Br?nsted acid promoted one-pot synthesis of 4-aryl-3,4-dihydrocoumarins

Article abstract of DOI:10.1016/j.tet.2016.05.007

4-Aryl-3,4-dihydrocoumarins are a class of valuable molecules demonstrating attractive pharmaceutical and biological properties. In this paper, we designed a new and facile approach to synthesis of 4-aryl-3,4-dihydrocoumarin derivatives by Br?nsted acid c

Full text of DOI:10.1016/j.tet.2016.05.007

Tetrahedron xxx (2016) 1e5
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Brønsted acid promoted one-pot synthesis of 4-aryl-3,
4-dihydrocoumarins
,
a,
*
Cheng Chen b, Rui Zhang a, Long Lin a, Guang-Fu Yang a , Qiong-You Wu
*
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, PR
China
b State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, Wuhan University of Technology, Wuhan 430070, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
4-Aryl-3,4-dihydrocoumarins are a class of valuable molecules demonstrating attractive pharmaceutical
and biological properties. In this paper, we designed a new and facile approach to synthesis of 4-aryl-3,4-
dihydrocoumarin derivatives by Brønsted acid catalyzed FriedeleCrafts alkylation and cycloaddition
reaction. With this protocol, 15 examples of 4-aryl-3,4-dihydrocoumarins were successfully prepared
with yields ranging from 82 to 99%.
Received 21 March 2016
Received in revised form 4 May 2016
Accepted 5 May 2016
Available online xxx
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Dihydrocoumarins
FriedeleCrafts alkylation
Cycloaddition
Brønsted acid
Perchloric acid
1. Introduction
catalytic hydrogenation,14,15 treatment of cinnamic acid derivatives
(cinnamic acids,16e24 cinnamoyl chlorides,25 or cinnamate es-
Coumarins have widely existed in a variety of natural products,
pharmaceuticals, and agrochemicals, and they are attractive due to
their anti-inflammatory, anti-aging, anti-oxidative and anti-cancer
activities.1 Besides, dihydrocoumarins have been frequently used as
food flavouring2 and fragrance in cosmetics,3 and they are also
well-known in perfumery industries.4 Among this class of com-
pounds, 4-aryl-3,4-dihydrocoumarins are particularly interesting
since they exhibit promising activities such as anti-herpetic,5 anti-
bacterial,6,7 anti-viral,8 anti-hypertension,9 anti-inflammatory,10
antioxidant activities,1 as well as aldose reductase inhibition11
and protein kinase inhibition.12 For instance, the dihy-
drocoumarin 1 is a synthetic compound showing excellent in vitro
anti-bacterial activity against members of the Tripanosoma family
(Fig. 1).6,7 In addition, compound 2, a natural dihydrocoumarin,
demonstrates outstanding anti-inflammatory and antioxidant ac-
tivities (Fig. 1).13
ters26,27) with phenols, annulation reactions of phenols with other
reagents,28e30 the use of oxidants on acids,31e35 arylacrylate lac-
tonization,6,7,36 and one-pot synthesis via Fischer carbenes.37
Fig. 1. Representative examples of synthetic and natural 4-aryl-3,4-dihydrocoumarins.
Owing
to
the
diverse
advantages
of
4-aryl-3,4-
dihydrocoumarins, it is of vital importance to develop efficient
synthetic approaches for this kind of compounds. Conventional
methods for their synthesis include the transition-metal-mediated
Although various methods have been developed, it is still highly
desirable to design a facile and economic route for synthesis of 4-
aryl dihydrocoumarins under mild reaction conditions. Through
literature survey, we poured our attention to a report by Claude
et al. describing an efficient intramolecular cycloaddition reaction
from a secondary alcohol group and an ester moiety in the presence
* Corresponding authors. Tel.: þ86 27 67867800; fax: þ86 27 67867141; e-mail
addresses: gfyang@mail.ccnu.edu.cn (G.-F. Yang), qywu@mail.ccnu.edu.cn
(Q.-Y. Wu).
http://dx.doi.org/10.1016/j.tet.2016.05.007
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Chen, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.007

2
C. Chen et al. / Tetrahedron xxx (2016) 1e5
of a Brønsted acid (Fig. 2a).38 In addition, the Bra group39 and the
Barbero group40 reported Brønsted-acid-catalyzed alkylation of
arenes (or heteroarenes) with benzylic alcohols (Fig. 2b). Notably,
both the intramolecular lactone formation and the intermolecular
arylation could be promoted by Brønsted acids. Thus, we envi-
sioned that the combination of these two processes into
a Brønsted-acid-mediated one-pot fashion should provide a con-
venient approach to synthesis of 4-aryl dihydrocoumarins (Fig. 2c).
for the reaction. To our delight, compound 5a was obtained in 90%
isolated yield after 930 min at 0 ꢀC by using dichloromethane as
solvent (entry 1). When the Brønsted acid was changed to con-
centrated HCl or p-toluenesulfonic acid, comparable yields were
observed, but quite long reaction time (1440 min for each case,
entries 2e3) is necessary. Fortunately, methanesulfonic acid and
perchloric acid were found to accelerate the reaction efficiently
and yield 5a in excellent yields, and the reaction time was
shortened from 1440 min to no more than 30 min (entries 4e5).
Compared with methanesulfonic acid, perchloric acid is a better
promoter in terms of a slightly higher yield (88% in entry 4 vs 90%
in entry 5) and shorter reaction time (30 min in entry 4 vs 20 min
in entry 5). Except the strong acids mentioned above, acetic acid,
a weaker acid, was also investigated. However, no reaction was
observed even the reaction time was prolonged to 1440 min
(entry 6). Therefore, perchloric acid was identified as the optimal
Brønsted acid. Secondly, we investigated the effect of the amount
of perchloric acid on the product yield. It was found that when the
acid amount increased from 2.0 equiv to 3.0 equiv, the reaction
could be completed within 10 min and a slightly improved yield of
92% was produced (entry 7). After setting up the acid amount, we
next optimized the influence of solvent on the product yield.
Among the solvent investigated, acetonitrile was demonstrated to
be the best one and provided a yield of 95% within the same re-
action time (entries 8e14). Interestingly, when the reaction was
performed in a diluted solution by increasing the volume of the
acetonitrile from 2 mL to 3 mL, a further improvement of the yield
of 99% was achieved (entry 15). Therefore, the optimized reaction
conditions, identified as 3 (1.0 mmol), 4 (2.0 mmol), Brønsted acid
(3.0 mmol), and solvent (3.0 mL), were used for further study until
otherwise noted.
Fig. 2. One-pot synthesis of 4-aryl dihydrocoumarin derivatives through combination
of intermolecular arylation and intramolecular cyclization.
2. Results and discussion
With the optimized reaction conditions in hand, the substrate
scope and limitations of this method were investigated. A range
of 4-aryl dihydrocoumarins were obtained in excellent yields
(Table 2). tert-Butyl 3-hydroxy-3-(2-hydroxyphenyl)propanoate
In order to examine the feasibility of our methodology, we
selected the reaction of 3a and 4a as a model reaction for opti-
mization of reaction conditions (Table 1). Initially, screening of
different Brønsted acids were performed. Trifluoroacetic acid, ac-
tive for reactions shown in both Fig. 2a and b, was first attempted
Table 2
Investigation of the substrate scope
Table 1
Optimization of reaction conditionsa
l
l
Entry Brønsted acid Solvent 3a: 4a: Brønsted acid Time (min) Yieldb
1
2
3
4
5
6
7
8
TfOH
conc. HCl
TsOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
CHCl3
THF
Acetone 1:2:3
MeOH
Et2O
MeCN
MeCN
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:3
1:2:3
1:2:3
1:2:3
930
1440
1440
30
20
1440
10
10
10
10
10
90%
85%
85%
88%
90%
ec
MsOH
HClO4
AcOH
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
HClO4
92%
91%
90%
50%
65%
55%
90%
95%
99%
9
10
11
12
13
14
15d
1:2:3
1:2:3
1:2:3
1:2:3
10
10
10
10
a
3a (1.0 mmol), 4a (2.0 mmol), Brønsted acid (2.0 mmol), and solvent (2.0 mL)
were used.
b
c
Isolated yields.
No reaction.
3.0 mL acetonitrile was used.
l
l
l
d
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C. Chen et al. / Tetrahedron xxx (2016) 1e5
3
(3a), with both R1 and R2 as H, reacted smoothly with various
electron-rich arenes to give compounds 5ae5d with the yields
ranging from 84% to 99%. Heteroarenes such as 2-methylfuran
and 2-methylthiophene can also tolerate this reaction and pro-
duced the respective products 5e and 5f in good yields. In addi-
tion, tert-butyl 3-hydroxy-3-(2-hydroxyphenyl)propanoate (3b)
where a methyl group was assembled at the R1 position was
further utilized as the starting material. The results indicated that
1,3-dimethoxybenzene (4a), anisole (4b), 1,3-dimethoxy-2-
methylbenzene (4d), 2-methylthiophene (4f) and 1-methyl-1H-
indole (4g) could be successfully transformed into the corre-
sponding dihydrocoumarins with a quaternary carbon atom at the
benzylic position (5ge5k). It was worth noting that no note-
worthy steric effect was observed in terms of the excellent yields
obtained. Moreover, incorporation of a methyl group at the p-
position of phenolic ring of compound 3 did not have significant
influence on the product yields since compound 5le5o with the
yields ranging from 84% to 93% were obtained depending on the
aryl substituent introduced.
The plausible mechanism of the reaction was described in
Scheme 1. It was assumed that compound 5a could be obtained via
two processes including a process featuring an SN1-type alcohol
nucleophilic substitution via a benzylic carbenium species (also
called FriedeleCrafts alkylation)39,40 and a cycloaddition process,38
and the major difference of the two pathways lies in the sequence
of the two processes. In pathway 1, treatment of 3a with perchloric
acid initially afforded a benzylic carbocation I, which then reacted
with 4a to give intermediate II. Afterwards, intermediate II could go
through an intramolecular cycloaddition under an acidic condition
to generate 5a with elimination of tert-butanol. In pathway 2,
Brønsted acid-aided intramolecular cycloaddition occurred first to
produce intermediated III, which could be then transformed to the
corresponding carbenium ion IV in the presence of perchloric acid.
Finally, the final product 5a could be yielded via reaction of in-
termediate IV and 4a.
the reaction conditions implied that the economic perchloric acid
was the optimal Brønsted acid. Under the optimized reaction
conditions, a variety of 4-aryl-3,4-dihydrocoumarins were effi-
ciently synthesized in good to excellent yields. Considering the
reaction mechanism, we proposed that two processes, an SN1-type
alcohol nucleophilic substitution (or FriedeleCrafts alkylation) and
a cycloaddition reaction, could be realized in one pot with the aid of
perchloric acid.
4. Experimental section
4.1. General considerations
1H NMR spectra were recorded on a VARIAN Mercury-Plus 600
spectrometer in CDCl3 with TMS as the internal reference, 13C NMR
spectra were recorded in CDCl3 on a VARIAN Mercury-Plus 600
(151 MHz) spectrometer, and chemical shifts (d) are given in ppm
relative to the centre line of a triplet at 77.0 ppm of CDCl3. The
following abbreviations are used to designate multiplicities:
s¼singlet, d¼doublet, t¼triplet, dd¼doublet of doublets, brs¼broad
singlet, m¼multiplet. MS spectra were determined using a Trace
MS 2000 organic mass spectrometry, and the signals were given in
m/z. HRMS was taken on an Agilent 6520 Accurate-Mass Q-TOF
instrument. Melting points were taken on a Buchi B-545 melting
point apparatus and are uncorrected. Ordinary reagents and sol-
vents were commercially available and treated with standard
methods before use. Besides, compounds
4 including 1,3-
dimethoxybenzene (4a), anisole (4b), 1,2-dimethoxybenzene (4c),
1,3-dimethoxy-2-methylbenzene (4d), 2-methylfuran (4e), 2-
methylthiophene (4f), 1-methyl-1H-indole (4g) were also pur-
chased from commercial suppliers.
4.2. General procedure for synthesis of compounds 3ae3c
(Scheme 2)
3. Conclusion
In summary, we have developed a simple, mild and efficient
method for synthesis of 4-aryl-3,4-dihydrocoumarins. Screening of
Scheme 2. Synthesis of 3ae3c.
To a solution of diisopropyl amine (55.0 mmol) in THF (60 mL)
was added dropwisely n-butyl lithium solution (55.0 mmol) at
ꢁ78 ꢀC under inert atmosphere, and the mixture was stirred for
20 min at the same temperature. Then t-butyl acetate (55.0 mmol)
was added slowly to the above mixture, followed by dropwise
addition of salicylaldehyde (22.0 mmol) after 1 h. Afterwards, the
mixture was stirred for additional 1.5 h and 15% citric acid solution
(60 mL) was added. The mixture was then extracted with EtOAc
(3ꢂ60 mL), and the resulted organic layer was washed with water
(2ꢂ50 mL), brine (50 mL), dried over Na2SO4, concentrated, and
purified by column chromatography to afford the pure product
(3a).
Synthesis of 3b and 3c was similar with that of 3a.
4.3. General procedure for synthesis of compounds 5ae5o
(Scheme 3)
To a solution of 3 (2.00 mmol) in acetonitrile (3 mL) was added
dropwisely HClO4 (6.00 mmol) at 0 ꢀC. Then 4 (4.00 mmol) was
added and the reaction mixture was stirred at 0 ꢀC for 10 min.
Scheme 1. The plausible mechanism of the formation of 5.
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4
C. Chen et al. / Tetrahedron xxx (2016) 1e5
CDCl3): 167.62,151.53,149.30,148.39,132.58,128.72,128.27,126.00,
124.63, 119.66, 117.05, 111.43, 110.52, 55.92, 55.71, 40.29, 37.19;
MS (EI): m/z¼284.22 (Mþ).
4.4.7. 4-(2,4-Dimethoxy-3-methylphenyl)chroman-2-one
(5d). White solid: mp 92.5e94.0 ꢀC. Isolated yield: 99%. 1H NMR
Scheme 3. Synthesis of 5 from 3 and 4.
(600 MHz, CDCl3):
d
7.28 (dd, J¼7.8, 7.6 Hz, 1H), 7.13 (d, J¼7.6 Hz,
Afterwards, the mixture was directly purified by column chroma-
tography to afford the pure products (5ae5o).
1H), 7.06 (dd, J¼7.4, 7.2 Hz, 1H), 6.96 (d, J¼7.2 Hz, 1H), 6.74 (d,
J¼8.8 Hz, 1H), 6.59 (d, J¼8.4 Hz, 1H), 4.65 (t, J¼7.2 Hz, 1H), 3.80 (s,
3H), 3.70 (s, 3H), 3.01e3.00 (m, 2H), 2.19 (s, 3H); 13C NMR (151 MHz,
CDCl3): 167.94, 158.23, 157.15, 151.89, 128.47, 128.28, 126.28, 125.38,
124.56, 124.38, 119.97, 116.98, 106.51, 61.20, 55.64, 36.49, 34.33,
9.50; MS (EI): m/z¼298.24 (Mþ); HRMS (ESI): m/z calcd for
4.4. Analytical data for compounds 3ae3c and 5ae5o
4.4.1. tert-Butyl 3-hydroxy-3-(2-hydroxyphenyl)propanoate (3a).
White solid: mp 87.5e89.0 ꢀC. Isolated yield: 89%. 1H NMR
C
18H19O4 [MþH]þ: 299.12779; Found: 299.12787.
(600 MHz, CDCl3):
d
8.31 (s, 1H), 7.18 (dd, J¼7.4, 7.2 Hz, 1H), 6.96 (d,
J¼7.8 Hz,1H), 6.88 (d, J¼8.4 Hz,1H), 6.83 (dd, J¼7.8, 7.7 Hz, 1H), 5.24
(d, J¼10.2 Hz, 1H), 4.66 (s, 1H), 2.91e2.86 (m, 1H), 2.66e2.62 (m,
1H), 1.49 (s, 9H); 13C NMR (151 MHz, CDCl3): 172.57, 155.71, 129.17,
126.60, 125.34, 119.81, 117.38, 82.25, 71.60, 41.75, 28.04; MS (EI): m/
z¼238.12 (Mþ). HRMS (ESI): m/z calcd for C13H18O4Na [MþNa]þ:
261.10973; Found 261.10626.
4.4.8. 4-(5-Methylfuran-2-yl)chroman-2-one (5e).43 Pale yellow oil.
Isolated yield: 82%. 1H NMR (600 MHz, CDCl3)
7.6 Hz, 1H), 7.18e7.08 (m, 3H), 5.89e5.86 (m, 2H), 4.33 (t, J¼6.0 Hz,
1H), 3.21e3.16 (m, 1H), 3.02e2.97 (m, 1H), 2.24 (s, 3H); 13C NMR
(151 MHz, CDCl3): 167.41, 152.37, 151.37, 150.78, 128.94, 128.18,
124.57, 123.47, 117.19, 107.69, 106.17, 34.74, 34.03, 13.52; MS (EI): m/
z¼228.16 (Mþ).
d
7.30 (dd, J¼7.8,
4.4.2. tert-Butyl 3-hydroxy-3-(2-hydroxyphenyl)butanoate (3b).41
Pale yellow oil. Isolated yield: 98%. 1H NMR (600 MHz, CDCl3):
4.4.9. 4-(5-Methylthiophen-2-yl)chroman-2-one (5f). Pale yellow
d
9.35 (s, 1H), 7.15 (dd, J¼7.4, 7.2 Hz, 1H), 6.98 (d, J¼7.8 Hz, 1H), 6.87
oil. Isolated yield: 84%. 1H NMR (600 MHz, CDCl3)
d
7.31 (dd, J¼7.4,
(d, J¼7.8 Hz, 1H), 6.79 (dd, J¼7.4, 7.2 Hz, 1H), 5.72 (s, 1H), 3.07 (d,
J¼16.8 Hz, 1H), 2.65 (d, J¼16.2 Hz, 1H), 1.61 (d, J¼7.2 Hz, 3H), 1.42 (s,
9H); 13C NMR (151 MHz, CDCl3): 172.72, 156.08, 129.06, 128.89,
124.80, 119.27, 117.81, 82.63, 76.19, 45.21, 28.51, 27.89; MS (EI): m/
z¼252.06 (Mþ).
7.2 Hz,1H), 7.18 (d, J¼7.2 Hz,1H), 7.14e7.10 (m, 2H), 6.57 (s, 2H), 4.51
(t, J¼6.0 Hz, 1H), 3.09 (d, J¼6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR
(151 MHz, CDCl3): 167.14, 151.22, 140.96, 139.76, 129.02, 128.02,
125.57, 125.11, 125.02, 124.66, 117.23, 37.34, 36.36, 15.29; MS (EI): m/
z¼244.08 (Mþ); HRMS (ESI): m/z calcd for C14H12O2SNa [MþNa]þ:
267.04502; Found: 267.04555.
4.4.3. tert-Butyl 3-hydroxy-3-(2-hydroxy-5-methylphenyl)butanoate
(3c). Pale yellow oil. Isolated yield: 84%. 1H NMR (600 MHz,
4.4.10. 4-(2,4-Dimethoxyphenyl)-4-methylchroman-2-one
CDCl3):
d
9.12 (brs, 1H), 6.95 (d, J¼6.6 Hz, 1H), 6.78e6.76 (m, 2H),
(5g). White solid: mp 110.4e111.8 ꢀC. Isolated yield: 90%. 1H NMR
5.64 (brs, 1H), 3.06 (d, J¼15.6 Hz, 1H), 2.64 (d, J¼16.2 Hz, 1H), 2.24
(s, 3H), 1.60 (s, 3H), 1.42 (s, 9H); 13C NMR (151 MHz, CDCl3):
172.82, 153.76, 129.52, 128.60, 128.16, 125.35, 117.60, 82.58, 76.17,
45.27, 28.54, 28.49, 27.96, 27.91, 20.63; MS (EI): m/z¼266.25 (Mþ);
HRMS (ESI): m/z calcd for C15H22O4Na [MþNa]þ: 289.14103;
Found: 289.13871.
(600 MHz, CDCl3):
d
7.24 (d, J¼7.2 Hz, 1H), 7.08e7.05 (m, 2H), 7.01
(d, J¼7.2 Hz, 1H), 6.90 (d, J¼8.4 Hz, 1H), 6.46 (s, 1H), 6.40 (d,
J¼8.4 Hz, 1H), 3.80e3.79 (m, 4H), 3.63 (s, 3H), 2.59 (d, J¼15.6 Hz,
1H), 1.73 (s, 3H); 13C NMR (151 MHz, CDCl3): 168.62, 160.34, 158.38,
150.60, 131.29, 128.37, 127.91, 126.07, 124.26, 123.87, 116.92, 103.77,
99.95, 55.23, 54.97, 40.84, 39.92, 26.56. MS (EI): m/z¼298.15 (Mþ);
HRMS (ESI): m/z calcd for C18H19O4 [MþH]þ: 299.12779; Found:
299.12839.
4.4.4. 4-(2,4-Dimethoxyphenyl)chroman-2-one (5a). White solid:
mp 81.5e83.0 ꢀC. Isolated yield: 99%. 1H NMR (600 MHz, CDCl3):
d
7.29e7.28 (m, 1H), 7.11 (d, J¼7.8 Hz, 1H), 7.07 (dd, J¼7.4, 7.2 Hz,
4.4.11. 4-(4-Methoxyphenyl)-4-methylchroman-2-one
(5h). Pale
7.31 (dd,
1H), 7.03 (d, J¼6.6 Hz, 1H), 6.74 (d, J¼8.4 Hz, 1H), 6.48 (s, 1H), 6.38
(d, J¼7.8 Hz, 1H), 4.59 (t, J¼6.6 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H),
3.09e3.06 (m, 1H), 2.98e2.94 (m, 1H); 13C NMR (151 MHz, CDCl3):
168.11, 160.25, 157.73, 151.95, 128.66, 128.31, 125.29, 124.39, 121.14,
116.81, 104.18, 98.83, 55.25, 55.09, 35.30, 34.92; MS (EI): m/
z¼284.12 (Mþ). HRMS (ESI): m/z calcd for C17H17O4 [MþH]þ:
285.11214; Found: 285.10972.
yellow oil. Isolated yield: 89%. 1H NMR (600 MHz, CDCl3):
d
J¼8.0, 7.8 Hz, 1H), 7.22 (d, J¼7.8 Hz, 1H), 7.17 (dd, J¼8.0, 7.8 Hz, 1H),
7.11e7.08 (m, 3H), 6.82 (d, J¼9.0 Hz, 2H), 3.77 (s, 3H), 3.24 (d,
J¼15.6 Hz, 1H), 2.81 (d, J¼15.6 Hz, 1H), 1.72 (s, 3H); 13C NMR
(151 MHz, CDCl3): 167.57, 158.44, 151.08, 135.84, 131.03, 128.60,
127.25, 126.50, 124.63, 117.23, 113.95, 55.15, 43.81, 40.47, 27.57;
MS (EI): m/z¼268.13 (Mþ); HRMS (ESI): m/z calcd for C17H17O3
[MþH]þ: 269.11722; Found: 269.11735.
4.4.5. 4-(4-Methoxyphenyl)chroman-2-one (5b).26 White solid: mp
130.6e132.1 ꢀC. Isolated yield: 84%. 1H NMR (600 MHz, CDCl3):
4.4.12. 4-(2,4-Dimethoxy-3-methylphenyl)-4-methylchroman-2-one
d
7.31e7.28 (m,1H), 7.12 (d, J¼7.8 Hz,1H), 7.10e7.07 (m, 3H), 6.98 (d,
(5i). White solid: mp 96.2e97.7 ꢀC. Isolated yield: 92%. 1H NMR
J¼7.8 Hz, 1H), 6.88 (d, J¼9.0 Hz, 2H), 4.30 (t, J¼7.2 Hz, 1H), 3.80 (s,
3H), 3.07e2.97 (m, 2H); 13C NMR (151 MHz, CDCl3): 167.77, 158.94,
151.62, 132.15, 128.68, 128.59, 128.25, 126.18, 124.60, 117.05, 114.43,
55.27, 39.84, 37.16; MS (EI): m/z¼254.11 (Mþ).
(600 MHz, CDCl3):
d
7.24 (d, J¼7.2 Hz,1H), 7.10 (d, J¼7.8 Hz,1H), 7.06
(dd, J¼8.0, 7.8 Hz, 1H), 6.99e6.94 (m, 2H), 6.57 (d, J¼8.4 Hz, 1H),
3.92 (d, J¼16.2 Hz, 1H), 3.82 (s, 3H), 3.20 (s, 3H), 2.63 (d, J¼16.2 Hz,
1H), 2.11 (s, 3H), 1.69 (s, 3H); 13C NMR (151 MHz, CDCl3): 168.26,
158.59, 158.08, 150.40, 131.93, 128.37, 127.96, 126.61, 124.82, 124.16,
120.26, 116.92, 104.61, 60.00, 55.35, 41.46, 40.10, 27.79, 10.21;
MS (EI): m/z¼312.17 (Mþ); HRMS (ESI): m/z calcd for C19H21O4
[MþH]þ: 313.14344; Found: 313.14076.
4.4.6. 4-(3,4-Dimethoxyphenyl)chroman-2-one (5c).42 White solid:
mp 108.7e110.0 ꢀC. Isolated yield: 88%. 1H NMR (600 MHz, CDCl3):
d
7.30 (dd, J¼7.8, 7.6 Hz, 1H), 7.13 (d, J¼8.4 Hz, 1H), 7.09 (dd, J¼8.0,
7.8 Hz, 1H), 7.00 (d, J¼7.8 Hz, 1H), 6.83 (d, J¼7.8 Hz, 1H), 6.69 (d,
J¼8.4 Hz, 1H), 6.67 (s, 1H), 4.29 (t, J¼7.2 Hz, 1H), 3.87 (s, 3H), 3.83 (s,
3H), 3.09e3.05 (m, 1H), 3.03e2.99 (m, 1H); 13C NMR (151 MHz,
4.4.13. 4-Methyl-4-(5-methylthiophen-2-yl)chroman-2-one
(5j). Pink oil. Isolated yield: 95%. 1H NMR (600 MHz, CDCl3):
d 7.32
Please cite this article in press as: Chen, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.007

C. Chen et al. / Tetrahedron xxx (2016) 1e5
5
(dd, J¼8.0, 7.8 Hz, 1H), 7.28 (d, J¼7.8 Hz, 1H), 7.17 (dd, J¼8.0, 7.8 Hz,
(ESI): m/z calcd for
273.09420.
C
16H17O2S [MþH]þ: 273.09438; Found:
1H), 7.10 (d, J¼8.4 Hz, 1H), 6.54e6.53 (m, 2H), 3.20 (d, J¼15.6 Hz,
1H), 2.91 (d, J¼15.6 Hz, 1H), 2.41 (s, 3H), 1.78 (s, 3H); 13C NMR
(151 MHz, CDCl3): 167.01, 150.61, 146.47, 139.45, 130.34, 128.93,
125.87, 124.74, 124.69, 124.28, 117.19, 44.59, 39.50, 28.28, 15.21;
MS (EI): m/z¼258.08 (Mþ); HRMS (ESI): m/z calcd for C15H15O2S
[MþH]þ: 259.07873; Found: 259.07875.
Acknowledgements
This research was supported by the National Natural Science
Foundation of China (Nos. 21272091, 21472063 and 21502062).
4.4.14. 4-Methyl-4-(1-methyl-1H-indol-3-yl)chroman-2-one
Supplementary data
(5k). Pale yellow oil. Isolated yield: 92%. 1H NMR (600 MHz,
CDCl3):
d 7.34e7.29 (m, 2H), 7.23e6.98 (m, 6H), 6.83 (s, 1H), 3.77
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2016.05.007.
(s, 3H), 3.54 (d, J¼15.6 Hz, 1H), 2.78 (d, J¼16.2 Hz, 1H), 1.82 (s,
3H). 13C NMR (151 MHz, CDCl3): 168.13, 150.80, 137.92, 130.44,
128.39, 127.09, 126.92, 125.02, 124.54, 121.64, 120.48, 118.95,
117.47, 117.01, 109.69, 43.01, 37.31, 32.66, 26.78; MS (EI): m/
z¼291.14 (Mþ); HRMS (ESI): m/z calcd for C19H18NO2 [MþH]þ:
292.13321; Found: 292.13266.
References and notes
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4.4.15. 4-(2,4-Dimethoxyphenyl)-4,6-dimethylchroman-2-one
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(5l). White solid: mp 137.4e138.7 ꢀC. Isolated yield: 93%. 1H NMR
(600 MHz, CDCl3):
d
7.05 (d, J¼8.4 Hz, 1H), 6.96 (d, J¼8.4 Hz, 1H),
6.86 (d, J¼8.4 Hz, 1H), 6.82 (s, 1H), 6.46 (s, 1H), 6.39 (d, J¼9.0 Hz,
1H), 3.80e3.76 (m, 4H), 3.66 (s, 3H), 2.57 (d, J¼16.2 Hz, 1H), 2.27 (s,
3H), 1.73 (s, 3H); 13C NMR (151 MHz, CDCl3): 168.63, 160.17, 158.33,
148.52, 133.66, 130.78, 128.37, 128.31, 126.32, 123.90, 116.52, 103.66,
99.86, 55.09, 54.89, 40.80, 39.81, 26.35, 20.74; MS (EI): m/z¼312.16
(Mþ); HRMS (ESI): m/z calcd for C19H21O4 [MþH]þ: 313.14344;
Found: 313.14060.
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4.4.16. 4-(4-Methoxyphenyl)-4,6-dimethylchroman-2-one
(5m). Pale yellow oil. Isolated yield: 86%. 1H NMR (600 MHz,
CDCl3)
d
7.11e7.08 (m, 3H), 7.00e6.98 (m, 2H), 6.82 (d, J¼9.0 Hz,
2H), 3.78 (s, 3H), 3.21 (d, J¼15.6 Hz, 1H), 2.78 (d, J¼16.2 Hz, 1H),
2.33 (s, 3H), 1.70 (s, 3H); 13C NMR (151 MHz, CDCl3): 167.81,
158.38, 149.02, 135.96, 134.22, 130.62, 129.06, 127.27, 126.81,
116.94, 113.91, 55.16, 43.97, 40.41, 27.59, 20.93; MS (EI): m/
z¼282.14 (Mþ); HRMS (ESI): m/z calcd for C18H19O3 [MþH]þ:
283.13287; Found: 283.13276.
4.4.17. 4-(2,4-Dimethoxy-3-methylphenyl)-4,6-dimethylchroman-2-
24. Kamat, D. P.; Tilve, S. G.; Kamat, V. P. Tetrahedron Lett. 2012, 53, 4469.
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one (5n). White solid: mp 117.4e118.7 ꢀC. Isolated yield: 84%. 1H
NMR (600 MHz, CDCl3):
d
7.03 (d, J¼8.4 Hz, 1H), 6.99 (d, J¼8.4 Hz,
26. Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T. Tetrahedron 2005, 61, 9291.
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1H), 6.95 (d, J¼8.4 Hz, 1H), 6.75 (s, 1H), 6.57 (d, J¼8.4 Hz, 1H),
3.87 (d, J¼15.6 Hz, 1H), 3.83 (s, 3H), 3.21 (s, 3H), 2.59 (d,
J¼15.6 Hz, 1H), 2.24 (s, 3H), 2.11 (s, 3H), 1.68 (s, 3H); 13C NMR
(151 MHz, CDCl3): 168.45, 158.51, 158.07, 148.32, 133.59, 131.52,
128.45, 128.37, 126.87, 124.80, 120.20, 116.63, 104.58, 59.94, 55.29,
41.54, 40.04, 27.70, 20.60, 10.16; MS (EI): m/z¼326.17 (Mþ); HRMS
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20H22O4K [MþK]þ: 365.11497; Found:
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11666.
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C
365.11168.
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4.4.18. 4,6-Dimethyl-4-(5-methylthiophen-2-yl)chroman-2-one
ꢀ
(5o). Pale yellow oil. Isolated yield: 85%. 1H NMR (600 MHz, CDCl3):
6503.
d
7.10 (d, J¼8.4 Hz,1H), 7.06 (s, 1H), 6.98 (d, J¼8.4 Hz,1H), 6.53e6.52
39. Le Bras, J.; Muzart, J. Tetrahedron 2007, 63, 7942.
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(m, 2H), 3.16 (d, J¼15.6 Hz, 1H), 2.86 (d, J¼15.6 Hz, 1H), 2.41 (s, 3H),
2.33 (s, 3H), 1.59 (s, 3H); 13C NMR (151 MHz, CDCl3): 167.11, 148.56,
146.61, 139.30, 134.30, 129.92, 129.43, 126.17, 124.72, 124.25, 116.94,
44.74, 39.43, 28.29, 20.90, 15.17; MS (EI): m/z¼272.18 (Mþ); HRMS
Please cite this article in press as: Chen, C.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.05.007