Process research on arylnaphthalene lignan aza-analogues: a new palladium-catalyzed benzannulation of α,β-bisbenzylidenesuccinic acid derivatives

Article abstract of DOI:10.1016/j.tet.2006.06.090

The discovery of a new Pd-catalyzed benzannulation reaction of bisbenzylidenesuccinimide during process research on arylnaphthalene lignan aza-analogues is described. An extension of the Pd-catalyzed benzannulation to the regiospecific synthesis of variou

Full text of DOI:10.1016/j.tet.2006.06.090

Tetrahedron 62 (2006) 8539–8549
Process research on arylnaphthalene lignan aza-analogues:
a new palladium-catalyzed benzannulation of a,b-
bisbenzylidenesuccinic acid derivatives
*
Hideya Mizufune, Minoru Nakamura and Hiroyuki Mitsudera
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited,
2-17-85 Jusohonmachi, Yodogawaku, Osaka 532-8686, Japan
Received 14 May 2006; accepted 21 June 2006
Available online 17 July 2006
Abstract—The discovery of a new Pd-catalyzed benzannulation reaction of bisbenzylidenesuccinimide during process research on arylnaph-
thalene lignan aza-analogues is described. An extension of the Pd-catalyzed benzannulation to the regiospecific synthesis of various arylnaph-
thalene lignan aza-analogues utilizing classical Stobbe condensation is included.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
succinic acid derivatives discovered during process research
on 1-arylnaphthalene lignan aza-analogues.2
The objective of process chemistry in the pharmaceutical in-
dustry is to develop an efficient synthetic process for a new
drug candidate that is cost effective, safe and easy to apply,
environmentally friendly, and robust enough for large-scale
preparation, to support both preclinical and clinical studies
and also commercial purpose. In order to realize such a pro-
cess, chemists utilize state-of-the-art methods of organic
synthesis. In addition, a new method of synthesis discovered
during process chemistry research can contribute to organic
synthesis. This relationship is mutually beneficial to both
fields of chemistry. In this paper, we disclose a new Pd-
catalyzed benzannulation reaction1 of a,b-bisbenzylidene-
1-Arylnaphthalene lignans3 occur widely in nature and
have several regioisomers as a structural feature. Helioxanthin
1, Justicidin E 2, and Taiwanin C 3 are representative,
bearing
a ‘curved’ 7,8-methylenedioxynaphthalene or
‘straight’ 6,7-methylenedioxynaphthalene and ‘up’ 3-lactone
or ‘down’ 2-lactone carbonyl moiety. Since each regioisomer
varies in its bioactivities,3b–d analogues, particularly nitrogen-
containing types, have been studied as potent candidates. For
example, hydrazide compound 4 of antiviral activity,4a cyano-
naphthalene 5 as a 5-lipoxygenase inhibitor,4b and amide
analogue 7 for PDE-V inhibitor4c have been reported to date.
O
O
O
O
O
O
O
O
O
O
O
Ar
Ar =
O
Ar
Ar
O
O
1 (Helioxanthin)
2 (Justicidin E)
3 (Taiwanin C)
Cl
O
O
RO
CN
N
NR'
NH
NH
R =
COOMe
O
OH
R' = (CH2)2
O
O
O
O
OH
Br
MeO
OMe
O
4
5
6
Keywords: Lignans; Palladium and compounds; Naphthalenes; Biaryls.
* Corresponding author. Fax: +81 6 6300 6251; e-mail: mizufune_hideya@takeda.co.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.090

8540
H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
O
R1 = F, R2 = H, n = 0 : 7a
NH
R
1 = F, R2 = H, n = 1 : 7b
R1 - R2 = CH2OCH2, n = 0 : 7c
O
n
O
O
R2
R1
O
O
O
NH
A
O
A
NH
O
O
Benzannulation
O
O
B
O
B
O
8 (Taiwanin A)
(A)
(B)
Scheme 1.
1-Arylnaphthalene lignan analogues2 7a–c, with a ‘curved’
7,8-methylenedioxynaphthalene and ‘up’ lactam or imide
moiety, have been studied in Takeda Pharmaceutical Co.
as new drug candidates. A number of methods have been
developed to construct the arylnaphthalene lignan skeleton,
represented by the key reaction of the strategy, intermole-
cular5 or intramolecular Diels–Alder reactions,6 conjugate
addition reactions,7 biaryl coupling reactions,8 and a benzan-
nulation reaction.9 However, to achieve the regiospecific
synthesis of the target compounds 7a–c, we decided to
explore a new method based on the strategy shown in
Scheme 1, in which the target arylnaphthalene (A) would
be prepared via the benzannulation10 of bisbenzylidenesuc-
cinimide (B). The substrate (B) is also of interest as an
aza-analogue of the natural lignan Taiwanin A 8, having
antithrombotic activity.11
bisbenzylidenesuccinimide 11a–c were prepared by the
Wittig reaction12 using a stable phosphorane 9 with a benz-
aldehyde and the Knoevenagel reaction of monobenzylid-
enesuccinimide 10a–c with a benzaldehyde. In the process,
as well as symmetrical type 11a–b, unsymmetrical bisben-
zylidenesuccinimide 11c was prepared as a single isomer
(Table 1) independent of the order in which 6-bromopi-
peronal and 4-fluorobenzaldehyde were used in the two
condensation reactions. Since the Wittig reaction using
a stable phosphorane gives the product of the (E)-configu-
ration, this result supports the notion that a bisbenzylidene-
succinic acid derivative usually forms an (E)/(E)-type
isomer.13
Next, the thermal cyclization of symmetrical bisbenzylid-
enesuccinimide 11a in DMF was studied. While the heat-
ing of the DMF solution at 140 ꢀC under an atmosphere of
nitrogen gave dihydronaphthalene 12, the corresponding
conditions under ambient atmosphere provided naphthal-
ene 13 with dehydrogenation. To avoid the reaction at
the 6-position of the 3,4-piperonyl group, we investigated
the thermal cyclization of unsymmetrical bisbenzylidene-
succinimide 11c bearing bromine as a protective group.
A complex reaction mixture with a small amount of the
desired naphthalene 14 was given under a higher tempera-
ture (190 ꢀC in NMP) condition. On the other hand, to
2. Results and discussion
2.1. Discovery of a Pd-catalyzed benzannulation reac-
tion of a,b-bisbenzylidenesuccinimide during process
research on arylnaphthalene lignan analogues
Initially, the cyclization of bisbenzylidenesuccinimide was
studied under various conditions. As shown in Scheme 2,
O
O
O
Ar
Ph3P
PPh3
Ar CHO
MeOH
NH
NH
NH
O
AcOH
94%
O
O
O
O
9
O
O
Ar =
F
10a
Br
10c
10b
O
O
O
O
O
O
O
NH
Ar CHO
Br
NH
R
R
O
Piperidine - AcOH
EtOH / THF
F
O
O
11c
R = H : 11a
R = Br : 11b
Scheme 2.

H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
Table 1. Syntheses of mono- or bisbenzylidenesuccinimide 10a–c, 11a–c
8541
Based on the discovery of the Pd-catalyzed benzannulation
reaction, we have achieved the regiospecific synthesis of
‘curved’ 7,8-methylenedioxy-substituted naphthalene 7b in
combination with directed ortho metalation. Thus, a key
intermediate, 2-iodopiperonal 17, prepared by Young’s
metalation synthesis15 was condensed with monobenzylid-
enesuccinimide 10c to give bisbenzylidenesuccinimide 11d,
which was then converted to naphthalene 7b by the Pd-
catalyzed benzannulation. In the process, each product was
easily isolated in high purity only by crystallization suitable
for a large-scale preparation (Scheme 4).
Compound
Yield
(%)
Purity (%)
by HPLC
1H NMR signal of
benzylidene moiety
10a
10b
10c
11a
11b
11c (via 10b)
11c (via 10c)
88
82
83
83
82
80
81
99.8
99.4
99.9
98.9
94.2
93.4
98.1
7.31 (1H, t, J¼2.3 Hz)
7.53 (1H, t, J¼2.3 Hz)
7.39 (1H, t, J¼2.2 Hz)
7.49 (2H, s)
7.43 (2H, s)
7.44 (1H, s) and 7.59 (1H, s)
The same as above
O
accelerate the dehydrogenation, stoichiometric use of
Pd(OAc)2 in AcOH for the cyclization afforded naphtha-
lene 15 with dehydrobromination. This surprising result in-
spired us to try a catalytic Heck reaction with Pd(OAc)2
(10 mol %)/Et3N in DMF at 100 ꢀC, for the cyclization
of 11c to give naphthalene 15 in 74% yield. In addition,
the Pd-catalyzed reaction of the symmetrical bisbenzyl-
idene form 11b provided naphthalene 16 with only mono-
dehydrobromination. To our knowledge, there had been
no report regarding the generation of benzene ring using
the intramolecular Heck reaction of an arylhalide or a
vinylhalide with the conjugated 1,3-diene system before
our preliminary report1a for the synthesis of Helioxanthin
based on the discovery of a Pd-catalyzed benzannulation
of bisbenzylidensuccimide derivatives. Therefore, our dis-
covery will contribute to general synthesis14 of naphtha-
lene derivatives (Scheme 3).
F
NH
I
10c
O
O
O
O
Ref. 15
a
O
CHO
CHO
b
17
O
I
O
O
NH
O
O
c
NH
O
O
F
O
7b
11d
F
Scheme 4. Reagentsandconditions:(a)n-BuLi, N,N,N0-trimethylethylenedi-
amine, DME–THF then n-BuLi, I2, 46%; (b) piperidine, AcOH, EtOH, 79%;
(c) Pd(OAc)2 (10 mol %), Et3N (2.2 equiv), DMF, 110 ꢀC; 80 min, 78%.
O
DMF
O
O
140°C
O
NH
O
under N2
12
O
O
O
Ar
NH
O
DMF
O
O
O
140°C
Ar =
NH
O
O
O
O
in Air
49%
11a
O
13
Ar
Br
O
O
NMP
190°C
NH
O
+ various products
O
in Air
O
O
14
NH
Br
F
F
O
O
Pd(OAc)2
(10 mol%)
O
O
NH
11c
Et3N / DMF
under N2
74%
O
15
F
O
O
O
Pd(OAc)2
(10 mol%)
O
O
O
O
O
NH
O
NH
O
Et3N / DMF
under N2
Br
Br
Br
80%
16
O
11b
O
Scheme 3.

8542
H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
group via dehydration of the corresponding amide yielded
the bisbenzylidene form 21, which was then converted into
2-cyanonaphthalene 22 by subsequent Pd-catalyzed benzan-
nulation. Halfester 20 was also transformed to the corre-
sponding hydroxamic acid derivative 23, which was
cyclized to furnish naphthoimide 24 by sequential hydroxy-
imide formation and the Pd-catalyzed benzannulation
(Scheme 5).
2.2. Extension of the new Pd-catalyzed benzannulation
to the regiospecific synthesis of various arylnaphthalene
lignan analogues
Next our objective is to extend the Pd-catalyzed benzannula-
tion to the synthesis of other aza-analogues utilizing classical
Stobbe condensation in two stages. The first Stobbe conden-
sation of diethyl succinate with 4-fluorobenzaldehyde 18
gave the monobenzylidene form 19. The second reaction of
19 with 2-iodopiperonal 17 provided bisbenzylidene half-
ester 20 as a key intermediate, in which the ester moiety of
19 distant from the reacting carbon was selectively saponi-
fied in a typical Stobbe condensation manner.10a–c Conver-
sion of the carboxyl moiety of halfester 20 to a cyano
By changing the order in which the 2-iodopieronylidene
moiety is installed into Stobbe’s halfester, the regiospecific
synthesis of different substituted aza-analogues can be
achieved. Indeed, as shown in Scheme 6, the first Stobbe’s
condensation of diethyl succinate with 2-iodopiperonal 17
O
I
17
CHO
O
OMe
OMe
O
F
CHO
a, b
F
O
c
18
19
O
I
O
OMe
CN
O
O
F
O
OMe
d, e
O
f
I
CN
O
22
O
O
O
21
OMe
OH
F
O
I
O
F
O
h
O
N
OH
g
OMe
NHOH
20
O
O
O
F
O
24
F
23
Scheme 5. Reagents and conditions: (a) (CH2COOEt)2, NaOMe, MeOH then aq NaOH, 36%; (b) MeOH, H2SO4, 94%; (c) NaOMe, MeOH, 74%; (d) (COCl)2,
cat. DMF, THF then aq NH3, 91%; (e) (COCl)2, cat. DMF, THF, 91%; (f) Pd(OAc)2 (10 mol %), K2CO3 (2.2 equiv), NMP, 110 ꢀC, 50 min, 32%; (g) (COCl)2,
cat. DMF, THF then NH2OH, 68%; (h) Pd(OAc)2 (10 mol %), Et3N (2.2 equiv), DMF, 110 ꢀC, 45 min, 69%.
I
O
O
O
I
O
O
O
O
O
CHO
O
O
OMe
OMe
OH
O
a, b
CHO
O
I
c
OMe
O
25
17
O
O
O
26
I
NMe2
OMe
O
O
O
O
O
O
e
O
NMe2
OMe
d
28
O
O
27
O
O
I
26
O
I
O
NH
O
O
O
O
O
O
j
O
OH
OH
NH
f
g, h, i
O
O
NOE
O
O
7c
O
29
30
Scheme 6. Reagents and conditions: (a) (CH2COOEt)2, NaOMe, MeOH, aq NaOH, 62%; (b) MeOH, H2SO4, 84%; (c) NaOMe, MeOH, 82%; (d) (COCl)2, cat.
DMF, THF then Me2NH, 67%; (e) Pd(OAc)2 (20 mol %), AcOK (2.2 equiv), NMP, 9%; (f) LiEt3BH, THF, 67%; (g) EtI, K2CO3, DMF; (h) PBr3, MePh; (i) aq
NH3, THF–MeOH, 35% based on 29; (j) Pd(OAc)2 (10 mol %), AcOK (2.2 equiv), NMP, 110 ꢀC, 40 min, 48% (HPLC yield 72%).

H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
8543
gave the monobenzylidene 25, which was then converted
into bisbenzylidene halfester 26 by the second condensation
with piperonal. Since halfester 26 bore a carboxyl moiety the
near 2-iodopieronylidene group, conversion of the carboxyl
into a N,N-dimethylamide group and subsequent Pd-cata-
lyzed benzannulation introduced the amide moiety as a nitro-
gen-containing substituent to the 3-position of naphthalene
derivative 28. As well as compound 21, the acyclic bisben-
zylidene 27 gave lower yield of the Pd-catalyzed benzannu-
lation than the bisbenzylidenesuccinimides. Moreover, the
super-hydride reduction16 of an ester moiety of halfester
26 afforded the hydroxy form 29, which was transformed
into lactam 30 by a sequence of esterization, bromination,
and amination. The geometrical configuration of a,b-bis-
benzylidene-g-lactam 30 was confirmed as (E,E)-configura-
tion, on the basis of the NOESY spectrum study focusing
on a relationship between benzylidene and lactone protone.
The bisbenzylidenelactam 30 was cyclized by a Pd catalyst
to provide the lactam analogue 7c bearing an ‘up’ carbonyl
moiety.
does not undergo syn b-hydride elimination to yield the
naphthalene 7a, 34 is converted into p-allylpalladium com-
plex 35, which isomerizes into s-dihydronaphthalenylpalla-
dium complex 32 allowing syn b-hydride elimination.
3. Conclusion
In conclusion, a new Pd-catalyzed benzannulation of bisbenz-
ylidenesuccinimides has been discovered during process re-
search on arylnaphthalene lignan analogues. Furthermore, an
extension of the benzannulation to the regiospecific synthesis
of various arylnaphthalene lignan analogues has been
achieved utilizing classical Stobbe condensation.
4. Experimental
4.1. General remarks
Melting points were recorded on a Yanagimoto micro melt-
ing apparatus and are uncorrected. IR spectra were recorded
on a Horiba FT-210 spectrophotometer. H NMR spectra
were recorded on a Bruker DPX-300 spectrometer. Elemen-
tal analyses and mass spectra were analyzed by Takeda
Analytical Research Ltd. HPLC was performed on a YMC-
Pack ODS-A302 column (150 mmꢁ4.6 mm I.D.) with
0.05 M KH2PO4 in water and acetonitrile (50:50) at 25 ꢀC.
Detection was effected with a Hitachi spectrophotometric
detector at 254 nm.
Discussion about the possible mechanism of the novel benz-
annulation reaction of (E,E)-a,b-bisbenzylidene-g-lactam
30 inspired us to recognize the role of its 1,3-diene system.
The following reaction mechanism including two conceiv-
able processes is proposed in Scheme 7. In the first process,
the oxidative addition of palladium(0) into the C–I bond of
30 generates s-arylpalladium complex 31 based on the
(E,E)-type isomer. Despite the steric hindrance of the other
aryl group, the stable palladium(II) complex with the 1,3-di-
ene system (square planar complex) accelerates syn insertion
of an intramolecular alkenyl double bond into the C–Pd
bond, to give d-dihydronaphthalenylpalladium complex
32. Then, the palladium(II) species 32 smoothly undergoes
syn b-hydride elimination to yield the naphthalene product
7a. In the other process, (E,E)-type s-arylpalladium com-
plex 31 is isomerized to (E,Z)-type s-arylpalladium com-
plex 33 due to the delocalized p-electron system on the
1,3-diene complex with the palladium(II) species. The sub-
sequent syn insertion of an intramolecular alkenyl double
bond to the C–Pd bond provides s-dihydronaphthalenylpal-
ladium complex 34. Although the reaction intermediate 34
1
4.2. Pd-catalyzed benzannulation reaction of
a,b-bisbenzylidenesuccinimide
4.2.1. 3-(Triphenylphosphoranylidene)pyrrolidine-2,5-
dione 9. A mixture of maleimide (66.6 g, 688 mmol), triphe-
nylphosphine (180 g, 686 mmol), and acetone (670 ml) was
heated under reflux for 1 h. After cooling, the resulting
precipitate was filtered, washed with acetone (200 ml), and
dried in vacuo at 40 ꢀC to give 9 (233 g, yield 94%) as a
colorless solid, which was used for the next step without
further purification.
Pd(0)
O
30
NH
O
(E)
O
O
O
O
NH
7a
NH
O
IPd
Ar
O
PdI
-
HPdI
O
O
H
Ar
(E)
O
Syn - elimination
31
32
(E) / (Z) -
Syn - insertion
isomerization
-
HPdI
O
O
(E)
O
NH
PdI
Ar
O
O
NH
NH
O
O
O
IPd
PdI
O
H
Ar
H
(Z)
Ar
33
34
35
Scheme 7.

8544
H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
4.2.2. 3-(1,3-Benzodioxol-5-ylmethylene)pyrrolidine-2,5-
dione 10a (method A). A mixture of phosphorane 9
(2.35 g, 6.66 mmol), piperonal (1.00 g, 6.66 mmol), and
methanol (20 ml) was heated under reflux for 1 h and
10 min, then cooled at room temperature. The resulting crys-
tal was filtered, washed with methanol (5 ml), and dried in
vacuo at 40 ꢀC to give 10a (1.36 g, yield 88%) as a colorless
crystalline powder: mp 230 ꢀC (decomposed), 1H NMR
(DMSO-d6, TMS, 300 MHz) d (ppm): 3.61 (2H, d,
J¼2.3 Hz), 6.10 (2H, s), 7.01 (1H, d, J¼8.1 Hz), 7.1–7.2
(2H, m), 7.30 (1H, t, J¼2.3 Hz), 11.4 (1H, br), IR (ATR,
cmꢂ1): 1695, 1645, 1498, 1180, 1027, MS (EI, m/z): (M+)
231; Elemental analysis: calcd for C12H9NO4, C: 62.34, H:
3.92, N: 6.06, found C: 62.15, H: 3.78, N: 6.07.
4.83 mmol), and ethanol (30 ml) for 11 h under reflux to
give 11b (2.07 g, yield 82%) as a yellow crystalline powder:
mp 245 ꢀC (decomposed), 1H NMR (DMSO-d6, TMS,
300 MHz) d (ppm): 5.96 (4H, s), 5.97 (2H, s), 7.24 (2H,
s), 7.38 (2H, s), 11.7 (1H, br), IR (ATR, cmꢂ1): 1755,
1702, 1471, 1263, 1116, 1034, MS (EI, m/z): (M+2) 521,
(M) 519; Elemental analysis: calcd for C20H11NO6Br2, C:
46.10, H: 2.13, N: 2.69, found C: 45.86, H: 2.13, N: 2.72.
4.2.7. 3-[(6-Bromo-1,3-benzodioxol-5-yl)methylene]-4-
(4-fluorobenzylidene)pyrrolidine-2,5-dione 11c. Follow-
ing the method B, compound 10b (1.50 g, 4.84 mmol) was
treated with 4-fluorobenzaldehyde (0.813 g, 6.55 mmol),
piperidine (0.558 g, 6.55 mmol), acetic acid (0.393 g,
6.55 mmol), and ethanol (30 ml) for 6 h under reflux to
give the title compound (1.60 g, yield 80%) as a yellow crys-
talline powder: mp 244 ꢀC (decomposed), 1H NMR
(DMSO-d6, TMS, 300 MHz) d (ppm): 5.84 (2H, s), 6.07
(2H, s), 6.77–6.83 (2H, m), 6.94–6.99 (2H, m), 7.18 (2H,
s), 7.44 (1H, s), 7.59 (1H, s), 11.72 (1H, br), IR (KBr,
cmꢂ1): 1760, 1706, 1473, 1421, 1238, 833, 648, MS (EI,
m/z): (M+2) 417, (M) 415; Elemental analysis: calcd for
C19H11NO4BrF, C: 54.83, H: 2.66, N: 3.37, found C:
54.53, H: 2.55, N: 3.25.
4.2.3. 3-[(6-Bromo-1,3-benzodioxol-5-yl)methylene]pyr-
rolidine-2,5-dione 10b. Following the method A, phosphor-
ane 9 (4.71 g, 13.1 mmol) was treated with 6-bromo-3,4-
methylenedioxybenzaldehyde (3.00 g, 13.1 mmol) in meth-
anol (60 ml) for 1.5 h under reflux to give 10b (3.34 g, yield
82%) as a pale yellow powder: mp 265 ꢀC (decomposed), 1H
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 3.65 (2H, d,
J¼2.3 Hz), 6.16 (2H, s), 7.25 (1H, s), 7.39 (1H, s), 7.53
(1H, t, J¼2.3 Hz), 11.5 (1H, br), IR (ATR, cmꢂ1): 1765,
1695, 1501, 1348, 1205, 1038, MS (EI, m/z): (M+1) 311,
(M) 309; Elemental analysis: calcd for C12H8BrNO4, C:
46.48, H: 2.60, N: 4.52, found C: 46.56, H: 2.67, N: 4.27.
Following the method B, compound 10c (2.69 g, 13.1 mmol)
was treated with 6-bromo-3,4-methylenedioxybenzalde-
hyde (3.00 g, 13.1 mmol), piperidine (1.12 g, 13.1 mmol),
acetic acid (0.787 g, 13.1 mmol), and ethanol (53.8 ml) to
give the title compound (4.41 g, yield 81%).
4.2.4. 3-(4-Fluorobenzylidene)pyrrolidine-2,5-dione 10c.
Following the method A, phosphorane
9 (29.0 g,
80.6 mmol) was treated with 4-fluorobenzaldehyde
(10.0 g, 80.6 mmol) in methanol (100 ml) for 1.5 h under re-
flux to give 10c (13.9 g, yield 83%) as a colorless crystalline
4.2.8. 9-(1,3-Benzodioxol-5-yl)-5H-[1,3]benzodiox-
olo[5,6-f]isoindole-6,8(5aH,7H)-dione 12. A mixture of
compound 11a (6.00 g, 16.5 mmol) and N,N-dimethylform-
amide (120 ml) was heated at 140 ꢀC for 96 h under a nitro-
gen atmosphere. The reaction mixture was allowed to stand
at room temperature, and then ethyl acetate (180 ml), tetra-
hydrofuran (60 ml), and H2O (180 ml) were added. The
aqueous layer was separated and extracted with ethyl acetate
(2ꢁ60 ml). The combined organic layer was washed with
H2O and concentrated in vacuo to give crude compound
12, which indicated a 66% peak area on HPLC analysis.
The residue was purified with silica-gel column chromato-
graphy (eluent: hexane/acetate) and washed with ethanol
and ethyl acetate to give the title compound (0.63 g, yield
16%) as a pale yellow crystalline powder: mp 261–263 ꢀC,
1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 2.79 (1H,
t, J¼15.7 Hz), 3.07 (1H, dd, J¼15.3 and 6.5 Hz), 3.66
(1H, dd, J¼16.6 and 6.5 Hz), 5.9–6.1 (2H, m), 6.09 (2H,
d, J¼3.9 Hz), 6.33 (1H, s), 6.5–7.0 (2H, m), 6.96 (1H, d,
J¼8.0 Hz), 7.05 (1H, s), 11.2 (1H, br), 13C NMR (DMSO-
d6, TMS, 300 MHz) d (ppm): 28.03, 40.79, 101.11,
101.51, 107.57, 108.28, 109.05, 122.58, 128.38, 129.19,
131.63, 142.58, 146.08, 146.52, 147.41, 148.04, 167.65,
176.43, IR (ATR, cmꢂ1): 1759, 1702, 1484, 1236, 1032,
639, MS (EI, m/z): (M+) 363; Elemental analysis: calcd for
C20H13NO6, C: 66.12, H: 3.61, N: 3.86, found C: 65.91,
H: 3.55, N: 3.90, HPLC purity: 98.5%.
1
powder: mp 210 ꢀC (decomposed), H NMR (DMSO-d6,
TMS, 300 MHz) d (ppm): 3.64 (2H, d, J¼2.2 Hz), 7.28–
7.34 (2H, m), 7.39 (1H, t, J¼2.2 Hz), 7.67–7.72 (2H, m),
11.4 (1H, br), IR (ATR, cmꢂ1): 1765, 1707, 1650, 1510,
1350, 1184, MS (EI, m/z): (M+) 205; Elemental analysis:
calcd for C11H8NO2F, C: 64.39, H: 3.93, N: 6.83, found C:
64.28, H: 3.95, N: 6.86.
4.2.5. 3,4-Bis(1,3-benzodioxol-5-ylmethylene)pyrroli-
dine-2,5-dione 11a (method B). A mixture of compound
10a (350 mg, 1.51 mmol), piperonal (227 mg, 1.51 mmol),
and piperidine (129 mg, 1.51 mmol) in ethanol (3.5 ml)
and tetrahydrofuran (3.5 ml) was heated under reflux for
18 h. The reaction mixture was then allowed to stand at
room temperature, and the resulting crystals were filtered
and washed with ethanol/tetrahydrofuran (1:1, 1.2 ml) and
dried in vacuo at 40 ꢀC to give 11a (456 mg, yield 83%) as
1
a yellow crystalline powder: mp 249 ꢀC (decomposed), H
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 5.90 (4H, s),
6.30 (2H, d, J¼1.2 Hz), 6.62 (2H, d, J¼8.1 Hz), 6.65 (2H,
dd, J¼8.1 and 1.2 Hz), 7.49 (2H, s), 11.5 (1H, br), IR
(ATR, cmꢂ1): 1692, 1485, 1246, 1037, 925, MS (EI, m/z):
(M+) 363; Elemental analysis: calcd for C20H13NO6, C:
66.12, H: 3.61, N: 3.86, found C: 65.89, H: 3.76, N: 3.87.
4.2.6. 3,4-Bis[(6-bromo-1,3-benzodioxol-5-yl)methyl-
ene]pyrrolidine-2,5-dione 11b. Following the method B,
compound10b(1.50 g,4.84 mmol)wastreatedwith6-bromo-
3,4-methylenedioxybenzaldehyde (1.11 g, 4.83 mmol),
piperidine (411 mg, 4.83 mmol), acetic acid (290 mg,
4.2.9. 5-(1,3-Benzodioxol-5-yl)-6H-[1,3]benzodiox-
olo[5,6-f]isoindole-6,8(7H)-dione 13.
compound 11a (350 mg, 0.963 mol) and N,N-dimethyl-
A
mixture of
formamide (7 ml) was heated at 140 ꢀC for 20 h under an

H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
8545
ambient atmosphere. The reaction mixture was then allowed
to stand at room temperature, ethyl acetate (15 ml) and H2O
(15 ml) were added. The aqueous layer was separated and
extracted with ethyl acetate. The combined organic layers
were washed with H2O, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was washed with ethyl
acetate and then ethanol to give the title compound
(170 mg, yield 49%) as a colorless crystalline powder: mp
299 ꢀC (decomposed), 1H NMR (DMSO-d6, TMS,
300 MHz) d (ppm): 6.13 (2H, d, J¼11.6 Hz), 6.22 (2H, d,
J¼1.6 Hz), 6.80 (1H, dd, J¼7.9 and 1.6 Hz), 6.9–7.0 (2H,
m), 7.05 (1H, d, J¼7.9 Hz), 7.73 (1H, s), 8.22 (1H, s),
11.2 (1H, br), IR (ATR, cmꢂ1): 1767, 1722, 1469, 1253,
1039, MS (EI, m/z): (M+) 361; Elemental analysis: calcd
for C20H11NO6$0.5H2O, C: 64.87, H: 3.27, N: 3.78, found
C: 65.27, H: 3.20, N: 3.84.
3.6 mmol), and N,N-dimethylformamide (31.2 ml) for 2 h
at 100 ꢀC to give the title compound (1.06 g, yield 80%) as
a pale yellow crystalline powder: mp 301 ꢀC (decomposed),
1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 6.19 (2H, d,
J¼13.0 Hz), 6.24 (2H, s), 6.76 (1H, s), 6.97 (1H, s), 7.39
(1H, s), 7.73 (1H, s), 8.31 (1H, s), 11.3 (1H, br), IR (ATR,
cmꢂ1): 1706, 1464, 1231, 1024, 640, 437, MS (EI, m/z):
(M+2) 441, (M) 439, HRMS: calcd for C20H10NO6Br,
438.9691, found 438.9689.
4.2.13. 2-Iodo-3,4-methylenedioxybenzaldehyde (2-iodo-
piperonal) 17. (The following procedure is a modification
of Young’s 2-iodopiperonal synthesis.)
To a stirred mixture of N,N,N0-trimethylethyldiamine
(29.4 g, 288 mmol) and 1,2-dimethoxyethane (DME)
(180 ml) was added 1.6 M n-BuLi in hexanes (180 ml,
288 mmol) at 0–10 ꢀC under a nitrogen atmosphere. After
further stirring at the same temperature for 1 h, a DME
(540 ml) solution of piperonal (35.1 g, 234 mmol) was
added to the mixture. After more stirring at 0–10 ꢀC for
1 h, the resulting mixture was diluted with tetrahydrofuran
(360 ml), followed by 1.6 M n-BuLi in hexanes (225 ml,
360 mmol). The mixture was stirred at room temperature
for 4.5 h, and iodine (107 g, 421 mmol) was added portion-
wise from ꢂ60 to ꢂ70 ꢀC. The reaction mixture was then
warmed up to room temperature for 22 h, and satd aq
Na2S2O3 (350 ml) was added to it. The aqueous layer was
separated and extracted with ethyl acetate (175 ml+90 ml).
The combined organic layers were washed with brine, dried
over anhydrous MgSO4, and concentrated in vacuo. The con-
centrated residue was recrystallized from ethanol (320 ml)
to give the title compound as the first crop (28.2 g). The sec-
ond crop (1.7 g) was obtained from the mother liquor (yield
46%) as a colorless crystalline powder: 1H NMR (DMSO-d6,
TMS, 300 MHz) d (ppm): 6.25 (2H, s), 7.07 (1H, d,
J¼8.2 Hz), 7.47 (1H, d, J¼8.2 Hz), 9.80 (1H, s), MS (EI):
(M+) 276; Elemental analysis: calcd for C8H5O3I, C:
34.81, H: 1.83, I: 45.98, found C: 34.85, H: 1.80, I: 46.01.
4.2.10. 5-Bromo-10-(4-fluorophenyl)-7H-[1,3]benzodiox-
olo[4,5-f]isoindole-7,9(8H)-dione 14. A mixture of com-
pound 11c (2.00 g, 4.81 mmol) and N-methylpyrrolidone
(20 ml) was heated at 190 ꢀC for 9.5 h under an ambient at-
mosphere. The reaction mixture was then allowed to stand at
room temperature, before ethyl acetate, tetrahydrofuran, and
1 M HCl were added to it. The aqueous layer was separated
and extracted with ethyl acetate. The combined organic
layers were washed with 1 M HCl and then H2O, dried
over anhydrous MgSO4, and concentrated in vacuo to give
crude compound 14, which indicated a 13% peak area on
HPLC analysis. The residue was purified with silica-gel col-
umn chromatography (eluent: hexane/acetate) and recrystal-
lized from hexane and ethyl acetate to give the title
compound (36.3 mg, yield 1.8%) as a yellow crystalline
1
powder: mp 305 ꢀC (decomposed), H NMR (DMSO-d6,
TMS, 300 MHz) d (ppm): 5.98 (2H, s), 6.94–7.25 (2H, m),
7.39–7.44 (2H, m), 8.06 (1H, s), 8.43 (1H, s), 11.4 (1H,
br), IR (ATR, cmꢂ1): 1712, 1278, 1134, 1061, 635, 499,
MS (EI, m/z): (M+2) 415, (M) 413; Elemental analysis:
calcd for C19H9BrFNO4, C: 55.10, H: 2.19, N: 3.38, found
C: 54.89, H: 2.29, N: 3.11, HPLC purity: 96.7%.
4.2.11. 5-(4-Fluorophenyl)-6H-[1,3]benzodioxolo[5,6-
f]isoindole-6,8(7H)-dione 15 (method C). A mixture of
compound 11b (1.00 g, 2.40 ml), Pd(OAc)2 (53.9 mg,
0.24 mmol), triethylamine (291 mg, 2.88 mmol), and N,N-
dimethylformamide (20 ml) was stirred at room temperature
under a nitrogen atmosphere for 1 h and the resulting mix-
ture was heated at 100 ꢀC for 1 h. After the reaction mixture
had stood at room temperature, 1 M HCl (20 ml) was added
to give a precipitate. The solid was filtered, washed with
ethanol/tetrahydrofuran (1:1), and dried in vacuo at 40 ꢀC
to give the title compound (593 mg, yield 74%) as a colorless
crystalline powder: mp 328 ꢀC (decomposed), 1H NMR
(DMSO-d6, TMS, 300 MHz) d (ppm): 5.98 (2H, s), 6.59
(1H, s), 7.04–7.20 (4H, m), 7.47 (1H, s), 8.03 (1H, s), 11.2
(1H, br), IR (ATR, cmꢂ1): 1765, 1704, 1463, 1244, 1037,
750, 640, MS (EI, m/z): (M+) 335; Elemental analysis: calcd
for C19H10FNO4, C: 68.06, H: 3.01, N: 4.18, found C: 67.93,
H: 2.94, N: 4.09.
4.2.14. 3-(4-Fluorobenzylidene)-4-[(4-iodo-1,3-benzo-
dioxol-5-yl)methylene]pyrrolidine-2,5-dione 11d. Fol-
lowing the method B, compound 10c (4.15 g, 18.1 mmol)
was treated with 2-iodopiperonal (5.00 g, 13.1 mmol), piper-
idine (1.54 g, 18.1 mmol), acetic acid (1.09 g, 18.1 mmol),
and ethanol (83 ml) under reflux for 4.5 h to give the title
compound (6.62 g, yield 79%) as a colorless crystalline
1
powder: H NMR (DMSO-d6, TMS, 300 MHz) d (ppm):
6.03–6.13 (4H, m), 6.73–6.78 (2H, m), 6.88–6.92 (2H, m),
7.44 (1H, s), 7.56 (1H, s), 11.7 (1H, br), IR (ATR, cmꢂ1):
1701, 1453, 1227, 1173, 1038, 936, 446, MS (EI, m/z):
(M+) 463, HRMS: calcd for C19H11NO4FI, 462.9717, found
462.9734; Elemental analysis: calcd for C19H11FNO4I$
0.5H2O, C: 48.33, H: 2.56, N: 2.97, found C: 48.56, H:
2.34, N: 2.90.
4.2.15. 10-(4-Fluorophenyl)-7H-[1,3]benzodioxolo[4,5-
f]isoindole-7,9(8H)-dione 7b. A mixture of compound
11d (6.57 g, 14.2 ml), Pd(OAc)2 (319 mg, 1.42 mmol), tri-
ethylamine (3.16 g, 31.2 mmol), and N,N-dimethylform-
amide (131 ml) was stirred at room temperature under
a nitrogen atmosphere for 1 h and the resulting mixture
was heated at 110 ꢀC for 1 h and 20 min. After the reaction
4.2.12. 5-(6-Bromo-1,3-benzodioxol-5-yl)-6H-[1,3]benzo-
dioxolo[5,6-f]isoindole-6,8(7H)-dione 16. Following the
method C, compound 11b (1.56 g, 3 mmol) was treated with
Pd(OAc)2 (67.4 mg, 0.3 mmol), triethylamine (353 mg,

8546
H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
mixture had stood at room temperature, its insoluble part
was filtered out and washed with N,N-dimethylformamide
(50 ml). To the combined filtrate and washing were added
ethyl acetate (260 ml) and 5% aq Na2S2O3$5H2O
(140 ml). The aqueous layer was separated and extracted
with ethyl acetate (130 ml+65 ml). The combined organic
layers were washed with H2O (2ꢁ200 ml) and concentrated
in vacuo. The residue was washed with tetrahydrofuran/
EtOH (1:4, 25 ml) and dried in vacuo at 40 ꢀC to give the
title compound (3.70 g, yield 78%) as a yellow crystalline
powder: mp 285 ꢀC (decomposed), 1H NMR (DMSO-
d6, TMS, 300 MHz) d (ppm): 5.72 (2H, s), 6.95–7.01
(2H, m), 7.17–7.22 (2H, m), 7.35 (1H, d, J¼8.6 Hz), 7.20
(1H, d, J¼8.6 Hz), 8.17 (1H, s), 11.1 (1H, br), IR (ATR,
cmꢂ1): 1756, 1716, 1284, 1348, 1057, 637, 447, MS
(EI, m/z): (M+) 335; Elemental analysis: calcd for
C19H10FNO4$0.5H2O, C: 66.28, H: 3.22, N: 4.07, found
C: 66.49, H: 3.30, N: 4.08, HPLC purity: 96.8%.
6 M HCl (37 ml, 222 mmol) was added. The precipitate
was filtered and washed with H2O (254 ml) to give the title
compound (18.1 g, yield 82%). The second crop (497 mg)
was obtained from the mother liquor of the first crystals
(total yield 74%) as a pale yellow crystalline powder:
mp 209 ꢀC (decomposed), 1H NMR (DMSO-d6, TMS,
300 MHz) d (ppm): 3.70 (3H, s), 6.08 (2H, s), 6.8–6.9
(2H, m), 7.1–7.2 (2H, m), 7.3–7.4 (2H, m), 7.63 (1H, s),
7.68 (1H, s), 12.8 (1H, br), IR (KBr, cmꢂ1): 1700, 1683,
1600, 1232, 1047, 773, MS (EI, m/z): (M+) 496; Elemental
analysis: calcd for C20H14O6FI, C: 48.41, H: 2.84, found
C: 48.49, H: 2.87.
4.3.3. Methyl 3-cyano-4-(4-fluorophenyl)-2-[(4-iodo-1,3-
benzodioxol-5-yl)methylene]but-3-enoate 21. To a stirred
mixture of compound 20 (16.4 g, 33.0 mmol), tetrahydrofu-
ran (328 ml), and N,N-dimethylformamide (3.3 ml), thionyl
chloride (41 ml) was added dropwise at room temperature
and the resulting mixture was heated for 2 h under reflux.
After cooling, the reaction mixture was added dropwise to
a stirred mixture of 28% aq NH3 (328 ml) and tetrahydro-
furan (164 ml) at ice-cold temperature. After further stirring
at the same temperature for 2 h, concd HCl (250 ml) and
water (400 ml) were added and the reaction mixture was ex-
tracted with ethyl acetate (100 mlꢁ2 and 50 ml). The com-
bined organic layers were concentrated in vacuo and the
concentrated residue was washed with methanol (50 ml) to
give methyl 3-(aminocarbonyl)-4-(4-fluorophenyl)-2-[(4-
iodo-1,3-benzodioxol-5-yl)methylene]but-3-enoate (14.9 g,
4.3. Pd-catalyzed benzannualtion to regiospecific syn-
theses of various arylnaphthalene lignan analogues
(Schemes 5 and 6)
4.3.1. Dimethyl 2-(4-fluorobenzylidene)succinate 19. To
a stirred mixture of diethyl succinate (52.0 g, 299 ml),
28% NaOMe in methanol (43.4 g, 225 mmol), and methanol
(87 ml) was added dropwise 4-fluorobenzaldehyde (18.6 g,
150 mmol) in methanol (46 ml) under reflux and the result-
ing mixture was heated for 2 h under reflux, then treated with
2 M-NaOH (298 ml) for 2 h at the same condition. After
standing at room temperature, the reaction mixture was
concentrated in vacuo and the resulting residue was recrys-
tallized from ethyl acetate to give 2-(4-fluorobenzylidene)-
succinic acid (8.16 g) as colorless crystals. The second
crop (4.04 g) was obtained from the mother liquor of the first
crystals (total yield 36%) as a colorless crystalline powder:
1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 3.36 (2H,
s), 7.26–7.31 (2H, m), 7.45–7.50 (2H, m), 7.73 (1H, s),
12.5 (2H, br), IR (ATR, cmꢂ1): 1673, 1309, 1218, 916,
829, 537, MS (EI, m/z): (M+) 224; Elemental analysis: calcd
for C11H9O4F, C: 58.93, H: 4.05, found C: 59.14, H: 4.00.
1
yield 91%) as a pale yellow crystalline powder: H NMR
(DMSO-d6, TMS, 300 MHz) d (ppm): 3.67 (3H, s), 6.08
(2H, s), 6.87 (1H, d, J¼8.8 Hz), 7.03 (1H, d, J¼8.8 Hz),
7.0–7.3 (5H, m), 7.38 (1H, s), 7.46 (1H, br), 7.71 (1H, s),
IR (ATR, cmꢂ1): 1702, 1674, 1460, 1228, 1047, 772, MS
(EI, m/z): (M+) 495; Elemental analysis: calcd for
C20H15FINO5, C: 48.50, H: 3.05, N: 2.83, found C: 48.49,
H: 3.28, N: 2.68.
To a stirred mixture of the above amide (14.7 g, 29.6 mmol),
tetrahydrofuran (294 ml), and N,N-dimethylformamide
(4.4 ml), oxalyl chloride (14.7 ml) was added dropwise at
room temperature and the resulting mixture was stirred at
room temperature for 3 h. To the reaction mixture was added
H2O (394 ml) and extracted with ethyl acetate (149 mlꢁ2).
The combined organic layer was washed with H2O
(300 mlꢁ2), dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was washed with methanol to give
the title compound 21 (12.8 g, yield 91%) as a pale yellow
To a stirred mixture of 2-(4-fluorobenzylidene)succinic acid
(12.1 g, 54.0 mmol) and methanol (242 ml) was added
concd H2SO4 (5.30 g, 54.0 mmol) and refluxed for 18 h. Af-
ter cooling, the reaction mixture was concentrated in vacuo.
To the residue was added H2O (121 ml) and extracted with
ethyl acetate (121 ml+61 ml). The combined organic layers
were washed with H2O (187 mlꢁ2), dried over anhydrous
MgSO4, and concentrated in vacuo to give the title com-
pound as a pale yellow oil (12.8 g, yield 94%), which was
used for the next step without further purification: 1H
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 3.51 (2H, s),
3.64 (3H, s), 3.75 (3H, s), 7.26–7.32 (2H, m), 7.47–7.52
(2H, m), 7.81 (1H, s), IR (Neat, cmꢂ1): 2954, 1739, 1712,
1602, 1508, 1436.
1
crystalline powder: mp 173–177 ꢀC, H NMR (DMSO-d6,
TMS, 300 MHz) d (ppm): 3.66 (3H, s), 6.16 (2H, s), 6.96
(1H, d, J¼8.8 Hz), 7.04 (1H, d, J¼8.8 Hz), 7.1–7.3
(2H, m), 7.4–7.5 (2H, m), 7.71 (1H, s), 7.84 (1H, s),
IR (KBr, cmꢂ1): 2208, 1718, 1598, 1457, 1216, 925, MS
(EI, m/z): (M+) 477; Elemental analysis: calcd for
C20H13FINO4, C: 50.34, H: 2.75, N: 2.94, found C: 50.53,
H: 2.84, N: 2.64.
4.3.2. 2-(4-Fluorobenzylidene)-4-(4-iodo-1,3-benzo-
dioxol-5-yl)-3-(methoxycarbonyl)but-3-enoic acid 20. To
a stirred mixture of compound 19 (12.7 g, 46.3 mmol), com-
pound 17 (12.8 g, 46.3 mmol), and methanol (254 ml) was
added 28% NaOMe in methanol (21.4 g, 111 mmol) and re-
fluxed for 3.5 h. After the cooling of the reaction mixture,
4.3.4. Methyl 8-cyano-9-(4-fluorophenyl)naphtho[1,2-
d][1,3]dioxole-7-carboxylate 22. A mixture of compound
21 (12.1 g, 25.4 mmol), Pd(OAc)2 (570 mg, 2.54 mmol), po-
tassium carbonate (7.73 g, 55.9 mmol), and N-methylpyrro-
lidone (242 ml) was stirred at room temperature under N2 for
1 h and then heated at 110 ꢀC for 4 h. The reaction mixture

H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
8547
was allowed to stand at room temperature, and any insoluble
matter was filtered off and washed with N-methylpyrroli-
done (30 ml). The filtrate and washing were combined,
washed with satd Na2S2O3 (300 ml) and H2O (300 ml), dried
over anhydrous MgSO4, and concentrated in vacuo. The resi-
due was purified with silica-gel column chromatography to
give the title compound as a pale yellow crystalline powder
(2.80 g, 32%): mp 224 ꢀC (decomposed), 1H NMR (DMSO-
d6, TMS, 300 MHz) d (ppm): 3.58 (3H, s), 6.35 (2H, s), 7.3–
7.4 (2H, m), 7.4–7.5 (2H, m), 7.62 (1H, d, J¼8.8 Hz), 7.95
(1H, d, J¼8.8 Hz), 8.76 (1H, s), IR (KBr, cmꢂ1): 2217,
1708, 1459, 1274, MS (EI, m/z): (M+) 349; Elemental anal-
ysis: calcd for C20H12FNO4, C: 68.77, H: 3.46, N: 4.01,
found C: 68.56, H: 3.41, N: 3.93.
4.3.7. Dimethyl 2-[(4-iodo-1,3-benzodioxol-5-yl)methyl-
ene]succinate 25. To a stirred mixture of compound 17
(26.7 g, 96.7 mmol), diethyl succinate (33.6 g, 193 mmol),
and methanol (135 ml) was added 28% NaOMe in methanol
(28.0 g, 145 mmol) and the resulting mixture was refluxed
for 3 h and 25 min. NaOH (2 M, 267 ml) was then added
and the mixture was refluxed for 3 h. After cooling, the reac-
tion mixture was concentrated in vacuo. To the residue were
added H2O (134 ml) and concd HCl (134 ml) and the mix-
ture was extracted with ethyl acetate (267 ml+134 mlꢁ2).
The combined organic layers were washed with water
(300 mlꢁ2), dried over anhydrous MgSO4, and concentrated
in vacuo. The residue was washed with ethyl acetate (67 ml)
to give 2-[(4-iodo-1,3-benzodioxol-5-yl)methylene]succinic
1
acid (22.6 g, 62%) as a colorless crystalline powder: H
4.3.5. Methyl 4-(4-fluorophenyl)-3-[(hydroxyamino)car-
bonyl]-2-[(4-iodo-1,3-benzodioxol-5-yl)methylene]but-3-
enoate 23 (method D). To a stirred mixture of compound 20
(2.00 g, 4.03 mmol), tetrahydrofuran (20 ml), chloroform
(20 ml), and N,N-dimethylformamide (0.4 ml), oxalyl chlo-
ride (5 ml) was added dropwise at room temperature. After
being stirred at room temperature for 5 h, the reaction mix-
ture was concentrated in vacuo. A tetrahydrofuran (50 ml)
solution of the above residue was added dropwise to a stirred
mixture of hydroxylamine hydrochloride (2.44 g,
40.3 mmol), tetrahydrofuran (20 ml), and satd NaHCO3
(20 ml) at ice-cold temperature. After further stirring for
1 h at the same temperature, 6 M HCl (20 ml) was added
to the reaction mixture and extracted with ethyl acetate
twice. The combined organic layer was washed with H2O,
dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was washed with a mixture of ethyl acetate
and n-hexane to give the title compound (1.40 g, yield
68.0%) as a pale yellow crystalline powder: mp 206 ꢀC (de-
composed), 1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm):
3.68 (3H, s), 6.08 (2H, s), 6.8–6.9 (1H, m), 7.0–7.3 (6H, m),
7.74 (1H, s), 8.94 (1H, br), 10.8 (1H, br), IR (KBr, cmꢂ1):
1695, 1656, 1506, 1461, 1226, MS (EI, m/z): (M+) 511;
Elemental analysis: calcd for C20H15FINO6, C: 46.99,
H: 2.96, N: 2.74, found C: 47.11, H: 2.91, N: 2.64.
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 3.24 (2H, s),
6.14 (2H, s), 6.87 (1H, d, J¼8.0 Hz), 7.00 (1H, d,
J¼8.0 Hz), 7.56 (1H, s), 12.6 (2H, br), IR (KBr, cmꢂ1):
2918, 1734, 1697, 1460, 1284, MS (FAB, m/z): (MꢂH)ꢂ
375.
To a stirred mixture of 2-[(4-iodo-1,3-benzodioxol-5-yl)-
methylene]succinic acid (22.5 g, 59.8 mmol) and methanol
(225 ml) was added concd H2SO4 (5.87 g, 59.8 mmol) and
the resulting mixture was refluxed for 15 h and 40 min.
After cooling, the reaction mixture was concentrated
in vacuo. To the residue was added H2O (200 ml) and
extracted with ethyl acetate (300 ml+150 mlꢁ2). The com-
bined organic layers were washed with H2O (300 mlꢁ2),
dried over anhydrous MgSO4, and concentrated in vacuo.
The residue was washed with methanol (170 ml) and dried
in vacuo at 40 ꢀC to give the title compound (20.2 g, 84%)
as a colorless crystalline powder: mp 130–133 ꢀC, 1H
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 3.39 (2H, s),
3.62 (3H, s), 3.76 (3H, s), 6.15 (2H, s), 6.85 (1H, d,
J¼8.0 Hz), 6.98 (1H, d, J¼8.0 Hz), 7.62 (1H, s), IR
(KBr, cmꢂ1): 2958, 1718, 1460, 1429, 1373, 1333, 1230,
1180, MS (EI, m/z): (M+) 404; Elemental analysis: calcd
for C14H13IO6, C: 41.61, H: 3.24, I: 31.40, found C:
41.45, H: 3.27, I: 31.55.
4.3.6. 10-(4-Fluorophenyl)-8-hydroxy-7H-[1,3]benzo-
dioxolo[4,5-f]isoindole-7,9(8H)-dione 24 (method E). A
mixture of compound 23 (164 mg, 0.321 mmol), Pd(OAc)2
4.3.8. 4-(1,3-Benzodioxol-5-yl)-2-[(4-iodo-1,3-benzo-
dioxol-5-yl)methylene]-3-(methoxycarbonyl)but-3-enoic
acid 26. To a stirred mixture of compound 25 (15.0 g,
37.1 mmol), piperonal (6.13 g, 40.8 mmol), and methanol
(150 ml) was added 28% NaOMe in methanol (17.2 g,
89.0 mmol) and refluxed for 5 h. After the mixture was
cooled, concd HCl (14.8 ml, 178 mmol) was added. The pre-
cipitate was filtered and washed with H2O (60 ml) to give the
title compound (15.9 g, yield 82%) as a pale yellow crystal-
(7.2 mg,
0.0321 mmol),
triethylamine
(71.4 mg,
0.706 mmol), and N,N-dimethylformamide (3.3 ml) was
stirred for 1 h at room temperature and then at 110 ꢀC for
45 min. The reaction mixture was allowed to stand at room
temperature, and all insoluble matter was filtered off
and washed with N,N-dimethylformamide. To the combined
filtrate and washing was added aq Na2S2O3 and extracted
with ethyl acetate three times. The combined organic
layers were washed with H2O twice, dried over anhydrous
MgSO4, and concentrated in vacuo. The resulting residue
was washed with methanol and dried in vacuo at 40 ꢀC to
give the title compound (78.1 mg, yield 69%) as a yellow
crystalline powder: mp 256 ꢀC (decomposed), 1H NMR
(DMSO-d6, TMS, 300 MHz) d (ppm): 5.95 (2H, s), 7.1–
7.3 (2H, m), 7.4–7.5 (2H, m), 7.58 (1H, d, J¼8.6 Hz), 7.93
(1H, d, J¼8.6 Hz), 8.45 (1H, s), 10.8 (1H, br), IR (ATR,
cmꢂ1): 1714, 1508, 1290, 1068, 880, 723, MS (EI, m/z):
(M+) 351, HRMS: calcd for C19H10NO5F, 351.0543, found
351.0548.
1
line powder: mp 207 ꢀC (decomposed), H NMR (DMSO-
d6, TMS, 300 MHz) d (ppm): 3.66 (3H, s), 6.04 (2H, s),
6.08 (2H, d, J¼2.7 Hz), 6.79 (1H, d, J¼8.2 Hz), 6.83 (1H,
d, J¼8.2 Hz), 6.87–6.97 (3H, m), 7.58 (1H, s), 7.73 (1H,
s), 12.9 (1H, br), IR (KBr, cmꢂ1): 1716, 1672, 1460, 1230,
MS (EI, m/z): (M+) 522; Elemental analysis: calcd for
C21H15IO8$0.5H2O, C: 47.48, H: 3.04, I: 23.89, found C:
47.64, H: 2.94, I: 23.80.
4.3.9. Methyl 2-(1,3-benzodioxol-5-ylmethylene)-3-[(di-
methylamino)carbonyl]-4-(4-iodo-1,3-benzodioxol-5-yl)-
but-3-enoate 27. Following the method D, compound 26
(3.00 g, 5.74 mmol) was treated with tetrahydrofuran

8548
H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
(30 ml), N,N-dimethylformamide (0.6 ml), and oxalyl chlo-
ride (7.59 ml, 57.4 mmol) to give the corresponding acid
chloride, which was treated with dimethylamine hydrochlo-
ride (4.68 g, 57.4 mmol), satd NaHCO3 (60 ml), and tetrahy-
drofuran (45 ml) to provide the title compound (3.05 g, yield
97%) as a pale yellow crystalline powder: mp 190–191 ꢀC,
1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 2.8–3.2
(6H, br), 3.70 (3H, s), 6.01 (4H, s), 6.4–6.7 (2H, m), 6.7–
6.9 (3H, m), 7.17 (1H, s), 7.48 (1H, s), IR (ATR, cmꢂ1):
1689, 1630, 1449, 1170, 1040, 932, MS (EI, m/z): (M+)
549; Elemental analysis: calcd for C23H20NO7I, C: 50.29,
H: 3.67, N: 2.55, found C: 50.22, H: 3.58, N: 2.62.
To the residual oil was added toluene (24 ml), followed by
PBr3 (657 mg), and the resulting mixture was stirred at
room temperature for 1 h. To the reaction mixture was added
H2O (50 ml) and extracted with ethyl acetate (50 ml) twice.
The combined organic layers were washed with H2O
(50 ml), dried over anhydrous MgSO4, and concentrated
in vacuo to leave an oil.
To the residual oil were added tetrahydrofuran (12 ml), 28%
aq NH3 (24 ml), and methanol (12 ml) and the resulting
mixture was stirred at room temperature for 11 h. After the
reaction mixture was concentrated in vacuo, ethyl acetate
(50 ml) and H2O (50 ml) were added to the residue. The aque-
ous layer was separated and extracted with ethyl acetate
(50 ml). The combined organic layers were washed with
H2O (50 ml), dried over anhydrous MgSO4 and concentrated
in vacuo. The residue was purified with silica-gel column
chromatography (eluent: toluene/ethyl acetate) to give the
4.3.10. Methyl 9-(1,3-benzodioxol-5-yl)-7-[(dimethylamino)-
carbonyl]naphtho[1,2-d][1,3]dioxole-8-carboxylate 28. Fol-
lowing the method E, compound 27 (1.10 g, 2 mmol) was
treated with Pd(OAc)2 (89.8 mg, 0.4 mmol), AcOK
(432 mg, 4.4 mmol), and N-methylpyrrolidone (22 ml) at
110 ꢀC for 4 h, which was followed by purification with
column chromatography (eluent: hexanes/AcOEt) and crys-
tallization from aq methanol, to give the title compound
(74.8 mg, yield 8.9%) as a pale yellow crystalline powder:
1H NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 2.64 (3H,
s), 2.85 (3H, s), 3.67 (3H, s), 6.00 (2H, s), 6.15 (2H, s),
6.8–7.0 (3H, s), 7.25 (1H, d, J¼8.6 Hz), 7.47 (1H, d,
J¼8.6 Hz), 7.81 (1H, s), IR (ATR, cmꢂ1): 1737, 1617,
1459, 1223, 1200, 1111, MS (EI, m/z): (M+) 421; Elemental
analysis: calcd for C23H19NO7$0.5H2O, C: 64.18, H: 4.68,
N: 3.08, found C: 64.17, H: 4.82, N: 3.17, HPLC purity:
99.6%.
1
title compound as a yellow solid (405 mg, yield 35%): H
NMR (DMSO-d6, TMS, 300 MHz) d (ppm): 4.07 (2H, s),
5.84 (2H, s), 5.99 (1H, d, J¼1.3 Hz), 6.02 (2H, s), 6.15 (1H,
d, J¼8.2 Hz), 6.19 (1H, d, J¼8.2 Hz), 6.37 (1H, dd, J¼1.3
and 8.1 Hz), 6.50 (1H, d, J¼8.1 Hz), 6.53 (1H, s), 7.12 (1H,
s), 8.41 (1H, br s), IR (KBr, cmꢂ1): 1697, 1454, 1249, 1037,
MS (EI, m/z): (M+) 475, HRMS: calcd for C20H14NO5I,
474.9914, found 474.9917, HPLC purity: 98.7%.
4.3.13. 10-(1,3-Benzodioxol-5-yl)-8,9-dihydro-7H-
[1,3]benzodioxolo[4,5-f]isoindol-7-one 7c. A mixture of
compound 30 (300 mg, 0.631 mmol), Pd(OAc)2 (14.2 mg,
0.0631 mmol), AcOK (136 mg, 1.39 mmol), and N-methyl-
pyrrolidone (6 ml) was stirred at room temperature for 1 h
and the resulting mixture was heated at 110 ꢀC for 40 min.
After the reaction mixture had stood at room temperature,
insoluble matter was filtered off and washed with N-methyl-
pyrrolidone (3 ml) and ethyl acetate (10 ml). To the com-
bined filtrate and washing was added aq Na2S2O3 (35 ml)
and extracted with ethyl acetate (20 ml+15 ml+15 ml). The
combined organic layers were washed with 1 M HCl
(2ꢁ30 ml) and brine (2ꢁ30 ml), and concentrated in vacuo.
The residue was washed with tetrahydrofuran/ethanol (1:1,
0.5 ml) and dried in vacuo at 40 ꢀC to give the title
compound as yellow crystals (106 mg, yield 48%): mp:
4.3.11. 4-(1,3-Benzodioxol-5-yl)-3-(hydroxymethyl)-2-
[(4-iodo-1,3-benzodioxol-5-yl)methylene]-but-3-enoic
acid 29. Under a nitrogen atmosphere, compound 29 (2.00 g,
3.83 mmol) was suspended in tetrahydrofuran (6 ml) and
cooled at 0–10 ꢀC. To the suspension was added dropwise
1.0 M LiBHEt3 in tetrahydrofuran (25.2 ml, 25.2 mmol),
maintaining the temperature below 10 ꢀC, and stirred at
this temperature for 1 h. To the reaction mixture were added
50% aq acetic acid (3 ml) and H2O. The resultant mixture
was extracted with ethyl acetate three times. The combined
organic layers were washed with H2O, dried over anhydrous
MgSO4, and concentrated in vacuo. The residue was crystal-
lized from ethyl acetate/n-hexane (2:1) to give the title com-
pound (1.26 g, yield 67%) as a pale yellow crystalline
1
250–251 ꢀC (lit.2 mp: 252–254 ꢀC), H NMR (DMSO-d6,
TMS, 300 MHz) d (ppm): 4.20 (2H, s), 5.95 (2H, dd,
J¼6.3 and 0.9 Hz), 6.09 (2H, dd, J¼14.1 and 0.8 Hz), 6.87
(1H, dd, J¼7.9 and 1.6 Hz), 6.96 (1H, d, J¼7.9 Hz), 7.00
(1H, d, J¼1.6 Hz), 7.43 (1H, d, J¼8.7 Hz), 7.95 (1H, d,
J¼8.7 Hz), 8.29 (1H, s), 8.58 (1H, br), IR (KBr, cmꢂ1):
1701, 1635, 1495, 1460, 1439, 1272, MS (EI, m/z): (M+)
347; Elemental analysis: calcd for C20H13NO5$0.75H2O,
C: 66.57, H: 4.19, N: 3.88, found C: 66.65, H: 4.18, N:
4.16, HPLC purity: 96.9%.
1
powder: H NMR (DMSO-d6, TMS, 300 MHz) d (ppm):
3.8–4.0 (3H, m), 5.97 (2H, s), 6.10 (2H, s), 6.57 (1H, s),
6.69 (1H, dd, J¼8.2 and 1.6 Hz), 6.7–6.9 (3H, m), 7.25
(1H, d, J¼8.2 Hz), 7.63 (1H, s), IR (KBr, cmꢂ1): 3384,
1691, 1459, 1255, 1232, MS (FAB): (MꢂH) 493; Elemental
analysis: calcd for C20H15IO7, C: 48.60, H: 3.06, I: 25.68,
found C: 48.38, H: 3.13, I: 25.31 and 25.42.
4.3.12. 4-(1,3-Benzodioxol-5-ylmethylene)-3-[(4-iodo-
1,3-benzodioxol-5-yl)methylene]pyrrolidin-2-one 30. A
mixture of compound 29 (1.2 g), iodoethane (2.83 g,
18.2 mmol), K2CO3 (1.26 g, 9.10 mmol), and N,N-dimethyl-
formamide (8.18 ml) was stirred at room temperature for
2 h. To the reaction mixture was added H2O (50 ml) and
extracted with ethyl acetate (100 ml+50 ml+50 ml). The
combined organic layers were washed with H2O (50 ml),
dried over anhydrous MgSO4, and concentrated in vacuo
to leave an oil.
The palladium-catalyzed reaction of compound 30 (25 mg)
was carried out as before. The reaction mixture was assayed
by HPLC under the following conditions to indicate a 72%
yield of compound 7c.
HPLC conditions: YMC-Pack ODS-A302 column
(150 mmꢁ4.6 mm I.D.) with 0.05 M KH2PO4 in water and
acetonitrile (60:40) at 25 ꢀC. Detection was effected with
a Hitachi spectrophotometric detector at 254 nm.

H. Mizufune et al. / Tetrahedron 62 (2006) 8539–8549
8549
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Acknowledgements
The authors wish to thank Mr. H. Mizutani for the measure-
ment of the NOESY spectrum.
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