Total synthesis of benzo[c]phenanthridine alkaloids based on a microwave-assisted electrocyclic reaction of the aza 6π-electron system and structural revision of broussonpapyrine

Article abstract of DOI:10.1016/j.tet.2010.11.066

Total syntheses of the des-N-methyl (nor) type of benzo[c]phenanthridine alkaloids 1a-f and 19 and benzo[c]phenanthridine alkaloids, chelerythrine (2d), and broussonpapyrine (2f) were achieved. The key step was the construction of tetracyclic 10,11-dihydrobenzo[c]phenanthridines using a microwave-assisted electrocyclic reaction of the 2-cycloalkenylbenzaldoxime methyl ether 4 as an aza 6π-electron system, which was derived in two steps from a Suzuki-Miyaura cross-coupling reaction of 2-bromobenzaldehyde 6 with 2-(3,4-dihydro-6,7- methylenedioxynaphthyl)boronic acid pinacol ester 7. In addition, the exact structure of broussonpapyrine (2f) (2,3,9,10-tetraoxygenated type) was determined to be chelerythrine (2d).

Full text of DOI:10.1016/j.tet.2010.11.066

Tetrahedron 67 (2011) 1320e1333
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of benzo[c]phenanthridine alkaloids based on a
microwave-assisted electrocyclic reaction of the aza 6
structural revision of broussonpapyrine
p-electron system and
*
Yuhsuke Ishihara, Shuhei Azuma, Tominari Choshi , Kakujirou Kohno, Kanako Ono,
*
Hiroyuki Tsutsumi, Takashi Ishizu, Satoshi Hibino
Graduate School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 October 2010
Received in revised form 17 November 2010
Accepted 17 November 2010
Available online 24 November 2010
Total syntheses of the des-N-methyl (nor) type of benzo[c]phenanthridine alkaloids 1aef and 19 and benzo
[c]phenanthridine alkaloids, chelerythrine (2d), and broussonpapyrine (2f) were achieved. The key step was
the construction of tetracyclic 10,11-dihydrobenzo[c]phenanthridines using a microwave-assisted electro-
cyclic reaction of the 2-cycloalkenylbenzaldoxime methyl ether 4 as an aza 6p-electron system, which was
derived in two steps from a SuzukieMiyaura cross-coupling reaction of 2-bromobenzaldehyde 6 with 2-
(3,4-dihydro-6,7-methylenedioxynaphthyl)boronic acid pinacol ester 7. In addition, the exact structure of
broussonpapyrine (2f) (2,3,9,10-tetraoxygenated type) was determined to be chelerythrine (2d).
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
the final or semifinal stage. Synthetic methodologies until 1999
were clarified and summarized in an excellent review.8 Despite the
Benzo[c]phenanthridine alkaloids are a family of tetracyclic aro-
matic compounds, isolated mainly from the Rutaceae, Papaveraceae,
and Fumariaceae plants.1 The benzo[c]phenanthridines are an in-
teresting structure having the isoquinoline part, many of which show
a wide range of pharmacological properties including anti-tumor
activity.2,3 Among the benzo[c]phenanthridines, nitidine (2a)
and fagaronine exhibit potential antileukemic activity through the
inhibition of topoisomerases,2e4 while sanguinarine (2e) shows an-
tibacterial and antifungal activities.4d,e The 7-hydroxy-8-methoxy-5-
methyl-2,3-methylenedioxybenzo[c]phenanthridinium hydrogen
sulfate (NK109) (2c), as a topoisomerase II inhibitor, was the prom-
ising compounds. However, the activity of NK109 was not exhibited
on the clinical trial.5 NK314, exhibiting significant anti-tumor activity
against drug-resistant human tumor cell lines, is a novel synthetic
benzo[c]phenanthridine fused with pyrrolidine ring at the N5-C6
positions that has entered clinical trials as an anti-tumor agent.6
Synthetic studies started in 1937,7 and since then, they have
attracted much attention from the synthetic organic chemists
during over the past seventy years.1,8e10,13,20 Many synthetic ap-
proaches to the benzo[c]phenanthridine nucleus have been repor-
ted, and their routes involve the construction of either B or C ring in
numerous reports on benzo[c]phenanthridine alkaloids, to date,
highly efficient synthesis remains a challenge.
We are developing the synthesis of the bioactive nitrogen-
containing fused-heteroaromatic compounds including natural
products based on a thermal electrocyclic reaction either a 6
an aza 6 -electron system involving an aromatic or hetero-
aromatic double bond in principle.11 Recently, we reported
p- or
p
the total synthesis of furoisoquinoline,12a phenanthridine,12b
b-
carboline,12c azaanthraquinone,12d and benzo[c]phenanthridine13
alkaloids based on a microwave (MW)-assisted electrocyclic re-
action of the aza 6p-electron system. We here describes the full
detailed synthesis of benzo[c]phenanthridines 1aef, and 2f as
depicted in Fig. 1. The aim of the synthetic plan is to design
a synthesis of 11,12-dihydrobenzo[c]phenanthridine framework 3,
which would be derived from a 2-cycloalkenylbenzaldoxime
methyl ether 4 through a new bond formation between the C4b
and N5-positions in the tetracyclic benzo[c]phenanthridine by
a microwave-assisted electrocyclic reaction as shown in Scheme 1.
An appropriate substituted 2-cycloalkenylbenzaldoxime methyl
ether 4 and its precursor 5 would be provided by the Suzukie
Miyaura coupling reaction14 between 2-bromobenzaldehyde 6
and 3,4-dihydro-6,7-methylenedioxynaphthylboronic acid pina-
col ester (7). This design would be applicable to the preparation of
2,3,8,9-, 2,3,7,8-, and 2,3,9,10-, three types of tetraoxygenated
benzo[c]phenanthridines 1aef and 2f (Scheme 1).
* Corresponding authors. E-mail address: choshi@fupharm.fukuyama-u.ac.jp
(T. Choshi).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.066

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1321
1
12
O-triflate 10, which was performed to the Stille reaction with allyl
tributyltin in the presence of PdCl2(PPh3)2 and LiCl to give the dia-
llylbenzene 11. Olefin metathesis of diallylbenzene 11 with the
Grubbs’s 1 catalyst afforded the 1,4-dihydronaphthalene 12, which
was subjected to hydroboration followed by oxidation to yield 2-
hydroxytetrahydronaphthalene 13. The alcohol 13 was subsequently
oxidized by pyridinium chlorochromate (PCC) in CH2Cl2 to give the
2
3
O
O
O
O
R4
R4
R1
11
C
D
10
R3
R2
R3
R2
9
8
4
A
B
N
N
5
Me
7
R1
6
1a : R1=R4=H, R2=R3=OMe
(nornitidine)
2a : R1=R4=H, R2=R3=OMe
(nitidine)
known b b-tetralone was immediately
-tetralone 8.16 The unstable
1b : R1=R4=H, R2+R3=OCH2O
(noravicine)
2b : R1=R4=H, R2+R3=OCH2O
(avicine)
treated with N-phenylbis(trifluoromethanesulfonamide) (Tf2NPh)
and LDA to produce the triflate 14, which was converted to the nec-
1c : R1=OH, R2=OMe, R3=R4=H 2c : R1=OH, R2=OMe, R3=R4=H
essary pinacol borate
7
with bis(pinacolato)diborone and
(isodecarine)
(NK109)
1d : R1=R2=OMe, R3=R4=H
(norchelerythrine)
2d : R1=R2=OMe, R3=R4=H
(chelerythrine)
PdCl2(dppf).14c Analternative synthesisof the 6,7-methylenedioxy-
b-
tetralone (8) wasachieved in58% overallyieldina five-step sequence.
The pinacol borate 7 was obtained by additional two steps through
the triflate 14 (72%).
At first, 2,3,8,9-tetraoxygenated benzo[c]phenanthridines,
nornitidine (1a)1,17 and noravicine (1b)1,17 were chosen as target
compounds (Scheme 3). The SuzukieMiyaura reaction of 2-bromo-
4,5-dimethoxybenzaldehyde (6a)18 and 2-bromo-4,5-methyl-
enedioxybenzaldehyde (6b)18 with the pinacol borate 7 smoothly
proceeded in the presence of PdCl2(PPh3)2 to yield the 2-cyclo-
1e : R1+R2=OCH2O, R3=R4=H
(norsanguinarine)
2e : R1+R2=OCH2O, R3=R4=H
(sanguinarine)
1f : R1=R2=H, R3=OH, R4=OMe 2f : R1=R2=H, R3=R4=OMe
(zanthoxyline)
(broussonpapyrine)
1g : R1=R2=H, R3=R4=OMe
(O-methylzanthoxyline)
1h : R1=OMe, R2=OH, R3=R4=H
(decarine)
Fig. 1.
O
O
O
O
O
O
R4
R1
R4
R1
R4
R3
R2
R3
R2
R3
R2
NOMe
N
N
R1
R4
1
3
4
R4
O
O
O
O
R3
O
Br
R3
R2
Me
Me
O
+
B
O
Me
R2
CHO
O
O
CHO
R1
R1
Me
7
5
8
6
Scheme 1.
2. Result and discussions
alkenylbenzaldehydes 5a (98%) and 5b (78%) (Table 1: Runs 1 and 2).
Treatment of the resulting 5a and 5b with hydroxylamine methyl
ether gave the oxime methyl ethers 4a (95%) and 4b (98%), which
were performed to an MW-assisted electrocyclic reaction at 180 ꢀC
in 1,2-dichlorobenzene to produce the 10,11-dihydrobenzo[c]phe-
nanthridines 3a19 (84%) and 3b17b,19 (94%), respectively (Table 2:
To obtain a necessary pinacol borate 7, we initially attempted an
alternative synthesis of 6,7-methylenedioxy-b-tetralone (8) (Scheme
2). Treatment of 2-allyl-4,5-methylenedioxyphenol (9)15 with tri-
fluoromethanesulfonic anhydride (Tf2O) and pyridine afforded the
allyltributyltin, LiCl
Tf2O
OH
OTf
O
O
O
O
O
O
pyridine
PdCl2(PPh3)2, dppf
CH2Cl2
DMF
180oC, 2 h, 99%
rt, 2 h, 93%
9
10
11
Grubbs's I
catalyst
i) BH3, THF, 0oC, 1 h
OH
O
O
O
PCC
CH2Cl2
CH2Cl2
ii) 28% H2O2, 3M NaOH
50oC, 1 h, 86%
O
50oC, 1 h, 99%
rt, 1.5 h, 74%
12
13
Me
Me
bis(pinacolate)-
diborane
O
B
Me
AcOK
LDA
OTf
O
O
O
O
O
O
PdCl2(dppf)
Tf2NPh
O
Me
DMSO
O
THF
70oC, 1h, 86%
-78oC to rt
4 h, 84%
7
14
8
Scheme 2.

1322
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
R4
R1
O
O
O
R4
R1
R3
R2
Br
R3
R2
Me
O
O
B
O
Table 1
Me
+
CHO
CHO
Me
Me
6a : R1=R4=H, R2=R3=OMe
5a : R1=R4=H, R2=R3=OMe
7
6b : R1=R4=H, R2+R3=OCH2O
5b : R1=R4=H, R2+R3=OCH2O
5c : R1=OH, R2=OMe, R3=R4=H
5d : R1=R2=OMe, R3=R4=H
5e : R1+R2=OCH2O, R3=R4=H
5f : R1=R2=H, R3=R4=OMe
6c : R1=OAc, R2=OMe, R3=R4=H
6d : R1=R2=OMe, R3=R4=H
6e : R1+R2=OCH2O, R3=R4=H
6f : R1=R2=H, R3=R4=OMe
6g : R1=R2=H, R3=OAc, R4=OMe
5g : R1=R2=H, R3=OH, R4=OMe
O
O
O
R4
R4
MeONH2·HCl
R3
R3
O
Table 2
AcONa
NOMe
N
R2
R2
EtOH
80 oC, 1 h
64-98%
R1
R1
4a : R1=R4=H, R2=R3=OMe
3a : R1=R4=H, R2=R3=OMe
3b : R1=R4=H, R2+R3=OCH2O
3c : R1=OAc, R2=OMe, R3=R4=H
3d : R1=R2=OMe, R3=R4=H
3e : R1+R2=OCH2O, R3=R4=H
3f : R1=R2=H, R3=R4=OMe
4b : R1=R4=H, R2+R3=OCH2O
4c : R1=OH, R2=OMe, R3=R4=H
15 : R1=OAc, R2=OMe, R3=R4=H
4d : R1=R2=OMe, R3=R4=H
Ac2O, DMAP
Et3N, CH2Cl2
80oC, 1 h, 94%
4e : R1+R2=OCH2O, R3=R4=H
4f : R1=R2=H, R3=R4=OMe
3g : R1=R2=H, R3=OH, R4=OMe
17 : R1=R2=H, R3=OAc, R4=OMe
Ac2O, DMAP
Et3N, CH2Cl2
80oC, 1 h, Q.Y.
4g : R1=R2=H, R3=OH, R4=OMe
16 : R1=R2=H, R3=OAc, R4=OMe
1a : nornitidine
1b : noravicine
O
R4
NaHCO3
R3
10% Pd-C
18 : O-acetylisodecarine
1c : isodecarine
O
MeOH, H2O
N
60oC, 3 h, 74%
1,2-dichlorobenzene
180 oC, 5h
R2
1d : norchelerythrine
1e : norsanguinarine
19 : norbroussonpapyrine
20 : O-acetylzanthoxyline
1fa : zanthoxyline
R1
60-97%
NaHCO3
MeOH, H2O
10% NaOH, (MeO)2SO2
MeOH, rt, 12 h, 77%
60oC, 3 h, Q.Y.
1ga : O-methylzanthoxyline
Scheme 3.
Table 1
SuzukieMiyaura reactions between 6aeg and 7
R4
O
O
O
R4
R3
R2
Br
Me
O
R3
R2
O
B
O
Me
+
CHO
CHO
R1
6a-g
Me
Me
R1
7
5a-g
Run
Starting material
Compd.
Pd Catalyst
Time (h)
Product
Compd.
R
Yield (%)
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
R1¼R4¼H, R2¼R3¼OMe
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(dppf)
PdCl2(dppf)
PdCl2(PPh3)2
PdCl2(dppf)
0.5
0.5
1
5a
5b
5c
5d
5e
5f
98
78
96
75
97
72
54
R1¼R4¼H, R2þR3¼OCH2O
R1¼OAc, R2¼OMe, R3¼R4¼H
R1¼R2¼OMe, R3¼R4¼H
1
R1þR2¼OCH2O, R3¼R4¼H
R1¼R2¼H, R3¼R4¼OMe
0.5
0.5
1
6g
R1¼R2¼H, R3¼OAc, R4¼OMe
5g
Runs 2 and 4). In the case of conventional conditions without MW,
the yields of 3a and 3b were 45% and 57% (Table 2: Runs 1 and 3).
Finally, the dihydrobenzo[c]phenanthridines 3a and 3b were oxi-
dized by refluxing with 10% PdeC in 1,2-dichlorobenzene to give
nornitidine (1a: 97%)17 and noravicine (1b: 74%).17 The overall yields
of 1a and 1b were 76% and 53% in a four-step sequence after the
SuzukieMiyaura reaction.
(1e)1,22 were synthesized as follows (Scheme 3). Namely, the Suzukie
Miyaura reaction of 2-acetoxy-6-bromo-3-methoxybenzaldehyde
(6c),23 6-bromo-2,3-dimethoxybenzaldehyde (6d),23 and 6-bromo-
2,3-methylenedioxybenzaldehyde (6e)24 with the pinacol borate 7 in
the presence of PdCl2(PPh3)2 or PdCl2(dppf) afforded the 2-cyclo-
alkenylbenzaldehydes 5c (96%), 5d (75%), and 5e (97%), respectively
(Table 1: Runs 3, 4, and 5). The deacetylated compound 5c was
obtained in the cross-coupling reaction of 6c with 7. Three 2-cyclo-
alkenylbenzaldehydes 5c, 5d, and 5e were converted to the
Next, 2,3,7,8-tetraoxygenated benzo[c]phenanthridines, iso-
decarine (1c),1,10d,20 norchelerythrine (1d),1,21 and norsanguinarine

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1323
Table 2
Thermal electrocyclic reaction of aza 6
p
-electron systems
O
O
O
R4
R4
R3
R2
R3
R2
Δ
O
NOMe
N
1,2-dichlorobenzene
R1
4a-g, 15 and 16
R1
3a-g, 17
Run
Starting material (S.M.)
Temp (ꢀC)
Time (h)
MW
Product
Compd.
Compd.
R
Yield (%)
1
2
3
4
5
6
7
8
4a
4a
4b
4b
15
15
4d
4d
4e
4e
4f
R1¼R4¼H, R2¼R3¼OMe
180
180
180
180
180
180
180
180
180
180
180
180
180
200
180
200
12
2.5
12
2
3
1
3
1
7
4
7
4
6
4
7
5
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
ꢁ
þ
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
3f
45
84
57
94
49
77
49
84
37
95
R1¼R4¼H, R2¼R3¼OMe
R1¼R4¼H, R2þR3¼OCH2O
R1¼R4¼H, R2þR3¼OCH2O
R1¼OAc, R2¼OMe, R3¼R4¼H
R1¼OAc, R2¼OMe, R3¼R4¼H
R1¼R2¼OMe, R3¼R4¼H
R1¼R2¼OMe, R3¼R4¼H
9
R1þR2¼OCH2O, R3¼R4¼H
R1þR2¼OCH2O, R3¼R4¼H
R1¼R2¼H, R3¼R4¼OMe
10
11
12
13
14
15
16
S.M. Recover
80
S.M. Recover
75
24
67
4f
R1¼R2¼H, R3¼R4¼OMe
3f
4g
4g
16
16
R1¼R2¼H, R3¼OH, R4¼OMe
R1¼R2¼H, R3¼OH, R4¼OMe
R1¼R2¼H, R3¼OAc, R4¼OMe
R1¼R2¼H, R3¼OAc, R4¼OMe
3g
3g
17
17
corresponding oxime ethers 4c (95%), 4d (92%), and 4e (64%). Acety-
lation of the oxime ether 4c with Ac2O in the presence of 4-N,N-
dimethyaminopyridine (DMAP) and Et3N in CH2Cl2 afforded the
O-acetyl oxime ether 15 (94%), and then three oximes 15, 4d, and 4e
were subjected to an MW-assisted electrocyclic reaction at 180 ꢀC to
give the desired 11,12-dihydrobenzo[c]phenanthridines 3c (77%), 3d
(84%), and 3e (95%), respectively (Table 2: Runs 6, 8, and 10). In the
conditions of electrocyclic reaction of 15, 4d, and 4e without MW,
good results were not obtained (Table 2: Runs5, 7, and 9). Oxidation of
3c, 3d, and 3e in a similar way provided the O-acetylisodecarine (18:
93%), norchelerythrine (1d: 91%),21,22c and norsanginarine (1e:
60%),22 respectively. O-Acetylisodecarine 18 was hydrolyzed with
KHCO3 in an aqueous MeOH to produce isodecarine (1c: 74%).10d,20
The overall yields of 1c, 1d, and 1e were 45% (six-steps), 53%, and
35% (four-steps), respectively.
Furthermore, we attempted a synthesis of 2,3,9,10-tetraoxy-
genated benzo[c]phenanthridine, norbroussonpapyrine (19), the
precursor of broussonpapyrine (2f),25 and zanthoxyline (1f)26
(Scheme 3). The SuzukieMiyaura reaction of 2-bromo-3,4-dime-
thoxybenzaldehyde (6f)27 and 4-acetoxy-2-bromo-3-methoxy
benzaldehyde (6g)28 with the pinacol borate 7 gave the 2-cyclo-
alkenylbenzaldehyde 5f (72%) and the deacetylated 2-cycloalkenyl-
benzaldehyde 5g (54%). Subsequent treatment of 5f and 5g with
hydroxylaminemethyletheryieldedtheoximeethers4f(90%) and 4g
(95%). Acetylation of 4g with Ac2O in the presence of DMAP afforded
the acetylated 16 (Q.Y.). The oximes 4f, 4g, and 16 were performed to
an MW-assisted electrocyclic reaction at 200 ꢀC (external) to give the
desired tetracyclic dihydrobenzo[c]phenanthridines 3f (80%), 3g
(75%), and acetylated 17 (67%), respectively (Table 2: Runs 12,14, and
16). Under conventional conditions of Runs 11, 13, and 15 (Table 2)
without MW, these reactions produced low yield or resulted in re-
covery of the starting material. Finally, dihydrobenzo[c]phenan-
thridines 3f, 3g, and 17 were converted to norbroussonpapyrine (19)
(80%), zanthoxyline (1fa) (95%), and O-acetylzanthoxyline (20) (95%),
respectively, in a similar manner. Hydrolysis of 20 with an aqueous
NaHCO3 in MeOH afforded 1fa (Q.Y.). The overall yields of 19 and 1fa
were 41%and 35%infoursteps. The routeof theacetylated20through
the acetylated 17 provided 31% overall yield in six steps. Based on this
result, it was found that there is no necessity for protecting the
phenolic group in thisring closure (Table 2: Run14). O-Methylation of
the synthetic zanthoxyline (1fa) with dimethyl sulfate and 10% NaOH
afforded O-methylzanthoxyline (1ga) (77%). Thus, the synthesis of
2,3,9,10-tetraoxygenated benzo[c]phenanthridines 19 and 1fa were
also established. Our synthetic norbroussonpapyrine (19) and syn-
thetic O-methylzanthoxyline (1ga) should be consistent with
O-methylzanthoxyline (1g) reported by Morel group,26 but the NMR
spectral data of 19 and/or 1ga was not identical with those of 1g
(Tables 3 and 4). Although, 1H NMR spectral data of the reported
O-methylzanthoxyline (1g) was nearly the same as those of synthetic
norchelerythrine (1d), 13C NMR spectral data of 1g and 1d was
extremely superimposed. Therefore, the reported O-methyl-
zanthoxyline(1g)wasestimated to benorchelerythrine(1d)(Tables 3
and 4). It was recently reported by Abe group29 that the correct
structure of the reported zanthoxyline (1f) by Morel group26 is
8-hydroxy-7-methoxy-2,3-methylenedioxybenzo[c]phenanthridine
(decarine) (1h), but not 9-hydroxy-10-methoxy-2,3-methylenedioxy-
benz[c]phenanthridine (1fb)29 or 7-hydroxy-8-methoxy-2,3-methy-
lenedioxybenzo[c]phenanthridine (isodecarine) (1c). Our synthetic
9-hydroxy-10-methoxy-2,3-methylenedioxybenzo[c]phenanthridine
(1fa) was consistent with the reported 1fb by Abe group29 on the
comparison of the NMR spectral data (Tables 5 and 6).
Conversion of norbroussonpapyrine (19) to broussonpapyrine
(2fa and 2fb) was achieved by applying the procedures of the
Ishikawa30 and Simanek.10d Namely, treatment of 19 with formic
acid followed by reduction with NaBH4 gave the N-methylated
5,6-dihydrobenzo[c]phenanthridine 21, which was oxidized by
Jones reagent followed by treatment with diluted hydrochloric
acid to yield broussonpapyrine chloride (2fa). N-Methylation of 19
with methyl trifluoromethanesulfonate afforded broussonpapyr-
ine trifluoromethanesulfonate (2fb) (Scheme 4). The NMR spectral
data of synthetic 2f (Cl), however, were not identical with those of
the reported broussonpapyrine (2f)25 (Tables 7 and 8). For
a structure analysis of the reported broussonpapyrine (2f), our
synthetic norchelerythrine (1d) was converted to chelerythrine
(2d) through the dihydro-compound in the same way30 (Scheme
4). The NMR spectral data of our synthetic chelerythrine (2d)
was more closely related to the data of reported broussonpapyrine
(2f), besides the synthetic 2d was consistent with chelerythrine

1324
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
Table 3
Comparison of 1H NMR spectral dataa
[d
(ppm), (Dd)b]
O
O
O
O
OMe
MeO
N
MeO
N
OMe
1d : norchelerythrine
19 : norbroussonpapyryne
1g : O-methylzanthoxyline
1g: O-Methylzanthoxyline
1ga: O-Methylzanthoxyline
19: Norbroussonpapyrine
1d: Norchelerythrine
reported by Morelc,26
(synthetic compound)d
(synthetic compound)d
(synthetic compound)d
4.02, s
4.06, s
6.05, s
7.12, s
7.27, d
7.59, d
8.24, d
8.24, d
8.65, s
9.67, s
(9-OCH3)
(10-OCH3)
(eOeCH2eOe)
(C-1)
(C-8)
(C-12)
(C-7)
(C-11)
(C-4)
4.00, s
4.09, s
6.13, s
7.27, s
7.43, d
7.86, d
7.89, d
9.33, d
8.75, s
9.24, s
(ꢁ0.02)
(0.03)
(0.08)
(0.15)
(0.16)
(0.27)
(ꢁ0.35)
(1.09)
(0.10)
(ꢁ0.43)
4.00, s
4.09, s
6.12, s
7.26, s
7.43, d
7.86, d
7.89, d
9.33, d
8.75, s
9.25, s
(ꢁ0.02)
4.06, s
4.13, s
6.13, s
7.27, s
7.60, d
7.85, d
8.36, d
8.37, d
8.72, s
9.75, s
(0.04)
(0.03)
(0.07)
(0.14)
(0.16)
(0.27)
(ꢁ0.35)
(1.09)
(0.10)
(ꢁ0.42)
(0.07)
(0.08)
(0.15)
(0.33)
(0.26)
(0.12)
(0.13)
(0.07)
(0.08)
(C-6)
a
NMR spectral data were measured in CDCl3.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
400 MHz 1H NMR.
300 MHz 1H NMR.
d
Table 4
Comparison of 13C NMR spectral dataa (ppm), (Dd)b]
[d
1g: O-Methylzanthoxyline reported
1ga: O-Methylzanthoxyline
19: Norbroussonpapyrine
(synthetic compound)d
1d: Norchelerythrine
by Morelc,26
(synthetic compound)d
(synthetic compound)d
57.0
61.8
(9-OCH3)
(10-OCH3)
(eOeCH2eOe)
(C-4)
(C-1)
(C-7)
56.5
60.1
(ꢁ0.5)
(ꢁ1.7)
(0)
56.5
60.1
(ꢁ0.5)
56.8
61.9
(ꢁ0.2)
(ꢁ1.7)
(0)
(0.1)
(0)
101.3
102.3
104.3
118.2
118.2
119.2
120.0
121.9
127.0
128.3
129.3
129.8
140.2
145.6
146.5
148.4
148.5
149.4
101.3
102.6
103.8
113.5
119.6
122.9
123.1
125.9
126.4
127.4
128.8
130.1
141.7
145.5
148.1
148.5
151.6
154.4
101.3
102.5
103.9
113.5
119.6
122.9
123.1
126.0
126.4
127.4
128.7
130.1
141.5
145.5
148.1
148.5
151.5
154.5
101.3
102.2
104.4
118.2
118.3
118.7
120.0
121.9
127.1
128.1
129.2
129.7
140.0
145.2
146.6
148.3
148.5
149.4
(0.3)
(0.2)
(ꢁ0.1)
(0.1)
(0)
(0.1)
(ꢁ0.5)
(0)
(ꢁ0.5)
(ꢁ4.7)
(1.4)
(3.7)
(3.1)
(ꢁ0.4)
(ꢁ4.7)
(1.4)
(3.7)
(3.1)
(C-11)
(C-8)
(C-10b)
(C-10a)
(C-12)
(C-6a)
(C-4a)
(C-12a)
(C-4b)
(C-10)
(C-6)
(4.0)
(4.1)
(0)
(ꢁ0.6)
(ꢁ0.9)
(ꢁ0.5)
(0.3)
(ꢁ0.6)
(ꢁ0.9)
(ꢁ0.6)
(0.3)
(0.1)
(ꢁ0.2)
(ꢁ0.1)
(ꢁ0.1)
(ꢁ0.2)
(ꢁ0.4)
(0.1)
(ꢁ0.1)
(0)
(1.5)
(1.3)
(ꢁ0.1)
(ꢁ0.1)
(1.6)
(1.6)
(C-2)
(C-3)
(C-9)
(0.1)
(3.1)
(5.0)
(0.1)
(3.0)
(5.1)
(0)
a
NMR spectral data were measured in CDCl3.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
100 MHz 13C NMR.
75 MHz 13C NMR.
d
(2d) provided by Ishikawa in all respect (Tables 7 and 8). The
structure of synthetic 2fb (CF3SO3) was also confirmed by X-ray
single crystallographic analysis (Fig. 2). Consequently, it was
found that the exact structure of the reported broussonpapyrine
(2f) is 7,8-dimethoxy-N-methyl-2,3-methylendioxybenzo[c]phe-
nanthridinium (chelerythrine) (2d). Moreover, the first syntheses
of 9,10-dimethoxy-2,3-methylenedioxybenzo[c]phenanthridine
(19) and 9,10-dimethoxy-N-methyl-2,3-methylenedioxybenzo[c]
phenanthridinium chloride (2fa) (and trifluoromethanesulfonate
2fb) were achieved.
tetracyclic 10,11-dihydrobenzo[c]phenanthridine framework 3aeg
and 17 based on the SuzukieMiyaura reaction between 2-bromo-
benzaldehydes 6 and 2-(3,4-dihydro-6,7-methylenedioxynaphthyl)
boronic acid pinacol ester (7), followed by the bond formation be-
tween C4b and N5 at the position of the tetracyclic ring using an
MW-assisted thermal electrocyclic reaction of the 6p-electron sys-
tem as a key step. Subsequent dehydrogenation of 3aeg and 17 with
10% PdeC afforded eight benzo[c]phenanthridines 1aeb, 18, 1dee,
19, 20, and 1fa. O-Acetyl derivatives 18 and 20 were converted to
isodecarine 1c and 9-hydroxy-10-methoxybenzo[c]phenanthridine
(zanthoxyline) (1fa) by hydrolysis. The synthetic zanthoxyline (1fa)
was converted to O-methylzanthoxyline (1ga), which was closely
superimposed with synthetic norbroussonpapyrine (19). Our syn-
thetic zanthoxyline (1fa) was consistent with 9-hydroxy-10-
methoxybenzo[c]phenanthridine (zanthoxyline) (1fb) by Abe
3. Conclusion
A versatile synthesis of benzo[c]phenanthridines and benzo[c]
phenanthridine alkaloids was achieved by the constructing the

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1325
Table 5
Comparison of 1H NMR spectral dataa
[d
(ppm), (Dd)b]
OMe
O
O
O
O
O
O
HO
N
N
N
HO
MeO
OMe
OH
1c : isodecarine
1f : zanthoxyline
1h : decarine
1f: Zanthoxyline
1fa: Zanthoxyline
1fb: Zanthoxyline
1h: Decarine
reported by Abe29
1c: Isodecarine
(synthetic compound)d
reported by Morelc,26
(synthetic compound)d
reported by Abe29
4.09, s
6.09, s
7.46, s
7.61, d
7.92, d
8.42, d
8.46, d
8.57, s
9.61, s
(10-OCH3)
(eOeCH2eOe)
(C-1)
(C-8)
(C-12)
(C-7)
(C-11)
(C-4)
(C-6)
3.88, s
6.21, s
7.48, s
7.42, d
7.93, d
7.93, d
9.26, d
8.58, s
9.21, s
(ꢁ0.21)
(0.12)
(0.02)
3.88, s
6.21, s
7.48, s
7.43, d
7.94, d
7.94, d
9.21, d
8.58, s
9.27, s
(ꢁ0.21)
4.01, s
6.20, s
7.50, s
7.57, d
7.95, d
8.46, d
8.50, d
8.53, s
9.57, s
(ꢁ0.08)
3.98, s
6.20, s
7.48, s
7.70, d
7.93, d
8.23, d
8.49, d
8.51, s
9.65, s
(ꢁ0.11)
(0.11)
(0.02)
(0.09)
(0.01)
(ꢁ0.19)
(0.03)
(ꢁ0.06)
(0.04)
(0.12)
(0.02)
(0.11)
(0.04)
(ꢁ0.19)
(ꢁ0.18)
(ꢁ0.04)
(0.01)
(0.02)
(0.03)
(ꢁ0.49)
(0.80)
(0.01)
(ꢁ0.40)
(ꢁ0.48)
(0.81)
(0.01)
(ꢁ0.34)
(0.04)
(0.04)
(ꢁ0.04)
(ꢁ0.04)
a
NMR spectral data were measured in DMSO-d6.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
400 MHz 1H NMR.
300 MHz 1H NMR.
d
Table 6
Comparison of 13C NMR spectral dataa
[
d
(ppm), (Dd)b]
1fa: Zanthoxyline
1f: Zanthoxyline
1fb: Zanthoxyline
1h: Decarine
reported by Abe29
1c: Isodecarine
reported by Morelc,26
(synthetic compound)d
reported by Abe29
(synthetic compound)d
61.9
(10-OCH3)
(eOeCH2eOe)
(C-4)
(C-1)
(C-7)
(C-11)
(C-10a)
(C-8)
(C-6a)
(C-12)
(C-12a)
(C-10)
(C-6)
59.5
101.6
101.6
104.0
119.0
119.1
122.1
126.2
126.4
126.8
129.7
142.9
147.9
148.4
151.9
153.1
(-2.4)
(ꢁ0.4)
(ꢁ0.8)
(ꢁ1.1)
(0.1)
(0.1)
(0.3)
(0.6)
(ꢁ1.0)
(ꢁ1.3)
(ꢁ0.2)
(ꢁ0.3)
(2.4)
(0.3)
(3.2)
(4.2)
59.7
101.7
101.7
104.2
119.1
119.3
122.1
126.4
126.6
127.0
129.9
143.1
148.1
148.5
151.9
153.4
(ꢁ2.2)
61.4
100.9
102.0
105.0
118.7
119.2
121.4
125.6
127.2
128.2
129.7
142.7
145.1
148.1
148.5
148.8
(ꢁ0.5)
56.9
101.1
101.6
104.5
118.7
118.9
119.8
127.0
127.1
128.3
129.4
142.8
144.3
146.7
148.0
148.1
(ꢁ5.0)
(ꢁ0.9)
(ꢁ0.8)
(ꢁ0.6)
(ꢁ0.2)
(ꢁ0.1)
(ꢁ2.0)
(1.4)
102.0
102.4
105.1
118.9
119.0
121.8
125.6
127.4
128.1
129.9
143.2
145.5
148.1
148.7
148.9
(ꢁ0.3)
(ꢁ0.7)
(ꢁ0.9)
(0.2)
(ꢁ1.1)
(ꢁ0.4)
(ꢁ0.1)
(ꢁ0.2)
(0.2)
(0.3)
(0.3)
(0.8)
(ꢁ0.8)
(ꢁ1.1)
(0)
(ꢁ0.4)
(0)
(ꢁ0.2)
(0.1)
(ꢁ0.2)
(ꢁ0.5)
(ꢁ0.4)
(0)
(ꢁ0.3)
(0.2)
(ꢁ0.5)
(ꢁ0.4)
(ꢁ1.2)
(ꢁ1.4)
(ꢁ0.7)
(ꢁ0.8)
(ꢁ0.1)
(2.6)
(C-9)
(C-2)
(C-3)
(0.4)
(3.2)
(4.5)
(ꢁ0.2)
(ꢁ0.1)
a
NMR spectral data were measured in DMSO-d6.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
100 MHz 13C NMR.
75 MHz 13C NMR.
d
group29 in all respects. In addition, 9,10-dimethoxy-N-methyl-2,
3-methylenedioxybenzo[c]phenanthridinium chloride (brousson-
papyrine) (2fa) was synthesized from 9,10-dimethoxy-2,3-methyl-
enedioxybenzo[c]phenanthridine (norbroussonpapyrine) (19).
Based on the comparison of NMR spectral data, it was found that the
exact structure of the reported broussonpapyrine (2f) by Qin
group25 is the known chelerythrine (2d). Although, 9,10-dimethoxy-
N-methyl-2,3-methylenedioxybenzo[c]phenanthridinium chloride
(2fa) and 9-hydroxy-10-methoxy-2,3-methylenedioxybenzo[c]
phenanthridine (1fa) were unnatural compounds, our synthetic
methodology was confirmed to be applicable for the synthesis of the
2,3,9,10-tetraoxygenated type of benzo[c]phenanthridine.
spectrometer. Nuclear magnetic resonance spectra were taken with
a JEOL JNM AL-300 and JNM-ECA500 instruments using tetrame-
thylsilane as an internal standard. Mass spectra were measured by
Shimadzu QP-5050, JEOL JMS-700, and Waters LCT spectrometers
by direct inlet system, respectively. The reaction of microwave
(MW) irradiation was carried out by Discover of CEM Co. Ltd. with
2450 MHz. Anhydrous THF, CH2Cl2, and DMF were used commer-
cially available solvents (Cica reagents) for organic synthesis. 1,2-
Dichlorobenzene, using for an MW-assisted electrocyclic reaction,
was degassed before use. Silica gel (Merck Art 7744, 60e100 mesh)
was used for column chromatography.
4.1.1. 1-Allyloxy-3,4-methylenedioxy-6-trifluoromethanesulfonyloxy-
benzene 10. A solution of Tf2O (4 mL, 24 mmol) was added to an
ice-cooled solution of phenol 915 (4 g, 20 mmol) and pyridine
(2.1 mL, 30 mmol) in CH2Cl2 (200 mL) under an N2 atmosphere.
After being stirred at rt for 12 h, the mixture was quenched
with water. The mixture was extracted with CH2Cl2. The CH2Cl2
layer was washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
4. Experimental section
4.1. General
Melting points were determined on a Yanagimoto micro-melt-
ing point apparatus MP-500D and are uncorrected. Infrared spectra
were recorded with ATR method on a Shimadzu FTIR-8000

1326
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
O
O
OMe
OMe
OMe
CF3SO3Me
MeO
MeO
O
O
toluene
90oC, 30 min
81%
CF3SO3
N
N
Me
19
2fb
1) HCOOH, rt, 12 h
2) NaBH4, rt, 30 min, 54%
O
O
OMe
Jone's reagent
MeO
MeO
O
O
acetone
0oC, 30 min
82%
Cl
N
N
Me
Me
2fa
21
O
O
O
O
1) HCOOH, rt, 12 h
2) NaBH4, rt, 30 min
N
N
3) Jone's reagent
acetone
Cl
MeO
MeO
Me
OMe
OMe
0oC, 30 min, 61%
1d
2d
Scheme 4.
Table 7
Comparison of 1H NMR spectral dataa
[d
(ppm), (Dd)b]
O
O
O
OMe
MeO
O
N
N
Me
2f : broussonpapyrine
MeO
Me
X
Cl
OMe
2d : chelerythrine
2f: Broussonpapyrine
2fa: Broussonpapyrine
2d: Chelerythrine
2d: Chelerythrine
reported by Qinc,25
(Cl:synthetic compound)d
(synthetic compound)d
(provided by Ishikawa)c
4.15, s
4.25, s
5.00, s
6.28, s
7.58, s
8.16, s
8.20, d
8.21, d
8.64, d
8.68, d
9.98, s
(9-OCH3)
(10-OCH3)
(NeCH3)
(eOeCH2eOe)
(C-1)
(C-4)
(C-12)
(C-7)
4.22, s
4.00, s
4.84, s
6.26, s
7.54, s
8.11, s
8.17, d
8.37, d
9.48, d
7.95, d
9.78, s
(0.07)
4.14, s
4.28, s
4.99, s
6.27, s
7.55, s
8.18, s
8.20, d
8.20, d
8.64, d
8.67, d
9.97, s
(ꢁ0.01)
(0.03)
(ꢁ0.01)
(0.01)
(ꢁ0.03)
(0.02)
(0)
4.14, s
4.29, s
4.99, s
6.27, s
7.54, s
8.17, s
8.18, d
8.20, d
8.62, d
8.65, d
9.96, s
(ꢁ0.01)
(ꢁ0.25)
(ꢁ0.16)
(ꢁ0.02)
(ꢁ0.04)
(ꢁ0.05)
(ꢁ0.03)
(0.16)
(0.04)
(ꢁ0.01)
(ꢁ0.01)
(ꢁ0.04)
(0.01)
(ꢁ0.02)
(ꢁ0.01)
(ꢁ0.02)
(ꢁ0.03)
(ꢁ0.02)
(ꢁ0.01)
(C-11)
(C-8)
(C-6)
(0.84)
(0)
(ꢁ0.73)
(ꢁ0.01)
(ꢁ0.01)
(ꢁ0.20)
a
NMR spectral data were measured in CD3OD.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
500 MHz 1H NMR.
300 MHz 1H NMR.
d
chromatography (silica gel, 50 g) using EtOAcehexane (1:9 v/v) as
an eluent to give the oily triflate 10 (6.5 g, 93%). 1H NMR (300 MHz,
mixture was filtered off through Celite pad and the filtrate was
extracted with EtOAc. The EtOAc layer was washed with water and
brine, dried over Na2SO4, and concentrated under reduced pressure.
The residuewaspurifiedbycolumnchromatography (silica gel,100 g)
using hexane as an eluent to give the oily diallylbenzene 11 (11.7 g,
CDCl3) d: 3.34e3.42 (2H, m), 5.07e5.21 (2H, m), 5.79e5.96 (1H, m),
6.00 (2H, s), 6.73 (1H, s), 6.74 (1H, s). MS (EI) m/z: 310 (Mþ). HRMS
(EI) calcd for C11H9F3O5S 310.0123; found 310.0122.
100%). 1H NMR (300 MHz, CDCl3)
d
: 3.29 (4H, d, J¼5.9 Hz), 4.96e5.06
4.1.2. 1,2-Diallyloxy-4,5-methylenedioxybenzene 11. A solution of
allyl tributyltin (21 mL, 80 mmol) was added to a mixture of the O-
triflate 10 (17.5 g, 60 mmol), LiCl (3.6 g, 80 mmol), PdCl2(PPh3)2 (0.5 g,
0.6 mmol), and dppf (0.3 g, 0.6 mmol) in DMF (100 mL) at rt under an
argon atmosphere. The stirred mixture was heated for 2 h at 180 ꢀC,
which was cooled to rt. After being quenched with an aqueous solu-
tion of KF (30%), and then the mixture was stirred at rt for 2 h. The
(4H, m), 5.84e5.98 (4H, m), 6.66 (2H, s). MS (EI) m/z: 202 (Mþ). HRMS
(EI) calcd for C13H14O2 202.0994; found 202.0986.
4.1.3. 1,4-Dihydro-6,7-methylenedioxynaphthalene 12. A stirred mix-
ture of the diallylbenzene 11 (2 g, 9.17 mmol) and Grubbs first
(400 mg, 0.49 mmol) in CH2Cl2 (40 mL) was heated at 50 ꢀC for 1 h
under N2 atmosphere. After removal of solvent the residue was

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1327
Table 8
Comparison of 13C NMR spectral dataa
[
d
(ppm), (Dd)b]
2fa: Broussonpapyrine
2f: Broussonpapyrine
2d: Chelerythrine
2d: Chelerythrine
reported by Qinc,25
(Cl:synthetic compound)d
(synthetic compound)d
(provided by Ishikawa)c
52.94
57.6
62.8
(NeCH3)
(9-OCH3)
(10-OCH3)
(eOeCH2eOe)
(C-4)
(C-1)
(C-11)
(C-7)
(C-6a)
(C-4a)
(C-12a)
(C-8)
(C-10a)
(C-12)
(C-4b)
(C-10b)
(C-10)
(C-3)
(C-2)
(C-6)
(C-9)
51.98
57.8
60.9
(ꢁ0.96)
52.94
57.6
62.9
(0)
(0)
(0.1)
(0.1)
(0.1)
(0)
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(ꢁ0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0.1)
(0)
52.99
57.6
62.9
(0.05)
(0)
(0.1)
(0.1)
(0)
(0)
(0)
(0)
(0)
(0.2)
(ꢁ1.9)
(ꢁ0.1)
(0)
(ꢁ0.8)
(ꢁ1.2)
(0.8)
104.3
105.1
107.1
119.5
119.9
120.9
121.8
127.1
127.5
130.1
132.6
133.5
134.3
147.5
150.8
151.0
151.8
152.1
104.2
105.1
106.3
118.3
120.7
121.5
123.3
125.8
129.5
131.2
132.0
134.5
134.9
146.3
150.3
151.2
155.8
162.4
104.4
105.2
107.1
119.6
120.0
121.0
121.9
127.2
127.4
130.2
132.7
133.6
134.4
147.6
150.8
151.0
151.9
152.2
104.4
105.1
107.1
119.5
119.9
120.9
121.8
127.1
127.4
130.1
132.6
133.5
134.3
147.5
150.8
151.0
151.8
152.1
(0.6)
(1.5)
(0)
(0)
(ꢁ1.3)
(2.0)
(ꢁ0.1)
(1.1)
(0)
(ꢁ0.6)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(0)
(1.0)
(0.6)
(ꢁ1.2)
(ꢁ0.5)
(0.2)
(4.0)
(10.3)
(0)
(0.1)
(0.1)
a
NMR spectral data were measured in CD3OD.
b
c
Values in parentheses refer to the difference in chemical shift between the synthetic data and the reported data.
125 MHz 13C NMR.
75 MHz 13C NMR.
d
Fig. 2. ORTEP drawing of synthetic 2fb (trifluoromethanesulfonate).
purified by column chromatography using EtOAcehexane (1:9 v/v)
as an eluent to give the oily dihydronaphthalene 12 (1.8 g, 99%). 1H
(1H, s). MS (EI) m/z: 192 (Mþ). HRMS (EI) calcd for C11H12O3
192.0786; found 192.0813.
NMR(300 MHz, CDCl3) d: 3.30 (4H, s), 5.80e5.82 (4H, m), 6.57 (2H, s).
MS (EI) m/z: 174 (Mþ). HRMS (EI) calcd for C11H10O2 174.0681; found
4.1.5. 6,7-Methylenedioxy-b-tetralone 8. A mixture of the 2-naphthol
174.0677.
13 (430 mg, 2.24 mmol), PCC (2.4 g, 11.20 mmol), and Celite (2.4 g)
was stirred at rt for 1.5 h under N2 atmosphere. After diluted with
Et2O, the mixture was filtered off through Celite pad. The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 50 g) using EtOAcehexane (1:9
4.1.4. 1,2,3,4-Tetrahydro-6,7-methylenedioxy-2-naphthol 13. An ice-
cooled solution of BH3$THF (1.4 mL, 1.6 mmol) was added to a so-
lution of the dihydronaphthalene 12 (560 mg, 3.2 mmol) in THF
(25 mL) under N2 atmosphere. After being stirred at the same
temperature for 1 h, an aqueous 3 M NaOH (0.52 mL, 1.6 mmol)
followed by an aqueous 30% H2O2 (0.52 mL, 4.6 mmol) were added
to the mixture, and then the resulting mixture was stirred at the
same temperature for 1 h. After quenched with water, the mixture
was extracted with EtOAc. The EtOAc layer was washed with water
and brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, 10 g) using EtOAcehexane (1:9 v/v) as an eluent to give
the tetrahydronaphthol 13 (530 mg, 86%), mp 78e79 ꢀC
v/v) as an eluent to give the
93e94 ꢀC (EtOAcehexane) (lit.16a mp 91e92 ꢀC and lit.16b mp
97e98 ꢀC). IR (ATR) : 1699 cmꢁ1 (C]O). 1H NMR (300 MHz, CDCl3)
b-tetralone 8 (314 mg, 74%), mp
n
d
: 2.50e2.54 (2H, m), 2.94e2.99 (2H, m), 3.48 (2H, s), 5.93 (2H, s),
6.60 (1H, s), 6.71 (1H, s). MS (EI) m/z: 190 (Mþ). HRMS (EI) calcd for
C11H10O3 190.0629; found 190.0624.
4.1.6. 3,4-Dihydro-6,7-methylenedioxy-2-trifluoromethanesulfonyloxy-
naphthalene 14. A solution of b-tetralone 8 (360 mg, 1.89 mmol) in
THF (5 mL) was added to a solution of LDA [prepared from i-Pr2NH
(0.36 mL, 2.84 mmol) and n-BuLi (2.6 M in hexane, 0.9 mL,
2.84 mmol)] at ꢁ78 ꢀC under N2 atmosphere. The mixture was stirred
(EtOAcehexane). 1H NMR (300 MHz, CDCl3)
2.62e3.03 (4H, m), 4.08e4.19 (1H, m), 5.88 (2H, s), 6.54 (1H, s), 6.56
d: 1.56e2.07 (2H, m),

1328
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
at the same temperature at 30 min, and then Tf2NPh (675 mg,
1.89 mmol) in THF (5 mL) was added to the mixture. The reaction
temperature was gradually raised up to rt for 4 h. The mixture was
quenched with water, and then the mixture was extracted with Et2O.
The Et2O layer was washed with water and brine, dried over Na2SO4,
and concentrated. The residue was purified by column chromatog-
raphy (silica gel, 10 g) using EtOAcehexane (1:19 v/v) as an eluent to
7 (45 mg, 0.15 mmol), K2CO3 (41 mg, 0.3 mmol), and PdCl2(PPh3)2
(7 mg, 0.01 mmol) in anhyd MeOH (4 mL) and DMF (1 mL) were used
to give the naphthylbenzaldehyde 5c (31 mg, 96%), mp 180e181 ꢀC
(EtOAcehexane). IR (ATR)
CDCl3) : 2.61e2.66 (2H, m), 2.86e2.91 (2H, m), 3.93 (3H, s), 5.94
n
: 1635 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
(2H, s), 6.27 (1H, s), 6.62 (1H, s), 6.70 (1H, s), 6.84 (1H, d, J¼8.1 Hz),
7.09 (1H, d, J¼8.1 Hz), 10.13 (1H, s), 12.08 (1H, s). MS (EI) m/z: 324
(Mþ). HRMS (EI) calcd for C19H16O5 324.0998; found 324.1025.
give the oily triflate 14 (490 mg, 84%). 1H NMR (300 MHz, CDCl3)
d:
2.61e2.67 (2H, m), 2.93e2.99 (2H, m), 5.94 (2H, s), 6.35 (1H, s), 6.58
(1H, s), 6.64 (1H, s). MS (EI) m/z: 322 (Mþ). HRMS (EI) calcd for
C12H9F3O5S 322.0123; found 322.0133.
4.2.4. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2,3-dimethoxy
benzaldehyde 5d. 6-Bromo-2,3-dimethoxybenzaldehyde (6d)23
(30 mg, 0.12 mmol), naphthylboronic acid pinacol ester 7 (55 mg,
0.18 mmol), K2CO3 (51 mg, 0.37 mmol), and PdCl2(dppf) (7 mg,
0.01 mmol) in anhyd MeOH (6 mL) and DMF (2 mL) were used to
give the naphthylbenzaldehyde 5d (31 mg, 75%), mp 148e149 ꢀC
4.1.7. 3,4-Dihydro-6,7-methylendioxynaphthylboronic acid pinacol
ester 7. A mixture of the triflate 14 (250 mg, 0.78 mmol), bis(pina-
colato)diborone, AcOK, and PdCl2(dppf) (7 mg, 0.008 mmol) in
DMSO (20 mL) was stirred at 80 ꢀC for 1 h. The reaction mixture was
quenched with water, and then the mixture was extracted with
EtOAc. The EtOAc layer was washed with water and brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, 10 g) using
EtOAcehexane (1:19 v/v) as an eluent to give the naphthylboronic
acid pinacol ester7 (200 mg, 86%), mp 92e94 ꢀC (EtOAcehexane).1H
(EtOAcehexane). IR (ATR)
CDCl3) : 2.44e2.49 (2H, m), 2.88e2.93 (2H, m), 3.92 (3H, s), 3.96
n
: 1685 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
(3H, s), 5.92 (2H, s), 6.22 (1H, s), 6.59 (1H, s), 6.67 (1H, s), 7.03 (1H, d,
J¼8.4 Hz), 7.10 (1H, d, J¼8.4 Hz), 10.38 (1H, s). MS (EI) m/z: 338 (Mþ).
HRMS (EI) calcd for C20H18O5 338.1154; found 338.1157.
4.2.5. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2,3-methyl-
enedioxybenzaldehyde 5e. 6-Bromo-2,3-methylenedioxybenzalde-
hyde (6e)24 (20 mg, 0.09 mmol), naphthylboronic acid pinacol ester 7
(52 mg, 0.18 mmol), K2CO3 (36 mg, 0.26 mmol), and PdCl2(dppf)
(7 mg, 0.01 mol) in anhyd MeOH (4 mL) and DMF (1 mL) were used
to give the naphthylbenzaldehyde 5e (28 mg, 97%), mp 153e155 ꢀC
NMR (300 MHz, CDCl3) d: 1.30 (12H, s), 2.30e2.36 (2H, m), 2.63e2.68
(2H, m), 5.91 (2H, s), 6.62 (2H, s), 7.08 (1H, s). MS (EI) m/z: 300 (Mþ).
HRMS (EI) calcd for C17H21BO4 300.1533; found 300.1534.
4.2. General procedure of SuzukieMiyaura reaction between
2-bromobenzaldehyde 6 and 3,4-dihydro-6,7-methylenedioxy-
naphthylboronic acid pinacol ester 7
(EtOAcehexane). IR (ATR)
CDCl3) : 2.58e2.63 (2H, m), 2.86e2.92 (2H, m), 5.93 (2H, s), 6.16
n
: 1679 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
(2H, s), 6.27 (1H, s), 6.61 (1H, s), 6.69 (1H, s), 6.87 (1H, d, J¼8.1 Hz),
6.99 (1H, d, J¼8.1 Hz), 10.13 (1H, s). MS (EI) m/z: 322 (Mþ). HRMS (EI)
calcd for C19H14O5 322.0841; found 322.0843.
A mixture of bromobenzaldehyde 6, the naphthylboronic acid
pinacol ester7, K2CO3, and PdCl2(PPh3)2 inanhydMeOHand DMFwas
stirred at 80 ꢀC for 0.5e1 h under N2 atmosphere. The reaction mix-
ture was quenched with water, and then the mixture was extracted
with EtOAc. The EtOAc layer was washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography using EtOAcehexane (1:19
v/v) as an eluent to give the naphthylbenzaldehyde 5.
4.2.6. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-3,4-dimethoxy-
benzaldehyde
5f. 2-Bromo-3,4-dimethoxybenzaldehyde
(6f)27
(50 mg, 0.20 mmol), the naphthylboronic acid pinacol ester 7
(93 mg, 0.31 mmol), K2CO3 (87 mg, 0.62 mmol), PdCl2(PPh3)2 (7 mg,
0.01 mmol) in anhyd MeOH (8 mL) and DMF (2 mL) were used to give
the oily naphthylbenzaldehyde 5f (50 mg, 72%). IR (ATR)
n
: 1676 cmꢁ1
4.2.1. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-4,5-dimethoxy-
(C]O). 1H NMR (300 MHz, CDCl3)
d: 2.89e2.94 (2H, m), 3.79 (3H, s),
benzaldehyde
5a. 2-Bromo-4,5-dimethoxybenzaldehyde
(6a)18
3.96e3.98 (5H, m), 5.94 (2H, s), 6.28 (1H, s), 6.61 (1H, s), 6.72 (1H, s),
6.98 (1H, d, J¼8.8 Hz), 7.79 (1H, d, J¼8.8 Hz),10.03 (1H, s). MS (EI) m/z:
338 (Mþ). HRMS (EI) calcd for C20H18O5 338.1154; found 338.1149.
(50 mg, 0.20 mmol), naphthylboronic acid pinacol ester 7 (200 mg,
0.62 mmol), K2CO3 (83 mg, 0.6 mmol), and PdCl2(PPh3)2 (7 mg,
0.01 mmol) in anhyd MeOH (8 mL) and DMF (2 mL) were used to give
the 2-naphthylbenzaldehyde 5a (68 mg, 98%), mp 145e147 ꢀC
4.2.7. 2-(3,4-Dihydro-6.7-methylenedioxy-2-naphthyl)-4-hydroxy-3-
methoxybenzaldehyde 5g. 4-Acetoxy-2-bromo-3-methoxybenzal-
dehyde (6g)28 (220 mg, 0.81 mmol), the naphthylboronic acid
pinacol ester 7 (267 mg, 0.89 mmol), K2CO3 (336 mg, 2.43 mmol),
PdCl2(dppf) (24 mg, 0.03 mmol) in anhyd MeOH (12 mL) and DMF
(3 mL) were used to give the naphthylbenzaldehyde 5g (130 mg,
(EtOAcehexane). IR (ATR)
CDCl3) : 2.64e2.70 (2H, m), 2.89e2.94 (2H, m), 3.96 (3H, s), 3.97 (3H,
n
: 1660 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
s), 5.94 (2H, s), 6.30 (1H, s), 6.63 (1H, s), 6.71 (1H, s), 6.81 (1H, s), 7.47
(1H, s), 10.09 (1H, s). MS (EI) m/z: 338 (Mþ). HRMS (EI) calcd for
C20H18O5 338.1154; found 338.1158.
54%), mp 153e155 ꢀC (EtOAcehexane). IR (ATR)
n
: 1666 cmꢁ1 (C]O).
4.2.2. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-4,5-meth-
ylenedioxybenzaldehyde 5b. 2-Bromopiperonal (6b)18 (40 mg,
0.17 mmol), naphthylboronic acid pinacol ester 7 (80 mg,
0.26 mmol), K2CO3 (36 mg, 0.26 mmol), and PdCl2(PPh3)2 (7 mg,
0.01 mmol) in anhyd MeOH (4 mL) and DMF (1 mL) were used to
give the naphthylbenzaldehyde 5b (44 mg, 78%), mp 182e184 ꢀC
1H NMR (300 MHz, CDCl3)
d: 2.64 (2H, br s), 2.91e2.96 (2H, m), 3.80
(3H, s), 5.95 (2H, s), 6.38 (2H, s), 6.62 (1H, s), 6.72 (1H, s), 7.15 (1H, d,
J¼8.4 Hz), 7.74 (1H, d, J¼8.4 Hz), 10.01 (1H, s). MS (EI) m/z: 324 (Mþ).
HRMS (EI) calcd for C19H16O5 324.0998; found 324.1127.
(EtOAcehexane). IR (ATR)
(300 MHz, CDCl3)
5.94 (2H, s), 6.06 (2H, s), 6.26 (1H, s), 6.61 (1H, s), 6.70 (1H, s),
6.82 (1H, s), 7.41 (1H, s), 10.04 (1H, s). MS (EI) m/z: 322 (Mþ).
HRMS (EI) calcd for C19H14O5 322.0841; found 322.0843.
n
:
1670 cmꢁ1 (C]O). 1H NMR
4.3. General procedure of benzaldehyde O-methyl oximes 4
d
: 2.60e2.65 (2H, m), 2.90 (2H, t, J¼8.1 Hz),
A mixture of the naphthylbenzaldehydes 5, MeONH2$HCl, and
AcONa in EtOH was stirred at 80 ꢀC for 1 h. After removal of solvent
followed by addition of water, the mixture was extracted with
EtOAc. The EtOAc layer was washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. The resi-
due was purified by column chromatography using EtOAcehexane
(1:19 v/v) as an eluent to give the benzaldoxime O-methyl ethers 4.
4.2.3. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2-hydroxy-3-
methoxybenzaldehyde
5c. 2-Acetoxy-6-bromo-3-methoxybenzal-
dehyde (6c)23 (30 mg, 0.1 mmol), naphthylboronic acid pinacol ester

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1329
1
4.3.1. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-4,5-dime-
thoxybenzaldehyde O-methyloxime 4a. The naphthylbenzaldehyde
5a (100 mg, 0.30 mmol), MeONH2$HCl (37 mg, 0.44 mmol), and
AcONa (37 mg, 0.44 mmol) in EtOH (10 mL) were used to give the
oxime ether 4a (103 mg, 95%), mp 119e120 ꢀC (EtOAcehexane). 1H
ether 4g (203 mg, 95%), mp 152e153 ꢀC (EtOAcehexane). H NMR
(300 MHz, CDCl3) :2.53(2H, brs), 2.86e2.91 (2H, m), 3.75 (3H, s), 3.92
d
(3H, s), 5.88 (1H, s), 5.94 (2H, s), 6.30 (1H, s), 6.62 (1H, s), 6.70 (1H, s),
6.92 (1H, d, J¼8.6 Hz), 7.63 (1H, d, J¼8.6 Hz), 8.15 (1H, s). MS (EI) m/z:
353 (Mþ). HRMS (EI) calcd for C20H19NO5 353.1263; found 353.1278.
NMR (300 MHz, CDCl3) d: 2.52e2.57 (2H, m), 2.83e2.89 (2H, m),
3.90 (3H, s), 3.95 (3H, s), 5.93 (3H, s), 6.24 (1H, s), 6.61(1H, s), 6.68
(1H, s), 6.72 (1H, s), 7.39 (1H, s), 8.25 (1H, s). MS (EI) m/z: 367 (Mþ).
HRMS (EI) calcd for C21H21NO5 367.1420; found 367.1433.
4.3.8. 2-Acetoxy-6-(3,4-dihydro-6,7-methylenedioxy-2-naphthyl)-3-
methoxybenzaldehyde O-methyloxime 15. A solution of the oxime ether
4c (41 mg, 0.12 mmol) and Ac2O (0.03 mL, 0.17 mmol) in the presence
of DMAP (12 mg, 0.10 mmol) and Et3N (0.03 mL, 0.17 mmol) in CH2Cl2
(5 mL) was stirred at 80 ꢀC for 1 h. The reaction mixture was quenched
with water, and then the mixture was extracted with CH2Cl2. The
CH2Cl2 layer was washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 10 g) using EtOAcehexane (1:9 v/
v) as an eluent to give the acetate (43 mg, 94%), mp 141e143 ꢀC
4.3.2. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-4,5-methyl-
enedioxybenzaldehyde O-methyloxime 4b. The naphthylbenzal-
dehyde 5b (42 mg, 0.13 mmol), MeONH2$HCl (19 mg, 0.20 mmol),
and AcONa (19 mg, 0.20 mmol) in EtOH (5 mL) were used to give
the oxime ether 4b (45 mg, 98%), mp 178e180 ꢀC (EtOAc-hexane).
1H NMR (300 MHz, CDCl3)
d: 2.47e2.53 (2H, m), 2.82e2.87 (2H, m),
3.93 (3H, s), 5.92 (2H, s), 5.99 (2H, s), 6.21 (1H, s), 6.60 (1H, s), 6.67
(1H, s), 6.71 (1H, s), 7.36 (1H, s), 8.22 (1H, s). MS (EI) m/z: 351 (Mþ).
HRMS (EI) calcd for C20H17NO5 351.1107; found 351.1126.
(EtOAcehexane). IR (ATR)
CDCl3) : 2.34 (3H, s), 2.48e2.53 (2H, m), 2.81e2.86 (2H, m), 3.85 (3H,
n
: 1768 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
s), 3.93 (3H, s), 5.92 (2H, s), 6.28 (1H, s), 6.60 (1H, s), 6.67 (1H, s), 6.97
(1H, d, J¼8.6 Hz), 7.15 (1H, d, J¼8.6 Hz), 8.10 (1H, s). MS (EI) m/z: 395
(Mþ). HRMS (EI) calcd for C22H21NO6 395.1369; found 395.1360.
4.3.3. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2-hydroxy-
3-methoxybenzaldehyde O-methyloxime 4c. The naphthylbenzal-
dehyde 5c (55 mg, 0.17 mmol), MeONH2$HCl (21 mg, 0.25 mmol),
and AcONa (21 mg, 0.25 mmol) in EtOH (10 mL) were used to give
the oxime ether 4c (57 mg, 95%), mp 189e190 ꢀC (EtOAcehexane).
4.3.9. 4-Acetoxy-2-(3,4-dihydro-6,7-methylenedioxy-2-naphthyl)-3-
methoxybenzaldehyde O-methyloxime 16. A solution of the oxime
ether 4g (58 mg, 0.16 mmol) and Ac2O (0.03 mL, 0.17 mmol) in the
presence of DMAP (20 mg, 0.16 mmol) and Et3N (0.03 mL, 0.17 mmol)
in CH2Cl2 (5 mL) was stirred at 80 ꢀC for 1 h. The reaction mixture
was quenched with water, and then the mixture was extracted with
CH2Cl2. The CH2Cl2 layer was washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 10 g) using
EtOAcehexane (1:9 v/v) as an eluent to give the oily acetate (60 mg,
1H NMR (300 MHz, CDCl3)
d: 2.49e2.55 (2H, m), 2.83e2.88 (2H, m),
3.92 (3H, s), 3.98 (3H, s), 5.93 (2H, s), 6.23 (1H, s), 6.60 (1H, s), 6.68
(1H, s), 6.76 (1H, d, J¼8.3 Hz), 6.90 (1H, d, J¼8.3 Hz), 8.44 (1H, s),
10.59 (1H, s). MS (EI) m/z: 353 (Mþ). HRMS (EI) calcd for C20H19NO5
353.1263; found 353.1273.
4.3.4. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2,3-dime-
thoxybenzaldehyde O-methyloxime 4d. The naphthylbenzaldehyde
5d (116 mg, 0.34 mmol), MeONH2$HCl (50 mg, 0.60 mmol), and
AcONa (49 mg, 0.60 mmol) in EtOH (5 mL) were used to give the
oxime ether 4d (115 mg, 92%), mp 73e75 ꢀC (EtOAcehexane). 1H
100%). IR(ATR) n d: 2.26
:1766 cmꢁ1 (C]O). 1H NMR (300 MHz, CDCl3)
(3H, s), 2.44 (2H, br s), 2.76e2.81 (2H, m), 3.65 (3H, s), 3.85 (3H, s),
5.84 (2H, s), 6.18 (1H, s), 6.53 (1H, s), 6.61 (1H, s), 6.95 (1H, d,
J¼8.6 Hz), 7.61 (1H, d, J¼8.6 Hz), 8.10 (1H, s). MS (EI) m/z: 395 (Mþ).
HRMS (EI) calcd for C22H21NO6 395.1369; found 395.1352.
NMR (300 MHz, CDCl3) d: 2.44e2.50 (2H, m), 2.81e2.86 (2H, m)
3.84 (3H, s), 3.88 (3H, s), 3.92 (3H, s), 5.91 (2H, s), 6.32 (1H, s), 6.60
(1H, s), 6.66 (1H, s), 6.90 (1H, d, J¼8.8 Hz), 7.01 (1H, d, J¼8.8 Hz),
8.35 (1H, s). MS (EI) m/z: 367 (Mþ). HRMS (EI) calcd for C21H21NO5
367.1420; found 367.1436.
4.4. General procedure of thermal electrocyclic reaction with
MW irradiation
An each mixture of the oxime ethers 4aeg, 15, and 16 in 1,2-
dichlorobenzene was stirred at 180e200 ꢀC (external) under N2
atmosphere under microwave irradiation. After removal of solvent,
the residue was purified by column chromatography (silica gel)
using EtOAc (1:19 v/v) as an eluent to give the corresponding 11,12-
dihydrobenzo[c]phenanthridines 3aeg, and 17, respectively (Table
2). All thermal electrocyclic reactions without MW irradiation
were carried out by the same procedure except MW, and the results
were also shown in Table 2.
4.3.5. 6-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-2,3-methyl-
enedioxybenzaldehyde O-methyloxime 4e. The naphthylbenzal-
dehyde 5e (130 mg, 0.40 mmol), MeONH2$HCl (51 mg, 0.61 mmol),
and AcONa (51 mg, 0.61 mmol) in EtOH (10 mL) were used to give the
oxime ether 4e (90 mg, 64%), mp 137e138 ꢀC (EtOAcehexane). 1H
NMR (300 MHz, CDCl3) d: 2.48e2.53 (2H, m), 2.82e2.87 (2H, m), 3.99
(3H, s), 5.92 (2H, s), 6.10 (2H, s), 6.26 (1H, s), 6.60 (1H, s), 6.67 (1H, s),
6.77 (1H, s, J¼8.1 Hz), 6.81 (1H, d, J¼8.1 Hz), 8.21 (1H, s). MS (EI) m/z:
351 (Mþ). HRMS (EI) calcd for C21H17NO5 351.1107; found 351.1089.
4.4.1. 11,12-Dihydro-8,9-dimethoxy-2,3-methylenedioxybenzo[c]phe-
nanthridine 3a. The oxime ether 4a (13 mg, 0.04 mmol) in 1,2-di-
chlorobenzene (1.5 mL) with MW was used to give the dihydrobenzo
[c]phenanthridine 3a (10 mg, 84%), mp 230e232 ꢀC (EtOAcehexane)
4.3.6. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-3,4-dime-
thoxybenzaldehyde O-methyloxime 4f. The naphthylbenzaldehyde
5f (68 mg, 0.20 mmol), MeONH2$HCl (24 mg, 0.30 mmol), AcONa
(24 mg, 0.30 mmol) in EtOH (10 mL) were used to give the oily
(lit.19 mp 218e220 ꢀC). 1H NMR (300 MHz, CDCl3)
d: 2.93e2.98 (2H,
oxime ether 4f (70 mg, 90%). 1H NMR (300 MHz, CDCl3)
d:
m), 3.17e3.23 (2H, m), 4.05 (3H, s), 4.06 (3H, s), 5.98 (2H, s), 6.75 (1H,
s), 7.21 (2H, d, J¼2.2 Hz), 7.90 (1H, s), 8.96 (1H, s). MS (EI) m/z: 335
(Mþ). HRMS (EI) calcd for C20H17NO4 335.1158; found 335.1161.
2.84e2.89 (2H, m), 3.76 (3H, s), 3.89e3.97 (8H, m), 5.92 (2H, s), 6.20
(1H, s), 6.60 (1H, s), 6.69 (1H, s), 6.88 (1H, d, J¼8.8 Hz), 7.66 (1H, d,
J¼8.8 Hz), 8.16 (1H, s). MS (EI) m/z: 367 (Mþ). HRMS (EI) calcd for
C21H21NO5 367.1120; found 367.1145.
4.4.2. 11,12-Dihydro-2,3,8,9-bismethylenedioxybenzo[c]phenan-
thridine 3b. The oxime ether 4b (20 mg, 0.06 mmol) in 1,2-di-
chlorobenzene (1.5 mL) with MW was used to give the dihydrobenzo
[c]phenanthridine 3b (17 mg, 94%), mp 296e298 ꢀC (EtOAcehexane)
4.3.7. 2-(3,4-Dihydro-6,7-methylenedioxy-2-naphthyl)-4-hydroxy-
3-methoxybenzaldehyde O-methyloxime 4g. The naphthylbenzal-
dehyde 5g (194 mg, 0.60 mmol), MeONH2$HCl (88 mg, 1.05 mmol),
AcONa (86mg,1.05mmol)inEtOH(10mL) were usedto give theoxime
(lit.17b mp >300 ꢀC and lit.19 mp 288 ꢀC). 1H NMR (300 MHz, CDCl3)
d:
2.91e2.96 (2H, m), 3.12e3.17 (2H, m), 5.98 (2H, s), 6.10 (2H, s), 6.74

1330
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
(1H, s), 7.19 (1H, s), 7.29 (1H, s), 7.88 (1H, s), 8.90 (1H, s). MS (EI) m/z:
was stirred at 180 ꢀC for 5e7 h. After removal of solvent, the residue
was purified by column chromatography using EtOAcehexane (1:9
v/v) as an eluent to give the corresponding benzo[c]phenan-
thridines 1a,b, 18, 1d,e, 19, and 20, respectively. Compound 1c was
obtained from 18 by hydrolysis.
319 (Mþ). HRMS (EI) calcd for C19H13NO4 319.0845; found 319.0861.
4.4.3. 7-Acetoxy-11,12-dihydro-8-methoxy-2,3-methylenedioxybenzo
[c]phenanthridine 3c. The oxime ether 15 (24 mg, 0.06 mmol) in 1,2-
dichlorobenzene (1.5 mL) with MW was used to give the dihy-
drobenzo[c]phenanthridine 3c (17 mg, 77%), mp 191e194 ꢀC
4.5.1. 8,9-Dimethoxy-2,3-methylenedioxybenzo[c]phenanthridine
(nornitidine) 1a. The 11,12-dihydrobenzo[c]phenanthridine 3a
(30 mg, 0.03 mmol) and 10% PdeC (30 mg) in 1,2-dichlorobenzene
(5 mL) were used to give nornitidine (1a) (29 mg, 97%), mp
278e281 ꢀC (EtOAcehexane) (lit.17a mp 281e282 ꢀC and lit.17b mp
(EtOAcehexane). IR (ATR)
CDCl3) : 2.48 (3H, s), 2.92e2.97 (2H, m), 3.22e3.28 (2H, m), 3.98
n
: 1768 cmꢁ1 (C]O). 1H NMR (300 MHz,
d
(3H, s), 5.98 (2H, s), 6.75 (1H, s), 7.54 (1H, d, J¼9.2 Hz), 7.89 (1H, s),
7.94 (1H, d, J¼9.2 Hz), 9.19 (1H, s). MS (EI) m/z: 363 (Mþ). HRMS (EI)
calcd for C21H17NO5 363.1107; found 363.1103.
281e282 ꢀC). 1H NMR (300 MHz, CDCl3)
d: 4.10 (3H, s), 4.17 (3H, s),
6.14 (2H, s), 7.28 (1H, s), 7.41 (1H, s), 7.84 (1H, d, J¼9.2 Hz), 7.91 (1H,
4.4.4. 11,12-Dihydro-7,8-dimethoxy-2,3-methylenedioxybenzo[c]phe-
nanthridine 3d. The oxime ether 4d (41 mg, 0.11 mmol) in 1,2-di-
chlorobenzene (1.5 mL) with MW was used to give the dihydrobenzo
[c]phenanthridine 3d (30 mg, 84%), mp 172e174 ꢀC (EtOAcehexane).
s), 8.31 (1H, d, J¼9.2 Hz), 8.72 (1H, s), 9.25 (1H, s). 13C NMR (75 MHz,
DMSO-d6) d: 55.8, 56.2, 101.1, 101.5, 102.5, 104.6, 107.8, 119.3, 119.8,
122.0, 126.4, 128.3, 128.4, 129.4, 139.7, 148.0, 148.1, 149.8, 150.1,
153.2. MS (EI) m/z: 333 (Mþ). HRMS (EI) calcd for C20H15NO4
333.1001; found 333.1021.
1H NMR (300 MHz, CDCl3)
d: 2.91e2.97 (2H, m), 3.21e3.26 (2H, m),
4.02 (3H, s), 4.07 (3H, s), 5.98 (2H, s), 6.75 (1H, s), 7.50 (1H, d,
J¼9.5 Hz), 7.77 (1H, d, J¼9.5 Hz), 7.93 (1H, s), 9.48 (1H, s). MS (EI) m/z:
335 (Mþ). HRMS (EI) calcd for C20H17NO4 335.1158; found 335.1155.
4.5.2. 2,3,8,9-Bismethylenedioxybenzo[c]phenanthridine (noravicine)
1b. The11,12-dihydrobenzo[c]phenanthridine3b(16mg, 0.05mmol)
and 10% PdeC (16 mg) in 1,2-dichlorobenzene (5 mL) were used to
give noravicine (1b) (12 mg, 75%), mp 312 ꢀC (EtOAcehexane) (lit.17a
4.4.5. 11,12-Dihydro-2,3,7,8-bismethylendioxybenzo[c]phenan-
thridine 3e. The oxime ether 4e (21 mg, 0.06 mmol) in 1,2-di-
chlorobenzene (1 mL) with MW was used to give the dihydrobenzo
[c]phenanthridine 3e (20 mg, 95%), mp 237e238 ꢀC (CHCl3ehex-
mp 325 ꢀC and lit.17b mp >300 ꢀC). 1H NMR (300 MHz, DMSO-d6)
d:
6.20 (2H, s), 6.27 (2H, s), 7.50 (1H, s), 7.67 (1H, s), 7.92 (1H, d, J¼8.8 Hz),
8.31 (1H, s), 8.51 (1H, d, J¼8.8 Hz), 8.52 (1H, s), 9.25 (1H, s). 13C NMR
ane). 1H NMR (300 MHz, CDCl3)
d: 2.91e2.96 (2H, m), 3.21e3.25
(75 MHz, DMSO-d6) d: 100.1, 101.1, 101.5, 102.2, 104.6, 104.9, 119.2,
(2H, m), 5.98 (2H, s), 6.24 (2H, s), 6.75 (1H, s), 7.38 (1H, d, J¼8.8 Hz),
7.58 (1H, d, J¼8.8 Hz), 7.90 (1H, s), 9.24 (1H, s). MS (EI) m/z: 319
(Mþ). HRMS (EI) calcd for C19H13NO4 319.0845; found 319.0861.
120.3, 123.2, 123.3, 126.6, 128.2, 129.4, 130.3, 139.9, 147.9, 148.1, 150.1,
151.6. MS (EI) m/z: 317 (Mþ). HRMS (EI) calcd for C19H11NO4 317.0668;
found 317.0674.
4.4.6. 11,12-Dihydro-9,10-dimethoxy-2,3-methylenedioxybenzo[c]phe-
nanthridine 3f. The oxime ether 4f (44 mg, 0.12 mmol) in 1,2-di-
chlorobenzene (1.5 mL) with MW was used to give the dihydrobenzo
[c]phenanthridine 3f (32 mg, 80%), mp 161 ꢀC (EtOAcehexane). 1H
4.5.3. 7-Acetoxy-8-methoxy-2,3-methylenedioxybenzo[c]phenan-
thridine (O-acetylisodecarine) 18. The 11,12-dihydrobenzo[c]phe-
nanthridine 3c (28 mg, 0.08 mmol) and 10% PdeC (20 mg) in 1,
2-dichlorobenzene (5 mL) were used to give acetylisodecarine 18
NMR (300 MHz, CDCl3)
d: 2.83e2.89 (2H, m), 3.71e3.76 (2H, m), 3.86
(26 mg, 93%), mp 261e262 ꢀC (CHCl3ehexane). IR (ATR)
n:
(3H, s), 4.04 (3H, s), 5.98 (2H, s), 6.75 (1H, s), 7.33 (1H, d, J¼8.8 Hz),
7.73 (1H, d, J¼8.8 Hz), 7.87 (1H, s), 9.02 (1H, s). MS (EI) m/z: 335 (Mþ).
HRMS (EI) calcd for C20H17NO4 335.1158; found 335.1144.
1743 cmꢁ1 (C]O). 1H NMR (300 MHz, CDCl3)
d: 2.54 (3H, s), 4.03
(3H, s), 6.14 (2H, s), 7.28 (1H, s), 7.65 (1H, J¼9.2 Hz), 7.88 (1H, d,
J¼9.2 Hz), 8.37 (1H, d, J¼9.0 Hz), 8.54 (1H, d, J¼9.0 Hz), 8.69 (1H, s),
9.46 (1H, s). MS (EI) m/z: 361 (Mþ). HRMS (EI) calcd for C21H15NO5
361.0950; found 361.0956.
4.4.7. 11,12-Dihydro-9-hydroxy-10-methoxy-2,3-methylenediox-
ybenzo[c]phenanthridine 3g. The oxime ether 4g (180 mg,
0.51 mmol) in 1,2-dichlorobenzene (3 mL) with MW was used to
give the dihydrobenzo[c]phenanthridine 3g (123 mg, 75%), mp
4.5.4. 7-Hydroxy-8-methoxy-2,3-methylenedioxybenzo[c]phenan-
thridine (isodecarine) 1c. A mixture of the O-acetylisodecarine 18
(12 mg, 0.03 mmol) and NaHCO3 (6 mg, 0.07 mmol) in MeOH (10 mL)
and H2O (2 mL) was stirred at 60 ꢀC for 3 h. The mixture was diluted
with water, and then the mixture was extracted with EtOAc. The
EtOAc layer was washed with water and brine, dried over Na2SO4,
and concentrated under reduced pressure. The residue was purified
by general procedure described above to give isodecarine (1c) (8 mg,
74%), mp 239e241 ꢀC (CHCl3ehexane) (lit.20 mp 225e227 ꢀC and
230e232 ꢀC (EtOAcehexane). 1H NMR (300 MHz, CDCl3)
d:
2.83e2.88 (2H, m), 3.65e3.70 (2H, m), 3.79 (3H, s), 5.99 (2H, s), 6.51
(1H, s), 6.75 (1H, s), 7.27 (1H, d, J¼8.8 Hz), 7.68 (1H, d, J¼8.8 Hz),
7.88 (1H, s), 9.00 (1H, s). MS (EI) m/z: 321 (Mþ). HRMS (EI) calcd for
C19H15NO4 321.1001; found 321.0997.
4.4.8. 9-Acetoxy-11,12-dihydro-10-methoxy-2,3-methylenediox-
ybenzo[c]phenanthridine 17. The oxime ether 16 (34 mg,
0.09 mmol) in 1,2-dichlorobenzene (3 mL) with MW was used to
give the dihydrobenzo[c]phenanthridine 17 (21 mg, 67%), mp
lit.10d mp 265e268 ꢀC). 1H NMR (300 MHz, CDCl3)
d: 4.08 (3H, s), 6.13
(2H, s), 6.24 (1H, br s), 7.27 (1H, s), 7.54 (1H, d, J¼9.0 Hz), 7.85 (1H, d,
J¼8.8 Hz), 8.16 (1H, d, J¼9.0 Hz), 8.35 (1H, d, J¼8.8 Hz), 8.73 (1H, s),
182e184 ꢀC (EtOAcehexane). IR (ATR)
(300 MHz, CDCl3)
n
: 1749 cmꢁ1 (C]O). 1H NMR
9.79 (1H, s). 13C NMR (75 MHz, DMSO-d6)
d: 56.9, 101.1, 101.6, 104.5,
d
: 2.43 (3H, s), 2.83e2.88 (2H, m), 3.68e3.73 (2H,
113.3, 117.4, 118.7, 118.9, 119.8, 127.0, 127.1, 128.3, 129.4, 138.9, 142.8,
144.3, 146.7, 148.0, 148.1. MS (EI) m/z: 319 (Mþ). HRMS (EI) calcd for
C19H13NO4 319.0845; found 319.0819.
m), 3.83 (3H, s), 5.99 (2H, s), 6.75 (1H, s), 7.27 (1H, d, J¼8.8 Hz), 7.73
(1H, d, J¼8.8 Hz), 7.88 (1H, s), 9.09 (1H, s). MS (EI) m/z: 363 (Mþ).
HRMS (EI) calcd for C21H17NO5 363.1107; found 363.1104.
4.5.5. 7,8-Dimethoxy-2,3-methylenedioxybenzo[c]phenanthridine
(norchelerythrine) 1d. The 11,12-dihydrobenzo[c]phenanthridine
3d (30 mg, 0.09 mmol) and 10% PdeC (30 mg) in 1,2-di-
chlorobenzene (5 mL) were used to give norchelerythrine (1d)
(27 mg, 91%), mp 210e212 ꢀC (CHCl3ehexane) (lit.21a mp
210e217 ꢀC, lit.21b mp 210e212 ꢀC, and lit.17a,22a mp 215e216 ꢀC). 1H
4.5. General procedure of benzo[c]phenanthridines 1a,b, 18,
1c from 18, 1d,e, 19, and 20 from 11,12-dihydrobenzo[c]
phenanthridines 3aeg, and 17
An each mixture of 11,12-dihydrobenzo[c]phenanthridines
3aeg, and 17 in the presence of 10% PdeC in 1,2-dichlorobenzene
NMR (300 MHz, CDCl3) d: 4.06 (3H, s), 4.13 (3H, s), 6.13 (2H, s), 7.27

Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
1331
(1H, s), 7.60 (1H, d, J¼9.0 Hz), 7.85 (1H, d, J¼8.8 Hz), 8.36 (1H, d,
J¼9.0 Hz), 8.37 (1H, d, J¼8.8 Hz), 8.72 (1H, s), 9.75 (1H, s). 13C NMR
methoxy-2,3-methylenedioxybenzo[c]phenanthridine
(zan-
thoxyline) (1fa) (16 mg, 100%), mp 226e227 ꢀC (EtOAcehexane).
The NMR data were identical with those of above data (Section
4.5.9).
(75 MHz, CDCl3) d: 56.8, 61.9, 101.3, 102.2, 104.4, 118.2, 118.3, 118.7,
120.0, 121.9, 127.1, 128.1, 129.2, 129.7, 140.0, 145.2, 146.6, 148.3,
148.5, 149.4. MS (EI) m/z: 333 (Mþ). HRMS (EI) for C20H15NO4 calcd
for 333.1001; found 333.0999.
4.5.11. O-Methylation of 9-hydroxy-10-methoxy-2,3-methylenedioxy-
bemzo[c]phenanthridine (zanthoxyline) 1fa (O-methylzanthoxyline
1ga). A solution of zanthoxyline (1fa) (20 mg, 0.062 mmol) in MeOH
(5 mL) and an aqueous 10% NaOH (0.118 mL, 0.29 mmol) was stirred
at rt for 1 h. Dimethyl sulfate (0.024 mL, 0.26 mmol) was added to
the solution. After being stirred at rt for 12 h, the mixture was
quenched with water and extracted with 10% MeOHeCHCl3. The
CHCl3 layer was washed with water and brine, dried over K2CO3, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 5 g) using EtOAcehexane (1:9 v/
v) to give the O-methylzanthoxyline (1ga) (16 mg, 77%), mp
206e208 ꢀC, which was consistent with the synthetic nor-
broussonpapyrine (19) in all respects.
4.5.6. 2,3,7,8-Bismethylenedioxybenzo[c]phenanthridine (norsangui-
narine) 1e. The 11,12-dihydrobenzo[c]phenanthridine 3e (25 mg,
0.08 mmol) and 10% PdeC (10 mg) in 1,2-dichlorobenzene (5 mL)
were used to give norsanguinarine (1e) (15 mg, 60%), mp
282e283 ꢀC (CHCl3ehexane) (lit.22a mp 278e280 ꢀC, lit.22b mp
280e281 ꢀC, and lit.22c mp 285e287 ꢀC). 1H NMR (300 MHz, DMSO-
d6)
d
: 6.21 (2H, s), 6.38 (2H, s), 7.52 (1H, s), 7.69 (1H, d, J¼8.8 Hz),
7.99 (1H, d, J¼8.8 Hz), 8.40 (1H, d, J¼8.8 Hz), 8.50 (1H, s), 8.55 (1H,
d, J¼8.8 Hz), 9.40(1H, s). 13C NMR (75 MHz, CDCl3)
d: 101.0, 101.6,
102.9, 104.5, 111.9, 114.3, 116.3, 118.9, 120.1, 127.2, 127.6. 128.4, 129.5,
138.8, 143.1, 144.6, 145.2, 148.1, 148.3. MS (EI) m/z: 317 (Mþ). HRMS
(EI) calcd for C19H11NO4 317.0668; found 317.0674.
4.5.12. 5,6-Dihydro-9,10-dimethoxy-N-methyl-2,3-methylenedioxy-
benzo[c]phenanthridine 21 from 9,10-dimethoxy-2,3-methylenedioxy-
benzo[c]phenanthridine (norbroussonpapyrine) 19. Norbrousson-
papyrine(19) (15 mg, 0.05mmol) inHCO2H(2mL)wasstirredfor12h
at rt, and then NaBH4 (168 mg, 4.4 mmol) was added portionwise to
the solution at rt. After being stirred at rt for 30 min, the mixture was
adjusted to weakly alkaline with an aqueous 10% NaOH and extracted
with CHCl3. The CHCl3 layer was washed with water and brine, dried
over K2CO3, and concentrated under reduced pressure. The residue
was purified by column chromatography (silica gel, 5 g) using
EtOAcehexane (1:19, v/v) as an eluent to give the 5,6-dihydro-N-
methylbenzo[c]phenanthridine 21 (8 mg, 54%), mp 168e170 ꢀC
4.5.7. 9.10-Dimethoxy-2,3-methylenedioxybenzo[c]phenanthridine
(norbroussonpapyrine) 19. The 11,12-dihydrobenzo[c]phenan-
thridine 3f (92 mg, 0.27 mmol) and 10% PdeC (138 mg) in 1,2-di-
chlorobenzene (10 mL) were used to give norbroussonpapyrine
(19) (72 mg, 80%), mp 206e208 ꢀC (EtOAcehexane). 1H NMR
(300 MHz, CDCl3) d: 4.00 (3H, s), 4.09 (3H, s), 6.12 (2H, s), 7.26 (1H,
s), 7.43 (1H, d, J¼8.8 Hz), 7.86 (1H, d, J¼9.2 Hz), 7.89 (1H, d,
J¼8.8 Hz), 8.75 (1H, s), 9.25 (1H, s), 9.33 (1H, d, J¼9.2 Hz). 13C NMR
(75 MHz, CDCl3) d: 56.5, 60.1, 101.3, 102.5, 103.9, 113.5, 119.6, 122.9,
123.1, 126.0, 126.4, 127.4, 128.7, 130.1, 141.5, 145.5, 148.1, 148.5, 151.5,
154.5. MS (EI) m/z: 333 (Mþ). HRMS (EI) calcd for C20H15NO4
333.1001; found 333.0997.
(EtOAcehexane). 1H NMR (300 MHz, CDCl3)
d: 2.59 (3H, s), 3.73 (3H,
s), 3.93(3H, s), 4.06(2H, s), 6.05(2H, s), 6.90(1H, d,J¼8.1Hz), 6.99(1H,
d, J¼8.1 Hz), 7.13 (1H, s), 7.50 (1H, d, J¼8.8 Hz), 7.70 (1H, s), 8.44 (1H, d,
J¼8.8 Hz). MS (EI) m/z: 349 (Mþ). HRMS (EI) calcd for C21H19NO4
349.1314; found 349.1324.
4.5.8. 9-Acetoxy-10-methoxy-2,3-methylenedioxybenzo[c]phenan-
thridine (O-acetylzanthoxyline) 20. The 11,12-dihydrobenzo[c]phe-
nanthridine 17 (18 mg, 0.05 mmol) and 10% PdeC (27 mg) in 1,
2-dichlorobenzene (3 mL) were used to give O-acetylzanthoxyline
20 (17 mg, 95%), mp 212e213 ꢀC (EtOAcehexane). IR (ATR)
n
:
4.5.13. 9,10-Dimethoxy-N-methyl-2,3-methylenedioxybenzo[c]phe-
nanthridinium chloride (broussonpapyrine chloride) 2fa from 21. The
Jones reagent (0.042 mL) was added to a stirred solution of the
resulting 5,6-dihydro-N-methylbenzo[c]phenanthridine 21 in
acetone (2 mL) under ice-cooling. The mixture was stirred at the
same temperature for 30 min, and basified with an aqueous 10%
NaOH, which was extracted with CHCl3. The CHCl3 layer was
washed with water and brine, dried over K2CO3, and concen-
trated under reduced pressure. The residue was dissolved in
a small amount of CHCl3, and then diluted HCl was added
dropwise to the solution under ice-cooling. The resulting pre-
cipitates were collected by filtration (9 mg, 82%) to give brous-
sonpapyrine chloride (2fa), mp 152e153 ꢀC (CHCl3eMeOH) (lit.25
mp 201e205 ꢀC). 1H NMR and 13C NMR spectra of synthetic 2fa
were shown in Tables 7 and 8. TOFMS (ESI) calcd for C21H18NO4
348.1236; found 348.1220 (Mþ).
1749 cmꢁ1 (C]O). 1H NMR (300 MHz, CDCl3)
d: 2.48 (3H, s), 3.97
(3H, s), 6.14 (2H, s), 7.28 (1H, s), 7.47 (1H, d, J¼8.6 Hz), 7.88 (1H, d,
J¼9.2 Hz), 7.92 (1H, d, J¼8.6 Hz), 8.76 (1H, s), 9.21 (1H, d, J¼9.2 Hz),
9.33 (1H, s). MS (EI) m/z: 361 (Mþ). HRMS (EI) calcd for C21H15NO5
361.0950; found 361.0928.
4.5.9. 9-Hydroxy-10-methoxy-2,3-methylenedioxybenzo[c]phenan-
thridine(zanthoxyline) 1fa. The 11,12-dihydrobenzo[c]phenanthridine
3g (18 mg, 0.05 mmol) and 10% PdeC (27 mg) in 1,2-dichlorobenzene
(2 mL) were used to give 9-hydroxy-10-methoxy-2,3-methyl-
enedioxy-benzo[c]phenanthridine (zanthoxyline) (1fa) (17 mg, 95%),
mp 226e227 ꢀC (EtOAcehexane) (lit.26 mp 220e222ꢀꢀC). 1H NMR
(300 MHz, CDCl3)
d
: 3.93 (3H, s), 6.14 (2H, s), 7.28 (1H, d, J¼8.6 Hz),
7.43 (1H, s), 7.86 (1H, d, J¼8.6 Hz), 7.87 (1H, d, J¼9.2 Hz), 8.75 (1H, s),
9.06 (1H, d, J¼9.2 Hz), 9.24 (1H, s). 13C NMR (75 MHz, CDCl3)
d: 60.8,
101.3, 102.6, 104.0, 117.1, 118.6, 122.0, 123.1, 126.6, 126.7, 126.8, 128.8,
130.2, 141.9, 142.1, 148.3, 148.7, 151.4, 151.5. MS (EI) m/z: 319 (Mþ).
HRMS (EI) calcd for C19H13NO4 319.0845; found 319.0838.
4.5.14. 9,10-Dimethoxy-2,3-methylenedioxybenzo[c]phenan-
thridinium trifluoromethanesulfonate (broussonpapyrine trifluoro-
methanesulfonate) 2fb from 9,10-dimethoxy-2,3-methylenedioxy-
benzo[c]phenanthridine (norbroussonpapyrine) 19. A mixture of
norbroussonpapyrine (19) (20 mg, 0.06 mmol) and methyl tri-
fluoromethanesulfonate (39 mg, 0.24 mmol) in dry toluene (4 mL)
was stirred in a sealed tube at 90 ꢀC for 0.5 h. After being cooled to
rt, the precipitated solid was filtered off, washed with heated tol-
uene, which was recrystallized from CHCl3eMeOH to give 2fb
(24 mg, 81%), mp 216e218 ꢀC (CHCl3eMeOH). 1H NMR (300 MHz,
4.5.10. Hydrolysis of 9-acetoxy-10-methoxy-2,3-methylenedioxy-
benzo[c]phenanthridine (O-acetylzanthoxyline) 20. The 9-acetoxy-
benzo[c]phenanthridine 20 (17 mg, 0.05 mmol) was treated with
an aqueous NaHCO3 in MeOH (10 mL) at 60 ꢀC for 3 h, and then the
mixture was diluted with water. The mixture was extracted with
EtOAc. The EtOAc layer was washed with water and brine, dried
over Na2SO4, and concentrated under reduced pressure. The res-
idue was purified by column chromatography (silica gel, 5 g) using
EtOAcehexane (1:9 v/v) as an eluent to give 9-hydroxy-10-
CD3OD)
d: 3.99 (3H, s), 4.21 (3H, s), 4.83 (3H, s), 6.26 (2H, s), 7.52
(1H, s), 7.94 (1H, d, J¼9.2 Hz), 8.09 (1H, s), 8.14 (1H, d, J¼9.2 Hz),

1332
Y. Ishihara et al. / Tetrahedron 67 (2011) 1320e1333
8.36 (1H, d, J¼8.8 Hz), 9.44 (1H, d, J¼8.8 Hz), 9.75 (1H, s). 13C NMR
References and notes
(75 MHz, CD3OD) d: 52.0, 57.8, 60.9, 104.2, 105.0, 106.2, 118.2, 120.7,
1. (a) Ishii, H.; Ishikawa, T. Yakugaku Zasshi 1981, 101, 663e687; (b) Krane, B. D.;
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Solis, P. N.; Gupta, M. P.; Claeys, M.; Pieters, L.; Vauquelin, G.; Vlietinck, A. J. Planta
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121.4,123.2,125.7,129.4,131.1,132.0, 134.4,134.8,146.3, 150.3,151.2,
155.8, 162.4. 19F NMR (500 MHz, CD3OD)
d
: ꢁ78.4 (s). TOFMS (ESI)
calcd for C21H18NO4 348.1236; found 348.1226 (Mþ).
4.5.15. X-ray crystal structure determination for 2fb. A single crystal
of 2fb, which was crystallized from CHCl3eMeOH, was determined
by a Rigaku RAXIS RAPID II. The structure was solved by direct
methods using SIR2004 and expanded using Fourier techniques. All
calculations were performed using the Crystal Structure crystallo-
graphic software package except for refinement, which was per-
formed using SHELXL-97. The crystal data of 2fb have been
deposited in CCDC with number 776,353. Crystal data of 2fb:
2C21H18NO4$2CF3SO3$CHCl3; orthorhombic, space group Pna21,
ꢀ
ꢀ
ꢀ
a¼14.3231(3) A, b¼17.7869(3) A, c¼18.3620(3) A, V¼4677.95
(15) A ; Z¼4; Dc¼1.582 g cmꢁ3; R¼0.0967, Rw¼0.3161, GOF¼1.191.
3
ꢀ
The ORTEP drawing is illustrated in Fig. 2.
4.5.16. 7,8-Dimethoxy-N-methyl-2,3-methylenedioxybenzo[c]phe-
nanthridinium chloride (chelerythrine chloride) 2d from 7,8-dime-
thoxy-2,3-methylenedioxybenzo[c]phenanthridine (norchelerythrine)
1d. A solution of norchelerythrine (1d) (10 mg, 0.03 mmol) in
HCO2H (2 mL) was stirred for 12 h, and then NaBH4 (111 mg,
2.93 mmol) was added to the solution at rt. After being stirred at rt
for 30 min, the mixture was adjusted to weakly alkaline with an
aqueous 10% NaOH and extracted with CHCl3. The CHCl3 layer was
washed with water and brine, dried over K2CO3, and concentrated
under reduced pressure. The residue was purified by column
chromatography (silica gel, 5 g) using EtOAcehexane (1:19, v/v) as
an eluent to give the 5,6-dihydrochelerythrine (7 mg, 67%), mp
221e224 ꢀC (lit.30 mp 220e224 ꢀC), which was used to the oxi-
dation step. The Jones reagent (0.063 mL) was added to a stirred
solution of the resulting 5,6-dihydrochelerythrine in acetone
(10 mL) under ice-cooling. The mixture was stirred at the same
temperature for 30 min, and basified with an aqueous NaOH,
which was extracted with CHCl3. The CHCl3 layer was washed
with water and brine, dried over K2CO3, and concentrated under
reduced pressure. The residue was dissolved in a small amount of
CHCl3, and then 10% HCl was added dropwise to the solution
under ice-cooling. The resulting precipitates were collected by
filtration to give chelerythrine chloride 2d (7 mg, 91%), mp
194e195 ꢀC (MeOHeacetone) (lit.30a mp 192e193 ꢀC and lit.30b mp
203e206 ꢀC). 1H NMR and 13C NMR spectra of synthetic 2d were
shown in Tables 7 and 8.
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We thank Professor Tsutom Ishikawa, Graduate School of
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spectral measurements. Furthermore, we thank Associate Professor
Yasuo Shida, Tokyo Pharmaceutical University (Analytical Center)
for the measurement of TOFMS. This work was partly supported by
a Grant-in Aid for Scientific Research (C) of the Japan Society for the
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Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.066. These data include
MOL files and InChIKeys of the most important compounds de-
scribed in this article.

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