Synthesis of thio- and furan-fused heterocycles: Furopyranone, furopyrrolone, and thienopyrrolone derivatives

Article abstract of DOI:10.1016/j.tet.2014.05.071

We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-

Full text of DOI:10.1016/j.tet.2014.05.071

Tetrahedron 70 (2014) 5993e5998
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Synthesis of thio- and furan-fused heterocycles: furopyranone,
furopyrrolone, and thienopyrrolone derivatives
a
a
a
b
a,
€
*
Merve Ergun , Cagatay Dengiz , Merve Sinem Ozer , Ertan S¸ ahin , Metin Balci
a Department of Chemistry, Middle East Technical University, 06800 Ankara, Turkey
Department of Chemistry, Ataturk University, 25240 Erzurum, Turkey
b
€
a r t i c l e i n f o
a b s t r a c t
Article history:
We report herein the synthesis of a novel class of compounds, ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl
carbonate, (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-c]pyran-4,6(7H)-dione, 5-oxo-N-phenyl-
2,5-dihydro-4H-furo[3,2-b]pyrrole-4-carboxamide, and 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]
pyrrole-4-carboxamide starting from the corresponding acid derivatives. Intramolecular cyclization in
the presence of thionyl chloride formed the target fused ring systems. Additional transformation was
seen in the cyclization of furan-fused heterocycle. A mechanism was proposed based on experimental
and computational findings.
Received 10 March 2014
Received in revised form 1 May 2014
Accepted 19 May 2014
Available online 20 June 2014
Keywords:
Acyl azide
Furopyranone
Furopyrrolone
Thienopyrrolone
Curtius rearrangement
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Fusing furan rings with other heterocycles results in new char-
acteristics. Furopyranones (4) and furopyrrolones (5) are key ex-
Furan and thiophene derivatives are of great importance due to
their crucial role in synthetic organic chemistry.1e6 They have been
proven to exhibit a wide range of biological activities and so they
exist in a number of commercially available pharmaceuticals such
as furazolidone (1),7 ranitidine (2),8 and tioconazole (3) (Fig. 1).9
amples of furan-fused heterocyclic systems that have crucial roles
(Fig. 2).10e14 For instance neo-tanshinlactone (6), a furopyranone
derivative, is reported to be 20 times more selective than anti-
estrogenic tomoxifen citrate, which is clinically used in breast
cancer therapies.15
Fig. 2. Structures of some furan-fused heterocycles.
Based on known examples,9,16 thio- and furan-fused heterocy-
cles have the potential to possess biological activities.
Therefore we were inspired to work on the development of new
synthetic methodologies for thio- and furan-fused heterocycles.
Starting from diacid 7, we aimed here to prepare of the furopyr-
anone 8 and furopyrrolone 9 derivatives (Scheme 1).
Fig. 1. Structures of some commercially available drugs containg furan or thiophene
ring.
2. Results and discussion
The starting compounds 12 and 13 were synthesized using
* Corresponding author. E-mail address: mbalci@metu.edu.tr (M. Balci).
previous methodologies in which commercially available dimethyl
http://dx.doi.org/10.1016/j.tet.2014.05.071
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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M. Ergun et al. / Tetrahedron 70 (2014) 5993e5998
Scheme 1. The synthetic strategy for furopyranone 8 and furopyrrolone 9 derivatives.
1,3-acetonedicarboxylate (10) was reacted with chloro-
acetaldehyde in pyridine to yield furan diester 12,17 and with 2,5-
dihydroxy-1,4-dithiane (11) and lithium bromide in dioxane to
yield thiophene diester 1318 (Scheme 2).19
Fig. 3. ORTEP drawing of furopyrandione 17. Thermal ellipsoids are shown at 40%
probability level.
In order to achieve this goal, furan diacid 14 was reacted with
concentrated HCl in dichloromethane from which the carboxylic
acid group connected to the methylene group in 14 was selectively
converted to ester functionality to form monoester 18.22,23 The
monoester 18 was then reacted with oxalyl chloride in dichloro-
methane to give the acyl chloride 19. To introduce the nitrogen
atom into the molecule, Curtius rearrangement,24e28 one of the
most convenient methods to generate urea and urethane de-
rivatives, was performed on acyl azide 20 in benzene, which was
generated by the reaction of acyl chloride 19 with sodium azide in
acetone. The isocyanate 21 formed by the Curtius rearrangement,
was mixed with aniline to yield the corresponding urea ester 22.
Then the ester functionality of the molecule 22 was hydrolyzed
with 10% NaOH in a dioxane/water mixture to give urea acid 23.
Finally the intramolecular cyclization of the molecule 23 was ach-
ieved by adding thionyl chloride in chloroform forming the rear-
ranged product 24 (Scheme 4). The structure of 24 was established
by 1H and 13C NMR spectra. Finally X-ray diffraction analysis of 24
confirmed unambiguously the proposed structure (Fig. 4).
Scheme 2. Synthesis of furan and thiophene diesters 12 and 13.
For the synthesis of furopyranone derivatives, the key com-
pound was the furan diacid 14. A previously published method by
Balci et al.20 was applied to the furan diacid 14, which was obtained
by the reaction of furan diester 12 with potassium carbonate in
a methanol/water mixture.21 According to this method, furan diacid
14 was then treated with triethylamine and then with ethyl
chloroformate, which yielded the cyclization product furopyranone
15. For the synthesis of further furopyranone derivatives, a modi-
fied VilsmeiereHaack reaction was applied to diacid 14. Treatment
of furan diacid 14 with thionyl chloride, dimethyformamide, pyri-
dine and tetrabutylammonium bromide as a catalyst in dichloro-
methane resulted in the formation of 17 (Scheme 3). We assume
that the diacid 14 first undergoes a cyclization reaction to form the
anhydride 16 followed by a condensation reaction of the methylene
functionality in 16 with the dimethyl formamide to give 17. The
confirmation of the structure of furopyrandione 17 was achieved by
X-ray analysis (Fig. 3).
Scheme 4. Attempt to synthesize target furopyrrolone derivative 9.
Scheme 3. Synthesis of furopyranone 15 and furopyrandione 17.
After the characterization of the unexpected product 24, we also
aimed to apply the same methodology to synthesize the corre-
sponding thienopyrrolone derivative starting from thiophene di-
acid 25. For regiospecific formation of the monoester 26, diacid 25
was treated with HCl in methanol at 40 ꢀC (Scheme 5).29 The
After the synthesis of furopyranone 15 and furopyrandione 17,
we turned our attention to furo- and thienopyrrolone 9 framework
construction, starting from diacid 7, for which a nitrogen atom must
be inserted into the molecule.

M. Ergun et al. / Tetrahedron 70 (2014) 5993e5998
5995
4.1 kcal molꢁ1 and 0.2 kcal molꢁ1 than the nonrearranged isomers
31 and 30, respectively (Fig. 5). Additional computational efforts in
determining single-point energies at B3LYP/6-311G(2df,2p) levels
of theory gave a similar outcome for the furopyrrolone derivative
24. Single point solvation calculations with the polarized contin-
uum model (PCM) were carried out with chloroform since it was
used as solvent in experimental studies. The rearranged isomer 24
was found to be more stable by 4.9 kcal molꢁ1. However, it was
found that thienopyrrolone 30 derivative was more stable com-
pared to its isomer by 0.4 kcal molꢁ1, which is in agreement with
the experimental results.31
Fig. 4. (a) ORTEP drawing of furopyrrolone 24. Thermal ellipsoids are shown at 40%
probability level. (b) Dimeric structure with the H-bonding geometry.
Fig. 5. At B3LYP/6-31G* level (PCM solvation in CHCl3) geometry optimized structures
for 24, 30, 31, and 32.
Based on experimental and computational results, we proposed
a mechanism outlined in Scheme 6 for the formation of compound
24. The first step is in situ acyl chloride formation from urea-acid
23. Acyl chloride 33 may undergo cyclization via intramolecular
nucleophilic attack from the NH group directly connected to the
furan ring. This transformation was also supported by the isolation
of the thienopyrrolone derivative 30 without further reaction.
Ketoeenol tautomerism of 31 and protonation give compound 24
as the sole product.
Scheme 5. Synthesis of thienopyrrolone 30.
monoester 26 was reacted with triethylamine and ethyl chlor-
oformate in dichloromethane, followed by sodium azide addition to
yield acyl azide 27.
The application of the Curtius rearrangement to 27 followed by
the addition of aniline in toluene yielded the urea-ester 28, which
was then hydrolyzed by 10% NaOH in a dioxane/water mixture to
form urea acid 29.
Finally the intramolecular cyclization reaction was achieved by
adding thionyl chloride in chloroform to urea-acid 29 to give the
thienopyrrolone derivative 30.
The results of the cyclization reactions vary considerably,
depending on the heteroatoms. The thiophene structure in 30 was
preserved, but the furan structure in 24 was isomerized to a con-
jugated dienone structure. Accordingly, we conclude that the
aromaticity of the five-membered ring should play an important
role in this transformation. It is well known that the aromaticity
of the two five-membered rings increases in the order of
furan<<thiophene.30
Scheme 6. Proposed mechanism for the synthesis of compound 24.
3. Conclusion
In order to address this question we carried out geometry op-
timization calculations at the B3LYP/6-31G* levels of theory on 24,
30, 31, and 33. Relative free enthalpy comparison of the resulting
geometries showed that rearranged isomers of the furopyrrolone
24 and thienopyrrolone 32 derivatives are more stable by
The presented results show the importance of acyl azide based
cyclizations for the formation of valuable heterocyclic systems. We
have developed a method for the construction of furo- and thie-
nopyrrolone derivatives starting from furan and thiophene di-
carboxylic acids. The method developed here can be applied to the

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M. Ergun et al. / Tetrahedron 70 (2014) 5993e5998
synthesis of further heterocycles as well as introduction of further
substituents.
(100 MHz, CDCl3) d 162.5, 156.0, 154.3, 150.6, 144.8, 108.6, 107.8,
86.2, 66.7, 14.1; vmax (ATR) 1774, 1623, 1565, 1232, 1167, 1065 cmꢁ1
[found: C, 53.78; H, 3.61. C10H8O6 requires C, 53.58; H, 3.60, O.
42.82]; HRMS calcd for C10H8O6 (MþNa)þ: 247.02131, found:
247.02467.
4. Experimental section
4.1. General
4.1.4. Synthesis of (7E)-7-[(dimethylamino)methylene]-4H-furo[3,2-
c]pyran-4,6(7H)-dione (17). Benzene (7 mL), dimethyl formamide
(2.8 mL) and thionyl chloride (2.3 mL) were mixed in a dropping
funnel and two separate layers were formed in 5 min. The lower
layer was added to a mixture of diacid 14 (2.36 g 13.9 mmol),
tetrabutylammonium bromide (0.6 g, 1.9 mmol), and pyridine
(3.2 mL) in 100 mL dichloromethane. The solution was kept stir-
ring at room temperature overnight. Then the solution was
washed with saturated NaHCO3 solution (3ꢂ50 mL) and the
combined organic extracts were washed with 1 M HCl solution
(3ꢂ50 mL) and with water (2ꢂ25 mL). The organic layer was dried
over MgSO4 and the solvent was evaporated under vacuum. The
residue was then purified by column chromatography (SiO2, 120 g)
eluting with ethyl acetate to yield the compound 17 (1.53 g,
7.4 mmol) in 53% yield as pale yellow solid, mp 154e155 ꢀC.
Nuclear magnetic resonance (1H NMR and 13C NMR) spectra
were recorded on a Bruker Instrument Avance Series-Spectrospin
DPX-400 Ultrashield instrument in acetone-d6, CDCl3, CD3OD, and
DMSO-d6 with TMS as internal reference. Chemical shifts (d) were
expressed in units parts per million (ppm). Spin multiplicities were
given as singlet (s), doublet (d), doublet of doublets (dd), triplet (t)
and quartet (q) and coupling constants (J) were reported in Hertz
(Hz). IR spectra were recorded on a Perkin Elmer 980 spectrometer.
Elemental analysis were determined on a Leco CHNS-932 in-
strument (Ataturk University). Melting points were determined on
a
Thomas-Hoover capillary melting point apparatus. Column
chromatography was performed on silica gel (60-mesh, Merck), TLC
was carried out on Merck 0.2 mm silica gel 60 F254analytical alu-
minum plates.
Rf¼0.18; 1H NMR (400 MHz, CD3OD)
d
8.07 (s, 1H, H-10), 7.50 (d,
4.1.1. Synthesis of methyl 2-(2-methoxy-2-oxoethyl)-3-furoate
J2,3¼2.2 Hz, 1H, H-2), 6.76 (d, J3,2¼2.2 Hz, 1H, H-3), 3.48 (s, 3H,
(12).17 A solution of chloroacetaldehyde (26.5 mL, 45%) in water
NCH3), 3.47 (s, 3H, NCH3); 13C NMR (100 MHz, CDCl3)
d 164.8,
was added dropwise to
a
solution of dimethyl 1,3-
159.4, 157.9, 154.8, 141.8, 108.1, 104.0, 85.6, 49.1, 43.0; vmax (ATR)
1752, 1694, 1608, 1529, 1476, 1432, 1391, 1312, 1271, 1116, 1082,
1051; HRMS calcd for C10H9NO4 (MþH)þ: 208.06043, found:
208.06348.
acetonedicarboxylate (10) (25.0 g, 143.5 mmol) in pyridine
(50 mL) with stirring. Stirring was continued for 24 h at 50 ꢀC. Then
the reaction mixture was extracted with water and ethyl acetate.
The organic layer was washed successively with 2 M HCl, 5%
NaHCO3, 10% NaOH and brine, and then dried over MgSO4. The
solvent was evaporated and the product was purified by silica gel
column chromatography eluting with hexane/ethyl acetate (3:1)
gave 12 as a colorless liquid (22.8 g, 80%). Rf¼0.43; 1H NMR
4.1.5. 2-(2-Methoxy-2-oxoethyl)-3-furoic acid (18). To a stirred so-
lution of diacid 14 (3.5 g, 20.6 mmol) in 90 mL of dichloromethane/
methanol (2:1) mixture, 15 drops of concentrated HCl were added.
This mixture was kept stirring at 42 ꢀC for 24 h. After the com-
pletion of the reaction, the solvent was evaporated to give the crude
product, which was then separated by column chromatography
(160 g, SiO2, hexane/EtOAc, 3:1). The first fraction was identified as
diester 12 (0.450 g,11%), and the second fraction was the monoester
18 (3.10 g, 82%), white solid, mp 81e83 ꢀC. Rf¼0.21; 1H NMR
(400 MHz, CDCl3)
d
7.31 (d, J5,4¼2.0 Hz,1H, H-5), 6.67 (d, J4,5¼2.0 Hz,
1H, H-4), 4.05 (s, 2H, CH2), 3.79 (s, 3H, OCH3), 3.69 (s, 3H, OCH3); 13
C
NMR (100 MHz, CDCl3)
51.6, 33.5.
d 169.1, 163.9, 154.2, 141.9, 115.5, 110.8, 52.4,
4.1.2. 2-(Carboxymethyl)-3-furoic acid (14). To a solution of diester
12 (5.0 g, 25.2 mmol) in 60 mL solution of 1:1 CH3OH/H2O was
added K2CO3 (10.0 g, 72.4 mmol). The solution was refluxed for
24 h. Then the reaction mixture was acidified with concentrated
HCl (15 mL) and extracted with ethyl acetate (3ꢂ50 mL). The or-
ganic phase was dried over MgSO4 and concentrated under reduced
pressure to give diacid 1426 as white powder (3.97 g, 23.3 mmol) in
(400 MHz, CDCl3)
d
7.37 (d, J5,4¼2.0 Hz, 1H, H-5), 6.75 (d,
J4,5¼2.0 Hz, 1H, H-4), 4.11 (s, 2H, CH2), 3.74 (s, 3H, OCH3). 13C NMR
(100 MHz, CDCl3) d 169.1, 169.0, 155.6, 142.3, 115.3, 111.2, 52.6, 33.7;
vmax (ATR) 3149, 3127, 2957, 2685, 2614, 1728, 1681, 1324, 1280,
1246, 1166 cmꢁ1 [found: C, 52.41; H, 4.17. C8H8O5 requires C, 52.18;
H, 4.38].
92% yield, mp 210e212 ꢀC. 1H NMR (400 MHz, DMSO-d6)
d
12.67 (br
4.1.6. Synthesis of methyl [3-(chlorocarbonyl)-2-furyl]acetate
(19). Oxalyl chloride (1.7 mL, 19.8 mmol) was added to a stirred
solution of monoester 18 (3.10 g, 16.8 mmol) in 40 mL dichloro-
methane, followed by addition of dimethyl formamide (5 drops) as
catalyst. After stirring this mixture for 1 h at room temperature, the
solvent was evaporated to give acyl chloride 19 (3.27 g, 96%), which
was used without purification for the next step. 1H NMR (400 MHz,
s, 2H, eOH), 7.65 (d, J4,5¼2.0 Hz,1H, H-5), 6.66 (d, J5,4¼2.0 Hz,1H, H-
4), 3.97 (s, 2H, CH2). 13C NMR (100 MHz, DMSO-d6)
d 169.9, 164.4,
154.8, 142.3, 115.6, 110.9 and 33.4.
4.1.3. Ethyl 4-oxo-4H-furo[3,2-c]pyran-6-yl carbonate (15). To a so-
lution of diacid 14 (1.50 g, 8.8 mmol) in 10 mL of THF at 0 ꢀC,
triethylamine (1.80 mL, 13.2 mmol) in 6 mL THF was added drop-
wise and the mixture was stirred for 30 min. This was followed by
slow addition of a cooled solution of ethyl chloroformate (1.65 mL,
17.6 mmol) in 6 mL of THF and the reaction mixture was stirred at
the same temperature for 30 min. The mixture was extracted with
ethyl acetate (2ꢂ15 mL) and water (20 mL) and the organic phase
was washed with saturated NaHCO3 solution (3ꢂ40 mL) and with
water (2ꢂ25 mL). Then organic layer was dried over MgSO4. After
that, compound 15 (0.81 g, 3.6 mmol) was obtained and purified on
silica gel column chromatography using hexane/ethyl acetate as
eluent (3:1) in 41% yield as white crystals, mp 82e83 ꢀC. Rf¼0.44;
CDCl3)
4.03 (s, 2H, CH2), 3.71 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
167.8, 162.1, 156.2, 142.4, 120.5, 112.7, 52.7, 33.8; vmax (ATR) 3135,
2955, 1750, 1574, 1436, 1338, 1251, 1171 cmꢁ1
d
7.37 (d, J5,4¼2.1 Hz, 1H, H-5), 6.79 (d, J4,5¼2.1 Hz, 1H, H-4),
d
.
4.1.7. Synthesis of 1-[2-(2-methoxy-2-oxoethyl)-3-furoyl]triaza-1,2-
dien-2-ium (20).20 To a solution of acyl chloride 19 (3.07 g,
15.2 mmol) in 40 mL of acetone, NaN3 (1.47 g, 22.6 mmol) in 8 mL of
chilled water was added dropwise at 0 ꢀC. This mixture was stirred
for 1 h at 0 ꢀC. Then, 100 mL water was added and the mixture was
extracted with ethyl acetate (2ꢂ100 mL). The combined organic
extracts were dried over MgSO4, and then concentrated to give the
acyl azide 20 (3.07 g, 97%) as colorless liquid. 1H NMR (400 MHz,
1H NMR (400 MHz, CDCl3)
d
7.51 (d, J2,3¼2.1 Hz, 1H, H-2), 6.88 (dd,
J3,2¼2.1 Hz, J3,7¼0.8 Hz, 1H, H-3), 6.43 (d, J7,3¼0.8 Hz, 1H, H-7), 4.36
(q, J¼7.2 Hz, 2H, CH2), 1.39 (t, J¼7.2 Hz, 3H, CH3); 13C NMR
CDCl3)
d
7.30 (d, J5,4¼2.0 Hz, 1H, H-5), 6.63 (d, J4,5¼2.0 Hz, 1H, H-4),

M. Ergun et al. / Tetrahedron 70 (2014) 5993e5998
5997
4.06 (s, 2H, CH2), 3.68 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3)
168.6, 168.2, 155.4, 142.2, 116.9, 110.5, 52.5, 33.7; vmax (ATR) 2955,
2154, 2133, 1742, 1686, 1601, 1420, 1299, 1133 cmꢁ1
1236, 1108, 1084 cmꢁ1; HRMS calcd for C13H10N2O3 (MꢁH)ꢁ:
d
241.06187, found: 241.06241.
.
4.1.12. Synthesis of methyl [3-(azidocarbonyl)thiophen-2-yl]acetate
4.1.8. Synthesis of methyl (3-isocyanato-2-furyl)acetate (21). A so-
lution of acyl azide 20 (3.05 g, 14.6 mmol) in 35 mL of dry benzene
was stirred at reflux temperature for 24 h. Then, solvent was
evaporated under vacuum to give the isocyanate 21 as yellowish
(27). To a solution of acid 2629 (50.0 mg, 0.25 mmol) in 5 mL THF,
NEt3 (53
Then, ethyl chloroformate (55
m
L, 0.38 mmol) was added at 0 ꢀC and stirred for 30 min.
mL, 0.58 mmol) was added and stir-
red at 0 ꢀC for 30 min. After addition of NaN3 (33.0 mg, 0.50 mmol),
the reaction mixture was stirred for 1 h at 0 ꢀC. Later, 10 mL water
was added and the mixture was extracted with Et2O (2ꢂ25 mL).
The combined organic layers were dried over MgSO4 and concen-
trated. The product was purified with column chromatography on
silica gel (10 g) eluting with diethyl ether to give pale yellow solid
liquid (2.51 g, 95%). 1H NMR (400 MHz, CDCl3)
d
7.15 (d, J5,4¼2.1 Hz,
1H, H-5), 6.19 (d, J4,5¼2.1 Hz, 1H, H-4), 3.63 (s, 2H, CH2), 3.56 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3)
169.0, 141.7, 140.2, 128.3, 116.9,
109.4, 52.4, 31.3; vmax (ATR) 2272, 1742, 907, 730 cmꢁ1
d
.
4.1.9. Synthesis of methyl {3-[(anilinocarbonyl)amino]-2-furyl}ace-
tate (22). To a solution of isocyanate 21 (2.51 g 13.9 mmol) in
40 mL dichloromethane, 1.5 mL (16.4 mmol) aniline was added
at room temperature. Then this mixture was kept stirring at
room temperature for 15 min. After evaporation of the solvent
the crude product was purified by silica gel column chroma-
tography (SiO2, 90 g) eluting with hexane/ethyl acetate mixture
(1:1) to give urea-ester as 22 a white powder (3.61 g, 95%), mp
27 (54.0 mg, 96%). Rf¼0.83; 1H NMR (400 MHz, CDCl3)
d 7.40 (d,
J¼5.4 Hz, 1H), 7.16 (d, J¼5.4 Hz, 1H), 4.24 (s, 2H, CH2), 3.74 (s, 3H,
OMe); 13C NMR (100 MHz, CDCl3)
123.8, 52.5, 34.6; vmax (ATR) 3116, 2952, 2139, 1719, 1663, 1524,
1437, 1232, 1173, 1070, 1006, 933, 846, 715 cmꢁ1
d 170.2, 168.2, 146.2, 130.3, 129.0,
.
4.1.13. Synthesis of methyl {3-[(phenylcarbamoyl)-amino]thiophen-
2-yl}acetate (28). A solution of acyl azide 27 (0.15 g, 0.67 mmol) in
5 mL of dry toluene was stirred at reflux temperature for 6 h. Then,
142e143 ꢀC. Rf¼0.36; 1H NMR (400 MHz, CD03OD)
d
7.39 (dd,
0
0
0
0
0
0
0
0
0
J2 ,3 ¼J6 ,5 ¼8.7 Hz, J2 ,4 ¼J6 ,4 ¼1.2 Hz, 2H, H-2 , H-6 ), 7.36 (d,
aniline (70 mL, 0.80 mmol) was added at rt and the resulting mix-
0
0
0
0
0
0
0
0
J5,4¼2.0 Hz, 1H, H-5), 7.29 (quasi t, J3 ,2 ¼J3 ,4 ¼J5 ,6 ¼J5 ,4 ¼7.2 Hz,
ture was stirred for 15 min. After removal of the solvent, the crude
product was purified by column chromatography on SiO2 (20 g)
eluting with hexane/EtOAc (5:1, 3:1) and urea-ester 28 was
recrystallized from chloroform under petroleum ether atmosphere
to give white powder (180.0 mg, 93%), mp 158e160 ꢀC. Rf¼0.16
2H, H-30, 50), 7.01 (tt, J4 ,3 ¼J4 ,5 ¼7.2 Hz, J4 ,2’ ¼J4 ,6 ¼1.2 Hz, 1H, H-
0
0
0
0
0
0
0
0
40), 6.62 (d, 1H, J4,5¼2.0 Hz, H-4), 3.74 (s, 2H, CH2), 3.70 (s, 3H,
OCH3); 13C NMR (100 MHz, CDCl3)
d 170.7, 154.8, 141.9, 138.5,
129.1, 128.5, 123.6, 121.8, 120.2, 110.3, 52.7, 31.8; vmax (ATR)
3288, 1739, 1557, 1495, 1340, 1221, 1163, 1095 cm-1; [found: C,
61.59; H, 5.03; N, 10.06. C14H14N2O4 requires C, 61.31; H, 5.14; N,
10.21].
(hexane/EtOAc 3:1); 1H NMR (400 MHz, CDCl3)
d 7.35 (br d,
J¼8.0 Hz, 2H, benzene), 7.28 (br t, J¼7.6 Hz, 2H, benzene) 7.21 (s, 2H,
thiophene), 7.06 (br t, J¼7.3 Hz, 1H, benzene), 6.98 (br s, 2H, NH),
3.77 (s, 2H, CH2), 3.66 (s, 3H, OMe); 13C NMR (100 MHz, CDCl3)
4.1.10. Synthesis of {3-[(anilinocarbonyl)amino]-2-furyl}acetic acid
(23). To a stirred solution of urea-ester 22 (3.81 g, 13.9 mmol) in
60 mL dioxane/water mixture (2:1) was added 4 mL of 10% NaOH
solution at room temperature. Then this mixture was kept stirring at
60 ꢀC for 2 h. Then, concentrated HCl (15 mL) was added dropwise to
the reaction mixture. The resulting mixturewas extracted with ethyl
acetate (2ꢂ100 mL) and the organic layer was dried over MgSO4.
Finally, the acid 23 was obtained by evaporating the solvent under
vacuum as a white solid (2.89 g, 80%), mp 201e202 ꢀC. 1H NMR
d 171.7, 154.3, 138.4, 134.3, 129.1, 125.7, 123.7, 123.6, 120.5, 52.7, 32.5.
vmax (ATR) 278, 2950, 2920, 1735, 1639, 1583, 1549, 1446, 1240,
1206, 743, 693, 664, 631 cmꢁ1; HRMS calcd for C14H14N2O3S
(MþNa)þ: 313.06173, found: 313.06410.
4.1.14. Synthesis of {3-[(phenylcarbamoyl)amino]thiophen-2-yl}ace-
tic acid (29). To a stirred solution of urea-ester 28 (100.0 mg,
0.34mmol) in15 mL dioxane/water mixture(2:1)wasadded 0.1 mL of
10% NaOH at room temperature. Then, this mixture was kept stirring
at 60 ꢀC for 2 h. Then concentrated HCl (2 mL) was added to the re-
action mixture and the resulting mixture was extracted with ethyl
acetate (4ꢂ20 mL) and the organic layer was dried over MgSO4. Fi-
nally, the urea-acid 29 was obtained by evaporating the solvent. The
compound was recrystallized from chloroform under petroleum
ether atmosphere to give white crystals (87.0 mg, 91%), mp
(400 MHz, DMSO-d6) d 12.58 (br s, 1H, COOH), 8.60 (s, 1H, NH), 8.10
0
0
0
0
(s, 1H, NH), 7.46 (d, J5,4¼2.0 Hz, 1H, H-5), 7.42 (bd, J2 ,3 ¼J6 ,5 ¼7.9 Hz0,
2H, H-20 and H-60), 7.26 (bt, J3 ,2 ¼J5 ,6 ¼J3 ,4 ¼J5 ,4 ¼7.9 Hz, 2H, H-3
0
0
0
0
0
0
0
0
and H-50), 6.95 (bt, J4 ,3 ¼J4 ,5 ¼7.9 Hz, 1H, H-4 ) 6.73 (d, J4,5¼2.0 Hz,
0
0
0
0
0
1H, H-4), 3.64 (s, 2H, CH2); 13C NMR (100 MHz, DMSO-d6)
d 170.6,
152.6, 140.6, 139.8, 136.0, 128.8, 122.3, 121.7, 118.0, 108.3 and 31.8;
vmax (ATR) 3292, 3145,1703,1598,1559,1445,1430,1289,1245 cm-1
;
179e181 ꢀC.1H NMR (400 MHz, acetone-d6)
d 8.49 (br s,1H, NH), 7.86
HRMS calcd for C13H12N2O4 (MþH)þ: 261.08698, found: 261.08817.
(br s, 1H, NH), 7.53 (dd, J¼8.7, 0.9 Hz, 2H, benzene), 7.41 (d, J¼5.4 Hz,
1H, thiophene), 7.31e7.19 (m, 3H), 6.97 (tt, J¼7.4,1.0 Hz,1H, benzene),
4.1.11. Synthesis of 5-oxo-N-phenyl-2,5-dihydro-4H-furo[3,2-b]pyr-
role-4-carboxamide (24). To a stirred solution of acid 23 (0.5 g,
1.9 mmol) in 20 mL of CHCl3 (ethanol free), 0.2 mL thionyl chloride
was added at room temperature. Then this mixture was heated to
reflux temperature and kept stirring for 24 h. The solvent was
evaporated to give of the crude product, which was then purified by
column chromatography (21.0 g SiO2; hexane/ethyl acetate 3:1) to
give compound 24 as white crystals from CHCl3/n-hexane (3:1)
(0.21 g, 45%), mp 155e157 ꢀC. Rf¼0.33; 1H NMR (400 MHz, CDCl3)
3.77 (s, 2H, CH2); 13C NMR: (100 MHz, acetone-d6)
d 172.1,154.0,140.9,
135.8, 129.5, 125.4, 123.1, 122.9, 119.4, 32.9. vmax (ATR) 3282, 2909,
1696, 1640, 1579, 1545, 1444, 1294, 1238, 897, 744, 655, 629; HRMS
calcd for C13H12N2O3S (MþNa)þ: 299.04608, found: 299.04890.
4.1.15. Synthesis of 5-oxo-N-phenyl-5,6-dihydro-4H-thieno[3,2-b]
pyrrole-4-carboxamide (30). To a stirred solution of urea-acid 29
(45.0 mg, 0.16 mmol) in 20 mL CHCl3 (ethanol free), 50 mL SOCl2 was
added at room temperature. Then, the reaction mixture was heated
to reflux temperature and kept stirring for 24 h. The solvent was
evaporated to give crude product, which was purified by column
chromatography on silica gel (10 g) eluting with hexane/EtOAc
(2:1) to give purple solid 30 (26.5 mg, 63%), mp 111e113 ꢀC.
0
0
0
0
0
0
0
d
10.17 (s, 1H, NH), 7.56 (dd, J2,3 ¼J6 ,5 ¼8.6 Hz, J2 ,4 ¼J6 ,4 ¼1.2 Hz, 2H,
H-20 and H- 60), 7.30e7.40 (m, 2H, H-30 and H-50), 7.13 (tt,
0
0
0
0
0
0
0
0
0
J4 ,3 ¼J4 ,5 ¼7.4 Hz, J4 ,2 ¼J4 ,6 ¼1.2 Hz, 1H, H-4 ), 6.58 (dt, J3,2¼2.0 Hz,
J3,6¼1.6 Hz,1H, H-3), 5.46 (dd, J2,3¼2.0 Hz, J6,2¼1.1 Hz, 2H, H-2), 5.07
(dt, J6,3¼1.6 Hz, J6,2¼1.1 Hz, 1H, H-6); 13C NMR (100 MHz, CDCl3)
Rf¼0.55; 1H NMR (400 MHz, CDCl3)
d 10.23 (br s, 1H), 7.54e7.63 (m,
3H, benzene and thiophene), 7.36 (t, J¼7.9 Hz, 2H, benzene), 7.30 (d,
J¼5.1 Hz, 1H, thiophene), 7.14 (t, J¼7.4 Hz, 1H, benzene), 3.86 (s, 2H,
d
176.1, 175.2, 148.4, 137.2, 133.5, 129.2, 124.4, 120.2, 112.6, 86.5 and
84.1. vmax (ATR) 3108, 1717, 1666, 1596, 1556, 1500, 1448, 1355, 1290,

5998
M. Ergun et al. / Tetrahedron 70 (2014) 5993e5998
CH2). 13C NMR (100 MHz, CDCl3)
d
179.0, 148.2, 142.8, 137.2, 129.2,
Department of Chemistry at Middle East Technical University and
the Turkish Academy of Sciences (TUBA) for their financial support
of this work.
126.8, 124.6, 120.5, 117.7, 115.5, 37.3. vmax (ATR) 3242, 3095, 2910,
1726, 1701, 1599, 1553, 1499, 1448, 1291, 1227, 1191, 1076, 696;
HRMS calcd for C14H14N2O3S (MꢁH)-: 257.03902, found: 257.04081.
Supplementary data
4.2. X-ray crystal structure analysis of 17 and 24
These data include the 1H and 13C NMR spectra of compounds
(24 pages). Supplementary data related to this article can be found
at http://dx.doi.org/10.1016/j.tet.2014.05.071.
For the crystal structure determination, single-crystals of the
compounds 17 and 24 were used for data collection on a four-circle
Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-
dimensional area IP detector). Graphite-monochromated Mo-Ka
ꢀ
radiation (
l
¼0.71073 A) and oscillation scans technique with
D
w¼5ꢀ
References and notes
for one image were used for data collection. The lattice parameters
were determined by the least-squares methods on the basis of all
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4.2.1. Crystal data for (17). C10H9NO4, crystal system, space group:
monoclinic, P21/n; (no: 14); unit cell dimensions: a¼7.0237(4),
ꢀ
ꢀ
b¼12.2539(6), c¼11.0368(37) A,
a¼90,
b
¼939.712(3),
g¼90 A;
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3
ꢀ
3
volume: 936.30(9) A ; Z¼4; calculated density: 1.470 g/cm ; ab-
sorption coefficient: 0.115 mmꢁ1; F(000): 432;
q-range for data
_
_
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collection 2.5e26.4ꢀ; refinement method: full matrix least-square
on F2; data/parameters: 1281/139; goodness-of-fit on F2: 1.102; fi-
14. Koza, G.; Karahan, E.; Balci, M. Helv. Chim. Acta 2010, 93, 1698e1704.
15. Wang, X.; Bastow, K. F.; Sun, C.-M.; Lin, Y. L.; Yu, H. J.; Don, M. J.; Wu, T. S.;
Nakamura, S.; Lee, K. H. J. Med. Chem. 2004, 47, 5816e5819.
nal R-indices [I>2
s
(I)]: R1¼0.064, wR2¼0.166; largest diff. peak and
ꢀꢁ3
hole: 0.187 and ꢁ0.290 e A
.
ꢁ
16. Eroglu, H. E.; Koca, I.; Yıldırım, I. Cytotechnology 2011, 63, 407e413.
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2005, WO2005087779 A1 20050922.
4.2.2. Crystal data for (24). C13H10N2O3, crystal system, space
group: monoclinic, C2/c; (no:15); unit cell dimensions:
ꢀ
19. Koza, G.; Balci, M. Tetrahedron 2011, 67, 8679e8684.
a¼27.7731(8), b¼5.2110(1), c¼15.4807(4) A,
a¼90,
b
¼92.951(2),
€
20. Ozcan, S.; Balci, M. Tetrahedron 2008, 64, 5531e5540.
3
ꢀ
ꢀ
g
¼90 A; volume: 2237.61(10) A ; Z¼8; calculated density: 1.438 g/
€
21. Kilikli, A. A.; Dengiz, C.; Ozcan, S.; Balci, M. Synthesis 2011, 22, 3697e3705.
cm3; absorption coefficient: 0.105 mmꢁ1; F(000): 1008;
q-range for
22. Dengiz, C¸ .; Balci, M. Turk. J. Chem. 2013, 37, 220e227.
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Green, I. Eur. J. Org. Chem. 2010, 16, 3080e3092.
data collection 2.6e26.7ꢀ; refinement method: full matrix least-
square on F2; data/parameters: 1809/164; goodness-of-fit on F2:
24. Curtius, T. J. Prakt. Chem. 1894, 50, 275e294.
€
1.075; final R-indices [I>2
peak and hole: 0.444 and ꢁ0.284 e A
s
(I)]: R1¼0.096, wR2¼0.239; largest diff.
ꢀꢁ3
25. Dengiz, C.; Ozcan, S.; S¸ ahin, E.; Balci, M. Synthesis 2010, 8, 1365e1370.
€
26. Koza, G.; Keskin, S.; Ozer, M. S.; Cengiz, B.; S¸ ahin, E.; Balci, M. Tetrahedron 2013,
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69, 395e409.
CCDC-988941 (17) and 989578 (24) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
€
27. Ozcan, S.; Dengiz, C.; Deliomeroglu, M. K.; Sahin, E.; Balci, M. Tetrahedron Lett.
2011, 52, 1495e1497.
€
28. Koza, G.; Ozcan, S.; S¸ ahin, E.; Balci, M. Tetrahedron 2009, 65, 5973e5976.
€
29. For similar transformation see: Ozer, M. S.; Koza, G.; S¸ ahin, E.; Balci, M. Tetra-
hedron Lett. 2013, 54, 6553e6556.
30. Horner, K. E.; Karadakov, P. B. J. Org. Chem. 2013, 78, 8037e8043.
31. Frisch, M. J., et al. Gaussian 09, Revision A.1; Gaussian: Wallingford CT, 2009; See
the SD for the full list of the authors.
Acknowledgements
32. Rigaku/MSC, 9009 New Trails Drive, The Woodlands, TX 77381.
33. Sheldrick, G. M. SHELXS97 and SHELXL97; University of Gottingen: Germany,
The authors are indebted to the Scientific and Technological
€
Research Council of Turkey (TUBITAK, Grant No: 110-R001), the
1997.