Benzofurans as Efficient Dienophiles
14.5, 17.0, 21.1, 27.0, 34.2, 35.3, 65.0, 86.3, 110.0, 120.3, 125.4,
125.8, 130.3, 131.5, 136.0, 158.9, 161.9, 195.0; IR (NaCl) ν 3391,
3047, 3014, 2932, 2857, 1681, 1476, 1241, 1157 cm-1; MS (CI,
i-butane) m/z (relative intensity) 298 [M + H]+ (100); HRMS calcd
for C18H20NO3 [M + H]+ 298.1444, found 298.1457.
3.65 (s, 3H), 5.40 (d, J ) 6.0 Hz, 1H), 7.14-7.26 (m, 2H), 7.31
(d, J ) 6.0 Hz, 1H), 7.39 (d, J ) 7.9 Hz, 1H), 7.58 (s, 1H), 7.67
(d, J ) 8.3 Hz, 1H); 13C NMR δ 43.2, 53.8, 82.4, 108.2, 112.0,
117.8, 121.4, 123.6, 124.4, 125.4, 143.5, 155.8, 160.9, 169.2, 189.3;
IR (NaCl) ν 3152, 3107, 3075, 2955, 2933, 2848, 1746, 1682, 1599,
1453, 1273 cm-1; MS (CI, i-butane) m/z (relative intensity) 273
[M + H]+ (100). Anal. Calcd for C15H12O5: C, 66.17; H, 4.44.
Found: C, 66.19; H, 4.42.
Representative Procedure for the Cycloaddition of Benzofu-
ran 10b with 2-Trimethylsilyloxybutadiene (16). High-Pressure
Activation. To a solution of benzofuran 10b (0.049 g, 0.2 mmol)
in anhydrous THF (0.9 mL), stirred at room temperature under
argon, was added 2-trimethylsilyloxybutadiene (16) (0.142 g, 1
mmol). The resulting mixture was transferred into a high-pressure
vessel and compressed at 1.6 GPa, 50 °C for 48 h. After
decompression, the solvent and excess of diene were removed under
reduced pressure. The excess diene was removed by bulb-to-bulb
distillation under reduced pressure (60 °C/0.2 mmHg). The residue
was dissolved in MeOH (5 mL), SiO2 was added, and the mixture
was stirred overnight. The reaction mixture was filtered over Celite,
washed with EtOAc, and purified by flash chromatography on silica
(EtOAc/cyclohexane 1:9 to 3:7) to furnish 17d as a colorless oil
High-Pressure Activation in the Presence of an Excess of
Diene. To a solution of benzofuran 8 (0.100 g, 0.49 mmol) in
anhydrous CH2Cl2 (1.8 mL), at room temperature, under argon,
was added Danishefsky’s diene 18 (0.48 mL, 2.45 mmol). The
resulting mixture was transferred into a high-pressure vessel and
compressed at 1.2 GPa for 24 h. After decompression, the solvent
was removed under reduced pressure. The excess diene was
removed by bulb-to-bulb distillation under reduced pressure (60
°C/0.2 mmHg). The residue was dissolved in MeOH (5 mL), SiO2
was added, and the mixture was stirred overnight. The reaction
mixture was filtered over Celite, washed with EtOAc, and purified
by flash chromatography on silica (EtOAc/cyclohexane 1:9-1:1)
1
(0.046 g, 73%): H NMR δ 0.92 (t, J ) 7.2 Hz, 3H), 1.10 (t, J )
1
furnished 22b as a white solid (0.145 g, 73%): H NMR δ 1.92
7.2 Hz, 3H), 1.91-2.04 (m, 1H), 2.30-2.38 (m, 1H), 2.55-2.60
(m, 2H), 2.87-2.94 (m, 4H), 3.25-3.47 (m, 2H), 5.52 (dd, J )
3.8, 3.8 Hz, 1H), 6.78 (d, J ) 7.5 Hz, 1H), 6.93 (dd, J ) 7.5, 7.5
Hz, 1H), 7.21 (ddd, J ) 1.2, 7.5, 7.5 Hz, 1H), 7.34 (dd, J ) 1.2,
7.5 Hz, 1H); 13C NMR δ 12.5, 13.8, 31.6, 35.3, 38.9, 42.1, 42.5,
59.3, 82.6, 110.3, 121.8, 124.7, 125.3, 130.6, 159.7, 166.0, 200.7,
208.1; IR (NaCl) ν 2976, 2935, 2842, 1723, 1640, 1478, 1462,
1252 cm-1; MS (EI) m/z (relative intensity) 315 [M+•] (3), 187
(49), 131 (33), 100 (100), 72 (71), 55 (97). Anal. Calcd for
C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C, 68.49; H, 6.86;
N, 4.45.
(dd, J ) 2.3, 18.5 Hz, 1H), 2.45 (d, J ) 3.8 Hz, 2H), 2.59 (dd, J
) 3.4, 18.5 Hz, 1H), 2.71-3.13 (m, 4H), 3.24 (s, 3H), 3.59 (s,
3H), 3.62 (s, 3H), 4.20 (m, 1H), 5.20 (dd, J ) 4.1, 4.1 Hz, 1H),
5.85 (m, 1H), 6.74 (d, J ) 8.1 Hz, 1H), 6.83 (ddd, J ) 0.8, 7.6,
7.6 Hz, 1H), 7.17-7.24 (m, 2H); 13C NMR δ 39.2, 43.2, 43.7, 44.0,
52.4, 56.7, 57.2, 78.9, 80.5, 81.6 (2C), 100.3, 110.6, 120.8, 125.9,
126.3, 131.2, 160.4, 173.1, 201.8, 207.5; IR (NaCl) ν 3029, 2948,
2930, 2837, 2930, 1723, 1478, 1461, 1248 cm-1; MS (EI) m/z
(relative intensity) 404 [M+•] (5), 372 (13), 217 (65), 202 (15),
185 (32), 157 (16), 131 (100), 115 (14), 101 (12), 84 (47). Anal.
Calcd for C21H24O8: C, 64.51; H, 5.41. Found: C, 64.46; H, 5.59.
Computational Details. Full geometry optimizations were
systematically conducted with no symmetry restraints using the
Gaussian 03 program28 within the framework of the density
functional theory (DFT). Unless otherwise mentioned, the hybrid
B3LYP exchange-correlation functional29 was used, associated to
the 6-31G** basis set for all atoms. This level of theory has been
previously shown to be reliable for similar organic systems30 and
was confirmed from the validation computations reported in this
study. Implicit solvation by THF using the PCM model31 was also
examined by single point calculation on the optimized structures
and was shown to be of no significant effect: it is thus not used
unless otherwise mentionned. Frequencies were evaluated within
the harmonic approximation, and the stationary points were
characterized in order to verify that minima (reactants, intermediates
and adducts) and transition states (TS) have zero and one imaginary
frequency, respectively. Thermal and pressure corrections to the
Representative Procedure for the Cycloaddition of Benzofu-
ran 8 with 1-Methoxy-3-trimethylsilyloxybutadiene (18). High-
Pressure Activation. To a solution of benzofuran 8 (0.204 g, 1
mmol) in anhydrous THF (5.5 mL) at room temperature under
argon, was added Danishefsky’s diene 18 (0.195 mL, 1 mmol).
The resulting mixture was transferred into a high-pressure vessel
and compressed at 1.2 GPa for 8 h. After decompression, the solvent
was removed under reduced pressure. The excess of diene was
removed by bulb-to-bulb distillation under reduced pressure (60
°C/0.2 mmHg). The residue was dissolved in MeOH (5 mL), and
NH4F (0.040 g, 1 mmol) was added at -30 °C. The resulting
mixture was stirred for 15 min and was then concentrated under
reduced pressure. Purification by flash chromatography on Florisil
1
(EtOAc/cyclohexane 1:9-1:1) afforded 19b (0.170 g, 56%): H
NMR δ 2.04 (dd, J ) 1.9, 18.1 Hz, 1H), 2.65 (dd, J ) 3.8, 18.1
Hz, 1H), 2.73 (dd, J ) 3.4, 18.1 Hz, 1H), 2.89 (dd, J ) 3.0, 18.1,
1H), 3.14 (s, 3H), 3.89 (s, 3H), 4.55-4.56 (m, 1H), 5.78 (dd, J )
3.4, 3.8 Hz, 1H), 6.74 (dd, J ) 0.8, 7.9 Hz, 1H), 6.87 (ddd, J )
0.8, 7.9, 7.9 Hz, 1H), 7.17 (ddd, J ) 1.1, 7.9, 7.9 Hz, 1H), 7.69
(dd, J ) 1.1, 7.9 Hz, 1H); 13C NMR δ 37.6, 40.9, 53.2, 56.2, 63.2,
80.6, 81.2, 110.6, 121.7, 125.3, 126.4, 131.0, 159.4, 161.6, 190.0,
205.9; IR (NaCl) ν 3072, 3066, 3028, 2953, 2931, 2832, 1732,
1591, 1477, 1281 cm-1; MS (EI) m/z (relative intensity) 304 [M+•]
(25), 145 (100), 131 (67), 100 (46); HRMS calcd for C16H17O6 [M
+ H]+ 305.1059, found 305.1025.
(28) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian,
H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg,
J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.;
Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill,
P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
Gaussian, Inc., Wallingford, CT, 2004.
(29) (a) Lee, C.; Yang, W.; Parr, R. G. Phys ReV. B 1988, 37, 785. (b)
Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H Chem. Phys. Lett. 1989, 157, 200.
(c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(30) See for instance: (a) Khuong, K. S.; Beaudry, C. M.; Trauner, D. K.;
Houk, N J. Am. Chem. Soc. 2005, 127, 3688. (b) Afarinkia, K.; Beapark, M. J.;
Ndibwami, A J. Org. Chem. 2005, 70, 1122. (c) Arroyo, P. M.; Picher, T.;
Domingo, L. R.; Terrier, F Tetrahedron 2005, 61, 7359.
Lewis Acid Activation. To a stirring solution of the benzofuran
8 (0.100 g, 0.5 mmol) in dry CH2Cl2 (2 mL) was added ZnCl2
(0.007 g, 0.05 mmol) at room temperature. The mixture was stirred
for 30 min, and Danishefsky’s diene 18 (0.480 mL, 2.5 mmol) was
then added. After 192 h stirring at room temperature, the solvent
was removed under reduced pressure. Excess diene was then
removed by bulb-to-bulb distillation under reduced pressure (60
°C/0.2 mmHg). The residue was dissolved in MeOH (5 mL), SiO2
was added, and the mixture was stirred overnight. The reaction
mixture was filtered over Celite, washed with EtOAc, and then
purified by flash chromatography on silica (EtOAc/cyclohexane
1:9-3:7) afforded21b as a white solid (0.084 g, 62%, mp 114 °C):
1H NMR δ 3.11 (d, J ) 16.6 Hz, 1H), 3.34 (d, J ) 16.6 Hz, 1H),
(31) M.Cossi, G.; Scalmani, N.; Rega, V; Barone, J. Chem. Phys. 2002, 117,
43, and references therein.
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