N-Acylamide Methylenation-Enamide RCM
δ 22.0 (CH3), 28.1 (CH3), 35.2 (CH2), 80.5 (C), 105.8 (CH2), 116.8
(CH2), 126.8 (CH), 127.3 (CH), 128.7 (CH), 129.8 (CH), 136.2
(CH), 137.5 (C), 140.7 (C), 144.3 (C), 153.2 (C); HRMS (CI) calcd
for C17H24NO2 274.1807 (M + 1), found 274.1882.
General Procedure for the RCM Step. A solution of the
appropriate enamide (1 mmol) and the second generation Grubbs
catalyst (0.06 mmol) in anhydrous toluene was stirred at 80 or 110
°C under Ar and monitored by TLC to establish completion of the
reaction. In some cases, a new addition of the catalyst was needed
(see text). The reaction mixture was concentrated, and the resulting
residue was chromatographed (flash, SiO2).
five- or six-membered cyclic enamides (indoles, 1,4-dihydro-
quinolines, and 1,2-dihydroisoquinolines) from amides derived
from ortho-alkenyl anilines or benzylamines. The extension to
higher homologues is also possible, although limited by the
interference of alkene isomerization processes in the slow RCM
step. From some substrates, in particular, styrene derivatives,
the direct annulation is observed in the titanium-mediated step,
which probably occurs through an olefin metathesis-intramo-
lecular olefination tandem process.
Experimental Section
1-(Methoxycarbonyl)-3-methylindole (3, Table 1, entry 3).
Crystallized from Et2O; 90% yield. The NMR spectra match the
literature data.34
1-(Methoxycarbonyl)-2-methylindole (4, Table 1, entry 4).
Elution with 97:3 hexanes/AcOEt; 85% yield. The NMR spectra
match the literature data.35
1-(Methoxycarbonyl)indole (5, Table 1, entry 5). Elution with
97:3 hexanes/AcOEt; 90% yield. The NMR spectra match the
literature data.34
1-(Methoxycarbonyl)-2-methyl-1,4-dihydroquinoline (10a, Table
2, entry 1). Elution with 9:1 hexanes/AcOEt; 80% yield; 1H NMR
(CDCl3, 300 MHz) δ 2.17 (m, 3H), 3.15 (d, J ) 4.8 Hz, 2H), 3.80
(s, 3H), 5.52 (tq, J ) 1, 1, 1, 4.8, 4.8 Hz, 1H), 7.10 (m, 2H), 7.20
(m, 1H), 7.57 (d, J ) 7.6 Hz, 1H); 13C NMR (CDCl3, 75.4 MHz)
δ 20.1 (CH3), 28.3 (CH2), 52.9 (CH3), 116.5 (CH), 124.3 (CH),
125.0 (CH), 125.5 (CH), 126.8 (CH), 133.0 (C), 138.1 (C), 139.2
(C), 154.0 (C); HRMS (CI) calcd for C12H14NO2 204.1024 (M +
1), found 204.1045.
1-(tert-Butoxycarbonyl)-2-methyl-1,4-dihydroquinoline (10b,
Table 2, entry 2). Elution with 9:1 hexanes/AcOEt; 80% yield;
1H NMR (CDCl3, 200 MHz) δ 1.53 (s, 9H), 2.14 (br q, J ) 1.4
Hz, 3H), 3.14 (m, 2H), 5.45 (m, 1H), 7.08 (m, 1H), 7.20 (m, 2H),
7.61 (d, J ) 8.2 Hz, 1H); HRMS (CI) calcd for C15H20NO2 (M +
1) 246.3248, found 246.3259.
General Procedure for the Dimethyltitanocene Methylena-
tion. MeLi (1.6 M) in Et2O (1.32 mL, 2.1 mmol) was slowly added
in the dark under Ar to a suspension of Cp2TiCl2 (249 mg, 1 mmol)
in anhydrous Et2O (4 mL) cooled at 0 °C. After stirring at 0 °C for
1 h, the reaction mixture was poured into H2O (5 mL). The organic
layer was concentrated and dried to give Cp2TiMe2 as an orange
solid. A solution of the above solid (1 mmol) in anhydrous toluene/
pyridine (100:1, 6 mL) was added under Ar to a solution of the
appropriate amide (0.67 mmol) in anhydrous toluene (1 mL) at room
temperature, and the resulting mixture was stirred at reflux
temperature in the dark for 4 h. The solvent was removed, and the
resulting residue was treated with 8:2 Et2O/CH2Cl2. The precipitate
was filtered and the filtrate concentrated. The reaction mixture was
1
analyzed by H NMR. Enamides 2a-f and 9a,b were purified by
flash chromatography. The others were directly used in the RCM
step.
Methyl (1-Methylethenyl)[2-(1-methylethenyl)phenyl]car-
bamate (2a, Table 1, entry 1). Elution with 9:1 hexanes/AcOEt;
1
45% yield; H NMR (CDCl3, 300 MHz) δ 2.02 (m, 3H), 2.08 (d,
J ) 0.6 Hz, 3H), 3.64 (s, 3H), 4.43 (s, 1H), 4.65 (q, J ) 1.2 Hz,
1H), 4.95 (m, 1H), 5.14 (m, 1H), 7.14 (m, 1H), 7.25-7.30 (m,
3H); 13C NMR (CDCl3, 75.4 MHz) δ 21.7 (CH3), 23.3 (CH3), 52.8
(CH3), 106.6 (CH2), 115.4 (CH2), 127.3 (CH), 127.6 (CH), 129.1
(CH), 129.2 (CH), 138.8 (C), 141.6 (C), 142.8 (C), 145.3 (C), 154.5
(C); HRMS (CI) calcd for C14H18NO2 231.1259 (M + 1), found
231.1338.
1-(tert-Butoxycarbonyl)-1,4-dihydroquinoline (10c, Table 2,
entry 3). Unstable compound; elution with 1:1 hexanes/CH2Cl2;
1
45% yield; H NMR (CDCl3, 200 MHz) δ 1.57 (s, 9H), 3.33 (dd,
J ) 1, 4 Hz, 2H), 5.26 (dt, J ) 4.4, 4.4, 7.2 Hz, 1H), 6.90 (dt, J
) 1.4, 1.4, 7.6 Hz, 1H), 7.05 (m, 2H), 7.19 (m, 1H), 7.90 (d, J )
8 Hz, 1H).
tert-Butyl (1-Methylethenyl)[2-(1-methylethenyl)phenyl]car-
bamate (2b, Table 1, entry 2). Elution with 9:1 hexanes/AcOEt;
65% yield; H NMR (CDCl3, 200 MHz) δ 1.39 (s, 9H), 2.05 (s,
1
6H), 4.39 (s, 1H), 4.58 (d, J ) 1 Hz, 1H), 4.99 (m, 1H), 5.13 (m,
1H), 7.05 (m, 1H), 7.25 (m, 3H); HRMS (CI) calcd for C17H24-
NO2 273.1729 (M + 1), found 273.1807.
2-(Methoxycarbonyl)-3-methyl-1,2-dihydroisoquinoline (18a,
Table 3, entry 1). Unstable compound; elution with 85:15 hexanes/
AcOEt; 55% yield. The NMR spectra match the literature data.36
Methyl [2-(1-Methylethenyl)phenyl]vinylcarbamate (2c, Table
1, entry 3). Elution with 98:2 hexanes/AcOEt; 61% yield; 1H NMR
(CDCl3, 200 MHz) δ 1.98 (s, 3H), 3.66 (br s, 3H), 3.84 (d, J )
15.8 Hz, 1H), 4.29 (d, J ) 8.8 Hz, 1H), 4.90 (br s, 1H), 5.09 (m,
1H), 7.12 (m, 1H), 7.25-7.40 (m, 4H); 13C NMR (CDCl3, 75.4
MHz) δ 23.4 (CH3), 53.2 (CH3), 94.5 (CH2), 115.1 (CH2), 127.9
(CH), 128.3 (CH), 129.3 (CH), 129.4 (CH), 134.3 (C), 135.0 (CH),
142.2 (C), 142.7 (C), 154.2 (C); HRMS (CI) calcd for C13H16NO2
217.1103 (M + 1), found 217.1181.
2-(tert-Butoxycarbonyl)-3-methyl-1,2-dihydroisoquinoline (18b,
Table 3, entry 2). Unstable compound; elution with 95:5 hexanes/
AcOEt; 50% overall yield from amide 16b; 1H NMR (CDCl3, 200
MHz) δ 1.49 (s, 9H), 2.25 (d, J ) 1.2 Hz, 3H), 4.69 (s, 2H), 5.95
(q, J ) 1.2 Hz, 1H), 7.01 (d, J ) 7.2 Hz, 1H), 7.10-7.25 (m, 3H);
13C NMR (CDCl3, 75.4 MHz) δ 21.6 (CH3), 28.4 (CH3), 47.6 (CH2),
81.2 (C), 114.1 (CH), 123.5 (CH), 124.8 (CH), 126.3 (CH), 127.4
(CH), 130.8 (C), 132.6 (C), 138.0 (C), 152.6 (C).
2-(tert-Butoxycarbonyl)-1,2-dihydroisoquinoline (18c, Table
3, entry 3). Unstable compound; elution with 95:5 hexanes/AcOEt;
60% yield. The NMR spectra match the literature data.37
Methyl (2-Allylphenyl)(1-methylethenyl)carbamate (9a, Table
1
2, entry 1). Elution with 82:18 hexanes/AcOEt; 51% yield; H
NMR (CDCl3, 300 MHz) δ 2.07 (d, J ) 0.8 Hz, 3H), 3.29 (d, J )
6.2 Hz, 2H), 3.65 (s, 3H), 4.52 (s, 1H), 4.68 (q, J ) 1.2 Hz, 1H),
5.06 (m, 1H), 5.13 (m, 1H), 5.88 (m, 1H), 7.12 (m, 1H), 7.20-
7.30 (m, 3H); 13C NMR (CDCl3, 75.4 MHz) δ 21.8 (CH3), 35.2
(CH2), 52.9 (CH3), 106.4 (CH2), 116.4 (CH2), 127.0 (CH), 127.7
(CH), 128.7 (CH), 130.0 (CH), 135.9 (CH), 137.7 (C), 139.8 (C),
144.1 (C), 154.6 (C); HRMS (CI) calcd for C14H18NO2 231.1259
(M + 1), found 231.1338.
tert-Butyl (2-Allylphenyl)(1-methylethenyl)carbamate (9b,
Table 2, entry 2). Elution with 95:5 hexanes/AcOEt; 55% yield;
1H NMR (CDCl3, 300 MHz) δ 1.38 (s, 9H), 2.05 (s, 3H), 3.30 (m,
2H), 4.47 (s, 1H), 4.62 (s, 1H), 5.03 (m, 1H), 5.17 (m, 1H), 5.92
(m, 1H), 7.13 (m, 1H), 7.22 (m, 3H); 13C NMR (CDCl3, 75.4 MHz)
3-(tert-Butoxycarbonyl)-9-(methoxymethyl)-1,2,3,4-tetrahydro-
γ-carboline (22). The unstable cyclic enamide obtained after the
RCM step was treated at room temperature with 5% Pd/C in MeOH
under a H2 atmosphere for 4 h; elution with 9:1 hexanes/AcOEt;
35% yield from amide 20; 1H NMR (CDCl3, 200 MHz) δ 1.51 (s,
9H), 2.88 (m, 2H), 3.24 (s, 3H), 3.85 (m, 2H), 4.65 (s, 2H), 5.39
(34) Wenkert, E.; Alonso, M. E.; Gottlieb, H. E.; Sanchez, E. L. J. Org.
Chem. 1977, 42, 3945-3949.
(35) Nagarathnam, D. Synthesis 1992, 743-745.
(36) Beugelmans, R.; Chastanet, J.; Roussi, G. Tetrahedron 1984, 40,
311-314.
(37) Clarl, R. D.; Jahangir. Heterocycles 1991, 32, 1699-1703.
J. Org. Chem, Vol. 71, No. 18, 2006 7033