Synthesis and mechanism of formation of oxadeazaflavines by microwave thermal cyclization of ortho-halobenzylidene barbiturates

Article abstract of DOI:10.1590/S0103-50532011001100012

The thermal cyclization reaction of o-halobenzylidene barbiturates was developed as an efficient and simple method for the preparation of oxadeazaflavines. The use of solid state reaction conditions with microwave irradiation afforded the products in 5 mi

Full text of DOI:10.1590/S0103-50532011001100012

J. Braz. Chem. Soc., Vol. 22, No. 11, 2101-2107, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
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Article
A
Synthesis and Mechanism of Formation of Oxadeazaflavines by Microwave Thermal
Cyclization of ortho-Halobenzylidene Barbiturates
,
a
J. Daniel Figueroa-Villar* and Sandra C. G. de Oliveira
Grupo de Química Medicinal, Departamento de Química, Instituto Militar de Engenharia,
Praça General Tibúrcio 80, Praia Vermelha, 22290-270 Rio de Janeiro-RJ, Brazil
A reação de ciclização térmica de o-halobenzilideno barbituratos foi desenvolvida como um
simples e eficiente método para a preparação de oxadeazaflavinas. A utilização de condições de
reação em estado sólido com irradiação de microondas forneceu os produtos em 5 min e com
rendimentos entre 47 e 98%. Os resultados experimentais das sínteses e a análise termogravimétrica
das reações concordam com os resultados da simulação do mecanismo por modelagem molecular,
indicando que a reação ocorre através de uma ciclização hetero-Diels-Alder intra-molecular,
seguida por um processo rápido de re-aromatização.
The thermal cyclization reaction of o-halobenzylidene barbiturates was developed as an
efficient and simple method for the preparation of oxadeazaflavines. The use of solid state reaction
conditions with microwave irradiation afforded the products in 5 min with 47 to 98% yield.
Experimental synthetic results and thermogravimetric reaction analyses agree with the molecular
modeling mechanism simulation, indicating that this reaction occurs through an intramolecular
hetero-Diels-Alder cyclization followed by fast re-aromatization.
Keywords: oxadeazaflavines, o-halobenzylidene barbiturates, microwave irradiation,
intramolecular hetero-Diels-Alder
Introduction
reported two new simple and complementary methods
for the preparation of oxadeazaflavines from barbituric
16,17
Oxadeazaflavines (2H-chromeno[2,3-d]pyrimidine-
acid.
The first method uses the condensation reaction
2
,4-(3H)-diones or 10-oxa-5-deazaflavines) are interesting
of salicylaldehyde and analogues with barbituric acid at
room temperature to yield an orange oxonium salt that
affords oxadeazaflavines under dehydrating conditions,
as shown in Scheme 1. Unfortunately, this method only
functions well with salicylaldehydes without effective
electron-withdrawing groups at the aromatic ring.
compounds with great potential as intermediates for the
synthesis of new heterocyclic systems and as selective
organic oxidants under mild conditions. Also, derivatives
and analogues of oxadeazaflavines display important
1-8
16
3
9
-12
bioactivity, being potential drugs.
For many years,
several chemists tried without success to prepare the
simplest oxadeazaflavine by the direct reaction of barbituric
The second method, which is based on the thermal
cyclization of o-halobenzylidene barbiturates, can be
applied with success to starting materials containing
electron-withdrawing and electron-donating groups at the
13-15
acid with salicylaldehyde, thus making necessary the use
of more complex synthetic procedures to obtain the desired
1
-3
17
products. In the beginning of the 1990 decade there were
aromatic ring. The draw of this last method is the need
1
6
Scheme 1. Synthesis of oxadeazaflavines from salicylaldehyde and barbituric acid.
*e-mail: figueroa@ime.eb.br

2
102
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
for relatively long reaction times at high temperatures, for
example 1.5 hours at 260 °C, affording oxadeazaflavines
in medium to low yields (50% or lower). On the other
hand, because benzylidene barbiturates are easy to prepare
In order to decrease the reaction time with microwave
irradiation we proceeded to test the reaction in the presence
of sodium chloride as a solid heat dispersion agent. The
reaction was tested using a 2:1 mixture of the starting
material (1) with NaCl. Under those conditions it was found
that the use of NaCl as heat dispersing media lead to 98%
yield of 2 in only 5 min of reaction time.
1
7-20
by reaction of benzaldehydes with barbituric acid
and have been used as starting materials for different
2
1-28
reactions,
the optimization of the second reaction
method is important.
With these results in hand we decided to study the
effect of the halogen atom on the reaction. Therefore,
the thermal cyclization reaction was carried out using
the benzylidenes from of 2-fluorobenzaldehyde (3),
2-chlorobenzaldehyde (4) and 2-bromobenzaldehyde (5).
For these compounds, the cyclization reaction was first
carried out in a thermal balance (TGA) without NaCl, to
determine the reaction temperature and the lost of mass.
In order to determine the reaction times and yields, the
same three reactions were carried out using microwave
irradiation without NaCl. Interestingly, when the reaction
with microwaves was carried out with the starting
materials 3, 4 and 5, the yield without the presence of
NaCl was 88, 81 and 47%, respectively. However, when
the reaction was executed with NaCl the yields were very
similar (97-99%). The data for the thermo gravimetric
and the microwave assisted reactions without NaCl is
summarized in Table 1.
The data from Table 1 indicates that, as expected, the
mass loss for each reaction agrees with the emission of an
HX molecule (X = F, Cl and Br). The comparison of the
results with the different halogenated starting materials
suggests that a higher electronegativity and smaller atomic
size favors the reaction. For example, it can be observed
that the cyclization reaction occurs at lower temperature
for the fluorinated benzylidene barbiturate 3 (198 °C),
and at higher temperatures for the brominated analogue 5
(227 °C), indicating that the greater electronegativity and
smaller size of fluorine favors the reaction. When comparing
the reaction results of the bromo and chlorobenzylidene
barbiturates is interesting to notice that it occurs at about the
One important procedure to improve reactions and
decrease their environmental impact is the exclusion
of solvents in combination with the use of microwave
2
9-35
irradiation.
The use of microwaves has an important
36-40
effect to improve yields and reduce reaction times.
In this work, we have used solvent-free microwave
irradiation for the very efficient solid state synthesis of
oxadeazaflavines from o-halobenzylidene barbiturates. The
simulation results of the reaction mechanism by molecular
modeling, which combine with the synthesis results and
the thermogravimetric analysis, indicate that this reaction
occurs through an intermolecular hetero-Diels-Alder
reaction.
Results and Discussion
In order to determine if the conversion of o-haloaryl
barbiturylidenes to oxadeazaflavines could be carried out
with success using microwaves as the activation energy
source, we conducted the cyclization reaction of the
benzylidene from 6-bromopiperonal under conventional
and microwave heating conditions, as shown in Scheme 2.
As a first result it was found that the reaction time
with microwave irradiation without solvent was 60 min,
affording compound 2 in 95% yield. On the other hand,
the conventional heating procedure required the use of
Dowtherm-A as solvent and a reaction time of 60 min
at 260 °C, affording only 50% yield. If the reaction with
conventional heating was maintained for longer times there
was decomposition of product 2.
Scheme 2. Thermal cyclization of the 6-bromopiperonylidene barbiturate (1) to produce 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]pyrimidine-2,4(3H)-
dione (2) .

Vol. 22, No. 11, 2011
Figueroa-Villar and Oliveira
2103
Table 1. Yields, reaction times and reaction temperatures for the thermal cyclization of the ortho-halobenzylidene barbiturates 3, 4 and 5
c
Reaction
time / min
Reaction
Temperature / ( C)
Calculated
mass loss / (%)
Experimental
mass loss / (%)
Yield /
(%)
Compound
c
b
o
b
3
4
5
30
30
40
198
228
227
8.55
14.57
27.43
8.70
15.65
31.50
88
81
47
b
c
Data obtained from the reactions by thermogravimetric monitoring. Data obtained from the microwave-assisted reactions.
same temperature for both compounds (228 and 227 °C).
However, the reaction occurs faster for the chlorinated
compound 4 (30 min) affording 81% yield, while the
reaction for the brominated compound 5 is slower (40 min)
and gives a lower yield (47%).
of the whole process. Therefore, the activation energy for
this initial step should be the activation energy for the
whole reaction. Also, in this first step, the presence of the
bulkier and less electronegative bromine atom would be
unfavorable, due to the steric effect, while the presence of
the small and more electronegative fluorine atom would
be favorable.
In order to correlate the experimental data with the
proposed reaction mechanism we carried out a molecular
modeling study to determine the activation energy of each
proposed step. For this, we calculated the energy of the
starting materials (3, 4 and 5), the transition states (TS1
and TS2), the intermediate (INT1) and the products (6 and
HX). Because of the solid state nature of the reaction, all the
calculations were conducted in vacuum.All the calculations
were carried out using the B3LYP method with the 6-31G*
basis set with the Spartan06 program, and the results are
shown in Table 2.
–
In solution, Br is considered a better leaving group
–
–
than Cl or F , but this could not be the case for the reaction
without solvent.Also, the synthesis results suggest that the
best leaving group nature of bromide is not an important
factor for the reaction, being evident that a greater atom
size may cause steric hindrance for the first step of the
cyclization reaction.
Based on these results we proposed the reaction
mechanism shown in Scheme 3, which is a very logical
possibility. The first mechanism step would be an
intramolecular hetero-Diels-Alder cyclization, leading to
the first transition state (TS1), with loss of aromaticity on
the benzylidene ring, leading to the reaction intermediate
(
INT1). The second reaction step would be the conversion
The results from Table 2 show that the activation energies
for the 2-bromo derivative (5) and the 2-chloro derivative (4)
of INT1 to the oxadeazaflavine (6) by the loss of the HX
molecule through the second transition state (TS2). The
activation energy for the first step (Ea1) corresponds
to the energy difference between the reagent and TS1.
For the second reaction step the activation energy (Ea2)
corresponds to the energy difference between INT1 and
TS2. It is worth mentioning that the product energy
corresponds to the addition of the energies of HX and
compound 6. Because the loss of aromaticity the first step
of the proposed mechanism, which is the initial electro-
cyclic C-O bond formation, is the rate determining step
-1
are very similar, 42.41 and 39.21 kcal mol , respectively,
-
1
being about 10 kcal mol higher than the activation
energy for the fluorine derivative (3). These results are in
agreement with the experimental data, which shows that the
reaction temperature for compound 3 is 30 °C lower than
for compounds 4 and 5, which reactions occur at about the
same temperature, 228 °C and 227 °C, respectively. Also,
the slower reaction time and lower yield for the brominated
substrate may be partially explained by its activation energy
-1
being 3.2 kcal mol higher than that for the chlorinated
Scheme 3. Proposed mechanism for the thermal cyclization reaction of o-halobenzylidene barbiturates.

2
104
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
Table 2. Calculated (B3LYP 6-31G*) energies for the reagents (3, 4 and 5), transition states (TS1 and TS2) and intermediate (INT1) of the proposed
reaction mechanism
-1
Energy / (kcal mol )
INT1
Halogen
Reagent
-99.96
-61.38
-49.05
TS1
AE1
29.81
39.21
42.41
TS2
Product
-91.11
-43.45
-29.34
AE2
10.84
0.01
F
-69.85
-22.17
-6.64
-80.68
-69.84
-22.16
-21.69
Cl
-22.17
Br
-21.69
0.00
d
Sum of the energy of 6 and HX.
benzylidene barbiturate. Since the activation energy
difference for the reagents 4 and 5 is so small, other effects
should be involved to describe their reaction difference.
Interestingly, the second activation energy (Ea2), which is
much lower for all the reactions, is zero for 4and 5, indicating
that in these two cases does not exist a second transition
state. The graphic of correlation between the relative energy
and the reaction coordinate for reaction mechanism the
fluorinated reagent (3) is shown in Scheme 4, making clear
that in the case of this reagent exists an intermediate (INT1)
and two transition states (TS1 and TS2), different from the
brominated and chlorinated reagents 4 and 5.
of barbituric acid and the desired o-halobenzaldehyde, in
yields normally greater than 90%, thus leading to overall
yields above 85%. Since this methodology can be applied to
any type of o-halobenzaldehyde, we believe that this is the
most convenient reported route to prepare oxadeazaflavines.
The experimental data obtained from the
thermogravimetric monitoration of the thermal reactions
agree with the reaction activating energies calculated
by molecular modeling, suggesting that this reaction
occurs first through a rate-determining intramolecular
heteronuclear Diels-Alder-type cyclization, followed by
re-aromatization by elimination of HX (X = F, Cl, Br) to
yield the oxadeazaflavine.
The efficiency of this reaction in terms of high yields, short
reaction times and its green chemistry nature is of significant
importance, especially on the application of oxadeazaflavines
as starting materials for preparation of new heterocyclic
compounds with different applications. Our actual focus on
oxadeazaflavines is their potential applications in medicinal
chemistry and as starting materials in organic synthesis. For
example, oxadeazaflavines could be used as strong Michael
acceptors, as was conducted for the addition of barbituric
acid to produce 5-(2,4,6-trioxo-hexahydropyrimidin-5-yl)-
21
1
H-chromeno[2,3-d]pyrimidine-2,4(3H,5H)-dione, which
is used as anion for the preparation of Zn(II) complexes as
41
water clusters. Also, some oxadeazaflavines are sirtuin
inhibitors, an important activity against aging, apoptosis
Scheme 4. Graphic of relative energy vs reaction coordinate for the
mechanism of formation of oxadeazaflavine from the fluorinated
reagent (3).
42
and transgenic nematodes, as well as effect against cancer
43
cells. These compounds could also be used to prepare
analogues of 2-deoxo-phenyl-5-deazaflavines, which are a
Conclusions
44
new class of antitumor agents. Because oxadeazaflavines
45
Our results indicate that oxadeazaflavines can be most
conveniently obtained by the solid state thermal cyclization
of orto-halobenzylidene barbiturates using microwave
irradiation without any solvent and with the presence of NaCl.
This methodology leads to much better yields (usually above
are easily reduced by oxidation of some alcohols, another
actual interests in this type of compounds is their use as
specific selective oxidants.
Experimental
95%) and shorter reaction times, than for the conventionally
heating reaction. It was observed that the reaction times can
be significantly decreased and the yields increased when
NaCl is used as a heat dispersion agent mixed with the starting
material, the orto-halobenzylidene barbiturates. The starting
materials are easily obtained by Knovenagel condensation
General
All reagents were purchased from Sigma-Aldrich
Chemical Company and were used without any previous
purification. All the solvents were purchased from Merck

Vol. 22, No. 11, 2011
Figueroa-Villar and Oliveira
2105
and were distilled before being used. The thin layer
chromatographic analyses were carried out using Merck pre-
coated silica gel plates on aluminum. Melting points were
measured in a Fisher-Jones apparatus and are uncorrected.
Compound 1 was obtained as yellow-orange solid in 96%
o
-1
yield; mp 260 C (dec.); IR (KBr pellet) n /cm : 3426,
max
3198, 3084, 1754, 1700, 1684, 1581, 1488, 1430, 1383,
1
1327, 1265, 1130, 1036, 934, 837, 505, and 420. H NMR
(
98% DMSO-d , 300 MHz) d (ppm) 11.36 (s, 1H), 11.18
6
Spectroscopy measurements
(s, 1H), 8.24 (s, 1H), 7.56 (s, 1H), 7.34 (s, 1H) and 6.15 (s,
13
2
H). C NMR (98% DMSO-d , 75 MHz) d (ppm) 162.9,
6
The NMR spectra were determined in a Varian
UNITY-300 spectrometer operating at 300 MHz for
hydrogen and 75 MHz for carbon. All the samples were
161.1, 152.0, 150.9, 150.0, 146.2, 126.2, 119.3, 118.7,
112.1, 111.9 and 102.7.
run in 5 mm NMR tubes using DMSO-d as solvent and
Synthesis of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]
pyrimidine-2,4(3H)-dione (2) by conventional heating
1.0 g (2.9 mmol) of o-bromopiperonylidene barbiturate
(1) was dissolved in 50 mL of Dowtherm-A and heated
at 260 °C for 1 h. After filtration of the reaction mixture
the solid product was washed with petroleum ether and
recrystallized from acetic acid yielding 2 as a brown solid,
6
TMS as internal standard. The IR spectra were recorded
in a Perkin-Elmer 1710 FTIR spectrometer using samples
at 1% in KBr pellets.
Thermogravimetric analysis
o
-1
The thermogravimetric monitoring of the thermal
reaction was conducted using 5.0 mg of each starting
material (compounds 3, 4 and 5) in a thermogravimetric
analyzer Shimadzu TGA-50.
0.38 g (50% yield); mp > 390 C; IR (KBr pellet) n /cm :
max
3171, 3051, 2832, 1700, 1678, 1632, 1608, 1561, 1487,
1456, 1403, 1285, 1251, 1128, 1070, 852, 767, 540, 508
1
and 441. H NMR (98% DMSO-d , 300 MHz) d (ppm)
6
1
1.30 (s, 1H), 8.81 (s, 1H), 7.54 (s, 1H), 7.49 (s, 1H) and
13
Molecular modeling
6.31 (s, 2H). C NMR (98% DMSO-d , 75 MHz) d (ppm)
6
1
64.5, 162.7, 159.8, 154.2, 150.3, 149.5, 140.9, 112.4,
The molecular modeling calculations were carried
out in a computer with an Intel dual 2.66 GHz processor
with 2048 Mb RAM using the Spartan06 package. The
calculations were performed using the functional density
112.2, 110.4, 102.3 and 96.7. LREIMS e/z (int.) 258.00
(100), 215.05 (65), 187.05 (55), 149.03 (57), 135.12 (4),
123.11 (6), 109.10 (9), 97.10 (15), 83.08 (20), 69.06 (37)
and 57.04 (47).
(DFT) B3LYP method with the 6-31G* basis set.A similar
procedure was used with the transition state module of
the Spartan06 package, which was used for the transition
state geometry optimization and energy calculations.
For the proposed transition state calculations it was also
included the calculation of the infrared spectrum, in order to
guarantee, with the presence of a single imaginary vibration
mode, the transition state nature of the entity.
Synthesis of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]
pyrimidine-2,4(3H)-dione (2) by microwave heating
without NaCl
0.10 g (0.29 mmol) of 1 was set in a glass vial connected
with a bubbling flask containing a saturated solution of
NaHCO in a commercial microwave oven. The flask
3
was heated with microwaves (1100 W) for 5 min in a
Discover 1 (CEM) reactor. The reaction was repeated
using microwave heating times of 10, 20, 30, 40, 50, 60,
70 and 80 min. The solid reaction mixtures were washed
with a 10:1 ethanol:DMSO mixture (1 mL) and then with
pure ethanol (2×1 mL) to yield pure 2 as a mustard solid.
The best result (95% yield) was obtained in 60 min of
microwave irradiation.
General procedure for the preparation of the benzylidene
barbiturates 1, 2 and 3
A solution of 0.128 g (10 mmol) of barbituric acid in
20 mL of 95% ethanol was mixed with 1.1 mmol of the
desired aldehyde dissolved in 10 mL of the same solvent.
The mixture was kept under reflux for 1 h. After cooling
to room temperature, the reaction mixture was filtered
by suction and the solid product recrystallized from 95%
ethanol.
Synthesis of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]
pyrimidine-2,4(3H)-dione (2) by microwave heating with
NaCl
The same procedure as before was carried out but using
a mixture of 0.10 g (0.29 mmol) of 1 grounded with 0.2 g
of NaCl and heating for 5 min. In this case, pure 2 was
obtained after dissolving the reaction mixture in hot ethyl
Synthesis of o-bromopiperonylidene barbiturate (1)
Compound 1 was prepared according to the described
generalprocedureusing2.29g(10mmol)ofbromopiperonal.

2
106
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
acetate, filtering out the sodium chloride and cooling the
filtrate to yield crystals of pure 2 in 98% yield.
of 10 min. A sample of the reaction mixture was analyzed
by thin layer chromatography after every 10 min of
reaction until observing the complete disappearance of
the starting material. The solid reaction residue was then
washed with a 10:1 ethanol:DMSO mixture. Product 6 was
obtained as an amorphous light brown solid with a melting
Synthesis of o-fluorobenzylidene barbiturate (3)
Compound 3 was prepared according to the described
general procedure, using 0.136 g (1.1 mmol) of
o-fluorobenzaldehyde. Compound 3 was obtained as yellow
o
point of 325-328 C in 47 to 88% yield. IR (KBr pellet)
-1
-1
crystalsin82%yield;mp270-272ºC;IR(KBrpellet)nmax/cm :
n
/cm : 3439, 2833, 1682, 1636, 1608, 1458 and 1321.
max
1
1
3
438, 2835, 1728, 1683, 1603, 1438 and 1320. H NMR
H NMR (DMSO-d , 300 MHz) d (ppm) 7.92-7.86 (m,
6
(
98% DMSO-d , 300 MHz) d (ppm) 7.24 (dd, 1H, J 1.5
2H), 8.27-8.19 (m, 2H), 9.69 (s, 1H) and 11.50 (s, 1H).
C NMR (DMSO-d , 75 MHz) d (ppm) 163.7, 158.0,
6
6
1
3
and 7.3 Hz), 7.30 (dd, 1H, J 1.8 and 7.5 Hz), 7.54 (d, 1H,
J 8.1 Hz), 7.94(d, 1H, J 5.7 Hz), 8.28 (s, 1H), 11.30 (s,
1
157.21, 153.6, 147.0, 142.7, 132.7, 130.1, 120.3, 117.4 and
108.7. Elemental analysis: calc. for C H O N : C 61.68, H
13
H) and 11.48 (s, 1H). C NMR (DMSO-d , 300 MHz)
6
11
6
3
2
d (ppm) 115.4, 121.4, 121.6, 123.9, 132.3, 133.7, 145.8,
50.3, 160.7, 161.1 and 162.8.
2.80, N 13.08; found: C 61.03, H 2.69, N 13.06.
1
Procedure for the preparation of the 2H-chromeno[2,3-d]
pyrimidine-2,4(3H)-diones (oxadeazaflavine) with
microwave heating using sodium chloride
Synthesis of o-chlorobenzylidene barbiturate (4)
Compound 4 was prepared according to the described
general procedure, using 0.155 g (1.1 mmol) of
o-chlorobenzaldehyde, and was obtained as yellow crystals
It was used the same procedure described for the
preparation of the oxadeazaflavine, but mixing the starting
material (0.3 mmol) with 0.2 g of NaCl. In this case the
reaction mixture was monitored by thin layer chromatography
every 1.0 min of microwave heating (1100 W) until all the
starting material disappeared. The best reaction time for the
three starting materials was 5 min. The reaction mixture was
dissolved in 50 mL of hot ethylacetate, filtered to eliminate
the NaCl and the filtrate was concentrated to dryness under
vacuum to afford pure 6 as an amorphous light brown solid.
The yields for all cases varied from 97 to 99%.
-
1
in 81% yield; mp 214-216 ºC; IR (KBr pellet) n /cm :
max
1
3
441, 2836, 1754, 1693, 1597, 1433, 1322. H NMR
(
(
DMSO-d , 300 MHz) d (ppm) 7.36 (t, 1H, J 6.0 Hz), 7.45
6
dd, 1H, J 6.0 Hz), 7.53 (d, 1H, J 6.0 Hz), 7.75 (d, 1H, J 6.0
1
3
Hz), 8.30 (s, 1H), 11.29 (s, 1H) and 11.52 (s, 1H). C NMR
DMSO-d , 300 MHz) d (ppm) 121.8, 126.4, 129.0, 132.0,
(
6
1
32.1, 132.3, 133.3, 150.0, 150.3, 161.0 and 162.73 ppm.
Synthesis of o-bromobenzylidene barbiturate (5)
Compound 5 was prepared according to the described
general procedure, using 0.203 g (1.1 mmol) of
o-bromobenzaldehyde, and was obtained as yellow crystals
Supplementary Information
-1
in 86% yield; mp 220-223 ºC; IR (KBr pellet) nmax/cm :
-
1
3
440, 2845, 1730, 1691, 1601, 1431 and 1321 cm .
Supplementary information (Figures S1-S21) is
available free of charge at http://jbcs.sbq.org.br as a PDF
file.
1
H NMR (DMSO-d , 300 MHz) d (ppm) 7.36 (dd,1H, J 8.0
6
and 9.0 Hz), 7.39 (dd,1H, J 8.0 and 9.0 Hz), 7.68 (d, 1H,
J 8.0 Hz), 7.71 (d, 1H, J 9.0 Hz), 8.22 (s, 1H), 11.28 (s,
13
1
H), 11.50 ppm (s, 1H). C NMR (DMSO-d , 300 MHz)
Acknowledgments
6
d (ppm) 121.4, 123.4, 126.9, 132.0, 132.1, 134.2, 150.3,
52.0, 161.0 and 162.7 ppm.
1
The authors are grateful to Coordenação de Pesquisa
e Estudos Superiores (CAPES-Pródefesa), Conselho
Nacional de Desenvolvimento Científico e Tecnológico
(CNPq), and Fundação Carlos Chagas Filho de Amparo
à Pesquisa do Estado de Rio de Janeiro (FAPERJ) and
Instituto Nacional de Biologia Estrutural e Bioimagem
(IMBEB) for their financial support.
Procedure for the preparation of the 2H-chromeno[2,3-d]
pyrimidine-2,4(3H)-diones (oxadeazaflavine) with
microwave heating
The o-haloaryl barbiturylydenes 1, 2 and 3 (0.3 mmol)
were placed in a flat bottom flask connected to a glass tube
submerged in a saturated sodium bicarbonate solution to
capture the acid produced by the reaction. The flask was
set inside a commercial microwave reactor Discover 1
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(
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J. Braz. Chem. Soc., Vol. 22, No. 11, S1-S11, 2011.
Printed in Brazil - ©2011 Sociedade Brasileira de Química
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103 - 5053 $6.00+0.00
Supplementary Information
SI
Synthesis and Mechanism of Formation of Oxadeazaflavines by Microwave Thermal
Cyclization of ortho-Halobenzylidene Barbiturates
,
a
J. Daniel Figueroa-Villar* and Sandra C. G. de Oliveira
Grupo de Química Medicinal, Departamento de Química, Instituto Militar de Engenharia,
Praça General Tibúrcio 80, Praia Vermelha, 22290-270 Rio de Janeiro-RJ, Brazil
1
Figure S1. H NMR spectrum (DMSO-d , 300 MHz) of 6-bromopiperonylidene barbiturate (1).
6
*e-mail: figueroa@ime.eb.br

S2
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
13
Figure S2. C NMR spectrum (DMSO-d , 75 MHz) of 6-bromopiperonylidene barbiturate (1).
6
13
Figure S3. Expanded C NMR spectrum of 6-bromopiperonylidene barbiturate (1).

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1
Figure S4. H NMR spectrum (DMSO-d , 300 MHz) of ortho-fluorobenzylidene barbiturate (3).
6
13
Figure S5. C NMR spectrum (DMSO-d , 300 MHz) of ortho-fluorobenzylidene barbiturate (3).
6

S4
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
13
Figure S6. Expanded C NMR spectrum of ortho-fluorobenzylidene barbiturate (3).
1
Figure S7. H NMR spectrum (DMSO-d , 300 MHz) of ortho-chlorobenzylidene barbiturate (4).
6

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Figure S8. C NMR spectrum (DMSO-d , 300 MHz) of ortho-chlorobenzylidene barbiturate (4).
6
13
Figure S9. Expanded C NMR spectrum of ortho-chlorobenzylidene barbiturate (4).

S6
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
1
Figure S10. H NMR spectrum (DMSO-d , 300 MHz) of ortho-fluorobenzylidene barbiturate (5).
6
13
Figure S11. C NMR spectrum (DMSO-d , 300 MHz) of ortho-fluorobenzylidene barbiturate (5).
6

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Figure S12. Expanded C NMR spectrum of ortho-fluorobenzylidene barbiturate (5).
Figure S13. Thermogravimetric analysis (TGA) graphic of ortho-fluorobenzylidene barbiturate (3).

S8
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
Figure S14. Thermogravimetric analysis (TGA) graphic of ortho-chlorobenzylidene barbiturate (4).
Figure S15. Thermogravimetric analysis (TGA) graphic of ortho-bromobenzylidene barbiturate (5).

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Figure S16. C NMR spectrum (DMSO-d , 75 MHz) of 2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione (oxadeazaflavine).
6
1
Figure S17. H NMR spectrum (DMSO-d , 300 MHz) of 2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione (oxadeazaflavine).
6

S10
Synthesis and Mechanism of Formation of Oxadeazaflavines
J. Braz. Chem. Soc.
Figure S18. IR spectrum of 2H-chromeno[2,3-d]pyrimidine-2,4(3H)-dione (oxadeazaflavine).
1
Figure S19. H NMR spectrum (DMSO-d , 300 MHz) of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]pyrimidine-2,4(3H)-dione (2).
6

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Figure S20. H NMR spectrum (DMSO-d , 300 MHz) of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]pyrimidine-2,4(3H)-dione (2).
6
Figure S21. IR spectrum of 2H-[1,3]dioxolo[4’,5’:6,7]chromeno[2,3-d]pyrimidine-2,4(3H)-dione (2).