Synthesis of dihydrobenzo[h]coumarins and their 4-methyl analogs

Article abstract of DOI:10.1080/00397910500282943

Dihydrobenzo[h]coumarins (5a-7a) and their 4-methyl analogs (5b-7b) were synthesized from 1-naphthol via two different synthetic routes. One pathway is the direct condensation of 5,8-dihydro-1-naphthol (9) with malic acid or ethyl acetoacetate, affording 7,10-dihydrobenzo[h]coumarins 7a and 7b, respectively. The other is through the oxidation of 7,8,9,10-tetrahydrobenzo[h] coumarins (15a-b), followed by the reduction of the carbonyl group and dehydration of hydroxyl group, giving 7,8-dihydrobenzo[h]coumarins (5a, b) and 9,10-dihydrobenzo[h]coumarins (6a, b). The regio selectivities for the oxidation reactions of 15a, b were rationalized on the basis of quantum chemical calculations and further confirmed by the X-ray crystallographic analysis of the derivatives of oxidation products. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500282943

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Synthesis of Dihydrobenzo[h]coumarins and
Their 4‐Methyl Analogs
a
a
a
Yang Wang , Shaoxu Huang & Peng Xia
a
Department of Medicinal Chemistry, School of Pharmacy , Fudan
University , Shanghai, China
Published online: 20 Aug 2006.
To cite this article: Yang Wang , Shaoxu Huang & Peng Xia (2005) Synthesis of Dihydrobenzo[h]coumarins and
Their 4‐Methyl Analogs, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:24, 3141-3156
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Synthetic Communications , 35: 3141–3156, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500282943
Synthesis of Dihydrobenzo[h]coumarins
and Their 4-Methyl Analogs
Yang Wang, Shaoxu Huang, and Peng Xia
Department of Medicinal Chemistry, School of Pharmacy,
Fudan University, Shanghai, China
Abstract: Dihydrobenzo[h]coumarins (5a–7a) and their 4-methyl analogs (5b–7b)
were synthesized from 1-naphthol via two different synthetic routes. One pathway is
the direct condensation of 5,8-dihydro-1-naphthol (9) with malic acid or ethyl
acetoacetate, affording 7,10-dihydrobenzo[h]coumarins 7a and 7b, respectively. The
other is through the oxidation of 7,8,9,10-tetrahydrobenzo[h] coumarins (15a–b),
followed by the reduction of the carbonyl group and dehydration of hydroxyl group,
giving 7,8-dihydrobenzo[h]coumarins (5a, b) and 9,10-dihydrobenzo[h]coumarins
(6a, b). The regio selectivities for the oxidation reactions of 15a, b were rationalized
on the basis of quantum chemical calculations and further confirmed by the X-ray
crystallographic analysis of the derivatives of oxidation products.
Keywords: Dihydrobenzo[h]coumarins, 4-methyl-dihydrobenzo[h]coumarins, 7,8,9,10-
tetrahydrobenzo[h]coumarins, oxidation, regioselectivity
INTRODUCTION
0
0
3
,4 -Di-O-(2)-camphanoyl-(þ)-cis-khellactone (DCK, 1) and numerous
DCK analogs have been demonstrated to have an extremely potent inhibitory
activity against HIV-1 replication in H9 lymphocytic cells in previous
[
1–6]
research.
Selected modifications to the DCK skeleton are very desirable
to clarify the mechanism of action and identify the pharmacophores in this
class of potent anti-HIV agents. To this end, a new series of DCK analogs,
Received in Japan April 27, 2005
Address correspondence to Peng Xia, Department of Medicinal Chemistry, School
of Pharmacy, Fudan University, Shanghai 200032, China. Tel. and Fax: þ86 21
54237563; E-mail: pxia@shmu.edu.cn
3
141

3
142
Y. Wang, S. Huang, and P. Xia
Figure 1. Structures of DCK (1), 7-carbo-DCK analogs (2) and their regioisomers
3, 4), and dihydrobenzo[h]coumarins 5–7.
(
namely 7-carbo-DCK derivatives (2a, b) and their corresponding regioisomers
3, 4) (Fig. 1) were designed. Compounds 2a, b can be considered the bioiso-
steres of DCK analogs, which might provide valuable insight into the effect of
-oxygen atoms and 8,8-dimethyl groups on the anti-HIV activity. Moreover,
(
7
the regioisomers (3, 4) might shed some light on the positional effect of two
camphanoyl ester groups on the activity. According to retrosynthetic
analysis, dihydrobenzo[h]coumarins (5a–7a) and their 4-methyl analogs
(5b–7b) are the key intermediates for the synthesis of 2–4. More
important, the coumarin derivatives themselves also represent one type of
fundamental heterocyclic compounds with several bioactivities, and
[7–9]
excellent results have been shown in a decade of extensive research.
Herein, we report the synthesis and characterization of a variety of
dihydrobenzo[h]coumarins 5–7 (Fig. 1).
RESULTS AND DISCUSSION
As shown in Scheme 1, the key intermediate to synthesize 7a, b is 5,8-
dihydro-l-naphthol (9), which was prepared in a 71% yield by Birch
[
10]
reduction from 1-naphthol (8) with Li/NH (liq.)
We previously reported
that the condensation reaction of 9 with ethyl acetoacetate gave 4-methyl-
,10-dihydrobenzo[h]coumarin (7b) together with an aromatized by-product
3
7

Dihydrobenzo[h]coumarins and Analogs
3143
Scheme 1. Synthetic route of 7a, b: (i) Li/NH (liq.), 2788C; (ii) paraformaldehyde,
3
2
,6-lutidine, SnCl
COCH COOC
POCl , benzene, reflux, 1 h.
4
, toluene, 95–1008C, 10 h; (iii) Ac
2
O, NaOAc, 1608C, 8 h; (iv) CH
2 5
COCH COOC H ,
3
2
2
H
5
, CH SO H, Na SO , 1208C, 5 h; and (v) CH
3
3
2
3
3
2
3
[
11]
4
-methylbenzo[h]coumarin (11).
It was found that the reaction conditions,
particularly the absolutel absence of oxygen, is critical for this acid-catalyzed
condensation of 9 to 7b, which otherwise almost completely converts to the aro-
matized product 11. Under the optimized conditions, that is, under Ar atmos-
phere with CH SO H as a catalyst in the presence of antioxidant Na SO at
3
3
2
3
100–1208C, 7b and 11 could be obtained in the ratio of 70:30 with moderate
yield (49%). The better yield (60–71%) of 7b was obtained by using POCl3
instead of CH SO H or p-toluenesulfonic acid as the catalyst in refluxing
3
3
[
12,13]
benzene.
No aromatized product 11 was observed under these reaction
conditions, which is probably due to the low reaction temperature. A trial of
the synthesis of 7a through the condensation of 9 with malic acid in HOAc
in the presence of H SO demonstrated that only benzo[h]coumarin was
2
4
obtained. Alternatively, the synthesis of 7a was accomplished under Ar by
the condensation of 5,8-dihydro-l-hydroxynaphthalene-2-carbaldehyde (10)
with acetic anhydride in the presence of sodium acetate. Compound 10 was
obtained in 60% yield by treatment of phenol (9) with paraformaldehyde in
[14]
toluene in the presence of SnCl coupled with 2,6-lutidine.
4
According to retrosynthetic analysis, 5,6-dihydro-1-naphthol (12) and
,8-dihydro-1-naphthol (13) may act as the key synthetic precursors for 5
and 6, respectively. However the attempts to prepare 12 and 13 by regioisome-
7
[
15]
rization of 9 under basic condition
always resulted in an inseparable
mixture (Scheme 2). Thus, we switched our attention to the synthesis of 5
and 6 through an alternative route.
As illustrated in Scheme 3, the synthesis of 5, 6 was accomplished via a
five-step reaction sequence. 5,6,7,8-Tetrahydro-l-naphthol (14) was prepared
in 74% yield by reducing cheap and readily available 1-naphthol (8)
[16]
with Raney Ni-A1 alloy in an alkaline aqueous solution. The conden-
sation of 14 with malic acid in HOAc in the presence of H SO gave
2
4

3
144
Y. Wang, S. Huang, and P. Xia
Scheme 2. Regioisomerization of 9.
,8,9,10-tetrahydrobenzo[h]coumarin (15a) in a yield of 60%. The yield was
7
greatly enhanced in comparison with the literature method (16% yield).
[17]
The condensation of 14 with ethyl acetoacetate in the presence of POCl3
furnished the expected 4-methyl-7,8,9,10-tetrahydrobenzo[h]coumarin (15b)
in a yield of 70%.
[
18]
The oxidation of both 15a and 15b with CrO in HOAc
3
afforded two
products with different polarities (R ¼ 0.3 and 0.05, on silica-gel plate,
f
eluent: hexane–EtOAc3:1), respectively. The compounds with larger Rf
values are the major products (42% or 51% yields), and the others having
1
smaller R values are the minors (22% or 9%). From their H NMR,
13
C
f
NMR, and MS spectra, it is clear that the benzylic 7- or 10-positions CH2
of 15a and 15b have been oxidized to a carbonyl group, affording two regio-
isomers 16a, b and 17a, b, respectively. However, we were unable to distin-
guish 16 and 17 from each other simply on the basis of these data. After many
trials for growing single crystals of these ketone products failed, we calculated
the electronic density distribution at 7- and 10-carbons of compounds 15a, b
using DFT (B3LYP) implemented in the Gaussian98 suite of programs. The
results indicated that the 7-carbons of 15a, b possess higher electronic
densities than those of 10-carbons (Table 1), suggesting that 7-position
Scheme 3. Synthetic route of 5, 6: (i) Raney Ni-Al alloy, 1% aq. KOH/water, 908C,
2
h; (ii) 15a: malic acid, H
POCl , 1008C, 18 h; (iii) CrO
v) 2% H SO , reflux, 6–16 h.
2
SO
4
, HOAc, 1308C, 6 h; 15b: CH
3
COCH COOC
2
2 5
H ,
3
3
, HOAc, rt, 3 days; (iv) NaBH
, CH OH, 1–4 h;
4 3
(
2
4

Dihydrobenzo[h]coumarins and Analogs
3145
a
Table 1. Electronic distribution of C7 and C10 in compounds 15a, b
Atomic charges with
hydrogens sumed
into heavy atoms
Atomic
charges
Compound
Diagram
C7: 20.3471,
H: 0.1573,
H: 0.1497
C7: 20.0400
C10:
2
C10: þ0.0026
15a
0.3285,
H: 0.1700,
H: 0.1611
C7: 20.3473,
H: 0.1564,
H: 0.1489
C7: 20.0420
C10: þ0.0027
C10:
2
15b
0.3275,
H: 0.1698,
H: 0.1604
a
All the calculations were performed at the DFT level using the hybrid functional
B3LYP with the Gaussian98 suite of programs. All atoms were treated with an all-
ꢀ
electron 6-31 basis set.
carbons should be easier to be oxidized than 10-position carbons. Therefore,
the major oxidation products of 15a, b were tentatively assigned to be 16a
(42% yield) and 16b (51% yield) with larger R value, and the minors 17a
f
(22% yield) and 17b (9% yield) with smaller R values, respectively. In
f
comparison with the oxidation of 15a, the higher regioselectivity for the
reaction of 15b might be attributed to its bigger difference of the electronic
distribution at 7-carbon (20.0420) and 10-carbon (þ0.0027).
In addition, the calculation on the dipole moments of compounds 16a, b
and 17a, b demonstrated that the former have smaller m values and thus are
less polar components with bigger R values (Table 2). Accordingly, these
f
results are consistent with speculation based on the calculation of electronic
distribution mentioned previously, which was further confirmed by the
X-ray crystallographic analysis of the reduction product of 16a and the
reduction –dehydration product of 16b (Figs. 2 and 3).
[
19]
[20]
.
and KMnO /CuSO 5H O were
4 4 2
Other oxidants such as CANL
also examined and resulted in low yield or no reaction.
Reduction of 16a, b and 17a, b with NaBH in methanol gave 7-hydroxy
4
or 10-hydroxy-7,8,9,10-tetrahydrobenzo[h]coumarin (19a, 18a) and their
4
-methyl analogs (19b, 18b) in the yields of 79% and 66%, and 74% and

3
146
Y. Wang, S. Huang, and P. Xia
Table 2. Calculated dipole moments of
compounds 16a, b and 17a, b
Dipole moments
(
Debye)
Compounds
1.6215
7.4681
2.2173
7.7861
16a
17a
16b
17b
9
1
4%, respectively. The X-ray single-crystal diffraction of 7-hydroxy-7,8,9,
0-tetrahydrobenzo[h]coumarin (19a) is shown in Fig. 2.
,8-Dihydrobenzo[h]coumarin (5a) and its 4-methyl analog 5b were
7
obtained by the dehydration of 18a and 18b in refluxing acidic aqueous
solution (2% H SO ) in the yields of 76% and 90%, respectively.
2
4
9
,10-Dihydrobenzo[h]coumarin (6a) and its 4-methyl analog 6b were
obtained similarly from 19a and 19b in the yields of 99% and 66%, respec-
tively. The X-ray single-crystal diffraction of 6b is shown in Fig. 3.
According to the bond lengths illustrated in Table 3, the location of double
bonds formed from dehydration could be confirmed; namely, the dehydration
product of 19b is 4-methyl-9,10-dihydrobenzo[h]coumarin (6b).
In summary, a series of new important heterocycles dihydrobenzo[h]
coumarins (5–7) were successfully synthesized from 1-naphthol via two
different synthetic routes. The regioselectivities for the oxidation reactions
of 7,8,9,10-tetrahydrobenzo[h]coumarins (15) were rationalized with
quantum chemical calculations and further confirmed by the X-ray crystallo-
graphic analysis of the derivatives of the oxidation products.
Figure 2. Molecular structure of compound 19a.

Dihydrobenzo[h]coumarins and Analogs
3147
Figure 3. Molecular structure of compound 6b.
EXPERIMENTAL
Melting points are uncorrected. Reactions were monitored by TLC on 0.2- mm
silica-gel plates, and the spots were visualized by ultraviolet light.
Flash-column chromatography was performed on silica gel (300–400
1
13
mesh). H NMR and C NMR spectra were recorded on a Varian Mercury
00 spectrometer at 300.13 and 75.47 MHz, respectively, and the solvent
used was CDCl unless indicated. All chemical shifts were reported in d
3
3
1
13
units with reference to TMS ( H) or the signals of the solvent ( C).
Elemental analysis was performed on an Elemental Vario EL apparatus.
Mass spectra (EI) were taken on a Agilent 5973 N MSD spectrometer.
HRMS data were determined on a Kratos Concept 1H spectrometer, Bruker
ApexIII 7.0 Tesla FTMS or IonSpec 4.7 Tesla FTMS instrument.
5
literature,
,8-Dihydro-l-naphthol (9). Following the procedure described in
10]
[
compound 9 was obtained from 8 as a white solid (yield,
[
10]
1
7
1%): mp 69–718C (lit.
d 3.26–3.30 (m, 2H, 5-H), 3.39–3.42 (m, 2H, 8-H), 4.77 (bs, 1H, O-H),
.86–5.92 (m, 2H, 6-H, 7-H), 6.60 (d, J ¼ 7.9 Hz, 1H, 4-H), 6.72
d, J ¼ 7.6 Hz, 1H, 2-H), 7.04 (t, J ¼ 7.9 Hz, 1H, 3-H).
-Methyl-7,10-dihydrobenzo[h]coumarin (7b). The compound was
72–73.58C). H NMR (300 MHz, CDCl3)
5
(
4
[12,13]
synthesized following the modified procedure described in literature.
A mixture of 5,8-dihydro-l-naphthol (9) (0.15 g, 1.0 mmol), ethyl acetoacetate
2 g, 15.4 mmol), and phosphoryl chloride (1.5 g, 10 mmol) was refluxed in
(
benzene (4 mL) for 1 h. The solvent was removed under vacuum, and the
residue was neutralized with saturated aqueous NaHCO3 to pH7 and

3
148
Y. Wang, S. Huang, and P. Xia
Table 3. Selected bond lengths [nm] for
compound 6b
Compound
Bond length
O(1)-C(1)
O(2)-C(1)
O(2)-C(5)
C(1)-C(2)
C(2)-C(3)
C(2)-H(1)
C(8)-C(9)
C(8)-H(2)
C(9)-H(3)
C(10)-C(11)
C(10)-H(4)
C(11)-C(12)
C(3)-C(4)
C(4)-C(14)
C(4)-C(5)
C(4)-C(9)
C(5)-C(6)
C(6)-C(7)
C(6)-C(13)
C(7)-C(8)
C(7)-C(10)
C(11)-H(5)
C(12)-C(13)
C(12)-H(6)
C(12)-H(7)
C(13)-H(8)
C(13)-H(9)
C(14)-H(10)
C(14)-H(11)
C(14)-H(12)
0.1210(2)
0.1369(2)
0.1386(2)
0.1436(3)
0.1338(3)
0.096(2)
0.1361(3)
0.098(2)
0.097(2)
0.1321(3)
0.099(3)
0.1492(3)
0.1446(3)
0.1497(3)
0.1392(2)
0.1406(3)
0.1382(3)
0.1405(3)
0.1510(3)
0.1398(3)
0.1461(3)
0.191(3)
0.1521(3)
0.102(2)
0.091(3)
0.103(2)
0.092(2)
0.098(3)
0.098(3)
0.094(4)
extracted with CH Cl (3 ꢁ 10 mL). The combined extracts were washed with
2
2
water and brine and dried (MgSO ). After removal of the solvent under
4
vacuum, the residue was chromatographed over silica gel using a mixture of
petroleum–EtOAc (4:1) as eluent to afford compound 7b (0.15 g, 71%) as
[
12]
1
colorless crystals: mp 154–1558C (lit,
:
150–1528C).
H NMR
300 MHz, CDCl ) d 2.43 (s, 3H, 4-CH ), 3.47–3.56 (m, 4H, 7-CH , 10-
(
3
3
2
CH ), 5.88–6.00 (m, 2H, 8-H, 9-H), 6.25 (s, lH, 3-H), 7.06 (d, J ¼ 8.4 Hz,
2
1
3
lH, 5-H), 7.41 (d, J ¼ 8.1 Hz, 1H, 6-H). C NMR (CDCl , 75 MHz) d
3
1
1
61.17, 152.84, 151.12, 138.89, 124.21, 123.78, 123.18, 122.76, 121.62,
17.44, 113.78, 29.63, 23.75, 18.76. MS (El) m/z (%): 212 (M , 100), 184
þ
(
23), 169 (15), 155 (14), 141 (9), 115 (9).

Dihydrobenzo[h]coumarins and Analogs
3149
5,8-Dihydro-l-hydroxynaphthalene-2-carbaldehyde (10). A50-mLflask
containing 5,8-dihydro-l-naphthol (9) (3 g, 20.5 mmol), SnCl4 (0.72 mL,
1
.634 g, 2.05 ꢁ 3 mmol), 2,6-lutidine (2.79 mL, 20.5 ꢁ 1.16 mmol), and
toluene (12 mL) was purged with argon. After the reaction mixture was
stirred for 30 min, well-ground paraformaldehyde (1.5 g, 20.5 ꢁ 2.5 mmol)
was added. The mixture was stirred for 10 h at 95–1008C, and then it
was allowed to cool to room temperature. The solution was acidified
to pH , 2 with 2.0 M aqueous HCl and extracted with ether (3 ꢁ 30 mL).
The combined organic extracts were dried over anhydrous Na SO , and the
2
4
solvent was removed under the reduced pressure. The residue was purified
by flash column chromatography (silica gel, hexane–ethyl acetate, 10:1) to
give 10 as a yellow solid (2.14 g, 60%): mp 43–458C. IR (neat): 3033,
2
1
1
2
861, 1635, 1497, 1426, 1310, 1221, 1085, 983, 740 cm
300 MHz, CDCl ) d 3.28–3.32 (m, 2H, 8-H), 3.39–3.45 (m, 2H, 5-H),
. H NMR
(
3
5
4
2
1
1
.82–5.88 (m, 1H, 7-H), 5.91–5.98 (m, 1H, 6-H), 6.76 (d, J ¼ 8.1 Hz, 1H,
-H), 7.32 (d, J ¼ 8.1 Hz, 1H, 3-H), 9.81 (s, 1H, 1-OH), 11.44 (s, 1H,
1
-CHO). C NMR (CDCl , 75 MHz) d 196.08, 159.55, 144.29, 130.49,
3
3
24.11, 123.21, 122.96, 119.97, 117.96, 30.27, 23.27. MS (EI) m/z (%):
þ
74 (M , 1.69), 169 (65.54), 147 (17.02), 119 (18.17), 97 (44.44), 69
(100.00), 59 (16.87), 45 (18.81). Anal. calcd. for C H O : C, 75.84;
H, 5.79, found: C, 75.54 H, 5.96.
11 10 2
7
,10-Dihydrobenzo[h]coumarin (7a). A drop concentrated H SO was
2 4
added to a flask containing 10 (0.31 g, 1.78 mmol), acetic anhydride (0.53 g,
.5 mL, 5.2 mmol), and NaOAc (0.21 g, 2.56 mmol). The mixture was
0
heated at 1608C for 8 h. After cooling to room temperature, the solution
was poured into water (20 mL), extracted with ether (3 ꢁ 20 mL), and dried
over anhydrous Na SO . Product 7a was obtained as a yellow solid after
2
4
purification by chromatography on a silica-gel column (hexane–acetate,
1
6
3
1
:1) (0.117 g, 33%): mp 162–1648C. H NMR (300 MHz, CDCl )d 3.46–
3
.55 (m, 4H, 7-H, 10-H), 5.90–6.01 (m, 2H, 8-H, 9-H), 6.38 (d, J ¼ 9.6 Hz,
H, 3-H), 7.05 (d, J ¼ 7.8 Hz, 1H, 6-H), 7.29 (d, J ¼ 7.8 Hz, 1H, 5-H), 7.69
1
3
(
d, J ¼ 9.6 Hz, 1H, 4-H). C NMR (CDCl , 75 MHz) d 161.20, 151.64,
3
1
2
43.81, 139.08, 124.95, 124.51, 123.57, 123.24, 122.66, 116.31, 115.10,
9.68, 23.50. MS (El) m/z (%): 198 (M , 100.00), 197 (25.26), 170
þ
(33.09), 169 (28.41), 141 (62.12), 115 (39.71). HRMS calcd. mass for
C H O :198.0681, found 198.0662.
1
3 10 2
5
from 8 following the literature procedure
mp 66–688C (lit. : 67–698C). H NMR (300 MHz, CDCl ) d 1.75–1.87
,6,7,8-Tetrahydro-1-naphthol (14). Compound 14 was prepared
as white needles (yield, 74%):
[16]
[
21]
1
3
(
m, 4H, 6-H, 7-H), 2.64 (t, J ¼ 6.0 Hz, 2H, 8-H), 2.75 (t, J ¼ 6.5 Hz,
2
H, 5-H), 4.71 (s, 1H, 1-OH), 6.60 (d, J ¼ 7.8 Hz, 1H, 2-H), 6.68
1
3
(
d, J ¼ 7.8 Hz, 1H, 4-H), 6.99 (t, J ¼ 7.8 Hz, 1H, 3-H). C NMR (CDCl ,
3
7
2
5 MHz) d 153.34, 142.21, 138.90, 125.93, 123.29, 121.52, 111.72, 29.53,
2.72, 22.70, 22.69.

3
150
Y. Wang, S. Huang, and P. Xia
7
,8,9,10-tetrahydrobenzo[h]coumarin (15a). Compound 15a was
A well-
[17]
synthesized from 14 following a modified literature procedure.
ground mixture of 5,6,7,8-tetrahydro-l-naphthol (14) (3 g, 20.2mmol) and
malic acid (4.2 g, 31.3 mmol) was added to a hot solution of concentrated
sulfuric acid (10 mL) in acetic acid (5 mL). The mixture was stirred and
kept at 1308C for 6 h, and then it was allowed to cool to room temperature
and poured carefully onto ice water (50 mL) while it was stirred vigorously
for 30 min. The aqueous solution was extracted with ethyl acetate
(
saturated NaHCO (aq.), and brine and dried over anhydrous MgSO . After
3 ꢁ 30 mL), and the combined organic fractions were washed with H O,
3 4
2
the removal of the solvent, the residue was submitted to flash-column
chromatography (silica gel, petroleum-ethyl acetate, 5:1) to afford 15a as
[17]
1
white needles (2.42 g, 60%): mp 150–1528C (lit. : 147–1488C). H NMR
300 MHz, CDCl ) d 1.83–1.85 (m, 4H, 8-H, 9-H), 2.84–2.93 (m, 4H, 7-H,
(
3
1
0-H), 6.35 (d, J ¼ 9.3 Hz, 1H, 3-H), 7.01 (d, J ¼ 8.1 Hz, 1H, 6-H), 7.21
1
3
(
d, J ¼ 8.1 Hz, 1H, 5-H), 7.66 (d, J ¼ 9.3 Hz, 1H, 4-H). C NMR (CDCl ,
3
7
1
1
5 MHz) d 161.40, 152.17, 143.92, 142.46, 125.52, 125.25, 124.33, 116.09,
14.92, 29.92, 22.48, 22.43, 22.04. MS (El) m/z (%): 200 (M , 100.00),
72 (62.91), 144 (43.73), 128 (17.97), 115 (24.28). HRMS calcd. mass for
þ
C H O :200.0837, found 200.0838.
1
3 12 2
9,10-Dihydro-8H-benzo[h]coumarin-7-one (16a) and 8,9-dihydro-
H-benzo[h]coumarin-10-one (17a). CrO3 (1.05 g, 9 mmol) in H O
7
2
(
0.4 mL) and HOAc (2.5 mL) were dropwise added to a flask containing
,8,9,10-tetrahydrobenzo[h]coumarin (15a) (0.6 g, 3 mmol) in 4.5 mL of
7
acetic acid while stirring in an ice bath. After addition, the cooling bath was
removed and the solution was stirred for 72 h. The mixture was neutralized
with 2.0 M aqueous NaOH and extracted with CH Cl (3 ꢁ 30 mL). The
2
2
combined organic layers were washed with H O (3 ꢁ 10 mL) and brine and
2
dried over anhydrous Na SO . After removal of the solvent under the
2
4
reduced pressure, the residue was purified by column chromatography on
silica gel (hexane–ethyl acetate, 5:1) to give the major product 16a as a
white solid (0.27 g, 42%) and the minor product 17a as a yellow solid
(
0.14 g, 22%). 16a: mp 236–2388C. IR (KBr): 3081, 2951, 2878, 1727,
681, 1482, 1282, 1106, 968, 906, 865, 853 cm . H NMR (300 MHz,
21
1
CDCl ) d 2.18–2.26 (m, 2H, 9-H), 2.73 (t, J ¼ 6.8 Hz, 2H, 8-H), 3.18
3
(
t, J ¼ 6.2 Hz, 2H, 10-H), 6.54 (d, J ¼ 9.5 Hz, 1H, 3-H), 7.44
(
d, J ¼ 8.1 Hz, 1H, 5-H), 7.74 (d, J ¼ 9.5 Hz, 1H, 4-H), 7.97 (d, J ¼ 8.1 Hz,
þ
1
1
2
H, 6-H). MS (EI) m/z (%): 214 (M , 100.00), 186 (98.17), 158 (65.13),
30 (47.62), 102 (37.78). HRMS calcd. mass for C H O :214.0630; found
1
3 10 3
14.0625. 17a: mp 169–1718C. IR (KBr): 3059, 2919, 1728, 1697, 1621,
21
1
1
594, 1550, 1426, 1305, 1287, 1189, 1175, 1133, 934, 879, 841, 779 cm
.
H NMR (300 MHz, CDCl ) d 2.11–2.20 (m, 2H, 8-H), 2.73 (t, J ¼ 6.6 Hz,
3
2
H, 9-H), 3.06 (t, J ¼ 6.0 Hz, 2H, 7-H), 6.44 (d, J ¼ 9.6 Hz, 1H, 3-H), 7.19
(
d, J ¼ 8.1 Hz, 1H, 6-H), 7.56 (d, J ¼ 7.8 Hz, 1H, 5-H), 7.68 (d, J ¼ 9.3 Hz,
þ
1
H, 4-H). MS (EI) m/z (%): 214 (M , 66.23), 186 (100.00), 158 (22.16),

Dihydrobenzo[h]coumarins and Analogs
30 (44.43), 102 (30.00). HRMS (MALDI-DHB) calcd. mass for C H O
3 10 3
3151
1
1
þ
[
M þ Na]: 237.0522; found 237.0496.
0-Hydroxy-7,8,9,10-tetrahydrobenzo[h]coumarin
24 mg, 0.63 mmol) was added to a flask containing 17a (119 mg,
.56 mmol) and methanol (4 mL). After stirring at rt for 1 h, the solvent was
removed under vacuum, and the residue was purified on a silica-gel column
hexane–ethyl acetate, 1:1) to give 18a as a white solid (80 mg, 66%): mp
1
(18a). NaBH4
(
0
(
1
1
2
2
23–1258C. H NMR (300 MHz, CDCl ) d 1.79–1.94 (m, 2H, 8-H), 1.99–
.07 (m, 1H, 9-H), 2.11–2.18 (m, 1H, 9-H), 2.77–2.83 (m, 1H, 10-OH),
.88–2.91 (m, 1H, 7-H), 2.96–2.97 (m, 1H, 7-H), 5.34 (br, 1H, 10-H), 6.37
3
(
d, J ¼ 9.3 Hz, 1H, 3-H), 7.06 (d, J ¼ 8.1 Hz, 1H, 6-H), 7.32 (d, J ¼ 7.8 Hz,
1
3
1
d 160.67, 152.95, 143.97, 142.88, 126.62, 126.52, 125.46, 116.58, 115.05,
6
H, 5-H), 7.69 (d, J ¼ 9.6 Hz, 1H, 4-H). C NMR (CDCl , 75 MHz)
3
þ
1.24, 30.61, 29.99, 17.61. MS (EI) m/z (%): 216 (M , 46.27), 198 (69.67),
1
calcd. mass for C H O :216.0786;found 216.0781.
88 (22.53), 160 (100.00), 131 (41.77), 115 (33.12), 77 (26.49). HRMS
1
3 12 3
7
,8-Dihydrobenzo[h]coumarin (5a). A suspension of 18a (490 mg,
.27 mmol) in aqueous H SO (2%, 13 mL) was refluxed for 6 h under
2
2
4
stirring. After cooling to room temperature, the mixture was extracted with
ethyl acetate (3 ꢁ 20 mL), and the combined organic fractions were washed
with H O, saturated NaHCO (aq.), and brine and dried over anhydrous
2
3
Na SO . After removal of the solvent under the reduced pressure, the
4
2
residue was purified by column chromatography on silica gel (petroleum–
ethyl acetate, 1:1) to provide product 5a as a white solid (340 mg, 76%):
1
mp 99–1018C. H NMR (300 MHz, CDCl ) d 2.32–2.41 (m, 2H, 8-H),
3
2
1
7
.87 (t, J ¼ 8.4 Hz, 2H, 7-H), 6.17–6.23 (m, 2H, 9-H), 6.34 (d, J ¼ 9.3 Hz,
H, 3-H), 7.01–7.07 (m, 2H, 6-H, 10-H), 7.22 (d, J ¼ 7.8 Hz, 1H, 5-H),
þ
.65 (d, J ¼ 9.6 Hz, 1H, 4-H). MS (EI) m/z (%): 198 (M , 100.00), 197
(29.06), 170 (31.83), 169 (28.43), 141 (56.68) 139 (20.34), 115 (35.71).
þ
HRMS (MALDI-DHB) calcd. mass for C H O [M þ Na]: 221.0573;
1
3 10 2
found 221.0574.
-Hydroxy-7,8,9,10-tetrahydrobenzo[h]coumarin (19a). Following
the same procedure for the preparation of 18a, 19a was obtained from
7
1
16a as a white solid (yield, 79%): mp 160–1628C. H NMR (300 MHz,
CDCl ) d 1.80–1.95 (m, 3H, 9-H, 7-OH), 2.00–2.10 (m, 2H, 8-H),
3
2
7
.80–2.91 (m, 1H, 10-H), 2.96–3.06 (m, 1H, 10-H), 4.84–4.86 (m, 1H,
-H), 6.41 (d, J ¼ 9.6 Hz, 1H, 3-H), 7.35 (d, J ¼ 7.8 Hz, 1H, 6-H), 7.43
1
3
(d, J ¼ 7.5 Hz, 1H, 5-H), 7.69 (d, J ¼ 10.2 Hz, 1H, 4-H). C NMR
(CDCl , 75 MHz) d 161.14, 151.55, 143.68, 143.29, 125.60, 125.07,
3
1
24.28, 117.28, 115.90, 67.90, 31.74, 22.47, 17.92. MS (EI) m/z (%):
þ
2
16 (M , 88.56), 198 (100.00), 188 (90.90), 159 (65.85), 131 (39.89),
15 (34.58), 77 (31.15). HRMS calcd. mass for C H O :216.0786;
1
found 216.0787.
1
3 12 3
Single crystal X-ray diffraction data of 19a. Crystal with dimensions
of 0.511 mm ꢁ 0.267 mm ꢁ 0.083 mm for compound 19a was selected and

3
152
Y. Wang, S. Huang, and P. Xia
mounted on a Bruker Smart CCD diffractometer with graphite mono-
chromatized Mo Ka radiation (l ¼ 0.071073 nm). Diffraction data were
collected using v-2u scans at room temperature (293 K). A perspective
view of the structure is depicted in Fig. 2. Empirical formula: C H O .
1
3 12 3
Formula weight: 216.23. Crystal system: monoclinic. Space group: Cc. Unit
cell dimensions: a ¼ 2.5765 (3) nm, b ¼ 0.72986 (8) nm, c ¼ 2.2733 (3)
3
nm, b ¼ 107.486(4)8. V ¼ 4.0773 (8) nm . Theta range for data collection
3
is from 1.66 to 28.438. Z ¼ 16. Dc ¼ 1.409 g/cm . F(000) ¼ 1824. Refine-
2
ment method: full-matrix least-squares on F . Goodness of fit on F : 0.906.
2
Final R indices [I . 2s(I)]: 0.0691, 0.1549. R indices (all data): 0.0957,
0
3
.1718. Largest did peak and hole: 0.295 and 2338 e/nm .
9,10-Dihydrobenzo[h]coumarin (6a). Following the same procedure
for the preparation of 5a, 6a was obtained from 19a as a white solid (yield,
1
9
9%): mp 122–1248C. H NMR (300 MHz, CDCl ) d 2.35–2.43 (m, 2H,
3
9
-H), 3.04 (t, J ¼ 8.7Hz, 2H, 10-H), 6.18–6.24 (m, 1H, 8-H), 6.34
(
d, J ¼ 9.3 Hz, 1H, 3-H), 6.51 (d, J ¼ 13.2 Hz, 1H, 7-H), 6.96
(
d, J ¼ 8.1 Hz, 1H, 6-H), 7.26 (d, J ¼ 7.5 Hz, 1H, 5-H), 7.65 (d, J ¼ 9.3 Hz,
1
H, 4-H). C NMR (75 MHz, CDCl ) d 161.20, 150.92, 143.76, 137.77,
3
1
1
3
32.00, 126.94, 125.65, 122.29, 117.82, 115.05, 22.15, 19.01. MS (EI) m/z
þ
(
%): 198 (M , 100.00), 170 (31.27), 155 (12.43), 141 (63.31), 128 (5.61),
þ1
1
15 (49.31). HRMS (MALDI-DHB) calcd. mass for C H O [M þ H]:
1
3 11 2
1
99.0754; found 199.0731.
-Methyl-7,8,9,10-tetrahydrobenzo[h]coumarin (15b). POCl (1.9mL)
4
3
was added to a flask containing 14 (3.0 g, 23 mmol) and ethyl acetoacetate
3.0 g, 23 mmol). The mixture was heated at 1008C for 18 h. After cooling
to room temperature, the solution was neutralized with saturated Na CO
(
2
3
(aq.) and extracted with ethyl acetate (3 ꢁ 30 mL). The combined organic
layers were washed with water (20 mL) and brine (20 mL), and dried over
anhydrous MgSO . After the removal of the solvent under the reduced
4
pressure, the residue was submitted to silica-gel chromatography separation
petroleum–ethyl acetate, 5:1) to afford product 15b as a white solid (3.0 g,
0%). Recrystallization from petroleum–ethyl acetate yielded white
(
7
[
17]
1
needles: mp 114–1168C (lit. : 119–1208C). H NMR (300 MHz, CDCl )
3
d 1.79–1.85 (m, 4H, 8-H, 9-H), 2.40 (s, 3H, 4-CH ), 2.82–2.91 (m, 4H,
3
7
-H, 10-H), 6.20 (s, 1H, 3-H), 7.01 (d, J ¼ 8.1 Hz, 1H, 6-H), 7.32
1
3
(
d, J ¼ 8.1 Hz, 1H, 5-H). C NMR (CDCl , 75 MHz) d 161.22, 152.84,
3
1
2
51.48, 142.12, 125.43, 124.85, 120.89, 117.05, 113.46, 29.74, 22.61,
2.33, 22.06, 18.68. MS (EI) m/z (%): 214 (M , 100.00), 186 (100.00), 171
þ
(
C, 78.48; H, 6.59. found: C, 78.32; H, 6.91.
39.81), 158 (100.00), 128 (43.27), 115 (45.05). Anal. calcd. for C H O :
4 14 2
1
4
-Methyl-9,10-dihydro-8H-benzo[h]coumarin-7-one
(16b)
(17b). Following
and
4-methyl-8,9-dihydro-7H-benzo[h]coumarin-10-one
the same procedure for the preparation of 16a and 17a, 16b and 17b were
obtained from 15b as a white solid (yield, 51%) and a yellow solid (yield,
1
9%), respectively. 16b: mp 226–2288C. H NMR (300 MHz, CDCl3)

Dihydrobenzo[h]coumarins and Analogs
3153
d 2.17–2.25 (m, 2H, 9-H), 2.49 (s, 3H, 4-CH ), 2.72 (t, J ¼ 6.3 Hz, 2H, 8-H),
3
3
5
1
3
.18 (t, J ¼ 6.3 Hz, 2H, 10-H), 6.40 (s, 1H, 3-H), 7.56 (d, J ¼ 8.4 Hz, 1H,
1
3
-H), 7.98 (d, J ¼ 8.4 Hz, 1H, 6-H). C NMR (CDC1 , 75 MHz) d 197.30,
3
60.16, 152.09, 150.77, 134.44, 132.66, 122.84, 122.15, 122.00, 116.62,
8.51, 22.53, 22.11, 18.80. MS (EI) m/z (%): 228 (M , 100.00), 213
þ
(
27.49), 200 (100.00), 172 (84.19), 144 (44.86), 115 (59.67). HRMS calcd.
1
mass for C H O 228.0786; found 228.0778. 17b: mp 147–1498C. H
1
4 12 3
NMR (300 MHz, CDCl ) d 2.11–2.19 (m, 2H, 8-H), 2.44 (s, 3H, 4-CH3),
2
3
.73 (t, J ¼ 6.6 Hz, 2H, 9-H), 3.05 (t, J ¼ 6.0 Hz, 2H, 7-H), 6.31 (s, 1H,
1
3
3
-H), 7.20 (d, J ¼ 8.4 Hz, 1H, 6-H), 7.68 (d, J ¼ 8.4 Hz, 1H, 5-H).
C
NMR (CDCl , 75 MHz) d 195.27, 159.81, 152.65, 151.59, 149.39, 128.53,
3
1
24.32, 121.36, 118.96, 114.72, 40.47, 30.70, 22.57, 19.00. MS (EI) m/z
þ
(
%): 228 (M , 74.22), 200 (100.00), 172 (29.95), 144 (52.17), 115 (69.67).
þI
HRMS (MALDI-DHB) calcd. mass for C H O [M þ Na] 251.0679;
1
4 12 3
found 251.0675.
0-Hydroxy-4-methyl-7,8,9,10-tetrahydrobenzo[h]coumarin (18b).
Following the same procedure for the preparation of 18a, 18b was obtained
1
1
from 17b as a white solid (yield, 94%): mp 158–1608C. H NMR
(
300 MHz, CDC1 ) d 1.83–2.20 (m, 4H, 8-H, 9-H), 2.43 (s, 3H, 4-CH3),
3
2
3
.77–2.95 (m, 3H, 7-H, 10-OH), 5.33–5.35 (m, 1H, 10-H), 6.25 (s, 1H,
3
1
-H), 7.08 (d, J ¼ 8.4 Hz, 1H, 6-H), 7.45 (d, J ¼ 8.4 Hz, 1H, 5-H).
C
NMR (CDCl , 75 MHz) d 160.57, 153.04, 152.30, 142.60, 126.63, 125.11,
3
1
23.16, 117.63, 113.58, 61.26, 30.59, 29.85, 18.78, 17.52. MS (EI) m/z
þ
(
%): 230 (M , 49.37), 212 (73.32), 202 (21.45), 174 (100.00), 146 (47.31),
45 (44.92), 128 (31.54), 115 (72.79), 91 (28.31), 77 (33.10), 39 (40.58).
1
þ1
HRMS (MALDI-DHB) calcd. mass for C H O [M þ Na]: 253.0835;
1
4 14 3
found 253.0848.
-Methyl-7,8-dihydrobenzo[h]coumarin (5b). Following the same
procedure for the preparation of 5a, 5b was obtained from 18b as a white
4
1
solid (yield, 90%): mp 76–788C. H NMR (300 MHz, CDCl ) d 2.33–2.43
3
(
m, 5H, 4-CH3, 8-H), 2.88 (t, J ¼ 8.1 Hz, 2H, 7-H), 6.17–6.24 (m, 2H,
3
MS (EI) m/z (%): 212 (M , 57.14), 182 (31.19), 169 (15.08), 149 (81.28),
-H, 9-H), 7.05–7.12 (m, 2H, 6-H, 10-H), 7.36 (d, J ¼ 7.5 Hz, 1H, 5-H).
þ
8
mass for C H O :212.0832; found 212.0854.
5 (55.12), 71 (72.46), 57 (100.00), 43 (76.56), 41 (44.84). HRMS calcd.
1
4 12 2
7
Following the same procedure for the preparation of 18a, 19b was obtained
-hydroxy-4-methyl-7,8,9,10-tetrahydrobenzo[h]coumarin
(19b).
1
from 16b as a white solid (yield, 74%): mp 195–1978C. H NMR
(
300 MHz, CDCl ) d 81.84–1.95 (m, 3H, 9-H, 7-OH), 2.00–2.09 (m, 2H,
3
8
1
6
1
3
2
-H), 2.43 (s, 3H, 4-CH3), 2.86–2.91 (m, 1H, 10-H), 2.96–3.04 (m, 1H,
0-H), 4.84–4.86 (m, 1H, 7-H), 6.27 (s, 1H, 3-H), 7.44 (d, J ¼ 8.4 Hz, 1H,
1
3
-H), 7.48 (d, J ¼ 8.4 Hz, 1H, 5-H). C NMR (CDCl , 75 MHz) d 161.09,
3
52.68, 151.00, 143.14, 125.68, 123.94, 121.70, 118.38, 114.42, 67.90,
1.73, 22.69, 18.75, 18.01. MS (EI) m/z (%): 230 (M , 91.53), 212 (98.91),
02 (78.65), 173 (93.53), 145 (49.32), 128 (42.05), 115 (100.00), 91
þ

3
154
Y. Wang, S. Huang, and P. Xia
(
45.74), 77 (45.35). HRMS calcd. mass for C H O : 230.0943; found
1
4 14 3
230.0929.
4-Methyl-9,10-dihydrobenzo[h]coumarin (6b). Following the same
procedure for the preparation of 5a, 6b was obtained from 19b as a white
1
solid (yield, 66%): mp 150–1528C. H NMR (300 MHz, CDCl ) d 2.39–
3
2
.43 (m, 5H, 4-CH , 9-H), 3.05 (t, J ¼ 8.4 Hz, 2H, 10-H), 6.20–6.24
3
(
m, 2H, 3-H, 8-H), 6.49–6.53 (m, 1H, 7-H), 6.99 (d, J ¼ 8.4 Hz, 1H, 6-H),
1
3
7.40 (d, J ¼ 7.5 Hz, I H, 5-H). C NMR (CDCl , 75 MHz) d 161.14,
1
1
3
52.63, 150.41, 137.61, 131.84, 126.85, 122.33, 122.23, 121.96, 118.87,
13.81, 22.24, 19.20, 18.72. MS (EI) m/z (%): 212 (M , 100.00), 184
þ
(
41.62), 169 (28.59), 155 (34.19), 128 (32.10), 115 (46.35). HRMS calcd.
mass for C H O : 212.0832; found 212.0833.
1
4 12 2
Single crystal X-ray diffraction data of 6b. A crystal with dimensions
of 0.566 mm ꢁ 0.248 mm ꢁ 0.087 mm for compound 6b was selected and
mounted on a Bruker Smart CCD diffractometer with graphite monochroma-
tized Mo Ka radiation (l ¼ 0.071073 nm). Diffraction data were collected
using v-2u scans at room temperature (293 K). A perspective view of the
structure is depicted in Fig. 3 and the selected bond lengths are listed in
Table 3. Empirical formula: C H O . Formula weight: 212.24. Crystal
1
4 12 2
system: monoclinic. Space group: P2(1)/c. Unit cell dimensions:
a ¼ 0.73063 (11) nm, b ¼ 2.0333 (3) nm, c ¼ 0.73063 (11) nm,
3
(
3 ¼ 96.507(3)8. V ¼ 1.0784 (3) nm . Theta range for data collection is
3
from 2.98 to 25.998. Z ¼ 4. Dc ¼ 1.307 g/cm . F(000) ¼ 448. Refinement
2
2
method: full-matrix least-squares on F . Goodness of fit on F : 0.975. Final
R indices [I . 2s (I)]: 0.0596, 0.1431. R indices (all data): 0.0839, 0.1556.
3
Largest diff. peak and hole: 0.231 and 2237 e/nm .
ACKNOWLEDGMENT
This research was supported by grants from the National Natural Science
Foundation of China (No. 20272010 and 30200348) awarded to P. Xia
and Y. Chen, respectively, and the research grant (No. 2000246069) for
Ph.D. program from National Education Administration of China awarded
to P. Xia.
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