P.B. Wakchaure et al. / Tetrahedron xxx (2015) 1e7
5
then cooled to room temperature and poured onto water (200 mL)
under stirring. The precipitated product was collected by filtration
and washed with water and MeOH. The obtained product was dried
under vacuum to provide colorless solidꢁ1(2, 3.80 g, 60%). Mp
1H), 5.08 (d, J¼11.1 Hz, 1H), 4.22 (q, J¼7.1 Hz, 2H), 3.91 (s, 3H),
3.47e3.33 (m, 2H), 1.20 (t, J¼7.1 Hz, 3H); 13C NMR (101 MHz, ace-
tone-d6)
d 165.2, 153.7, 147.0, 138.8, 129.2, 129.2, 129.1, 128.9, 125.0,
123.2, 113.4, 88.8, 75.1, 63.5, 56.2, 32.4, 14.1; HRMS (EI) m/z calcd.
190e192 ꢀC. IR (Neat) 1753, 1707, 1650 cm
;
1H NMR (400 MHz,
For C19H22NO6 [MþH]þ: 360.1447, found: 360.1444.
DMSO-d6)
J¼7.4,1.8 Hz,1H), 7.14e7.05 (m, 2H), 6.62 (s,1H), 4.95 (s, 2H), 3.86 (s,
3H); 13C NMR (101 MHz, DMSO-d6)
165.4, 155.6, 152.6,145.7, 137.1,
d 11.19 (s, 1H), 10.35 (s, 1H), 7.44e7.28 (m, 5H), 7.23 (dd,
4.6. Ethyl 5-(benzyloxy)-6-methoxy-1,2,3,4-
tetrahydroisoquinoline-3-carboxylate hydrochloride 6a
d
128.7, 128.3, 128.3, 128.1, 127.3, 124.5, 120.8, 113.3, 102.8, 74.6, 55.9;
HRMS (EI) m/z calcd. For C18H17N2O4 [MþH]þ: 325.1188, found:
325.1193.
Step I (intermediate B): To a stirred solution of compound 5
(4.5 g, 13.0 mmol) in AcOH (45 mL) at room temperature was added
zinc dust (6.55 g, 100.0 mmol). The exotherm was maintained be-
low 60e65 ꢀC by controlled addition of Zn dust. After the com-
pletion of addition, the reaction was continued further at 60 ꢀC. LC-
MS and TLC after 2 h of stirring confirmed the completion of re-
action. The reaction mixture was then cooled to room temperature
and filtered. The insoluble inorganic solid was washed by AcOH
(20 mL). The combined colorless filtrate was evaporated to dryness.
The crude product obtained was dissolved in DCM (100 mL),
washed with water (3ꢂ50 mL), satd aq NaHCO3 (3ꢂ50 mL) and
brine, dried over MgSO4, filtered and evaporated to dryness to
provide aminoester intermediate B (3.90 g) as colorless oil, which
was used in next step without any purification.
4.4. 4-[2-(Benzyloxy)-3-methoxybenzyl]-1,3-dihydro-2H-imi-
dazol-2-one 4
To the stirred suspension of compound 2 (3.00 g, 9.0 mmol) and
Zn dust (2.40 g, 37.0 mmol) in MeOH (60 mL), conc. HCl (3 mL) was
added dropwise under stirring. The reaction mixture was heated at
70 ꢀC for 30 min. During this time the starting material started
dissolving slowly. A second portion of conc. HCl (3 mL) was added
slowly, dissolving all starting material. After stirring for 30 min the
reaction mixture was then cooled to room temperature and the
excess unreacted Zn dust was removed by filtration. The filtrate was
then poured to water (200 mL) under stirring. The precipitated
product was separated by filtration and washed with water. The
obtained product was recrystallized from MeOH to provide color-
less solid (4, 1.74 g, 61%). Mp 155e157 ꢀC. IR (Neat) 1685,
Step II: The solution of above obtained aminoester intermediate
B in 2N HCl (aq) (39 mL) was purged with nitrogen gas for 30 min
and then 37% aq formaldehyde solution (4 mL, 39.9 mmol, 3 equiv)
was added under stirring. The reaction was continued further for
24 h at room temperature under nitrogen atmosphere. The pre-
cipitated hydrochloride salt of product was filtered, washed with
water (40 mL) and suction dried. The obtained moist product was
dried under vacuum to furnish pure compound 6a (3.6 g, 76% over
1600 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 9.71 (br s, 1H), 9.43 (br
s, 1H), 7.49e7.42 (m, 2H), 7.42e7.31 (m, 3H), 7.05e6.93 (m, 2H),
6.75 (dd, J¼7.5, 1.7 Hz, 1H), 5.83e5.68 (m, 1H), 4.92 (s, 2H), 3.83 (s,
3H), 3.52 (s, 2H); 13C NMR (101 MHz, DMSO-d6)
d 154.9, 152.4,
145.2,137.8, 132.2,128.3,128.1,127.9,123.9,121.4,120.5,111.3, 104.9,
73.8, 55.8, 25.4; HRMS (EI) m/z calcd. For C18H19N2O3 [MþH]þ:
311.1396, found: 311.1407.
two steps). Mp 165e167 ꢀC. IR (Neat) 1748, 1452 cmꢁ1
;
1H NMR
(400 MHz, DMSO-d6) 10.09 (s, 2H), 7.55e7.29 (m, 5H), 7.07 (d,
d
J¼8.6 Hz, 1H), 7.01 (d, J¼8.6 Hz, 1H), 4.98 (d, J¼1.2 Hz, 2H), 4.38 (dd,
J¼11.0, 5.2 Hz, 1H), 4.32e4.15 (m, 4H), 3.85 (s, 3H), 3.21 (dd, J¼17.3,
4.5. Ethyl 3-(2-(benzyloxy)-3-methoxyphenyl)-2-
nitropropanoate 5
5.2 Hz, 1H), 2.90 (dd, J¼17.3, 11.0 Hz, 1H), 1.24 (t, J¼7.1 Hz, 3H); 13
C
NMR (101 MHz, DMSO-d6)
d 168.2, 151.2, 144.4, 137.5, 128.4, 128.0,
124.8, 122.2, 121.0, 112.1, 73.7, 62.0, 56.0, 52.8, 43.2, 23.6, 13.9;
HRMS (ESI) m/z calcd. For C20H24NO4 [MþH]þ: 342.1705, found:
342.1705.
Step
I (intermediate A): A mixture of 2-(benzyloxy)-3-
methoxybenzaldehyde (1, 5.00 g, 21.0 mmol), ethyl nitroacetate
(3.29 g, 25.0 mmol) and Et2NH$HCl (3.39 g, 31.0 mmol) in anhy-
drous toluene (100 mL) was heated under nitrogen atmosphere at
130 ꢀC. The formed water was removed using a DeaneStark as-
sembly. Heating was stopped after 12 h and reaction mixture was
cooled to room temperature. The toluene was evaporated to dry-
ness and the obtained residue was dissolved in DCM (50 mL). The
organic layer was washed with water (3ꢂ50 mL), brine and dried
over MgSO4, filtered and evaporated to dryness. The yellow oily
compound obtained (8.10 g) was directly subjected for next syn-
thetic step without any purification.
4.7. Ethyl 5-(benzyloxy)-2-(2,2-diphenylacetyl)-6-methoxy-
1,2,3,4-tetrahydroisoquinoline-3-carboxylate 7
To a stirred solution of compound 6a (1.0 g, 2.64 mmol) in DCM
(20 mL) was added diphenylacetyl chloride (0.85 g, 3.70 mmol)
under nitrogen atmosphere. After adding catalytic DMAP (16 mg,
0.132 mmol), Et3N (1.1 mL, 7.92 mmol) was added drop wise at
room temperature and reaction was continued. After 30 min when
TLC and LC-MS analysis showed complete consumption of the
starting material, the reaction mixture was diluted with DCM
(20 mL). The organic layer was washed by 2N HCl (3ꢂ30 mL), satd
aq NaHCO3 (3ꢂ30 mL), brine and dried over MgSO4. The organic
layer was filtered, evaporated to dryness and further purified by
flash column chromatography with 15% EtOAc in petroleum ether
to provide a colorless solid (7, 1.20 g, 85% yield). Mp 96e98 ꢀC. IR
(Neat) 1732, 1639, 1294 cmꢁ1; NMR shows presence of amide
Step II: The above obtained intermediate A was dissolved in
CHCl3 (150 mL) and IPA (50 mL). The reaction mixture was cooled to
0
ꢀC and then silica gel (50 g, 230e400 mesh) was added under
stirring. Subsequently NaBH4 (3.8 g, 103.0 mmol) was added over
5e7 min. The reaction mixture was stirred at room temperature for
2 h and then quenched by adding 5 mL AcOH. The reaction mixture
was filtered to remove silica gel, the silica gel was washed with
CHCl3 (100 mL) and the combined filtrate evaporated to dryness.
The crude residue obtained was dissolved in DCM (100 mL) and
washed by water (3ꢂ100 mL), brine and dried over MgSO4. The
organic layer was filtered, evaporated to dryness and further pu-
rified by flash column chromatography with 10% EtOAc in petro-
leum ether to provide thick oil (5, 4.95 g, 67% over two steps). IR
rotamers. 1H NMR (400 MHz, acetone-d6)
d 7.53e7.43 (m, 2H),
7.43e7.16 (m, 13H), 6.94 (d, J¼2.4 Hz, 0.7H), 6.88 (d, J¼8.4 Hz, 0.7H),
6.72 (dt, J¼8.4, 0.8 Hz, 0.7H), 5.66 (s, 0.7H), 5.57 (s, 0.3H), 5.26 (dd,
J¼6.2, 4.0 Hz, 0.7H), 5.23 (dd, J¼5.9, 2.6 Hz, 0.3H), 5.05 (d, J¼11.0 Hz,
0.7H), 5.01 (d, J¼11.0 Hz, 0.3H), 4.97e4.83 (m, 2H), 4.55 (d,
J¼15.1 Hz, 0.7H), 4.41 (d, J¼17.1 Hz, 0.3H), 4.09e3.88 (m, 2H), 3.86
(s, 1H), 3.85 (s, 2H), 3.48 (dd, J¼16.4, 2.5 Hz, 0.3H), 3.43 (dd, J¼16.1,
4.0 Hz, 0.7H), 2.87 (dd, J¼16.2, 6.2 Hz, 0.7H), 2.56 (dd, J¼16.4,
5.9 Hz, 0.3H), 1.08 (t, J¼7.1 Hz, 2H), 1.01 (t, J¼7.1 Hz, 1H); 13C NMR
(Neat) 1748, 1559, 1269 cmꢁ1
7.51e7.46 (m, 2H), 7.41e7.31 (m, 3H), 7.06e6.98 (m, 2H),
6.78e6.75 (m, 1H), 5.59 (dd, J¼9.4, 6.0 Hz, 1H), 5.16 (d, J¼11.1 Hz,
;
1H NMR (400 MHz, acetone-d6)
d