Application of a catalytic palladium biaryl synthesis reaction, via C-H functionalization, to the total synthesis of Amaryllidaceae alkaloids

Article abstract of DOI:10.1016/j.tet.2004.08.030

The total synthesis of the Amaryllidaceae alkaloids dehydroanhydrolycorine, hippadine, pratosine, anhydrolycorine, assoanine, anhydrolycorin-7-one and oxoassoanine was achieved from the appropriate N-benzylisatin precursors using an intramolecular, palladium catalyzed, dehydrohalogenation, biaryl synthesis reaction to establish the carbon skeleton of the natural products. In order to avoid the formation of regioisomers in the cyclization reactions it was found necessary to incorporate the halogen on the benzyl group. Borane reduction of the 7H-pyrrolo[3,2,1-de]phenanthridine-4,5-dione derivatives gave 7H-pyrrolo[3,2,1-de]- and 4,5-dihydro-7H-pyrrolo[3,2,1-de]-phenanthridines (dehydroanhydrolycorine, dehydroassoanine, anhydrolycorine and assoanine). The former were readily reduced to the latter with NaCNBH₃ to give anhydrolycorine and assoanine. These compounds were then oxidized to anhydrolycorin-7-one and oxoassoanine whilst the same mixtures of borane reduction products could be oxidized to give hippadine and pratosine. N-benzylisatin derivatives (5) were used as masked indoles that were transformed into pyrrolo[3,2,1-de]phenanthridinone derivatives (1 or 2) in a concise manner via C-H functionalization, involving a palladium catalysed dehydrohalogenation reaction, followed by reduction and oxidation reactions.

Full text of DOI:10.1016/j.tet.2004.08.030

Tetrahedron 60 (2004) 9889–9900
Application of a catalytic palladium biaryl synthesis reaction,
via C–H functionalization, to the total synthesis of
Amaryllidaceae alkaloids
†
Jose C. Torres, Angelo C. Pinto and Simon J. Garden
*
´
´ ˆ ´
Departamento de Quımica Organica, Bloco A, Instituto de Quımica, Universidade Federal do Rio de Janeiro, Ilha do Funda˜o,
CEP 21945-900 Rio de Janeiro, Brazil
Received 21 April 2004; revised 13 August 2004; accepted 16 August 2004
Available online 11 September 2004
Abstract—The total synthesis of the Amaryllidaceae alkaloids dehydroanhydrolycorine, hippadine, pratosine, anhydrolycorine, assoanine,
anhydrolycorin-7-one and oxoassoanine was achieved from the appropriate N-benzylisatin precursors using an intramolecular, palladium
catalyzed, dehydrohalogenation, biaryl synthesis reaction to establish the carbon skeleton of the natural products. In order to avoid the
formation of regioisomers in the cyclization reactions it was found necessary to incorporate the halogen on the benzyl group. Borane
reduction of the 7H-pyrrolo[3,2,1-de]phenanthridine-4,5-dione derivatives gave 7H-pyrrolo[3,2,1-de]- and 4,5-dihydro-7H-pyrrolo[3,2,1-
de]-phenanthridines (dehydroanhydrolycorine, dehydroassoanine, anhydrolycorine and assoanine). The former were readily reduced to the
latter with NaCNBH3 to give anhydrolycorine and assoanine. These compounds were then oxidized to anhydrolycorin-7-one and
oxoassoanine whilst the same mixtures of borane reduction products could be oxidized to give hippadine and pratosine.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The use of palladium, in catalytic or stoichiometric
quantities, has become an indispensable tool for the
synthesis of heterocyclic compounds.2 The synthetic
strategies that have been developed for the synthesis of
the pyrrolophenanthridine alkaloids are no exception. All of
these strategies, that use palladium, have in common the
synthesis of the biaryl linkage between a phenyl group and
an indole or indoline derivative. Suzuki aryl–aryl cross
couplings have been employed for the synthesis of
ungeramine, hippadine (1b), anhydrolycorinone (2b)
and oxoassoanine (2d).3 Stille cross couplings using a
7-stannylindoline derivative were investigated by Iwao and
Watanabe for the synthesis of 1b, 2b, 2d and pratosine
(1d).4 These authors also transformed anhydrolycorine (2a)
into kalbretorine (1g) via a directed ortho lithiation
followed by boration and oxidation. Grigg and co-workers
used a Pd(OAc)2/(Me3Sn)2 system to prepare 1b in a
cyclization between two aryl iodides.5
The Amaryllidaceae alkaloids constitute a structurally
diverse group of almost 200 alkaloids isolated from the
majority of the genera of the family Amaryllidaceae.1 The
structures have been classified into mainly seven groups.
Many of these alkaloids possess significant biological
activity and this has in many ways, as well as the structural
diversity, stimulated synthetic efforts and the pursuit of new
synthetic methodologies. A sub-group of the lycorine
structure is represented in Figure 1. This sub-group has
either a pyrrolo[3,2,1-de]phenanthridine (1) or a dihydro-
pyrrolo[3,2,1-de]phenanthridine (2) skeleton where R1–4
may be a hydroxy, methoxy or a fused methylenedioxy ring
(R2/R3). Positively charged quaternary nitrogen (XZH:
vasconine and tortuesine) and neutral zwitterionic (R1Z
OK, XZH: ungeremine, criasbetaine and zeflabetaine)
compounds have also been isolated.1
A few examples of the use of palladium for the cyclization
of N-benzoylindole derivatives are known. These cycliza-
tions are dependant upon the structure of the substrate.
Itahara observed that the Pd(OAc)2 oxidative cyclization
occurred at C-2 of the indole resulting in the formation of
isoindolo[2,1-a]indole derivatives.6 Black and co-workers
obtained similar results for the oxidative cyclization of
N-piperonylindole and methoxybenzoylindole derivatives
Keywords: Amaryllidaceae alkaloids; Pyrrolophenanthridine; Biaryl syn-
thesis; Palladium catalysis; Dehydrohalogenation; C–H activation; C–H
functionalization; Indoledione.
* Corresponding author. Tel.: C55-21-2562-7367; fax: C55-21-2562-
7256; e-mail: garden@iq.ufrj.br
´ ´
† Present address: Centro Federal de Educac¸a˜o Tecnologica de Quımica de
´ ´
Nilopolis, Nilopolis, Rio de Janeiro, Brazil.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.030

9890
J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
Figure 1. Generalized structures for pyrrolo[3,2,1-de]phenanthridine (1) and dihydropyrrolo[3,2,1-de]phenanthridine (2) alkaloids (1c is unknown as a natural
product).
using stoichiometric quantities of Pd(OAc)2.7 Later these
workers anticipated that activation of the benzo-ring of the
indole nucleus with methoxy groups (4,6-disubstituted)
would allow regioselective C-7 cyclization to occur in
preference to C-2 cyclization. In addition, it was shown that
the desired C-7 regioselectivity could be guaranteed by
oxidative cyclization of N-benzoylindolines and subsequent
oxidation to the pyrrolophenanthridinone.8 Grigg and
co-workers favoured the investigation of catalytic methods
and observed that the Heck reaction9 of N-(2-iodobenzoyl)-
indole, and the 3-methylindole derivative, resulted in
cyclization at C-2 of the indole nucleus when they used
10 mol% Pd(OAc)2 and 20 mol% PPh3, in the presence of
K2CO3 and Et4NCl, in refluxing acetonitrile.10 Other
investigations have also revealed the preference for
cyclization at C-2 when the halogen was bonded to the
N-benzoyl or N-benzyl fragment of the indole substrate.11
Harrowven and co-workers have made use of an intra-
molecular Ullmann type coupling reaction to give 1a which
was then oxidized to 1b.18
Other notable methods for the synthesis of these alkaloids
include radical cyclizations19 and intramolecular cyclo-
addition reactions.20
2. Results and discussion
Our approach to the synthesis of the natural products 1 and 2
was based upon the early construction of the entire carbon
framework. It was envisaged that benzylation of isatin and
subsequent palladium catalyzed synthesis of the biaryl
linkage would result in the obtention of the appropriate
carbon skeleton.21 Subsequent reduction and oxidation
reactions would be utilized to finish the syntheses of the
natural products 1(a, b and d), 2(a–d) as well as the
unknown 1c and analogous derivatives (Fig. 2).
Harayama and co-workers have recently investigated the
palladium catalyzed cyclizations of N-2-halobenzylindolines.
They found that these reactions gave mixtures of the cyclized
dihydropyrrolophenanthridine and oxidized dihydropyrrolo-
phenanthridinone as well as the reduced benzylindoline and
In previous studies of the reactivity of isatin (3),22 we have
demonstrated that these compounds may be considered as
masked indoles. The reduction of 3 and its’ derivatives to
indoles in high yields by THF solutions of BH3$THF has
some distinct advantages over the use of other hydride
reagents,23 though, as of yet, has been rarely exploited for
natural product synthesis.23c,24 Therefore, the synthetic
approach for the formation of the biaryl bond using an
N-benzyl isatin derivative followed by BH3$THF reduction
of the dioxindole nucleus guarantees the construction of the
pyrrolo[3,2,1-de]phenanthridine skeleton (1) and avoids the
problem of regioselective cyclization at C-7 of the indole
nucleus.6–8,10,11
oxidized benzylindole.12 Knolker has reported the palladium
¨
catalyzed cyclization of N-2-iodo-3,4-methylenedioxyben-
zyltetrahydroindole under air to give 2b in 29% yield.13
Nucleophilic substitution of either ortho-methoxy or ortho-
iodo aromatic substituents in aryloxazolines or benzaldi-
mines, respectively, have been investigated as a means for
the construction of the biaryl linkage. In the former case,
Hutchings and Meyers required 5 steps to obtain 2d in
moderate overall yield by coupling a bromoindoline
Grignard reagent with the appropriate oxazoline followed
by subsequent transformations.14 Similar procedures were
later applied to the synthesis of 2b and dihydrokalbretorine,
DDQ oxidation of these compounds yielded 1b, 1d and
1g.15 In the latter case, Flippin and co-workers prepared
vasconine by coupling an indolinylcopper reagent with the
appropriate ortho-iodobenzaldimine in an Ullmann type
biaryl synthesis. Vasconine was then transformed into
assoanine (2c) and 2d.16 A similar methodology was applied
later to the synthesis of the pyrrolophenanthridinium
alkaloids tortuosine, criasbetaine, and ungeremine.17
The N-benzylisatin derivatives (5) used in this study were
readily prepared from the appropriate 3 and benzyl chloride
(4) in the presence of K2CO3 and NaI in DMF or by the use
of CaH2 and DMF (Table 1) (Scheme 1).25,26
A previous study had revealed the necessity to transform the
keto-carbonyl group of 5 into the spiro-dioxolane 6 to
facilitate formation of the biaryl linkage by palladium
catalysis.26,27 The dioxolanes 6 were prepared by acid

J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
9891
Figure 2. Retroanalysis for the synthesis of pyrrolo- and dihydropyrrolo-[3,2,1-de]phenanthridinones: R2/R3ZH or –OCH3 or –OCH2O–; when X1ZI or Br,
X2ZH; when X1ZH, X2ZI or Br.
catalysis with azeotropic removal of water using ethylene
glycol and toluene. With the appropriate substrates in hand,
previously determined conditions for the palladium
catalyzed synthesis of the biaryl linkage were applied.26
The substrate (0.1 M in DMF) was heated in the presence
of 10 mol% Pd(OAc)2, 1.0 mol equiv of Bu4NBr, and
5 mol equiv of KOAc (oil bath temperature 100 8C). No
particular precautions, such as an inert atmosphere, or
anhydrous DMF, were required and the cyclizations were
routinely performed exposed to the atmosphere. The
oxopyrrolophenanthridine derivatives (7) were obtained in
greater than 85% yield from the respective iodide substrates
(6a, c, and d) after workup and purification. The bromide 6b
required a considerably longer reaction time and gave a less
satisfactory yield (Table 2).
that the regioselectivity of these reactions is opposite to that
previously observed by Black and co-workers,8 and is
consistent with that recently reported by Harayama and
colleagues in similar palladium catalyzed biaryl forming
reactions.28
(1)
When compounds 6e and 6f were treated under the
aforementioned palladium catalyzed reaction conditions,
two regioisomeric products were obtained as a more or less
1:3 mixture (Eq. 1). The principal isomer was separated by
repeated crystallization from MeOH and identified as 7e0.
Subjection of 6g to the biaryl forming reaction gave a good
yield (43%) of 7e at 46% conversion of the substrate. Thus
with an unambiguous method for the regiospecific synthesis
of 7e and the purification of 7e0 from the mixture it was
a 10 mol% Pd(OAc)2, Bu4NBr, KOAc, DMF.
The reaction mechanism for formation of the biaryl bond is
presently debatable and it is possible to envisage a number
of scenarios (Fig. 3).29 Initial oxidative addition of an in situ
generated anionic Pd(0) species to the aryl halide would
give ArPd(II)OAcS2 (where S is a solvent molecule).30 This
Pd(II) complex could evolve giving rise to the formation of
an h2-arene complex by loss of one of the ligating solvent
molecules.31 Such an h2-arene complex can be envisioned
as a precursor to any of the proposed scenarios (Fig. 3) that
1
possible to assign all the signals in the H and 13C NMR
spectra of the mixtures of 7e and 7e0. It is interesting to note
Table 1. Substrates used in this study
Compound
R2/R3
R1
X1
X2
5a
5b
5c
5d
5e
5f
H
CH3
H
H
I
H
Br
I
–OCH2O–
–OCH2O–
OCH3
–OCH2O–
–OCH2O–
–OCH2O–
H
H
H
Br
I
H
I
CH3
CH3
CH3
H
H
Br
5g
H
Scheme 1. For identification of the substituents see Table 1: (a) DMF, K2CO3, NaI; (b) (CH2OH)2, toluene, H2SO4; (c) sub. 0.1 M in DMF, 10 mol% Pd(OAc)2,
1 equiv Bu4NBr, 5 equiv KOAc, 100 8C; (d) 6 N HCl/THF (1:1, v/v) reflux.

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J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
Table 2. Cyclization and dioxolane hydrolysis reaction products
Product
R2/R3
R1
Yield (%), [Reac.
Time, hrs] mp (8C)
Product
Yield mp
(8C)
6a/7a
6b/7b
6c/7b
6d/7d
6e/7e/7e0
6f/7e/7e0
6g/7e
H
CH3
H
H
98 [3], 191–3
69 [24]
8a
8b
96, 237–8
92, 235–7
–OCH2O–
–OCH2O–
OCH3
–OCH2O–
–OCH2O–
–OCH2O–
95 [5], 226–8
87 [10], 188–190
42a [16]
H
8d
87, 240–2
8
7
CH3
CH3
CH3
97b [6]
43 [29]c, 243–5
a
1
A mixture of two regioisomers (1:3.2) as determined by H NMR.
b
c
1
A mixture of two regioisomers (1:3.0) as determined by H NMR, mp of 7e0 is 217–9 8C.
20 mol% PPh3 in place of the Bu4NBr.
result in C–H functionalization.32 Alternatively, the for-
mation of an h1-arene complex, as an intermediate, may
precede the formation of the palladacycle.33 In the first
scenario, the h2-arene complex (or the h1-arene complex)
would evolve by addition of the s-Pd–C aryl bond to the
aromatic ring in a Heck type reaction giving rise to a trans
disposed arrangement of the Pd and hydrogen to be
eliminated. In Heck reactions such eliminations occur in a
syn manner. In order to regenerate Pd(0) it would be
necessary for a base to abstract the proton, resulting in
aromatization of the benzoid ring and the elimination of
Pd(0) or for stereomutation of the p-allyl palladium to occur
resulting in a cis relationship with respect to the hydrogen to
be eliminated.10,34 The second scenario proposes that the
reaction mechanism passes via a classical aromatic electro-
philic substitution to give a cis-diarylpalladium species that
would eliminate Pd(0) forming the biaryl bond. Such a
mechanism may or may not include a s-complex inter-
mediate of finite lifetime and is expected to show a normal
aryl-substituent effect where electron releasing groups
increase the rate of reaction.35 However, such substituent
effects have been called into question.36 The third scenario
is that an h2-arene (or an h1-arene) aryl-Pd complex
precedes an agostic interaction between the palladium and
the carbon–hydrogen bond.37 An agostic effect may
possibly represent a transition state for C–H activation
which ultimately results in the formation of the cis-
diarylpalladium (II) species.33,36,38
The dioxolane products 7(a, b and d) were hydrolyzed in
refluxing 50% aqueous 6 N HCl/THF for 5 h. Evaporation
of the THF resulted in the precipitation of the dark red/
purple compounds 8 in greater than 85% yield. Rigby and
Mateo reported an alternative method for what was claimed
to be the synthesis of compound 8b.39 Both the physical and
the spectroscopic properties detailed for compound 8b as
prepared by Rigby and Mateo are inconsistent with those
obtained in this study.
With compounds 8 in hand, attention was turned to
Figure 3. Reaction mechanism scenarios. In all three cases equivalent scenarios may be envisioned where the halogen would have initially been bonded to the
oxindole system. No distinction is implied by the ligand (L) as to whether it is an anionic or neutral ligand and indeed L2 could be a combination of such ligands
(scenarios 2 and 3).

J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
9893
Scheme 2. Reduction of compounds 8: (a) BH3$THF (3 mol equiv); (b) oxidation; (c) NaCNBH3, AcOH; (d) KMnO4, NaOH, CH2Cl2 (compounds 9, 10, 11
and 12: R1ZCH3, R2,ZR3ZH).
investigate the reduction reaction employing BH3$THF. A
solution of BH3$THF was added to THF solutions of
compounds 8. The reactions were maintained at room
temperature for 3 h then hydrolyzed. Normal workup of the
hydrolyzed reactions gave the crude products. In the case of
8a, compound 9 could be obtained in up to 92% yield. This
compound was characterized spectroscopically, the vinylic
indole proton signals being observed at 6.43 and 7.07 ppm
as doublets (JZ2.9 Hz). In contrast to 8a, the reduction of
both 8b and 8d with BH3$THF gave a mixture of the
respective 1a/2a and 1c/2c. In the case of the reaction of 8b
the mixture was quantified as being a 7:3 ratio of 1a:2a.
These compounds were unambiguously identified in the 1H
NMR spectrum from the presence of the vinylic indole CH
doublets in 1a (6.50 and 7.07 ppm, JZ2.8 Hz) and the
presence of the two vicinial CH2 triplets in 2a (3.00 and
3.30 ppm, JZ7.8 Hz). The obtention of substantial quan-
tities of compounds 2 (a and c) was unexpected based upon
our previous experience of the reduction of dioxindole
derivatives.23 The mixtures of 1a/2a and 1c/2c could not be
chromatographically separated without substantial losses
and were found to darken when exposed to the atmosphere
at room temperature for any appreciable time. This is most
likely due to oxidation of the samples as both anhydroly-
corine (2a) and assoanine (2c) are known to undergo
autoxidation in the presence of air and acid.19c However, the
obtention of a mixture was not seen as a drawback, but
rather, the mixture could be used to obtain either compounds
1 (XZO) or 2 (XZO), Figure 1. Compounds 1 (XZO)
could, in principle, be obtained by oxidation of either 1
(XZ2H) or 2 (XZ2H), whilst compounds 2 (XZO) could
be obtained by reduction of 1 (XZ2H) to 2 (XZ2H)
followed by oxidation to give 2 (XZO), Figure 1 and
Scheme 2.
NaCNBH3, AcOH, and to directly oxidize crude 10 to give
11 (Scheme 2). When 8a was reduced to 10, in this manner,
and then directly oxidized with oxonew, in a mixture of
water/acetone and NaHCO3, compound 11 was obtained
with a global yield of 30%. The structure of 11 was
confirmed spectroscopically. The introduction of the amide
carbonyl was observed in the IR (1641 cmK1) and in the 13
C
NMR (160.1 ppm) and by the disappearance of the C-7
methylene hydrogens. The presence of the indoline
methylene groups (C4/C5) was confirmed by the two
triplets at 3.38 and 4.47 ppm (JZ8.2 Hz). An accurate mass
measurement of the molecular ion was consistent with that
expected for the structure of 11.
When compound 8b was subjected to the same sequence of
reactions, with the aim of obtaining anhydrolycorin-7-one
(2b), an amorphous colourless solid of relatively high
melting point (227–243 8C) was obtained. It is suspected
that this solid was a mixture of 4,5-dihydropyrrolo-9,10-
methylenedioxyphenanthridinium salts though the solid
could not be properly characterized. Treatment of this
amorphous solid with KMnO4 under basic conditions gave
2b in a global yield (from 8b) of 31%, Scheme 3. However,
when 8b was reduced to 2a then oxidized with KMnO4,
anhydrolycorin-7-one (2b) was obtained in a global yield of
75%. Applying the same three reaction sequence to 8d gave
oxoassoanine (2d) in a global yield of 72%. The spectro-
scopic and melting point data were found to be consistent
with published data.15,19g,41
Having secured the syntheses of anhydrolycorin-7-one (2b)
and oxoassoanine (2d) via the air unstable anhydrolycorine
(2a) and assoanine (2c), a formal synthesis of hippadine
(1b) and pratosine (1d), via oxidation with DDQ, was also
complete.4,15,19d,42 However, with the mixtures of 1a/2a and
1c/2c it was envisaged that a one pot oxidation could lead to
the pyrrolophenanthridinones 1b and 1d. Initially, 9 was
treated with MnO2–SiO2 in refluxing benzene. The volatiles
were removed and the solid residue was chromatographed
resulting in the isolation of 12 in 53% yield (Scheme 2).
Treatment of the mixtures 1a/2a and 1c/2c, in a similar
manner, resulted in the partial oxidation of the mixtures
Compound 9 was reduced with NaCNBH3 in AcOH at room
temperature to give 10 in 54% yield.40 This product readily
decomposed on exposure to the atmosphere but was
1
characterized by H NMR which revealed the presence of
two triplets at 2.98 and 3.32 ppm (JZ7.8 Hz). As a
consequence of the instability of 10 it was decided to try
reducing 8a to give 10, via the sequence (i) BH3$THF, (ii)

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J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
where 1b (35% yield) and 1d (36% yield) were the only
eluted products from the respective reactions. These
products were recrystallized from MeOH before spectro-
scopic analysis. Further elution of the column, in the case of
the synthesis of 1b, using MeOH, resulted in the obtention
of an amorphous solid. This solid was treated with KMnO4
under basic conditions resulting in the obtention of 2b in
21% yield after workup. The products 1b and 1d
gave compatible analyses with those reported in the
literature.15,41,42
and are reported as uncorrected values. Column chroma-
tography was performed using silica gel (70–230 mesh,
Merck). 1H and 13C NMR spectra were recorded using
Bruker (200 and 300 MHz) spectrometers. The PENDANT
pulse sequence was used to distinguish C, CH, CH2 and CH3
in the 13C NMR.50 Mass spectra were obtained by electron
impact (70 eV) on a VG Autospec or Hewlett–Packard (GC-
MS) spectrometers. Infra-red spectra were recorded using a
Perkin–Elmer 1600 FT-IR as KBr discs or films.
3.2. N-Benzylisatins
In conclusion, the natural products 1 (a, b, d) and 2 (a, b, c,
and d) have been prepared in a concise manner from
N-benzylisatin derivatives via a palladium catalyzed
dehydrohalogenation aryl–aryl coupling reaction. The
reaction conditions are based upon those developed by
Jeffery43 for the Heck reaction and permit that the palladium
catalyzed reactions occur under milder conditions than
those originally reported in similar biaryl coupling reac-
tions.44 The cyclization of a meta-substituted N-benzyl-7-
haloisatin derivative resulted in a mixture of regioisomers
and is therefore only a regioselective route to the natural
products or analogues. The syntheses were completed
through the use of combined reduction (BH3$THF and
NaCNBH3) and oxidation (KMnO4) reactions or by
oxidation of the products obtained from the borane
reduction of the respective 8. In the case of 2b and 2d,
global yields of the order of 50% were obtained through a
sequence of seven reactions starting from the respective
isatin 3 and benzyl chloride 4.
A mixture of the respective isatin (10.0 mmol) and K2CO3
(2.00 g, 14.5 mmol) in DMF (10 ml) was stirred with
heating (40–60 8C) for 1 h. To the resulting dark coloured
suspension were added, the benzyl chloride (11.0 mmol)
and KI (0.33 g, 2.0 mmol). Stirring and heating (40–60 8C)
were continued until TLC revealed that the reaction had
completed. The reaction mixture was hydrolysed with
aqueous hydrochloric acid (100 ml, 0.2 mol lK1), extracted
with ethyl acetate (4!20 ml) and dried over anhydrous
sodium sulfate. The solvent was removed under vacuum,
and the residue was purified by filtration through a short
column of silica using CH2Cl2. Recrystallization from ethyl
acetate/hexane (1:1) gave analytically pure samples.
3.2.1. 1-Benzyl-7-iodo-5-methyl-indole-2,3-dione (5a).
Red crystals, 89–94%, mp 145–147 8C. IR (nmax, cmK1):
3052, 2919, 1737, 1612, 1559, 1476, 1436, 1332, 1133, 879,
767, 731. MS (% rel. int.): 377(MC, 54), 320(6), 286(94),
230(14), 193(9), 165(10), 103(28), 91(100). 1H NMR
(300 MHz, CDCl3): d 2.24 (s, 3H, CH3), 5.42 (s, 2H,
CH2-benzyl), 7.18–7.29 (m, 5H, CH-phenyl), 7.42 (d, 1H,
JZ1.6 Hz, H-4), 7.74 (d, 1H, JZ1.6 Hz, H-6). 13C NMR
(75.5 MHz, CDCl3): d 20.1 (CH3), 43.69 (CH2-benzyl), 73.8
(C-7), 120.7 (C), 126.2 (CH), 126.5 (2!CH), 127.6 (CH),
128.9 (2!CH), 136.0 (C), 136.1 (C), 148.8 (C), 151.2 (CH),
159.4 (C-2), 182.9 (C-3). Anal. for C16H12INO2: C 50.95; H
3.21; N 3.71 (calcd); C, 50.91; H, 3.18; N 3.49 (found).
3. Experimental
3.1. General
DMF was used as received or distilled under reduced
pressure. All other solvents were distilled over standard
drying agents under nitrogen before use. 7-Bromo-5-
methylisatin was prepared by bromination of 5-methylisatin
in 95% ethanol with bromine; 7-iodo-5-methylisatin was
prepared by iodination using aqueous KICl2;45 the benzyl
chlorides were prepared by reaction of the respective
benzyl alcohol (2-iodo-4,5-methyenedioxybenzyl alcohol,46
2-bromo-4,5-methyenedioxybenzyl alcohol,47 2-iodo-4,5-
dimethoxybenzyl alcohol48) with SOCl2 in CH2Cl2. MnO2–
3.2.2. 1-(20-Bromo-40,50-methylenedioxybenzyl)-indole-
2,3-dione (5b). Orange crystals, 87–91%, mp 191–192 8C.
IR (nmax, cmK1): 3080, 3057, 2924, 2890, 1746, 1732, 1610,
1498, 1471, 1433, 1365, 1346, 1279, 1244, 1175, 1113,
1
1036, 929, 877, 860, 756. H NMR (200 MHz, CDCl3): d
4.91 (s, 2H, CH2-benzyl), 5.96 (s, 2H, OCH2O), 6.69 (s, 1H,
H-60), 6.81 (d, 1H, JZ7.6 Hz, H-7), 7.04 (s, 1H, H-30), 7.13
(t, 1H, JZ7.6 Hz, H-5), 7.53 (t, 1H, JZ7.6 Hz, H-6), 7.64
(d, 1H, JZ7.6 Hz, H-4). 13C NMR (50.3 MHz, CDCl3): d
44.1 (CH2-benzyl), 102.3 (OCH2O), 108.2 (CH), 111.4
(CH), 113.1 (CH), 113.6 (C), 117.9 (C), 124.3 (CH), 125.7
49
SiO2 was prepared according to the indicated literature
procedure. All other starting materials were obtained from
commercial suppliers and were generally used without
further purification. Melting points were determined on a
Mel-Temp II-Laboratory Devices Inc, capillary apparatus
Scheme 3. Obtention of anhydrolycorinone (2b) and hippadine (1b). (a) BH3$THF (3 mol equiv); (b) NaCNBH3, AcOH; (c) Oxonee, NaHCO3, H2O/acetone;
(d) KMnO4, NaOH, CH2Cl2; (e) MnO2–SiO2, benzene, reflux.

J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
9895
(CH), 126.7 (C), 138.8 (CH), 148.4 (C), 148.6 (C), 150.6
(C), 158.6 (C-2), 183.2 (C-3).
223–225 8C. IR (nmax, cmK1): 3036, 2980, 2957, 2907,
1736, 1623, 1595, 1503, 1482, 1440, 1359, 1340, 1236,
1113, 1035, 930, 864, 837, 780. 1H NMR (200 MHz,
CDCl3): d 2.32 (s, 3H, CH3), 4.94 (s, 2H, CH2-benzyl), 5.95
(s, 2H, OCH2O), 6.68 (s, 1H, H-60), 6.69 (d, 1H, JZ7.6 Hz,
H-7), 7.04 (s, 1H, H-30), 7.33 (d, 1H, JZ7.6 Hz, H-6), 7.45
(s, 1H, H-4). 13C NMR (50.3 MHz, CDCl3): d 20.9 (CH3),
44.1 (CH2-benzyl), 102.2 (OCH2O), 108.2 (CH), 111.2
(CH), 113.1 (CH), 113.5 (C), 117.9 (C), 126.0 (CH), 126.8
(C), 134.2 (C), 139.2 (CH), 148.3 (C), 148.4 (C), 148.5 (C),
158.7 (C-2), 183.4 (C-3).
3.2.3. 1-(20-Iodo-40,50-methylenedioxybenzyl)-indole-2,3-
dione (5c). Orange crystals, 84–92%, mp 191–193 8C. IR
(nmax, cmK1): 3076, 2886, 1746, 1732, 1610, 1495, 1471,
1
1432, 1362, 1347, 1243, 1174, 1035, 927, 756. H NMR
(200 MHz, CDCl3): d 4.91 (s, 2H, CH2-benzyl), 5.95 (s, 2H,
OCH2O), 6.65 (s, 1H, H-60), 6.74 (d, 1H, JZ7.5 Hz, H-7),
7.14 (t, 1H, JZ7.5 Hz, H-5), 7.29 (s, 1H, H-30), 7.52 (t, 1H,
JZ7.5 Hz, H-6), 7.64 (d, 1H, JZ7.5 Hz, H-4). 13C NMR
(50.3 MHz, CDCl3): d 49.2 (CH2-benzyl); 85.9 (C-20),
102.2 (OCH2O), 107.7 (CH), 111.7 (CH), 117.9 (C), 119.1
(CH), 124.4 (CH), 125.7 (CH), 129.6 (C), 138.8 (CH), 148.6
(C), 149.4 (C), 150.6 (C), 158.6 (C-2), 183.1 (C-3). Anal. for
C16H10INO4: C, 47.20; H, 2.48; N, 3.44 (calcd); C, 46.97;
H, 2.54; N, 3.27 (found).
3.3. N-Benzylisatin ethylenedioxy ketals
The appropriate N-benzylisatin (10.0 mmol), ethylene-
glycol (10 ml), p-toluenesulfonic acid (a few crystals) and
toluene (30 ml) were refluxed (z5 h) with azeotropic
removal of water until TLC revealed complete reaction.
3.2.4. 1-(20-Iodo-40,50-dimethoxybenzyl)-indole-2,3-dione
On complete reaction the solvent was removed under
vacuum, and the residue was treated with aqueous sodium
bicarbonate (5%, 30 ml) and extracted with ethyl acetate
(4!15 ml). The organic phase was dried with anhydrous
sodium sulfate, the solvent removed under reduced pressure
and the crude product purified by silica gel column
chromatography using CH2Cl2 as eluent. The products
were recrystallized from ethyl acetate/hexane (1:4).
(5d). Orange crystals, 90–92%, 173–174 8C. IR (nmax
,
cmK1): 3079, 2997, 2941, 2837, 1740, 1614, 1504, 1469,
1443, 1345, 1251, 1213, 1162, 1023, 873, 752. MS (% rel.
1
int.): 423(MC, 7), 296(100), 277(50). H NMR (300 MHz,
CDCl3): d 3.72 (s, 3H, CH3O), 3.87 (s, 3H, CH3O), 4.95 (s,
2H; CH2-benzyl), 6.70 (s, 1H, H-50), 6.82 (d, 1H, JZ7.5 Hz,
H-7), 7.15 (t, 1H, JZ7.5 Hz, H-5), 7.27 (s, 1H, H-20), 7.51
(t, 1H, JZ7.5 Hz, H-6), 7.63 (d, 1H, JZ7.5 Hz, H-4). 13C
NMR (50.3 MHz, CDCl3): d 49.1 (CH2-benzyl), 56.2
(CH3O), 56.4 (CH3O), 86.4 (C-20), 110.8 (CH), 112.0
(CH), 117.9 (C), 121.9 (CH), 124.3 (CH), 125.6 (CH), 128.9
(C), 138.8 (CH), 149.7 (C), 150.3 (C), 150.7 (C), 158.7
(C-2), 183.2 (C-3). Anal. for C17H14INO4: C, 48.25; H,
3.33; N, 3.31 (calcd); C, 48.15; H, 3.39; N, 3.42 (found).
3.3.1. 1-Benzyl-3,3-ethylenedioxy-7-iodo-5-methyl-
indole-2-one (6a). Colourless crystals, 84–94%, 146–
147 8C. IR (nmax, cmK1): 3085, 3058, 3030, 2970, 2946,
2905, 1737, 1623, 1567, 1471, 1438, 1414, 1299, 1154,
1038, 999, 945, 866, 725. MS (% rel. int.): 421(MC, 25),
1
330(100), 286(37), 91(63). H NMR (300 MHz, CDCl3): d
3.2.5.
7-Bromo-1-(30,40-methylenedioxybenzyl)-5-
2.24 (s, 3H, CH3), 4.31–4.39 (m, 2H, ketal), 4.54–4.62 (m,
2H, ketal), 5.33 (s, 2H, CH2-benzyl), 7.15–7.32 (m, 6H, H-4
and 5!CH-phenyl), 7.54 (s, 1H, C-6). 13C NMR
(75.5 MHz, CDCl3): d 20.3 (CH3), 43.3 (CH2-benzyl),
66.2 (2!CH2-ketal), 72.4 (C-7), 101.1 (C-3), 126.0 (CH),
126.4 (2!CH), 127.2 (CH), 128.8 (2!CH), 135.3 (C),
136.8 (C), 142.1 (C), 144.5 (CH), 174.6 (C-2).
methyl-indole-2,3-dione (5e). Orange crystals, 85%, mp
157–159 8C. IR (nmax, cmK1): 3061, 2929, 2884, 2790,
1741, 1731, 1619, 1571, 1503, 1480, 1448, 1326, 1248,
1158, 1135, 1037, 928, 816, 801. MS (% rel. int.): 375/
373(MC, 20/21), 240/238(28), 135(100). 1H NMR
(200 MHz, CDCl3): d 2.31 (s, 3H, CH3), 5.31 (s, 2H,
CH2-benzyl), 5.94 (s, 2H, OCH2O), 6.75 (m, 3H, H-20, H-50
and H-60), 7.43 (s, 1H, H-4), 7.49 (s, 1H, H-6). 13C NMR
(50.3 MHz, CDCl3): d 20.3 (CH3), 44.4 (CH2-benzyl), 101.3
(OCH2O), 104.2 (C-7), 107.5 (CH), 108.6 (CH), 120.2
(CH), 121.0(C), 125.6(CH), 130.0(C), 135.8(C),144.3(CH),
145.5 (C), 147.3 (C), 148.2 (C), 159.3 (C-2), 182.7 (C-3).
3.3.2. 1-(20-Bromo-40,50-methylenedioxybenzyl)-3,3-
ethylenedioxy-indole-2-one (6b). Colourless crystals,
82%, mp 175–177 8C. IR (nmax, cmK1): 3108, 3050, 2979,
2910, 1734, 1621, 1499, 1481, 1468, 1424, 1366, 1321,
1243, 1185, 1131, 1043, 959, 933, 872, 831, 750. 1H NMR
(200 MHz, CDCl3): d 4.32–4.44 (m, 2H, ketal), 4.55–4.67
(m, 2H, ketal), 4.83 (s, 2H, CH2-benzyl), 5.92 (s, 2H,
OCH2O), 6.62 (s, 1H, H-60), 6.67 (d, 1H, JZ7.5 Hz, H-7),
7.02 (s, 1H, H-30), 7.08 (dt, 1H, JZ1.2, 7.5 Hz, H-5), 7.29
(dt, 1H, JZ1.2, 7.5 Hz, H-6), 7.40 (dd, 1H, JZ1.2, 7.5 Hz,
H-4). 13C NMR (50.3 MHz, CDCl3): d 43.4 (CH2-benzyl),
66.1 (2!CH2-ketal), 102.0 (OCH2O), 102.4 (C-3), 108.0
(CH), 109.9 (CH), 112.9 (CH), 113.3 (C), 123.8 (CH), 124.1
(C), 125.1 (CH), 127.4 (C), 131.9 (CH), 143.6 (C), 148.1
(C), 148.2 (C), 173.8 (C-2).
3.2.6. 7-Iodo-1-(30,40-methylenedioxybenzyl)-5-methyl-
indole-2,3-dione (5f). Orange Crystals, 83%, 165–166 8C.
IR (nmax, cmK1): 3059, 2925, 2883, 2789, 1731, 1616, 1502,
1478, 1446, 1326, 1247, 1155, 1137, 1037, 928, 808, 711.
1H NMR (300 MHz, CDCl3): d 2.28 (s, 3H, CH3), 5.36 (s,
2H, CH2-benzyl), 5.94 (s, 2H, OCH2O), 6.69–6.77 (m, 3H,
H-20, H-50 and H-60), 7.46 (s, 1H, H-4), 7.79 (s, 1H, H-6).
13C NMR (75.5 MHz, CDCl3): d 20.1 (CH3), 43.3 (CH2-
benzyl), 73.8 (C-7), 101.3 (OCH2O), 107.3 (CH), 108.6
(CH), 120.0 (CH), 120.8 (C), 126.3 (CH), 129.7 (C), 136.0
(C), 147.2 (C), 148.2 (C), 148.7 (C), 151.2 (CH), 159.4
(C-2), 182.7 (C-3).
3.3.3.
1-(20-Iodo-40,50-methylenedioxybenzyl)-3,3-
ethylenedioxy-indole-2-one (6c). Colourless crystals, 88–
95%, mp 191–193 8C. IR (nmax, cmK1): 3095, 3043, 2975,
2906, 1731, 1622, 1497, 1478, 1467, 1422, 1362, 1247,
1185, 1129, 1044, 960, 931, 750. 1H NMR (300 MHz,
3.2.7.
methyl-indole-2,3-dione (5g). Orange crystals, 74%, mp
1-(20-Bromo-40,50-methylenedioxybenzyl)-5-

9896
J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
CDCl3): d 4.33–4.45 (m, 2H, ketal), 4.55–4.67 (m, 2H,
ketal), 4.77 (s, 2H, CH2-benzyl), 5.92 (s, 2H, OCH2O), 6.59
(s, 1H, H-60), 6.62 (d, 1H, JZ7.6 Hz, H-7), 7.09 (t, 1H,
JZ7.6 Hz, H-5), 7.27 (s, 1H, H-30), 7.29 (t, 1H, JZ7.6 Hz,
H-6), 7.40 (d, 1H, JZ7.6 Hz, H-4). 13C NMR (50.3 MHz,
CDCl3): d 48.6 (CH2-benzyl), 66.1 (2!CH2-ketal), 85.6
(C-20), 102.0 (OCH2O), 102.5 (C-3), 107.7 (CH), 110.2
(CH), 118.9 (CH), 123.8 (CH), 124.1 (C), 125.1 (CH), 130.4
(C), 132.0 (CH), 143.6 (C), 148.3 (C), 149.3 (C), 173.7
(C-2). Anal. for C18H14INO5: C, 47.91; H, 3.13; N, 3.10
(calcd); C, 48.23; H, 3.31; N, 3.23 (found).
crystals, 89%, mp 218–220 8C. IR (nmax, cmK1): 3073,
2964, 2904, 1733, 1635, 1605, 1500, 1484, 1429, 1359,
1300, 1273, 1239, 1181, 1112, 1036, 998, 932, 853, 821,
736. MS (% rel. int.): 419/417(MC, 1/1), 338(86), 238(23),
215(14), 204(100), 160(47), 104(16), 77(12). 1H NMR
(300 MHz, CDCl3): d 2.30 (s, 3H, CH3), 4.34–4.37 (m, 2H,
ketal), 4.60–4.63 (m, 2H, ketal), 4.81 (s, 2H, CH2-benzyl),
5.92 (s, 2H, OCH2O), 6.55 (d, 1H, JZ8.0 Hz, H-7), 6.60 (s,
1H, H-60), 7.01 (s, 1H, H-30), 7.08 (dd, 1H, JZ1.0, 8.0 Hz,
H-6), 7.22 (d, 1H, JZ1.0 Hz, H-4). 13C NMR (75.5 MHz,
CDCl3): d 21.1 (CH3), 43.5 (CH2-benzyl), 66.1 (2!CH2-
ketal), 102.1 (OCH2O), 102.6 (C-3), 108.0 (CH), 109.8
(CH), 112.9 (CH), 113.3 (C), 124.0 (C), 125.8, 127.6, 132.2,
133.6, 141.2 (C-7a), 148.1 (C), 148.2 (C), 173.8 (C-2). Anal.
for C19H16BrNO5: C, 54.56; H, 3.86; N, 3.35 (calcd); C,
54.80; H, 4.01; N, 3.46 (found).
3.3.4. 1-(20-Iodo-40,50-dimethoxybenzyl)-3,3-ethylene-
dioxy-indole-2-one (6d). Colourless crystals, 93–94%, mp
130–131 8C. IR (nmax, cmK1): 3088, 2966, 2906, 2842,
1721, 1617, 1507, 1464, 1445, 1372, 1250, 1211, 1161,
1126, 1022, 946, 865, 762. MS (% rel. int.): 467(MC, 2),
1
340(100), 277(22), 190(73), 146(37). H NMR (300 MHz,
3.4. Palladium catalysed coupling reactions
CDCl3): d 3.67 (s, 3H, CH3O), 3.85 (s, 3H, CH3O), 4.34–
4.38 (m, 2H, ketal), 4.61–4.66 (m, 2H, ketal), 4.81 (s, 2H,
CH2-benzyl), 6.59 (s, 1H, H-60), 6.65 (d, 1H, JZ7.6 Hz,
H-7), 7.10 (t, 1H, JZ7.6 Hz, H-5), 7.23 (s, 1H, H-30), 7.25
(t, 1H, JZ7.6 Hz, H-6), 7.39 (d, 1H, JZ7.6 Hz, H-4). 13C
NMR (50.3 MHz, CDCl3): d 48.2 (CH2-benzyl), 56.0
(CH3O), 56.4 (CH3O), 66.1 (2!CH2-ketal), 85.8 (C-20),
102.6 (C-3), 110.3 (2!CH), 121.8, 123.8, 124.1, 125.0,
129.6, 131.9, 143.6 (C), 149.2 (C), 150.1 (C), 173.9 (C-2).
The appropriate N-benzylisatin ketal (1.0 mmol), Pd(OAc)2
(23.0 mg, 0.1 mmol), Bu4NBr (322 mg, 1.1 mmol), KOAc
(490.0 mg, 5.0 mmol) and DMF (10 ml) were heated on an
oil bath (100 8C, bath temp) in a round bottom flask and the
reaction accompanied by TLC. On complete reaction,
distilled water (50 ml) was added to the reaction mixture
which was then extracted with ethyl acetate (4!15 ml). The
organic phase was dried with anhydrous sodium sulfate and
the solvent was removed under reduced pressure. The
residue was chromatographed on a silica gel column using
hexane/ethyl acetate (4:1) as eluent. Products could be
recrystallized from MeOH/H2O.
3.3.5. 7-Bromo-3,3-ethylenedioxy-1-(30,40-methylene-
dioxybenzyl)-5-methyl-indole-2-one (6e). Colourless
crystals, 98%, mp 115–116 8C. IR (nmax, cmK1): 2974,
2901, 1732, 1625, 1500, 1479, 1444, 1304, 1244, 1156,
1039, 1000, 942, 916, 858, 798. MS (% rel. int.): 419/
417(MC, 14/15), 284/282(100/98), 238/240(35), 135(91),
103(18), 77(41). 1H NMR (300 MHz, CDCl3): d 2.26 (s, 3H,
CH3), 4.22–4.38 (m, 2H, ketal), 4.53–4.64 (m, 2H, ketal),
5.18 (s, 2H, CH2-benzyl), 5.90 (s, 2H, OCH2O), 6.66–6.74
(m, 3H, H-20, H-50, H-60), 7.16 (s, 1H, H-4), 7.24 (s, 1H,
H-6). 13C NMR (75.5 MHz, CDCl3): d 20.5 (CH3), 43.9
(CH2-benzyl), 66.2 (2!CH2-ketal), 101.4 (C-3), 102.8 (C
and OCH2O), 107.3 (CH), 108.5 (CH), 119.8 (CH), 125.2
(CH), 127.4 (C), 130.8 (C), 135.1 (C), 137.5 (CH), 138.9
(C), 146.9 (C) 148.0 (C), 174.4 (C-2).
3.4.1. 4,4-Ethylenedioxy-6,7-dihydro-2-methyl-pyr-
rolo[3,2,1-de]phenanthridin-5-one (7a). White crystals,
96–98%, 191–193 8C. IR (nmax, cmK1): 3058, 2975, 2954,
2889, 1719, 1636, 1500, 1449, 1349, 1268, 1204, 1054,
1029, 1000, 949, 864, 774, 741. MS (% rel. int.): 293(MC,
33), 264(100), 220(29), 193(27), 192(22), 165(17), 110(31),
96(29), 82(28). 1H NMR (300 MHz, CDCl3): d 2.35 (s, 3H,
CH3), 4.29–4.34 (m, 2H, ketal), 4.57–4.61 (m, 2H, ketal),
4.91 (s, 2H, H-7), 7.07 (s, 1H, H-3), 7.12 (d, 1H, JZ7.3 Hz,
H-8), 7.23 (t, 1H, JZ7.3 Hz, H-9), 7.29 (t, 1H, JZ7.3 Hz,
H-10), 7.45 (s, 1H, H-1), 7.70 (d, 1H, JZ7.3 Hz, H-11). 13C
NMR (75.5 MHz, CDCl3): d 21.6 (CH3), 42.4 (CH2-
benzyl), 66.0 (2!CH2-ketal), 103.4 (C), 117.2 (C), 122.4
(CH), 122.7 (C), 124.6 (CH), 125.1 (CH), 127.8 (CH), 128.1
(CH), 128.3 (C), 128.5 (CH), 128.9 (C), 133.3 (C), 137.1
(C), 172.9 (C-5). Anal. for C18H15NO3: C 73.71, H 5.15, N
4.76 (calcd); C 73.23, H 5.04, N 4.62 (found).
3.3.6. 3,3-Ethylenedioxy-7-iodo-1-(30,40-methylenedioxy-
benzyl)-5-methyl-indole-2-one (6f). Colourless crystals,
90–92%, mp 129–131 8C. IR (nmax, cmK1): 2970, 2944,
2891, 1733, 1619, 1492, 1473, 1437, 1328, 1243, 1154,
1037, 1001, 948, 854, 813, 737. MS (% rel. int.): 465(MC,
13), 330(100), 286(30), 135(39), 77(14). 1H NMR
(300 MHz, CDCl3): d 2.25 (s, 3H, CH3), 4.31–4.36 (m,
2H, ketal), 4.57–4.62 (m, 2H, ketal), 5.23 (s, 2H, CH2-
benzyl), 5.92 (s, 2H, OCH2O), 6.64 (d, 1H, JZ8.0 Hz,
H-50), 6.69 (s, 1H, H-20), 6.74 (d, 1H, JZ8.0 Hz, H-60), 7.20
(d, 1H, JZ1.0 Hz, H-6), 7.56 (d, 1H, JZ1.0 Hz, H-6). 13C
NMR (75.5 MHz, CDCl3): d 20.3 (CH3), 43.0 (CH2-
benzyl), 66.1(2!CH2-ketal), 72.4 (C-7), 101.1 (C-3),
101.2 (OCH2O), 107.2 (CH), 108.5 (CH), 119.6 (CH),
126.0 (CH), 127.2 (C), 130.5 (C), 135.3 (C), 142.0 (C),
144.5 (CH), 146.8 (C), 148.1 (C), 174.6 (C-2).
3.4.2. 4,4-Ethylenedioxy-6,7-dihydro-9,10-methylene-
dioxy-pyrrolo[3,2,1-de]phenanthridin-5-one (7b). White
crystals, 69–95%, 226–228 8C (decomp.). IR (nmax, cmK1):
3047, 2969, 2900, 1716, 1638, 1508, 1475, 1369, 1238,
1188, 1153, 1042, 1020, 939, 885, 787, 744. MS (% rel.
int.): 323(MC, 42), 294(100), 250(37), 223(27), 222(18),
164(23), 138(14), 124(30), 110(14), 96(43), 82(39), 69(25).
1H NMR (300 MHz, CDCl3): d 4.31–4.39 (m, 2H, ketal),
4.54–4.61 (m, 2H, ketal), 4.88 (s, 2H, H-7), 6.00 (s, 2H,
OCH2O), 6.61 (s, 1H, H-8), 7.03 (t, 1H, JZ7.6 Hz, H-2),
7.18 (s, 1H, H-11), 7.19 (d, 1H, JZ7.6 Hz, H-3), 7.49 (d,
1H, JZ7.6 Hz, H-1). 13C NMR (75.5 MHz, CDCl3): d 42.9
(CH2-benzyl), 66.0 (2!CH2-ketal), 101.8 (OCH2O), 102.9
3.3.7. 1-(20-Bromo-40,50-methylenedioxybenzyl)-3,3-
ethylenedioxy-5-methyl-indole-2-one (6g). Colourless

J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
9897
(CH), 103.5 (C), 107.8 (CH), 117.8 (C), 122.3 (C), 122.6
(C), 122.7 (C), 123.7 (CH), 123.80 (CH), 123.85 (CH),
139.0 (C), 148.1 (C), 148.3 (C), 173.1 (C-5). HRMS for
C18H13NO5: 323.0794 (calcd); 323.0796 (found).
(6 mol lK1, 10.0 ml) were heated at reflux for 5 h. The THF
was removed under reduced pressure resulting in the
precipitation of red crystals. These were removed by
filtration, washed with distilled water and air dried.
3.4.3. 4,4-Ethylenedioxy-6,7-dihydro-9,10-dimethoxy-
pyrrolo[3,2,1-de]phenanthridin-5-one (7d). White
crystals, 81–87%, mp 188–190 8C. IR (nmax, cmK1): 3067,
2966, 2909, 2839, 1719, 1635, 1613, 1531, 1467, 1407,
1358, 1255, 1217, 1185, 1149, 1048, 1002, 940, 854, 780,
737. MS (% rel. int.): 339(MC, 42), 310(100), 266(21),
239(28). 1H NMR (300 MHz, CDCl3): d 3.89 (s, 3H,
CH3O), 3.95 (s, 3H, CH3O), 4.31–4.39 (m, 2H, ketal), 4.54–
4.65 (m, 2H, ketal), 4.88 (s, 2H, H-7), 6.60 (s, 1H, H-8), 7.03
(t, 1H, JZ7.5 Hz, H-2), 7.16 (s, 1H, H-11), 7.18 (d, 1H,
JZ7.5 Hz, H-3), 7.53 (d, 1H, JZ7.5 Hz, H-1). 13C NMR
(75.5 MHz, CDCl3): d 42.4 (C-7), 56.20 and 56.21(2!
CH3O), 66.0 (2!CH2-ketal), 103.4 (C), 105.4 (CH), 110.3
(C-H), 117.8 (C), 120.8 (C), 121.4 (C) 122.6 (C), 123.5
(CH), 123.6 (CH), 123.7 (CH), 139.0 (C), 148.9 (C), 149.6
(C), 173.1 (C-5). HRMS for C19H17NO5: 339.1107 (calcd);
339.1107 (found).
3.5.1. 6,7-Dihydro-2-methyl-pyrrolo[3,2,1-de]phenan-
thridin-4,5-dione (8a). Dark red crystals, 94–96%, mp
237–238 8C. IR (nmax, cmK1): 3059, 2920, 2862, 1731,
1626, 1491, 1355, 1305, 1122, 767. MS (% rel. int.):
249(MC, 47), 220(100), 193(34), 192(35), 165(27),
1
110(21), 95(41). H NMR (300 MHz, CDCl3): d 2.36 (s,
3H, CH3), 5.01 (s, 2H, H-7), 7.15 (d, 1H, JZ7.2 Hz, H-8),
7.22 (s, 1H, H-3), 7.31 (td, 1H, JZ1.3, 7.2 Hz, H-9), 7.36 (t,
1H, JZ7.2 Hz, H-10), 7.67 (s, 1H, H-1), 7.74 (dd, 1H,
1
JZ1.3, 7.2 Hz, H-11). H NMR (300 MHz, DMSO-d6): d
2.30 (s, 3H, CH3), 4.94 (s, 2H, H-7), 7.22 (s, 1H, H-3), 7.29–
7.36 (m, 3H, H-8, H-9 and H-10), 7.93 (d, 1H, JZ7.8 Hz,
H-11), 7.95 (s, 1H, H-1). 13C NMR (50.3 MHz, DMSO-d6):
d 21.0 (CH3), 42.3 (C-7), 116.7 (C), 118.2 (C), 123.1 (CH),
124.5 (CH), 127.2 (C), 128.4 (CH), 128.6 (CH), 129.4 (CH),
129.5 (C), 131.3 (CH), 133.3 (C), 144.9 (C), 158.2 (C-5),
183.7 (C-4). Anal. for C16H11NO2: C 77.10, H 4.45, N 5.62
(calcd.); C 77.19, H 4.41, N 5.71 (found).
3.4.4. 4,4-Ethylenedioxy-6,7-dihydro-2-methyl-9,10-
methylenedioxy-pyrrolo[3,2,1-de]phenanthridin-5-one
(7e). White crystals, 24–43%, 243–245 8C. IR (nmax, cmK1):
3064, 2972, 2905, 2856, 1713, 1640, 1501, 1470, 1391,
1363, 1239, 1199, 1154, 1052, 1031, 997, 946, 931, 864,
848, 830, 748. MS (% rel. int.): 337(MC, 34), 308(100),
3.5.2. 6,7-Dihydro-9,10-methylenedioxy-pyrrolo[3,2,1-
de]phenanthridin-4,5-dione (8b). Dark red crystals, 92%,
mp 235–237 8C. IR (nmax, cmK1): 3053, 2919, 2852, 2780,
1732, 1632, 1598, 1507, 1476, 1426, 1388, 1356, 1308,
1239, 1201, 1036, 1020, 927, 867, 775. MS (% rel. int.):
279(MC, 53), 250(100), 223(25), 164(15). 1H NMR
(200 MHz, Acetone-d6): d 5.00 (s, 2H, H-7), 6.09 (s, 2H,
OCH2O), 6.90 (s, 1H, H-8), 7.11 (t, 1H, JZ7.7 Hz, H-2),
7.35 (d, 1H, JZ7.7 Hz, H-3), 7.48 (s, 1H, H-11), 7.99 (d,
1H, JZ7.7 Hz, H-1). 1H NMR (200 MHz, CD3CN): d 5.48
(s, 2H, H-7), 6.58 (s, 2H, OCH2O), 7.33 (s, 1H, H-8), 7.63 (t,
1H, JZ7.6 Hz, H-2), 7.90 (d, 1H, JZ7.6 Hz, H-3), 7.91 (s,
1H, H-11), 8.40 (d, 1H, JZ7.6 Hz, H-1). 1H NMR
(200 MHz, DMSO-d6): d 4.89 (s, 2H, H-7), 6.08 (s, 2H,
OCH2O), 6.94 (s, 1H, H-8), 7.04 (t, 1H, JZ7.6 Hz, H-2),
7.33 (d, 1H, JZ7.6 Hz, H-3), 7.58 (s, 1H, H-11), 8.01 (d,
1H, JZ7.6 Hz, H-1). 13C NMR (50.3 MHz, DMSO-d6): d
42.6 (C-7), 102.1 (OCH2O), 103.5 (CH), 108.4 (CH), 116.5
(C), 118.8 (C), 121.2 (C), 123.3 (CH), 123.6 (C), 123.8
(CH), 130.5 (CH), 146.5 (C), 148.1 (C), 148.5 (C), 158.3
(C-5), 183.6 (C-4). HRMS for C16H9NO4: 279.0532 (calcd);
279.0532 (found).
1
264(24), 237(26), 131(16), 103(13). H NMR (200 MHz,
CDCl3/DMSO-d6): d 2.27 (s, 3H, CH3), 4.20–4.26 (m, 2H,
ketal), 4.42–4.49 (m, 2H, ketal), 4.77 (s, 2H, H-7), 5.93 (s,
2H, OCH2O), 6.56 (s, 1H, H-8), 6.93 (s, 1H, H-3), 7.14 (s,
1H, H-1), 7.52 (s, 1H, H-11). 13C NMR (50.3 MHz, CDCl3/
DMSO-d6): d 20.8 (CH3), 42.0 (C-7), 65.2 (2!CH2-ketal),
101.0 (OCH2O), 102.0 (CH), 102.9 (C), 107.0 (CH), 116.7
(C), 121.5 (C), 121.8 (C), 122.0 (C), 123.4 (CH), 123.5
(CH), 132.5 (C), 147.4 (C), 147.5 (C), 172.1 (C-5). Anal. for
C19H15NO5: C 67.65, H 4.48, N 4.15 (calcd.); C 67.59, H
4.53, N 4.27 (found).
3.4.5. 4,4-Ethylenedioxy-6,7-dihydro-2-methyl-10,11-
methylenedioxy-pyrrolo[3,2,1-de]phenanthridin-5-one
(7e0). White crystals, 74%, 217–219 8C. IR (nmax, cmK1):
3032, 2968, 2904, 1724, 1635, 1506, 1494, 1463, 1442,
1366, 1272, 1247, 1198, 1111, 1064, 1022, 948, 927, 869,
794, 711. MS (% rel. int.): 337(MC, 28), 308(100), 264(25),
1
237(21). H NMR (200 MHz, DMSO-d6): d 2.31 (s, 3H,
3.5.3. 6,7-Dihydro-9,10-dimethoxy-pyrrolo[3,2,1-de]-
phenanthridin-4,5-dione (8d). Dark red crystals, 86–
92%, mp 240–242 8C. IR (nmax, cmK1): 3028, 2989, 2924,
2856, 1743, 1726, 1625, 1610, 1525, 1465, 1444, 1359,
1259, 1219, 1147, 1057, 976, 861, 779, 754, 742. MS (% rel.
int.): 295(MC, 89), 266(100), 239(24), 213(16), 196(10),
153(14), 127(14). 1H NMR (300 MHz, CDCl3/DMSO-d6): d
3.88 (s, 3H, OCH3), 3.94 (s, 3H, OCH3), 4.99 (s, 2H, H-7),
6.71 (s, 1H, H-8), 7.07 (t, 1H, JZ7.7 Hz, H-2), 7.26 (s, 1H,
H-11), 7.32 (d, 1H, JZ7.7 Hz, H-3), 7.85 (d, 1H, JZ7.7 Hz,
H-1). 1H NMR (200 MHz, DMSO-d6): d 3.78 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 4.90 (s, 2H, H-7), 6.94 (s, 1H,
H-8), 7.06 (t, 1H, JZ7.5 Hz, H-3), 7.33 (d, 1H, JZ7.5 Hz,
H-3), 7.46 (s, 1H, H-11), 8.10 (d, 1H, JZ7.5 Hz, H-1). 13C
NMR (50.3 MHz, DMSO-d6): d 42.2 (C-7), 56.1 (OCH3),
56.3 (OCH3), 106.6 (CH), 111.5 (CH), 116.5 (C), 119.0 (C),
CH3), 4.25–4.31 (m, 2H, ketal), 4.36–4.42 (m, 2H, ketal),
4.81 (s, 2H, H-7), 6.18 (s, 2H, OCH2O), 6.80 (d, 1H;
JZ8.0 Hz, H-8), 6.89 (d; 1H; JZ8.0 Hz, H-9), 7.14 (s, 1H,
H-3), 7.74 (s, 1H, H-1). 13C NMR (50.3 MHz, DMSO-d6): d
21.6 (CH3), 42.7 (C-7), 66.2 (2!CH2-ketal), 102.3, 103.2,
108.7, 112.0, 115.1, 121.4, 123.1, 123.6, 125.5, 128.4,
133.2, 137.0, 144.7, 147.6, 172.6 (C-5). Anal. for
C19H15NO5: C 67.65, H 4.48, N 4.15 (calcd.); C 67.59, H
4.53, N 4.27 (found).
3.5. 6,7-Dihydro-pyrrolo[3,2,1-de]phenanthridin-4,5-
diones
4,4-Ethylenedioxy-6,7-dihydro-pyrrolo[3,2,1-de]phenan-
thridin-5-ones (3 mmol), THF (10.0 ml) and aqueous HCl

9898
J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
119.5 (C), 121.8 (C), 123.0 (CH), 123.7 (CH), 130.5 (CH),
146.5 (C), 149.1 (C), 150.1 (C), 158.3 (C-5), 183.7 (C-4).
Anal. for C17H13NO4: C 69.15, H 4.44, N 4.74 (calcd.); C
69.11, H 4.46, N 4.81 (found).
mixture was stirred at room temperature. After 3 h, the
mixture was cooled on an ice bath, neutralized with aqueous
NaOH (10%) and extracted with dichloromethane
(4!15 ml).
The solvent was removed under reduced pressure, NaHCO3
(252.0 mg, 3 mmol) and acetone (3.0 ml) were added.
Oxonew (650.0 mg, 1.0 mmol) was slowly added to the
mixture and stirred to room temperature. After 30 min,
isopropanol (1 ml) was added, and solvent was removed
under vacuum. The residue was chromatographed on silica
gel column using heptane/dichloromethane (1:1) as eluent
and the product recrystallized from methanol/water (1:1).
3.6. Alkaloids
3.6.1. Reduction with BH3–THF. The appropriate pyr-
rolophenanthridin-4,5-dione (1.0 mmol) was dissolved in
anhydrous THF (5 ml) and cooled on an ice water bath
under a slowly flowing nitrogen atmosphere. A solution of
BH3$THF (1 mol lK1, 3.0 mmol) was added dropwise by
syringe to the stirred reaction. The reaction was
monitored by TLC and on complete reaction aqueous HCl
(3.0 mol lK1, 3 ml) was added dropwise. The mixture was
subsequently neutralized with aqueous NaOH (10%),
saturated aqueous NaCl was added and the mixture
extracted with CH2Cl2(3!15 ml). The organic phase was
further washed with water (1!15 ml), dried over Na2SO4
and the solvent removed under reduced pressure. The crude
product was chromatographed on a silica gel column using
dichloromethane/hexane (2:1) as eluent.
3.6.3.1. 4,5-Dihydro-2-methyl-pyrrolo[3,2,1-de]-
phenanthridin-7-one (11). White crystals, 32%, mp 197–
200 8C. IR (nmax, cmK1): 3069, 3030, 2964, 2915, 2856,
1641, 1624, 1600, 1504, 1366, 1344, 1287, 1181, 1032, 888,
854, 766, 722, 689. MS (% rel. int.): 235(MC, 100),
1
234(99), 219(20). H NMR (300 MHz, CDCl3): d 2.47 (s,
3H, CH3), 3.38 (t, 2H, JZ8.2 Hz, H-4), 4.47 (t, 1H,
JZ8.2 Hz, H-5), 7.15 (s, 1H, H-3), 7.57 (td, 1H, JZ1.0,
7.8 Hz, H-10), 7.70 (s, 1H, H-1), 7.74 (td, 1H, JZ1.0,
7.8 Hz, H-9), 8.18 (d, 1H, JZ7.8 Hz, H-8), 8.54 (dd, 1H,
JZ1.0, 7.8 Hz, H-11). 13C NMR (75.5 MHz, CDCl3): d
21.9 (CH3), 27.5 (C-4), 46.8 (C-5), 116.6 (C), 120.0 (CH),
122.2 (CH), 126.0 (CH), 127.6 (C), 127.9 (CH), 128.6 (CH),
131.0 (C), 132.1 (CH), 133.3 (C), 134.0 (C), 138.0 (C),
160.1 (C-7). HRMS for C16H13NO: 235.0997 (calcd);
235.0994 (found).
3.6.1.1. 6,7-Dihydro-2-methyl-pyrrolo[3,2,1-de]-
phenanthridine (9). White crystals, 90–92%, mp 135–
137 8C. IR (nmax, cmK1): 3099, 3031, 2919, 2857, 1508,
1451, 1385, 1329, 1271, 1210, 854, 778, 755, 714. MS (%
rel. int.): 219(MC, 54), 218(100), 108(23). 1H NMR
(300 MHz, CDCl3): d 2.47 (s, 3H, CH3), 5.50 (s, 2H,
H-7), 6.43 (d, 1H, JZ2.9 Hz, H-4), 7.07 (d, 1H, JZ2.9 Hz,
H-5), 7.14 (d, 1H, JZ7.5 Hz, H-8), 7.21–7.32 (m, 4H, H-1,
H-3, H-9, H-10), 7.89 (d, 1H, JZ7.5 Hz, H-11). 13C NMR
(75.5 MHz, CDCl3): d 22.1 (CH3), 48.0 (C-7), 102.0 (CH),
115.4 (CH), 118.1 (C), 120.4 (CH), 122.8 (CH), 126.2 (CH),
126.4 (C), 127.4 (CH), 127.8 (CH), 127.9 (CH), 129.7 (C),
130.3 (C), 130.5 (C), 132.2 (C). HRMS for C16H13N:
219.1048 (calcd); 219.1050 (found).
3.6.4. Reduction with NaCNBH3 and subsequent oxi-
dation with KMnO4. To the crude product (w1 mmol)
from the BH3$THF reduction reaction was added
NaCNBH3 (189.0 mg, 3.0 mmol) and the mixture was
cooled to 10 8C. Acetic acid (3 ml) was added dropwise and
the mixture was stirred at room temperature. After 3 h, the
mixture was cooled on an ice bath, neutralized with
aqueous NaOH (10%) and extracted with dichloromethane
(4!15 ml).
3.6.2. Reduction with NaCNBH3–AcOH. To the crude
product (w1 mmol) from the BH3$THF reduction reaction
was added NaCNBH3 (189.0 mg, 3 mmol) and the mixture
was cooled to 10 8C. Acetic acid (3 ml) was added dropwise
and the mixture was stirred at room temperature. After 3 h,
the mixture was cooled on an ice bath, neutralized with
aqueous NaOH (10%) and extracted with dichloromethane
(4!15 ml). Evaporation of the solvent under reduced
pressure gave the crude product. This was quickly filtered
through a short column of silica eluting with CH2Cl2.
Evaporation of the solvent gave the product.
The organic phase was concentrated (w10 ml), aqueous
NaOH (3 mol lK1, 10 ml) and KMnO4 (316.0 mg,
2.0 mmol) were added. The suspension was stirred vigor-
ously at room temperature for 2 h, filtered through Celite
and extracted with dichloromethane (3!15 ml). The
organic phase was washed with aqueous Na2SO3 (5% w/v,
15 ml), with distilled water (1!15 ml) and dried over
NasSO4. The solvent was removed under vacuum. The
residue was chromatographed on a silica gel column using
dichloromethane/methanol (9:1) as eluent and the product
was recrystallized from methanol/water (1:1).
3.6.2.1. 4,5,6,7-Tetrahydro-2-methyl-pyrrolo[3,2,1-
de]phenanthridine (10). A semi-solid material that rapidly
darkened when exposed to the atmosphere. 1H NMR
(200 MHz, CDCl3): 2.31 (s, 3H, CH3), 2.98 (t, 2H,
JZ7.8 Hz, H-4,), 3.32 (t, 2H, JZ7.8 Hz, H-5), 4.10 (s, 2H,
H-7), 6.88 (s, 1H, H-3), 7.11–7.33 (m, 4H, H-1, H-8,
H-9, H-10), 7.66 (d, 1H, JZ7.4 Hz, H-11).
3.6.4.1. 4,5-Dihydro-9,10-dimethoxy-pyrrolo[3,2,1-
de]phenanthridin-7-one (Oxoassoanine) (2d). White
crystals, 68–75%, mp 267–268 8C (lit.: 266–26915; 266–
26719g 8C). IR (nmax, cmK1): 3063, 3016, 3005, 2839, 1644,
1607, 1521, 1478, 1436, 1364, 1303, 1273, 1210, 1125,
1030, 870, 777, 766. MS (% rel. int.): 281(MC, 100),
3.6.3. Reduction with NaCNBH3 and subsequent oxi-
dation with Oxonee. To the crude product from the
reduction reaction using BH3$THF (w1 mmol) was added
NaCNBH3 (189.0 mg, 3 mmol) and the mixture cooled to
10 8C. Acetic acid (3 ml) was added dropwise and the
1
280(31), 266(12), 238(20). H NMR (200 MHz, CDCl3): d
3.43 (t, 2H, JZ8.2 Hz, H-4), 4.04 (s, 3H, OCH3), 4.08 (s,
3H, CH3), 4.44 (t, 2H, JZ8.2 Hz, H-5), 7.21 (t, 1H,
JZ7.5 Hz, H-2), 7.30 (d, 1H, JZ7.5 Hz, H-3), 7.52 (s, 1H,

J. C. Torres et al. / Tetrahedron 60 (2004) 9889–9900
9899
H-8), 7.80 (d, 1H, JZ7.5 Hz, H-1), 7.93 (s, 1H, H-11). 13
C
3.6.5.3. 2-Methyl-pyrrolo[3,2,1-de]phenanthridin-7-
one (12). White crystals, 40–53%, mp 157–158 8C. IR
(nmax, cmK1): 3132, 3099, 3073, 2922, 2858, 1676, 1634,
1595, 1484, 1449, 1385, 1353, 1304, 1292, 1174, 1151, 847,
787, 759, 728, 691. MS (% rel. int.): 233(MC, 100),
NMR (50.3 MHz, CDCl3): d 27.6 (C-4), 46.7 (C-5), 56.3
(OCH3), 56.4 (OCH3), 103.1 (CH), 108.9 (CH), 116.9 (C),
119.3 (CH), 121.5 (C), 123.3 (CH), 123.7 (CH), 128.6 (C),
131.1 (C), 139.5 (C), 149.8 (C), 153.0 (C), 159.8 (C-7).
1
232(80), 204(10), 176(9). H NMR (200 MHz, CDCl3): d
2.60 (s, 3H, CH3), 6.83 (d, 1H, JZ3.6 Hz, H-4), 7.55 (s, 1H,
H-3), 7.60 (td, 1H, JZ1.1, 8.0 Hz, H-9), 7.78 (td, 1H,
JZ1.1, 8.0 Hz, H-10), 7.82 (s, 1H, H-1), 8.00 (d, 1H,
JZ3.6 Hz, H-5), 8.24 (d, 1H, JZ8.0 Hz, H-11), 8.59
(dd, 1H, JZ1.1, 8.0 Hz, H-8). 13C NMR (50.3 MHz,
CDCl3): d 22.2 (CH3), 111.0 (CH), 116.3 (C), 119.6 (CH),
122.7 (CH), 123.5 (CH), 123.6 (CH), 127.3 (C), 128.1 (CH),
128.7 (C), 129.7 (CH), 130.1 (C), 133.1 (CH), 133.9 (C),
134.6 (C), 158.8 (C-7). HRMS for C16H11NO: 233.0841
(calcd); 233.0848 (found).
3.6.4.2. 4,5-Dihydro-9,10-methylenedioxy-pyrrolo-
[3,2,1-de]phenanthridin-7-one (Anhydrolycorin-7-one)
(2b). White crystals, 75%, mp 228–229 8C (lit.: 231–
23219g; 230–23120e,g; 228–23041 8C). IR (nmax, cmK1):
3057, 2968, 2908, 1643, 1614, 1587, 1505, 1484, 1468,
1393, 1370, 1352, 1257, 1035, 933, 857, 763. MS (% rel.
int.): 265(MC, 100), 264(92), 234(7), 206(18), 178(19). 1H
NMR (200 MHz, CDCl3): d 3.42 (t, 2H, JZ8.2 Hz, H-4),
4.47 (t, 2H, JZ8.2 Hz, H-5), 6.13 (s, 2H, OCH2O), 7.19 (t,
1H, JZ7.7 Hz, H-2), 7.29 (d, 1H, JZ7.7 Hz, H-3), 7.53 (s,
1H, H-8), 7.73 (d, 1H, JZ7.7 Hz, H-1), 7.90 (s, 1H, H-11).
13C NMR (50.3 MHz, CDCl3): d 27.6 (C-4), 46.6 (C-5),
101.0 (CH), 102.2 (OCH2O), 106.9 (CH), 116.9 (C), 119.5
(CH), 123.1 (C), 123.4 (CH), 123.9 (CH), 130.7 (C), 131.0
(C), 139.4 (C), 148.5 (C) 151.9 (C), 159.6 (C-7).
Acknowledgements
The authors thank the Brazilian National Research Council
(CNPq), the State of Rio de Janeiro (FAPERJ), and SJG also
thanks the Fundac¸a˜o Oswaldo Cruz, Farmanguinhos, Rio de
Janeiro, (PAPES II) for financial support of this work.
3.6.5. Oxidation with MnO2–SiO2. To the crude product
(w1 mmol) from the BH3$THF reduction reaction was
added MnO2–SiO2 (3.0 mmol of MnO2) and solvent (15 ml
of anhydrous benzene or THF). The suspension was heated
under reflux for 4 h, the solvent was removed and the
residue was chromatographed on a short silica gel column
using dichloromethane/methanol (20:1) as eluent. The
solids were recrystallized from methanol.
References and notes
1. Hoshino, O. The Amaryllidaceae alkaloids. In The Alkaloids;
Cordell, G. A., Ed.; Academic Press: San Diego, 1998;
Vol. 51; pp 323–424
3.6.5.1. 9,10-Methylenedioxy-pyrrolo[3,2,1-de]-
phenanthridin-7-one (Hippadine) (1b). White crystals,
2. (a) Tsuji, J. Palladium Reagents and Catalysts. Innovations in
Organic Synthesis; John Wiley and Sons. Inc.: New York,
1995. (b) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic
Chemistry; Pergamon: Oxford, 2000; Vol. 20.
35%, mp 217–218 8C (lit.: 217–21815,41 8C). IR (nmax
,
cmK1): 3148, 2958, 2920, 2850, 1672, 1618, 1526, 1479,
1458, 1392, 1365, 1312, 1285, 1243, 1118, 1029, 932, 878,
801, 765, 722. MS (% rel. int.): 263(MC, 100), 205(6),
3. (a) Siddiqui, M. A.; Snieckus, V. Tetrahedron Lett. 1990, 31,
1523–1526. (b) Banwell, M. G.; Bissett, B. D.; Busato, S.;
Cowden, C. J.; Hockless, D. C. R.; Holman, J. W.; Read, R. W.;
Wu, A. W. J. Chem. Soc., Chem. Commun. 1995, 2551–2553.
4. Iwao, M.; Takehara, H.; Obata, S.; Watanabe, M. Heterocycles
1994, 38, 1717–1720.
1
177(24), 150(12). H NMR (200 MHz, CDCl3): d 6.15 (s,
2H, OCH2O), 6.88 (d, 1H, JZ3.4 Hz, H-4), 7.45 (t, 1H,
JZ7.7 Hz, H-2), 7.61 (s, 1H, H-11), 7.73 (d, 1H, JZ7.7 Hz,
H-3), 7.88 (d, 1H, JZ7.7 Hz, H-1), 7.95 (s, 1H, H-8), 8.02
(d, 1H, JZ3.4 Hz, H-5). 13C NMR (50.3 MHz, CDCl3): d
101.8 (CH), 102.5 (OCH2O), 108.1 (CH), 110.9 (CH), 116.8
(C), 118.5 (CH), 122.6 (C), 122.7 (CH), 123.7 (CH), 124.1
(CH), 128.5 (C), 131.1 (C), 131.7 (C), 148.6 (C), 152.7 (C),
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233–234 8C (lit.: 234–23515 8C). IR (nmax, cmK1): 3149,
3111, 3006, 2936, 2836, 1668, 1603, 1529, 1509, 1440,
1363, 1314, 1273, 1213, 1142, 1105, 1001, 870, 765. MS (%
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1
193(15), 165(15). H NMR (200 MHz, CDCl3): d 4.05 (s,
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