Flavone-nitrogen heterocycle conjugate formation by 1,3-dipolar cycloadditions

Article abstract of DOI:10.1002/ejoc.201101185

Azomethine ylides generated in situ from the reaction of N-[2-, 3- and 4-(chromon-2-yl)phenyl]glycine and paraformaldehyde can be trapped with dipolarophiles in 1,3-dipolar cycloaddition reactions to yield flavone-nitrogen heterocycle dyads. These azometh

Full text of DOI:10.1002/ejoc.201101185

FULL PAPER
DOI: 10.1002/ejoc.201101185
Flavone–Nitrogen Heterocycle Conjugate Formation by 1,3-Dipolar
Cycloadditions
Regina M. S. Sousa,[a] Diana C. G. A. Pinto,[a] Artur M. S. Silva,*[a] Vanda Vaz Serra,[a]
Ana I. R. N. A. Barros,[b] Maria A. F. Faustino,[a] Maria G. P. M. S. Neves,[a] and
José A. S. Cavaleiro[a]
Keywords: Nitrogen heterocycles / Flavones / Porphyrinoids / Ylides / Cycloaddition / Medicinal chemistry
Azomethine ylides generated in situ from the reaction of N-
[2-, 3- and 4-(chromon-2-yl)phenyl]glycine and paraformal-
dehyde can be trapped with dipolarophiles in 1,3-dipolar cy-
cloaddition reactions to yield flavone–nitrogen heterocycle
dyads. These azomethine ylides proved to be reactive with
electron-poor dipolarophiles, affording the expected adducts.
The use of microwave irradiation as an alternative source of
heating has significant advantages and allows a reduction of
both reaction time and temperature. The use of benzalde-
hydes as dipolarophiles afforded flavone–oxazolidine dyads,
and the results indicate that electron-withdrawing groups in
the para position of the benzaldehyde increases the di-
polarophile reactivity. This work was also extended to the
use of meso-tetrakis(pentafluorophenyl)porphyrin as a di-
polarophile, allowing new flavone–dihydroporphyrin conju-
gates to be prepared.
Taking into consideration the important properties of
flavone derivatives, and the fact that drug resistance influ-
ences the successful outcomes of the treatment of several
diseases, a major research effort to find alternative com-
pounds has been undertaken. In this context, the synthesis
of molecules with dual functions may be a good strategy
for the discovery of new drugs or improvements to already
known biological properties. For instance, flavone–amino
acid conjugates improve the bioavailability of flavones,[14]
and flavone-17β-estradiol conjugates improve the binding
affinity towards estrogen receptors.[15] In fact, the most im-
portant targets are flavone–nitrogen heterocycle conjugates.
To give a few examples, we can highlight the monoamides
based on benzimidazole–flavones, such as compound 1,
which exhibit significant antibacterial activity,[16] or the
imidazole–flavone derivative 2, which significantly inhibits
aromatase,[17] and flavopiridol 3, which is a cyclin-depend-
ent kinase inhibitor that is now in Phase II clinical trials
for a number of different malignancies (Figure 1).[18]
1,3-Dipolar cycloaddition reactions are one of the most
used methodologies in the synthesis of heterocycles, includ-
ing natural compounds and new promising drugs.[19] The
application of this type of reaction was also reported for the
synthesis of tetrazoles linked to flavones.[20] In our research
group, we also obtained new flavone–fullerene deriva-
tives[21] by 1,3-dipolar cycloaddition reactions of azome-
thine ylides to C60. Taking into account all the described
applications and potential biological activities, we have de-
signed a synthetic route to flavone–nitrogen heterocycle
conjugates that involves the 1,3-dipolar cycloaddition of
azomethine ylides, generated in situ from the reaction of N-
Introduction
Flavonoids are phenolic secondary plant metabolites that
are ubiquitous in the plant kingdom. At present, they com-
prise more than 6000 chemically distinct natural com-
pounds,[1] and are assigned to different groups according to
their structure.[2] Owing to their ubiquity in plants, they are
important constituents of the human diet and this constant
exposure to a wide variety of flavonoids seems to have
health benefits.[3] A wealth of beneficial properties have
been reported,[4] with the main proposed health optimizing
activities being due to the following actions: (i) antioxidant
properties through the ability to scavenge reactive species
or through their influence on the redox status;[5] (ii) modu-
lation of several enzymes or cell receptors;[6] (iii) protecting
neurons against stress-induced injury;[7] (iv) inhibition of
enzymes that can be associated with several diseases, in par-
ticular, those that can inactivate carcinogens.[8] These find-
ings suggest that flavonoids can be used in active medicinal
formulations.[9] Among the flavonoid classes, flavones are
the most important, not only because they display interest-
ing biological activities,[10] but also because several of the
naturally occurring flavones and their synthetic analogues
display anticancer,[11] anti-inflammatory,[12] and antioxi-
dant[13] activities, to mention just a few examples.
[a] Department of Chemistry & QOPNA, University of Aveiro,
3810-193 Aveiro, Portugal
Fax: +351-234-370084
E-mail: artur.silva@ua.pt
[b] Department of Chemistry,
University of Trás-os-Montes e Alto Douro,
5001-911 Vila Real, Portugal
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Flavone-Nitrogen Heterocycle Conjugates
Scheme 1. Synthesis of N-flavonylglycine derivatives 5a–c.
Our first choice was to test a recent methodology in
which the reductive amination of aldehydes and ketones is
Figure 1. Chemical structures of flavone–nitrogen heterocycle dy-
ads presenting important biological properties: N-cyclohexyl-2-
(4-oxo-2-phenyl-4H-chromen-6-yl)-1H-benzo[d]imidazole-6- effected by sodium triacetoxyborohydride.[31] We tested this
carboximidamide (1), 3-[(1H-imidazol-1-yl)methyl]-2-(4-
approach with aminoflavone 4c, but the desired product 5c
nitrophenyl)-4H-chromen-4-one (2), and flavopiridol [2-(2-chlo-
was obtained in only modest yield (46%). Therefore, we
rophenyl)-5,7-dihydroxy-8-(3-hydroxy-1-methylpiperidin-4-yl)-
tested another reducing agent, sodium cyanoborohyd-
4H-chromen-4-one] (3).
ride,[32] in the reductive amination of aminoflavone 4c and
glyoxylic acid. The procedure was efficient and simple, and
the desired compound 5c was obtained with very good yield
(78%). The other N-flavonylglycine derivatives 5a–b were
also obtained in very good yields (75–80%), by using the
same methodology. The characterization of these new N-
flavonylglycine derivatives was accomplished by NMR
[2-, 3- and 4-(chromon-2-yl)phenyl]glycine and paraformal-
dehyde, with several dipolarophiles [N-methylmaleimide, di-
methyl fumarate, dimethyl maleate, dimethyl acetylenedi-
carboxylate (DEAD), 4-phenyl-3H-1,2,4-triazole-3,5(4H)-
spectroscopic analysis, and the most important features in
dione (PTAD)].
1
the H and 13C NMR spectra are the resonances of 3ЈЈ-H
Furthermore, following our interest in the synthesis of
flavonoid–porphyrin conjugates,[22] and in the functionali-
zation of porphyrins through cycloaddition reactions,[23]
namely using 1,3-dipolar cycloaddition approaches,[24] the
studies were extended to the use of meso-tetrakis(pentafluo-
rophenyl)porphyrin as a dipolarophile.
In fact, the efficiency of porphyrinic derivatives as photo-
sensitizers in the photodynamic therapy (PDT) of cancer
diseases, age-related macular degeneration,[25] and in the
photodynamic inactivation of several pathogenic microor-
ganisms,[26–28] is strongly dependent of their structural fea-
tures. In this context, the synthesis of new flavone–chlorin
conjugates can be a good approach to obtain new active
molecules.
(δ = 6.80–6.94 ppm) and 5ЈЈ-H (δ = 8.02–8.19 ppm), and of
C-3ЈЈ (δ = 103.3–106.9 ppm) and C-4ЈЈ (δ = 176.6–
177.2 ppm), which confirm the chromone skeleton. The gly-
cine moiety presents the characteristic resonances due to 2-
H (δ = 3.56–3.94 ppm), C-2 (δ = 44.1–46.0 ppm), and C-1 (δ
= 171.9–172.6 ppm). The flavone B ring presents a different
substitution pattern and, consequently, the numbering sys-
tem of this ring is different from one derivative to another
1
(Figure 2), and the H and 13C NMR spectra also present
1
some differences. The H NMR spectrum of N-flavonylgly-
cine 5c is the simplest, with two doublets at δ = 6.72 and
7.88 ppm (J = 8.8 Hz), corresponding to the para-substi-
Results and Discussion
Our study started with the synthesis of 2-{[2-, 3- and
4-(4-oxo-4H-chromen-2-yl)phenyl]amino}acetic acids 5a–c,
here designated as N-flavonylglycine derivatives. Taking
into consideration that we had developed an efficient meth-
odology for the synthesis of nitroflavone derivatives[29] and
from those also the corresponding amino-derivatives,[30] we
set up a strategy to obtain the N-flavonylglycine derivatives
5a–c by using the aminoflavones and glyoxylic acid as start-
ing materials (Scheme 1).
Figure 2. Numbering system of N-flavonylglycine derivatives 5a–c.
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133

A. M. S. Silva et al.
FULL PAPER
tuted aromatic ring. For the other N-flavonylglycine deriva- Initially, the reaction of N-flavonylglycine 5c, paraformal-
1
tives, the H NMR spectra present more signals, however, dehyde, and N-methylmaleimide was studied in a range of
their multiplicity and coupling constants still allowed their solvents, such as N,N-dimethylformamide (DMF), toluene,
unequivocal assignment. For instance, the broad singlet due 1,2-dichlorobenzene, and 1,2,4-trichlorobenzene. Our re-
to 2Ј-H resonance (δ = 7.25 ppm) in the 1H NMR spectrum sults indicate that, at lower temperature (less than 200 °C),
of 5b is characteristic of a meta-substitution pattern.
only traces of the expected product were obtained, but by
Subsequently, we studied the reactivity of azomethine conducting the reaction in 1,2,4-trichlorobenzene at reflux
ylides, which were obtained from N-flavonylglycine deriva- temperature there was almost full conversion of the N-fla-
tives and paraformaldehyde, in 1,3-dipolar cycloaddition re- vonylglycine 5c into the expected adduct 6c (Table 1, en-
actions with electron-poor and electron-rich dipolarophiles. try 1). Confirmation of the structure was accomplished
1
To start this study, we chose the least sterically hindered N- mainly by analysis of the H and 13C NMR spectra, with
flavonylglycine 5c, and the dipolarophiles shown in Table 1. the 13C NMR spectral assignments facilitated by 2D NMR
Table 1. 1,3-Dipolar cycloaddition reactions of azomethine ylides, generated in situ from the reaction of N-flavonylglycine 5c and para-
formaldehyde, with several dipolarophiles.
[a] Fl.1 = flavone type c.
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Flavone-Nitrogen Heterocycle Conjugates
experiments. The 1H NMR spectrum of compound 6c at δ = 3.72–3.89 ppm, suggesting that the trans configura-
shows, in addition to the flavone protons, a singlet at δ = tion of the methoxycarbonyl groups can cause this effect.
3.07 ppm due to the resonance of the methyl protons NCH3
When β-nitrostyrene was used (Table 1, entry 7) the de-
and two doublets at δ = 3.55 and 4.07 ppm corresponding sired dyad 12c was obtained in low yield, and attempts to
to 3a,6a-H and 4trans,6trans-H, respectively. The trans config- improve it were unsuccessful. The structure was corrobo-
1
uration is, in this example, related to the protons 3a,6a-H, rated by detailed analysis of H, 13C, HSQC, and HMBC
1
which only shows a vicinal coupling constant (J = 10.7 Hz) NMR spectra. The H NMR spectrum of compound 12c
with 4cis,6cis-H. The less shielded protons 4cis,6cis-H (δ = shows, in addition to the flavone protons, two multiplets in
3.35–3.45 ppm), due to the close proximity to the carbonyl the aromatic region due to the resonance of the phenyl pro-
groups, appear as a multiplet. The carbon resonance assign- tons, and in the aliphatic region the pyrrolidine protons.
ment of the carbonyl groups C-1 and C-3 was made on Analysis of the COSY and NOESY NMR spectra of this
the basis of the HMBC spectrum. The correlations between compound allowed the assignment of these proton reso-
protons NCH3, 4,6-H and 3a,6a-H, and the signal at δ = nances and to establish the configuration of the pyrrolidine
178.3 ppm indicate that the carbon resonance of C-1 and ring as depicted in Table 1, entry 7. These data indicate that
C-3 appears at the same chemical shift as carbon C-4ЈЈ. 3-H (δ = 4.25 ppm) and 4-H (δ = 5.17 ppm) have trans con-
Methylenic carbon atoms C-4,6, as well as the methynic figuration, which means that the dipolarophile configura-
carbon atoms C-3a,6a, were assigned by analysis of the tion was preserved.
HSQC correlations, and all present the expected chemical
Use of DEAD or PTAD (Table 1, entries 5 and 6) did
shifts. This satisfactory result prompted us to extend our not afforded the desired dyads and, again, all attempts to
studies to other electron-poor dipolarophiles, such as di- obtained the dyads failed. When the former reagent was
methyl maleate, dimethyl fumarate (Table 1, entries 2 and used, we always obtained a compound in very good yield
3), and dimethyl acetylenedicarboxylate (Table 1, entry 4), that was identified as N-methyl-N-[4-(4-oxo-4H-chromen-2-
which afforded the expected dyads in good to excellent yl)phenyl]formamide (10c) (Scheme 2). The structure was
yields (61–93%).
proposed on the basis of the mass spectrum (m/z = 280
We then explored the possibility of using microwave irra- [M + H]+) and on the fact that the H NMR spectrum of
diation as an alternative heating source to obtain the de- compound 10c shows, in addition to the flavone protons,
sired adducts. It was seen that lower temperatures and two singlets at δ = 3.40 and 8.67 ppm; the first signal being
shorter reaction times [from 75 to 10 min in the case of 6c characteristic of an N-methyl group and the second being
(Table 1, entry 1)] can be used. In all the other cases, micro- characteristic of an aldehyde proton. The correlation found
wave irradiation led to reductions in reaction times of in the 2D HSQC spectrum confirms that the carbon reso-
1
around 20%.
nances are also characteristic of these types of carbon
Verification of the structures of the obtained adducts atoms (δ = 31.6 ppm for N-CH3 and δ = 161.8 ppm for N-
was, again, made possible by conducting NMR experi- CHO). Because all the data point to a structure containing
1
ments. In the H and 13C NMR spectra of adducts 7c, 8c, the formamide group bearing a flavonyl moiety attached to
and 9c some similarities were found, such as the singlet at the nitrogen atom, we presume that the formed azomethine
δ = 3.75–3.89 ppm due to methyl protons, and the signals ylide reacts with water to form the alcohol 16c, which is
at δ = 51.8–52.6 and 163.5–172.2 ppm corresponding to the oxidized in situ to product 10c by DEAD (Scheme 2). It is
carbon resonances of the methoxycarbonyl group. In the known that water is produced during the in situ formation
case of compound 9c, the resonance of the carbonyl is less of the azomethine ylide and can be more reactive than
deshielded due to the fact that it is linked to an aromatic DEAD. On the other hand, there is evidence that DEAD
1
carbon atom. The H NMR spectrum of compound 9c is can act as an oxidant[33] (Scheme 2).
also in agreement with the oxidized form, showing, in ad-
dition to the flavone protons, only a singlet in the aromatic
region (δ = 7.71 ppm), corresponding to 2,5-H resonances.
Analysis of the 2D HSQC spectrum allowed the assignment
of C-2,5 resonances at δ = 125.9 ppm. In the case of com-
1
pounds 7c and 8c, the H NMR spectra clearly points to
the presence of a pyrrolidine system. The configuration
could not be confirmed due to the fact that the protons
appeared as multiplets, and coupling constant calculations
and other NMR experiments were not possible. Therefore,
due to the fact that in compound 7c, 2,5-H protons resonate
at δ = 3.71–3.86 ppm and those of 3,4-H resonate at δ =
3.50–3.55 ppm (assignments that were confirmed by the 2D
HSQC spectrum correlations), the dipolarophile stereo-
chemistry is preserved. In addition, in the case of com-
pound 8c, 2,5-H resonances occur at different chemical
shifts: two protons at δ = 3.64–3.68 ppm and a second two [4-(4-oxo-4H-chromen-2-yl)phenyl]formamide (10c).
Scheme 2. Proposed mechanism for the synthesis of N-methyl-N-
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In the reaction with PTAD, we also obtained the unex- the reactivity of one of our azomethine ylides with 4-nitro-
pected product 11c in low yield (Table 1, entry 6; 16%). and 4-methoxybenzaldehyde (Table 1, entries 10 and 11).
Nevertheless, we were able to validate the proposed struc- The obtained results showed that there is an enhancement
ture and suggest a mechanism (Scheme 3). Again, the struc- in the reactivity of our azomethine ylide with benzaldehyde
ture was confirmed by the obtained mass spectrum (m/z = bearing an electron-withdrawing group, confirming their
469 [M + H]+) and from the results of NMR spectroscopic good reactivity relative to electron-poor dipolarophiles. The
1
experiments. In the aromatic region of the H NMR spec- 1H NMR spectra of compounds 14c and 15c shows extra
trum, in addition to the flavone protons, two multiplets signals in the aromatic region due to the 5-aryl group of
were observed due to the proton resonances of the N- the oxazolidine ring; two doublets characteristic of a para-
1
phenyl group. The H NMR spectrum of 11c shows three substituted aromatic ring. We can highlight the doublets at
singlets between δ = 5 and 6 ppm, each one corresponding δ = 8.29 and 6.94 ppm corresponding to the resonance of
to one methylene group. In the proposed structure we have the protons ortho to the nitro and methoxy groups, respec-
placed two methylene groups in the 1,2,4-triazolidine moi- tively. The chemical shifts observed are in agreement with
ety and one in the 1,3,4,6-oxatriazepane-5,7-dione moiety. the literature data for the deshielding effect of the nitro
Based on their correlation in 2D HMBC it was possible to group and shielding effect of the methoxyl group. The ali-
1
assign the resonance of 1-H at δ = 5.40 ppm and of C-3 at phatic region of the H NMR spectra of these compounds
δ = 148.4 ppm, whereas 6-H and 8-H were unequivocally is more complicated than in the case of oxazolidine 13c,
assigned to the signals at δ = 5.61 and 5.14 ppm, respec- due to the presence of a stereocenter at carbon C-5. Conse-
tively. It was also possible to assign the resonance of carbon quently, protons 4-H are inequivalent in these cases and
C-5 at δ = 152.0 ppm. These data indicated the structure the most relevant resonance in the aliphatic region is the
depicted in Table 1, entry 6, so we think that the 1,3-dipolar resonance corresponding to 5-H at δ = 5.23 and 5.41 ppm
cycloaddition occurs first to give intermediate 17c, which, for 15c and 14c, respectively. In each case, the signal ap-
by reaction with paraformaldehyde and intramolecular re- pears as a broad double doublet consistent with a cis (J
arrangements, afforded product 11c (Scheme 3).
Because the latter three electron-poor dipolarophiles H, and a long distance coupling with 2-H (J ≈ 3 Hz).
were not as successful as hoped, we decided to test the reac- The results obtained in 1,3-dipolar cycloaddition reac-
≈ 6 Hz) and trans (J ≈ 8 Hz) coupling constant with two 4-
tivity of the azomethine ylide with 2,3-dihydrofuran, which tions of the azomethine ylide generated in situ from the
is an electron-rich dipolarophile. However, the reaction reaction of N-flavonylglycine 5c and paraformaldehyde with
product was not the expected adduct, but a new compound, electron-poor dipolarophiles, encouraged us to study the
which was obtained in moderate yield (Table 1, entry 8). scope of the reaction by using N-flavonylglycines 5a and 5b,
The proposed structure could be confirmed by its mass but using only the electron-poor dipolarophiles that gave
spectrum (m/z = 294 [M + H]+) and by NMR analysis as good results with 5c (Table 2). The yields were, in almost
2-[4-(oxazolidin-3-yl)phenyl]-4H-chromen-4-one (13c). The all cases, very good and the use of microwave irradiation
1H NMR spectrum of compound 13c shows just the flavone was also found to be a good approach because it allowed
resonances in the aromatic region and the oxazolidine reso- the reaction time to be reduced and, in some cases, im-
nances in the aliphatic region. The 4-H and 5-H resonances proved the yields, except in the reaction of N-flavonylgly-
appear at δ = 3.51 and 4.23 ppm, respectively, as triplets cine 5a with dimethyl acetylenedicarboxylate (Table 2, en-
due to their coupling to each other (J = 6.4 Hz). The other try 4). All the expected adducts were obtained and the
signal is a singlet at δ = 4.95 ppm due to 2-H. This result structures were established by NMR spectroscopic analysis
led us to conclude that the azomethine ylide did not react and by comparing their data with those of the previous dis-
with the electron-rich dipolarophile 2,3-dihydrofuran but cussed compounds. It is clear that, in all cases, the best re-
with another formaldehyde molecule. With some experience sults were obtained when N-methylmaleimide and dimethyl
of reactions between ylides and aldehydes,[34] we performed fumarate were used as dipolarophiles.
the reaction without dipolarophile (Table 1, entry 9) and
When the reactions were performed in the presence of
obtained the oxazolidine derivative 13c in very good yield. meso-tetrakis(pentafluorophenyl)porphyrin (18), the condi-
To establish the scope and/or limitations of this method tions had to be adapted to this dipolarophile. It was ob-
towards the synthesis of oxazolidine derivatives, we tested served that the best yields for the expected chlorin adducts
Scheme 3. Proposed mechanism for the synthesis of 8-[4-(4-oxo-4H-chromen-2-yl)phenyl]-4-phenyldihydro-1H-[1,2,4]triazolo[1,2-
c][1,3,4,6]oxatriazepine-3,5(4H,7H)-dione (11c).
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Flavone-Nitrogen Heterocycle Conjugates
Table 2. 1,3-Dipolar cycloaddition reactions to azomethine ylides generated in situ from the reaction of N-flavonylglycine 5a or N-
flavonylglycine 5b and paraformaldehyde.[a]
[a] Fl.2 = flavone type a; Fl.3 = flavone type b.
19a–c were obtained in toluene heated to reflux, and using
The obtained results show that this methodology can be
successive additions of paraformaldehyde and N-[(chro- applied successfully to obtain several flavone–chlorin conju-
mon-2-yl)phenyl]glycines 5a–c (Scheme 4). Good yields gates. The visible spectrum of the main conjugates confirms
were obtained for 19b (53%) and 19c (57%) when the less the chlorin-type structure (λmax = 651 nm) and the 1H
hindered glycines 5b and 5c were used, whereas for the more NMR spectra shows two multiplets (δ = 3.66–3.71 and
hindered glycine 5a, the expected chlorin adduct 19a was 3.89–4.00 ppm) in the aliphatic region, corresponding to the
obtained in lower yield (22%). For the more reactive ylides, methylene protons of the tetrahydropyrrole ring and one
minor amounts of other compounds were also detected. multiplet (δ = 5.51–5.56 ppm) that can be assigned to the
Their mass spectra (m/z = 1502 [M + H]+) and UV/Vis H-β pyrrolic proton, which is typical of chlorin-type com-
spectra suggested that bis-addition occurred, affording bac- pounds. The aromatic region of the 1H NMR spectra
teriochlorins and isobacteriochlorins, which is consistent shows, in addition to the flavone resonances, a singlet at δ
with previous observations noted the literature.[35a,35b]
= 8.49 ppm due to the resonance of β-pyrrolic protons
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Experimental Section
General Methods: Melting points were determined with a Büchi
melting point apparatus and are uncorrected. 1H, 19F and 13C
NMR spectra were recorded with a Bruker 300 spectrometer
[300.13 MHz (1H), 75.47 MHz (13C), 282.38 MHz (19F)]. TMS (δ
= 0 ppm) was used as internal reference for 1H and 13C NMR spec-
tra, and C6F6 (δ –163 ppm) for 19F NMR spectra. Data for 1H
NMR spectra are presented as follows: chemical shift (δ, ppm),
multiplicity [s (singlet), br. s (broad singlet), d (doublet), t (triplet),
q (quartet), and m (multiplet)], coupling constant [J, Hz] and inte-
gration. Data for 13C NMR spectra are reported in terms of chemi-
cal shift (δ, ppm). Unequivocal 1H assignments were made with the
aid of 2D COSY (1H/1H) and NOESY (800 ms mixing time) spec-
tra; 13C assignments were made on the basis of 2D HSQC (1H/13C)
and HMBC (delays for one-bond and long-range JC–H couplings
were optimized for 145 and 7 Hz, respectively) experiments. High-
resolution mass spectral analyses (HRMS-ESI+) were performed
with a microTOF (focus) mass spectrometer. Ions were generated
with an ApolloII (ESI) source. Ionization was achieved by electro-
spray, with the use of a voltage of 4500 V applied to the needle,
and a counter voltage between 100 and 150 V applied to the capil-
lary. High-resolution mass spectra (HRMS-EI, 70 eV) were mea-
sured with a VG Autospec M spectrometer. Elemental analyses
were obtained with a Carlo–Erba 1108 CHNS analyzer. Reactions
under microwave irradiation were performed with an Ethos
SYNTH microwave labstation (Milestone Inc.) using glassware
setup for atmospheric-pressure reactions (temperature measure-
ment with a fiber-optic probe). Silica gel (60 F254, Merck) was
used for TLC, and the spots were detected with UV light (254 nm).
Flash column chromatography was carried out with silica gel 60
(Merck).
Scheme 4. Synthesis of flavone–porphyrin conjugates 19a–c.
12,13-H and two doublets at δ = 8.43–8.45 and 8.74–
8.75 ppm with a characteristic coupling constant (J =
4.9 Hz) of β-pyrrolic protons 7,18-H and 8,19-H. Finally, it
is worth mentioning that a resonance at δ ≈ –1.8 ppm can
also be seen, which is due to internal NH protons and is a
characteristic singlet in the 1H NMR spectra of chlorin-
type compounds.
General Procedure for the Preparation of the N-Flavonylglycine De-
rivatives 5a–c
Conclusions
Method A: Glyoxylic acid (61.3 mg, 0.67 mmol) was added to a
suspension of the appropriate aminoflavone 4a–c (66.3 mg,
0.28 mmol) in methanol (2 mL) and phosphate buffer solution (1 m,
0.4 mL, pH 7.4). Sodium cyanoborohydride (56.9 mg, 0.91 mmol)
was then slowly added. The mixture was heated at reflux under
nitrogen for 5 h (5a), 2 h (5b), 3 h (5c). The reaction mixture was
Reactions of paraformaldehyde with N-[2-, 3- and 4-
(chromon-2-yl)phenyl]glycine can successfully generate azo-
methine ylides, which can be subsequently trapped with
electron-poor dipolarophiles. These 1,3-dipolar cycload-
dition reactions have been studied and a new synthesis of then poured onto ice (5 g) and water (10 mL) and acidified to pH 3
with 20% hydrochloric acid. The obtained solid was removed by
filtration and recrystallized from methanol to afford the title com-
pounds in moderate to good yields: 5a (62.0 mg, 75%), 5b
(66.1 mg, 80%), 5c (64.4 mg, 78%).
flavones–nitrogen heterocyclic conjugates has been estab-
lished. Under microwave irradiation conditions, these pyr-
role and/or pyrrolidine derivatives were obtained in shorter
reaction times and, in some cases, in better yields. The use
of benzaldehydes and meso-tetrakis(pentafluorophenyl)por- Method B: Glyoxylic acid (59.8 mg, 0.65 mmol) was added to a
suspension of 4Ј-aminoflavone 4c (51.4 mg, 0.22 mmol) in acetoni-
trile (3 mL). Sodium triacetoxyborohydride (276 mg, 1.30 mmol)
was then added in one portion. The mixture was heated to reflux
under nitrogen for 22 h. The reaction mixture was then poured
onto ice (10 g) and water (20 mL) and acidified to pH 3 with 20%
hydrochloric acid. The obtained solid was removed by filtration,
washed with water, and purified by silica gel column chromatog-
raphy with gradient elution (CH2Cl2 to CH2Cl2/MeOH, 1:1) to af-
ford the title compound 5c in moderate yield (29.3 mg, 46%).
phyrin as dipolarophiles was also studied and afforded the
corresponding flavone–oxazolidine or flavone–chlorin dy-
ads. In this study, an unexpected dyad was obtained, flav-
one[1,2,4]triazolo[1,2-c][1,3,4,6]oxatriazepine. The yield in
this case was not good, but the important features in the
obtained dyad indicate that further studies would be benefi-
cial.
In summary, almost all these described reactions allowed
new and efficient synthetic methods to be established that
can be used to generate novel flavone–pyrrole, –pyrroli-
dine, –chlorin and –oxazolidine conjugates. Considering the
important biological properties established for the flavone
skeleton, the synthesis of these dyads deserves to be further
explored because we envisage that this procedure can be
used to generate important new heterocycles.
2-{[2-(4-Oxo-4H-chromen-2-yl)phenyl]amino}acetic Acid (5a): Yel-
1
low solid; m.p. 226.9–227.4 °C (ethanol). H NMR (300.13 MHz,
CDCl3, 20 °C): δ = 3.56 (br. s, 2 H, 2-H), 6.89 (s, 1 H, 3ЈЈ-H), 6.90
(t, J = 8.0 Hz, 1 H, 4Ј-H), 7.20 (d, J = 8.0 Hz, 1 H, 6Ј-H), 7.23–
7.25 (m, 2 H, 5Ј,3Ј-H), 7.40 (dt, J = 1.0, 7.7 Hz, 1 H, 6ЈЈ-H), 7.50
(dd, J = 1.0, 7.7 Hz, 1 H, 8ЈЈ-H), 7.68 (dt, J = 1.4, 7.7 Hz, 1 H,
7ЈЈ-H), 8.19 (dd, J = 1.4, 7.7 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR
138
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Eur. J. Org. Chem. 2012, 132–143

Flavone-Nitrogen Heterocycle Conjugates
(75.47 MHz, CDCl3, 20 °C): δ = 46.0 (C-2), 106.9 (C-3ЈЈ), 112.1 145.9 (C-1Ј), 156.6 (C-9ЈЈ), 163.7 (C-2ЈЈ), 177.9 (C-4ЈЈ), 178.3 (C-
(C-6Ј), 118.1 (C-4Ј), 118.4 (C-3Ј), 118.6 (C-8ЈЈ), 123.2 (C-10ЈЈ), 1,3) ppm. MS (ESI+): m/z (%) = 375 (64) [M + H]+, 397 (100) [M
124.9 (C-5ЈЈ), 125.4 (C-6ЈЈ), 131.8 (C-2Ј), 132.6 (C-5Ј), 134.0 (C- + Na]+, 413 (6) [M + K]+. C22H18N2O4: calcd. C 70.58, H 4.85, N
7ЈЈ), 148.6 (C-1Ј), 156.0 (C-9ЈЈ), 163.9 (C-2ЈЈ), 171.9 (C-1), 176.7
(C-4ЈЈ) ppm. MS (FAB+): m/z (%) = 296 (100) [M + H]+.
C17H13NO4: calcd. C 69.15, H 4.41, N 4.75; found C 69.43, H 4.34,
N 4.55.
7.48; found C 70.36, H 4.87, N 7.05.
(3aR*,6aS*)-2-Methyl-5-[3-(4-oxo-4H-chromen-2-yl)phenyl]tetra-
hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (6b): Yellow solid;
m.p. 268–269 °C (ethanol). 1H NMR (300.13 MHz, CDCl3, 20 °C):
δ = 3.05 (s, 3 H, N-CH3), 3.29–3.37 (m, 2 H, 4cis,6cis-H), 3.53 (d, J
2-{[3-(4-Oxo-4H-chromen-2-yl)phenyl]amino}acetic Acid (5b): Yel-
1
low solid; m.p. 233.9–234.6 °C (ethanol). H NMR (300.13 MHz, = 7.8 Hz, 2 H, 3a,6a-H), 4.11 (d, J = 10.4 Hz, 2 H, 4trans,6trans-H),
CDCl3, 20 °C): δ = 3.94 (br. s, 2 H, 2- H), 6.80–8.84 (m, 1 H, 4Ј-
H), 6.94 (s, 1 H, 3ЈЈ-H), 7.25 (br. s, 1 H, 2Ј-H), 7.28–7.30 (m, 2 H,
5Ј,6Ј-H), 7.51 (t, J = 7.5 Hz, 1 H, 6ЈЈ-H), 7.76 (d, J = 8.0 Hz, 1 H,
6.81 (s, 1 H, 3ЈЈ-H), 6.88–6.92 (m, 1 H, 6Ј-H), 7.26 (s, 1 H, 2Ј-H),
7.36–7.47 (m, 2 H, 4Ј,5Ј-H), 7.44 (ddd, J = 1.0, 7.7, 7.7 Hz, 1 H,
6ЈЈ-H), 7.60 (d, J = 8.0 Hz, 1 H, 8ЈЈ-H), 7.73 (ddd, J = 1.7, 7.7,
8ЈЈ-H), 7.85 (ddd, J = 1.5, 7.5, 8.0 Hz, 1 H, 7ЈЈ-H), 8.06 (dd, J = 8.0 Hz, 1 H, 7ЈЈ-H), 8.24 (dd, J = 1.7, 7.7 Hz, 1 H, 5ЈЈ-H) ppm. 13
C
1.5, 7.5 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, NMR (75.47 MHz, CDCl3, 20 °C): δ = 25.5 (N-CH3), 44.2 (C-
20 °C): δ = 44.5 (C-2), 106.7 (C-3ЈЈ), 109.3 (C-2Ј), 114.3 (C-5Ј or 3a,6a), 51.3 (C-4,6), 107.9 (C-3ЈЈ), 112.1 (C-2Ј), 117.3 (C-4Ј), 117.8
C-6Ј), 115.9 (C-4Ј), 118.5 (C-8ЈЈ), 123.4 (C-10ЈЈ), 124.8 (C-5ЈЈ), (C-6Ј), 118.1 (C-8ЈЈ), 124.0 (C-10ЈЈ), 125.3 (C-6ЈЈ), 125.7 (C-5ЈЈ),
125.5 (C-6ЈЈ), 129.7 (C-5Ј or C-6Ј), 131.8 (C-3Ј), 134.4 (C-7ЈЈ), 148.9 130.0 (C-5Ј), 132.9 (C-3Ј), 133.8 (C-7ЈЈ), 148.0 (C-1Ј), 156.3 (C-9ЈЈ),
(C-1Ј), 155.7 (C-9ЈЈ), 163.5 (C-2ЈЈ), 172.6 (C-1), 177.2 (C-4ЈЈ) ppm.
MS (FAB+): m/z (%) = 296 (100) [M + H]+. C17H13NO4: calcd. C
69.15, H 4.41, N 4.75; found C 69.39, H 4.44, N 4.55.
163.6 (C-2ЈЈ), 178.5 (C-1,3,4ЈЈ) ppm. MS (ESI+): m/z (%) = 375
(100) [M + H]+, 397 (46) [M + Na]+, 413 (13) [M + K]+. HRMS:
calcd. for [C22H19N2O4]+ 375.13393; found 375.13368.
2-{[4-(4-Oxo-4H-chromen-2-yl)phenyl]amino}acetic Acid (5c): Yel-
low solid; m.p. 231.6–232.9 °C (ethanol). H NMR (300.13 MHz, hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (6c): Yellow solid;
CDCl3, 20 °C): δ = 3.94 (br. s, 2 H, 2-H), 6.72 (d, J = 8.8 Hz, 2 H,
(3aR*,6aS*)-2-Methyl-5-[4-(4-oxo-4H-chromen-2-yl)phenyl]tetra-
1
m.p. 263–265 °C (ethanol). 1H NMR (300.13 MHz, CDCl3, 20 °C):
2Ј,6Ј-H), 6.80 (s, 1 H, 3ЈЈ-H), 7.46 (dt, J = 1.2, 7.8 Hz, 1 H, 6ЈЈ-H), δ = 3.04 (s, 3 H, N-CH3), 3.35–3.45 (m, 2 H, 4cis,6cis-H), 3.55 (d, J
7.79 (d, J = 7.8 Hz, 1 H, 8ЈЈ-H), 7.79 (dt, J = 1.5, 7.8 Hz, 1 H, 7ЈЈ- = 8.0 Hz, 2 H, 3a,6a-H), 4.07 (d, J = 10.7 Hz, 2 H, 4trans,6trans-H),
H), 7.88 (d, J = 8.8 Hz, 2 H, 3Ј,5Ј-H), 8.02 (dd, J = 1.2, 7.8 Hz, 1 6.71 (s, 1 H, 3ЈЈ-H), 6.79 (d, J = 8.9 Hz, 2 H, 2Ј,6Ј-H), 7.40 (ddd,
H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 44.1 J = 0.7, 7.7, 7.8 Hz, 1 H, 6ЈЈ-H), 7.54 (d, J = 8.1 Hz, 1 H, 8ЈЈ-H),
(C-2), 103.3 (C-3ЈЈ), 112.1 (C-2Ј,6Ј), 117.7 (C-4Ј), 118.2 (C-8ЈЈ), 7.68 (ddd, J = 1.7, 7.7, 8.1 Hz, 1 H, 7ЈЈ-H), 7.84 (d, J = 8.9 Hz, 2
123.4 (C-10ЈЈ), 124.7 (C-5ЈЈ), 125.1 (C-6ЈЈ), 127.8 (C-3Ј,5Ј), 133.8 H, 3Ј,5Ј-H), 8.21 (dd, J = 1.7, 7.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR
(C-7ЈЈ), 151.6 (C-1Ј), 155.5 (C-9ЈЈ), 163.7 (C-2ЈЈ), 172.0 (C-1), 176.6 (75.47 MHz, CDCl3, 20 °C): δ = 25.5 (N-CH3), 44.1 (C-3a,6a), 50.6
(C-4ЈЈ) ppm. MS (FAB+): m/z (%) = 296 (100) [M + H]+. (C-4,6), 105.3 (C-3ЈЈ), 114.3 (C-2Ј,6Ј), 117.9 (C-8ЈЈ), 121.5 (C-4Ј),
C17H13NO4: calcd. C 69.15, H 4.41, N 4.75; found C 69.25, H 4.34,
N 4.80.
123.9 (C-10ЈЈ), 125.0 (C-6ЈЈ), 125.6 (C-5ЈЈ), 127.7 (C-3Ј,5Ј), 133.4
(C-7ЈЈ), 149.8 (C-1Ј), 156.1 (C-9ЈЈ), 163.5 (C-2ЈЈ), 178.3 (C-
1,3,4ЈЈ) ppm. MS (ESI+): m/z (%) = 375 (100) [M + H]+, 397 (6)
[M + Na]+, 749 (3) [2M+H]+. C22H18N2O4: calcd. C 70.58, H 4.85,
N 7.48; found C 70.36, H 4.87, N 7.05.
General Procedure for the Synthesis of Flavone–Nitrogen Heterocy-
cle Dyads 6a–c, 7a–c, 8a–c, 9a–c, and 10c–12c under Classical Heat-
ing Conditions: Paraformaldehyde (15.2 mg, 0.51 mmol) and the
appropriate dipolarophile (5 equiv.) were added to a solution of
flavonylglycine 5a–c (30.0 mg, 0.10 mmol) in 1,2,4-trichloroben-
zene (3 mL). The mixture was heated to reflux under nitrogen from
20 to 210 min (Table 1 and Table 2). The solution was cooled to
room temperature, and the solvent was removed by silica gel col-
umn chromatography eluting with hexane. Changing the eluting
system to a (9:1) mixture of CH2Cl2/acetone afforded the title com-
pounds in moderate to good yields: 6a (29.3 mg, 77%), 6b
(30.8 mg, 81%), 6c (34.9 mg, 92%), 7a (18.2 mg, 44%), 7b
(33.1 mg, 80%), 7c (38.5 mg, 93%), 8a (35.6 mg, 86%), 8b
(35.2 mg, 85%), 8c (36.0 mg, 87%), 9a (27.9 mg, 68%), 9b
(3R*,4S*)-Dimethyl 1-[2-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
ine-3,4-dicarboxylate (7a): Yellow oil. 1H NMR (300.13 MHz,
CDCl3, 20 °C): δ = 3.32–3.35 (m, 2 H, 3,4-H), 3.55–3.60 (m, 4 H,
2,5-H), 3.66 (s, 6 H, CO2CH3), 6.52 (s, 1 H, 3ЈЈ-H), 6.94 (ddd, 1
H, 4Ј-H, J = 2.0, 8.2, 8.2 Hz), 6.96 (dd, 1 H, 6Ј-H, J = 2.0, 8.0 Hz),
7.37–7.51 (m, 3 H, 6ЈЈ,5Ј,3Ј-H), 7.50–7.52 (m, 1 H, 8ЈЈ-H), 7.70
(ddd, 1 H, 7ЈЈ-H, J = 1.6, 7.8, 7.8 Hz), 8.26 (dd, 1 H, 5ЈЈ-H, J =
1.6, 8.0 Hz) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 45.0
(C-3,4), 51.9 (C-2,5), 52.2 (CO2CH3), 111.6 (C-3ЈЈ), 115.2 (C-6Ј),
118.1 (C-8ЈЈ), 118.7 (C-4Ј), 119.9 (C-2Ј), 123.8 (C-10ЈЈ), 125.2 (C-
6ЈЈ), 125.7 (C-5ЈЈ), 131.5 (C-3Ј), 131.7 (C-5Ј), 133.7 (C-7ЈЈ), 146.7
(13.1 mg, 32%), 9c (24.9 mg, 61%), 10c (18.8 mg, 67%), 11c (C-1Ј), 156.3 (C-9ЈЈ), 166.2 (C-2ЈЈ), 171.7 (CO2CH3), 178.4 (C-
(11.2 mg, 16%), 12c (10.0 mg, 24%).
4ЈЈ) ppm. MS (ESI+): m/z (%) = 408 (100) [M + H]+, 430 (85) [M +
Na]+. HRMS: calcd. for [C23H21NO6]+ 407.1369; found 407.1361.
(3aR*,6aS*)-2-Methyl-5-[2-(4-oxo-4H-chromen-2-yl)phenyl]tetra-
hydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (6a): Yellow solid; Dimethyl (3R*,4S*)-1-[3-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
m.p. 168–169 °C (ethanol). 1H NMR (300.13 MHz, CDCl3, 20 °C):
ine-3,4-dicarboxylate (7b): Yellow solid; m.p. 152–153 °C (ethanol).
δ = 3.07 (s, 3 H, N-CH3), 3.03–3.13 (m, 2 H, 4cis,6cis-H), 3.28 (dd, 1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.49–3.53 (m, 2 H, 3,4-
J = 1.9, 5.3 Hz, 2 H, 3a,6a-H), 3.74 (d, J = 10.1 Hz, 2 H, H), 3.75 (s, 6 H, CO2CH3), 3.70–3.84 (m, 4 H, 2,5-H), 6.74 (dd, J
4trans,6trans-H), 6.58 (s, 1 H, 3ЈЈ-H), 7.06 (d, J = 8.1 Hz, 1 H, 6Ј-H), = 2.1, 8.0 Hz, 1 H, 6Ј-H), 6.83 (s, 1 H, 3ЈЈ-H), 7.06 (t, J = 2.1 Hz,
7.17 (ddd, J = 1.0, 7.6, 7.7 Hz, 1 H, 4Ј-H), 7.41–7.43 (m, 2 H,
5Ј,6ЈЈ-H), 7.43 (d, J = 8.0 Hz, 1 H, 8ЈЈ-H), 7.58 (dd, J = 1.6, 7.7 Hz,
1 H, 3Ј-H), 7.68 (ddd, J = 1.7, 7.8, 8.0 Hz, 1 H, 7ЈЈ-H), 8.26 (dd,
J = 1.7, 8.2 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3,
1 H, 2Ј-H), 7.28 (d, J = 8.0 Hz, 1 H, 4Ј-H), 7.38 (t, J = 8.0 Hz, 1
H, 5Ј-H), 7.43 (ddd, J = 1.0, 7.8, 7.9 Hz, 1 H, 6ЈЈ-H), 7.60 (d, J =
8.0 Hz, 1 H, 8ЈЈ-H), 7.71 (ddd, J = 1.7, 7.8, 8.0 Hz, 1 H, 7ЈЈ-H),
8.24 (dd, J = 1.7, 7.9 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz,
20 °C): δ = 25.5 (N-CH3), 44.1 (C-3a,6a), 54.1 (C-4,6), 110.9 (C- CDCl3, 20 °C): δ = 45.0 (4, C-3), 49.6 (C-2,5), 52.3 (CO2CH3),
3ЈЈ), 118.1 (C-8ЈЈ), 118.5 (C-6Ј), 123.2 (C-4Ј), 123.9 (C-10ЈЈ), 125.3 107.7 (C-3ЈЈ), 109.1 (C-2Ј), 114.7 (C-4Ј), 114.9 (C-6Ј), 118.2 (C-8ЈЈ),
(C-6ЈЈ), 125.9 (C-5ЈЈ,2Ј), 130.5 (C-3Ј), 131.8 (C-5Ј), 133.5 (C-7ЈЈ), 124.0 (C-10ЈЈ), 125.2 (C-6ЈЈ), 125.7 (C-5ЈЈ), 129.9 (C-5Ј), 132.7 (C-
Eur. J. Org. Chem. 2012, 132–143
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
139

A. M. S. Silva et al.
FULL PAPER
3Ј), 133.7 (C-7ЈЈ), 147.2 (C-1Ј), 156.3 (C-9ЈЈ), 164.2 (C-2ЈЈ), 171.9 + H]+, 430 (6) [M + Na]+. C23H21NO6: calcd. C 67.80, H 5.20, N
(CO2CH3), 178.6 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 408 (100) [M
+ H]+, 430 (20) [M + Na]+. C23H21NO6: calcd. C 67.80, H 5.20, N
3.44; found C 67.78, H 5.20, N 3.45.
3.44; found C 67.62, H 5.58, N 3.76.
Dimethyl 1-[2-(4-Oxo-4H-chromen-2-yl)phenyl]-1H-pyrrole-3,4-di-
carboxylate (9a): Yellow solid; m.p. 185–186 °C (ethanol). 1H
NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.78 (s, 6 H, CO2CH3),
6.50 (s, 1 H, 3ЈЈ-H), 7.12 (dd, J = 0.9, 8.4 Hz, 1 H, 8ЈЈ-H), 7.39
(ddd, J = 0.9, 7.6, 7.8 Hz, 1 H, 6ЈЈ-H), 7.39 (s, 2 H, 2,5-H), 7.49
(dd, J = 1.6, 7.5 Hz, 1 H, 6Ј-H), 7.59–7.71 (m, 3 H, 7ЈЈ,4ЈЈ,5ЈЈ-H),
7.77 (dd, J = 1.8, 7.5 Hz, 1 H, 3Ј-H), 8.17 (dd, J = 1.6, 78 Hz, 1
H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 51.6
(CO2CH3), 112.0 (C-3ЈЈ), 117.0 (C-3,4), 118.0 (C-8ЈЈ), 123.5 (C-
10ЈЈ), 125.5 (C-5ЈЈ,6ЈЈ), 127.5 (C-6Ј), 128.8 (C-2,5), 129.1 (C-2Ј),
129.5 (C-4Ј), 130.6 (C-3Ј), 132.2 (C-5Ј), 134.2 (C-7ЈЈ), 137.4 (C-1Ј),
156.0 (C-9ЈЈ), 162.0 (C-2ЈЈ), 163.4 (CO2CH3), 177.9 (C-4ЈЈ) ppm.
MS (ESI+): m/z (%) = 404 (13) [M + H]+, 426 (100) [M + Na]+.
HRMS: calcd. for [C23H17NO6]+ 403.1056; found 403.1057.
Dimethyl (3R*,4S*)-1-[4-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
ine-3,4-dicarboxylate (7c): Yellow solid; m.p. 197–198 °C (ethanol).
1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.50–3.55 (m, 2 H, 3,4-
H), 3.75 (s, 6 H, CO2CH3), 3.71–3.86 (m, 4 H, 2,5-H), 6.65 (d, J =
9.0 Hz, 2 H, 2Ј,6Ј-H), 6.74 (s, 1 H, 3ЈЈ-H), 7.40 (ddd, J = 1.0, 7.7,
7.8 Hz, 1 H, 6ЈЈ-H), 7.55 (d, J = 8.1 Hz, 1 H, 8ЈЈ-H), 7.62 (ddd, J
= 1.6, 7.7, 8.1 Hz, 1 H, 7ЈЈ-H), 7.85 (d, J = 9.0 Hz, 2 H, 3Ј,5Ј-H),
8.22 (dd, J = 1.6, 7.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz,
CDCl3, 20 °C): δ = 44.9 (C-3,4), 49.4 (C-2,5), 52.4 (CO2CH3), 104.6
(C-3ЈЈ), 111.8 (C-2Ј,6Ј), 117.8 (C-8ЈЈ), 119.0 (C-4Ј), 124.0 (C-10ЈЈ),
124.8 (C-6ЈЈ), 125.2 (C-5ЈЈ), 127.8 (C-3Ј,5Ј), 133.3 (C-7ЈЈ), 149.2 (C-
1Ј), 156.1 (C-9ЈЈ), 164.2 (C-2ЈЈ), 171.7 (CO2CH3), 178.3 (C-
4ЈЈ) ppm. MS (ESI+): m/z (%) = 408 (100) [M + H]+, 430 (13) [M
+ Na]+, 446 (4) [M + K]+. C23H21NO6: calcd. C 67.80, H 5.20, N
3.44; found C 68.00, H 5.24, N 3.55.
Dimethyl 1-[3-(4-Oxo-4H-chromen-2-yl)phenyl]-1H-pyrrole-3,4-di-
carboxylate (9b): Yellow solid; m.p. 208–209 °C (ethanol). 1H
NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.90 (s, 6 H, CO2CH3),
6.89 (s, 1 H, 3ЈЈ-H), 7.47 (ddd, J = 1.1, 7.7, 7.8 Hz, 1 H, 6ЈЈ-H),
7.58–7.70 (m, 2 H, 6Ј,5Ј-H), 7.65 (d, J = 8.1 Hz, 1 H, 8ЈЈ-H), 7.71
(s, 2 H, 2,5-H), 7.76 (ddd, J = 1.7, 7.7, 8.1 Hz, 1 H, 7ЈЈ-H), 7.92
(dt, J = 1.7, 7.7 Hz, 1 H, 4Ј-H), 8.00 (t, J = 1.7 Hz, 1 H, 2Ј-H),
8.25 (dd, J = 1.7, 7.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz,
CDCl3, 20 °C): δ = 51.8 (CO2CH3), 108.5 (C-3ЈЈ), 118.0 (C-3,4),
118.2 (C-8ЈЈ), 118.8 (C-2Ј), 123.89 (C-6Ј), 123.93 (C-10ЈЈ), 125.4 (C-
4Ј), 125.6 (C-6ЈЈ), 125.8 (C-5ЈЈ), 126.3 (C-2,5), 130.8 (C-5Ј), 134.0
(C-3Ј), 134.2 (C-7ЈЈ), 140.0 (C-1Ј), 156.2 (C-9ЈЈ), 161.5 (C-2ЈЈ),
163.6 (CO2CH3), 178.1 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 404 (23)
[M + H]+, 426 (100) [M + Na]+. HRMS: calcd. for [C23H17NO6]+
403.1056; found 403.1054.
Dimethyl (3R*,4R*)-1-[2-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
ine-3,4-dicarboxylate (8a): Yellow oil. 1H NMR (300.13 MHz,
CDCl3, 20 °C): δ = 3.45–3.52 (m, 6 H, 2,3,4,5-H), 3.64 (s, 6 H,
CO2CH3), 6.60 (s, 1 H, 3ЈЈ-H), 6.94 (d, J = 5.0 Hz, 1 H, 6Ј-H), 6.99
(ddd, J = 0.4, 4.5, 4.5 Hz, 1 H, 4Ј-H), 7.39–7.45 (m, 2 H, 6ЈЈ, 5Ј-
H), 7.48–7.50 (m, 2 H, 8ЈЈ,3Ј-H), 7.70 (ddd, J = 1.0, 4.7, 4.7 Hz, 1
H, 7ЈЈ-H), 8.25 (dd, J = 1.0, 4.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR
(75.47 MHz, CDCl3, 20 °C): δ = 45.3 (C-3,4), 52.4 (C-2,5), 52.6
(CO2CH3), 111.3 (C-3ЈЈ), 116.0 (C-6Ј), 118.2 (C-8ЈЈ), 119.8 (C-4Ј),
121.5 (C-2Ј), 123.8 (C-10ЈЈ), 125.2 (C-6ЈЈ), 125.7 (C-5ЈЈ), 131.5 (C-
3Ј), 131.7 (C-5Ј), 133.7 (C-7ЈЈ), 146.5 (C-1Ј), 156.3 (C-9ЈЈ), 166.1
(C-2ЈЈ), 172.4 (CO2CH3), 178.5 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) =
408 (100) [M + H]+, 430 (74) [M + Na]+. HRMS: calcd. for
[C23H21NO6]+ 407.1369; found 407.1369.
Dimethyl 1-[4-(4-Oxo-4H-chromen-2-yl)phenyl]-1H-pyrrole-3,4-di-
carboxylate (9c): Yellow solid; m.p. 231–232 °C (ethanol). 1H NMR
(300.13 MHz, CDCl3, 20 °C): δ = 3.89 (s, 6 H, CO2CH3), 6.86 (s,
1 H, 3ЈЈ-H), 7.46 (ddd, J = 0.9, 7.5, 7.7 Hz, 1 H, 6ЈЈ-H), 7.58–7.62
(m, 3 H, 2Ј,6Ј-H and 8ЈЈ-H), 7.71 (s, 2 H, 2,5-H), 7.71–7.75 (m, 1
H, 7ЈЈ-H), 8.07 (d, J = 8.8 Hz, 2 H, 3Ј,5Ј-H), 8.25 (dd, J = 1.5,
7.7 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ
= 51.8 (CO2CH3), 108.0 (C-3ЈЈ), 118.1 (C-3,4), 118.2 (C-8ЈЈ), 121.2
(C-2Ј,6Ј), 123.9 (C-10ЈЈ), 125.5 (C-6ЈЈ), 125.8 (C-5ЈЈ), 125.9 (C-2,5),
128.1 (C-3Ј,5Ј), 131.0 (C-4Ј), 134.0 (C-7ЈЈ), 141.0 (C-1Ј), 156.2 (C-
9ЈЈ), 161.7 (C-2ЈЈ), 163.5 (CO2CH3), 178.2 (C-4ЈЈ) ppm. MS (ESI+):
m/z (%) = 404 (12) [M + H]+, 426 (100) [M + Na]+, 442 (8) [M +
K]+. HRMS: calcd. for [C23H17NO6]+ 403.1056; found 403.1054.
Dimethyl (3R*,4R*)-1-[3-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
ine-3,4-dicarboxylate (8b): Yellow solid; m.p. 124–126 °C (ethanol).
1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.63–3.67 (m, 4 H, 3,4-
H and 2,5-H), 3.79 (s, 6 H, CO2CH3), 6.74 (dd, J = 1.6, 7.8 Hz, 1
H, 6Ј-H), 6.82 (s, 1 H, 3ЈЈ-H), 7.06 (t, J = 1.6 Hz, 1 H, 2Ј-H), 7.30
(dd, J = 1.6, 7.8 Hz, 1 H, 4Ј-H), 7.38 (t, J = 7.8 Hz, 1 H, 5Ј-H),
7.43 (ddd, J = 1.1, 7.6, 7.7 Hz, 1 H, 6ЈЈ-H), 7.60 (d, J = 8.0 Hz, 1
H, 8ЈЈ-H), 7.71 (ddd, J = 1.7, 7.7, 8.0 Hz, 1 H, 7ЈЈ-H), 8.24 (dd, J
= 1.7, 7.6 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3,
20 °C): δ = 45.4 (C-3,4), 50.2 (C-2,5), 52.6 (CO2CH3), 107.7 (C-
3ЈЈ), 109.5 (C-2Ј), 115.0 (C-4Ј), 115.3 (C-6Ј), 118.2 (C-8ЈЈ), 124.0
(C-10ЈЈ), 125.2 (C-6ЈЈ), 125.7 (C-5ЈЈ), 130.0 (C-5Ј), 132.7 (C-3Ј),
133.7 (C-7ЈЈ), 147.2 (C-1Ј), 156.3 (C-9ЈЈ), 164.1 (C-2ЈЈ), 172.5
(CO2CH3), 178.6 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 408 (100) [M
+ H]+, 430 (12) [M + Na]+. C23H21NO6: calcd. C 67.80, H 5.20, N
3.44; found C 67.69, H 5.46, N 3.76.
N-Methyl-N-[4-(4-oxo-4H-chromen-2-yl)phenyl]formamide
(10c):
1
Yellow oil. H NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.40 (s, 3
H, N-CH3), 6.83 (s, 1 H, 3ЈЈ-H), 7.34 (d, J = 8.8 Hz, 2 H, 3Ј,5Ј-H),
7.45 (ddd, J = 1.0, 7.6, 7.8 Hz, 1 H, 6ЈЈ-H), 7.59 (br. d, J = 8.1 Hz,
1 H, 8ЈЈ-H), 7.73 (ddd, J = 1.7, 7.6, 8.1 Hz, 1 H, 7ЈЈ-H), 8.00 (d, J
= 8.8 Hz, 2 H, 2Ј,6Ј-H), 8.24 (dd, J = 1.7, 7.8 Hz, 1 H, 5ЈЈ-H), 8.67
(s, 1 H, N-CHO) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ =
31.6 (N-CH3), 107.5 (C-3ЈЈ), 118.0 (C-8ЈЈ), 121.4 (C-2Ј,6Ј), 123.9
(C-10ЈЈ), 125.4 (C-6ЈЈ), 125.8 (C-5ЈЈ), 127.7 (C-3Ј,5Ј), 129.2 (C-4Ј),
133.9 (C-7ЈЈ), 144.8 (C-1Ј), 156.2 (C-9ЈЈ), 161.8 (N-CHO), 162.2
(C-2ЈЈ), 178.3 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 280 (63) [M +
H]+, 430 (15) [M + Na]+. HRMS: calcd. for [C22H19N2O4]+
375.13393; found 375.13366.
Dimethyl (3R*,4R*)-1-[4-(4-Oxo-4H-chromen-2-yl)phenyl]pyrrolid-
ine-3,4-dicarboxylate (8c): Yellow solid; m.p. 217–219 °C (ethanol).
1H NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.64–3.68 (m, 4 H, 3,4-
H and 2,5-H), 3.78 (s, 6 H, CO2CH3), 3.72–3.89 (m, 2 H, 2,5-H),
6.64 (d, J = 8.9 Hz, 2 H, 2Ј,6Ј-H), 6.72 (s, 1 H, 3ЈЈ-H), 7.39 (ddd,
J = 1.1, 7.6, 7.8 Hz, 1 H, 6ЈЈ-H), 7.54 (d, J = 7.9 Hz, 1 H, 8ЈЈ-H),
7.67 (ddd, J = 1.6, 7.6, 7.9 Hz, 1 H, 7ЈЈ-H), 7.84 (d, J = 8.9 Hz, 2
H, 3Ј,5Ј-H), 8.22 (dd, J = 1.6, 7.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR
(75.47 MHz, CDCl3, 20 °C): δ = 45.4 (C-3,4), 48.2 (C-2,5), 52.6 8-[4-(4-Oxo-4H-chromen-2-yl)phenyl]-4-phenyldihydro-1H-[1,2,4]tri-
(CO2CH3), 104.7 (C-3ЈЈ), 112.0 (C-2Ј,6Ј), 117.8 (C-8ЈЈ), 119.2 (C-
4Ј), 124.9 (C-10ЈЈ), 125.2 (C-6ЈЈ), 125.6 (C-5ЈЈ), 127.8 (C-3Ј,5Ј),
azolo[1,2-c][1,3,4,6]oxatriazepine-3,5(4H,7H)-dione (11c): Yellow
oil. H NMR (300.13 MHz, CDCl3, 20 °C): δ = 5.14 (s, 2 H, 8-H),
1
133.3 (C-7ЈЈ), 149.1 (C-1Ј), 156.1 (C-9ЈЈ), 164.1 (C-2ЈЈ), 172.2 5.40 (s, 2 H, 1-H), 5.61 (s, 2 H, 6-H), 6.75 (s, 1 H, 3ЈЈ-H), 7.14 (d,
(CO2CH3), 178.3 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 408 (100) [M
J = 8.2 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 7.31 (d, J = 7.8 Hz, 2 H, 2Ј,6Ј-H),
140
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Flavone-Nitrogen Heterocycle Conjugates
7.30–7.38 (m, 3 H, 3ЈЈЈ,4ЈЈЈ,5ЈЈЈ-H), 7.42 (br. dd, J = 7.5, 7.8 Hz, 1
compounds in poor (15c; 5.7 mg, 14%) and good yields (14c;
H, 6ЈЈ-H), 7.55 (dd, J = 0.9, 8.1 Hz, 1 H, 8ЈЈ-H), 7.70 (ddd, J = 30.0 mg, 73%).
1.6, 7.5, 8.1 Hz, 1 H, 7ЈЈ-H), 7.89 (d, J = 7.8 Hz, 2 H, 3Ј,5Ј-H),
2-{4-[5-(4-Nitrophenyl)oxazolidin-3-yl]phenyl}-4H-chromen-4-one
(14c): Yellow solid; m.p. 229–230 °C (ethanol). 1H NMR
(300.13 MHz, CDCl3, 20 °C): δ = 3.39 (t, J = 8.5 Hz, 1 H, 4trans
8.23 (dd, J = 1.6, 7.8 Hz, 1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz,
CDCl3, 20 °C): δ = 63.3 (C-6), 72.0 (C-1), 83.4 (C-8), 106.6 (C-3ЈЈ),
117.5 (C-2Ј,6Ј), 118.0 (C-8ЈЈ), 123.9 (C-10ЈЈ), 125.2 (C-6ЈЈ), 125.6
(C-2ЈЈЈ,6ЈЈЈ), 125.7 (C-5ЈЈ), 127.9 (C-3Ј,5Ј), 128.5 (C-4ЈЈЈ), 129.2 (C-
3ЈЈЈ,5ЈЈЈ), 130.8 (C-4Ј), 133.7 (C-7ЈЈ), 142.6 (C-1ЈЈЈ), 145.7 (C-1Ј),
148.4 (C-3), 152.0 (C-5), 156.2 (C-9ЈЈ), 168.8 (C-2ЈЈ), 178.3 (C-
4ЈЈ) ppm. MS (ESI+): m/z (%) = 469 (100) [M + H]+, 491 (34) [M
+ Na]+, 507 (6) [M + K]+. HRMS: calcd. for [C25H21N2O4]+
413.14958; found 413.14932.
-
H), 3.99 (dd, J = 6.5, 8.5 Hz, 1 H, 4cis-H), 5.15 (d, J = 2.6 Hz, 1
H, 2-H), 5.30 (d, J = 2.6 Hz, 1 H, 2-H), 5.41 (dd, J = 6.5, 8.5 Hz,
1 H, 5-H), 6.61 (d, J = 9.0 Hz, 2 H, 2Ј,6Ј-H), 6.73 (s, 1 H, 3ЈЈ-H),
7.64 (d, J = 8.7 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 7.41 (ddd, J = 1.1, 7.5, 7.7 Hz,
1 H, 6ЈЈ-H), 7.55 (dd, J = 1.1, 8.4 Hz, 1 H, 8ЈЈ-H), 7.66–7.71 (m, 1
H, 7ЈЈ-H), 7.87 (d, J = 9.0 Hz, 2 H, 3Ј,5Ј-H), 8.22 (dd, J = 1.6,
7.7 Hz, 1 H, 5ЈЈ-H), 8.29 (d, J = 8.7 Hz, 2 H, 3ЈЈЈ,5ЈЈЈ-H) ppm. 13
C
2-{4-[(3S*,4S*)-3-Nitro-4-phenylpyrrolidin-1-yl]phenyl}-4H-
chromen-4-one (12c): Yellow solid; m.p. 226–227 °C (ethanol). 1H
NMR (300.13 MHz, CDCl3, 20 °C): δ = 3.77 (dd, J = 4.8, 10.0 Hz,
NMR (75.47 MHz, CDCl3, 20 °C): δ = 52.8 (C-4), 79.0 (C-5), 81.2
(C-2), 105.1 (C-3ЈЈ), 112.3 (C-2Ј,6Ј), 117.9 (C-8ЈЈ), 120.6 (C-4Ј),
124.0 (C-3ЈЈЈ,5ЈЈЈ and C-10ЈЈ), 125.0 (C-6ЈЈ), 126.8 (C-2ЈЈЈ,6ЈЈЈ),
1 H, 2-H), 4.01–4.16 (m, 3 H, 2,5-H), 4.25 (dt, J = 4.8, 7.1 Hz, 1 128.0 (C-3Ј,5Ј), 125.6 (C-5ЈЈ), 133.4 (C-7ЈЈ), 145.8 (C-1ЈЈЈ), 147.0
H, 3-H), 5.17 (dt, J = 4.3, 7.1 Hz, 1 H, 4-H), 6.73 (d, J = 8.9 Hz,
(C-1Ј), 148.0 (C-4ЈЈЈ), 156.2 (C-9ЈЈ), 163.7 (C-2ЈЈ), 178.3 (C-
2 H, 2Ј,6Ј-H), 6.76 (s, 1 H, 3ЈЈ-H), 7.27 (dd, J = 1.7, 7.9 Hz, 2 H, 4ЈЈ) ppm. MS (ESI+): m/z (%) = 415 (100) [M + H]+, 437 (35) [M
2ЈЈЈ,6ЈЈЈ-H), 7.34–7.44 (m, 4 H, 6ЈЈ,3ЈЈЈ,4ЈЈЈ,5ЈЈЈ-H), 7.56 (d, J = + Na]+, 453 (6) [M + K]+. HRMS: calcd. for [C24H18N2O5 + H]+
7.9 Hz, 1 H, 8ЈЈ-H), 7.68 (ddd, J = 1.7, 7.8, 7.9 Hz, 1 H, 7ЈЈ-H), 415.1288; found 415.1283.
7.90 (d, J = 8.9 Hz, 2 H, 3Ј,5Ј-H), 8.23 (dd, J = 1.7, 8.0 Hz, 1 H,
2-[4–85-(4-Methoxyphenyl)oxazolidin-3-yl]phenyl-4H-chromen-4-
5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 48.5 (C-
one (15c): Yellow solid; m.p. 163–164 °C (ethanol). 1H NMR
3), 50.8 (C-5), 52.4 (C-2), 89.4 (C-4), 105.0 (C-3ЈЈ), 112.3 (C-2Ј,6Ј),
(300.13 MHz, CDCl3, 20 °C): δ = 3.42 (t, J = 8.4 Hz, 1 H, 4trans
-
117.9 (C-8ЈЈ), 120.1 (C-4Ј), 124.0 (C-10ЈЈ), 125.0 (C-6ЈЈ), 125.6 (C-
5ЈЈ), 127.0 (C-2ЈЈЈ,6ЈЈЈ), 128.0 (C-3Ј,5Ј), 128.3 (C-4ЈЈЈ), 129.4 (C-
3ЈЈЈ,5ЈЈЈ), 133.4 (C-7ЈЈ), 137.9 (C-1ЈЈЈ), 148.5 (C-1Ј), 156.2 (C-9ЈЈ),
163.9 (C-2ЈЈ), 178.3 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 413 (100)
[M + H]+, 435 (5) [M + Na]+, 451 (3) [M + K]+. HRMS: calcd.
for [C22H19N2O4]+ 375.13393; found 375.13385.
H), 3.83 (s, 3 H, OCH3), 3.85 (dd, J = 6.3, 8.4 Hz, 1 H, 4cis-H),
5.08 (d, J = 2.7 Hz, 1 H, 2-H), 5.23 (dd, J = 6.3, 8.4 Hz, 1 H, 5-
H), 5.24 (d, J = 2.7 Hz, 1 H, 2-H), 6.59 (d, J = 8.9 Hz, 2 H, 2Ј,6Ј-
H), 6.73 (s, 1 H, 3ЈЈ-H), 6.94 (d, J = 8.8 Hz, 2 H, 3ЈЈЈ,5ЈЈЈ-H), 7.38
(d, J = 8.8 Hz, 2 H, 2ЈЈЈ,6ЈЈЈ-H), 7.36–7.43 (m, 1 H, 6ЈЈ-H), 7.54
(d, J = 8.0 Hz, 1 H, 8ЈЈ-H), 7.67 (ddd, J = 1.6, 7.7, 8.0 Hz, 1 H,
7ЈЈ-H), 7.86 (d, J = 8.9 Hz, 2 H, 3Ј,5Ј-H), 8.22 (dd, J = 1.6, 8.0 Hz,
1 H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 52.7
(C-4), 55.3 (OCH3), 80.0 (C-5), 80.7 (C-2), 104.9 (C-3ЈЈ), 112.0 (C-
2Ј,6Ј), 114.1 (C-3ЈЈЈ,5ЈЈЈ), 117.9 (C-8ЈЈ), 119.8 (C-4Ј), 124.0 (C-10ЈЈ),
124.9 (C-6ЈЈ), 127.8 (C-2ЈЈЈ,6ЈЈЈ), 128.0 (C-3Ј,5Ј), 129.3 (C-1ЈЈЈ),
130.0 (C-5ЈЈ), 133.3 (C-7ЈЈ), 147.4 (C-1Ј), 156.2 (C-9ЈЈ), 159.9 (C-
4ЈЈЈ), 164.0 (C-2ЈЈ), 178.3 (C-4ЈЈ) ppm. MS (ESI+): m/z (%) = 400
General Procedure for the Synthesis of Flavone–Nitrogen Heterocy-
cle Dyads 13c: Paraformaldehyde (15.7 mg, 0.52 mmol) was added
to a solution of N-flavonylglycine 5c (30.8 mg, 0.10 mmol) in 1,2,4-
trichlorobenzene (3 mL). The mixture was heated to reflux under
nitrogen for 60 min. The solution was cooled to room temperature,
and the solvent was removed by silica gel column chromatography
eluting with hexane. Changing the eluting system to a (1:2) mixture
of hexane/ethyl acetate afforded the title compound 13c in good
yield (26.7 mg, 87%).
(100) [M
+ +
H]+, 422 (6) [M Na]+. HRMS: calcd. for
[C25H21NO4]+ 399.1471; found 399.1462.
2-[4-(Oxazolidin-3-yl)phenyl]-4H-chromen-4-one (13c): Yellow solid;
General Procedure for the Synthesis of Flavone–Nitrogen Heterocy-
cle Dyads 6a–c, 7a–c, 8a–c, and 9a–c under Microwave Irradiation:
m.p. 180–182 °C (ethanol). 1H NMR (300.13 MHz, CDCl3, 20 °C):
δ = 3.51 (t, J = 6.4 Hz, 2 H, 4-H), 4.23 (t, J = 6.4 Hz, 2 H, 5-H), A mixture of paraformaldehyde (15.2 mg, 0.51 mmol), the appro-
4.95 (s, 2 H, 2-H), 6.57 (d, J = 9.0 Hz, 2 H, 2Ј,6Ј-H), 6.71 (s, 1 H, priate dipolarophile (5 equiv.), and N-flavonylglycine 5a–c
3ЈЈ-H), 7.40 (ddd, J = 1.0, 7.7, 7.8 Hz, 1 H, 6ЈЈ-H), 7.54 (dd, J = (30.0 mg, 0.10 mmol) in 1,2,4-trichlorobenzene (3 mL), in a two-
1.0, 8.0 Hz, 1 H, 8ЈЈ-H), 7.67 (ddd, J = 1.7, 7.7, 8.1 Hz, 1 H, 7ЈЈ- necked glassware apparatus, provided with a magnetic stirring bar,
H), 7.84 (d, J = 9.0 Hz, 2 H, 3Ј,5Ј-H), 8.22 (dd, J = 1.7, 7.8 Hz, 1
fiber-optic temperature control and reflux condenser, was irradi-
H, 5ЈЈ-H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 45.6 ated [800 W maximum power, 170 °C maximum temperature and
(C-4), 67.4 (C-5), 80.3 (C-2), 104.8 (C-3ЈЈ), 112.0 (C-2Ј,6Ј), 117.8 from 10 to 5 min. (see Tables 1 and 2)]. The solution was cooled to
(C-8ЈЈ), 119.6 (C-4Ј), 124.0 (C-10ЈЈ), 124.9 (C-6ЈЈ), 125.6 (C-5ЈЈ),
room temperature, and the solvent was removed by silica gel col-
128.0 (C-3Ј,5Ј), 133.3 (C-7ЈЈ), 147.4 (C-1Ј), 156.1 (C-9ЈЈ), 164.0 (C- umn chromatography eluting with hexane. Changing the eluting
2ЈЈ), 178.3 (C-4ЈЈ) ppm. MS (ESI+): m/z (%)
=
294 (100)
system to a (9:1) mixture of CH2Cl2/acetone afforded the title com-
pounds in moderate to good yields: 6a (30.4 mg, 80%), 6b
(29.7 mg, 78%), 6c (36.1 mg, 95%), 7a (31.9 mg, 77%), 7b
(34.4 mg, 83%), 7c (32.7 mg, 79%), 8a (35.6 mg, 86%), 8b
(33.9 mg, 82%), 8c (32.3 mg, 78%), 9a (19.3 mg, 47%), 9b
(17.6 mg, 43%), 9c (27.0 mg, 66%).
[M + H]+, 316 (15) [M + Na]+, 332 (6) [M + K]+. HRMS: calcd.
for [C18H15NO3]+ 293.1052; found 293.1053.
General Procedure for the Synthesis of Flavone–Nitrogen Heterocy-
cle Dyads 14c–15c: Paraformaldehyde (15.8 mg, 0.53 mmol) and
the appropriate benzaldehyde [para-nitrobenzaldehyde (16.0 mg,
0.11 mmol) or para-methoxybenzaldehyde (30.6 mg, 0.22 mmol)] General Procedure for the Synthesis of Flavone–Chlorin Dyads 19a–
were added to a solution of N-flavonylglycine 5c (31.1 mg,
0.11 mmol) in 1,2,4-trichlorobenzene (3 mL). The mixture was
heated to reflux under nitrogen for 60 min. The solution was cooled
to room temperature, and the solvent was removed by silica gel
column chromatography eluting with hexane. Changing the eluting
system to a (1:2) mixture of hexane/ethyl acetate afforded the title
c: Paraformaldehyde (6.5 mg, 0.22 mmol) and N-flavonylglycine
5a–c (10.2 mg, 0.035 mmol) were added to a solution of meso-tet-
rakis(pentafluorophenyl)porphyrin (18; 20.8 mg, 0.021 mmol) in
toluene (4 mL). The mixture was heated to reflux under nitrogen
for 16 h. During this period, the reaction was monitored by TLC
and, if necessary, two more portions of paraformaldehyde and N-
Eur. J. Org. Chem. 2012, 132–143
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141

A. M. S. Silva et al.
FULL PAPER
flavonylglycine 5a–c were added. Water (20 mL) was then added
and the resulting mixture was extracted with chloroform. The or-
ganic layer was collected and dried with anhydrous sodium sulfate,
and the solution was concentrated to dryness. The residue was puri-
fied by silica gel column chromatography with gradient elution
(light petroleum/CH2Cl2, 1:1 to 1:2) to afford the title compounds
19a (5.7 mg, 22%), 19b (13.8 mg, 53%), or 19c (14.8 mg, 57%).
3a,21a), 54.6 (C-1,3), 96.6, 105.1 (C-3ЈЈ), 106.6, 113.5 (C-2Ј,6Ј),
117.8 (C-8ЈЈ), 120.7, 123.9 (C-12,13), 124.0 (C-6ЈЈ), 124.9 (C-5ЈЈ),
125.6 (C-3Ј,5Ј), 127.7 (C-7,18 or C-8,17), 128.2 (C-7,18 or C-8,17),
132.6 (C-7ЈЈ), 133.3, 135.4, 140.3, 149.3, 153.0, 156.1, 163.6, 168.2,
178. 3 (C-4ЈЈ) ppm. 19F NMR (282.38 MHz, CDCl3, 20 °C): δ =
–184.93 to –184.75 (m, 4 F, Ar-F-meta), –183.31 (dt, J = 8.4,
21.8 Hz, 2 F, Ar-F-meta), –182.87 (dt, J = 8.4, 21.8 Hz, 2 F, Ar-F-
meta), –174.95 (t, J = 20.9 Hz, 2 F, Ar-F-para), –173.78 (t, J =
21.8 Hz, 2 F, Ar-F-para), –160.53 to –160.26 (m, 6 F, Ar-F-ortho),
–158.43 (dd, J = 5.8, 21.8 Hz, 2 F, Ar-F-ortho) ppm. MS (FAB+):
m/z (%) = 1237 (100) [M]+, 975 (17) [M + H]+-C2H4N-flavonyl.
HRMS: calcd. for [C61H23F20N5O2 + H]+ 1238.1605; found
1238.1588.
2-[2-(4-Oxo-4H-chromen-2-yl)phenyl]-5,10,15,20-tetrakis(penta-
fluorophenyl)-3,3a,21,21a-tetrahydropyrrolo[3,4-b]porphyrin (19a):
Green solid. UV/Vis λmax (CH2Cl2) [log(ε/103 mol–1 cm–1)] = 404
(5.33), 503 (4.03), 598 (3.24), 651 (4.68) nm. 1H NMR
(300.13 MHz, CDCl3, 20 °C): δ = –1.79 (s, 2 H, NH), 3.66–3.71
(m, 2 H, 1-H or 3-H), 3.89–3.94 (m, 2 H, 1-H or 3-H), 5.51–5.53
(m, 2 H, 3a,21a-H), 6.50 (d, J = 8.6 Hz, 1 H, 6Ј-H), 6.63 (s, 1 H,
3ЈЈ-H), 7.07–7.33 (m, 3 H, 3Ј,4Ј,5Ј-H), 7.43 (t, J = 7.9 Hz, 1 H, 6ЈЈ-
H), 7.56 (d, J = 7.9 Hz, 1 H, 8ЈЈ-H), 7.75 (t, J = 7.9 Hz, 1 H, 7ЈЈ-
H), 8.20 (d, J = 7.9 Hz, 1 H, 5ЈЈ-H), 8.45 (d, J = 4.9 Hz, 2 H, 7,18-
H or 8,17-H), 8.49 (s, 2 H, 12,13-H), 8.75 (d, J = 4.9 Hz, 2 H, 7,18-
H or 8,17-H) ppm. 19F NMR (282.38 MHz, CDCl3, 20 °C): δ =
–184.87 (dt, J = 8.2, 21.5 Hz, 2 F, Ar-F-meta), –183.67 (dt, J = 8.6,
22.9 Hz, 2 F, Ar-F-meta), –182.86 (dt, J = 6.7, 22.9 Hz, 2 F, Ar-F-
meta), –175.01 (t, J = 21.5 Hz, 2 F, Ar-F-para), –173.92 (t, J =
22.9 Hz, 2 F, Ar-F-para), –160.47 (dd, J = 8.6, 22.9 Hz, 2 F, Ar-F-
ortho), –160.36 to –160.28 (m, 4 F, Ar-F-ortho), –158.49 (dd, J =
6.7, 22.9 Hz, 2 F, Ar-F-ortho) ppm. MS (FAB+): m/z (%) = 1238
(100) [M + H]+, 975 (15) [M + H]+-C2H4N-flavone. HRMS: calcd.
for [C61H23F20N5O2 + H]+ 1238.1605; found 1238.1585.
Acknowledgments
Thanks are due to the University of Aveiro, to Fundação para a
Ciência e a Tecnologia (FCT) and Fundo Europeu de Desenvolvi-
mento Regional (FEDER) for funding the Organic Chemistry Re-
search Unit (project PEst-C/QUI/UI0062/2011). The authors also
thank the Portuguese National NMR Network (RNRMN), which
was supported with funds from the FCT.
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H, 6ЈЈ-H), 7.56 (d, J = 8.3 Hz, 1 H, 8ЈЈ-H), 7.75 (ddd, J = 1.6, 7.5,
8.3 Hz, 1 H, 7ЈЈ-H), 8.20 (dd, J = 1.6, 7.5 Hz, 1 H, 5ЈЈ-H), 8.45 (d,
J = 4.9 Hz, 2 H, 7,18-H or 8,17-H), 8.49 (s, 2 H, 12,13-H), 8.75 (d,
J = 4.9 Hz, 2 H, 7,18-H or 8,17-H), ppm. 13C NMR (75.47 MHz,
CDCl3, 20 °C): δ = 51.6 (C-3a,21a), 55.2 (C-1,3), 96.7, 106.5, 107.6
(C-3ЈЈ), 111.4, 116.5, 116.9, 117.8 (C-8ЈЈ), 123.9 (C-12,13), 125.2
(C-6ЈЈ), 125.3 (C-5ЈЈ), 128.2 (C-7,18 or C-8,17), 129.0, 129.8, 132.5
(C-7,18 or C-8,17), 132.6 (C-7ЈЈ), 133.8, 135.3, 140.4, 147.6, 152.9,
156.2, 163.3 (C-1Ј), 168.6 (C-3Ј), 178. 4 (C-4ЈЈ) ppm. 19F NMR
(282.38 MHz, CDCl3, 20 °C): δ = –184.87 (dt, J = 8.2, 21.5 Hz,
2 F, Ar-F-meta), –183.67 (dt, J = 8.6, 22.9 Hz, 2 F, Ar-F-meta),
–182.86 (dt, J = 6.7, 22.9 Hz, 2 F, Ar-F-meta), –175.01 (t, J =
21.5 Hz, 2 F, Ar-F-para), –173.92 (t, J = 22.9 Hz, 2 F, Ar-F-para),
–160.47 (dd, J = 8.6, 22.9 Hz, 2 F, Ar-F-ortho), –160.36 to –160.28
(m, 4 F, Ar-F-ortho), –158.49 (dd, J = 6.7, 22.9 Hz, 2 F, Ar-F-
ortho) ppm. MS (FAB+): m/z (%) = 1238 (100) [M + H]+, 975 (17)
[M + H]+-C2H4N-flavone. HRMS: calcd. for [C61H23F20N5O2
H]+ 1238.1605; found 1238.1582.
+
2-[4-(4-Oxo-4H-chromen-2-yl)phenyl]-5,10,15,20-tetrakis(penta-
fluorophenyl)-3,3a,21,21a-tetrahydropyrrolo[3,4-b]porphyrin (19c):
Green solid. UV/Vis λmax (CH2Cl2) [log(ε/103 mol–1 cm–1)] = 405
(5.33), 503 (4.05), 598 (3.25), 651 (4.69) nm. 1H NMR
(300.13 MHz, CDCl3, 20 °C): δ = –1.80 (s, 2 H, NH), 3.66–3.70
(m, 2 H, 1-H or 3-H), 3.93–4.00 (m, 2 H, 1-H or 3-H), 5.53–5.56
(m, 2 H, 3a,21a-H), 8.43 (d, J = 4.9 Hz, 2 H, 7,18-H or 8,17-H),
8.49 (s, 2 H, 12,13-H), 8.74 (d, J = 4.9 Hz, 2 H, 7,18-H or 8,17-
H) ppm. 13C NMR (75.47 MHz, CDCl3, 20 °C): δ = 51.5 (C-
142
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