Reaction of substituted furan-2-carboxaldehydes and furo[b]pyrrole type aldehydes with hippuric acid

Article abstract of DOI:10.3390/90100011

4-Heteroarylidene-2-phenyl-1,3-oxazol-5(4H)-ones were prepared by reactions of hippuric acid with substituted furan-2-carboxaldehydes or furo[b]pyrrole type aldehydes. The reactivity of various furan-2-carboxaldehyde derivatives in this reaction is discussed. The effect of microwave irradiation on some condensation reactions was compared with "classical" conditions. The results show that microwave irradiation shortens the reaction times while affording comparable yields. Elementary analysis, UV, IR and 1D NMR proved the structure of new synthesised compounds. 2D NMR spectroscopic measurements confirmed that the configuration at the carbon-carbon double bond corresponds to the pure E isomers of the products.

Full text of DOI:10.3390/90100011

Molecules 2004, 9, 11-21
molecules
ISSN 1420-3049
http://www.mdpi.org
Reaction of Substituted Furan-2-carboxaldehydes and
Furo[b]pyrrole Type Aldehydes with Hippuric Acid
Zita Puterová 1, Heinz Sterk 2 and Alžbeta Krutošíková 1,*
1
Department of Chemistry, Faculty of Natural Sciences, University of St. Cyril and Methodius in
Trnava, SK-917 01 Trnava, Slovak Republic, Tel. +421 3 5565 372, Fax +421 3 5565 185.
2
Institute of Chemistry, Karl-Franzens University of Graz, A-8010 Graz, Austria.
* Author to whom correspondence should be addressed; e-mail: krutosik@ucm.sk
Received: 20 October 2003; in revised form: 14 January 2004 /Accepted: 15 January 2004 / Published:
31 January 2004
Abstract: 4-Heteroarylidene-2-phenyl-1,3-oxazol-5(4H)-ones were prepared by reactions
of hippuric acid with substituted furan-2-carboxaldehydes or furo[b]pyrrole type
aldehydes. The reactivity of various furan-2-carboxaldehyde derivatives in this reaction is
discussed. The effect of microwave irradiation on some condensation reactions was
compared with “classical” conditions. The results show that microwave irradiation
shortens the reaction times while affording comparable yields. Elementary analysis, UV,
IR and 1D NMR proved the structure of new synthesised compounds. 2D NMR
spectroscopic measurements confirmed that the configuration at the carbon-carbon double
bond corresponds to the pure E isomers of the products.
Keywords: 5-Arylfuran-2-carboxaldehydes; furo[3,2-b]pyrrole-2-carboxaldehydes; furo-
[2,3-b]pyrrole-2-carboxaldehydes; hippuric acid; microwave irradiation; 1,3-oxazol-
1
5(4H)-ones; furo[3,2-b]pyrrole-5-carboxylates; furo[2,3-b]pyrrole-5-carboxylates; H- and
13C-NMR, COSY, NOESY, HSQC, HMBC.

Molecules 2004, 9
12
Introduction
During the past few decades many results have been published in the area of the synthesis and the
study of physical and chemical properties of heterocyclic compounds containing a furan ring connected
to or fused with a benzene ring or with different heterocyclic systems. Substituted furans are ubiquitous
structural units in natural products and pharmaceuticals [1] and have been widely used as synthetic
intermediates [2,3].
Substituted furan-2-carboxaldehydes 1a-e and furo[b]pyrrole type aldehydes 2a-e, 3a,b are
heteroaromatic compounds which posses a C2 carbonyl group that may act as a reactive centre for
various condensation reactions. Many of the published condensation products are biologically active
compounds [4,5] or can be used as intermediates in organic synthesis [6,7].
Reaction of aldehydes 1a-3b with hippuric acid led to the products 4a-6b containing a 1,3-oxazol-
5(4H)-one ring. The use of 1,3-oxazol-5(4H)-ones as starting materials for synthesis is well known.
They are used as convenient reagents for the synthesis of α,β unsaturated α-amino acids [8], cyclic
analogues of natural amino acids [9] or as intermediates for the synthesis of new heterocyclic
compounds [10]. The most common method for their preparation is the Erlenmeyer-Plöchl reaction, a
cyclodehydration-condensation of the appropriate aldehyde and hippuric acid in dry acetic anhydride
catalysed by acetate anion (using sodium or calcium acetate as a support/catalyst) [11-14]. The
formation of the carbon-carbon double bond usually leads to the creation of 1,3-oxazol-5(4H)-ones as a
mixture of Z and E isomers; for example, furan-2-carboxaldehyde and thiophene-2-carboxaldehyde
[11,12] and also substituted benzaldehydes [13] give oxazolones as such mixtures of two isomers.
The aim of this study was to synthesise some new condensation products of 1a-e, 2a-e and 3a,b by
their reactions with hippuric acid (Schemes 2-4). We aimed to incorporate these heterocyclic
biologically active moieties into new heterocyclic systems. We also wished to compare the “classical”
method with the effect of microwave irradiation and to find conditions to increase the yield or the rate
of condensations. Microwave irradiation is an unconventional method of chemical reaction activation
indicated to be suitable for use in reactions of thermolabile compounds because it shortens the exposure
of the reaction mixtures to high temperatures [15-18].
We also present the synthesis of 5-(2-bromophenyl)furan-2-carboxaldehyde (1a) by Meerwein´s
method (Scheme 1). The starting material 5-(2-bromophenyl)furan-2-carboxaldehyde (1a) was prepared
under the conditions of Meerwein´s reaction from 2-bromoaniline and furan-2-carboxaldehyde, as we
used before in the case of various 5-aryl-2-carboxaldehydes [19]. Compound 1a was obtained in 23%
yield and its IR spectrum showed the characteristic band for the carbonyl group appearing at 1691 cm-1.
The signal for the aldehyde hydrogen was observed at 9.69 ppm in the 1H-NMR spectra.

Molecules 2004, 9
13
Scheme 1
Br
Br
4
3
1. NaNO , HCl
5
2
2
NH2
CHO
2. furan-2-carboxaldehyde,
O
CuCl
2
1a
The condensation products of aldehydes 1a-3b with hippuric acid catalysed by potassium acetate
[18] were prepared in dry acetic anhydride as shown in Schemes 2-4. The condensations of 1a-e were
also performed under microwave conditions, reducing the reaction times while affording yields
comparable to those achieved in the reactions carried out under “classical” conditions (Table 1).
Microwave irradiated procedures were performed using irradiation at a power output of 350W.
Reaction times were only 1-2 minutes and work up was very easy. The reaction conditions were the
same in both procedures except for the amounts of acetic anhydride and potassium acetate used (see
Experimental). In the microwave assisted procedure the reaction mixture was fully dissolved after
irradiation and the reaction started immediately upon dissolution. The reaction mixture was irradiated
in 30 seconds intervals (TLC controlled) to prevent overheating which causes unselective reactions and
for certain aldehydes more degradation products were also observed when the reaction times were
longer than is listed in Table 1.
Scheme 2
R1
R1
4´´
3´
PhCONHCH2CO2H
Ac2O, AcOK
4´
3´´
2
N
1´´
4
2´´
R
R
2´ CH
CHO
5´
O
O
6
O
5
O
1a-e
4a-e
R
R1
H
a 2-BrC6H4
b 3-NO2C6H4
c 3-CF3C6H4
d CH3
H
H
CH3
e CH=CH-CH=CH
5-Arylfuran-2-carboxaldehydes 1a-c reacted with hippuric acid giving (4E)-2-phenyl-4-{[5-(R-
phenyl)-2-furyl]methylene}-1,3-oxazol-5(4H)-ones (3a-c) (Scheme 2) in high yields (70-83%) after
short reaction times.

Molecules 2004, 9
Table 1. Comparisons between “classical” and microwave procedures
14
Classical conditions
Reaction time
MW reaction
Compound
Reaction time
Yield, %
Yield, %
(min.)
(min.)
4a
4b
4c
4d
4e
15
30
15
60
83
70
80
62
67
1
1.5
1.5
2
72
74
73
67
70
20
2
The yield of the other two condensation products, (4E)-2-phenyl-4-[(4,5-dimethylfuran-2-
yl]methylene-1,3-oxazol-5(4H)-one (3d) and (4E)-2-phenyl-4-[(1-benzofuran-2-yl]methylene-1,3-
oxazol-5(4H)-one (3e) (Scheme 2) was about 10-20% lower. The same situation was observed in the
case of furo[3,2-b]pyrrole type aldehydes 2a-d and furo[2,3-b]pyrrole type aldehydes 3a,b (Schemes 3
and 4). The products, methyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[3,2-b]-
pyrrole-5-carboxylates (5a-d) and methyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)-methyl]-
furo[2,3-b]pyrrole-5-carboxylates (6a,b) were obtained in yields of 53-81%. During the reaction of
both systems we found that 5-arylated furan-2-carboxaldehydes (1a-c) are more reactive than 4,5-
dimethylfuran-2-carboxaldehyde (1d), benzofuran-2-carboxaldehyde (1e) and furo[b]pyrrole type
aldehydes (2a-3b). Furo[b]type aldehydes are heterocyclic analogues of the pentalene dianion and their
electron-rich system [20] makes the carbonyl group attached at C2 of the fused system less reactive
than the carbonyl group in the 5-arylated furan-2-carboxaldehydes used in this reaction.
The reaction time of the condensation depends on both the solubility of the starting aldehydes and
their properties. Substituted furan-2-carboxaldehydes 1a-e are more soluble in acetic anhydride than
furo[b]pyrrole type aldehydes 2a-3b. Electron-withdrawing groups on the benzene ring of 1a-c activate
the C2 carbonyl group and the reactions are fast (reaction time max. 30 minutes). The carbonyl group at
C2 of the aldehydes 1e, 2a-3b is less active in these reactions than in the case of 1a-c and the reaction
time is at least 60 minutes.
Scheme 3
R
N
R
4´
3´
N4
R1O2C
5
3
R1O2C
N
PhCONHCH2CO2H
Ac2O, AcOK
2
2´
CHO
CH
6
O
7
O
O
O
2a-d
5a-d
5 R
R1
a H
CH3
C2H5
C2H5
C2H5
b H
c CH3
d Bn

Molecules 2004, 9
15
Scheme 4
4´
3´
4
3
N
2
2´
PhCONHCH2CO2H
Ac2O, AcOK
5
CHO
H3CO2C
CH
H3CO2C
7
O
O
N
R
O
6N
R
O
3a,b
6a,b
R for a = CH3 b = MOM
All condensation products are stable solids, which are rather sparingly soluble in common solvents,
and with high melting points. They display characteristic colours, a feature that is also observed in their
corresponding UV-VIS spectra. The absorption maximum appears in the VIS area at around 400-470
nm. The characteristic bands found in the IR spectra correspond to the carbon-carbon double bond
(1650-1640 cm-1) and C=O lactone (1790-1770 cm-1).
1
The H-NMR spectra of the synthesised compounds 4a-6b display the signals of the double bond
13
H-5 in the 7.07-7.89 ppm range. The chemical shift of the C-5 double bond carbon in the C-NMR
spectra of 4a-e typically ranges from 116-118 ppm. The 1H and 13C chemical shifts for compounds 4a-e
were assigned using gs (gradient selected)-H,H COSY (Correlated spectroscopy); 1D-gs-NOESY
(Nuclear Overhauser spectroscopy); gs-HSQC (Heteronuclear Quantum Coherence spectroscopy) and
HMBC (Heteronuclear Multiple Bond Correlation spectroscopy). H,H-COSY provided us proton-
proton connectivity and 1D-NOESY showed through-space interactions of the olefínic proton H-6 and
the furan H-3´ β-proton. Determination of the actual position of the H-6 protons compared to the
carbonyl group of the heterocyclic ring system was established by using the size of the scalar coupling
between H-6 and the carbonyl carbon. It turns out that the coupling constant is 4.6 Hz. According to the
literature [23] this size is indicative of a situation where the proton and the carbonyl are in a Z
arrangement, which means that this compound exists as a pure E isomer. The other compounds 4a-e
13
behave similarly. The C chemical shifts assignment was straightforward using HSQC and HMBC
spectra. 1H-NMR spectra were measured for products 5a-6b. These products are structural analogues of
4e and their proton spectra are similar to that of 4e. Based on this observation we can declare that
products 5a-6b also exist as a pure E isomers. The signal of the NH proton of 5a,b and also the signals
of the protons in methyl or ethyl group in the ester moieties were the same before [24-27] and after
condensation, which proved that amino and ester group did not undergo any reaction with the hippuric
acid. The complete chemical shifts for all synthesised compounds are listed in Experimental part.
Conclusions
The synthesis of 2-phenyl-4-(furan-2-yl)methylene-1,3-oxazol-5(4H)-ones, methyl-2-[(E)-(5-oxo-2-
phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[3,2-b]pyrrol-5-carboxylates and their [2,3-b]isomers
showed the different reactivity of the starting aldehydes. The reactions of substituted furan-2-

Molecules 2004, 9
16
carboxaldehydes, which were performed under “classical” conditions as well as using microwave
irradiation, showed that the yields were almost the same, but the reactions in the microwave oven were
noticeably faster. All synthesised compounds were characterised by spectroscopic measurements and
were proven to be the pure E isomers.
Acknowledgements
A. K. thanks the VEGA Grant Agency of Slovak Ministry of Education for financial support of
project No. 1/0069/03.
Experimental
General
The following starting compounds were prepared according to literature procedures: 1d [21], 1e
[22], 2a-d, and 3a,b [24-27]. Melting points were determined using a Kofler hotplate apparatus and are
uncorrected. All solvents were pre-distilled and dried appropriately prior to use. The terms
“concentration and evaporation” refer to the removal of volatile materials under reduced pressure on a
Buchi Rotovapor. Substances stated to be identical were so with respect to mps, mixed mps and IR
spectra. Microwave assisted reactions were carried out in a Whirlpool domestic type microwave oven at
350 W. The apparatus was adapted for laboratory applications – n-heptane was used as coolant for the
condenser. Elemental analyses were determined using a Carlo Erba CHNS-OEA 1108-Elemental
Analyser. Infrared spectra were recorded on the following spectrophotometers: Magna IR-760 (Nicolet)
(compounds 1a, 4a-c) and FTIR Galaxy 7020 (for 4d,e) using KBr pellets (1 mg/300 mg KBr) with
only major absorbencies being quoted. UV spectra were measured on a WPA UV/VIS Diode-Array
spectrophotometer (Cambridge, UK) in methanol. Results are reported as λmax (log ε) (λmax in nm, ε in
m2mol-1). 1H (500 MHz)- and 13C (125 MHz)-NMR spectra of compounds 4a-e were measured at 320K
on a BRUKER AVANCE spectrometer equipped with a 5mm broadband probe with z-gradients and a
SGI computer. Two dimensional gs (gradient selected)-H,H-COSY; 1D-gs-NOESY; gs-HSQC, gs-
HMBC techniques were measured using standard software programs provided by Bruker. The 1H-NMR
(400 MHz) spectra of compound 1a, 5a-6b were measured on a BRUKER B-ACS-60 instrument. The
measurements were done using DMSO-d6 as solvent with TMS as an internal standard reference.
Coupling constants (J) are quoted to the nearest 0.1 Hz. Chemical shifts (δ-scale) are quoted in parts
per million and following abbreviations are used: s = singlet; d = doublet; t = triplet; q = quartet; m =
multiplet; br = broad.

Molecules 2004, 9
17
5-(2-Bromophenyl)furan-2-carboxaldehyde (1a)
2-Bromoaniline (21.5g, 0.136 mol) was dissolved in a mixture of concentrated HCl (33.7 mL) and
H2O (22.5 mL). The solution was cooled to 0°C and diazotized at 0-5°C with sodium nitrite (9.5 g,
0.138 mol) dissolved in H2O (25 mL). The solution was stirred for another 10 min, filtered and then
furan-2-carboxaldehyde (15.4 g, 0.16 mol) in H2O (50 mL) was added along with a solution of
CuCl2·2H2O (5 g, 0.04 mol) in H2O (25 mL) at a temperature of 10-15 °C. The reaction mixture was
slowly warmed up to 40°C and stirred at this temperature for 4h. The precipitate was filtered with
suction, washed with water and an aqueous solution of sodium hydrogen carbonate (5%) and the steam
distilled. After removing the volatiles the residue was separated by suction filtration, dried and
crystallised. Yield: 9.2 g (23%), m.p. 80-82°C (n-heptane). For C11H7BrO2 (249.96) calculated: 52.62%
C, 2.81% H, 31.82% Br; found: 52.50% C, 2.84% H, 31.73% Br; IR νmax/cm-1 1691 (C=O), 1377
1
(C-O); UV: 312, (3.49); H-NMR δH: 9.69 (s, 1H, CH=O), 7.69 (d, 1H, J 3,4 3.74 Hz, H-3), 7.37 (d,
1H, J 3,4 3.74 Hz, H-4), 7.47-7.92 (m, 4H, ArH). 13C-NMR δC: 177.4 (CHO), 159.67 (C-5), 149.82 (C-
2), 128.6 (C-4), 122.2 (C-3), 134.86, 130.68, 129.88, 119.48, 114.61.
(4E)-2-Phenyl-4-{[5-(2-bromophenyl)-2-furyl]methylene}-1,3-oxazol-5(4H)-one (4a)
A mixture of 5-(2-bromophenyl)furan-2-carboxaldehyde (1a, 0.4 g, 2 mmol), hippuric acid (0.4 g,
2.4 mmol) and potassium acetate (0.3 g, 3 mmol) in acetic anhydride (10 mL) was refluxed with
stirring for 15 min. (reaction progress was monitored by TLC using 3:1 isohexane-ethyl acetate as
eluent). The mixture was then cooled down and neutralised by addition of solid potassium carbonate.
The solid product was separated by filtration, dried and purified by crystallisation. Yield: 83%; m.p.
168-171°C (ethanol); For C20H12BrNO3 (394.2) calculated: 60.93% C, 3.07% H, 20.27% Br, 3.55% N;
found: 60.79% C, 3.12% H, 20.16% Br, 3.60% N; IR νmax/cm-1 1791 (C=O), 1650 (C=C), 1327 (C-O
furan), 1245 (C-O lactone), 1024 (C-H furan); UV: 419, (3.70); 1H-NMR δH: 8.19-7.70 (m, 5H, H-2´´,
H-3´´, H-4´´, H-5´´, H-6´´), 8.05-7.68 (m, 4H, ArH), 7.76 (d, 1H, J 3´,4´ 3.7 Hz, H-4´), 7.55 (d, 1H, J
3´,4´ 3.7 Hz, H-3´), 7.31 (s, 1H, H-6); 13C-NMR δC: 166.68 (C-5), 162.54 (C-2), 154.67 (C-5´), 149.82
(C-2´), 133.64 (C-4´´), 130.21 (C-4), 129.4 (C-3´´), 128.6 (C-4´), 127.98 (C-2´´), 125.22 (C-1´´), 122.2
(C-3´), 116.88 (C-6), 134.86, 130.68, 129.88, 119.48, 114.61.
According to this same procedure the following compounds were prepared:
(4E)-4-{[5-(3-Nitrophenyl)-2-furyl]methylene}-2-phenyl-1,3-oxazol-5(4H)-one (4b). Reaction time: 30
min. Yield: 70%; m.p. 223-227°C (ethanol); For C20H12N2O5 (360.3) calculated: 66.67% C, 3.36% H,
7.77% N; found: 66,64% C, 3.29% H, 7,72% N; IR νmax/cm-1 1783 (C=O), 1654 (C=C), 1347 (C-O
furan), 1243 (C-O lactone), 1028 (C-H furan); UV: 444, (3.77); 1H-NMR δH: 8.32-7.82 (m, 4H, ArH),
8.25-7.70 (m, 5H, H-2´´, H-3´´, H-4´´, H-5´´, H-6´´), 7.69 (d, 1H, J 3´,4´ 3.7 Hz, H-4´), 7.60 (d, 1H, J
3´,4´ 3.7 Hz, H-3´), 7.34 (s, 1H, H-6); 13C-NMR δC: 166.34 (C-5), 162.43 (C-2), 154.62 (C-5´), 150.45

Molecules 2004, 9
18
(C-2´), 133.53 (C-4´´), 130.42 (C-4), 129.25 (C-3´´), 127.89 (C-2´´), 125.14 (C-1´´), 123.12 (C-4´),
116.51 (C-6), 149.59, 130.82, 130.42, 125.12, 118.57.
(4E)-2-Phenyl-4-({5-[3-(trifluromethyl)phenyl]-2-furyl}methylene)-1,3-oxazol-5(4H)-one (4c). The
reaction time: 15 min. Yield: 80%; m.p. 172-174°C (ethanol); For C21H12F3NO3 (383.3) calculated:
65.80% C, 3.16% H, 3.65% N; found: 65.69% C, 3.22% H, 3.72% N; IR νmax/cm-1 1785 (C=O), 1651
1
(C=C), 1331 (C-O furan), 1242 (C-O lactone), 1030 (C-H furan); UV: 419, (3.70). H-NMR δH: 8.32-
8.19 (m, 4H, ArH), 7.82-7.66 (m, 5H, H-2´´, H-3´´, H-4´´, H-5´´, H-6´´), 7.71(d, 1H, J 3´,4´ 3.6 Hz, H-
13
4´), 7.58 (d, 1H, J 3´,4´ 3.6 Hz, H-3´), 7.34 (s, 1H, H-6); C-NMR δC: 166.47 (C-5), 162.34 (C-2),
155.31 (C-5´), 150.32 (C-2´), 133.57 (C-4), 130.5 (C-4´´), 129.96 (C-3´´), 129.29 (C-2´´), 125.19 (C-
1´´), 128.18 (C-4´), 123.01 (C-3´), 120.7 (q, CF3), 116.62 (C-6), 130.41, 130.26, 129.83, 125.81,
112.02, 111.69.
(4E)-4-[4,5-Dimethyl-2-furyl)methylene]-2-phenyl-1,3-oxazol-5(4H)-one (4d). The reaction time: 60
min. Yield: 62%; m.p. 149-151°C (ethanol); For C16H13NO3 (267.3) calculated: 71.90% C, 4.90% H,
5.24% N; found: 74.60% C, 3.88% H, 4.74% N; IR νmax/cm-1: 1789 (C=O (E)), 1767 (C=O (Z)), 1641
(C=C), 1329 (C-O furan), 1254 (C-O lactone), 1020 (C-H furan); UV 336, (3.32); 1H-NMR δH: 8.07 (d,
2H, J2´´,3´´ 7.35 Hz, H-2´´, H-6´´), 7.74 (t, 1H, J3´´,4´´ 7.29 Hz, H-4´´), 7.60 (t, 2H, H-3´´, H-5´´), 7.50
13
(s, 1H, H-3´), 7.07 (s, 1H, H-6), 2.3 (s, 3H, CH3), 2.02 (s, 3H, CH3); C-NMR δC: 167 (C-5), 161.4
(C-2), 155 (C-5´), 147.8 (C-2´), 133.4 (C-4´´), 129.5 (C-3´´, C-5´´), 128.2 (C-4), 127.9 (C-2´´, C-6´´),
125.5 (C-1´´), 124.8 (C-3´), 120.2 (C-4´), 117.8 (C-6), 12.3 (CH3), 9.7 (CH3).
(4E)-4-(1-Benzofuran-2-ylmethylene)-2-phenyl-1,3-oxazol-5(4H)-one (4e). The reaction time: 20 min.
Yield: 67%; m.p. 183-186°C (ethanol); For C18H11NO3 (289.3) calculated: 74.73% C, 3.83% H, 4.84%
N; found: 74.60% C, 3.88% H, 4.72% N; IR νmax/cm-1: 1793 (C=O), 1644 (C=C), 1329 (C-O furan),
1255 (C-O lactone), 1000 (C-H furan); UV: 331, (3.76); 1H-NMR δH: 8.17 (d, 2H, J2´´,3´´ 7.78 Hz, H-
2´, H-6´´), 8.03 (s, 1H, H-3´), 7.74 (t, 1H, J3´´,4´´ 7.4 Hz, H-4´´), 7.65 (t, 2H, H-3´´, H-5´´), 7.32 (s,
1H, H-6), 7.81-7.34 (m, 4H, ArH); 13C-NMR δC: 166.5 (C-5), 163.8 (C-2), 155.8 (C-5´), 151.7 (C-2´),
134.3 (C-4´´), 133.7 (C-4), 129.7 (C-3´´, C-5´´), 128.7 (C-4´), 128.5 (C-2´´, C-6´´), 125.3 (C-1´´), 117.5
(C-6), 116 (C-3´); 127.8, 124.3, 123.0, 111.9.
Methyl 2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]-4H-furo[3,2-b]pyrrole-5-carboxylate
(5a). The reaction time: 60 min. Yield: 53%; m.p. 305-311°C (ethanol); For C18H12N2O5 (336.3)
calculated: 64.29% C, 3.60% H, 8.33% N; found: 64.39% C, 3.52% H, 8.22% N; UV: 463, (3.41);
1H-NMR. δH: 12.1 (br s, 1H, NH), 8.11 (d, 2H, J2´,3´ 8.0 Hz, H-2´, H-6´), 7.71 (t, 1H, J3´,4´ 8.0 Hz,
J4´,5´ 8.0 Hz, H-4´), 7.64 (d, 2H, J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.59 (s, 1H, H-7), 7.23 (s,
1H, H-3), 6.87 (s, 1H, H-6), 3.84 (s, 3H, CO2CH3).

Molecules 2004, 9
19
Ethyl 2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]-4H-furo[3,2-b]pyrrole-5-carboxylate
(5b). The reaction time: 60 min. Yield: 74%; m.p. 295-300°C (ethanol); For C19H14N2O5 (350.3)
calculated: 65.14% C, 4.03% H, 8.00% N; found: 64.94% C, 4.13% H, 7.95% N; UV: 463, (3.44);
1H-NMR δH: 12.05 (br s, 1H, NH), 8.11 (d, 2H, J2´,3´ 8.0 Hz, H-2´, H-6´), 7.72 (t, 1H, J3´,4´ 8.0 Hz,
J4´,5´8.0 Hz, H-4´), 7.64 (t, 2H, J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.60 (s, 1H, H-7), 7.23 (s,
1H, H-3), 6.84 (s, 1H, H-6), 4.32 (q, 2H, CO2CH2CH3 ), 1.32 (t, 3H, CO2CH2CH3 ).
Ethyl 4-Methyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[3,2-b]pyrrole-5-carboxy-
late (5c). The reaction time: 30 min. Yield: 90%; m.p. 174-177°C (ethanol); For C20H16N2O5 (364.4)
calculated: 63.93% C, 4.43% H, 7.69% N; found: 63.88% C, 4.52% H, 7.84% N; UV: 463, (3.38); 1H-
NMR δH: 8.17 (d, 2H, J2´,3´ 8.0 Hz, H-2´, H-6´), 7.89 (s, 1H, H-7), 7.70 (t, 1H, J3´,4´ 8.0 Hz, J4´,5´
8.0 Hz, H-4´), 7.63 (t, 2H, J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.22 (s, 1H, H-3), 6.87 (s, 1H, H-
6), 4.28 (q, 2H, CO2CH2CH3 ), 4.00 (s, 3H, NCH3), 1,32 (t, 3H, CO2CH2CH3 ).
Ethyl 4-Benzyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[3,2-b]pyrrole-5-carboxy-
late (5d). The reaction time: 30 min. Yield: 81%; m.p. 175-179°C (ethanol); For C26H20N2O5 (440.4)
calculated: 70.90% C, 4.58% H, 76.36% N; found: 71.03% C, 4.52% H, 76.28% N; UV: 468, (3.89);
1H-NMR δH: 8.12 (d, 2H, J2´,3´ 8.0 Hz, H-2´, H-6´), 7.72 (t, 1H, J3´,4´ 8.0 Hz, J4´,5´ 8.0 Hz, H-4´),
7.65 (t, 2H, J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.58 (s, 1H, H-7), 7,21-7,39 (m, 5H, ArH), 7.19
(s, 1H, H-3), 6.97 (s, 1H, H-6), 5.75 (s, 2H, NCH2), 4.24 (q, 2H, CO2CH2CH3 ), 1.26 (t, 3H,
CO2CH2CH3)
Methyl 6-Methyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[2,3-b]pyrrole-5-car-
boxylate (6a). The reaction time: 120 min. Yield: 66%; m.p. 255-260°C (ethanol); For C19H14N2O5
(350.3) calculated: 65.14% C, 4.03% H, 8.00% N; found: 65.04% C, 4.26% H, 8.05% N; UV: 453,
1
(3.78); H-NMR δH: 8.13 (d, 2H, J2´,3´ 8.0 Hz, H-2´, H-6´), 7.80 (s, 1H, H-7), 7.70 (t, 1H, J3´,4´ 8.0
Hz, J4´,5´ 8.0 Hz, H-4´), 7.63 (t, 2H, , J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.27 (s, 1H, H-3), 7.01
(s, 1H, H-4), 3.97 (s, 3H, NCH3), 3.81 (s, 3H, CO2CH3).
Methyl 6-Methoxymethyl-2-[(E)-(5-oxo-2-phenyl-1,3-oxazol-5(4H)-ylidene)methyl]furo[2,3-b]-pyrrole-
5-carboxylate (6b). The reaction time: 60 min. Yield: 70%; m.p. 165-168°C (ethanol); For C20H16N2O6
(380.3) calculated: 63.16% C, 4.24% H, 7.37% N; found: 63.01% C, 4.17% H, 7.28% N; UV: 444
1
(3.50); H-NMR δH: 8.12 (d, 2H, J2´,3´ 8,0 Hz, H-2´, H-6´), 7.80 (s, 1H, H-7), 7.71 (t, 1H, J3´,4´ 8.0
Hz, J4´,5´ 8.0 Hz, H-4´), 7.63 (t, 2H, J2´,3´ 8.0 Hz, J5´,6´ 8.0 Hz, H-3´, H-5´), 7.26 (s, 1H, H-3), 7.11
(s, 1H, H-4), 5.79 (s, 2H, NCH2), 3.81 (s, 3H, CO2CH3 ), 3.27 (s, 3H, OCH3).
Compounds 4a-e were also prepared using microwave irradiation according to the following procedure:

Molecules 2004, 9
20
A mixture of substituted furan-2-carboxaldehyde 1a-e (1 mmol), hippuric acid (1.2 mmol) and
potassium acetate (a catalytic amount) in acetic anhydride (0.03 mmol, 3mL) was irradiated in a
microwave tube for 1-2 min. at 350W (reaction progress monitored by TLC with 3:1 isohexane-ethyl
acetate as eluent). After cooling down, the solid product was separated by filtration, dried and purified
by crystallisation. The results of “classical” and microwave conditions are shown in Table 1.
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