The Journal of Organic Chemistry
Article
CDCl3) δH 9.75 (br s, 1H), 7.56 (d, J = 6.8 Hz, 1H), 7.56−7.51 (m,
3H), 7.48 (dd, J = 7.6, 7.3 Hz, 1H), 7.50−7.47 (m, 1H), 7.29−7.19
(m, 3H), 2.95 (t, J = 7.4 Hz, 2H), 2.61 (t, J = 7.4 Hz, 2H), 2.06 (s,
3H). 13C {1H} NMR (100 MHz, CDCl3) δC 176.9, 139.9, 136.9,
133.3, 130.9, 128.6 (2C), 128.4, 127.9, 127.6, 127.5 (2C), 126.9 (2C),
126.9, 122.3, 119.8, 27.5, 19.9, 16.2. (2-Methyl-4,5-dihydro-1H-
benzoindol-3-yl)(phenyl)methanone (12b): 1H NMR (400 MHz,
CDCl3) δH 9.60 (br s, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.56−7.54
(m, 3H), 7.50 (dd, J = 7.5, 7.4 Hz, 1H), 7.48−7.45 (m, 1H), 7.26−
7.17 (m, 3H), 2.98 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.5 Hz, 2H), 1.94
(s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δC 186.1, 140.2, 137.0,
133.8, 131.0, 130.1, 129.0, 128.6, 128.3, 128.3 (2C), 127.6, 127.5,
127.5, 126.9, 122.8, 120.8, 29.7, 19.6, 11.7.
Dimethyl 2-(((E/Z)-(1-Phenylethylidene)amino)oxy)maleate
(5a).19 General Procedure A. To a stirred solution of DABCO (45
mg, 0.37 mmol) and (E)-acetophenone oxime (2a, 500 mg, 3.7 mmol)
in dichloromethane (32 mL) was added dropwise a mixture of
dimethylacetylene dicarbonate (3, 455 μL, 3.7 mmol) in dichloro-
methane (12 mL). The mixture was concentrated under reduced
pressure and the residue purified by flash column chromatography on
silica gel (6:1 petroleum ether/ethyl acetate) to afford dimethyl 2-
(((E/Z)-(1-phenylethylidene)amino)oxy)maleate (5a, 762 mg, 79%)
as a colorless oil that is an inseparable E/Z mixture (1:8): IR (CHCl3)
ν (cm−1), 3435, 3086, 2953, 2888, 2494, 1956, 1722, 1642, 1573,
1437, 1308, 1274, 1135, 1026, 946, 844, 637 cm−1; HRMS (ESI) m/z
[M + Na]+ calcd for C14H15NO5Na 300.0843, found 300.0849. (E)-
1
isomer: H NMR (400 MHz, CDCl3) δH 7.72−7.64 (m, 2H), 7.47−
Pyrrole 11c:12c. General Procedure E. (E)-4-phenyl-4-(((E)-(1-
phenylethylidene)amino)oxy)but-3-en-2-one (10c, 100 mg, 0.36
mmol), [Au(PPh3)Cl] (18 mg, 0.036 mmol), and AgBF4 (7 mg,
0.036 mmol) in toluene (2 mL) were heated to 100 °C for 18 h. The
residue was purified by flash column chromatography on silica gel
(15:1 petroleum ether/ethyl acetate) to afford an inseparable (1:5)
mixture of 1-(2,5-diphenyl-1H-pyrrol-3-yl)ethanone and (2-methyl-5-
phenyl-1H-pyrrol-3-yl)(phenyl)methanone (11c:12c, 54 mg, 57%) as
a brown oil: IR (CHCl3) ν (cm−1) 3441, 1730, 1448, 1110, 934 cm−1;
HRMS (ESI) m/z [M + Na]+ calcd for C18H15NNa, 284.1046, found
284.1037. 1-(2,5-Diphenyl-1H-pyrrol-3-yl)ethanone (11c): 1H NMR
(400 MHz, CDCl3) δH 9.69 (br s, 1H), 7.72 (dd, J = 7.6, 7.8 Hz, 2H),
7.63−7.59 (m, 2H), 7.54−7.50 (m, 2H), 7.42−7.40 (m, 2H), 7.35−
7.31 (m, 2H), 6.57 (d, J = 3.0 Hz, 1H), 2.10 (s, 3H); 13C {1H} NMR
(100 MHz, CDCl3) δC 186.4, 183.8, 136.1, 129.7 (2C), 129.3 (2C),
129.1 (2C), 128.7, 128.6, 128.3, 128.2 (2C), 128.0, 127.7, 110.8, 29.7.
7.41 (m, 3H), 5.93 (s, 1H), 3.95 (s, 3H), 3.72 (s, 3H), 2.39 (s, 3H);
13C NMR (100 MHz, CDCl3) δC 166.4, 163.0, 161.7, 160.6, 134.2,
1
130.7, 128.6 (2C), 126.7 (2C), 96.0, 52.9, 51.5, 13.8 (Z)-isomer: H
NMR (400 MHz, CDCl3) δH 7.66−7.60 (m, 2H), 7.43−7.37 (m, 3H),
6.04 (s, 1H), 3.87 (s, 3H), 3.69 (s, 3H), 2.46 (s, 3H); 13C NMR (100
MHz, CDCl3) δC 165.0, 162.9, 160.1, 153.4, 134.6, 130.2, 128.4 (2C),
126.6 (2C), 105.5, 52.7, 51.7, 13.6.
Ethyl 3-(((E/Z)-(1-Phenylethylidene)amino)oxy)acrylate (6a).19
General Procedure A. To a stirred solution of DABCO (36 mg, 0.3
mmol) and (E)-acetophenone oxime (2a, 400 mg, 3.0 mmol) in
dichloromethane (24 mL) was added dropwise a mixture of ethyl
propiolate (303 μL, 3.0 mmol) in dichloromethane (9 mL). The
mixture was concentrated under reduced pressure and the residue
purified by flash column chromatography on silica gel (4:1 petroleum
ether/ethyl acetate) to afford ethyl 3-(((E/Z)-(1-phenylethylidene)-
amino)oxy)acrylate (6a, 503 mg, 72%) as a colorless oil that is an
inseparable E/Z mixture (8:1): IR (CHCl3) ν (cm−1) 3180, 2961,
2872, 2728, 1701, 1615, 1573, 1465, 1312, 1129, 1048, 896, 840, 640;
HRMS (ESI) m/z [M + Na]+ calcd for C13H15NO3Na 256.0945,
found 256.0949. (E)-Isomer: 1H NMR (400 MHz, CDCl3) δH 8.11 (d,
J = 12.6 Hz, 1H), 7.74−7.67 (m, 2H), 7.46−7.37 (m, 3H), 5.71 (d, J =
12.6 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.37 (s, 3H), 1.31 (t, J = 7.1,
3H); 13C NMR (100 MHz, CDCl3) δC 167.6, 161.9, 160.3, 134.6,
1
(2-Methyl-5-phenyl-1H-pyrrol-3-yl)(phenyl)methanone (12c): H NMR
(400 MHz, CDCl3) δH 9.52 (br s, 1H), 7.70 (dd, J = 7.4, 7.2 Hz, 2H),
7.61 (d, J = 7.6, 7.2 Hz, 2H), 7.52−7.48 (m, 4H), 7.45−7.42 (m, 2H),
6.47 (d, J = 2.9 Hz, 1H), 2.03 (s, 3H); 13C {1H} NMR (100 MHz,
CDCl3) δC 188.6, 139.9, 137.4, 131.2, 130.9, 130.7, 129.1 (2C), 128.4
(s, 2C), 128.3, 128.2 (2C), 128.2, 125.0 (2C), 111.5, 14.1.
Pyrrole 21. To a stirred solution of DABCO (9 mg, 0.07 mmol) and
(E/Z)-1-(furan-2-yl)ethanone oxime (2r, 100 mg, 0.80 mmol) in
toluene (1.30 mL) was added dimethyl acetylenedicarboxylate (3, 98
μL, 0.80 mmol), and the resultant mixture was subjected to a two-stage
microwave irradiation sequence (stage 1, 80 °C, 10 min; stage 2, 170
°C, 45 min). Ditert-butyl dicarbonate (262 mg, 1.20 mmol), DMAP
(10 mg, 0.08 mmol), and triethylamine (111 μL, 0.80 mmol) were
added and the resultant mixture was stirred at rt for 30 min. The
mixture was concentrated under reduced pressure, and the residue was
purified by flash column chromatography on silica gel (9:1 petroleum
ether/ethyl acetate) to afford 1-tert-butyl 2,3-dimethyl 5-(furan-2-yl)-
1H-pyrrole-1,2,3-tricarboxylate (21, 143 mg, 51%) as a dark brown oil:
IR (CHCl3) ν (cm−1) 3631, 3458, 3008, 2945, 2838, 2460, 2337, 2010,
1741, 1603, 1515, 1445, 1371, 1252, 1155, 1125, 1016, 908, 848, 660
cm−1; 1H NMR (300 MHz, CDCl3) δH 7.49 (d, J = 5.0 Hz, 1H), 6.71
(s, 1H), 6.53 (d, J = 3.8 Hz, 1H), 6.44 (dd, J = 5.0, 3.8 Hz, 1H), 3.97
(s, 3H), 3.84 (s, 3H), 1.45 (s, 9H); 13C {1H} NMR (75 MHz, CDCl3)
δc 163.1, 162.4, 147.5, 144.7, 142.6, 132.4, 125.3, 117.4, 114.0, 111.0,
110.3, 86.3, 53.0, 51.9, 27.5; HRMS (ESI) m/z [M + H]+ calcd for
C17H19NO7 350.1235, found 350.1218.
Mechanistic Study: Synthesis of starting materials and other
intermediates. (E)-Acetophenone Oxime (2a).18 A stirred solution of
pyridine (0.66 mL, 8.3 mmol), acetophenone (1.0 g, 8.3 mmol), and
hydroxylamine·HCl (0.87 g, 8.3 mmol) were refluxed in ethanol (50
mL) for 12 h. The solvent was removed under reduced pressure and
water (30 mL) and EtOAc (30 mL) were added. The organic layer was
dried over sodium sulfate and the solvente removed under reduced
pressure to afford (E) acetophenone oxime (2a, 1.02 g, 91%) as a
white solid: mp 56−58 °C (lit.18 mp 55−60 °C); IR (CHCl3) ν
(cm−1) 3250, 3112, 3060, 3035, 2930, 1490, 1371, 1302, 1082, 1005,
927, 754, 690 cm−1; 1H NMR (300 MHz, CDCl3) δH 8.59 (br s, 1H),
7.71−7.59 (m, 2H), 7.44−7.34 (m, 3H), 2.32 (s, 3H); 13C {1H} NMR
(75 MHz, CDCl3) δC 155.9, 136.4, 129.2, 128.4 (2C), 126.0 (2C),
12.4; HRMS (ESI) m/z [M + Na]+ calcd for C8H9NONa 158.0577,
found 158.0581.
1
130.4, 128.6 (2C), 126.9 (2C), 97.3, 59.8, 14.3, 13.6. (Z)-Isomer: H
NMR (400 MHz, CDCl3) δH 7.77−7.68 (m, 2H), 7.49 (d, J = 7.5 Hz,
1H), 7.49−7.45 (m, 3H), 4.94 (d, J = 7.5 Hz, 1H), 4.24 (q, J = 7.1 Hz,
2H), 1.31 (t, J = 7.1 Hz, 3H), 2.48 (s, 3H). 13C NMR (100 MHz,
CDCl3) δC 165.2, 159.9, 159.2, 134.6, 130.2, 128.3 (2C), 125.9 (2C),
94.3, 59.7, 14.1, 13.6.
Dimethyl 1-Benzyl-1H-1,2,3-triazole-4,5-dicarboxylate (17).65 To
a stirred solution of dimethyl acetylenedicarboxylate (3, 60 μL, 0.5
mmol) in toluene (0.5 mL) at rt was added benzyl azide (73 μL, 0.55
mmol). The reaction mixture was stirred at 100 °C for 3 h and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (3:1 petroleum ether/ethyl
acetate) to afford dimethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxy-
late (17, 0.13 g, 93%) as a white solid: mp 65−67 °C (lit.65 mp 64−66
1
°C); IR (CHCl3) ν (cm−1) 2255, 1734, 1497, 1061, 825 cm−1; H
NMR (400 MHz, CDCl3) δH 7.33−7.15 (m, 5H, H), 5.41 (s, 2H),
3.92 (s, 3H), 3.84 (s, 3H); 13C {1H} NMR (100 MHz, CDCl3) δc
159.9, 158.3, 139.7, 133.4, 129.3, 128.5, 128.4, 127.5, 53.5, 52.8, 52.2;
HRMS (ESI) m/z [M + Na]+ calcd for C13H13 N3NaO4 298.0799,
found 298.0802.
Ethyl 1-Benzyl-1H-1,2,3-triazole-4-carboxylate/Ethyl 1-Benzyl-
1H-1,2,3-triazole-5-carboxylate (18a:18b).66 To a stirred solution
of ethyl propiolate (4, 51 μL, 0.50 mmol) in toluene (0.5 mL) at rt was
added benzyl azide (73 μL, 0.55 mmol). The reaction mixture was
stirred at 100 °C for 3 h and concentrated under reduced pressure.
The residue was purified by flash column chromatography on silica gel
(4:1 petroleum ether/ethyl acetate) to afford a separable mixture of
regioisomers (6:1) ethyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate/
ethyl 1-benzyl-1H-1,2,3-triazole-5-carboxylate (18a:18b, 97 mg,
94%) as white solids: mp 81−83 °C (lit.66 mp 82−83 °C); IR
(CHCl3) ν (cm−1) 3630, 3458, 3154, 3008, 2945, 2838, 2461, 2019,
1721, 1603, 1549, 1463, 1376, 1334, 1240, 1073, 1014, 909, 840, 660
cm−1; HRMS (ESI) m/z [M + Na]+ calcd for C12H13 N3NaO2
K
dx.doi.org/10.1021/jo302349k | J. Org. Chem. XXXX, XXX, XXX−XXX