Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins

Article abstract of DOI:10.1007/s11164-013-1212-2

Efficient synthetic access to highly functionalized 3,4-cyclohexane-annelated coumarins has been achieved by combining two methods. First, the important intermediates multisubstituted cyclic ?2-keto esters were prepared conveniently by condensing a variet

Full text of DOI:10.1007/s11164-013-1212-2

Res Chem Intermed
DOI 10.1007/s11164-013-1212-2
Synthesis of highly functionalized 3,4-cyclohexane-
annelated coumarins
•
•
•
Chao-Yue Chen Xiao-Mei Zhang Jian-Jun Shi
Jie He
Received: 23 December 2012 / Accepted: 16 April 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Efficient synthetic access to highly functionalized 3,4-cyclohexane-
annelated coumarins has been achieved by combining two methods. First, the
important intermediates multisubstituted cyclic b-keto esters were prepared con-
veniently by condensing a variety of benzaldehydes with ethyl acetoacetate. A
series of highly functionalized 3,4-cyclohexane-annelated coumarins were then
synthesized by Amberlyst-15-catalyzed Pechmann condensation of multisubstituted
cyclic b-keto esters with phenols. This synthetic method has the advantages of mild
reaction conditions, good tolerance of a variety of functional groups, and satisfac-
tory yields.
Keywords Coumarins Á Cyclic b-keto esters Á Highly functionalized
3,4-cyclohexane-annelated coumarins Á Pechmann condensation Á Synthesis
Introduction
Coumarin and its derivatives have a wide range of pharmacological properties
including antitumor, antibacterial, and antiviral activity, and anti-HIV, anti-
inflammatory, and anticoagulant properties [1, 2]. Some have been successfully
used for treatment of neurodegenerative diseases, for example Alzheimer’s disease
[3, 4]. Because of their unique optical properties, coumarins are, moreover, widely
used as flash pumpable laser dyes or for photographic purposes [2]. 3,4-
Cyclohexane-annelated coumarins 1 (Fig. 1) have recently received increasing
attention because of their biological activity [5–10]. The method most widely used
C.-Y. Chen (&) Á X.-M. Zhang Á J.-J. Shi Á J. He
School of Chemical Engineering, Anhui University of Science and Technology,
No.168, Shungeng Middle Road, Huainan 232001, Anhui,
People’s Republic of China
e-mail: njuchaoyuechen@163.com
123

C. Chen et al.
Fig. 1 Structure of
3,4-cyclohexane-annelated
coumarins 1
O
O
R
R'
1
for synthesis of this class of coumarin is the Pechmann reaction, which involves
condensation of phenols with six-membered cyclic b-keto esters [5–15]. The
classical Pechmann procedure, however, requires harsh reaction conditions, for
example the use of strong acids (e.g., concentrated sulfuric acid) in large excess and,
often, long reaction times; another disadvantage is that functional group tolerance is
poor [1, 2, 5–15]. Because of these disadvantages, the scope of the procedure is
limited to synthesis of 3,4-cyclohexane-annelated coumarins with limited or no
functionality.
We envisaged synthesis of a variety of highly functionalized 3,4-cyclohexane-
annelated coumarins 1 by Pechmann condensation of phenols with multisubstituted
cyclic b-keto esters 2a–f (Scheme 1), which are readily prepared from inexpensive,
readily available starting materials. Unfortunately, this method often suffers from
low yields because the harsh reaction conditions are incompatible with the
functional groups and because of the ring strain experienced by multisubstituted
cyclic b-keto esters 2a–f during cyclization. In this work, a relatively mild
procedure for high-yield preparation of highly functionalized 3,4-cyclohexane-
annelated coumarins 1 was eventually established after screening a range of
catalysts for Pechmann condensation.
Results and discussion
To initiate our study, the multisubstituted cyclic b-keto ester intermediates (ethyl
cyclohexanone-2-carboxylate b-keto esters) 2a–f required for further transforma-
tions were prepared in excellent yields by condensing a variety of benzaldehydes
with ethyl acetoacetate. The key step in this reaction is reported to be a tandem
Knoevenagel condensation–Michael addition–aldol reaction sequence [16, 17].
Cyclic b-keto esters 2b and resorcinol were then chosen as model reactants to
investigate and optimize the Pechmann reaction conditions (Table 1). When
protonic acid catalysts, for example 12.0 M sulfuric acid and trifluoroacetic acid
(TFA), were used in the reaction, the Pechmann product ethyl 3,9-dihydroxy-9-
methyl-7-phenyl-7,8,10-trihydro-6H-dibenzo[c]pyran-6-one-8-carboxylate 1d was
isolated in only 18 and 37 % yield, respectively, with dehydration and hydrolysis
products (Table 1, entries 1 and 2). p-Toluenesulfonic acid (TsOH) and polyphos-
phoric acid (PPA) in toluene were completely ineffective (entries 3 and 4). To
minimize unwanted side reactions we then investigated several milder Lewis acid
catalysts and solid acid catalysts [18, 19] for the reaction. However, use of such
Lewis acid catalysts as molecular I2, SnCl2, FeCl3, ZnCl2, and ZrCl4 furnished no
coumarin 1d (entries 5 to 9). In contrast, the solid acid catalysts zeolite, Amberlite
IR120, and Amberlyst-15 were found to enable effective preparation of coumarin 1d
123

Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
R2
OH
O
R1
O
O
O
O
O
H
R3
Pechmann condensation
piperidine
or Me2NH
R1
+ 2
O
O
O
OH
2a-f
R2
O
O
R1
R3
O
HO
1a-m
O
Scheme 1 Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
Table 1 Evaluation of the Pechmann reaction conditions
NO2
HO
O
O
NO2
reaction
conditions
O
O
O
HO
OH
+
O
O
O
HO
OH
2b
O
1d
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yield (%)
1
H2SO4
TFA
–
0–r.t.
12
12
12
12
12
12
12
12
12
12
12
12
12
12
18
37
0
2
–
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
3
TsOH
PPA
Toluene
Toluene
Toluene
CH3CN
Toluene
CHCl3
Toluene
Toluene
Toluene
Toluene
CH3CN
CH3OH
4
Trace
0
5
I2
6
SnCl2
FeCl3
ZnCl2
ZrCl4
Zeolite
0
7
0
8
0
9
0
10
11
12
13
14
15
47
72
61
57
Amberlite IR120
Amberlyst-15
Amberlyst-15
Amberlyst-15
123

C. Chen et al.
Table 2 Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
Time Yield
cyclohexane
keto esters
β
-
3,4-cyclohexane-annelated
coumarins
Entry Phenols
(h)
(%)
H3C
O
O
O
O
O
H3
C
OH
O
O
O
1
2
3
4
24
41
HO
O
OH
1a
2a
NO2
H3
C
O
O
NO2
O
O
O
H3
C
OH
O
24
12
12
46
69
72
O
O
HO
O
O
OH
1b
2b
HO
O
O
O
O
HO
OH
O
O
O
HO
O
OH
1c
2a
NO2
HO
O
O
NO2
O
O
O
HO
OH
O
O
O
HO
O
OH
1d
2b
CH3
HO
O
O
CH3
O
O
O
HO
OH
O
5
12
73
O
O
HO
O
OH
1e
2c
OCH3
HO
O
O
OCH 3
O
O
O
O
HO
OH
O
6
7
8
12
12
12
70
65
80
O
O
O
HO
O
OH
OH
1f
2d
HO
O
O
O
O
O
HO
OH
O
HO
O
2e
1g
OH
HO
O
O
O
O
O
OH
HO
OH
O
O
O
HO
OH
O
2a
1h
123

Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
Table 2 continued
Time Yield
cyclohexane
keto esters
β
- 3,4-cyclohexane-annelated
coumarins
Entry Phenols
(h)
(%)
NO2
OH
HO
O
O
NO2
OH
O
O
O
HO
OH
9
12
82
O
O
O
HO
O
OH
1i
2b
OH
O
O
O
HO
O
O
OH
O
O
HO
OH
10
12
12
8
78
77
87
O
OH
HO
O
2e
1j
OH
O
O
O
O
O
HO
O
O
OH
O
O
HO
OH
11
O
OH
HO
O
2f
1k
HO
O
O
O
O
HO
OH
O
O
OH
O
12
HO
O
OH
OH
1l
2a
NO2
HO
O
O
NO2
HO
OH
O
O
OH
O
13
8
85
O
O
HO
O
OH
OH
1m
2b
(entries 10 to 12). Among these catalysts, the highest yield was obtained with
Amberlyst-15 [18]. The highest yield of the desired coumarin 1d was obtained when
Amberlyst-15 was used in toluene under reflux (entries 12).
Under the optimized reaction conditions, a series of monohydric and polyhydric
phenols could be conveniently converted to the corresponding highly functionalized
3,4-cyclohexane-annelated coumarins 1a–m (Table 2). As expected, electron-rich
phenols underwent faster coupling with cyclic b-keto esters 2, and gave essentially
higher yields of the products. The reactivity of 1,3,5-trihydroxybenzene with cyclic
b-keto esters was observed to be the highest among all the phenols (Table 2, entries
12 and 13). This is mainly because of the presence of three meta-hydroxyl groups
which act as electron-donating groups and, hence, enhance the activity of its
addition to cyclic b-keto esters. The reactivity of 1,2,3-trihydroxybenzene with
cyclic b-keto esters was observed to be lower than that of 1,3,5-trihydroxybenzene,
123

C. Chen et al.
presumably because of steric hindrance by hydroxyl groups (entries 8 to 11).
Similarly, because of the presence of only two hydroxyl groups meta to each other,
1,3-dihydroxybenzene was found to be less reactive than trihydroxybenzene and
afforded the products with slightly diminished yields (entries 3 to 7). As for
monohydric phenols, 3-methylphenol led to lower yields and needed longer times.
Phenol and some of its derivatives bearing electron-withdrawing groups, for
example 3-chlorophenol and 3-nitrophenol failed to react. It was found that both
aromatic and aliphatic cyclic b-keto esters 2a–f undergo the Pechmann conden-
sation smoothly. The yields of the tricyclic coumarins 1a–m from cyclic b-keto
esters 2a–f are lower than reported yields of common coumarins from straight chain
b-keto esters, for example ethyl (or methyl) acetoacetate; this may be attributed to
the ring strain experienced by cyclic b-keto esters 2a–f during cyclization. Another
remarkable feature of this procedure is the good tolerance of these reaction
conditions by a variety of functional groups, for example ether, ester, hydroxyl, and
nitro groups.
Conclusions
In summary, we have combined two reliable methods to enable efficient synthetic
access to highly functionalized 3,4-cyclohexane-annelated coumarins 1a–m. First,
important intermediates ethyl cyclohexanone-2-carboxylate b-keto esters 2a–f were
readily prepared by condensing ethyl acetoacetate with a variety of benzaldehydes.
Highly functionalized 3,4-cyclohexane-annelated coumarins 1a–m were then
obtained by Pechmann condensation of cyclic b-ketoesters 2a–f with phenols
catalyzed by Amberlyst-15 in toluene. The main features of this method are:
1
use of inexpensive and readily available reagents, for example ethyl acetoac-
etate, aromatic and/or aliphatic aldehydes, and phenols, as starting materials;
and
2
the applicability of the Pechmann condensation to a wide range of reaction
substrates, for example monohydric, dihydric, and trihydric phenols, and
aromatic and/or aliphatic cyclic b-ketoesters 2a–f.
Common functional groups, for example sensitive ether, ester, hydroxyl, and
nitro, are, furthermore, stable during this procedure, because of its mild reaction
conditions. This method is a valuable alternative for synthesis of highly
functionalized 3,4-cyclohexane-annelated coumarins and will find application in
the synthesis of natural products.
Experimental
All reagents were obtained from commercial suppliers and used without further
1
purification. H NMR and 13C NMR spectra were recorded on a Bruker ARX-300
(300 MHz) NMR spectrometer. Mass spectra (ESI) were obtained on a Finnigan-
Mat LCQ mass spectrometer. Elemental analysis was performed on an Elementar
123

Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
Vario MICRO CUBE (Germany). Melting points were determined on an electrically
heated RK-Z melting point apparatus (Analytical Instrument Factory, Tianjin,
China) and are uncorrected.
Preparation of multisubstituted cyclohexane b-keto esters 2a–f
Multisubstituted cyclohexane b-keto esters 2a–f were prepared in accordance with
literature methods [16, 20–22]. Diethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclo-
hexane-1,3-dicarboxylate (2a), white solid, mp: 153–155 °C (lit. [20]. 156 °C).
Diethyl 4-hydroxy-4-methyl-2-(4-nitrophenyl)-6-oxocyclohexane-1,3-dicarboxylate
(2b), white solid, mp: 187–189 °C (lit. [20] 188 °C). Diethyl 4-hydroxy-4-methyl-
2-(4-methylphenyl)-6-oxocyclohexane-1,3-dicarboxylate (2c), colorless needles,
mp: 144–146 °C (lit. [16]. 146 °C). Diethyl 4-hydroxy-2-(4-methoxyphenyl)-4-
methyl-6-oxocyclohexane-1,3-dicarboxylate (2d), white solid, mp: 143–144 °C (lit.
[16]. 142 °C). Diethyl 4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate
(2e), colorless liquid [21]. Diethyl 2,4-dimethyl-4-hydroxy-6-oxocyclohexane-1,3-
dicarboxylate (2f), white solid, mp: 74–77 °C (lit. [22]. 75–77 °C).
General procedure for synthesis of highly functionalized 3,4-cyclohexane-
annelated coumarins 1a–m
Amberlyst-15 (0.1 g) was added to a mixture of phenol (1.2 mmol) and cyclohexane
b-keto ester (1.0 mmol) in toluene (20 mL) and the mixture was heated under reflux
for different times (Table 2). When the reaction was complete (monitored by TLC),
the catalyst was isolated by filtration and washed with ethyl acetate. The filtrate was
collected, the solvent was removed under vacuum, and the crude product was
purified by column chromatography on silica gel, with 1:1 EtOAc–hexane as eluent,
to afford 1a–m.
Ethyl 3,9-dimethyl-9-hydroxy-6-oxo-7-phenyl-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1a)
1
White solid, mp 180–182 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 7.49 (d,
J = 7.8 Hz, 1H), 7.28–7.19 (m, 3H), 7.14–7.10 (m, 4H), 4.37 (d, J = 10.8 Hz, 1H),
4.13–4.03 (m, 2H), 3.50 (s, 1H), 3.16 (d, J = 18.0 Hz, 1H), 2.84 (dd, J = 18.0,
2.4 Hz, 1H), 2.75 (d, J = 10.5 Hz, 1H), 2.44 (s, 3H), 1.44 (s, 3H), 1.06 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, CDCl3) d (ppm): 174.9, 159.4, 152.9, 145.2, 142.5, 142.0,
128.6, 127.3, 126.8, 125.2, 123.4, 122.9, 117.2, 117.0, 68.4, 61.1, 58.3, 44.1, 38.5,
28.3, 21.6, 14.0. MS (ESI) m/z [M ? H]? Calcd. for C24H25O5: 393.17; found: 393.25.
Anal. Calcd. for C24H24O5: C, 73.45; H, 6.16. Found: C, 73.50; H, 6.19.
Ethyl 3,9-dimethyl-9-hydroxy-7-(4-nitrophenyl)-6-oxo-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1b)
1
White solid, mp 213–215 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 8.09 (d,
J = 8.4 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.12 (d,
123

C. Chen et al.
J = 7.8 Hz, 1H), 7.05 (s, 1H), 4.47 (d, J = 11.1 Hz, 1H), 4.10–4.00 (m, 2H), 3.19
(d, J = 18.0 Hz, 1H), 2.89 (d, J = 18.0 Hz, 1H), 2.72 (d, J = 11.1 Hz, 1H), 2.41
(s, 3H), 1.44 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3) d (ppm):
174.0, 159.6, 152.8, 150.7, 146.75, 146.68, 142.7, 128.3, 125.6, 123.9, 123.7, 121.3,
116.96, 116.90, 68.5, 61.4, 57.6, 43.8, 38.6, 28.1, 21.6, 14.1. MS (ESI) m/z [M ? H]?
Calcd. for C24H24NO7: 438.16; found: 438.28. Anal. Calcd. for C24H23NO7: C, 65.90;
H, 5.30. Found: C, 65.95; H, 5.33.
Ethyl 3,9-dihydroxy-9-methyl-7-phenyl-7,8,10-trihydro-6H-dibenzo[c]pyran-6-one-
8-carboxylate (1c)
1
White solid, mp 245–248 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.42 (s,
1H), 7.61 (d, J = 8.7 Hz, 1H), 7.22–7.08 (m, 5H), 6.82 (dd, J = 8.7, 2.1 Hz, 1H),
6.67 (d, J = 2.1 Hz, 1H), 4.70 (s, 1H), 4.27(d, J = 10.5 Hz, 1H), 4.05–3.92 (m,
2H), 3.11 (dd, J = 18.3, 2.1 Hz, 1H), 2.96 (d, J = 18.0 Hz, 1H), 2.76 (d,
J = 10.5 Hz, 1H), 1.33 (s, 3H), 1.05 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
DMSO-d6) d (ppm): 172.0, 160.7, 159.6, 154.3, 147.2, 144.3, 128.4, 128.3, 126.5,
126.3, 120.1, 113.3, 112.4, 102.4, 68.2, 60.2, 60.2, 58.8, 43.0, 40.4, 28.4, 14.6. MS
(ESI) m/z [M ? H]? Calcd. for C23H23O6: 395.15; found: 395.10. Anal. Calcd. for
C23H22O6: C, 70.04; H, 5.62. Found: C, 70.12; H, 5.67.
Ethyl 3,9-dihydroxy-9-methyl-7-(4-nitrophenyl)-6-oxo-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1d)
1
White solid, mp 252–254 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.47 (s,
1H), 8.08 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 8.7 Hz, 2H),
6.82 (dd, J = 8.4, 2.4 Hz, 1H), 6.67 (d, J = 2.4 Hz, 1H), 4.84 (s, 1H), 4.39 (d,
J = 10.5 Hz, 1H), 4.05–3.90 (m, 2H), 3.15 (d, J = 18.6 Hz, 1H), 2.98 (d,
J = 18.6 Hz, 1H), 2.82 (d, J = 11.1 Hz, 1H), 1.34 (s, 3H), 1.03 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 171.5, 161.0, 159.7, 154.3, 152.7,
148.4, 146.4, 129.8, 126.5, 123.7, 118.8, 113.5, 112.2, 102.4, 68.1, 60.5, 57.9, 43.0,
40.5, 28.2, 14.5. MS (ESI) m/z [M ? H]? Calcd. for C23H22NO8: 440.13; found:
440.25. Anal. Calcd. for C23H21NO8: C, 62.87; H, 4.82. Found: C, 70.12; H, 5.67.
Ethyl 3,9-dihydroxy-9-methyl-6-oxo-7-(4-methylphenyl)-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1e)
1
White solid, mp 247–249 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.40 (s,
1H), 7.59 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 7.5 Hz, 1H), 6.97 (d, J = 8.7 Hz, 2H),
7.20 (d, J = 7.5 Hz, 1H), 6.80 (dd, J = 8.4, 2.1 Hz, 1H), 6.66 (s, 1H), 4.67 (s, 1H),
4.23 (d, J = 10.2 Hz, 1H), 4.06–3.89 (m, 2H), 3.08 (d, J = 18.0 Hz, 1H), 2.93 (d,
J = 18.0 Hz, 1H), 2.72 (d, J = 10.5 Hz, 1H), 2.20 (s, 3H), 1.31 (s, 3H), 1.06 (t,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 172.0, 160.6, 159.5,
154.3, 146.9, 141.3, 135.3, 129.0, 128.2, 126.3, 120.3, 113.2, 112.4, 102.3, 68.2,
60.2, 58.8, 42.5, 28.4, 21.1, 14.6. MS (ESI) m/z [M ? H]? Calcd. for C24H25O6:
123

Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
409.17; found: 409.25. Anal. Calcd. for C24H24O6: C, 70.57; H, 5.92. Found: C,
70.60; H, 5.95.
Ethyl 3,9-dihydroxy-7-(4-methoxyphenyl)-9-methyl-6-oxo-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1f)
1
White solid, mp 148–150 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.39 (s,
1H), 7.58 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.80 (d, J = 8.7 Hz, 1H),
6.74 (d, J = 8.7 Hz, 2H), 6.66 (s, 1H), 4.53 (s, 1H), 4.22 (d, J = 10.5 Hz, 1H),
4.06–3.91 (m, 2H), 3.67 (s, 3H), 3.08 (d, J = 17.4 Hz, 1H), 2.93 (d, J = 17.4 Hz,
1H), 2.74 (d, J = 10.2 Hz, 1H), 1.32 (s, 3H), 1.06 (t, J = 7.2 Hz, 3H). 13C NMR
(75 MHz, DMSO-d6) d (ppm): 172.1, 160.6, 159.5, 158.0, 154.3, 146.7, 136.1,
129.3, 126.3, 120.4, 113.8, 113.2, 112.4, 102.3, 68.2, 60.2, 58.9, 55.4, 42.1, 40.4,
28.4, 14.6. MS (ESI) m/z [M ? H]? Calcd. for C24H25O7: 425.16; found: 425.20.
Anal. Calcd. for C24H24O7: C, 67.91; H, 5.70. Found: C, 67.96; H, 5.73.
Ethyl 3,9-dihydroxy-9-methyl-6-oxo-7,8,10-trihydro-6H-benzo[c]chromene-8-
carboxylate (1g)
1
White solid, mp 189–190 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.36 (s,
1H), 7.50 (d, J = 8.7 Hz, 1H), 6.77 (dd, J = 8.4, 2.4 Hz, 1H), 6.69 (d, J = 2.4 Hz,
1H), 4.74 (s, 1H), 4.16–4.03 (m, 2H), 2.92–2.53 (m, 5H), 1.32 (s, 3H), 1.20 (t,
J = 7.2 Hz, 3H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 173.1, 161.0, 160.5,
153.8, 146.3, 125.6, 116.6, 113.3, 112.2, 102.5, 67.7, 60.3, 48.0, 39.7, 28.5, 25.0,
14.7. MS (ESI) m/z [M ? H]? Calcd. for C17H18O6: 319.12; found: 319.15. Anal.
Calcd. for C17H18O6: C, 64.14; H, 5.70. Found: C, 64.16; H, 5.73.
Ethyl 9-methyl-6-oxo-7-phenyl-3,4,9-trihydroxy-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1h)
1
White solid, mp 243–245 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 9.89 (s,
1H), 9.19 (s, 1H), 7.22–7.03 (m, 6H), 6.81 (d, J = 8.7 Hz, 1H), 4.67 (s, 1H), 4.28
(d, J = 10.5 Hz, 1H), 4.07–3.89 (m, 2H), 3.08 (dd, J = 18.0, 1.8 Hz, 1H), 2.93 (d,
J = 18.0 Hz, 1H), 2.74 (d, J = 10.5 Hz, 1H), 1.32 (s, 3H), 1.04 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 172.0, 159.5, 149.0, 147.4, 144.5,
143.0, 132.4, 128.4, 128.3, 126.5, 120.0, 115.2, 113.1, 112.6, 68.2, 60.2, 58.8, 45.0,
43.0, 28.4, 14.6. MS (ESI) m/z [M ? H]? Calcd. for C23H23O7: 411.14; found:
411.25. Anal. Calcd. for C23H22O7: C, 67.31; H, 5.40. Found: C, 67.35; H, 5.42.
Ethyl 9-methyl-7-(4-nitrophenyl)-3,4,9-trihydroxy-6-oxo-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1i)
1
White solid, mp 159–162 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 9.99 (s,
1H), 9.23 (s, 1H), 8.09 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.7 Hz, 2H), 7.12 (d,
J = 8.7 Hz, 1H), 6.83 (d, J = 8.7 Hz, 1H), 4.83 (s, 1H), 4.41 (d, J = 9.9 Hz, 1H),
4.05–3.91 (m, 2H), 3.14 (dd, J = 17.7, 1.5 Hz, 1H), 2.97 (d, J = 17.7 Hz, 1H), 2.82
123

C. Chen et al.
(d, J = 11.1 Hz, 1H), 1.33 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
DMSO-d6) d (ppm): 171.5, 159.7, 152.9, 149.3, 148.7, 146.4, 143.0, 132.4, 129.7,
123.6, 118.7, 115.4, 113.0, 112.8, 68.1, 60.5, 57.9, 43.0, 40.5, 28.2, 14.6. MS (ESI)
m/z [M ? H]? Calcd. for C23H22NO9: 456.13; found: 456.20. Anal. Calcd. for
C23H21NO9: C, 60.66; H, 4.65. Found: C, 60.70; H, 4.68.
Ethyl 9-methyl-3,4,9-trihydroxy-6-oxo-7,8,10-trihydro-6H-benzo[c]chromene-8-
carboxylate (1j)
1
White solid, mp 177–179 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 9.87 (s,
1H), 9.23 (s, 1H), 6.98 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 4.72 (s, 1H),
4.16–4.03 (m, 2H), 2.84–2.55 (m, 5H), 1.32 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). 13C
NMR (75 MHz, DMSO-d6) d (ppm): 173.1, 160.9, 148.7, 146.6, 142.5, 132.5,
116.4, 114.4, 113.0, 112.6, 67.7, 60.3, 48.0, 39.8, 28.6, 25.1, 14.6. MS (ESI) m/z
[M ? H]? Calcd. for C17H19O7: 335.11; found: 335.18. Anal. Calcd. for C17H18O7:
C, 61.07; H, 5.43. Found: C, 61.11; H, 5.45.
Ethyl 7,9-dimethyl-3,4,9-trihydroxy-6-oxo-7,8,10-trihydro-6H-benzo[c]chromene-
8-carboxylate (1k)
1
White solid, mp 238–241 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 9.87 (s,
1H), 9.22 (s, 1H), 7.00 (d, J = 8.7 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 4.51 (s, 1H),
4.22–4.10 (m, 2H), 3.17–3.12 (m, 1H), 2.82 (s, 1H), 2.45 (d, J = 10.2 Hz, 1H), 1.31
(s, 3H), 1.23 (t, J = 7.2 Hz, 3H), 1.16 (d, J = 6.9 Hz, 2H). 13C NMR (75 MHz,
DMSO-d6) d (ppm): 173.1, 160.1, 148.7, 146.5, 142.6, 132.3, 121.3, 114.9, 113.3,
112.6, 67.7, 60.4, 57.3, 40.4, 31.2, 28.7, 18.9, 14.7. MS (ESI) m/z [M ? H]? Calcd.
for C18H21O7: 349.13; found: 349.20. Anal. Calcd. for C18H20O7: C, 62.06; H, 5.79.
Found: C, 62.10; H, 5.82.
Ethyl 9-methyl-6-oxo-7-phenyl-1,3,9-trihydroxy-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1l)
1
White solid, mp 279–281 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.44 (s,
1H), 10.14 (s, 1H), 7.19–7.05 (m, 5H), 6.27 (d, J = 1.8 Hz, 1H), 6.11 (d,
J = 1.8 Hz, 1H), 4.51 (s, 1H), 4.21 (d, J = 10.8 Hz, 1H), 4.05–3.90 (m, 2H), 3.40
(d, J = 18.9 Hz, 1H), 3.18 (d, J = 18.9 Hz, 1H), 1.25 (s, 3H), 1.03 (t, J = 7.2 Hz,
3H). 13C NMR (75 MHz, DMSO-d6) d (ppm): 172.2, 160.4, 159.5, 157.9, 155.6,
148.7, 145.0, 128.4, 128.2, 126.3, 118.6, 102.6, 99.7, 94.7, 68.0, 60.1, 58.2, 44.8,
42.9, 28.7, 14.6. MS (ESI) m/z [M ? H]? Calcd. for C23H23O7: 411.14; found:
411.19. Anal. Calcd. for C23H22O7: C, 67.31; H, 5.40. Found: C, 67.37; H, 5.44.
Ethyl 9-methyl-7-(4-nitrophenyl)-1,3,9-trihydroxy-6-oxo-7,8,10-trihydro-6H-
benzo[c]chromene-8-carboxylate (1m)
1
White solid, mp 270–272 °C. H NMR (300 MHz, DMSO-d6) d (ppm): 10.53 (s,
1H), 10.23 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.29 (d,
123

Synthesis of highly functionalized 3,4-cyclohexane-annelated coumarins
J = 2.1 Hz, 1H), 6.12 (d, J = 2.1 Hz, 1H), 4.67 (s, 1H), 4.35 (d, J = 10.5 Hz, 1H),
4.05–3.90 (m, 2H), 3.44 (d, J = 17.7 Hz, 1H), 3.25 (d, J = 17.7 Hz, 1H), 2.73 (d,
J = 10.8 Hz, 1H), 1.28 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz,
DMSO-d6) d (ppm): 171.7, 160.8, 159.6, 158.1, 155.6, 153.4, 149.9, 146.3, 129.6,
123.6, 117.2, 102.5, 99.9, 94.7, 68.0, 60.4, 57.3, 44.8, 43.0, 28.5, 14.5. MS (ESI) m/z
[M ? H]? Calcd. for C23H22NO9: 456.13; found: 456.25. Anal. Calcd. for
C23H21NO9: C, 60.66; H, 4.65. Found: C, 60.68; H, 4.68.
Acknowledgments The authors gratefully acknowledge financial support from the Provincial Key
Project of Natural Science Research for Colleges and Universities of Anhui Province of China
(KJ2011A091).
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