The Journal of Organic Chemistry
NOTE
122.3, 124.0, 126.5, 128.1, 129.6, 129.7, 133.6, 136.9, 140.6, 159.0;
HRMS obsd 323.0389, calcd 323.0394 for C14H16N2O2Br (M + H).
(R)-2,2,2-Trichloro-1-(1-(2-bromo)phenylethyl-1H-pyrrol-2-yl)eth-
20.8, 56.4, 59.9, 108.3, 119.0, 123.0, 123.4, 125.5, 126.3, 128.0, 133.3, 142.8,
160.9; HRMS obsd 322.0437, calcd 322.0441 for C15H17NO2Br, M + H.
General Procedure for Conversion of Trichloroacetyl to
Amide. The substrate (0.2 mmol) was treated with 2 M MeNH2 in
THF (0.5 mL) at room temperature for 3À5 h. The reaction mixture
was then concentrated followed by column chromatography purification
on silica gel (hexanes/ethyl acetate) to give the title compound.
(R)-1-(2-Bromophenylethyl)-1H-pyrrol-N-methyl-2-carboxamide
(1o): viscous liquid; 98% yield; 1H NMR (500 MHz, CDCl3) δ 1.81 (d,
J = 7.0 Hz, 3H), 2.86 (d, J = 5.5 Hz, 3H), 5.78 (br, 1H), 6.13À6.15 (m,
1H), 6.54 (dd, J = 4.0, 1.5 Hz, 1H), 6.78 (q, J = 7.0 Hz, 1H), 6.85À6.86
(m, 1H), 6.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.10 (dt, J = 7.0, 1.5 Hz, 1H), 7.23
(dt, J = 7.0, 1.5 Hz, 1H), 7.55 (dd, J = 8.0, 1.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 20.9, 26.2, 55.8, 107.5, 111.9, 123.5, 123.7, 126.3, 126.6,
127.7, 128.8, 133.3, 142.6, 162.4; HRMS obsd 307.0440, calcd 307.0444
for C14H16N2OBr, M + H.
(R)-1-(2-Bromobenzyl)-1H-pyrrol-N-methyl-2-carboxamide (1p): white
solid; 99% yield; mp 96À98 °C; IR (KBr, cmÀ1) 1028, 1260, 1542, 1647,
3020, 3469; 1H NMR (500 MHz, CDCl3) δ2.90(d, J=5.0Hz, 3H), 5.68(s,
2H), 5.87 (br, 1H), 6.17 (dd, J = 4.0, 2.5 Hz, 1H), 6.58 (dd, J = 4.0, 1.5 Hz,
1H), 6.62 (dd, J=8.0, 1.0Hz, 1H), 6.77(dd,J= 2.5, 1.5 Hz, 1H), 7.10 (dt, J=
8.0, 2.0 Hz, 1H), 7.18 (dt, J = 8.0, 2.0 Hz, 1H), 7.54 (dd, J = 8.0, 1.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 26.2, 52.2, 108.2, 111.9, 122.3, 126.0, 127.3,
127.8, 128.1, 128.8, 132.6, 138.5, 162.5. Anal. Calcd for C13H13N2OBr: C,
53.26; H, 4.47; N, 9.56. Found: C, 53.14; H, 4.53; N, 9.59.
General Procedure for Palladium-Catalyzed Cyclizations.
To a solution of substrate (0.1 mmol) in DMF or dioxane (1 mL) were
added Pd(OAc)2 (0.01 mmol) or Pd2(dba)3 (0.005 mmol), no ligand
(conditions C) or a ligand (0.01À0.02 mmol) [Sphos (conditions D),
PPh3 (conditions E), or Xantphos (condition F)], and anhydrous K2CO3
or Cs2CO3 (0.5 mmol). The reaction mixture was heated at 100 or
120 °C for 24 h in a screw-capped vial and then concentrated under
reduced pressure. Excess ethyl acetate was added to the solid black
residue. The organic layer was washed with water and brine, dried over
anhydrous Na2SO4, and then filtered. The filtrate was concentrated
followed by column chromatography purification on silica gel (hexanes/
ethyl acetate) to give the title compounds.
1
an-1-one (1j-TCA): viscous liquid; 62% yield; H NMR (400 MHz,
CDCl3) δ 1.82 (d, J = 7.0 Hz, 3H), 6.27 (dd, J = 4.5, 1.5 Hz, 1H), 6.57 (q,
J = 7.0 Hz, 1H), 6.85 (dd, J = 7.0, 1.5 Hz, 1H), 7.07À7.09 (m, 1H), 7.13
(dt,J=7.0,1.5Hz,1H),7.23(dt,J= 7.0, 1.5 Hz, 1H), 7.56 (dd, J= 7.5, 1.5 Hz,
1H), 7.60 (dd, J = 4.5, 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9,
57.4, 109.3, 122.0, 124.0, 124.9, 126.5, 127.9, 129.3, 129.8, 133.5, 141.3,
172.5; HRMS obsd 392.9092, calcd 392.9090 for C14H11NOCl3Br.
(R)-2,2,2-Trichloro-1-(2-bromobenzyl-1H-pyrrol-2-yl)ethan-1-one
(1k-TCA): white solid; 51% yield; mp 96À98 °C; 1H NMR (500 MHz,
CDCl3) δ 5.63 (s, 2H), 6.34 (dd, J = 4.0, 2.5 Hz, 1H), 6.53 (dd, J = 8.0,
1.5 Hz, 1H), 7.03 (dd, J = 2.5, 1.5 Hz, 1H), 7.15 (dt, J = 8.0, 2.0 Hz, 1H),
7.21 (dt, J = 8.0, 2.0 Hz, 1H), 7.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.64 (dd, J =
4.0, 1.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 53.9, 96.2, 109.8,
121.7, 122.4, 124.7, 127.3, 128.0, 129.2, 132.9, 133.3, 136.9, 172.8;
HRMS obsd 378.8936, calcd 378.8933 for C13H9NOCl3Br.
(R)-Ethyl 1-(1-(2-bromo)phenylethyl)-1H-indole-3-carboxylate (1l):
white solid; 55% yield; mp 94À96 °C; 1H NMR (500 MHz, CDCl3) δ
1.45 (t, J = 7.5 Hz, 3H), 1.93 (d, J = 7.5 Hz, 3H), 4.39À4.46 (m, 2H),
6.03 (q, J = 7.0 Hz, 1H), 6.80 (dd, J = 7.5, 1.5 Hz, 1H), 7.10À7.17 (m,
4H), 7.19À7.24 (m, 1H), 7.60 (dd, J = 7.5, 1.5 Hz, 1H), 8.13 (s, 1H),
8.17 (d, J = 8.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.6, 20.5,
55.2, 59.8, 107.9, 110.7, 121.7, 122.1, 122.3, 122.9, 126.5, 128.3, 129.4,
131.3, 133.1, 137.5, 138.0, 141.5, 165.0; HRMS obsd 372.0593, calcd
372.0602 (C19H19NO2Br, M + H).
(R)-2,2,2-Trichloro-1-(1-(2-bromo)phenylethyl-1H-indol-3-yl)-
ethan-1-one (1l-TCA): viscous liquid; 74% yield; 1H NMR (500 MHz,
CDCl3) δ 1.98 (d, J = 7.0 Hz, 3H), 6.10 (q, J = 7.0 Hz, 1H), 6.82 (dd, J =
7.0, 2.0 Hz, 1H), 7.14À7.23 (m, 4H), 7.32À7.36 (m, 1H), 7.62À7.64
(m, 1H), 8.42 (d, J = 8.0 z, 1H), 8.50 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.4, 55.7, 55.8, 96.9, 105.8, 111.0, 122.4, 122.7, 123.9, 124.2,
126.2, 128.5, 129.7, 133.3, 134.3, 136.4, 139.9, 176.8; HRMS obsd
442.9245, calcd 442.9246 for C18H13NOCl3Br.
Ethyl 1-(2-bromophenethyl)-1H-imidazole-5-carboxylate (1m): vis-
cous liquid; 65% yield; 1H NMR (500 MHz, CDCl3) δ 1.39 (t, J = 7.0
Hz, 3H), 3.23 (t, J = 7.0 Hz, 2H), 4.36 (q, J = 7.0 Hz, 2H), 4.55 (t, J = 7.0
Hz, 2H), 6.98 (dd, J = 8.0, 2.0 Hz, 1H), 7.11 (dt, J = 7.0, 1.5 Hz, 1H), 7.18
(dt, J = 7.0, 1.5 Hz, 1H), 7.25 (s, 1H), 7.56 (dd, J = 7.0, 1.5 Hz, 1H), 7.72
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.2, 37.5, 46.3, 60.4, 122.3,
124.3, 131.0, 132.8, 132.9, 136.7, 137.7, 137.8, 141.9, 160.2; HRMS obsd
323.0389, calcd 323.0392 for C14H16N2O2Br, M + H.
Ethyl 5-methylimidazo[2,1-a]isoindole-3-carboxylate (2a): white
solid; 93% yield; mp 75À77 °C; IR (KBr, cmÀ1) 2925, 1695, 1243;
1H NMR (500 MHz, CDCl3) δ 1.41 (t, J = 7.0 Hz, 3H), 1.77 (d, J = 7.0
Hz, 3H), 4.39 (q, J = 7.0 Hz, 2H), 5.38 (q, J = 7.0 Hz, 1H), 7.41À7.48 (m,
3H), 7.86À7.90 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 14.5, 19.8, 58.5,
60.7, 120.8, 122.1, 122.9, 128.2, 128.6, 128.8, 145.0, 148.9, 155.9, 160.2;
HRMS obsd 243.1129, calcd 243.1128 for C14H15N2O2, M + H.
Ethyl 5-methylimidazo[5,1-a]isoindole-3-carboxylate (2b): white
Ethyl 1-(2-bromophenyl-1-propanol)-1H-imidazole-5-carboxylate
1
(1n): viscous liquid; 67% yield; H NMR (500 MHz, CDCl3) δ 1.36
1
(t, J = 7.5 Hz, 3H), 2.09À2.16 (m, 2H), 2.74 (t, J = 8.5 Hz, 2H), 4.32 (q, J
= 7.0 Hz, 2H), 4.38 (t, J = 7.0 Hz, 2H), 7.08 (dt, J = 7.0, 1.5 Hz, 1H), 7.19
(dd, J = 7.0, 2.0 Hz, 1H), 7.22À7.25 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H),
7.60 (d, J = 1.5 Hz, 1H), 7.75 (d, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.5, 31.3, 33.3, 46.7, 60.6, 122.8, 124.5, 127.7, 128.1, 130.3,
133.1, 138.2, 140.1, 142.1, 160.4; HRMS obsd 337.0546, calcd 337.0546
for (C15H18N2O2Br, M + H).
General Procedure for Conversion of Trichloroacetyl to
Ethyl Ester. The substrate (0.2 mmol) dissolved in 1 mL of EtOH was
treated with 21% NaOEt in EtOH (0.1 mL) at room temperature for
1À3 h. The reaction mixture was then concentrated followed by column
chromatography purification on silica gel (hexanes/ethyl acetate) to give
the title compound.
(R)-Ethyl 1-(2-bromophenylethyl)-1H-pyrrol-2-carboxylate (1j): vis-
cous liquid; 88% yield; 1H NMR (400 MHz, CDCl3) δ 1.23 (t, J = 7.5 Hz,
3H), 1.79 (d, J = 7.5 Hz, 3H), 4.13À4.24(m, 2H), 6.20 (dd, J = 4.0, 3.0 Hz,
1H), 6.61 (q, J = 7.0 Hz, 1H), 6.71 (dd, J = 8.0, 1.5 Hz, 1H), 7.01À7.03 (m,
1H), 7.05 (dd, J = 4.0, 2.0 Hz, 1H), 7.11 (dt, J = 8.0, 1.5 Hz, 1H), 7.19À7.23
(m, 1H), 7.55 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.5,
solid; 45% yield; mp 100À102 °C; H NMR (500 MHz, CDCl3) δ
1.46 (t, J = 7.0 Hz, 3H), 1.79 (d, J = 7.0 Hz, 3H), 4.43À4.48 (m, 2H),
5.57 (q, J = 7.0 Hz, 1H), 7.33À7.36 (m, 2H), 7.39À7.42 (m, 2H),
7.59À7.61 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 14.5, 20.3, 60.0,
61.6, 120.6, 120.7, 123.2, 127.8, 128.5, 128.6, 141.8, 147.7, 159.0; HRMS
obsd 243.1128, calcd 243.1133 for C14H15N2O2 (M + H).
Ethyl 5-methylpyrrolo[2,1-a]isoindole-3-carboxylate (2c): viscous
liquid; 82% yield; IR (KBr, cmÀ1) 748, 1110, 1141, 1254, 1446, 1695,
2978; 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J = 7.0 Hz, 3H), 1.75 (d,
J = 7.0 Hz, 3H), 4.38 (q, J = 7.0 Hz, 2H), 5.51 (q, J = 7.0 Hz, 1H), 6.35 (d,
J = 4.0 Hz, 1H), 7.11 (d, J = 4.0 Hz, 1H), 7.27À7.31 (m, 1H), 7.35À7.41
(m, 2H), 7.56 (d, J = 7.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 14.6,
20.9, 60.0, 60.1, 99.7, 119.7, 120.5, 121.2, 122.6, 126.7, 128.1, 131.4,
142.7, 147.6, 161.0; HRMS obsd 242.1181, calcd 242.1175 for
C15H16NO2, M + H.
Ethyl 5-methylindolo[2,1-a]isoindole 3-carboxylate (2d): viscous
liquid; 52% yield (ca. 90% pure); 1H NMR (500 MHz, CDCl3) δ 1.53
(t, J = 7.0 Hz, 3H), 1.80 (d, J = 7.0 Hz, 3H), 4.52 (q, J = 7.0 Hz, 2H), 5.36
(q, J = 7.0 Hz, 1H), 7.26À7.30 (m, 2H), 7.42À7.52 (m, 4H), 8.27À8.30
8481
dx.doi.org/10.1021/jo201237h |J. Org. Chem. 2011, 76, 8477–8482