Divergent synthesis of biflavonoids yields novel inhibitors of the aggregation of amyloid β (1-42)

Article abstract of DOI:10.1039/c7ob00804j

Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly explored within drug discovery. There is considerable structural diversity possible within this compound class and large regions of po

Full text of DOI:10.1039/c7ob00804j

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Received 00th January 20xx,
Divergent Synthesis of Biflavonoids Yields Novel Inhibitors of the
Aggregation of Amyloid β (1-42)
Tze Han Sum,a Tze Jing Sum,a Súil Collins,a,b Warren R. J. D. Galloway,a David G. Twigg,a Florian
Hollfelderb and David R. Spring*a
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Biflavonoids are associated with a variety of biologically useful properties. However, synthetic biflavonoids are poorly
explored within drug discovery. There is considerable structural diversity possible within this compound class and large
regions of potentially biologically relevant biflavonoid chemical space remain untapped or underexplored. Herein, we
report the development of a modular and divergent strategy towards biflavonoid derivatives which enabled the step-
economical preparation of a structurally diverse collection of novel unnatural biflavonoids. Preliminary studies established
that the strategy could also be successfully extended to the preparation of very rare triflavonoids, which are also expected
to be useful tools for biological intervention. Prompted by previous inhibitory studies with flavonoid libraries, amyloid
anti-aggregation screening was performed, which led to the identification of several structurally novel inhibitors of the
aggregation of the amyloid β peptide (Aβ42). Aggregated Aβ42 is a pathological hallmark of Alzheimer’s disease and the use
of small molecules to inhibit the aggregation process has been identified as a potentially valuable therapeutic strategy for
disease treatment. Methylated biaurones were associated with highest levels of potency (the most active compound had
an IC50 value of 16 µM), establishing this scaffold as a starting point for inhibitor development.
1
are based around a limited range of structures.
Indeed, there
Introduction
remain large regions of potentially biologically relevant biflavonoid
chemical space that is underexplored.1,14 Thus, there is a need for
new and robust strategies for the generation of collections of
unnatural biflavonoids with higher levels of structural diversity so
that the biological potential of this compounds class can be more
fully explored and exploited.1 Herein, we report the development
of a divergent strategy towards biflavonoid derivatives. Application
of this strategy enabled the step-economical preparation of a
structurally diverse collection of novel biflavonoids, with variation
in the nature of both the flavonoid units (substituted aurone and
flavone) and linker moiety, from readily-accessible starting
materials. In addition, the strategy was also successfully extended
to the preparation of very rare triflavonoid analogues, which are
also expected to have interesting biological properties. Screening
of the library compounds in anti-aggregation assays with amyloid β
peptide 1-42 (Aβ42), a pathological hallmark of Alzheimer’s disease
(AD), led to the identification of several structurally novel
aggregation inhibitors. 15 The use of small molecules to prevent this
aggregation process is considered a potential strategy for the
development of new therapies for AD.16,17 Of the compounds
examined, methylated biaurones were associated with the highest
levels of potency; the most active of these had an IC50 value
comparable to epigallocatechin gallate (EGCG), an AD treatment
candidate which has reached phase III clinical trials.18,19 The
Biflavonoids are a family of polyphenolic compounds characterised
by the presence of two flavonoid units conjoined through an alkyl
or alkoxy-based linker.1 Natural biflavonoids, found in many fruits,
vegetables and plants, are associated with a variety of biologically
1, 2
useful properties
(such as anti-cancer3, anti-inflammatory4, anti-
microbial5, anti-viral6, anti-clotting7, anti-bacterial8. anti-fungal9 and
anti-oxidant10 activities) and in many cases the bioactivity of a
biflavonoid is greater than that of the constituent monomer(s)9, 11
(Figure 1). Synthetic biflavonoids have also been found to exhibit
interesting biological activities, similar to their aforementioned
1, 9, 11-13
natural analogues.
However, despite these attractive
poorly explored
compound family within drug discovery.1 The variation possible in
flavonoid units, coupled with large number of possible
features, synthetic bioflavonoids represent
a
a
permutations in the position and nature of the inter-flavonoid
linkage, means that there is considerable structural diversity
possible within the biflavanoid compound class1. Whilst there exist
a
number of different approaches for the production of
biflavonoids, these typically generate compound collections that
methylated biaurone scaffold could therefore represent
a
potentially valuable starting point for further studies into the
development of new inhibitors or probe molecules to target Aβ42
aggregation.
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oxidation of 726 would furnish the biflavones 8, whereas mercury(II)
acetate-mediated oxidative cyclization27 would yield biaurones 9. It
was presumed that bichalcones 7 could be readily accessed via the
Claisen-Schmidt aldol condensation28 between bialdehydes 6 and
the corresponding acetophenones 5.
O
O
OH
O
O
OH
HO
O
OH
OH
Divergent synthesis of diverse biflavones and biaurones
OH
OH
O
In this study, three commercially available bialdehyde building
blocks were selected for use: isophthalaldehyde (10),
terephthaldehyde (11) and 4,4’-biphenyldicarboxaldehyde (12).
These were combined with a range of acetophenone derivatives to
yield bichalcones, which could then be readily converted into the
desired biflavones and biaurones by oxidative cyclisation (Schemes
2-4). Yields at each stage were generally moderate-to-good.
Overall, this route enabled concise, modular and step-efficient
access to a library of 34 unnatural substituted biflavonoids (17
biflavones and 17 biaurones, 29 of which are previously
unreported) based around a diverse range of structures from a
small set of readily available building blocks. Crucially, variation in
the substitution pattern around the flavonoid units and the position
and nature of the aryl linkage unit between them was achieved.
The library compounds contain potential biomolecular-interacting
elements (for example, hydrogen-bonding groups) and several
compounds contain an aryl-bromide group, which could provide a
synthetic handle for further elaboration or diversification.
O
HO
HO
Lanaroflavone (1)
O
O
Amentoflavone (2)
OH
OH
OH
OH
O
O
HO
O
HO
Robustaflavone (3)
OH
OH
O
HO
OH HO
OH
OH
O
HO
O
HO
Aulacomniumbiaureusidin (4)
O
O
OH
Preliminary studies into the synthesis of triflavonoids
Fig. 1. Examples of naturally occurring biflavonoids. Amongst the biflavones
(compounds of the general form 8, see Scheme 1) amentoflavone (2) exhibits
both anti-fungal and anti-inflammatory activities,20 robustaflavone (3) is a potent
inhibitor of the Hepatitis B virus21 while lanaroflavone (1) displays anti-malarial
We were interested in the possibility that our divergent approach
could be extended to the preparation of triflavonoids. Thus, it was
envisaged that the use of tri-aldehyde building blocks would enable
access to trichalcones, which could then be divergently converted
to triflavones or triaurones by application of iodine- or mercury(II)
acetate-based oxidative conditions respectively. As proof-of-
principle, we targeted the generation of triflavone 73 and triaurone
74. These could both be readily accessed from tricarbaldehyde 71
and acetophenone 13 (Scheme 5). This establishes the general
feasibility of our approach for the synthesis of triflavonoids, a
structurally rare and biologically interesting compound class.
properties22
. The biaurone (a compound of the general form 9, see Scheme 1)
aulacomniumbiaureusidin (4) was isolated from Aulacomnium palustre.23
Results and discussions
Outline of the divergent synthetic strategy
Inspired by our previous studies on flavonoid synthesis,24,25 we
envisaged a divergent strategy for the synthesis of biflavones 8 and
biaurones 9 that centered on the use of a bichalcone scaffold 7 as
the key branching point (Scheme 1). It was anticipated that
application of different oxidative cyclisation methods would provide
access to both target dimeric frameworks; iodine-mediated
O
O
O
O
HO
iodine
R
R
R
R
DMSO
Claisen-
OH
O
HO
5
Schmidt aldol
condensation
O
oxidative
R
R
biflavones (8)
cyclisation
+
O
O
bichalcones (7)
mercury (II)
acetate
R
O
Key branch point
6
O
O
O
O
biaurones (9)
Scheme 1. Outline of divergent synthetic strategy towards biflavones and biaurones.
2 | J. Name., 2012, 00, 1-3
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HO
O
R1
R2
13; R1 = OMe, R2 = H, R3 = H
14; R1 = H, R2 = OMe, R3 = H
15; R1 = H, R2 = H, R3 = OMe
16; R1 = OMe, R2 = OMe, R3 = H
17; R1 = OMe, R2 = H, R3 = OMe
18; R1 = H, R2 = Br, R3 = H
2 x
O
O
+
R3
10
13-19
KOH
19; R1 = R2 = -OCH2O-, R3 = H
EtOH
20; R1 = OMe, R2 = H, R3 = H; 52%
21; R1 = H, R2 = OMe, R3 = H; 23%
22; R1 = H, R2 = H, R3 = OMe; 81%
R1
OH
O
HO
O
R1
R2
R2 23; R1 = OMe, R2 = OMe, R3 = H; 43%
24; R1 = OMe, R2 = H, R3 = OMe; 99%
25; R1 = H, R2 = Br, R3 = H; 75%
R3
R3
20-26
I2
DMSO
Hg(OAc)2
Pyridine
26; R1 = R2 = -OCH2O-, R3 = H; 41%
R1
R1
R1
O
O
O
O
R1
R2
R2
O
O
R2
R2
R3
R3
27-33
R3
R3
O
O
34-40
27; R1 = OMe, R2 = H, R3 = H; 60%
28; R1 = H, R2 = OMe, R3 = H; 65%
29; R1 = H, R2 = H, R3 = OMe; 78%
30; R1 = OMe, R2 = OMe, R3 = H; 46%
31; R1 = OMe, R2 = H, R3 = OMe; 80%
32; R1 = H, R2 = Br, R3 = H; 91%
34; R1 = OMe, R2 = H, R3 = H; 27%
35; R1 = H, R2 = OMe, R3 = H; 58%
36; R1 = H, R2 = H, R3 = OMe; 84%
37; R1 = OMe, R2 = OMe, R3 = H; 44%
38; R1 = OMe, R2 = H, R3 = OMe; 60%
39; R1 = H, R2 = Br, R3 = H; 86%
33; R1 = R2 = -OCH2O-, R3 = H; 28%
40; R1 = R2 = -OCH2O-, R3 = H; 10%
Scheme 2. Divergent synthesis using bialdehdye 10 as building block.
HO
R1
R2
13; R1 = OMe, R2 = H, R3 = H
14; R1 = H, R2 = OMe, R3 = H
15; R1 = H, R2 = H, R3 = OMe
17; R1 = OMe, R2 = H, R3 = OMe
18; R1 = H, R2 = Br, R3 = H
2 x
O
O
+
O
R3
11
13-15, 17,18
KOH
EtOH
R3
O
41; R1 = OMe, R2 = H, R3 = H; 42%
42; R1 = H, R2 = OMe, R3 = H; 79%
43; R1 = H, R2 = H, R3 = OMe; 84%
44; R1 = OMe, R2 = H, R3 = OMe; 71%
45; R1 = H, R2 = Br, R3 = H; 80%
R2
HO
R1
R2
R1
OH
41-45
O
R3
I2
Hg(OAc)2
Pyridine
R1
R3
O
O
O
DMSO
R2
R1
R3
R2
O
O
R2
R3
O
O
R1
R2
O
51-55
R1
46; R1 = OMe, R2 = H, R3 = H; 67%
47; R1 = H, R2 = OMe, R3 = H; 26%
48; R1 = H, R2 = H, R3 = OMe; 22%
49; R1 = OMe, R2 = H, R3 = OMe; 51%
50; R1 = H, R2 = Br, R3 = H; 87%
51; R1 = OMe, R2 = H, R3 = H; 95%
52; R1 = H, R2 = OMe, R3 = H; 76%
53; R1 = H, R2 = H, R3 = OMe; 99%
54; R1 = OMe, R2 = H, R3 = OMe; 90%
55; R1 = H, R2 = Br, R3 = H; 44%
46-50
R3
Scheme 3. Divergent synthesis using bialdehdye 11 as building block.
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HO
O
R1
R2
13; R1 = OMe, R2 = H, R3 = H
2 x
O
O
14; R1 = H, R2 = OMe, R3 = H
15; R1 = H, R2 = H, R3 = OMe
17; R1 = OMe, R2 = H, R3 = OMe
18; R1 = H, R2 = Br, R3 = H
+
R3
13-15, 17,18
12
KOH
EtOH
O
R3
56; R1 = OMe, R2 = H, R3 = H; 47%
57; R1 = H, R2 = OMe, R3 = H; 32%
58; R1 = H, R2 = H, R3 = OMe; 89%
59; R1 = OMe, R2 = H, R3 = OMe; 80%
60; R1 = H, R2 = Br, R3 = H; 89%
R2
R1
R1
OH
HO
R2
56-60
R3
O
I2
Hg(OAc)2
Pyridine
O
DMSO
R3
R1
O
O
R2
R3
R2
O
66-70
R1
O
R2
R3
O
O
O
61-65
R3
R1
61; R1 = OMe, R2 = H, R3 = H; 69%
62; R1 = H, R2 = OMe, R3 = H; 59%
63; R1 = H, R2 = H, R3 = OMe; 79%
66; R1 = OMe, R2 = H, R3 = H; 30%
67; R1 = H, R2 = OMe, R3 = H; 63%
68; R1 = H, R2 = H, R3 = OMe; 89%
69; R1 = OMe, R2 = H, R3 = OMe; 44%
70; R1 = H, R2 = Br, R3 = H; 87%
R2
R1
64; R1 = OMe, R2 = H, R3 = OMe; 69%
65; R1 = H, R2 = Br, R3 = H; 46%
Scheme 4. Divergent synthesis using bialdehdye 12 as building block.
Inhibition of Aβ42 aggregation
O
OMe
OMe
The inhibitory activity of the compound library against the
aggregation of amyloid beta (1-42) (Aβ42), a principal
neuropathic agent in Alzheimer’s disease (AD),15 was
investigated. Although inhibition of Aβ42 aggregation has
long been acknowledged as a promising strategy for the
development of AD therapeutics16, drug candidates have
frequently failed in clinical trials,29,30 so the need for further
candidates remains. A variety of chalcone and flavonoid
derivatives,31-33 as well as several naturally occurring
biflavonoids,11 have shown amyloid anti-aggregation
activity, thereby prompting investigation of the inhibitory
effects of biflavonoid library.
KOH
O
O
OH
HO
EtOH
71
+
O
O
HO
2 x
OMe
72; 52%
OH
13
O
I2
Hg(OAc)2
O
DMSO
Pyridine
OMe
MeO
OMe
O
A Thioflavin T (ThT) assay was used to assess the anti-
aggregation activity of the library compounds (Figure 2A).
An enhancement in fluorescence intensity of this dye is
O
O
O
O
O
OMe
observed upon binding to amyloid fibrils, giving
a
characteristic time course of amyloid aggregation (Fig. 2A)
in association with fibril formation. Changes in the
aggregation kinetics and final fluorescence intensity value,
upon addition of small molecules, are indicative of
inhibitory or modulatory effects on the aggregation
process. Of the 34 compounds examined, 24 were either
inactive, insoluble or overly fluorescent under the assay
O
O
O
O
73; 28%
O
O
OMe
OMe
74; 52%
Scheme 5. Divergent synthesis of triflavone 73 and triaurone 74.
OMe
conditions, see ESI for details)
. For 10 compounds
aggregation time courses could be recorded (Fig. 2A) and
the methylated biaurones were observed to show the
greatest inhibitory activities. For reference three chalcone
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derivatives known to exert an inhibitory effect, EGCG,34,35
myricetin36,37 and morin,38 were assayed simultaneously,
and their percentage inhibition values shown in Figure 2B .
A)
B)
Compound
% Inhibition
Compound
A
β42
40
39
6 ± 2
40
39
35
70
68
11 ± 2
14 ± 3
26 ± 2
34 ± 1
35 ± 1
38 ± 2
42 ± 2
42 ± 1
52 ± 3
73 ± 1
78 ± 1
95 ± 1
35
1.0
70
68
66
67
morin
66
55
0.5
0.0
Morin
34
67
52
55
34
Myricetin
EGCG
0
5
10
15
52
Time (hr)
myricetin
EGCG
C)
Concentration compound 52 (ꢀM)
Concentration EGCG (ꢀM)
OH
D)
HO
OH
OH
OH
O
HO
O
O
HO
O
OMe
O
Morin
OH
OH
O
MeO
OH
OH
O
52
OH
OH
O
HO
O
O
OH
EGCG
OH
Myricetin
OH
OH
OH
O
Figure 2. A) Aβ42 aggregation profiles in the ThT assay with the addition of biflavonoids. Aβ42 curve (blue) represent the time course of Aβ42 aggregation (initial concentration of 10
μM Aβ42 peptide). Inhibited aggregation is observed with the addition of active small molecules (concentration of 50 μM). See Experimental Section for full details. Data represent
the average results of three independent biological repeats. B) Percentage inhibition of Aβ42 aggregation achieved by a selection of the biaurones (50 μM concentration), morin ,
myricetin and EGCG relative to that of Aβ42 alone (10 μM), calculated from the saturation phase of the Aβ42 aggregation profiles shown in panel A). 100% represents complete
aggregation inhibition and 0% shows no inhibition. C) Variation in aggregation rate with compound concentration for compound 52 and EGCG. IC50 values calculated by taking the
slope of the ThT aggregation curve (as in panel A) to represent the aggregation rate. The aggregation rate with a range of inhibitor concentrations (0.5 to 100 µM) was plotted
using Graphpad®. D) Structures of the reference chalcones used in the ThT assay and 52, the most active compound identified in this study.
Compound 52 was found to be the most potent, with an
inhibitory activity comparable to that of myricetin and
greater than that of morin (Figure 2B, structures shown in
Figure 2D). An IC50 value of 15.8 ± 3.7 μM was calculated
based on the concentration dependence of inhibition for
52. The apparent affinity of biaurone 52 was comparable to
that measured for the phase III clinical trial drug EGCG (IC50
6.4 ± 0.7 μM) (Figure 2C).
All of the biaurone derivatives examined have the same
general structure, being composed two aurone ring systems
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connected through a linker moiety. Reinke and Gestwicki
have previously reported a structure-activity relationship
(SAR) study on amyloid-beta aggregation inhibition by a
structurally related series of compounds that contain two
interconnected phenyl ring systems.39 They postulated that
Conclusions
Herein, we have reported the successful development of a
modular and divergent strategy towards structurally diverse
biflavonoid derivatives from readily-accessible bialdehyde
and acetophenone building-blocks. Our strategy therefore
enables the probing of underexplored regions of
biflavonoid chemical space, which could facilitate greater
exploration and exploitation of the biological potential of
this compound class. A total of 34 substituted biflavonoids
(17 biflavones and 17 biaurones) based around a diverse
range of structures was generated in this study, of which 29
are previously unreported. Conceivably, the synthetic
strategy could be applied on a larger scale using a greater
there are two docking sites on the A
β surface that can
accommodate the aromatic end groups of such ligands and
it was found that compound activity was affected by the
substitution pattern of the aromatic ring systems and the
length and flexibility of the linker region. Our screening
data for the biaurones is broadly consistent with these
observations.
For more detailed structure-activity
information the number of compounds tested is too small.
However, based on the limited evidence available, a para-
substituted phenyl linker is consistently associated with
higher levels of inhibitory activity than a meta-substituted
phenyl linker, with the di-phenyl linker in-between these
extremes (compare e.g. 35 vs 52 and 67 and 55 vs 70). It is
not readily apparent why all biflavones were largely inactive
in the ThT assay. Several biaurones were better inhibitors
then their biflavone equivalents (that is, biflavones
incorporating the same linker moiety and the same
substituents around the aromatic end groups; compare e.g.
range of building-blocks.
Preliminary studies also
demonstrated that this approach could be successfully
extended to the preparation of very rare triflavonoid
analogues that are also expected to be of biological
interest.
performed, which led to the identification of several
structurally novel inhibitors of the aggregation of Aβ42
Amyloid anti-aggregation screening was
,
which has long been acknowledged as a promising strategy
for the development of Alzheimer’s disease therapeutics.16
This work adds to the repertoire of inhibitors: all active
52 vs 47
imply that flavone groups are relatively poorly
accommodated by any docking sites on the on the A
, 55 vs 50 and 34 vs 27). This observation may
compounds were biau
r
ones, while biflavones were all
Methylated biaurones
β
found to lack inhibitory properties
.
surface. Starting from the trends observed here on Aβ42
aggregation inhibition in the biaurone series, systematic
exploration of the effects identified by Reinke and
Gestwicki39 (namely linker length, flexibility and orientation)
may lead to more potent compounds. It would also be
interesting to investigate the effects of heteroaromatic
linkers upon inhibitory activity and physicochemical
properties.
were associated with highest levels of potency, highlighting
the potential value of this scaffold as a starting point for the
development of next-generation inhibitors or probe
molecules that target Aβ42 aggregation. Notably, one
library compound, was found to have an IC50 value which is
comparable to EGCG, an Alzheimer’s and Parkinson’s
disease treatment candidate that reached phase II and III
clinical trials.
Blood brain barrier (BBB) permeation is an important
consideration in Alzheimer’s drug research.40 Thus far the
degree of BBB permeation achieved by 52, the most potent
compound identified in this study, has not been
experimentally determined, due to known difficulties in
pertaining accurate data.41 However, comparison of it’s
physiochemical properties with the those associated with
Experimental section
Chemical synthesis
General information and materials
optimal brain exposure (molecular weight
≤
360;
All reagents and solvents were purchased from commercial
sources and used without further purification unless otherwise
stated. All the experiments were carried out under a nitrogen
atmosphere unless otherwise stated. Melting points were
measured using a Büchi B545 melting point apparatus and are
uncorrected. Thin layer chromatography (TLC) was performed
on precoated Merck silica gel GF254 plates. IR spectra were
topological polar surface area between 40 and 90 Å2;
lipophilicity calculated partition coefficient ≤3; number of
hydrogen bond donors ≤ 0.5)42 suggests that the compound
fits a selection of the criteria (molecular weight = 366;
topological polar surface area = 52.6; lipophilicity calculated
partition coefficient = 4.9-5.6; number of hydrogen bond
donors = 0),43 with scope for improvement in future lead
recorded on
a
Perkin-Elmer Spectrum One (FT-IR)
optimisation studies.
It is worth noting that such
spectrophotometer. Flash column chromatography was
performed on silica gel (230-400 mesh). 1H NMR and 13C NMR
were recorded on a Bruker Avance 500 MHz instrument in CDCl3
and DMSO-d6. HRMS was recorded on a Micromass Q-TOF mass
spectrometer or a Waters LCT Premier Time of Flight mass
spectrometer.
parameters focus on the ability of small molecule to
passively diffuse into the brain, whereas as other factors
such as active of facilitated transport may be at play.44 In
employing these guidelines BBB permeability can therefore
be underestimated, and experimental techniques would be
required to further probe this issue.”
6 | J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
General Procedure A: Synthesis of bichalcones or trichalcone
(GP-A)
°C. TLC Rf = 0.47 (CH2Cl2). IR νmax (neat)/cm-1: 3003w (C-H str),
2844w (C-H str), 1638m (C=O str), 1620m, 1571s (C=C str),
1507m, 1478w, 1467w, 1444m, 1362s, 1327w, 1302w, 1292w,
1231s, 1219s, 1210s, 1133s, 1019s. 1H NMR (500 MHz, CDCl3): δ
3.89 (6H, s, 2 × -OCH3), 6.51-6.55 (4H, m, ArH), 7.52 (1H, t, J 8.0
Hz, ArH), 7.64 (2H, d, J 15.2 Hz, 2 × -CH=CHCO-), 7.72 (2H, d, J 7.6
Hz, ArH), 7.87 (2H, d, J 8.8 Hz, ArH), 7.89 (1H, br s, ArH), 7.92
(2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 13.38 (2H, s, 2 × OH). 13C NMR
(500 MHz, CDCl3): δ 55.6, 101.1, 107.9, 114.0, 121.4, 128.5,
129.7, 130.1, 131.3, 135.7, 143.3, 166.4, 166.8, 191.5. LCMS
(ES+) m/z = 431.2 ([M+H]+, tr = 5.26 min). HRMS (ESI+) m/z =
431.1486 [M+H]+ found, C26H23O6+ required 431.1489.
To a stirred solution of KOH (12.0 equiv) in absolute EtOH (100
o
mL) cooled to 0 C in an ice-bath was added dropwise a solution
of the corresponding bialdehyde or trialdehyde (1.0 equiv) and
acetophenone (2.0 equiv or 3.0 equiv). The reaction mixture was
stirred at 0 oC for 1 h and then at room temperature for 72 h
under nitrogen or until TLC analysis indicated complete
consumption of starting material. The resulting mixture was
then poured into ice-water (200 mL) and acidified to pH 3-4 with
3 M HCl. The aqueous solution was extracted with CHCl3 (3 × 100
mL) and the combined organic layer was washed with satd
NaHCO3 (2 × 100 mL), brine (2 × 100 mL), dried over anhydrous
MgSO4, filtered and the solvent removed under reduced
pressure. The crude residue was purified by flash column
chromatography over silica or successive recrystallization from
hot MeOH or CHCl3 to afford the corresponding bichalcones or
trichalcone.
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(2-hydroxy-5-
methoxyphenyl)prop-2-en-1-one)
(21)
A
mixture
of
acetophenone 14 (2.52 g, 15.2 mmol), bialdehyde 10 (1.03 g,
7.68 mmol) and KOH (5.37 g, 95.7 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by flash column chromatography (SiO2, PE/EtOAc; 5:1)
to afford bichalcone 21 (750 mg, 23%) as a bright orange fluffy
solid. m.p. 138-140 °C. TLC Rf = 0.48 (PE/EtOAc; 2:1). IR νmax
(neat)/cm-1: 2913w (C-H str), 2834w (C-H str), 1644m (C=O str),
1570s (C=C str), 1485s, 1411w, 1350s, 1278m, 1266m, 1244m,
1222w, 1196s, 1175m, 1165s, 1035m, 1020s. 1H NMR (500 MHz,
CDCl3): δ 3.84 (6H, s, 2 × -OCH3), 6.96 (2H, d, J 9.2 Hz, ArH), 7.14
(2H, dd, J 9.2, 3.2 Hz, ArH), 7.34 (2H, d, J 2.8 Hz, ArH), 7.49 (1H, t,
J 7.6 Hz, ArH), 7.59 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 7.69 (2H,
dd, J 7.6, 1.2 Hz, ArH), 7.82 (1H, br s, ArH), 7.88 (2H, d, J 15.2 Hz,
2 × -CH=CHCO-), 12.32 (2H, s, 2 × OH). 13C NMR (500 MHz,
CDCl3): δ 56.0, 112.7, 119.3, 119.4, 121.0, 124.1, 129.0, 129.6,
130.3, 135.3, 144.2, 151.7, 157.9, 192.9. LCMS (ES+) m/z = 431.2
([M+H]+, tr = 2.19 min). HRMS (ESI+) m/z = 431.1486 [M+H]+
found, C26H23O6+ required 431.1489.
General Procedure B: Synthesis of biflavones or triflavone (GP-
B)
To
a stirred solution of the corresponding bichalcone or
trichalcone (1.0 equiv) in DMSO (10 mL) was added iodine (0.1
equiv). The reaction mixture was stirred at 120 oC for 24 h under
a nitrogen atmosphere. The resulting mixture was allowed to
cool to room temperature and then poured into ice-water (50
mL). The aqueous solution was extracted with CHCl3 (3 × 50 mL)
and the combined organic layer was washed with H2O (2 × 50
mL), brine (2 × 50 mL), dried over anhydrous MgSO4, filtered and
the solvent removed under reduced pressure. The crude residue
was purified by flash column chromatography over silica to
afford the corresponding biflavones or triflavone.
General Procedure C: Synthesis of biaurones or triaurone (GP-
C)
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(2-hydroxy-6-
To
a
stirred solution of the corresponding bichalcone or
methoxyphenyl)prop-2-en-1-one)
(22)
A
mixture
of
trichalcone (1.0 equiv) in pyridine (10 mL) was added mercury(II)
acetate (2.0 equiv or 3.0 equiv). The reaction mixture was stirred
at 110 oC for 1 h under a nitrogen atmosphere. The resulting
mixture was allowed to cool to room temperature and then
poured into ice-water (50 mL) and acidified to pH 3-4 with 3 M
HCl. The aqueous solution was extracted with CHCl3 (3 × 50 mL)
and the combined organic layer was washed with H2O (2 × 50
mL), brine (2 × 50 mL), dried over anhydrous MgSO4, filtered and
the solvent removed under reduced pressure. The crude residue
was purified by flash column chromatography over silica and/or
recrystallization from CHCl3 or MeOH to afford the
corresponding biaurones or triaurone.
acetophenone 15 (2.79 g, 16.8 mmol), bialdehyde 10 (1.12 g,
8.35 mmol) and KOH (5.35 g, 95.3 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 22
(2.93 g, 81%) as a bright yellow-orange powdery solid. m.p. 168-
170 °C. TLC Rf = 0.48 (CH2Cl2). IR νmax (neat)/cm-1: 2940w (C-H
str), 2844w (C-H str), 1632s (C=O str), 1608m, 1559s (C=C str),
1476w, 1457s, 1432s, 1347m, 1321w, 1299w, 1276w, 1228s,
1199w, 1182w, 1168m, 1086s, 1034m. 1H NMR (500 MHz,
CDCl3): δ 3.98 (6H, s, 2 × -OCH3), 6.46 (2H, dd, J 8.5, 1.0 Hz, ArH),
6.64 (2H, dd, J 8.5, 1.0 Hz, ArH), 7.39 (2H, t, J 8.5 Hz, ArH), 7.48
(1H, t, J 7.5 Hz, ArH), 7.67 (2H, dd, J 7.5, 1.5 Hz, ArH), 7.79 (1H,
br s, ArH), 7.82 (2H, d, J 15.5 Hz, 2 × -CH=CHCO-), 7.90 (2H, d, J
16.0 Hz, 2 × -CH=CHCO-), 13.08 (2H, s, 2 × OH). 13C NMR (500
MHz, CDCl3): δ 56.0, 101.6, 111.0, 111.9, 128.4, 128.9, 129.5,
129.6, 136.1, 136.1, 141.9, 161.0, 164.9, 194.3. LCMS (ES+) m/z
= 431.2 ([M+H]+, tr = 1.84 min). HRMS (ESI+) m/z = 431.1471
[M+H]+ found, C26H23O6+ required 431.1489.
Synthesis of bichalcones and trichalcone
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(2-hydroxy-4-
methoxyphenyl)prop-2-en-1-one)
(20)
A
mixture
of
acetophenone 13 (1.28 g, 7.70 mmol), bialdehyde 10 (500 mg,
3.73 mmol) and KOH (2.67 g, 44.7 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 20
(639 mg, 40%) as a bright yellow powdery solid. m.p. 290-292
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(2-hydroxy-4,5-
dimethoxyphenyl)prop-2-en-1-one) (23)
A
mixture of
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DOI: 10.1039/C7OB00804J
ARTICLE
Journal Name
+
acetophenone 16 (1.46 g, 7.44 mmol), bialdehyde 10 (530 mg,
3.95 mmol) and KOH (2.85 g, 50.8 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 23
(837 mg, 43%) as a bright orange powdery solid. m.p. 226-228
°C. TLC Rf = 0.46 (PE/EtOAc; 1:1). IR νmax (neat)/cm-1: 2940w (C-H
str), 2830w (C-H str), 1633s (C=O str), 1560s (C=C str), 1510s
(C=C str), 1445m, 1436m, 1396s, 1354s, 1277s, 1247m, 1233m,
(ESI+) m/z = 526.9486 [M+H]+ found, C24H17O4Br2 required
526.9494.
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(6-
hydroxybenzo[d][1,3]dioxol-5-yl)prop-2-en-1-one)
(26)
A
mixture of acetophenone 19 (1.36 g, 7.55 mmol), bialdehyde 10
(530 mg, 3.95 mmol) and KOH (2.88 g, 51.3 mmol) in absolute
EtOH (100 mL) was reacted according to GP-A. The crude residue
was purified by flash column chromatography (SiO2, CH2Cl2) to
afford bichalcone 26 (747 mg, 41%) as a bright orange powdery
solid. m.p. 246-248 °C. TLC Rf = 0.43 (CH2Cl2). IR νmax (neat)/cm-1:
2921w (C-H str), 1636s (C=O str), 1617s, 1578s (C=C str), 1502m
(C=C str), 1477s, 1422s, 1343s, 1264s, 1221s, 1180m, 1168m,
1106s, 1035s. 1H NMR (500 MHz, CDCl3): δ 6.04 (4H, s, 2 × -
OCH2O-), 6.53 (2H, s, ArH), 7.29 (2H, s, ArH), 7.52 (1H, t, J 7.6 Hz,
ArH), 7.54 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 7.72 (2H, dd, J 7.6,
1.2 Hz, ArH), 7.87 (1H, br s, ArH), 7.92 (2H, d, J 15.6 Hz, 2 × -
CH=CHCO-), 13.76 (2H, s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ
99.0, 102.0, 106.1, 112.5, 121.4, 128.7, 129.7, 130.1, 135.6,
140.7, 143.5, 154.8, 163.9, 191.0. LCMS (ES+) m/z = 459.1
([M+H]+, tr = 1.82 min). HRMS (ESI+) m/z = 481.0877 [M+Na]+
found, C26H18O8Na+ required 481.0894.
1
1203s, 1156s, 1043m, 1028s. H NMR (500 MHz, CDCl3): δ 3.95
(6H, s, 2 × -OCH3), 3.96 (6H, s, 2 × -OCH3), 6.53 (2H, s, ArH), 7.27
(2H, s, ArH, overlain by CDCl3), 7.53 (1H, d, J 8.0 Hz, ArH), 7.57
(2H, d, J 15.2 Hz, 2 × -CH=CHCO-), 7.74 (2H, dd, J 7.6, 1.2 Hz,
ArH), 7.88 (1H, br s, ArH), 7.94 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-),
13.34 (2H, s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ 56.2, 57.0,
100.9, 110.8, 111.9, 121.4, 129.0, 129.6, 130.0, 135.7, 142.1,
143.4, 157.3, 162.0, 191.1. LCMS (ES+) m/z = 491.3 ([M+H]+, tr =
+
2.06 min). HRMS (ESI+) m/z = 491.1723 [M+H]+ found, C28H27O8
required 491.1706.
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(2-hydroxy-4,6-
dimethoxyphenyl)prop-2-en-1-one) (24)
A
mixture of
acetophenone 17 (2.95 g, 15.0 mmol), bialdehyde 10 (1.07 g,
7.98 mmol) and KOH (5.37 g, 95.7 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH and CHCl3 to afford
bichalcone 24 (3.29 g, 99%) as a bright yellow powdery solid.
m.p. 250-252 °C. TLC Rf = 0.38 (CH2Cl2). IR νmax (neat)/cm-1:
2946w (C-H str), 2847w (C-H str), 1623s (C=O str), 1584s (C=C
str), 1552s (C=C str), 1487w, 1452m, 1439m, 1414w, 1344s,
1319w, 1278s, 1218s, 1212s, 1162s, 1113s, 1036m. 1H NMR (500
MHz, CDCl3): δ 3.86 (6H, s, 2 × -OCH3), 3.95 (6H, s, 2 × -OCH3),
5.99 (2H, d, J 2.4 Hz, ArH), 6.13 (2H, d, J 2.0 Hz, ArH), 7.47 (1H, t,
J 7.6 Hz, ArH), 7.64 (2H, d, J 8.4 Hz, ArH), 7.78 (1H, br s, ArH),
7.80 (2H, d, J 16.0 Hz, 2 × -CH=CHCO-), 7.94 (2H, d, J 15.6 Hz, 2 ×
-CH=CHCO-), 14.23 (2H, s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ
55.6, 56.0, 91.4, 93.8, 106.3, 128.4, 128.7, 129.3, 129.4, 136.3,
141.4, 162.5, 166.4, 168.4, 192.5. LCMS (ES+) m/z = 491.3
([M+H]+, tr = 1.91 min). HRMS (ESI+) m/z = 491.1696 [M+H]+
found, C28H27O8+ required 491.1700.
(2E,2’E)-3,3’-(1,4-Phenylene)bis(1-(2-hydroxy-4-
methoxyphenyl)prop-2-en-1-one)
(41)
A
mixture
of
acetophenone 13 (2.52 g, 15.2 mmol), bialdehyde 11 (1.05 g,
7.83 mmol) and KOH (5.40 g, 96.2 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 41
(1.40 g, 42%) as a bright yellow powdery solid. m.p. 264-266 °C.
TLC Rf = 0.38 (CH2Cl2). IR νmax (neat)/cm-1: 2949w (C-H str),
2848w (C-H str), 1641s (C=O str), 1563s (C=C str), 1513s (C=C
str), 1447w, 1421s, 1376s, 1351s, 1312s, 1289s, 1242s, 1223m,
1
1195m, 1152s, 1035s, 1019s. H NMR (500 MHz, CDCl3): δ 3.89
(6H, s, 2 × -OCH3), 6.51-6.53 (4H, m, ArH), 7.64 (2H, d, J 15.6 Hz,
2 × -CH=CHCO-), 7.72 (4H, s, ArH), 7.85 (2H, d, J 8.8 Hz, ArH),
7.90 (2H, d, J 15.2 Hz, 2 × -CH=CHCO-), 13.39 (2H, s, 2 × OH). 13
C
NMR (500 MHz, CDCl3): δ 55.6, 101.1, 107.9, 114.1, 121.5, 129.1,
131.2, 136.9, 143.1, 166.4, 166.8, 191.5. LCMS (ES+) m/z = 431.2
([M+H]+, tr = 1.87 min). These characterisation data are in
accordance with that previously reported in the literature.45
(2E,2’E)-3,3’-(1,3-Phenylene)bis(1-(5-bromo-2-
hydroxyphenyl)prop-2-en-1-one)
(25)
A
mixture
of
acetophenone 18 (3.26, 15.2 mmol), bialdehyde 10 (1.07 g, 7.98
mmol) and KOH (5.38 g, 95.9 mmol) in absolute EtOH (100 mL)
was reacted according to GP-A. The crude residue was purified
by recrystallization from MeOH to afford bichalcone 25 (3.16 g,
75%) as a bright yellow powdery solid. m.p. 248-250 °C. TLC Rf =
0.65 (CH2Cl2). IR νmax (neat)/cm-1: 2950w (C-H str), 1740w, 1639s
(C=O str), 1570s (C=C str), 1468s, 1436w, 1400w, 1356m, 1337m,
1310w, 1291w, 1279w, 1263m, 1232m, 1192s, 1168s, 1084w,
(2E,2’E)-3,3’-(1,4-Phenylene)bis(1-(2-hydroxy-5-
methoxyphenyl)prop-2-en-1-one)
(42)
A
mixture
of
acetophenone 14 (2.54 g, 15.3 mmol), bialdehyde 11 (1.05 g,
7.83 mmol) and KOH (5.40 g, 96.2 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 42
(2.66 g, 79%) as a dark orange powdery solid. m.p. 246-248 °C.
TLC Rf = 0.41 (CH2Cl2). IR νmax (neat)/cm-1: 2961w (C-H str),
2836w (C-H str), 1643m (C=O str), 1568s (C=C str), 1485s,
1416m, 1357m, 1303w, 1286w, 1266s, 1201m, 1175s, 1035m,
1
1021m. H NMR (500 MHz, CDCl3): δ 6.98 (2H, d, J 8.8 Hz, ArH),
7.56-7.62 (3H, m, ArH), 7.65 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-),
7.80 (2H, dd, J 8.0, 1.6 Hz, ArH), 7.94 (1H, br s, ArH), 8.00 (2H, d,
J 15.6 Hz, 2 × -CH=CHCO-), 8.05 (2H, d, J 2.4 Hz, ArH), 12.67 (2H,
s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ 110.5, 120.5, 120.7,
121.1, 129.3, 129.9, 130.8, 131.8, 135.3, 139.2, 145.2, 162.5,
192.5. LCMS (ES+) m/z = 528.9 ([M+H]+, tr = 2.20 min). HRMS
1
1020s. H NMR (500 MHz, CDCl3): δ 3.87 (6H, s, 2 × -OCH3), 7.01
(2H, d, J 9.2 Hz, ArH), 7.18 (2H, dd, J 9.2, 3.2 Hz, ArH), 7.38 (2H,
d, J 2.8 Hz, ArH), 7.67 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 7.75 (4H,
s, ArH), 7.94 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 12.31 (2H, s, 2 ×
OH). 13C NMR (500 MHz, CDCl3): δ 56.2, 113.0, 119.5, 119.6,
8 | J. Name., 2012, 00, 1-3
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ARTICLE
121.4, 124.0, 129.2, 136.9, 144.1, 151.8, 158.0, 193.1. LCMS
(ES+) m/z = 431.2 ([M+H]+, tr = 1.85 min). These characterisation
data are in accordance with that previously reported in the
literature.46
CH=CHCO-), 8.04 (2H, d, J 2.4 Hz, ArH), 12.68 (2H, s, 2 × OH). 13
C
NMR (500 MHz, CDCl3): δ 110.5, 120.8, 120.8, 121.2, 129.5,
131.8, 136.8, 139.2, 145.0, 162.6, 192.4. LCMS (ES-) m/z = 527.0
([M-H]-, tr = 2.52 min). These characterisation data are in
accordance with that previously reported in the literature.46
(2E,2’E)-3,3’-(1,4-Phenylene)bis(1-(2-hydroxy-6-
methoxyphenyl)prop-2-en-1-one)
(43)
A
mixture
of
(2E,2’E)-3,3’-([1,1’-Biphenyl]-4,4’-diyl)bis(1-(2-hydroxy-4-
acetophenone 15 (2.50 g, 15.0 mmol), bialdehyde 11 (1.02 g,
7.60 mmol) and KOH (5.43 g, 96.8 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 43
(2.76 g, 84%) as a bright yellow powdery solid. m.p. 228-230 °C.
TLC Rf = 0.43 (CH2Cl2). IR νmax (neat)/cm-1: 2947w (C-H str),
2843w (C-H str), 1634m (C=O str), 1587m (C=C str), 1563s (C=C
str), 1476m, 1456m, 1435w, 1418m, 1361m, 1332w, 1238s,
1206m, 1200m, 1168m, 1088s, 1038m. 1H NMR (500 MHz,
CDCl3): δ 3.98 (6H, s, 2 × -OCH3), 6.45 (2H, dd, J 8.5, 1.0 Hz, ArH),
6.64 (2H, dd, J 8.5, 1.0 Hz, ArH), 7.38 (2H, t, J 8.5 Hz, ArH), 7.66
(4H, s, ArH), 7.80 (2H, d, J 15.5 Hz, 2 × -CH=CHCO-), 7.91 (2H, d, J
15.5 Hz, 2 × -CH=CHCO-), 13.11 (2H, s, 2 × OH). 13C NMR (500
MHz, CDCl3): δ 56.0, 101.5, 111.0, 111.9, 128.5, 128.9, 136.1,
137.1, 141.7, 161.0, 164.9, 194.2. LCMS (ES+) m/z = 431.2
([M+H]+, tr = 1.84 min). These characterisation data are in
accordance with that previously reported in the literature.47
methoxyphenyl)prop-2-en-1-one)
(56)
A
mixture
of
acetophenone 13 (1.63 g, 9.81 mmol), bialdehyde 12 (1.02 g,
4.85 mmol) and KOH (3.53 g, 62.9 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 56
(1.15 g, 47%) as a bright yellow powdery solid. m.p. 248-250 °C.
TLC Rf = 0.41 (CH2Cl2). IR νmax (neat)/cm-1: 2968w (C-H str),
2843w (C-H str), 1635s (C=O str), 1574s (C=C str), 1552m (C=C
str), 1508m (C=C str), 1500w, 1432m, 1363s, 1286m, 1216s,
1203s, 1123s, 1025m, 1017m, 1002m. 1H NMR (500 MHz,
CDCl3): δ 3.89 (6H, s, 2 × -OCH3), 6.50-6.54 (4H, m, ArH), 7.65
(2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 7.72 (4H, d, J 8.4 Hz, ArH), 7.77
(4H, d, J 8.4 Hz, ArH), 7.87 (2H, d, J 8.8 Hz, ArH), 7.95 (2H, d, J
15.6 Hz, 2 × -CH=CHCO-), 13.45 (2H, s, 2 × OH). 13C NMR (500
MHz, CDCl3): δ 55.6, 101.1, 107.9, 114.1, 120.5, 127.5, 129.2,
131.2, 134.4, 142.1, 143.6, 166.3, 166.8, 191.7. LCMS (ES+) m/z
= 507.3 ([M+H]+, tr = 2.04 min). These characterisation data are
in accordance with that previously reported in the literature.48
(2E,2’E)-3,3’-(1,4-Phenylene)bis(1-(2-hydroxy-4,6-
dimethoxyphenyl)prop-2-en-1-one) (44)
A
mixture of
(2E,2’E)-3,3’-([1,1’-Biphenyl]-4,4’-diyl)bis(1-(2-hydroxy-5-
acetophenone 17 (2.82 g, 14.4 mmol), bialdehyde 11 (1.05 g,
7.83 mmol) and KOH (5.42 g, 96.6 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 44
(2.73 g, 71%) as a dull yellow powdery solid. m.p. 288-290 °C.
TLC Rf = 0.34 (CH2Cl2). IR νmax (neat)/cm-1: 2944w (C-H str),
2843w (C-H str), 1619s (C=O str), 1588s (C=C str), 1565s (C=C
str), 1489w, 1449w, 1438m, 1415m, 1346s, 1287w, 1216s,
1159s, 1110s, 1033w. 1H NMR (500 MHz, CDCl3): δ 3.86 (6H, s, 2
× -OCH3), 3.95 (6H, s, 2 × -OCH3), 5.99 (2H, d, J 2.4 Hz, ArH), 6.13
(2H, d, J 2.4 Hz, ArH), 7.65 (4H, s, ArH), 7.79 (2H, d, J 15.6 Hz, 2 ×
-CH=CHCO-), 7.96 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 14.26 (2H, s,
2 × OH). 13C NMR (500 MHz, CDCl3): δ 55.6, 55.9, 91.3, 93.8,
106.4, 128.4, 128.8, 137.2, 141.2, 162.5, 166.4, 168.5, 192.3.
LCMS (ES+) m/z = 491.2 ([M+H]+, tr = 1.94 min). HRMS (ESI+) m/z
= 491.1685 [M+H]+ found, C28H27O8+ required 491.1700.
methoxyphenyl)prop-2-en-1-one)
(57)
A
mixture
of
acetophenone 14 (1.60 g, 9.63 mmol), bialdehyde 12 (1.00 g,
4.76 mmol) and KOH (3.46 g, 61.2 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 57
(780 mg, 32%) as a bright orange powdery solid. m.p. 214-216
°C. TLC Rf = 0.11 (CH2Cl2). IR νmax (neat)/cm-1: 2970w (C-H str),
2839w (C-H str), 1636m (C=O str), 1568s (C=C str), 1548m (C=C
str), 1486s, 1461w, 1410m, 1353s, 1309m, 1275m, 1261s,
1241w, 1180s, 1040m, 1013w, 1002m. 1H NMR (500 MHz,
CDCl3): δ 3.88 (6H, s, 2 × -OCH3), 7.01 (2H, d, J 8.8 Hz, ArH), 7.18
(2H, dd, J 9.2, 2.8 Hz, ArH), 7.41 (2H, d, J 2.8 Hz, ArH), 7.67 (2H,
d, J 15.2 Hz, 2 × -CH=CHCO-), 7.74 (4H, d, J 8.4 Hz, ArH), 7.79 (4H,
d, J 8.4 Hz, ArH), 7.98 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 12.38
(2H, s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ 56.2, 113.0, 119.4,
119.7, 120.4, 123.9, 127.6, 129.3, 134.2, 142.4, 144.8, 151.7,
158.0, 193.2. LCMS (ES+) m/z = 507.2 ([M+H]+, tr = 2.00 min).
HRMS (ESI+) m/z = 529.1607 [M+Na]+ found, C32H26O6Na+
required 529.1622.
(2E,2’E)-3,3’-(1,4-Phenylene)bis(1-(5-bromo-2-
hydroxyphenyl)prop-2-en-1-one)
(45)
A
mixture
of
acetophenone 18 (3.30 g, 15.3 mmol), bialdehyde 11 (1.09 g,
8.13 mmol) and KOH (5.37 g, 95.7 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 45
(3.43 g, 80%) as a bright yellow-orange powdery solid. m.p. >300
°C. TLC Rf = 0.68 (CH2Cl2). IR νmax (neat)/cm-1: 2969w (C-H str),
1738w, 1639s (C=O str), 1568s (C=C str), 1468s, 1415m, 1398w,
1367m, 1336m, 1303w, 1289w, 1269m, 1234w, 1194s, 1086w,
(2E,2’E)-3,3’-([1,1’-Biphenyl]-4,4’-diyl)bis(1-(2-hydroxy-6-
methoxyphenyl)prop-2-en-1-one)
(58)
A
mixture
of
acetophenone 15 (1.62 g, 9.75 mmol), bialdehyde 12 (1.00 g,
4.76 mmol) and KOH (3.44 g, 61.3 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 58
(2.14 g, 89%) as a bright yellow-orange powdery solid. m.p. 238-
240 °C. TLC Rf = 0.43 (CH2Cl2). IR νmax (neat)/cm-1: 2939w (C-H
str), 2839w (C-H str), 1627m (C=O str), 1577m (C=C str), 1548s
(C=C str), 1474m, 1453s, 1433m, 1354s, 1238s, 1199w, 1183s,
1
1023s. H NMR (500 MHz, CDCl3): δ 6.98 (2H, d, J 8.8 Hz, ArH),
7.61 (2H, dd, J 8.8, 2.4 Hz, ArH), 7.65 (2H, d, J 15.6 Hz, 2 × -
CH=CHCO-), 7.79 (4H, s, ArH), 7.97 (2H, d, J 15.6 Hz, 2 × -
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ARTICLE
Journal Name
1167m, 1089s, 1037m, 1025m, 1003w. 1H NMR (500 MHz,
CDCl3): δ 3.99 (6H, s, 2 × -OCH3), 6.46 (2H, dd, J 8.5, 1.0 Hz, ArH),
6.65 (2H, dd, J 8.5, 1.0 Hz, ArH), 7.39 (2H, t, J 8.5 Hz, ArH), 7.70
(4H, d, J 8.5 Hz, ArH), 7.73 (4H, d, J 8.5 Hz, ArH), 7.86 (2H, d, J
15.5 Hz, 2 × -CH=CHCO-), 7.93 (2H, d, J 15.5 Hz, 2 × -CH=CHCO-),
13.15 (2H, s, 2 × OH). 13C NMR (500 MHz, CDCl3): δ 56.0, 101.6,
111.0, 112.0, 127.4, 127.8, 129.1, 134.9, 136.0, 141.9, 142.2,
161.0, 164.9, 194.3. LCMS (ES+) m/z = 507.2 ([M+H]+, tr = 2.00
A. The crude residue was purified by recrystallization from
MeOH to afford trichalcone 72 (972 mg, 52%) as a bright yellow
powdery solid. m.p. 278-280 °C. TLC Rf = 0.50 (CH2Cl2). IR νmax
(neat)/cm-1: 2926w (C-H str), 2843w (C-H str), 1714w, 1637m
(C=O str), 1619m, 1572s (C=C str), 1508m (C=C str), 1443w,
1360s, 1280w, 1265w, 1212s, 1154w, 1128s, 1021m. 1H NMR
(500 MHz, CDCl3): δ 3.90 (9H, s, 3 × -OCH3), 6.52 (3H, d, J 2.4 Hz,
ArH), 6.56 (3H, dd, J 8.8, 2.4 Hz, ArH), 7.69 (3H, d, J 15.2 Hz, 3 × -
CH=CHCO-), 7.91 (3H, d, J 9.2 Hz, ArH), 7.92 (3H, s, ArH), 7.94
(3H, d, J 16.0 Hz, 3 × -CH=CHCO-), 13.34 (3H, s, 3 × OH). 13C NMR
(500 MHz, CDCl3): δ 55.7, 101.1, 108.1, 114.0, 122.4, 129.6,
131.3, 136.5, 142.4, 166.6, 166.9, 191.2. LCMS (ES+) m/z = 607.2
([M+H]+, tr = 2.17 min). HRMS (ESI+) m/z = 629.1764 [M+Na]+
found, C36H30O9Na+ required 629.1782.
+
min). HRMS (ESI+) m/z = 507.1802 [M+H]+ found, C32H27O6
required 507.1802.
(2E,2’E)-3,3’-([1,1’-Biphenyl]-4,4’-diyl)bis(1-(2-hydroxy-4,6-
dimethoxyphenyl)prop-2-en-1-one) (59)
A mixture of 2-
hydroxy-4,6-dimethoxyacetophenone 17 (1.88 g, 9.58 mmol),
bialdehyde 12 (1.01 g, 4.80 mmol) and KOH (3.45 g, 61.5 mmol)
in absolute EtOH (100 mL) was reacted according to GP-A. The
crude residue was purified by recrystallization from MeOH to
afford bichalcone 59 (2.17 g, 80%) as a bright yellow powdery
solid. m.p. 268-270 °C. TLC Rf = 0.17 (CH2Cl2). IR νmax (neat)/cm-1:
2938w (C-H str), 2838w (C-H str), 1608s (C=O str), 1579s (C=C
str), 1547s (C=C str), 1498w, 1481w, 1440m, 1406m, 1343s,
1295m, 1214s, 1186m, 1153s, 1114s, 1035m, 1023w, 1002w. 1H
NMR (500 MHz, CDCl3): δ 3.86 (6H, s, 2 × -OCH3), 3.96 (6H, s, 2 ×
-OCH3), 6.00 (2H, d, J 2.4 Hz, ArH), 6.14 (2H, d, J 2.4 Hz, ArH),
7.68-7.73 (8H, m, ArH), 7.84 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-),
7.97 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 14.31 (2H, br s, 2 × OH).
13C NMR (500 MHz, CDCl3): δ 55.6, 55.9, 91.3, 93.8, 106.4, 127.4,
127.7, 129.0, 135.1, 141.7, 141.7, 162.5, 166.3, 168.5, 192.5.
Synthesis of biflavones and triflavone
2,2’-(1,3-Phenylene)bis(7-methoxy-4H-chromen-4-one) (27) A
mixture of bichalcone 20 (207 mg, 0.482 mmol) and I2 (81.2 mg,
0.314 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 27 (123 mg, 60%)
as a pale yellow-white powdery solid. m.p. 288-290 °C. TLC Rf =
0.31 (5% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2931w (C-H str),
2838w (C-H str), 1626s (C=O str), 1602s, 1578m (C=C str), 1501w
(C=C str), 1481w, 1436s, 1373m, 1359s, 1276w, 1260m, 1235w,
1202w, 1164m, 1128w, 1088m, 1037w, 1026m. 1H NMR (500
MHz, CDCl3): δ 3.98 (6H, s, 2 × -OCH3), 6.87 (2H, s, 2 × -C=CH),
7.00-7.02 (4H, m, ArH), 7.67 (1H, t, J 8.0 Hz, ArH), 8.03 (2H, dd, J
8.0, 1.2 Hz, ArH), 8.13 (2H, d, J 8.4 Hz, ArH), 8.41 (1H, br s, ArH).
13C NMR (500 MHz, CDCl3): δ 56.0, 100.3, 108.1, 114.9, 117.7,
123.6, 127.0, 128.6, 129.8, 132.8, 158.0, 161.6, 164.4, 177.6.
LCMS (ES+) m/z = 427.2 ([M+H]+, tr = 1.75 min). HRMS (ESI+) m/z
= 427.1161 [M+H]+ found, C26H19O6+ required 427.1176.
LCMS (ES+) m/z
= = 2.10 min). These
567.2 ([M+H]+, tr
characterisation data are in accordance with that previously
reported in the literature.48
(2E,2’E)-3,3’-([1,1’-Biphenyl]-4,4’-diyl)bis(1-(5-bromo-2-
hydroxyphenyl)prop-2-en-1-one)
(60)
A
mixture
of
acetophenone 18 (2.12 g, 9.86 mmol), bialdehyde 12 (1.08 g,
5.14 mmol) and KOH (3.50 g, 62.4 mmol) in absolute EtOH (100
mL) was reacted according to GP-A. The crude residue was
purified by recrystallization from MeOH to afford bichalcone 60
(2.77 g, 89%) as a bright yellow-orange powdery solid. m.p. 258-
260 °C. TLC Rf = 0.65 (CH2Cl2). IR νmax (neat)/cm-1: 2938w (C-H
str), 1738w, 1637s (C=O str), 1563s (C=C str), 1496w, 1465s,
1398m, 1362m, 1335s, 1308m, 1289m, 1279m, 1264m, 1232w,
1179s, 1085w, 1015m, 1003m. 1H NMR (500 MHz, CDCl3): δ 6.97
(2H, d, J 8.8 Hz, ArH), 7.60 (2H, dd, J 9.2, 2.4 Hz, ArH), 7.64 (2H,
d, J 16.0 Hz, 2 × -CH=CHCO-), 7.75 (4H, d, J 8.4 Hz, ArH), 7.81 (4H,
d, J 8.4 Hz, ArH), 8.01 (2H, d, J 15.6 Hz, 2 × -CH=CHCO-), 8.05 (2H,
d, J 2.4 Hz, ArH), 12.76 (2H, s, 2 × OH). 13C NMR (500 MHz,
CDCl3): δ 110.5, 119.6, 120.7, 121.3, 127.7, 129.5, 131.8, 134.0,
139.0, 142.6, 145.8, 162.5, 192.6. LCMS (ES-) m/z = 603.0 ([M-H]-
, tr = 2.42 min). HRMS (ESI-) m/z = 600.9658 [M-H]- found,
C30H19O4Br2+ required 600.9656.
2,2’-(1,3-Phenylene)bis(6-methoxy-4H-chromen-4-one) (28) A
mixture of bichalcone 21 (203 mg, 0.472 mmol) and I2 (30.6 mg,
0.121 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-10% MeOH/CH2Cl2) to afford biflavone 28 (131 mg, 65%)
as a pale yellow-white powdery solid. m.p. >300 °C. TLC Rf = 0.36
(5% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3075w (C-H str), 2834w
(C-H str), 1630s (C=O str), 1611s, 1578m (C=C str), 1565m (C=C
str), 1484s, 1464s, 1434m, 1362s, 1293m, 1281m, 1244m,
1
1205s, 1132w, 1079m, 1023s. H NMR (500 MHz, CDCl3): δ 3.95
(6H, s, 2 × -OCH3), 6.93 (2H, s, 2 × -C=CH), 7.36 (2H, dd, J 9.0, 3.0
Hz, ArH), 7.59 (2H, d, J 9.0 Hz, ArH), 7.63 (2H, d, J 3.0 Hz, ArH),
7.71 (1H, t, J 8.0 Hz, ArH), 8.08 (2H, dd, J 8.0, 2.0 Hz, ArH), 8.49
(1H, t, J 1.5 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ 56.0, 104.9,
107.5, 119.6, 123.9, 124.1, 124.6, 128.9, 129.9, 133.0, 151.1,
157.2, 161.9, 178.2. LCMS (ES+) m/z = 427.2 ([M+H]+, tr = 1.96
+
min). HRMS (ESI+) m/z = 427.1168 [M+H]+ found, C26H19O6
required 427.1176.
(2E,2’E,2’’E)-3,3’,3’’-(Benzene-1,3,5-triyl)tris(1-(2-hydroxy-4-
methoxyphenyl)prop-2-en-1-one) (72) A mixture of 2-hydroxy-
4-methoxyacetophenone 13 (1.56 g, 9.39 mmol), benzene-1,3,5-
tricarbaldehyde 71 (503 mg, 3.10 mmol) and KOH (2.32 g, 41.3
mmol) in absolute EtOH (100 mL) was reacted according to GP-
2,2’-(1,3-Phenylene)bis(5-methoxy-4H-chromen-4-one) (29) A
mixture of bichalcone 22 (307 mg, 0.714 mmol) and I2 (33.8 mg,
0.133 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
10 | J. Name., 2012, 00, 1-3
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(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 29 (237 mg, 78%)
as a white powdery solid. m.p. >300 °C. TLC Rf = 0.55 (10%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3019w (C-H str), 2842w (C-H
str), 1633s (C=O str), 1600s (C=C str), 1568m (C=C str), 1477s,
1459m, 1437m, 1382s, 1316s, 1267s, 1214m, 1191w, 1089s,
as a pale yellow-white powdery solid. m.p. >300 °C. TLC Rf = 0.25
(1% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2919w (C-H str), 2851w
(C-H str), 1738w, 1631s (C=O str), 1602s, 1559m (C=C str),
1478w, 1460s, 1435m, 1354m, 1328w, 1288w, 1245w, 1212w,
1138w, 1119w, 1092w, 1037m. 1H NMR (500 MHz, CDCl3): δ
6.95 (2H, s, 2 × -C=CH), 7.56 (2H, d, J 8.8 Hz, ArH), 7.74 (1H, t, J
8.0 Hz, ArH), 7.86 (2H, dd, J 8.8, 2.4 Hz, ArH), 8.10 (2H, dd, J 8.0,
1.6 Hz, ArH), 8.40 (2H, d, J 2.4 Hz, ArH), 8.46 (1H, br s, ArH). 13C
NMR (500 MHz, CDCl3): δ 108.4, 119.1, 120.1, 124.0, 125.3,
128.5, 129.3, 130.1, 132.7, 137.1, 155.0, 162.3, 176.8. LCMS
(ES+) m/z = 525.0 ([M+H]+, tr = 2.19 min). HRMS (ESI+) m/z =
522.9181 [M+H]+ found, C24H13O4Br2+ required 522.9175.
1
1072m, 1042m, 1026s. H NMR (500 MHz, CDCl3): δ 4.04 (6H, s,
2 × -OCH3), 6.85 (2H, s, 2 × -C=CH), 6.88 (2H, d, J 8.4 Hz, ArH),
7.23 (2H, d, J 8.4 Hz, ArH), 7.62-7.70 (3H, m, ArH), 8.04 (2H, dd, J
8.0, 1.6 Hz, ArH), 8.44 (1H, br s, ArH). 13C NMR (500 MHz, CDCl3):
δ 56.6, 106.7, 109.8, 110.2, 114.6, 123.5, 128.7, 129.8, 132.5,
134.1, 158.3, 159.8, 159.9, 178.2. LCMS (ES+) m/z = 427.1
([M+H]+, tr = 1.49 min). HRMS (ESI+) m/z = 427.1164 [M+H]+
found, C26H19O6+ required 427.1176.
6,6’-(1,3-Phenylene)bis(8H-[1,3]dioxolo[4,5-g]chromen-8-one)
(33) A mixture of bichalcone 26 (167 mg, 0.365 mmol) and I2
(96.7 mg, 0.381 mmol) in DMSO (10 mL) was reacted according
to GP-B. The crude residue was purified by flash column
chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone
33 (46.4 mg, 28%) as a pale yellow-white powdery solid. m.p.
>300 °C. TLC Rf = 0.35 (5% MeOH/CH2Cl2). IR νmax (neat)/cm-1:
3051w (C-H str), 2916w (C-H str), 1739w, 1636s (C=O str), 1611s,
1502w (C=C str), 1457s, 1437m, 1361s, 1252s, 1174m, 1140m,
1032s. 1H NMR (500 MHz, CDCl3): δ 6.16 (4H, s, 2 × -OCH2O-),
6.87 (2H, s, 2 × -C=CH), 7.05 (2H, s, ArH), 7.58 (2H, s, ArH), 7.69
(1H, t, J 8.0 Hz, ArH), 8.03 (2H, dd, J 8.0, 1.6 Hz, ArH), 8.41 (1H,
br s, ArH). 13C NMR (500 MHz, CDCl3): δ 98.1, 102.4, 102.6,
107.8, 119.1, 123.6, 128.6, 129.9, 132.9, 146.5, 153.1, 153.6,
161.5, 177.2. LCMS (ES+) m/z = 455.1 ([M+H]+, tr = 1.67 min).
2,2’-(1,3-Phenylene)bis(6,7-dimethoxy-4H-chromen-4-one) (30)
A mixture of bichalcone 23 (61.6 mg, 0.126 mmol) and I2 (21.1
mg, 0.0831 mmol) in DMSO (10 mL) was reacted according to
GP-B. The crude residue was purified by flash column
chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone
30 (28.3 mg, 46%) as a pale yellow-white powdery solid. m.p.
>300 °C. TLC Rf = 0.38 (5% MeOH/CH2Cl2). IR νmax (neat)/cm-1:
2924w (C-H str), 2837w (C-H str), 1739w, 1627s (C=O str), 1594s
(C=C str), 1507s (C=C str), 1475s, 1456s, 1431s, 1365m, 1346s,
1
1264s, 1217s, 1198s, 1166m, 1081s, 1027w. H NMR (500 MHz,
CDCl3): δ 4.00 (6H, s, 2 × -OCH3), 4.08 (6H, s, 2 × -OCH3), 6.91
(2H, s, 2 × -C=CH), 7.07 (2H, s, ArH), 7.55 (2H, s, ArH), 7.66 (1H, t,
J 7.0 Hz, ArH), 8.03 (2H, dd, J 7.6, 1.2 Hz, ArH), 8.41 (1H, br s,
ArH). 13C NMR (500 MHz, CDCl3): δ 56.4, 56.7, 99.8, 104.2, 107.6,
117.3, 123.4, 128.4, 129.8, 132.8, 147.9, 152.3, 154.8, 161.4,
+
HRMS (ESI+) m/z = 455.0787 [M+H]+ found, C26H15O8 required
177.5. LCMS (ES+) m/z = 487.2 ([M+H]+, tr = 1.57 min). HRMS
455.0767.
+
(ESI+) m/z
=
487.1414 [M+H]+ found, C28H23O8 required
487.1393.
2,2’-(1,4-Phenylene)bis(7-methoxy-4H-chromen-4-one) (46) A
mixture of bichalcone 41 (205 mg, 0.476 mmol) and I2 (93.2 mg,
0.367 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 46 (136 mg, 67%)
as a pale yellow powdery solid. m.p. >300 °C. TLC Rf = 0.32 (5%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3066w (C-H str), 2844w (C-H
str), 1622s (C=O str), 1588s (C=C str), 1502w (C=C str), 1438s,
1421m, 1376m, 1354s, 1301w, 1286m, 1257s, 1238s, 1203m,
1166m, 1129m, 1092m, 1047w, 1019m. 1H NMR (500 MHz,
CDCl3): δ 3.97 (6H, s, 2 × -OCH3), 6.85 (2H, s, 2 × -C=CH), 7.00-
7.03 (4H, m, ArH), 8.06 (4H, s, ArH), 8.15 (2H, d, J 8.5 Hz, ArH).
13C NMR (500 MHz, CDCl3): δ 55.9, 100.5, 108.4, 114.7, 117.8,
126.6, 127.1, 134.4, 158.0, 161.5, 164.4, 177.6. LCMS (ES+) m/z
= 427.1 ([M+H]+, tr = 1.69 min). HRMS (ESI+) m/z = 449.0980
[M+Na]+ found, C26H18O6Na+ required 449.0996.
2,2’-(1,3-Phenylene)bis(5,7-dimethoxy-4H-chromen-4-one) (31)
A mixture of bichalcone 24 (303 mg, 0.618 mmol) and I2 (26.7
mg, 0.105 mmol) in DMSO (10 mL) was reacted according to GP-
B. The crude residue was purified by flash column
chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone
31 (239 mg, 80%) as a pale yellow-white powdery solid. m.p.
288-290 °C. TLC Rf = 0.56 (10% MeOH/CH2Cl2). IR νmax (neat)/cm-
1: 2989w (C-H str), 2948w (C-H str), 1640s (C=O str), 1596s (C=C
str), 1572s (C=C str), 1489m, 1457m, 1424m, 1395w, 1339s,
1273m, 1216m, 1203s, 1162s, 1110s, 1059m, 1034w. 1H NMR
(500 MHz, CDCl3): δ 3.98 (6H, s, 2 × -OCH3), 3.98 (6H, s, 2 × -
OCH3), 6.42 (2H, d, J 2.0 Hz, ArH), 6.68 (2H, d, J 2.0 Hz, ArH), 6.81
(2H, s, 2 × -C=CH), 7.64 (1H, t, J 8.0 Hz, ArH), 8.00 (2H, dd, J 8.0,
2.0 Hz, ArH), 8.37 (1H, t, J 2.0 Hz, ArH). 13C NMR (500 MHz,
CDCl3): δ 56.0, 56.5, 92.9, 96.5, 109.3, 109.6, 123.1, 128.3, 129.7,
132.4, 159.4, 159.9, 160.9, 164.3, 177.5. LCMS (ES+) m/z = 487.2
([M+H]+, tr = 1.72 min). HRMS (ESI+) m/z = 487.1384 [M+H]+
found, C28H23O8+ required 487.1387.
2,2’-(1,4-Phenylene)bis(6-methoxy-4H-chromen-4-one) (47) A
mixture of bichalcone 42 (214 mg, 0.498 mmol) and I2 (70.5 mg,
0.278 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 47 (55.7 mg, 26%)
as a pale yellow-white powdery solid. m.p. >300 °C. TLC Rf = 0.38
(5% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2921w (C-H str), 1737w,
1647s (C=O str), 1615s, 1580m (C=C str), 1510w (C=C str), 1484s,
1459m, 1426m, 1413w, 1359s, 1352s, 1294m, 1258w, 1201s,
2,2’-(1,3-Phenylene)bis(6-bromo-4H-chromen-4-one) (32)
A
mixture of bichalcone 25 (222 mg, 0.421 mmol) and I2 (95.1 mg,
0.375 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 32 (191 mg, 87%)
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ARTICLE
Journal Name
1125m, 1074s, 1048m, 1020s, 1010m. 1H NMR (500 MHz,
CDCl3): δ 3.94 (6H, s, 2 × -OCH3), 6.92 (2H, s, 2 × -C=CH), 7.34
(2H, dd, J 9.6, 2.4 Hz, ArH), 7.56 (2H, d, J 9.6 Hz, ArH), 7.63 (2H,
d, J 2.4 Hz, ArH), 8.10 (4H, s, ArH). 13C NMR (500 MHz, CDCl3): δ
56.0, 104.9, 107.7, 119.6, 124.2, 124.6, 126.8, 134.5, 151.1,
157.2, 161.7, 178.1. LCMS (ES+) m/z = 427.2 ([M+H]+, tr = 1.91
min). These characterisation data are in accordance with that
previously reported in the literature.46
126.9, 128.5, 134.4, 137.1, 155.0, 162.0, 176.8. LCMS (ES+) m/z
= 524.9 ([M+H]+, tr = 2.17 min). These characterisation data are
in accordance with that previously reported in the literature.46
2,2’-([1,1’-Biphenyl]-4,4’-diyl)bis(7-methoxy-4H-chromen-4-
one) (61) A mixture of bichalcone 56 (215 mg, 0.423 mmol) and
I2 (46.8 mg, 0.184 mmol) in DMSO (10 mL) was reacted
according to GP-B. The crude residue was purified by flash
column chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford
biflavone 61 (147 mg, 69%) as a pale yellow-green powdery
solid. m.p. >300 °C. TLC Rf = 0.28 (5% MeOH/CH2Cl2). IR νmax
(neat)/cm-1: 2922w (C-H str), 2849w (C-H str), 1625s (C=O str),
1607s, 1570s (C=C str), 1499m, 1439s, 1405m, 1377s, 1358m,
1319w, 1275m, 1252m, 1199m, 1163s, 1134m, 1091s, 1016m,
1004m. 1H NMR (500 MHz, CDCl3): δ 3.97 (6H, s, 2 × -OCH3), 6.85
(2H, s, 2 × -C=CH), 7.02-7.04 (4H, m, ArH), 7.83 (4H, d, J 8.5 Hz,
ArH), 8.05 (4H, d, J 8.5 Hz, ArH), 8.17 (2H, d, J 9.0 Hz, ArH). 13C
NMR (500 MHz, CDCl3): δ 55.9, 100.5, 107.7, 114.5, 117.9, 126.8,
127.1, 127.7, 131.5, 142.7, 158.0, 162.4, 164.3, 177.8. LCMS
(ES+) m/z = 503.2 ([M+H]+, tr = 1.80 min). HRMS (ESI+) m/z =
503.1506 [M+H]+ found, C32H23O6+ required 503.1489.
2,2’-(1,4-Phenylene)bis(5-methoxy-4H-chromen-4-one) (48) A
mixture of bichalcone 43 (227 mg, 0.526 mmol) and I2 (88.0 mg,
0.347 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 48 (151 mg, 22%)
as a pale yellow-white powdery solid. m.p. >300 °C. TLC Rf = 0.50
(10% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2935w (C-H str), 2842w
(C-H str), 1739w, 1633s (C=O str), 1599s (C=C str), 1513w (C=C
str), 1476s, 1437m, 1417s, 1374s, 1327m, 1286m, 1268s, 1092s,
1
1070m, 1030s, 1011w. H NMR (500 MHz, CDCl3): δ 4.03 (6H, s,
2 × -OCH3), 6.83 (2H, s, 2 × -C=CH), 6.87 (2H, d, J 8.5 Hz, ArH),
7.18 (2H, d, J 8.5 Hz, ArH), 7.62 (2H, t, J 8.5 Hz, ArH), 8.05 (4H, s,
ArH). 13C NMR (500 MHz, CDCl3): δ 56.5, 106.7, 110.0, 110.1,
114.7, 126.6, 134.0, 158.2, 159.7, 159.8, 178.1. LCMS (ES+) m/z
= 427.2 ([M+H]+, tr = 1.53 min). HRMS (ESI+) m/z = 427.1166
[M+H]+ found, C26H19O6+ required 427.1176.
2,2’-([1,1’-Biphenyl]-4,4’-diyl)bis(6-methoxy-4H-chromen-4-
one) (62) A mixture of bichalcone 57 (231 mg, 0.455 mmol) and
I2 (91.4 mg, 0.360 mmol) in DMSO (10 mL) was reacted
according to GP-B. The crude residue was purified by flash
column chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford
biflavone 62 (134 mg, 59%) as a pale yellow-white powdery
solid. m.p. >300 °C. TLC Rf = 0.39 (5% MeOH/CH2Cl2). IR νmax
(neat)/cm-1: 3066w (C-H str), 2937w (C-H str), 1736w, 1635s
(C=O str), 1615s, 1576s (C=C str), 1483s, 1452w, 1434m, 1405m,
1361s, 1320m, 1287m, 1252m, 1205m, 1127m, 1079s, 1049m,
2,2’-(1,4-Phenylene)bis(5,7-dimethoxy-4H-chromen-4-one) (49)
A mixture of bichalcone 44 (212 mg, 0.432 mmol) and I2 (77.4
mg, 0.305 mmol) in DMSO (10 mL) was reacted according to GP-
B. The crude residue was purified by flash column
chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone
49 (107 mg, 51%) as a pale yellow-white powdery solid. m.p.
>300 °C. TLC Rf = 0.44 (10% MeOH/CH2Cl2). IR νmax (neat)/cm-1:
2981w (C-H str), 2844w (C-H str), 1633s (C=O str), 1588s (C=C
str), 1566s (C=C str), 1491m, 1462m, 1418s, 1346s, 1292m,
1
1014m, 1002w. H NMR (500 MHz, CDCl3): δ 3.94 (6H, s, 2 × -
OCH3), 6.90 (2H, s, 2 × -C=CH), 7.33 (2H, d, J 8.8 Hz, ArH), 7.56
(2H, d, J 9.2 Hz, ArH), 7.63 (2H, s, ArH), 7.83 (4H, d, J 8.0 Hz,
ArH), 8.06 (4H, d, J 8.0 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ
56.0, 104.9, 107.0, 119.5, 123.9, 124.6, 126.9, 127.7, 131.5,
142.7, 151.1, 157.1, 162.6, 178.3. LCMS (ES+) m/z = 503.2
([M+H]+, tr = 1.94 min). HRMS (ESI+) m/z = 503.1470 [M+H]+
found, C32H23O6+ required 503.1489.
1
1264w, 1216m, 1202s, 1162s, 1117s, 1107s, 1058m, 1029w. H
NMR (500 MHz, CDCl3): δ 3.95 (6H, s, 2 × -OCH3), 3.99 (6H, s, 2 ×
-OCH3), 6.42 (2H, d, J 2.0 Hz, ArH), 6.62 (2H, d, J 2.0 Hz, ArH),
6.77 (2H, s, 2 × -C=CH), 8.02 (4H, s, ArH). 13C NMR (500 MHz,
CDCl3): δ 55.8, 56.5, 92.9, 96.4, 109.4, 109.9, 126.4, 134.0, 159.3,
159.9, 161.0, 164.3, 177.4. LCMS (ES+) m/z = 487.1 ([M+H]+, tr =
+
1.53 min). HRMS (ESI+) m/z = 487.1376 [M+H]+ found, C28H23O8
2,2’-([1,1’-Biphenyl]-4,4’-diyl)bis(5-methoxy-4H-chromen-4-
one) (63) A mixture of bichalcone 58 (206 mg, 0.407 mmol) and
I2 (12.8 mg, 0.0504 mmol) in DMSO (10 mL) was reacted
according to GP-B. The crude residue was purified by flash
column chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford
biflavone 63 (162 mg, 79%) as a pale yellow powdery solid. m.p.
>300 °C. TLC Rf = 0.50 (10% MeOH/CH2Cl2). IR νmax (neat)/cm-1:
3020w (C-H str), 2843w (C-H str), 1631s (C=O str), 1601s, 1573m
(C=C str), 1498w, 1476s, 1459m, 1438m, 1405m, 1377s, 1330w,
1309s, 1269s, 1094s, 1071m, 1036m, 1018m, 1000w. 1H NMR
(500 MHz, CDCl3): δ 4.03 (6H, s, 2 × -OCH3), 6.81 (2H, s, 2 × -
C=CH), 6.86 (2H, d, J 8.0 Hz, ArH), 7.18 (2H, dd, J 8.5, 1.0 Hz,
ArH), 7.61 (2H, t, J 8.5 Hz, ArH), 7.80 (4H, d, J 8.5 Hz, ArH), 8.02
(4H, d, J 8.5 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ 56.5, 106.5,
109.2, 110.2, 114.6, 126.7, 127.6, 131.1, 133.8, 142.6, 158.3,
159.8, 160.5, 178.3. LCMS (ES+) m/z = 503.2 ([M+H]+, tr = 1.64
required 487.1387.
2,2’-(1,4-Phenylene)bis(6-bromo-4H-chromen-4-one) (50)
A
mixture of bichalcone 45 (221 mg, 0.418 mmol) and I2 (97.9 mg,
0.386 mmol) in DMSO (10 mL) was reacted according to GP-B.
The crude residue was purified by flash column chromatography
(SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone 50 (191 mg, 87%)
as a pale yellow-white powdery solid. m.p. >300 °C. TLC Rf = 0.40
(3% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3039w (C-H str), 2922w
(C-H str), 1738w, 1629s (C=O str), 1600s, 1564m (C=C str),
1515m (C=C str), 1461m, 1438s, 1355m, 1328w, 1295w, 1252m,
1213w, 1133m, 1094w, 1042s, 1014w. 1H NMR (500 MHz,
CDCl3): δ 6.94 (2H, s, 2 × -C=CH), 7.53 (2H, d, J 8.8 Hz, ArH), 7.84
(2H, dd, J 8.8, 2.4 Hz, ArH), 8.10 (4H, s, ArH), 8.40 (2H, d, J 2.0 Hz,
ArH). 13C NMR (500 MHz, CDCl3): δ 108.6, 119.0, 120.1, 125.3,
12 | J. Name., 2012, 00, 1-3
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+
min). HRMS (ESI+) m/z = 503.1485 [M+H]+ found, C32H23O6
Synthesis of biaurones and triaurone
required 503.1489.
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(6-
methoxybenzofuran-3(2H)-one) (34) A mixture of bichalcone 20
(102 mg, 0.237 mmol) and Hg(OAc)2 (151 mg, 0.474 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2, 1%
MeOH/CH2Cl2) to afford biaurone 34 (27.0 mg, 27%) as a pale
yellow-white powdery solid. m.p. 228-230 °C. TLC Rf = 0.25 (1%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2919w (C-H str), 2842w (C-H
str), 1700m (C=O str), 1651m (C=C str), 1591s (C=C str), 1498m,
1440s, 1339m, 1324m, 1265s, 1193m, 1150s, 1124s, 1112s,
1093s, 1018m. 1H NMR (500 MHz, CDCl3): δ 3.98 (6H, s, 2 × -
OCH3), 6.80 (2H, dd, J 8.4, 2.0 Hz, ArH), 6.87 (2H, d, J 2.0 Hz,
ArH), 6.89 (2H, s, 2 × -C=CH), 7.55 (1H, t, J 7.6 Hz, ArH), 7.75 (2H,
d, J 8.8 Hz, ArH), 7.94 (2H, dd, J 8.0, 1.6 Hz, ArH), 8.45 (1H, br s,
ArH). 13C NMR (500 MHz, CDCl3): δ 56.1, 96.7, 111.1, 112.4,
114.7, 126.0, 129.4, 132.0, 133.1, 134.0, 148.2, 167.7, 168.7,
2,2’-([1,1’-Biphenyl]-4,4’-diyl)bis(5,7-dimethoxy-4H-chromen-4-
one) (64) A mixture of bichalcone 59 (201 mg, 0.355 mmol) and
I2 (57.0 mg, 0.225 mmol) in DMSO (10 mL) was reacted
according to GP-B. The crude residue was purified by flash
column chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford
biflavone 64 (138 mg, 69%) as a pale yellow-white powdery
solid. m.p. >300 °C. TLC Rf = 0.46 (10% MeOH/CH2Cl2). IR νmax
(neat)/cm-1: 2915w (C-H str), 2837w (C-H str), 1635s (C=O str),
1603s, 1571s (C=C str), 1491m, 1458m, 1420w, 1404w, 1348s,
1315s, 1271m, 1215s, 1202m, 1159s, 1116s, 1056s, 1034w,
1002w. 1H NMR (500 MHz, CDCl3): δ 3.95 (6H, s, 2 × -OCH3), 3.99
(6H, s, 2 × -OCH3), 6.42 (2H, s, ArH), 6.62 (2H, s, ArH), 6.76 (2H, s,
2 × -C=CH), 7.80 (4H, d, J 8.0 Hz, ArH), 8.00 (4H, d, J 8.0 Hz, ArH).
13C NMR (500 MHz, CDCl3): δ 55.8, 56.5, 92.9, 96.2, 109.2, 109.4,
126.6, 127.6, 131.1, 142.5, 159.9, 160.1, 161.0, 164.1, 177.5.
LCMS (ES+) m/z = 563.2 ([M+H]+, tr = 1.85 min). HRMS (ESI+) m/z
= 563.1691 [M+H]+ found, C34H27O8+ required 563.1700.
183.0. LCMS (ES+) m/z = 427.1 ([M+H]+, tr = 1.89 min). HRMS
+
(ESI+) m/z
=
427.1183 [M+H]+ found, C26H19O6 required
427.1176.
2,2’-([1,1’-Biphenyl]-4,4’-diyl)bis(6-bromo-4H-chromen-4-one)
(65) A mixture of bichalcone 60 (203 mg, 0.335 mmol) and I2
(55.2 mg, 0.217 mmol) in DMSO (10 mL) was reacted according
to GP-B. The crude residue was purified by flash column
chromatography (SiO2, 1-5% MeOH/CH2Cl2) to afford biflavone
65 (92.0 mg, 46%) as a pale yellow-green powdery solid. m.p.
>300 °C. TLC Rf = 0.39 (5% MeOH/CH2Cl2). IR νmax (neat)/cm-1:
2955w (C-H str), 2868w (C-H str), 1731w, 1636s (C=O str), 1607s,
1567s (C=C str), 1549m (C=C str), 1496m, 1461s, 1430s, 1350s,
1316s, 1277w, 1232w, 1156m, 1137w, 1040w, 1002w. 1H NMR
(500 MHz, CDCl3): δ 6.92 (2H, s, 2 × -C=CH), 7.53 (2H, d, J 8.8 Hz,
ArH), 7.81-7.85 (6H, m, ArH), 8.06 (4H, d, J 8.0 Hz, ArH), 8.40 (2H,
d, J 2.4 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ 107.8, 118.8,
120.0, 125.4, 127.0, 127.8, 128.5, 131.1, 136.9, 143.0, 155.0,
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(5-
methoxybenzofuran-3(2H)-one) (35) A mixture of bichalcone 21
(202 mg, 0.470 mmol) and Hg(OAc)2 (303 mg, 0.949 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by recrystallization from CHCl3 to afford
biaurone 35 (117 mg, 58%) as a bright yellow powdery solid.
m.p. 278-280 °C. TLC Rf = 0.34 (0.5% MeOH/CH2Cl2). IR νmax
(neat)/cm-1: 3076w (C-H str), 2837w (C-H str), 1706s (C=O str),
1648s (C=C str), 1600s (C=C str), 1489s, 1434m, 1318m, 1297m,
1276s, 1253w, 1196s, 1182m, 1172m, 1115s, 1020s. 1H NMR
(500 MHz, CDCl3): δ 3.87 (6H, s, 2 × -OCH3), 6.94 (2H, s, 2 × -
C=CH), 7.26-7.31 (6H, m, ArH, overlain by CDCl3), 7.57 (1H, t, J
7.6 Hz, ArH), 7.97 (2H, d, J 7.6 Hz, ArH), 8.43 (1H, br s, ArH). 13C
NMR (500 MHz, CDCl3): δ 56.0, 105.4, 112.2, 113.8, 121.7, 126.5,
129.5, 132.5, 133.1, 134.3, 148.1, 156.2, 161.4, 185.0. LCMS
(ES+) m/z = 427.2 ([M+H]+, tr = 2.01 min). HRMS (ESI+) m/z =
427.1162 [M+H]+ found, C26H19O6+ required 427.1176.
163.0, 177.0. LCMS (ES+) m/z = 601.0 ([M+H]+, tr = 2.22 min).
+
HRMS (ESI+) m/z
=
598.9488 [M+H]+ found, C30H17Br2O4
required 598.9494.
2,2’,2’’-(Benzene-1,3,5-triyl)tris(7-methoxy-4H-chromen-4-one)
(73) A mixture of trichalcone 72 (205 mg, 0.338 mmol) and I2
(88.4 mg, 0.348 mmol) in DMSO (10 mL) was reacted according
to GP-B. The crude residue was purified by flash column
chromatography (SiO2, 1-10% MeOH/CHCl3) to afford triflavone
73 (57.6 mg, 28%) as a pale yellow powdery solid. m.p. >300 °C.
TLC Rf = 0.38 (3% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3076w (C-H
str), 2932w (C-H str), 2842w (C-H str), 1739w, 1625s (C=O str),
1603s, 1503m (C=C str), 1436s, 1371s, 1354s, 1275m, 1262m,
1236m, 1199m, 1160s, 1129m, 1087s, 1020m. 1H NMR (500
MHz, CDCl3): δ 4.05 (9H, s, 3 × -OCH3), 7.06-7.09 (6H, m, 3 × -
C=CH and ArH), 7.14 (3H, d, J 2.4 Hz, ArH), 8.19 (3H, d, J 8.8 Hz,
ArH), 8.60 (3H, s, ArH). 13C NMR (500 MHz, CDCl3): δ 56.2, 100.2,
108.8, 115.6, 117.7, 125.7, 127.1, 133.9, 158.1, 160.5, 164.8,
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(4-
methoxybenzofuran-3(2H)-one) (36) A mixture of bichalcone 22
(207 mg, 0.480 mmol) and Hg(OAc)2 (319 mg, 0.999 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2,
0.5% MeOH/CH2Cl2) to afford biaurone 36 (172 mg, 84%) as a
bright yellow powdery solid. m.p. 248-250 °C. TLC Rf = 0.45 (2%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2938w (C-H str), 2840w (C-H
str), 1702s (C=O str), 1643s (C=C str), 1594s (C=C str), 1491s,
1422m, 1348m, 1324m, 1284m, 1250s, 1213w, 1158w, 1136w,
1076s, 1061s. 1H NMR (500 MHz, CDCl3): δ 4.03 (6H, s, 2 × -
OCH3), 6.66 (2H, d, J 8.4 Hz, ArH), 6.89 (2H, s, 2 × -C=CH), 6.95
(2H, d, J 8.0 Hz, ArH), 7.53 (1H, t, J 8.0 Hz, ArH), 7.62 (2H, d, J 8.0
Hz, ArH), 7.92 (2H, dd, J 8.0, 1.6 Hz, ArH), 8.42 (1H, br s, ArH). 13
C
177.6. LCMS (ES+) m/z = 601.1 ([M+H]+, tr = 2.00 min). HRMS
NMR (500 MHz, CDCl3): δ 56.3, 104.8, 105.3, 110.8, 111.1, 129.3,
132.1, 133.1, 133.9, 138.6, 147.2, 158.6, 167.1, 182.4. LCMS
(ES+) m/z = 427.1 ([M+H]+, tr = 1.80 min). HRMS (ESI+) m/z =
427.1164 [M+H]+ found, C26H19O6+ required 427.1176.
+
(ESI+) m/z
=
601.1477 [M+H]+ found, C36H25O9 required
601.1493.
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ARTICLE
Journal Name
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(5,6-
(6Z,6’Z)-6,6’-(1,3-
dimethoxybenzofuran-3(2H)-one) (37) A mixture of bichalcone
23 (95.6 mg, 0.195 mmol) and Hg(OAc)2 (142 mg, 0.446 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2,
0.5% MeOH/CH2Cl2) to afford biaurone 37 (42.0 mg, 44%) as a
bright yellow powdery solid. m.p. >300 °C. TLC Rf = 0.40 (3%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2937w (C-H str), 2835w (C-H
str), 1687m (C=O str), 1647m (C=C str), 1605s (C=C str), 1496s,
1477s, 1437s, 1328m, 1278s, 1240m, 1221s, 1192s, 1130s,
Phenylenebis(methanylylidene))bis([1,3]dioxolo[4,5-
f]benzofuran-7(6H)-one) (40) A mixture of bichalcone 26 (105
mg, 0.229 mmol) and Hg(OAc)2 (150 mg, 0.470 mmol) in pyridine
(10 mL) was reacted according to GP-C. The crude residue was
purified by flash column chromatography (SiO2, 0.5%
MeOH/CH2Cl2) and recrystallized from CHCl3 to afford biaurone
40 (10.2 mg, 10%) as a bright yellow powdery solid. m.p. >300
°C. TLC Rf = 0.38 (1% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3051w
(C-H str), 2917w (C-H str), 1702m (C=O str), 1652m, 1615s (C=C
str), 1488m, 1460s, 1325w, 1300m, 1280m, 1228w, 1189w,
1178m, 1115s, 1034m. 1H NMR (500 MHz, DMSO-d6): δ 6.23
(4H, s, 2 × -OCH2O-), 6.87 (2H, s, 2 × -C=CH), 7.21 (2H, s, ArH),
7.25 (2H, s, ArH), 7.63 (1H, t, J 8.0 Hz, ArH), 8.04 (2H, dd, J 8.0,
1.6 Hz, ArH), 8.39 (1H, br s, ArH). 13C NMR (500 MHz, DMSO-d6):
δ 94.9, 101.2, 103.3, 110.5, 113.7, 129.7, 132.1, 132.7, 145.3,
147.9, 156.2, 156.3, 164.4, 181.9. LCMS (ES+) m/z = 455.1
([M+H]+, tr = 2.02 min). HRMS (ESI+) m/z = 455.0763 [M+H]+
found, C26H15O8+ required 455.0761.
1
1103s, 1027w, 1001m. H NMR (500 MHz, CDCl3): δ 3.93 (6H, s,
2 × -OCH3), 4.06 (6H, s, 2 × -OCH3), 6.89 (2H, s, 2 × -C=CH), 6.90
(2H, s, ArH), 7.20 (2H, s, ArH), 7.53 (1H, t, J 7.6 Hz, ArH), 7.95
(2H, dd, J 7.6, 1.2 Hz, ArH), 8.36 (1H, br s, ArH). 13C NMR (500
MHz, CDCl3): δ 56.4, 56.8, 95.7, 104.1, 111.2, 112.9, 129.4,
131.9, 133.1, 134.3, 146.7, 148.3, 157.9, 163.6, 183.5. LCMS
(ES+) m/z = 487.3 ([M+H]+, tr = 1.79 min). HRMS (ESI+) m/z =
487.1371 [M+H]+ found, C28H23O8+ required 487.1387.
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(4,6-
dimethoxybenzofuran-3(2H)-one) (38) A mixture of bichalcone
24 (105 mg, 0.213 mmol) and Hg(OAc)2 (134 mg, 0.421 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2, 1%
MeOH/CH2Cl2) to afford biaurone 38 (62.1 mg, 60%) as a pale
yellow-white powdery solid. m.p. 296-298 °C. TLC Rf = 0.45 (5%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2938w (C-H str), 2842w (C-H
str), 1697m (C=O str), 1650w (C=C str), 1588s (C=C str), 1503m
(C=C str), 1468m, 1423m, 1363w, 1346m, 1241m, 1215s, 1154s,
1087s, 1037w. 1H NMR (500 MHz, CDCl3): δ 3.96 (6H, s, 2 × -
OCH3), 3.98 (6H, s, 2 × -OCH3), 6.17 (2H, d, J 1.6 Hz, ArH), 6.49
(2H, d, J 1.6 Hz, ArH), 6.83 (2H, s, 2 × -C=CH), 7.50 (1H, t, J 8.0 Hz,
ArH), 7.88 (2H, dd, J 7.6, 1.2 Hz, ArH), 8.39 (1H, br s, ArH). 13C
NMR (500 MHz, CDCl3): δ 56.2, 56.3, 89.4, 94.2, 105.2, 110.1,
129.2, 131.6, 133.2, 133.7, 148.2, 159.5, 169.2, 180.7. LCMS
(ES+) m/z = 487.1 ([M+H]+, tr = 1.75 min). These characterisation
data are in accordance with that previously reported in the
literature.49
(2Z,2’Z)-2,2’-(1,4-Phenylenebis(methanylylidene))bis(6-
methoxybenzofuran-3(2H)-one) (51) A mixture of bichalcone 41
(49.4 mg, 0.115 mmol) and Hg(OAc)2 (84.4 mg, 0.265 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2, 1%
MeOH/CH2Cl2) to afford biaurone 51 (47.0 mg, 95%) as a bright
yellow-orange powdery solid. m.p. 288-290 °C. TLC Rf = 0.55 (1%
MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2941w (C-H str), 2848w (C-H
str), 1693m (C=O str), 1642m (C=C str), 1605s (C=C str), 1585s
(C=C str), 1498m, 1440m, 1350m, 1323w, 1296w, 1267s, 1192m,
1116s, 1093s, 1015m. 1H NMR (500 MHz, CDCl3): δ 3.95 (6H, s, 2
× -OCH3), 6.76-6.79 (4H, m, ArH), 6.81 (2H, s, 2 × -C=CH), 7.72
(2H, d, J 8.4 Hz, ArH), 7.95 (4H, s, ArH). 13C NMR (500 MHz,
CDCl3): δ 56.1, 96.7, 110.9, 112.2, 114.7, 125.9, 131.6, 133.5,
148.4, 167.6, 168.5, 182.8. LCMS (ES+) m/z = 427.0 ([M+H]+, tr =
5.25 min). HRMS (ESI+) m/z = 427.1178 [M+H]+ found, C26H19O6
+
required 427.1176.
(2Z,2’Z)-2,2’-(1,4-Phenylenebis(methanylylidene))bis(5-
(2Z,2’Z)-2,2’-(1,3-Phenylenebis(methanylylidene))bis(5-
methoxybenzofuran-3(2H)-one) (52) A mixture of bichalcone 42
(106 mg, 0.245 mmol) and Hg(OAc)2 (153 mg, 0.481 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by flash column chromatography (SiO2, 1%
MeOH/CH2Cl2) and recrystallized from MeOH to afford biaurone
52 (79.0 mg, 76%) as a bright orange powdery solid. m.p. >300
°C. TLC Rf = 0.47 (1% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3072w
(C-H str), 2950w (C-H str), 1704s (C=O str), 1647s, 1620w (C=C
str), 1599s (C=C str), 1489s, 1435m, 1421m, 1322m, 1281m,
1190m, 1164m, 1129m, 1110s, 1098s, 1023s. 1H NMR (500 MHz,
CDCl3): δ 3.87 (6H, s, 2 × -OCH3), 6.90 (2H, s, 2 × -C=CH), 7.25
(2H, t, J 2.0 Hz, ArH), 7.29 (4H, t, J 1.2 Hz, ArH), 8.01 (4H, s, ArH).
13C NMR (500 MHz, CDCl3): δ 56.0, 105.4, 112.0, 113.8, 126.4,
131.8, 146.1, 147.3, 148.3, 156.2, 161.2, 184.9. LCMS (ES+) m/z
= 427.1 ([M+H]+, tr = 1.96 min). HRMS (ESI+) m/z = 426.1111
[M+H]+ found, C26H19O6+ required 426.1098.
bromobenzofuran-3(2H)-one) (39) A mixture of bichalcone 25
(203 mg, 0.384 mmol) and Hg(OAc)2 (265 mg, 0.832 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by recrystallization from CHCl3 to afford
biaurone 39 (173 mg, 86%) as a pale yellow-brown powdery
solid. m.p. >300 °C. TLC Rf = 0.27 (CH2Cl2). IR νmax (neat)/cm-1:
3066w (C-H str), 1713s (C=O str), 1649s, 1602s (C=C str), 1596s
(C=C str), 1456s, 1424m, 1336w, 1291m, 1259s, 1193m, 1180s,
1171s, 1134m, 1116s, 1052w. 1H NMR (500 MHz, CDCl3): δ 6.98
(2H, s, 2 × -C=CH), 7.31 (2H, d, J 8.8 Hz, ArH), 7.59 (1H, t, J 8.0 Hz,
ArH), 7.81 (2H, dd, J 8.8, 2.0 Hz, ArH), 7.97 (2H, d, J 2.0 Hz, ArH),
8.00 (2H, dd, J 8.0, 1.2 Hz, ArH), 8.40 (1H, br s, ArH). 13C NMR
(500 MHz, CDCl3): δ 113.1, 114.7, 116.6, 123.2, 127.5, 129.6,
132.8, 132.9, 134.6, 139.7, 147.2, 164.8, 183.3. LCMS (ES+) m/z
= 525.1 ([M+H]+, tr = 2.30 min). HRMS (ESI+) m/z = 522.9162
[M+H]+ found, C24H13O4Br2+ required 522.9181.
14 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7OB00804J
ARTICLE
(2Z,2’Z)-2,2’-(1,4-Phenylenebis(methanylylidene))bis(4-
according to GP-C. The crude residue was purified by flash
column chromatography (SiO2, 0.5% MeOH/CH2Cl2) and
recrystallized from CHCl3 to afford biaurone 66 (45.7 mg, 30%)
as a bright yellow-orange powdery solid. m.p. 264-266 °C. TLC Rf
= 0.44 (1% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2921w (C-H str),
2835w (C-H str), 1688m (C=O str), 1644m, 1589s (C=C str),
1551m (C=C str), 1495m (C=C str), 1443m, 1347w, 1321m,
1271m, 1191m, 1129s, 1112s, 1099s, 1014m, 1003m. 1H NMR
(500 MHz, CDCl3): δ 3.96 (6H, s, 2 × -OCH3), 6.78-6.82 (4H, m,
ArH), 6.88 (2H, s, 2 × -C=CH), 7.73-7.76 (6H, m, ArH), 8.01 (4H, d,
J 8.4 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ 56.1, 96.7, 111.3,
112.2, 114.9, 125.9, 127.4, 131.9, 132.0, 141.1, 148.1, 167.5,
168.5, 182.9. LCMS (ES+) m/z = 503.2 ([M+H]+, tr = 2.11 min).
methoxybenzofuran-3(2H)-one) (53) A mixture of bichalcone 43
(202 mg, 0.470 mmol) and Hg(OAc)2 (309 mg, 0.969 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by recrystallization from CHCl3 to afford
biaurone 53 (199 mg, 99%) as a bright yellow-orange powdery
solid. m.p. >300 °C. TLC Rf = 0.21 (1% MeOH/CH2Cl2). IR νmax
(neat)/cm-1: 2968w (C-H str), 2840w (C-H str), 1698s (C=O str),
1652s, 1594s (C=C str), 1509w (C=C str), 1495s (C=C str), 1458w,
1355w, 1300w, 1280w, 1251s, 1165m, 1073s. 1H NMR (500
MHz, CDCl3): δ 4.03 (6H, s, 2 × -OCH3), 6.66 (2H, d, J 8.4 Hz, ArH),
6.86 (2H, s, 2 × -C=CH), 6.92 (2H, d, J 8.0 Hz, ArH), 7.61 (2H, t, J
8.0 Hz, ArH), 7.99 (4H, s, ArH). 13C NMR (500 MHz, CDCl3): δ
56.3, 104.8, 105.4, 110.8, 111.0, 131.6, 133.6, 138.6, 147.5,
158.6, 167.0, 182.3. LCMS (ES+) m/z = 427.1 ([M+H]+, tr = 1.83
+
HRMS (ESI+) m/z = 503.1487 [M+H]+ found, C32H23O6 required
503.1489.
min). HRMS (ESI+) m/z = 427.1165 [M+H]+ found, C26H19O6
+
required 427.1176.
(2Z,2’Z)-2,2’-([1,1’-Biphenyl]-4,4’-
diylbis(methanylylidene))bis(5-methoxybenzofuran-3(2H)-one)
(67) A mixture of bichalcone 57 (206 mg, 0.406 mmol) and
Hg(OAc)2 (265 mg, 0.832 mmol) in pyridine (10 mL) was reacted
according to GP-C. The crude residue was purified by
recrystallization from CHCl3 to afford biaurone 67 (128 mg, 63%)
as a bright yellow-orange powdery solid. m.p. 284-286 °C. TLC Rf
= 0.56 (0.5% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3072w (C-H str),
2948w (C-H str), 1705s (C=O str), 1645s, 1597s (C=C str), 1491s
(C=C str), 1437w, 1317m, 1282m, 1201s, 1162m, 1122m, 1112s,
1102m, 1025m, 1004w. 1H NMR (500 MHz, CDCl3): δ 3.87 (6H, s,
2 × -OCH3), 6.95 (2H, s, 2 × -C=CH), 7.26-7.30 (6H, m, ArH), 7.77
(4H, d, J 8.4 Hz, ArH), 8.04 (4H, d, J 8.4 Hz, ArH). 13C NMR (500
MHz, CDCl3): δ 56.0, 105.3, 112.5, 113.8, 121.8, 126.3, 127.4,
132.0, 132.1, 141.3, 148.0, 156.2, 161.2, 184.9. LCMS (ES+) m/z
= 503.2 ([M+H]+, tr = 2.18 min). HRMS (ESI+) m/z = 525.1293
[M+Na]+ found, C32H22O6Na+ required 525.1309.
(2Z,2’Z)-2,2’-(1,4-Phenylenebis(methanylylidene))bis(4,6-
dimethoxybenzofuran-3(2H)-one) (54) A mixture of bichalcone
44 (204 mg, 0.415 mmol) and Hg(OAc)2 (283 mg, 0.888 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by recrystallization from CHCl3 to afford
biaurone 54 (181 mg, 90%) as a bright yellow powdery solid.
m.p. >300 °C. TLC Rf = 0.30 (3% MeOH/CH2Cl2). IR νmax (neat)/cm-
1: 2999w (C-H str), 2843w (C-H str), 1694m (C=O str), 1647w,
1609s (C=C str), 1590s (C=C str), 1502w (C=C str), 1466w, 1428w,
1362m, 1327w, 1248m, 1211s, 1153s, 1085s, 1038w. 1H NMR
(500 MHz, CDCl3): δ 3.95 (6H, s, 2 × -OCH3), 3.98 (6H, s, 2 × -
OCH3), 6.17 (2H, d, J 1.6 Hz, ArH), 6.43 (2H, d, J 1.6 Hz, ArH), 6.79
(2H, s, 2 × -C=CH), 7.94 (4H, s, ArH). 13C NMR (500 MHz, CDCl3): δ
56.2, 56.3, 89.3, 94.1, 105.2, 110.0, 131.4, 133.5, 148.4, 159.5,
169.0, 169.1, 180.5. LCMS (ES+) m/z = 487.2 ([M+H]+, tr = 1.75
min). These characterisation data are in accordance with that
previously reported in the literature.49
(2Z,2’Z)-2,2’-([1,1’-Biphenyl]-4,4’-
diylbis(methanylylidene))bis(4-methoxybenzofuran-3(2H)-one)
(68) A mixture of bichalcone 58 (100 mg, 0.197 mmol) and
Hg(OAc)2 (137 mg, 0.428 mmol) in pyridine (10 mL) was reacted
according to GP-C. The crude residue was purified by flash
column chromatography (SiO2, 1% MeOH/CH2Cl2) and
recrystallized from MeOH to afford biaurone 68 (88.5 mg, 89%)
as a bright yellow powdery solid. m.p. 298-300 °C. TLC Rf = 0.37
(2% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 2944w (C-H str), 2841w
(C-H str), 1698m (C=O str), 1648m, 1594s (C=C str), 1492s (C=C
str), 1439w, 1353w, 1317m, 1281m, 1251s, 1197m, 1163m,
1074s, 1002w. 1H NMR (500 MHz, CDCl3): δ 4.04 (6H, s, 2 × -
OCH3), 6.66 (2H, d, J 8.0 Hz, ArH), 6.90 (2H, s, 2 × -C=CH), 6.93
(2H, d, J 8.0 Hz, ArH), 7.61 (2H, t, J 8.0 Hz, ArH), 7.75 (4H, d, J 8.4
Hz, ArH), 8.01 (4H, d, J 8.4 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ
56.3, 104.8, 105.2, 110.9, 111.4, 127.4, 131.9, 132.1, 138.4,
141.1, 147.1, 158.6, 167.0, 182.3. LCMS (ES+) m/z = 503.2
([M+H]+, tr = 1.91 min). HRMS (ESI+) m/z = 503.1486 [M+H]+
found, C32H23O6+ required 503.1489.
(2Z,2’Z)-2,2’-(1,4-Phenylenebis(methanylylidene))bis(5-
bromobenzofuran-3(2H)-one) (55) A mixture of bichalcone 45
(208 mg, 0.393 mmol) and Hg(OAc)2 (266 mg, 0.835 mmol) in
pyridine (10 mL) was reacted according to GP-C. The crude
residue was purified by recrystallization from CHCl3 to afford
biaurone 55 (90.5 mg, 44%) as a bright orange powdery solid.
m.p. >300 °C. TLC Rf = 0.40 (PE/CH2Cl2; 2:1). IR νmax (neat)/cm-1:
3081w (C-H str), 1702s (C=O str), 1639s, 1591s (C=C str), 1509w
(C=C str), 1449s, 1422m, 1347w, 1293m, 1259s, 1196m, 1174s,
1
1132m, 1110s, 1046w. H NMR (500 MHz, CDCl3): δ 6.94 (2H, s,
2 × -C=CH), 7.29 (2H, s, ArH), 7.79 (2H, dd, J 8.8, 2.0 Hz, ArH),
7.96 (2H, d, J 2.0 Hz, ArH), 8.01 (4H, s, ArH). 13C NMR (500 MHz,
CDCl3): δ 112.9, 114.7, 116.6, 123.2, 127.5, 132.0, 133.6, 139.6,
147.5, 164.7, 183.1. LCMS (ES-) m/z = 523.9 ([M-H]-, tr = 2.28
min). HRMS (ESI+) m/z = 522.9180 [M+H]+ found, C24H13O4Br2
+
required 522.9181.
(2Z,2’Z)-2,2’-([1,1’-Biphenyl]-4,4’-
diylbis(methanylylidene))bis(6-methoxybenzofuran-3(2H)-one)
(66) A mixture of bichalcone 56 (153 mg, 0.302 mmol) and
Hg(OAc)2 (208 mg, 0.653 mmol) in pyridine (10 mL) was reacted
(2Z,2’Z)-2,2’-([1,1’-Biphenyl]-4,4’-
diylbis(methanylylidene))bis(4,6-dimethoxybenzofuran-3(2H)-
one) (69) A mixture of bichalcone 59 (102 mg, 0.180 mmol) and
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DOI: 10.1039/C7OB00804J
ARTICLE
Journal Name
Hg(OAc)2 (114 mg, 0.359 mmol) in pyridine (10 mL) was reacted
according to GP-C. The crude residue was purified by flash
column chromatography (SiO2, 0.5% MeOH/CH2Cl2) to afford
biaurone 69 (45.0 mg, 44%) as a bright yellow powdery solid.
m.p. >300 °C. TLC Rf = 0.24 (3% MeOH/CH2Cl2). IR νmax (neat)/cm-
1: 3004w (C-H str), 2841w (C-H str), 1694m (C=O str), 1648m,
1587s (C=C str), 1500m (C=C str), 1457m, 1416w, 1360m,
1330m, 1255s, 1208s, 1146s, 1084s, 1037m, 1002w. 1H NMR
(500 MHz, CDCl3): δ 3.95 (6H, s, 2 × -OCH3), 3.98 (6H, s, 2 × -
OCH3), 6.17 (2H, d, J 1.6 Hz, ArH), 6.44 (2H, d, J 1.6 Hz, ArH), 6.83
(2H, s, 2 × -C=CH), 7.73 (4H, d, J 8.4 Hz, ArH), 7.98 (2H, d, J 8.4
Hz, ArH). 13C NMR (500 MHz, CDCl3): δ 56.2, 56.3, 89.3, 94.1,
105.3, 110.2, 127.3, 131.7, 132.2, 140.9, 148.1, 159.5, 169.0,
180.6. LCMS (ES+) m/z = 563.1 ([M+H]+, tr = 1.87 min). These
characterisation data are in accordance with that previously
reported in the literature.49
Aβ preparation
Aβ42 was prepared as previously described.33 Briefly, Aβ42 (1 mg)
was purchased from Eurogentec Ltd as a lyophilised powder. The
peptide was dissolved in trifluroacetic acid (TFA,
1 mL),
sonicated in an ice-water bath for 60 sec, then lyophilised. Ice
cold 1,1,1,3,3,3-hexafluro-2-propanol (HFIP, 1 mL) was added to
re-suspend the peptide. The sample was sonicated for 60 sec at
0 °C, then aliquoted into 20 µL portions. The HFIP was removed
in the vacuum desiccator overnight and the lyophilised samples
were stored at -80 °C until use. The required concentration of
Aβ42 was prepared by dissolving the sample in dimethyl
sulfoxide (DMSO) (5% of total solvent volume), then adding
sodium phosphate buffer (50 mM, pH 7.4). The solution was
sonicated at 0 °C for 3 min, then centrifuged at 13,400 r.p.m for
30 min at 0 °C to separate any aggregated species.
Thioflavin T Assay
(2Z,2’Z)-2,2’-([1,1’-Biphenyl]-4,4’-
ThT was purchased from AbCam (Cambridge). Final
concentrations of 10 µM Aβ42, 20 µM ThT and 50 µM
compound in sodium phosphate buffer (50 mM, pH 7.4) were
used for all samples. The assay samples (100 µL) were mixed in a
black non-binding 96-well plate (Greiner Bio-One, Switzerland)
which was sealed (Nunc, polyolefin acrylate film) and loaded
into the fluorescence plate reader (Tecan, Switzerland) at 37 ° C.
Fluorescence kinetics were measured at 5 min reading intervals,
with 15 sec shaking before each read. The excitation and
emission wavelengths were 440 and 480 nm respectively.
diylbis(methanylylidene))bis(5-bromobenzofuran-3(2H)-one)
(70) A mixture of bichalcone 60 (210 mg, 0.348 mmol) and
Hg(OAc)2 (220 mg, 0.689 mmol) in pyridine (10 mL) was reacted
according to GP-C. The crude residue was purified by
recrystallization from CHCl3 to afford biaurone 70 (182 mg, 87%)
as a bright yellow-orange powdery solid. m.p. >300 °C. TLC Rf =
0.38 (CH2Cl2). IR νmax (neat)/cm-1: 3021w (C-H str), 1706s (C=O
str), 1698s, 1639s (C=C str), 1588s (C=C str), 1497w (C=C str),
1455s, 1322w, 1296w, 1259s, 1207w, 1172s, 1119s, 1047w,
1002w. 1H NMR (500 MHz, CDCl3): δ 6.99 (2H, s, 2 × -C=CH), 7.30
(2H, d, J 8.8 Hz, ArH), 7.77-7.80 (6H, m, ArH), 7.96 (2H, d, J 2.0
Hz, ArH), 8.03 (4H, d, J 8.4 Hz, ArH). 13C NMR (500 MHz, CDCl3): δ
113.5, 114.7, 116.5, 123.4, 127.4, 127.5, 131.7, 132.3, 139.4,
141.6, 147.1, 164.7, 183.2. LCMS (ES+) m/z = 602.1 ([M+H]+, tr =
Acknowledgements
We thank the Cambridge Commonwealth Trust and
Cambridge Home and European Scholarship Scheme for the
awards of scholarships to T.H.S., T.J.S and S.C. The research
leading to these results has received funding from the
2.67 min). HRMS (ESI+) m/z
C30H17O4Br2+ required 598.9494.
=
598.9500 [M+H]+ found,
European Research Council under the European Union
’s
Seventh Framework Programme (FP7/2007–2013)/ERC
(2Z,2’Z,2’’Z)-2,2’,2’’-(Benzene-1,3,5-
grant agreement n° [279337/DOS]. The authors also thank
AstraZeneca, the European Union (EU), the Engineering and
Physical Sciences Research Council (EPSRC), the
Biotechnology and Biological Sciences Research Council
(BBSRC), the Medical Research Council (MRC), and the
Wellcome Trust for funding. Data accessibility: all data
supporting this study are included in the paper and
provided as Supporting Information accompanying this
paper.
triyltris(methanylylidene))tris(6-methoxybenzofuran-3(2H)-
one) (74) A mixture of trichalcone 72 (102 mg, 0.168 mmol) and
Hg(OAc)2 (160 mg, 0.502 mmol) in pyridine (10 mL) was reacted
according to GP-C. The crude residue was purified by flash
column chromatography (SiO2, 1-5% MeOH/CHCl3) and
recrystallized from CHCl3 to afford triaurone 74 (53.1 mg, 52%)
as a pale yellow-brown powdery solid. m.p. >300 °C. TLC Rf =
0.40 (2% MeOH/CH2Cl2). IR νmax (neat)/cm-1: 3074w (C-H str),
2947w (C-H str), 2842w (C-H str), 1698m (C=O str), 1649m,
1591s (C=C str), 1499m (C=C str), 1440s, 1346m, 1328m, 1265s,
1194m, 1151m, 1124s, 1112s, 1095s, 1015m. 1H NMR (500 MHz,
CDCl3): δ 4.01 (9H, s, 3 × -OCH3), 6.82 (3H, dd, J 8.4, 2.0 Hz, ArH),
6.94 (3H, d, J 1.6 Hz, ArH), 6.96 (3H, s, 3 × -C=CH), 7.76 (3H, d, J
8.4 Hz, ArH), 8.46 (3H, s, ArH). 13C NMR (500 MHz, CDCl3): δ
56.2, 96.7, 110.5, 112.7, 114.6, 126.0, 133.7, 134.3, 148.6, 167.9,
168.8, 183.0. LCMS (ES+) m/z = 601.1 ([M+H]+, tr = 2.18 min).
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16 | J. Name., 2012, 00, 1-3
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