
9d
10d
11d
5
85
87
87
87
5
5
5
a Reaction conditions: Unless indicated otherwise, Cu(MeCN)4PF6 (5 mol%)
and L1 ligand (6 mol%) in solvent (1.0 mL) was stirred at rt for 30 min under
Ar. Then, the reaction was cooled down to –75 °C, and 1a (0.1 mmol), 2a
(0.125 mmol), and additive (0.03 mmol) were added at –75 °C, and the
mixture was stirred at –75 °C for 24 h.
Apart from screening of the catalyst complex, some oth-
er factors that may affect the reactivity and selectivity of
the reaction were investigated as well (Table 2). Firstly, we
tested the catalyst loading by halving or doubling the stan-
dard catalyst loading. When 2.5 mol% of catalyst was used,
the enantioselectivity decreased dramatically from 82 to
25% (Table 2, entry 2). The ee value was maintained by us-
ing 10 mol% catalyst. However, the yield was reduced from
73 to 42%, which resulted from the increasing amount of
by-product (Table 2, entry 3). Next, the solvents of the reac-
tion were screened. When CHCl3 was used as a solvent, the
enantiomeric excess was slightly improved but the yield
was decreased to 38% (Table 2, entry 4). Other solvents,
such as DCE, C6H5Cl, and MeOtBu did not offer any enhance-
ment of reactivity and stereoselectivity in this transforma-
tion (Table 2, entries 5–7). Then, we tried to slow down the
reactivity to increase the enantioselectivity by diluting the
system. An increased dilution with 4 mL of CH2Cl2 provided
product 3aa in higher yield and higher ee (Table 2, entry 8
versus 1). Finally, the additives were investigated. The anion
of the silane played an important role regarding the reac-
tion reactivity. The yield dropped to 11% when TMSCN was
used (Table 2, entry 9), while TMSOTf offered 82% yield
with a slightly higher enantioselectivity (Table 2, entry 10).
The best additive was TMSI, which provided the corre-
sponding product in 93% yield with 87% ee (Table 2, entry
11). Therefore, the optimal reaction conditions were deter-
b Isolated yields.
c Determined by HPLC analysis (OJ-3, hexane/2-propanol = 99.5:0.5,
1.0 mL/min).
d DCM (4.0 mL) was used instead.
With the optimized reaction conditions in hand, we fur-
ther examined the scope of substituted thiochromones
(Scheme 3). Most of the substrates with Me or MeO groups
reacted with methyl magnesium bromide smoothly and af-
forded the expected thiochromanones 3aa–ga in good to
moderate yields (59–99%) and enantioselectivities (72–
87%). The enantioselectivity was a bit decreased in reac-
tions with substrates containing F, Cl, or Br groups (3ha–la)
. When substrate 1m bearing a strong electron-withdraw-
ing group (CF3) was used under these conditions, only 38%
ee was obtained (3ma). Substrate 1n with extended aro-
matic structure gave 69% yield and 66% ee (3na). Both the
reactivity and enantioselectivity were significantly influ-
enced by the steric properties of the nucleophile. Unexpect-
edly, ethyl magnesium bromide, which was assumed to be a
better alkyl nucleophile in the asymmetric conjugate addi-
tion, gave 92% yield but only with 18% ee (3ab). Other much
bulkier groups gave worse ee values in this transformation.
Actually, methyl organometallic nucleophiles have always
been problematic in asymmetric conjugate additions of or-
ganometallic nucleophiles to electron-deficient ,-unsatu-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E

D
S. Luo et al.
Letter
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O
O
5 mol% Cu(MeCN)4PF6
6 mol% (R,S)-PPF-PtBu2
R
R
MeMgBr
+
TMSI, DCM, –75 °C
S
S
1a–p
2a–d
3aa–pa
O
O
S
O
S
O
O
O
S
O
S
MeO
S
S
S
3aa
3ba
19 h
3ca
18 h
3da
3ea
22 h
3fa
3ga
19 h
24 h
18 h
22 h
93% yield
87% ee
72% yield
85% ee
59% yield
78% ee
67% yield
83% ee
98% yield
83% ee
99% yield
72% ee
75% yield
80% ee
O
O
O
O
O
O
O
F
Cl
Br
F3C
S
S
F
S
S
S
S
S
F
3ha
3ia
3ja
3ka
3la
3ma
3na
24 h
61% yield
49% ee
22 h
96% yield
73% ee
39 h
61% yield
63% ee
24h
74% yield
58% ee
22 h
82% yield
66% ee
25 h
57% yield
38% ee
24 h
69% yield
66% ee
With use of other Grignard reagents:
O
O
O
S
O
O
S
S
nHex
S
S
nBu
3ab
22 h
3ac
24 h
3ad
18 h
3ae
18 h
3af
18 h
92% yield
18% ee
65% yield
1% ee
41% yield
9% ee
54% yield
11% ee
36% yield
14% ee
Scheme 3 Scope of thiochromones and Grignard reagents. Reaction conditions: Unless indicated otherwise, Cu(MeCN)4PF6 (5 mol%) and L1 ligand (6
mol%) in DCM (4.0 mL) were stirred at rt for 30 min under Ar. Then, the mixture was cooled down to –75 °C, and 1a–p (0.2 mmol), 2a–d (0.3 mmol),
and TMSI (0.06 mmol) were added. Isolated yields are given. Enantiomeric excess determined by HPLC analysis. See ref. 15
rated systems.14 Herein, we provide an alternative and effi-
cient method for the enantioselective incorporation of
methyl groups into thiochromones.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610225.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In conclusion, we have successfully developed the
Cu(MeCN)4PF6/(R,S)-PPF-PtBu2-catalyzed conjugate addition
of alkyl Grignard reagents to thiochromones, providing an
efficient access to a series of chiral 2-methylthiochroma-
nones in good yield (up to 96% yield) and relatively high en-
antioselectivity (up to 87% ee). Although there are some
limitations in this transformation, the method allows the
introduction of methyl groups to thiochromanones in an
asymmetric version which will unlock the opportunities of
the thiochromanone scaffold leading to more structural di-
versity in drug design and discovery.
References and Notes
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Funding Information
This work was supported by the Guangdong “Climbing” Program of
China (Project No. pdjh2017c0023) and National 13th Five-year Key
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Letter
Synlett
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An oven-dried vial fitted with a stirring bar was charged with
[Cu(MeCN)4]PF6 (3.73 mg, 5 mol%) and (R,S)-PPF-PtBu2 (6.51 mg,
6 mol%) in DCM (4.0 mL) and the mixture was stirred at rt for 30
min. Then, thiochromone 1a (0.20 mmol) was added and the
mixture was then stirred at –75 °C for another 10 min. MeMgBr
(0.30 mL, 0.30 mmol, 1.5 equiv; 1 M solution in THF) and iodo-
trimethylsilane (85 L, 0.6 mmol, 3.0 equiv) were simultane-
ously added dropwise to the vial and the resulting mixture was
stirred at –75 °C until the reaction was completed. The reaction
was quenched with HCl aq (10%) and the mixture was stirred
for 30 min at rt. Then, it was extracted with EtOAc and the
organic layer was collected and concentrated under vacuum.
The residue was purified by chromatography on silica gel
(EtOAc/n-pentane 1:80) to obtain the desired products.
6-Methoxy-2-methylthiochroman-4-one (3ba)
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25
Yellow liquid (29.8 mg, 72% yield). []D = –59.320 (c 1.00,
CH2Cl2). ee was determined to be 85% by HPLC analysis with a
Chiralcel OJ-3 column (hexane/2-propanol 99.5:0.5, 1.0
mL/min, 254 nm); tr (minor) = 36.8 min, tr (major) = 44.6 min.
1H NMR (400 MHz, CDCl3):  = 7.62 (d, J = 2.9 Hz, 1 H), 7.18 (d,
J = 8.7 Hz, 1 H), 7.03 (dd, J = 8.7, 2.9 Hz, 1 H), 3.84 (s, 3 H), 3.62
(dqd, J = 13.7, 6.8, 3.1 Hz, 1 H), 3.02 (dd, J = 16.6, 3.0 Hz, 1 H),
(4) (a) Goldfarb, D. S. US Patent 20090163545, 2014. (b) Guo, C.;
Fang, L.; Liu, Y.; Su, X.; Li, C.; Sun, L.; Luo, W.; Liang, L.; Huang, Y.
CN Patent 101434595B, 2014.
(5) Hoettecke, N.; Rotzoll, S.; Albrecht, U.; Lalk, M.; Fischer, C.;
Langer, P. Bioorg. Med. Chem. 2008, 16, 10319.
(6) Choi, E. J.; Lee, J. I.; Kim, G. H. Int. J. Mol. Med. 2012, 29, 252.
(7) (a) Sangeetha, S.; Muthupandi, P.; Sekar, G. Org. Lett. 2015, 17,
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Choudhary, R.; Paknia, F.; Mathew, T.; Olah, G. A. Org. Lett. 2015,
17, 6170. (d) Palani, T.; Park, K.; Song, K. H.; Lee, S. Adv. Synth.
Catal. 2013, 355, 1160. (e) Ali, A.; Ahmad, V. U.; Liebscher, J. Eur.
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(b) Cui, D-M.; Kawamura, M.; Shimada, S.; Hayashi, T.; Tanaka,
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(9) (a) Kumar, P.; Rao, A. T.; Pandey, B. Synth. Commun. 1994, 24,
3297. (b) Lemke, M. K.; Schwab, P.; Fischer, P.; Tischer, S.; Witt,
M.; Noehringer, L.; Rogachev, V.; Jäger, A.; Kataeva, O.; Fröhlich,
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6844.
2.76 (dd, J = 16.5, 11.6 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 3 H) ppm. 13
C
NMR (100 MHz, CDCl3):  = 194.69, 157.40, 133.23, 131.16,
128.79, 122.50, 111.15, 55.57, 48.00, 36.68, 20.37 ppm. HRMS
(ESI-ion trap): m/z: [M + H]+ calcd for C11H13O2S: 209.0631;
found: 209.0627.
6-fluoro-2-methylthiochroman-4-one (3ia)
Yellow liquid (38 mg, 96% yield). []D25 = –85.050 (c 1.00, CH2Cl2).
ee was determined to be 73% by HPLC analysis with a Chiralcel
OJ-3 column (hexane/2-propanol 97:3, 1.0 mL/min, 254 nm);
tr (minor) = 9.0 min, tr (major) = 9.8 min. 1H NMR (400 MHz,
CDCl3):  = 7.78 (dd, J = 9.3, 2.9 Hz, 1 H), 7.24 (dd, J = 8.7, 5.0 Hz,
1 H), 7.14 (ddd, J = 8.7, 7.8, 2.9 Hz, 1 H), 3.72–3.56 (m, 1 H), 3.02
(dd, J = 16.6, 3.0 Hz, 1 H), 2.75 (dd, J = 16.6, 11.6 Hz, 1 H), 1.44 (d,
J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):  = 193.82,
160.62 (d, J = 244 Hz), 137.10 (d, J = 3.0 Hz), 131.90 (d, J = 5.8
Hz), 129.39 (d, J = 6.9 Hz), 121.52 (d, J = 23 Hz), 115.13 (d, J = 22
Hz), 47.68, 36.76 20.44 ppm. HRMS (ESI-ion trap): m/z: [M + H]+
calcd for C10H10OFS: 197.0431; found: 197.0424.
(10) (a) Feng, H.; Jeffriesa, M.; Gravesa, B.; Grahama, S.; Pollarda, D.;
Pang, G.; Chen, H. Tetrahedron 2017, 73, 5745. (b) Meng, L.; Jin,
M. Y.; Wang, J. Org. Lett. 2016, 18, 4986.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E