Total Synthesis of Tetrahydroisoquinoline-Based Bioactive Natural Products Laudanosine, Romneine, Glaucine, Dicentrine, and Their Unnatural Analogues Isolaudanosine and Isoromneine

Article abstract of DOI:10.1055/s-0036-1588920

Starting from suitably substituted homophthalic acids, total synthesis of titled alkaloids have been demonstrated in very good yields. The obtained natural products laudanosine and romneine were utilized to accomplish synthesis of two isoquinoline-based alkaloids glaucine and dicentrine. Base-induced selective generation of two different types of benzylic carbanions, their coupling reactions with 3,4-dimethoxybenzyl mesylate, and the regioselective iodination followed by intramolecular aryl-aryl coupling reactions to form the fused biaryl systems were the strategic steps.

Full text of DOI:10.1055/s-0036-1588920

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–I
paper
A
R. Jangir, N. P. Argade
Paper
Synthesis
Total Synthesis of Tetrahydroisoquinoline-Based Bioactive Natural
Products Laudanosine, Romneine, Glaucine, Dicentrine, and Their
Unnatural Analogues Isolaudanosine and Isoromneine
R
Ravi Jangir
Narshinha P. Argade*
NMe
R
R
R
R
R
O
reduction
BF3, base
(i) benzylation
BF3
Me
Division of Organic Chemistry, National Chemical
Laboratory (CSIR), Pune 411 008, India
np.argade@ncl.res.in
(ii) iodination
(iii) aryl–aryl
coupling
N
NMe
glaucine (23%)
dicentrine (25%)
MeO
O
OMe
(R = OMe; R–R = OCH2O)
R
R
NMe
(i) benzylation
(ii) imide formation
R
R
CO2Me
CO2Me
R
CH2O2Me
CO2Me
base
(iii) reduction
R
(R = OMe; R–R = OCH2O)
isolaudanosine (21%)
isoromneine (45%)
MeO
OMe
Received: 21.09.2016
Accepted after revision: 14.11.2016
Published online: 09.12.2016
sis of bioactive natural products for more than past two de-
cades.22–27 Our present synthetic proposal towards the se-
lected target compounds is mainly based on (i) generation
of two different benzylic carbanionic species by altering a
sequence of reduction in homophthalic imides/esters, (ii)
their coupling reactions with benzyl mesylate instead of
lachrymator benzyl halides, and (iii) regioselective mono-
iodination followed by intramolecular aryl–aryl coupling
reactions leading to the fused biaryl compounds. In this
context, we herein report the total synthesis of designated
bioactive alkaloids starting from the corresponding ho-
mophthalic acids (Schemes 1–3).
DOI: 10.1055/s-0036-1588920; Art ID: ss-2016-t0656-op
Abstract Starting from suitably substituted homophthalic acids, total
synthesis of titled alkaloids have been demonstrated in very good
yields. The obtained natural products laudanosine and romneine were
utilized to accomplish synthesis of two isoquinoline-based alkaloids
glaucine and dicentrine. Base-induced selective generation of two dif-
ferent types of benzylic carbanions, their coupling reactions with 3,4-
dimethoxybenzyl mesylate, and the regioselective iodination followed
by intramolecular aryl–aryl coupling reactions to form the fused biaryl
systems were the strategic steps.
Key words homophthalic acids, benzylic carbanions, benzylations,
aryl–aryl couplings, isoquinoline alkaloids, synthesis
R
R
R
R
R
R
NMe
NMe
NMe
Isoquinoline alkaloids are important from their struc-
tural architectures and a wide range of biological activities
point of view. Homophthalic acids bear an appropriate car-
bon skeleton and functional groups and serve as a central
precursors for the synthesis of isoquinoline alkaloids.1–5
Laudanosine (from the roots of Polyalthia cerasoides),6 rom-
neine (from the leaves of Ctyptrxarya chinensis),7 glaucine
(from the bark of Artabotrys lastouwillmsis),8 and dicen-
trine (from parts of Ocotea leucoxylon)9 have been isolated
from various plant species and they exhibit potential anti-
cancer, antineuropsychiatric, vasorelaxing, GABA receptor,
and anticough activities10–13 (Figure 1). Large number of
synthetic approaches to achieve total synthesis of these al-
kaloids have been reported in the earlier and contemporary
literature by means of activation of benzylic positions and
oxidative intramolecular cyclizations.14–21 We have been us-
ing cyclic anhydrides and their derivatives for total synthe-
MeO
MeO
MeO
OMe
OMe
OMe
laudanosine (R = OMe)
romneine (R–R = OCH2O)
glaucine (R = OMe)
dicentrine (R–R = OCH2O)
isolaudanosine (R = OMe)
isoromneine (R–R = OCH2O)
Figure 1 Tetrahydroisoquinoline based bioactive alkaloids
Reactions of homophthalic acids 1a–c with methyl-
amine in refluxing o-dichlorobenzene directly furnished
the corresponding known homophthalimides 2a/c and an
unknown homophthalimide 2b in very good yields via the
formation of corresponding homophthalamic acids fol-
lowed by intramolecular dehydrative cyclizations28
(Scheme 1). Imides 2a–c on LiAlH4 reduction delivered the
desired tetrahydroisoquinolines 3a–c in 80–82% yields. Tet-
rahydroisoquinolines 3a–c on reaction with BF3·OEt2 in re-
fluxing THF formed the corresponding boron complexes
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

B
R. Jangir, N. P. Argade
Paper
Synthesis
3,4-dimethoxy-
benzyl mesylate
R
R
R
R
R
R
R
O
MeNH2, o-Cl2C6H4
CO2H
CO2H
LiAlH4, THF
reflux, 5 h
(i) BF3, THF, reflux, 3 h
BF3
Me
NMe
N
–78 °C to 25 °C, 3 h
reflux, 10 h
NMe
(ii) LDA, THF, –78 °C
10 min
R
1a R = H
2a 78%
2b 75%
2c 76%
3a 82%
3b 80%
3c 80%
O
4a–c
1b R = OMe
1c R–R = OCH2O
R
R
R
R
R
R
I2, AgOCOCF3, TFA
CHCl3, 25 °C, 24 h
MeOH
Pd(OAc)2, PhDavePhos
K2CO3, DMF, reflux, 24 h
BF3
NMe
NMe
N
NMe
reflux, 8 h
R
R
Me
OMe
OMe
OMe
OMe
MeO
I
OMe
5a–c
OMe
6a 83%
6b 71% (laudanosine)
6c 73% (romneine)
7b 79%
7c 79%
OMe
8b 52% (glaucine)
8c 55% (dicentrine)
Scheme 1 Homophthalimides reduction, alkylation, iodination, and intramolecular aryl–aryl coupling reactions leading to isoquinoline-based alka-
loids
containing a quaternary nitrogen atom, which on treatment
with LDA was transformed to the required carbanionic spe-
cies 4a–c.17 The carbanionic species 4a–c on reactions with
relatively less reactive 3,4-dimethoxybenzyl acetate failed
to deliver the desired products 6a–c. However, the carban-
ionic species 4a–c smoothly reacted with the freshly pre-
pared 3,4-dimethoxybenzyl mesylate to form the interme-
diates 5a–c. Compounds 5a–c on refluxing in methanol un-
derwent the expected deboronation and furnished the
desired products 6a (83%), laudanosine (6b, 71%), and rom-
neine (6c, 73%). Above mentioned transformations of tetra-
hydroisoquinolines 3a–c to the products 6a–c were carried
out in one-pot without isolation of formed the intermedi-
ates 5a–c. Attempted N-iodosuccinimide-induced iodina-
tions of laudanosine (6b) and romneine (6c) were selective,
but those reactions did not reach to completion (~50 to 55%
conversions; by 1H NMR analysis).
Unfortunately, both the starting materials and products
had almost the same Rf values and all of our attempts to
separate them were unsuccessful. However, the silver tri-
fluoroacetate/TFA-mediated regioselective iodination of
laudanosine (6b) and romneine (6c) exclusively provided
the desired pure products 7b,c in 79% yield. Base-induced
generation of the corresponding internal aryne intermedi-
ate from compound 7b is known to provide a mixture of
undesired products instead of the aimed glaucine (8b).29
Initially performed aryl–aryl coupling reactions of com-
pounds 7b,c by using the well-known Pd(OAc)2/TBAB cata-
lytic system delivered the desired alkaloids glaucine (8b)
and dicentrine (8c), respectively, but only in ~20% yield. Fi-
nally, an efficient catalytic pathway developed by Fagnou et
al.30 by employing the 2-(diphenylphosphino)-2′-(N,N-di-
methylamino)biphenyl (PhDavePhos) as a suitable ligand
for such type of intramolecular aryl–aryl coupling reactions
was used to improve the yields. Palladium-catalyzed intra-
molecular coupling reactions of compounds 7b,c under
Fagnou et al.30 conditions successfully delivered the desired
glaucine (8b) and dicentrine (8c) in 52 and 55% yields.
Though several syntheses of glaucine (8b) and dicentrine
(8c) have been known; it is a remarkable approach involv-
ing an intramolecular aryl–aryl coupling reaction, which is
difficult from the geometry point of view.30,31 The unnatu-
ral product 6a and all other four alkaloids 6b,c and 8b,c
were highly prone for air oxidations and they were also
sensitive to the silica gel column chromatographic purifica-
tions. Hence all of them were essentially purified by quick
neutral alumina column chromatography. The obtained an-
alytical and spectral data for natural products 6b,c and 8b,c
were in complete agreement with reported data.7,9,15,20
In the next part of our studies, we chose a pathway en-
compassing simple base-mediated benzylation of active
benzylic methylene position in dimethyl homophthalates
9a–c and the sequential reductions of formed compounds
to design isomeric unnatural products 16a–c (Scheme 2).
As shown in Scheme 2, the products 11a–c were synthe-
sized via base-induced condensations of dimethyl homoph-
thalates 9a–c with 3,4-dimethoxybenzaldehyde followed by
esterification of the formed intermediate monocarboxylic
acids using SOCl2 in MeOH to solely deliver the trans-prod-
ucts 10a–c in 82, 82 and 81% yields. Esterifications of inter-
mediate monocarboxylic acids were essential for purifica-
tion and the subsequent smooth C=C bond reduction. Final-
ly, the cinnamates 10a–c on catalytic hydrogenation
delivered the products 11a–c in 87–91% yields. Dimethyl
homophthalates 9a–c32 on LDA-induced coupling reactions
with 3,4-dimethoxybenzyl mesylate also exclusively deliv-
ered the corresponding benzylated products 11a–c but in
65–70% yields. Products 11a–c on base-induced monohy-
drolysis of more reactive unconjugated ester moiety fur-
nished the corresponding intermediate carboxylic acids.
Above specified acids on treatment with methylamine gen-
erated the corresponding ammonium salts, which on re-
fluxing in o-dichlorobenzene formed imides 12a–c. Imides
12a,c were fairly stable and were obtained in 80/79% yields;
however all our attempts to isolate the formed imide 12b
(checked by TLC) met with failure. Plausibly, an instanta-
neous oxidative hydrolytic cleavage could be the cause for
inherent instability of imide 12b.27 Imides 12a,c on LiAlH4
reduction furnished the desired target compounds 16a and
isoromneine (16c) in 77% yield. As portrayed in Scheme 2,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

C
R. Jangir, N. P. Argade
Paper
Synthesis
O
(i) NaOMe, MeOH
R
3,4-dimethoxy-
benzaldehyde
0 to 25 °C, 7 h
R
CO2Me
CO2Me
R
CO2Me
CO2Me
R
CO2Me
CO2Me
NMe
O
(i) 10% KOH, MeOH
reflux, 5 h
Pd(OH)2, EtOH, H2
R
R
R
R
(ii) MeNH2, o-Cl2C6H4
(ii) SOCl2, MeOH
6 h
reflux, 8 h
(89/87/91%)
MeO
MeO
reflux, 10 h
MeO
9a R = H
9b R = OMe
9c R–R = OCH2O
12a 80%
12b unstable
12c 79%
10a 82%
10b 82%
10c 81%
11a 89%
11b 87%
11c 91%
MeO
MeO
MeO
(i) LDA, THF, –78 °C, 10 min; (ii) 3,4-dimethoxybenzyl mesylate, –78 °C to 25 °C, 3 h (65–70%)
LiAlH4, THF
reflux, 6 h
O
O
O
R
R
R
concd HCl
EtOH
R
LiAlH4, THF
NMe
OH
NMe
Pd(OH)2, EtOH, H2
reflux, 24 h
NMe
NMe
NaBH4, EtOH
0 to 25 °C, 7 h
12a
12c
0 to 25 °C, 12 h
R
R
R
R
MeO
MeO
MeO
MeO
14a 74%
14c 77%
15a 89%
15c 92%
16a 77% (from 12a)
87% (from 15a)
16c 77% (from 12c)
82% (from 15c)
13a
13c
MeO
MeO
MeO
MeO
Scheme 2 Dimethyl homophthalates alkylation, imide formation and reductions constituting the isomeric isoromneine
MeO
CO2Me
CONHMe
MeO
MeO
CO2Me
CO2H
MeO
CH2OH
CH2NHMe
NMe
MeNH2, EDCI
(i) SOCl2, CH2Cl2, 8 h
(ii) 2 N NaOH
10% KOH, MeOH
25 °C, 6 h
LiAlH4, THF
reflux, 6 h
11b
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
Et3N, CH2Cl2
25 °C, 24 h
18b 64%
19b
17b 83%
16b 55%
MeO
MeO
MeO
MeO
Scheme 3 Stepwise synthesis of isolaudanosine
the products 16a,c were also obtained from the corre-
sponding imides 12a,c in a stepwise fashion via NaBH4 re-
duction, acid-induced dehydration, catalytic hydrogena-
tion, and final LiAlH4 reduction route in very good overall
yields.
As depicted in Scheme 3, we alternatively planned to
synthesize the target compound 16b starting from the di-
ester 11b. Selective monohydrolysis of diester 11b provided
an acid 17b, which on EDCI-induced coupling with methyl-
amine formed the ester-amide 18b in very good yield. Fi-
nally, LiAlH4 reduction of ester 18b to the corresponding in-
termediate alcohol 19b followed by reaction with SOCl2 and
base furnished the cyclized yet another isomeric product
isolaudanosine (16b) in 55% yield over two steps (Scheme
3). The products 16a–c were also immediately purified by
using neutral alumina column chromatography for stability
issues.
In summary, total syntheses of tetrahydroisoquinoline
based bioactive alkaloids have been completed from the re-
spective homophthalic acids via generation of two different
types of benzylic carbanions and uncommon intramolecu-
lar aryl–aryl coupling reactions. Application of benzyl
mesylate instead of benzyl bromide as a coupling partner is
significant from both its non-lachrymatory nature and
yields point of view. The generation of fused biaryl systems
via intramolecular coupling reactions is noteworthy from
basic chemistry and application point of view. Present ap-
proach to natural and unnatural tetrahydroisoquinoline-
based products is general in nature and will be useful for
rational design of the focused mini-libraries of their ana-
logues and congeners for SAR studies.
Melting points are uncorrected. The 1H NMR spectra were recorded
on 200, and 400 MHz NMR spectrometers using TMS as an internal
standard. The 13C NMR spectra were recorded on 200 NMR (50 MHz),
400 NMR (100 MHz), and 500 NMR (125 MHz) spectrometers. Mass
spectra were taken on an MS-TOF mass spectrometer. HRMS (ESI)
were taken on an Orbitrap (quadrupole plus ion trap) and TOF mass
analyzer. The IR spectra were recorded on an FT-IR spectrometer.
Commercially available starting materials and reagents were used.
2-Methylisoquinoline-1,3(2H,4H)-dione (2a)
To homophthalic acid (1a; 1.80 g, 10.00 mmol) was added a 40% aq
solution of methylamine (5 mL) at r.t. and the reaction mixture was
stirred for 5 min. It was then concentrated in vacuo and dried at the
vacuum pump. To the obtained salt was added o-dichlorobenzene (20
mL) and the mixture was vigorously refluxed for 10 h. The reaction
mixture was allowed to cool to r.t. The direct silica gel column chro-
matographic purification of the resulting reaction mixture using
EtOAc–PE (1:3) as an eluent gave the pure product 2a as a white solid;
yield: 1.36 g (78%); mp 119–121 °C.
IR (CHCl3): 1710, 1664 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.38 (s, 3 H), 4.06 (s, 2 H), 7.28 (d, J = 8
Hz, 1 H), 7.45 (t, J = 8 Hz, 1 H), 7.60 (dt, J = 8, 2 Hz, 1 H), 8.23 (dd, J = 8,
2 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 26.8, 36.3, 125.3, 127.1, 127.7, 129.1,
133.6, 134.0, 165.1, 170.2.
MS (ESI): m/z (%) = 176 (7, [M + H]+).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

D
R. Jangir, N. P. Argade
Paper
Synthesis
6,7-Dimethoxy-2-methylisoquinoline-1,3(2H,4H)-dione (2b)
1H NMR (CDCl3, 200 MHz): δ = 2.44 (s, 3 H), 2.65 (t, J = 6 Hz, 2 H), 2.83
(t, J = 6 Hz, 2 H), 3.48 (s, 2 H), 5.89 (s, 2 H), 6.49 (s, 1 H), 6.57 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 29.2, 45.9, 52.8, 57.9, 100.6, 106.3,
Prepared similarly from acid 1b by using the above specified proce-
dure; faint yellow solid; yield: 1.32 g (75%); mp 198–200 °C.
IR (CHCl3): 1748, 1709, 1659, 1603 cm–1
1H NMR (CDCl3, 200 MHz): δ = 3.36 (s, 3 H), 3.96 (s, 6 H), 3.98 (s, 2 H),
.
108.4, 126.7, 127.4, 145.6, 146.0.
MS (ESI): m/z (%) = 192 (100, [M + H]+).
6.67 (s, 1 H), 7.63 (s, 1 H).
1-(3,4-Dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line (6a)
13C NMR (CDCl3, 125 MHz): δ = 26.7, 36.1, 56.18, 56.24, 108.6, 110.1,
117.9, 128.2, 148.8, 153.8, 164.9, 170.5.
To a stirred solution of amine 3a (750 mg, 5.06 mmol) in THF (10 mL)
was added BF3·OEt2 (1.40 mL, 5.56 mmol) and the mixture was re-
fluxed for 3 h. The mixture was then cooled and LDA (2 M, 3.03 mL)
was added dropwise at –78 °C to form the corresponding carbanion
4a. A solution of 3,4-dimethoxybenzyl mesylate (1.37 g, 5.56 mmol)
in THF (5 mL) was added to the above specified mixture and it was
further stirred for 3 h to form the alkylated borane complex 5a. The
reaction mixture was then concentrated in vacuo, MeOH (15 mL) was
added to the obtained residue, and the mixture was refluxed for 8 h.
It was allowed to cool to r.t. and concentrated in vacuo. The obtained
residue was basified with aq ammonia (10 mL) and extracted with
CH2Cl2 (3 × 25 mL). The combined organic layers were washed with
brine (25 mL) and dried (Na2SO4). Concentration of the organic layer
in vacuo and neutral alumina column chromatographic purification
of the resulting residue using CH2Cl2–MeOH (19:1) as an eluent gave
the pure product 6a as a thick gum; yield: 1.25 g (83%).
MS (ESI): m/z (%) = 236 (100, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C12H14NO4: 236.0917; found:
236.0917.
6-Methyl[1,3]dioxolo[4,5-g]isoquinoline-5,7(6H,8H)-dione (2c)
Prepared similarly from acid 1c by using the above specified proce-
dure; faint yellow solid; yield: 1.33 g (76%); mp 142–143 °C.
IR (CHCl3): 1708, 1665 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.34 (s, 3 H), 3.94 (s, 2 H), 6.06 (s, 2 H),
6.66 (s, 1 H), 7.59 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 26.7, 36.4, 102.1, 106.4, 107.9, 119.4,
130.2, 147.8, 152.5, 164.5, 170.2.
MS (ESI): m/z (%) = 220 (80, [M + H]+).
IR (CHCl3): 1665, 1608 cm–1
.
2-Methyl-1,2,3,4-tetrahydroisoquinoline (3a)
1H NMR (CDCl3, 200 MHz): δ = 2.53 (s, 3 H), 2.70–2.95 (m, 4 H), 3.05–
3.23 (m, 2 H), 3.74 (s, 3 H), 3.86 (s, 3 H), 3.70–3.90 (m, 1 H), 6.52 (d, J =
2 Hz, 1 H), 6.65–6.85 (m, 3 H), 7.00–7.15 (m, 3 H).
13C NMR (CDCl3, 50 MHz): δ = 26.2, 40.8, 42.9, 47.3, 55.6, 55.7, 65.0,
110.7, 112.8, 121.5, 125.1, 125.8, 127.9, 128.6, 132.2, 134.5, 137.6,
147.1, 148.2.
A solution of imide 2a (1.20 g, 6.81 mmol) in THF (10 mL) was added
dropwise to LiAlH4 in THF (10 mL) at 0 °C and the reaction mixture
was refluxed for 5 h. The mixture was cooled in an ice bath and
quenched with sat. aq Na2SO4 (5 mL). The mixture was filtered and
the filtrate was concentrated in vacuo. Neutral alumina column chro-
matographic purification of the obtained residue using CH2Cl2–MeOH
(19:1) as an eluent afforded amine 3a as a yellow solid; yield: 827 mg
(82%); mp 120–122 °C (Lit.33 mp 122–123 °C).
MS (ESI): m/z (%) = 298 (98, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO2: 298.1802; found:
IR (CHCl3): 1661, 1609 cm–1
.
298.1803.
1H NMR (CDCl3, 200 MHz): δ = 2.47 (s, 3 H), 2.70 (t, J = 6 Hz, 2 H), 2.95
(t, J = 6 Hz, 2 H), 3.60 (s, 2 H), 6.97–7.07 (m, 1 H), 7.07–7.17 (m, 3 H).
13C NMR (CDCl3, 50 MHz): δ = 29.1, 46.0, 52.8, 57.9, 125.5, 126.0,
1-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetra-
hydroisoquinoline (Laudanosine, 6b)
126.3, 128.5, 133.7, 134.6.
MS (ESI): m/z (%) = 148 (32, [M + H]+).
Prepared similarly from amine 3b by using the above specified proce-
dure; yellow solid; yield: 918 mg (71%); mp 112–114 °C (Lit.15 mp
114–116 °C).
IR (CHCl3): 1666, 1601 cm–1
.
6-Methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinoline (3b)
1H NMR (CDCl3, 200 MHz): δ = 2.55 (s, 3 H), 2.60–2.93 (m, 4 H), 3.05–
3.22 (m, 2 H), 3.58 (s, 3 H), 3.63–3.75 (m, 1 H), 3.79 (s, 3 H), 3.84 (s, 3
H), 3.85 (s, 3 H), 6.06 (s, 1 H), 6.56 (s, 1 H), 6.61 (s, 1 H), 6.63 (d, J = 8
Hz, 1 H), 6.77 (d, J = 8 Hz, 1 H).
Prepared similarly from imide 2b by using the above specified proce-
dure; yellow solid; yield: 850 mg (80%); mp 83–84 °C (Lit.34 mp 78–
80 °C).
IR (CHCl3): 1662, 1610 cm–1
.
13C NMR (CDCl3, 50 MHz): δ = 25.2, 40.7, 42.4, 46.7, 55.4, 55.66, 55.71,
55.8, 64.7, 110.9, 111.0, 111.1, 112.9, 121.8, 125.7, 128.8, 132.2, 146.2,
147.2 (2 C).
1H NMR (CDCl3, 200 MHz): δ = 2.43 (s, 3 H), 2.65 (t, J = 6 Hz, 2 H), 2.83
(t, J = 6 Hz, 2 H), 3.49 (s, 2 H), 3.82 (s, 3 H), 3.83 (s, 3 H), 6.50 (s, 1 H),
6.58 (s, 1 H).
MS (ESI): m/z (%) = 358 (97, [M + H]+).
13C NMR (CDCl3, 50 MHz): δ = 28.6, 45.9, 52.8, 55.78, 55.82, 57.4,
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO4: 358.2013; found:
358.2011.
109.2, 111.3, 125.6, 126.4, 147.1, 147.4.
MS (ESI): m/z (%) = 208 (99, [M + H]+).
5-(3,4-Dimethoxybenzyl)-6-methyl-5,6,7,8-tetrahydro[1,3]dioxo-
6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (3c)
lo[4,5-g]isoquinoline (Romneine, 6c)7
Prepared similarly from imide 2c by using the above specified proce-
dure; yellow solid; yield: 838 mg (80%); mp 67–68 °C (Lit.35 mp 61–
62 °C).
Prepared similarly from amine 3c by using the above specified proce-
dure; thick gum; yield: 977 mg (73%).
IR (CHCl3): 1662, 1607 cm–1
.
IR (CHCl3): 1662, 1608 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

E
R. Jangir, N. P. Argade
Paper
Synthesis
1H NMR (CDCl3, 200 MHz): δ = 2.49 (s, 3 H), 2.40–2.62 (m, 1 H), 2.65–
2.90 (m, 3 H), 3.00–3.20 (m, 2 H), 3.70 (t, J = 6 Hz, 1 H), 3.80 (s, 3 H),
3.86 (s, 3 H), 5.86 (d, J = 2 Hz, 2 H), 6.24 (s, 1 H), 6.54 (s, 1 H), 6.62 (d,
J = 2 Hz, 1 H), 6.68 (dd, J = 6, 2 Hz, 1 H), 6.78 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 25.6, 41.0, 42.4, 46.6, 55.8 (2 C), 65.0,
100.5, 107.9, 108.3, 110.8, 112.7, 121.5, 127.2, 130.3, 132.1, 145.2,
145.8, 147.2, 148.4.
and extracted with CH2Cl2 (3 × 25 mL). The combined organic layers
were washed with brine (25 mL) and dried (Na2SO4). Concentration of
the organic layer in vacuo and neutral alumina column chromato-
graphic purification of the resulting residue using CH2Cl2–MeOH
(19:1) as an eluent gave the pure product 8b as a brown solid; yield:
29 mg (20%). Method B: To a mixture of compound 7b (100 mg, 0.21
mmol), K2CO3 (57.14 mg, 0.41 mmol), Pd(OAc)2 (21 mg, 20 mol%), and
the ligand PhDave-Phos (105 mg) was added DMF (3 mL) at 25 °C un-
der argon atmosphere [the ratio of Pd(OAc)2 and ligand is 7 mg/mL of
Pd(OAc)2 with 35 mg/mL of the ligand]. The reaction mixture was
heated at 120 °C for 24 h. The mixture was allowed to cool to r.t., bas-
ified with aq ammonia (5 mL), and extracted with CH2Cl2 (3 × 25 mL).
The combined organic layers were washed with brine (20 mL) and
dried (Na2SO4). Concentration of the organic layer in vacuo and neu-
tral alumina column chromatographic purification of the resulting
residue using CH2Cl2–MeOH (19:1) as an eluent provided the pure
product 8b as a brown solid; yield: 38 mg (52%); mp 120–122 °C (Lit.8
mp 119 °C).
MS (ESI): m/z (%) = 342 (98, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO4: 342.1700; found:
342.1698.
1-(2-Iodo-4,5-dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-
tetrahydroisoquinoline (7b)
To a stirred solution of compound 6b (500 mg, 1.40 mmol) and
CF3CO2H (0.50 mL) in CHCl3 (20 mL) was added CF3CO2Ag (310 mg,
1.40 mmol) and I2 (353 mg, 1.40 mmol) and the mixture was further
stirred for 24 h at r.t. The mixture was concentrated in vacuo and bas-
ified with aq ammonia (10 mL) and further extracted with CH2Cl2 (3 ×
25 mL). The combined organic layers were washed with 5% aq
Na2S2O3 (20 mL), H2O (20 mL) and brine (20 mL), and dried (Na2SO4).
Evaporation of the solvent in vacuo and neutral alumina column
chromatographic purification of the resulting residue using CH2Cl2–
MeOH (19:1) as an eluent gave the pure product 7b as a yellow crys-
talline solid; yield: 534 mg (79%); mp 106–107 °C.
IR (CHCl3): 1604 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.58 (s, 3 H), 2.45–2.75 (m, 3 H), 2.98–
3.12 (m, 3 H), 3.12–3.25 (m, 1 H), 3.66 (s, 3 H), 3.89 (s, 3 H), 3.91 (s, 3
H), 3.94 (s, 3 H), 6.60 (s, 1 H), 6.79 (s, 1 H), 8.10 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 29.1, 34.5, 44.0, 53.3, 55.8 (2 C), 55.9,
60.2, 62.5, 110.3, 110.8, 111.6, 124.4, 126.9 (2 C), 128.8, 129.2, 144.3,
147.5, 148.0, 152.0.
IR (CHCl3): 1669, 1602 cm–1
.
MS (ESI): m/z (%) = 356 (98, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C21H26NO4: 356.1856; found:
1H NMR (CDCl3, 200 MHz): δ = 2.57 (s, 3 H), 2.60–2.75 (m, 2 H), 2.80–
3.05 (m, 2 H), 3.15–3.40 (m, 2 H), 3.55 (s, 3 H), 3.73 (s, 3 H), 3.84 (s, 6
H), 3.75–3.95 (m, 1 H), 5.97 (s, 1 H), 6.56 (s, 1 H), 6.59 (s, 1 H), 7.22 (s,
1 H).
13C NMR (CDCl3, 50 MHz): δ = 24.6, 42.2, 44.6, 46.1, 55.4, 55.7, 55.8,
56.1, 62.8, 89.3, 111.2, 111.3, 114.4, 121.3, 125.4, 127.5, 134.2, 146.3,
147.5, 147.9, 148.8.
356.1856.
10,11-Dimethoxy-7-methyl-6,7,7a,8-tetrahydro-5H-[1,3]dioxo-
lo[4′,5′:4,5]benzo[1,2,3-de]benzo[g]quinoline (Dicentrine, 8c)9
Prepared from the iodo compound 7c according to Method A; brown
crystalline solid; yield: 29 mg (20%).
MS (ESI): m/z (%) = 484 (99, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C21H27INO4: 484.0979; found:
Prepared from the iodo compound 7c according to Method B; brown
crystalline solid; yield: 40 mg (55%); mp 179–180 °C (Lit.21 mp 176–
177 °C).
484.0972.
IR (CHCl3): 1598 cm–1
.
5-(2-Iodo-4,5-dimethoxybenzyl)-6-methyl-5,6,7,8-tetrahy-
1H NMR (CDCl3, 200 MHz): δ = 2.57 (s, 3 H), 2.40–2.79 (m, 3 H), 2.99–
3.25 (m, 4 H), 3.93 (s, 6 H), 5.94 (d, J = 2 Hz, 1 H), 6.09 (d, J = 2 Hz, 1 H),
6.53 (s, 1 H), 6.79 (s, 1 H), 7.68 (s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 29.1, 34.2, 43.9, 53.5, 55.9, 56.1, 62.4,
100.6, 106.8, 110.5, 111.2, 116.6, 123.5, 126.3, 126.6, 128.3, 141.8,
146.6, 147.7, 148.2.
dro[1,3]dioxolo[4,5-g]isoquinoline (7c)
Prepared similarly from amine 6c by using the above specified proce-
dure; yellow crystalline solid; yield: 540 mg (79%); mp 115–117 °C.
IR (CHCl3): 1650, 1599 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.47 (s, 3 H), 2.40–2.65 (m, 1 H), 2.70–
3.00 (m, 3 H), 3.00–3.35 (m, 2 H), 3.74 (s, 3 H), 3.65–3.80 (m, 1 H),
3.85 (s, 3 H), 5.85 (s, 2 H), 6.18 (s, 1 H), 6.56 (s, 2 H), 7.22 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 25.2, 42.6, 45.2, 46.1, 55.8, 56.0, 63.2,
89.0, 100.4, 108.27, 108.34, 114.3, 121.3, 127.3, 130.0, 134.5, 145.1,
145.9, 147.9, 148.7.
MS (ESI): m/z (%) = 340 (40, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO4: 340.1543; found:
340.1543.
Methyl (E)-2-[1-(3,4-Dimethoxyphenyl)-3-methoxy-3-oxoprop-1-
en-2-yl]benzoate (10a)
MS (ESI): m/z (%) = 468 (97, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H23INO4: 468.0666; found:
A fresh solution of NaOMe in MeOH was prepared by the addition of
Na (486 mg, 21.15 mmol) to stirred MeOH (30 mL) at 0 °C. To the
above solution was added homophthalate 9a (2.00 g, 9.61 mmol) and
then a solution of 3,4-dimethoxybenzaldehyde (1.75 g, 10.58 mmol)
in MeOH (10 mL) was added dropwise. The mixture was stirred for 7
h, allowed to cool to r.t., and concentrated in vacuo. The resulting res-
idue was acidified with aq 2 N HCl (10 mL), filtered, washed with H2O
(10 mL), and dried. To the solution of above residue in MeOH (25 mL)
was dropwise added SOCl2 (14 mL) at 0 °C and the mixture was re-
fluxed for 6 h. The mixture was allowed to cool to r.t. and concentrat-
468.0660.
1,2,9,10-Tetramethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-diben-
zo[de,g]quinoline (Glaucine, 8b)20
Method A: To a stirred solution of compound 7b (200 mg, 0.42 mmol)
in DMF (15 mL) was added K2CO3 (343 mg, 2.48 mmol), TBAB (266
mg, 0.82 mmol), and Pd(OAc)2 (10 mg, 10 mol%) at 25 °C under argon
atmosphere, and the mixture was heated at 120 °C for 24 h. The mix-
ture was allowed to cool to r.t., basified with aq ammonia (10 mL),
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

F
R. Jangir, N. P. Argade
Paper
Synthesis
ed in vacuo. The resulting residue was dissolved in EtOAc (25 mL) and
the organic layer was washed with H2O (15 mL) and brine (15 mL),
and dried (Na2SO4). Concentration of the organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of the result-
ing residue using EtOAc–PE (3:7) as an eluent gave the pure product
10a as a white crystalline solid; yield: 2.80 g (82%); mp 110–112 °C.
The obtained crude product was directly purified by silica gel column
chromatography by using EtOAc–PE (2:3) as an eluent to provide
product 11a as a thick oil; yield: 1.27 g (89%).
IR (CHCl3): 1721, 1595 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.98 (dd, J = 14, 6 Hz, 1 H), 3.36 (dd, J =
14, 8 Hz, 1 H), 3.61 (s, 3 H), 3.79 (s, 3 H), 3.83 (s, 3 H), 3.85 (s, 3 H),
4.96 (t, J = 8 Hz, 1 H), 6.60–6.78 (m, 3 H), 7.32 (dd, J = 8, 2 Hz, 1 H),
7.37–7.52 (m, 2 H), 7.86 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 39.4, 49.1, 51.9, 52.0, 55.6, 55.8, 110.9,
112.4, 121.1, 126.9, 128.8, 129.6, 130.6, 131.7, 132.1, 140.0, 147.4,
148.4, 167.7, 173.9.
IR (CHCl3): 1718, 1598 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.39 (s, 3 H), 3.74 (s, 3 H), 3.80 (s, 3 H),
3.81 (s, 3 H), 6.29 (d, J = 2 Hz, 1 H), 6.65–6.80 (m, 2 H), 7.26 (dd, J = 8,
2 Hz, 1 H), 7.40–7.55 (m, 2 H), 7.75 (s, 1 H), 8.13 (dd, J = 8, 2 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 52.0, 52.1, 55.1, 55.7, 110.5, 112.1,
125.0, 127.3, 127.9, 130.5, 130.6, 130.8, 131.7, 132.7, 138.0, 138.3,
148.2, 149.7, 166.8, 167.9.
MS (ESI): m/z (%) = 381 (71, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O6Na: 381.1309; found:
MS (ESI): m/z (%) = 379 (99, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C20H20O6Na: 379.1152; found:
381.1299.
379.1142.
Methyl 2-[3-(3,4-Dimethoxyphenyl)-1-methoxy-1-oxopropan-2-
yl]-4,5-dimethoxybenzoate (11b)
Methyl (E)-2-[1-(3,4-Dimethoxyphenyl)-3-methoxy-3-oxoprop-1-
en-2-yl]-4,5-dimethoxybenzoate (10b)
Prepared similarly from 10b by using the above specified procedure;
white crystalline solid; yield: 1.24 g (87%); mp 101–102 °C.
Prepared similarly from homophthalate 9b and 3,4-dimethoxybenz-
aldehyde by using the above specified procedure; white crystalline
solid; yield: 2.54 g (82%); mp 106–108 °C.
IR (CHCl3): 1721, 1597 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.98 (dd, J = 14, 6 Hz, 1 H), 3.33 (dd, J =
14, 8 Hz, 1 H), 3.61 (s, 3 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 3.86 (s, 3 H),
3.89 (s, 3 H), 3.90 (s, 3 H), 5.09 (t, J = 8 Hz, 1 H), 6.72 (s, 3 H), 6.90 (s, 1
H), 7.43 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 39.6, 48.6, 51.9, 52.0, 55.7, 55.8, 56.0 (2
C), 110.9, 111.1, 112.3, 113.2, 121.08, 121.13, 131.8, 134.5, 147.2,
147.3, 148.6, 151.9, 167.1, 174.3.
IR (CHCl3): 1711, 1602 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.51 (s, 3 H), 3.76 (s, 3 H), 3.77 (s, 3 H),
3.79 (s, 3 H), 3.83 (s, 3 H), 3.97 (s, 3 H), 6.43 (s, 1 H), 6.65 (s, 1 H), 6.70
(s, 2 H), 7.66 (s, 1 H), 7.71 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 51.9, 52.2, 55.3, 55.7, 56.1 (2 C), 110.6,
112.5, 113.3, 113.7, 122.2, 124.7, 127.4, 130.7, 132.3, 137.7, 148.19,
148.22, 149.7, 152.6, 166.4, 168.2.
MS (ESI): m/z (%) = 441 (83, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C22H26O8Na: 441.1520; found:
MS (ESI): m/z (%) = 439 (100, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C22H24O8Na: 439.1363; found:
441.1520.
439.1363.
Methyl 6-[3-(3,4-Dimethoxyphenyl)-1-methoxy-1-oxopropan-2-
yl]benzo[d][1,3]dioxole-5-carboxylate (11c)
Methyl (E)-6-[1-(3,4-Dimethoxyphenyl)-3-methoxy-3-oxoprop-1-
en-2-yl]benzo[d][1,3]dioxole-5-carboxylate (10c)
Prepared similarly from 10c by using the above specified procedure;
white crystalline solid; yield: 1.30 g (91%); mp 83–84 °C.
Prepared similarly from homophthalate 9c and 3,4-dimethoxybenz-
aldehyde by using the above specified procedure; white crystalline
solid; yield: 2.57 g (81%); mp 89–91 °C.
IR (CHCl3): 1722, 1612 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.93 (dd, J = 14, 6 Hz, 1 H), 3.29 (dd, J =
12, 8 Hz, 1 H), 3.61 (s, 3 H), 3.82 (s, 3 H), 3.83 (s, 6 H), 5.11 (dd, J = 10,
8 Hz, 1 H), 6.01 (d, J = 2 Hz, 2 H), 6.73 (s, 3 H), 6.94 (s, 1 H), 7.34 (s, 1
H).
13C NMR (CDCl3, 50 MHz): δ = 39.5, 48.5, 51.9 (2 C), 55.6, 55.7, 101.9,
108.5, 110.3, 110.9, 112.3, 121.1, 122.7, 131.6, 136.4, 146.3, 147.3,
148.4, 150.8, 166.8, 174.0.
IR (CHCl3): 1714, 1610 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.54 (s, 3 H), 3.75 (s, 3 H), 3.77 (s, 3 H),
3.84 (s, 3 H), 6.03 (d, J = 2 Hz, 2 H), 6.44 (d, J = 2 Hz, 1 H), 6.60 (s, 1 H),
6.73 (s, 2 H), 7.59 (s, 1 H), 7.69 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 52.0, 52.2, 55.3, 55.8, 102.1, 110.6,
110.7, 111.4, 112.5, 123.9, 124.7, 127.3, 130.7, 134.3, 137.8, 147.4,
148.3, 149.7, 151.3, 166.0, 168.0.
MS (ESI): m/z (%) = 425 (100, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C21H22O8Na: 425.1207; found:
MS (ESI): m/z (%) = 423 (100, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C21H20O8Na: 423.1050; found:
425.1205.
423.1048.
4-(3,4-Dimethoxybenzyl)-2-methylisoquinoline-1,3(2H,4H)-dione
(12a)
Methyl 2-[3-(3,4-Dimethoxyphenyl)-1-methoxy-1-oxopropan-2-
yl]benzoate (11a)
Compound 11a (905 mg, 2.53 mmol) was added to a stirred 10% aq
KOH (15 mL) and MeOH (15 mL) mixture at 0 °C. The reaction mixture
was refluxed for 5 h, allowed to cool to r.t., and acidified with aq 2 N
HCl (25 mL). The filtered residue was dissolved in EtOAc (25 mL) and
the organic layer was washed with H2O (10 mL) and brine (10 mL),
and dried (Na2SO4). The dried organic layer was concentrated in vac-
uo. To the resulting residue was added 40% aq solution of MeNH2
(1.20 mL) and stirred for 5 min. Then toluene (10 mL) was added to
To a stirred solution of the unsaturated diester 10a (1.42 g, 4.00
mmol) in EtOH (20 mL) was added a catalytic amount of Pd(OH)2 (25
mg, 0.20 mmol) and the reaction mixture was refluxed under the bal-
loon pressure of H2 atmosphere for 8 h. The mixture was allowed to
cool to r.t., filtered through a pad of Celite, and concentrated in vacuo.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

G
R. Jangir, N. P. Argade
Paper
Synthesis
the above mixture and stirred again for 5 min and concentrated in
vacuo. To the obtained residue was added o-dichlorobenzene (20 mL)
and the mixture was refluxed for 10 h and allowed to cool to r.t. Di-
rect silica gel column chromatographic purification of the resulting
solution using EtOAc–PE (1:3) as an eluent gave pure product 12a as a
thick yellow oil; yield: 657 mg (80%).
HRMS (ESI): m/z [M + H]+ calcd for C19H20NO3: 310.1438; found:
310.1432.
8-(3,4-Dimethoxybenzyl)-6-methyl[1,3]dioxolo[4,5-g]isoquinolin-
5(6H)-one (14c)
Prepared similarly from 12c by using the above specified procedure;
yellow solid; yield: 360 mg (77%); mp 195–197 °C.
IR (CHCl3): 1713, 1664, 1601 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.18 (s, 3 H), 3.22 (dd, J = 12, 8 Hz, 1 H),
3.38 (dd, J = 12, 8 Hz, 1 H), 3.57 (s, 3 H), 3.78 (s, 3 H), 4.20 (t, J = 8 Hz, 1
H), 6.05 (s, 1 H), 6.23 (dd, J = 8, 2 Hz, 1 H), 6.59 (d, J = 8 Hz, 1 H), 7.21
(d, J = 8 Hz, 1 H), 7.42 (t, J = 8 Hz, 1 H), 7.59 (dt, J = 8, 2 Hz, 1 H), 8.06
(d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 26.4, 43.1, 48.1, 55.5, 55.6, 110.6, 112.2,
121.2, 125.8, 127.2, 127.46, 127.54, 128.5, 133.1, 138.0, 148.1, 148.3,
164.2, 173.3.
IR (CHCl3): 1657, 1607 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.56 (s, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H),
3.90 (s, 2 H), 6.04 (s, 2 H), 6.67–6.77 (m, 3 H), 6.81 (d, J = 8 Hz, 1 H),
6.90 (s, 1 H), 7.83 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 35.6, 37.0, 55.9 (2 C), 101.6, 101.7,
106.0, 111.3, 111.7, 114.8, 120.5, 121.8, 130.5, 131.3, 134.1, 147.5,
147.7, 149.1, 151.7, 161.5.
MS (ESI): m/z (%) = 376 (100, [M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO5: 354.1336; found:
MS (ESI): m/z (%) = 348 (47, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C19H19NO4Na: 348.1206; found:
354.1334.
348.1197.
4-(3,4-Dimethoxybenzyl)-2-methyl-3,4-dihydroisoquinolin-
1(2H)-one (15a)
8-(3,4-Dimethoxybenzyl)-6-methyl[1,3]dioxolo[4,5-g]isoquino-
line-5,7(6H,8H)-dione (12c)
To a stirred solution of unsaturated lactam 14a (250 mg, 0.81 mmol)
in EtOH (15 mL) was added a catalytic amount of Pd(OH)2 (28 mg,
0.20 mmol) and the reaction mixture was refluxed under the balloon
pressure H2 atmosphere for 24 h. The mixture was allowed to cool to
r.t., filtered through a pad of Celite, and concentrated in vacuo. The
obtained crude product was directly purified by silica gel column
chromatographic purification using EtOAc–PE (2:3) as an eluent to
provide 15a as a yellow crystalline solid; yield: 224 mg (89%); mp
108–109 °C.
Prepared similarly from 11c by using the above specified procedure;
thick oil; yield: 656 mg (79%).
IR (CHCl3): 1712, 1663, 1600 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.15 (s, 3 H), 3.17 (dd, J = 12, 4 Hz, 1 H),
3.55 (dd, J = 12, 6 Hz, 1 H), 3.68 (s, 3 H), 3.79 (s, 3 H), 4.08 (t, J = 8 Hz, 1
H), 6.00–6.10 (m, 2 H), 6.23 (s, 1 H), 6.24 (dd, J = 8, 2 Hz, 1 H), 6.60 (s,
1 H), 6.61 (d, J = 8 Hz, 1 H), 7.45 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 26.5, 43.1, 48.2, 55.7 (2 C), 102.0, 106.5,
107.5, 110.7, 112.2, 120.2, 121.4, 127.6, 134.4, 147.5, 148.1, 148.4,
152.1, 163.7, 173.4.
IR (CHCl3): 1646, 1600 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.78 (dd, J = 12, 12 Hz, 1 H), 2.91 (dd,
J = 12, 8 Hz, 1 H), 3.00–3.10 (m, 1 H), 3.14 (s, 3 H), 3.21 (dd, J = 12, 4
Hz, 1 H), 3.68 (dd, J = 12, 4 Hz, 1 H), 3.82 (s, 3 H), 3.88 (s, 3 H), 6.55 (d,
J = 4 Hz, 1 H), 6.68 (dd, J = 8, 4 Hz, 1 H), 6.82 (d, J = 8 Hz, 1 H), 7.03 (dd,
J = 8, 4 Hz, 1 H), 7.32–7.41 (m, 2 H), 8.12 (dd, J = 8, 4 Hz, 1 H).
MS (ESI): m/z (%) = 392 (100, [M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H20NO6: 370.1285; found:
370.1284.
13C NMR (CDCl3, 50 MHz): δ = 35.3, 39.89, 39.94, 50.8, 55.7, 55.8,
111.1, 112.2, 121.0, 126.8, 127.1, 128.3, 128.4, 131.4 (2 C), 141.5,
147.6, 148.8, 164.5.
MS (ESI): m/z (%) = 334 (69, [M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO3: 312.1594; found:
4-(3,4-Dimethoxybenzyl)-2-methylisoquinolin-1(2H)-one (14a)
To a stirred solution of compound 12a (488 mg, 1.50 mmol) in EtOH
(20 mL) was added NaBH4 (456 mg, 12.00 mmol) at 0 °C. The mixture
was stirred under argon atmosphere for 7 h at 0 °C while 2 drops of a
solution of aq 2 N HCl (2 mL) and EtOH (8 mL) were added at intervals
of 15 min. The excess of NaBH4 was quenched at 0 °C by the addition
of aq 2 N HCl in EtOH (10 mL) until the mixture was acidic. The reac-
tion mixture was concentrated in vacuo and the obtained residue was
dissolved in EtOAc (25 mL). The organic layer was washed with H2O
(15 mL), brine (15 mL), and dried (Na2SO4). Concentration of the dried
organic layer in vacuo followed by silica gel column chromatographic
purification of the resulting residue using EtOAc–PE (2:3) as an eluent
gave the pure product 14a as a light yellow crystalline solid; yield:
344 mg (74%); mp 176–178 °C.
312.1589.
8-(3,4-Dimethoxybenzyl)-6-methyl-7,8-dihydro[1,3]dioxolo[4,5-
g]isoquinolin-5(6H)-one (15c)
Prepared similarly from 14c by using the above specified procedure;
thick gum; yield: 231 mg (92%).
IR (CHCl3): 1645, 1605 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.74 (dd, J = 12, 8 Hz, 1 H), 2.87 (dd, J =
12, 4 Hz, 1 H), 2.90–2.97 (m, 1 H), 3.11 (s, 3 H), 3.15 (d, J = 12 Hz, 1 H),
3.62 (dd, J = 12, 4 Hz, 1 H), 3.85 (s, 3 H), 3.88 (s, 3 H), 5.99 (s, 2 H), 6.51
(s, 1 H), 6.59 (s, 1 H), 6.68 (d, J = 8 Hz, 1 H), 6.83 (d, J = 8 Hz, 1 H), 7.57
(s, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 35.3, 40.0, 40.1, 50.8, 55.8, 55.9, 101.4,
106.7, 108.3, 111.3, 112.2, 121.1, 122.8, 131.5, 137.4, 146.9, 147.7,
148.9, 150.2, 164.2.
IR (CHCl3): 1652, 1599 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.57 (s, 3 H), 3.83 (s, 3 H), 3.86 (s, 3 H),
3.98 (s, 2 H), 6.70–6.82 (m, 4 H), 7.43–7.50 (m, 1 H), 7.55–7.63 (m, 2
H), 8.48 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 35.1, 36.9, 55.8 (2 C), 111.3, 111.8,
115.1, 120.6, 123.1, 126.1, 126.6, 128.1, 131.4, 131.5, 131.9, 136.7,
147.6, 149.0, 162.3.
MS (ESI): m/z (%) = 355 (17, [M]+).
MS (ESI): m/z (%) = 332 (82, [M + Na]+).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

H
R. Jangir, N. P. Argade
Paper
Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C20H22NO5: 356.1492; found:
356.1491.
and the filtrate was concentrated in vacuo. Neutral alumina column
chromatographic purification of the residue using CH2Cl2–MeOH
(19:1) as an eluent afforded 16a as a thick oil; yield: 150 mg (87%).
2-[4,5-Dimethoxy-2-(methoxycarbonyl)phenyl]-3-(3,4-dimeth-
oxyphenyl)propanoic Acid (17b)
Method B: A solution of imide 12a (162 mg, 0.50 mmol) in THF (2 mL)
was dropwise added to LiAlH4 (56.8 mg, 1.50 mmol) in THF (2 mL) at
0 ° C. The reaction mixture was refluxed for 6 h and the reaction was
quenched with sat. aq Na2SO4 (5 mL). The mixture was filtered and
the filtrate was concentrated in vacuo. Neutral alumina column chro-
matographic purification of the residue using CH2Cl2–MeOH (19:1) as
an eluent afforded 16a as a thick oil; yield: 114 mg (77%).
Compound 11b (180 mg, 0.43 mmol) was added to a mixture of 10%
aq KOH (20 mL) and MeOH (20 mL) at 0 °C. The reaction mixture was
stirred for 6 h and acidified with aq 2 N HCl (25 mL). The mixture was
filtered and the obtained residue was dissolved in EOAc (20 mL). The
organic layer was washed with H2O (10 mL) and brine (10 mL), and
dried (Na2SO4). Concentration of the dried organic layer in vacuo fol-
lowed by silica gel column chromatographic purification of the result-
ing residue using EtOAc–PE (1:1) as an eluent gave the pure product
17b as a thick gum; yield: 145 mg (83%).
IR (CHCl3): 1651, 1594 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.39 (dd, J = 12, 4 Hz, 1 H), 2.40 (s, 3 H),
2.58 (dd, J = 12, 2 Hz, 1 H), 2.87 (dd, J = 14, 12 Hz, 1 H), 2.98–3.12 (m,
2 H), 3.41 (d, J = 14 Hz, 1 H), 3.76 (d, J = 16 Hz, 1 H), 3.88 (s, 3 H), 3.89
(s, 3 H), 6.75–6.88 (m, 3 H), 7.00–7.25 (m, 4 H).
IR (CHCl3): 2700–2500, 1735, 1678 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 3.01 (dd, J = 14, 6 Hz, 1 H), 3.32 (dd, J =
12, 8 Hz, 1 H), 3.62 (s, 3 H), 3.82 (s, 3 H), 3.84 (s, 3 H), 3.92 (s, 3 H),
3.93 (s, 3 H), 5.20 (dd, J = 10, 6 Hz, 1 H), 6.73 (s, 2 H), 6.79 (s, 1 H), 6.95
(s, 1 H), 7.59 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 39.7, 48.8, 52.0, 55.6, 55.8, 55.95, 56.03,
110.9, 111.2, 112.2, 114.0, 119.4, 121.2, 131.7, 136.1, 147.3, 147.4,
148.6, 152.9, 172.2, 174.2.
13C NMR (CDCl3, 50 MHz): δ = 40.7, 42.0, 46.3, 55.77, 55.84, 56.1, 58.6,
111.1, 112.5, 121.1, 125.8, 126.1, 126.3, 128.3, 133.3, 134.8, 137.8,
147.2, 148.7.
MS (ESI): m/z (%) = 320 (50, [M + Na]+).
HRMS (ESI): m/z [M + H]+ calcd for C19H24NO2: 298.1802; found:
298.1798.
MS (ESI): m/z (%) = 427 (100, [M + Na]+).
HRMS (ESI): m/z [M + Na]+ calcd for C21H24O8Na: 427.1363; found:
8-(3,4-Dimethoxybenzyl)-6-methyl-5,6,7,8-tetrahydro[1,3]dioxo-
lo[4,5-g]isoquinoline (Isoromneine, 16c)
427.1356.
Prepared similarly from 15c by using the above specified Method A;
brown solid; yield: 142 mg (82%).
Methyl 2-[3-(3,4-Dimethoxyphenyl)-1-(methylamino)-1-oxopro-
pan-2-yl]-4,5-dimethoxybenzoate (18b)
Prepared also from 12c by using the above specified Method B; brown
solid; yield: 115 mg (77%); mp 59–60 °C.
To a stirred solution of acid 17b (118 mg, 0.29 mmol) in CH2Cl2 (10
mL) were added MeNH2·HCl (24 mg, 0.35 mmol), EDCI (140 mg, 0.73
mmol), Et3N (0.13 mL, 0.88 mmol), and a catalytic amount of DMAP at
0 °C under argon atmosphere. The reaction mixture was allowed to
reach 25 °C and stirred for 24 h. The reaction was quenched with H2O
(10 mL) and the mixture was extracted with CH2Cl2 (2 × 10 mL). The
combined organic layers were washed with brine (10 mL) and dried
(Na2SO4). Concentration of the dried organic layer in vacuo followed
by neutral alumina column chromatographic purification of the re-
sulting residue using CH2Cl2–MeOH (19:1) as an eluent afforded the
pure product 18b as a thick gum; yield: 78 mg (64%).
IR (CHCl3): 1648, 1603 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 2.41 (s, 3 H), 2.41 (dd, J = 20, 4 Hz, 1 H),
2.56 (dd, J = 12, 4 Hz, 1 H), 2.84 (dd, J = 12, 12 Hz, 1 H), 2.95–3.05 (m,
2 H), 3.37 (d, J = 16 Hz, 1 H), 3.70 (d, J = 16 Hz, 1 H), 3.88 (s, 6 H), 5.90
(s, 2 H), 6.51 (s, 1 H), 6.69 (s, 1 H), 6.76 (s, 1 H), 6.77 (d, J = 8 Hz, 1 H),
6.83 (d, J = 8 Hz, 1 H).
13C NMR (CDCl3, 100 MHz): δ = 40.3, 41.8, 45.8, 55.8, 55.9 (2 C), 58.2,
100.7, 106.1, 108.0, 111.1, 112.4, 121.1, 126.9, 130.6, 132.8, 145.9,
146.2, 147.3, 148.8.
MS (ESI): m/z (%) = 342 (98, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C20H24NO4: 342.1700; found:
IR (CHCl3): 3382, 1707, 1665, 1596 cm–1
.
1H NMR (CDCl3, 200 MHz): δ = 2.71 (d, J = 6 Hz, 3 H), 2.88 (dd, J = 14, 6
Hz, 1 H), 3.51 (dd, J = 12, 8 Hz, 1 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 3.87 (s,
3 H), 3.89 (s, 3 H), 3.98 (s, 3 H), 4.77 (dd, J = 8, 6 Hz, 1 H), 6.60–6.75
(m, 4 H), 7.21 (s, 1 H), 7.31 (s, 1 H).
13C NMR (CDCl3, 50 MHz): δ = 26.2, 38.4, 48.0, 52.2, 55.7, 55.8, 56.0,
56.1, 110.7, 111.0, 112.0, 112.6 120.78, 120.82, 132.4, 136.6, 147.0,
147.2, 148.5, 152.4, 168.3, 173.4.
342.1700.
4-(3,4-Dimethoxybenzyl)-6,7-dimethoxy-2-methyl-1,2,3,4-tetra-
hydroisoquinoline (Isolaudanosine, 16b)
A solution of amide-ester 18b (58 mg, 0.14 mmol) in THF (8 mL) was
dropwise added to LiAlH4 in THF (8 mL) at 0 °C and the mixture was
refluxed for 6 h. The reaction was quenched with sat. aq Na2SO4 (5
mL) and filtered. Concentration of the filtrate in vacuo resulted in the
crude amino alcohol 19b. To a solution of SOCl2 (0.03 mL, 0.42 mmol)
in CH2Cl2 (5 mL) was added the solution of amino alcohol 19b in the
same solvent in a dropwise fashion. The reaction mixture was al-
lowed to stir for 8 h and the reaction was quenched with aq 2 N NaOH
(10 mL). The mixture was extracted with CH2Cl2 (2 × 10 mL) and the
combined organic layers were washed with brine (15 mL) and dried
(Na2SO4). Concentration of organic layer in vacuo followed by neutral
alumina column chromatographic purification of the resulting resi-
due using CH2Cl2–MeOH (19:1) as an eluent afforded pure product
16b as a thick gum; yield: 28 mg (55%).
MS (ESI): m/z (%) = 418 (99, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C22H28NO7: 418.1860; found:
418.1859.
4-(3,4-Dimethoxybenzyl)-2-methyl-1,2,3,4-tetrahydroisoquino-
line (16a)
Method A: A solution of lactam 15a (180 mg, 0.58 mmol) in THF (5
mL) was dropwise added to LiAlH4 (24.2 mg, 0.64 mmol) in THF (5
mL) at 0 °C. The reaction mixture was stirred for 12 h and the reaction
was quenched with sat. aq Na2SO4 (5 mL). The mixture was filtered
IR (CHCl3): 1652, 1601 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I

I
R. Jangir, N. P. Argade
Paper
Synthesis
1H NMR (CDCl3, 200 MHz): δ = 2.32–2.45 (m, 1 H), 2.40 (s, 3 H), 2.57
(dd, J = 12, 4 Hz, 1 H), 2.75–3.10 (m, 3 H), 3.34 (d, J = 14 Hz, 1 H), 3.69
(d, J = 14 Hz, 1 H), 3.77 (s, 3 H), 3.85 (s, 3 H), 3.88 (s, 6 H), 6.54 (s, 2 H),
6.70–6.85 (m, 3 H).
13C NMR (CDCl3, 100 MHz): δ = 40.4, 42.1, 46.3, 55.8, 55.85 (2 C),
55.91, 56.7, 58.2, 109.0, 111.1, 111.2, 112.6, 121.3, 126.7, 129.5, 133.3,
147.2, 147.27, 147.29, 148.8.
(10) Cui, W.; Iwasa, K.; Tokuda, H.; Kashihara, A.; Mitani, Y.;
Hasegawa, T.; Nishiyama, Y.; Moriyasu, M.; Nishino, H.;
Hanaoka, M.; Mukai, C.; Takeda, K. Phytochemistry 2006, 67, 70.
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Chagraoui, A. Bioorg. Med. Chem. 2005, 13, 3699.
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MS (ESI): m/z (%) = 358 (99, [M + H]+).
HRMS (ESI): m/z [M + H]+ calcd for C21H28NO4: 358.2013; found:
358.2003.
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Acknowledgment
R.J. thanks CSIR, New Delhi, for the award of research fellowship.
N.P.A. thanks Science and Engineering Research Board (SERB), New
Delhi for financial support. We gratefully acknowledge the financial
support from CSIR-Network Project.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588920.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–I