Synthesis of 8-oxoprotoberberines using acid-mediated cyclization or the Heck reaction

Article abstract of DOI:10.1007/s00706-011-0656-6

A facile method of synthesizing 8-oxoprotoberberines is described from 6-benzoyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline-5-carbaldehyde via acid-mediated cyclization or from 2-(2-iodophenethyl)isoquinolin-1(2H)-one via the Heck reaction. The present method offers several advantages, such as good yields and a simple procedure. Springer-Verlag 2011.

Full text of DOI:10.1007/s00706-011-0656-6

Monatsh Chem (2012) 143:825–830
DOI 10.1007/s00706-011-0656-6
ORIGINAL PAPER
Synthesis of 8-oxoprotoberberines using acid-mediated cyclization
or the Heck reaction
•
Anfeng Chen Kun Zhao Hankun Zhang
•
•
•
Xianwen Gan Min Lei Lihong Hu
•
Received: 20 January 2011 / Accepted: 6 September 2011 / Published online: 29 October 2011
Ó Springer-Verlag 2011
Abstract A facile method of synthesizing 8-oxoproto-
berberines is described from 6-benzoyl-5,6,7,8-tetrahydro-
[1,3]dioxolo[4,5-g]isoquinoline-5-carbaldehyde via acid-
mediated cyclization or from 2-(2-iodophenethyl)isoquin-
olin-1(2H)-one via the Heck reaction. The present method
offers several advantages, such as good yields and a simple
procedure.
[12–14]. Thus, the development of a simple and efficient
method for the synthesis of protoberberines is demanded.
Our group has been researching the synthesis and
pharmacological properties of natural products [22–27].
Recently, we have focused on the synthesis of proto-
berberines because of their diverse biological properties
[28, 29]. We noted that Wakchaure et al. reported the
synthesis of dehydrogusanlung D and dehydroisogusanlung
D using a similar synthetic route involving the Heck
reaction. However, the reaction time of their synthesis was
long, and two different reaction conditions were used to syn-
thesize two compounds. Hence, we wish to report an efficient
and general protocol for the synthesis of 8-oxoprotoberberines
Keywords 8-Oxoprotoberberines Á Acid-mediated Á
Cyclization Á Heck reaction
Introduction
from
6-benzoyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]iso-
Protoberberine alkaloids (Fig. 1) constitute an important
class of natural products that are typically characterized by a
tetracyclic ring skeleton with an isoquinoline core [1, 2].
Due to their diverse biological properties, such as antitumor,
antiviral, and antimicrobial activities [3–11], considerable
attention has been focused on the efficient synthesis of
these alkaloids [12–21]. However, previously reported
methods require the use of harsh conditions [13, 14], involve
lengthy sequences with low overall yields [18], need com-
plicated starting materials [18, 19, 21], and various
substituted protoberberine derivatives are in short supply
quinoline-5-carbaldehyde (3) via acid-mediated cyclization
or 2-(2-iodophenethyl)isoquinolin-1(2H)-one (5) via the Heck
reaction (Scheme 1).
Results and discussion
Our strategy commenced with the preparation of com-
pound 3d. To achieve this, a condensation reaction
between (5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquino-
lin-5-yl)methanol (1) [30, 31] and 3,4-dimethoxybenzoic
A. Chen and K. Zhao contributed equally to this work.
R1
A
A. Chen Á K. Zhao Á H. Zhang Á X. Gan Á M. Lei (&) Á
L. Hu (&)
B
N
O
Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, Shanghai 201203,
People’s Republic of China
C
D
R2
e-mail: mlei@mail.shcnc.ac.cn
L. Hu
e-mail: simmhulh@mail.shcnc.ac.cn
Fig. 1 Structure of protoberberines
123

826
A. Chen et al.
Scheme 1
O
O
O
O
Acid-mediated
cyclization
N
O
N
O
O
R1
R1
R2
R2
3
4
1
2
2
1
3a
: R = R = H
4b
: R = H; R = OCH3 Yield: 65%
2
1
4d: R1 = R2 = OCH3
Yield: 67%
3b
: R = H; R = OCH3
2
1
1
2
3c
: R = H; R = Cl
4a
4c
: R = R = H
No Reaction
No Reaction
3d: R1 = R2 = OCH3
2
1
: R = H; R = Cl
O
O
N
O
O
O
HO
NH
R1
R2
OH
2
1
R7
R5
R4
R6
R8
R9
N
O
O
R3
R6
Heck reaction
R5
R4
N
R9
R7
I
R8
R3
4
5
: R3 = R6 = R7 = R8 = R9 = H; R4, R5 = -OCH2O-
5e
: R3 = R6 = R9 = H; R4, R5 = -OCH2O-; R7, R8 = -OCH2O-
5f
: R3 = R6 = R9 = H; R4, R5 = -OCH2O-; R7 = R8 = OCH3
5g
5h: R3 = R6 = R7 = R8 = H; R4, R5 = -OCH2O-; R9 = NO2
: R3 = R6 = R7 = R8 = R9 = H; R4 = R5 = OCH3
5i
: R3 = R6 = R9 = H; R4 = R5 = OCH3; R7, R8 = -OCH2O-
5j
5k
: R3 = R6 = R9 = H; R4 = R5 = R7 = R8 = OCH3
5l: R3 = R6 = R7 = R8 = H; R4 = R5 = OCH3; R9 = NO2
6
7
8
9
: R = R = R = R = H; R3 = R4 = R5 = OCH3
5m
5n
6
9
: R = R = H; R3 = R4 = R5 = OCH3; R7 , R8 = -OCH2O-
5o: R6 = R9 = H; R3 = R4 = R5 = R7= R8 = OCH3
5p: R6 = R7 = R8 = H; R3 = R4 = R5 = OCH3; R9 = NO2
acid was carried out to yield the compound 2d, which
furnished compound 3d via subsequent oxidation by
o-iodoxybenzoic acid (IBX) in a mixture of toluene and
DMSO. After 3d had been obtained, acid-mediated
cyclization to convert 3d to 4d was explored, and the
results are summarized in Table 1.
As shown in Table 1, Lewis acids such as BF3ÁEt2O and
TiCl4 were unsuitable for the cyclization (Table 1, entries 1
123

Synthesis of 8-oxoprotoberberines
827
Table 1 Effects of different reaction conditions on the cyclization
of 3d
Table 2 Optimizing the conditions of the Heck reaction for the
cyclization of 5e
O
O
O
O
O
N
O
N
O
N
O
Cyclization
Heck
reaction
O
N
O
O
HO
O
I
O
O
5e
4e
O
O
3d
4d
Entry Palladium
Ligands Bases
Additives Solvent Yield/
a
Entry
Acid
Temperature/°C
Time/h
Yield/%a
%
1b
2c
3c
4c
5d
6d
7d
8d
9d
a
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
P(o-tol)3 Et3N
None
CH3CN Trace
1
BF3ÁEt2O
BF3ÁEt2O
TiCl4
RT
50
12
24
12
24
12
8
NRd
NRd
NRd
NRd
5
PPh3
PPh3
PPh3
None
None
Et3N
Ag2CO3 DMF
18
20
10
70
20
55
52
58
2
K2CO3 Ag2CO3 DMF
Cs2CO3 Ag2CO3 DMF
K2CO3 n-Bu4NBr DMF
K2CO3 n-Bu4NBr DMF
K2CO3 n-Bu4NBr DMF
Cs2CO3 n-Bu4NBr DMF
K2CO3 n-Bu4NBr DMF
3
RT
50
4
TiCl4
5
CF3COOH
CF3COOH
RT
50
6
13
7
H2SO4/AcOHb
H2SO4/AcOHb
HCl/AcOHc
HCl/AcOHc
HCl/AcOHc
HCl/AcOHc
HCl/AcOHc
RT
60
12
16
12
8
17
Pd(PPh3)2Cl2 None
Pd(OAc)2
Pd(OAc)2
None
PPh3
8
48
9
RT
60
23
10
11
12
13
a
55
Isolated yields after chromatography on silica gel
b
60
16
24
16
67
Reaction conditions: palladium (5 mol%), ligand (10 mol%), base
(2 equiv), 85 °C
60
56
c
Reaction conditions: palladium (13 mol%), ligand (26 mol%), base
(2.2 equiv), additive (2 eq), 150 °C
80
43
Isolated yields after chromatography on silica gel
d
Reaction conditions: palladium (10 mol%), bases (2 eq), additive
(1 equiv), 110 °C
b
c
d
All reactions were performed with H2SO4/AcOH (1:5)
All reactions were performed with HCl/AcOH (1:1)
No reaction was observed
reaction could not proceed smoothly. Therefore, we turned
our attention towards the synthesis of 4 from 5 [20] via the
Heck reaction to obtain various 8-oxoprotoberberine
derivatives.
and 3). Moreover, raising the reaction temperature and
extending the reaction time did not lead to any of the target
product 4d in the presence of BF3ÁEt2O or TiCl4 (Table 1,
entries 2 and 4). A trace amount of the desired product 4d
was observed when the reaction was stirred in CF3CO2H
(Table 1, entries 5 and 6). We then carried out the cycli-
zation reaction in different mixed acid systems (Table 1,
entries 7–11). The target product 4d [19] was obtained in
67% yield at 60 °C for 16 h in HCl/AcOH (Table 1, entry
11). Using a higher temperature or a longer reaction time
reduced the yield of compound 4d (Table 1, entries 12 and
13) due to the decomposition of 4d under strongly acidic
conditions.
We took the Heck reaction of 5e as a model reaction to
search for suitable reaction conditions. As shown in
Table 2, the conditions employed by Fukuyama for the
Heck reaction of 5e using Pd2(dba)3 as the catalyst and
Et3N as base in CH3CN at 85 °C for 18 h [32] were
examined initially (Table 2, entry 1). Unfortunately, only a
trace amount of the target product 4e was observed.
Continuing our investigation into the conditions of the
Heck reaction, we optimized the reaction conditions of
compound 5e in terms of the catalyst [Pd(PPh3)4,
Pd(PPh3)2Cl2, or Pd(OAc)2], ligand [PPh3 or P(o-tol)3],
additive [Ag2CO3 or n-Bu4NBr], and base [Et3N, K2CO3,
or Cs2CO3] (Table 2, entries 2–9) [33], among the
catalyzed conditions, the presence of n-Bu4NBr as addi-
tive, 10 mol% Pd(OAc)2, and 2 equiv of K2CO3 in
DMF at 110 °C for 5 h (Table 2, entries 5) proved to be
the best.
Subsequently, the optimized conditions were used to
synthesize 4a–4c. However, 3a and 3c could not be
cyclized successfully to afford the corresponding products
4a and 4c, while 4b was obtained in 65% yield. This
indicated that the strong electron-donating substituents
(e.g., OMe) on aromatic ring D are indispensable to the
cyclization. When aromatic ring D carried weak electron-
donating substituents (e.g., Cl), or even no substituent, the
With the optimal reaction conditions identified, com-
pounds 5f–5p were transformed into the corresponding
123

828
A. Chen et al.
Table 3 Synthesis of 8-oxoprotoberberines 4e–4p
R7
R5
R4
R6
N
R8
R9
N
O
O
R3
R6
R7
Heck reaction
R5
R4
R9
X
R8
R3
4e-4p
5e 5p
-
Entry
Product
R3
R4
R5
R6
R7
H
R8
H
R9
Yield/%a [refs.]b
1
4e
4f
H
H
H
H
H
H
H
H
–OCH2O–
–OCH2O–
–OCH2O–
–OCH2O–
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
70 [15]
74 [34]
65 [34]
62
2
–OCH2O–
3
4g
4h
4i
OCH3
OCH3
H
4
H
NO2
H
5
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
69 [15]
76 [35]
67 [36]
64 [37]
60
6
4j
OCH3
–OCH2O–
H
7
4k
4l
OCH3
OCH3
OCH3
H
H
8
OCH3
H
NO2
H
9
4m
4n
4o
4p
OCH3
OCH3
OCH3
OCH3
OCH3
H
H
10
11
12
a
OCH3
–OCH2O–
OCH3
H
H
62
OCH3
OCH3
H
H
44
OCH3
NO2
42
Isolated yields after chromatography on silica gel
b
References in which the compounds have been reported
8-oxoprotoberberine derivatives in moderate to good yields
ranging from 42 to 76%. As illustrated in Table 3, the
steric hindrance seemed to have an effect on the results.
For example, compounds 5e–5l gave the desired products
with 64–76% yields (Table 3, entries 1–8), while
42–62% yields were obtained when 5m–5p were used as
substrates (Table 3, entries 9–12) because of the ortho-
methoxy group at the position R3 on ring A of com-
pounds 4m–4p, or the ortho-nitro group at the position
R9 on ring D of the compound 4p. In summary, the
palladium-catalyzed Heck reaction of compounds 5e–5p
has been carried out in moderate to good yields
(42–76%). In particular, we successfully synthesized the
compounds 4h, 4l, and 4p, which have an electron-
withdrawing group (NO2) on aromatic ring D. To the
best of our knowledge, this is the first report of the
synthesis of these compounds.
protoberberines. Therefore, this protocol is a good addition
to the existing methods.
Experimental
NMR spectra were recorded on a Varian Mercury VX300
Fourier transform spectrometer. The chemical shifts are
reported in ppm using the signals of CDCl3 as internal stan-
dards for the 1H and 13C spectra. EI–MS were obtained on a
Shimadzu GCMS-QP5050A spectrometer. ESI–MS were run
on a Bruker Esquire 3000 plus spectrometer in MeOH. Melting
points were determined with a WRS-1B apparatus. Thin-layer
chromatographic (TLC) plates (silica gel 60 GF, with glass
support) fromYantaiJiangyouCompanywere used to monitor
the progress of the reaction and were visualized with 254 nm
UV light. Unless otherwise mentioned, all chemicals and
materials were used as received from commercial suppliers
without further purification. Tetrahydrofuran (THF) was
distilled from sodium/benzophenone under nitrogen. Dichlo-
romethane (DCM) was distilled from calcium hydride.
In conclusion, the 8-oxoprotoberberines were success-
fully synthesized using acid-mediated cyclization or the
Heck reaction. Our synthesis provides a simple and
versatile method for synthesizing diverse substituted
123

Synthesis of 8-oxoprotoberberines
829
General procedure for the synthesis of compounds
2a–2d
3.94 (s, 6H), 3.53 (m, 1H), 2.98–2.67 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3): d = 173.2, 150.7, 149.0, 146.9,
146.5, 127.8, 127.1, 125.7, 120.0, 110.8, 110.4, 108.5,
107.5, 101.0, 67.1, 56.1, 56.0, 55.9, 42.2, 29.3 ppm;
ESI–MS: m/z = 371.2 ([M ? 1]?).
To a solution of 208 mg (5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-
g]isoquinolin-5-yl)methanol (1, 1 mmol) in 10 cm3 CH2Cl2
at room temperature, 210 mg 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide hydrochloride (EDCI, 1.1 mmol),
30 mg 1-hydroxybenzotriazole (HOBt, 0.2 mmol), 111 mg
Et3N (1.1 mmol), and different benzoic acids (1.1 mmol)
were added. The resulting mixture was stirred for 5 h and
then diluted with 20 cm3 CH2Cl2. The organic phase was
washed with 2 N HCl and brine. The organic solvent was
dried over anhydrous sodium sulfate and concentrated in
vacuo. The residue was purified by gel silica column chro-
matography, eluting with CHCl3:MeOH = 120:1 to provide
the pure products 2a–2d.
General procedure for the synthesis of compounds
4b, 4d
To a mixture of 2a–2d (1 mmol) and 420 mg IBX
(1.5 mmol), 1 cm3 toluene and 1 cm3 DMSO were added.
After stirring at room temperature for 5 h, the reaction
mixture was diluted with 20 cm3 H2O and extracted with
ethyl acetate (2 9 20 cm3). The organic phase was washed
with a saturated solution of NaHCO3 and brine. The
organic solvent was dried over anhydrous sodium sulfate.
Concentration gave a residue to which was added 1 cm3
concentrated HCl and 1 cm3 AcOH at room temperature.
After stirring the reaction mixture for 16 h, ammonia
solution and EtOAc were added and the organic phase was
washed with H2O and brine. The organic solvent was dried
over anhydrous sodium sulfate and concentrated in vacuo.
The residue was purified by gel silica column chromatog-
raphy eluting with CHCl3:MeOH = 120:1 to provide the
pure products 4b, 4d.
[7,8-Dihydro-5-(hydroxymethyl)-[1,3]dioxolo[4,5-g]iso-
quinolin-6(5H)-yl]phenylmethanone (2a, C18H17NO4)
White solid; m.p.: 53–55 °C; 1H NMR (300 MHz, CDCl3):
d = 7.45 (m, 5H), 6.72 (s, 1H), 6.60 (s, 1H), 5.92 (s, 2H), 5.74
(m, 1H), 4.08–3.47 (m, 4H), 2.97–2.61 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3): d = 173.0, 146.8, 146.5, 135.7,
130.0, 128.6, 127.2, 126.8, 125.6, 108.5, 107.3, 101.0, 66.9,
55.6, 42.1, 29.2 ppm; ESI–MS: m/z = 311.2 ([M ? 1]?).
[7,8-Dihydro-5-(hydroxymethyl)-[1,3]dioxolo[4,5-g]iso-
quinolin-6(5H)-yl](3-methoxyphenyl)methanone
5,6-Dihydro-10-methoxy-8H-benzo[g]-1,3-benzodi-
oxolo[5,6-a]quinolizin-8-one (4b, C19H15NO4)
(2b, C19H19NO5)
White solid; m.p.: 198–200 °C; 1H NMR (300 MHz,
CDCl3): d = 7.82 (s, 1H), 7.49 (d, J = 8.7 Hz, 1H), 7.27
(d, J = 8.7 Hz, 1H), 7.24 (s, 1H), 6.83 (s, 1H), 6.72 (s,
1H), 6.01 (s, 2H), 4.36 (t, J = 6.0 Hz, 2H), 3.94 (s, 3H),
2.91 (t, J = 6.0 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d = 161.8, 158.6, 148.5, 147.5, 135.4, 130.9,
129.9, 127.9, 125.8, 124.1, 123.3, 108.1, 107.7, 104.9,
101.9, 101.6, 55.8, 40.0, 28.7 ppm; HR-ESI–MS:
m/z = 321.1007 (calcd for C19H15NO4 321.1001).
White solid; m.p.: 50–52 °C; 1H NMR (300 MHz, CDCl3):
d = 7.34 (m, 1H), 7.02 (m, 3H), 6.72 (s, 1H), 6.60 (s, 1H),
5.94 (s, 2H), 5.73 (m, 1H), 4.09-3.79 (m, 3H), 3.86 (s, 3H),
3.53 (m, 1H), 2.92–2.62 (m, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d = 172.7, 159.6, 146.9, 146.5, 137.0, 129.7, 127.3,
125.5, 118.7, 116.1, 112.1, 108.5, 107.3, 101.0, 67.1, 55.6,
55.4, 42.1, 29.2 ppm; ESI–MS: m/z = 341.2 ([M ? 1]?).
(3-Chlorophenyl)[7,8-dihydro-5-(hydroxymethyl)-[1,3]-
dioxolo[4,5-g]isoquinolin-6(5H)-yl]methanone
(2c, C18H16ClNO4)
General procedure for the synthesis of compounds
4e–4p
White solid; m.p.: 128–131 °C; 1H NMR (300 MHz,
CDCl3): d = 7.46–7.27 (m, 4H), 6.71 (s, 1H), 6.63 (s,
1H), 5.95 (s, 2H), 5.72 (m, 1H), 4.08–3.50 (m, 4H),
2.96–2.63 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3):
d = 171.2, 146.9, 146.6, 137.3, 134.7, 130.1, 130.0, 129.7,
127.0, 125.4, 124.9, 108.6, 107.3, 101.2, 66.8, 55.5, 42.2,
29.2 ppm; ESI–MS: m/z = 345.1 ([M ? 1]?).
A mixture of the appropriate 2-(2-iodophenethyl)isoquin-
olin-1(2H)-one
5
(0.119 mmol), 2.69 mg Pd(OAc)2
(0.012 mmol), 33 mg K2CO3 (0.239 mmol), and 38.36 mg
n-Bu4NBr (0.119 mmol) in 3 cm3 dry DMF was heated to
110 °C for 5 h. The reaction mixture was quenched with a
saturated solution of NH4Cl. The organic phase was
washed with H2O and brine. The organic solvent was dried
over anhydrous sodium sulfate and concentrated in vacuo.
The residue was purified by gel silica column chromato-
graphy, eluting with petroleum:EtOAc = 5:1 to provide
the pure products 4e–4p.
[7,8-Dihydro-5-(hydroxymethyl)-[1,3]dioxolo[4,5-g]iso-
quinolin-6(5H)-yl](3,4-dimethoxyphenyl)methanone
(2d, C20H21NO6)
White solid; m.p.: 75–78 °C; 1H NMR (300 MHz, CDCl3):
d = 7.07 (m, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.72 (s, 1H),
6.62 (s, 1H), 5.95 (s, 2H), 5.69 (m, 1H), 4.03–3.91 (m, 3H),
123

830
A. Chen et al.
5,6-Dihydro-12-nitro-8H-benzo[g]-1,3-benzodioxolo-
[5,6-a]quinolizin-8-one (4h, C18H12N2O5)
(s, 3H), 2.92 (t, J = 6 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d = 161.1, 155.1, 153.7, 145.1, 142.3, 138.0,
134.4, 133.8, 131.0, 129.7, 126.6, 124.9, 116.0, 106.8,
100.5, 61.3, 61.2, 56.3, 40.1 ppm; HR-ESI–MS:
m/z = 382.1172 (calcd for C20H18N2O6 382.1165).
Orange solid; m.p.: 247–250 °C; 1H NMR (300 MHz,
CDCl3): d = 8.75 (d, J = 7.8 Hz, 1H), 8.43 (d,
J = 7.8 Hz, 1H), 7.72 (s, 1H), 7.48 (t, J = 7.8 Hz, 1H),
7.33 (s, 1H), 6.73 (s, 1H), 6.05 (s, 2H), 4.33 (t, J = 6 Hz,
2H), 2.94 (t, J = 6 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d = 161.0, 150.0, 148.0, 144.5, 141.4, 134.8,
131.2, 131.0, 130.1, 126.6, 124.8, 123.2, 108.2, 106.0,
102.0, 96.5, 40.0, 28.4 ppm; HR-ESI–MS: m/z = 336.0750
(calcd for C18H12N2O5 336.0746).
Acknowledgments This work was supported by the Chinese
National Science & Technology Major Project ‘‘Key New Drug
Creation and Manufacturing Program’’ (grants 2009ZX09301-001
and 2009ZX09102-022), the National Natural Science Foundation of
China (grants 30925040, 90713046, 30772638, and U0633008), CAS
Foundation (grants KSCX2-YW-R-168 and KSCX2-YW-R-179),
Shanghai Commission of Science and Technology (grants
08DZ2291300, 09DZ2291200, and 09431902100) and the National
Hi-Tech Research and Development Program Grant of China (grants
2007AA09Z402, 2007AA02Z147, and 2008AA02Z105).
5,6-Dihydro-1,2,3-trimethoxy-8H-dibenzo[a,g]quinolizin-
8-one (4m, C20H19NO4)
White solid; m.p.: 128–131 °C; 1H NMR (300 MHz,
CDCl3): d = 8.43 (d, J = 8.1 Hz, 1H), 7.61 (d, J =
8.1 Hz, 1H), 7.60 (s, 1H), 7.57 (t, J = 8.1 Hz, 1H), 7.45
(t, J = 8.1 Hz, 1H), 6.59 (s, 1H), 4.33 (t, J = 6 Hz, 2H),
3.95 (s, 3H), 3.94 (s, 3H), 3.85 (s, 3H), 2.89 (t, J = 6 Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3): d = 162.4, 154.1,
153.0, 137.1, 133.9, 133.6, 132.3, 132.1, 127.9, 126.7,
126.6, 124.8, 116.8, 107.0, 106.7, 61.4, 61.1, 56.2, 40.0,
30.1 ppm; HR-ESI–MS: m/z = 337.1320 (calcd for
C20H19NO4 337.1314).
References
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5,6-Dihydro-1,2,3-trimethoxy-8H-benzo[a][1,3]benzodiox-
olo[5,6-g]quinolizin-8-one (4n, C21H19NO6)
White solid; m.p.: 169–171 °C; 1H NMR (300 MHz,
CDCl3): d = 7.78 (s, 1H), 7.52 (s, 1H), 6.90 (s, 1H),
6.57 (s, 1H), 6.57 (s, 2H), 4.30 (t, J = 6 Hz, 2H), 3.92
(s, 3H), 3.91 (s, 3H), 3.83 (s, 3H), 2.87 (t, J = 6 Hz, 2H)
ppm; 13C NMR (75 MHz, CDCl3): d = 161.5, 153.9,
152.8, 152.0, 147.8, 142.1, 134.3, 133.4, 132.8, 120.4,
116.7, 107.0, 106.6, 105.8, 104.2, 101.7, 61.4, 61.1, 56.2,
39.9, 30.1 ppm; HR-ESI–MS: m/z = 381.1219 (calcd for
C21H19NO6 381.1212).
18. Wakchaure PB, Easwar S, Puranik VG (2008) Tetrahedron
64:1786
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29. Cheng Z, Chen AF, Hu LH, Li JY, Li J (2010) Bioorg Med Chem
18:5915
5,6-Dihydro-1,2,3,10,11-pentamethoxy-8H-
dibenzo[a,g]quinolizin-8-one (4o, C22H23NO6)
White solid; m.p.: 127–129 °C; 1H NMR (300 MHz,
CDCl3): d = 7.80 (s, 1H), 7.56 (s, 1H), 6.92 (s, 1H),
6.58 (s, 1H), 4.33 (t, J = 6 Hz, 2H), 4.01 (s, 3H), 4.00
(s, 3H), 3.92 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 2.88
(t, J = 6 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3):
d = 161.6, 153.8, 153.6, 152.7, 149.3, 133.3, 132.7, 132.6,
118.9, 116.9, 107.8, 107.0, 106.5, 106.3, 106.0, 61.3, 61.1,
56.4, 56.3, 56.2, 39.9, 30.1 ppm; HR-ESI–MS: m/z =
397.1530 (calcd for C22H23NO6 397.1525).
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5,6-Dihydro-1,2,3-trimethoxy-12-nitro-8H-
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dibenzo[a,g]quinolizin-8-one (4p, C20H18N2O6)
Orange solid; m.p.: 168–170 °C; 1H NMR (300 MHz,
CDCl3): d = 8.75 (d, J = 8.1 Hz, 1H), 8.41 (s, 1H), 8.38
(d, J = 8.1 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 6.59 (s, 1H),
4.32 (t, J = 6 Hz, 2H), 4.00 (s, 3H), 3.93 (s, 3H), 3.91
123