Efficient Synthesis of Functionalized 4 H -Chromenes via an Fe(OTf) 3 -Catalyzed Cyclization Reaction of Phenols and Ketones

Article abstract of DOI:10.1055/s-0036-1591021

The iron(III) triflate catalyzed cyclization reaction of phenols and ketones is described; the reaction provides a direct approach to 4 H -chromene derivatives. 4 H -Chromene is an important structural fragment of many pharmaceuticals, natural products, and functional materials. The 4 H -chromene synthetic protocol possesses many advantages, such as using readily available and inexpensive starting materials and a non-toxic catalyst, high selectivity, and operational simplicity, which offer attractive industrial prospects from the point of view of green and sustainable chemistry.

Full text of DOI:10.1055/s-0036-1591021

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–K
paper
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de
K. Deng et al.
Paper
Synthesis
Efficient Synthesis of Functionalized 4H-Chromenes via an
Fe(OTf)3-Catalyzed Cyclization Reaction of Phenols and Ketones
Kai Denga
OH
Qi-Yong Huaib
Hui-Jing Li*a
Jun-Hu Wanga
Hui-Ru Yanga
Ying Liua
R
O
Fe(OTf)3 (10 mol%)
X
+ 2
+ 2 H2O
R
O
R
DCE, 90 °C, 12 h
X
X = Me, t-Bu, OMe, Cl, Ph
R = phenyl and substituted phenyl, alkyl
25 examples
31–85% yield
Yan-Chao Wu*a,c
0
0
0
0
0-
0
0
2
0-
1
1
1
7-
4
8
4
• readily available starting materials
• mild conditions
• tolerance of air and moisture
• broad substrate scope
a School of Marine Science and Technology, Harbin Institute of Technology,
Weihai 264209, P. R. of China
b Marine College, Shandong University, Weihai 264209, P. R. of China
c Beijing National Laboratory for Molecular Sciences, Institute of Chemistry
Chinese Academy of Sciences, Beijing 100190, P. R. of China
ycwu@iccas.ac.cn
Received: 20.11.2017
Accepted: 10.12.2017
Published online: 11.01.2018
DOI: 10.1055/s-0036-1591021; Art ID: ss-2017-f0739-op
reaction of active polyphenols and ketones in the presence
of p-toluenesulfonic acid in n-hexane under reflux (100 °C,
sealed tube).20 We developed an H2SO4-promoted 4H-
chromene synthesis via the tandem reaction of readily
available phenols and acetophenones at 50 °C under sol-
vent-free conditions.21 These two 4H-chromene synthetic
protocols (Scheme 1, a) are limited in their application by
the need for harsh conditions (p-TsOH or H2SO4). To over-
come this inherent problem, the use of a suitable Lewis acid
is required.22 Indeed, Liu, Xu, and co-workers developed an
efficient 4H-chromene synthesis via the AuCl3/3AgOTf-cat-
alyzed tandem reaction of phenols and ketones (Scheme 1,
b).23 As this reaction did not occur under the action of ei-
ther AuCl3 or AgOTf alone,23 Au(OTf)3 is actually the effec-
tive promoter. In contrast to AuCl3, FeCl3 was a relatively ef-
fective promoter for this reaction (i.e., 0% versus 26%,
Scheme 1, b).23 Based on these results, we envisioned
Fe(OTf)3 as a potentialexcellent promoter for the tandem
reaction of phenols and ketones.
Compared with other Lewis acids, iron salts are un-
doubtedly the most appealing Lewis acids because iron is
abundant, inexpensive, and nonhazardous.24,25 As a conse-
quence, a huge amount of effort has been dedicated to the
application of iron salts in the construction of organic com-
pounds.24 On the other hand, iron salts also have the follow-
ing properties: stability, nontoxicity, and metabolizability.
Thus iron compounds play a significant role in the physio-
logical activity of human beings and show a powerful cata-
lytic ability to promote many bioactivities.25 Accordingly,
iron-catalyzed reactions have been especially taken advan-
tage of in the cosmetic, food, and medicinal industries. It is
not an exaggeration to declare that using a suitable iron salt
as the Lewis acid would be a significant breakthrough in
4H-chromene synthesis in terms of economic efficiency,
safety, and low waste disposal. Associate with our previous
work on the practical synthesis of various functional com-
Abstract The iron(III) triflate catalyzed cyclization reaction of phenols
and ketones is described; the reaction provides a direct approach to 4H-
chromene derivatives. 4H-Chromene is an important structural frag-
ment of many pharmaceuticals, natural products, and functional mate-
rials. The 4H-chromene synthetic protocol possesses many advantages,
such as using readily available and inexpensive starting materials and a
non-toxic catalyst, high selectivity, and operational simplicity, which
offer attractive industrial prospects from the point of view of green and
sustainable chemistry.
Key words iron catalyst, 4H-chromene, cyclization reaction, synthesis,
4H-1-benzopyran
4H-Chromenes have been a subject of consistent inter-
est due to the presence of their structural motifs in many
pharmaceuticals, functional materials, and natural prod-
ucts.1 It is well-known that 4H-chromenes display a broad
range of important biological activities, such as antiprolif-
erative,2 antifungal,3 antiviral,4 antimicrobial,5 antitubercu-
lar,6 antileishmanial,7 antioxidative,8 and anticancer9 prop-
erties. Certain examples of 4H-chromenes as the pivotal
fragment in the construction of natural products and me-
dicinal molecules have been reported;10,11 these com-
pounds were applied in medicine,12 health care products,13
and some functional materials.14 Hence, various methods
for the synthesis of 4H-chromenes have been developed:
(1) format reagent method;15 (2) microwave-assisted alke-
nylation reaction;16 (3) FeCl3-catalyzed tandem benzylation
and cyclization reaction;17 (4) deep eutectic solvent meth-
od;18 and (5) sodium bisulfate promoted approach.19 How-
ever, these 4H-chromene synthetic strategies usually re-
quire a heavy metal catalyst, an organocatalyst, or unavail-
able starting materials. In this context, Wu and co-workers
reported an elegant 4H-chromene synthesis by the tandem
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K. Deng et al.
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a) Wu,20 Li's21 work
OH
Ar
O
H2SO4 or p-TsOH
X
+
X
Ar
O
Ar
b) Liu and Xu's work23
AuCl3/3AgOTf
99% yield
O
Ph
OH
AuCl3 or AgOTf
0% yield
+
Ph
O
Ph
FeCl3
26% yield
c) This work
OH
R
O
Fe(OTf)3 (10 mol%)
X
+ 2
R
O
R
X
Scheme 1 Synthesis of 4H-chromenes
pounds,26 herein we report an economic synthesis of 4H-
chromenes via an iron(III)-catalyzed tandem reaction of
phenols and ketones (Scheme 1, c). Initially, the reaction
conditions were evaluated by using 2-naphthol (1a) and ac-
etophenone (2a) as a probe, and the valuable results are
listed in Table 1.
Table 1 Survey of Conditions for the Reaction of 2-Naphthol with Ace-
tophenonea
Ph
Ph
OH
O
+
+
Ph
2a
O
Ph
Ph
Ph
The treatment of 1a (1.0 equiv) and 2a (2.5 equiv) in the
presence of Fe(OTf)3 (0.05 equiv) in 1,2-dichloroethane
(DCE) at 50 °C for 12 hours gave 4H-chromene 3a in 8%
yield (entry 1). The yield of 4H-chromene 3a increased from
8% to 31% when the reaction was conducted at 70 °C under
otherwise the same conditions (entries 1 and 2). A series of
catalysts were tested for this reaction, in which Fe(OTf)3
was found to be a relatively effective catalyst (entries 2–17).
The most effective reaction temperature was found to be
90 °C (entries 2 and 18–21). The yield of byproduct 4a in-
creased dramatically when the reaction was performed at
temperatures higher than 90 °C (entries 19–21). The sol-
vent played an important role in this reaction. With the use
of tetrahydrofuran, N,N-dimethylformamide, or ethanol as
the solvent, no reaction took place and the starting materi-
als were recovered (entries 22–24). With the use of n-hex-
ane, toluene, or xylene as the solvent, or under solvent-free
conditions, lower yields were observed in comparison to
that with DCE as solvent (entries 19 and 25–28). Byproduct
4a became the major product when the reaction was per-
formed in nitromethane or 1,4-dioxane (entries 29 and 30).
Further parameter optimization identified the most effec-
tive catalyst loading as 5 mol% (entries 19 and 31–32). The
reaction went smoothly under an atmosphere of air or ar-
gon (entries 19 and 33). Furthermore, the excellent yield
was maintained on scaling up the reaction using 1.44 g of
1a (10.0 mmol) (entry 34).
1a
3a
4a
Entry
Catalyst
Conditions
Yield (%)
3a
4a
1
2
Fe(OTf)3
Fe(OTf)3
Fe(OTf)2
Fe(Cp)2
Fe(NO3)3
Fe2(SO4)3
FeCl3
DCE, 50 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 70 °C
DCE, 80 °C
8
0
31
0
trace
3
0
0
0
0
0
0
0
0
0
0
0
4
0
5
0
6
0
7
trace
0
8
Cu(OTf)2
AgOTf
9
0
10
11
12
13
14
15
16
17
18
Mg(OTf)2
Al(OTf)3
Ga(OTf)3
Zn(OTf)2
Bi(OTf)3
Hf(OTf)4
Sn(OTf)2
TfOH
0
0
0
0
16
5
trace
0
<5
0
0
trace
5
Fe(OTf)3
53
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Table 1 (continued)
2-naphthol were also investigated and they reacted
smoothly with 2a and 2b, respectively, to give 4H-
chromenes 3l and 3m in 79% and 71% yields (entries 12 and
13). As in the case of 2-naphthol (1a), 1-naphthol (1d) re-
acted equally well with acetophenones 2e,f,h,l to afford 4H-
chromenes 3n–q in moderate to good yields (entries 14–
17), irrespective of whether the acetophenone substrate
bears a weak electron-donating group (entry 14), a strong
electron-donating group (entry 15), or a strong electron-
withdrawing group (entry 16). On the other hand, various
phenols such as 4-substituted phenols 1e–h, 2,4-disubsti-
tuted phenol 1i, 3,4-disubstituted phenol 1j, and 3,4,5-
disubstituted phenol 1k were also investigated and these
reacted successfully with acetophenone 2c under the stan-
dard conditions to obtain 4H-chromenes 3r–x in 53–80%
yields (entries 18–24). By treatment of naphthalene-2,6-
diol (1l) with acetophenone (2a) in the presence of Fe(OTf)3
(5 mol%) in 1,2-dichloroethane at 110 °C for 12 hours, tetra-
cyclic product 3y was isolated in 65% yield (entry 25). These
reactions are easy to perform without the need for an inert
atmosphere, and displayed a wide substrate scope.
Entry
Catalyst
Conditions
Yield (%)
3a
84
4a
11
19
20
21
22
23
24
25
26
27
28
29
30
31b
32c
33d
34e
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
DCE, 90 °C
DCE, 100 °C
DCE, 110 °C
THF, 90 °C
73
46
0
23
52
0
DMF, 90 °C
0
0
EtOH, 90 °C
n-hexane, 90 °C
toluene, 90 °C
xylene, 90 °C
0
0
72
50
52
12
12
14
32
25
30
trace
36
11
12
solvent-free, 90 °C 33
CH3NO2, 90 °C 17
1,4-dioxane, 90 °C trace
DCE, 90 °C
DCE, 90 °C
DCE, 90 °C
DCE, 90 °C
42
61
83
84
The reaction mechanism of this 4H-chromene synthetic
method was next studied, and the representative results
are given in Scheme 2. A small amount of 1,3,5-triphenyl-
benzene (4a) was also generated when the reaction was
performed under the standard conditions (Table 1, entry
19). The yield of byproduct 4a increased to 36% when the
reaction was performed in the absence of 1a under other-
wise identical conditions, in which a trace of dypnone (5a)
was also detected (Scheme 2, a). The reaction temperature
played an important role in the formation of 4a (Table 1, en-
tries 19–21). Cyclotrimerization of 2a in the presence of
Fe(OTf)3 (5 mol%) in DCE at 110 °C for 12 hours gave 1,3,5-
triphenylbenzene (4a) in 67% yield (Scheme 2, b). This is
also the case when the cyclotrimerization of 2a was per-
formed in the presence of p-toluenesulfonic acid.27 As men-
tioned by Jia and co-workers, only a trace of 4a was detect-
ed when the cyclotrimerization of 2a was performed in the
presence of p-toluenesulfonic acid (5 mol%) at 80 °C for 12
hours.27 In contrast, the yield of 4a increased to 85% when
the reaction was performed at 130 °C for 10 hours under
otherwise identical conditions.27 We had previously ob-
served that the rearrangement of dypnones to 1,3,5-triaryl-
benzenes goes smoothly under obviously milder conditions
in comparison to the cyclotrimerization of acetophenones
to 1,3,5-triarylbenzenes [p-TsOH (10 mol%), 80 °C vs 130–
148 °C].28 We found that rearrangement of dypnone (5a)
occurs smoothly in the presence of Fe(OTf)3 (5 mol%) at
90 °C to give 1,3,5-triphenylbenzene (4a) in 65% yield
(Scheme 2, c). The reaction of dypnone (5a) with acetophe-
none (2a) goes equally well under the standard conditions
(Scheme 2, d) to give 4a in 69% yield. The results indicated
that the formation of byproduct 4a is not favored in the re-
action with 2-naphthol (1a, 1 equiv) under the action of
Fe(OTf)3 (0.05 equiv) in DCE at 90 °C for 12 hours and this
a General conditions: 1a (1.0 mmol), 2a (2.5 mmol), catalyst (0.05 mmol),
solvent (1.0 mL), 12 h (sealed tube).
b Fe(OTf)3 (0.01 mmol) was used.
c Fe(OTf)3 (0.10 mmol) was used.
d Under an argon atmosphere.
e Scale of reaction: 1a (1.44 g, 10.0 mmol).
Next we investigated the scope of the reaction using the
optimized reaction conditions (Table 2). Acetophenones
2a–e reacted effectively with 2-naphthol (1a) in the pres-
ence of Fe(OTf)3 (0.05 equiv) for 12 hours in 1,2-dichlo-
roethane at 90 °C in an atmosphere of air (1 atm) to give
4H-chromenes 3a–e in 67–85% yields (entries 1–5). This re-
activity of the acetophenones was observed in all cases, in
absence of a substituting group and as well when a weak
electron-withdrawing group (entries 2–4) or a weak elec-
tron-donating group (entry 5) was present in para position.
Inert acetophenones, such as 4′-nitroacetophenone (2f) and
4′-(trifluoromethyl)acetophenone (2g) reacted with 1a to
afford products 3f,g in 33% and 68% yields, respectively, un-
der the standard conditions, albeit with a longer reaction
time (i.e., 12 hours vs 36 hours, entries 6 and 7). As the de-
activated acetophenones 2f,g prevented the cyclization re-
action using the reported procedure in the literature,20 the
method expanded the substrate scope of the acetophe-
nones. Moreover, the cyclization reaction of 1a with steri-
cally hindered acetophenone 2h went favorably under the
same conditions to give product 3h in 55% yield (entry 8);
this reaction did not take place using the AuCl3/3AgOTf pro-
cedure.23 Aliphatic ketones 2i–k reacted uneventfully with
1a to afford the corresponding products 3i–k in 43–62%
yields (entries 9–11). 7-Bromo-2-naphthol (1b) and 6-bromo-
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D
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reaction instead affords 4H-chromene 3a. Indeed, treat-
ment of dypnone (5a, 1 equiv) with 1a under the standard
conditions gave 3a and 1,3,5-triphenylbenzene (4a) in 53%
and 42% yields, respectively (Scheme 2, e), reflecting the
limited contribution of dypnones 5 to this iron(III)-cata-
lyzed cyclization reaction of phenols 1 and acetophenones
2.
Table 2 Fe(OTf)3-Catalyzed Tandem Reaction of Phenols with Ketonesa
Y
O
OH
Fe(OTf)3
X
X
+
Y
Y
90 °C, 12 h
O
1
2
3
Entry
1 (X)
2 (Y)
Product: Yield
Y
O
Y
Y
O
OH
1
1a
1a
1a
1a
1a
1a
1a
2a (H)
3a: 84%
3b: 73%
3c: 85%
3d: 77%
3e: 67%
3f: 33%
3g: 68%
2
2b (4-F)
3
2c (4-Cl)
2d (4-Br)
2e (4-Me)
2f (4-NO2)
2g (4-CF3)
4
5
6b
7b
O
OH
O
8
9
1a
2h
3h: 55%
O
O
OH
1a
2i
3i: 62%
O
O
OH
10b
1a
2j
3j: 43%
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Table 2 (continued)
Entry
1 (X)
2 (Y)
Product: Yield
O
O
OH
11b
1a
2k
3k: 46%
Br
Br
O
Y
O
OH
12
1b
2a (H)
3l: 79%
F
Br
Br
O
Y
O
OH
F
13
1c
2b (4-F)
3m: 71%
Y
O
Y
O
OH
Y
14
1d
1d
1d
2e (4-Me)
2f (4-NO2)
2l (4-OMe)
3n: 69%
3o: 31%
3p: 76%
15b
16
OH
O
O
17
1d
2h
3q: 53%
Y
O
Y
OH
X
X
Y
O
18
19
1e (4-Me)
1f (4-t-Bu)
2c (4-Cl)
2c (4-Cl)
3r: 66%
3s: 74%
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Table 2 (continued)
Entry
1 (X)
1g (4-Ph)
2 (Y)
2c (4-Cl)
Product: Yield
20
21
22
23
3t: 58%
3u: 80%
3v: 61%
3w: 74%
1h (4-OMe)
1i (2,4-Me2)
1j (3,4-Me2)
2c (H)
2c (4-Cl)
2c (4-Cl)
Cl
OH
O
Y
O
Cl
Cl
Cl
24
1k
2c (4-Cl)
3x: 53%
Ph
O
HO
O
Ph
Y
Ph
OH
O
Ph
25c
1l
2a (H)
3y: 65%
a General conditions: 1 (1.0 mmol), 2 (2.5 mmol), Fe(OTf)3 (0.05 mmol), DCE (1 mL), 90 °C, 12 h (sealed tube).
b The reaction was performed for 36 h.
c Using 2a (5 equiv) at 110 °C.
Ph
phenones 2 followed by dehydration gives dypnones 5,
which are next converted into compounds 8 by intermolec-
ular Michael addition with phenols 1. Intramolecular hemi-
acetalization of 8 followed by dehydration affords 4H-
chromenes 3 (Scheme 3).
O
Fe(OTf)3
O
O
(a)
(b)
+
Ph
Ph
DCE, 90 °C
12 h
Ph
2a
Ph
Ph
4a: 36%
Ph
5a: trace
Fe(OTf)3
DCE, 110 °C
12 h
Ph
2a
Ph
Ph
O
OH
Fe(OTf)3
Fe(OTf)3
O
HO
O
Ar
4a: 67%
Ar
Ar
Ar
Ph
+
Aldol
enolization
Ar
Ar
reaction
O
2
6
2
7
Fe(OTf)3
(c)
(d)
OH
Ar
O
Ph
O
Ph
DCE, 90 °C
12 h
Ph
Ph
Ph
O
Ar
5a
4a: 65%
Fe(OTf)3
Fe(OTf)3
– H2O
+
X
X
Ph
Ar
Michael
addition
OH
O
Fe(OTf)3
5
1
8
+
DCE, 90 °C
12 h
Ph
Ph
Ph
2a
Ar
Ar
Ph
Ph
5a
4a: 69%
Fe(OTf)3
Fe(OTf)3
(a)
X
X
OH
hemiacetalization
dehydration
Ar
O
O
Ar
Ph
OH
Ph
9
3
1a
+
Fe(OTf)3
O
Scheme 3 Proposed mechanism
(e)
+
O
DCE, 90 °C
12 h
Ph
Ph
Ph
Ph
3a: 53%
4a: 42%
5a
In summary, we have developed a practical cyclization
reaction of phenols and ketones that provides a facile syn-
thesis of 4H-chromenes from readily available and inexpen-
sive starting materials. Sterically hindered or inert aceto-
phenones, such as 1-acetonaphthone, 4′-(trifluoromethyl)-
acetophenone, and 4′-nitroacetophenone, which prevented
the cyclization reaction using procedures reported in the
Scheme 2 Verification experiments
Based on the above results and related reports in the lit-
erature, a possible reaction mechanism is illustrated in
Scheme 3. The aldol-type condensation reaction of aceto-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

G
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Synthesis
literature, are suitable substrates in the present 4H-
chromene synthetic protocol. The use of an iron salt as the
Lewis acid is desirable in terms of economic efficiency,
safety, and low waste disposal, which offers attractive in-
dustrial prospects from the point of view of green and sus-
tainable chemistry. Further mechanistic investigations as
well as applications of this method are in progress.
FTIR (film): 3056, 2966, 2926, 2853, 1713, 1673, 1598, 1575, 1490,
1468, 1397, 1381, 1369, 1319, 1289, 1202, 1094, 1074, 1012, 830,
812, 748 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 7.5
Hz, 2 H), 7.49 (d, J = 8.7 Hz, 1 H), 7.38–7.12 (m, 9 H), 5.21 (s, 1 H), 2.14
(s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 148.6, 148.5, 142.4, 134.3, 132.1, 131.9,
131.8, 131.1, 129.6, 128.9, 128.7, 128.6, 128.5, 128.4, 126.0, 125.8 (d),
123.7, 118.1, 108.9, 40.5, 29.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H19Cl2O: 417.0808; found:
417.0792.
Common reagents and materials were purchased from commercial
sources and purified by recrystallization or distillation. Where neces-
sary, organic solvents were routinely dried and/or distilled prior to
use and stored over molecular sieves under argon. Organic extracts
were, in general, dried over anhyd Na2SO4. TLC plates were visualized
by exposure to UV light. NMR spectra were referenced to the NMR
solvents (1H, CDCl3: δ = 7.26; 13C, CDCl3: δ = 77.0; DMSO-d6: δ =
39.43).
1,3-Bis(4-bromophenyl)-1-methyl-1H-benzo[f]chromene (3d)
White solid; yield: 389.6 mg (77%); mp 181–182 °C.
FTIR (film): 3025, 2966, 2924, 2855, 1667, 1621, 1491, 1453, 1401,
1324, 1289, 1262, 1093, 1014, 828 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 8.7 Hz, 2 H), 7.56–7.23 (m,
11 H), 7.15 (t, J = 8.4 Hz, 1 H), 5.22 (s, 1 H), 2.14 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 149.0, 148.6, 142.5, 132.5, 131.9, 131.7,
131.4, 131.1, 129.6, 129.0, 128.8, 126.1, 126.0, 125.9, 123.8, 122.5,
120.0, 118.1, 118.0, 108.9, 40.6, 28.9.
1-Methyl-1,3-diphenyl-1H-benzo[f]chromene (3a); Typical Proce-
dure
The mixture of 2-naphthol (1a, 99%, 145.6 mg, 1.0 mmol), acetophe-
none (2a, 98%, 303.4 mg, 2.5 mmol), and Fe(OTf)3 (98%, 25.1 mg, 0.05
mmol) in 1,2-dichloroethane (1 mL) was stirred at 90 °C (sealed tube)
for 12 h, cooled to r.t., quenched with sat. NaHCO3 solution (20 mL),
and extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with brine, dried (anhyd Na2SO4), filtered, and concen-
trated. The residue was purified by column chromatography (silica
gel) to afford 3a as a pale yellow oil; yield: 292.7 mg (84%).
HRMS (ESI): m/z [M + H]+ calcd for C26H19Br2O: 504.9797; found:
504.9790.
1-Methyl-1,3-di(4-tolyl)-1H-benzo[f]chromene (3e)
White solid; yield: 251.9 mg (67%); mp 165–166 °C.
FTIR (film): 2920, 2849, 1647, 1513, 1322, 1232, 812 cm–1
.
FTIR (film): 3055, 2960, 2925, 2853, 1678, 1671, 1599, 1572, 1506,
1490, 1465, 1396, 1372, 1313, 1288, 1261, 1227, 1204, 1094, 1077,
1H NMR (400 MHz, CDCl3): δ = 7.71–7.56 (m, 5 H), 7.32–7.08 (m, 9 H),
5.21 (s, 1 H), 2.34 (s, 3 H), 2.28 (s, 3 H), 2.13 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.9, 147.4, 142.8, 138.1, 135.2,
131.8, 131.5, 131.0, 129.2, 129.1, 128.9, 128.7, 126.9, 126.3, 125.5,
124.4, 123.4, 119.0, 118.3, 108.5, 40.4, 29.1, 21.2, 20.9.
1014, 962, 893, 858, 814, 748 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.70–7.65 (m, 4 H), 7.53 (d, J = 8.7 Hz, 1
H), 7.43 (d, J = 7.5 Hz, 2 H), 7.33–7.04 (m, 9 H), 5.27 (s, 1 H), 2.14 (s, 3
H).
13C NMR (75 MHz, CDCl3): δ = 150.1, 148.9, 142.9, 133.8, 131.9, 131.4,
129.3, 128.8, 128.5, 128.3, 128.2, 127.0, 126.3, 125.8, 125.6, 124.5,
123.5, 118.8, 118.3, 109.1, 40.8, 29.0.
HRMS (ESI): m/z [M + H]+ calcd for C26H21O: 349.1587; found:
349.1585.
HRMS (ESI): m/z [M + H]+ calcd for C28H25O: 377.1900; found:
377.1910.
1-Methyl-1,3-bis(4-nitrophenyl)-1H-benzo[f]chromene (3f)
Yellow foam; yield: 144.5 mg (33%).
FTIR (film): 1622, 1514, 1347, 854 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.25–8.10 (m, 5 H), 7.84–7.62 (m, 6 H),
1,3-Bis(4-fluorophenyl)-1-methyl-1H-benzo[f]chromene (3b)
7.36–7.25 (m, 3 H), 5.42 (s, 1 H), 2.26 (s, 3 H).
White solid; yield: 280.3 mg (73%); mp 159–160 °C.
13C NMR (100 MHz, CDCl3): δ = 156.4, 148.4, 147.8, 147.4, 146.3,
142.5, 139.3, 130.3, 129.3, 127.9, 126.33, 126.28, 125.6, 125.3, 124.2,
124.1, 123.7, 123.4, 118.0, 110.7, 41.4, 29.0.
FTIR (film): 1640, 1599, 1494, 1437, 1381, 1089, 1008, 813 cm–1
1H NMR (400 MHz, CDCl3): δ = 7.72–7.62 (m, 4 H), 7.54–7.31 (m, 4 H),
.
7.25–7.11 (m, 2 H), 7.06–6.93 (m, 4 H), 5.18 (s, 1 H), 2.15 (s, 3 H).
Anal. Calcd for C26H18N2O5: C, 71.23; H, 4.14; N, 6.39. Found: C, 71.45;
H, 4.01; N, 6.58.
13C NMR (100 MHz, CDCl3): δ = 163.5 (d, 1JC-F = 188 Hz, 1 C), 160.3 (d,
4
1JC-F = 185 Hz, 1 C), 148.7, 145.9 (d, JC-F = 4 Hz, 1 C), 142.3, 131.9,
131.2, 129.8 (d, 4JC–F = 4 Hz, 1 C), 129.5, 128.9, 128.5 (d, 3JC–F = 10 Hz, 1
C), 126.4 (d, 3JC–F = 11 Hz, 1 C), 126.1, 125.7, 123.7, 118.5, 118.2, 115.3
(d, 2JC–F = 28 Hz, 1 C), 115.2 (d, 2JC–F = 29 Hz, 1 C), 108.6, 40.3, 29.2.
1-Methyl-1,3-bis[4-(trifluoromethyl)phenyl]-1H-benzo-
[f]chromene (3g)
White solid; yield: 329.1 mg (68%); mp 132–134 °C.
HRMS (ESI): m/z [M + H]+ calcd for C26H19F2O: 385.1399; found:
385.1401.
FTIR (film): 2934, 2360, 1618, 1411, 1323, 1232, 1166, 1122, 1072,
1015, 908, 814, 734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.79–7.76 (m, 4 H), 7.65–7.58 (m, 6 H),
7.44–7.42 (d, J = 8.5 Hz, 1 H), 7.38–7.35 (d, J = 8.8 Hz, 1 H), 7.30–7.28
(d, J = 8.8 Hz, 1 H), 7.19–7.15 (t, J = 7.3 Hz, 1 H), 5.34 (s, 1 H), 2.23 (s, 3
H).
1,3-Bis(4-chlorophenyl)-1-methyl-1H-benzo[f]chromene (3c)
White solid; yield: 354.4 mg (85%); mp 172–173 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

H
K. Deng et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 153.5, 148.6, 142.5, 136.9, 132.1,
131.0, 130.4 (q, JC–F = 32 Hz, 1 C), 129.9, 129.1, 128.3 (q, JC–F = 32.3 Hz,
1 C), 127.3, 126.1, 125.9, 125.7 (q, JC–F = 3.6 Hz, 1 C), 125.3 (q, JC–F = 3.7
Hz, 1 C), 124.8, 123.9, 122.8, 122.7, 118.1, 117.7, 109.9, 41.0, 28.9.
HRMS (ESI): m/z [M + H]+ calcd for C28H19F6O: 485.1262; found:
485.1260.
1H NMR (400 MHz, CDCl3): δ = 8.16 (d, J = 8.6 Hz, 1 H), 7.76 (d, J = 8.1
Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.40 (t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.4
Hz, 1 H), 7.18 (d, J = 8.7 Hz, 1 H), 3.04–2.97 (m, 1 H), 2.60 (d, J = 8.7 Hz,
1 H), 2.28 (dd, J1 = 9.1 Hz, J2 = 21.1 Hz, 2 H), 2.00–1.56 (m, 8 H), 1.27–
1.21 (m, 4 H), 1.09 (d, J = 5.7 Hz, 3 H), 0.95 (d, J = 6.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.1, 134.7, 130.3, 130.1, 128.8,
128.7, 125.6, 125.5, 125.1, 122.6, 120.1, 118.5, 76.7, 34.1, 32.8, 32.0,
31.7, 31.2, 30.2, 30.1, 29.7, 29.6, 29.0, 22.5, 22.1.
1-Methyl-1,3-di(1-naphthyl)-1H-benzo[f]chromene (3h)
Green foam; yield: 246.4 mg (55%).
HRMS (ESI): m/z [M + H]+ calcd for C24H29O: 333.2213; found:
333.2212.
FTIR (film): 3054, 2959, 2923, 2851, 1626, 1595, 1511, 1454, 1396,
1373, 1259, 1210, 1163, 1015, 862, 815, 798, 778, 747 cm–1
.
9-Bromo-1-methyl-1,3-diphenyl-1H-benzo[f]chromene (3l)
White solid; yield: 337 mg (79%); mp 187–188 °C.
1H NMR (400 MHz, CDCl3): δ = 8.21–6.92 (m, 20 H), 5.28 (s, 1 H), 2.01
(s, 3 H).
FTIR (film): 2979, 2359, 1737, 1614, 1498, 1445, 1373, 1320, 1044,
13C NMR (100 MHz, CDCl3): δ = 144.9, 143.5, 140.8, 136.6, 135.0,
134.0, 133.5, 131.9, 130.2, 129.1, 128.9, 128.8, 128.3, 127.7, 127.4,
126.7, 126.3, 126.1, 126.0, 125.9, 125.8, 125.5, 125.4, 125.1, 124.3,
120.3, 115.1, 104.2, 102.5, 102.0, 38.4, 29.7.
HRMS (ESI): m/z [M + H]+ calcd for C34H25O: 449.1900; found:
449.1903.
835, 762, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.76 (d, J = 1.3 Hz, 1 H), 7.73–7.70 (m, 3
H), 7.61 (d, J = 8.6 Hz, 1 H), 7.51–7.49 (m, 2 H), 7.39–7.29 (m, 7 H),
7.25 (t, J = 7.3 Hz, 1 H), 5.32 (s, 1 H), 2.16 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.4, 142.9, 133.5, 132.7, 130.2,
130.1, 129.0, 128.6, 128.5, 128.4, 128.2, 127.3, 127.0, 126.8, 126.1,
124.4, 120.0, 118.7, 118.3, 108.8, 40.6, 28.8.
1-Methyl-1,3-dipropyl-1H-benzo[f]chromene (3i)
Yellow oil; yield: 173.6 mg (62%).
HRMS (ESI): m/z [M + H]+ calcd for C26H20BrO: 427.0692; found:
427.0695.
FTIR (film): 2958, 2931, 2871, 1740, 1463, 1372, 1345, 1235, 1046,
813, 748 cm–1
.
8-Bromo-1,3-bis(4-fluorophenyl)-1-methyl-1H-ben-
zo[f]chromene (3m)
1H NMR (400 MHz, CDCl3): δ = 8.35 (d, J = 8.7 Hz, 1 H), 7.75–7.73 (m, 1
H), 7.60 (d, J = 8.8 Hz, 1 H), 7.41 (t, J = 8.8 Hz, 1 H), 7.32 (t, J = 8.8 Hz, 1
H), 7.04 (d, J = 8.8 Hz, 1 H), 4.30 (s, 1 H), 2.61–2.53 (m, 2 H), 2.18 (t, J =
7.4 Hz, 2 H), 1.75 (s, 3 H), 1.64 (qd, J1 = 7.4 Hz, J2 = 14.7 Hz, 3 H), 1.40–
1.34 (m, 2 H), 1.26 (s, 2 H), 0.99 (t, J = 7.4 Hz, 3 H).
White solid; yield: 328.7 mg (71%); mp 199–200 °C.
FTIR (film): 3057, 2967, 2927, 1674, 1602, 1508, 1381, 1370, 1319,
1232, 1160, 1014, 837, 813, 746 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 149.6, 147.5, 132.5, 131.4, 129.2,
128.5, 125.4, 125.4, 123.2, 118.4, 118.3, 108.0, 45.7, 37.0, 34.7, 32.0,
19.9, 19.6, 14.4, 13.5.
1H NMR (400 MHz, CDCl3): δ = 8.44 (d, J = 8.4 Hz, 1 H), 7.85–7.77 (m, 3
H), 7.62–7.38 (m, 5 H), 7.17–7.13 (m, 2 H), 7.03–7.00 (m, 2 H), 5.45 (s,
1 H), 1.94 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C20H25O: 281.1900; found:
281.1902.
13C NMR (100 MHz, CDCl3): δ = 163.3 (d, 1JC–F = 179 Hz, 1 C), 160.9 (d,
4
1JC–F = 176 Hz, 1 C), 145.7 (d, JC–F = 3 Hz, 1 C), 145.1, 144.6, 133.1,
130.4 (d, 4JC–F = 3 Hz, 1 C), 129.2 (d, 3JC–F = 8 Hz, 1 C), 127.6, 126.6 (d,
3JC-F = 8 Hz, 1 C), 126.4, 126.2, 125.6, 124.1, 123.2, 121.8, 121.7, 115.3
(d, 2JC–F =50 Hz, 1 C), 115.1 (d, 2JC-F = 49 Hz, 1 C), 106.8, 39.6, 30.5.
1′,2′,3′,4′-Tetrahydrospiro[cyclohexane-1,5′-diben-
zo[c,f]chromene] (3j)
HRMS (ESI): m/z [M + H]+ calcd for C26H18BrF2O: 463.0504; found:
Yellow oil; yield: 130.7 mg (43%).
463.0507.
FTIR (film): 2929, 2853, 1737, 1593, 1447, 1371, 1236, 1044, 998,
806, 745 cm–1
.
4-Methyl-2,4-di(4-tolyl)-4H-benzo[h]chromene (3n)
Yellow oil; yield: 259.4 mg (69%).
1H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.6 Hz, 1 H), 7.76 (d, J = 7.9
Hz, 1 H), 7.64 (d, J = 8.7 Hz, 1 H), 7.41–7.37 (m, 1 H), 7.30 (t, J = 7.4 Hz,
1 H), 7.19 (d, J = 8.7 Hz, 1 H), 2.75 (t, J = 5.6 Hz, 2 H), 2.23 (t, J = 6.3 Hz,
2 H), 1.98 (d, J = 13.3 Hz, 2 H), 1.84–1.64 (m, 8 H), 1.49–1.44 (m, 4 H).
FTIR (film): 3054, 3025, 2961, 2923, 2854, 1672, 1574, 1511, 1454,
1380, 1319, 1289, 1201, 1100, 1074, 1015, 810, 748 cm–1
.
13C NMR (100 MHz, CDCl3): δ = 150.1, 135.1, 130.3, 130.0, 128.8,
128.7, 125.8, 125.6, 125.1, 122.6, 120.3, 118.4, 77.2, 31.3, 31.1, 25.5,
25.2, 23.4, 22.9, 21.5.
1H NMR (400 MHz, CDCl3): δ = 8.47 (d, J = 8.7 Hz, 1 H), 7.78–7.49 (m, 5
H), 7.44–7.27 (m, 4 H), 7.25–7.05 (m, 4 H), 5.49 (s, 1 H), 2.41 (s, 3 H),
2.32 (s, 3 H), 1.93 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C22H25O: 305.1900; found:
305.1901.
13C NMR (100 MHz, CDCl3): δ = 147.2, 145.8, 144.8, 138.3, 135.7,
133.0, 131.7, 129.1, 128.9, 127.6, 127.5, 126.1, 125.9, 125.8, 124.7,
124.3, 122.8, 122.4, 121.9, 106.7, 39.7, 29.7, 21.3, 20.9;
HRMS (ESI): m/z [M + H]+ calcd for C28H25O: 377.1900; found:
377.1910.
3′,4-Dimethyl-1′,2′,3′,4′-tetrahydrospiro[cyclohexane-1,5′-diben-
zo[c,f]chromene] (3k)
Yellow solid; yield: 152.7 mg (46%); mp 135–136 °C.
4-Methyl-2,4-bis(4-nitrophenyl)-4H-benzo[h]chromene (3o)
Yellow foam; yield: 135.8 mg (31%).
FTIR (film): 2949, 2921, 2853, 1738, 1456, 1371, 1234, 1045, 989,
810, 745 cm–1
.
FTIR (film): 2958, 2923, 2852, 1599, 1517, 1395, 1368, 1346, 1261,
1211, 1106, 810, 752 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

I
K. Deng et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 8.71 (d, J = 8.4 Hz, 2 H), 8.16 (d, J = 8.4
Hz, 2 H), 7.83–7.57 (m, 6 H), 7.47 (d, J = 8.0 Hz, 2 H), 6.90 (d, J = 8.0 Hz,
2 H), 5.30 (s, 1 H), 2.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 156.7, 147.1, 145.8, 145.2, 144.3,
133.3, 129.7, 127.7, 126.9, 126.5, 125.6, 124.2, 123.42, 123.37, 122.5,
121.9, 121.8, 121.6, 120.7, 105.3, 43.3, 29.7.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.64 (m, 2 H), 7.37–7.33 (m, 4 H),
7.29–7.27 (m, 2 H), 7.25 (dd, J1 = 2.3 Hz, J2 = 8.6 Hz, 1 H), 7.08 (d, J =
8.6 Hz, 1 H), 6.98 (d, J = 2.3 Hz, 1 H), 5.39 (s, 1 H), 1.89 (s, 3 H), 1.24 (s,
9 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 147.9, 146.4, 145.4, 134.2,
132.6, 131.8, 128.6, 128.4, 128.2, 127.0, 125.9, 124.8, 124.7, 115.9,
106.8, 39.6, 34.3, 31.3, 30.4.
Anal. Calcd for C26H18N2O5: C, 71.23; H, 4.14; N, 6.39. Found: C, 71.32;
H, 4.05; N, 6.53.
HRMS (ESI): m/z [M + H]+ calcd for C26H25Cl2O: 423.1277; found:
423.1280.
2,4-Bis(4-methoxyphenyl)-4-methyl-4H-benzo[h]chromene (3p)
Pale yellow oil; yield: 310 mg (76%).
2,4-Bis(4-chlorophenyl)-4-methyl-6-phenyl-4H-chromene (3t)
Pale yellow oil; yield: 256.9 mg (58%).
FTIR (film): 2964, 2924, 2854, 1666, 1490, 1276, 1085, 833, 819 cm–1
.
FTIR (film): 3053, 2957, 2926, 2853, 1609, 1596, 1578, 1511, 1461,
1385, 1277, 1251, 1179, 1083, 1034, 831, 814, 794, 772 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 7.6 Hz, 2 H), 7.61 (d, J = 7.6
Hz, 2 H), 7.59 (d, J = 8.3 Hz, 1 H), 7.35–7.11 (m, 5 H), 6.88 (d, J = 6.4 Hz,
2 H), 6.70 (d, J = 6.4 Hz, 2 H), 5.14 (s, 1 H), 3.79 (s, 3 H), 3.74 (s, 3 H),
2.12 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.7, 157.5, 148.9, 142.8, 142.5,
131.8, 131.6, 129.1, 128.8, 128.0, 126.5, 126.4, 125.9, 125.5, 123.4,
119.0, 118.3, 113.8, 113.6, 107.8, 55.3, 55.1, 40.1, 29.2.
1H NMR (400 MHz, CDCl3): δ = 7.70–7.60 (m, 3 H), 7.47–7.29 (m, 11
H), 7.21–7.15 (m, 2 H), 5.41 (s, 1 H), 1.92 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.6, 148.2, 145.4, 140.8, 135.1,
132.4, 132.2, 129.1, 128.8, 128.7, 128.6, 128.4, 128.2, 127.1, 127.0,
126.8, 126.5, 126.0, 117.0, 106.9, 39.7, 30.5.
HRMS (ESI): m/z [M + H]+ calcd for C28H21Cl2O: 443.0964; found:
443.0961.
HRMS (ESI): m/z [M + H]+ calcd for C28H25O3: 409.1798; found:
409.1793.
2,4-Bis(4-phenyl)-6-ethoxy-4-methyl-4H-chromene (3u)
Yellow solid; yield: 317.6 mg (80%); mp 100–101 °C.
4-Methyl-2,4-di(1-naphthyl)-4H-benzo[h]chromene (3q)
FTIR (film): 3372, 2969, 2357, 1666, 1496, 1445, 1275, 1205, 1049,
Green foam; yield: 237.4 mg (53%).
FTIR (film): 2960, 2922, 2851, 1487, 1378, 1260, 1080, 808, 766 cm–1
759, 735, 699 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.74–7.72 (m, 2 H), 7.45–7.30 (m, 8 H),
7.20 (t, J = 7.30 Hz, 1 H), 7.09 (d, J = 8.9 Hz, 1 H), 6.76 (dd, J1 = 3.0 Hz, J2
= 8.9 Hz, 1 H), 5.41 (s, 1 H), 3.69 (s, 3 H), 1.90 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 155.4, 149.6, 146.1, 144.5, 134.2,
129.3, 128.3, 128.2, 128.1, 127.3, 126.0, 124.6, 117.1, 113.1, 113.0,
106.1, 55.5, 40.1, 30.3.
1H NMR (400 MHz, CDCl3): δ = 8.52 (d, J = 8.4 Hz, 1 H), 7.96 (d, J = 8.4
Hz, 2 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.71–7.30 (m, 15 H), 7.12 (d, J = 8.4
Hz, 1 H), 5.63 (s, 1 H), 2.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 149.0, 145.6, 144.8, 141.3, 140.7,
140.6, 139.0, 133.3, 133.1, 128.9, 128.7, 128.1, 127.54, 127.49, 127.2,
127.1, 127.0, 126.4, 126.3, 126.1, 125.9, 125.2, 124.3, 123.0, 122.0,
121.8, 107.3, 39.9, 29.7.
HRMS (ESI): m/z [M + H]+ calcd for C23H21O2: 329.1536; found:
329.1539.
HRMS (ESI): m/z [M + H]+ calcd for C34H25O: 449.1900; found:
449.1902.
2,4-Bis(4-chlorophenyl)-4,6,8-trimethyl-4H-chromene (3v)
Pale yellow solid; yield: 240.9 mg (61%); mp 105–108 °C.
2,4-Bis(4-chlorophenyl)-4,6-dimethyl-4H-chromene (3r)
Pale yellow oil; yield: 251.4 mg (66%).
FTIR (film): 2966, 2924, 2852, 1670, 1598, 1492, 1438, 1401, 1375,
1329, 1296, 1278, 1260, 1216, 1147, 1093, 1040, 1012, 919, 859, 833,
FTIR (film): 2968, 2928, 2857, 1664, 1591, 1494, 1397, 1316, 1291,
808, 744, 716, 678 cm–1
.
1234, 1089, 1008, 813, 724 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.56 (d, J = 8.1 Hz, 2 H), 7.28–7.17 (m, 6
H), 6.77 (s, 1 H), 6.47 (s, 1 H), 5.28 (s, 1 H), 2.32 (s, 3 H), 2.09 (s, 3 H),
1.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.6, 146.2, 145.3, 134.2, 132.8,
132.3, 131.9, 129.8, 128.8, 128.5, 128.3, 127.2, 126.1, 125.9, 125.4,
106.7, 39.7, 29.7, 20.7, 16.2.
1H NMR (400 MHz, CDCl3): δ = 7.70–7.60 (m, 4 H), 7.36–7.28 (m, 4 H),
7.03–6.72 (m, 2 H), 6.72 (s, 1 H), 5.35 (s, 1 H), 2.22 (s, 3 H), 1.85 (s, 3
H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 148.0, 141.4, 134.3, 133.1,
129.1, 128.8, 128.53, 128.47, 128.4, 128.3, 127.5, 126.0, 125.0, 116.3,
106.7, 39.5, 29.7, 20.8.
HRMS (ESI): m/z [M + H]+ calcd for C24H21Cl2O: 395.0964; found:
395.0963.
HRMS (ESI): m/z [M + H]+ calcd for C23H19Cl2O: 381.0807; found:
381.0810.
2,4-Bis(4-chlorophenyl)-4,6,7-trimethyl-4H-chromene (3w)
Pale yellow oil; yield: 292.3 mg (74%).
6-tert-Butyl-2,4-bis(4-chlorophenyl)-4-methyl-4H-chromene (3s)
Yellow solid; yield: 313 mg (74%); mp 96–97 °C.
FTIR (film): 2969, 2921, 1672, 1494, 1397, 1324, 1283, 1089, 1008,
FTIR (film): 2963, 2868, 1737, 1495, 1400, 1322, 1257, 1092, 1035,
837, 805 cm–1
.
819, 743 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.71–7.32 (m, 8 H), 7.01 (s, 1 H), 6.75
(s, 1 H), 5.42 (s, 1 H), 2.30 (s, 3 H), 2.19 (s, 3 H), 1.91 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

J
K. Deng et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 148.5, 148.0, 145.4, 136.2, 134.2,
132.7, 129.0, 128.9, 128.7, 128.5, 128.4, 128.2, 125.9, 125.0, 117.2,
106.8, 39.2, 30.3, 19.4, 19.1.
HRMS (ESI): m/z [M + H]+ calcd for C24H21Cl2O: 395.0964; found:
395.0969.
Funding Information
This work was supported by the National Natural Science Foundation
of China (21672046, 21372054), the Fundamental Research
Funds for the Central Universities
(HIT.NSRIF.201701,
201708),
and the Natural Science Foundation of Shandong (2015ZRA10064).
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6-Chloro-2,4-bis(4-chlorophenyl)-4,5,7-trimethyl-4H-chromene
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Yellow oil; yield: 227.3 mg (53%).
Supporting Information
FTIR (film): 2981, 2928, 2359, 1737, 1492, 1393, 1312, 1238, 1093,
Supporting information for this article is available online at
1045, 1012, 830 cm–1
.
https://doi.org/10.1055/s-00xx-xxxxxxx.
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1H NMR (400 MHz, CDCl3): δ = 7.56 (m, 2 H), 7.32–7.18 (m, 6 H), 6.98
(s, 1 H), 5.12 (s, 1 H), 2.39 (s, 3 H), 1.89 (s, 3 H), 1.88 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.8, 148.4, 142.0, 136.1, 135.3,
134.2, 132.0, 131.7, 131.2, 128.6, 128.4, 128.1, 125.7, 123.9, 116.9,
108.2, 40.5, 28.6, 20.8, 19.0.
References
(1) (a) Hatakeyama, S.; Ochi, N.; Numata, H.; Takano, S. Chem.
Commun. 1998, 1202. (b) Gonzalez, R.; Martin, N.; Seoane, C.;
Marco, J. L.; Albert, A.; Cano, F. H. Tetrahedron Lett. 1992, 33,
3809. (c) Wu, Y. C.; Liu, L.; Liu, Y. L.; Wang, D.; Chen, Y. J. J. Org.
Chem. 2007, 72, 9383. (d) Jeso, V.; Nicolaou, K. C. Tetrahedron
Lett. 2009, 50, 1161. (e) Wu, Y. C.; Li, H. J.; Liu, L.; Liu, Z.; Wang,
D.; Chen, Y. J. Org. Biomol. Chem. 2011, 9, 2868. (f) Wu, Y. C.; Li,
H. J.; Liu, L.; Demoulin, N.; Liu, Z.; Wang, D.; Chen, Y. J. Adv.
Synth. Catal. 2011, 353, 907. (g) Yao, C.; Jiang, B.; Li, T.; Qin, B.;
Feng, X.; Zhang, H.; Wang, C.; Tu, S. Bioorg. Med. Chem. Lett.
2011, 21, 599. (h) Wu, Y. C.; Li, H. J.; Liu, L.; Demoulin, N.; Liu, Z.;
Wang, D.; Chen, Y. J. Synlett 2011, 1573. (i) Li, H.-J.; Wang, J.-L.;
Wang, R.; Luo, D.-H.; Wu, Y.-C. J. Chem. 2013, Article ID 106908;
http://www.hindawi.com/journals/jchem/. (j) Li, H. J.; Luo, D.
H.; Wu, Q. X.; Dai, C. Y.; Shen, Z. L.; Wu, Y. C. Chin. Chem. Lett.
2014, 25, 1235. (k) Costa, M.; Dias, T. A.; Brito, A.; Proença, F.
Eur. J. Med. Chem. 2016, 123, 487.
HRMS (ESI): m/z [M + H]+ calcd for C24H20Cl3O: 429.0574; found:
429.0575.
4,10-Dimethyl-2,4,8,10-tetraphenyl-4,10-dihydrochromeno[6,5-
f]chromene (3y)
Pale yellow oil; yield: 369.2 mg (65%).
FTIR (film): 3058, 2965, 2360, 2342, 1654, 1599, 1447, 1324, 1261,
906, 762, 731, 699, 668 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.66–7.64 (d, J = 7.4 Hz, 4 H), 7.56–7.54
(d, J = 9.4 Hz, 2 H), 7.49–7.47 (d, J = 7.4 Hz, 4 H), 7.38–7.34 (m, 10 H),
7.24–7.21 (t, J = 7.0 Hz, 2 H), 7.01–7.00 (d, J = 9.4 Hz, 2 H), 5.25 (s, 2 H),
2.19 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 150.3, 147.1, 142.7, 133.8, 129.8,
128.5, 128.2, 128.2, 127.1, 127.0, 125.8, 124.4, 119.7, 117.4, 109.0,
40.9, 29.4.
(2) Aryapour, H.; Mahdavi, M.; Mohebbi, S. R.; Zali, M. R.;
Foroumadi, A. Arch. Pharmacal Res. 2012, 35, 1573.
(3) Xu, Z. Q.; Pupek, K.; Suling, W. J.; Enache, L.; Flavin, M. T. Bioorg.
Med. Chem. 2006, 14, 4610.
HRMS (ESI): m/z [M + H]+ calcd for C42H33O2: 569.2479; found:
569.2475.
(4) Martínez-Grau, A.; Marco, J. L. Bioorg. Med. Chem. Lett. 1997, 7,
3165.
(5) Sangani, C. B.; Shah, N. M.; Patel, M. P.; Patel, R. G. Med. Chem.
Res. 2013, 22, 3831.
1,3,5-Triphenylbenzene (4a)
White solid; mp 172–174 °C.
FTIR (film): 1648, 1048, 1026, 997, 827, 766, 633 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.81 (s, 3 H), 7.73–7.71 (m, 6 H), 7.51–
7.48 (m, 6 H), 7.42–7.39 (m, 3 H).
(6) Kamdar, N. R.; Haveliwala, D. D.; Mistry, P. T.; Patel, S. K. Med.
Chem. Res. 2011, 20, 854.
(7) Narender, T.; Shweta Gupta, S. Bioorg. Med. Chem. Lett. 2004, 14,
3913.
(8) Symeonidis, T.; Chamilos, M.; Hadjipavlou-Litina, D. J.;
Kallitsakis, M.; Litinas, K. E. Bioorg. Med. Chem. Lett. 2009, 19,
1139.
13C NMR (100 MHz, DMSO-d6): δ = 141.6, 140.0, 128.8, 127.6, 127.1,
124.3.
Anal. Calcd for C24H18: C, 94.08; H, 5.92. Found: C, 94.18; H, 5.99.
Dypnone (5a)
(9) Das, S. G.; Hermanson, D. L.; Bleeker, N.; Lowman, X.; Li, Y.;
Kelekar, A.; Xing, C. ACS Chem. Biol. 2013, 8, 327.
Pale yellow oil.
(10) (a) Appel, B.; Saleh, N. N. R.; Langer, P. Chem.–Eur. J. 2006, 12,
1221. (b) Nising, C. F.; Ohnemuller, U. K.; Brase, S. Angew. Chem.
Int. Ed. 2006, 45, 307.
FTIR (film): 3027, 2919, 1658, 1601, 1575, 1493, 1448, 1380, 1356,
1275, 1214, 1179, 1047, 1025, 951, 868, 855, 753, 693 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.04–7.40 (m, 10 H), 7.20 (d, J = 0.3 Hz,
1 H), 2.64 (d, J = 0.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.3, 154.7, 142.4, 139.1, 132.2,
(11) (a) Corey, E. J.; Wu, L. I. J. Am. Chem. Soc. 1993, 115, 9327.
(b) Salni, D.; Sargent, M. V.; Skelton, B. W.; Soediro, I.; Sutisna,
M.; White, A. H.; Yulinah, E. Aust. J. Chem. 2002, 55, 229.
(c) Shaheen, F.; Ahmad, M.; Nahar Khan, S.; Samreen Hussain,
S.; Anjum, S.; Tashkhodjaev, B.; Choudhary, M. I. Eur. J. Org.
Chem. 2006, 2371. (d) Wang, J. L.; Liu, D.; Zhang, Z. J.; Shan, S.;
Han, X.; Srinivasula, S. M.; Huang, Z. Proc. Natl. Acad. Sci. U. S. A.
2000, 97, 7124.
128.9, 128.3, 128.2, 128.0, 126.2, 121.7, 18.5.
Anal. Calcd for C16H14O: C, 86.45; H, 6.35. Found: C, 86.58; H, 6.23.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K

K
K. Deng et al.
Paper
Synthesis
(12) For selected examples see: (a) Engler, T. A.; LaTessa, K. O.;
Iyengar, R.; Chai, W.; Agrios, K. Bioorg. Med. Chem. 1996, 4,
1755. (b) Elomri, A.; Mitaku, S.; Michel, S.; Skaltsounis, A. L.;
Tillequin, F.; Koch, M.; Rolland, Y. J. Med. Chem. 1996, 39, 4762.
(c) Kidwai, M.; Saxena, S. M.; Khan, K. R.; Thukral, S. S. Bioorg.
Med. Chem. Lett. 2005, 15, 4295. (d) Tahtaoui, C.; Demailly, A.;
Guidemann, C.; Joyeux, C.; Schneider, P. J. Org. Chem. 2010, 75,
3781.
(13) (a) Mukai, K.; Okabe, K.; Hosose, H. J. Org. Chem. 1989, 54, 557.
(b) Jankun, J.; Selman, S. H.; Swiercz, R. Nature (London) 1997,
387, 561.
(14) (a) Paramonov, S.; Delbaere, S.; Fedorova, O.; Fedorov, Y.;
Lokshin, V.; Samat, A.; Vermeersch, G. J. Photochem. Photobiol.
2010, 209, 111. (b) Evans, R. A.; Such, G. K. Aust. J. Chem. 2005,
58, 825.
(15) Zacheis, D.; Dhar, A.; Lu, S.; Madler, M. M.; Klucik, J.; Brown, C.
W.; Berlin, K. D. J. Med. Chem. 1999, 42, 4434.
(16) Rao, V. K.; Kaswan, P.; Parang, K.; Kumar, A. Org. Biomol. Chem.
2015, 13, 11072.
(17) Fan, J.; Wang, Z. Chem. Commun. 2008, 5381.
(18) Azizi, N.; Mariami, M.; Edrisi, M. Dyes Pigm. 2004, 100, 215.
(19) Aoyama, T.; Yamamoto, T.; Miyota, S.; Hayakawa, M.; Takido, T.;
Kodomari, M. Synlett 2014, 25, 1571.
(20) Xue, W. J.; Li, Q.; Gao, F. F.; Zhu, Y. P.; Wang, J. G.; Zhang, W.;
Wu, A. X. ACS Comb. Sci. 2012, 14, 478.
(23) Liu, Y.; Qian, J.; Lou, S.; Zhu, J.; Xu, Z. J. Org. Chem. 2010, 75,
1309.
(24) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104,
6217. (b) Correa, A.; Mancheño, O. G.; Bolm, C. Chem. Soc. Rev.
2008, 37, 1108. (c) Bauer, E. B. Curr. Org. Chem. 2008, 12, 1341.
(d) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293.
(e) Gaillard, S.; Renaud, J. L. ChemSusChem 2008, 1, 505.
(f) Junge, K.; Schröder, K.; Beller, M. Chem. Commun. 2011, 47,
4849.
(25) (a) Alves, M. H. M. E.; Nascimento, G. A.; Cabrera, M. P.; da Cruz
Silvério, S. I.; Nobre, C.; Teixeira, J. A.; de Carvalho, L. B. Food
Chem. 2017, 226, 75. (b) Valko, M.; Morris, H.; Cronin, M. T. D.
Curr. Med. Chem. 2005, 12, 1161. (c) Hentze, M. W.;
Muckenthaler, M. U.; Andrews, N. C. Cell 2004, 117, 285. (d) Lill,
R. Nature (London) 2009, 460, 831. (e) Rosenzweig, A. C.;
Brandstetter, H.; Whittington, D. A.; Nordlund, P.; Lippard, S. J.;
Frederick, C. A. Proteins: Struct., Funct., Genet. 1997, 29, 141.
(26) (a) Li, H. J.; Wu, Y. Y.; Wu, Q. X.; Wang, R.; Dai, C. Y.; Shen, Z. L.;
Xie, C. L.; Wu, Y. C. Org. Biomol. Chem. 2014, 12, 3100. (b) Wu, Q.
X.; Li, H. J.; Wang, H. S.; Zhang, Z. G.; Wang, C. C.; Wu, Y. C.
Synlett 2015, 26, 243. (c) Li, H. J.; Wang, R.; Gao, J.; Wang, Y. Y.;
Luo, D. H.; Wu, Y. C. Adv. Synth. Catal. 2015, 357, 1393. (d) Li, H.
J.; Wang, C. C.; Zhu, S.; Dai, C. Y.; Wu, Y. C. Adv. Synth. Catal.
2015, 357, 583. (e) Wang, Q.; Wang, M.; Li, H. J.; Zhu, S.; Liu, Y.;
Wu, Y. C. Synthesis 2016, 48, 3985. (f) Ji, Y. Z.; Wang, M.; Li, H. J.;
Liu, Y.; Wu, Y. C. Eur. J. Org. Chem. 2016, 4077. (g) Wang, H. S.; Li,
H. J.; Wang, J. L.; Wu, Y. C. Green Chem. 2017, 19, 2140. (h) Wang,
J. L.; Li, H. J.; Wang, H. S.; Wu, Y. C. Org. Lett. 2017, 19, 3811.
(27) Zhao, Y.; Li, J.; Li, C.; Yin, K.; Ye, D.; Jia, X. Green Chem. 2010, 12,
1370.
(21) Li, H. J.; Deng, K.; Luo, D. H.; Liu, D. H.; Wang, J. L.; Lin, C. H.; Wu,
Y. C. RSC Adv. 2014, 4, 26316.
(22) (a) Corma, A.; Garcia, H. Chem. Rev. 2003, 103, 4307.
(b) Coulombel, L.; Grau, F.; Weiwer, M.; Favier, I.; Chaminade,
X.; Heumann, A.; Dunach, E. Chem. Biodivers. 2008, 5, 1070.
(c) Landa, A.; Richter, B.; Johansen, R. L.; Minkkilä, A.;
Jørgensen, K. A. J. Org. Chem. 2007, 72, 240. (d) Hahn, C. Chem.–
Eur. J. 2004, 10, 5888. (e) Bothwell, J. M.; Krabbe, S. W.; Mohan,
R. S. Chem. Soc. Rev. 2011, 40, 4649.
(28) Deng, K.; Huai, Q. Y.; Shen, Z. L.; Li, H. J.; Liu, C.; Wu, Y. C. Org.
Lett. 2015, 17, 1473.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–K