Combinatorial synthesis of structurally diverse triazole-bridged flavonoid dimers and trimers

Article abstract of DOI:10.3390/molecules21091230

Flavonoids are a large family of compounds associated with a broad range of biologically useful properties. In recent years, synthetic compounds that contain two flavonoid units linked together have attracted attention in drug discovery and development projects. Numerous flavonoid dimer systems, incorporating a range of monomers attached via different linkers, have been reported to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to several favourable attributes including proven biological relevance and metabolic stability) and triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this compound type arguably remains underexplored within drug discovery. Herein, we report a modular strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers and also very rare heterotrimers from readily available starting materials. Application of this strategy has enabled step-efficient and systematic access to a library of structurally diverse compounds of this sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid successfully incorporated.

Full text of DOI:10.3390/molecules21091230

molecules
Article
Combinatorial Synthesis of Structurally Diverse
Triazole-Bridged Flavonoid Dimers and Trimers
Tze Han Sum , Tze Jing Sum , Warren R. J. D. Galloway , Súil Collins 1,2, David G. Twigg 1,
1
1
1
Florian Hollfelder 2 and David R. Spring *
1,
1
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK;
ths29@cam.ac.uk (T.H.S.); tjs76@cam.ac.uk (T.J.S.); wrjdg2@cam.ac.uk (W.R.J.D.G.); sc806@cam.ac.uk (S.C.);
dgt24@cam.ac.uk (D.G.T.)
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK;
2
fh111@cam.ac.uk
*
Correspondence: spring@ch.cam.ac.uk; Tel.: +44-1223-336-498
Academic Editor: Andrea Trabocchi
Received: 29 July 2016; Accepted: 8 September 2016; Published: 16 September 2016
Abstract: Flavonoids are a large family of compounds associated with a broad range of biologically
useful properties. In recent years, synthetic compounds that contain two flavonoid units linked
together have attracted attention in drug discovery and development projects. Numerous flavonoid
dimer systems, incorporating a range of monomers attached via different linkers, have been reported
to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring
system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to
several favourable attributes including proven biological relevance and metabolic stability) and
triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently
been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid
dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this
compound type arguably remains underexplored within drug discovery. Herein, we report a modular
strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers
and also very rare heterotrimers from readily available starting materials. Application of this strategy
has enabled step-efficient and systematic access to a library of structurally diverse compounds of this
sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid
successfully incorporated.
Keywords: flavonoid; triazole; dimer; trimer; hybridization; structural diversity
1
. Introduction
Flavonoids are a large family of polyphenolic compounds that represent dietary constituents
of importance to good health as well as a potentially important new class of pharmaceutical lead
substrates [ ]. There are several subclasses of flavonoids, including aurones, chalcones, coumarins,
flavones and isoflavones, which serve as the core structural units of numerous biologically active
molecules [ ]. In recent years, synthetic compounds that contain two such flavonoid units linked
together (so-called flavonoid dimers) have garnered attention from the synthetic and medicinal
chemistry communities [ 17]. The generation of species that integrate two pharmacophoric entities
both homo- and hetero-dimers) is a common strategy in drug discovery [18 19] and numerous
flavonoid dimer systems, incorporating a range of monomers linked in a variety of ways, have been
reported to exhibit biologically useful properties [ 17]. From a medicinal chemistry perspective,
1–3
4–7
8–
(
,
8–
the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety owing to
various favourable properties including ease of synthesis, proven biological relevance and metabolic
Molecules 2016, 21, 1230; doi:10.3390/molecules21091230
www.mdpi.com/journal/molecules

Molecules 2016, 21, 1230
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stability [11
,18
,20]; indeed, triazole-bridged flavonoid dimers possessing anticancer [10
,11] and
antimalarial [11] activities have recently been reported (Figure 1). However, there are relatively
few examples of libraries of triazole-bridged flavonoid dimers, and the diversity of flavonoid subunits
present within these is typically limited. Thus, the triazole-bridged flavonoid dimer compound
type arguably remains underexplored within drug discovery. We were interested in investigating
the biological potential of triazole-bridged flavonoid dimers further and so sought access to a more
structurally diverse collection of such compounds incorporating a wide range of flavonoid units.
In addition, we were also interested in accessing triazole-bridged trimeric derivatives, which are
also expected to have interesting biological properties. Though the synthesis of triazole-bridged
flavonoid trimers has previously been reported [10], compounds of this sort are very rare and they
have received relatively little attention from synthetic and medicinal chemists. Herein, we report the
development of a modular strategy for the synthesis of novel triazole-bridged flavonoid heterodimers
and heterotrimers. Application of this strategy has enabled concise and systematic access to a library
of 46 structurally diverse compounds of this sort (41 dimers and five trimers) from readily available
starting materials.
O
O
(
a)
O
flavone
O
flavone
flavone
O
O
O
N N
O
O
O
N
HO
O
O
(b)
O
N N
O
O
O
N
chalcone
O
(
c)
O
O
O
O
N N
N
O
coumarin
O
chalcone
Figure 1. Three examples of biologically active triazole-linked flavonoid dimers. The flavonoid
subunits in each example are highlighted in colours. ( ) A modulator of multidrug resistance in some
cancers [10]; ( ) A modulator of multidrug resistance in some cancers [10]; ( ) A compound with
a
b
c
anticancer activity and antimalarial activity [11].
2
. Results and Discussion
2
.1. Outline of the Synthetic Strategy
Inspired by previous studies on the synthesis of triazole-linked flavonoid libraries [10,11] we
envisaged a branching-type strategy to access triazole-bridged flavonoid dimers and trimers, based
around the use of iterative copper-catalysed “click”-type alkyne-azide 1,3-dipolar cycloadditions
(Scheme 1) [21]. It was anticipated that flavonoid monomer units bearing a terminal alkyne
group (“alkyne-flavonoid” building blocks) could be reacted with a range of flavonoid monomer
units bearing a terminal azide group (“azido-flavonoid” building blocks) to furnish diverse and
novel triazole-bridged flavonoid homo- and hetero-dimers (of the general structure
A, Scheme 1).
The presence of a free hydroxyl functionality in either monomer unit would allow for post-cyclisation
introduction of a terminal alkyne group in the dimers, thus providing the necessary synthetic handle
for a further cycloaddition with varied alkyne-flavonoids to furnish structurally diverse triflavonoid
derivatives of the general forms
B and C (Scheme 1). The presence of additional synthetic handles in
any given monomer unit should also allow for further elaboration of the dimers and trimers. Overall, it
was anticipated that this modular strategy would enable step-efficient and facile access to a structurally
diverse library of triazole-bridged flavonoid dimers and trimers through the use of a variety of different
flavonoid building blocks belonging to different flavonoid structural subclasses.

Molecules 2016, 21, 1230
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R1
R2
N
3
R1 = OH
R2 = OH
R
1
N
N
N
R2
A
N
N
N
N
N
OH
N
R2
R1
HO
Br
Br
N
N
N
N
N
N
R2
O
O
N
O
R1
N
R
3
R
3
N
3
3
N
N
N
N
R2
N
O
N
N
R1
N
N
N
N
B
C
R
3
R3
R'
Flavonoid
building
blocks:
R'
R
R'
R
O
O
O
R
OH
O
Chalcone
Flavonol
Aurone
O
=
R'
O
O
R
R
R
O
O
R'
O
Isoflavone
Flavone
Coumarin
O
Scheme 1. Overview of the branching-type strategy towards structurally diverse triazole-bridged
flavonoid heterodimers and heterotrimers. It was anticipated that homo- dimers and trimers could
also be accessed through the use of appropriate building blocks.
2
.2. Building Block Design and Synthesis
In order to facilitate the generation of structural diversity in the final compound collection,
building blocks belonging to a variety of flavonoid structural subclasses (chalcone, coumarin,
flavone, aurone, flavonol and isoflavone, see Scheme 1) and derivatives thereof were targeted.
Structural diversity, including functional group diversity, within building blocks of some subclasses
was also sought in order to further increase the overall structural diversity of the final library
(as well as providing a means of introducing additional biomolecular-interacting elements into the
library compounds, for example, additional bio-relevant heterocyclic motifs and hydrogen-bonding
functionalities). Variation in the position of the key alkyne/azide ligation handles around the flavonoid
structures was also envisaged as a strategy to further increase library structural diversity, since this
would enable access to different structural isomers of any given dimers/trimers. On the basis
of synthetic tractability, various alkyne-chalcones, flavones and isoflavones and azido-chalcone,
flavonols and flavones were targeted. Hydroxyl-substituted building blocks were also required
in order to allow access to trimeric species (as outlined in Scheme 1). Based on predicted synthetic
accessibility, the syntheses of a hydroxyl-substituted alkyne-chalcone, alkyne-flavonol, azido-chalcone
and azido-flavonol were targeted.
2
.2.1. Synthesis of the Alkyne-Flavonoid Building-Blocks
Alkyne-Chalcones
Hydroxyl-substituted alkyne-chalcone
alkylation with propargyl bromide proceeded smoothly to yield aldehyde
Claisen-Schmidt aldol reaction with acetophenone 3 yielded the target compound 4 (Scheme 2) [22].
4
was accessed from phenol
1
via a two-step sequence:
and subsequent
2

Molecules 2016, 21, 1230
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HO
O
O
OH
Br
K CO
O
O
O
O
3
O
O
2
3
O
O
Acetone
Reflux
HO
O
KOH, EtOH,
0 oC to rt
1
2; 74%
4; 39%
Scheme 2. Synthesis of hydroxyl-substituted alkyne-chalcone building block 4.
Structurally diverse alkyne-chalcone building blocks 20
incorporating a range of heteroaromatic scaffolds and an unusual ferrocenyl motif, were generated
from aldehydes respectively by Claisen-Schmidt aldol condensation with various acetophenone
derivatives followed by propargylation (Scheme 3).
–26, including chalconoid derivatives
5–9
R3
R2
O
2
3
4
1
0; R = OH, R = H, R = H
R2
O
R3
2
3
4
Br
K CO
R4
11; R = H, R = OH, R = OMe
2
3
4
R1
O
R1
12; R = OH, R = H, R = Br
R4
2
3
20-26
H
o
Acetone
Reflux
KOH, EtOH, 0 C to rt
1
3-19
5-9
Aldehyde
Ketone
Aldol product
Alkyne-chalcone
O
O
OH
O
O
O
11
O
O
O
O
5
13; 63%
20; 93%
O
Br
O
O
1
2
Br
O
N
6
HO
N
N
N
N
1
4; 94%
21; 96%
23; 98%
HO
O
O
O
N
10a
1
5; 27%
7
O
OH
O
O
N
1
1
N
O
O
N
O
O
1
1
1
6; 55%
O
7
22; 92%
24; 94%
26; 81%
HO
O
O
O
O
O
12
O
Br
Br
7; 47%
8
O
O
O
O
10a
Fe
Fe
Fe
Fe
HO
8; 72%
9
O
O
O
O
O
11
Fe
O
Fe
OH
19; 86%
9
25; 91%
Scheme 3. Synthesis of alkyne-chalcone building blocks 20–26.

Molecules 2016, 21, 1230
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Alkyne-Flavones
Propargylation of commercially available flavones 27
alkyne-flavones 30
core unit (Scheme 4) [23,24].
–
29 proceeded smoothly to furnish
–
32 with the alkyne synthetic handle appended at various positions on the flavone
1
2
3
Br
CO
2
7; R = OH, R = H, R = H
R3
R2
O
O
1
2
3
2
8; R = H; R = OH, R = H
K
2
3
3
0-32
R1
Ph
1
2
3
29; R = H; R = H, R = OH
Acetone, Reflux
O
O
Ph
O
O
O
Ph
O
O
O
O
30; 99% (from 27)
31; 87% (from 28)
32; 95% (from 29)
Scheme 4. Synthesis of alkyne-flavone building blocks 30–32.
Alkyne-Flavonol
The preparation of alkyne-flavonol 36 commenced with the synthesis of chalcone 35 via the
Claisen-Schmidt reaction of the alkyne-substituted benzaldehyde 34 with acetophenone 10. Subsequent
Algar-Flynn-Oyamada (AFO) oxidation [22] of the chalcone 35 proceeded smoothly to furnish 36
(Scheme 5).
HO
O
Br
K CO
O NaOH
H O
O
10
HO
O
OH
O
2
3
2
2
O
O
Acetone
Reflux
KOH
EtOH
O
EtOH
rt
OH
36; 73%
O
33
34; 91%
35; 77%
0 oC to rt
Scheme 5. Synthesis of alkyne-flavonol building block 36.
Alkyne-Isoflavones
The preparation of the alkyne-isoflavone building blocks 45 and 46 commenced with the acylation
of commercially available substituted phenols 37 and 38 with phenylacetic acids 39 and 40 to afford
the deoxybenzoins 41 and 42 [25]. Subsequent cyclization of 41 and 42 in methanesulfonyl chloride
afforded the corresponding isoflavones 43 and 44 which then underwent propargylation to yield the
desired alkyne-isoflavones 45 and 46 (Scheme 6) [25].
CO H
2
R O
2
OR2
O
3
9; R = H
2
R O
1
OH
40; R = CH
2
3
BF .OEt
R
1
O
OH
3
2
CH SO Cl
3
2
3
7; R = CH
o
41; R = CH , R = H; 78%
42; R = H, R = CH ; 36%
1
3
80 C
1
3
2
BF .OEt
3
2
o
3
8; R = H
1
1
2
3
DMF, 90 C
R O
1
O
R O
1
O
O
Br
K CO
2
3
O
OR2
OR2
Acetone
4
4
5; R = CH , R = CH CCH; 93% Reflux
43; R = CH , R = H; 57%
1 3 2
44; R = H, R = CH ; 77%
1 2 3
1
3
2
2
6; R = CH CCH, R = CH ; 60%
1
2
2
3
Scheme 6. Synthesis of alkyne-isoflavones 45 and 46.

Molecules 2016, 21, 1230
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Alkyne-Coumarin
Alkyne-coumarin 48 was synthesised by propargylation of hydroxycoumarin 47 in the presence
of anhydrous potassium carbonate (Scheme 7) [11].
Br
OH
O
O
O
K CO
2
3
47
Acetone
Reflux
48; 58%
O
O
Scheme 7. Synthesis of alkyne-coumarin 48.
Alkyne-Aurone
Alkyne-aurone 56 was prepared from commercially available phloroglucinol 49 (Scheme 8)
Condensation with chloroacetonitrile in the presence of ZnCl furnished imine 50 26]. Subsequent
hydrolysis under acidic conditions afforded ketone 51 which was then treated with methanolic sodium
methoxide to give hydroxybenzofuranone 52 26]. Methyl protection of the free hydroxyl groups
.
[
2
[
afforded benzofuranone 53 which was then condensed with 3-hydroxybenzaldehyde 54 under basic
conditions to yield hydroxyaurone 55. Subsequent propargylation gave the desired alkyne-aurone 56
in an excellent yield (Scheme 8).
NC Cl
HO
OH
HO
OH
HO
OH
ZnCl , HCl
2
1 M HCl
Reflux
Cl
Cl
Et O
NaOCH3
OH
2
OH NH HCl
OH O
51; 25%
0 oC to rt
MeOH
Reflux
49
50; 20%
O
HO
HO
O
HO
5
4
O
CH3I
K CO
3
O
O
O
KOH, H O
2
2
Br
K CO
Acetone
Reflux
O
o
O
MeOH, rt
O
DMF, 80 C
OH
O
2
3
O
5
3; 79%
52; 71%
5
5; 78%
O
O
O
56; 96%
O
O
Scheme 8. Synthesis of alkyne-aurone 56.
.2.2. Synthesis of the Azido-Flavonoid Building Blocks
Azido-Coumarin
2
Azido-coumarin 58 was prepared from readily available hydroxycoumarin 47 by alkylation
to form 57) followed by reaction with sodium azide (Scheme 9) [27].
(
Br
N3
Br
OH
O
O
Br
K CO
NaN3
2
3
Acetone, Reflux
o
O
O
O
O
DMF, 100 C
O
O
47
57; 16%
58; 98%
Scheme 9. Synthesis of azido-coumarin 58.

Molecules 2016, 21, 1230
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Azido-Chalcones
Hydroxyl-substituted azido-chalcone 61 was prepared by a three step sequence from
phenolic aldehyde 33 (Scheme 10). Reaction with 1,2-dibromoethane generated aldehyde 59 and
subsequent nucleophilic substitution with sodium azide produced azide 60 in an excellent yield.
Claisen-Schmidt aldol condensation with ketone 10b then yielded the target compound 61
[22].
Alternatively, Claisen-Schmidt aldol condensation of aldehydes 64 66 and with readily-prepared
–
7
azido-ketone 63 furnished azido-chalcone building blocks 67–70 respectively (Scheme 11) [22].
Br
Br
HO
O
O
K CO
2
Br
NaN
3
N3
3
O
O
O
Acetone
Reflux
DMF
o
60; 99%
59; 35%
100 C
HO
33
O
HO
O
N3
KOH, EtOH
0 oC to rt
O
10b
6
1; 77%
Scheme 10. Synthesis of azido-chalcone 61.
O
N3
O
O
R1
O
63
N3
R1
O
H
O
o
67-70
7
, 64-66 KOH, EtOH, 0 C to rt
O
Aldehyde
Azido-chalcone
O
O
O
O
O
N3
6
4
5
67; 74%
68; 79%
O
O
O
O
O
O
O
O
O
O
O
N3
6
O
O
O
O
O
O
O
6
6
N3
69; 82%
70; 37%
O
O
O
O
O
O
O
N3
O
7
N
N
O
Synthesis of 63:
Br
Br
K CO
NaN
DMF
Reflux
3
OH
O
O
O
O
Br
N3
2
3
O
Acetone
Reflux
O
11
O
62; 24%
O
63; 98%
Scheme 11. Synthesis of azido-chalcones 67–70.
Azido-Flavonols
Aldehydes 59 and 72 and 73, generated by alkylation of 33
,2-dibromoethane, were reacted with sodium azide to form 60 and 74 and 75 respectively (Scheme 12).
Subsequent aldol condensation with acetophenones 10 or (see Scheme 12) furnished chalcones 61
and 76 78 and AFO proceeded smoothly in all cases to furnish azido-flavonols 79 and 80 82 in good
yields [22].
, 71 and 1 respectively with
1
3
–
–

Molecules 2016, 21, 1230
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Br
R2
R2
Br
K CO
R1
R1
NaN , DMF
2
3
3
O
Acetone, Reflux
O
o
1
00 C
3
7
1
3; R = OH, R = H
59; R = OCH CH Br, R = H; 35%
72; R = OCH CH Br, R = OCH ; 25%
1 2 2 2 3
73; R = OCH , R = OCH CH Br; 22%
1 3 2 2 2
1 2
1
2
2
2
1; R = OH, R = OCH
1
2
3
; R = OCH , R = OH
1
3
2
R2
o
R1
KOH, EtOH, 0 C to rt
HO
O
R3
O
10; R = H
3
60; R = OCH CH N , R = H; 99%
1 2 2 3 2
74; R = OCH CH N , R = OCH ; 98%
1 2 2 3 2 3
3
; R = OCH3
3
7
5; R = OCH , R = OCH CH N ; 98%
1 3 2 2 2 3
R2
6
7
7
7
1; R = OCH CH N , R = H, R = H; 77%
R1
HO
R3
1 2 2 3 2 3
6; R = OCH CH N , R = H, R = OCH ; 64%
1
2
2
3
2
3
3
7; R = OCH CH N , R = OCH , R = H; 46%
1
2
2
3
2
3
3
O
8; R = OCH , R = OCH CH N , R = H; 59%
1
3
2
2
2
3
3
NaOH
H O
MeOH, rt
2
2
R2
R1 79; R = OCH CH N , R = H, R = H; 80%
1
2
2
3
2
3
8
0; R = OCH CH N , R = H, R = OCH ; 61%
1 2 2 3 2 3 3
R3
O
O
81; R = OCH CH N , R = OCH , R = H; 77%
1
2
2
3
2
3
3
OH
82; R = OCH , R = OCH CH N , R = H; 78%
1 3 2 2 2 3 3
Scheme 12. Synthesis of azido-flavonols 79–82.
Azido-Flavones
Azido-flavones 85 and 86 were readily accessed from commercially available hydroxyflavones 28
and 29 by reaction with 1,2-dibromoethane to forge 83 and 84 followed by nucleophilic substitution
with sodium azide (Scheme 13) [10,28]. Azido-flavone 87 was prepared in an excellent yield from
chalcone 76 by an iodine-mediated oxidative cyclization (Scheme 14).
Br
Br
R2
R1
O
O
R2
O
O
K CO
2
3
83; R = OCH CH Br, R = H; 22%
1 2 2 2
Acetone R1
Reflux
8
4; R = H, R = OCH CH Br; 65%
1
2
2
2
2
8; R = OH, R = H
1 2
o
NaN , DMF, 100 C
29; R = H, R = OH
3
1
2
R2
R1
O
8
5; R = OCH CH N , R = H; 93%
1 2 2 3 2
86; R = H, R = OCH CH N ; 91%
1
2
2
2 3
O
Scheme 13. Synthesis of azido-flavones 85–86.
O
N3
O
OH
O
O
I2
N3
O
O
O
o
DMSO, 130 C
76
87; 91%
Scheme 14. Synthesis of azido-flavone 87.

Molecules 2016, 21, 1230
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Azido-Aurones
Mercury(II) acetate-mediated oxidative cyclization of chalcones 61 and 76 furnished azido-aurones
8 and 89 respectively in excellent yields (Scheme 15) [29].
8
R1
R1
OH
O
Hg(OAc)2
O
N3
N3
O
o
Pyridine, 110 C
O
O
6
1; R = H
88; R = H; 88%
1
1
7
6; R = OCH3
89; R = OCH ; 96%
1 3
1
Scheme 15. Synthesis of azido-aurones 88–89.
2
.2.3. Synthesis of Triazole-Bridged Flavonoid Dimers
With the alkyne- and azido-flavonoid building blocks in hand, we were ready to forge a series of
dimeric combinations via triazole formation. Thus, various pairs of building blocks were subjected
to standard copper-mediated “click” cycloaddition conditions to generate 41 distinct and diverse
triazole-bridged flavonoid dimers (compounds 90–130, Schemes 16–20). The reactions generally
proceeded smoothly and with high levels of regioselectivity and isolated yields of the target compounds
were typically moderate-to-good. Six different biologically-relevant flavonoid structural subclasses
(chalcone, flavonol, aurone, flavone, coumarin and isoflavone) were successfully incorporated into
the dimer library together with other biologically-relevant features, and variation within building
blocks belonging to certain subclasses allowed for the generation of additional structural diversity
in the library and the concomitant introduction of additional biomolecule-interacting elements
(for example, the varied heterocyclic motifs exhibited by the chalcone-chalcone dimers 90–97).
Several compounds also featured groups that could provide synthetic handles for further elaboration or
diversification (for example, compounds 96 and 97 and 105 and 106 contain a hydroxyl group and the
aryl-bromide group present in 107 and 108 could conceivably be exploited in various metal-catalysed
cross-coupling processes).
2
.2.4. Synthesis of Triazole-Bridged Flavonoid Trimers
Propargylation of the free phenolic hydroxyl groups of triazole-bridged flavonoid dimers 126
,
122
,
9
2
and 110 and 106 led to the formation of alkyne-capped derivatives 131
–
135 respectively. These were
successfully coupled with three azido-flavonoid building blocks (86 for 131 and 132; 87 for 133
;
and 89 for 134 and 135) via copper-catalysed triazole formation to furnish five structurally diverse
triazole-bridged flavonoid trimers 136–140 (Scheme 21).
2
.3. Preliminary Biological Screening
A representative sample of 13 final triazole-bridged dimers (90
–
93
,
112
–
114
,
122
,
123
,
125
,
126
, 129
and 130) was screened for inhibitory activity against the aggregation of amyloid beta (
1–
42) (Aβ42), a
pathological hallmark of Alzheimer’s disease [30]. Aggregation of the monomeric form of the peptide
into oligomeric and fibrillar species is associated with disease onset and progression. As such, the
identification of compounds capable of inhibiting the aggregation process holds great potential for
the development of therapeutic agents [31]. Flavonoid and chalcone derivatives have previously
shown activity in perturbing the aggregation of Aβ, with compounds such as EGCG myricetin and
morin displaying inhibitory activity in a variety of biophysical and in vivo tests [32
–
35]. It has also
been shown that dimeric flavonoids can display enhanced inhibitory activity than their monomeric
counterparts [36], suggesting that the libraries synthesised may be effective at targeting this peptide
aggregation pathway. The ability of the triazole-linked dimers to inhibit the A 42
β
aggregation was
assessed using a thioflavin T (THT) assay (Figure 2). Three of the compounds screened were found

Molecules 2016, 21, 1230
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to have moderate inhibitory activity, with 92 found to be the most potent and comparable to the
inhibitor morin.
It is difficult to draw any firm conclusions at this time regarding structure-activity relationships
in the triazole-bridged dimer compound class due to the relatively small sample size and some
issues with the solubility and fluorescence behaviour of some compounds under the assay conditions.
Nevertheless, this preliminary screen has identified structurally novel A 42
β
aggregation inhibitors
which could represent interesting scaffolds for further study in this regard.
Chalcone
CuSO .5H O
N
N
4
2
N
Chalcone
4
, 20, 22, 23
Chalcone
1, 67-70
Chalcone
Sodium ascorbate
t-BuOH, H O, rt
90-97
N3
2
6
O
O
O
O
O
N
N
N
90; 27% (from 20 and 67)
O
O
O
O
O
O
O
O
O
O
O
N N
91; 47% (from 20 and 69)
O
O
N
O
O
N
O
O
O
N
N
O
OH
O
O
O
92; 64% (from 4 and 69)
O
O
O
O
O
O
93; 96% (from 20 and 68)
N N
O
O
O
N
O
O
O
O
O
94; 70% (from 22 and 69)
O
O
N
N N
O
O
O
N
O
O
O
N
O
O
95; 97% (from 22 and 70)
N
N N
O
N
O
O
O
N
O
O
9
6; 55% (from 23 and 61)
N
N
O
Fe
N
O
O
HO
9
7; 80% (from 25 and 61) O
N
N
N
O
O
HO
Scheme 16. Synthesis of triazole-bridged chalcone-chalcone dimers.

Molecules 2016, 21, 1230
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Flavone
CuSO .5H O
N
N
4
2
N
Chalcone
3
0-32
Flavone
Sodium ascorbate
t-BuOH, H O, rt
2
Chalcone
98-104
N3
6
7-69
O
O
O
O
O
O
N
N
N
N
O
O
O
N
O
O
N
O
O
O
O
O
9
8; 36% (from 30 and 67)
99; 35% (from 30 and 68)
O
O
O
O
O
O
O
O
N
N
N
N
O
N
O
N
O
O
O
O
O
O
O
100; 67% (from 30 and 69) O
101; 87% (from 31 and 67)
O
O
O
O
O
O
O
O
102; 75% (from 31 and 69)
N
N
O
O
N
N
O
O
O
O
O
O
O
103; 76% (from 31 and 68)
N
N
O
O
N
N
N
O
O
104; 64% (from 32 and 69)
O
O
O
O
O
O
Scheme 17. Synthesis of triazole-bridged flavone-chalcone dimers.

Molecules 2016, 21, 1230
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Chalcone
CuSO .5H O
N
N
4
2
N
Flavonol
21, 24-26
Chalcone
Sodium ascorbate
t-BuOH, H2O, rt
Flavonol
105-108
N3
79-82
O
N
N N
Fe
O
O
O
105; 40% (from 26 and 80)
HO
O
O
O
Fe
O
N
O
N
O
106; 38% (from 25 and 79)
N
O
HO
O
N
O
O
N
N
N
O
O
107; 40% (from 21 and 82)
HO
O
O
Br
Br
O
O
O
108; 42% (from 24 and 81)
O
N
N
O
O
N
O
HO
Scheme 18. Synthesis of triazole-bridged chalcone-flavonol dimers.

Molecules 2016, 21, 1230
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CuSO .5H O
4
2
N
N
N
N3
Sodium ascorbate
t-BuOH, H O, rt
2
flavone
flavone
Ph
Ph
110; 47% (from 30 and 79)
O
O
O
O
O
O
O
O
flavonol
N
N
N
N
O
O
N
O
Ph
N
1
09; 92% (from 30 and 85) flavone
HO
Ph
O
O
N
O
HO
N
N
isoflavone
N
N
O
N
O
O
O
flavone
12; 95% (from 46 and 85)
chalcone O
O
O
O
coumarin
1
O
126; 78% (from 48 and 61)
O
O
O
O
O
O
N
O
N
OH
HO
O
O
N
flavonol
N N
coumarin
127; 16% (from
flavonol
N
O
N
O
O
flavonol
1
11; 14% (from 36 and 79)
HO
4
8 and 79)
O
O
flavone
O
isoflavone
O
O
O
coumarin
N
N
O
HO
flavonol
O
O
O
N
N
O
O
O
N
1
15; 12% (from 46 and 79)
1
28; 63% (from 30 and 58) O
O
O
N N
N
aurone
O
O
aurone
O
O
coumarin
O
O
O
N
1
25; 85% (from 56 and 88)
N
N
O
O
O
N
N
N
O
O
O
aurone
O
coumarin
O
O
O
1
O
30; 69% (from 46 and 58)
O
isoflavone
129; 53% (from 48 and 89)
O
O
isoflavone
O
N N
O
N
O
124; 55% (from 46 and 89)
O
O
aurone
O
O
Scheme 19. Synthesis of some triazole-bridged dimers.

Molecules 2016, 21, 1230
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CuSO .5H O
4
2
N
N
N
N3
Sodium ascorbate
t-BuOH, H O, rt
2
O
O
isoflavone-chalcone
O
N
O
N
O
O
113; 31% (from 45 and 69)
N
O
O
O
O
O
O
O
O
N
O
O
N
N
O
O
O
O
O
114; 63% (from 46 and 68)
O
chalcone-aurone
O
N
O
O
N N
N
O
N N
O
O
O
N
1
16; 40% (from 20 and 88)
Br
N
N
O
N
O
1
19; 21% (21 and 88)
O
O
N
O
O
O
O
O
O
O
1
18; 48% (22 and 89)
Fe
O
O
N
N
N
1
17; 78% (from 26 and 88)
O
O
O
flavone-aurone
O
O
O
O
Ph
O
O
O
N
N
Ph
O
N
N
O
O
N
O
O
O
N
1
21; 49% (from 31 and 89)
N
O
1
20; 63% (from 30 and 89)
flavonol-aurone
aurone-flavonol
O
N
N
O
O
O
O
O
N
N
O
O
OH
N
O
O
O
OH
O
O
123; 14% (from 56 and 80)
122; 42% (from 36 and 88)
O
Scheme 20. Synthesis of some triazole-bridged dimers.

Molecules 2016, 21, 1230
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N3
N
N
O
O
CuSO .5H O
N
4
2
N
N
N
N
n
N
N
m
m
Sodium ascorbate
t-BuOH, H O, rt
n
2
coumarin-chalcone-flavone
aurone-flavone-flavone
O
N
N
N
N
N
N
O
O
O
O
O
N
O
O
O
O
N
N
O
O
O
N
N
O
O
O
N
O
1
36; 67% (from 131 and 86)
O
O
137; 49% (from 132 and 86)
O
O
chalcone-chalcone-flavone
flavone-flavone-aurone
O
O
O
O
N
1
1
38; 5% (from
33 and 87)
O
O
O
O
O
N N
O
139; 36% (from 134 and 89)
O
O
O
N
N
O
N
N
N
O
O
O
O
N
O
chalcone-flavone-aurone
Fe
N
N N
O
N
O
O
O
O
N N
O
O
O
O
N
N
N
O
140; 3% (from 135 and 89)
O
O
O
O
O
O
Scheme 21. Synthesis of triazole-bridged trimers.

Molecules 2016, 21, 1230
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Figure 2. Percentage inhibition of A 42
β
aggregation achieved by compounds 92
, 122 and 126 (50 µM
concentration) relative to that of A 42 alone (10
β
µM), where 100% represents complete aggregation
inhibition and 0% shows no inhibition. The data represents the averages and standard error from the
results of three independent biological repeats. Inhibitory effect of morin determined under identical
assay conditions.
3
3
3
. Materials and Methods
.1. Chemical Synthesis
.1.1. General Information
All non-aqueous reactions were performed under a constant stream of dry nitrogen using
oven-dried glassware. Standard practices were employed when handling moisture and air-sensitive
materials. All reagents and solvents were purchased from commercial sources and used without further
purification unless otherwise stated. Room temperature refers to ambient temperature. Temperatures
◦
of 0 C were maintained using an ice-water bath. Petroleum ether was distilled before use. Ethyl acetate
and methanol were distilled from calcium hydride. Melting points were measured using a Büchi B545
melting point apparatus and are uncorrected. Thin layer chromatography (TLC) was performed
on pre-coated silica gel GF254 plates (Merck, Kenilworth, NJ, USA). Infrared (IR) spectra were
recorded on a Spectrum One (FT-IR) spectrophotometer (Perkin-Elmer, Waltham, MA, USA) with
−
1
internal referencing. Absorption maxima (νmax) are reported in wavenumbers (cm ). Flash column
chromatography was performed on silica gel (230–400 mesh). H-NMR and 13C-NMR were recorded
1
on an Avance 500 MHz instrument (Bruker, Billerica, MA, USA) in CDCl or (CD ) CO. Chemical shifts
3
3 2
1
13
(δ) are quoted in ppm, to the nearest 0.01 ppm ( H-NMR) or 0.1 ppm ( C-NMR) and are referenced

Molecules 2016, 21, 1230
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to the residual non-deuterated solvent peak. H-NMR and 13C-NMR data for all compounds can be
1
found in Supplementary Materials. LCMS analysis was performed on an ACQUITY H-Class UPLC
(
Waters, Milford, MA, USA) with an ESCi Multi-Mode Ionisation Waters SQ Detector 2 spectrometer
using MassLynx 4.1 software. LC system: solvent A: 2 mM NH OAc in H O/MeCN (95:5); solvent B:
4
2
MeCN; solvent C: 2% aqueous formic acid; gradient: 5%–95% B with constant 5% C over 1 min at flow
rate of 0.6 mL/min. High resolution mass spectrometry (HRMS) measurements were recorded on a
Q-TOF mass spectrometer (Micromass, Cary, NC, USA) or a Waters LCT Premier Time of Flight mass
spectrometer. Mass values are quoted within the error limits of
mass ionisation technique.
±
5 ppm mass units. ESI+ refers to the
3
.1.2. General Synthetic Procedures
General Procedure A: Synthesis of Biflavonoid Triazole Hybrids (GP-A). To a stirred solution of
alkyne flavonoid (1.0 equiv.) and azide flavonoid (1.0 equiv.) in t-BuOH/H O (1:1, 40 mL) were
2
added CuSO4
at room temperature for 24 h or until TLC analysis indicated complete consumption of starting
material. The resulting mixture was poured into H O (100 mL) and the aqueous solution was extracted
·
5H O (1.1 equiv.) and sodium ascorbate (2.5 equiv.). The reaction mixture was stirred
2
2
with CHCl (3
×
100 mL). The combined organic layer was washed with H O (2
×
100 mL), brine
3
2
(2 × 100 mL), dried over anhydrous MgSO , filtered and the solvent removed under reduced pressure.
4
The crude residue was purified by flash column chromatography over silica and recrystallized from
MeOH to afford the corresponding biflavonoid triazole hybrids.
General Procedure B: Synthesis of Alkyne Biflavonoid Triazole Hybrids (GP-B). To a stirred solution
of the corresponding biflavonoid triazole hybrid (1.0 equiv.) in dry acetone (50 mL) were added
propargyl bromide (3.0 equiv.) and anhydrous K CO (3.0 equiv.). The reaction mixture was heated at
2
3
reflux with stirring for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete
consumption of starting material. The resulting mixture was allowed to cool to room temperature and
the solvent removed in vacuo. The crude residue was re-suspended in CHCl (50 mL) and the organic
3
layer was washed with H O (2
and evaporated to dryness. The crude residue was purified by flash column chromatography over
silica to afford the corresponding propynyloxy biflavonoid triazole hybrid.
×
100 mL), brine (2
×
100 mL), dried over anhydrous MgSO , filtered
4
2
General Procedure C: Synthesis of Propynyloxy flavonoids or benzaldehydes (GP-C). To a stirred
solution of the corresponding flavonoid or benzaldehyde (1.0 equiv.) in dry acetone (50 mL) were added
anhydrous K CO (3.0 equiv.) and propargyl bromide (3.0 equiv.). The reaction mixture was heated at
2
3
reflux with stirring for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete
consumption of starting material. The resulting mixture was allowed to cool to room temperature
and the solvent removed in vacuo. The crude residue was re-suspended in CHCl (100 mL) and the
3
organic layer was washed with H O (2
filtered and evaporated to dryness. The crude residue was purified by flash column chromatography
over silica to afford the corresponding propynyloxy flavonoids or benzaldehydes.
×
100 mL), brine (2
×
100 mL), dried over anhydrous MgSO4,
2
General Procedure D: Synthesis of Chalcones (GP-D). To a stirred solution of KOH (12.0 equiv.)
◦
in absolute EtOH (100 mL) cooled to 0 C in an ice-bath were added dropwise a solution of the
corresponding acetophenone (1.0 equiv.) and aldehyde (1.0 equiv.) in EtOH (20 mL). The reaction
◦
mixture was stirred at 0 C for 1 h and then at room temperature for 72 h under a nitrogen atmosphere
or until TLC analysis indicated complete consumption of starting material. The resulting mixture was
then poured into ice-water (100 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was
extracted with CHCl (3
×
100 mL) and the combined organic layer was washed with satd NaHCO3
3
(2 × 100 mL), brine (2 × 100 mL), dried over anhydrous MgSO , filtered and the solvent removed
4
under reduced pressure. The crude residue was purified by flash column chromatography over silica
and/or recrystallized from MeOH or absolute EtOH to afford the corresponding chalcones.

Molecules 2016, 21, 1230
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General Procedure E: Synthesis of Indole or Pyrrole 2-hydroxychalcones (GP-E). To a stirred solution
of indole or pyrrole aldehyde (1.0 equiv.) and the corresponding 2-hydroxyacetophenone (1.0 equiv.
in absolute EtOH (100 mL) was added piperidine (1.0 equiv.). The reaction mixture was heated at
reflux for 24 h under a nitrogen atmosphere or until TLC analysis indicated complete consumption of
starting material. The reaction mixture was allowed to cool to room temperature, poured into ice-water
)
(100 mL) and then acidified to pH 3–4 with 3 M HCl. The resulting suspension was filtered and the
precipitate washed with ice-water (2 100 mL), suction-dried and recrystallized from MeOH to afford
×
the corresponding indole or pyrrole chalcones.
General Procedure F: Synthesis of Flavonols (GP-F). To a stirred solution of the corresponding chalcone
(
0.30 mmol) in MeOH (20 mL) were added 16% NaOH (aq) (0.60 mL) and 15% H O (0.30 mL).
2 2
The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere or until
TLC analysis indicated complete consumption of starting material. The resulting mixture was then
poured into ice-water (50 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was
extracted with CHCl (3
×
50 mL) and the combined organic layer was washed with satd NaHCO3
3
(2 × 50 mL), brine (2 ×
50 mL), dried over anhydrous MgSO , filtered and the solvent removed under
4
reduced pressure. The crude residue was purified by flash column chromatography over silica to
afford the corresponding flavonols.
General Procedure G: Synthesis of Phenylethanones (GP-G). To a stirred solution of substituted phenol
(
1.2 equiv.) in BF3
·
OEt (50 mL) was added the corresponding phenylacetic acid (1.0 equiv.) and the
2
◦
reaction mixture was heated at 80 C for 8 h under a nitrogen atmosphere. The resulting dark solution
was allowed to cool to room temperature and slowly poured into ice-water (100 mL). The organic layer
was separated and the aqueous layer was extracted with EtOAc (3
×
100 mL). The combined organic
layer was washed with satd NaHCO (2 100 mL), brine (2 100 mL), dried over anhydrous MgSO ,
×
×
3
4
filtered and evaporated to dryness. The crude residue was purified by flash column chromatography
over silica to afford the corresponding phenylethanones.
General Procedure H: Synthesis of Isoflavones (GP-H). To a stirred solution of the corresponding
phenylethanone (1.0 equiv.) in dry DMF (15 mL) was carefully added BF3
under a nitrogen atmosphere. To this mixture, methanesulfonyl chloride (3.0 equiv.) was added at
·
OEt (4.0 equiv.) over 10 min
2
◦
◦
5
5 C, stirred for 1 h and then heated at 80 C for 24 h. The resulting dark solution was allowed to
cool to room temperature and then poured with rapid stirring into ice-water (100 mL). The resulting
precipitate was filtered, washed with H O (2 100 mL), suction-dried and re-dissolved in EtOAc
100 mL). The organic solution was washed with H O (2 100 mL), brine (2 100 mL), dried over
×
2
(
×
×
2
anhydrous MgSO , filtered and evaporated to dryness. The crude residue was purified by flash column
4
chromatography over silica to afford the corresponding isoflavones.
General Procedure I: Synthesis of Bromoalkylated flavonoids or benzaldehdyes (GP-I). To a stirred
solution of the corresponding flavonoid or benzaldehyde (1.0 equiv.) in dry acetone (50 mL) or
dry DMF (50 mL) were added anhydrous K CO (3.0 equiv.) and 1,2-dibromoethane (3.0 equiv.).
2
3
The reaction mixture was heated at reflux with stirring for 24 h under a nitrogen atmosphere or until
TLC analysis indicated complete consumption of starting material. The resulting mixture was allowed
to cool to room temperature and the solvent removed in vacuo. The crude residue was re-suspended
in CHCl (100 mL) and the organic layer was washed with H O (2
×
100 mL), brine (2
×
100 mL),
3
2
dried over anhydrous MgSO , filtered and evaporated to dryness. The crude residue was purified
4
by flash column chromatography over silica to afford the corresponding bromoalkylated flavonoids
or benzaldehydes.
General Procedure J: Synthesis of Azido flavonoids or benzaldehydes (GP-J). To a stirred solution
of the corresponding bromoalkylated flavonoids or benzaldehydes (1.0 equiv.) in dry DMF (30 mL)
◦
was added NaN (3.0 equiv.). The reaction mixture was heated at 100 C with stirring for 3 h under
3
a nitrogen atmosphere. The resulting mixture was allowed to cool to room temperature and poured

Molecules 2016, 21, 1230
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into H O (100 mL). The aqueous solution was extracted with CHCl (3
×
100 mL) and the combined
2
3
organic layer was washed with H O (2
×
100 mL), brine (2
×
100 mL), dried over anhydrous MgSO ,
4
2
filtered and evaporated to dryness to afford the corresponding azido flavonoids or benzaldehydes and
were used without further purification.
General Procedure K: Synthesis of Aurones (GP-K). To a stirred solution of the corresponding chalcone
(
1.0 equiv.) in pyridine (10 mL) was added Hg(OAc) (1.0 equiv.). The reaction mixture was heated
2
◦
at 110 C with stirring for 1 h under a nitrogen atmosphere. The resulting mixture was then poured
into ice-water (50 mL) and acidified to pH 3–4 with 3 M HCl. The aqueous solution was extracted
with CHCl (3
×
50 mL) and the combined organic layer was washed with H O (2
×
50 mL),
3
2
brine (2
×
50 mL), dried over anhydrous MgSO , filtered and the solvent removed under reduced
4
pressure. The crude residue was purified by flash column chromatography over silica to afford the
corresponding aurones.
3
.2. Synthetic Procedures
3
.2.1. Building Block Synthesis
4-Methoxy-3-(prop-2-yn-1-yloxy)benzaldehyde (2). A mixture of isovanillin (1, 10.0 g, 65.7 mmol),
propargyl bromide (8.78 mL, 98.6 mmol) and anhydrous K CO (18.2 g, 131 mmol) in dry
2
3
acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column
chromatography (SiO , CH Cl ) to afford benzaldehyde
2
(9.23 g, 74%) as a white fluffy solid.
2
2
2
◦
−1
m.p. 78–80 C. TLC R = 0.21 (CH Cl ). IR νmax (neat)/cm : 3229m (C
≡
C-H str), 3096w (C-H str),
f
2
2
2
839w (C-H str), 2124w (C
≡
C str), 1671s (C=O str), 1599s (C=C str), 1586s (C=C str), 1508s (C=C str),
1
1
436m, 1407m, 1387m, 1261s, 1229s, 1161s, 1129s, 1012s. H-NMR (500 MHz, CDCl ):
δ
2.55 (1H, t,
CH), 7.01 (1H, d,
J = 8.0 Hz, ArH), 7.53 (1H, dd, J = 8.0, 1.6 H z, ArH), 7.55 (1H, d, J = 1.6 Hz, ArH), 9.87 (1H, s, CHO).
3
J = 2.4 Hz, -OCH C
≡
CH), 3.97 (3H, s, -OCH ), 4.83 (2H, d, J = 2.4 Hz, -OCH C
≡
2
3
2
13
C-NMR (500 MHz, CDCl ):
δ 56.2, 56.6, 76.4, 77.7, 110.9, 112.0, 127.3, 129.9, 147.3, 154.9, 190.7. LCMS
3
+
(
ES+) m/z = 191.2 ([M + H] , t = 3.09 min). These characterisation data are in accordance with that
R
previously reported in the literature [37].
E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(4-methoxy-3-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (
of benzaldehyde (2.05 g, 10.8 mmol), acetophenone (1.80 g, 10.8 mmol) and KOH (3.02 g, 53.8 mmol)
in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash
(
4). A mixture
2
3
column chromatography (SiO , PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone
4
2
◦
(
1.42 g, 39%) as a bright yellow-orange fluffy solid. m.p. 144–146 C. TLC R = 0.37 (PE/EtOAc; 2:1).
f
−
1
IR νmax (neat)/cm : 3506w (br) (O-H str), 3229 m (C
2
≡
C-H str), 3081w (C-H str), 2973w (C-H str),
C str), 1633m (C=O str), 1572 m (C=C str), 1556s (C=C str), 1507s (C=C str), 1466 m, 1440s,
111w (C
≡
1
1
361s, 1339s, 1260s, 1206s, 1170m, 1126s, 1018s. H-NMR (500 MHz, CDCl ):
δ
2.58 (1H, t, J = 2.0 Hz
CH),
.49–6.52 (2H, m, ArH), 6.94 (1H, d, J = 8.4 Hz, ArH), 7.32 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.35 (1H, d,
J = 1.2 Hz, ArH), 7.45 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.83 (1H, d, J = 8.4 Hz, ArH), 7.85 (1H, d,
J = 15.6 Hz, -CH=CHCO-), 13.53 (1H, s, OH). 13C-NMR (500 MHz, CDCl3):
55.6, 56.0, 56.9, 76.3, 78.1,
01.0, 107.7, 111.7, 113.8, 114.1, 118.3, 124.3, 127.7, 131.1, 144.3, 146.9, 152.2, 166.1, 166.6, 191.7. LCMS
,
3
-OCH C
≡
CH), 3.87 (3H, s, -OCH ), 3.94 (3H, s, -OCH ), 4.85 (2H, d, J = 2.4 Hz, -OCH C
≡
2
3
3
2
6
δ
1
+
+
+
(
ES+) m/z = 339.2 ([M + H] , t = 1.70 min). HRMS (ESI+) m/z = 339.1224 [M + H] found, C H O
R 20 19 5
required 339.1227.
(E)-1-(4-Hydroxy-3-methoxyphenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (13). A mixture of aldehyde 5
(7.40 mL, 60.8 mmol), acetophenone 11 (10.0 g, 60.3 mmol) and KOH (16.9 g, 302 mmol) in absolute
EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash column
chromatography (SiO , PE/EtOAc; 5:1) to afford chalcone 13 (10.7 g, 63%) as a bright yellow-orange
2
◦
−1
powdery solid. m.p. 148–150 C. TLC R = 0.40 (PE/EtOAc; 1:1). IR νmax (neat)/cm : 3180m (br)
f
(
O-H str), 2991w (C-H str), 2836w (C-H str), 1643m (C=O str), 1602m (C=C str), 1560s (C=C str), 1508s

Molecules 2016, 21, 1230
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1
(
C=C str), 1461w, 1424s, 1338m, 1296s, 1278s, 1248s, 1166s, 1048m, 1026s. H-NMR (500 MHz, CDCl ):
3
δ
3.86 (3H, s, -OCH ), 3.98 (3H, s, -OCH ), 6.23 (1H, s, OH), 6.94 (2H, d, J = 9.0 Hz, ArH), 7.00 (1H,
3 3
d, J = 8.0 Hz, ArH), 7.45 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.61 (2H, d, J = 8.5 Hz, ArH), 7.64–7.66
13
(
2H, m, ArH), 7.79 (1H, d, J = 16.0 Hz, -CH=CHCO-). C-NMR (500 MHz, CDCl3):
δ 55.4, 56.1, 110.5,
1
13.7, 114.3, 119.3, 123.5, 127.8, 130.1, 131.2, 143.8, 146.8, 150.2, 161.5, 188.6. LCMS (ES+) m/z = 285.2
+
([M + H] , t = 1.75 min). These characterisation data are in accordance with that previously reported
R
in the literature [38].
E)-1-(5-Bromo-2-hydroxyphenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (14). A mixture of indole
aldehyde (1.03 g, 6.47 mmol), acetophenone 12 (1.38 g, 6.42 mmol) and piperidine (0.62 mL,
.28 mmol) in absolute EtOH (100 mL) was reacted according to GP-E. The crude residue was purified
by recrystallization from MeOH to afford chalcone 14 (2.15 g, 94%) as a bright orange fluffy solid.
(
6
6
◦
−1
m.p. 250–252 C. TLC R = 0.45 (PE/EtOAc 2:1). IR νmax (neat)/cm : 3101w (C-H str), 2885w
f
(
1
C-H str), 1626s (C=O str), 1541m (C=C str), 1513s (C=C str), 1462m, 1387m, 1375m, 1344m, 1295m,
1
252s, 1177s, 1126s, 1074s, 1028s, 1014m. H-NMR (500 MHz, CDCl ):
δ
3.88 (3H, s, -NCH ), 6.93
3
3
(1H, d, J = 8.8 Hz, ArH), 7.38–7.40 (3H, m, ArH), 7.49–7.56 (2H, m, ArH), 7.55 (1H, d, J = 15.6 Hz,
-
CH=CHCO-), 8.00–8.03 (2H, m, ArH), 8.23 (1H, d, J = 15.2 Hz, -CH=CHCO-), 13.25 (1H, br s, OH).
1
3
C-NMR (500 MHz, CDCl3):
31.5, 135.6, 138.1, 138.4, 140.4, 162.4, 192.5. LCMS (ES+) m/z = 358.0 ([M + H] , t = 4.96 min). HRMS
δ
33.5, 110.2, 110.3, 113.1, 113.6, 120.5, 120.8, 121.7, 122.1, 123.6, 126.1,
+
1
(
R
+
+
ESI+) m/z = 356.0279 [M + H] found, C H O NBr required 356.0281.
18 15 2
(
7
E)-1-(2-Hydroxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (15). A mixture of pyrrole aldehyde
(4.00 mL, 37.2 mmol), acetophenone 10 (4.50 mL, 37.4 mmol) and piperidine (3.80 mL, 38.5 mmol)
in absolute EtOH (100 mL) was reacted according to GP-E. The crude residue was purified by
recrystallization from MeOH to afford chalcone 15 (2.28 g, 27%) as a bright yellow-orange powdery
◦
−1
solid. m.p. 98–100 C. TLC R = 0.45 (PE/EtOAc; 3:1). IR νmax (neat)/cm : 3112w (C-H str), 2937w
f
(
1
C-H str), 1627s (C=O str), 1579w (C=C str), 1549s (C=C str), 1479s, 1440m, 1412m, 1384m, 1356w,
1
338m, 1290m, 1260s, 1249s, 1203s, 1182w, 1155s, 1092w, 1061s, 1025s. H-NMR (500 MHz, CDCl ):
3
δ
7
7
3.81 (3H, s, -NCH ), 6.26–6.27 (1H, m, ArH), 6.87 (1H, t, J = 2.0 Hz, ArH), 6.91–6.96 (2H, m, ArH),
3
.02 (1H, dd, J = 8.4, 0.8 Hz, ArH), 7.40 (1H, d, J = 14.8 Hz, -CH=CHCO-), 7.48 (1H, t, J = 8.4 Hz, ArH),
.89 (1H, dd, J = 8.0, 2.0 Hz, ArH), 7.92 (1H, d, J = 14.8 Hz, -CH=CHCO-), 13.14 (1H, s, OH). 13C-NMR
(
1
500 MHz, CDCl3): δ 34.4, 110.2, 113.3, 114.5, 118.5, 118.7, 120.2, 128.6, 129.2, 130.2, 132.8, 135.8, 163.4,
+
+
93.1. LCMS (ES+) m/z = 228.1 ([M + H] , t = 1.68 min). HRMS (ESI+) m/z = 228.1020 [M + H]
R
+
found, C H O N required 228.1019.
14
14
2
(
E)-1-(4-Hydroxy-3-methoxyphenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (16). A mixture of pyrrole
aldehyde (3.30 mL, 30.7 mmol), acetophenone 11 (5.02 g, 30.2 mmol) and KOH (10.2 g, 182 mmol)
in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash
7
column chromatography (SiO , PE/EtOAc; 5:1) and recrystallized from absolute EtOH to afford
2
◦
chalcone 16 (4.28 g, 55%) as a dark red-brown powdery solid. m.p. 150–152 C. TLC R = 0.31
PE/EtOAc; 1:1). IR νmax (neat)/cm : 3177m(br) (O-H str), 2958w (C-H str), 2930w (C-H str), 1630m
f
−
1
(
(
1
C=O str), 1600m (C=C str), 1587m (C=C str), 1543s (C=C str), 1508s (C=C str), 1478m, 1380w, 1333m,
1
270s, 1218m, 1196s, 1169s, 1052s, 1031s. H-NMR (500 MHz, CDCl ):
δ
3.77 (3H, s, -NCH ), 3.99
3
3
(3H, s, -OCH3), 6.18 (1H, s, OH), 6.23 (1H, t, J = 3.2 Hz, ArH), 6.81 (1H, t, J = 2.0 Hz, ArH), 6.84
(
7
5
1H, dd, J = 4.0, 1.6 Hz, ArH), 6.99 (1H, d, J = 8.8 Hz, ArH), 7.32 (1H, d, J = 15.2 Hz, -CH=CHCO-),
.62–7.64 (2H, m, ArH), 7.81 (1H, d, J = 14.8 Hz, -CH=CHCO-). 1 C-NMR (500 MHz, CDCl3):
3
δ
34.3,
6.1, 109.6, 110.4, 112.0, 113.7, 116.4, 123.1, 127.5, 130.3, 131.5, 131.5, 146.8, 150.0, 188.1. LCMS (ES+)
+
+
+
m/z = 258.1 ([M + H] , t = 1.40 min). HRMS (ESI+) m/z =280.0935 [M + Na] found, C H O NNa
R
15 15
3
required 280.0944.
(E)-1-(5-Bromo-2-hydroxyphenyl)-3-(furan-2-yl)prop-2-en-1-one (17). A mixture of furan aldehyde
8
(1.20 mL, 14.5 mmol), acetophenone 12 (3.06 g, 14.2 mmol) and KOH (4.70 g, 83.8 mmol) in absolute

Molecules 2016, 21, 1230
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EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization
◦
from MeOH to afford chalcone 17 (1.97 g, 47%) as a bright yellow-orange fluffy solid. m.p. 80–82 C
.
−
1
TLC R = 0.50 (PE/EtOAc; 3:1). IR νmax (neat)/cm : 3128w (C-H str), 3046w (C-H str), 2868w
f
(
1
C-H str), 1638m (C=O str), 1567s (C=C str), 1548s (C=C str), 1467s, 1364m, 1335s, 1296m, 1258s, 1202s,
1
177s, 1077w, 1013s. H-NMR (500 MHz, CDCl ):
δ
6.56–6.57 (1H, m, ArH), 6.82 (1H, d, J = 3.6 Hz
,
3
ArH), 6.93 (1H, d, J = 8.8 Hz, ArH), 7.45 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.56 (1H, dd, J = 9.2
,
2
.4 Hz, ArH), 7.60 (1H, d, J = 0.8 Hz, ArH), 7.70 (1H, d, J = 15.2 Hz, -CH=CHCO-), 8.00 (1H, d,
13
J = 2.4 Hz, ArH), 12.83 (1H, s, OH). C-NMR (500 MHz, CDCl3):
δ
110.4, 113.0, 116.8, 117.8, 120.5,
+
121.2, 131.8, 131.9, 138.8, 145.8, 151.3, 162.4, 192.3. LCMS (ES+) m/z = 293.1 ([M + H] , t = 1.85 min).
R
These characterisation data are in accordance with that previously reported in the literature [39].
E)-3-(Ferrocenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (18). A mixture of ferrocene aldehyde (4.77 g,
2.3 mmol), acetophenone 10 (2.70 mL, 22.4 mmol) and KOH (7.63 g, 136 mmol) in absolute EtOH
(
9
2
(
100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization from
◦
MeOH to afford chalcone 18 (4.99 g, 67%) as a dark purple microcrystalline solid. m.p. 162–164 C.
TLC R = 0.43 (PE/EtOAc; 7:1). IR νmax (neat)/cm : 3315w(br) (O-H str), 3088w (C-H str), 1742w
−
1
f
(
1
C=O str), 1627m, 1554s (C=C str), 1489s, 1440m, 1383w, 1347m, 1302s, 1271m, 1246m, 1206s, 1158m,
1
104m, 1048w, 1023m, 1002w. H-NMR (500 MHz, CDCl ):
δ
4.21 (5H, s, -C H ), 4.55 (2H, t, J = 2.0 Hz
,
3
5
5
-
C H ), 4.65 (2H, t, J = 2.0 Hz, -C H ), 6.94 (1H, t, J = 8.0 Hz, ArH), 7.03 (1H, dd, J = 8.5, 1.0 Hz,
5 4 5 4
ArH), 7.26 (1H, d, J = 15.0 Hz, -CH=CHCO-, overlain by CDCl ), 7.49 (1H, t, J = 8.5 Hz, ArH), 7.87
3
13
(
(
1H, dd, J = 8.0, 1.0 Hz, ArH), 7.91 (1H, d, J = 15.0 Hz, -CH=CHCO-), 13.07 (1H, s, OH). C-NMR
500 MHz, CDCl3):
δ
69.3, 69.9, 71.8, 78.8, 116.7, 118.6, 118.6, 120.0, 129.3, 135.9, 147.9, 163.6, 192.7.
+
LCMS (ES+) m/z = 333.1 ([M + H] , t = 1.87 min). These characterisation data are in accordance with
R
that previously reported in the literature [40].
(
9
E)-3-(Ferrocenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-en-1-one (19). A mixture of ferrocene aldehyde
(3.86 g, 18.0 mmol), acetophenone 11 (3.05 g, 18.4 mmol) and KOH (6.10 g, 109 mmol) in
absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash
column chromatography (SiO , PE/EtOAc; 5:1) to afford chalcone 19 (5.61 g, 86%) as a dark purple
2
◦
−1
microcrystalline solid. m.p. 78–80 C. TLC R = 0.29 (PE/EtOAc; 2:1). IR νmax (neat)/cm : 3098w(C-H
f
str), 2835w (C-H str), 1743w, 1642m, (C=O str) 1588s (C=C str), 1563s (C=C str), 1511s (C=C str), 1462m,
1
1
424s, 1359m, 1347m, 1281s, 1264s, 1189s, 1162s, 1026s, 1001w. H-NMR (500 MHz, CDCl ):
δ. 3.95
3
(3H, s, -OCH ), 4.17 (5H, s, -C H ), 4.47 (2H, t, J = 2.0 Hz, -C H ), 4.59 (2H, t, J = 2.0 Hz, -C H ), 6.54
3 5 5 5 4 5 4
(
1H, br s, OH), 7.00 (1H, d, J = 8.0 Hz, ArH), 7.16 (1H, d, J = 15.0 Hz, -CH=CHCO-), 7.60 (1H, dd,
J = 8.5, 1.5 Hz, ArH), 7.63 (1H, d, J = 1.5 Hz, ArH), 7.76 (1H, d, J = 15.5 Hz, -CH=CHCO-). 13C-NMR
(
500 MHz, CDCl3): δ 56.0, 68.8, 69.7, 71.2, 79.3, 110.5, 113.8, 118.5, 123.2, 131.1, 145.8, 146.8, 150.1, 187.9.
+
+
LCMS (ES+) m/z = 363.1 ([M + H] , t = 1.66 min). HRMS (ESI+) m/z = 363.0595 [M + H] found,
C H O Fe required 363.0600.
R
+
20
19
3
(E)-1-(3-Methoxy-4-(prop-2-yn-1-yloxy)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (20). A mixture of
chalcone 13 (1.02 g, 3.57 mmol), propargyl bromide (0.63 mL, 7.07 mmol) and anhydrous K CO
2
3
(1.49 g, 10.8 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was
purified by flash column chromatography (SiO , CH Cl ) to afford chalcone 20 (1.07 g, 93%) as a
2
2
2
◦
−1
pale yellow powdery solid. m.p. 168–170 C. TLC R = 0.41 (CH Cl ). IR νmax (neat)/cm : 3251w
f
2
2
(
C
≡
C-H str), 2990w (C-H str), 2835w (C-H str), 2116w (C C str), 1651s (C=O str), 1598s (C=C str),
≡
1
577s (C=C str), 1508s (C=C str), 1466m, 1421s, 1382w, 1323m, 1257s, 1229s, 1165s, 1145s, 1056w, 1015s.
H-NMR (500 MHz, CDCl3):
1
δ
2.57 (1H, t, J = 2.4 Hz, -OCH C CH), 3.87 (3H, s, -OCH ), 3.98 (3H, s,
≡
2
3
-OCH ), 4.87 (2H, d, J = 2.4 Hz, -OCH C CH), 6.95 (2H, d, J = 8.8 Hz, ArH), 7.11 (2H, d, J = 8.4 Hz,
≡
3
2
ArH), 7.44 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.62 (2H, d, J = 8.8 Hz, ArH), 7.65 (1H, d, J = 2.0 Hz,
ArH), 7.68 (1H, dd, J = 8.4, 2.0 Hz, ArH), 7.80 (1H, d, J = 15.6 Hz, -CH=CHCO-). 13C-NMR (500 MHz,
CDCl3):
δ 55.4, 56.1, 56.6, 76.4, 77.8, 111.3, 112.3, 114.4, 119.3, 122.3, 127.7, 130.1, 132.6, 144.0, 149.7,

Molecules 2016, 21, 1230
22 of 59
+
1
50.7, 161.6, 188.7. LCMS (ES+) m/z = 323.2 ([M + H] , t = 1.56 min). HRMS (ESI+) m/z = 323.1265
R
+
+
[M + H] found, C H O required 323.1278.
20 19 4
(
E)-1-(5-Bromo-2-(prop-2-yn-1-yloxy)phenyl)-3-(1-methyl-1H-indol-3-yl)prop-2-en-1-one (21). A mixture
of indole chalcone 14 (2.07 g, 5.81 mmol), propargyl bromide (1.50 mL, 16.8 mmol) and anhydrous
K CO (2.52 g, 18.2 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue
2
3
was purified by flash column chromatography (SiO , CH Cl ) to afford chalcone 21 (2.20 g, 96%)
2
2
2
◦
−1
as a bright yellow powdery solid. m.p. 126–128 C. TLC R = 0.20 (CH Cl ). IR νmax (neat)/cm
:
f
2
2
3
257w (C
≡
C-H str), 3070w (C-H str), 2942w (C-H str), 2114w (C C str), 1638s (C=O str), 1587m
≡
(
C=C str), 1544s (C=C str), 1524s (C=C str), 1473m, 1373s, 1269s, 1213m, 1176s, 1133m, 1073m, 1006s.
H-NMR (500 MHz, CDCl ): δ 2.55 (1H, t, J = 2.4 Hz, -OCH C≡CH), 3.82 (3H, s, -NCH ), 4.79 (2H, d,
1
3
2
3
J = 2.4 Hz, -OCH C
≡
CH), 7.03 (1H, d, J = 9.2 Hz, ArH), 7.26–7.38 (3H, m, ArH), 7.38 (1H, d, J = 16.0 Hz,
2
-
(
5
CH=CHCO-), 7.41 (1H, s, ArH), 7.55 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.77 (1H, d, J = 2.4 Hz, ArH), 7.88
1H, d, J = 15.6 Hz, -CH=CHCO-), 8.01 (1H, d, J = 8.0 Hz, ArH). 13C-NMR (500 MHz, CDCl3):
33.3,
6.6, 76.4, 77.8, 110.0, 112.9, 114.3, 115.3, 121.0, 121.5, 121.6, 123.2, 126.0, 132.6, 132.9, 134.3, 134.8, 138.2,
δ
+
138.6, 154.6, 191.0. LCMS (ES+) m/z = 396.1 ([M + H] , t = 1.98 min). HRMS (ESI+) m/z = 394.0425
R
+
+
[M + H] found, C H NO Br required 394.0443.
21 17 2
(
E)-1-(3-Methoxy-4-(prop-2-yn-1-yloxy)phenyl)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-en-1-one (22). A mixture
of pyrrole chalcone 16 (1.00 g, 3.89 mmol), propargyl bromide (0.70 mL, 7.86 mmol) and anhydrous
K CO (1.61 g, 1.17 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue
2
3
was purified by flash column chromatography (SiO , PE/EtOAc; 3:1) to afford chalcone 22 (1.06 g,
2
◦
9
2%) as a bright yellow powdery solid. m.p. 164–166 C. TLC R = 0.41 (PE/EtOAc; 1:1). IR νmax
f
−
1
(
neat)/cm : 3234m (C
C=C str), 1561s (C=C str), 1515m (C=C str), 1483m, 1416w, 1374m, 1346s, 1272s, 1179m, 1129s, 1087w,
042m, 1012m. 1H-NMR (500 MHz, CDCl3):
2.56 (1H, t, J = 2.5 Hz, -OCH C CH), 3.78 (3H, s,
NCH ), 3.98 (3H, s, -OCH ), 4.86 (1H, d, J = 2.5 Hz, -OCH C CH), 6.23–6.24 (1H, m, ArH), 6.82
1H, t, J = 2.0 Hz, ArH), 6.85 (1H, dd, J = 4.0, 1.0 Hz, ArH), 7.10 (1H, d, J = 8.0 Hz, ArH), 7.32 (1H, d,
J = 15.0 Hz, -CH=CHCO-), 7.64–7.67 (2H, m, ArH), 7.82 (1H, d, J = 15.0 Hz, -CH=CHCO-). 13C-NMR
≡
C-H str), 2995w (C-H str), 2866w (C-H str), 1739m (C=O str), 1645m, 1598s,
(
1
-
(
δ
≡
2
≡
3
3
2
(
1
500 MHz, CDCl3):
δ
34.4, 56.1, 56.6, 76.4, 77.8, 109.7, 111.2, 112.1, 112.4, 116.4, 122.0, 127.6, 130.3,
+
31.7, 132.9, 149.6, 150.5, 188.1. LCMS (ES+) m/z = 296.2 ([M + H] , t = 1.57 min). HRMS (ESI+)
R
+
+
m/z = 294.1119 [M − H] found, C H O N required 294.1125.
18
16
3
(
E)-3-(1-Methyl-1H-pyrrol-2-yl)-1-(2-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (23). A mixture of pyrrole
chalcone 15 (308 mg, 1.32 mmol), propargyl bromide (0.25 mL, 2.81 mmol) and anhydrous K CO
2
3
(568 mg, 4.11 mmol) in dry acetone (20 mL) was reacted according to GP-C. The crude residue was
purified by flash column chromatography (SiO , PE/EtOAc; 3:1) to afford chalcone 23 (352 mg,
2
−
8%) as a bright yellow viscous oil. TLC R = 0.34 (PE/EtOAc; 2:1). IR νmax (neat)/cm : 3283w
f
1
9
(
C
≡
C-H str), 3072w (C-H str), 2923w (C-H str), 2120w (C
≡
C str), 1698w (C=O str), 1647m, 1598s (C=C
1
str), 1580s (C=C str), 1564s (C=C str), 1480s, 1450m, 1330m, 1287s, 1217s, 1113w, 1057m, 1018s. H-NMR
(
-
500 MHz, CDCl3):
OCH C CH), 6.20–6.21 (1H, m, ArH), 6.78–6.80 (2H, m, ArH), 7.08–7.12 (2H, m, ArH), 7.19 (1H, d,
J = 15.2 Hz, -CH=CHCO-), 7.47 (1H, t, J = 8.8 Hz, ArH), 7.65 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.66
1H, dd, J = 7.6, 2.0 Hz, ArH). 13C-NMR (500 MHz, CDCl3):
34.5, 56.4, 75.9, 78.2, 109.6, 112.8, 113.3,
21.8, 121.9, 127.7, 130.2, 130.5, 130.5, 131.1, 132.2, 155.7, 191.9. LCMS (ES+) m/z = 266.1 ([M + H]+
δ
2.54 (1H, t, J = 2.4 Hz, -OCH C
≡
CH), 3.74 (3H, s, -NCH ), 4.79 (2H, d, J = 2.4 Hz,
2
3
≡
2
(
1
δ
,
+
+
t = 1.57 min). HRMS (ESI+) m/z = 266.1183 [M + H] found, C H NO required 266.1181.
R
17 16
2
(E)-1-(5-Bromo-2-(prop-2-yn-1-yloxy)phenyl)-3-(furan-2-yl)prop-2-en-1-one (24). A mixture of furan
chalcone 17 (2.02 g, 6.89 mmol), propargyl bromide (1.30 mL, 14.6 mmol) and anhydrous K CO
2
3
(2.90 g, 21.0 mmol) in dry acetone (100 mL) was reacted according to GP-C. The crude residue was
purified by flash column chromatography (SiO , CH Cl ) to afford chalcone 24 (2.14 g, 94%) as a pale
2
2
2
◦
−1
:
yellow-brown powdery solid. m.p. 82–84 C. TLC R = 0.21 (PE/CH Cl ; 1:1). IR νmax (neat)/cm
f
2
2

Molecules 2016, 21, 1230
23 of 59
3
224m (C
≡
C-H str), 3118w (C-H str), 2118w (C
≡
C str), 1660m (C=O str), 1600s (C=C str), 1586m
(C=C str), 1554m (C=C str), 1476m, 1394m, 1313w, 1276m, 1211s, 1180m, 1131m, 1079w, 1048m,
1
1
012s. H-NMR (500 MHz, CDCl ):
δ
2.54 (1H, t, J = 2.4 Hz, -OCH C
≡
CH), 4.78 (2H, d, J = 2.4 Hz,
CH), 6.50–6.51 (1H, m, ArH), 6.70 (1H, d, J = 3.6 Hz, ArH), 7.03 (1H, d, J = 8.8 Hz, ArH),
.21 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.40 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.52 (1H, d, J = 1.2 Hz,
3
2
-OCH C
≡
2
7
13
ArH), 7.56 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.73 (1H, d, J = 2.4 Hz, ArH). C-NMR (500 MHz, CDCl3):
56.6, 76.5, 77.6, 112.6, 114.3, 115.4, 116.2, 123.8, 130.4, 131.6, 133.0, 135.0, 145.1, 151.5, 154.8, 190.5.
δ
+
+
LCMS (ES+) m/z = 333.0 ([M + H] , t = 1.89 min). HRMS (ESI+) m/z = 330.9973 [M + H] found,
C H O Br required 330.9970.
R
+
16
12
3
(E)-3-(Ferrocenyl)-1-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (25). A mixture of ferrocene
chalcone 19 (1.01 g, 2.79 mmol), propargyl bromide (0.50 mL, 5.61 mmol) and anhydrous K CO
2
3
(1.18 g, 8.56 mmol) in dry acetone (50 mL) was reacted according to GP-C. The crude residue was
purified by flash column chromatography (SiO , CH Cl ) to afford chalcone 25 (1.01 g, 91%) as a dark
2
2
2
◦
red-purple microcrystalline solid. m.p. 128–130 C. TLC R = 0.47 (0.5% MeOH/CH Cl ). IR νmax
C-H str), 3008w (C-H str), 2939w (C-H str), 2114w (C C str), 1646s (C=O
str), 1595m (C=C str), 1567s (C=C str), 1506m (C=C str), 1456m, 1413s, 1345w, 1295s, 1259s, 1194m,
f
2
2
−
1
(
neat)/cm : 3225m (C
≡
≡
1
1
159s, 1136s, 1107m, 1060w, 1044m, 1020s. H-NMR (500 MHz, CDCl3):
δ
2.56 (1H, t, J = 2.5 Hz,
-
OCH C
≡
CH), 3.96 (3H, s, -OCH ), 4.18 (5H, s, -C H ), 4.48 (2H, t, J = 2.0 Hz, -C H ), 4.60 (2H, t,
2
3
5
5
5
4
J = 2.0 Hz, -C H ), 4.85 (2H, d, J = 2.0 Hz, -OCH C
J = 15.5 Hz, -CH=CHCO-), 7.61–7.63 (2H, m, ArH), 7.75 (1H, d, J = 15.0 Hz, -CH=CHCO-). C-NMR
≡
CH), 7.09 (1H, d, J = 8.5 Hz, ArH), 7.15 (1H, d,
5
4
2
13
(
1
[
500 MHz, CDCl3):
δ
56.0, 56.5, 68.9, 69.7, 71.2, 76.3, 77.8, 79.3, 111.2, 112.3, 118.5, 122.1, 132.6, 146.0,
+
49.5, 150.4, 187.9. LCMS (ES+) m/z = 401.1 ([M + H] , t = 1.81 min). HRMS (ESI+) m/z = 401.0823
R
+
+
M + H] found, C H O Fe required 401.0840.
23 21 3
(
3
E)-3-(Ferrocenyl)-1-(2-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (26). A mixture of chalcone 18 (1.02 g,
.07 mmol), propargyl bromide (0.54 mL, 6.02 mmol) and anhydrous K CO (1.20 g, 8.68 mmol) in
2
3
dry acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column
chromatography (SiO , PE/CH Cl ; 1:1) to afford chalcone 26 (919 mg, 81%) as a bright red powdery
2
2
2
◦
−1
solid. m.p. 90–92 C. TLC R = 0.38 (CH Cl ). IR νmax (neat)/cm : 3257m (C
≡
C-H str), 2924w
C str), 1654s (C=O str), 1587s (C=C str), 1480m, 1448m, 1356w,
f
2
2
(
1
C-H str), 2850w (C-H str), 2117w (C
≡
1
345w, 1289m, 1211s, 1159w, 1104m, 1058m, 1016s, 1001s. H-NMR (500 MHz, CDCl ):
δ
2.56 (1H, t,
3
J = 2.5 Hz, -OCH C CH), 4.19 (5H, s, -C H ), 4.46 (2H, t, J = 2.0 Hz, -C H ), 4.56 (2H, t, J = 2.0 Hz,
≡
2
5 5 5 4
-
C H ), 4.79 (2H, d, J = 2.5 Hz, -OCH C
≡
CH), 6.95 (1H, d, J = 16.0 Hz, -CH=CHCO-), 7.09–7.13 (2H,
5
4
2
m, ArH), 7.47 (1H, t, J = 9.0 Hz, ArH), 7.50 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.58 (1H, dd, J = 7.5,
.5 Hz, ArH). 13C-NMR (500 MHz, CDCl3):
1
1
δ
56.3, 69.0, 69.8, 71.2, 76.0, 78.2, 79.0, 113.3, 121.7, 124.6,
+
30.1, 130.5, 131.9, 146.2, 155.4, 192.5. LCMS (ES+) m/z = 371.1 ([M + H] , t = 1.96 min). HRMS (ESI+)
R
+
+
m/z = 370.0639 [M] found, C H O Fe required 370.0651.
22
18
2
3-(Prop-2-yn-1-yloxy)flavone (30). A mixture of 3-hydroxyflavone 27 (2.06 g, 8.65 mmol), propargyl
bromide (1.50 mL, 16.8 mmol) and anhydrous K CO (3.48 g, 25.2 mmol) in dry acetone (100 mL) was
2
3
reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO ,
2
◦
CH Cl ) to afford flavone 30 (2.38 g, 99%) as a pale yellow-white powdery solid. m.p. 104–106 C.
2
2
−
1
TLC R = 0.24 (CH Cl ). IR νmax (neat)/cm : 3254m (C
≡
C-H str), 2946w (C-H str), 2114w (C C str),
612s (C=O str), 1600s, 1557s (C=C str), 1468s, 1445m, 1399s, 1354m, 1345m, 1279w, 1234w, 1195s, 1185s,
≡
f
2
2
1
1
1
148s, 1110m, 1079w, 1036m. H-NMR (500 MHz, CDCl ):
CH), 7.42 (1H, t, J = 8.0 Hz, ArH), 7.50–7.54 (3H, m, ArH), 7.56 (1H, d,
J = 8.4 Hz, ArH), 7.70 (1H, t, J = 8.4 Hz, ArH), 8.14–8.16 (2H, m, ArH), 8.27 (1H, dd, J = 8.0, 1.6 Hz, ArH).
59.1, 76.1, 78.5, 118.0, 123.9, 124.7, 125.7, 128.3, 128.9, 130.7, 130.9, 133.5,
38.5, 155.2, 156.7, 174.8. LCMS (ES+) m/z = 277.5 ([M + H] , t = 4.47 min). These characterisation
δ
2.33 (1H, t, J = 2.4 Hz, -OCH C CH), 5.00
≡
3
2
(2H, d, J = 2.4 Hz, -OCH C
≡
2
13
C-NMR (500 MHz, CDCl3):
δ
+
1
R
data are in accordance with that previously reported in the literature [23].

Molecules 2016, 21, 1230
24 of 59
6-(Prop-2-yn-1-yloxy)flavone (31). A mixture of 6-hydroxyflavone 28 (2.00 g, 8.39 mmol), propargyl
bromide (1.50 mL, 16.8 mmol) and anhydrous K CO (3.50 g, 25.3 mmol) in dry acetone (100 mL) was
2
3
reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO ,
2
◦
1
% MeOH/CH Cl ) to afford flavone 31 (2.03 g, 87%) as a white crystalline solid. m.p. 170–172 C
.
2
2
−
1
TLC R = 0.44 (1% MeOH/CH Cl ). IR νmax (neat)/cm : 3266m (C
2
≡
C-H str), 3059w (C-H str),
C str), 1623s (C=O str), 1606s, 1582s (C=C str), 1568s (C=C str), 1497m, 1482m, 1455s, 1365s,
f
2
2
116w (C
≡
1
1
283m, 1259m, 1234m, 1186s, 1144s, 1075m, 1048m, 1007s. H-NMR (500 MHz, CDCl ):
δ
2.57 (1H, t,
CH), 6.77 (1H, s, -C=CH), 7.31 (1H, dd,
J = 9.2, 3.2 Hz, ArH), 7.46–7.51 (4H, m, ArH), 7.65 (1H, d, J = 3.2 Hz, ArH), 7.86–7.88 (2H, m, ArH).
3
J = 2.4 Hz, -OCH C
≡
CH), 4.76 (2H, d, J = 2.4 Hz, -OCH C
≡
2
2
13
C-NMR (500 MHz, CDCl3):
δ
56.3, 76.0, 77.7, 106.4, 106.7, 119.6, 123.9, 124.4, 126.1, 128.9, 131.4, 131.6,
+
151.3, 154.7, 163.0, 177.9. LCMS (ES+) m/z = 277.0 ([M + H] , t = 1.56 min). These characterisation
R
data are in accordance with that previously reported in the literature [24].
-(Prop-2-yn-1-yloxy)flavone (32). A mixture of 7-hydroxyflavone 29 (990 mg, 4.16 mmol), propargyl
bromide (0.748 mL, 8.39 mmol) and anhydrous K CO (1.75 g, 12.7 mmol) and in dry acetone (100 mL)
7
2
3
was reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO ,
2
◦
1
% MeOH/CH Cl ) to afford flavone 32 (1.10 g, 95%) as an off-white powdery solid. m.p. 216–218 C.
2
2
−
1
TLC R = 0.44 (2% MeOH/CH Cl ). IR νmax (neat)/cm : 3194w (C C-H str), 2921w (C-H str), 2115w
≡
f
2
2
(
C
≡
C str), 1619s (C=O str), 1591s (C=C str), 1568s (C=C str), 1496m, 1451s, 1435s, 1378s, 1350m, 1268m,
1
1
229m, 1168s, 1135s, 1091s, 1017s. H-NMR (500 MHz, CDCl ):
δ
2.62 (1H, t, J = 2.4 Hz, -OCH C CH),
.83 (2H, d, J = 2.4 Hz, -OCH C CH), 6.77 (1H, s, -C=CH), 7.05 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.09
≡
3
2
4
≡
2
(
1H, d, J = 2.4 Hz, ArH), 7.51–7.55 (3H, m, ArH), 7.90–7.93 (2H, m, ArH), 8.17 (1H, d, J = 8.8 Hz, ArH).
1
3
C-NMR (500 MHz, CDCl3):
57.7, 161.9, 163.1, 177.7. LCMS (ES+) m/z = 277.0 ([M + H] , t = 1.54 min). These characterisation
δ
56.2, 76.6, 77.3, 101.8, 107.6, 114.7, 118.4, 126.2, 127.2, 129.0, 131.5, 131.8,
+
1
R
data are in accordance with that previously reported in the literature [24].
-(Prop-2-yn-1-yloxy)benzaldehyde (34). A mixture of benzaldehyde 33 (10.2 g, 83.7 mmol), propargyl
bromide (14.6 mL, 164 mmol) and anhydrous K CO (22.7 g, 165 mmol) in dry acetone (200 mL)
4
2
3
was reacted according to GP-C. The crude residue was purified by flash column chromatography
◦
(
SiO , CH Cl ) to afford benzaldehyde 34 (12.2 g, 91%) as a white crystalline solid. m.p. 88–90 C.
2
2
2
−
1
TLC R = 0.49 (CH Cl ). IR νmax (neat)/cm : 3205m (C
2
1
d, J = 2.4 Hz, -OCH C
CHO). C-NMR (500 MHz, CDCl ):
=
≡
C-H str), 2971w (C-H str), 2837w (C-H str),
C str), 1739s (C=O str), 1679s, 1601s, 1576s (C=C str), 1508m (C=C str), 1428w, 1384s, 1245s,
f
2
2
123w (C
≡
1
217s, 1170s, 1009s. H-NMR (500 MHz, CDCl ):
δ
2.58 (1H, t, J = 2.4 Hz, -OCH C
≡
CH), 4.77 (2H,
3
2
≡
CH), 7.08 (2H, d, J = 8.8 Hz, ArH), 7.85 (2H, d, J = 8.8 Hz, ArH), 9.89 (1H, s,
δ 55.9, 76.3, 77.5, 115.1, 130.5, 131.8, 162.3, 190.7. LCMS (ES+) m/z
161.1 ([M + H] , t = 1.65 min). These characterisation data are in accordance with that previously
2
13
3
+
R
reported in the literature [41].
E)-1-(2-Hydroxyphenyl)-3-(4-(prop-2-yn-1-yloxy)phenyl)prop-2-en-1-one (35). A mixture of benzaldehyde
(5.04 g, 31.5 mmol), acetophenone 10 (3.76 mL, 31.2 mmol), and KOH (10.6 g, 189 mmol) in absolute
(
3
4
EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization
◦
from MeOH to afford chalcone 35 (6.67 g, 77%) as a bright yellow powdery solid. m.p. 144–146 C
.
−
1
TLC R = 0.45 (PE/EtOAc; 3:1). IR νmax (neat)/cm : 3487w (O-H str), 3240m (C
≡
C-H str), 2923w
f
(
1
C-H str), 2124w (C
368m, 1299s, 1270m, 1203m, 1177s, 1159s, 1027s. H-NMR (500 MHz, CDCl ):
≡
C str), 1634s (C=O str), 1604m, 1559s (C=C str), 1509s (C=C str), 1488s, 1442m,
1
δ
2.58 (1H, t, J = 2.4 Hz
,
3
-
OCH C
≡
CH), 4.75 (2H, d, J = 2.4 Hz, -OCH C
≡
CH), 6.94 (1H, t, J = 7.6 Hz, ArH), 7.03 (3H, d,
2
2
J = 8.4 Hz, ArH), 7.49 (1H, t, J = 8.4 Hz, ArH), 7.54 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.63 (2H, d,
J = 8.8 Hz, ArH), 7.89 (1H, d, J = 15.2 Hz, -CH=CHCO-), 7.90–7.92 (1H, m, ArH), 12.93 (1H, s, OH).
1
3
C-NMR (500 MHz, CDCl3):
δ
55.8, 76.1, 77.9, 115.3, 118.0, 118.5, 118.7, 120.0, 128.0, 129.5, 130.4,
+
1
36.1, 145.0, 159.7, 163.5, 193.5. LCMS (ES+) m/z = 279.1 ([M + H] , t = 1.75 min). HRMS (ESI+)
R
+
+
m/z = 279.1005 [M + H] found, C H O required 279.1016.
18
15
3

Molecules 2016, 21, 1230
25 of 59
0
3
-Hydroxy-4 -(prop-2-yn-1-yloxy)flavone (36). A mixture of chalcone 35 (2.02 g, 7.26 mmol), 16% NaOH
(
14.4 mL) and 15% H O (7.19 mL) in MeOH (50 mL) was reacted according to GP-F. The crude residue
2 2
was purified by flash column chromatography (SiO , 1% MeOH/CH Cl ) to afford flavonol 36 (1.56 g,
2
2
2
◦
7
3%) as a pale yellow-white powdery solid. m.p. 194–196 C. TLC R = 0.44 (0.5% MeOH/CH Cl ). IR
C-H str), 3260w (O-H str), 2979w (C-H str), 2119w (C C str), 1599s (C=O
str), 1562s (C=C str), 1507m (C=C str), 1483m, 1470m, 1427m, 1411m, 1233s, 1216m, 1180s, 1120s, 1109s,
2.58 (1H, t, J = 2.4 Hz, -OCH C
CH), 7.00 (1H, br s, OH), 7.14 (2H, d, J = 9.2 Hz, ArH), 7.42 (1H, t, J = 8.0 Hz, ArH), 7.58
1H, d, J = 8.4 Hz, ArH), 7.70 (1H, t, J = 8.4 Hz, ArH), 8.25–8.28 (3H, m, ArH). C-NMR (500 MHz,
CDCl3): 55.8, 76.0, 78.0, 115.0, 118.2, 120.7, 124.4, 124.4, 125.4, 129.5, 133.4, 137.8, 145.0, 155.3, 158.9,
73.2. LCMS (ES+) m/z = 293.1 ([M + H] , t = 1.62 min). HRMS (ESI+) m/z = 315.0618 [M + Na]
f
2
2
−
1
νmax (neat)/cm : 3271s (C
≡
≡
1
1017s. H-NMR (500 MHz, CDCl ):
δ
≡
CH), 4.79 (2H, d, J = 2.4 Hz
,
3
2
-OCH C
≡
2
1
3
(
δ
+
+
1
R
+
found, C H O Na required 315.0628.
18
12
4
1
7
-(2-Hydroxy-4-methoxyphenyl)-2-(4-hydroxyphenyl)ethan-1-one (41). A mixture of phenol 37 (8.70 mL,
9.32 mmol) and phenylacetic acid 39 (10.1 g, 66.3 mmol) in BF3 OEt (85.0 mL, 677 mmol) was reacted
according to GP-G. The crude residue was purified by flash column chromatography (SiO , CH Cl )
·
2
2
2
2
◦
to afford phenylethanone 41 (13.2 g, 78%) as a white powdery solid. m.p. 158–160 C. TLC R = 0.38
f
−
1% MeOH/CH Cl ). IR νmax (neat)/cm : 3469w(br) (O-H str), 3221w(br ) (O-H str), 2984w (C-H
2 2
1
(
str), 2904w (C-H str), 1706w (C=O str), 1613s (C=C str), 1518s (C=C str), 1450m, 1437s, 1381m, 1354s,
1
1
291s, 1224s, 1202s, 1127s, 1021m. H-NMR (500 MHz, (CD ) CO):
δ
3.85 (3H, s, -OCH ), 4.19 (2H,
3
2
3
s, -COCH ), 6.42 (1H, d, J = 2.8 Hz, ArH), 6.49 (1H, dd, J = 8.8, 2.4 Hz, ArH), 6.80 (2H, d, J = 8.8 Hz,
2
ArH), 7.16 (2H, d, J = 8.4 Hz, ArH), 7.98 (1H, d, J = 9.2 Hz, ArH), 8.29 (1H, br s, OH), 12.80 (1H, s, OH).
1
3
C-NMR (500 MHz, (CD ) CO):
δ
43.7, 55.4, 101.0, 107.5, 113.2, 115.6, 125.9, 130.6, 133.1, 156.6, 166.0,
3
2
+
1
66.5, 203.5. LCMS (ES+) m/z = 259.1 ([M + H] , t = 1.47 min). These characterisation data are in
R
accordance with that previously reported in the literature [42].
-(2,4-Dihydroxyphenyl)-2-(4-methoxyphenyl)ethan-1-one (42). A mixture of phenol 38 (8.00 g, 72.7 mmol)
and phenylacetic acid 40 (10.2 g, 61.5 mmol) in BF3 OEt (70.0 mL, 557 mmol) was reacted according to
1
·
2
GP-G. The crude residue was purified by recrystallization from CHCl to afford phenylethanone
3
◦
4
2
(5.67 g, 36%) as a pale yellow-white powdery solid. m.p. 168–170 C. TLC R = 0.50 (1%
MeOH/CH Cl ). IR νmax (neat)/cm : 3349s(br) (O-H str), 2917w (C-H str), 2838w (C-H str), 1614s
f
−
1
2
2
(
1
C=O str), 1607s (C=C str), 1590s (C=C str), 1510s (C=C str), 1500m (C=C str), 1436m, 1412w, 1351s,
1
299m, 1239m, 1174s, 1129m, 1105w, 1023s. H-NMR (500 MHz, (CD ) CO):
δ
3.76 (3H, s, -OCH3),
3
2
4
.22 (2H, s, -COCH ), 6.33 (1H, d, J = 2.0 Hz, ArH), 6.44 (1H, dd, J = 9.2, 2.4 Hz, ArH), 6.88 (2H, d,
2
J = 8.8 Hz, ArH), 7.26 (2H, d, J = 8.8 Hz, ArH), 7.96 (1H, d, J = 8.8 Hz, ArH), 9.46 (1H, s, OH), 12.73 (1H,
s, OH). 13C-NMR (500 MHz, (CD ) CO):
δ
43.6, 54.8, 103.0, 108.2, 112.8, 114.1, 127.3, 130.7, 133.7, 159.0,
3
2
+
165.0, 166.1, 203.1. LCMS (ES+) m/z = 259.1 ([M + H] , t = 1.52 min). These characterisation data are
R
in accordance with that previously reported in the literature [43].
0
4
(
-Hydroxy-7-methoxyisoflavone (43). A mixture of phenylethanone 41 (2.00 g, 7.74 mmol), BF3 OEt2
·
3.90 mL, 31.1 mmol) and MeSO Cl (1.80 mL, 23.3 mmol) in dry DMF (50 mL) was reacted according
2
to GP-H. The crude residue was purified by flash column chromatography (SiO , PE/EtOAc; 2:1) to
2
◦
afford isoflavone 43 (1.18 g, 57%) as a white powdery solid. m.p. 232–234 C. TLC R = 0.39 (PE/EtOAc;
:1). IR νmax (neat)/cm : 3210m(br) (O-H str), 3014w (C-H str), 1621s (C=O str), 1583s (C=C str),
563m (C=C str), 1517s (C=C str), 1439s, 1373w, 1253s, 1205w, 1170w, 1095m, 1050m, 1019m. H-NMR
f
−
1
1
1
1
(
(
500 MHz, (CD ) CO): δ 3.97 (3H, s, -OCH ), 6.89 (2H, d, J = 8.4 Hz, ArH), 7.04–7.07 (2H, m, ArH), 7.48
3 2 3
2H, d, J = 8.8 Hz, ArH), 8.10 (1H, d, J = 8.8 Hz, ArH), 8.19 (1H, s, -C=CH), 8.44 (1H, s, OH). C-NMR
13
(
1
500 MHz, (CD ) CO):
δ
55.8, 100.4, 114.7, 115.2, 118.5, 123.7, 124.7, 127.4, 130.4, 152.7, 157.6, 158.2,
3
2
+
64.4, 175.1. LCMS (ES+) m/z = 269.1 ([M + H] , t = 1.41 min). These characterisation data are in
R
accordance with that previously reported in the literature [42].

Molecules 2016, 21, 1230
26 of 59
7
-Hydroxy-4’-methoxyisoflavone (44). A mixture of phenylethanone 42 (2.02 g, 7.82 mmol), BF3
·
OEt2
(
3.90 mL, 31.1 mmol) and MeSO Cl (1.80 mL, 23.2 mmol) in dry DMF (50 mL) was reacted according
2
to GP-H. The crude residue was purified by flash column chromatography (SiO , PE/EtOAc; 1:1) and
2
recrystallized from CHCl to afford isoflavone 44 (1.62 g, 77%) as a dark yellow powdery solid. m.p.
3
◦
−1
2
42–244 C. TLC R = 0.26 (PE/EtOAc; 1:1). IR νmax (neat)/cm : 3126s(br) (O-H str), 2993w (C-H str),
f
2
836w (C-H str), 1637m (C=O str), 1621m, 1594s (C=C str), 1568m (C=C str), 1512s (C=C str), 1451s,
1
1
3
2
384m, 1273m, 1178s, 1099m, 1045m, 1025s. H-NMR (500 MHz, (CD ) CO):
.83 (3H, s, -OCH ), 6.92 (1H, d, J = 2.0 Hz, ArH), 6.98 (2H, d, J = 9.2 Hz, ArH), 7.01 (1H, dd, J = 8.8,
.4 Hz, ArH), 7.56 (2H, d, J = 8.8 Hz, ArH), 8.07 (1H, d, J = 8.4 Hz, ArH), 8.18 (1H, s, -C=CH). C-NMR
δ
3.20 (1H, br s, OH),
3
2
3
13
(
1
500 MHz, (CD ) CO):
δ
54.9, 102.5, 113.7, 115.1, 117.9, 124.3, 124.9, 127.8, 130.4, 152.8, 158.2, 159.8,
3
2
+
62.6, 175.0. LCMS (ES+) m/z = 269.1 ([M + H] , t = 1.47 min). These characterisation data are in
R
accordance with that previously reported in the literature [44].
0
7
-Methoxy-(4 -(prop-2-yn-1-yloxy)isoflavone (45). A mixture of isoflavone 43 (602 mg, 2.25 mmol),
propargyl bromide (0.50 mL, 5.61 mmol) and anhydrous K CO (1.09 g, 7.91 mmol) in dry
2
3
acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column
chromatography (SiO , 1% MeOH/CH Cl ) to afford isoflavone 45 (641 mg, 93%) as a white powdery
2
2
2
◦
−1
solid. m.p. 162–164 C. TLC R = 0.45 (1% MeOH/CH Cl ). IR νmax (neat)/cm : 3289m (C C-H
str), 3083w (C-H str), 2953w (C-H str), 1645s (C=O str), 1624s, 1606s, 1579m (C=C str), 1513s (C=C str),
456m, 1442s, 1378s, 1285m, 1262s, 1245s, 1192s, 1176s, 1103s, 1050w, 1017s. H-NMR (500 MHz,
≡
f
2
2
1
1
CDCl3):
OCH C
δ
2.54 (1H, t, J = 2.4 Hz, -OCH C CH), 3.92 (3H, s, -OCH ), 4.73 (2H, d, J = 2.4 Hz,
≡
2
3
-
≡
CH), 6.86 (2H, d, J = 2.0 Hz, ArH), 7.00 (1H, dd, J = 8.8, 2.0 Hz, ArH), 7.05 (2H, d, J = 8.8 Hz
,
2
ArH), 7.52 (2H, d, J = 8.8 Hz, ArH), 7.93 (1H, s, -C=CH), 8.21 (2H, d, J = 8.8 Hz, ArH). 13C-NMR
(
1
[
500 MHz, CDCl3):
δ
55.8, 75.6, 78.5, 100.1, 114.5, 114.9, 118.4, 124.7, 125.2, 127.8, 130.1, 152.1, 157.5,
+
57.9, 164.0, 175.7. LCMS (ES+) m/z = 307.1 ([M + H] , t = 1.59 min). HRMS (ESI+) m/z =307.0959
R
+
+
M + H] found, C H O required 307.0965.
19 15 4
0
4
-Methoxy-7-(prop-2-yn-1-yloxy)isoflavone (46). A mixture of isoflavone 44 (810 mg, 3.02 mmol),
propargyl bromide (0.55 mL, 6.17 mmol) and anhydrous K CO (1.25 g, 9.01 mmol) in dry
2
3
acetone (50 mL) was reacted according to GP-C. The crude residue was purified by flash column
chromatography (SiO , CH Cl ) to afford isoflavone 46 (550 mg, 60%) as a white powdery solid. m.p.
2
2
2
◦
−1
1
3
50–152 C. TLC R = 0.32 (0.5% MeOH/CH Cl ). IR νmax (neat)/cm : 3281m (C
≡
C-H str), 3259m,
C str), 1624s (C=O str), 1608s, 1597s (C=C str), 1565m
f
2
2
078w (C-H str), 2950w (C-H str), 2116w (C
≡
(C=C str), 1513s (C=C str), 1440s, 1373m, 1326w, 1295m, 1271s, 1237s, 1176s, 1109w, 1095s, 1052m,
1
1033s, 1016s. H-NMR (500 MHz, CDCl ):
δ
2.61 (1H, t, J = 2.0 Hz, -OCH C
≡
CH), 3.85 (3H, s, -OCH3),
CH), 6.98 (2H, d, J = 8.4 Hz, ArH), 6.98 (1H, d, J = 2.4 Hz, ArH),
.05 (1H, dd, J = 8.8, 2.4 Hz, ArH), 7.51 (2H, d, J = 8.8 Hz, ArH), 7.93 (1H, s, -C=CH), 8.24 (1H, d,
3
2
4
7
.81 (1H, d, J = 2.4 Hz, -OCH C
≡
2
J = 8.8 Hz, ArH). 13C-NMR (500 MHz, CDCl3):
δ
55.3, 56.2, 76.6, 77.3, 101.5, 113.9, 114.8, 119.0, 124.1,
+
124.9, 127.9, 130.1, 152.1, 157.6, 159.6, 161.6, 175.8. LCMS (ES+) m/z = 307.1 ([M + H] , t = 1.62 min).
R
These characterisation data are in accordance with that previously reported in the literature [45].
-(Prop-2-yn-1-yloxy)-2H-chromen-2-one (48). A mixture of 4-hydroxycoumarin 47 (5.06 g, 31.2 mmol),
propargyl bromide (6.20 mL, 69.6 mmol) and anhydrous K CO (8.74 g, 63.2 mmol) in dry
4
2
3
acetone (100 mL) was reacted according to GP-C. The crude residue was purified by flash column
chromatography (SiO , CH Cl ) to afford coumarin 48 (3.60 g, 58%) as a white fluffy solid. m.p.
2
2
2
◦
−1
1
54–156 C. TLC R = 0.24 (CH Cl ). IR νmax (neat)/cm : 3281m (C C-H str), 3240m, 3078w (C-H
C str), 1714s (C=O str), 1688m, 1622s, 1610m (C=C str), 1568m (C=C str), 1493m, 1453m,
409m, 1361m, 1329w, 1274s, 1248s, 1194w, 1179m, 1155w, 1145m, 1107s, 1032w. H-NMR (500 MHz,
≡
f
2
2
str), 2131w (C
≡
1
1
CDCl3):
δ
2.68 (1H, t, J = 2.4 Hz, -OCH C
≡
CH), 4.88 (2H, d, J = 2.4 Hz, -OCH C CH), 5.84 (1H, s,
≡
2
2
-
C=CH), 7.29–7.34 (2H, m, ArH), 7.57 (1H, t, J = 8.4 Hz, ArH), 7.84 (1H, dd, J = 8.0, 1.2 Hz, ArH).
1
3
C-NMR (500 MHz, CDCl3):
δ 56.8, 75.7, 77.9, 91.7, 115.4, 116.8, 123.1, 124.0, 132.6, 153.3, 162.4, 164.2.

Molecules 2016, 21, 1230
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LCMS (ES+) m/z = 201.1 ([M + H]+, t = 1.47 min). These characterisation data are in accordance with
R
that previously reported in the literature [46].
2
-(2-Chloro-1-iminoethyl)-1,3,5-benzentriol hydrochloride (50). To a stirred solution of phloroglucinol 49
(
5.02 g, 39.8 mmol) and chloroacetonitrile (2.50 mL, 39.5 mmol) in Et O (100 mL) was added anhydrous
2
◦
ZnCl (0.558 g, 4.09 mmol). The reaction mixture was cooled to 0 C and HCl gas was bubbled through
the solution for 30 min. The resulting mixture was stirred at 0 C for 3 h and further 24 h at room
2
◦
temperature. The resulting suspension was filtered and the precipitate was washed with ice-cold
Et O (2
×
50 mL) and suction-dried to afford hydrochloric salt 50 (1.87 g, 20%) as a pale yellow-white
2
◦
powdery solid and was used without further purification in the next step. m.p. 240–242 C. IR νmax
−
1
(neat)/cm : 3389m (N-H str), 3257m(br) (O-H str), 3184s(br) (O-H str), 2968w (C-H str), 1646m, 1616s
(
1
C=C str), 1591s (C =C str), 1531w (C=C str), 1457m, 1383m, 1366s, 1291m, 1248s, 1175s, 1128w, 1065m,
1
050s, 1024w. H-NMR (500 MHz, DMSO-d ):
δ
5.46 (2H, s, -CH -), 6.07 (1H, d, J = 1.2 Hz, ArH), 6.26
6
2
(
1H, d, J = 1.2 Hz, ArH), 9.90 (1H, s, OH), 10.84 (1H, s, OH), 11.80 (1H, br s, NH), 12.54 (1H, s, OH).
1
3
C-NMR (500 MHz, DMSO-d6):
δ 75.3, 90.1, 96.9, 99.3, 160.4, 172.8, 173.7, 176.0. These characterisation
data are in accordance with that previously reported in the literature [47].
2
(
,4,6-Trihydroxy-2-chloroacetophenone (51). A mixture of imine salt 50 (1.80 g, 7.56 mmol) and 1 M HCl
100 mL) were heated at reflux with stirring for 1 h. The resulting red solution was blown under a
steady stream of nitrogen and the residual solid was re-suspended in H O (50 mL). The precipitate
2
was filtered, washed with ice-water (2
×
50 mL), suction-dried and re-dissolved in EtOAc (50 mL). The
50 mL), brine (2 50 mL), dried over anhydrous Na SO ,
filtered and evaporated to dryness. The crude residue was purified by flash column chromatography
organic solution was washed with H O (2
×
×
2
2
4
(
2
SiO , PE/EtOAc; 1:1) to afford acetophenone 51 (389 mg, 25%) as a white powdery solid. m.p.
2
◦ −1
36–238 C. TLC R = 0.32 (PE/EtOAc; 1:1). IR νmax (neat)/cm : 3422m (br) (O-H str), 3372s(br)
f
(
1
O-H str), 3068w (C-H str), 2962w (C-H str), 1640m (C=O str), 1598s (C=C str), 1521m (C=C str),
1
456s, 1376s, 1331w, 1279m, 1213s, 1164s, 1073s, 1017m. H-NMR (500 MHz, DMSO-d ):
δ
4.98 (2H,
6
13
s, -COCH -), 5.84 (2H, s, ArH), 10.55 (1H, s, OH), 12.07 (2H, s, OH). C-NMR (500 MHz, DMSO-d ):
δ
2
6
+
51.0, 94.7, 102.5, 163.9, 165.5, 194.7. LCMS (ES+) m/z = 203.0 ([M + H] , t = 1.26 min). These
R
characterisation data are in accordance with that previously reported in the literature [26].
Dihydroxybenzofuran-3(2H)-one (52). To a stirred solution of acetophenone 51 (5.00 g, 24.7 mmol) in
MeOH (100 mL) was added NaOMe (4.88 g, 90.3 mmol) and the mixture was heated at reflux for 2 h
under nitrogen. The reaction mixture was allowed to cool to room temperature, acidified with 1 M HCl
and the solvent removed under reduced pressure. The resulting dark residue was then re-dissolved in
EtOAc (100 mL). The organic solution was washed with H O (2
×
100 mL), brine (2
×
100 mL), dried
2
over anhydrous MgSO , filtered and evaporated to dryness. The crude residue was purified by flash
4
column chromatography (SiO , PE/EtOAc; 1:1) to afford benzofuranone 52 (2.90 g, 71%) as a pale
2
◦
−1
brown-white powdery solid. m.p. 280–282 C. TLC R = 0.16 (PE/EtOAc; 1:1). IR νmax (neat)/cm
:
f
3
331s(br) (O-H str), 3164m(br) (O-H str), 3062w (C-H str), 1671m (C=O str), 1607s (C=C str), 1533w
1
(
(
(
(
C=C str), 1457m, 1422w, 1399m, 1369m, 1336m, 1261w, 1227m, 1157s, 1064s, 1042m, 1012m. H-NMR
13
500 MHz, DMSO-d6):
500 MHz, DMSO-d6):
δ
4.55 (2H, s, -OCH CO-), 5.91 (2H, s, ArH), 10.59 (2H, br s, OH). C-NMR
2
δ
74.9, 90.1, 96.2, 102.7, 157.5, 167.6, 175.6, 194.0. LCMS (ES+) m/z = 167.1
[M + H]+, t = 1.27 min). These characterisation data are in accordance with that previously reported
R
in the literature [26].
4,6-Dimethoxybenzofuran-3(2H)-one (53). To a stirred solution of dihydroxybenzofuranone 52 (2.02 g,
1
2
2.2 mmol) in dry DMF (50 mL) were added CH I (2.30 mL, 37.0 mmol) and anhydrous K CO (3.35 g,
4.2 mmol). The resulting dark red-brown suspension was heated at 80 C for 1 h under a nitrogen
3
2
3
◦
atmosphere. The reaction mixture was then allowed to cool to room temperature, poured into ice-water
(
(
100 mL) and extracted with EtOAc (3
×
100 mL). The combined organic layer was washed with H O
2
3
×
100 mL), brine (2 100 mL), dried over anhydrous MgSO , filtered and evaporated to dryness.
×
4

Molecules 2016, 21, 1230
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The crude residue was purified by flash column chromatography (SiO , PE/EtOAc; 1:1) to afford
2
◦
benzofuranone 53 (1.87 g, 79%) as a pale yellow-white powdery solid. m.p. 148–150 C. TLC R = 0.23
PE/EtOAc; 1:1). IR νmax (neat)/cm : 2979w (C-H str), 2949w (C-H str), 1699s (C=O str), 1616s
C=C str), 1585s (C=C str), 1500m (C=C str), 1463m, 1431m, 1366m, 1342m, 1288m, 1217s, 1186s, 1160s,
f
−
1
(
(
1
1
099s, 1052m, 1021m. H-NMR (500 MHz, CDCl ):
δ
3.83 (3H, s, -OCH ), 3.87 (3H, s, -OCH ), 4.55
3
3
3
13
(
2H, s, -OCH CO-), 5.97 (1H, d, J = 1.6 Hz, ArH), 6.11 (1H, d, J = 2.0 Hz, ArH). C-NMR (500 MHz,
2
CDCl3):
δ ,
55.9, 55.9, 75.4, 88.8, 92.9, 104.7, 158.7, 169.7, 177.0, 194.9. LCMS (ES+) m/z = 195.1 ([M + H]+
tR = 1.52 min). These characterisation data are in accordance with that previously reported in the
literature [26].
0
4
,6-Dimethoxy-3 -hydroxyaurone (55). To a stirred solution of benzofuranone 53 (1.01 g, 5.20 mmol) in
MeOH (20 mL) was added 3-hydroxybenzaldehyde 54 (0.760 g, 6.22 mmol) followed by the addition
of KOH (1.50 g, 26.6 mmol) in H O (20 mL). The reaction mixture was stirred at room temperature
2
for 2 h and then poured into H O (2
×
100 mL). The resulting suspension was neutralized to pH 7
with 3 M HCl and extracted with CHCl (3 50 mL). The combined organic layer was washed with
100 mL), brine (100 mL), dried over anhydrous MgSO , filtered and evaporated to dryness
2
×
3
H O (3
2
×
4
under reduced pressure. The crude residue was purified by flash column chromatography (SiO ,
2
PE/EtOAc; 1:1) and recrystallized from MeOH to afford aurone 55 (1.21 g, 78%) as a bright yellow
◦
−1
powdery solid. m.p. 178–180 C. TLC R = 0.35 (PE/EtOAc; 1:2). IR νmax (neat)/cm : 3254m(br)
f
(
1
O-H str), 2944w (C-H str), 2842w (C-H str), 1688m (C=O str), 1649m, 1612s (C=C str), 1586s (C=C str),
501m (C=C str), 1447s, 1430w, 1338m, 1303m, 1249m, 1214s, 1153s, 1138m, 1087s, 1038w. H-NMR
1
(
500 MHz, (CD ) CO): δ 3.94 (3H, s, -OCH ), 3.98 (3H, s, -OCH ), 6.32 (1H, d, J = 2.0 Hz, ArH), 6.56 (1H,
3 2 3 3
d, J = 1.6 Hz, ArH), 6.56 (1H, s, -C=CH), 6.91 (1H, ddd, J = 8.0, 2.4, 0.8 Hz, ArH), 7.30 (1H, t, J = 8.0 Hz
ArH), 7.40 (1H, d, J = 7.6 Hz, ArH), 7.47 (1H, t, J = 2.0 Hz, ArH), 8.57 (1H, s, OH). C-NMR (500 MHz,
,
13
(
1
CD ) CO):
δ
55.9, 56.2, 89.7, 94.4, 104.8, 109.4, 116.8, 117.5, 122.8, 130.0, 134.1, 148.1, 157.9, 159.7, 169.2,
3
2
+
69.5, 179.4. LCMS (ES+) m/z = 299.2 ([M + H] , t = 1.71 min). These characterisation data are in
R
accordance with that previously reported in the literature [48].
0
4
,6-Dimethoxy-3 -(prop-2-yn-1-yloxy)aurone (56). A mixture of aurone 55 (505 mg, 1.69 mmol), propargyl
bromide (0.30 mL, 3.37 mmol) and anhydrous K CO (701 mg, 5.07 mmol) in dry acetone (30 mL) was
2
3
reacted according to GP-C. The crude residue was purified by flash column chromatography (SiO2,
.5% MeOH/CH Cl ) to afford aurone 56 (545 mg, 96%) as a pale yellow-white powdery solid. m.p.
0
2
2
◦
−1
152–154 C. TLC R = 0.46 (1% MeOH/CH Cl ). IR νmax (neat)/cm : 3219m (C C-H str), 3007w
≡
f
2
2
(
C-H str), 2940w (C-H str), 2110w (C
≡
C str), 1686s (C=O str), 1654m, 1612s (C=C str), 1589s (C=C str),
1
1504s (C=C str), 1454m, 1423m, 1347m, 1313m, 1266m, 1215s, 1154m, 1094s, 1040m, 1019w. H-NMR
(
4
6
500 MHz, CDCl3):
.75 (2H, d, J = 2.5 Hz, -OCH C
.72 (1H, s, -C=CH), 6.99 (1H, ddd, J = 8.0, 2.5, 1.0 Hz, ArH), 7.35 (1H, t, J = 8.0 Hz, ArH), 7.46 (1H,
δ
2.57 (1H, t, J = 2.5 Hz, -OCH C CH), 3.91 (3H, s, -OCH ), 3.95 (3H, s, -OCH ),
≡
2
3 3
≡
CH), 6.12 (1H, d, J = 2.0 Hz, ArH), 6.37 (1H, d, J = 2.0 Hz, ArH),
2
13
d, J = 7.5 Hz, ArH), 7.54 (1H, t, J = 1.5 Hz, ArH). C-NMR (500 MHz, CDCl3):
δ 55.9, 56.1, 56.2, 75.7,
7
8.3, 89.2, 94.0, 105.1, 110.3, 115.9, 117.1, 124.6, 129.7, 133.9, 148.0, 157.6, 159.4, 169.0, 180.6. LCMS
+
+
+
(
ES+) m/z = 337.2 ([M + H] , t = 1.83 min). HRMS (ESI+) m/z = 337.1062 [M + H] found, C H O
R 20 17 5
required 337.1071.
4-(2-Bromoethoxy)-2H-chromen-2-one (57). A mixture of 4-hydroxycoumarin 47 (5.14 g, 31.7 mmol),
1
,2-dibromoethane (3.19 mL, 37.0 mmol) and anhydrous K CO (8.56 g, 61.9 mmol) in dry
2
3
acetone (100 mL) was reacted according to GP-I. The crude residue was purified by flash column
chromatography (SiO , CH Cl ) to afford coumarin 57 (1.33g, 16%) as a white powdery solid. m.p.
2
2
2
◦
−1
1
1
1
76–178 C. TLC R = 0.41 (PE/EtOAc 1:1). IR νmax (neat)/cm : 3044w (C-H str), 2982w (C-H str),
f
716s (C=O str), 1627s, 1607s, 1566m (C=C str), 1496m, 1454m, 1407s, 1369s, 1330m, 1272m, 1246s,
1
225s, 1184s, 1147m, 1111s, 1067w, 1034s. H-NMR (500 MHz, CDCl3):
δ 3.77 (2H, t, J = 6.0 Hz,
-
OCH CH Br), 4.46 (2H, t, J = 6.0 Hz, -OCH CH Br), 5.68 (1H, s, -C=CH), 7.31 (1H, t, J = 8.0 Hz, ArH),
2 2 2 2
7.34 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.58 (1H, t, J = 8.5 Hz, ArH), 7.88 (1H, dd, J = 7.5, 1.5 Hz, ArH).

Molecules 2016, 21, 1230
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1
3
C-NMR (500 MHz, CDCl ):
δ
27.6, 68.4, 90.9, 115.3, 116.8, 123.1, 124.0, 132.7, 153.3, 162.5, 164.9. LCMS
3
+
(
ES+) m/z = 271.0 ([M + H] , t = 1.53 min). These characterisation data are in accordance with that
R
previously reported in the literature [49].
-(2-Azidoethoxy)-2H-chromen-2-one (58). A mixture of coumarin 57 (679 mg, 2.52 mmol) and NaN3
370 mg, 5.69 mmol) in dry DMF (20 mL) was reacted according to GP-J. The reaction mixture was
worked up to afford coumarin 58 (571 mg, 98%) as an off-white powdery solid and was used without
4
(
◦
−1
further purification. m.p. 150–152 C. TLC R = 0.40 (1% MeOH/CH Cl ). IR νmax (neat)/cm
:
f
2
2
3
075w (C-H str), 2947w (C-H str), 2125s (N str), 1732s (C=O str), 1623s, 1609s, 1566s (C=C str), 1495s,
3
1
1
453m, 1417s, 1371s, 1277m, 1236s, 1180s, 1147s, 1109s, 1032s. H-NMR (500 MHz, CDCl ):
δ
3.75 (2H,
3
t, J = 5.0 Hz, -OCH CH N ), 4.32 (2H, t, J = 5.0 Hz, -OCH CH N ), 5.70 (1H, s, -C=CH), 7.31 (1H, t,
2
2
3
2
2
3
J = 8.0 Hz, ArH), 7.34 (1H, dd, J = 8.5, 0.5 Hz, ArH), 7.58 (1H, t, J = 8.5 Hz, ArH), 7.84 (1H, dd, J = 8.0,
1
1
.5 Hz, ArH). 13C-NMR (500 MHz, CDCl3):
62.5, 165.1. LCMS (ES+) m/z = 232.1 ([M + H] , t = 1.70 min). These characterisation data are in
δ
49.6, 68.2, 90.9, 115.2, 116.8, 123.0, 124.1, 132.7, 153.3,
+
R
accordance with that previously reported in the literature [27].
-(2-Bomoethoxy)benzaldehyde (59). A mixture of benzaldehyde 33 (20.0 g, 164 mmol), 1,2-dibromoethane
28.5 mL, 331 mmol) and anhydrous K CO (46.0 g, 333 mmol) in dry acetone (100 mL) was reacted
4
(
2
3
according to GP-I. The crude residue was purified by flash column chromatography (SiO , CH Cl )
2
2
2
◦
to afford benzaldehyde 59 (13.2 g, 35%) as a white powdery solid. m.p. 56–58 C. TLC R = 0.41
f
−
CH Cl ). IR νmax (neat)/cm : 2967w (C-H str), 1679s (C=O str), 1601s (C=C str), 1577s (C=C str),
2 2
1
(
1
1
508m (C=C str), 1458m, 1422m, 1392m, 1317w, 1300m, 1282m, 1249s, 1229s, 1211s, 1160s, 1107w, 1068s,
1
008s. H-NMR (500 MHz, CDCl ):
δ 3.68 (2H, t, J = 6.4 Hz, -OCH CH Br), 4.39 (2H, t, J = 6.4 Hz,
2 2
3
13
-OCH CH Br), 7.03 (2H, d, J = 8.8 Hz, ArH), 7.86 (2H, d, J = 8.8 Hz, ArH), 9.91 (1H, s, CHO). C-NMR
2 2
+
(500 MHz, CDCl3): δ 28.4, 67.9, 114.8, 130.5, 132.0, 163.0, 190.7. LCMS (ES+) m/z = 231.0 ([M + H] ,
tR = 1.56 min). These characterisation data are in accordance with that previously reported in the
literature [50].
4
-(2-Azidoethoxy)benzaldehyde (60). A mixture of benzaldehyde 59 (12.8 g, 56.0 mmol) and NaN (7.36 g,
3
113 mmol) in dry DMF (100 mL) was reacted according to GP-J. The reaction mixture was worked
up to afford benzaldehyde 60 (10.6 g, 99%) as a pale yellow viscous oil and was used without further
−
1
purification. TLC R = 0.38 (CH Cl ). IR νmax (neat)/cm : 2942w (C-H str), 2837w (C-H str), 2100s
f
2
2
(
1
N str), 1682s (C=O str), 1598s (C=C str), 1578s (C=C str), 1508s (C=C str), 1427w, 1395w, 1304m,
3
1
247s, 1213s, 1157s, 1110m, 1052m, 1008w. H-NMR (500 MHz, CDCl3):
δ
3.64 (2H, t, J = 5.0 Hz,
-
OCH CH N ), 4.22 (2H, t, J = 5.0 Hz, -OCH CH N ), 7.02 (2H, d, J = 8.5 Hz, ArH), 7.84 (2H, d,
2 2 3 2 2 3
13
J = 9.0 Hz, ArH), 9.88 (1H, s, CHO). C-NMR (500 MHz, CDCl ):
1
δ 49.9, 67.1, 114.7, 130.3, 131.9, 163.0,
3
+
90.7. LCMS (ES+) m/z = 193.2 ([M + H] , t = 1.62 min). These characterisation data are in accordance
R
with that previously reported in the literature [50].
E)-3-(4-(2-Azidoethoxy)phenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one (61). A mixture of benzaldehyde 60
4.90 g, 25.6 mmol), acetophenone 10 (3.09 mL, 25.7 mmol) and KOH (8.70 g, 155 mmol) in absolute
(
(
EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by recrystallization
◦
from MeOH to afford chalcone 61 (6.13 g, 77%) as a bright yellow powdery solid. m.p. 142–144 C.
−
1
TLC R = 0.48 (PE/EtOAc; 2:1). IR νmax (neat)/cm : 2932w (C-H str), 2874w (C-H str), 2107m (N str),
f
3
2
070m, 1636s (C=O str), 1602s, 1575s (C=C str), 1560s (C=C str), 1508s (C=C str), 1488s, 1424m, 1345m,
1
1299m, 1271m, 1244m, 1201m, 1059m, 1031m. H-NMR (500 MHz, CDCl ):
δ
3.63 (2H, t, J = 5.0 Hz
,
,
,
3
-OCH CH N ), 4.19 (2H, t, J = 5.0 Hz, -OCH CH N ), 6.93–6.98 (3H, m, ArH), 7.03 (1H, dd, J = 8.5
2 2 3 2 2 3
1
.0 Hz, ArH), 7.49 (1H, t, J = 8.5 Hz, ArH), 7.54 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.63 (2H, d, J = 8.5 Hz
ArH), 7.89 (1H, d, J = 15.5 Hz, -CH=CHCO-), 7.92 (1H, dd, J = 8.5, 2.0 Hz, ArH), 12.94 (1H, s, OH).
1
3
C-NMR (500 MHz, CDCl3):
δ
50.0, 67.0, 115.0, 117.9, 118.5, 118.7, 120.0, 127.9, 129.5, 130.5, 136.2,
+
1
45.0, 160.5, 163.5, 193.5. LCMS (ES+) m/z = 310.1 ([M + H] , t = 1.80 min). These characterisation
R
data are in accordance with that previously reported in the literature [51].

Molecules 2016, 21, 1230
30 of 59
1
1
-(4-(2-Bromoethoxy)-3-methoxyphenyl)ethan-1-one (62). A mixture of acetophenone 11 (10.0 g, 60.3 mmol),
,2-dibromoethane (10.5 mL, 122 mmol) and anhydrous K CO (12.6, 91.5 mmol) in dry DMF (100 mL)
2
3
was reacted according to GP-I. The crude residue was purified by flash column chromatography (SiO ,
2
◦
CH Cl ) to afford acetophenone 62 (3.90 g, 24%) as a white powdery solid. m.p. 98–100 C. TLC
R = 0.16 (CH Cl ). IR νmax (neat)/cm : 3075w (C-H str), 2971w (C-H str), 1760w, 1671s (C=O str),
2
2
−
1
f
2
2
1
1
585s (C=C str), 1507s (C=C str), 1460m, 1412s, 1385w, 1359m, 1263s, 1220s, 1171m, 1144s, 1076s, 1030s,
1
008s. H-NMR (500 MHz, CDCl ):
δ 2.58 (3H, s, -COCH3), 3.70 (2H, t, J = 6.8 Hz, -OCH CH Br), 3.94
2 2
3
(
3H, s, -OCH ), 4.41 (2H, t, J = 6.8 Hz, -OCH CH Br), 6.91 (1H, d, J = 8.8 Hz, ArH), 7.55–7.57 (2H, m,
3 2 2
13
ArH). C-NMR (500 MHz, CDCl ):
LCMS (ES+) m/z = 275.0 ([M + H] , t = 1.43 min). These characterisation data are in accordance with
δ 26.3, 28.2, 56.1, 68.7, 111.0, 112.2, 123.0, 131.4, 149.5, 151.7, 196.7.
3
+
R
that previously reported in the literature [52].
1
-(4-(2-Azidoethoxy)-3-methoxyphenyl)ethan-1-one (63). A mixture of acetophenone 62 (3.50 g, 12.8 mmol)
and NaN (1.25 g, 19.2 mol) in DMF (30 mL) was reacted according to GP-J. The reaction mixture was
3
worked up to afford phenylethanone 63 (2.94 g, 98%) as a pale brown residual oil which solidified
upon standing to give a pale brown crystalline solid and used without further purification. m.p.
◦ −1
8–60 C. TLC R = 0.30 (0.5% MeOH/CH Cl ). IR νmax (neat)/cm : 3088w (C-H str), 2956w (C-H
f
2 2
5
str), 2110s (N str), 2067m, 1742w, 1671s (C=O str), 1589s (C=C str), 1508s (C=C str), 1471m, 1419s,
3
1
1
355m, 1270s, 1216s, 1177m, 1151s, 1080m, 1036s. H-NMR (500 MHz, CDCl ):
δ
2.56 (3H, s, -COCH3),
3
3
.68 (2H, t, J = 5.2 Hz, -OCH CH N ), 3.91 (3H, s, -OCH ), 4.23 (2H, t, J = 5.2 Hz, -OCH CH N ), 6.89
2 2 3 3 2 2 3
13
(1H, d, J = 8.0 Hz, ArH), 7.53–7.55 (2H, m, ArH). C-NMR (500 MHz, CDCl ):
δ
26.2, 50.0, 56.0, 67.7,
3
+
110.7, 111.9, 122.9, 131.2, 149.4, 151.9, 196.7. LCMS (ES+) m/z = 236.0 ([M + H] , t = 1.45 min). These
R
characterisation data are in accordance with that previously reported in the literature [52].
(E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(3,4-dimethoxyphenyl)prop-2-en-1-one (67). A mixture of
benzaldehyde 64 (1.48 g, 8.91 mmol), acetophenone 63 (2.04 g, 8.67 mmol) and KOH (2.41 g, 43.0 mmol)
in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash
column chromatography (SiO , PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone
2
◦
6
7
(2.61 g, 79%) as a pale yellow-green powdery solid. m.p. 106–108 C. TLC R = 0.28 (PE/EtOAc;
:1). IR νmax (neat)/cm : 2940w (C-H str), 2838w (C-H str), 2112s (N str), 2068m, 1648s (C=O str),
595s (C=C str), 1568s (C=C str), 1509s (C=C str), 1458m, 1419m, 1355w, 1312m, 1261s, 1242s, 1199m,
159m, 1139s, 1036s, 1021s. H-NMR (500 MHz, CDCl ):
f
−
1
1
1
1
3
1
δ 3.67 (2H, t, J = 5.2 Hz, -OCH CH N ),
2 2 3
3
3
6
.91 (3H, s, -OCH ), 3.93 (3H, s, -OCH ), 3.94 (3H, s, -OCH ), 4.23 (2H, t, J = 5.2 Hz, -OCH CH N ),
3 3 3 2 2 3
.88 (1H, d, J = 8.4 Hz, ArH), 6.92 (1H, d, J = 8.0 Hz, ArH), 7.15 (1H, d, J = 2.0 Hz, ArH), 7.22 (1H,
dd, J = 8.4, 2.0 Hz, ArH), 7.39 (1H, d, J = 15.6 Hz, -CH=CHCO-), 7.61–7.65 (2H, m, ArH), 7.75 (1H, d,
J = 15.2 Hz, -CH=CHCO-). 13C-NMR (500 MHz, CDCl3):
49.9, 55.8, 56.0, 67.7, 110.1, 111.0, 111.4,
11.9, 119.4, 122.4, 122.8, 127.8, 132.2, 144.2, 149.1, 149.6, 151.2, 151.7, 188.5. LCMS (ES+) m/z = 384.2
[M + H]+, t = 3.98 min). These characterisation data are in accordance with that previously reported
δ
1
(
R
in the literature [52].
(
E)-1-(4-(2-Azidoethoxy)-3-methoxyphenyl)-3-(2,3,4-trimethoxyphenyl)prop-2-en-1-one (68). A mixture of
benzaldehyde 65 (1.70 g, 8.66 mmol), acetophenone 63 (2.02 g, 8.59 mmol) and KOH (2.39 g, 42.6 mmol)
in absolute EtOH (100 mL) was reacted according to GP-D. The crude residue was purified by flash
column chromatography (SiO , PE/EtOAc; 5:1) and recrystallized from MeOH to afford chalcone 68
2
◦
(
2.61 g, 74%) as a pale yellow-green powdery solid. m.p. 114–116 C. TLC R = 0.35 (PE/EtOAc; 1:1).
IR νmax (neat)/cm : 2945w (C-H str), 2836w (C-H str), 2119s (N str), 2072m, 1743w, 1644m (C=O
f
−
1
3
str), 1588m (C=C str), 1560s (C=C str), 1519m (C=C str), 1494s, 1466m, 1420s, 1246s, 1149s, 1093s, 1042s.
1
H-NMR (500 MHz, CDCl3):
δ 3.66 (2H, t, J = 5.2 Hz, -OCH CH N ), 3.87 (3H, s, -OCH ), 3.88 (3H, s,
2 2 3 3
-
OCH ), 3.92 (3H, s, -OCH ), 3.93 (3H, s, -OCH ), 4.23 (2H, t, J = 5.0 Hz, -OCH CH N ), 6.70 (1H, d,
3 3 3 2 2 3
J = 8.8 Hz, ArH), 6.91 (1H, d, J = 8.8 Hz, ArH), 7.37 (1H, d, J = 8.8 Hz, ArH), 7.55 (1H, d, J = 16.0 Hz
CH=CHCO-), 7.61–7.63 (2H, m, ArH), 7.97 (1H, d, J = 15.6 Hz, -CH=CHCO-). 13C-NMR (500 MHz,
CDCl3): 49.9, 55.9, 60.8, 61.2, 67.7, 107.5, 111.5, 112.0, 120.8, 121.9, 122.4, 123.7, 132.4, 139.3, 142.3,
,
-
δ