First intramolecular Diels-Alder reactions using chromone derivatives: Synthesis of chromeno[3,4-: B] xanthones and 2-(benzo [c] chromenyl)chromones

Article abstract of DOI:10.1039/c7nj05185a

A series of novel (E)-2-(2-propargyloxystyryl)chromones and (E,E)-2-[4-(2-propargyloxyphenyl)buta-1,3-dien-1-yl]chromones were designed and synthesized via aldol condensation of 2-methylchromones with 2-propargyloxy(benzaldehyde and cinnamaldehyde), respectively. Both chromone derivatives were used as substrates in microwave-assisted intramolecular Diels-Alder reactions, affording chromeno[3,4-b]xanthones and 2-(benzo[c]chromenyl)chromones. This is the first report involving chromone derivatives in intramolecular Diels-Alder reactions for the synthesis of new oxygen heterocycles, namely xanthone- and flavone-type compounds.

Full text of DOI:10.1039/c7nj05185a

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
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First intramolecular Diels-Alder reactions using chromone
derivatives: synthesis of chromeno[3,4-b]xanthones and 2-
Received 00th January 20xx,
Accepted 00th January 20xx
(benzo[c]chromenyl)chromones
a
a,b
a
a,
DOI: 10.1039/x0xx00000x
Hélio M. T. Albuquerque, Clementina M. M. Santos, José A. S. Cavaleiro and Artur M. S. Silva *
www.rsc.org/
A series of novel (E)-2-(2-propargyloxystyryl)chromones and of (E,E)-2-[4-(2-propargyloxyphenyl)buta-1,3-dien-1-
yl]chromones were designed and synthesized through aldol condensation of 2-methylchromones with 2-
propargyloxy(benzaldehyde and cinnamaldehyde), respectively. Both chromone derivatives were used as substrates in
microwave-assisted intramolecular Diels-Alder reactions, affording chromeno[3,4-b]xanthones and 2-
(benzo[c]chromenyl)chromones. This is the first report involving chromone derivatives in intramolecular Diels-Alder
reactions for the synthesis of new oxygen heterocycles, namely xanthone- and flavone-type compounds.
synthesis of novel propargyloxychromone derivatives to be
used as substrates in intramolecular DA reactions. This is the
first report involving chromone derivatives in intramolecular
Introduction
Chromone (or 4H-chromen-4-one), a natural occurring 6-O-
membered heterocycle, is widely found as the basic core in a
large variety of compounds that exhibits important biological
DA reactions under microwave (MW) irradiation, allowing the
synthesis of chromeno[3,4-b]xanthones and 2-
1
,2
(benzo[c]chromenyl)chromones. Moreover, the prepared
compounds can present enhanced biological properties since
they combine the xanthone and chromene nucleus, and the
benzochromene and chromone moieties in the same
properties. This ring system is also a useful substrate for
further functionalization, which can be achieved through
oxidation, condensation, conjugate addition or Diels-Alder
3
,4
(
DA) reactions. In fact, DA reaction is one of the most
1
5-18
molecules (hybrid drug concept).
powerful cycloaddition reaction in organic synthesis and
particularly, in the construction of 6-membered rings,
combining dienes and dienophiles with different substitution
Results and Discussion
5
,6
patterns. There are countless examples of natural products
and other complex structures synthesized through this
approach, with outstanding degree of control and a high level
Synthesis of the starting chromones
The starting (E)-2’-propargyloxy-2-styrylchromones 4a-d were
prepared in good yields (73-86%) through base-catalyzed aldol
condensation of the appropriate 2-methylchromone 2a-d with
7
of predictability for this process. Inspired by the versatility of
intermolecular DA reaction, intramolecular DA reactions has
also been employed in the total synthesis of several polycyclic
ortho-propargyloxybenzaldehyde
required benzaldehyde was obtained by propargylation of
the commercially available salicylaldehyde with propargyl
3 [Scheme 1, (ii)]. The
8
natural products, using one or multiple steps strategies.
3
Although some chromone derivatives such as 2- or 3-
styrylcromones have been involved in DA reactions, either as
1
bromide in the presence of potassium carbonate in refluxing
acetone [Scheme 1, (i)].
9
-12
dienes or dienophiles,
to the best of our knowledge, there
are no reports involving chromone derivatives in
intramolecular DA reactions. Thus, following our previous
reports dealing with the reactivity of (E)-2-(4-arylbut-1-en-3-
CHO
a) R1 = R2 = H
+
Br
1
2
b) R = OMe, R = H
c) R = H, R2 = OMe
OH
1
1
yn-1-yl)chromones
and
(E,E)-2-(4-arylbuta-1,3-dien-1-
3,14
herein we envisaged the
d) R1 = R2 = OMe
1
95% (i)
5'
yl)chromones in DA reactions,
6
'
4'
3'
R1
β
O
O
1'
CHO
O
(ii)
2'
R1
8
8a
4a
O
4
O
+
73-86%
7
2
α
1
''
R2
2
6
3
2''
5
a-d
3
R2
3''
O
4a-d
Scheme 1: Synthesis of (E)-2’-propargyloxy-2-styrylchromones 4a-d. Reagents
and conditions: (i) K CO , acetone, reflux, 2 h; (ii) Na, EtOH, r.t., 3-6 h.
2 3
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The main features in the H NMR spectra of (E)-2’-
Scheme
3
: Synthesis of ortho-benzyloxycinnamaldehyde 10
CO , BnBr, acetone, reflux, 16 h; (ii) Acrolein diethyl acetal,
, Pd(OAc) , DMF, 90 , 16 h.
. Reagents and
propargyloxy-2-styrylchromones 4a-d are the presence of: i) conditions: (i) K
2
3
n
Bu
4
NOAc, K
2
CO
3
2
℃
two doublets at δ 6.81-6.91 and 7.81-7.94 ppm assigned to
vinylic protons H-α and H-β, respectively, in a trans
3
configuration ( JHα-Hβ 16.2 Hz); ii) a singlet at δ 6.19-6.35 ppm
The base-catalyzed aldol condensation of 2-methylchromones
2b-d with cinnamaldehyde 10 afforded the desired chromones
b-d in good yields [Scheme 4, (i)]. The next step of this
assigned to proton H-3; and iii) a doublet and a triplet at δ
6
4.83-4.85 and 2.58 ppm assigned to protons H-1’’ and H-3’’,
strategy involved the selective cleavage of the benzyl group
using a mixture of AcOH/HCl (37%) (10% v/v), followed by
propargylation with propargyl bromide, which afforded the
desired chromones 7b-d in good overall yields [Scheme 4, (ii),
respectively (see Scheme 1 for numbering).
The synthesis of (E,E)-2-[4-(2-propargyloxyphenyl)buta-1,3-
dien-1-yl]chromones was not straightforward. The initial
strategy involved the base-catalyzed aldol condensation of 2-
methylchromone 2a with the commercially available ortho-
(iii)].
1
The main structural features found in the H NMR spectra of
chromones 7a-d are: i) a doublet and a triplet at δ 4.78-4.80
and 2.56-2.57 ppm assigned to protons H-1’’ and H-3’’,
respectively; ii) a doublet at δ 6.27-6.36 ppm assigned to
methoxycinnamaldehyde 5, affording the methoxy substituted
chromone 6a in good yield [Scheme 2, (i)]. Then, the methyl
group was cleaved with boron tribromide and the
propargylation was accomplished with propargyl bromide in
the presence of potassium carbonate as base, giving the
desired O-propargyl-2-butadienylchromone 7a in good overall
yield (85%) [Scheme 2, (ii) and (iii)]. This strategy was applied
3
proton H-α in a trans configuration ( JHα-Hβ = 15.2 Hz); and iii) a
doublet at δ 7.26-7.31 ppm assigned to proton H-δ, in a trans
3
configuration as well ( JHα-Hβ ~ 15.5-16.1 Hz) (see Scheme 4 for
numbering).
to the 2-methylchromone derivative 2b
, however, the
demethylation step lead to the undesired cleavage of both
1
methyl groups (2’-OMe and 7-OMe). The analysis of the H
NMR spectrum of the crude product of the reaction with
boron tribromide showed the presence of two singlets
corresponding to protons 2’-OH and 7-OH, as well as another
3
singlet corresponding to 7-OCH . The existence of a 7-OH
group of the chromone moiety creates another undesired
propargylation site, avoiding the selective propargylation of 2’-
OH. Therefore, it was necessary to employ a different strategy
Scheme 4: Synthesis of chromones 7b-d. Reagents and conditions: (i) Na, EtOH,
r.t., 4-6 h; (ii) AcOH/HCl (10% v/v), 100
acetone, reflux, 5 h.
for the synthesis of chromones 7b-d
.
2 3
℃, 16 h; (iii) K CO , propargyl bromide,
R
O
2
2
a R = H
b R = OMe
Intramolecular Diels-Alder reactions
2'
OMe
O
(ii),(iii)
O
+
(
i)
Once achieved the synthesis of the propargyloxychromone
derivatives 4a-d and 7a-d, they were used as templates for
MW-assisted intramolecular DA reactions. The (E)-2’-
propargyloxy-2-styrylchromone 4a was used as model
substrate to prepare chromeno[3,4-b]xanthone derivatives. A
careful optimization of the reaction conditions under MW
irradiation was performed. Several attempts were carried out
by varying the solvents, temperatures, reaction times and
R
7
O
O
85%
R = H
O
CHO 75-80%
OMe
6a R = H
aa R = OMe
O
7a
5
6
Scheme 2: Synthesis of chromones 6a, 6aa and 7a. Reagents and conditions: (i)
Na, EtOH, r.t., 2-3 h; (ii) BBr
acetone, reflux, 5 h.
3 2 2 2 3
, CH Cl , r.t., 2 h; (iii) K CO , propargyl bromide,
The new strategy relied on the preparation of a specific Lewis acid activation (Table 1). Chromeno[3,4-b]xanthone 12a
cinnamaldehyde 10 with an appropriate ortho protecting was obtained in fair to good yields (38-60%) using N-methyl-2-
group, which could be selectively cleaved using less harsh pyrrolidone (NMP) or 1,2,4-trichlorobenzene (1,2,4-TCB) as
conditions (Scheme 3). Having this in mind, 2-iodophenol
was benzylated with benzyl bromide (BnBr) in the presence of lower temperature and using DMF as solvent xanthone 12a
potassium carbonate, affording the aryl iodide
in almost was obtained in very low yield (Table 1, entries 3-5). The
8
solvents, at elevated temperature (Table 1, entries 3-5). At
9
quantitative yield [Scheme 3, (i)]. Then, the desired formation of this compound could be explained on the basis of
cinnamaldehyde 10 was obtained through the palladium- a sequence of reactions involving firstly intramolecular DA
catalyzed cross-coupling reaction of aryl iodide
diethyl acetal, following a previously reported procedure
Scheme 3, (ii)].
9
with acrolein reaction, followed by olefin migration and in situ oxidation to
1
9
afford chromeno[3,4-b]xanthone 12a (Scheme 5). To prove
this concept, derivative 11 was isolated in low yields (Table 1,
entries 2-5, 7, 9-10) and its formation follows the same
sequence of reactions without the in situ oxidation step
[
(Scheme 5). In order to push the reaction towards the oxidized
product, oxidizing agents such as 1,4-benzoquinone, 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and chloranil
2
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were added to the crude reaction (Table 1, entries 6-8) and the the chromeno[3,4-b]xanthone 12a obtained as the only
best results were achieved in the presence of chloranil, being product in 75% yield (Table 1, entry 8).
Table 1: MW-assisted intramolecular DA reaction using (E)-2’-propargyloxy-2-styrylchromone (4a).
b
a
a
a
Entry
Solvent
DMF
Lewis acid
T (°C)
165
200
200
200
200
200
200
200
200
220
200
165
200
200
165
200
200
200
Time (min)
40
12a Yield (%)
11 Yield (%)
4a Recovered (%)
1
2
3
4
5
−
−
−
−
−
−
−
−
−
−
4
−
93
66
33
23
20
−
DMF
40
4
26
NMP
40
38
54
60
10
50
75
60
50
10
7
20
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
−
40
21
60
10
c
6
60
−
d
7
60
11
traces
traces
15
14
−
e
8
60
−
9
80
8
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
60
8
Sc(OTf)
Sc(OTf)
3
3
60
−
40
traces
92
−
SnCl
2
60
8
traces
AlCl
3
60
10
3
traces
−
Sc(OTf)
3
40
−
−
−
−
91
−
−
AuCl
40
6
−
−
−
40
29
37
51
40
−
80
a
b
c
d
Isolated yield. 0.5 equiv of Lewis acid. Addition of 0.1 equiv of DDQ to the crude mixture. Heating for 30 min at 100 °C under MW irradiation; Addition of 0.1 equiv
e
of 1,4-benzoquinone to the crude mixture. Heating for 30 min at 50 °C under MW irradiation. Addition of 0.1 equiv of chloranil to the crude mixture. Heating for 30
min at 80 °C under MW irradiation. DMF = Dimethylformamide; NMP = N-Methyl-2-pyrrolidone; 1,2,4-TCB = 1,2,4-Trichlorobenzene.
Scheme 6: MW-assisted synthesis of chromeno[3,4-b]xanthones 12a-d. Reagents
and conditions: (i) 1,2,4-TCB, MW, 200
℃, 60 min. Chloranil, MW, 80 °C, 30 min.
The
chromeno[3,4-b]xanthones
12a-d
were
easily
Scheme 5: Proposed mechanism for the formation of compounds 11 and 12a
.
distinguished from their chromone precursors 4a-d by the
1
analysis of their H NMR spectra. The absence of the signals of
The effect of the addition of a series of Lewis acids was
evaluated in solvent and solvent-free conditions, however, in
all cases, the chromeno[3,4-b]xanthone 12a was only obtained
in low yields (Table 1, entries 11-16). Attempts to perform the
reaction in solvent-free conditions were not advantageous
affording compound 12a in only 29-37% yield (Table 1, entries
the vinylic protons H-α and H-β, as well as the signal of proton
H-3, and the presence of three singlets at δ 8.04-8.12; 7.61-
7
.76 and 5.20-5.23 ppm assigned to protons H-7, H-14 and H-6,
respectively (see Scheme 6 for numbering), confirmed the
structure of compounds 12a-d
.
In the case of chromones 7a-d, the presence of two dienes
may lead to distinct intramolecular-DA products (reaction on
diene-3,2:α,β or diene-α,β:γ,δ – see Scheme 4 for numbering).
Previous work on MW-assisted DA reactions of similar
butadienylchromones with N-methylmaleimide as dienophile,
showed that the reaction is selective towards the most
reactive diene-α,β:γ,δ in the presence of scandium triflate as
1
7-18).
The best reaction conditions obtained for chromone derivative
were applied to derivatives 4b-d affording the
corresponding chromeno[3,4-b]xanthones 12b-d in good yields
Scheme 6).
4a
,
(
1
4
Lewis acid. Therefore, the intramolecular DA reaction of
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chromones 7a-d was carried out using the optimized reaction starting material was observed, and several unidentified
conditions obtained for chromones 4a-d (Scheme 7). byproducts were obtained. This suggests that the allyloxy
Interestingly, the (benzo[c]chromenyl)chromones 13a-d were substituent was not reactive as dienophile in intramolecular
obtained as the only product in good yields (78-85%) (Scheme DA reactions when compared to the propargyloxy substituent.
7).
The chromone derivative 17 was prepared through
deprotection of 6a, followed by allylation of the formed
hydroxychromone [Scheme 9, (i)/(ii)]. Despite the unsuccessful
intramolecular DA reaction on compound 15, we also
attempted it in compound 17 using the same reaction
conditions used for its analogue 7a [Scheme 9, (iii)].
Unfortunately, the reaction afforded several unidentified
byproducts and no intramolecular DA product was observed.
4
'
5
'
3'
2'
6
'
5'b
7'
5'a
10'
O
1'a
(
i)
R1
8
8a
7
O
2
O
R1
O
O
8' 9'a
9'
78-85%
6
4
3
4a
5
7a-d
R2
a) R1 = R2 = H b) R1 = OMe, R2 = H
c) R1 = H, R2 = OMe d) R1 = R2 = OMe
O
13a-d
R2
Scheme 7: MW-assisted synthesis of 2-(benzo[c]chromenyl)chromones 13a-d
℃
.
, 60 min and then chloranil,
Reagents and conditions: (i) 1,2,4-TCB, MW, 200
MW, 80 °C, 30 min.
OMe
O
(
i)/(ii)
O
O
78%
O
O
1
The main features observed in the H NMR spectra of 2-
(benzo[c]chromenyl)chromones 13a-d are the presence of: i) a
6a
17
iii)
Decomposition
singlet at δ 5.19-5.23 ppm assigned to protons H-10’; ii) a
doublet at δ 7.78-7.84 ppm assigned to proton H-6’; and iii) a
double of doublets at δ 7.86-7.94 ppm assigned to proton H-7’.
Concerning the signal of proton H-9’, it was observed as a
(
Scheme 9: Synthesis of chromone derivative 17. Reagents and conditions: (i)
doublet at δ 7.66-7.71 ppm for derivatives 13b-d, and as BBr , CH Cl , r.t., 2 h; (ii) K CO , allyl bromide, acetone, reflux, 4 h; (iii) 1,2,4-TCB,
3
2
2
2
3
MW, 200 °C, 60 min.
multiplet at δ 7.69-7.75 ppm for derivative 13a (see Scheme 7
for numbering). The absence of the signals corresponding to
the vinylic protons H-α, H-β, H-γ and H-δ, as well as the
remaining presence of the singlet assigned to proton H-3,
Conclusions
clearly indicates that the intramolecular DA reaction occurred In conclusion, we prepared in good yields a series of novel (E)-
in the diene-α,β:γ,δ, followed by in situ dehydrogenation of 2’-propargyloxy-2-styryl]chromones and of (E,E)-2-[4-[2-
the formed adduct.
So far, the reactivity of a terminal alkyne as dienophile in base-catalyzed aldol condensation of 2-methylchromones with
intramolecular DA reaction was addressed in good overall the appropriate salicylaldehyde and ortho-
propargyloxyphenyl)buta-1,3-dien-1-yl]chromones
through
yields (75-85%). In addition, we decided to further evaluate (methoxy/benzyloxy)cinnamaldehyde (in the latter case
the same kind of reaction with a terminal alkene as dienophile. cleavage of protecting groups and propargylation steps were
Thus, the intramolecular DA reaction was also attempted in necessary), which were further used as substrates in
the allyloxy-substituted chromone derivative 15
.
intramolecular DA reactions. Chromeno[3,4-b]xanthones and
-(benzo[c]chromenyl)chromones were obtained via MW-
2
O
assisted intramolecular DA reaction, followed by in situ
dehydrogenation. 2’-Allyloxy-2-stryrylchromone and 2’-
allyloxy-2-(4-arylbuta-1,3-dien-1-yl)chromone derivatives were
also prepared and considered for intramolecular DA reactions.
However, in the first case, a Claisen rearrangement product
was obtained instead of the expected intramolecular DA
product; in the later case, the intramolecular DA reaction did
(
i)
(ii)
1%
O
O
O
O
O
O
OH
2
a
2
+
CHO
91%
15
16
O
14
Scheme 8: Synthesis and Claisen rearrangement of chromone 15. Reagents and not occur due to the thermal decomposition of the chromone
conditions: (i) Na, EtOH, r.t., 2 h; (ii) DMF, MW, 165 °C, 40 min.
reagent.
Compound 15 was prepared
as described for
propargyloxychromone 4a, using the commercially available 2-
Experimental
(allyloxy)benzaldehyde 14 [Scheme 8, (i)]. Concerning the
Materials and methods
intramolecular DA reaction on compound 15, two reaction
attempts were carried out. When the reaction was performed Melting points were measured with a Büchi B-540 apparatus.
in DMF under MW irradiation at 165 °C, compound 16 was NMR spectra were recorded with Bruker Avance 300 (300.13
1
13
1
obtained in 21% yield, which results from the Claisen MHz for H and 75.47 MHz for C) and 500 (500.13 MHz for H
1
3
rearrangement of compound 15 [Scheme 8, (ii)]. Increasing the and 125.77 MHz for C) spectrometers. Chemical shifts (δ) are
reaction temperature for 200 °C also under MW irradiation reported in ppm and coupling constants (J) in Hz; the internal
and using 1,2,4-TCB as solvent, complete degradation of the standard was TMS. Unequivocal C assignments were made
1
3
4
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with the aid of 2D gHSQC and gHMBC (delays for one-bond- 110.5 (C-3), 112.8 (C-3’), 118.0 (C-8), 121.2 (C-α), 121.9 (C-5’),
long range JC/H couplings were optimized for 145 and 7 Hz, 124.2 (C-4a), 124.7 (C-1’), 124.9 (C-6), 125.7 (C-5), 128.3 (C-6’),
respectively) experiments. Positive-ion ESI mass spectra were 130.9 (C-4’), 132.0 (C-β), 133.7 (C-7), 155.9 (C-2’), 156.1 (C-8a),
+
+
acquired with a QTOF 2 instrument [dilution of 1 μL of the 162.3 (C-2), 178.6 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd
sample in chloroform solution (ca. 10–5 m) in 200 μL of 0.1% for C20
trifluoroacetic acid/methanol solution. Nitrogen was used as
15 3
H O : 303.1021; found 303.1011.
(
E)-7-methoxy-2-[2-(prop-2-yn-1-yloxy)styryl]chromone (4b)
nebuliser gas and argon as collision gas. The needle voltage
was set at 3000 V, with the ion source at 80 °C and the
desolvation temperature at 150 °C. The cone voltage was 35 V.
Other low- and high-resolution mass spectra (EI, 70 eV) were
measured with VG Autospec Q and M spectrometers.
Preparative thin-layer chromatography was performed with
Merck silica gel (60 DGF254). All chemicals and solvents used
were obtained from commercial sources and used as received
or dried by standard procedures. MW-assisted reactions were
carried out in a CEM Discover SP apparatus.
1
Light yellow solid; yield 303 mg (73%); mp 151-153
500 MHz, CDCl ): δ 2.58 (t, 1H, H-3’’, J 2.4 Hz), 3.95 (s, 3H, 7-
OCH ), 4.85 (d, 2H, H-1’’, J 2.4 Hz), 6.28 (s, 1H, H-3), 6.88 (d,
℃. H NMR
(
3
3
1
2
1
H, H-α, J 16.2 Hz), 6.95-6.98 (m, 2H, H-6, H-8), 7.05-7.10 (m,
H, H-3’, H-5’), 7.37 (ddd, 1H, H-4’, J 8.3; 7.3; 1.7 Hz), 7.61 (dd,
H, H-6’, J 7.7; 1.7 Hz), 7.89 (d, 1H, H-β, J 16.2 Hz), 8.10 (d, 1H,
13
3
H-5, J 9.2 Hz) ppm. C NMR (75 MHz, CDCl ): δ 55.9 (C-1’’),
5
1
1
3
6.3 (7-OCH ), 76.1 (C-3’’), 78.2 (C-2’’), 100.4 (C-8), 110.5 (C-3),
12.8 (C-3’), 114.1 (C-6), 118.1 (C-4a), 121.3 (C-α), 121.9 (C-5’),
24.8 (C-1’), 127.0 (C-5), 128.2 (C-6’), 130.7 (C-4’), 131.4 (C-β),
Synthetic procedures
155.8 (C-2’), 157.8 (C-8a), 161.9 (C-2), 164.1 (C-7), 178.0 (C-4)
+
+
17 4
ppm. HRMS (ESI ): m/z [M+H] calcd for C21H O : 333.1121;
General procedure for the synthesis of 2-methyl-4H-chromen-4-
ones 2a-d. The 2-methylchromones 2a-d were synthesized
according to procedures previously described in the literature and
found 333.1123.
(
E)-5-methoxy-2-[2-(prop-2-yn-1-yloxy)styryl]chromone (4c)
2
0
1
showed identical spectroscopic and analytical data.
Light yellow solid; yield 311 mg (75%); mp 180-182
500 MHz, CDCl ): δ 2.58 (t, 1H, H-3’’, J 2.3 Hz), 3.99 (s, 3H, 5-
OCH ), 4.83 (d, 2H, H-1’’, J 2.3 Hz), 6.26 (s, 1H, H-3), 6.80 (d,
℃. H NMR
(
3
General procedure for the synthesis of 2-(prop-2-yn-1-
yloxy)benzaldehyde 3. K CO (6.84 g, 49.5 mmol) and propargyl
3
2
3
1
H, H-6, J 8.3 Hz), 6.83 (d, 1H, H-α, J 16.2 Hz), 7.06 (dt, 1H, H-
’, J 7.5; 0.9 Hz), 7.07 (dd, 1H, H-3’, J 8.5; 0.9 Hz), 7.13 (dd, 1H,
bromide (3.22 mL, 36.3 mmol) were added to a solution of
salicylaldehyde (4.0 g, 33 mmol) in acetone (100 mL). The resulting
mixture was refluxed for 2 h. After that period, the reaction mixture
was poured into ice (100 g) and water (100 mL) and the pH adjusted
to 4 with dilute HCl (10%). The precipitate was recovered by
filtration and washed with water (50 mL). White solid; yield 5.0 g
5
H-8, J 8.3; 0.9 Hz), 7.36 (ddd, 1H, H-4’, J 8.5; 7.5; 0.9 Hz), 7.56
t, 1H, H-7, J 8.3 Hz), 7.59 (dd, 1H, H-6’, J 7.5; 1.7 Hz), 7.85 (d,
13
(
1
3
H, H-β, J 16.2 Hz) ppm. C NMR (75 MHz, CDCl ): δ 56.3 (C-
1’’), 56.5 (5-OCH ), 76.1 (C-3’’), 78.2 (C-2’’), 106.2 (C-6), 110.2
3
(
C-8), 112.1 (C-3), 112.8 (C-3’), 114.8 (C-4a), 120.9 (C-α), 121.8
): δ (C-5’), 124.8 (C-1’), 128.2 (C-6’), 130.6 (C-4’), 131.4 (C-β), 133.6
.58 (t, 1H, H-3’, J 2.4 Hz), 4.84 (d, 2H, H-1’, J 2.4 Hz), 7.07-7.14 (m, (C-7), 155.8 (C-2’), 158.1 (C-8a), 159.7 (C-5), 160.1 (C-2), 178.5
2
1 1
(
95%); mp 68-70 ℃ (Lit. 69-70 ℃) . H NMR (300 MHz, CDCl
3
2
2
6
+
+
H, H-3, H-5), 7,58 (ddd, 1H, H-4, J 8.3; 7.3; 1.8 Hz), 7.87 (dd, 1H, H- (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for C H O :
21 17 4
, J 7.7; 1.8 Hz), 10.49 (s, 1H, CHO) ppm.
333.1121; found 333.1129.
General procedure for the synthesis of (E)-2-[2-(prop-2-yn-1- (E)-5,7-dimethoxy-2-[2-(prop-2-yn-1-yloxy)styryl]chromone
(
4d)
White solid; yield 331 mg (73%); mp 190-193
MHz, CDCl ): δ 2.58 (t, 1H, H-3’’, J 2.4 Hz), 3.93 (s, 3H, 7-OCH
.95 (s, 3H, 5-OCH ), 4.84 (d, 2H, H-1’’, J 2.4 Hz), 6.19 (s, 1H, H-
), 6.36 (d, 1H, H-6, J 2.3 Hz), 6.58 (d, 1H, H-8, J 2.3 Hz), 6.81
yloxy)styryl]chromones 4a-d. To a mixture of sodium (110 mg, 5
1
℃
. H NMR (500
mmol) in ethanol (5 mL) were added the appropriate 2-
methylchromone
2a-d
(1.25
mmol)
and
the
O-
3
3
),
3
3
3
propargylbenzaldehyde 3 (250 mg, 1.56 mmol). The resulting
mixture was stirred at room temperature for 3-6 h. After that
period, the mixture was poured into ice (20 g) and water (30 mL)
and pH adjusted to 4 with dilute HCl (10%). The precipitate was
(d, 1H, H-α, J 16.2 Hz), 7.04-7.07 (m, 1H, H-5’), 7.08 (dd, 1H, H-
3
’, J 8.4; 1.0 Hz), 7.35 (ddd, 1H, H-4’, J 8.4; 7.3; 1.7 Hz), 7.59
1
dd, 1H, H-6’, J 7.7; 1.7 Hz), 7.81 (d, 1H, H-β, J 16.2 Hz) ppm. C
3
(
removed by filtration, taken in CH
2 2
Cl and purified by silica gel
3 3
NMR (75 MHz, CDCl ): δ 55.8 (7-OCH ), 56.2 (C-1’’), 56.4 (5-
column chromatography using CH Cl as eluent.
2
2
OCH
a), 112.1 (C-3), 112.8 (C-3’), 121.0 (C-5’), 121.9 (C-α), 124.9
C-1’), 128.2 (C-6’), 130.5 (C-4’), 130.8 (C-β), 155.8 (C-2’), 159.6
and 159.7 (C-2 and C-8a), 160.9 (C-5), 164.0 (C-7), 177.8 (C-4)
3
), 76.1 (C-3’’), 78.2 (C-2’’), 92.9 (C-8), 96.0 (C-6), 109.8 (C-
4
(
E)-2-[2-(prop-2-yn-1-yloxy)styryl]chromone (4a)
Light green solid; yield 325 mg (86%); mp 137-138
500 MHz, CDCl ): δ 2.58 (t, 1H, H-3’’, J 2.4 Hz), 4.85 (d, 2H, H-
’’, J 2.4 Hz), 6.35 (s, 1H, H-3), 6.91 (d, 1H, H-α, J 16.2 Hz), 7.07
ddd, 1H, H-5’ J 7.6; 7.4; 1.0 Hz), 7.09 (dd, 1H, H-3’, J 8.6; 1.0
Hz), 7.37 (ddd, 1H, H-4’, J 8.6; 7.4; 1.7 Hz), 7.40 (ddd, 1H, H-6, J
.0; 7.1; 1.1 Hz), 7.57 (dd, 1H, H-8, J 8.5; 1.1 Hz), 7.62 (dd, 1H,
H-6’, J 7.6; 1.7 Hz), 7.69 (ddd, 1H, H-7, J 8.5; 7.1; 1.7 Hz), 7.94
1
(
℃
. H NMR
(
3
+
+
19 5
ppm. HRMS (ESI ): m/z [M+H] calcd for C22H O : 363.1227;
1
found 363.1229.
(
Synthesis of (E,E)-2-[4-(2-methoxyphenyl)buta-1,3-dien-1-
yl]chromone (6a) and (E,E)-7-methoxy-2-[4-(2-
methoxyphenyl)buta-1,3-dien-1-yl]chromone (6aa). To
8
a
1
3
(d, 1H, H-β, J 16.2 Hz), 8.20 (dd, 1H, H-5, J 8.0; 1.7 Hz) ppm. C
mixture of sodium (110 mg, 5 mmol) in ethanol (5 mL) were
3
NMR (125 MHz, CDCl ): δ 56.3 (C-1’’), 76.1 (C-3’’), 78.2 (C-2’’),
added the appropriate 2-methylchromone 2a and 2b (1.15
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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DOI: 10.1039/C7NJ05185A
ARTICLE
Journal Name
mmol) and the ortho-methoxycinnamaldehyde 5 (253 mg, 1.56 CH Cl (3 x 50 mL), dried over anhydrous Na SO and the
2 2 2 4
mmol). The resulting mixture was stirred at room temperature solvent evaporated to dryness. The residue was purified by
for 2-3 h. After that period, the mixture was poured into ice preparative TLC using CH Cl /EtOAc (5:1) as eluent.
20 g) and water (30 mL) and pH adjusted to 4 with dilute HCl Orange solid; yield 183 mg (85%); mp 160-162
10%). The precipitate was removed by filtration, taken in MHz, CDCl ): δ 2.57 (t, 1H, H-3’’, J 2.4 Hz), 4.80 (d, 2H, H-1’’, J
.4 Hz), 6.26 (s, 1H, H-3), 6.36 (d, 1H, H-α, J 15.2 Hz), 6.97-7.06
m, 3H, H-3’, H-5’, H-γ), 7.28-7.34 (m, 1H, H-4’), 7.31 (d, 1H, H-
δ, J 15.7 Hz), 7.39 (ddd, 1H, H-6, J 7.9; 7.1; 0.8 Hz), 7.43-7.52
m, 1H, H-β), 7.51 (dd, 1H, H-8, J 8.5; 0.8 Hz), 7.57 (dd, 1H, H-
’, J 7.9; 1.6 Hz), 7.68 (ddd, 1H, H-7, J 8.5; 7.1; 1.7 Hz), 8.19 (dd,
2
2
1
(
℃. H NMR (500
(
3
2
2 2
CH Cl and purified by silica gel column chromatography using
(
CH Cl as eluent.
2
2
(E,E)-2-[4-(2-methoxyphenyl)buta-1,3-dien-1-yl]chromone
(
(
6a)
6
1
13
Yellow solid; yield 285 mg (75%); mp 103-105
MHz, CDCl ): δ 3.91 (s, 3H, 2’-OCH
H, H-α, J 15.3 Hz), 6.92 (dd, 1H, H-3’, J 8.3; 1.0 Hz), 6.98 (dt, (C-8), 121.8 (C-5’), 123.2 (C-α), 124.2 (C-4a), 124.9 (C-6), 125.7
℃
. H NMR (300 1H, H-5, J 7.9; 1.7 Hz) ppm. C NMR (125 MHz, CDCl ): δ 56.3
3
3
3
), 6.25 (s, 1H, H-3), 6.35 (d, (C-1’’), 75.9 (C-3’’), 78.3 (C-2’’), 110.2 (C-3), 112.7 (C-3’), 117.8
1
1
2
H, H-5’, J 7.6; 1.0 Hz), 6.98-7.07 (m, 1H, H-γ), 7.27-7.32 (m, (C-5), 125.9 (C-1’), 127.2 (C-6’), 127.9 (C-γ), 129.9 (C-4’), 133.7
H, H-4’, H-δ), 7.38 (ddd, 1H, H-6, J 8.0; 7.1; 1.1 Hz), 7.42-7.51 (C-7), 133.9 (C-δ), 138.3 (C-β), 155.3 (C-2’), 156.0 (C-8a), 162.0
+
+
C-2), 178.5 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for
(
(m, 1H, H-β), 7.49 (dd, 1H, H-8, J 8.7; 1.1 Hz), 7.54 (dd, 1H, H-
22 17 3
C H O
: 329.1172; found 329.1175.
6
’, J 7.6; 1.7 Hz), 7.67 (ddd, 1H, H-7, J 8.7; 7.1; 1.7 Hz), 8.19 (dd,
13
1H, H-5, J 8.0; 1.7 Hz) ppm. C NMR (75 MHz, CDCl ): δ 55.5
3
General procedure for the synthesis of (E,E)-2-{4-[2-
benzyloxy)phenyl]buta-1,3-dien-1-yl}chromones 6b-d. To a
mixture of sodium (110 mg, 5 mmol) in ethanol (5 mL) were
(2’-OCH
3
), 110.1 (C-3), 111.1 (C-3’), 117.8 (C-8), 120.8 (C-5’),
(
1
1
1
22.9 (C-α), 124.2 (C-4a), 124.9 (C-6), 125.2 (C-1’), 125.7 (C-5),
27.3 (C-6’), 127.7 (C-γ), 130.1 (C-4’), 133.6 (C-7), 134.4 (C-δ), added the appropriate 2-methylchromone 2b-d (1.25 mmol)
38.5 (C-β), 156.0 (C-8a), 157.4 (C-2’), 162.1 (C-2), 178.4 (C-4) and the ortho-benzyloxycinnamaldehyde 10 (372 mg, 1.56
+
+
ppm. HRMS (ESI ): m/z [M+H] calcd for C20
H
17
O
3
: 305.1178; mmol). The resulting mixture was stirred at room temperature
for 4-6 h. After that period, the mixture was poured into ice
found 305.1170.
(
(
20 g) and water (30 mL) and pH adjusted to 4 with dilute HCl
10%). The precipitate was removed by filtration, taken in
(
E,E)-7-methoxy-2-[4-(2-methoxyphenyl)buta-1,3-dien-1-
yl]chromone (6aa)
CH
CH
2
Cl
Cl
2
and purified by silica gel column chromatography using
as eluent.
1
. H NMR (500
Yellow solid; yield 308 mg (80%); mp 129-131
℃
2
2
MHz, CDCl
s, 1H, H-3), 6.33 (d, 1H, H-α, J 15.2 Hz), 6.90 (d, 1H, H-8, J 2.4
Hz), 6.90-6.92 (m, 1H, H-3’), 6.95 (dd, 1H, H-6, J 8.8; 2.4 Hz),
.96-6.99 (m, 1H, H-5’), 7.02 (ddd, 1H, H-γ, J 15.7; 11.0; 0.8
3 3 3
): δ 3.90 (s, 3H, 2’-OCH ), 3.93 (s, 3H, 7-OCH ), 6.19
(
E,E)-2-{4-[2-(benzyloxy)phenyl]buta-1,3-dien-1-yl}-7-
(
methoxychromone (6b)
1
Yellow solid; yield 436 mg (85%); mp 139-142
℃
. H NMR (500
),
.16 (s, 1H, H-3), 6.27 (d, 1H, H-α, J 15.2 Hz), 6.90 (d, 1H, H-8, J
.3 Hz), 6.93 (dd, 1H, H-6, J 8.8; 2.3 Hz), 6.96-7.04 (m, 3H, H-γ,
6
3 3 2 6 5
MHz, CDCl ): δ 3.91 (s, 3H, 7-OCH ), 5.14 (s, 2H, 2’-OCH C H
Hz), 7.26-7.29 (m, 1H, H-δ), 7.29 (ddd, 1H, H-4’, J 8.2; 7.4; 1.7
Hz), 7.43 (ddd, 1H, H-β, J 15.2; 11.0; 0.8 Hz), 7.53 (dd, 1H, H-6’,
6
2
13
J 7.7; 1.7 Hz), 8.09 (d, 1H, H-5, J 8.8 Hz) ppm. C NMR (75
MHz, CDCl ): δ 55.5 (2’-OCH ), 55.8 (7-OCH ), 100.2 (C-8),
10.0 (C-3), 111.1 (C-3’), 113.9 (C-6), 118.0 (C-4a), 120.8 (C-5’),
H-3’, H-5’), 7.27 (ddd, 1H, H-4’, J 8.2; 7.4; 1.6 Hz), 7.32 (d, 1H,
H-δ, J 15.7 Hz), 7.37-7.49 (m, 6H, H-β, 2’-OCH ), 7.57 (dd,
H, H-6’, J 7.7; 1.6 Hz), 8.08 (d, 1H, H-5, J 8.8 Hz) ppm. C NMR
125 MHz, CDCl ): δ 55.9 (7-OCH ), 70.4 (2’-OCH ), 100.2
C-8), 110.1 (C-3), 112.5 (C-3’), 114.1 (C-6), 118.0 (C-4a), 121.2
3
3
3
2 6 5
C H
1
1
1
1
13
1
22.9 (C-α), 125.3 (C-1’), 127.0 (C-5), 127.2 (C-6’), 127.7 (C-γ),
30.0 (C-4’), 134.0 (C-δ), 137.9 (C-β), 157.3 (C-2’), 157.7 (C-8a),
61.7 (C-2), 164.1 (C-7), 177.9 (C-4) ppm.
(
(
3
3
2 6 5
C H
(C-5’), 123.1 (C-α), 125.6 (C-1’), 127.0 (C-5), 127.1 (C-6’), 127.6
C-2,6 of 2’-OCH ), 127.8 (C-γ), 128.2 (C-4 of 2’-OCH ),
28.7 (C-3,5 of 2’-OCH ), 130.0 (C-4’), 133.7 (C-δ), 136.8
C-1 of 2’-OCH ), 137.8 (C-β), 156.5 (C-2’), 157.8 (C-8a),
(
2
C
6
H
5
2 6 5
C H
Synthesis of (E,E)-2-{4-[2-(prop-2-yn-1-yloxy)phenyl]buta-1,3-
dien-1-yl}chromone (7a). A solution of BBr in CH Cl 1M (1.64
mL) was added to a solution under nitrogen atmosphere of
chromone derivative 6a (200 mg, 0.657 mmol) in CH Cl (5
mL). The resulting mixture was stirred at room temperature
1
2 6 5
C H
3
2
2
(
2 6 5
C H
+
1
61.6 (C-2), 164.1 (C-7), 177.9 (C-4) ppm. HRMS (ESI ): m/z
+
2
2
23 4
[M+H] calcd for C27H O : 411.1591; found 411.1601.
for 2 h. After that period, the mixture was poured into ice (5 g) (E,E)-2-{4-[2-(benzyloxy)phenyl]buta-1,3-dien-1-yl}-5-
and water (15 mL) and the slurry was stirred until the methoxychromone (6c)
1
formation of a precipitate. The precipitate was removed by Yellow solid; yield 410 mg (80%); mp 125-127
filtration and washed with water (100 mL) and ethyl ether (50 MHz, CDCl ): δ 3.98 (s, 3H, 5-OCH
mL). To a stirring mixture of the precipitate in acetone (30 mL) 6.15 (s, 1H, H-3), 6.23 (d, 1H, H-α, J 15.3 Hz), 6.79 (dd, 1H, H-6,
was added K CO
(136 mg, 1.5 equiv) and propargyl bromide J 8.4; 0.9 Hz), 6.97 (dd, 1H, H-3’, J 8.4; 1.0 Hz), 6.97-7.05 (m,
0% m/m in xylene (0.2 mL; 3 equiv). The resulting mixture 2H, H-γ, H-5’), 7.07 (dd, 1H, H-8, J 8.4; 0.9 Hz), 7.25-7.28 (m,
was stirred at reflux for 5 h. After that period, the mixture was 1H, H-4’), 7.30 (d, 1H, H-δ, J 15.7 Hz), 7.34-7.49 (m, 6H, H-β, 2’-
poured into ice (5 g) and water (15 mL) and pH adjusted to 4 OCH ), 7.53 (t, 1H, H-7, J 8.4 Hz), 7.56 (dd, 1H, H-6’, J 7.6;
with dilute HCl (10%). The aqueous layer was extracted with 1.5 Hz) ppm. C NMR (125 MHz, CDCl
℃
. H NMR (500
3
3 2 6 5
), 5.15 (s, 2H, 2’-OCH C H ),
2
3
8
2 6 5
C H
1
3
3
3
): δ 56.5 (5-OCH ), 70.4
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 7 of 11
Pl Ne ae swe Jdoo u nr no at l ao df j Cu sh te mm ai sr tgr iyn s
View Article Online
DOI: 10.1039/C7NJ05185A
Journal Name
ARTICLE
+
+
(
2’-OCH
’), 114.7 (C-4a), 121.1 (C-5’), 122.6 (C-α), 125.7 (C-1’), 127.2 for C23
C-6’), 127.6 (C-2,6 of 2’-OCH ), 127.9 (C-γ), 128.1 (C-4 of
’-OCH ), 128.7 (C-3,5 of 2’-OCH ), 129.9 (C-4’), 133.6
and 133.7 (C-δ and C-7), 136.8 (C-1 of 2’-OCH ), 137.8 (C-
β), 156.5 (C-2’), 158.1 (C-8a), 159.7 and 159.9 (C-2 and C-5),
2
C
6
H
5
), 106.2 (C-6), 110.0 (C-8), 111.7 (C-3), 112.5 (C- 164.1 (C-7), 177.9 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd
3
19 4
H O
: 359.1278; found 359.1285.
(
2 6 5
C H
(
E,E)-5-methoxy-2-{4-[2-(prop-2-yn-1-yloxy)phenyl]buta-1,3-
2
2
C
6
H
5
2 6 5
C H
dien-1-yl}chromone (7c)
2
C
6
H
5
1
. H NMR (500
Yellow solid; yield 140 mg (80%); mp 103-105
℃
+
+
MHz, CDCl ): δ 2.56 (t, 1H, H-3’’, J 2.4 Hz), 3.98 (s, 3H, 5-OCH ),
3 3
1
23 4
78.4 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for C27H O :
4
.79 (d, 2H, H-1’’, J 2.4 Hz), 6.17 (s, 1H, H-3), 6.29 (d, 1H, H-α, J
5.2 Hz), 6.80 (dd, 1H, H-6, J 8.4; 1.0 Hz), 6.97-7.04 (m, 3H, H-
4
11.1591; found 411.1596.
1
(
E,E)-2-{4-[2-(benzyloxy)phenyl]buta-1,3-dien-1-yl}-5,7-
3’, H-5’, H-γ), 7.07 (dd, 1H, H-8, J 8.4; 1.0 Hz), 7.27 (d, 1H, H-δ, J
15.5 Hz), 7.28-7.31 (m, 1H, H-4’), 7.39 (ddd, 1H, H-β, J 15.2;
dimethoxychromone (6d)
1
Yellow solid; yield 385 mg (70%); mp 180-183
℃. H NMR (500 11.0; 0.9 Hz), 7.55 (t, 1H, H-7, J 8.4 Hz), 7.56 (dd, 1H, H-6’, J
1
3
MHz, CDCl
s, 2H, 2’-OCH
Hz), 6.34 (d, 1H, H-6, J 2.3 Hz), 6.52 (d, 1H, H-8, J 2.3 Hz), 6.96- 111.8 (C-3), 112.7 (C-3’), 114.7 (C-4a), 121.8 (C-5’), 122.8 (C-α),
3
): δ 3.90 (s, 3H, 7-OCH
3
), 3.93 (s, 3H, 5-OCH
3
), 5.14 7.9; 1.7 Hz) ppm. C NMR (75 MHz, CDCl
3
): δ 56.3 (C-1’’), 56.5
(
2
C
6
H
5
), 6.09 (s, 1H, H-3), 6.21 (d, 1H, H-α, J 15.3 (5-OCH
3
), 75.8 (C-3’’), 78.4 (C-2’’), 106.2 (C-6), 110.0 (C-8),
7
.03 (m, 3H, H-3’, H-5’, H-γ), 7.25-7.28 (m, 1H, H-4’), 7.29 (d, 126.0 (C-1’), 127.2 (C-6’), 128.0 (C-γ), 129.8 (C-4’), 133.3 (C-δ),
H, H-δ, J 15.8 Hz), 7.33-7.49 (m, 6H, H-β, 2’-OCH ), 7.56 133.6 (C-7), 137.6 (C-β), 155.2 (C-2’), 158.1 (C-8a), 159.8 (C-2
1
2 6 5
C H
1
dd, 1H, H-6’, J 7.7; 1.7 Hz) ppm. C NMR (125 MHz, CDCl
3
+
+
): δ and C-5), 178.4 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for
(
3
5
9
1
5.8 (7-OCH
3
), 56.4 (5-OCH
3
), 70.4 (2’-OCH
2
C
6
H
5
23 19 4
), 92.7 (C-8), C H O : 359.1278; found 359.1285.
6.0 (C-6), 109.4 (C-4a), 111.8 (C-3), 112.5 (C-3’), 121.1 (C-5’),
22.7 (C-α), 125.7 (C-1’), 127.1 (C-6’), 127.6 (C-2,6 of 2’-
(
E,E)-5,7-dimethoxy-2-{4-[2-(prop-2-yn-1-yloxy)phenyl]buta-
,3-dien-1-yl}chromone (7d)
Yellow solid; yield 142 mg (75%); mp 95-98
MHz, CDCl ): δ 2.56 (t, 1H, H-3’’, J 2.4 Hz), 3.92 (s, 3H, 7-OCH
3.94 (s, 3H, 5-OCH ), 4.78 (d, 2H, H-1’’, J 2.4 Hz), 6.11 (s, 1H, H-
3), 6.27 (d, 1H, H-α, J 15.2 Hz), 6.35 (d, 1H, H-6, J 2.3 Hz), 6.52
d, 1H, H-8, J 2.3 Hz), 6.96-7.02 (m, 3H, H-3’, H-5’, H-γ), 7.26 (d,
H, H-δ, J 15.7 Hz), 7.27-7.31 (m, 1H, H-4’), 7.36 (ddd, 1H, H-β,
1
OCH
,5 of 2’-OCH
OCH ), 137.2 (C-β), 156.5 (C-2’), 159.4 (C-2), 159.7 (C-8a),
60.9 (C-5), 164.0 (C-7), 177.7 (C-4) ppm. HRMS (ESI ): m/z
2
C
6
H
5
), 127.9 (C-γ), 128.2 (C-4 of 2’-OCH
2
C
6
H
5
), 128.7 (C-
1
℃
. H NMR (500
),
3
2 6 5
C H
), 129.9 (C-4’), 133.2 (C-δ), 136.8 (C-1 of 2’-
3
3
2 6 5
C H
+
3
1
+
25 5
[M+H] calcd for C28H O : 441.1697; found 441.1714.
(
1
General procedure for the synthesis of (E,E)-2-{4-[2-(prop-2-
yn-1-yloxy)phenyl]buta-1,3-dien-1-yl}chromones 7b-d. To a
stirring mixture of AcOH/HCl 37% (10% v/v) (10 mL) was added
the appropriate chromone derivative 6b-d (0.487 mmol). The
13
C
J 15.2; 11.0; 0.9 Hz), 7.56 (dd, 1H, H-6’, J 8.0; 1.6 Hz) ppm.
NMR (125 MHz, CDCl ): δ 55.8 (7-OCH ), 56.3 (C-1’’), 56.4 (5-
OCH ), 75.8 (C-3’’), 78.4 (C-2’’), 92.7 (C-8), 96.0 (C-6), 109.4 (C-
a), 111.8 (C-3), 112.7 (C-3’), 121.8 (C-5’), 122.9 (C-α), 126.0
3
3
3
4
resulting mixture was stirred at 100 ℃ for 16 h. After that
period, the mixture was poured into ice (5 g) and water (15
(
(
(
C-1’), 127.1 (C-6’), 128.0 (C-γ), 129.7 (C-4’), 133.0 (C-δ), 137.1
C-β), 155.2 (C-2’), 159.3 (C-2), 159.7 (C-8a), 160.9 (C-5), 164.0
+
C-7), 177.7 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for
: 389.1384; found 389.1399.
mL), the aqueous layer was extracted with EtOAc (3 x 50 mL),
+
dried over anhydrous Na
dryness. To a stirring mixture of the residue in acetone (30 mL)
was added K CO (101 mg, 1.5 equiv) and propargyl bromide Synthesis of 1-benzyloxy-2-iodobenzene (9).
0% m/m in xylene (0.13 mL, 3 equiv). The mixture was 13.6 mmol) and benzyl bromide (1.19 mL, 10.0 mmol) were
refluxed for 5 h. After that period, the mixture was poured into added to a solution of 2-iodophenol (2 g, 9.1 mmol) in
ice (5 g) and water (15 mL) and the pH adjusted to 4 with acetone (100 mL). The resulting mixture was stirred at reflux
dilute HCl (10%). The aqueous layer was extracted with CH Cl for 16 h. After that period, the mixture was poured into ice
3 x 50 mL), dried over anhydrous Na SO and the solvent (100 g) and water (100 mL) and the pH was adjusted to 4 with
evaporated to dryness. The residue was purified by dilute HCl (10%). The aqueous layer was extracted with CH Cl
and the solvent
2 4
SO and the solvent evaporated to
24 21 5
C H O
2
3
2 3
K CO (1.89 g,
8
8
2
2
(
2
4
2
2
preparative TLC using CH
2
Cl
2
/EtOAc (5:1) as eluent.
(3 x 100 mL), dried over anhydrous Na
evaporated to dryness. Colorless oil; yield 2.80 g (99%). H
NMR (300 MHz, CDCl ): δ 5.15 (s, 2H, 1-OCH ), 6.72 (dt,
1H, H-4, J 7.6; 1.4 Hz), 6.86 (dd, 1H, H-6, J 8.2; 1.4 Hz), 7.27
ddd, 1H, H-5, J 8.2; 7.6; 1.6 Hz), 7.32-7.51 (m, 5H, 1-
2 4
SO
1
(E,E)-7-methoxy-2-{4-[2-(prop-2-yn-1-yloxy)phenyl]buta-1,3-
3
2 6 5
C H
dien-1-yl}chromone (7b)
Yellow solid; yield 145 mg (83%); mp 137-139
MHz, CDCl
1
. H NMR (300
℃
(
3
): δ 2.57 (t, 1H, H-3’’, J 2.4 Hz), 3.93 (s, 3H, 7-OCH
3
),
13
OCH
2
C
6
H
5
), 7.80 (dd, 1H, H-3, J 7.6; 1.6 Hz) ppm. C NMR (75
): δ 70.8 (1-OCH ), 86.8 (C-2), 112.7 (C-6), 122.8
C-4), 127.0 (C-2,6 of 1-OCH ), 127.9 (C-4 of 1-OCH ),
), 129.4 (C-5), 136.5 (C-1 of 1-
4
1
1
1
5
5
1
1
1
.79 (d, 2H, H-1’’, J 2.4 Hz), 6.19 (s, 1H, H-3), 6.33 (d, 1H, H-α, J
5.2 Hz), 6.91-7.05 (m, 5H, H-6, H-8, H-3’, H-5’, H-γ), 7.29 (d,
H, H-δ, J 16.1 Hz), 7.26-7.33 (m, 1H, H-4’), 7.43 (dd, 1H, H-β, J
5.2; 10.9 Hz), 7.56 (dd, 1H, H-6’, J 7.9; 1.7 Hz), 8.09 (d, 1H, H-
MHz, CDCl
3
2 6 5
C H
(
2
C
6
H
5
2 6 5
C H
1
28.6 (C-3,5 of 1-OCH
), 139.6 (C-3), 157.2 (C-1) ppm. HRMS (ESI ): m/z
M+H] calcd for C13 12IO: 310.9933; found 310.9938.
2 6 5
C H
+
1
3
2 6 5
OCH C H
, J 8.8 Hz) ppm. C NMR (75 MHz, CDCl
6.3 (C-1’’), 75.8 (C-3’’), 78.4 (C-2’’), 100.2 (C-8), 110.2 (C-3),
12.7 (C-3’), 114.0 (C-6), 118.0 (C-4a), 121.8 (C-5’), 123.2 (C-α), Synthesis of (E)-3-[2-(benzyloxy)phenyl]acrylaldehyde (10).
3
): δ 55.8 (7-OCH
3
),
+
[
H
n
25.9 (C-1’), 127.0 (C-5), 127.2 (C-6’), 127.9 (C-γ), 129.8 (C-4’), Acrolein diethyl acetal (4.1 mL, 27 mmol), Bu
4
NOAc (5.4 g, 18
(61 mg, 0.27
33.5 (C-δ), 137.7 (C-β), 155.3 (C-2’), 157.7 (C-8a), 161.6 (C-2), mmol), K CO (1.86 g, 13.5 mmol) and Pd(OAc)
2
3
2
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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New Journal of Chemistry
Page 8 of 11
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DOI: 10.1039/C7NJ05185A
ARTICLE
Journal Name
3
mmol) were added to a solution of 1-benzyloxy-2-iodobenzene CDCl ): δ 68.0 (C-6), 110.9 (C-14), 117.9 and 118.0 (C-4 and C-
9
(2.80 g, 9 mmol) in DMF (10 mL). The mixture was stirred at 12), 120.7 (C-7a), 121.4 (C-14b), 121.9 (C-8a), 122.5 and 122.6
90 ℃ for 16 h. After that period, the mixture was poured into (C-2 and C-7), 124.1 (C-10), 124.4 (C-1), 126.7 (C-9), 127.6 (C-
ice (50 g) and water (50 mL), the pH was adjusted to 1 with 6a), 131.5 (C-3), 134.9 (C-11), 137.0 (C-14a), 155.6 (C-4a),
+
dilute HCl (10%), and the aqueous mixture was stirred at room 156.2 (C-12a), 156.5 (C-13a), 176.6 (C-8) ppm. HRMS (ESI ):
+
temperature for 15 min. Then, it was extracted with Et
00 mL), dried over anhydrous Na SO and the solvent
evaporated to dryness. The crude residue was purified by silica
gel column chromatography using CH Cl as eluent. White
solid; yield 1.50 g (70%); mp 56-58
CDCl ): δ 5.16 (s, 2H, 2-OCH ), 6.77 (dd, 1H, H-α, J 16.1; 7.9
Hz), 6.98-7.01 (m, 1H, H-5), 6.99 (d, 1H, H-3, J 7.9 Hz), 7.33-
2
O (3 x m/z [M+H] calcd for C20
H
13
O
3
: 301.0859; found 301.0864.
1
2
4
1
1-methoxy-6H,8H-chromeno[3,4-b]xanthen-8-one (12b)
1
White solid; yield 27 mg (81%); mp 223-225
MHz, CDCl ): δ 3.95 (s, 3H, 11-OCH ), 5.21 (s, 2H, H-6), 6.89 (d,
H, H-12, J 2.4 Hz), 6.95 (dd, 1H, H-10, J 8.9; 2.4 Hz), 7.04 (dd,
H, H-4, J 8.2; 1.2 Hz), 7.12 (dt, 1H, H-2, J 7.6; 1.2 Hz), 7.34
℃. H NMR (500
2
2
1
3
3
℃
. H NMR (300 MHz,
1
1
3
2 6 5
C H
(
ddd, 1H, H-3, J 8.2; 7.6; 1.6 Hz), 7.71 (s, 1H, H-14), 7.79 (dd,
7
.44 (m, 6H, 2-OCH
.90 (d, 1H, H-β, J 16.1 Hz), 9.66 (d, 1H, CHO, J 7.9 Hz) ppm.
): δ 70.6 (2-OCH ), 112.8 (C-3), 121.2
C-5), 123.3 (C-1), 127.4 (C-2,6 of 2-OCH ), 128.3 (C-4 of 2-
OCH ), 128.7 (C-6), 128.8 (C-3,5 of 2-OCH ), 129.0 (C-
α), 132.7 (C-4), 136.3 (C-1 of 2-OCH ), 148.0 (C-β), 157.4
2 6 5
C H , H-4), 7.58 (dd, 1H, H-6, J 8.1; 1.7 Hz),
1
3
1H, H-1, J 7.6; 1.6 Hz), 8.09 (s, 1H, H-7), 8.24 (d, 1H, H-9, J 8.9
7
C
13
Hz) ppm. C NMR (125 MHz, CDCl
), 100.3 (C-12), 110.6 (C-14), 113.3 (C-10), 115.8 (C-8a), 118.0
C-4), 120.8 (C-14b), 121.5 (C-7a), 122.5 and 122.6 (C-2 and C-
), 124.3 (C-1), 127.5 (C-6a), 128.3 (C-9), 131.3 (C-3), 136.5 (C-
14a), 155.6 (C-4a), 156.5 (C-13a), 158.1 (C-12a), 165.1 (C-11),
3 3
): δ 55.9 (11-OCH ), 68.0 (C-
NMR (75 MHz, CDCl
3
2 6 5
C H
6
(
2 6 5
C H
(
2
C
6
H
5
2 6 5
C H
7
2 6 5
C H
+
+
(C-2), 194.6 (CHO) ppm. HRMS (ESI ): m/z [M+Na] calcd for
+
+
1
3
15 4
75.7 (C-8) ppm. HRMS (ESI ): m/z [M+H] calcd for C21H O :
16 14 2
C H O
Na: 261.0886; found 261.0890.
31.0965; found 331.0971.
Synthesis of 14,14a-dihydro-6H,8H-chromeno[3,4-b]xanthen-
-one (11). This compound was isolated from the MW-assisted
9
-methoxy-6H,8H-chromeno[3,4-b]xanthen-8-one (12c)
8
1
White solid; yield 27 mg (82%); mp 257-258
MHz, CDCl ): δ 4.02 (s, 3H, 9-OCH
1H, H-10, J 8.3; 0.9 Hz), 7.03 (dd, 1H, H-4, J 8.1; 1.2 Hz), 7.06
dd, 1H, H-12, J 8.3; 0.9 Hz), 7.10 (dt, 1H, H-2, J 7.5; 1.2 Hz),
.33 (ddd, 1H, H-3, J 8.1; 7.5; 1.6 Hz), 7.60 (t, 1H, H-11, J 8.3
Hz), 7.66 (s, 1H, H-14), 7.77 (dd, 1H, H-1, J 7.5; 1.6 Hz), 8.06 (s,
℃
. H NMR (500
intramolecular DA reaction of chromone derivative 4a (0.1
3
3
), 5.20 (s, 2H, H-6), 6.80 (dd,
mmol, 30 mg) in DMF, NMP or 1,2,4-TCB as solvents (see Table
1
). White solid; mp 215-217 °C. H NMR (500 MHz, CDCl
1
2
4
1
3
7
7
1
9
3
): δ
(
.89 (t, 1H, H-14, J 17.1 Hz), 3.27 (dd, 1H, H-14, J 17.1; 8.1 Hz),
.09 (ddd, 1H, H-14a, J 17.1; 8.1; 3.2 Hz), 4.53 (dd, 1H, H-6, J
2.5; 1.8 Hz), 4.78 (d, 1H, H-6, J 12.5 Hz), 6.85 (dd, 1H, H-7, J
.2; 1.8 Hz), 6.97 (dd, 1H, H-4, J 8.1; 1.2 Hz), 7.01 (dt, 1H, H-2, J
.5; 1.2 Hz), 7.18-7.21 (m, 1H, H-3), 7.25-7.26 (m, 1H, H-1),
.42 (ddd, 1H, H-10, J 8.0; 7.1; 1.1 Hz), 7.47 (dd, 1H, H-12, J 8.6;
.1 Hz), 7.66 (ddd, 1H, H-11, J 8.6; 7.1; 1.7 Hz), 8.26 (dd, 1H, H-
7
13
1
H, H-7) ppm. C NMR (75 MHz, CDCl
C-6), 105.5 (C-10), 110.0 and 110.2 (C-12 and C-14), 112.5 (C-
a), 117.9 (C-4), 121.5 (C-14b), 121.9 (C-7a), 122.4 and 122.7
C-2 and C-7), 124.3 (C-1), 127.5 (C-6a), 131.2 (C-3), 134.8 (C-
11), 136.3 (C-14a), 155.3 (C-13a), 155.6 (C-4a), 158.2 (C-12a),
3 3
): δ 56.5 (9-OCH ), 68.0
(
8
(
1
3
, J 8.0; 1.7 Hz). C NMR (75 MHz, CDCl
3
): δ 33.5 (C-14a), 34.6
+
+
1
60.7 (C-9), 175.9 (C-8) ppm. HRMS (ESI ): m/z [M+H] calcd
: 331.0965; found 331.0971.
(
C-14), 68.8 (C-6), 115.7 (C-7), 115.8 (C-7a), 117.7 (C-4), 118.0
C-12), 121.7 (C-2), 123.9 (C-8a), 124.9 (C-14b), 125.2 (C-10),
15 4
for C21H O
(
1
26.2 (C-9), 128.06 and 128.13 (C-1 and C-3), 130.2 (C-6a), 9,11-dimethoxy-6H,8H-chromeno[3,4-b]xanthen-8-one (12d)
1
1
33.4 (C-11), 154.6 (C-4a), 155.8 (C-12a), 164.2 (C-13a), 174.2 White solid; yield 28 mg (78%); mp 249-250
MHz, CDCl ): δ 3.92 (s, 3H, 11-OCH ), 3.98 (s, 3H, 9-OCH
s, 2H, H-6), 6.34 (d, 1H, H-10, J 2.3 Hz), 6.50 (d, 1H, H-12, J 2.3
℃
. H NMR (500
(C-8).
3
3
3
), 5.20
(
General procedure for the synthesis of 6H,8H-chromeno[3,4-
b]xanthen-8-ones 12a-d. The appropriate (E)-2’-propargyloxy-
Hz), 7.03 (dd, 1H, H-4, J 8.2; 1.2 Hz), 7.10 (dt, 1H, H-2, J 7.5; 1.2
Hz), 7.32 (ddd, 1H, H-3, J 8.2; 7.5; 1.6 Hz), 7.61 (s, 1H, H-14),
13
2
-styrylchromone 4a-d (0.1 mmol) and 1,2,4-TCB (0.3 mL) were
mixed in a closed glass vessel. The resulting mixture was
heated under MW irradiation at 200 for 60 min. After that
7.76 (dd, 1H, H-1, J 7.5; 1.6 Hz), 8.04 (s, 1H, H-7) ppm. C NMR
(
3 3 3
75 MHz, CDCl ): δ 55.8 (11-OCH ), 56.4 (9-OCH ), 68.0 (C-6),
℃
9
1
1
1
1
2.8 (C-12), 95.2 (C-10), 107.3 (C-8a), 109.9 (C-14), 117.9 (C-4),
21.6 (C-14b), 122.0 (C-7a), 122.4 and 122.7 (C-2 and C-7),
24.2 (C-1), 127.4 (C-6a), 131.1 (C-3), 135.8 (C-14a), 155.2 (C-
3a), 155.5 (C-4a), 159.8 (C-12a), 162.0 (C-9), 164.9 (C-11),
period, chloranil (10 µmol, 2.5 mg) was added to the crude
mixture and it was heated under MW irradiation at 80 °C for
30 min. The resulting mixture was dissolved in CH
2 2
Cl (5 mL)
and purified by preparative TLC using CH Cl as eluent.
2
2
+
+
17 5
74.8 (C-8) ppm. HRMS (ESI ): m/z [M+H] calcd for C22H O :
6
H,8H-chromeno[3,4-b]xanthen-8-one (12a)
White solid; yield 22 mg (75%); mp 209-211
MHz, CDCl ): δ 5.23 (s, 2H, H-6), 7.05 (dd, 1H, H-4, J 8.1; 1.2
Hz), 7.13 (dt, 1H, H-2, J 7.7; 1.2 Hz), 7.35 (ddd, 1H, H-3, J 8.1;
361.1071; found 361.1076.
General procedure for the synthesis of 2-(6H-
benzo[c]chromen-8-yl)-4H-chromen-4-ones 13a-d. The
1
℃
. H NMR (300
3
appropriate chromone derivative 7a-d (0.1 mmol) and 1,2,4-
7.7; 1.6 Hz), 7.39 (ddd, 1H, H-10, J 8.0; 7.1; 1.1 Hz), 7.51 (dd,
1H, H-12, J 8.4; 1.1 Hz), 7.74 (ddd, 1H, H-11, J 8.4; 7.1; 1.7 Hz),
7.76 (s, 1H, H-14), 7.81 (dd, 1H, H-1, J 7.7; 1.6 Hz), 8.12 (s, 1H,
TCB (0.3 mL) were mixed in a closed glass vessel. The resulting
mixture was heated under MW irradiation at 200
℃ for 60
1
3
min. After that period, chloranil (10 µmol, 2.5 mg) was added
to the crude mixture and it was heated under MW irradiation
H-7), 8.34 (dd, 1H, H-9, J 8.0; 1.7 Hz) ppm. C NMR (75 MHz,
8
| J. Name., 2012, 00, 1-3
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DOI: 10.1039/C7NJ05185A
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ARTICLE
at 80 °C for 30 min. After that period, the crude was dissolved 1H, H-4’, J 7.7; 1.2 Hz), 7.27-7.33 (m, 1H, H-3’), 7.66 (d, 1H, H-
in CH Cl (5 mL) and purified by preparative TLC using 9’, J 1.6 Hz), 7.76 (dd, 1H, H-5’, J 7.7; 1.7 Hz), 7.78 (d, 1H, H-6’, J
hexane/EtOAc (9:7) as eluent.
2
2
1
3
8.2 Hz), 7.86 (dd, 1H, H-7’, J 8.2; 1.6 Hz) ppm. C NMR (75
MHz, CDCl ): δ 55.8 (7-OCH ), 56.4 (5-OCH ), 68.3 (C-10’), 92.8
(C-8), 96.2 (C-6), 108.9 (C-3), 109.3 (C-4a), 117.6 (C-2’), 122.0
C-5’a), 122.2 (C-9’), 122.4 and 122.5 (C-4’ and C-6’), 123.7 (C-
3
3
3
2
-(6H-benzo[c]chromen-8-yl)-4H-chromen-4-one (13a)
1
White solid; yield 28 mg (85%); mp 229-232
MHz, CDCl ): δ 5.23 (s, 2H, H-10’), 6.85 (s, 1H, H-3), 7.04 (dd,
H, H-2’, J 8.1; 1.2 Hz), 7.11 (dt, 1H, H-4’, J 7.6; 1.2 Hz), 7.32
ddd, 1H, H-3’, J 8.1; 7.6; 1.6 Hz), 7.44 (ddd, 1H, H-6, J 8.0; 7.1;
.0 Hz), 7.60 (dd, 1H, H-8, J 8.7; 1.0 Hz), 7.69-7.75 (m, 2H, H-7,
H-9’), 7.79 (dd, 1H, H-5’, J 7.6; 1.6 Hz), 7.84 (d, 1H, H-6’, J 8.2
Hz), 7.94 (dd, 1H, H-7’, J 8.2; 2.0 Hz), 8.25 (dd, 1H, H-5, J 8.0; Synthesis of (E)-2-(2-allyloxystyryl)-4H-chromen-4-one (15).
℃. H NMR (300
(
3
5
1
1
’), 126.0 (C-7’), 130.5 and 130.6 (C-8’ and C-3’), 131.9 (C-9’a),
1
33.0 (C-5’b), 155.1 (C-1’a), 159.8 and 160.0 (C-2 and C-8a),
(
+
60.9 (C-5), 164.1 (C-7), 177.5 (C-4) ppm. HRMS (ESI ): m/z
1
+
[M+H] calcd for C24
H
19
O
5
: 387.1227; found 387.1233.
1
3
1
3
1
6
8
1
3
.7 Hz) ppm. C NMR (75 MHz, CDCl ): δ 68.3 (C-10’), 107.4 (C- To a mixture of sodium (110 mg, 5 mmol) in ethanol (5 mL)
), 117.7 (C-2’), 118.1 (C-8), 121.9 (C-5’a), 122.5; 122.6 and were added the 2-methylchromone 2a (200 mg, 1.25 mmol)
22.7 (C-4’, C-6’ and C-9’), 123.8 (C-5’), 124.0 (C-4a), 125.3 (C- and the O-allyloxybenzaldehyde 14 (253 mg, 1.56 mmol). The
), 125.8 (C-5), 126.4 (C-7’), 130.716 and 130.724 (C-3’ and C- resulting mixture was stirred at room temperature for 2 h.
’), 132.0 (C-9’a), 133.5 (C-5’b), 133.9 (C-7), 155.2 (C-1’a), After that period, the mixture was poured into ice (20 g) and
+
56.2 (C-8a), 162.8 (C-2), 178.4 (C-4) ppm. HRMS (ESI ): m/z water (30 mL) and pH adjusted to 4 with dilute HCl (10%). The
+
[M+H] calcd for C22
H
15
O
3
: 327.1016; found 327.1019.
precipitate was removed by filtration, taken in CH
purified by silica gel column chromatography using CH
eluent. Yellow solid; yield 346 mg (91%); mp 109-111 °C. H
NMR (500 MHz, CDCl ): δ 4.68 (dt, 2H, H-1’’, J 5.1; 1.6 Hz), 5.37
dq, 1H, H-3’’, J 10.6; 1.6 Hz), 5.50 (dq, 1H, H-3’’, J 17.2; 1.6 Hz),
2
Cl
2
and
2
Cl
2
as
1
2-(6H-benzo[c]chromen-8-yl)-7-methoxy-4H-chromen-4-one
(
13b)
White solid; yield 29 mg (81%); mp 184-187
MHz, CDCl ): δ 3.95 (s, 3H, 7-OCH ), 5.22 (s, 2H, H-10’), 6.78 (s,
H, H-3), 6.99-7.05 (m, 3H, H-6, H-8, H-2’), 7.10 (dt, 1H, H-4’, J
.6; 1.3 Hz), 7.31 (ddd, 1H, H-3’, J 8.1; 7.6; 1.6 Hz), 7.71 (d, 1H,
1
3
℃
. H NMR (300
(
3
3
6.14 (ddt, 1H, H-2’’, J 17.2; 10.5; 5.1 Hz), 6.34 (s, 1H, H-3), 6.93
1
7
(
d, 1H, H-α, J 16.2 Hz), 6.95 (dd, 1H, H-3’, J 8.3; 1.0 Hz), 7.02
dt, 1H, H-5’, J 7.5; 1.0 Hz), 7.34 (ddd, 1H, H-4’, J 8.3; 7.5; 1.7
(
H-9’, J 1.7 Hz), 7.78 (dd, 1H, H-5’, J 7.6; 1.6 Hz), 7.82 (d, 1H, H-
Hz), 7.39 (ddd, 1H, H-6, J 8.0; 7.1; 1.1 Hz), 7.55 (dd, 1H, H-8, J
8.5; 1.1 Hz), 7.60 (dd, 1H, H-6’, J 7.5; 1.7 Hz), 7.68 (ddd, 1H, H-
6
’, J 8.2 Hz), 7.91 (dd, 1H, H-7’, J 8.2; 1.7 Hz), 8.14 (d, 1H, H-5, J
1
3
3 3
9.5 Hz) ppm. C NMR (75 MHz, CDCl ): δ 55.9 (7-OCH ), 68.3
7
, J 8.5; 7.1; 1.6 Hz), 7.97 (d, 1H, H-β, J 16.2 Hz), 8.20 (dd, 1H,
(
C-10’), 100.4 (C-8), 107.3 (C-3), 114.5 (C-6), 117.7 (C-2’), 117.9
C-4a), 121.9 (C-5’a), 122.4; 122.5 and 122.6 (C-4’, C-6’ and C-
13
H-5, J 8.0; 1.6 Hz). C NMR (75 MHz, CDCl
10.3 (C-3), 112.6 (C-3’), 117.8 and 117.9 (C-8 and C-3’’), 120.9
C-α), 121.1 (C-5’), 124.2 and 124.3 (C-1’ and C-4a), 124.9 (C-6),
3
): δ 69.2 (C-1’’),
(
1
9
8
1
’), 123.8 (C-5’), 126.3 (C-7’), 127.1 (C-5), 130.6 (C-3’), 130.8 (C-
(
’), 132.0 (C-9’a), 133.3 (C-5’b), 155.1 (C-1’a), 158.0 (C-8a),
+
62.3 (C-2), 164.2 (C-7), 177.8 (C-4) ppm. HRMS (ESI ): m/z
125.6 (C-5), 128.4 (C-6’), 131.0 (C-4’), 132.4 (C-β), 132.9 (C-2’’),
133.6 (C-7), 156.1 (C-2’), 157.1 (C-8a), 162.5 (C-2), 178.6 (C-4).
+
[M+H] calcd for C23
H
17
O
4
: 357.1121; found 357.1127.
Synthesis of (E)-2-(3-allyl-2-hydroxystyryl)-4H-chromen-4-one
2
-(6H-benzo[c]chromen-8-yl)-5-methoxy-4H-chromen-4-one
(
16). The chromone derivative 15 (30 mg, 0.1 mmol) and 1,2,4-
TCB (0.3 mL) were mixed in a closed glass vessel. The resulting
mixture was heated under MW irradiation at 200 for 60
min. After that period, the crude mixture was dissolved in
CH Cl (5 mL) and purified by preparative TLC using
hexane/EtOAc (9:7) as eluent. Yellow solid; yield 6 mg (21%);
(
13c)
White solid; yield 30 mg (85%); mp 227-229
MHz, CDCl ): δ 4.00 (s, 3H, 5-OCH ), 5.20 (s, 2H, H-10’), 6.75 (s,
H, H-3), 6.83 (dd, 1H, H-6, J 8.4; 0.9 Hz), 7.02 (dd, 1H, H-2’, J
.1; 1.2 Hz), 7.09 (dt, 1H, H-4’, J 7.5; 1.2 Hz), 7.15 (dd, 1H, H-8,
1
℃
. H NMR (300
℃
3
3
1
8
2
2
J 8.4; 0.9 Hz), 7.27-7.33 (m, 1H, H-3’), 7.58 (t, 1H, H-7, J 8.4 Hz),
.68 (d, 1H, H-9’, J 1.9 Hz), 7.75-7.81 (m, 1H, H-5’), 7.79 (d, 1H,
1
mp 185-187 °C. H NMR (500 MHz, CDCl
J 6.3; 1.7 Hz), 5.28-5.32 (m, 2H, H-3’’), 5.86 (s, 1H, 2’-OH), 6.06
ddt, 1H, H-2’’, J 15.9; 10.7; 6.2 Hz), 6.34 (s, 1H, H-3), 6.92 (d,
3
): δ 3.50 (dt, 1H, H-1’’,
7
1
3
H-6’, J 8.1 Hz), 7.88 (dd, 1H, H-7’, J 8.1; 1.9 Hz) ppm. C NMR
75 MHz, CDCl ): δ 56.5 (5-OCH ), 68.3 (C-10’), 106.5 (C-6),
08.9 (C-3), 110.1 (C-8), 114.6 (C-4a), 117.6 (C-2’), 122.0 (C-
(
(
3
3
1H, H-α, J 16.1 Hz), 6.94-6.97 (t, 1H, H-5’, J 7.8 Hz), 7.14 (dd,
1H, H-4’, J 7.8; 1.6 Hz), 7.39 (ddd, 1H, H-6, J 8.0; 7.3; 1.0 Hz),
7.49 (dd, 1H, H-6’, J 7.8; 1.6 Hz), 7.53 (dd, 1H, H-8, J 8.4; 1.0
1
5
1
5
’a), 122.3; 122.4 and 122.5 (C-4’, C-6’ and C-9’), 123.7 (C-5’),
26.2 (C-7’), 130.4 (C-8’), 130.6 (C-3’), 131.9 (C-9’a), 133.2 (C-
’b), 133.8 (C-7), 155.1 (C-1’a), 158.2 (C-8a), 159.8 (C-5), 160.5
Hz), 7.67 (ddd, 1H, H-7; J 8.4; 7.3; 1.7 Hz), 7.93 (d, 1H, H-β, J
13
16.1 Hz), 8.20 (dd, 1H, H-5, J 8.0; 1.7 Hz). C NMR (75 MHz,
+
+
(C-2), 178.3 (C-4) ppm. HRMS (ESI ): m/z [M+H] calcd for
3
CDCl ): δ 35.9 (C-1’’), 110.3 (C-3), 117.8 and 117.9 (C-8 and C-
23 17 4
C H O
: 357.1121; found 357.1123.
3’’), 121.07 and 121.10 (C-5’ and C-α), 123.1 (C-1’), 124.1 (C-
2
-(6H-benzo[c]chromen-8-yl)-5,7-dimethoxy-4H-chromen-4-
4a), 124.9 (C-6), 125.4 (C-3’), 125.6 (C-5), 127.1 (C-6’), 132.0 (C-
4’), 132.4 (C-β), 133.7 (C-7), 135.8 (C-2’’), 153.7 (C-2’), 156.0
one (13d)
1
White solid; yield 30 mg (78%); mp 178-181
℃
. H NMR (300 (C-8a), 162.4 (C-2), 178.6 (C-4).
), 5.19
s, 2H, H-10’), 6.38 (d, 1H, H-6, J 2.3 Hz), 6.59 (d, 1H, H-8, J 2.3
3 3 3
MHz, CDCl ): δ 3.93 (s, 3H, 7-OCH ), 3.96 (s, 3H, 5-OCH
Synthesis of (1E,3E)-2-[4-(2-allyloxyphenyl)buta-1,3-dien-1-
yl]-4H-chromen-4-one (17). A solution of BBr in CH Cl 1M
(
3
2
2
Hz), 6.69 (s, 1H, H-3), 7.02 (dd, 1H, H-2’, J 8.1; 1.2 Hz), 7.09 (dt,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 9
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Page 10 of 11
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DOI: 10.1039/C7NJ05185A
ARTICLE
Journal Name
(
1.64 mL) was added to a solution under nitrogen atmosphere
6
7
Foster, R. A. A.; Willis, M. C. Chem. Soc. Rev. 2013, 42, 63.
Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.;
Vassilikogiannakis, G. Angew. Chem. Int. Ed. 2002, 41, 1668.
Heravi, M. M.; Vavsari, V. F. RSC Adv. 2015, 5, 50890.
Silva, A. M. S.; Silva, A. M. G.; Tomé, A. C.; Cavaleiro, J. A. S.
Eur. J. Org. Chem. 1999, 135.
of chromone derivative 6a (200 mg, 0.657 mmol) in CH Cl (5
2
2
mL). The resulting mixture was stirred at room temperature
for 2 h. After that period, the mixture was poured into ice (5 g)
and water (15 mL) and the slurry was stirred until the
8
9
formation of a precipitate. The precipitate was removed by 10 Pinto, D. C. G. A.; Silva, A. M. S.; Brito, C. M.; Sandulache, A.;
Carrillo, J. R.; Prieto, P.; Díaz-Ortiz, A.; de la Hoz, A.;
filtration and washed with water (100 mL) and ethyl ether (50
Cavaleiro, J. A. S. Eur. J. Org. Chem. 2005, 2973.
1 Patoilo, D. T.; Silva, A. M. S.; Pinto, D. C. G. A.; Tomé, A. C.;
mL). To a stirring mixture of the precipitate in acetone (30 mL)
1
2 3
was added K CO (136 mg, 1.5 equiv) and allyl bromide (0.2
Cavaleiro, J. A. S. J. Heterocycl. Chem. 2007, 44, 1345.
mL; 3 equiv). The resulting mixture was stirred at reflux for 4 h. 12 Patoilo, D. T.; Silva, A. M. S.; Pinto, D. C. G. A.; Santos, C. M.
After that period, the mixture was poured into ice (5 g) and
water (15 mL) and pH adjusted to 4 with dilute HCl (10%). The
M.; Tomé, A. C.; Cavaleiro, J. A. S. Tetrahedron Lett. 2012, 53,
722.
3 Albuquerque, H. M. T.; Santos, C. M. M.; Cavaleiro, J. A. S.;
Silva, A. M. S. Eur. J. Org. Chem. 2015, 4732.
4 Albuquerque, H. M. T.; Santos, C. M. M.; Lima, C. F. R. A. C.;
Santos, L. M. N. B. F.; Cavaleiro, J. A. S.; Silva, A. M. S. Eur. J.
Org. Chem. 2017, 87.
2
1
1
aqueous layer was extracted with CH
over anhydrous Na SO and the solvent evaporated to dryness.
The residue was purified by preparative TLC using
CH Cl /EtOAc (5:1) as eluent. Yellow solid; yield 169 mg (78%);
mp 120-122 °C. H NMR (500 MHz, CDCl
2 2
Cl (3 x 50 mL), dried
2
4
2
2
1
15 Costa, M.; Dias, T. A.; Brito, A.; Proença, F. Eur. J. Med. Chem.
016, 123, 487.
3
): δ 4.63 (dt, 2H, H-1’’,
2
6 Patil, S. A.; Patil, R.; Pfeffer, L. M.; Miller, D. D. Future Med.
Chem. 2013, 5, 1647.
J 5.2; 1.5 Hz), 5.35 (dq, 1H, H-3’’, J 10.5; 1.5 Hz), 5.47 (dq, 1H,
H-3’’, J 17.3; 1.5 Hz), 6.13 (ddt, 1H, H-2’’, J 17.3; 10.5; 5.2 Hz),
1
6.25 (s, 1H, H-3), 6.35 (d, 1H, H-α, J 15.2 Hz), 6.91 (dd, 1H, H-3’, 17 Patil, S. A.; Patil, S. A.; Patil, R. Future Med. Chem. 2015, 7,
J 8.4; 1.0 Hz), 6.98 (dt, 1H, H-5’, J 7.6; 1.0 Hz), 7.03 (ddd, 1H, H-
γ, J 15.7; 11.0; 0.7 Hz), 7.27-7.30 (m, 1H, H-4’), 7.34 (d, 1H, H-δ,
J 15.7 Hz), 7.38 (ddd, 1H, H-6, J 7.9; 7.1; 1.1 Hz), 7.47 (ddd, 1H,
H-β, J 15.2; 11.0; 0.8 Hz), 7.51 (dd, 1H, H-8, J 8.4; 1.1 Hz), 7.55
893.
8 Nepali, K.; Sharma, S.; Sharma, M.; Bedi, P. M.; Dhar, K. L.
Eur. J. Med. Chem. 2014, 77, 422.
9 Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Org. Lett. 2003, 5, 777.
0 Shaw, A. Y.; Chang, C.-Y.; Liau, H.-H.; Lu, P.-J.; Chen, H.-L.;
Yang, C.-N.; Li, H.-Y. Eur. J. Med. Chem. 2009, 44, 2552.
1
1
2
(
dd, 1H, H-6’, J 7.6; 1.7 Hz), 7.67 (ddd, 1H, H-7; J 8.4; 7.1; 1.7
1
Hz), 8.19 (dd, 1H, H-5, J 7.9; 1.7 Hz). C NMR (75 MHz, CDCl
3
): 21 Khoshkholgh, M. J.; Balalaie, S.; Bijanzadeh, H. R.; Gross, J. H.
Arkivoc 2009, 9, 114.
3
δ 69.2 (C-1’’), 110.1 (C-3), 112.5 (C-3’), 117.8 and 117.9 (C-8
and C-3’’), 121.0 (C-5’), 122.9 (C-α), 124.2 (C-4a), 124.9 (C-6),
125.5 (C-1’), 125.6 (C-5), 127.2 (C-6’), 127.6 (C-γ), 130.0 (C-4’),
133.1 (C-2’’), 133.6 (C-7), 134.2 (C-δ), 138.4 (C-β), 156.0 (C-2’),
156.4 (C-8a), 162.0 (C-2), 178.4 (C-4).
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Thanks are due to University of Aveiro and FCT/MEC for the
financial support of the QOPNA research unit
(FCTUID/QUI/00062/2013) through national founds and,
where applicable, co-financed by the FEDER, within the
PT2020 Partnership Agreement, and to the Portuguese NMR
Network, as well as to the Instituto Politécnico de Bragança.
H.M.T.A. is grateful to FCT for his PhD grant
(SFRH/BD/86277/2012).
Notes and references
1
2
3
4
5
Gaspar, A.; Matos, M. J.; Garrido, J.; Uriarte, E.; Borges, F.
Chem. Rev. 2014, 114, 4960.
Keri, R. S.; Budagumpi, S.; Pai, R. K.; Balakrishna, R. G. Eur. J.
Med. Chem. 2014, 78, 340
Ibrahim, M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A. Arkivoc
2
010, (i), 98.
Santos, C. M. M.; Silva, A. M. S. Eur. J. Org. Chem. 2017
115.
,
3
Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515.
1
0 | J. Name., 2012, 00, 1-3
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Page 11 of 11
New Journal of Chemistry
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DOI: 10.1039/C7NJ05185A
Chromeno[3,4-b]xanthones and 2-(benzo[c]chromenyl)
chromones were obtained via MW-assisted
intramolecular DA reaction, followed by in situ
dehydrogenation.