A. Correa et al. / Tetrahedron 62 (2006) 11100–11105
11103
(100); HRMS calcd for C14H12FNO2: 245.0852, found:
245.0853.
NH); 13C NMR (CDCl3) d 55.3, 55.8, 56.5 (OCH3), 102.5,
111.8 (CH), 113.3 (C), 114.0, 118.7, 121.6, 122.8, 129.4
(CH), 130.8, 139.2, 142.7, 142.9, 152.4, 156.2 (C), 166.4
(CO); IR (KBr) 3313 (NH), 1638 (CO); MS (EI) m/z (%)
378 (M+, 7), 256 (27), 212 (100), 184 (25), 154 (14);
HRMS calcd for C22H22N2O4: 378.1580, found: 378.1579.
4.2.5. Methyl 3-phenylaminothiophene-2-carboxylate
(3e). According to the typical procedure, ester 3e was
obtained from commercially available methyl 3-aminothio-
phene-2-carboxylate (2e) in 69% yield as a yellowish solid
after purification by column chromatography (CH2Cl2) fol-
lowed by crystallization from Et2O: mp 66–67 ꢀC (Et2O);
1H NMR (CDCl3) d 3.88 (s, 3H, OCH3), 7.04–7.20 (m,
4H, Harom), 7.31–7.37 (m, 3H, Harom), 8.81 (br s, 1H, NH);
13C NMR (CDCl3) d 51.3 (OCH3), 102.8 (C), 117.8,
120.2, 122.9, 129.3, 131.7 (CH), 141.3, 151.3 (C), 165.0
(CO); IR (KBr) 3331 (NH), 1667 (CO); MS (EI) m/z (%)
233 (M+, 44), 201 (100), 173 (32); HRMS calcd for
C12H11NO2S: 233.0511, found: 233.0519.
4.3.3. 4-Chloro-N-(4-methoxyphenyl)-2-phenylamino-
benzamide (4c). According to the typical procedure, benz-
amide 4c was obtained from N-phenylaminoester 3c in 70%
yield as a white solid after purification by crystallization
from Et2O: mp 144–145 ꢀC (Et2O); 1H NMR (CDCl3)
d 3.80 (s, 3H, OCH3), 6.70–6.74 (m, 1H, Harom), 6.89 (d,
J¼8.7, 2H, Harom), 7.05–7.28 (m, 3H, Harom), 7.31–7.46
(m, 6H, Harom), 7.77 (br s, 1H, NH), 9.35 (br s, 1H, NH);
13C NMR (CDCl3) d 55.4 (OCH3), 114.2, 114.5 (CH),
116.0 (C), 117.6, 121.7, 122.8, 123.5, 128.6, 129.4 (CH),
130.1, 138.7, 140.2, 147.2, 156.9 (C), 167.1 (CO); IR
(KBr) 3308 (NH), 1637 (CO); MS (EI) m/z (%) 354
(M++2, 4), 352 (M+, 11), 230 (24), 195 (100), 167 (70);
HRMS calcd for C20H17ClN2O2: 352.0979, found:
352.0982.
4.2.6. Methyl 4-cyano-3-phenylaminothiophene-2-carb-
oxylate (3f). According to the typical procedure, aminoester
3f was obtained from commercially available methyl 3-amino-
4-cyanothiophene-2-carboxylate (2f) in 57% yield as a white
solid after purification by column chromatography (CH2Cl2)
followed by crystallization from Et2O: mp 159–160 ꢀC
(Et2O); 1H NMR (CDCl3) d 3.89 (s, 3H, OCH3), 7.19–7.26
(m, 3H, Harom), 7.36–7.41 (m, 2H, Harom), 7.89 (s, 1H,
Harom), 8.62 (br s, 1H, NH); 13C NMR (CDCl3) d 51.9
(OCH3), 103.2 (C), 105.3 (C), 112.8 (CN), 123.9, 125.9,
129.1, 141.3 (CH), 139.4, 151.1 (C), 163.9 (CO); IR (KBr)
3331 (NH), 2228 (CN), 1667 (CO); MS (EI) m/z (%) 258
(M+, 75), 226 (100), 197 (53), 154 (22), 120 (40), 77 (62);
HRMS calcd for C13H10N2O2S: 258.0463, found: 258.0467.
4.3.4. 5-Fluoro-N-(4-methoxyphenyl)-2-phenylamino-
benzamide (4d). According to the typical procedure, benza-
mide 4d was obtained from N-phenylaminoester 3d in 70%
yield as a white solid after purification by crystallization
from Et2O: mp 144–145 ꢀC (Et2O); 1H NMR (CDCl3)
3.81 (s, 3H, OCH3), 6.90 (d, J¼8.9, 2H, Harom), 6.97–7.11
(m, 4H, Harom), 7.28–7.36 (m, 4H, Harom), 7.43 (d, J¼8.8,
2H, Harom), 7.98 (br s, 1H, NH), 8.54 (br s, 1H, NH); 13C
NMR (CDCl3) d 55.4 (OCH3), 114.0 (d, J¼23.4, CH),
119.0 (d, J¼30.0, CH), 114.1, 118.9, 119.5 (CH), 121.1 (d,
J¼5.7, C), 122.1, 122.8, 129.3 (CH), 130.2, 140.9, 142.0,
156.8 (C), 155.7 (d, J¼239.0, C), 166.2 (CO); IR (KBr)
3308 (NH), 1643 (CO); MS (EI) m/z (%) 336 (M+, 65),
214 (86), 185 (99), 123 (100), 108 (80), 77 (26); HRMS
calcd for C20H17FN2O2: 336.1274, found: 336.1273.
4.3. Typical procedure for the amidation reaction.
Preparation of para-methoxyphenylamides 4a–f and 7
4.3.1. Synthesis of N-(4-methoxyphenyl)-2-phenylamino-
benzamide (4a). A solution of AlMe3 (8.81 mmol, 2.0 M in
toluene) was added dropwise to a cooled (0 ꢀC) suspension
of para-anisidine (1.08 g, 8.81 mmol) in CH2Cl2 (45 mL).
When the addition was complete, the reaction mixture was
allowed to warm to room temperature and stirring was
continued for 45 min until the gas evolution ceased. Then,
a solution of methyl N-phenylanthranilate (3a) (1.00 g,
4.40 mmol) in CH2Cl2 (8 mL) was added and the mixture
was heated under reflux overnight. The reaction mixture
was cooled to room temperature and was carefully quenched
with 5% aq HCl (20 mL). The organic layer was separated
and the aqueous layer extracted with CH2Cl2 (3ꢂ15 mL).
The combined organic extracts were washed with a saturated
aqueous solution of NaHCO3 (15 mL) and brine (15 mL).
Then, the organic layer was dried over sodium sulfate, fil-
tered, and the solvent was evaporated at reduced pressure.
The resulting residue was purified by crystallization from
Et2O to afford benzamide 4a (69%) as a white solid.12
4.3.5. N-(4-Methoxyphenyl)-3-phenylaminothiophene-2-
carboxamide (4e). According to the typical procedure,
amide 4e was obtained from N-phenylaminoester 3e in
82% yield as a white solid after purification by crystalliza-
1
tion from Et2O: mp 136–138 ꢀC (Et2O); H NMR (CDCl3)
d 3.80 (s, 3H, OCH3), 6.88–6.90 (m, 2H, Harom), 7.00–7.04
(m, 1H, Harom), 7.13–7.43 (m, 9H, Harom+NH), 9.40 (br s,
1H, NH); 13C NMR (CDCl3) d 55.4 (OCH3), 114.1, 119.6,
119.7, 122.4, 122.9, 127.5, 129.2 (CH), 105.6, 130.4,
141.8, 150.1, 156.6 (C), 163.2 (CO); IR (KBr) 3296 (NH),
1590 (CO); MS (EI) m/z (%) 324 (M+, 46), 201 (95), 173
(81), 158 (65), 123 (100), 108 (72), 77 (53); HRMS calcd
for C18H16N2O2S: 324.0932, found: 324.0936.
4.3.6. 4-Cyano-N-(4-methoxyphenyl)-3-phenylamino-
thiophene-2-carboxamide (4f). According to the typical
procedure, amide 4f was obtained from N-phenylaminoester
3f in 68% yield as a white solid after purification by crystal-
lization from Et2O: mp 133–134 ꢀC (Et2O); 1H NMR
(CDCl3) d 3.76 (s, 3H, OCH3), 6.80 (d, J¼8.8, 2H, Harom),
6.98 (d, J¼7.9, 2H, Harom), 7.08 (t, J¼7.3, 1H, Harom),
7.27–7.31 (m, 4H, Harom), 7.87 (s, 1H, Harom), 7.88 (br s,
1H, NH), 8.41 (br s, 1H, NH); 13C NMR (CDCl3) d 55.3
(OCH3), 107.7 (C), 112.9 (CN), 114.0, 119.5, 122.6,
4.3.2. 4,5-Dimethoxy-N-(4-methoxyphenyl)-2-phenyl-
aminobenzamide (4b). According to the typical procedure,
benzamide 4b was obtained from N-phenylaminoester 3b in
69% yield as a white solid after purification by crystalliza-
1
tion from Et2O: mp 122–123 ꢀC (Et2O); H NMR (CDCl3)
d 3.71 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 3.78 (s, 3H,
OCH3), 6.76–6.93 (m, 4H, Harom), 6.99–7.02 (m, 2H, Harom),
7.19–7.36 (m, 5H, Harom), 8.44 (br s, 1H, NH), 8.96 (br s, 1H,