Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction

Article abstract of DOI:10.1039/C8OB02527D

Aminoxanthones constitute a group of therapeutically promising compounds that so far have been synthetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized aminoxanthones by an easy to perform, one-step multi

Full text of DOI:10.1039/C8OB02527D

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Tandem synthesis of 4-aminoxanthones is
controlled by a water-assisted tautomerization:
Cite this: DOI: 10.1039/c8ob02527d
a general straightforward reaction†
Ana Bornadiego, Jesús Díaz * and Carlos F. Marcos
*
Aminoxanthones constitute a group of therapeutically promising compounds that so far have been syn-
thetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized
aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonyl-
chromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cyclo-
addition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aro-
matization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran
tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-deter-
mining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated
energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straight-
forward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process
has also been applied to the synthesis of biologically important chromenophenantridines and secalonic
acid related xanthone dimers.
Received 11th October 2018,
Accepted 14th January 2019
DOI: 10.1039/c8ob02527d
rsc.li/obc
synthesis of biologically relevant dimeric xanthones are rela-
tively scarce, making them synthetically challenging targets.6
Introduction
Xanthones are secondary metabolites occurring in many In a recent work, we have reported the generation of 2-amino-
plants, fungi, lichens and bacteria.1 They exist as either par- furanes by a [4 + 1] cycloaddition of α,β-unsaturated carbonyl
tially hydrogenated or fully aromatized derivatives and often compounds and isocyanides. These 2-aminofuran intermedi-
exhibit distinct biological activities, which depend on the ates have been conveniently trapped in situ with dienophiles to
degree of oxidation of the rings and their substitution give anilines with good yields.7 We have found that 4-aminodi-
pattern.2 Many biologically active xanthones contain hydrogen hydroxanthones (7)8 and 4-aminoxanthones (8)9 could be pre-
bond donating or accepting substituents, such as hydroxyl or pared through a similar tandem [4 + 1]–[4 + 2] cycloaddition of
amino groups, which facilitate key interactions with their bio- 3-carbonylchromones (1), isocyanides (2) and dienophiles (3)
logical targets.3 For instance, aminoxanthones have been pro- (Scheme 1).
posed as chemotherapeutic agents for the treatment of dis-
The mechanism of the reaction is explained by a [4 + 1]
eases, such as diabetes, HIV, and multidrug resistant cancers, cycloaddition of the 3-carbonylchromone (1) with the iso-
due to their interaction with negatively charged nucleic acids, cyanide (2) to give an iminolactone intermediate (4).
proteins and cell substructures.4
Tautomerization to aminofuran (5), which suffers a [4 + 2]
Although different methods for the synthesis of xanthones cycloaddition with the dienophile (3), leads to 7-oxabicyclo
are available, they are mostly limited to fully aromatized [2.2.1]heptane (6). This is readily transformed to 1-hydroxydi-
derivatives. Moreover, the introduction of amino substituents hydroxanthone (7) by the opening of the oxygen bridge
almost invariably implies long, indirect procedures and harsh assisted by the nitrogen lone pair. Dehydration finally affords
reaction conditions.5 Additionally, literature reports on the the aromatic 4-aminoxanthone (8; Scheme 1).
So far, this reaction was limited to electron-poor chromones
such as those containing electron-withdrawing groups
Laboratory of Bioorganic Chemistry & Membrane Biophysics (L.O.B.O.),
attached to the carbonyl, which we thought would favour the
School of Veterinary Sciences, University of Extremadura, 10071 Cáceres, Spain.
first [4 + 1] cycloaddition leading to the purportedly highly
E-mail: cfernan@unex.es, jdal@unex.es
reactive 2-aminofuran intermediate.8,9
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, computational details, product characterization data, and 1H and 13C
NMR spectra for new compounds (PDF and zip). See DOI: 10.1039/c8ob02527d
In this full paper, we demonstrate that it is possible to
extend this methodology8,9 to synthesize diversely substituted
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Results and discussion
Electron-poor 3-methoxalylchromone (1a, Table 1), in which a
CO2CH3 substituent is on the carbonyl group, was initially
chosen as starting material in order to facilitate the formation
of the 2-aminofuran, which we hypothesized would rapidly
react with the dienophile.9 To our delight, the reaction of
methoxalylchromones (1a–e), isocyanides (2a–g) and cyclic
maleic acid derivatives (3a–d) in THF at 25–35 °C readily
afforded 4-aminoxanthone-1-carboxylates (8a–t) with yields up
to 99% (Table 1). Reaction times range from 24 to 144 h and
the products were isolated with high purity by simple filtration
from the reaction medium.
The process shows wide tolerance to different substituents
on the chromone core, isocyanides and maleic acid derivatives.
As a result, xanthones with diverse substituents on both aro-
matic rings are obtained. However, a closer analysis of the
results displayed in Table 1 show that, unexpectedly, donor sub-
stituents on the chromone aromatic ring, such as 7-methoxy
(Table 1, entry 8) and 6-methyl (Table 1, entry 10) seem to
facilitate the overall process, considerably reducing the time of
the reaction. Conversely, the electron-withdrawing group-
containing 6-chlorochromone requires longer reaction times
and/or higher temperatures (Table 1, entries 9, 12 and 20).
These results are not consistent with the initial mechanistic
hypothesis of a slow [4 + 1] cycloaddition followed by a rapid
Scheme 1 Our synthesis of xanthones and dihydroxanthones.
xanthones and dihydroxanthones, starting from carbonylchro-
mones containing both electron-withdrawing and electron-
donating groups. A complete theoretical mechanistic study has
been performed in order to delimitate the scope and limit-
ations of this process.
Table 1 General synthesis of 4-aminoxanthones from methoxalylchromones (1a–e)a
Entry
Chromone
R1
R2
R3
Isocyanide
R4
Dienophile
X
T, °C
Time, h
Product (yield, %)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1c
1a
1b
1a
1b
1a
1b
1d
1c
H
H
H
H
H
H
H
H
H
H
Benzo
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Me
H
H
H
H
H
H
H
OMe
H
H
H
H
H
OMe
H
OMe
H
OMe
H
H
2a
2b
2c
2d
2e
2f
2g
2a
2a
2a
2a
2b
2a
2a
2a
2a
2a
2d
2b
2c
c-C6H11
t-Bu
2,6-Me2C6H3
PhCH2
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
3d
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-C6H5
N-CH3
N-CH3
O
35
35
35
35
35
35
35
25
35
25
25
35
35
35
25
25
25
25
25
85
96
96
144
78
22
22
49
24
96
24
140
120
32
23
96
72
72
72
80
6
8a (99)
8b (93)
8c (67)
8d (93)
8e (97)
8f (99)
8g (82)
8h (99)
8i (81)
8j (75)
8k (30)
8l (85)
8m (94)
8n (81)
8o (83)
8p (87)
8q (86)
8r (30)
8s (70)
8t (53)
C5H11
4-MeOC6H4
CH2CO2t-Bu
c-C6H11
c-C6H11
c-C6H11
c-C6H11
t-Bu
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
PhCH2
9
10
11
12
13
14
15
16
17
18
19
20
Cl
H
H
H
H
H
H
Me
Cl
O
NH
NH
NH
H
H
H
t-Bu
2,6-Me2C6H3
NH
a General procedure: isocyanide 2 (1.1 equiv.) and dienophile 3 (1.1 equiv.) were added under nitrogen to a solution of chromenone 1 (1 equiv.)
in THF and stirred at the specified temperature.
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[4 + 2] trapping of the 2-aminofuran. Thus a detailed study of
As the synthesis of both xanthones (8) and dihydrox-
the mechanism became necessary in order to both find anthones (7) was successfully carried out from chromones con-
optimal reaction conditions and broaden the scope of the reac- taining electron-donating or electron-withdrawing groups on
tion. Nonetheless, good yields are generally obtained regard- the aromatic ring, we wondered if the extension of this reac-
less of the nature of these substituents.
tion to 3-carbonylcromones other than 3-methoxalylchro-
Interestingly, the use of non-symmetric dienophiles con- mones would be possible. This would allow the formation of
taining only one electron-withdrawing group (3e–f) makes the xanthones with different substituents on carbon 1. Notably,
isolation of the [4 + 1]/[4 + 2] cycloadduct (7) prior to aromati- the substituent on this position seems to be determinant for
zation possible (Table 2). Notably, the Diels–Alder reaction was the biological activity of xanthones.12
shown to be regioselective, exclusively leading to the
Accordingly, 3-carbonylchromones containing both elec-
1-hydroxy-1H-xanthen-9(2H)-ones (7u–ae) with the electron- tron-withdrawing and electron-donating substituents on the
withdrawing group on position C3.8 The lack of acidic hydro- carbonyl group were prepared in order to be used in the syn-
gens on C2 precludes the spontaneous dehydration to aro- thesis of xanthones. Thus, 3-acetylchromones (1f, Y = CH3)
matic 4-aminoxanthones (8), which occurs when the reaction and 3-trifluoroacetylchromones (1g–h, Y = CF3) were readily
is performed with symmetric dienophiles. This constitutes a obtained from (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-
remarkably straightforward and efficient route to 1-hydroxy-9- 2-en-1-ones (9) and the corresponding anhydride (10), by a
oxo-2,9-dihydro-1H-xanthene-1-carboxylates (7), which are modification of Yokoe’s method (Scheme 2).13
structurally similar to biologically active globosuxanthones10
On the other hand, the reaction of 3-(dimethylamino)-1-(2-
and diversolonic acids.11 Here again, the reaction was hydroxyphenyl)propen-1-one (9) with ortho- or para-nitrobezoyl
shown to be tolerant of various isocyanides, dienophiles, and chlorides in Yokoe’s conditions always led to mixtures of the
substituents on the chromone (Table 2). Additionally, further desired benzoylchromones and unsubstituted chromones in
dehydration of dihydroxanthones (7) in the presence of a low yields. Consequently, we developed an alternative syn-
base such as DBU, cleanly leads to corresponding thesis through the Baylis–Hillman (B–H) condensation of chro-
aromatized xanthones (8). These can also be conveniently mone (11) and the corresponding nitro-substituted benzal-
obtained in a sequential two-step one-pot procedure, as shown dehydes (12), followed by oxidation of the resulting alcohols.
in Table 3.
The B–H reaction was successfully achieved in methanol,
The isolation of 1-hydroxydihydroxanthones (7u–ae) using sodium methoxide as a base.14 The adducts were cleanly
strongly supports the initially proposed reaction mechanism oxidised with MnO2,15 affording the expected chromones 1i–j
involving the sequence of [4 + 1] cycloaddition, iminolactone- in moderate yields (Scheme 2).
aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring
The reaction of these chromones (1f–j) with isocyanide (2a,
opening and aromatization (Scheme 1). However, again, e–f) and maleic acid derivatives (3a–d) in the conditions pre-
observing the influence of the chromone substituents on the viously used with methoxalylchromones was extremely slug-
reaction does not indicate the rate-determining step.
gish, and afforded the resulting xanthones (8) in poor yields
Table 2 Synthesis of 4-amino-1-hydroxydihydroxanthones
Entry
Chromone
R2
R3
Isocyanide
R4
Dienophile
R5
Time, h
Product (yield, %)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1a
1a
1b
1c
1d
1d
1d
H
H
Cl
Me
H
H
H
Cl
Me
Me
Me
H
OMe
H
H
H
H
OMe
H
H
H
2a
2a
2a
2a
2f
2a
2a
2a
2a
2f
c-C6H11
c-C6H11
c-C6H11
c-C6H11
4-MeOC6H4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
4-MeOC6H4
C5H11
3e
3e
3e
3e
3e
3f
3f
3f
3f
3f
3f
CN
CN
CN
CN
2
4.5
2
2
9
0.5
0.5
1
1
2
7u (81)a
7v (82)a
7w (83)a
7x (76)a
7y (28)a
7z (70)b
7aa (74)b
7ab (90)b
7ac (78)b
7ad (62)b
7ae (83)b
CN
COMe
COMe
COMe
COMe
COMe
COMe
9
10
11
H
2e
1
a Method A: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3e (2 equiv.) in THF is heated 2–9 h at 70 °C. b Method B: A solution of 1 (1 equiv.), 2 (1.2
equiv.), and 3f (1.2 equiv.) in THF is irradiated with MW 0.5–2 h in a close vial at 100 °C.
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Table 3 One-pot synthesis of xanthones (8) from asymmetric dienophiles (3e–f)
Entry
Chromone
R2
R3
Isocyanide
R4
Dienophile
R5
t1/t2, h
Product (yield, %)
1
2
3
4
5
6
7
8
1a
1a
1b
1c
1d
1a
1b
1c
1d
1d
1d
1b
1b
1c
1b
1c
1c
H
H
H
Cl
Me
H
H
H
OMe
H
H
H
OMe
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2f
2e
2b
2b
2b
2f
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
4-MeOC6H4
C5H11
t-Bu
t-Bu
t-Bu
4-MeOC6H4
4-MeOC6H4
C5H11
3e
3e
3e
3e
3e
3f
3f
3f
3f
3f
CN
CN
CN
CN
2/0.5
0.5/0.2
9/1
8u (78)a
8u (75)b
8v (65)a
2.5/0.5
5/1.5
0.5/1
1/1.5
1/0.3
6.5/1
3/0.5
1.5/1
3/0.5
1/0.2
3.5/0.5
3/0.5
8/0.5
0.5/0.5
8w (70)a
8x (68)a
CN
COMe
COMe
COMe
COMe
COMe
COMe
CN
CN
CN
CN
CN
8z (76)b
H
8aa (75)b
8ab (68)b
8ac (70)b
8ad (70)b
8ae (44)b
8af (69)a
8af (69)b
8ag (78)a
8ah (40)a
8ai (27)a
8aj (48)b
Cl
Me
Me
Me
H
H
Cl
H
9
10
11
12
13
14
15
16
17
H
3f
OMe
OMe
H
OMe
H
3e
3e
3e
3e
3e
3f
Cl
Cl
2f
2e
H
COMe
a Method A: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3e (2 equiv.) was heated in THF at 70 °C for 2–9 h before the addition of 2 equiv. DBU
and further heating of the reaction mixture for 25–75 min at the same temperature. b Method B: A solution of 1 (1 equiv.), 2 (1.2 equiv.), and 3f
(1.2 equiv.) in THF was irradiated with MW in a sealed vial at 100 °C for 0.5–6 h. Then DBU (2 equiv.) was added and the reaction mixture was
further irradiated of for 10–90 min.
Accordingly, the reaction with trifluoroacetylchromones (1g–h;
Table 4, entries 6, 8–11) and ortho-nitrobenzoylchromone (1i;
Table 4, entries 13–15) is typically completed in less than 30 h.
Intermediate reaction times were observed when para-nitro-
benzoylchromone (1j) was used (Table 4, entries 17–19, 21–22).
In an attempt to reduce the reaction times, the possible
catalytic effect of Lewis acids was explored. However, the
addition of either yttrium triflate or lithium perchlorate to the
reaction mixture led to longer reaction times (Table 4, entries
3 and 4).
The previous results demonstrate that the reaction is
equally feasible with 3-carbonylchromones containing both
electron-withdrawing and electron-donating substituents on
the carbonyl group. Additionally, different dienophiles and iso-
cyanides can also be used. Moreover, the data above indicate
that increasing the reaction temperature allows to readily
reach the activation energy, resulting in high yields and
Scheme 2 Synthesis of 3-carbonylchromones.
increased reaction rates. However, puzzlingly, there does not
seem to be a clear influence of the electronic nature of the
starting chromone on either the yields or the reaction times.
(Table 4, entries 1, 5, 7, 12, 16 and 20). However, increasing
As expected, the 3-component reaction of chromones 1g,h,j,
the reaction temperature to 80 °C affords the corresponding isocyanide 2a and asymmetric dienophiles 3e,f, carried out at
4-aminoxanthones 8ak–ax in moderate to excellent yields in a 100 °C, affords regioselectively the xanthones (8ay–ba) with no
reasonable reaction time (Table 4).
substituent in position 3 (Table 5).
Thus, the reaction with acetylchromone (1f) requires
Going a step forward, as the absence of an electron group
40 hours to complete. As expected, the reaction times with attached to the carbonyl group of 3-carbonylchromones does
more electron-poor chromones (1g–j) are significantly shorter. not seem to drastically affect their reactivity, we considered
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Table 4 3-Component reactions of chromones 1f–j with isocyanides and maleic acid derivatives
Entry
Chromone
R2
R3
Y
Isocyanide
R4
Dienophile
X
T, °C
Time
Product (yield, %)
1
2
3
4
5
6
7
8
1f
1f
1f
1f
1g
1g
1h
1h
1g
1h
1g
1i
1i
1i
1i
1j
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
OMe
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CF3
CF3
CF3
CF3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2f
2a
2a
2a
2a
2a
2a
2e
2e
2e
2e
2f
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
4-MeOC6H4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
C5H11
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3bf
3a
3a
3d
3c
3a
3a
3b
3d
3c
3c
3a
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-CH3
N-CH3
N-CH3
N-Ph
N-Ph
N-H
35
80
80
80
35
80
35
80
80
80
80
35
80
80
80
35
80
80
80
35
80
80
14 d
40 h
>7.5 d
68 h
8 d
21 h
14 d
13 h
17 h
31 h
31 h
6 d
8ak (39)
8ak (95)
8ak (IR)a,b
8ak (95)c
8al (31)
8al (61)
8am (29)
8am (58)
8an (26)
8ao (59)
8ap (53)
8aq (67)
8aq (77)
8ar (37)
8as (88)
8at (IR)b
8at (93)
8au (68)
8av (66)
8aw (IR)b
8aw (59)
8ax (51)
9
CF3
CF3
CF3
10
11
12
13
14
15
16
17
18
19
20
21
22
o-NO2Ph
o-NO2Ph
o-NO2Ph
o-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
p-NO2Ph
7 h
31 h
22 h
16 d
35 h
20 h
5 d
16 d
5 d
6 d
O
N-Ph
N-Ph
N-CH3
N-H
O
O
1j
1j
1j
1j
1j
1j
C5H11
C5H11
C5H11
4-MeOC6H4
H
H
H
N-Ph
a The experiment was made with 5% of yttrium triflate. b IR: incomplete reaction. c The experiment was made with 7% of lithium perchlorate.
Table 5 Reactions of chromones 1g,h,j with asymmetric dienophiles
Entry
Chromone
R2
R3
Y
Isocyanide
R4
Dienophile
R5
T, °C
t1, h
t2, min
Product (% yield)a
1
2
3
1g
1h
1j
H
H
H
H
OMe
H
CF3
CF3
p-NO2Ph
2a
2a
2a
c-C6H11
c-C6H11
c-C6H11
3e
3f
3e
CN
COMe
CN
100
100
100
2
2
5
20
30
15
8ay (28)
8az (41)
8ba (56)
a General procedure: a solution of 1 (1 equiv.), 2a (1.2 equiv.), and 3e (2 equiv.) or 3f (1.2 equiv.) in THF was irradiated with MW in a sealed vial at
100 °C for 2–5 h. Then DBU (2 equiv.) was added and the reaction mixture was further irradiated of for 15–30 min.
using 3-formylchromones as starting materials in the synthesis and 2). Thus, in order to find better reaction conditions, we
of xanthones.16,17 This provides two advantages: 3-formylchro- tried different solvents and temperatures (Table 6). To our
mones are readily available and the resulting xanthones that delight, when the reaction was performed in refluxing toluene
are unsusbstituted on position 1 could be easily transformed for 41 hours, the expected xanthone 8bb was obtained in 89%
into other xanthones of biological interest.
yield (Table 6, entry 3). The structure was confirmed by the
1
The reaction of 3-formylchromone (1k) with cyclohexyl iso- usual spectroscopic data. Significantly, H-NMR of 8bb shows
cyanide (2a) and N-phenylmaleimide (3a) in THF proceeds a singlet at 8.11 ppm, corresponding to the characteristic aro-
quite slowly, even at refluxing temperature (Table 6, entries 1 matic hydrogen in position 4 of the xanthone.
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Table 6 Reactions of 3-formylchromones with isocyanides and dienophilesa
Entry
Chromone
R2
R3
Isocyanide
R4
Dienophile
X
T, °C
Solvent
Time, h
Product (yield, %)
1
2
3
4
5
6
7
8
1k
1k
1k
1k
1k
1k
1k
1l
1m
1m
1m
1m
1k
1m
1k
1k
1k
1k
H
H
H
H
H
H
H
Cl
Me
Me
Me
Me
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2f
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
c-C6H11
t-Bu
3a
3a
3a
3a
3a
3a
3a
3a
3a
3d
3b
3c
3a
3a
3a
3a
3a
3c
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
N-H
35
80
THF
THF
168
107
41
11
26
68
44
25
60
48
59
62
124
29
41
95
360
360
8bb (IR)b
8bb (71)
110
110
110
110
150
110
110
110
110
110
110
110
110
110
35
Toluene
Toluene
Toluene
Dioxane
Dibutylether
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
8bb (89)
8bb (CM)c,d
8bb (44)e
8bb (90)
8bb (88)
8bc (92)
8bd (87)
8be (87)
8bf (70)
8bg (46)
8bh (58)
8bi (33)
9
10
11
12
13
14
15
16
17
18
N-CH3
O
N-Ph
N-Ph
N-Ph
N-Ph
N-Ph
O
t-Bu
4-MeOC6H4
CH2CO2t-Bu
t-Bu
8bj (42)
2g
2b
2b
8bk (85)
H
H
8bh (67, IR)b,17
8bl (33, IR)b,17
t-Bu
35
DCM
a General procedure: Isocyanide 2 (1.2 equiv.) and dienophile 3 (1.2 equiv.) were added under nitrogen to a solution of chromenone 1 (1 equiv.)
in the specified solvent and stirred at the specified temperature. b IR: the reaction did not reach completion and a mixture of starting materials
and product was obtained. c CM: complex mixture. d AlCl3 (5%mol). e Y(OTf)3 (5%mol).
The use of catalytic Lewis acids such as AlCl3 and Y(OTf)3
(Table 6, entries 4 and 5), does not improve the performance
of the reaction. Despite the increased reaction rate, several
side products are formed, the work up and isolation of the
product is complex and tedious, and the resulting yield is
lower.
The optimized reaction conditions were applied to other
combinations of commercially available formylchromones (1k–
m), maleimide derivatives (3a–d) and isocyanides (2a–g)
(Table 6, entries 8–18). The process gave moderate to excellent
yields and was shown to be tolerant to different isocyanides,
dienophiles, and substituents on the chromone. As previously
t
noted with chrome 1a, less hindered cyclohexyl or CH2CO2 Bu
isocyanide gave better results in the tandem reaction than tert-
butyl isocyanide, which took 5 days to complete in refluxing
toluene.
In a previous work, we have shown that 3-formylchromones
Scheme 3 Proposed mechanism for the reaction of formylchromones
and isocyanides.18
react with isocyanides to give chromenylmethylene furochro-
menones (14), purportedly through a 2-aminofuran intermedi-
ate (5; Scheme 3).18 This reaction takes just 5 to 8 hours in
refluxing THF, in contrast with the unexpectedly slow reaction
of 3-formylchromones, isocyanides and dienophiles, which was
DFT calculations
supposed to occur through the same 2-aminofuran intermedi- In an attempt to explain the lack of consistency between the
ate (4). Obviously, this suggests that either the [4 + 1] cyclo- experimental results and our initial mechanistic hypothesis of
addition leading to 2-aminofuran (5) is not the rate determining a slow [4 + 1] cycloaddition leading to iminolactone (4), fol-
step of the synthesis of xanthones (8; Scheme 1), or the mecha- lowed by a rapid tautomerization and [4 + 2] trapping of the
nism for the synthesis of 14 outlined in Scheme 3 is not valid.
2-aminofuran (5), we decided to carry out a computational
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study of all the reactants, products, and transition states. With
this aim, density functional theory (DFT) calculations were per-
formed with Gaussian 16. The geometries of the reactants, pro-
ducts, intermediates, and transition states (TS) involved in this
mechanistic study were fully optimized in both THF and
toluene with the Polarizable Continuum Model (PCM) at the
B3LYP/6-31+G* level of theory. The reaction was initially mod-
elled with 3-formylchromone (I, 1k), methyl isocyanide (II) and
N-methylmaleimide (3b) in THF (Scheme 4). The reliability of
the method and basis set used was further confirmed with cal-
culations at the PCM-M06-2X/6-31+G** level in Gaussian 09
(see ESI Table S5†).
The computational data reveals that the driving force of the
reaction is undoubtedly the thermodynamic stability of the
final xanthone (VII), with an energy value 43 kcal mol−1 lower
than the initial multicomponent precursors. According to the
proposed mechanism, 3-carbonyl chromone (I) and isocyanide
Scheme 5 Calculated TS for the iminolactone-aminofuran tautomeri-
zation, without and with the participation of water molecules.
(II) react to produce the intermediate iminolactone (IVa), calculations leads to much lower transition states (TSVa (H2O)
which is 8.5 kcal mol−1 less stable than the reactants and TSVa (2H2O); Scheme 5) of 50.4 and 44.5 kcal mol−1
,
(Scheme 4). In congruence with previous studies,19 we found respectively. However, the activation barrier for the tautomeri-
that this step proceeds through a [4 + 1] stepwise cyclo- zation step is still 36 kcal mol−1. This makes the tautomeriza-
addition, in which an activation energy of 30 kcal mol−1 must tion the rate limiting step of the overall process, and explains
be overcome to reach a first zwiterionic intermediate (III). This why heating is required for this reaction.
intermediate quickly reacts, crossing a small energy barrier of
We found an energy barrier of 23.1 kcal mol−1 for the [4 + 2]
cycloaddition of the aminofuran (V) and N-methylmaleimide
2.5 kcal mol−1, to form the iminolactone ring (IVa).
To our surprise, tautomerization of the iminolactone (IVa) (3b), which is considerably lower than that found for the imino-
to the aminofuran (V) was shown to be a high-energy cost lactone-aminofuran tautomerization (Tables 7 and 8). Finally,
process, which should reach a TS (TSVa) of 83.2 kcal mol−1 all the attempts to find TSs for the opening of the oxygen
(see ESI†). In order for this process to be feasible, either sol- bridge and dehydration steps were unsuccessful. These two
vents or other molecules should necessarily participate in the transformations likely have low energy barriers and take place
transition state. Water released in the final dehydration step quite quickly due to the much higher stability of the final
may assist the hydrogen shift process affording aminofuran xanthone (VII). Calculations using toluene instead of THF gave
(V). There is evidence that other similar tautomerism pro- similar energy values (Table 7).
cesses are assisted by either water or other solvent molecules.20
An alternative pathway for the transformation of zwitter-
Indeed, the inclusion of one or two molecules of water in the ionic intermediate III into aminofuran V can also be envi-
Scheme 4 Reaction profile for the multicomponent synthesis of xanthones (8), calculated at B3LYP/6-31+G* level of theory.
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Table 7 Energies of the principal transition states and intermediates calculated at B3LYP/6-31+G* level of theorya
Chromone (I) & methyl
isocyanide (II)
TSIII
Zwiterion (III)
TSIVa
Iminolactone (IVa)
TSVa (2H2O)
Aminofuran (V)
TSVI
Xanthone (VII)
1k (THF)
1k (toluene)
1a
1i
1j
30.03
31.14
28.10
30.54
30.21
27.76
30.24
25.18
26.15
27.11
30.33
32.29
32.26
28.89
29.62
8.54
7.13
14.64
7.04
44.54
41.56
42.07
42.09
39.48
2.68
1.05
3.76
−0.26
−5.92
25.76
25.22
38.51
33.00
27.91
−42.96
−43.97
−35.65
−36.43
−36.38
4.24
a Calculations were fully performed with Gaussian 16.
Table 8 Calculated energy barriers including the temperature thermodynamic effect
Room temperature
Real temperature of reaction
Δ(TSIII-I&II) Δ(TSIVa-III)
Δ(TSIII-I & (II)) Δ(TSIVa-III)
Δ(TSVa-IVa)
Δ(TSVI-V)
Δ(TSVa-IVa)
Δ(TSVI-V)
Chromone
[4 + 1] step 1
[4 + 1] step 2 tautomerization Diels–Alder [4 + 1] step 1 [4 + 1] step 2 tautomerization Diels–Alder
1k (THF)
1k (toluene) 31.14
1a
1i
1j
30.03
2.56
2.05
7.08
2.75
2.51
36.01
34.42
27.43
35.06
35.24
23.08
24.17
34.74
33.26
33.84
31.51
34.25
28.10
32.01
31.71
2.73
2.53
7.08
2.97
2.82
38.92
40.50
27.43
37.97
38.18
24.84
28.01
34.74
35.25
35.80
28.10
30.54
30.21
sioned, considering the direct abstraction of the hydrogen in CO2Me being out of the plane of the molecule. Also, the strong
chromone position 2 by the carbonylic oxygen (see ESI electron-withdrawing character of the substituent CO2Me
Mechanism B, Scheme S1 and Table S2†). DFT calculations enhances the acidity of the hydrogen α to the imine group in
show that this alternative mechanism requires overcoming a IVa, facilitating the tautomerization. As a result, the activation
maximum energy barrier (TSIVb) of 48.3 kcal mol−1, which is energy is only 27.4 kcal mol−1, significantly lower than the
significantly higher than the 44.5 kcal mol−1 corresponding to barrier corresponding to the [4 + 2] cycloaddition. This is in
the higher energy transition state (TSVa (2H2O)) in the first accordance with the experimental results, which demonstrate
proposed mechanism (see ESI†). Calculations also show that that the reaction with chromone 1a can take place at lower
this alternative TSIVb is not stabilized by water. Thus, the reac- temperature, between 25–35 °C. Furthermore, experimental
tion most probably occurs through the stepwise [4 + 1] cyclo- results with substituted methoxalylchromones (1a–e; Table 1)
addition leading to iminolactone IVa, followed by water-facili- show that electron-donating substituents on the aromatic ring
tated tautomerization to aminofuran V. Moreover, there are of the starting chromone seem to favor the reaction, which is
strong experimental evidences that support the mechanism via consistent with the rate-determining step being the [4 + 2]
the iminolactone-aminofuran tautomerization. These include cycloaddition in this case.
the isolation of related iminolactones reported in the litera-
ture21 and the influence of added water in the reaction rate reach each of the successive transition states, including the
(see below). temperature thermodynamic effect. The calculations show
Table 8 summarizes the activation energies required to
We also performed calculations with chromones substi- that, although aminofuran (V) is more stable in each case than
tuted with CO2Me (1a), o-nitrophenyl (1i) and p-nitrophenyl its iminolactone counterpart (IVa), their interconversion
(1j) on the carbonyl group (Tables 7 and 8). The reaction coor- requires the assistance of water and it is still a rather slow
dinates are similar for each of the four examples. The acti- process. Tautomerization is thus the rate determining step in
vation energies for the [4 + 1] and [4 + 2] reactions are moder- all the cases, except for the reactions with methoxalylchro-
ate in each case, between 23–35 kcal mol−1. The energy barrier mone (1a).
for the [4 + 1] cycloaddition is almost independent of the
On the other hand, a new rationale should be determined
nature of the substituent on the carbonyl group. On the con- for the synthesis of furochromones (14), as the mechanism
trary, the presence of electro-withdrawing groups in 1a,i–j showed in Scheme 3 is not compatible with the relatively short
results in significantly higher activation energies for the Diels– reaction times observed, considering the high energy barriers
Alder reaction (Tables 7 and 8).
for the aminolactone-aminofuran tautomerization.18 The for-
The iminolactone-aminofuran tautomerization is the mation of furochromones (14) can thus be explained by a viny-
slowest step in most of the cases, with energy barriers around logous aldol addition22 of a second chromone molecule on the
35 kcal mol−1. An exception is the reaction with chromone 1a, iminolactone (4), which implies that the aminofuran (5) does
in which intermediate IVa is destabilized by the substituent not even form (Scheme 6; cf. Scheme 3). The reaction may be
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2), and slightly lowered the yield from 71% to 69%. Similar
results were observed for the synthesis of xanthones 8bd
(Table 6, entry 9 and Table 9, entry 3) and 8bh (Table 6, entry
13 and Table 9, entry 4).
In order to evaluate the multicomponent synthesis of
xanthones toward the construction of more complex and natu-
rally occurring xanthone scaffolds, dimeric dihydroxanthone
188 and xanthone 19 were readily synthesized from commer-
cially available bisphenol (15). The common precursor bischro-
mone 17 was obtained by acetylation, acid catalyzed Fries
rearrangement,23 aldol condensation with dimethylformamide
dimethyl acetal and cyclization in the presence of 2-chloro-2-
oxoacetate (Scheme 7).
The reaction of bischromone 17, cyclohexyl isocyanide (2a),
and acrylonitrile (3e) under reflux in toluene successfully
afforded dihydroxanthone 18 with a 55% yield over three
steps.8 Similarly, when N-phenylmaleimide (3a) was substi-
Scheme 6 Mechanism for the synthesis of chromenylmethylene furo-
chromenones (14), based on computational studies.
catalyzed by external bases, such as water molecules or any tuted for acrylonitrile (3e), xanthone 19 was obtained with a
products or intermediates containing basic nitrogen atoms 79% yield (Scheme 7).
present in the reaction medium. Abstraction of the proton on
Interestingly, the new xanthones could be further trans-
C-3 of iminolactones and the subsequent addition of electro- formed into other polyheterocyclic molecules of biological
philes to C-5 in the presence of catalytic Lewis acid has been interest. For example, 1-aryl-substituted xanthones could be
reported by Chatani and co-workers.21a
useful intermediates for the synthesis of chromenophenantri-
In congruence with theoretical calculations, the addition of dines, which are interesting materials for organic electronic
water to the reaction medium should facilitate the tautomeri- applications24 and have shown high efficacy in tumor cell
zation reaction, speeding up the whole process. To probe this growth inhibition due to their telomeric DNA G-quadruplex
hypothesis, we performed some experiments in which 8 binding properties.25
equivalents of water was added to the reaction of fomylchro-
Therefore, 1-(ortho-nitrophenyl)xanthones 8aq–as were
mones (1k,m), isocyanides (2a,b), and N-phenylmalimide (3a), readily reduced and cyclized with iron in acetic acid at 130 °C
either in THF or toluene. As expected, the reactions were sig- to give phenanthridine derivatives 20aq–as (Scheme 8).
nificantly quicker, but lower yields were usually obtained. This
These phenantridines were highly intense red fluorescent,
could be attributed to the formation of side products, as in contrast to precursor xanthones, which show yellow fluo-
observed on tlc, and a consequent more complicated work up rescence. They show distinctive IR bands at ca. 1700 and
and purification (Table 9; cf. Table 6). Thus, xanthone 8bb was 1750 cm−1 (20aq, 20ar) or 1740 and 1800 cm−1 (20as), charac-
obtained in only 6 h in refluxing toluene (Table 9, entry 1), teristic of maleimides and maleic anhydrides, respectively.
compared to the 41 h required in anhydrous conditions This supports that cyclization of the intermediate aniline takes
(Table 6, entry 3). However, the yield was reduced from 89% in place through the carbonyl of the chromone, and the maleic
anhydrous conditions to 63% in the presence of water. moiety remains unchanged. This was also confirmed by the
Analogously, in THF, the addition of water reduced the reac- loss in 20aq of the 13C-NMR signal at 180 ppm corresponding
tion time from 107 (Table 6, entry 2) to 6 hours (Table 9, entry to the chromone carbonyl in the starting material.
Table 9 Synthesis of xanthones 8 in the presence of added water
Entry
Chromone
R2
R3
Isocyanide
R4
T, °C
Solvent
Time, h
Product (yield, %)
1
2
3
4
1k
1k
1m
1k
H
H
Me
H
H
H
H
H
2a
2a
2a
2b
c-C6H11
c-C6H11
c-C6H11
tBu
110
80
80
Toluene
THF
THF
6
6
5
5
8bb (63)
8bb (69)
8bd (67)
8bh (50)
80
THF
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Scheme 7 Synthesis of dimeric xanthones 18 and 19.
pates in the transition state facilitating the hydrogen shift
process. Accordingly, water was experimentally shown to sig-
nificantly increase the rate of the reaction.
We have demonstrated the utility of this methodology for
the synthesis of biologically relevant chromenophenantridines
and dimeric xanthones and dihydroxanthones structurally
related to secalonic acid. These compounds, that otherwise
require long and complex syntheses, can be straightforwardly
obtained with high yields and selectivity.
Scheme 8 Synthesis of phenanthridines.
Experimental section
Computational details
Quantum chemical computations were carried out with the
Gaussian 16 series of programs.26 Full geometry optimizations
of stable species were performed in the appropriate solvent by
Conclusions
In conclusion, we have successfully designed a straightforward employing the hybrid density functional B3LYP27 with the 6-
multicomponent synthesis of xanthones and dihydrox- 31+G(d) basis set.28 The B3LYP functional combines the Becke’s
anthones. The highly convergent and atom economic process three-parameter nonlocal hybrid exchange potential with the
takes place in one-pot, in very mild conditions and with no nonlocal correlation functional of Lee, Yang, and Parr. The
need of catalysts. Theoretical calculations demonstrate that nature of the stationary points was verified by analytical compu-
the reaction occurs as an ordered sequence of a [4 + 1] step- tations of harmonic vibrational frequencies. The reliability of the
wise cycloaddition, iminolactone-aminofuran tautomerization, calculations were performed at M06-2X29 with the 6-31+G(d,p)
[4 + 2] cycloaddition, oxygen ring opening and aromatization. basis set. Solvent effects were considered using the integral
Tautomerization is the rate-limiting step, and it has been equation formalism variant of the polarizable continuum model
shown to be possible only in the presence of water that partici- (IEF-PCM) with the Polarizable Continuum Model (PCM).30
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Synthesis of chromones (1f–1j)
Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.53–7.50 (m, 2H), 7.45–7.39
(m, 5H), 6.77 (bs, 1H, NH), 4.27 (m, 1H), 3.19 (s, 3H), 2.13 (m,
2H), 1.84 (m, 2H), 1.67–1.25 (m, 6H) ppm; 13C NMR (101 MHz,
CDCl3): 178.8 (C), 168.3 (C), 167.1 (C), 154.5 (C), 151.7 (C),
137.1 (C), 135.1 (CH), 131.8 (C), 131.6 (C), 129.1 (CH), 128.8
(CH), 128.3 (CH), 127.1 (CH), 126.8 (CH), 125.3 (CH), 125.0 (C),
123.0 (C), 122.6 (C), 117.3 (CH), 114.2 (C), 54.6 (CH),
34.9 (CH2), 25.8 (CH2), 24.9 (CH2), 15.9 (CH3) ppm; MS (CI)
m/z (%) 453 (M + 1, 39), 452 (M+, 13), 375 (22), 347 (93),
298 (100); HRMS (EI) Calcd for C28H24N2O4: 452.17361. Found:
452.1735.
3-Acetyl-4H-chromen-4-one (1f).31 A solution of (E)-3-(di-
methylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one 9a (214 mg,
1.16 mmol) in pyridine (1 mL) and two drops of piperidine
was cooled in an ice-bath and then acetic anhydride 10a
(1 mL, 9 mmol) was added dropwise. The reaction was let to
slowly reach the room temperature overnight and then it was
heated at 120 °C until the starting material was consumed
(2 hours). The residue was washed with saturated aqueous
brine (3 × 15 mL) and CuSO4 (3 × 15 mL) and extracted
with CH2Cl2 (3 × 15 mL). The organic phase was dried over
Na2SO4 and concentrated, and the crude was purified by
Dimethyl 4,4′-bis(cyclohexylamino)-1,1′,3,3′,10,10′-hexaoxo-
2,2′-diphenyl-1,1′,2,2′,3,3′,10,10′-octahydro-[8,8′-bichromeno
column
chromatography
(silica
gel,
hexane–EtOAc
[2,3-f]isoindole]-11,11′-dicarboxylate (19). Obtained as
a
gradient), giving the desired chromone 1f (129 mg,
59%), obtained as a white solid; mp: 128–132 °C (lit.31
125–128 °C).
yellow solid (79%); mp: 355 °C (dec); IR (cm−1): 3455, 2929,
1
1762, 1701, 1664, 1614; H NMR (500 MHz, CDCl3) δ 8.16 (s,
2H), 8.01 (d, J = 7.9 Hz, 2H), 7.59–7.42 (m, 11H), 6.78 (s, 2H),
4.34 (s, 2H), 4.18 (s, 6H), 4.12 (s, 1H), 2.15–1.30 (m, 20H) ppm;
13C NMR (126 MHz, CDCl3): 175.1 (C), 167.7 (C), 166.8 (C),
164.7 (C), 154.2 (C), 148.8 (C), 138.7 (C), 136.2 (C), 134.4 (CH),
131.4 (C), 129.3 (CH), 128.4 (CH), 126.6 (CH), 124.2 (CH), 123.7
(C), 122.4 (C), 121.3 (C), 119.3 (CH), 118.2 (C), 112.6 (C), 54.4
(CH), 53.4 (CH3), 34.4 (CH2), 25.6 (CH2), 24.5 (CH2) ppm;
HRMS (ESI-ICP-Q-TOF) Calcd for C58H46N4O12 H−: 989.3039.
Found: 989.3069.
3-(2-Nitrobenzoyl)-4H-chromen-4-one (1i).32 To a solution of
4H-chromen-4-one 11 (184 mg, 1.25 mmol) and o-nitrobenzal-
dehyde 12a (158 mg, 1 mmol) in dry methanol (0.5 mL),
sodium tert-butoxide (27 mg, 0.267 mmol) in methanol
(2.5 mL) was added dropwise under a nitrogen atmosphere.
Once the chromone 11 was consumed (72 hours), a solution of
HCl 1N (2 mL) was added to the reaction mixture. The solvents
were removed in the rotary evaporator, and the residue was re-
dissolved in ethyl acetate and washed with H2O (3 × 15 mL).
The organic phase was dried over Na2SO4 and concentrated,
and the resulting solid was washed with methanol and ethyl Synthesis of 8-(cyclohexylamino)-6-phenyl-5H-chromeno[4,3,2-
acetate, giving the Baylis–Hillman intermediate 3-(hydroxy(2- gh]pyrrolo[3,4-k]phenanthridine-5,7(6H)-dione (20aq)
nitrophenyl)methyl)-4H-chromen-4-one (196 mg, 66%), as a
white solid.
A solution of xanthone 8aq (25 mg, 0.044 mmol) and iron
(18 mg, 0.323 mmol) in acetic acid (1 mL) was heated at
A
solution
of
3-(hydroxy(2-nitrophenyl)methyl)-4H-
130 °C under nitrogen until the starting xanthone was con-
sumed (15 h). Then the organic phase was filtered over Celite,
and washed with NaOH 2 M (3 × 20 mL), dried over Na2SO4
and purified by chromatographic column (gradient
AcOEt : hexane) yielding the desired product 13aq
(12 mg, 54%), obtained as a red solid; mp: 190 °C; IR (cm−1):
3423, 2924, 2849, 1745, 1693, 1586; 1H NMR (500 MHz,
CDCl3) δ 9.82 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 7.9 Hz, 1H), 7.85
(d, J = 8.0 Hz, 1H), 7.58–7.41 (m, 8H), 7.30 (t, J = 7.1 Hz, 1H),
7.15 (bs, NH, 1H), 7.08 (d, J = 8.0 Hz, 1H), 4.17 (m, 1H), 2.16
(m, 2H), 1.86 (m, 2H), 1.60–1.38 (m, 6H) ppm; 13C NMR
(101 MHz, CDCl3): 168.9 (C), 166.8 (C), 152.3 (C), 145.9 (C),
144.9 (C), 144.7 (C), 134.6 (C), 132.4 (CH), 131.9 (C),
129.9 (CH), 129.4 (CH), 129.2 (CH), 128.9 (CH), 128.3 (CH),
127.1 (CH), 126.4 (CH), 125.6 (CH), 125.2 (CH), 124.3 (C), 122.3
(C), 121.0 (C), 119.0 (C), 118.4 (C), 117.8 (C), 116.6 (CH),
54.1 (CH), 35.1 (CH2), 25.8 (CH2), 24.9 (CH2) ppm; MS (CI) m/z
(%) 513 (M + 2, 33), 512 (M + 1, 59), 511 (M+, 41), 478 (14),
350 (10); HRMS (EI) Calcd for C33H25N3O3: 511.1896. Found:
511.1892.
chromen-4-one (96 mg, 0.38 mmol) and MnO2 (667 mg,
7.7 mmol) in CH2Cl2 (6 mL) was stirred at room temperature
under a nitrogen atmosphere until the starting material was
consumed (1.25 hours). Then the mixture was filtered over
Celite, washing with CH2Cl2 (20 mL), and the organic residue
was evaporated, giving a white solid, which was washed with
cyclohexane affording 1i (103 mg, 92%).
General procedure for the synthesis of xanthones (8a–bk)
Isocyanide 2a–g (1.2 mmol) and dienophile 3a–f (1.2 mmol)
are successively added to a solution of chromenone 1a–m
(1 mmol) in the appropriate solvent (2 mL). The resulting
mixture is stirred at the appropriate temperature under a nitro-
gen atmosphere until the chromone (1) is consumed. HCl 1 N
(2 mL) is then added to the reaction mixture, and after
30 minutes, the crude is washed with brine (15 mL), and
extracted with CH2Cl2 (3 × 15 mL). The organic phase is dried
over Na2SO4 and concentrated. The resulting residue is puri-
fied by column chromatography (silica gel, hexane–EtOAc
gradient), giving the desired product 8.
4-(Cyclohexylamino)-11-methyl-2-phenylchromeno[2,3-f]iso-
indole-1,3,10(2H)-trione (8ak). Obtained as a yellow solid
Conflicts of interest
(95% yield); mp: 214 °C; IR (cm−1): 3430, 2922, 2853, 1754,
1
1694, 1656, 1611; H NMR (500 MHz, CDCl3): δ 8.28 (d, J = 8.0 There are no conflicts to declare.
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16 A. Bornadiego Suárez, PhD thesis, University of
Extremadura, 2016.
Acknowledgements
We thank financial support from Junta de Extremadura and 17 M. B. Teimouri and S. Mohammadnia, Tetrahedron, 2018,
FEDER (IB16095). We are also grateful to CenitS and 74, 1767.
COMPUTAEX for allowing us the use of supercomputing 18 A. G. Neo, L. Garrido, J. Díaz, S. Marcaccini and
facilities.
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