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,