2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as Dienes in Diels–Alder Reactions – Experimental and Computational Studies

Article abstract of DOI:10.1002/ejoc.201601072

The synthesis and reactivity of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels–Alder (DA) reactions with several electron-poor and electron-rich dienophiles under microwave irradiation was studied. The optimized reaction conditions were achieved with N-methylmaleimide as the dienophile and Sc(OTf)₃(OTf = triflate) as a Lewis acid under microwave-assisted and solvent-free conditions. The Lewis acid improved the reaction yields as it prevented the adducts obtained from undergoing a second DA reaction; thus, the formation of a bisadduct was avoided. The α,β:γ,δ-diene of the starting chromones was the most reactive, and the computational results confirmed the experimental findings. Theoretical calculations also provided a rationale for the unexpected lack of reactivity shown by some dienophiles. The adducts prepared were dehydrogenated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); however, the aza adducts were sensitive to the highly energetic reaction conditions necessary for the aromatization.

Full text of DOI:10.1002/ejoc.201601072

A Journal of
Accepted Article
Title: 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes in Diels-
Alder reactions: experimental and computational studies
´
Authors: Helio M.T. Albuquerque; Clementina M.M. Santos; Carlos F.R.A.C. Lima;
´
Lu´ıs M.N.B.F. Santos; Jose A.S. Cavaleiro; Artur MS Silva
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601072
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2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones as dienes
in Diels‒Alder reactions: experimental and computational studies
Hélio M. T. Albuquerque,[a] Clementina M. M. Santos,[b] Carlos F. R. A. C. Lima,[a,c] Luís M. N. B. F.
Santos,[c] José A. S. Cavaleiro[a] and Artur M. S. Silva*[a]
Abstract: The synthesis and reactivity of 2-[(1E,3E)-4-arylbuta-1,3-
dien-1-yl]-4H-chromen-4-ones as dienes in Diels‒Alder (DA)
reactions towards several electron-poor and electron-rich
dienophiles under microwave irradiation was studied. The optimized
reaction conditions were achieved by using N-methylmaleimide as
dienophile and Sc(OTf)3 as Lewis acid under microwave-assisted
and solvent-free conditions. The Lewis acid improved the reaction
yields since it prevented the adducts obtained from undergoing a
second DA reaction, thus avoiding formation of a bisadduct. The
α,β:γ,δ-diene of the starting chromones was shown to be the most
reactive and the computational results confirmed the experimental
findings. Theoretical calculations also provided rationale for the
unexpected lack of reactivity by some dienophiles. The adducts
prepared were dehydrogenated by using DDQ, however, the aza-
adducts showed to be sensitive to the high energetic reaction
conditions necessary to perform the aromatization.
[4+2] cycloaddition reactions with the electron-rich dienophiles
enamines providing several xanthone-type compounds.[11]
Recently, the reactivity of (E)-2-(4-arylbut-1-en-3-yn-1-
yl)chromones in DA reactions with N-methylmaleimide as
dienophile was disclosed towards the synthesis of xanthone-
1,2,3-triazole dyads.[12] The diene system of (E)-2-(4-arylbut-1-
en-3-yn-1-yl)chromones proved to be unreactive under classic
heating conditions, however, under microwave irradiation DA
reaction took place affording the expected 1,2,3,4-
tetrahydroxanthone structure which was further transformed to
the aforementioned dyads. Meanwhile, our research group also
tested the reactivity of 3-styrylchromones as dienes in [4+2]
cycloaddition reactions with electron-poor dienophiles. Once
again, the respective adducts were obtained in better yields
using a microwave-assisted protocol than using classic heating
conditions. Taking into consideration the advantages of using
microwave irradiation in DA reactions, herein experimental and
computational studies on microwave-assisted DA reaction of 2-
[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones
with
Introduction
several electron-poor and electron-rich dienophiles are disclosed.
Accordingly to the reactivity of each diene system of the starting
chromones, it was expected to synthesize styryl-substituted
xanthones (via DA reaction on 3,2:α,β-diene) or aryl-substituted
flavones (via DA reaction on α,β:γ,δ-diene) but the results
indicate that only flavone-type compound are achieved (Figure
1).
Chromones (or 4H-chromen-4-ones) constitute a well-known
class of naturally occurring oxygen-containing heterocycles.
These compounds exhibit important biological properties such
as anticancer,[1] cytotoxic,[2] antioxidant,[1b, 3] anti-inflammatory,[4]
antifungal,[5] activities among others. Their reactivity in several
chemical transformations, namely, oxidations, thiations,
hydrogenations, photolysis, condensations, dimerizations and
Diels‒Alder (DA) reactions are widely reported in the literature.[6]
Since its discovery in 1928, DA reaction and its hetero variant
remains an active research field, being the key step in the
synthesis of a large variety of organic compounds.[7]
The first reports concerning the use of chromone derivatives as
dienes are known since 1954 and involved the DA reaction of 2-
styrylchromones with maleic anhydride[8] and later with N-
arylmaleimides[9] to afford the corresponding adducts 1,2,3,9a-
tetrahydroxanthones. However, in 1992 Letcher and Yue based
on extensive NMR and IR studies revised the structure of the
obtained adducts to the isomeric 1,2,3,4-tetrahydroxanthones.[10]
Years later, Kelkar et al. reported the use of 2-vinylchromones in
Figure 1. Two possible sites for DA reaction in 2-[(1E,3E)-4-arylbuta-1,3-dien-
1-yl]-4H-chromen-4-ones.
Both xanthone and flavone derivatives have unquestionable
biological benefits, as supported by several reports in literature
as anticancer, antioxidant and anti-inflammatory agents, among
others.[13] Although the activity of simple xanthone[14] or
flavone[15] scaffolds address only one biological target, in
complex multifactorial diseases such as cancer or Alzheimer’s,
there is a general belief that agents modulating more than one
target could have improved efficiency when compared to single
target drugs.[16] In the present work, N-(methyl and
phenyl)maleimides used as dienophiles provided dyads bearing
an isoindoline-1,3-dione unit, an interesting scaffold already
studied in multi-target approach for the treatment of cancer[17]
and Alzheimer’s disease.[18] Thus, it is expected that the novel
hybrid structures synthesized may have potential biological
[a]
Department of Chemistry & QOPNA, University of Aveiro, Campus
de Santiago, 3810-193 Aveiro, Portugal.
E-mail: artur.silva@ua.pt
https://sites.google.com/site/artursilvaua/silva-ams
School of Agriculture, Poly technic Institute of Bragança, Campus de
Santa Apolónia, 5300-253 Bragança, Portugal.
CIQ-UP, Department of Chemistry and Biochemistry, Faculty of
Sciences, University of Porto, Portugal.
[b]
[c]
Supporting information for this article is given via a link at the end of the
document.
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European Journal of Organic Chemistry
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relevance in the multi-target drug research field when compared
to simpler xanthone and flavone derivatives.
first one yielding the [endo/endo(cis)] adduct, or in the opposite
face giving the [endo/endo(trans)] adduct (Scheme 3). Then
each one of these diastereomers undergoes olefin migration
providing two diastereomers. In the NOESY spectrum of a
mixture enriched in diastereomer II of bisadduct 7c one can
deduce close proximity of H-5a with H-5b and H-14b and of H-
5b with H-8a, confirming the endo/endo(cis) diastereomer
(Scheme 3). In the spectrum of the reaction crude we can
observe the typical signals of the diastereomers I and II, but also
other small ones corresponding to H-8a, OMe and N-Me of other
two compounds, which were assigned to diastereomers III and
IV (trace amounts). Variations on temperature, reaction time and
dienophile amounts did not improve the yields of both adduct 5c
and bisadduct 7c (Table 1, entries 4-10). Interestingly, when the
reaction was carried out for 10 minutes, adduct 6c (NMR
features in SI) was isolated in 6% yield (Table 1, entry 5). In this
case, DA reaction occurred on 3,2:α,β-diene to give a styryl
substituted tetrahydroxanthene structure. By performing the
reaction at 130 ºC, it was possible to isolate derivative 4c in 8%
yield (Table 1, entry 10). This confirms that the more stable
adduct 5c results from the olefin migration of the expected DA
cycloadduct 4c (NMR features in SI). Our aforementioned
preliminary experimental results strongly suggest that α,β:γ,δ-
diene system is the most reactive, or at least afforded the more
thermodynamically stable DA product. To obtain more insights
on this DA reaction we have evaluated its thermodynamic
feasibility by computational methods at the M06-2X/6-31+G(d,p)
level of theory (detailed results presented in Table S1). We
started by the conformational analysis of the reactants 3a, 3c,
3d and 3e, since only the cis-double bonds are reactive towards
DA reaction.
Results and Discussion
DA reactions of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-
chromen-4-ones
2-[(1E,3E)-4-Arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones
3a-e
were prepared in good yields (68-80%) through the base-
catalyzed aldol condensation of 2-methyl-4H-chromen-4-one 1
with the appropriate cinnamaldehydes 2a-e according to a
previously reported methodology (Scheme 1).[19] The 2-methyl-
4H-chromen-4-one 1 was prepared in a previously reported
three-step Baker-Venkataraman sequence in good overall
yield,[14c] while the non-commercially available cinnamaldehydes
2b-d were obtained through
a palladium-catalyzed cross-
coupling reaction of aryl iodides with acrolein diethyl acetal.[20]
Scheme 1. Synthesis of chromones 3a-e used as dienes in DA reactions.
Following our previous results on microwave-assisted DA
reactions of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-
ones,[12] herein the initial attempts considered the DA reaction of
chromone 3c with increasing amounts of N-methylmaleimide in
dry DMF for 40 minutes at 160 °C under multimode microwave
irradiation (Table 1, entries 1-3). Adduct 5c (NMR features in SI)
was isolated as major product in 30-31% yield (Table 1, entries
1-3). The DA reaction occurred on α,β:γ,δ-diene and the
structure of adduct 5c arises from the olefin migration of the
expected DA cycloadduct 4c, which was further isolated (Table
1, entry 10). Bisadduct 7c was isolated as a mixture of four
diastereomers (two major diastereomers and traces of other
two) when large excess of N-methylmaleimide were employed
(Table 1, entries 6-9). Its formation should involve a cascade of
four reactions: DA reaction on α,β:γ,δ-diene to give intermediate
4c followed by olefin migration affording adduct 5c, then, the
diene present on such derivative undergoes a new DA reaction
yielding an intermediate structure which upon olefin migration
provides bisadduct 7c (Scheme 2). The formation of bisadduct
7c was further confirmed by reacting the isolated adduct 5c with
N-methylmaleimide under monomode microwave irradiation in
solvent-free conditions (Table 3). The two major diastereomers
found in a 52:48% mixture were assigned as structures I and II
(Scheme 3) and we were able to isolate in a pure form and fully
characterize the former one (NMR features in SI). The
stereochemistry of diastereomer I of bisadduct 7c was assessed
through the observed NOE cross-peaks of: i) H-14c with H-14b
and H-3a; ii) H-4 with H-3a and H-5, indicating the formation of
the endo product from the first DA reaction; iii) H-5b with H-5a
and H-8a, and no close proximity of H-5a with H-14b, suggests
that the second DA reaction also afforded an endo adduct.
However, the second addition can occur in the same face of the
The results indicate that at T = 160 °C (temperature at which
most reactions were carried out) the all trans-reactant is the
major species with a molar fraction of around 0.89. The species
with all cis-double bonds has a molar fraction of less than 0.01
and can in principle be ignored. The two reactive conformers cis-
3,2:α,β-diene (which upon DA reaction yields 6) and cis-α,β:γ,δ-
diene (which yields 4) are presented in small amounts, around
0.08 and 0.02, respectively. However, since conversion between
these isomers is rather fast at high temperatures, these
quantities should suffice for the respective DA reactions to
proceed smoothly.[21] The influence of the substituent R group
(Figure 1) in the conformational distribution was found to be
negligible. The calculated HOMO/LUMO energy levels confirm
the kinetic viability of the direct DA reaction when compared to
the calculated HOMO/LUMO orbitals of the N-methylmaleimide
dienophile (Table S4), and also vary very little with the
substituent R.
These results suggest that the influence of the R group on the
intrinsic thermodynamic and kinetic DA reactivity of 3 is of minor
importance, which is consistent with the rather large distance of
the substituent from the reactive diene centres. Hence, in order
to speed up the calculations only compound 3a (R = H) was
considered for the subsequent computational studies. We also
evaluated separately each possible reaction of 3a with N-
methylmaleimide yielding the four possible products (4a, 5a, 6a
and 7a) represented in Table 1. Since 4a, 5a and 6a are isomers
the direct comparison between their energies gives information
about which reaction pathway is thermodynamically preferred
(Table S2). The optimized structures of 4a, 5a, 6a and 7a are
presented in Table S5; various possible stable conformations
were found for these compounds but only the minimum energy
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European Journal of Organic Chemistry
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Table 1. Optimization of the DA reaction of chromone 3c with N-methylmaleimide under multimode MW irradiation.
NMM
T
Time
(min)
40
5c
7c
3c
Entry
(equiv)
(°C)
160
160
160
160
160
160
160
160
100
130
Yield (%)[a]
Yield (%)[d]
Recovered (%)[a]
1
2
1
3
31
30
30
35
22
48
21
21
25
30
−
−
10
40
−
3
5
40
7
−
4
5[b]
5
20
25
−
Traces
−
5
10
Traces
28
6
10
15
10
10
10
10
7
20
31
−
8
40
21
−
9
10[c]
20
17
Traces
Traces
10
Traces
Reactions were performed using chromone 3c in 10 µL of dry DMF as solvent. [a] Isolated yields. [b] Derivative 6c isolated in 6% yield. [c] Derivative 4c isolated
in 8% yield. [d] Isolated yields of a mixture of diastereomers. NMM – N-methylmaleimide.
Scheme 2. Tandem DA/olefin migration processes towards the formation of bisadduct 7c.
configurations were considered. The energetic analysis indicates
that the stability of 5a and 6a are very similar, ΔH298K(5a→6a) ≈
0 kJ·mol−1 (H298K is the calculated enthalpy at T = 298.15 K).
However, the energy difference between their precursors,
respectively 4a and 6ai, which are firstly formed after the DA
reaction and before olefin migration, is much more substantial,
ΔH298K(4a→6ai) ≈ 29 kJ·mol−1. The ΔH298K, in kJ·mol−1, for olefin
[−120, −150] kJ·mol−1. To better visualize these results Figure 2
illustrates the calculated relative enthalpy (T = 298.15 K) vs
reaction coordinate diagram for the Diels-Alder reaction of 3a
with N-methylmaleimide (yielding the two intermediates 4a and
6ai) and subsequent olefin migration (resulting in 5a and 6a,
respectively).
These results support the experimental findings by indicating
migration were calculated as −27 for 4a→5a and −57 for 6ai→6a. that: i) 6 should be a minor product of the DA reaction; ii) the
The computational results also indicate that the DA reactions
with N-methylmaleimide (3→4, 3→6, 5→7) are significantly
favoured energetically, with calculated ΔrH298K in the order of
preferred pathway for product 7 shall be a second DA reaction
on 5; iii) the olefin migration of the DA adducts should be
thermodynamically spontaneous.
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Scheme 3. Stereochemistry (NOESY) of olefin migration of 7c endo/endo(trans) and endo/endo(cis) products.
carbonyl groups of N-methylmaleimide or with the carbonyl
group of chromone 3c. The chelation with N-methylmaleimide
makes this dienophile more electron-poor and as
a
consequence, the DA reaction is favoured against an electron-
rich diene. Furthermore, the chelation of the Lewis acid with the
carbonyl group of chromone 3c makes the 3,2:α,β-diene more
electron-poor, unfavoring the DA reaction at this site (Figure 3,
A). The chelation with the carbonyl group of adduct 5c also
makes the newly formed diene more electron-poor, once again
unfavoring the DA reaction and consequently decreasing the
yield of bisadduct 7c (Figure 3, B).
Figure 2. Enthalpy (at T = 298.15 K) vs reaction coordinate diagram for the
Diels-Alder reaction of 3a with N-methylmaleimide, calculated using the M06-
2X/6-31+G(d,p) level of theory.
In order to improve the yields of adducts 5 the reaction was
carried out in solvent-free conditions under monomode
microwave irradiation. Thus, DA reaction of chromone 3c with N-
methylmaleimide was performed by varying the amount of
dienophile and the reaction time (Table 2, entries 1-5). The best
yield for adduct 5c (47%) was obtained in 10 minutes using 2
equiv of N-methylmaleimide, recovering 5% of the starting
chromone 3c (Table 2, entry 3). Running the reaction at 130 and
100 °C with 2 equiv of N-methylmaleimide for 15 minutes (Table
2, entries 6 and 7) afforded less by-products and the yield of
adduct 5c was higher at 130 °C, recovering 37% of the starting
chromone 3c. Taking into consideration the moderate yields of
adduct 5c the influence of Lewis acids was assessed.
Figure 3. Lewis acid effect on DA reaction. A: Chelation with chromone 3c
and N-methylmaleimide. B: Chelation with adduct 5c and N-methylmaleimide.
In order to reinforce this idea, DA reactions of adduct 5c with an
excess of N-methylmaleimide in the presence or absence of
Sc(OTf)3 were performed (Table 3, entries 1-3). Both DA
reactions performed in the absence of Sc(OTf)3 afforded
bisadduct 7c as mixture of diastereomers in 48 and 60% yield
recovering 20-37% of the starting adduct 5c (Table 3, entries 1
and 2). Running the reaction in the presence of a stoichiometric
amount of Sc(OTf)3 bisadduct 7c was obtained as a mixture of
diastereomers in only 15% yield and 75% of the adduct 5c was
recovered (Table 3, entry 3). These results confirm our
suspicions that the Lewis acid chelation makes the 3,2:α,β-diene
more electron-poor, directing the DA reaction towards the
adduct 5c.
Employing
a stoichiometric amount of AlCl3 at different
temperatures, adduct 5c was obtained in low yields (27-29%)
and 45-57% of the starting chromone 3c was recovered (Table 2,
entries 8 and 9). Changing the Lewis acid to Sc(OTf)3 and
varying the amount of dienophile, the yields of adduct 5c
increased to 62-67% and the best ones were achieved when 3
or 4 equiv of N-methylmaleimide were employed (Table 2,
entries 10-12). A single attempt was carried out using Sc(OTf)3
in 30 mol% for 10 minutes at 165 °C (Table 2, entry 13), but
unfortunately, the yield of adduct 5c decreased to 37%, implying
that the effect of Sc(OTf)3 is stoichiometric rather than catalytic.
In our particular case, the Lewis acid can complex with the
The best reaction conditions for adduct 5c were achieved using
3 molar equiv of N-methylmaleimide in the presence of 1 molar
equiv of Sc(OTf)3, for 10 minutes at 165 °C (Table 2, entry 11).
The same conditions were applied to chromones 3a,b,d,e (Table
2, entries 16-19) affording the corresponding adducts 5a,b,d,e in
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Table 2. Optimization of DA reaction of chromones 3a-e with N-methylmaleimide in solvent-free conditions under monomode MW irradiation.
NMM
T
Time
(min)
15
15
10
5
5
Yield (%)[a]
37
3
Entry
Derivative
Lewis acid
(equiv)
(°C)
165
165
165
165
165
130
100
165
130
165
165
165
165
165
130
165
165
165
165
Recovered (%)[a]
1
2
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3a
3b
3d
3e
1
2
2
2
5
2
2
2
2
2
3
4
3
2
2
3
3
3
3
−
33
−
−
44
3
−
47
5
4
5[d]
−
45
26
−
15
15
15
10
15
10
10
10
10
15
15
10
10
10
10
−
25
6
−
40
37
66
45
57
21
5
7
−
20
8
AlCl3
29
9
AlCl3
27
10
11
12
13[c]
14
15
16
17
18
19
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
62
67
67
8
37
−
59
26
17
−
47
77
55
14
−
71
52
25
[a] Isolated yields. [b] 100 mol % of Lewis acid. [c] 30 mol % of Lewis acid. [d] 25% of bisadduct 7c was isolated. NMM – N-methylmaleimide.
results indicate that Sc(OTf)3 shall bind preferentially to the
>C=O group of the chromone ring and chelation with other
groups/atoms of the diene and of the dienophile is of minor
importance. Chelation with a Lewis acid seems not to alter
significantly the shape of the HOMO/LUMO orbitals of 3a and 5a.
However, the computational results suggest that chelation
reduces the overall reactivity of the dienes towards DA reaction
because it: i) increases the HOMO/LUMO gap between diene
and dienophile (by decreasing the HOMO energy of the diene);
ii) decreases the double bond character of the reactive
chromone double bond, thus decreasing the reactivity of the
3,2:α,β-diene. Hence, according to the experimental and
computational findings, the most probable cause for Sc(OTf)3 to
increase the yield of product 5 is to, via chelation, reduce its
reactivity towards the second DA reaction that consumes it
affording bisadduct 7.
Table 3. DA reaction of adduct 5c with N-methylmaleimide in the presence or
absence of Sc(OTf)3
Time
(min)
20
Lewis
acid
7c
5c
Entry
Yield (%)[c]
Recovered (%)[a]
1
2
3[b]
48
60
15
37
20
75
30
20
Sc(OTf)3
Reactions performed using 6 molar equiv of N-methylmaleimide. [a] Isolated
yield. [b] 100 mol % of Lewis acid. [c] Isolated yields of a mixture of
diastereomers.
moderate to good yields (52-77%). To confirm our previous
suggestion for the formation of endo adduct 5, a NOESY
experiment was performed on adduct 5e addressing the
stereochemistry of the reaction. NOE cross-peaks showed close
proximity of H-3a with H-4 and H-7a indicating that adducts 5
are endo products (Figure 4).
Figure 4. Most important NOE cross-peaks of adduct 5e.
The effect of Lewis acid chelation was further evaluated by
computational chemistry at the M06-2X/6-31+G(d,p) level of
theory (the detailed results are presented as the ESI). The
With these results in hand, we turned our attention to the scope
of dienophiles in DA reactions with chromone 3c as depicted in
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European Journal of Organic Chemistry
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Table 4. N-phenylmaleimide afforded adduct 8 in 66% yield
(Table 4, entry 1). The reactivity of dimethyl and diethyl
acetylenedicarboxylate with chromone 3c was also tested,
affording the expected aromatic products 9a,b (NMR features in
SI) in 30-45% yield (Table 4, entries 2-4).
carrying the reaction at different temperatures and in the
presence or absence of DMF as solvent (Table 4, entries 7-9).
The reason for that may be the high temperatures employed in
DA reactions probably leading to the dimerization of PTAD[24]
which competes with the DA reaction. Electron-poor dienophiles
such as diethyl fumarate and maleate showed to be extremely
reluctant towards DA reaction with chromone 3c. Even at higher
temperatures and longer reaction times, no DA reaction was
observed. Instead, more degradation products and less
recovered chromone were detected (Table 4, entries 10-13).
Attempts involving the electron-rich dienophile 3,4-dihydro-2H-
pyran (Table 4, entries 14 and 15) were performed at different
temperatures but no DA reaction took place.
In general, the relative reactivity of the dienophiles is well
described by the calculated HOMO(diene)/LUMO(dienophile)
energy differences, with some tendency for higher yields to be
observed for lower HOMO/LUMO energy gaps. For instance, the
highest HOMO/LUMO gap was observed for the dienophile in
entries 14 and 15 (Table 4), the low reactivity of which may
explain why no DA reaction had occurred. The HOMO/LUMO
The dienophile scope was further extended to diethyl (DEAD)
and diisopropyl azodicarboxylates (DIAD) (Table 4, entries 5 and
6) affording the expected adducts 10a and 10b in 22 and 57%
yield, respectively. In the reaction with DEAD derivative 11 was
isolated as product of an Alder-ene reaction on adduct 10a, in
22% yield. The formation of this Alder-ene product 11 (NMR
features in SI) can be explained on the basis of a tandem
DA/Alder-ene process (Scheme 4). In order to avoid the
formation of the Alder-ene product 11 the reaction was
attempted at 80 and 100 °C, however no reaction products were
observed. By performing the reaction at 130 °C, cycloadduct 10a
was isolated in trace amounts together with unreacted chromone
3c and derivative 11 in 30% yield. 4-Phenyl-1,2,4-triazoline-3,5-
dione (PTAD) was expected to show similar or even improved
reactivity compared to maleimides or azodicarboxylates as
dienophiles. Unfortunately, no DA products were observed
Table 4. Dienophile scope in DA reaction of chromone 3c under monomode MW irradiation.
T
Time
(min)
Yield
(%)[a]
3c
Entry
1
Dienophile
Product
(°C)
Recovered (%)[a]
165
10
66
2
3
130
165
15
15
30
35
33
4
5[e]
6
165
165
165
15
15
10
45
22
57
[d]
[d]
7
8[c]
9[c]
165
130
165
10
10
10
63
40
[d]
10
11
12
13
14
130
165
165
200
100
10
10
40
40
15
No reaction
90
90
60
50
90
No reaction
[d]
[d]
No reaction
No reaction
15
165
15
90
Reactions were performed using chromone 3c in solvent-free or neat conditions. [a] Isolated yields. [b] Addition of 100 mol % of Sc(OTf)3. [c] 0.1 mL of DMF as
solvent. [d] Unidentified by-products. [e] Reaction with DEAD afforded the expected DA cycloadduct and other product from the tandem DA/Alder-ene process.
NMM – N-methylmaleimide.
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European Journal of Organic Chemistry
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FULL PAPER
absence of DA reaction may mostly be due to the extensive
decomposition of the dienophile in the reaction medium. For
entries 10 and 11 (Table 4) the absence of DA reaction is harder
to explain; the HOMO/LUMO gap is comparable to the most
reactive dienophiles, no unidentified by-products were detected
and most of the unreacted reagent was recovered. We therefore
turned our attention to the corresponding DA product analogous
to 5.
In fact, the optimized geometry of this product (presented in
Table S5) evidences the existence of significant steric repulsions
between the ester groups and the chromone and phenyl rings.
This increases the calculated ΔrH298K for the DA reaction
between 3a and diethyl fumarate, yielding the product analogous
to 5a, by about 10 and 40 kJ·mol−1 relative to, respectively, the
reactions 3a + N-methylmaleimide → 5a and the analogous
reactions involving the similar dienophiles used in entries 5 and
6 (Table 4 and Table S3). In these last cases the geometry of
the N centres in the DA products avoids significant steric
repulsions and the reactions are more favoured. This
computational analysis suggests that the Diels-Alder reaction
between 3 and the dienophiles in entries 10-13 (Table 4),
Scheme 4. Tandem DA/Alder-ene process towards the formation of derivative
11.
energies were calculated at the M06-2X/6-31+G(d,p) and
MP2/6-31+G(d,p) levels of theory. The detailed results are
presented in Table S4 and both methods predict similar
tendencies in HOMO/LUMO energies. However, there are some
cases that deviate from this analysis.In entries 7-9 and 12-13
(Table 4), although the calculated HOMO/LUMO gaps are
slightly higher than for the most reactive dienophiles, the
yielding the products analogous to
4
and/or 5), is
thermodynamically and/or kinetically less favored due to
significant intramolecular steric repulsions.
Table 5. Aromatization of adducts 5a-e.
DDQ
Heating
method
12
Yield (%)[a]
34
13c
Yield (%)[a]
Entry
Adduct
Solvent
T (°C)
Time
(equiv)
1
2
3
4
5
6
7
8
5c
5c
5c
5c
5a
5b
5d
5e
3
5
3
4
4
4
4
4
toluene
1,4-dioxane
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
1,2,4-TCB
100
100
190
165
165
165
165
165
4 h
60
52
15
oil bath
MW[c]
4 h
24 h
38
90
85
75
80
70
25 min
25 min
25 min
25 min
25 min
[a] Isolated yields. [b] Multimode MW irradiation. [c] Monomode MW irradiation. DDQ - 2,3-dichloro-5,6-dicyanobenzoquinone. 1,2,4-TCB - 1,2,4-trichlorobenzene.
oxidized derivative 13c was obtained in 52% yield. With 1,2,4-
TCB as solvent (Table 5, entry 3), the semi-oxidized derivative
13c was isolated in 15%, however the oxidized derivative 12c
was obtained in only 38% yield. The low yields of derivative 12c
can be explained on the basis of the stability given by the
presence of a conjugate diene in the semi-oxidized derivative
13c. Furthermore, the relatively long reaction times may
contribute for the degradation of either the starting adduct or the
oxidized products. MW-assisted reaction conditions were
employed in the oxidation of adduct 5c in 1,2,4-trichlorobenzene
(1,2,4-TCB) at 165 °C for 25 minutes (Table 5, entry 4), being
the desired oxidized derivative 12c obtained in 90% yield, and
no semi-oxidized product 13c detected. These reaction
conditions were applied to other adducts 5a,b,d,e affording the
oxidized products 12a,b,d,e (NMR features in SI) in high yields
Aromatization of DA adducts
Once adducts 5a-e were obtained, it would be interesting to
further aromatize them to flavone derivatives. A number of
methodologies using 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ) are available in the literature,[25] nevertheless, the initial
choice relied on a successful method previously employed by us
for similar oxidations.[12] Therefore, adduct 5c was heated in
toluene at 100 °C with 3 molar equiv of DDQ (Table 5, entry 1).
After 4 h the starting adduct 5c was consumed and the oxidized
product 12c was obtained in 34% yield, together with the semi-
oxidized product 13c (NMR features in SI) in 60% yield (Table 5,
entry 1). Using
a more polar solvent, 1,4-dioxane, and
increasing the amount of DDQ (Table 5, entry 2) only the semi-
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European Journal of Organic Chemistry
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FULL PAPER
(Table 5, entries 5-8). At this stage, derivatives 12a-e were
obtained in two steps, isolating the intermediate DA adducts 5a-
e in the first step, and further oxidizing them with DDQ. In order
to address if the oxidation of adducts 5 without purification was
advantageous, chromone 3c was allowed to react with N-
methylmaleimide in the presence of Sc(OTf)3 and oxidize the
formed adduct in 1,2,4-TCB at 165 °C for 25 minutes with DDQ,
in a one-pot process. The oxidized product 12c was obtained in
16% yield along with the isolation of adduct 5c in 28% yield. The
low yield of 12c can be explained by the chelation of the Lewis
acid with the carbonyl group of adduct 5c, which makes the
cyclohexene ring electron-poor by conjugation, disfavouring the
hydride abstraction by DDQ. The same experiment was
performed under the same reaction conditions but in absence of
the Lewis acid. Unfortunately, the reaction afforded the oxidized
product 12c only in 20% yield and no adduct 5c was isolated. In
the absence of Lewis acid, DA reaction affords more by-
products including the bisadduct 7c, and this may be the reason
that without Sc(OTf)3 the yield of the oxidized product 12c is not
improved. To sum up, the one-pot DA/oxidation processes
proved to be an inefficient and a disadvantageous methodology
when compared to the two step procedure.
the N-N single bond of the cycloadduct 10b broke up during the
oxidation reaction.
Conclusions
The α,β:γ,δ-diene system of chromones 3 showed to be the
most reactive in DA reactions with N-methylmaleimide as
dienophile, affording compounds 5, which results from a DA
reaction followed by a olefin migration. These results were
confirmed by computational studies, which indicated that
derivative 6 (DA on the 3,2:α,β-diene, followed by a olefin
migration) should be a minor product of DA reaction, being the
adducts
5 thermodynamically more stable. However, by
performing the DA reaction in DMF with an excess of N-
methylmaleimide, the yields of adducts 5 were lower and several
by-products were detected. The most relevant one resulted from
a tandem DA/olefin migration/DA/ olefin migration process,
affording bisadduct 7 as a mixture of diastereomers. The
formation of this by-product was prevented by using Sc(OTf)3 in
solvent-free conditions and consequently, the adducts 5 were
obtained in higher yields. The scope of dienophiles allowed us to
conclude that electron-poor dienophiles are most reactive and in
the case of electron-rich dienophiles, no DA reaction occurred.
The adducts obtained with maleimides were aromatized in high
yields using DDQ under microwave irradiation. However, in the
case of aza-adducts the aromatization was not straightforward
due to the sensitive N-N single bonds which easily broke up.
The combination of the experimental and computational findings
also indicates that the main features of the DA reactions studied
are well described by the thermodynamic stability of the reaction
products and intermediates, and the HOMO/LUMO evaluation of
dienes and dienophiles within the frontier molecular orbitals
(FMO) approach.
Scheme 5. Aromatization of adduct 8.
Adduct 8 was also oxidized employing the best reaction
conditions for adducts 5a-e, affording derivative 14 in 86% yield
(Scheme 5).
The oxidation of cycloadducts 10a,b was not straightforward,
because C-N bonds easily break upon oxidation. Therefore, the
initial oxidation conditions employed to cycloadduct 10a were
less harsh, using DDQ in 1,4-dioxane at 100 °C for 24 h.
Unfortunately, no oxidized product was detected and 72% of the
starting cycloadduct 10a was recovered. Therefore, highly
energetic conditions were employed using DDQ in 1,2,4-TCB at
165 °C under microwave irradiation for 25 minutes. Several
unidentified by-products were observed and no oxidized product
was detected.
Experimental Section
General
Melting points were measured with
a Büchi Melting Point B-540
apparatus. NMR spectra were recorded with a Bruker Avance 300
spectrometer (300.13 MHz for 1H and 75.47 MHz for 13C) or Bruker
Avance 500 spectrometer (500.13 MHz for H and 125.77 MHz for 13C).
1
Chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz;
the internal standard was TMS. Unequivocal 13C assignments were made
with the aid of 2D gHSQC and gHMBC (delays for one-bond long range J
C/H couplings were optimized for 145 and
7 Hz, respectively)
experiments. Positive-ion ESI mass spectra were acquired with a QTOF
2 instrument [dilution of 1 μL of the sample in chloroform solution (ca.
10–5 m) in 200 μL of 0.1% trifluoroacetic acid/methanol solution.
Nitrogen was used as 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. Elemental analyses were obtained
with a LECO 932 CHNS analyzer. Preparative thin-layer chromatography
was performed with Merck silica gel (60 DGF254). Column
chromatography was performed with Merck silica gel (60, 70–230 mesh).
All chemicals and solvents used were obtained from commercial sources
and used as received or dried by standard procedures.
Scheme 6. Aromatization of cycloadduct 10b.
Despite the unsuccessful attempts to oxidize cycloadduct 10a,
the aromatization of cycloadduct 10b was also attempted under
microwave irradiation (Scheme 6). The oxidation process
occurred although it was not efficient since the oxidized product
15b was isolated in only 17% yield. In the H NMR spectrum of
derivative 15b two broad singlets at δH 6.07 and 7.88 ppm
assigned to 1-NH and 4-NH protons, respectively, indicated that
1
General procedure for synthesis of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-
yl]-4H-chromen-4-ones 3a-e. Sodium (0.11 g, 4.8 mmol) was gradually
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European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
added to dry ethanol (5 mL), and the mixture was stirred until it reached
room temperature. 2-Methylchromone 1 (0.2 g, 1.2 mmol) and the
appropriate cinnamaldehyde 2a-e (1.5 mmol) were added and the
reaction mixture allowed to stand at room temperature until complete
disappearance of 2-methylchromone 1. The solution was then poured
into ice and water and the pH adjusted to 4 with diluted HCl. The solid
was removed by filtration, dissolved in dichloromethane, and purified by
silica gel column chromatography using dichloromethane as eluent. The
solvent was evaporated and the residue recrystallized from ethanol to
give the 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-4H-chromen-4-ones 3a-e.
J 8.7, 7.1, 1.7 Hz), 8.20 (dd, 1H, H-5, J 7.9, 1.7 Hz), 8.24 (d, 2H, H-3’,5’,
J 8.8 Hz). 13C NMR (75 MHz, CDCl3): δC 111.3 (C-3), 117.8 (C-8), 124.1
(C-4a), 124.3 (C-3’5’), 125.2 (C-6), 125.8 (C-5), 126.5 (C-α), 127.4 (C-
2’.6’), 131.2 (C-γ), 133.9 (C-7), 135.89 and 135.94 (C-β and C-δ), 142.5
(C-1’), 147.4 (C-4’), 156.0 (C-8a), 161.0 (C-2), 178.5 (C-4). EI-MS m/z
(%): 319 [(M+H)+, 57], 318 (M+•, 100), 289 (50), 288 (35), 272 (33), 197
(73), 152 (27), EI-HRMS m/z calcd for [C19H13NO4-H]+: 318.0766, found:
318.0765.
4-(4-Methoxyphenyl)-2-methyl-7-(4-oxo-4H-chromen-2-yl)-3a,4,7,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione 4c was isolated from the
reaction of chromone 3c (37 mg, 0.121 mmol) with N-methylmaleimide
(134 mg, 1.21 mmol) in dry DMF (10 µL) at 130 °C for 10 minutes in a
multimode microwave apparatus and the residue was purified by
preparative thin layer chromatography (TLC) using ethyl acetate:hexane
(1:1) as eluent. (4 mg, 8%). 1H NMR (300 MHz, CDCl3): δH 2.57 (s, 3H,
NCH3), 3.40-3.49 (m, 2H, H-3a, H-7a), 3.78 (s, 3H, OCH3), 3.95-3.99 (m,
1H, H-4), 4.25-4.27 (m, 1H, H-7), 6.14 (ddd, 1H, H-6, J 9.9, 4.4, 1.9 Hz),
6.33 (ddd, 1H, H-5, J 9.9, 5.0, 2.0 Hz), 6.40 (s, 1H, H-3’), 6.83 (d, 2H, H-
3’’,5’’, J 8.7 Hz), 7.00 (d, 2H, H-2’’,6’’, J 8.7 Hz), 7.43 (ddd, 1H, H-6’, J
8.0, 7.1, 1.1 Hz), 7.48 (dd, 1H, H-8’, J 8.3, 1.1 Hz), 7.70 (ddd, 1H, H-7’, J
8.3, 7.1, 1.7 Hz), 8.21 (dd, 1H, H-5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz,
CDCl3): δC 24.4 (NCH3), 37.3 (C-7), 39.0 (C-4), 42.3 (C-7a), 44.1 (C-3a),
55.2 (OCH3), 109.8 (C-3’), 113.8 (C-3’’,5’’), 117.9 (C-6’), 123.7 (C-4’a),
125.0 (C-6), 125.4 (C-6’), 125.9 (C-5’), 129.2 (C-1’’), 129.9 (C-2’’,6’’),
132.6 (C-5), 133.9 (C-7’), 156.7 (C-8’a), 159.0 (C-4’’), 167.9 (C-2’), 176.5
and 177.4 (C-1 and C-3), 178.2 (C-4’).
2-[(1E,3E)-4-Phenylbuta-1,3-dien-1-yl]-4H-chromen-4-one (3a): Yield
1
263 mg (80%), orange solid, mp 144-146 °C (from EtOH). H NMR (300
MHz, CDCl3): δH 6.27 (s, 1H, H-3), 6.38 (d, 1H, H-α, J 15.3 Hz), 6.91-
7.03 (m, 2H, H-γ, H-δ), 7.31-7.45 (m, H-6, H-β, H-3’,4’,5’), 7.48-7.51 (m,
1H, H-8), 7.52 (d, 2H, H-2’,6’, J 8.5 Hz), 7.68 (ddd, 1H, H-7, J 8.6, 7.1,
1.7 Hz), 8.19 (dd, 1H, H-5, J 7.9, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC
110.3 (C-3), 117.8 (C-8), 123.6 (C-α), 124.1 (C-4a), 125.0 (C-6), 125.7
(C-5), 127.1 (C-2’,6’, C-γ), 128.9 (C-3’,5’), 129.0 (C-4’), 133.7 (C-7),
136.3 (C-1’), 137.4 (C-β), 139.1 (C-δ), 156.0 (C-8a), 161.8 (C-2), 178.4
(C-4). EI-MS m/z (%): 274 (M+•, 35), 273 [(M-H)+, 100], 257 (26), 221 (24),
197 (48). EI-HRMS m/z calcd for C19H14O2: 274.0994, found: 274.0999.
2-[(1E,3E)-4-(4-Chlorophenyl)buta-1,3-dien-1-yl]-4H-chromen-4-one
1
(3b): Yield 259 mg (70%), yellow solid, mp 180-182 °C (from EtOH). H
NMR (300 MHz, CDCl3): δH 6.27 (s, 1H, H-3), 6.39 (d, 1H, H-α, J 15.2
Hz), 6.86-6.99 (m, 2H, H-γ, H-δ), 7.34 (d, 2H, H-3’,5’, J 8.6 Hz), 7.34-
7.48 (m, 2H, H-β, H-6), 7.42 (d, 2H, H-2’,6’, J 8.6 Hz), 7.50 (dd, 1H, H-8,
J 8.5, 1.1 Hz), 7.68 (ddd, 1H, H-7, J 8.5, 7.1, 1.7 Hz), 8.19 (dd, 1H, H-5, J
7.9, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 110.5 (C-3), 117.8 (C-8),
124.1 (C-4a), 124.2 (C-α), 125.0 (C-6), 125.7 (C-5), 127.6 (C-γ), 128.2
(C-2’,6’), 129.1 (C-3’,5’), 133.8 (C-7), 134.6 and 134.7 (C-1’ and C-4’),
137.0 (C-β), 137.6 (C-δ), 156.0 (C-8a), 161.6 (C-2), 178.4 (C-4). EI-MS
m/z (%): 310 [(M+H)+, 37Cl, 9], 309 (M+•, 37Cl, 23), 308 [(M+H)+, 35Cl, 28],
307 (M+•, 35Cl, 100), 291 (20), 197 (35), 152 (24). EI-HRMS m/z calcd for
[C19H1335ClO2-H]+: 307.0526, found: 307.0567.
General Procedure for the Synthesis of 2-Methyl-7-(4-oxo-4H-
chromen-2-yl)-4-aryl-3a,4,5,7a-tetrahydro-1H-isoindole-1,3(2H)-
diones 5a-e. N-methylmaleimide (40.3 mg, 0.363 mmol), Sc(OTf)3 (59.5
mg, 0.121 mmol) and the appropriate chromone 3a-e (0.121 mmol) were
mixed in a closed vessel. The resulting mixture was heated at 165 °C
under microwave irradiation (monomode apparatus) for 10 minutes. The
residue was dissolved in dichloromethane and purified by preparative
TLC using ethyl acetate:hexane (1:1) as eluent.
2-[(1E,3E)-4-(4-Methoxyphenyl)buta-1,3-dien-1-yl]-4H-chromen-4-one
(3c): Yield 292 mg (80%), yellow solid, mp 137-139 °C (from EtOH). H
2-Methyl-7-(4-oxo-4H-chromen-2-yl)-4-phenyl-3a,4,5,7a-tetrahydro-
1H-isoindole-1,3(2H)-dione (5a): Yield 36 mg (77%), white solid, mp
220-223 °C. 1H NMR (300 MHz, CDCl3): δH 2.59 (s, 3H, NCH3), 2.76-
2.82 (m, 2H, H-5), 3.49 (q, 1H, H-4, J 5.8 Hz), 3.60 (dd, 1H, H-3a, J 7.9,
5.8 Hz), 4.15 (dd, 1H, H-7a, J 7.9, 1.5 Hz), 6.65 (s, 1H, H-3’), 7.24-7.33
(m, 5H, H-2’’,3’’,4’’,5’’,6’’, H-6), 7.41 (ddd, 1H, H-6’, J 8.0, 7.1, 0.8 Hz),
7.48 (dd, 1H, H-8’, J 8.5, 0.8 Hz), 7.68 (ddd, 1H, H-7’, J 8.5, 7.1, 1.6 Hz),
8.21 (dd, 1H, H-5’, J 8.0, 1.6 Hz). 13C NMR (125 MHz, CDCl3): δC 24.4
(NCH3), 28.5 (C-5), 38.2 (C-4), 40.6 (C-7a), 45.2 (C-3a), 109.0 (C-3’),
117.9 (C-8’), 124.0 (C-4’a), 125.2 (C-6), 125.7 (C-6’), 126.8 (C-5’), 127.5
(C-7), 128.0 (C-2’’,6’’), 128.5 (C-3’’, 5’’), 133.8 (C-7’), 135.9 (C-4’’), 139.4
(C-1’’), 156.0 (C-8’a), 161.9 (C-2’), 174.0 (C-1), 176.3 (C-3), 178.5 (C-4’).
EI-MS m/z (%): 386 [(M+H]+, 24], 385 (M+•, 100), 274 (21), 273 (34). EI-
HRMS m/z calcd for C24H19NO4: 385.1314, found: 385.1319.
1
NMR (300 MHz, CDCl3): δH 3.84 (s, 3H, OCH3), 6.24 (s, 1H, H-3), 6.32 (d,
1H, H-α, J 15.3 Hz), 6.84-6.87 (m, 1H, H-δ), 6.90 (d, 2H, H-3’,5’, J 8.8
Hz), 6.90-6.96 (m, 1H, H-γ), 7.38 (ddd, 1H, H-6, J 8.2, 7.1, 0.9 Hz), 7.41-
7.44 (m, 1H, H-β), 7.43 (d, 2H, H-2’,6’, J 8.8 Hz), 7.49 (d, 1H, H-8, J 8.1
Hz), 7.67 (ddd, 1H, H-7, J 8.1, 7.1, 1.7 Hz), 8.18 (dd, 1H, H-5, J 8.2, 1.7
Hz). 13C NMR (75 MHz, CDCl3): δC 55.3 (OCH3), 109.9 (C-3), 114.3 (C-
3’,5’), 117.7 (C-8), 122.3 (C-α), 124.1 (C-4a), 124.8 (C-6), 125.0 (C-γ),
125.5 (C-5), 128.5 (C-2’,6’), 128.6 (C-1’), 133.6 (C-7), 137.8 (C-β), 138.9
(C-δ), 140.4 (C-8a), 160.3 (C-4’), 162.0 (C-2), 178.4 (C-4). EI-MS m/z
(%): 304 (M+•, 68), 303 [(M-H)+, 100], 287 (27), 197 (23). EI-HRMS m/z
calcd for C20H16O3: 304.1099, found: 304.1098.
2-[(1E,3E)-4-(4-Methylphenyl)buta-1,3-dien-1-yl]-4H-chromen-4-one
(3d): Yield 266 mg (77%), orange solid, mp 144-147 °C (from EtOH). H
1
4-(4-Chlorophenyl)-2-methyl-7-(4-oxo-4H-chromen-2-yl)-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (5b): Yield 28 mg (55%), white
solid, mp 209-211 °C. 1H NMR (300 MHz, CDCl3): δH 2.68 (s, 3H, NCH3),
2.68-2.79 (m, 2H, H-5), 3.42 (dt, 1H, H-4, J 7.8, 5.4 Hz), 3.59 (dd, 1H, H-
3a, J 8.1, 5.4 Hz), 4.19 (dd, 1H, H-7a, J 8.1, 1.7 Hz), 6.65 (s, 1H, H-3’),
7.21 (d, 2H, H-3’’,5’’, J 8.6 Hz), 7.20-7.24 (m, 1H, H-6), 7.29 (d, 2H, H-
2’’,6’’, J 8.6 Hz), 7.41 (ddd, 1H, H-6’, J 8.0, 7.1, 1.0 Hz), 7.47 (dd, 1H, H-
8’, J 8.5, 1.0 Hz), 7.69 (ddd, 1H, H-7’, J 8.5, 7.1, 1.7 Hz), 8.22 (dd, 1H, H-
5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 24.5 (NCH3), 28.1 (C-5),
37.8 (C-4), 40.9 (C-7a), 45.0 (C-3a), 109.2 (C-3’), 117.8 (C-8’), 124.0 (C-
4’a), 125.2 (C-6’), 125.8 (C-5’), 127.0 (C-7), 128.6 (C-2’’,6’’), 129.3 (C-
3’’,5’’), 133.3 (C-1’’), 133.9 (C-7’), 135.5 (C-6), 138.0 (C-4’’), 156.0 (C-
8’a), 161.6 (C-2’), 173.9 (C-3), 176.0 (C-1), 178.4 (C-4’). EI-MS m/z (%):
421 (M+•, 37Cl, 23), 419 (M+•, 35Cl, 100). EI-HRMS m/z calcd for
C24H1835ClNO4: 419.0924, found: 419.0938.
NMR (300 MHz, CDCl3): δH 2.37 (s, 3H, CH3), 6.25 (s, 1H, H-3), 6.35 (d,
1H, H-α, J 15.2 Hz), 6.88-6.99 (m, 2H, H-γ, H-δ), 7.19 (d, 2H, H-3’,5’, J
8.0 Hz), 7.36-7.46 (m, 2H, H-β, H-6), 7.39 (d, 2H, H-2’,6’, J 8.0 Hz), 7.49
(dd, 1H, H-8, J 8.5, 1.0 Hz), 7.67 (ddd, 1H, H-7, J 8.5, 7.1, 1.6 Hz), 8.19
(dd, 1H, H-5, J 8.0, 1.6 Hz). 13C NMR (75 MHz, CDCl3): δC 21.4 (CH3),
110.1 (C-3), 117.8 (C-8), 123.0 (C-α), 124.1 (C-4a), 124.9 (C-6), 125.7
(C-5), 126.2 (C-γ), 127.1 (C-2’,6’), 129.6 (C-3’,5’), 133.5 (C-1’), 133.6 (C-
7), 137.7 (C-β), 139.2 (C-δ, C-4’), 156.0 (C-8a), 161.9 (C-2), 178.4 (C-4).
EI-MS m/z (%): 288 (M+•, 40), 287 [(M-H)+, 100], 271 (22), 197 (33), EI-
HRMS m/z calcd for C20H16O2: 288.1150, found: 288.1149.
2-[(1E,3E)-4-(4-Nitrophenyl)buta-1,3-dien-1-yl]-4H-chromen-4-one
(3e): Yield 260 mg (68%), yellow solid, mp 198-200 C (from EtOH). 1H
NMR (300 MHz, CDCl3): δH 6.32 (s, 1H, H-3), 6.51 (d, 1H, H-α, J 15.2
Hz), 6.95-7.15 (m, 2H, H-γ, H-δ), 7.38-7.48 (m, 2H, H-β, H-6), 7.51 (dd,
1H, H-8, J 8.7, 1.0 Hz), 7.62 (d, 2H, H-2’,6’, J 8.8 Hz), 7.70 (ddd, 1H, H-7,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
4-(4-Methoxyphenyl)-2-methyl-7-(4-oxo-4H-chromen-2-yl)-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (5c): Yield 34 mg (67%), white
solid, mp 222-224 °C. 1H NMR (300 MHz, CDCl3): δH 2.60 (s, 3H, NCH3),
2.73-2.80 (m, 2H, H-5), 3.46 (q, 1H, H-4, J 5.7 Hz), 3.55 (dd, 1H, H-3a, J
7.8, 5.7 Hz), 3.77 (s, 3H, OCH3), 4.12 (dd, 1H, H-7a, J 7.8, 1.4 Hz), 6.63
(s, 1H, H-3’), 6.82 (d, 2H, H-3’’,5’’, J 8.7 Hz), 7.17 (d, 2H, H-2’’,6’’, J 8.7
Hz), 7.24 (td, 1H, H-6, J 4.8, 1.4 Hz), 7.40 (ddd, 1H, H-6’, J 7.7, 7.3, 0.8
Hz), 7.47 (dd, 1H, H-8’, J 8.3, 0.8 Hz), 7.68 (ddd, 1H, H-7’, J 8.3, 7.3, 1.6
Hz), 8.21 (dd, 1H, H-5’, J 7.7, 1.6 Hz). 13C NMR (75 MHz, CDCl3): δC
24.4 (NCH3), 29.0 (C-5), 37.5 (C-4), 40.4 (C-7a), 45.2 (C-3a), 55.2
(OCH3), 109.0 (C-3’), 113.8 (C-3’’,5’’), 117.9 (C-8’), 124.0 (C-4’a), 125.1
(C-6’), 125.7 (C-5’), 126.7 (C-7), 129.1 (C-2’’,6’’), 131.2 (C-1’’), 133.8 (C-
7’), 135.9 (C-6), 156.0 (C-8’a), 158.8 (C-4’’), 162.0 (C-2’), 174.1 (C-1),
176.5 (C-3), 178.5 (C-4’). EI-MS m/z (%): 415 (M+•, 5), 385 (26), 381
(100), 353 (27), 352 (22). EI-HRMS m/z calcd for C25H21NO5: 415.1420,
found: 415.1427.
Bisadduct 7c was isolated as a mixture of diastereomers from the
reaction of chromone 3c (37 mg, 0.121 mmol) with N-methylmaleimide
(202 mg, 1.815 mmol) in dry DMF (10 µL) at 160 °C in a multimode
microwave apparatus and the residue was purified and by preparative
TLC using ethyl acetate:hexane (4:1) as eluent. Further purification of the
mixture
of
diastereomers
by
preparative
TLC
using
dichloromethane:ethyl acetate (10:2) as eluent afforded the diastereomer
I. Diastereomer II was characterized by 1H and 13C NMR experiments
from mixture with diastereomer I (enriched in diastereomer II).
rel-(3aR,4R,5aR,5bR,8aR,14bS,14cS)-4-(4-Methoxyphenyl)-2,7-
dimethyl-3a,4,5,5a,5b,8a,14b,14c-octahydro-1H-chromeno[3,2-
e]isoindolo[4,5-g]isoindole-1,3,6,8,9(2H,7H)-pentaone
(7c)
(diastereomer I): White solid, mp 230-232 °C. 1H NMR (300 MHz,
CDCl3): δH 1.98-2.11 (m, 1H, H-5), 2.25-2.36 (m, 1H, H-5a), 2.79-2.84 (m,
1H, H-5), 2.93 and 2.94 (2s, 3H, 2- and 7-NCH3), 3.24 (ddd, 1H, H-14b, J
12.5, 4.0, 1.2 Hz), 3.36 (dd, 1H, H-5b, J 8.7, 4.9 Hz), 3.49 (dd, 1H, H-3a,
J 9.3, 6.2 Hz), 3.61-3.69 (m, 1H, H-4), 3.82 (s, 3H, OCH3), 4.14 (dd, 1H,
H-14c, J 9.3, 4.0 Hz), 4.72 (dd, 1H, H-8a, J 8.7, 1.3 Hz), 6.92 (d, 2H, H-
3’,5’, J 8.6 Hz), 7.16 (d, 2H, H-2’,6’, J 8.6 Hz), 7.39 (d, 1H, H-13, J 8.3
Hz), 7.39-7.44 (m, 1H, H-11), 7.66 (ddd, 1H, J 8.3, 7.2, 1.7 Hz), 8.29 (dd,
1H, H-10, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 24.8 and 25.1 (2-
and 7-NCH3), 25.5 (C-5), 31.6 (C-5a), 33.7 (C-14b), 37.0 (C-4), 39.3 (C-
8a), 40.3 (C-14c), 43.3 (C-5b), 45.7 (C-3a), 55.2 (OCH3), 113.7 (C-8b
and C-3’,5’), 117.5 (C-11), 123.4 (C-9a), 125.4 (C-13), 126.4 (C-10),
128.7 (C-2’,6’), 131.4 (C-1’), 133.9 (C-12), 155.2 (C-13a), 158.6 (C-4’),
164.0 (C-14a), 174.7 and 177.0 (C-6 and C-8), 175.9 and 176.1 (C-1, C-
3 and C-9). EI-MS m/z (%): 527 [(M+H)+, 26], 526 (M+•, 100), 414 (39),
EI-HRMS m/z calcd for C30H26N2O7: 526.1740, found: 526.1754.
2-Methyl-7-(4-oxo-4H-chromen-2-yl)-4-(4-methylphenyl)-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (5d): Yield 34 mg (71%), white
1
solid, mp 223-225 °C. H NMR (300 MHz, CDCl3): δH 2.31 (s, 3H, CH3),
2.61 (s, 3H, NCH3), 2.73-2.80 (m, 2H, H-5), 3.45 (q, 1H, H-4, J 5.7 Hz),
3.57 (dd, 1H, H-3a, J 7.9, 5.7 Hz), 4.14 (dd, 1H, H-7a, J 7.9, 1.4 Hz),
6.65 (s, 1H, H-3’), 7.10, 7.15 (AA’BB’, 4H, H-3’’,5’’; H-2’’,6’’, J 8.5 Hz),
7.23-7.26 (m, 1H, H-6), 7.41 (ddd, 1H, H-6’, J 7.7, 7.3, 1.0 Hz), 7.47 (dd,
1H, H-8’, J 8.2, 1.0 Hz), 7.68 (ddd, 1H, H-7’, J 8.2, 7.3, 1.6 Hz), 8.21 (dd,
1H, H-5’, J 7.7, 1.6 Hz). 13C NMR (75 MHz, CDCl3): δC 21.0 (CH3), 24.4
(NCH3), 28.5 (C-5), 37.9 (C-4), 40.6 (C-7a), 45.2 (C-3a), 109.0 (C-3’),
117.9 (C-8’), 124.0 (C-4’a), 125.1 (C-6’), 125.7 (C-5’), 126.7 (C-7), 127.8
(C-2’’,6’’), 129.1 (C-3’’,5’’), 133.8 (C-7’), 136.0 (C-6), 136.3 (C-1’’), 137.1
(C-4’’), 156.0 (C-8’a), 162.0 (C-2’), 174.1 (C-1), 176.3 (C-3), 178.5 (C-4’).
EI-MS m/z (%): 400 [(M+H)+, 23], 399 (M+•, 100), 395 (26), 287 (32). EI-
HRMS m/z calcd for C25H21NO4: 399.1471, found: 399.1476.
rel-(3aR,4R,5aS,5bS,8aS,14bS,14cS)-4-(4-Methoxyphenyl)-2,7-
dimethyl-3a,4,5,5a,5b,8a,14b,14c-octahydro-1H-chromeno[3,2-
e]isoindolo[4,5-g]isoindole-1,3,6,8,9(2H,7H)-pentaone
(7c)
2-Methyl-4-(4-nitrophenyl)-7-(4-oxo-4H-chromen-2-yl)-3a,4,5,7a-
tetrahydro-1H-isoindole-1,3(2H)-dione (5e): Yield 27 mg (52%), white
solid, mp 162-165 °C. 1H NMR (300 MHz, CDCl3): δH 2.78 (s, 3H, NCH3),
2.73-2.82 (m, 2H, H-5), 3.46 (dt, 1H, H-4, J 9.8, 5.1 Hz), 3.71 (ddd, 1H,
H-3a, J 8.1, 5.1, 1.3 Hz), 4.31 (d, 1H, H-7a, J 8.1 Hz), 6.70 (s, 1H, H-3’),
7.23 (ddd, 1H, H-6, J 6.3, 3.5, 1.1 Hz), 7.42 (ddd, 1H, H-6’, J 8.1, 7.1, 1.1
Hz), 7.44-7.49 (m, 1H, H-8’), 7.50 (d, 2H, H-2’’,6’’, J 8.6 Hz), 7.70 (ddd,
1H, H-7’, J 8.7, 7.1, 1.7 Hz), 8.20-8.23 (m, 1H, H-5’), 8.22 (d, 2H, H-3’’,5’’,
J 8.6 Hz). 13C NMR (75 MHz, CDCl3): δC 24.8 (NCH3), 26.9 (C-5), 38.5
(C-4), 41.6 (C-7a), 45.0 (C-3a), 109.4 (C-3’), 117.8 (C-8’), 123.6 (C-
3’’,5’’), 123.9 (C-4’a), 125.3 (C-6’), 125.8 (C-5’), 127.5 (C-7), 128.8 (C-
2’’,6’’), 134.0 (C-7’), 135.0 (C-6), 147.1 (C-4’’), 147.4 (C-1’’), 155.9 (C-
8’a), 161.1 (C-2’), 173.6 (C-1), 175.5 (C-3), 178.4 (C-4’). EI-MS m/z (%):
430 (M+•, 62), 400 (100), 396 (50), 383 (30), 368 (34). EI-HRMS m/z
calcd for C24H18N2O6: 430.1165, found: 430.1161.
(diastereomer II): 1H NMR (500 MHz, CDCl3): δH 2.17-2.20 (m, 1H, H-5),
2.89-2.94 (m, 1H, H-5a), 2.89 and 2.93 (2s, 3H, 2- and 7-NCH3), 3.30 (t,
1H, H-5b, J 8.3 Hz), 3.41-3.52 (m, 3H, H-5, H-4, H-14b), 3.55 (dd, 1H, H-
3a, J 7.8, 5.9 Hz), 3.74-3.79 (m, 1H, H-14c), 3.83 (s, 3H, OCH3), 4.64 (dd,
1H, H-8a, J 8.9, 1.2 Hz), 6.94 (d, 2H, H-3’,5’, J 8.8 Hz), 7.21 (d, 2H, H-
2’,6’, J 8.8 Hz), 7.35 (d, 1H, H-13, J 7.9 Hz), 7.39-7.44 (m, 1H, H-11),
7.62-7.70 (m, 1H, H-12), 8.28 (dd, 1H, H-10, J 8.0, 1.3 Hz). 13C NMR
(125 MHz, CDCl3): δC 23.8 (C-5), 25.1 and 25.3 (2- and 7-NCH3), 31.7
(C-5a), 35.5 (C-3a), 38.3 (C-8a), 38.8 (C-4), 39.3 (C-5b), 40.7 (C-14c),
45.6 (C-14b), 55.2 (OCH3), 113.7 (C-3’,5’), 114.8 (C-8b), 117.2 (C-11),
123.5 (C-9a), 125.2 (C-13), 126.6 (C-10), 128.8 (C-2’,6’), 131.9 (C-1’),
133.9 (C-12), 155.4 (C-13a), 158.6 (C-4’), 161.6 (C-14a), 174.0 and
177.6 (C-6 and C-8), 175.8, 175.9 and 176.2 (C-1, C-3 and C-9).
Synthesis
of
4-(4-Methoxyphenyl)-7-(4-oxo-4H-chromen-2-yl)-2-
(8). N-
phenyl-3a,4,5,7a-tetrahydro-1H-isoindole-1,3(2H)-dione
(E)-4-(4-Methoxystyryl)-2-methyl-3a,4,5,11b-
Phenylmaleimide (62.8 mg, 0.363 mmol), Sc(OTf)3 (59.5 mg, 0.121
mmol) and chromone 3c (0.121 mmol) were mixed in a closed vessel.
The resulting mixture was heated at 165 °C under microwave irradiation
(monomode apparatus) for 10 minutes. The residue was dissolved in
dichloromethane and purified by preparative TLC using ethyl
acetate:hexane (1:1) as eluent. Yield 38 mg (66%), white solid, mp 212-
214 °C. 1H NMR (300 MHz, CDCl3): δH 2.78-2.93 (m, 2H, H-5), 3.54-3.74
(m, 2H, H-3a, H-4), 3.75 (s, 3H, OCH3), 4.28 (dd, 1H, H-7a, J 7.1, 1.7 Hz),
6.62-6.65 (m, 1H, H-6), 6.64 (s, 1H, H-3’), 6.81 (d, 2H, H-3’’,5’’, J 8.7 Hz),
7.22 (d, 2H, H-3’’,5’’, J 8.7 Hz), 7.24-7.30 (m, 5H, H-2’’’,3’’’,4’’’,5’’’,6’’’),
7.39 (ddd, 1H, H-6’, J 7.9, 7.1, 1.0 Hz), 7.47 (dd, 1H, H-8’, J 8.6, 1.0 Hz),
7.67 (ddd, 1H, H-7’, J 8.6, 7.1, 1.7 Hz), 8.20 (dd, 1H, H-5’, J 7.9, 1.7 Hz)
13C NMR (75 MHz, CDCl3): δC 30.0 (C-5), 37.2 (C-4), 39.9 (C-7a), 44.8
(C-3a), 55.3 (OCH3), 108.9 (C-3’), 114.2 (C-3’’,5’’), 117.9 (C-8’), 124.0
(C-4’a), 125.1 (C-6’), 125.7 (C-5’), 126.2 (C-2’’’,6’’’), 126.5 (C-6), 128.5
(C-7), 128.8 (C-3’’’,5’’’), 129.5 (C-2’’,6’’), 131.0 (C-1’’’), 131.3 (C-1’’),
133.8 (C-7’), 135.8 (C-4’’’), 156.0 (C-8’a), 159.2 (C-4’’), 162.3 (C-2’),
173.0 (C-1), 175.6 (C-3), 178.4 (C-4’). EI-MS m/z (%): 478 [(M+H)+, 23],
477 (M+•, 81), 474 (29) 473 (100), 445 (36), 444 (45), 305 (23). EI-HRMS
m/z calcd for C30H23NO5: 477.1576, found: 477.1590.
tetrahydrochromeno[3,2-e]isoindole-1,3,11(2H)-trione 6c was isolated
from the reaction of chromone 3c (37 mg, 0.121 mmol) with N-
methylmaleimide (67 mg, 0.605 mmol) in dry DMF (10 µL) at 160 °C for
10 minutes in a multimode microwave apparatus and the residue was
purified by preparative TLC using ethyl acetate:hexane (1:1) as eluent.
Yield 3 mg (6%). 1H NMR (500 MHz, CDCl3): δH 2.73 (dd, 1H, H-5, J 17.3,
7.4 Hz), 2.87 (s, 3H, NCH3), 2.95 (dd, 1H, H-5, J 17.3, 4.2 Hz), 3.11-3.16
(m, 1H, H-4), 3.37 (dd, 1H, H-3a, J 8.2, 5.3 Hz), 3.79 (s, 3H, OCH3), 4.55
(d, 1H, H-11b, J 8.2 Hz), 6.19 (dd, 1H, H-α, J 15.7, 9.3 Hz), 6.49 (d, 1H,
H-β, J 15.7), 6.82 (d, 2H, H-3’,5’, J 8.6 Hz), 7.25 (d, 2H, H-2’,6’, J 8.6 Hz),
7.41-7.44 (m, 2H, H-7, H-9), 7.67 (ddd, 1H, H-8, J 8.2, 7.3, 1.4 Hz), 8.29
(dd, 1H, H-10, J 7.9, 1.4 Hz). 13C NMR (125 MHz, CDCl3): δC 24.8
(NCH3), 32.5 (C-5), 38.1 (C-11b), 39.0 (C-4), 44.5 (C-3a), 55.3 (OCH3),
112.8 (C-11a), 114.1 (C-3’,5’), 117.7 (C-7), 123.6 (C-α), 123.9 (C-10a),
125.3 (C-9), 126.4 (C-10), 127.7 (C-2’,6’), 129.0 (C-1’), 132.3 (C-β),
133.8 (C-8), 155.7 (C-6a), 159.5 (C-4’), 163.6 (C-5a), 175.1 (C-3), 176.0
(C-11), 176.5 (C-1).
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
Synthesis of Dialkyl 4'-Methoxy-4-(4-oxo-4H-chromen-2-yl)-[1,1'-
biphenyl]-2,3-dicarboxylates 9a,b. Dimethyl acetylenedicarboxylate (45
µL, 0.363 mmol) or diethyl acetylenedicarboxylate (58 µL, 0.363 mmol)
and chromone 3c (37 mg, 0.121 mmol) were mixed in a closed vessel.
The resulting mixture was heated at 165 °C under microwave irradiation
(monomode apparatus) for 15 minutes. The residue was dissolved in
dichloromethane and purified by preparative TLC using ethyl
acetate:hexane (1:1) as eluent.
Di-isopropyl
3-(4-methoxyphenyl)-6-(4-oxo-4H-chromen-2-yl)-3,6-
dihydropyridazine-1,2-dicarboxylate (10b): Yield 35 mg (57%), yellow
oil. 1H NMR (300 MHz, CDCl3): δH 0.530 and 0.97 (2d, 2 x 3H, 4’’’’,5’’’’-
CH3, J 6.2 Hz), 0.531 and 1.03 (2d, 2 x 3H, 4’’’,5’’’-CH3, J 6.2 Hz), 3.79 (s,
3H, 4’’-OCH3), 4.60 (sept, 1H, H-3’’’, J 6.3 Hz), 4.71 (sept, 1H, H-3’’’’, J
6.3 Hz), 5.87-5.92 (m, 2H, H-3, H-6), 6.19-6.32 (m, 2H, H-4, H-5), 6.86 (d,
2H, H-3’’,5’’, J 8.7 Hz), 7.33 (d, 2H, H-2’’,6’’, J 8.7 Hz), 7.40 (ddd, 1H, H-
6’, J 8.0, 7.1, 1.0 Hz), 7.50 (dd, 1H, H-8’, J 8.6, 1.0 Hz), 7.67 (ddd, 1H, H-
7’, J 8.6, 7.1, 1.7 Hz), 8.18 (dd, 1H, H-5’, J 8.0, 1.7 Hz). 13C NMR (75
MHz, CDCl3): δC 20.9 and 21.2 (5’’’’ and 4’’’’-CH3), 21.81 and 21.83 (5’’’
and 4’’’-CH3), 53.5 (C-6), 54.5 (C-6), 55.4 (4’’-OCH3), 69.9 (C-3’’’’), 70.3
(C-3’’’), 111.2 (C-3’), 113.8 (C-3’’,5’’), 118.3 (C-8’), 121.8 (C-4 or C-5),
123.9 (C-4’a), 125.3 (C-6’), 125.6 (C-5’), 129.6 and 129.7 (C-1 and C-4
or C-5), 129.8 (C-2’’,6’’), 133.9 (C-7’), 154.4 (C-1’’’’), 154.8 (C-1’’’), 156.4
(C-8’a), 159.7 (C-4’’), 163.9 (C-2’), 178.2 (C-4’). EI-MS m/z (%): 506 (M+•,
5), 420 (67), 403 (28), 333 (42), 318 (71), 317 (100), 316 (21), 305 (89),
303 (63), 302 (34), 197 (39). EI-HRMS m/z calcd for C28H30N2O7:
506.2053, found: 506.2061.
Dimethyl 4'-methoxy-4-(4-oxo-4H-chromen-2-yl)-[1,1'-biphenyl]-2,3-
dicarboxylate (9a): Yield 16 mg (30%), yellow solid, mp 226-227 °C. 1H
NMR (300 MHz, CDCl3): δH 3.69 and 3.76 (2s, 2 x 3H, 2,3-CO2CH3), 3.86
(s, 3H, 4’’-OCH3), 6.64 (s, 1H, H-3’), 6.97 (d, 2H, H-3’’,5’’, J 8.7 Hz), 7.31
(d, 2H, H-2’’,6’’, J 8.7 Hz), 7.42 (d, 1H, H-8’, J 8.1 Hz), 7.45 (td, 1H, H-6’,
J 7.7, 1.0 Hz), 7.60 (d, 1H, H-6, J 8.1 Hz), 7.67-7.73 (m, 1H, H-7’), 7.74
(d, 1H, H-5, J 8.1 Hz), 8.25 (dd, 1H, H-5’, J 8.1, 1.5 Hz). 13C NMR (75
MHz, CDCl3): δC 52.7 and 53.1 (2,3-CO2CH3), 55.3 (4’’-OCH3), 110.9 (C-
3’), 114.1 (C-3’’,5’’), 117.7 (C-8’), 123.8 (C-4’a), 125.6 (C-6’), 125.9 (C-5’),
129.4 (C-2’’,6’’), 130.3 (C-5), 130.4 (C-4), 131.0 (C-1’’), 131.4 (C-3),
132.4 (C-6), 133.3 (C-2), 134.1 (C-7’), 143.2 (C-1), 156.3 (C-8’a), 159.8
(C-4’’), 163.6 (C-2’), 167.6 and 168.2 (2,3-CO2CH3), 178.0 (C-4’). EI-MS
m/z (%): 445 [(M+H)+, 20], 444 (M+•, 100), 413 (36). EI-HRMS m/z calcd
for C26H20O7: 444.1209, found: 444.1214.
Synthesis of Diethyl 4-[1,2-bis(ethoxycarbonyl)hydrazinyl]-3-(4-
methoxyphenyl)-6-(4-oxo-4H-chromen-2-yl)-3,4-dihydropyridazine-
1,2-dicarboxylate (11). Diethyl azodicarboxylate solution (0.14 mL,
0.363 mmol) and chromone 3c (37 mg, 0.121 mmol) were mixed in a
closed vessel. The resulting mixture was heated at 130 °C under
microwave irradiation (monomode apparatus) for 10 minutes. The
residue was dissolved in dichloromethane and purified by preparative
TLC using ethyl acetate:hexane (1:1) as eluent. Yield 24 mg (30%),
yellow solid, mp 110-112 °C. 1H NMR (500 MHz, DMSO-d6, 80 °C): δH
0.81 and 1.10 (2t, 2 x 3H, 2 x CH3, J 7.0 Hz), 1.14-1.17 (m, 3H, CH3),
1.25 (t, 3H, CH3, J 7.0 Hz), 3.66-3.83 (m, 2H, CH2), 3.75 (s, 3H, OCH3),
4.01-4.09 (m, 4H, CH2), 4.13-4.20 (m, 2H, CH2), 5.07 (br s, 1H, H-3),
5.70 (br s, 1H, H-4), 6.49 (s, 1H, H-3’), 6.53 (br s, 1H, H-5), 6.92 (d, 2H,
H-3’’,5’’, J 8.5 Hz), 7.27 (d, 2H, H-2’’,6’’, J 8.5 Hz), 7.50 (ddd, 1H, H-6’, J
8.0, 7.2, 1.0 Hz), 7.61 (dd, 1H, H-8’, J 8.0, 1.0 Hz), 7.82 (ddd, 1H, H-7’, J
8.6, 7.2, 1.7 Hz), 8.05 (dd, 1H, H-5’, J 8.0, 1.7 Hz), 9.07 (br s, 1H, NH).
13C NMR (125 MHz, DMSO-d6, 80 °C): δC 13.2 (CH3), 13.7 (CH3), 13.81
(CH3), 13.83 (CH3), 54.9 (OCH3 and C-3), 60.7 (CH2), 61.8 (CH2), 62.0
(CH2), 62.2 (CH2 and C-4), 107.9 (C-3’), 113.7 (C-3’’,5’’), 117.8 (C-8’),
121.2 (C-5), 123.1 (C-4’a), 124.5 (C-5’), 125.3 (C-6’), 128.5 (C-2’’,6’’),
129.4 (C-1’’), 134.1 (C-7’), 136.0 (C-6), 152.4 (CO2), 153.3 (CO2), 154.3
(CO2), 154.4 (CO2), 155.1 (C-8’a), 158.2 (C-2’), 159.0 (C-4’’), 176.3 (C-
4’). EI-MS m/z (%): 652 (M+•, 1), 405 (96), 372 (74), 359 (50), 331 (96),
225 (77), 208 (100). EI-HRMS m/z calcd for C32H36N4O11: 652.2381,
found: 652.2386.
Diethyl
4'-methoxy-4-(4-oxo-4H-chromen-2-yl)-[1,1'-biphenyl]-2,3-
dicarboxylate (9b): Yield 20 mg (35%), yellow solid, mp 170-172 °C. 1H
NMR (300 MHz, CDCl3): δH 1.078 and 1.083 (2t, 2 x 3H, 2- and 3-
CO2CH2CH3, J 7.2 Hz), 3.86 (s, 3H, OCH3), 4.14 (q, 2H, 2-CO2CH2CH3, J
7.2 Hz), 4.21 (q, 2H, 3-CO2CH2CH3, J 7.2 Hz), 6.63 (s, 1H, H-3’), 6.96 (d,
2H, H-3’’,5’’, J 8.7 Hz), 7.32 (d, 2H, H-2’’,6’’, J 8.7 Hz), 7.42 (d, 1H, H-8’,
J 8.4 Hz), 7.45 (ddd, 1H, H-6’, J 8.0, 7.2, 1.2 Hz), 7.58 (d, 1H, H-6, J 8.0
Hz), 7.70 (ddd, 1H, H-7’, J 8.4, 7.2, 1.7 Hz), 7.72 (d, 1H, H-5, J 8.0 Hz),
8.26 (dd, 1H, H-5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 13.7 and
13.8 (2,3-CO2CH2CH3), 55.4 (OCH3), 61.8 (2-CO2CH2CH3), 62.3 (3-
CO2CH2CH3), 111.0 (C-3’), 114.0 (C-3’’,5’’), 117.8 (C-8’), 123.8 (C-4’a),
125.5 (C-6’), 125.9 (C-5’), 129.5 (C-2’’,6’’), 130.2 (C-5), 130.5 (C-4),
131.2 (C-1’’), 131.5 (C-3), 132.3 (C-6), 133.8 (C-2), 134.1 (C-7’), 143.2
(C-1), 156.3 (C-8’a), 159.8 (4’’), 163.9 (C-2’), 167.0 (3-CO2CH2CH3),
167.7 (2-CO2CH2CH3), 178.0 (C-4’). EI-MS m/z (%): 473 [(M+H)+, 20],
472 (M+•, 100), 399 (91), 327 (21). EI-HRMS m/z calcd for C28H24O7:
472.1522, found: 472.1524.
Synthesis of Dialkyl 3-(4-Methoxyphenyl)-6-(4-oxo-4H-chromen-2-
yl)-3,6-dihydropyridazine-1,2-dicarboxylates
10a,b.
Diethyl
azodicarboxylate toluene solution (0.14 mL, 0.363 mmol) or diisopropyl
azodicarboxylate (71 µL, 0.363 mmol) and chromone 3c (37 mg, 0.121
mmol) were mixed in a closed vessel. The resulting mixture was heated
at 165 °C under microwave irradiation (monomode apparatus) for 15 or
10 minutes, respectively. The residue was dissolved in dichloromethane
and purified by preparative TLC using ethyl acetate:hexane (1:1) as
eluent.
General Procedure for the Synthesis of 4-(4-Oxo-4H-chromen-2-yl)-
7-arylisoindoline-1,3-diones 12a-e and 14. DDQ (65.4 mg, 0.288
mmol) was added to a solution of the appropriate adduct 5a-e and 8
(0.072 mmol) in 1,2,4-TCB (0.5 mL). The mixture was heated at 165 °C
under microwave irradiation (monomode apparatus) for 25 minutes. The
residue was treated with a sodium bicarbonate aqueous solution (20 mL)
and the aqueous layer was extracted with dichloromethane (3 x 50 mL).
The organic layer was dried over anhydrous sodium sulfate and the
solvent evaporated to dryness. The residue was purified by preparative
TLC using hexane followed by ethyl acetate:hexane (9:7) as eluent.
Diethyl
3-(4-methoxyphenyl)-6-(4-oxo-4H-chromen-2-yl)-3,6-
dihydropyridazine-1,2-dicarboxylate (10a): Yield 13 mg (22%),
colorless oil. 1H NMR (300 MHz, CDCl3): δH 0.71-0.77 (m, 6H, 1,2-
CO2CH2CH3), 3.56-3.95 (m, 4H, 1,2-CO2CH2CH3), 3.80 (s, 3H, OCH3),
5.87-5.90 (m, 2H, H-3, H-6), 6.21-6.24 (m, 1H, H-4), 6.28-6.31 (m, 1H, H-
5), 6.45 (s, 1H, H-3’), 6.86 (d, 2H, H-3’’,5’’, J 8.6 Hz), 7.32 (d, 2H, H-2’’,6’’,
J 8.6 Hz), 7.40 (ddd, 1H, H-6’, J 8.0, 7.1, 1.1 Hz), 7.49 (d, 1H, H-8’, J 8.3
Hz), 7.67 (ddd, 1H, H-7’, J 8.3, 7.1, 1.7 Hz), 8.18 (dd, 1H, H-5’, J 8.0, 1.7
Hz). 13C NMR (75 MHz, CDCl3): δC 13.8 and 13.9 (1,2-CO2CH2CH3), 53.8
(C-6), 54.8 (C-3), 55.4 (OCH3), 62.3 and 62.5 (1,2-CO2CH2CH3), 111.1
(C-3’), 113.8 (C-3’’,5’’), 118.2 (C-8’), 121.9 (C-4), 123.8 (C-4’a), 125.3 (C-
6’), 125.7 (C-5’), 129.4 (C-1’’), 129.5 (C-5), 129.8 (C-2’’,6’’), 133.9 (C-7’),
154.9 and 155.5 (1,2-CO2CH2CH3), 156.4 (C-8’a), 159.7 (C-4’’), 163.8
(C-2’), 178.2 (C-4’). EI-MS m/z (%): 478 (M+•, 17), 405 (54), 390 (33), 389
(86), 318 (75), 317 (54), 303 (100), 197 (69). EI-HRMS m/z calcd for
C26H26N2O7: 478.1740, found: 478.1745.
2-Methyl-4-(4-oxo-4H-chromen-2-yl)-7-phenylisoindoline-1,3-dione
(12a): Yield 23 mg (85%), white solid, mp 243-245 °C. 1H NMR (300
MHz, CDCl3): δH 3.15 (s, 3H, NCH3), 6.76 (s, 1H, H-3’), 7.47 (ddd, 1H, H-
6’, J 8.0, 7.0, 1.0 Hz), 7.49-7.59 (m, 6H, H-2’’,3’’,4’’,5’’,6’’; H-8’), 7.73
(ddd, 1H, H-7’, J 8.5, 7.0, 1.7 Hz), 7.77 (d, 1H, H-5, J 8.0 Hz), 7.93 (d, 1H,
H-6, J 8.0), 8.29 (dd, 1H, H-5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3):
δC 24.1 (NCH3), 112.7 (C-3’), 118.2 (C-8’), 124.0 (C-4’a), 125.5 (C-6’),
125.8 (C-5’), 128.2 (C-2’’,6’’), 129.0 (C-3a), 129.2 (C-4’’), 129.4 (C-3’’,5’’
and C-7), 130.6 (C-7a), 133.9 (C-6), 134.2 (C-7’), 135.5 (C-1’’), 136.2 (C-
5), 143.1 (C-4), 156.6 (C-8’a), 160.9 (C-2’), 165.9 and 166.9 (C-1 and C-
3), 178.1 (C-4’). EI-MS m/z (%): 382 [(M+H)+, 21], 381 (M+•, 100), 353
(23), 325 (26). EI-HRMS m/z calcd for C24H15NO4: 381.1001, found:
381.1005.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
4-(4-Chlorophenyl)-2-methyl-7-(4-oxo-4H-chromen-2-yl)isoindoline-
1,3-dione (12b): Yield 22 mg (75%), white solid, mp 214-216 °C. 1H
NMR (300 MHz, CDCl3): δH 3.16 (s, 3H, NCH3), 6.75 (s, 1H, H-3’), 7.44-
7.55 (m, 6H, H-6’, H-8’, H-2’’,6’’, H-3’’5’’), 7.73 (ddd, 1H, H-7’, J 8.6, 7.1,
1.7 Hz), 7.74 (d, 1H, H-5, J 8.0 Hz), 7.94 (d, 1H, H-6, J 8.0 Hz), 8.28 (dd,
1H, H-5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 24.2 (NCH3),
112.8 (C-3’), 118.2 (C-8’), 124.0 (C-4’a), 125.5 (C-6’), 125.8 (C-5’), 128.5
(C-3’’,5’’), 129.0 (C-3a), 129.7 (C-7), 130.6 (C-7a), 130.7 (C-2’’,6’’), 133.9
(C-4’’), 134.1 (C-7’), 134.2 (C-6), 135.6 (C-1’’), 136.0 (C-5), 141.7 (C-4),
156.6 (C-8’a), 160.7 (C-2’), 165.8 and 166.8 (C-1 and C-3), 178.0 (C-4’).
EI-MS m/z (%): 417 (M+•, 37Cl, 24), 415 (M+•, 35Cl, 100). EI-HRMS m/z
calcd for C24H1435ClNO4: 415.0611, found: 415.0624.
477 (100), 473 (M+•, 95), 444 (54), 222 (77). EI-HRMS m/z calcd for
C30H19NO5: 473.1263, found: 473.1277.
4-(4-Methoxyphenyl)-2-methyl-7-(4-oxo-4H-chromen-2-yl)-3a,7a-
dihydro-1H-isoindole-1,3(2H)-dione 13c was obtained as by-product in
the synthesis of 4-(4-methoxyphenyl)-2-methyl-7-(4-oxo-4H-chromen-2-
yl)isoindoline-1,3-dione (12c) using the same procedure described above
but under classical heating conditions using toluene, 1,4-dioxane at 100
ºC and 1,2,4-TCB at 190 ºC. After a few hours, the oxidation reaction
afforded a mixture of the oxidized product 12c and semi-oxidized product
1
13c. Yield 15-60%, mp 214-216 °C. H NMR (300 MHz, CDCl3): δH 2.98
(s, 3H, NCH3), 3.85 (s, 3H, OCH3), 4.44 (d, 1H, H-7a, J 11.6 Hz), 4.61 (d,
1H, H-3a, J 11.6 Hz), 6.45 (dd, 1H, H-5, J 6.9, 1.8 Hz), 6.65 (s, 1H, H-3’),
6.95 (d, 2H, H-3’’,5’’, J 8.8 Hz), 7.14 (d, 1H, H-6, J 6.9 Hz), 7.40 (ddd, 1H,
H-6’, J 8.0, 7.1, 1.0 Hz), 7.47 (dd, 1H, H-8’, J 8.5, 1.0 Hz), 7.54 (d, 2H, H-
2’’,6’’, J 8.8 Hz), 7.67 (ddd, 1H, H-7’, J 8.5, 7.1, 1.7 Hz), 8.20 (dd, 1H, H-
5’, J 8.0, 1.7 Hz). 13C NMR (75 MHz, CDCl3): δC 25.8 (NCH3), 41.1 (C-7a),
43.7 (C-3a), 55.4 (OCH3), 108.8 (C-3’), 113.9 (C-3’’,5’’), 117.8 (C-8’),
119.9 (C-5), 121.5 (C-7), 124.1 (C-4’a), 125.1 (C-6’), 125.7 (C-5’), 127.9
(C-6), 128.1 (C-2’’,6’’), 129.7 (C-1’’), 133.8 (C-7’), 136.4 (C-4), 156.0 (C-
8’a), 160.5 (C-4’’), 161.8 (C-2’), 175.1 and 175.3 (C-1 and C-3), 178.3 (C-
4’). EI-MS m/z (%): 414 [(M+H)+, 24], 413 (M+•, 100). EI-HRMS m/z calcd
for C25H19NO5: 413.1263, found: 413.1261.
4-(4-Methoxyphenyl)-2-methyl-7-(4-oxo-4H-chromen-2-
yl)isoindoline-1,3-dione (12c): Yield 27 mg (90%), yellow solid, mp
1
217-219 °C. H NMR (300 MHz, CDCl3): δH 3.16 (s, 3H, NCH3), 3.90 (s,
3H, OCH3), 6.75 (s, 1H, H-3’), 7.04 (d, 2H, H-3’’,5’’, J 8.8 Hz), 7.46 (td,
1H, H-6’, J 7.7, 1.0 Hz), 7.50-7.52 (m, 1H, H-8’), 7.55 (d, 2H, H-2’’,6’’, J
8.8 Hz), 7.70-7.76 (m, 1H, H-7’), 7.75 (d, 1H, H-5, J 8.1 Hz), 7.90 (d, 1H,
H-6, J 8.1 Hz), 8.28 (dd, 1H, H-5’, J 7.7, 1.6 Hz). 13C NMR (75 MHz,
CDCl3): δC 24.1 (NCH3), 55.4 (OCH3), 112.6 (C-3’), 113.7 (C-3’’,5’’),
118.2 (C-8’), 124.0 (C-4’a), 125.4 (C-6’), 125.8 (C-5’), 127.7 (C-1’’), 128.6
(C-3a), 128.8 (C-7), 130.7 (C-7a), 130.9 (C-2’’,6’’), 133.9 (C-6), 134.1 (C-
7’), 136.1 (C-5), 142.9 (C-4), 156.6 (C-8’a), 160.5 (C-4’’), 161.0 (C-2’),
166.0 and 167.1 (C-1 and C-3), 178.1 (C-4’). EI-MS m/z (%): 412 [(M+H)+,
21], 411 (M+•, 100). EI-HRMS m/z calcd for C25H17NO5: 411.1107, found:
411.1106.
Synthesis of Diisopropyl [(1Z,3Z)-1-(4-Methoxyphenyl)-4-(4-oxo-4H-
chromen-2-yl)buta-1,3-diene-1,4-diyl]dicarbamate (15b). DDQ (56.3
mg, 0.248 mmol) was added to a solution of cycloadduct 10b (63 mg,
0.124 mmol) in 1,2,4-TCB (0.5 mL). The mixture was heated at 165 °C
under microwave irradiation (monomode apparatus) for 25 minutes. The
residue was treated with a sodium bicarbonate aqueous solution (10 mL)
and the aqueous layer was extracted with dichloromethane (3 x 15 mL).
The organic layer was dried over anhydrous sodium sulfate and the
solvent evaporated to dryness. The residue was purified by preparative
TLC using hexane followed by dichloromethane:ethyl acetate (10:1) as
eluent. Yield 8.8 mg (17%), yellow oil. 1H NMR (500 MHz, DMSO-d6,
75 °C): δH 0.82, 0.94, 1.20 and 1.25 (4 x d, 3H, CO2CH(CH3)2, J 6.2 Hz),
3.78 (s, 3H, OCH3), 4.60 and 4.84 (2 x sept, 1H, CO2CH(CH3)2, J 6.2 Hz),
6.05 (d, 1H, H-2, J 5.9 Hz), 6.07 (s, 1H, 1-NH), 6.26 (d, 1H, H-3, J 5.9
Hz), 6.47 (s, 1H, H-3’), 6.95 (d, 2H, H-3’’,5’’, J 8.9 Hz), 7.48-7.51 (m, 2H,
H-6’, H-8’), 7.54 (d, 2H, H-2’’,6’’, J 8.9 Hz), 7.83 (ddd, 1H, H-7’, J 8.7, 7.1,
1.7 Hz), 7.88 (br s, 1H, 4-NH), 8.04 (dd, 1H, H-8’, J 7.9, 1.7 Hz). 13C
NMR (125 MHz, DMSO-d6, 75 °C): δC = 20.7, 20.9, 21.4 and 21.5 [1,4-
NHCO2CH(CH3)2], 54.9 (OCH3), 67.75 and 67.80 [1,4-NHCO2CH(CH3)2],
79.7 (C-4), 94.3 (C-1), 108.8 (C-3’), 112.5 (C-3’’,5’’), 117.6 (C-8’), 122.8
(C-4’a), 124.5 (C-5’), 125.3 (C-6’), 127.3 (C-2’’,6’’), 127.6 (C-3), 133.1 (C-
1’’), 134.2 (C-7’), 136.7 (C-2), 150.5 and 154.5 [1,4-NHCO2CH(CH3)2],
155.2 (C-8’a), 158.5 (C-4’’), 163.7 (C-2’), 176.6 (C-4’). EI-MS m/z (%):
504 (M+•, 34), 418 (68), 377 (84), 358 (93), 332 (100). EI-HRMS m/z
calcd for C28H28N2O7: 504.1897, found: 504.1898.
2-Methyl-4-(4-oxo-4H-chromen-2-yl)-7-(methylphenyl)isoindoline-
1,3-dione (12d): Yield 23 mg (80%), white solid, mp 221-223 °C. 1H
NMR (300 MHz, CDCl3): δH 2.45 (s, 3H, CH3), 3.15 (s, 3H, NCH3), 6.75 (s,
1H, H-3’), 7.32 (d, 2H, H-3’’,5’’, J 8.0 Hz), 7.44-7.50 (m, 1H, H-6’), 7.48 (d,
2H, H-2’’,6’’, J 8.0 Hz), 7.52 (dd, 1H, H-8’, J 8.8, 1.0 Hz), 7.73 (ddd, 1H,
H-7’, J 8.8, 7.1, 1.5 Hz), 7.75 (d, 1H, H-5, J 8.0 Hz), 7.91 (d, 1H, H-6, J
8.0 Hz), 8.28 (dd, 1H, H-5’, J 7.9, 1.5 Hz). 13C NMR (75 MHz, CDCl3): δC
21.4 (CH3), 24.1 (NCH3), 112.7 (C-3’), 118.2 (C-8’), 124.0 (C-4’a), 125.5
(C-6’), 125.8 (C-5’), 128.9 (C-3a), 129.0 (C-3’’,5’’), 129.1 (C-7), 129.3 (C-
2’’,6’’), 130.6 (C-7a), 132.6 (C-1’’), 133.9 (C-6), 134.1 (C-7’), 136.2 (C-5),
139.4 (C-4’’), 143.2 (C-4), 156.6 (C-8’a), 161.0 (C-2’), 166.0 and 167.0
(C-1 and C-3), 178.1 (C-4’). EI-MS m/z (%): 395 (M+•, 100). EI-HRMS
m/z calcd for C25H17NO4: 395.1158, found: 395.1157.
2-Methyl-4-(4-nitrophenyl)-7-(4-oxo-4H-chromen-2-yl)isoindoline-1,3-
dione (12e): Yield 21 mg (70%), yellow solid, mp 266-269 °C. 1H NMR
(300 MHz, CDCl3): δH 3.17 (s, 3H, NCH3), 6.78 (s, 1H, H-3’), 7.48 (ddd,
1H, H-6’, J 8.0, 7.1, 1.0 Hz), 7.52 (d, 1H, H-8’, J 7.0 Hz), 7.72-7.78 (m,
1H, H-7’), 7.74 (d, 2H, H-2’’,6’’, J 8.9 Hz), 7.78 (d, 1H, H-5, J 8.0 Hz),
8.01 (d, 1H, H-6, J 8.0 Hz), 8,29 (dd, 1H, H-5’, J 8.0, 1.2 Hz), 8.38 (d, 2H,
H-3’’,5’’, J 8.9 Hz). 13C NMR (75 MHz, CDCl3): δC 24.3 (NCH3), 113.0 (C-
3’), 118.2 (C-8’), 123.4 (C-3’’,5’’), 124.0 (C-4’a), 125.6 (C-6’), 125.9 (C-5’),
129.5 (C-3a), 130.5 (C-2’’,6’’), 130.67 and 130.71 (C-7 and C-7a), 134.3
(C-7’, C-6), 135.7 (C-5), 140.1 (C-4), 141.9 (C-1’’), 148.2 (C-4’’), 156.6
(C-8’a), 160.2 (C-2’), 165.5 and 165.6 (C-1 and C-3), 177.9 (C-4’). EI-MS
m/z (%): 426 (M+•, 17), 396 (100). EI-HRMS m/z calcd for C24H14N2O6:
426.0852, found: 426.0855.
Computational details
All quantum chemical calculations were performed using the Gaussian
09 software package.[26] Optimized geometries and respective electronic
energies were computed at the M06-2X/6-31+G(d,p) level of theory.[27]
The structures found were confirmed to correspond to true minima by
frequency calculations at the same level of theory – no imaginary
frequencies were found. For some cases the enthalpies at T = 298 K,
H298K, were calculated by considering the contributions of Eel, zero-point
energy (ZPE) and thermal enthalpy to T = 298.15 K; no scaling factors
were used (this is a reasonable approximation for relative comparisons of
molecular energetics). The energies of the HOMO/LUMO molecular
orbitals (MO) for the optimized geometries of various dienes and
dienophiles were computed using M06-2X/6-31+G(d,p) (within the KS-
MO formalism) and MP2/6-31+G(d,p) (Hartree-Fock MOs). The
HOMO/LUMO energy gap between diene and dienophile was calculated
as ELUMO(dienophile) – EHOMO(diene), where ELUMO and EHOMO are the
calculated energies of the respective molecular orbitals. All calculations
were performed without symmetry restrictions.
4-(4-Methoxyphenyl)-7-(4-oxo-4H-chromen-2-yl)-2-
phenylisoindoline-1,3-dione (14): Yield 29 mg (86%), white solid, mp
1
271-272 °C. H NMR (300 MHz, CDCl3): δH 3.88 (s, 3H, OCH3), 6.75 (s,
1H, H-3’), 7.03 (d, 2H, H-3’’,5’’, J 8.8 Hz), 7.35-7.38 (m, 1H, H-4’’’), 7.39-
7.48 (m, 5H, H-6’, H-2’’’,6’’’, H-3’’’,5’’’), 7.50 (dd, 1H, H-8’, J 8.4, 0.6 Hz),
7.59 (d, 2H, H-2’’,6’’, J 8.8 Hz), 7.70 (ddd, 1H, H-7’, J 8.4, 7.2, 1.4 Hz),
7.84 (d, 1H, H-5, J 8.1 Hz), 7.96 (d, 1H, H-6, J 8.1 Hz), 8.27 (dd, 1H, H-5’,
J 8.0, 1.4 Hz). 13C NMR (75 MHz, CDCl3): δC 55.4 (OCH3), 112.7 (C-3’),
113.7 (C-3’’,5’’), 118.3 (C-8’), 124.0 (C-4’a), 125.5 (C-6’), 125.8 (C-5’),
126.7 (C-2’’’,6’’’), 127.6 (C-1’’), 128.0 (C-3a), 128.3 (C-4’’’), 129.0 (C-
3’’’,5’’’), 129.3 (C-7), 130.3 (C-7a), 131.0 (C-2’’,6’’), 131.3 (C-1’’’), 134.1
(C-7’), 134.5 (C-6), 136.6 (C-5), 143.5 (C-4), 156.7 (C-8’a), 160.6 (C-4’’),
161.2 (C-2’), 164.9 and 166.1 (C-1 and C-3), 178.1 (C-4). EI-MS m/z (%):
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
[9]
A. Mustafa, M. I. Ali, J. Org. Chem. 1956, 21, 849-851.
Acknowledgements
[10] R. M. Letcher, T.-Y. Yue, J. Chem. Res. (S) 1992, 248.
[11] A. S. Kelkar, R. M. Letcher, K.-K. Cheung, K.-F. Chiu, G. D. Brown, J.
Chem. Soc. Perkin Trans 1 2000, 3732-3741.
Thanks are due to University of Aveiro and FCT/MEC for the
financial support of the QOPNA research unit (FCT
UID/QUI/00062/2013) and CIQ-UP (Pest-C/QUI/UI0081/2013)
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. and C.F.R.A.C.L. are grateful
to FCT for their PhD (SFRH/BD/86277/2012) and Post-doc
(SFRH/BPD/77972/2011) grants, respectively.
[12] H. M. T. Albuquerque, C. M. M. Santos, J. A. S. Cavaleiro, A. M. S.
Silva, Eur. J. Org. Chem. 2015, 4732-4743.
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Borg-Karlson, U. Goransson, R. Verpoorte, Curr. Med. Chem. 2010, 17,
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Dai, X. Yuan, J. Kang, Z.-J. Zhu, R.-C. Yue, H. Yuan, B.-Y. Chen, W.-D.
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C. Proença, H. M. T. Albuquerque, D. Ribeiro, M. Freitas, C. M. M.
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381-392.
Keywords: Diels - Alder • Oxygen heterocycles • MW irradiation
• Lewis acid
[15] M. Singh, M. Kaur, O. Silakari, Eur. J. Med. Chem. 2014, 84, 206-239.
[16] K. Nepali, S. Sharma, M. Sharma, P. M. S. Bedi, K. L. Dhar, Eur. J.
Med. Chem. 2014, 77, 422-487.
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2007, 15, 5191-5197; b) K. Kanagalakshmi, M. Premanathan, R.
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Wu, Eur. J. Med. Chem. 2012, 54, 813-822.
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Bioorg. Med. Chem. 2015, 23, 1629-1637; b) N. Guzior, M. Bajda, M.
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This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
FULL PAPER
Key Topic Heterocyclic chemistry
Hélio M. T. Albuquerque, Clementina M.
M. Santos, Carlos F. R. A. C. Lima, Luis
M. N. B. F. Santos, José A. S. Cavaleiro,
Artur M. S. Silva*
Page No. – Page No.
Title: 2-[(1E,3E)-4-Arylbuta-1,3-dien-1-
yl]-4H-chromen-4-ones as dienes in
Diels‒Alder reactions: experimental
and computational studies
Experimental and computational studies on MW-assisted DA reactions of 2-[(1E,3E)-4-arylbuta-1,3-dien-1-yl]-
4H-chromen-4-ones with electron-poor and electron-rich dienophiles were performed. The main products arise
from tandem DA/1,3-olefin migration reactions, while Sc(OTf)3 prevented the formation of byproducts.
Theoretical studies helped to explain the lack of reactivity of some dienophiles.
[1]
aW. Huang, M.-Z. Liu, Y. Li, Y. Tan, G.-F. Yang, Bioorg. Med. Chem. 2007, 15, 5191-5197;
bK. Kanagalakshmi, M. Premanathan, R. Priyanka, B. Hemalatha, A. Vanangamudi, Eur. J.
Med. Chem. 2010, 45, 2447-2452.
[2]
[3]
F. M. Awadallah, T. A. El-Waei, M. M. Hanna, S. E. Abbas, M. Ceruso, B. E. Oz, O. O. Guler,
C. T. Supuran, Eur. J. Med. Chem. 2015, 96, 425-435.
aM. M. Dias, N. F. Machado, M. P. Marques, Food Funct. 2011, 2, 595-602; bA. Gomes, O.
Neuwirth, M. Freitas, D. Couto, D. Ribeiro, A. G. P. R. Figueiredo, A. M. S. Silva, R. S. G. R.
Seixas, D. C. G. A. Pinto, A. C. Tomé, J. A. S. Cavaleiro, E. Fernandes, J. L. F. C. Lima, Bioorg.
Med. Chem. 2009, 17, 7218-7226; cP. Yadav, B. Parshad, P. Manchanda, S. K. Sharma, Curr.
Top. Med. Chem. 2014, 14, 2552-2575.
[4]
aA. Gomes, E. Fernandes, A. M. S. Silva, D. C. G. A. Pinto, C. M. M. Santos, J. A. S. Cavaleiro,
J. L. F. C. Lima, Biochem. Pharmacol. 2009, 78, 171-177; bShaveta, A. Singh, M. Kaur, S.
Sharma, R. Bhatti, P. Singh, Eur. J. Med. Chem. 2014, 77, 185-192.
[5]
[6]
[7]
[8]
[9]
O. Prakash, R. Kumar, V. Parkash, Eur. J. Med. Chem. 2008, 43, 435-440.
M. A. Ibrahim, T. E. Ali, Y. A. Alnamer, Y. A. Gabr, Arkivoc 2010, (i), 98-135.
R. A. A. Foster, M. C. Willis, Chem. Soc. Rev. 2013, 42, 63-76.
A. Schönberg, A. Mustafa, G. Aziz, J. Am. Chem. Soc. 1954, 76, 4576-4577.
A. Mustafa, M. I. Ali, J. Org. Chem. 1956, 21, 849-851.
[10] R. M. Letcher, T.-Y. Yue, J. Chem. Res. (S) 1992, 248.
[11] A. S. Kelkar, R. M. Letcher, K.-K. Cheung, K.-F. Chiu, G. D. Brown, J. Chem. Soc. Perkin
Trans 1 2000, 3732-3741.
[12] H. M. T. Albuquerque, C. M. M. Santos, J. A. S. Cavaleiro, A. M. S. Silva, Eur. J. Org. Chem.
2015, 4732-4743.
[13] aH. R. El-Seedi, M. A. El-Barbary, D. M. El-Ghorab, L. Bohlin, A. K. Borg-Karlson, U.
Goransson, R. Verpoorte, Curr. Med. Chem. 2010, 17, 854-901; bJ. A. Manthey, K. Grohmann,
N. Guthrie, Curr. Med. Chem. 2001, 8, 135-153.
[14] aShagufta, I. Ahmad, Eur. J. Med. Chem. 2016, 116, 267-280; bM. Dai, X. Yuan, J. Kang, Z.-J.
Zhu, R.-C. Yue, H. Yuan, B.-Y. Chen, W.-D. Zhang, R.-H. Liu, Q.-Y. Sun, Eur. J. Med. Chem.
2013, 69, 159-166; cC. Proença, H. M. T. Albuquerque, D. Ribeiro, M. Freitas, C. M. M. Santos,
A. M. S. Silva, E. Fernandes, Eur. J. Med. Chem. 2016, 115, 381-392.
[15] M. Singh, M. Kaur, O. Silakari, Eur. J. Med. Chem. 2014, 84, 206-239.
[16] K. Nepali, S. Sharma, M. Sharma, P. M. S. Bedi, K. L. Dhar, Eur. J. Med. Chem. 2014, 77, 422-
487.
[17] P.-L. Zhao, W.-F. Ma, A.-N. Duan, M. Zou, Y.-C. Yan, W.-W. You, S.-G. Wu, Eur. J. Med.
Chem. 2012, 54, 813-822.
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201601072
FULL PAPER
[18] aN. Guzior, M. Bajda, J. Rakoczy, B. Brus, S. Gobec, B. Malawska, Bioorg. Med. Chem. 2015,
23, 1629-1637; bN. Guzior, M. Bajda, M. Skrok, K. Kurpiewska, K. Lewiński, B. Brus, A.
Pišlar, J. Kos, S. Gobec, B. Malawska, Eur. J. Med. Chem. 2015, 92, 738-749.
[19] C. I. C. Esteves, C. M. M. Santos, C. M. Brito, A. M. S. Silva, J. A. S. Cavaleiro, Synlett 2011,
2011, 1403-1406.
[20] G. Battistuzzi, S. Cacchi, G. Fabrizi, Org. Lett. 2003, 5, 777-780.
[21] aM. A. Murcko, H. Castejon, K. B. Wiberg, J. Phys. Chem. 1996, 100, 16162-16168; bW. A.
Herrebout, B. J. van der Veken, A. Wang, J. R. Durig, J. Phys. Chem. 1995, 99, 578-585.
[22] C. G. Neochoritis, T. Zarganes-Tzitzikas, J. Stephanidou-Stephanatou, Synthesis 2014, 46, 537-
585.
[23] D. L. Comins, J. T. Kuethe, T. M. Miller, F. C. Février, C. A. Brooks, J. Org. Chem. 2005, 70,
5221-5234.
[24] D. W. Borhani, F. D. Greene, J. Org. Chem. 1986, 51, 1563-1570.
[25] aD. Walker, J. D. Hiebert, Chem. Rev. 1967, 67, 153-195; bA. E. Wendlandt, S. S. Stahl, Angew.
Chem. Int. Ed. 2015, 54, 14638-14658.
[26] M. Frisch, G. Trucks, H. B. Schlegel, G. Scuseria, M. Robb, J. Cheeseman, G. Scalmani, V.
Barone, B. Mennucci, G. Petersson, Wallingford, CT 2009, 19, 227-238.
[27] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215-241.
This article is protected by copyright. All rights reserved