Synthesis of functional 4H-chromenes from phenols and acetophenones under solvent- and metal-free conditions

Article abstract of DOI:10.1039/c4ra03950e

Sulfuric-acid-promoted tandem reaction of phenols with acetophenones under solvent- and metal-free conditions has been developed, which afforded functional 4H-chromenes in good yields with water as the side product. Sulfuric acid appeared to serve the dual role of an efficient promoter and a suitable dehydrating agent.

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Synthesis of functional 4H-chromenes from phenols and acetophenones
under solvent- and metal-free conditions
Hui-Jing Li,*a,b Kai Deng,a Dong-Hui Luo,a De-Hui Liu,a Jun-Li Wang,a
Chun-Hua Lina and Yan-Chao Wu*a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Sulfuricꢀacidꢀpromoted tandem reaction of phenols with acetophenones under solventꢀ and metalꢀfree
conditions has been developed, which afforded functional 4Hꢀchromenes in good yields with water as the
side product. Sulfuric acid appeared to serve the dual role of an efficient promoter and a suitable
10 dehydrating agent.
gaining much attention for their low cost, safety, and ecoꢀ
friendliness. In connection with our consistent interest in the
50 development of practical strategies for the selective synthesis of
various functional heterocycles14, herein we would like to report a
facile synthesis of functional 4Hꢀchromenes via H2SO4ꢀpromoted
reaction of phenols with acetophenones without use of any
solvent or metalꢀcatalyst.
Introduction
4HꢀChromenes have been a subject of consistent interest due to
the presence of their structural motifs in a large number of natural
products1 and pharmaceuticals. Some of the biological activities
15 attributed to naturally occurring and synthetic 4Hꢀchromenes
include antioxidant2, antifungal3, antimicrobial4, antileishmanial5,
antiviral6, antitubercular7, antiproliferative8 and anticancer9. The
significance and prevalence of this class of compounds has
served to stimulate continual interest in synthetic community.
20 Accordingly, various synthetic methods have been developed for
the construction of 4Hꢀchromenes, which usually require a
55 Results and Discussion
The reaction of 2ꢀnaphthol (1a) with acetophenone (2a) was used
as a probe for evaluating the reaction conditions, and the
representative results are summarized in Table 1. Reaction of 1a
with 2a in the presence of one equivalent of concentrated H2SO4
60 could take place at 15 °C to afford 2,4ꢀbis(aryl)ꢀ4Hꢀchromene 3a
in 5% yield within 1 day (entry 1). An increased yield was
observed when the reaction was performed at 25 °C, reflecting
the temperature factor effect on this reaction (entries 1−2).
Aqueous hydrochloric acid (HCl), formic acid (HCO2H), acetic
65 acid (CH3CO2H), trichloroacetic acid (CCl3CO2H), trifluoroacetic
acid (CF3CO2H), diphenylphosphoric acid [(PhO)2P(O)OH] and
trifluoromethanesulfonic acid (TfOH) were not effective
promoters for this reaction. Treatment of 1a with 2a in nꢀhexane
at 25 °C for 1 day in the presence of these Brønsted acids did not
70 generate any products and the starting materials were recovered
(entries 3–9). Otherwise, pꢀtoluenesulfonic acid (pTsOH)
displayed some efficiency for this reaction, which afforded a
trace of 4Hꢀchromene 3a at 25 °C within 1 day (entry 10). Instead,
H2SO4 is the most efficient promoter for this reaction in all
75 screened Brønsted acids (entries 1–10). The yield of 3a was
increased to 78% by improving the reaction temperature to 60 °C
(entries 1–2 and 11–12). No further increase was observed when
the reaction temperature exceeded 60 °C, and byꢀproduct 4a (Fig.
1) was observed when this reaction was performed at 70 °C
80 (entries 12–13). With the use of toluene, 1,2ꢀdichloroethane(DCE)
and nitromethane (CH3NO2) in comparison to nꢀhexane,
relatively lower yields were observed (entries 12 and 14−16). In
contrast, H2SO4/CH3CO2H was an effective system for this kind
transition metalꢀcatalyst or/and an organocatalyst,
a high
temperature, and use of an organic solvent and unavailable
starting materials10−11. Recently, Liu and Xu have developed an
25 elegant AuCl3/3AgOTfꢀcatalyzed synthesis of 4Hꢀchromenes
from readily available ketones and phenols in 1,2ꢀdichloroethane
under reflux12, in which trifluoromethanesulfonic acid and
aqueous hydrochloric acid were found to be not the suitable
promoters. Wu and coꢀworkers have also developed an
30 impressive synthesis of chromenes from active polyphenols and
acetophenones in the presence of pꢀtoluenesulfonic acid in nꢀ
hexane under reflux (100 °C, sealed tube)13. As witnessed in the
above two examples, it is still a challenge to develop an efficient
Brønstedꢀacidꢀpromoted synthesis of 4Hꢀchromenes from readily
35 available phenols and acetophenones. Considering dehydrating
agents should be favourable in this kind of dehydrative reaction,
we envisioned that the addition of a little concentrated sulfuric
acid (H2SO4) to the reaction mixture would absorb the water
produced, and thereby facilitate the reaction of phenols with
40 acetophenones.
On the other hand, a huge amount of effort has been dedicated
to the development of chemical reactions in agreement with the
principles of green chemistry. Although various green solvents,
such as ionic liquids and water, have been extensively studied,
45 not using a solvent at all is definitely the best option, which
makes the development of solventꢀfree reactions a high priority.
The progress in the field of solventꢀ and metalꢀfree reactions is
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Table 1 Survey of conditions for the reaction of 2ꢀnaphthol (1a) with
acetophenone (2a)a
35 Table 2 H2SO4ꢀpromoted tandem reaction of phenols with acetophenones
under solventꢀfree conditionsa
OH
Ar
O
O
H2SO4
X
X
+
OH
Ar
promoters
50 °C, 1 d
O
Ar
+
1
2
3
conditions
O
1a
2a
Promoters
3a
Entry Phenols 1
Acetophenones 2
Products 3
Entry
Conditions
Yield
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21b
22
1.0 equiv. H2SO4
1.0 equiv. H2SO4
nꢀhexane, 15 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 25 °C
nꢀhexane, 40 °C
nꢀhexane, 60 °C
nꢀhexane, 70 °C
toluene, 60 °C
ClCH2CH2Cl, 60 °C
CH3NO2, 60 °C
CH3CO2H, 60 °C
solventꢀfree, 60 °C
solventꢀfree, 60 °C
solventꢀfree, 50 °C
solventꢀfree, 50 °C
H2O, 50 °C
5%
18%
0
0
0
0
0
0
0
trace
43%
78%
54%
73%
75%
72%
79%
80%
68%
81%
80%
0
OH
1.0 equiv. HCl (37%, H2O)
1.0 equiv. HCO2H
1.0 equiv. CH3CO2H
1.0 equiv. CCl3CO2H
1.0 equiv. CF3CO2H
1.0 equiv. (PhO)2P(O)OH
1.0 equiv. TfOH
1
O
1a
1a
2a
3a: 81%
F
Cl
Br
O
1.0 equiv. pTsOH
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
1.0 equiv. H2SO4
0.1 equiv. H2SO4
1.5 equiv. H2SO4
1.5 equiv. H2SO4
1.5 equiv. H2SO4
2
3
O
2b
3b: 74%
F
F
Cl
Br
O
1a
O
2c
3c: 83%
Cl
O
a General conditions: 1a (1.0 mmol), 2a (3.0 mmol) and promoter in
solvent (0.5 mL) or under solventꢀfree conditions for 1 day.
b Reaction was carried out at 1.45 g scale of 1a (10.0 mmol) under an air
atmosphere.
5
4
5
6
1a
1a
1a
O
2d
3d: 77%
Br
of reaction and might be useful for a large scale process with a
solid mixture of substrates (entry 17). Fortuitously, 3a was
O
10 obtained in 80% yield when the reaction was performed under
solventꢀfree conditions (entry 18). The yield of 3a was decreased
to 68% when the loading of H2SO4 was decreased from one
equivalent to 10 mol% (entry 19), indicating the H2SO4 loading
effect on this reaction. We envisioned that the reaction could go
15 smoothly when a more amount of H2SO4 was used. Gratifyingly,
by treating 1a (1 mmol), 2a (3 mmol) with one and a half
equivalents of concentrated H2SO4, 4Hꢀchromene 3a was
obtained in 81% yield at 50 °C under otherwise identical
conditions (entries 18 and 20). Furthermore, scaling up 1a to 1.45
20 g the reaction provided the yield at an excellent level, which was
easy to perform without the need of using an anhydrous solvent
(entry 21). The reaction did not work in the presence of water
(several drops) under otherwise identical conditions (entries 20
and 22), indicating that concentrated H2SO4 serves also as a
25 dehydrating agent.
With the optimized reaction conditions in hand, the scope of
the reaction was subsequently investigated, and the representative
results are summarized in Table 2. With the para position of
acetophenones bearing a hydrogen atom (entry 1), a weak
30 electronꢀwithdrawing group (entries 2–4) and a weak electronꢀ
donating group (entry 5), acetophenones 2a–e reacted smoothly
with 2ꢀnaphthol (1a) in the presence of H2SO4 (150 mol%) at 50
°C to afford 2,4ꢀbis(aryl)ꢀ4Hꢀchromenes 3a–e in 66–83% yields
within 1 day (entries 1–5). 4′ꢀNitroacetophenone (2f) reacted
O
2e
3e: 66%
NO2
O
O
2f
3f: 69%
NO2
NO2
7
8
1a
O
O
2g
3g: 52%
F
Br
OH
2b
O
Br
1b
3h: 75%
F
a General conditions: 1 (1.0 mmol), 2 (3.0 mmol) and H2SO4 (1.5 mmol)
at 50 °C for 1 day under solventꢀfree conditions.
2
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Table 2 (Contd.)
5
equally well with 1a under the standard conditions to give 4
chromene 3f in 69% yield (entry 6). It is worth mentioning that
deactivated acetophenone 2f prevented the tandem reaction in
toluenesulfonic acid system13. 1'ꢀAcetonaphthone
2g),
commercially available sterically hindered acetophenone, reacted
10 with 2ꢀnaphthol under the standard conditions to generate 4
Hꢀ
OH
Ar
p
ꢀ
O
H2SO4
(
a
X
X
+
Ar
50 °C, 1 d
O
Ar
1
2
3
Hꢀ
chromene 3g in 52% yield (entry 7). It is note worthy that
sterically hindered acetophenones resisted the AuCl3/3AgOTf
system in the tandem reaction of acetophenones with phenols12.
These results indicated that the present protocol might expand the
15 substrate scopes of acetophenones and phenols.
Entry Phenols 1
Acetophenones 2
Products 3
OH
9
2e
The tandem reaction of 6ꢀbromoꢀ2ꢀnaphthol
(1b) with
O
acetophenone 2a went smoothly under the standard conditions to
1c
1c
3i: 72%
generate 4
has also been investigated, which reacted with acetophenones 2e
under the standard conditions to afford 4 ꢀchromenes 3i
good yields (entries 9–12). 4ꢀPhenylphenol (1d) reacted with
acetophenone 2c uneventfully (entry 13). ꢀCresol (1e) reacted
smoothly with acetophenone 2c under the standard conditions to
give ꢀchromene 3n in 67% yield (entry 14). 2,4ꢀ
H
ꢀchromene 3h in 75% yield (entry 8). 1ꢀNaphthol (1c
)
NO2
–
20
h
H
–l in
10
11
2f
O
p
3j: 63%
NO2
4
H
25 Dimethylphenol (1f), a phenol more sterically hindered than
cresol, reacted equally well with acetophenone 2c to give 4
chromene 3o in 66% yield (entry 15). By treatment of active 3,4ꢀ
dimethylphenol (1g) with acetophenone 2c under the standard
p
ꢀ
Hꢀ
1c
2g
conditions, 4
30 16). A homogeneous reaction system is formed in each case
under the proposed reaction conditions. The yields of these 4
Hꢀchromene 3p was obtained in 83% yield (entry
O
3k: 65%
Hꢀ
OMe
chromenes could be improved under the standard conditions,
albeit with a lower temperature and a longer reaction time. When
these tandem reactions were performed at higher temperatures,
O
12
13
1c
35 byꢀproducts
4a (Fig. 1, 15–20% yields) along with 4
4
would be partially formed. For example, compound
ꢀchromenes 3a (60–
O
H
2h
3l: 70%
OMe
OMe
Cl
65% yields) was obtained when the reaction of acetophenone 2a
with phenol 1c was performed at 65–70 °C.
OH
2c
2c
2c
Ph
Ph
O
1d
3m: 68%
Cl
Cl
OH
14
15
4a
40
Fig. 1 Structure of byꢀproduct 4a
O
1e
3n: 67%
Chalcone 5c could be detected in the sulfuricꢀacidꢀpromoted
tandem reaction of phenol 1a with acetophenone 2c. Treatment of
chalcone 5c with 1a in the presence of H2SO4 at 50 °C afforded
Cl
Cl
OH
4
Hꢀchromene 3c in 86% yield within 1 day (Scheme 1),
45 indicating that chalcones are the intermediates in the tandem
reaction of phenols with acetophenones.
5
O
1f
3o: 66%
Cl
Cl
O
OH
H2SO4, 50 °C
1 d, 86%
Cl
1a
+
3c
16
2c
5c
Cl
Scheme 1 Tandem reaction of chalcone 5c with phenol 1a
O
1g
3p: 83%
Based on the above results, a possible reaction mechanism for
50 the sulfuricꢀacidꢀpromoted tandem reaction of phenols with
acetophenones is outlined in Fig. 2. The selfꢀcondensation of
Cl
a General conditions: 1 (1.0 mmol), 2 (3.0 mmol) and H2SO4 (1.5 mmol)
at 50 °C for 1 day under solventꢀfree conditions.
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acetophenones
converted to the intermediates
addition with phenols . Compounds
to form the intermediates . Finally, the cyclodehydration of
compounds affords 4 ꢀchromenes . On the other hand,
chalcones undergo an enolization followed by an aldolꢀtype
addition with acetophenones and a subsequent dehydration to
2
generates chalcones
by an intermolecular Michael
undergo a tautomerization
5
, which are in turn
synthesis are in progress in our research group.
6
1
6
Experimental
7
Procedure for H2SO4-promoted tandem reaction of phenols
with acetophenones under solvent-free conditions (Table 2)
5
7
H
3
5
40 The mixture of a phenol (1a–g, 1.0 mmol), an acetophenone (2a–
2
h
, 3.0 mmol) and concentrated sulfuric acid (98% H2SO4, 81.0
generate the intermediates 11. The intramolecular addition of
compounds 11 leads to the intermediates 12, which undergo a
10 dehydration to afford byꢀproducts 4.
ꢁL, 1.5 mmol) was stirred at 50 °C for 1 day. The reaction was
quenched with water (20 mL), and extracted with ethyl acetate (3
×
20 mL). The combined organic extracts were washed with
O
H
Ar
45 brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was purified by column
Ar
7
H
Ar
OH H
X
X
chromatography over silica gel to afford the 4
).
4H-Chromene 3a: Pale yellow oil; 1H NMR (300 MHz,
7.70 7.65 (m, 4H), 7.53 (d, = 8.7 Hz, 1H), 7.43 (d,
= 7.5 Hz, 2H), 7.33
7.04 (m, 9H), 5.27 (s, 1H), 2.14 (s, 3H); 13C
NMR (75 MHz, CDCl3) 150.1, 148.9, 142.9, 133.8, 131.9,
Hꢀchromene (3a–
O
OH
Ar
8
p
OH
Ar
H2O
Ar
Ar
50 CDCl3)
δ
–
J
J
X
X
–
6
O
Ar
O
O
3
δ
OH
H2O
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; FTIR (film):
55 3055, 2960, 2925, 2853, 1678, 1671, 1599, 1572, 1506, 1490,
1465, 1396, 1372, 1313, 1288, 1261, 1227, 1204, 1094, 1077,
1014, 962, 893, 858, 814, 748 cmꢀ1. HRMS (ESI) m/z: Calcd for
C26H21O [M+H]+: 349.1587. Found: 349.1585.
Ar
X
O
Ar
H
5
1
2
Ar
H
Ar
O
Ar
4H-Chromene 3b: White solids; m.p. = 159–160 °C; 1H NMR
Ar
Ar
2
OH
OH
Ar
Ar
60 (300 MHz, CDCl3)
δ
7.72–7.62 (m, 4H), 7.54–7.31 (m, 4H),
9
Ar
7.25 7.11 (m, 2H), 7.06
–
–
6.93 (m, 4H), 5.18 (s, 1H), 2.15 (s, 3H);
O
4
13C NMR (100 MHz, CDCl3)
δ 163.5 (d, JCꢀF = 188 Hz, 1C),
1
Ar
Ar
10
160.3 (d, 1JCꢀF = 185 Hz, 1C), 148.7, 145.9 (d, 4JCꢀF = 4 Hz, 1C),
Ar
Ar
Ar
Ar
4
142.3, 131.9, 131.2, 129.8 (d, JCꢀF = 4 Hz, 1C), 129.5, 128.9,
H
O
65 128.5 (d, 3JCꢀF = 10 Hz, 1C), 126.4 (d, 3JCꢀF = 11 Hz, 1C), 126.1,
125.7, 123.7, 118.5, 118.2, 115.3 (d, 2JCꢀF = 28 Hz, 1C), 115.2 (d,
2JCꢀF = 29 Hz, 1C), 108.6, 40.3, 29.2; FTIR (film): 1640, 1599,
1494, 1437, 1381, 1089, 1008, 813 cmꢀ1. HRMS (ESI) m/z: Calcd
for C26H19F2O [M+H]+: 385.1399. Found: 385.1401.
12
OH
H
11
Ar
Ar
Fig. 2 A possible reaction mechanism for the sulfuricꢀacidꢀpromoted
tandem reaction of phenols with acetophenones
The tandem reaction of chalcones
5 with acetophenones 2 to
15 generate byꢀproducts went slowly at a temperature less than 50
°C. However, a remarkable rateꢀenhancement was observed when
the temperature exceeded 60 °C. To prevent the formation of
, the sulfuricꢀacidꢀpromoted tandem reaction of
to afford 4 ꢀchromenes should
20 be performed at 30–50 °C. The completion of the reaction should
be accomplished by prolong the reaction time rather than by
improving the reaction temperature. When deactivated phenols,
such as 4ꢀnitrophenol and 4ꢀchlorophenol, were used, higher
temperatures were required. In these cases, byꢀproducts
25 the major products, indicating that deactivated phenols are not the
suitable substrates.
70
4H-Chromene 3c: White solids; m.p. = 172–173 °C; 1H NMR
(300 MHz, CDCl3) 7.73 (d, = 8.4 Hz, 2H), 7.60 (d, = 7.5 Hz,
2H), 7.49 (d, = 8.7 Hz, 1H), 7.38 7.12 (m, 9H), 5.21 (s, 1H),
2.14 (s, 3H); 13C NMR (75 MHz, CDCl3)
148.6, 148.5, 142.4,
134.3, 132.1, 131.9, 131.8, 131.1, 129.6, 128.9, 128.7, 128.6,
75 128.5, 128.4, 126.0, 125.8 (d), 123.7, 118.1, 108.9, 40.5, 29.0;
FTIR (film): 3056, 2966, 2926, 2853, 1713, 1673, 1598, 1575,
1490, 1468, 1397, 1381, 1369, 1319, 1289, 1202, 1094, 1074,
1012, 830, 812, 748 cmꢀ1. HRMS (ESI) m/z: Calcd for
C26H19Cl2O [M+H]+: 417.0808. Found: 417.0792.
4
δ
J
J
J
–
δ
compounds
4
phenols with acetophenones
1
2
H
3
4 became
80
4H-Chromene 3d: White solids; m.p. = 181–182 °C; 1H NMR
(300 MHz, CDCl3) 7.74 (d, = 8.7 Hz, 2H), 7.56 7.23 (m,
11H), 7.15 (t,
= 8.4 Hz, 1H), 5.22 (s, 1H), 2.14 (s, 3H); 13C
NMR (75 MHz, CDCl3) 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,
δ
J
–
J
δ
Conclusions
85 123.8, 122.5, 120.0, 118.1, 118.0, 108.9, 40.6, 28.9; FTIR (film):
3025, 2966, 2924, 2855, 1667, 1621, 1491, 1453, 1401, 1324,
1289, 1262, 1093, 1014, 828 cmꢀ1. HRMS (ESI) m/z: Calcd for
C26H19Br2O [M+H]+: 504.9797. Found: 504.9790.
In summary, sulfuricꢀacidꢀpromoted tandem reaction of phenols
with acetophenones proceeds smoothly under solventꢀ and metalꢀ
30 free conditions, which expands the substrate scopes of
acetophenones and phenols. The process provided a convenient,
cheap and environmentally benign approach for the synthesis of
4H-Chromene 3e: White solids; m.p. = 165–166 °C; 1H NMR
functional 4
H
ꢀchromenes, a structural motif for a large number of 90 (400 MHz, CDCl3)
δ
7.71
(s, 1H), 2.34 (s, 3H), 2.28 (s, 3H), 2.13 (s, 3H); 13C NMR (100
MHz, CDCl3) 148.9, 147.4, 142.8, 138.1, 135.2, 131.8, 131.5,
–7.56 (m, 5H), 7.32–7.08 (m, 9H), 5.21
natural products, pharmaceuticals and functional materials.
35 Applications of this protocol to the related natural product
δ
4
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131.0, 129.2, 129.1, 128.9, 128.7, 126.9, 126.3, 125.5, 124.4,
128.1, 127.54, 127.49, 127.2, 127.1, 127.0, 126.4, 126.3, 126.1,
123.4, 119.0, 118.3, 108.5, 40.4, 29.1, 21.2, 20.9; FTIR (film): 60 125.9, 125.2, 124.3, 123.0, 122.0, 121.8, 107.3, 39.9, 29.7; FTIR
2920, 2849, 1647, 1513, 1322, 1232, 812, cmꢀ1. HRMS (ESI)
m/z: Calcd for C26H21O [M+H]+: 377.1900. Found: 377.1910.
(film): 2960, 2922, 2851, 1487, 1378, 1260, 1080, 808, 766 cmꢀ1.
HRMS (ESI) m/z: Calcd for C34H25O [M+H]+: 449.1900. Found:
449.1902.
1
5
4H-Chromene 3f: Yellow foam; H NMR (400 MHz, CDCl3)
δ
8.25–
8.10 (m, 5H), 7.84
–
7.62 (m, 6H), 7.36
–
7.25 (m, 3H),
4H-Chromene 3l: Pale yellow oil; 1H NMR (400 MHz,
5.42 (s, 1H), 2.26 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
156.4, 65 CDCl3)
(d, = 8.3 Hz, 1H), 7.35
6.70 (d, = 6.4 Hz, 2H), 5.14 (s, 1H), 3.79 (s, 3H), 3.74 (s, 3H),
2.12 (s, 3H); 13C NMR (100 MHz, CDCl3)
159.7, 157.5, 148.9,
δ
7.70 (d,
J
= 7.6 Hz, 2H), 7.61(d,
J
= 7.6 Hz, 2H), 7.59
148.4, 147.8, 147.4, 146.3, 142.5, 139.3, 130.3, 129.3, 127.9,
J
–7.11 (m, 5H), 6.88 (d,
J
= 6.4 Hz, 2H),
126.33, 126.28, 125.6, 125.3, 124.2, 124.1, 123.7, 123.4, 118.0,
J
10 110.7, 41.4, 29.0; FTIR (film): 1622, 1514, 1347, 854 cmꢀ1. Anal.
Calcd. for C26H18N2O5: C, 71.23; H, 4.14; N, 6.39. Found: C,
71.45; H, 4.01; N, 6.58.
δ
142.8, 142.5, 131.8, 131.6, 129.1, 128.8, 128.0, 126.5, 126.4,
70 125.9, 125.5, 123.4, 119.0, 118.3, 113.8, 113.6, 107.8, 55.3, 55.1,
40.1, 29.2; FTIR (film): 3053, 2957, 2926, 2853, 1609, 1596,
1578, 1511, 1461, 1385, 1277, 1251, 1179, 1083, 1034, 831, 814,
794, 772 cmꢀ1. HRMS (ESI) m/z: Calcd for C28H25O3 [M+H]+:
409.1798. Found: 409.1793.
4H-Chromene 3g: Green foam; 1H NMR (400 MHz, CDCl3)
δ
8.21
–
6.92 (m, 20H), 5.28 (s, 1H), 2.01 (s, 3H); 13C NMR (100
144.9, 143.5, 140.8, 136.6, 135.0, 134.0, 133.5,
15 MHz, CDCl3)
δ
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; FTIR (film): 3054,
2959, 2923, 2851, 1626, 1595, 1511, 1454, 1396, 1373, 1259,
20 1210, 1163, 1015, 862, 815, 798, 778, 747 cmꢀ1. HRMS (ESI)
m/z: Calcd for C34H25O [M+H]+: 449.1900. Found: 449.1903.
75
4H-Chromene 3m: Pale yellow oil; 1H NMR (400 MHz,
CDCl3) 7.70 7.60 (m, 3H), 7.47 7.29 (m, 11H), 7.21 7.15 (m,
2H), 5.41 (s, 1H), 1.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
–
–
–
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,
4H-Chromene 3h: White solids; m.p. = 199–200 °C; 1H NMR 80 117.0, 106.9, 39.7, 30.5; FTIR (film): 2964, 2924, 2854, 1666,
(400 MHz, CDCl3)
δ
8.44 (d,
J
= 8.4 Hz, 1H), 7.85
7.00 (m, 2H), 5.45
163.3 (d,
–
7.77 (m, 3H),
1490, 1276, 1085, 833, 819 cmꢀ1. HRMS (ESI) m/z: Calcd for
C28H21Cl2O [M+H]+: 443.0964. Found: 443.0961.
7.62 7.38 (m, 5H), 7.17
–
–7.13 (m, 2H), 7.03–
25 (s, 1H), 1.94 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
4H-Chromene 3n: Pale yellow oil; 1H NMR (400 MHz,
1JCꢀF = 179 Hz, 1C), 160.9 (d, 1JCꢀF = 176 Hz, 1C), 145.7 (d, 4JCꢀF
CDCl3) δ 7.70–7.60 (m, 4H), 7.36–7.28 (m, 4H), 7.03–6.72 (m,
= 3 Hz, 1C), 145.1, 144.6, 133.1, 130.4 (d, JCꢀF = 3 Hz, 1C), 85 2H), 6.72 (s, 1H), 5.35 (s, 1H), 2.22 (s, 3H), 1.85 (s, 3H); 13C
4
3
3
129.2 (d, JCꢀF = 8 Hz, 1C), 127.6, 126.6 (d, JCꢀF = 8 Hz, 1C),
NMR (100 MHz, CDCl3) δ 148.4, 148.0, 141.4, 134.3, 133.1,
2
126.4, 126.2, 125.6, 124.1, 123.2, 121.8, 121.7, 115.3 (d, JCꢀF
=
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; FTIR (film): 2968, 2928, 2857,
1664, 1591, 1494, 1397, 1316, 1291, 1234, 1089, 1008, 813, 724
30 50 Hz, 1C), 115.1 (d, 2JCꢀF = 49 Hz, 1C), 106.8, 39.6, 30.5; FTIR
(film): 3057, 2967, 2927, 1674, 1602, 1508, 1381, 1370, 1319,
1232, 1160, 1014, 837, 813, 746 cmꢀ1. HRMS (ESI) m/z: Calcd 90 cmꢀ1. HRMS (ESI) m/z: Calcd for C23H19Cl2O [M+H]+: 381.0807.
for C26H18BrF2O [M+H]+: 463.0504. Found: 463.0507.
Found: 381.0810.
4H-Chromene 3o: Pale yellow solids; m.p. = 105–108 °C; H
NMR (400 MHz, CDCl3) 7.56 (d, = 8.1 Hz, 2H), 7.28 7.17
(m, 6H), 6.77 (s, 1H), 6.47 (s, 1H), 5.28 (s, 1H), 2.32 (s, 3H),
147.2, 145.8, 144.8, 95 2.09 (s, 3H), 1.74 (s, 3H); 13C NMR (100 MHz, CDCl3)
148.6,
146.2, 145.3, 134.2, 132.8, 132.3, 131.9, 129.8, 128.8, 128.5,
1
1
4H-Chromene 3i: Yellow oil; H NMR (400 MHz, CDCl3)
δ
35 8.47 (d,
7.25 7.05 (m, 4H), 5.49 (s, 1H), 2.41 (s, 3H), 2.32 (s, 3H), 1.93
(s, 3H); 13C NMR (100 MHz, CDCl3)
J
= 8.7 Hz, 1H), 7.78
–
7.49 (m, 5H), 7.44
–7.27 (m, 4H),
δ
J
–
–
δ
δ
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,
40 21.3, 20.9; FTIR (film): 3054, 3025, 2961, 2923, 2854, 1672,
1574, 1511, 1454, 1380, 1319, 1289, 1201, 1100, 1074, 1015,
128.3, 127.2, 126.1, 125.9, 125.4, 106.7, 39.7, 29.7, 20.7, 16.2;
FTIR (film): 2966, 2924, 2852, 1670, 1598, 1492, 1438, 1401,
1375, 1329, 1296, 1278, 1260, 1216, 1147, 1093, 1040, 1012,
810, 748 cmꢀ1. HRMS (ESI) m/z: Calcd for C26H21O [M+H]+: 100 919, 859, 833, 808, 744, 716, 678 cmꢀ1. HRMS (ESI) m/z: Calcd
377.1900. Found: 377.1910.
4H-Chromene 3j: Yellow foam; H NMR (400 MHz, CDCl3)
8.71 (d, = 8.4 Hz, 2H), 8.16 (d, = 8.4 Hz, 2H), 7.83 7.57
(m, 6H), 7.47 (d, = 8.0 Hz, 2H), 6.90 (d, = 8.0 Hz, 2H), 5.30
(s, 1H), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3)
156.7, 147.1, 105 CDCl3)
for C24H21Cl2O [M+H]+: 395.0964. Found: 395.0963.
1
4H-Chromene 3p: Pale yellow oil; 1H NMR (400 MHz,
45
δ
J
J
–
CDCl3)
1H), 2.30 (s, 3H), 2.19 (s, 3H), 1.91 (s, 3H); 13C NMR (100 MHz,
148.5, 148.0, 145.4, 136.2, 134.2, 132.7, 129.0, 128.9,
δ 7.71–7.32 (m, 8H), 7.01 (s, 1H), 6.75 (s, 1H), 5.42 (s,
J
J
δ
δ
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,
50 43.3, 29.7; FTIR (film): 2958, 2923, 2852, 1599, 1517, 1395,
1368, 1346, 1261, 1211, 1106, 810, 752 cmꢀ1. Anal. Calcd. for
C26H18N2O5: C, 71.23; H, 4.14; N, 6.39. Found: C, 71.32; H, 110 By-product 4a: White solids; m.p. = 172–174 °C; H NMR
128.7, 128.5, 128.4, 128.2, 125.9, 125.0, 117.2, 106.8, 39.2, 30.3,
19.4, 19.1; FTIR (film): 2969, 2921, 1672, 1494, 1397, 1324,
1283, 1089, 1008, 837, 805 cmꢀ1. HRMS (ESI) m/z: Calcd for
C24H21Cl2O [M+H]+: 395.0964. Found: 395.0969.
1
4.05; N, 6.53.
(400 MHz, CDCl3)
δ
7.81 (s, 3H), 7.73–7.71 (m, 6H), 7.51–7.48
4H-Chromene 3k: Green foam; 1H NMR (400 MHz, CDCl3)
δ
(m, 6H), 7.42–7.39 (m, 3H); 13C NMR (100 MHz, DMSOꢀ
d6) δ
55 8.52 (d,
Hz, 1H), 7.71
1H), 2.01 (s, 3H); 13C NMR (100 MHz, CDCl3)
J
= 8.4 Hz, 1H), 7.96 (d,
J
= 8.4 Hz, 2H), 7.79 (d,
J
= 8.0
141.6, 140.0, 128.8, 127.6, 127.1, 124.3; FTIR (film): 1648,
1048, 1026, 997, 827, 766, 633 cmꢀ1. Anal. Calcd. for C24H18: C,
–7.30 (m, 15H), 7.12 (d,
J
= 8.4 Hz, 1H), 5.63 (s,
δ
149.0, 145.6, 115 94.08; H, 5.92. Found: C, 94.18; H, 5.99.
144.8, 141.3, 140.7, 140.6, 139.0, 133.3, 133.1, 128.9, 128.7,
Chalcone 5c: White solids; m.p. = 151–152 °C; 1H NMR (400
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DOI: 10.1039/C4RA03950E
65
Wang, Chem. Eur. J., 2011, 17, 7781; (o) H. Dou, S. Gao, Z. Fu, S.
Liu, Chin. J. Org. Chem., 2011, 31, 1056; (p) B. Mohtat, H.
Djahaniani, I. Yavari, M. G. Dehbalaei and S. A. Jam, Chinese Chem.
Lett., 2011, 22, 771; (q) Z. Dong, X. Liu, J. Feng, M. Wang, L. Lin
and X. Feng, Eur. J. Org. Chem., 2011, 137.
MHz, CDCl3)
7.45 (d, = 8.4 Hz, 2H), 7.39 (d,
Hz, 1H), 2.56 (d,
= 1.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
190.3, 154.4, 140.9, 139.1, 137.5, 135.3, 129.7, 128.9, 128.8,
δ
7.92 (d,
J
= 8.8 Hz, 2H), 7.50 (d,
J
= 8.4 Hz, 2H),
J
J
= 8.8 Hz, 2H), 7.08 (q,
J
= 1.2
J
δ
5
127.8, 121.8, 18.8; FTIR (film): 2923, 2852, 1738, 1657, 1591, 70 11 For selected recent examples, see: (a) S. I. Bhat, A. R. Choudhury and
1488, 1364, 1278, 1213, 1093, 1011, 817 cmꢀ1. Anal. Calcd. for
D. R. Trivedi, RSC Adv., 2012, 2, 10556; (b) V. A. Osyanin, D. V.
Osipov and Y. N. Klimochkin, Tetrahedron, 2012, 68, 5612; (c) Y.
Gao, W. Yang and D. M. Du, Tetrahedron: Asymmetry, 2012, 23,
339; (d) Y. Sarrafi, E. Mehrasbi, A. Vahid and M. Tajbakhsh, Chin. J.
C16H12Cl2O: C, 66.00; H, 4.15. Found: C, 66.11; H, 4.06.
Acknowledgments
75
80
Catal., 2012, 33, 1486; (e) H. Mehrabi and N. Kamali, J. Iran. Chem.
Soc., 2012, 9, 599; (f) C. B. Sangani, N. M. Shah, M. P. Patel and
Ranjan G. Patel, J. Serb. Chem. Soc., 2012, 77, 1165; (g) M. G.
Dekamin, M. Eslami and A. Maleki, Tetrahedron, 2013, 69, 1074; (h)
L. Bian, J. Xu, L. Xie, J. Chen, H. Deng, M. Shao, T. Ding, H. Zhang
and W. Cao, Tetrahedron, 2013, 69, 6121; (i) J. H. Park, Y. R. Lee
and S. H. Kim, Tetrahedron, 2013, 69, 9682; (j) Y. Gao, D. M. Du,
Tetrahedron: Asymmetry, 2013, 24, 1312; (k) N. K. Shah, N. M. Shah,
M. P. Patel and R. G. Patel, J. Chem. Sci., 2013, 125, 525; (l) H. S. P.
Rao and V. S. Tangeti, J. Chem. Sci., 2013, 125, 777; (m) S. R. Kale,
S. S. Kahandal, A. S. Burange, M. B. Gawande and R. V. Jayaram,
Catal. Sci. Technol., 2013, 3, 2050; (n) G. Yin, H. Shi, L. Xu, X. Wei
and Q. Tao, Synthesis, 2013, 45, 334; (o) R. L. Magar, P. B. Thorat,
V. B. Jadhav, S. U. Tekale, S. A. Dake, B. R. Patil and R. P. Pawar, J.
Mol. Catal. A: Chem., 2013, 374–375, 118; (p) S. M. Baghbanian, N.
Rezaei and H. Tashakkorian, Green Chem., 2013, 15, 3446; (q) A.
Molla, E. Hossain and S. Hussain, RSC Adv., 2013, 3, 21517.
12 Y. Liu, J. Qian, S. Lou, J. Zhu and Z. Xu, J. Org. Chem., 2010, 75,
1309.
This work was supported by the Science and Technology
10 Development Project of Weihai (2011DXGJ13, 2012DXGJ02),
the Natural Science Foundation of Shandong (ZR2012BM002),
and the National Natural Science Foundation of China
(21272046).
Notes and references
85
15 a School of Marine Science and Technology, Harbin Institute of
Technology at Weihai, Shandong 264209, China. E-mails:
lihuijing@iccas.ac.cn, ycwu@iccas.ac.cn
b Beijing National Laboratory for Molecular Sciences (BNLMS), and Key
Laboratory of Molecular Recognition and Function, Institute of
20 Chemistry Chinese Academy of Sciences, Beijing 100190, China.
† Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data, and copies of NMR spectra (1H NMR
and 13C NMR) of compounds 3a–p, 4a and 5c. See DOI:
10.1039/b000000x/
90
13 (a) W. J. Xue, Q. Li, F. F. Gao, Y. P. Zhu, J. G. Wang, W. Zhang and
A. X. Wu, ACS Comb. Sci., 2012, 14, 478; for reactions of resorcinols
with ketones in the presence of pꢀtoluenesulfonic acid, see: (b) S. I.
Filimonov, N. G. Savinsky and E. M. Evstigneeva, Mendeleev
Commun., 2003, 13, 194.
95
25
30
35
40
45
50
55
60
1
(a) S. Hatakeyama, N. Ochi, H. Numata and S. Takano, J. Chem. Soc.,
Chem. Commun., 1988, 1202; (b) R. Gonzalez, N. Martin, C. Seoane,
J. L. Marco, A. Albert and F. H. Cano, Tetrahedron Lett, 1992, 33,
3809; (c) V. Jeso and K. C. Nicolaou, Tetrahedron Lett., 2009, 50,
1161; (d) C. Yao, B. Jiang, T. Li, B. Qin, X. Feng, H. Zhang, C.
Wang and S. Tu, Bioorg. Med. Chem. Lett., 2011, 21, 599.
T. Symeonidis, M. Chamilos, D. J. HadjipavlouꢀLitina, M. Kallitsakis
and K. E. Litinas, Bioorg. Med. Chem. Lett., 2009, 19, 1139.
Z. Q. Xu, K. Pupek, W. J. Suling, L. Enache and M.T. Flavin, Bioorg.
Med. Chem., 2006, 14, 4610.
C. B. Sangani, N. M. Shah, M. P. Patel, R. G. Patel, Med. Chem. Res.,
2013, 22, 3831.
T. Narender, Shweta, S. Gupta, Bioorg. Med. Chem. Lett., 2004, 14,
3913.
A. MartínezꢀGrau and J. L. Marco, Bioorg. Med. Chem. Lett., 1997, 7,
3165.
N. R. Kamdar, D. D. Haveliwala, P. T. Mistry, S. K. Patel, Med.
Chem. Res., 2011, 20, 854.
14 (a) Y. C. Wu, X. M. Zou, F. Z. Hu and H. Z. Yang, J. Heterocycl.
Chem., 2005, 42, 609; (b) Y. C. Wu, L. Liu, H. J. Li, D. Wang and Y.
J. Chen, J. Org. Chem., 2006, 71, 6592; (c) Y. C. Wu, Y. J. Chen, H. J.
Li, X. M. Zou, F. Z.Hu and H. Z. Yang, J. Fluorine Chem., 2006, 127,
409; (d) Y. C. Wu, L. Liu, D. Wang and Y. J. Chen, J. Heterocycl.
Chem., 2006, 43, 949; (e) Y. C. Wu, L. Liu, Y. L. Liu, D. Wang and
Y. J. Chen, J. Org. Chem., 2007, 72, 9383; (f) Y. C. Wu, H. J. Li, L.
Liu, D. Wang, H. Z. Yang and Y. J. Chen, J. Fluoresc., 2008, 18, 357;
(g) Y. C. Wu, H. J. Li and H. Z. Yang, Org. Biomol. Chem., 2010, 8,
3394; (h) Y. C. Wu, H. J. Li, L. Liu, N. Demoulin, Z. Liu, D. Wang
and Y. J. Chen, Adv. Synth. Catal., 2011, 353, 907; (i) Y. C. Wu, H. J.
Li, L. Liu, N. Demoulin, Z. Liu, D. Wang and Y. J. Chen, Synlett,
2011, 1573; (j) Y. C. Wu, H. J. Li, L. Liu, Z. Liu, D. Wang and Y. J.
Chen, Org. Biomol. Chem., 2011, 9, 2868.
100
105
110
2
3
4
5
6
7
8
9
H. Aryapour, M. Mahdavi, S. R. Mohebbi, M. R. Zali and A.
Foroumadi, Arch Pharm Res., 2012, 35, 1573.
S. G. Das, D. L. Hermanson, N. Bleeker, X. Lowman, Y. Li, A.
Kelekar and C. Xing, ACS Chem. Biol., 2013, 8, 327.
10 For selected examples, see: (a) J. Fan and Z. Wang, Chem. Commun.,
2008, 5381; (b) S. Gao, C. H. Tsai, C. Tseng and C. F. Yao,
Tetrahedron, 2008, 64, 9143; (c) A. Shaabani, R. Ghadari, A. Sarvary
and A. H. Rezayan, J. Org. Chem., 2009, 74, 4372; (d) K. Kumaravel
and G. Vasuki, Green Chem., 2009, 11, 1945; (e) M. N. Elinson, A. I.
Ilovaisky, V. M. Merkulova, P. A. Belyakov, A. O. Chizhov and G. I.
Nikishin, Tetrahedron, 2010, 66, 4043; (f) M. R. NaimiꢀJamal, S.
Mashkouri, A. Sharifi, Mol. Divers, 2010, 14, 473; (g) H. J. Li, J. L.
Wang, R. Wang, D. H. Luo and Y. C. Wu, J. Chem.,
Doi:10.1155/2013/106908; (h) M. Boominathan, M. Nagaraj, S.
Muthusubramanian and R. V. Krishnakumar, Tetrahedron, 2011, 67,
6057; (i) S. R. Kolla, Y. R. Lee, Tetrahedron, 2011, 67, 8271; (j) Z.
Du, W. Y. Siau and J. Wang, Tetrahedron Lett., 2011, 52, 6137; (k)
M. Gyuris, R. Madácsi, L. G. Puskás, G. K. Tóth, J. Wölfling and I.
Kanizsai, Eur. J. Org. Chem., 2011, 848; (l) B. Sadeghi, A.
Hassanabadi, S. Bidaki, J. Chem. Res., 2011, 666; (m) R. Ghorbaniꢀ
Vaghei, Z. ToghraeiꢀSemiromi and R. KarimiꢀNami, J. Braz. Chem.
Soc., 2011, 22, 905; (n) Q. Ren, W. Y. Siau,Z. Du,K. Zhang and J.
6
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DOI: 10.1039/C4RA03950E
Graphical Abstract
Synthesis of functional 4H-chromenes from phenols and acetophenones
under solvent- and metal-free conditions
Hui-Jing Li, Kai Deng, Dong-Hui Luo, De-Hui Liu, Jun-Li Wang, Chun-Hua Lin and
Yan-Chao Wu
O
O
I am here to help you,
I am a nice promoter
Give me your water,
O
I am thirsty
S
O
Ar
H
H
2H2O
Ar
O
H
H
H
O
H
H
O
X
X
O
Ar
Ar
Sulfuric-acid-promoted tandem reaction of phenols with acetophenones under
solvent- and metal-free conditions has been developed, which afforded functional 4H-
chromenes in good yields with water as the side product.