Synthesis of coumestan derivatives via FeCl3-mediated oxidative ring closure of 4-hydroxy coumarins

Article abstract of DOI:10.1021/jo2000644

A concise and efficient approach to the syntheses of coumestan analogues has been developed. The underpinning strategy involves a FeCl ₃-mediated direct intramolecular oxidative annellation of 4-hydroxy-3-phenyl-2H-chromen-2-one derivatives. Utilizing this synthetic protocol, a variety of coumestan derivatives were conveniently obtained from readily available reagents.

Full text of DOI:10.1021/jo2000644

ARTICLE
pubs.acs.org/joc
Synthesis of Coumestan Derivatives via FeCl3-Mediated Oxidative
Ring Closure of 4-Hydroxy Coumarins
Lina Tang, Yongle Pang, Qiao Yan, Liuqing Shi, Jianhui Huang, Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, China
S Supporting Information
b
ABSTRACT: A concise and efficient approach to the syntheses
of coumestan analogues has been developed. The underpinning
strategy involves a FeCl3-mediated direct intramolecular oxida-
tive annellation of 4-hydroxy-3-phenyl-2H-chromen-2-one deri-
vatives. Utilizing this synthetic protocol, a variety of coumestan
derivatives were conveniently obtained from readily available
reagents.
’ INTRODUCTION
to investigate their intramolecular oxidative annellation mediated
by anhydrous FeCl3. In our previous investigation on the for-
mation of benzo[b]furan-3-carboxylates, we found that the pre-
sence of the two electron-donating methoxy groups on the
benzene ring of the R-aryl ketones was crucial for the oxidative
intramolecular cyclization to occur.28 Bearing this in mind,
3-(3,4-dimethoxyphenyl)-4-hydroxy-2H-chromen-2-one (2a) was
chosen to test the feasibility of the ring closure. As expected, the
desired coumestan 1a was obtained in 86% yield after the reaction
mixture was stirred in DCE at room temperature for 12 h. It was
also found that the application of a combination of FeCl3 and SiO2
instead of FeCl3 alone delivered a better yield and allowed an
easier workup.34ꢀ37 Our further study showed that the introduc-
tion of a methyl group or methoxy group(s) to the phenyl ring A
does not affect the cyclization and the desired products 1bꢀd can
also be obtained in useful yields. Next, the monomethoxylated
coumarins 2eꢀh were also investigated under the same condi-
tions. Compounds2eꢀh alsofurnish the desiredcyclized products
1eꢀh in acceptable to good yields. This result was somewhat
contrary to our expectation since we had previously found that the
similar monomethoxylated R-aryl ketones bearing a benzylic ester
group hardly underwent cyclization to afford benzo[b]furans.28
Inspired by this finding, we decided to examine whether the other
coumarin substrates bearing substituents other than a methoxy
group at the para-position of the phenyl ring B can undergo the
expected oxidative cyclization. It was found that when the p-
methoxy group was replaced with a methyl group, substrate 2i,j
gave only a trace amount of the desired cyclized products 1i,j after
the reaction mixture was stirred at room temperature for 24 h.
However, when the reaction was carried out under reflux for 12 h,
the expected products 1i and 1j were achieved in moderate to
good yields. This result suggests that the presence of the electron-
donating methoxy group on the phenyl ring B is not the deter-
minant factor for the cyclization to occur. Encouraged by this
Coumestan, known systematically as 6H-benzofuro[3,2-c]-
[1]benzopyran-6-one, comprises a class of widely occurring
natural analogues which have been reported to possess diverse
pharmacological properties such as phytoestrogenic, antibacter-
ial, antifungal, antimyotoxic, and phytoalexine effects.1ꢀ6 Until
now, many synthetic approaches have been developed to con-
struct the basic fused-tetracyclic rings of coumestans.7ꢀ26 All of
these methods have their own merits in the preparation of the
individual target compounds. However, a general method that
can efficiently lead to diversified coumestan derivatives is still in
high demand. Herein, we describe a more convenient and less
complicated route to the syntheses of a variety of coumestan
analogues from readily available reagents.
In our approach, the target coumestan molecule 1 was retro-
synthetically disconnected by the cleavage of the aromatic
(phenyl ring B) sp2 carbonꢀoxygen bond to afford 4-hydroxy-
3-phenyl-2H- chromen-2-one 2. We envisaged that this coumarin
compound 2 might undergo FeCl3-mediated intramolecular cycliza-
tion via direct oxidative aromatic CꢀO bond formation,27 a strategy
that has been successfully applied by us to the syntheses of
3-functionalized benzo[b]furans from the readily available electron-
rich R-aryl ketones.28 Compound 2 can be prepared via intramole-
cular Claisen condensation of intermediate 3,29,30 which can be easily
tracked back to the substituted methyl salicylate 4 and phenylacetic
acid derivative 528 (Figure 1). Alternatively, the mono- or dimethoxy-
lated substrate 20 (on ring A) can be obtained from intermediate 6
through methoxycarbonylation and in situ lactonization.31 Com-
pound 6 can be prepared through a simple regioselective methylation
of 1,3-dihydroxyl phenol derivative 7, which can be easily formed by
the reaction of polyphenols 8 with benzyl cyanide derivative or
phenylacetic acid derivative 9catalyzedbyaLewisacid(Figure2).32,33
’ RESULTS AND DISCUSSION
With various substituted 4-hydroxy-3-phenyl-2H-chromen-2-
ones having been prepared by the above strategies, we proceeded
Received: January 17, 2011
Published: March 14, 2011
r
2011 American Chemical Society
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Scheme 1. Formation of Hydroxylated Coumestan via De-
methylation Mediated by BBr3
Figure 1. A general retrosynthetic analysis of coumestan 1.
bear concurrently both methoxy group and hydroxyl group(s) on
the phenyl rings A and B, we also applied our method to synthesize
the naturally occurring 13,38ꢀ41,39ꢀ42 which bears a hydroxyl group
on the phenyl ring A and a methoxy group on the phenyl ring B by
using a protectionꢀdeprotection protocol. To realize this goal, the
readily available 70 was treated with iPrCl under basic conditions,
and the regioselectively protected 10 was obtained in 55% yield.
Further treatment of 10 with dimethyl carbonate (DMC)/NaH in
reflux toluene gave 3-aryl-4-hydroxyl coumarin 11, which can
undergo FeCl3-mediated oxidative cyclization by our approach to
i
give the Pr-protected coumestan 12 in good yield.43 Finally, the
desired 13 was achieved via iPr-deprotection with AlCl3 in DCM
(Scheme 2).44 We assume that such a protectionꢀdeprotection
protocol can also be applied to the synthesis of other such
coumestan members.
Figure 2. Retrosynthetic analysis of the methoxylated substrate 20.
Because of the difference in reactivity caused by the subtle
change in the electronic configuration of the enol type substrate 2
in comparison with the previously employed carbonyl type of
substrate,28 we propose a different mechanistic pathway, which is
outlined in Scheme 3. A hydrogen atom is initially abstracted
from the enol substrate 2, possibly via a single electron transfer
(SET) process, facilitated by FeCl3. This process will furnish
oxygen radical A, stabilized by resonance structures B and C. A
second FeCl3-mediated SET process occurs to convert the
radical intermediate C to a benzene cation intermediate D, which
can be stabilized by a para-positioned methoxy, methyl, bromo,
or chloro group, but destabilized by a strong electron-with-
drawing trifluoromethyl group. The unsuccessful annellation of
2r might be attributed to the presence of a m-methoxy, which
cannot provide stabilization to the carbocation in intermediate D
via resonance effect. Next, the oxygen of the side chain carbonyl
group nucleophilicly attacks the ring carbocation to give E.
Finally, rearomatizaton of E by the loss of a proton gives the
title compounds 1 (Scheme 3).
Figure 3. Substrates that failed to undergo oxidative annellation.
finding, we started to test the coumarin compounds without any
aromatic substituent on the phenyl B and found that compounds
2kꢀm also afforded the cyclized coumestan derivatives 1kꢀm
at reflux temperature. Surprisingly, for the substrates bearing a
p-chloro or bromo (2nꢀp) group on phenyl ring B, the reaction
also furnished the cyclized products in acceptable yields under
reflux conditions. This result further demonstrates that the
electron-donating substituent on phenyl ring B is not indispensa-
ble for the annellation process of this class of coumarin substrates.
In our investigation of the scope and generality of this method,
we found that substrates with a p-trifluoromethyl group or a m-
methoxy group (2q,r) on the phenyl ring B failed to provide any
cyclized products at reflux conditions after 24 h (Figure 3).
Furthermore, no desired annellated product was separated when
substrate 2s, bearing an o-methyl group on the phenyl ring B, was
subjected to the identical conditions. The presence of the o-
methyl group that hinders free rotation of the phenyl ring B is
presumably the cause of the unsuccessful cyclization.
As many biologically active natural coumestan members
possess hydroxyl group(s) on either phenyl ring A or B, one of
the valuable applications of this method is to convert the mono-
or multimethoxylated coumestans to the corresponding hydro-
xylated compounds. For example, the hydroxylated coumestan
1f0, which is also a new compound, can be obtained from 1f via
the known BBr3-mediated demethylation approach (Scheme 1,
Table 1).7,38 Considering that somenatural coumestan compounds
’ CONCLUSION
In conclusion, we have reported herein a concise approach to
diversified coumestan-based compounds through a FeCl3-
mediated direct intramolecular oxidation of 4-hydroxyl-3-aryl
coumarin compounds. The present method uses readily available
starting materials at low cost and a simple workup. In view of the
broad range of interesting biological activities possessed by
coumestan compounds, this method shows promising potential
applications in exploring biologically potent compounds of the
coumestan family.
’ EXPERIMENTAL SECTION
General Information. 1H and 13C NMR spectra were recorded on
a 400 MHz spectrometer at 25 °C. Chemical shift values are given in
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Table 1. Synthesis of Coumestans 1 via Intramolecular Heterocyclization of 4-Hydroxy-3-phenyl-2H-chromen-2-one 2 Mediated
a
by FeCl3/SiO2
a Conditions: all reactions were carried out with 1 equiv of 1 and 2.5 equiv of anhydrous FeCl3/SiO2 in DCE at rt unless otherwise stated. b Yields after
silica gel chromatography. c Reaction occurred at reflux temperature.
ppm and referred as the internal standard to TMS: 0.00 ppm. The peak
patterns are indicated as follows: s, singlet; d, doublet; m, multiplet; and dd,
doublet of doublets. The coupling constants, J, are reported in hertz (Hz).
ESI-MS were obtained on an ion trap microspectrometer. High-resolution
mass spectra (HRMS) were obtained on a Q-TOF microspectrometer.
Melting points were determined with a national micromelting point appa-
ratus without corrections. 1,2-Dichloroethane, pyridine, Et2O, toluene, and
DCM were dried over CaH2 before use. Phosphorus oxychloride was
redistilled before use, and other reagents and solvents were purchased as
reagent grade and were used without further purification. Flash column
chromatography was performed over silica gel 200ꢀ300 m and the eluent
was a mixture of ethyl acetate and petroleum ether.
Preparation of Substrates
1. Preparation of Intermediates 3a,b, 3e,f, 3iꢀl, 3nꢀp, 3r,
s, and 2a,b, 2e,f, 2iꢀl, 2nꢀp, 2r,s.. The title coupounds were
prepared according to the procedures in refs 29 and 30.
Methyl 2-(2-(3,4-dimethoxyphenyl)acetoxy)benzoate, 3a:
white solid; yield 70%, mp 53ꢀ54 °C. 1H NMR (400 MHz, CDCl3) δ
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Scheme 2. Synthesis of 13 via FeCl3-Mediated Oxidative
Annellation Using a ProtectionꢀDeprotection Protocol
Methyl 2-(2-(4-methoxyphenyl)acetoxy)-3-methylbenzo-
ate, 3f: white solid, yield 51%, mp 52 °C. 1H NMR (400 MHz, CDCl3)
δ 7.82 (d, 1H, J = 7.6 Hz), 7.38ꢀ7.33 (m, 3H), 7.18 (t, 1H, J = 7.6 Hz),
6.90 (d, 2H, J = 8.4 Hz), 3.90 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 2.05 (s,
3H). 13C NMR (100 MHz, CDCl3) δ 170.00, 165.3, 158.9, 149.2, 135.4,
132.2, 130.7, 129.4, 125.7, 125.6, 123.2, 114.1, 55.3, 52.1, 40.3, 16.1.
ESI-MS m/z [M þ Na]þ 337.3. HRMS (ESI) calcd for C18H19O5
þ
[M þ H]þ 315.1227, found 315.1232.
Methyl 2-(2-p-tolyacetoxy)benzoate, 3i: white solid, yield
1
74%, mp 62 °C. H NMR (400 MHz, CDCl3) δ 8.10 (d, 1H, J = 6.8
Hz), 7.61 (t, 1H, J = 7.6 Hz), 7.42ꢀ7.36 (m, 3H), 7.28 (d, 2H, J = 7.6
Hz), 7.16 (d, 1H, J = 8.0 Hz), 4.02 (s, 2H), 3.87 (s, 3H), 2.45 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 170.4, 165.1, 150.7, 136.9, 133.8, 131.8,
130.4, 129.5, 129.4, 126.1, 123.8, 123.4, 52.2, 40.8, 21.2. ESI-MS m/z
[M þ Na]þ 307.4.
Methyl 3-methyl-2-(2-p-tolylacetoxy)benzoate, 3j: white
1
solid, yield 46%, mp 39 °C. H NMR (400 MHz, CDCl3) δ 7.83 (d,
1H, J = 8.0 Hz), 7.38 (d, 1H, J = 7.2 Hz), 7.32 (d, 2H, J = 7.6 Hz), 7.19 (t,
3H), 3.93 (s, 2H), 3.80 (s, 3H), 2.36 (s, 3H), 2.07 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 169.9, 165.3, 149.2, 136.9, 135.3, 132.2, 130.5,
129.5, 129.4, 129.3, 125.6, 123.2, 52.1, 40.8, 21.2, 16.1. ESI-MS m/z
[M þ H]þ 321.4. HRMS (ESI) calcd for C18H19O4þ [M þ H]þ 299.1278,
found 299.1278.
Scheme 3. Possible Mechanistic Pathway for the Formation
of the Coumestan Skeleton
Methyl 2-(2-phenylacetoxy)benzoate, 3k:30. white solid,
yield 68%, mp 55 °C (lit.29 mp 56 °C). 1H NMR (400 MHz, CDCl3)
δ 8.02ꢀ7.99 (dd, 1H, J = 8.0, 1.2 Hz), 7.55ꢀ7.51 (m, 1H), 7.43ꢀ7.25
(m, 6H), 7.06 (d, 1H, J = 8.0 Hz), 3.95 (s, 2H), 3.76 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 170.2, 165.0, 150.6, 133.8, 133.4, 131.8, 129.7, 128.7,
127.3, 126.1, 123.7, 123.3, 52.1, 41.2. ESI-MS m/z [M þ Na]þ 293.3.
Methyl 3-methyl-2-(2-phenylacetoxy)benzoate, 3l: white
solid, yield 48%, mp 53 °C. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, 1H,
J = 7.6 Hz), 7.44ꢀ7.28 (m, 6H), 7.17 (t, 1H), 3.96 (s, 2H), 3.78 (s, 3H),
2.04 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.7, 165.3, 149.1, 135.4,
133.6, 132.2, 129.7, 129.4, 128.7, 127.3, 125.7, 123.2, 52.1, 41.3, 16.0.
þ
ESI-MS m/z [M þ Na]þ 307.4. HRMS (ESI) calcd for C17H17O4
[M þ H]þ 285.1121, found 285.1126.
Methyl 2-(2-(4-chlorophenyl)acetoxy)benzoate, 3n: white
solid, yield 68%, mp 74ꢀ75 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (d,
1H, J = 7.6 Hz), 7.55ꢀ7.53 (m, 1H), 7.36ꢀ7.25 (m, 5H), 7.05 (d, 2H,
J = 8.0 Hz), 3.92 (s, 2H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
169.8, 164.8, 150.6, 133.9, 133.3, 131.9, 131.8, 131.1, 128.8, 126.2, 123.7,
123.1, 52.1, 40.4. ESI-MS m/z [M þ Na]þ 327.7.
8.01 (d, 1H, J = 8.0 Hz), 7.56ꢀ7.52 (m, 1H), 7.31 (t, 1H, J = 7.6 Hz),
7.06 (d, 1H, J = 8.0 Hz), 6.98ꢀ6.93 (m, 2H), 6.86 (d, 1H, J = 8.0Hz), 3.90
(s, 5H), 3.88 (s, 3H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.5,
164.9, 150.7, 149.0, 148.3, 133.8, 131.8, 126.1, 125.9, 123.7, 123.3, 121.8,
112.8, 111.3, 56.0, 55.9, 52.1, 40.7. ESI-MSm/z[M þ Na]þ 353.4. HRMS
(ESI) calcd for C18H19O6þ [M þ H]þ 331.1176, found 331.1179.
Methyl 2-(2-(3,4-dimethoxyphenyl)acetoxy)-3-methyl-
Methyl 2-(2-(4-bromophenyl)acetoxy)benzoate, 3o: white
solid, yield 68%, mp 82ꢀ83 °C. 1H NMR (400 MHz, CDCl3) δ 8.09 (d,
1H, J = 7.6 Hz), 7.63ꢀ7.56 (m, 3H), 7.39ꢀ7.36 (m, 3H), 7.13 (d, 1H,
J = 8.0 Hz), 3.98 (s, 2H), 3.87 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
169.8, 164.8, 150.6, 133.9, 132.4, 131.8, 131.7, 131.5, 126.2, 123.7, 123.1,
121.4, 52.2, 40.4. ESI-MS m/z [M þ Na]þ 371.0, 373.0. HRMS (ESI)
calcd for C16H14BrO4þ [M þ H]þ 349.0070, found 349.0073.
Methyl 2-(2-(4-bromophenyl)acetoxy)-3-methylbenzoate,
3p: white solid, yield 41%, mp 55 °C. 1H NMR (400 MHz, CDCl3) δ
7.83 (d, 1H, J = 7.6 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.39 (d, 1H, J = 7.2 Hz),
7.31 (d, 2H, J = 8.4 Hz), 7.21ꢀ7.18 (t, 1H), 3.93 (s, 2H), 3.81 (s, 3H), 2.08
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 169.2, 165.1, 149.1, 135.4, 132.5,
132.1, 131.7, 131.4, 131.4, 129.4, 125.8, 123.0, 121.4, 52.1, 40.5, 16.1. ESþI-
MS m/z [M þ Na]þ 384.6, 386.7. HRMS (ESI) calcd for C17H16BrO4
[M þ H]þ 363.0226, found 363.0227.
1
benzoate, 3b: white solid, yield 48%, mp 72 °C. H NMR (400
MHz, CDCl3) δ 7.83 (d, 1H, J = 7.6 Hz), 7.39 (d, 1H, J = 7.2 Hz), 7.19 (t,
1H, J = 7.6 Hz), 6.97 (t, 2H), 6.86 (d, 1H, J = 8.0 Hz), 3.89 (d, 8H), 3.81
(s, 3H), 2.06 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.0, 165.2, 149.2,
149.0, 148.3, 135.4, 132.2, 129.4, 126.0, 126.0, 123.1, 121.8, 112.7, 111.2,
55.9, 55.9, 52.1, 40.8, 16.1. ESI-MS m/z [M þ Na]þ 367.6. HRMS (ESI)
calcd for C19H21O6þ [M þ H]þ 345.1333; found 345.1337.
Methyl 2-(2-(4-methoxyphenyl)acetoxy)benzoate, 3e: white
solid, yield 76%, mp 81 °C. 1H NMR (400 MHz, CDCl3) δ 8.00 (d, 1H,
J = 7.6 Hz), 7.53 (t, 1H, J = 8.0 Hz), 7.34ꢀ7.28 (m, 3H), 7.06 (d, 1H,
J = 8.0 Hz), 6.90 (d, 2H, J = 8.4 Hz), 3.89 (s, 2H), 3.81 (s, 3H), 3.78
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.5, 165.0, 158.9, 150.7, 133.8,
131.8, 130.7, 126.0, 125.5, 123.8, 123.3, 114.1, 55.3, 52.2, 40þ.3. ESI-MS m/z
[M þ Na]þ 323.4. HRMS (ESI) calcd for C17H17O5 [M þ H]þ
301.1071, found 301.1072.
Methyl 2-(2-(3-methoxyphenyl)acetoxy)benzoate, 3r: col-
1
1
orless liquid, yield 49%. H NMR (400 MHz, H NMR (400 MHz,
CDCl3) δ 8.01ꢀ7.99 (dd, 1H, J = 7.6, 2.0 Hz), 7.54ꢀ7.50 (m, 1H),
7.31ꢀ7.25 (m, 2H), 7.06 (d, 1H, J = 8.0 Hz), 6.99 (d, 2H, J = 7.2 Hz),
6.86ꢀ6.84 (m, 1H), 3.92 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 170.1, 165.0, 159.8, 150.6, 134.8, 133.8, 131.8,
129.6, 126.1, 123.7, 123.3, 122.0, 115.2, 113.0, 55.2, 52.1, 41.1. ESI-MS
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m/z [M þ Na]þ 323.3. HRMS (ESI) calcd for C17H17O5þ [M þ H]þ
301.1071, found 301.1071.
(100 MHz, d6-DMSO) δ 162.3, 160.9, 151.1, 133.7, 132.6, 131.5, 128.5,
127.9, 125.5, 123.9, 121.9, 116.6, 106.4, 15.7. HRMS (ESI) calcd for
C16H13O3þ [M þ H]þ 253.0859, found 253.0869.
Methyl 3-methyl-2-(2-o-tolylacetoxy)benzoate, 3s: white
solid, yield 38%, mp 49 °C. H NMR (400 MHz, CDCl3) δ 7.82 (d,
3-(4-Chlorophenyl)-4-hydroxy-2H-chromen-2-one, 2n:45.
1
1
1H, J = 7.6 Hz), 7.37 (d, 2H, J = 7.6 Hz), 7.21ꢀ7.17 (m, 4H), 3.99 (s,
2H), 3.81 (s, 3H), 2.44 (s, 3H), 2.06 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 169.5, 165.3, 149.2, 137.1, 135.3, 132.2, 132.1, 130.6, 130.4,
129.4, 127.6, 126.2, 125.6, 123.2, 52.1, 39.0, 19.7, 16.0þ. ESI-MS m/z
[M þ Na]þ 321.3. HRMS (ESI) calcd for C18H19O4 [M þ H]þ
299.1278, found 299.1279.
white solid, yield 56%, mp 252 °C. H NMR (400 MHz, d6-DMSO) δ
8.04 (d, 1H, J=8.0Hz), 7.69ꢀ7.65(m, 1H), 7.50ꢀ7.38 (m, 6H). 13CNMR
(100 MHz, d6-DMSO) δ 162.2, 161.1, 152.8, 133.4, 132.9, 132.6, 131.5,
128.5, 124.5, 124.3, 116.8, 116.7, 105.4. ESI-MS m/z [M ꢀ H]ꢀ 271.3.
3-(4-Bromophenyl)-4-hydroxy-2H-chromen-2-one, 2o: white
solid, yield 70%, mp 242ꢀ245 °C (lit.50 mp 260 °C). 1H NMR (400 MHz,
d6-DMSO) δ 11.70 (s, 1H), 8.09 (t, 1H), 7.69ꢀ7.61 (m, 3H), 7.43ꢀ7.37
(m, 4H). 13C NMR (100 MHz, d6-DMSO) δ 162.2, 161.2, 152.8, 133.7,
132.9, 132.0, 131.4, 124.4, 124.4, 121.2, 116.9, 116.7, 105.4. ESI-MS m/z
[M ꢀ H]ꢀ 315.0, 317.1.
3-(3,4-Dimethoxyphenyl)-4-hydroxy-2H-chromen-2-one,
2a: white solid, yield 68%, mp 243ꢀ245 °C. 1H NMR (400 MHz, d6-
DMSO): δ 11.15 (br s, 1H), 7.97 (d, 1H, J = 7.6 Hz), 7.67ꢀ7.63 (t, 1H),
7.42ꢀ7.36 (m, 2H), 7.03ꢀ6.92 (m, 3H), 3.80 (s, 3H), 3.75 (s, 3H). 13C
NMR (100 MHz, d6-DMSO) δ 162.4, 160.4, 152.7, 148.9, 148.8, 132.6,
124.5, 124.4, 124.1, 124.0, 116.9, 116.6, 115.3, 112.1, 106.4, 56.0, 56.0.
ESI-MS m/z [M ꢀ H]ꢀ 297.1.
3-(4-Bromophenyl)-4-hydroxy-8-methyl-2H-chromen-2-one,
2p: white solid, yield 45%, mp 235 °C. 1H NMR (400 MHz, d6-DMSO) δ
7.85 (d, 1H, J = 7.6 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.54 (d, 1H, J = 7.2 Hz),
7.37 (d, 2H, J = 8.4 Hz), 7.28 (t, 1H, J = 7.6 Hz), 2.39 (s, 3H). 13C NMR
(100 MHz, d6-DMSO) δ 174.9, 162.1, 161.3, 151.1, 133.9, 133.7, 132.0,
131.4, 125.6, 123.9, 121.9, 121.2, 116.5, 105.2, 29.5. ESI-MS m/z [M ꢀ H]ꢀ
329.0, 331.0. HRMS (ESI) calcd for C16H12BrO3þ [M þ H]þ 330.9964,
found 330.9973.
4-Hydroxy-3-(4-nitrophenyl)-2H-chromen-2-one, 2q: pre-
pared according to the procedure in ref 45; white solid, yield 30%, mp
287ꢀ289 °C. 1H NMR (400 MHz, d6-DMSO) δ 8.06ꢀ8.04 (dd, 1H, J =
8.8, 1.2 Hz), 7.78 (d, 2H, J = 8.0 Hz), 7.71ꢀ7.65 (m, 3H), 7.45ꢀ7.39
(m, 2H).
3-(3,4-Dimethoxyphenyl)-4-hydroxy-8-methyl-2H-chromen-
2-one, 2b: white solid, yield 45%, mp >300 °C. 1HNMR (400 MHz, d6-
DMSO) δ 7.71 (d, 1H, J = 7.6 Hz), 7.49 (s, 1H), 7.31 (d, 1H, J = 8.0 Hz),
7.20 (d, 1H, J = 6.8 Hz), 6.96 (t, 1H), 6.78 (d, 1H, J = 8.4 Hz), 3.73 (s, 3H),
3.70 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 172.4, 164.2,
152.1, 147.5, 145.5, 132.4, 130.8, 124.2, 124.0, 123.6, 123.4, 121.2, 116.0,
111.3, 97.1, 56.2, 55.9, 16.0. ESI-MS m/z [M ꢀ H]ꢀ 311.2. HRMS (ESI)
calcd for C18H17O5þ [M þ H]þ 313.1071, found 313.1075.
4-Hydroxy-3-(4-methoxyphenyl)-2H-chromen-2-one, 2e:45.
1
white solid, yield 66%, mp 242ꢀ244 °C (lit.46 mp 242ꢀ243 °C). H
NMR (400 MHz, d6-DMSO) δ 11.23 (br, s, 1H), 8.00ꢀ7.98 (dd, 1H, J =
8.0, 1.2 Hz), 7.65 (t, 1H, J = 8.4 Hz), 7.42ꢀ7.36 (m, 2H), 7.33 (d, 2H, J =
8.8 Hz), 7.00 (d, 2H, J = 8.8 Hz), 3.80 (s, 3H). 13C NMR (100 MHz, d6-
DMSO) δ 162.5, 160.4, 159.1, 152.7, 132.7, 132.6, 124.4, 124.4, 124.1,
116.9, 116.6, 114.0, 106.3, 55.6. ESI-MS m/z [M ꢀ H]ꢀ 267.1.
4-Hydroxy-3-(3-methoxyphenyl)-2H-chromen-2-one, 2r:
1
white solid, yield 50%, mp 262ꢀ264 °C (lit.51 mp 265ꢀ266 °C). H
NMR (400 MHz, d6-DMSO) δ 11.33 (s, 1H), 8.01ꢀ7.98 (dd, 1H, J =
8.0, 0.8 Hz), 7.68ꢀ7.65 (m, 1H), 7.42ꢀ7.32 (m, 3H), 6.97ꢀ6.93 (m,
3H), 3.77 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 162.2, 160.7,
159.5, 152.8, 133.7, 132.8, 129.6, 124.5, 124.2, 123.8, 117.1, 116.9, 116.7,
113.7, 106.5, 55.5. ESI-MS m/z [M ꢀ H]ꢀ 267.1.
4-Hydroxy-3-(4-methoxyphenyl)-8-methyl-2H-chromen-
2-one, 2f: white solid, yield 50%, mp 208ꢀ210 °C. 1H NMR (400 MHz,
d6-DMSO) δ11.12 (br, s, 1H), 7.82 (d, 1H,J =7.6Hz), 7.51 (d, 1H,J=7.2
Hz), 7.34ꢀ7.25 (m, 3H), 6.99 (d, 2H, J = 8.4 Hz), 3.80 (s, 3H), 2.39 (s,
3H). 13C NMR (100 MHz, d6-DMSO) δ 162.5, 160.9, 159.0, 151.0, 133.5,
132.6, 125.4, 124.6, 123.8, 121.8, 116.8, 114.0, 105.9, 55.6, 15.7. HRMS
(ESI) calcd for C17H15O4þ [M þ H]þ 283.0965, found 283.0965.
4-Hydroxy-3-p-tolyl-2H-chromen-2-one, 2i: white solid, yield
37%, mp 221ꢀ222 °C (lit.47 mp 225ꢀ226 °C). 1H NMR (400 MHz, d6-
DMSO) δ 11.26 (br, s, 1H), 8.00 (d, 1H, J = 8.8 Hz), 7.67ꢀ7.63 (t, 1H),
7.42ꢀ7.36 (m, 2H), 7.30ꢀ7.23 (m, 4H), 2.36 (s, 3H). 13C NMR (100
MHz, d6-DMSO) δ 162.43, 160.6, 152.7, 137.1, 132.6, 131.3, 129.5,
129.1, 124.4, 124.2, 117.0, 116.6, 106.5, 21.4. HRMS (ESI) calcd for
C16H13O3þ [M þ H]þ 253.0859, found 253.0869.
4-Hydroxy-8-methyl-3-o-tolyl-2H-chromen-2-one, 2s. white
solid, yield 41%, mp >300 °C. 1H NMR (400 MHz, d6-DMSO) δ 11.17 (s,
1H), 7.81 (d, 1H, J = 8.0 Hz), 7.54 (d, 1H, J = 7.2 Hz),7.31ꢀ7.26 (m, 2H),
7.18ꢀ7.15 (m, 3H), 2.41 (s, 3H), 2.13 (s, 3H). 13C NMR (100 MHz, d6-
DMSO) δ 173.0, 161.9, 161.2, 151.3, 138.4, 133.7, 131.9, 130.3, 128.5,
127.3, 126.2, 123.9, 121.8, 116.5, 105.7, 19.þ8, 15.7. ESI-MS m/z [M ꢀ H]ꢀ
265.2. HRMS (ESI) calcd for C17H15O3 [M þ H]þ 267.1016, found
267.1019.
2. Preparation of the Substituted 3-Aryl-4-hydroxy Cou-
marins 2c, 2g, and 2m. (I) 7c, 7g and 7m were prepared according
to the procedure in ref 30.
1-(2,4-Dihydroxyphenyl)-2-(3,4-dimethoxyphenyl)ethanone,
7c: white solid, yield 72%, mp 177ꢀ179 °C (lit.32 mp 177ꢀ178 °C). 1H
NMR (400 MHz, d6-DMSO) δ12.55 (s, 1H), 10.64 (s, 1H), 7.93 (d, 1H, J=
8.8 Hz), 6.87 (t, 1H), 6.77 (d, 1H, J= 7.6 Hz), 6.38ꢀ6.36 (dd, 1H, J= 8.8, 6.0
Hz), 6.24 (d, 1H, J = 6.0 Hz), 4.18 (s, 2H), 3.70 (s, 6H). 13C NMR (100
MHz, d6-DMSO) δ 202.8, 165.4, 165.1, 149.1, 148.1, 134.0, 127.9, 122.0,
113.9, 112.6, 112.4, 108.7, 103.0, 55.99, 55.96, 44.2. ESI-MS m/z [M þ
Na]þ 311.5.
1-(2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone,
7g: white solid, yield 74%, mp 159 °C (lit.33 mp 159 °C). 1H NMR (400
MHz, d6-DMSO) δ 12.55 (s, 1H), 10.66 (s, 1H), 7.94 (d, 1H, J = 8.8
Hz), 7.20 (d, 2H, J = 8.8 Hz), 6.87 (d, 2H, J = 8.4 Hz), 6.40ꢀ6.37 (dd,
1H, J = 8.8, 2.4 Hz), 6.25 (d, 1H, J = 2.4 Hz), 4.20 (s, 2H), 3.72 (s, 3H).
13C NMR (100 MHz, d6-DMSO) δ 202.9, 165.4, 165.1, 158.5, 134.0,
131.0, 127.5, 114.3, 112.6, 108.7, 103.0, 55.5, 43.7. ESI-MS m/z [M ꢀ
H]ꢀ 257.2.
4-Hydroxy-8-methyl-3-p-tolyl-2H-chromen-2-one, 2j: white
solid, yield 46%, mp 167ꢀ169 °C. 1H NMR (400 MHz, CDCl3) δ 8.01
(d, 1H, J = 8.0 Hz), 7.86 (d, 1H, J = 7.6 Hz), 7.45 (t, 2H), 7.32ꢀ7.26 (m,
3H), 2.56 (s, 3H), 2.55 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.0,
158.2, 156.0, 151.9, 137.3, 132.9, 127.0, 126.4, 124.1, 121.3, 120.9, 119.3,
112.5, 111.9, 105.7, 21.9, 16.2. ESI-MS m/z [M þ H]þ 267.5. HRMS
(ESI) calcd for C17H15O3þ [M þ H]þ 267.1016, found 267.1022.
4-Hydroxy-3-phenyl-2H-chromen-2-one, 2k: white solid, yield
56%, mp 232ꢀ233 °C (lit.48 mp 232ꢀ233 °C). 1H NMR (400 MHz, d6-
DMSO) δ 11.38 (br s, 1H), 8.01 (d, 1H, J = 7.2 Hz), 7.67 (t, 1H, J = 7.2
Hz), 7.45ꢀ7.34 (m, 7H). 13C NMR (100 MHz, d6-DMSO) δ 162.4,
160.8, 152.8, 132.8, 132.6, 131.5, 128.5, 127.9, 124.4, 124.2, 117.0, 116.7,
106.6. ESI-MS m/z [M ꢀ H]ꢀ 237.0. The 1H NMR data were consistent
with that in the literature.12
4-Hydroxy-8-methyl-3-phenyl-2H-chromen-2-one, 2l: white
solid, yield 43%, mp 225ꢀ226 °C (lit.49 mp 251 °C). 1H NMR (400 MHz,
d6-DMSO) δ 11.32 (s, 1H), 7.85 (d, 1H, J = 8.0 Hz), 7.53 (d, 1H, J = 7.2
Hz), 7.46ꢀ7.34 (m, 5H), 7.28 (t, 1H, J = 7.6 Hz), 2.40 (s, 3H). 13C NMR
1-(2,4-Dihydroxyphenyl)-2-phenylethanone, 7m: white so-
1
lid, yield 65%, mp 106ꢀ107 °C. H NMR (400 MHz, d6-DMSO) δ
12.50 (s, 1H), 10.67 (s, 1H), 7.94 (d, 1H, J = 8.8 Hz), 7.32ꢀ7.20
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(m, 5H), 6.38 (d, 1H, J = 8.8 Hz), 6.24 (s, 1H), 4.27 (s, 2H). 13C NMR
(100 MHz, d6-DMSO) δ 202.6, 165.5, 165.1, 135.7, 134.0, 130.0, 128.9,
127.1, 112.7, 108.8, 103.0, 44.6. ESI-MS m/z [M ꢀ H]ꢀ 227.2.
(II) 6c, 6g, and 6m were prepared according to the procedure in
ref 32.
2-(3,4-Dimethoxyphenyl)-1-(2-hydroxy-4-methoxyphenyl)-
ethanone, 6c: white solid, yield 70%, mp 116ꢀ117 °C(lit.52 mp 118 °C).
1H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 7.76 (d, 1H, J = 8.8 Hz),
6.85ꢀ6.79 (m, 3H), 6.46ꢀ6.43 (m, 2H), 4.16 (s, 2H), 3.87 (s, 3H), 3.86 (s,
3H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 202.2, 166.2, 165.9,
149.1, 148.2, 132.0, 126.8, 121.5, 113.2, 112.5, 111.4, 107.9, 101.1, 55.9,
55.6, 44.5.
1-(2-Hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)-
ethanone, 6g: white solid, yield 72%, mp 101 °C (lit.53 mp 100ꢀ
102 °C). 1H NMR (400 MHz, CDCl3) δ 12.74 (s, 1H), 7.75 (d, 1H,
J = 8.8 Hz), 7.19 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H, J = 8.4 Hz),
6.46ꢀ6.43 (m, 2H), 4.16 (s, 2H), 3.83 (s, 3H), 3.79 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 202.3, 166.2, 165.9, 158.7, 132.0, 130.4, 126.4,
114.2, 113.2, 107.8, 101.1, 55.6, 55.3, 44.0.
1-(2-Hydroxy-4-methoxyphenyl)-2-phenylethanone, 6m:
white solid, yield 86%, mp 83ꢀ85 °C (lit.54 mp 87ꢀ88 °C). 1H NMR
(400 MHz, CDCl3) δ 12.85 (s, 1H), 7.84 (d, 1H, J = 8.8 Hz), 7.43ꢀ7.36
(m, 5H), 6.53 (d, 2H, J = 9.2 Hz), 4.29 (s, 2H), 3.90 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 202.0, 166.3, 165.9, 134.5, 132.1, 129.4, 128.8,
127.1, 113.2, 107.9, 101.1, 55.6, 44.9.
2-(3,4-Dimethoxyphenyl)-1-(2-hydroxy-4,6-dimethoxy-
phenyl)ethanone, 6d: white solid, yield 90%, mp 117 °C (lit.57 mp
118ꢀ119 °C). 1H NMR (400 MHz, CDCl3) δ 13.90 (s, 1H), 6.84 (d, 1H,
J = 8.4 Hz), 6.76 (d, 2H, J = 7.2 Hz), 6.08 (s, 1H), 5.94 (s, 1H), 4.28 (s,
2H), 3.87 (t, 12H). 13C NMR (100 MHz, CDCl3) δ 203.0, 167.9, 166.2,
162.6, 148.8, 147.8, 127.9, 121.8, 112.9, 111.2, 105.7, 93.8, 91.0, 55.9, 55.8,
55.6, 55.6, 49.9. ESI-MS m/z [2M þ Na]þ 687.5.
1-(2-Hydroxy-4,6-dimethoxyphenyl)-2-(4-methoxyphenyl)-
ethanone, 6h: white solid, yield 63%, mp 86ꢀ87 °C(lit.58 mp 88 °C). 1H
NMR (400 MHz, CDCl3) δ13.91 (s, 1H), 7.13 (d, 2H, J=8.4Hz), 6.87(d,
2H, J = 8.4 Hz), 6.07 (d, 1H, J = 2.0 Hz), 5.93 (d, 1H, J = 2.0 Hz), 4.27 (s,
2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.80 (s, 3H). 13C NMR (100 MHz, CDCl3)
δ 203.2, 167.9, 166.2, 162.6, 158.4, 130.6, 127.5, 113.9, 105.7, 93.7, 90.9,
55.6, 55.6, 55.3, 49.4. ESI-MS m/z [2M þ Na]þ 626.9.
(III) Compounds 2d and 2h were prepared according to the proce-
dure for the preparation of 2c.
3-(3,4-Dimethoxyphenyl)-4-hydroxy-5,7-dimethoxy-2H-
chromen-2-one, 2d: white solid, yield 60%, mp 200 °C (lit.31 mp
201 °C). 1H NMR (400 MHz, d6-DMSO) δ 7.09 (s, 1H), 7.01 (d, 1H,
J = 8.4 Hz), 6.88 (d, 1H, J = 8.4 Hz), 6.53 (s, 1H), 6.49 (s, 1H), 3.91 (s,
3H), 3.85 (s, 3H), 3.75 (s, 3H), 3.72 (s, 3H). 13C NMR (100 MHz, d6-
DMSO) δ 172.5, 164.5, 162.9, 162.4, 158.5, 155.7, 148.2, 147.7, 126.7,
124.0, 115.6, 111.5, 101.1, 95.6, 94.1, 57.3, 56.4, 56.0, 56.0. ESI-MS
m/z [M þ H]þ 359.3.
4-Hydroxy-5,7-dimethoxy-3-(4-methoxyphenyl)-2H-chro-
men-2-one, 2h: white solid, yield 61%, mp 242ꢀ243 °C (lit.31 mp
243ꢀ245 °C). 1H NMR (400 MHz, d6-DMSO) δ 9.99 (s, 1H), 7.32 (d,
2H, J = 7.2 Hz), 6.92 (d, 2H, J = 7.2 Hz), 6.65 (s, 1H), 6.59 (s, 1H), 3.98
(s, 3H), 3.86 (s, 3H), 3.76 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ
163.5, 162.1, 161.5, 158.6, 158.0, 155.3, 132.4, 124.6, 113.5, 102.2, 98.7,
96.0, 94.5, 57.6, 56.6, 55.5. ESI-MS m/z [M þ Na]þ 329.7.
(III) 2c, 2g, and 2m were prepared according to the procedure in
ref 30.
3-(3,4-Dimethoxyphenyl)-4-hydroxy-7-methoxy-2H-chro-
men-2-one, 2c: white solid, yield 70%, mp 212 °C (lit.52 mp 212 °C).
1H NMR (400 MHz, d6-DMSO) δ 11.03 (s, 1H), 7.87 (d, 1H, J = 8.8
Hz), 6.99ꢀ6.88 (m, 5H), 3.85 (s, 3H), 3.78 (s, 3H), 3.73 (s, 3H). 13C
NMR (100 MHz, d6-DMSO) δ 163.0, 162.8, 160.9, 154.5, 148.7, 148.7,
125.3, 124.8, 124.1, 115.4, 112.3, 112.1, 110.0, 103.9, 100.8, 56.4,
56.0, 55.9.
General Procedure for the Preparation of Coumestan
Analogues. To a solution of substituted 4-hydroxy coumarin 2 (2.5
mmol) in dried 1,2-dichloroethane (30 mL) was added ferric chloride/
SiO2 (50/50, w/w, 6.25 mmol) in one portion with stirring at ambient
or reflux temperature, and the reaction process was monitored by TLC
analysis. The reaction mixture was then evaporated under vacuum to
remove the solvent. The residue was purified by silica gel chromatog-
raphy to give the desired products.
4-Hydroxy-7-methoxy-3-(4-methoxyphenyl)-2H-chromen-
2-one, 2g: white solid, yield 74%, mp 214ꢀ216 °C (lit.55 mp 213-
214 °C). 1H NMR (400 MHz, d6-DMSO) δ 11.11 (s, 1H), 7.93 (d, 1H,
J = 8.4 Hz), 7.30 (d, 2H, J = 8.4 Hz), 6.97 (d, 4H, J = 8.4 Hz), 3.87 (s, 3H),
3.79 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 162.96, 162.89, 161.0,
158.9, 154.5, 132.7, 125.4, 124.7, 113.9, 112.3, 110.0, 103.7, 100.8, 56.4,
55.6. ESI-MS m/z [M ꢀ H]ꢀ 297.3.
8,9-Dimethoxy-6H-benzofuro[3,2-c]chromen-6-one, 1a:
white solid, mp 219ꢀ220 °C (lit.59 mp 223 °C). 1H NMR (400 MHz,
CDCl3) δ 7.95 (d, 1H, J = 7.6 Hz), 7.58ꢀ7.48 (m, 3H), 7.41ꢀ7.37 (m,
1H), 7.20 (s, 1H), 4.01 (s, 3H), 4.00 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 158.9, 158.4, 153.0, 150.4, 149.6, 148.2, 131.1, 124.6, 121.3,
117.4, 115.4, 113.0, 106.3, 102.3, 95.5, 56.6, 56.4. ESI-MS m/z [2M þ
Na]þ 615.2.
4-Hydroxy-7-methoxy-3-phenyl-2H-chromen-2-one, 2m:
1
white solid, yield 50%, mp 198ꢀ200 °C (lit.56 mp 198ꢀ200 °C). H
NMR (400 MHz, d6-DMSO) δ 11.26 (s, 1H), 7.94 (d, 1H, J = 8.4 Hz),
7.43ꢀ7.31 (m, 5H), 6.99 (d, 2H), 3.88 (s, 3H). 13C NMR (100 MHz, d6-
DMSO) δ 163.1, 162.7, 161.2, 154.6, 132.8, 131.6, 128.4, 127.7, 125.4,
112.4, 109.9, 104.1, 100.9, 56.4. ESI-MS m/z [M ꢀ H]ꢀ 267.1.
3. Preparation of the Substituted 3-Aryl-4-hydroxy Cou-
marins 2d and 2h. (I) 7d and 7h were prepared according to the
procedure in ref 32.
8,9-Dimethoxy-4-methyl-6H-benzofuro[3,2-c]chromen-6-
1
one, 1b: white solid, mp 229ꢀ231 °C (lit.60 mp 229ꢀ231 °C). H
NMR (400 MHz, CDCl3) δ 7.83 (d, 1H, J = 7.6 Hz), 7.57 (s, 1H), 7.45
(d, 1H, J = 7.2 Hz), 7.32 (d, 1H, J = 7.6 Hz), 7.23 (s, 1H), 4.08 (s, 3H),
4.05 (s, 3H), 2.61 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.3, 158.4,
151.4, 150.3, 149.5, 148.1, 132.4, 126.9, 124.1, 118.9, 115.5, 112.6, 106.0,
102.4, 95.5, 56.5, 56.4, 16.2. ESI-MS m/z [M þ H]þ 311.7.
2-(3,4-Dimethoxyphenyl)-1-(2,4,6-trihydroxyphenyl)-
ethanone, 7d: white solid, yield 65%, mp 179ꢀ180 °C (lit.46 mp
181 °C). 1H NMR (400 MHz, d6-DMSO) δ 12.23 (s, 2H), 10.39 (s, 1H),
6.87 - 6.84 (m, 2H), 6.72 (d, 1H, J = 8.0 Hz), 5.81 (s, 2H), 4.26 (s, 2H),
3.71 (d, 6H). 13C NMR (100 MHz, d6-DMSO) δ 203.1, 165.3, 164.7,
148.9, 147.9, 128.7, 122.1, 114.3, 112.2, 104.1, 95.2, 56.0, 55.9, 48.9. ESI-
MS m/z [M ꢀ H]ꢀ 303.3.
3,8,9-Trimethoxy-6H-benzofuro[3,2-c]chromen-6-one, 1c:
white solid, mp 255 °C (lit.61 mp 254 °C). 1H NMR (400 MHz, CDCl3)
δ 7.85 (d, 1H, J = 8.4 Hz), 7.50 (s, 1H), 7.18 (s, 1H), 6.98ꢀ6.96 (m, 2H),
4.00 (s, 3H), 3.98 (s, 3H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
162.4, 159.7, 158.7, 154.9, 150.0, 149.1, 148.0, 122.3, 115.6, 113.0, 106.3,
103.9, 102.3, 101.5, 95.6, 56.6, 56.4, 55.8. ESI-MS m/z [M þ H]þ 327.4.
1,3,8,9-Tetramethoxy-6H-benzofuro[3,2-c]chromen-6-one,
1d: white solid, mp 248ꢀ250 °C (lit.62 mp 247ꢀ248 °C). 1H NMR (400
MHz, CDCl3) δ 7.51 (s, 1H), 7.24 (s, 1H), 6.62 (s, 1H), 6.43 (s, 1H), 4.04
(s, 3H), 4.00 (s, 3H), 3.97 (s, 3H), 3.89 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 162.8, 159.4, 158.7, 156.5, 155.8, 150.0, 148.8, 147.9, 115.2,
2-(4-Methoxyphenyl)-1-(2,4,6-trihydroxyphenyl)ethanone,
7h: white solid, yield 67%, mp 198 °C (lit.48 mp 195ꢀ197 °C). 1H NMR
(400 MHz, d6-DMSO) δ 12.22 (s, 2H), 10.38 (s, 1H), 7.12 (d, 2H, J = 8.4
Hz, 6.83 (d, 2H, J = 8.4 Hz), 5.80 (s, 2H), 4.25 (s, 2H), 3.34 (s, 3H). 13C
NMR (100 MHz, d6-DMSO) δ 203.2, 165.3, 164.7, 158.3, 131.1, 128.2,
114.0, 104.1, 95.2, 55.5, 48.5. ESI-MS m/z [M ꢀ H]ꢀ 273.2.
(II) 6d and 6h were prepared according to the procedure in ref 32.
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103.4, 102.0, 98.2, 95.8, 95.7, 93.8, 56.5, 56.4, 55.9. ESI-MS m/z [2M þ
Na]þ 735.6.
8.07ꢀ8.03 (m, 2H), 7.70 (d, 1H, J = 1.2 Hz), 7.64 (t, 1H, J = 8.0, 7.6 Hz),
7.53 (d, 1H, J = 8.4 Hz), 7.48ꢀ7.42 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ 160.5, 157.7, 155.5, 153.7, 132.7, 132.3, 126.1, 124.8, 122.3,
122.2, 121.9, 117.6, 112.5, 112.4, 105.6. ESI-MS m/z [2M þ Na]þ
563.3/565.3.
9-Methoxy-6H-benzofuro[3,2-c]chromen-6-one, 1e: white
solid, mp 216 °C (lit.63 mp 212ꢀ213 °C). 1H NMR (400 MHz, CDCl3)
δ 8.00ꢀ7.97 (m, 2H), 7.59ꢀ7.56 (m, 1H), 7.49 (d, 1H, J = 8.4 Hz), 7.40
(t, 1H), 7.18 (d, 1H, J = 2.0 Hz), 7.07ꢀ7.05 (dd, 1H, J = 8.4, 2.0 Hz),
3.91 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 159.7, 159.3, 158.2, 156.8,
153.2, 131.3, 124.6, 122.0, 121.5, 117.4, 116.5, 113.6, 112.9, 106.1, 96.8,
55.9. ESI-MS m/z [2M þ Na]þ 555.0.
9-Bromo-6H-benzofuro[3,2-c]chromen-6-one, 1o: white so-
lid, mp 200ꢀ202 °C. 1H NMR (400 MHz, CDCl3) δ 8.01 (t, 2H, J = 8.4
Hz), 7.85 (s, 1H), 7.66ꢀ7.59 (m, 2H), 7.52 (d, 1H, J = 8.4 Hz), 7.43
(t, 1H). 13C NMR (100 MHz, CDCl3) δ 160.4, 157.7, 155.7, 153.8, 132.3,
128.8, 124.8, 122.7, 122.6, 121.9, 120.1, 117.6, 115.4, 112.4, 105.7. HRMS
(ESI) calcd for C15H8BrO3þ [M þ H]þ 314.9651, found 314.9659.
9-Bromo-4-methyl-6H-benzofuro[3,2-c]chromen-6-one, 1p:
white solid, mp 227 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, 1H, J = 8.4
Hz), 7.84 (d, 2H, J = 11.2 Hz), 7.58 (d, 1H, J = 8.0 Hz), 7.47 (d, 1H, J = 7.2
Hz), 7.31 (t, 1H, J = 7.6 Hz), 2.55 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
160.8, 157.7, 155.7, 152.2, 133.7, 128.7, 127.2, 124.4, 122.7, 119.9, 119.5,
115.3, 112.0, 105.4, 16.2. HRMS (ESI) calcd for C16H10BrO3þ [M þ H]þ
328.9808, found 328.9815.
9-Methoxy-4-methyl-6H-benzofuro[3,2-c]chromen-6-one,
1f: white solid, mp 196 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 1H,
J = 8.8 Hz), 7.79 (d, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 7.2 Hz), 7.27 (t, 1H),
7.16 (s, 1H), 7.04 (d, 1H, J = 8.4 Hz), 3.90 (s, 3H), 2.54 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ 159.7, 159.6, 158.2, 156.8, 151.6, 132.6,
127.0, 124.1, 122.0, 119.1, 116.5, 113.5, 112.5, 105.8, 96.7, 55.9, 16.1. ESI-
MS m/z [2M þ Na]þ 583.1. HRMS (ESI) calcd for C17H13O4þ [M þ
H]þ 281.0808, found 281.0814.
3,9-Dimethoxy-6H-benzofuro[3,2-c]chromen-6-one, 1g:
Procedure for the Synthesis of 1f0. 1f0 was prepared by BBr3
demethylation according to a similar procedure.38 White solid, yield
79%, mp >300 °C. 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H),
7.78 (d, 1H, J = 7.6 Hz), 7.72 (d, 1H, J = 8.4 Hz), 7.50 (d, 1H, J = 7.6 Hz),
7.33 (t, 1H, J = 7.6 Hz), 7.16 (d, 1H, J = 1.6 Hz), 6.98ꢀ6.95 (dd, 1H, J =
8.4, 2.0 Hz), 2.42 (s, 3H). 13C NMR (100 MHz, d6-DMSO) δ 159.0,
158.1, 157.5, 156.9, 151.3, 133.1, 126.5, 124.9, 121.6, 119.4, 114.8, 112.3,
105.6, 99.1, 16.0. ESI-MS m/z [2M þ Na]þ 555.3. HRMS (ESI) calcd
for C16H10O4þ [M þ H]þ 266.0579, found 266.0584.
1
white solid, mp 199ꢀ200 °C (lit.63 mp 198ꢀ199 °C). H NMR (400
MHz, CDCl3) δ 7.94 (d, 1H, J = 8.8 Hz), 7.86 (d, 1H, J = 9.2 Hz), 7.15 (s,
1H), 7.04 (d, 1H, J = 8.4 Hz), 6.97 (d, 2H, J = 6.8 Hz), 3.90 (s, 6H). 13C
NMR (100 MHz, CDCl3) δ 162.6, 160.1, 159.3, 158.5, 156.5, 155.1,
122.5, 121.6, 116.7, 113.2, 113.0, 106.1, 103.5, 101.4, 96.9, 55.9, 55.8. ESI-
MS m/z [2M þ Na]þ 615.2.
1,3,9-Trimethoxy-6H-benzofuro[3,2-c]chromen-6-one, 1h:
1
white solid, mp 224ꢀ227 °C (lit.6 mp 220ꢀ225 °C). H NMR (400
MHz, CDCl3) δ 7.94 (d, 1H, J = 8.4 Hz), 7.21 (d, 1H, J = 1.6 Hz),
7.05ꢀ7.02 (dd, 1H, J = 8.4, 1.6 Hz), 6.61 (d, 1H, J = 1.6 Hz), 6.42 (d, 1H,
J = 1.6 Hz), 4.04 (s, 3H), 3.90 (s, 3H), 3.89 (s, 3H). 13C NMR (100 MHz,
CDCl3) δ 163.0, 159.8, 159.0, 158.5, 156.7, 156.5, 156.1, 121.3, 116.2,
113.3, 103.0, 98.1, 96.8, 95.7, 93.8, 56.4, 55.9, 55.9. ESI-MS m/z [2M þ
Na]þ 675.4.
Procedure for the Synthesis of 13. (I) Compound 10 was
prepared according to the procedure in ref 66: white solid, yield 55%, mp
102 °C. 1H NMR (400 MHz, d6-DMSO) δ 12.56 (s, 1H, OH), 7.99 (d,
1H, J = 9.2 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.88 (d, 2H, J = 8.4 Hz), 6.52ꢀ
6.49 (dd, 1H, J = 8.8, 2.4 Hz), 6.45 (d, 1H, J = 2.4 Hz), 4.76ꢀ4.70 (m,
1H), 4.24 (s, 2H), 3.72 (s, 3H), 1.28 (d, 6H). 13C NMR (100 MHz, d6-
DMSO) δ 203.2, 165.0, 164.6, 158.5, 133.7, 131.0, 127.3, 114.3, 113.2,
108.7, 102.5, 70.5, 55.5, 43.9, 22.1. ESI-MS m/z [M þ H]þ 301.2. HRMS
(ESI) calcd for C18H21O4þ [M þ H]þ 301.1434, found 301.1437.
(II) Following the above procedure for 2c, compound 11 was ob-
tained as a white solid: yield 71%, mp 201ꢀ203 °C. 1H NMR (400 MHz,
d6-DMSO) δ 11.06 (s, 1H), 7.88 (d, 1H, J = 8.4 Hz), 7.30 (d, 2H, J = 8.8
Hz), 6.99ꢀ6.92 (m, 4H), 4.81ꢀ4.75 (m, 1H, CH), 3.79 (s, 3H), 1.32 (d,
6H). 13C NMR (100 MHz, d6-DMSO) δ 162.9, 161.2, 160.9, 158.9,
154.5, 132.7, 125.3, 124.6, 113.9, 113.3, 109.7, 103.7, 102.1, 70.6, 55.6,
9-Methyl-6H-benzofuro[3,2-c]chromen-6-one, 1i: white solid,
mp 198ꢀ200 °C. 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 2H), 7.59ꢀ7.42
(m, 4H), 7.26 (s, 1H), 2.54 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
159.4, 158.0, 155.8, 153.4, 137.5, 131.5, 126.5, 124.5, 121.7, 121.1, 120.7,
117.3, 112.7, 111.9, 105.8, 21.9. ESI-MS m/z [M þ H]þ 251.6. HRMS
(ESI) calcd for C16H11O3þ [M þ H]þ 251.0703, found 251.0709.
4,9-Dimethyl-6H-benzofuro[3,2-c]chromen-6-one, 1j: white
solid, mp 179 °C. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, 1H, J = 7.6 Hz),
7.44 (d, 1H, J = 7.6 Hz), 7.36 (s, 4H), 2.50 (s, 3H, 2.42 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ 159.9, 158.1, 155.9, 151.9, 137.3, 132.9, 126.9, 126.4,
124.1, 121.2, 120.9, 119.3, 112.4, 111.9, 105.6, 21.9, 16.1. HRMS (ESI)
calcd for C17H13O3þ [M þ H]þ 265.0859, found 265.0867.
þ
22.1. ESI-MS m/z [M þ H]þ 327.2. HRMS (ESI) calcd for C19H19O5
[M þ H]þ 327.1227, found 327.1227.
(III) Following the general procedure for the synthesis of 1aꢀp,
compound 12 was obtained as a white solid: yield 85%, mp 145 °C. 1H
NMR (400 MHz, CDCl3) δ 7.93 (d, 1H, J = 8.8 Hz), 7.84 (d, 1H, J = 8.8
Hz), 7.15 (d, 1H, J = 2.0 Hz), 7.04ꢀ7.02 (dd, 1H, J = 8.8, 2.0 Hz),
6.96ꢀ6.92 (m, 2H), 4.68ꢀ4.62 (m, 1H, CH), 3.90 (s, 3H), 1.42 (d, 6H).
13C NMR (100 MHz, CDCl3) δ 161.0, 160.1, 159.2, 158.6, 156.4, 155.2,
122.5, 121.6, 116.7, 114.2, 113.1, 105.8, 103.4, 102.9, 96.9, 70.8, 55.6, 21.9.
HRMS (ESI) calcd for C19H17O5þ [M þ H]þ 325.1071, found 325.1074.
(IV) Compound 1367 was prepared according to a similar procedure:44
6H-Benzofuro[3,2-c]chromen-6-one, 1k: white solid, mp
1
172ꢀ173 °C, (lit.64 mp 172ꢀ173 °C). H NMR (400 MHz, CDCl3)
δ 8.16ꢀ8.15 (m, 1H), 8.05 (d, 1H, J = 7.6 Hz), 7.69ꢀ7.60 (m, 2H),
7.53ꢀ7.41 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 160.0, 158.0,
155.5, 153.7, 131.9, 126.8, 125.2, 124.6, 124.7, 123.4, 121.9, 117.5, 112.6,
111.8, 105.9. ESI-MS m/z [2M þ Na]þ 495.1.
4-Methyl-6H-benzofuro[3,2-c]chromen-6-one, 1l: white so-
1
lid, mp 195ꢀ197 °C. H NMR (400 MHz, CDCl3) δ 8.20ꢀ8.18 (m,
1H), 7.89 (d, 1H, J = 7.6 Hz), 7.71ꢀ7.69 (d, 1H, J = 7.2 Hz), 7.55ꢀ7.48
(m, 3H), 7.34 (t, 1H), 2.60 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
160.4, 158.0, 155.5, 152.1, 133.2, 127.1, 126.6, 125.1, 124.2, 123.5, 121.9,
119.5, 112.3, 111.7, 105.6, 16.2. ESI-MS m/z [2M þ Na]þ 523.1.
3-Methoxy-6H-benzofuro[3,2-c]chromen-6-one, 1m: white
white solid, mp >300 °C. H NMR (400 MHz, d6-DMSO) δ 10.81 (s,
1
1H), 7.88 (d, 1H, J = 8.4 Hz), 7.79 (d, 1H, J = 8.8 Hz), 7.50 (d, 1H, J = 2.4
Hz), 7.12ꢀ7.10 (dd, 1H, J= 8.8, 2.0 Hz), 6.98ꢀ6.93(m, 2H), 3.87(s,3H).
13C NMR (100 MHz, d6-DMSO) δ 161.9, 159.3, 158.1, 157.6, 156.4,
155.3, 123.3, 121.1, 116.4, 114.4, 114.0, 104.6, 103.6, 102.4, 97.8, 56.4.
1
solid, mp 189 °C (lit.39 mp 190 °C). H NMR (400 MHz, CDCl3) δ
8.01ꢀ7.99 (m, 1H), 7.92 (t, 1H), 7.64 (d, 1H, J = 8.4 Hz), 7.46ꢀ7.42 (m,
2H), 7.01ꢀ6.99 (m, 2H), 3.93 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
163.3, 163.1, 155.7, 155.3, 132.0, 126.2, 125.1, 122.9, 122.9, 121.6, 113.2,
111.6, 105.9, 103.4, 101.5, 55.9. ESI-MS m/z [2M þ Na]þ 555.2.
9-Chloro-6H-benzofuro[3,2-c]chromen-6-one, 1n: white
solid, mp 229 °C (lit.65 mp 239 °C). 1H NMR (400 MHz, CDCl3) δ
’ ASSOCIATED CONTENT
S
Supporting Information. Spectral data for all synthe-
b
sized compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
(31) Gilbert, A. H.; McGookin, A.; Robertson, A. J. Chem. Soc.
1957, 3740.
(32) Badcock, G. G.; Cavill, G. W. K.; Robertson, A.; Whalley, W. B.
J. Chem. Soc. 1950, 2961.
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn and combinology@yahoo.com.
(33) Xiang, H.; Zhao, W.; Xiao, H.; Qian, L.; Yao, Y.; Li, X.; Liao, Q.
Bioorg. Med. Chem. 2010, 18, 3036.
(34) Keinan, B.; Mazur, Y. J. Org. Chem. 1978, 43, 1020.
(35) Jempty, T. C.; Miller, L. L.; Mazur, Y. J. Org. Chem. 1980,
45, 749.
(36) McKillop, A.; Young, D. W. Synthesis 1979, 481.
(37) Posner, G. W. Angew. Chem., Int. Ed. Engl. 1978, 17, 487.
(38) McOmie, J. F. W.; West, D. E. Org. Synth. 1969, 49, 50.
(39) Jurd., L. J. Org. Chem. 1964, 29, 3036.
’ ACKNOWLEDGMENT
Y. Du acknowledges the National Natural Science Foundation
of China (Nos. 20802048 and 21072148) and Cultivation
Foundation (B) for Young Faculty of Tianjin University (TJU-
YFF-08B68) for financial support. We also thank Professor Daisy
Zhang-Negrerie [Tianjin University] for revising our English text.
(40) Jurd., L. J. Org. Chem. 1959, 24, 1786.
(41) Martin, M.; Dewick, P. M. Phytochemistry 1980, 19, 2341.
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(43) For isopropyl groups in 3,30-diisopropoxybiphenyl being con-
currently removed in an aryl oxidative coupling reaction using excess
FeCl3 in CH2Cl2/MeOH, see: Bushby, R. J.; Lu, Z. Synthesis 2001, 763.
We thank one of the reviewers for bringing this to our attention. After
repetition of our reaction and some extended investigation, the following
results were obtained: (i) In addition to the expected 12, no deprotected
product 13 was observed when 11 was treated with 2.5 equiv of either
FeCl3/SiO2 (50/50, w/w) or FeCl3 alone in DCM at rt. (ii) Under
similar conditions, when the amount of FeCl3/SiO2 was increased to 5
equiv, no formation of compound 13 was detected either. (iii) When 5.0
equiv of FeCl3 was used and the reaction was operated at 50 °C, product
13 was observed and isolated in 42% yield, while 5.0 equiv of FeCl3/SiO2
gave only 15% yield of 13.
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