Synthesis of 1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Tic) Derivatives
(115 mg, 78%). Ϫ IR (neat): ν˜ ϭ 1742 cmϪ1. Ϫ 1H NMR
126.1, 126.7, 127.3, 129.6, 131.6, 132.6, 133.7, 133.9, 134.2, 134.4,
FULL PAPER
(300 MHz, CDCl3): δ ϭ 0.02 (s, 9 H), 1.11 (t, J ϭ 6.9 Hz, 3 H), 134.7, 135.9, 139.6, 143.6, 170.0, 182.7, 184.9. Ϫ HRMS (EI): m/z
2.40 (s, 3 H), 2.64 (d, J ϭ 3.6 Hz, 2 H), 3.93Ϫ3.99 (m, 3 H), 4.28 for C27H23NO6S: calcd. 489.1230; found 489.1246.
(1/2 ABq, J ϭ 5.4 Hz, 1 H), 4.79 (t, J ϭ 3.9 Hz, 1 H), 4.97 (s, 2 H),
Preparation of Compound 33: A solution of diene 24 (45 mg,
5.30 (s, 1 H), 7.25 (d, J ϭ 7.8 Hz, 2 H), 7.65 (d, J ϭ 8.1 Hz, 2 H).
0.13 mmol), DMAD (38 mg, 0.26 mmol), and a catalytic amount
Ϫ
13C NMR (75.43 MHz, CDCl3): δ ϭ 0.3, 14.2, 21.5, 42.1, 49.6,
of hydroquinone in dry toluene (3.5 mL) was placed in a thick-
walled glass tube. The tube was then sealed and the reaction mix-
ture was refluxed at 160 °C for 3 d. After opening the tube, the
contents were concentrated and the residue was chromatographed
on a silica gel column eluting with ethyl acetate/hexane (1:4) to give
the DA adduct (60 mg, 95%) as a colorless liquid. Subsequently, a
mixture of the DA adduct (58 mg, 0.121 mmol) and DDQ (37 mg,
0.145 mmol) in toluene (3.5 mL) was refluxed for 48 h. The reac-
tion mixture was then concentrated and the residue obtained was
purified by flash column chromatography (silica gel; ethyl acetate/
hexane, 1:4) to give the aromatized product 33 as a gummy material
56.7, 61.0, 113.2, 127.1, 129.1, 129.4, 136.8, 142.3, 143.1, 150.0,
169.5. Ϫ HRMS (EI): m/z for C19H26NO4S [M Ϫ CH3]: calcd.
392.1351; found 392.1347. Ϫ Further elution of the column with
ethyl acetate/hexane (1:10) gave the PausonϪKhand product 30 as
1
a gummy solid (10 mg, 7%). Ϫ H NMR (300 MHz, CDCl3): δ ϭ
0.17 (s, 9 H), 1.13 (t, J ϭ 6.9 Hz, 3 H), 1.84 (d, J ϭ 18.6 Hz, 2 H),
2.46 (s, 3 H), 2.69Ϫ2.76 (m, 1 H), 2.89Ϫ2.93 (m, 2 H), 3.44 (1/2
ABq, J ϭ 13.8 Hz, 1 H), 3.85Ϫ4.07 (m, 2 H), 4.13 (1/2 ABq, J ϭ
6.9 Hz), 5.02 (d, J ϭ 3.9 Hz, 1 H), 7.29 (d, J ϭ 8.1 Hz, 2 H), 7.77
(d, J ϭ 8.1 Hz, 2 H). Ϫ 13C NMR (75.43 MHz, CDCl3): δ ϭ 0.12,
14.7, 22.2, 33.5, 39.4, 42.2, 49.5, 56.2, 62.2, 127.9, 130.2, 137.5,
(50 mg, 87%). Ϫ IR (neat): ν ϭ 1736 cmϪ1. Ϫ UV (CHCl3): λmax
˜
141.8, 144.2, 169.6, 181.0, 210.9.
Ϫ HRMS (EI): m/z for
(ε Ϫ1 cmϪ1) ϭ 246.3 (24.035 ϫ 103). Ϫ 1H NMR (300 MHz,
CDCl3): δ ϭ 0.99 (t, J ϭ 7.2 Hz, 3 H), 2.40 (s, 3 H), 3.22 (d, J ϭ
6.0 Hz, 2 H), 3.81Ϫ3.98 (m, 2 H), 3.92 (s, 3 H), 3.94 (s, 3 H), 4.39
(1/2 ABq, J ϭ 16.2 Hz, 1 H), 4.74 (1/2 ABq, J ϭ 16.2 Hz, 1 H), 4.97
(dd, J ϭ 3.3, 6.0 Hz, 1 H), 7.19 (d, J ϭ 8.1 Hz, 1 H), 7.27 (d, J ϭ
8.1 Hz, 2 H), 7.69 (d, J ϭ 8.4 Hz, 1 H), 7.75 (d, J ϭ 8.1 Hz, 2 H).
C20H26NO4SSi [M Ϫ CH3]: calcd. 420.13009; found 420.1304.
Preparation of Compound 31: A solution of diene 23 (45 mg,
0.134 mmol), DMAD (32 mg, 0.099 mmol), and a catalytic amount
of hydroquinone in dry toluene (3.5 mL) was placed in a thick-
walled tube. The tube was then sealed and the reaction mixture was
refluxed at 160 °C for 3 d. After opening the tube, the contents
were concentrated and the residue was purified by flash column
chromatography (silica gel; ethyl acetate/hexane, 1:4) to give the
DielsϪAlder adduct as a colorless liquid (43 mg, 96%). Sub-
sequently, a mixture of the DA adduct (25 mg, 0.052 mmol) and
DDQ (11.8 mg, 0.082 mmol) in toluene (3.5 mL) was refluxed for
48 h. This mixture was then concentrated and the residue obtained
was purified by flash column chromatography (silica gel; ethyl acet-
ate/hexane, 1:4) to give the aromatized product 31 as a viscous solid
Ϫ
13C NMR (75.43 MHz, CDCl3): δ ϭ 13.8, 21.5, 32.1, 42.1, 52.4,
52.7, 53.1, 61.4, 126.8, 127.3, 128.1, 129.5, 129.6, 129.9, 133.1,
136.0, 136.5, 143.5, 165.6, 168.1, 169.5. Ϫ HRMS (EI): m/z for
C21H20NO8S: calcd. 446.1129; found 446.1074.
Preparation of Compound 34: A solution of diene 24 (52 mg,
0.155 mmol), naphthoquinone (48 mg, 0.31 mmol), and a catalytic
amount of hydroquinone in dry toluene (3.5 mL) was placed in a
thick-walled glass tube. The tube was then sealed and the reaction
mixture was refluxed at 160 °C for 3.5 d. After opening the tube,
the contents were concentrated and the residue was chromato-
graphed on a silica gel column eluting with ethyl acetate/hexane
(1:4) to give the DA adduct (53 mg, 70%) as a colorless liquid.
Subsequently, a mixture of the DA adduct (32 mg, 0.065 mmol)
and DDQ (14.7 mg, 0.065 mmol) in toluene (3.5 mL) was refluxed
for 48 h. The reaction mixture was then concentrated and the res-
idue obtained was purified by flash column chromatography (silica
gel; ethyl acetate/hexane, 1:4) to give 34 as a yellow sticky material
˜
Ϫ1. Ϫ UV (CHCl3): λmax
(24 mg, 97%). Ϫ IR (neat): ν ϭ 1736 cm
(ε Ϫ1 cmϪ1) ϭ 244 (34.01 ϫ 103). Ϫ 1H NMR (300 MHz, CDCl3):
δ ϭ 1.02 (t, J ϭ 7.2 Hz, 3 H), 2.41 (s, 3 H), 3.23 (d, J ϭ 3.6 Hz, 2
H), 3.88 (s, 6 H), 3.80Ϫ3.98 (m, 2 H), 4.52 (1/2 ABq, J ϭ 16.5 Hz,
1 H), 4.79 (1/2 ABq, J ϭ 16.2 Hz, 1 H), 5.05 (dd, J ϭ 3.6, 5.1 Hz,
1 H), 7.29 (d, J ϭ 8.1 Hz, 2 H), 7.44 (d, J ϭ 7.5 Hz, 2 H), 7.71 (d,
J ϭ 8.4 Hz, 2 H). Ϫ HRMS (EI): m/z for C21H20NO8S [M Ϫ
CH2CH3]: calcd. 446.1180; found 446.10749.
(20 mg, 64%). Ϫ IR (neat): ν ϭ 1736 cmϪ1. Ϫ UV (CHCl3): λmax
˜
Preparation of Compound 32: A solution of diene 23 (50 mg,
0.149 mmol), 1,4-naphthoquinone (60 mg, 0.37 mmol), and a cata-
lytic amount of hydroquinone in dry toluene (3.5 mL) was placed in
a thick-walled glass tube. The tube was then sealed and the reaction
mixture was refluxed at 160 °C for 3.5 d. After opening the tube,
the contents were concentrated and the residue was chromato-
graphed on a silica gel column eluting with ethyl acetate/hexane
(1:4) to give the DA adduct as a colorless liquid (56 mg, 77%).
Subsequently, a mixture of the DA adduct (36 mg, 0.073 mmol)
and DDQ (36 mg, 0.15 mmol) in toluene (3.5 mL) was refluxed for
72 h. The reaction mixture was then concentrated and the residue
obtained was purified by flash column chromatography (silica gel;
1
(ε Ϫ1 cmϪ1) ϭ 258 (45.029 ϫ 103), 335 (7.64 ϫ 103). Ϫ H NMR
(300 MHz, CDCl3): δ ϭ 1.00 (t, J ϭ 7.8 Hz, 3 H), 2.39 (s, 3 H),
3.31Ϫ3.34 (m, 2 H), 3.84Ϫ3.97 (m, 2 H), 4.85 (1/2 ABq, J ϭ
18.9 Hz, 1 H), 5.10 (dd, J ϭ 2.7, 6.3 Hz, 1 H), 5.61 (1/2 ABq, J ϭ
18.6 Hz, 1 H), 7.27 (d, J ϭ 9.0 Hz, 2 H), 7.54 (d, J ϭ 8.1 Hz, 2 H),
7.72Ϫ7.76 (m, 2 H), 7.79 (d, J ϭ 8.4 Hz, 2 H), 8.19Ϫ8.24 (m, 2
H). Ϫ 13C NMR (75.43 MHz, CDCl3): δ ϭ 13.8, 21.5, 33.1, 44.8,
52.7, 61.5, 126.2, 126.7, 127.3, 127.5, 129.5, 129.7, 132.3, 133.6,
133.8, 134.3, 134.4, 134.6, 135.2, 136.0, 139.1, 143.5, 169.7, 182.9,
184.8. Ϫ HRMS (EI): m/z for C27H23NO6S: calcd. 489.1238;
found 489.12461.
ethyl acetate/hexane, 1:4) to give the aromatized product 32 as a
Preparation of Compound 35: A solution of diene 26 (26 mg,
0.063 mmol), DMAD (18 mg, 0.127 mmol), and a catalytic amount
Ϫ1
˜
.
yellow sticky material (24 mg, 67%). Ϫ IR (neat): ν ϭ 1736 cm
Ϫ UV (CHCl3): λmax (ε Ϫ1 cmϪ1) ϭ 255 (46.030 ϫ 103), 334 (7.80 of hydroquinone in dry toluene (3.5 mL) was placed in a thick-
1
ϫ 103). Ϫ H NMR (300 MHz, CDCl3): δ ϭ 1.02 (t, J ϭ 7.2 Hz, walled glass tube. The tube was then sealed and the reaction mix-
3 H), 2.40 (s, 3 H), 3.64 (dd, J ϭ 6.9, 8.4 Hz, 1 H), 3.85Ϫ3.95 (m,
2 H), 4.17 (1/2 AXq, J ϭ 18.3 Hz, 1 H), 4.70 (1/2 ABq, J ϭ 16.2 Hz, contents were concentrated and the residue was chromatographed
1 H), 4.83 (1/2 ABq, J ϭ 15.9 Hz, 1 H), 5.06 (dd, J ϭ 1.8, 2.1,
on a silica gel column eluting with ethyl acetate/hexane (1:4) to give
ture was refluxed at 150 °C for 48 h. After opening the tube, the
7.2 Hz, 1 H), 7.77 (d, J ϭ 8.1 Hz, 2 H), 7.47 (d, J ϭ 8.1 Hz, 1 the DA adduct (26 mg, 76%) as a colorless liquid. Subsequently, a
H), 7.74Ϫ7.82 (m, 4 H), 8.23 (d, J ϭ 6.0 Hz, 3 H). Ϫ 13C NMR mixture of the DA adduct (25 mg, 0.045 mmol) and DDQ
(75.43 MHz, CDCl3): δ ϭ 13.9, 21.6, 22.7, 31.2, 45.0, 53.0, 61.3,
Eur. J. Org. Chem. 2001, 3375Ϫ3383
(10.3 mg, 0.082 mmol) in toluene (3.5 mL) was refluxed for 48 h.
3381