10.1002/ejoc.202000499
European Journal of Organic Chemistry
FULL PAPER
obtained
from
(Z)-2-(3,4-dimethoxyphenyl)-1-(4-isopropoxy-2,5-
solution was heated to reflux for 2 h, after which most of the EtOH was
removed by rotary evaporation until the potassium carboxylate salt began
to precipitate. The mixture was acidified with aqueous HCl (1 M), causing
the free carboxylic acid to begin precipitating and turning the supernatant
liquid bright yellow. The mixture was then extracted with CH2Cl2 (3 × 50
mL). The combined extracts containing the dissolved carboxylic acid
were washed with aqueous HCl (1 M; 100 mL) and brine (100 mL), dried
over MgSO4 and evaporated in vacuo to provide quantitative yields of
spectroscopically pure carboxylic acids. The high-resolution mass
spectra showed minor or no signals for the molecular ions, but ions for
the decarboxylated products were apparent. However, the presence of
dimethoxy-phenyl)-2-(6-isopropoxy-7-methoxy-3,4-dihydroisoquinolin-
1(2H)-ylidene)ethanone (33) (2.27 g, 3.84 mmol) according to the
general procedure as a colorless gel that gradually solidified after
purification by chromatography; Rf = 0.30 (hexane:EtOAc 3:2); m,p. 160-
161 °C (from MeOH); 1H NMR (300 MHz, CDCl3) δ 6.78 (dd, J = 8.1, 1.8
Hz, 1H), 6.76–6.71 (m, 3H), 6.69 (d, J = 1.8 Hz, 1H), 6.57 (s, 1H), 6.47
(s, 1H), 4.61 (br t, J ca 7.5 Hz, 2H), 4.51 (septet, J = 6.0 Hz, 2H), 4.06 (q,
J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.62 (s, 3H), 3.61 (s, 3H), 3.54 (s, 3H), 3.33
(s, 3H), 3.03 (t, J = 6.6 Hz, 2H), 1.37 (d, J = 6.0 Hz, 6H), 1.33 (d, J = 6.0
Hz, 6H), 0.96 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.0,
151.5, 148.4 (2 × C), 147.5, 146.4, 146.3, 144.1, 131.0, 128.4, 128.3,
125.7, 123.1, 121.5, 121.3, 119.0, 118.0, 116.8, 114.7, 114.0, 110.8,
109.3, 102.5, 72.1, 71.4, 59.6, 56.5, 56.3, 55.9, 55.7, 55.3, 42.8, 29.0,
1
the carboxylic acid was apparent in the H (D2O-exchangeable proton in
the range δ 7.0–7.6) and 13C NMR (C=O ca 150 ppm) spectra.
1-(3,4-Dimethoxyphenyl)-7-isopropoxy-2-(4-isopropoxy-2,5-
22.1 (4 × C), 13.8. HRMS (ESI) Found: [M + H]+, 660.3147; C38H46NO9
+
dimethoxyphenyl)-8,9-dimethoxypyrrolo-[2,1-a]isoquinoline-3-
carboxylic acid (38): The acid 38 (1.50 g, 2.27 mmol, ca 100%) was
obtained according to the general procedure from ethyl 1-(3,4-
dimethoxyphenyl)-7-isopropoxy-2-(4-isopropoxy-2,5-dimethoxy-phenyl)-
8,9-dimethoxypyrrolo[2,1-a]isoquinoline-3-carboxylate (36) (1.57 g, 2.28
mmol) as a pale brown solid, m.p. 76-79 °C; 1H NMR (400 MHz, CDCl3) δ
7.65 (d, J = 7.4 Hz, 1H), 7.54 (s, 1H, CO2H, exchanges with D2O), 7.04
(d, J = 7.2 Hz, 1H), 7.02–6.95 (m, 3H), 6.91 (d, J = 8.4 Hz, 1H), 6.70 (s,
1H), 6.53 (s, 1H), 4.67 (septet, J = 6.2 Hz, 1H), 4.50 (septet, J = 6.1 Hz,
1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.75 (s, 3H), 3.65 (s, 3H), 3.48 (s, 3H),
3.45 (s, 3H), 1.35 and 1.34 (2 × superimposed d, J = 6.4 and 6.0 Hz,
12H); 13C NMR (101 MHz, CDCl3) δ 152.6, 151.0, 148.9, 147.7, 146.5,
146.0, 144.1, 140.1, 130.5, 124.8, 124.0 (2 × C), 123.1, 122.9, 122.3,
117.9, 116.6, 116.5, 116.1, 114.9, 114.4, 111.3, 105.7, 102.6, 100.5,
requires 660.3167.
General
procedure
for
DDQ
oxidation
of
ethyl
5,6-
dihydropyrrolo[2,1-a]isoquinoline-3-carboxylates 34 and 35: The 5,6-
dihydropyrrolo[2,1-a]isoquinoline (1 mmol) was dissolved in CH2Cl2 (100
mL), to which was added DDQ (1.25 mmol). The solution, which
immediately turned a muddy-brown color, was left to stir at room
temperature for the specified time. Aqueous NaOH solution (2 M, 50 mL)
was added, and the phases were separated. The aqueous phase was re-
extracted with CH2Cl2 (2 × 20 mL), and the combined organic fractions
were washed with NaOH solution (2M, 50 mL), water (50 mL) and brine.
After drying over MgSO4, filtration, evaporation in vacuo, the
spectroscopically homogeneous products were obtained as foams in
quantitative yields.
75.9, 72.0, 60.6, 56.3, 56.1, 55.9 (2 × C), 55.3, 22.7 (2 × C), 22.2 (2 × C).
Ethyl
1-(3,4-dimethoxyphenyl)-7-isopropoxy-2-(4-isopropoxy-2,5-
CO2]+, 616.2908; C36H42NO8 requires
+
HRMS (ESI) Found: [M
616.2905.
–
dimethoxyphenyl)-8,9-dimethoxy-pyrrolo[2,1-a]isoquinoline-3-
carboxylate (36): Compound 36 (1.98 g, 28.8 mmol, 99%) was obtained
from ethyl 1-(3,4-dimethoxyphenyl)-7-isopropoxy-2-(4-isopropoxy-2,5-
dimethoxyphenyl)-8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline-3-
carboxylate (34) (2.00 g, 29.0 mmol) according to the general procedure
as a brownish solid foam, m.p. 85-86 °C; reaction time 18 h; 1H NMR
(400 MHz, CDCl3) δ 9.25 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H),
7.05 (s, 1H), 6.95–6.73 (m, 3H), 6.61 (s, 1H), 6.48 (s, 1H), 4.70 (septet, J
= 6.2 Hz, 1H), 4.50 (septet, J = 6.1 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.89
(s, 3H), 3.86 (s, 3H), 3.71 (s, 3H), 3.64 (s, 3H), 3.58 (s, 3H), 3.42 (s, 3H),
1.34 (d, J = 6.0 Hz, 12H), 0.98 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 162.1, 152.8, 151.5, 148.6, 147.9, 146.6, 146.1, 144.1, 141.5,
131.8, 129.6, 128.8, 123.8, 122.9, 121.9, 119.6, 119.4, 117.8, 116.7,
114.7, 113.4, 110.8 (br), 107.2, 102.3 (br), 101.3, 76.1, 72.1, 60.7, 59.5,
56.6, 56.3, 56.0, 55.8, 55.3, 22.72, 22.70, 22.1 (br, 2 × C), 13.8. HRMS
(ESI) Found: [M + H]+, 688.3116; C39H46NO10+ requires 688.3116.
1-(3,4-Dimethoxyphenyl)-8-isopropoxy-2-(4-isopropoxy-2,5-
dimethoxyphenyl)-9-methoxypyrrolo[2,1-a]isoquinoline-3-carboxylic
acid (39): The acid 39 (1.43 g, 2.27 mmol, 100%) was obtained
according to the general procedure from ethyl 1-(3,4-dimethoxyphenyl)-8-
isopropoxy-2-(4-isopropoxy-2,5-dimethoxy-phenyl)-9-methoxypyrrolo[2,1-
a]isoquinoline-3-carboxylate (37) (1.49 g, 2.27 mmol) as an off-white
crystalline solid, m.p. 182-184 °C (from MeOH); 1H NMR (300 MHz,
CDCl3) δ 7.66 (d, J = 7.2 Hz, 1H), 7.54 (s, 1H, CO2H, exchanges with
D2O), 7.20 (s, 1H), 6.99 (dd, J = 8.1, 1.8 Hz, 1H), 6.96 (d, J = 1.8 Hz,
1H), 6.95 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.71 (s, 1H), 6.61 (d, J = 1.8
Hz, 1H), 6.53 (s, 1H), 4.59 (septet, J = 6.1 Hz, 1H), 4.50 (septet, J = 6.1
Hz, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 3.64 (s, 3H), 3.49 (s, 3H), 3.45 (s,
3H), 1.39 (d, J = 6.1 Hz, 6H), 1.35 (d, J = 6.1 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 151.0, 149.8, 148.9, 147.6, 145.9, 145.8, 144.1, 130.6, 125.3,
124.0 (2 × C), 122.83, 122.76, 121.7, 121.1, 116.6, 116.0, 115.7, 114.8,
114.0, 112.1, 111.3, 110.4, 105.0, 102.5, 72.0, 71.2, 56.3, 56.08, 56.07,
55.9, 55.3, 22.2 (2 × C), 22.1 (2 × C). HRMS (ESI) Found: [M – CO2]+,
586.2834; C35H40NO7+ requires 586.2799.
Ethyl
1-(3,4-dimethoxyphenyl)-8-isopropoxy-2-(4-isopropoxy-2,5-
dimethoxyphenyl)-9-methoxy-pyrrolo[2,1-a]isoquinoline-3-
carboxylate (37): Compound 37 (796 mg, 1.21 mmol, 100%), was
obtained
from
ethyl
1-(3,4-dimethoxyphenyl)-8-isopropoxy-2-(4-
isopropoxy-2,5-dimethoxyphenyl)-9-methoxy-5,6-dihydropyrrolo[2,1-
a]isoquinoline-3-carboxylate (35) (800 mg, 1.21 mmol) according to the
general procedure as a brownish gel that gradually solidified; m.p. 96-
Conversion of pyrrolo[2,1-a]isoquinoline-3-carboxylic acids 38 and
39 into lamellarin isopropyl ethers 40 and 41 via acid chlorides: The
carboxylic acid (1.00 mmol) was dissolved in dry CH2Cl2 (100 mL), and
the solution was cooled to 0 °C under an atmosphere of argon. Oxalyl
chloride (2 equiv) was added by syringe, causing the color to become
deep orange. The stirred solution was warmed to room temperature, and
reaction was judged to be complete by NMR spectroscopy after 2-4 h.
The solvent was evaporated on a rotary evaporator, and the crude
amber-colored acid chloride was dissolved in a solution of NaI in MeCN
(1 g in 100 mL; 80 mL). NaCl began to precipitate within 30 min. The
suspension was stirred overnight, during which time a dense precipitate
of NaCl and desired lamellarin ether was formed. The solvent was
removed in vacuo and the residue was adsorbed onto silica gel (ca 5 g/g
of starting material) and washed through a pad of silica gel with EtOAc–
hexane (1:1) (ca 20 mL/g) until eluents no longer showed a bright blue
fluorescent spot at 254 nm by TLC. The solvent was removed and MeOH
(50 mL g−1) was added. The suspension was heated to boiling, then
allowed to cool to room temperature. The resulting solids, consisting of
1
100 °C; reaction time 4 h. H NMR (300 MHz, CDCl3) δ 9.31 (d, J = 7.5
Hz, 1H), 7.26 (s, 1H), 7.04 (s, 1H), 6.92 and 6.91–6.87 (overlapping d
and m, J = 7.5 Hz, 2H), 6.86–6.80 (m, 2H), 6.62 (s, 1H), 6.48 (s, 1H),
4.66 (septet, J = 6.1 Hz, 1H), 4.51 (septet, J = 6.1 Hz, 1H), 4.12 (q, J =
7.1 Hz, 2H), 3.86 (s, 3H), 3.70 (s, 3H), 3.64 (s, 3H), 3.57 (br s, 3H), 3.43
(s, 3H), 1.42 (d, J = 6.1 Hz, 6H), 1.35 (d, J = 6.1 Hz, 6H), 0.97 (t, J = 7.1
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.2, 151.5, 149.8, 148.5, 147.8,
147.4, 146.6, 144.1, 131.9, 130.2, 128.8, 123.8, 123.5 (2 × C), 119.7,
118.5, 117.9, 116.7, 114.6, 112.9, 111.9, 110.5, 105.6, 102.3, 72.1, 71.1,
59.4, 56.6, 56.3, 56.0, 55.7, 55.3, 22.1 (br, 2 × C), 22.0 (2 × C), 13.8.
HRMS (ESI) Found: [M + H]+, 658.3005; C38H44NO9+ requires 658.3011.
General procedure for hydrolysis of esters 36 and 37: A solution of
KOH (4.5 g, 80 mmol) in water (10 mL) was added to the ethyl
pyrrolo[2,1-a]isoquinoline-3-carboxylates (1.00 mmol), followed by EtOH
(100 mL) to ensure complete dissolution of the ester. The pale yellow
8
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