Efficient Synthesis of Chromenes from Vinyl o -Quinone Methides via a Bronsted Acid Catalyzed Electrocyclization Process

Article abstract of DOI:10.1055/s-0037-1609483

An efficient approach for the synthesis of chromene derivatives from vinyl o -quinone methides was established via a Bronsted acid catalyzed electrocyclization. By using this methodology, a series of structurally diversified chromenes was synthesized in a highly atom-economic and environmentally benign manner with generally good to excellent yields (up to 98% yield). This reaction will not only provide an efficient method for the construction of chromene scaffolds, but also enrich the research area of o -quinone methides.

Full text of DOI:10.1055/s-0037-1609483

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
S.-J. Liu et al.
Paper
Synthesis
Efficient Synthesis of Chromenes from Vinyl o-Quinone Methides
via a Brønsted Acid Catalyzed Electrocyclization Process
Si-Jia Liu1
R
O
O
R1
B-H
Xiao-Li Jiang1
Shu-Fang Wu
Man-Su Tu*
R
R
electrocyclization
18 examples
R
up to 98% yield
Guang-Jian Mei*
R1
Feng Shi*
0
0
0
0
0-
0
0
3
3-
9
2
2
0-
7
0
8
School of Chemistry and Materials Science, and the Key Laboratory of
Biotechnology for Medicinal Plants of Jiangsu Province, Jiangsu Normal
University, Xuzhou, 221116, P. R. of China
fshi@jsnu.edu.cn
guangjianM@jsnu.edu.cn
mstu2016@126.com
Received: 31.01.2018
Accepted after revision: 17.03.2018
Published online: 25.04.2018
OH
HO
OMe
Me
O
DOI: 10.1055/s-0037-1609483; Art ID: ss-2018-h0061-op
OMe
OH
O
NH
Cl
Abstract An efficient approach for the synthesis of chromene deriva-
tives from vinyl o-quinone methides was established via a Brønsted acid
catalyzed electrocyclization. By using this methodology, a series of
structurally diversified chromenes was synthesized in a highly atom-
economic and environmentally benign manner with generally good to
excellent yields (up to 98% yield). This reaction will not only provide an
efficient method for the construction of chromene scaffolds, but also
enrich the research area of o-quinone methides.
O
candenatenin E (I)
acolbifene (II)
NH2
N
OMe
OMe
MeO
O
O
N
Key words o-quinone methide, electrocyclization, Brønsted acid ca-
N
OMe
anti-inflammatory (III)
talysis, chromenes, heterocycles
tyrosine kinase
inhibitor (IV)
Chromenes make up a class of structurally important
heterocycles owing to their intrinsic properties and wide
applications in physical chemistry, medicinal chemistry,
and polymer science.2 In addition, compounds containing
chromene skeletons have been reported to display a wide
range of biological activities (Figure 1). For instance, the
natural product candenatenin E (I) exhibits potent cancer
cell cytotoxicity3 and acolbifene (II) shows antitumor ef-
fects and is a promising candidate for breast cancer treat-
ment.4 In addition, synthetic compound III processes anti-
inflammatory activity, and could be employed as a TNF-α
inhibitor.5 Compound IV is a tyrosine kinase inhibitor and
could be utilized in the treatment of proliferative diseases.6
In this context, the efficient synthesis of chromenes has
drawn continuous interest from the chemistry community.7
For the synthesis of chromenes, substantial efforts have
focused on different metal-catalyzed/mediated methodolo-
gies, where harsh conditions, expensive or toxic metal cata-
lysts, and external oxidants are often needed.8 On the other
hand, Brønsted acid catalysis is considered as one of the
most important and powerful strategies in organic chemis-
try for the synthesis of compounds by avoiding metal con-
HO
Figure 1 Bioactive compounds containing the chromene skeleton
tamination.9 Moreover, Brønsted acid catalysis is usually re-
garded as highly atom-economic and environmentally be-
nign. Consequently, it is highly desirable to utilize the
strategy of Brønsted acid catalysis in the development of new
methodologies for the synthesis of chromene derivatives.10
o-Quinone methides (o-QMs) have proven to be versa-
tile synthons for the synthesis of oxygen-containing hetero-
cycles.11 o-QM-involved reactions, such as 1,4-conjugate
additions,12 [4+1] annulations,13 [4+2] annulations,10b,c,14
and [4+3] annulations15 have been well-developed in recent
years. In particular, vinyl o-quinone methides (o-VQMs)
have emerged as a class of stable o-QMs and have been
widely applied in organic synthesis.12b,13a,b,15b,16 Our group
has a long-term program on the use of o-QMs or o-VQMs in
reactions.10c,13a,14c,15c In our previous work, a series of chiral
spirooxindole-based 2,3-dihydrobenzofuran scaffolds were
constructed with excellent enantioselectivities via a cata-
lytic asymmetric [4+1] cyclization of o-VQMs with 3-chlo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
S.-J. Liu et al.
Paper
Synthesis
a) Our previous work
O
Cl
O
O
O
O
O
O
NH
organocatalyst
[4+1] cyclization
+
O
R
R
N
H
Ar
Ar
b) This work
H
O
B
O
R
Brønsted
acid
R1
R1
O
R
R
R
R
R
chromenes
R1
electrocyclization
o-VQMs
Scheme 1 Discovery of electrocyclization of o-VQMs
rooxindoles (Scheme 1, a).13a During our investigations on
transformations involving o-VQMs, an electrocyclization17
phenomenon was often observed (Scheme 1, b) in the pres-
ence of a Brønsted acid (B-H). In this transformation, struc-
turally diversified chromenes with potential bioactivities
could be synthesized in a highly atom-economic and envi-
ronmentally benign manner with generally good to excel-
lent yields under mild conditions. Herein, we report the de-
tails of this efficient synthesis of chromenes from o-VQMs
via a Brønsted acid catalyzed electrocyclization process.
Our investigation started with reaction condition opti-
mization for the model reaction of o-VQM 1a (Table 1). First,
we found that this electrocyclization reaction could be car-
ried out at 50 °C in acetonitrile without any catalysts, af-
fording chromene product 3a in a poor yield (entry 1).
Then, a series of Brønsted acids were screened to find the
best catalyst (entries 2–9). To our delight, Brønsted acid 3a
could improve the yield significantly (entry 2). However,
Brønsted acids 3b–e failed to give an obvious increase in the
yield (entries 3–6). Notably, by using Brønsted acids 3f–h,
chromene product 3a could be obtained in good to excel-
lent yields (entries 7–9). Among them, Brønsted acid 3h,
benzene-1,3,5-tricarboxylic acid, was selected as the best
catalyst in terms of the yield (entry 9). In addition, several
representative solvents were evaluated (entries 10–14),
which revealed that none of them was better than acetoni-
trile in terms of the yield (entries 10–14 vs 9). Therefore,
the best conditions were those shown in entry 9, which
could offer product 2a in an excellent yield of 98%.
groups (entries 1–5). In contrast, o-VQM 1f bearing an elec-
tron-rich aromatic group afforded product 2f in a decreased
yield (entry 6 vs entries 1–5). In addition, the R1 group of
Table 1 Optimization of Reaction Conditionsa
CF3SO3H
TsOH
CH3CO2H
CF3CO2H
HBr
3c
3d
3b
3e
3a
HO2C
CO2H
CO2H
HO2C
CO2H
CO2H
3g
3f
3h
O
O
O
O
Ph
O
O
3 (10 mol%)
solvent, 50 °C
2a
1a
Ph
Entry
Cat.
Solvent
Yield (%)b
1
2
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
30
83
41
29
43
45
83
94
98
92
63
91
82
90
3a
3b
3c
3d
3e
3f
3
4
5
6
7
8
3g
3h
3h
3h
3h
3h
3h
With the optimal conditions in hand, we investigated
the substrate scope of this Brønsted acid catalyzed electro-
cyclization reaction of o-VQMs. As shown in Table 2, this re-
action is applicable to a variety of sesamol-derived o-VQMs
1 bearing various R and R1 groups, providing chromene
products 2 in generally good to excellent yields (73–98%). In
detail, it seemed that the electronic nature of the substitu-
ents had some influence on the yield. For example, excel-
lent yields could be obtained from o-VQMs 1a–e substitut-
ed with electron-withdrawing or electron-neutral aromatic
9
10
11
12
13
14
ClCH2CH2Cl
dioxane
THF
CHCl3
toluene
a Reaction conditions: 1a (0.1 mmol), cat. 3 (10 mol%), solvent (2 mL),
50 °C, 12 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
S.-J. Liu et al.
Paper
Synthesis
the o-VQM could be changed from a phenyl group to a
2-thienyl group, to generate the corresponding product 2g
in good yield (entry 7). It is worth noting that dimethyl-
substituted o-VQM 1h also proved to be a suitable substrate
for this electrocyclization reaction, with chromene product
2h formed in a good yield of 86% (entry 8).
Moreover, other phenol-derived o-VQMs could also be
employed as suitable substrates for this Brønsted acid cata-
lyzed electrocyclization reaction. As shown in Table 3, a se-
ries of 3,4-dimethoxyphenol-derived o-VQMs 4 was suc-
cessfully utilized in this reaction, affording structurally di-
versified chromene products 5 in generally good yields (65–
93%). The structures of all products 2 and 5 were unambig-
uously assigned by 1H and 13C NMR and IR spectroscopy and
HRMS.
In addition, this Brønsted acid catalyzed electrocycliza-
tion reaction of o-VQM 4a could be carried out on 0.5 mmol
scale to provide 5a an excellent yield of 91% under the stan-
dard reaction conditions (Scheme 2), a similar yield to that
of the smaller-scale reaction (Table 3, entry 1). Thus, this
preliminary result indicates that this approach could be
scaled up and has potential in the synthesis of biologically
important chromene motifs.
Table 2 Substrate Scope of o-VQMs 1a
O
O
O
R
O
O
O
R1
3h (10 mol%)
CH3CN, 50 °C
R
2
1
R1
Entry
1/2
R
R1
C6H5
Yield (%)b
1
2
3
4
5
6
7
8
a
b
c
H
98
94
98
96
93
73
74
86
H
2-FC6H4
3-ClC6H4
4-MeC6H4
4-ClC6H4
4-MeOC6H4
2-thienyl
Me
O
MeO
MeO
MeO
O
Ph
H
3h (10 mol%)
MeO
d
e
f
H
CH3CN, 50 °C
H
5a
129 mg (91%)
4a
0.5 mmol
Ph
H
g
h
H
Scheme 2 Larger-scale synthesis of product 5a
Me
a Reaction conditions: 1 (0.1 mmol), 3h (10 mol%), CH3CN (2 mL), 50 °C,
Table 4 Preliminary Investigation of a Catalytic Asymmetric Version of
the Electrocyclization of Substrate 1aa
12 h.
b Isolated yield.
R
6a, R = 4-ClC6H4
6b, R = 1-naphthyl
6c, R = 2-naphthyl
6d, R = 9-anthracenyl
6e, R = 9-phenanthrenyl
6f, R = 2,4,6-(i-Pr)3C6H2
6g, R = SiPh3
Table 3 Further Substrate Scope Expansiona
O
O
O
P
OH
O
MeO
R
O
MeO
R1
3h (10 mol%)
R
MeO
MeO
CH3CN, 50 °C
R
O
O
O
5
4
O
Ph
R1
O
6 (10 mol%)
*
CH3CN, 50 °C
O
Entry
4/5
R
R1
C6H5
Yield (%)b
2a
1a
1
2
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
Me
90
66
93
80
87
66
65
67
85
83
Ph
2-MeC6H4
2-MeOC6H4
2-FC6H4
Entry
6
Yield (%)b
ee (%)c
3
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
66
85
67
92
85
88
89
<5
<5
8
4
5
3-MeC6H4
3-ClC6H4
4-ClC6H4
4-MeOC6H4
2-thienyl
Me
6
<5
6
7
g
h
i
8
10
6
9
6g
10
j
a Reaction conditions: 1a (0.1 mmol), cat. 6 (10 mol%), CH3CN (2 mL),
a Reaction conditions: 4 (0.1 mmol), 3h (10 mol%), CH3CN (2 mL), 50 °C,
50 °C, 12 h.
12 h.
b Isolated yield.
b Isolated yield.
c The ee value was determined by HPLC.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
S.-J. Liu et al.
Paper
Synthesis
Finally, we performed a preliminary investigation on the
catalytic asymmetric version of the electrocyclization of
substrate 1a. As shown in Table 4, in the presence of several
representative chiral phosphoric acids 6, the electrocycliza-
tion of substrate 1a took place smoothly in generally good
yields. However, the enantioselectivities in all cases were
extremely low (less than 10% ee). Among these catalysts,
chiral phosphoric acid 6f could catalyze the electrocycliza-
tion reaction to afford product 2a in 10% ee (entry 6). The
low enantioselectivity of the reaction might be partly as-
cribed to the strong background reaction because the elec-
trocyclization of substrate 1a could occur in the absence of
any catalysts (Table 1, entry 1).
IR (KBr): 3686, 1682, 1651, 1557, 1505, 1495, 1486, 1471, 1259, 1157
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.56–7.44 (m, 1 H), 7.36–7.26 (m, 1 H),
7.17–7.01 (m, 2 H), 6.51 (s, 1 H), 6.47–6.42 (m, 1 H), 6.41 (s, 1 H),
6.22–6.14 (m, 1 H), 5.92–5.87 (m, 2 H), 5.68 (dd, J = 9.4, 3.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.9, 141.8, 129.8 (J = 8 Hz), 128.6,
124.5, 124.2, 120.9, 115.6, 114.2, 105.9, 101.0, 98.8, 70.6.
ESI-HRMS: m/z [M + H]+ calcd for C16H11FO3: 271.0765; found:
271.0775.
6-(3-Chlorophenyl)-6H-[1,3]dioxolo[4,5-g]chromene (2c)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 28.0 mg (98%); yellow solid; mp 63–64 °C.
IR (KBr): 3734, 2890, 1732, 1594, 1502, 1480, 1450, 1261, 1160, 1142
In summary, we have developed an efficient approach
for the synthesis of chromene derivatives from vinyl o-qui-
none methides via a Brønsted acid catalyzed electrocycliza-
tion. By using this methodology, a series of structurally di-
versified chromenes was synthesized in a highly atom-eco-
nomic and environmentally benign manner with generally
good to excellent yields (up to 98% yield). This reaction will
not only provide an efficient method for the construction of
chromene scaffolds, but also enrich the research contents of
o-quinone methides.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.36 (m, 2 H), 7.35–7.28 (m, 2 H),
6.51 (s, 1 H), 6.48–6.42 (m, 1 H), 6.38 (s, 1 H), 5.90–5.86 (m, 2 H),
5.80–5.75 (m, 1 H), 5.67 (dd, J = 9.7, 3.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 148.0, 141.9, 138.9, 134.1,
128.7, 128.4, 124.6, 121.5, 114.4, 105.9, 101.0, 98.9, 76.0.
ESI-HRMS: m/z [M + H]+ calcd for C16H11ClO3: 287.0470; found:
287.0498.
6-(p-Tolyl)-6H-[1,3]dioxolo[4,5-g]chromene (2d)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 25.6 mg (96%); red solid; mp 74–75 °C.
1H and 13C NMR spectra were measured at 400 and 100 MHz, respec-
tively. The solvent used for NMR spectroscopy was CDCl3, with te-
tramethylsilane as the internal reference. HRMS spectra were record-
ed on an LTQ-Orbitrap mass spectrometer. Analytical grade solvents
for chromatography were distilled before use, and commercially
available reagents were used as received.
IR (KBr): 3485, 3160, 1651, 1504, 1480, 1449, 1400, 1259, 1159, 1037
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.37–7.32 (m, 2 H), 7.21–7.14 (m, 2 H),
6.51 (s, 1 H), 6.46–6.41 (m, 1 H), 6.39 (s, 1 H), 5.90–5.86 (m, 2 H),
5.81–5.76 (m, 1 H), 5.70 (dd, J = 9.7, 3.6 Hz, 1 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.5, 147.8, 141.7, 138.2, 137.5,
129.2, 127.1, 124.2, 122.2, 114.5, 105.8, 101.0, 98.9, 76.7, 21.2.
Chromenes 2 and 5; General Procedure
Catalyst 3h (0.01 mmol) and o-VQM 1 or 4 (0.1 mmol) were mixed in
CH3CN (2 mL) in a tube. Then the reaction mixture was stirred at
50 °C for 12 h. After the reaction had been stopped, the reaction mix-
ture was directly purified by preparative TLC to afford pure product 2
or 5.
ESI-HRMS: m/z [M + H]+ calcd for C17H14O3: 267.1016; found:
267.1018.
6-(4-Chlorophenyl)-6H-[1,3]dioxolo[4,5-g]chromene (2e)
Preparative TLC (toluene–EtOAc, 10:1).
6-Phenyl-6H-[1,3]dioxolo[4,5-g]chromene (2a)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 26.5 mg (93%); yellow solid; mp 79–81 °C.
IR (KBr): 3687, 3617, 1732, 1682, 1557, 1505, 1480, 1455, 1261, 1160
cm–1
.
Yield: 24.6 mg (98%); red solid; mp 57–59 °C.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.36 (m, 2 H), 7.35–7.30 (m, 2 H),
6.51 (s, 1 H), 6.48–6.42 (m, 1 H), 6.38 (s, 1 H), 5.90–5.87 (m, 2 H),
5.80–5.75 (m, 1 H), 5.67 (dd, J = 9.7, 3.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 148.0, 141.9, 138.9, 134.1,
128.7, 128.4, 124.6, 121.5, 114.4, 105.9, 101.0, 98.9, 76.0.
IR (KBr): 2891, 1732, 1621, 1500, 1481, 1448, 1259, 1160, 1142, 1037
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52–7.46 (m, 2 H), 7.43–7.31 (m, 3 H),
6.54 (s, 1 H), 6.49–6.44 (m, 1 H), 6.44 (s, 1 H), 5.91–5.87 (m, 2 H),
5.86–5.81 (m, 1 H), 5.73 (dd, J = 9.7, 3.5 Hz, 1 H).
ESI-HRMS: m/z [M + H]+ calcd for C16H11ClO3: 287.0470; found:
287.0483.
13C NMR (100 MHz, CDCl3): δ = 148.5, 147.9, 141.8, 140.6, 128.6,
128.3, 127.1, 124.3, 122.2, 114.5, 105.9, 101.0, 98.9, 76.9.
ESI-HRMS: m/z [M + H]+ calcd for C16H12O3: 253.0859; found:
253.0853.
6-(4-Methoxyphenyl)-6H-[1,3]dioxolo[4,5-g]chromene (2f)
Preparative TLC (toluene–EtOAc, 10:1).
6-(2-Fluorophenyl)-6H-[1,3]dioxolo[4,5-g]chromene (2b)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 20.6 mg (73%); red solid; mp 71–73 °C.
IR (KBr): 3734, 3320, 1605, 1511, 1480, 1257, 1158, 1036 cm–1
.
Yield: 25.4 mg (94%); red solid; mp 53–55 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

E
S.-J. Liu et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.40–7.35 (m, 2 H), 6.91–6.87 (m, 2 H),
6.51 (s, 1 H), 6.46–6.41 (m, 1 H), 6.36 (s, 1 H), 5.89–5.85 (m, 2 H),
5.78–5.74 (m, 1 H), 5.69 (dd, J = 9.7, 3.6 Hz, 1 H), 3.80 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.8, 147.9, 143.4, 138.2, 136.0,
130.8, 128.2, 127.7, 126.1, 124.4, 121.9, 113.3, 109.8, 100.7, 74.6, 56.5,
55.9, 19.2.
13C NMR (100 MHz, CDCl3): δ = 159.7, 148.4, 147.8, 141.7, 132.5,
ESI-HRMS: m/z [M + H]+ calcd for C18H18O3: 283.1329; found:
128.7, 124.3, 122.2, 114.5, 113.9, 105.8, 100.9, 98.9, 76.5, 55.3.
283.1306.
ESI-HRMS: m/z [M + H]+ calcd for C17H14O4: 283.0965; found:
283.0994.
6,7-Dimethoxy-2-(2-methoxyphenyl)-2H-chromene (5c)
Preparative TLC (toluene–EtOAc, 10:1).
6-(2-Thienyl)-6H-[1,3]dioxolo[4,5-g]chromene (2g)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 27.8 mg (93%); yellow solid; mp 78–79 °C.
IR (KBr): 3868, 3674, 3310, 1716, 1558, 1507, 1456, 1275, 1229, 1193
Yield: 19.0 mg (74%); red solid; mp 64–65 °C.
cm–1
.
IR (KBr): 3627, 1504, 1480, 1261, 1143, 1036, 668 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.54–7.46 (m, 1 H), 7.32–7.26 (m, 1 H),
6.98–6.89 (m, 2 H), 6.55 (s, 1 H), 6.46 (s, 1 H), 6.44–6.39 (m, 1 H),
6.31–6.25 (m, 1 H), 5.67 (dd, J = 9.8, 3.6 Hz, 1 H), 3.87 (s, 3 H), 3.84 (s,
3 H), 3.82 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.9, 149.7, 147.9, 143.2, 129.2,
129.0, 127.8, 123.2, 122.4, 120.7, 113.2, 110.6, 109.9, 100.7, 71.3, 56.5,
55.9, 55.5.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 1 H), 7.10–7.08 (m, 1 H),
6.99–6.94 (m, 1 H), 6.53 (s, 1 H), 6.50–6.45 (m, 1 H), 6.38 (s, 1 H),
6.03–5.97 (m, 1 H), 5.90–5.85 (m, 2 H), 5.82 (dd, J = 9.7, 4.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 147.9, 143.4, 141.9, 126.7, 126.3,
126.2, 124.7, 121.2, 114.5, 105.8, 101.0, 99.2, 93.0, 71.5.
ESI-HRMS: m/z [M + H]+ calcd for C14H10O3S: 259.0424; found:
259.0456.
ESI-HRMS: m/z [M + H]+ calcd for C18H18O4: 299.1278; found:
299.1289.
6,6-Dimethyl-6H-[1,3]dioxolo[4,5-g]chromene (2h)
Preparative TLC (toluene–EtOAc, 10:1).
2-(2-Fluorophenyl)-6,7-dimethoxy-2H-chromene (5d)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 17.6 mg (86%); white solid; mp 57–59 °C.
IR (KBr): 3868, 3748, 2973, 2885, 1699, 1498, 1481, 1263, 1158, 1112
Yield: 23.0 mg (80%); red solid; mp 69–70 °C.
IR (KBr): 3749, 3742, 2936, 1732, 1652, 1646, 1539, 1506, 1488, 1229
cm–1
.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.47 (s, 1 H), 6.38 (s, 1 H), 6.20 (d,
J = 9.7 Hz, 1 H), 5.87 (s, 2 H), 5.47 (d, J = 9.7 Hz, 1 H), 1.39 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 147.5, 141.3, 128.1, 122.3,
114.2, 105.6, 100.9, 99.0, 76.0, 27.4.
ESI-HRMS: m/z [M + H]+ calcd for C12H12O3: 205.0859; found:
1H NMR (400 MHz, CDCl3): δ = 7.57–7.47 (m, 1 H), 7.33–7.26 (m, 1 H),
7.16–7.01 (m, 2 H), 6.56 (s, 1 H), 6.50–6.45 (m, 1 H), 6.44 (s, 1 H),
6.26–6.13 (m, 1 H), 5.66 (dd, J = 9.7, 3.4 Hz, 1 H), 3.83 (s, 3 H), 3.81 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 159.6 (J = 246), 149.9, 147.4, 143.5,
129.8 (J = 8), 128.7, 128.6, 124.2, 121.0, 115.5 (J = 21), 112.9, 109.8,
100.7, 70.6, 56.5, 55.9.
205.0886.
6,7-Dimethoxy-2-phenyl-2H-chromene (5a)
Preparative TLC (toluene–EtOAc, 10:1).
ESI-HRMS: m/z [M + H]+ calcd for C17H15FO3: 287.1078; found:
287.1073.
Yield: 24.2 mg (90%); red solid; mp 80–82 °C.
6,7-Dimethoxy-2-(m-tolyl)-2H-chromene (5e)
Preparative TLC (toluene–EtOAc, 10:1).
IR (KBr): 3851, 3835, 2833, 1738, 1732, 1557, 1506, 1463, 1275, 1193
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.44 (m, 2 H), 7.42–7.30 (m, 3 H),
6.57 (s, 1 H), 6.50–6.45 (m, 1 H), 6.44 (s, 1 H), 5.90–5.80 (m, 1 H), 5.69
(dd, J = 9.7, 3.4 Hz, 1 H), 3.84 (s, 3 H), 3.81 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 142.8, 138.6, 136.0, 123.9,
123.6, 122.3, 119.1, 117.5, 108.5, 105.1, 96.0, 72.3, 51.7, 51.1.
Yield: 24.4 mg (87%); red solid; mp 86–88 °C.
IR (KBr): 3868, 3851, 3325, 1732, 1716, 1557, 1539, 1506, 1274, 1193
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 2 H), 7.25–7.24 (m, 1 H),
7.17–7.12 (m, 1 H), 6.57 (s, 1 H), 6.48–6.45 (m, 1 H), 6.44 (s, 1 H),
5.85–5.76 (m, 1 H), 5.67 (dd, J = 9.7, 3.3 Hz, 1 H), 3.84 (s, 3 H), 3.81 (s,
3 H), 2.36 (s, 3 H).
ESI-HRMS: m/z [M + H]+ calcd for C17H16O3: 269.1172; found:
269.1173.
13C NMR (100 MHz, CDCl3): δ = 149.8, 147.6, 143.3, 140.7, 138.3,
129.1, 128.5, 127.8, 124.2, 123.8, 122.4, 113.2, 109.8, 100.7, 77.2, 56.5,
55.9, 21.4.
6,7-Dimethoxy-2-(o-tolyl)-2H-chromene (5b)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 18.7 mg (66%); red solid; mp 75–77 °C.
ESI-HRMS: m/z [M + H]+ calcd for C18H18O3: 283.1329; found:
283.1298.
IR (KBr): 3853, 3675, 3309, 2833, 1733, 1683, 1558, 1540, 1507, 1193
cm–1
.
2-(3-Chlorophenyl)-6,7-dimethoxy-2H-chromene (5f)
Preparative TLC (toluene–EtOAc, 10:1).
1H NMR (400 MHz, CDCl3): δ = 7.55–7.42 (m, 1 H), 7.25–7.17 (m, 3 H),
6.59 (s, 1 H), 6.53–6.47 (m, 1 H), 6.42 (s, 1 H), 6.14–5.98 (m, 1 H), 5.64
(dd, J = 9.7, 3.2 Hz, 1 H), 3.85 (s, 3 H), 3.82 (s, 3 H), 2.47 (s, 3 H).
Yield: 19.8 mg (66%); red solid; mp 86–88 °C.
IR (KBr): 3868, 3851, 3310, 1733, 1683, 1558, 1539, 1507, 1456, 1266
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
S.-J. Liu et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.35–7.28 (m, 3 H), 6.57
(s, 1 H), 6.51–6.46 (m, 1 H), 6.44 (s, 1 H), 5.83–5.79 (m, 1 H), 5.65 (dd,
J = 9.7, 3.5 Hz, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 6.52 (s, 1 H), 6.41 (s, 1 H), 6.24 (d, J =
9.7 Hz, 1 H), 5.47 (d, J = 9.7 Hz, 1 H), 3.83 (s, 3 H), 3.82 (s, 3 H), 1.41 (s,
6 H).
13C NMR (100 MHz, CDCl3): δ = 150.0, 147.2, 143.5, 142.8, 134.5,
129.9, 128.4, 127.2, 125.1, 124.3, 121.4, 113.0, 109.8, 100.7, 76.2, 56.5,
55.9.
13C NMR (100 MHz, CDCl3): δ = 149.6, 147.1, 143.0, 128.2, 121.9,
113.0, 109.6, 100.9, 76.0, 56.5, 55.9, 27.6.
ESI-HRMS: m/z [M + H]+ calcd for C13H16O3: 221.1172; found:
221.1184.
ESI-HRMS: m/z [M + H]+ calcd for C17H15ClO3: 303.0783; found:
303.0744.
2-(4-Chlorophenyl)-6,7-dimethoxy-2H-chromene (5g)
Preparative TLC (toluene–EtOAc, 10:1).
Funding Information
We much appreciate the financial support from NSFC (21702077 and
21772069), the Natural Science Foundation of Jiangsu Province
(BK20160003 and BK20170227), TAPP, and Six Kinds of Talents Proj-
Yield: 19.6 mg (65%); red solid; mp 64–65 °C.
IR (KBr): 3868, 3851, 3748, 3674, 1732, 1698, 1506, 1488, 1472, 1274
cm–1
.
ect of Jiangsu Province (SWYY-025).
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1H NMR (400 MHz, CDCl3): δ = 7.42–7.37 (m, 2 H), 7.36–7.31 (m, 2 H),
6.57 (s, 1 H), 6.51–6.46 (m, 1 H), 6.41 (s, 1 H), 5.83–5.79 (m, 1 H), 5.65
(dd, J = 9.7, 3.5 Hz, 1 H), 3.84 (s, 3 H), 3.82 (s, 3 H).
Supporting Information
13C NMR (100 MHz, CDCl3): δ = 150.0, 147.2, 143.5, 139.2, 134.1,
128.7, 128.5, 124.3, 121.6, 113.1, 109.8, 100.7, 76.2, 56.5, 55.9.
ESI-HRMS: m/z [M + H]+ calcd for C17H15ClO3: 303.0783; found:
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609483.
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References
6,7-Dimethoxy-2-(4-methoxyphenyl)-2H-chromene (5h)
Preparative TLC (toluene–EtOAc, 10:1).
(1) These authors contributed equally to this work.
(2) For selected reviews, see: (a) Pratap, R.; Ram, V. J. Chem. Rev.
2014, 114, 10476. (b) Costa, M.; Dias, T. A.; Brito, A.; Proenca, F.
Eur. J. Med. Chem. 2016, 123, 487.
(3) (a) Cheenpracha, S.; Karalai, C.; Ponglimanont, C.; Kanjana-
Opas, A. J. Nat. Prod. 2009, 72, 1395. (b) Chen, J.; Leng, H.; Duan,
Y.; Zhao, W.; Yang, G.; Guo, Y.; Chen, Y.; Hu, Q. Phytochem. Lett.
2013, 6, 144.
(4) Liby, K.; Rendi, M.; Suh, N.; Royce, D. B.; Risingsong, R.;
Williams, C. R.; Lamph, W.; Labrie, F.; Krajewski, S.; Xu, X.; Kim,
H.; Brown, P.; Sporn, M. B. Clin. Cancer Res. 2006, 12, 5902.
(5) Cheng, J.-F.; Ishikawa, A.; Ono, Y.; Arrhenius, T.; Nadzan, A.
Bioorg. Med. Chem. Lett. 2003, 13, 3647.
Yield: 19.9 mg (67%); red solid; mp 83–85 °C.
IR (KBr): 3868, 3851, 3318, 1732, 1716, 1557, 1539, 1506, 1456, 1256
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.41–7.36 (m, 2 H), 6.92–6.86 (m, 2 H),
6.57 (s, 1 H), 6.52–6.43 (m, 1 H), 6.40 (s, 1 H), 5.82–5.76 (m, 1 H), 5.67
(dd, J = 9.7, 3.5 Hz, 1 H), 3.84 (s, 3 H), 3.80 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 159.7, 149.8, 147.4, 143.3, 132.8,
128.7, 123.9, 122.3, 113.9, 113.2, 109.8, 100.8, 76.7, 56.5, 55.9, 55.3.
ESI-HRMS: m/z [M + H]+ calcd for C18H18O4: 299.1278; found:
299.1268.
(6) Chen, B.; Fairhurst, R. A.; Floersheimer, A.; Furet, P.; Jiang, S.; Lu,
W.; Marsilje, T. H.; Vaupel, A. Patent WO2011064211A1, 2011.
(7) For selected reviews, see: (a) Shi, Y.-L.; Shi, M. Org. Biomol.
Chem. 2007, 5, 1499. (b) Ferreira, S. B.; da Silva, F. d. C.; Pinto, A.
C.; Gonzaga, D. T. G.; Ferreira, V. F. J. Heterocycl. Chem. 2009, 46,
1080. (c) Majumdar, N.; Paul, N. D.; Mandal, S.; de Bruin, B.;
Wulff, W. D. ACS Catal. 2015, 5, 2329. (d) Sadek, K. U.;
Mekheimer, R. A. H.; Abd-Elmonem, M.; Abdel-Hameed, A.;
Elnagdi, M. H. Tetrahedron 2017, 28, 1462.
(8) For selected examples, see: (a) Wang, Z.-Q.; Lei, Y.; Zhou, M.-B.;
Chen, G.-X.; Song, R.-J.; Xie, Y.-X.; Li, J.-H. Org. Lett. 2011, 13, 14.
(b) Cui, Z.; Shang, X.; Shao, X.-F.; Liu, Z.-Q. Chem. Sci. 2012, 3,
2853. (c) Hornillos, V.; van Zijl, A. W.; Feringa, B. L. Chem.
Commun. 2012, 48, 3712. (d) Majumdar, N.; Korthals, K. A.;
Wulff, W. D. J. Am. Chem. Soc. 2012, 134, 1357. (e) Paul, N. D.;
Mandal, S.; Otte, M.; Cui, X.; Zhang, X. P.; de Bruin, B. J. Am.
Chem. Soc. 2014, 136, 1090. (f) Siyang, H.-X.; Wu, X.-R.; Ji, X.-Y.;
Wu, X.-Y.; Liu, P.-N. Chem. Commun. 2014, 50, 8514. (g) Zeng, B.-
S.; Yu, X.-Y.; Siu, P.-W.; Scheidt, K. A. Chem. Sci. 2014, 5, 2277.
(h) Wang, P.-S.; Liu, P.; Zhai, Y.-J.; Lin, H.-C.; Han, Z.-Y.; Gong, L.-
Z. J. Am. Chem. Soc. 2015, 137, 12732. (i) Kuppusamy, R.;
Muralirajan, K.; Cheng, C.-H. ACS Catal. 2016, 6, 3909. (j) Qiu, Y.-
F.; Song, X.-R.; Li, M.; Zhu, X.-Y.; Wang, A.-Q.; Yang, F.; Han, Y.-
P.; Zhang, H.-R.; Jin, D.-P.; Li, Y.-X.; Liang, Y.-M. Org. Lett. 2016,
18, 1514. (k) Liu, S.; Chen, K.; Lan, X.-C.; Hao, W.-J.; Li, G.; Tu, S.-
6,7-Dimethoxy-2-(2-thienyl)-2H-chromene (5i)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 23.2 mg (85%); red solid; mp 91–93 °C.
IR (KBr): 3699, 3687, 3673, 3627, 1698, 1683, 1652, 1557, 1506, 1274
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.27 (m, 1 H), 7.13–7.06 (m, 1 H),
7.01–6.93 (m, 1 H), 6.58 (s, 1 H), 6.54–6.48 (m, 1 H), 6.42 (s, 1 H),
6.08–6.00 (m, 1 H), 5.80 (dd, J = 9.7, 4.0 Hz, 1 H), 3.83 (s, 3 H), 3.80 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 149.9, 146.8, 143.7, 143.5, 126.7,
126.2, 126.1, 124.4, 121.3, 113.3, 109.7, 101.0, 71.6, 56.4, 55.9.
ESI-HRMS: m/z [M + H]+ calcd for C15H14O3S: 275.0737; found:
275.0735.
6,7-Dimethoxy-2,2-dimethyl-2H-chromene (5j)
Preparative TLC (toluene–EtOAc, 10:1).
Yield: 18.2 mg (83%); white solid; mp 97–98 °C.
IR (KBr): 3851, 3819, 3734, 3647, 2972, 1733, 1716, 1699, 1558, 1133
cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
S.-J. Liu et al.
Paper
Synthesis
J.; Jiang, B. Chem. Commun. 2017, 53, 10692. (l) Xia, J.; Nie, Y.;
Yang, G.; Liu, Y.; Zhang, W. Org. Lett. 2017, 19, 4884. (m) Zheng,
Y.; Qiu, L.; Hong, K.; Dong, S.; Xu, X. Chem. Eur. J. 2018, DOI
10.1002/chem.201704759. (n) Ma, C.; Zhao, Y. Org. Biomol.
Chem. 2018, 16, 703.
(13) For [4+1] annulations of o-QMs, see: (a) Jiang, X.-L.; Liu, S.-J.;
Gu, Y.-Q.; Mei, G.-J.; Shi, F. Adv. Synth. Catal. 2017, 359, 3341.
(b) Lian, X.-L.; Adili, A.; Liu, B.; Tao, Z.-L.; Han, Z.-Y. Org. Biomol.
Chem. 2017, 15, 3670. (c) Yang, Q.-Q.; Xiao, W.-J. Eur. J. Org.
Chem. 2017, 233.
(9) For related reviews, see: (a) Akiyama, T. Chem. Rev. 2007, 107,
5744. (b) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem.
Rev. 2014, 114, 9047. (c) Terada, M. Chem. Commun. 2008, 4097.
(d) Terada, M. Synthesis 2010, 1929. (e) Yu, J.; Shi, F.; Gong, L.-Z.
Acc. Chem. Res. 2011, 44, 1156.
(10) For some examples, see: (a) Gharpure, S. J.; Sathiyanarayanan,
A. M.; Vuram, P. K. RSC Adv. 2013, 3, 18279. (b) Hsiao, C.-C.; Raja,
S.; Liao, H.-H.; Atodiresei, I.; Rueping, M. Angew. Chem. Int. Ed.
2015, 54, 5762. (c) Zhao, J.-J.; Sun, S.-B.; He, S.-H.; Wu, Q.; Shi, F.
Angew. Chem. Int. Ed. 2015, 54, 5460.
(11) For related reviews, see: (a) Pathak, T. P.; Sigman, M. S. J. Org.
Chem. 2011, 76, 9210. (b) Willis, N. J.; Bray, C. D. Chem. Eur. J.
2012, 18, 9160. (c) Bai, W.-J.; David, J. G.; Feng, Z.-G.; Weaver, M.
G.; Wu, K.-L.; Pettus, T. R. R. Acc. Chem. Res. 2014, 47, 3655.
(d) Singh, M. S.; Nagaraju, A.; Anand, N.; Chowdhury, S. RSC Adv.
2014, 4, 55924. (e) Wang, Z.; Sun, J. Synthesis 2015, 47, 3629.
(f) Jaworski, A. A.; Scheidt, K. A. J. Org. Chem. 2016, 81, 10145.
(12) For selected 1,4-additions of o-QMs, see: (a) Mattson, A. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 4508. (b) Luan, Y.;
Schaus, S. E. J. Am. Chem. Soc. 2012, 134, 19965. (c) Guo, W. G.;
Wu, B.; Zhou, X.; Chen, P.; Wang, X.; Zhou, Y. G.; Liu, Y.; Li, C.
Angew. Chem. Int. Ed. 2015, 54, 4522. (d) Lewis, R. S.; Garza, C. J.;
Dang, A. T.; Pedro, T. K. A.; Chain, W. J. Org. Lett. 2015, 17, 2278.
(e) Zhao, W.; Wang, Z.; Chu, B.; Sun, J. Angew. Chem. Int. Ed.
2015, 54, 1910. (f) Wang, Z.; Ai, F.; Wang, Z.; Zhao, W.; Zhu, G.;
Lin, Z.; Sun, J. J. Am. Chem. Soc. 2015, 137, 383.
(14) For selected [4+2] annulations of o-QMs, see: (a) Saha, S.;
Schneider, C. Org. Lett. 2015, 17, 648. (b) Yu, X.-Y.; Chen, J.-R.;
Wei, Q.; Cheng, H.-G.; Liu, Z.-C.; Xiao, W.-J. Chem. Eur. J. 2016,
22, 6774. (c) Zhang, Y.-C.; Zhu, Q.-N.; Yang, X.; Zhou, L.-J.; Shi, F.
J. Org. Chem. 2016, 81, 1681. (d) Chen, P.; Wang, K.; Guo, W.; Liu,
X.; Liu, Y.; Li, C. Angew. Chem. Int. Ed. 2017, 56, 3689. (e) Wang,
Z.; Sun, J. Org. Lett. 2017, 19, 2334.
(15) For [4+3] annulations of o-QMs, see: (a) Izquierdo, J.; Orue, A.;
Scheidt, K. A. J. Am. Chem. Soc. 2013, 135, 10634. (b) Lv, H.; Jia,
W. Q.; Sun, L.-H.; Ye, S. Angew. Chem. Int. Ed. 2013, 52, 8607.
(c) Mei, G.-J.; Zhu, Z.-Q.; Zhao, J.-J.; Bian, C.-Y.; Chen, J.; Chen, R.-
W.; Shi, F. Chem. Commun. 2017, 53, 2768.
(16) For selected examples of o-VQMs-involved reactions, see: (a) Lv,
H.; You, L.; Ye, S. Adv. Synth. Catal. 2009, 351, 2822. (b) Adili, A.;
Tao, Z.-L.; Chen, D.-F.; Han, Z.-Y. Org. Biomol. Chem. 2015, 13,
2247. (c) Ref. 10b (d) Jin, J.-H.; Li, X.-Y.; Luo, X.; Fossey, J. S.;
Deng, W.-P. J. Org. Chem. 2017, 82, 5424. (e) Wang, Z.; Wang, T.;
Yao, W.; Lu, Y. Org. Lett. 2017, 19, 4126.
(17) (a) For an early example, see: Jurd, L. Tetrahedron 1977, 33, 163.
(b) For a mechanistic investigation, see: Bishop, L. M.; Winkler,
M.; Houk, K. N.; Bergman, R. G.; Trauner, D. Chem. Eur. J. 2008,
14, 5405. (c) For a catalytic asymmetric transformation, see:
Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc.
2011, 133, 3732.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G