Synthesis of oxidative dihydroxy metabolites of benzo[c]phenanthridines

Article abstract of DOI:10.1016/j.tet.2013.03.105

The synthesis of dihydroxybenzo[c]phenanthridines is described. 6-Bromo-2,3-dihydroxybenzaldehyde was reacted with naphtho[2,3-d][1,3]dioxol-5- amine via reductive amination to give the corresponding diol 19, which was subsequently protected with ethoxyme

Full text of DOI:10.1016/j.tet.2013.03.105

Tetrahedron 69 (2013) 4670e4678
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Synthesis of oxidative dihydroxy metabolites of benzo[c]
phenanthridines
*
ꢀ
ꢀꢁ
ꢁ
Jakub Styskala, Jan Hlavac, Petr Cankar
ꢀ
Institute of Molecular and Translational Medicine, Department of Organic Chemistry, Faculty of Science, Palacky University, 17. listopadu 1192/12,
771 46 Olomouc, Czech Republic
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of dihydroxybenzo[c]phenanthridines is described. 6-Bromo-2,3-dihydroxybenzaldehyde
was reacted with naphtho[2,3-d][1,3]dioxol-5-amine via reductive amination to give the correspond-
ing diol 19, which was subsequently protected with ethoxymethyl chloride (EOMCl). Radical cyclization
provided the EOM-protected dihydroxybenzo[c]phenanthridine 21, the key intermediate for the syn-
thesis of dihydroxybenzo[c]phenanthridines 1 and 2. The use of the EOM-protecting group proved to be
more favorable compared with a benzyl group. The high insolubility of chloride salts 1a and 2a, even in
water, was overcome by the substitution of its chloride counter-anion with trifluoroacetate. Dihydroxy
derivatives 1 and 2 are proposed as oxidative metabolites in the biosynthesis of the benzo[c]phenan-
thridine alkaloids.
Received 8 December 2012
Received in revised form 11 March 2013
Accepted 26 March 2013
Available online 1 April 2013
Keywords:
Benzo[c]phenanthridines
Oxidative dihydroxy metabolites
Nitrogen heterocycles
Radical cyclizations
Ó 2013 Elsevier Ltd. All rights reserved.
Nitrogen heterocycles
1. Introduction
analog of chelerythrine, NK109,8 was shown to have significant
growth-inhibitory activity against some drug-resistant tumor cell
The family of benzo[c]phenanthridine alkaloids contains con-
geners with a wide range of biological activity (Fig.1).1 For example,
sanguinarine exhibits multiple effects, such as antimicrobial2 and
antifungal.1b This active compound has been utilized in dental
hygiene products3 or as a feed additive.4 Another derivative, niti-
dine, is a known inhibitor of topoisomerases I/II5 and was also
identified as the major antimalarial component isolated from ex-
tracts of Toddalia asiatica,6 while chelerythrine, a regioisomer of
nitidine, is a potent protein kinase C inhibitor.7 The O-demethylated
lines. Likewise, synthetic analog NK314,9 in which ring C was fused
to a pyrrolidine cycle, exhibited anti-tumor activity as well.
The main natural sources of benzo[c]phenanthridine alkaloids
are Fumariaceae, Papaveraceae, and Rutaceae plants.10a Many
syntheses or approaches leading to the benzo[c]phenanthridine
tetracyclic core have been reported, but there is still demand for
more practical syntheses of these compounds. Synthetic strategies
are usually based on B- or C-ring closure utilizing various meth-
odologies, such as free radical-mediated, aryne-mediated, Bisch-
lereNapieralski, or transition metal-catalyzed reactions.10,11 These
syntheses are not simple with regard to the number of synthetic
steps and frequently have low scope in terms of functional variety
and tolerance.
Some research in the field of benzo[c]phenanthridine alkaloids
has been dedicated to the metabolism of these derivatives.12 As
a result of these studies, the formation of dihydroxy oxidative
metabolites was proposed (Fig. 2).
Recently, the metabolism of sanguinarine was proposed by
Deroussent and co-workers.12b The dihydroxybenzo[c]phenan-
thridine 2 was observed as the dominant oxidative metabolite
during incubation of sanguinarine with rat liver microsomes and
recombinant human cytochrome P450 (CYP). This metabolite is
formed via ring-cleavage and subsequent O-demethylation (Fig. 3).
Nevertheless, the evidence for these metabolites was often
based only on interpretation of LC/MS12b analyses, which could be
Fig. 1. Some benzo[c]phenanthridine alkaloids.
* Corresponding author. Tel.: þ420 585 634 437; fax: þ420 585 634 465; e-mail
ꢁ
address: cankar@orgchem.upol.cz (P. Cankar).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.105

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J. Styskala et al. / Tetrahedron 69 (2013) 4670e4678
4671
Fig. 2. Proposed oxidative metabolites.
Fig. 3. Proposed metabolic pathway of the dihydroxybenzo[c]phenanthridine metab-
olite 2.
potentially misleading. In such cases the comparison of analytical
data of the sample with the synthetic standard may be very useful.
Previously, we reported the synthesis of isodecarine as one of the
anticipated metabolites.11d
Scheme 1. Using benzyl as the protecting group.
In this work we described the synthesis of the sanguinarine
dihydroxy metabolite 2 and its N-demethylated analog 1. This
synthesis is applicable for preparation of a sufficient amount of
these compounds to serve as analytical standards, which can be
used for determination or identification of benzo[c]phenanthridine
oxidative metabolites in natural sources. Furthermore, the dihy-
droxy derivatives 1 and 2 can be subjected to evaluate their bi-
ological activity, which has never been described. According to our
best knowledge, the compound 2 has been described in several
papers only as a product isolated from natural sources12b,13 and
characterized only by chromatography methods and mass spec-
trometry. Derivative 1 has never been described.
The synthesis of the desired dihydroxy compounds is based on
our experience with the synthesis of isodecarine where the radical
cyclization leading to ring C closure was used to accomplish the
construction of the benzo[c]phenanthridine heterocyclic system.11d
Since the selective O-demethylation in the presence of methyl-
enedioxy moiety can be troublesome, the demethylation was car-
ried out early in the synthesis. Furthermore, attention focused on
the introduction of a benzyl or ethoxymethyl (EOM) protecting
group in order to obtain the desired dihydroxy derivatives 1 and 2
in the final step. Another important aim of this work was to explore
the scope of benzyl and EOM-protecting groups in the synthesis of
particular benzo[c]phenanthridine intermediates.
proceeded smoothly if the adjacent hydroxy group was unpro-
tected,11d the benzyl protecting group at this position was not fa-
vorable for reduction with sodium borohydride. Alternative
methodology11i utilizing dimethylaminoborane with acetic acid
provided amine 7 in high yield and purity.
A radical cyclization18 was applied to finish synthesis of the
benzo[c]phenanthridine heterocyclic core.11i,20 Using an excess of
both tri-n-butyltin hydride and AIBN, which were added in two
batches, increased the yield to 74% (purity above 90%) of the crude
benzyl-protected benzo[c]phenanthridine 8. Methylation of the
phenanthridine nitrogen with methyl triflate11c,d in the presence of
sodium hydride in toluene generated the corresponding quaternary
salt in situ, which was not isolated, and directly transformed into
the pseudobase 9 by treatment with ethanol. To obtain dihydrox-
ybenzo[c]phenanthridine 2a directly from the pseudobase 9, an
acid cleavage of the benzyl group with a strong acid was attempted
on the basis of described cleavage procedures for similar deriva-
tives.11i Treating pseudobase 9 with hydrochloric acid at 100 ꢀC for
1 h gave only a complicated mixture. Debenzylation under catalytic
hydrogenation at increased pressure gave dihydroxy derivative 10
as was reported under similar conditions by Nakanishi and co-
workers.8b
The dihydroxybenzo[c]phenanthridine 10 is soluble in common
solvents. The initially colorless solution turns a deep purple color
indicating oxidation by air oxygen, which was confirmed by an LC/
MS analysis showing formation of a product with molecular weight
320. If a tetrahydrofuran solution of the derivative 10 was acidified
with hydrochloric acid, a yellow-orange hydrochloride salt 11 was
precipitated. Surprisingly, the precipitate was almost insoluble in
common solvents including water. The elemental analysis supports
formation of hydrochloride salt 11. In comparison with the pre-
cursor 10 its 1H NMR spectrum was different and LC/MS analysis
revealed identical retention time and molecular mass as expected.
When a DMSO solution of hydrochloride salt 11 was left in an
NMR tube for 10 days, a yellow precipitate arose. Its 1H NMR
spectrum and LC/MS analysis confirmed structure assigned to
quaternary salt 2a. Evidently, spontaneous oxidation by air oxygen
occurred again. Afterward, identical spectral data were observed at
quaternary salts prepared via alternative synthetic routes.
2. Results and discussion
Commercially available 6-bromo-2-hydroxy-3-methoxyben-
zaldehyde 3 was chosen as a precursor for introduction of the
ring D substituted with two hydroxy groups (Scheme 1). A modified
demethylation procedure was carried out with boron tribromide to
give dihydroxybenzaldehyde 4.14
At first, benzyl bromide was used to protect both hydroxy
groups under similar conditions reported by Rastetter.15 The
resulting benzyl-protected benzaldehyde 5 was condensed with
naphtho[2,3-d][1,3]dioxol-5-amine11j,k,16 to obtain aldimine 6. In
the first attempt, the reduction of 6 to amine 7 with sodium bo-
rohydride in DMF failed, even upon heating at 140 ꢀC for 4 h. The
conversion was insufficient and, moreover, formation of other un-
known impurities was observed. Although aldimine reduction

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4672
Despite the fact that it was possible to reach the quaternary salt
group migration to form a presumed intermediate IV containing
two intramolecular hydrogen bonds, which stabilize the in-
termediate and simultaneously promote the final irreversible
elimination of ethanol and formaldehyde to afford the aldimine 13.
Despite the undesirable cleavage of the protecting group oc-
curred it was still possible to continue the synthesis leading to non-
methylated dihydroxybenzo[c]phenanthridines 1 (Scheme 2). Pre-
vious experiences with isodecarine synthesis showed that the ad-
jacent non-substituted hydroxy group enabled a simple aldimine
reduction under mild conditions and direct formation of an aro-
matized intermediate after radical cyclization without the need for
additional treatment with an oxidation agent.11d An alternative
hypothesis explaining spontaneous oxidation during the radical
cyclization step (intramolecular hydride transfer in an organotin
intermediate resulting in tributyltin hydride elimination) was also
offered.11d Indeed, the mild reduction of aldimine 13 with sodium
borohydride at room temperature led to the mono-protected amine
14 in high yield, and subsequent cyclization afforded directly the
mono-protected benzo[c]phenanthridine 15 without use of man-
ganese dioxide. A moderate yield in the cyclization step was par-
tially caused by a competitive radical debromination of the starting
amine 14. A final cleavage of the remaining EOM group with diluted
hydrochloric acid provided dihydroxybenzo[c]phenanthridine 1a
as a hydrochloride salt, which was almost insoluble in most com-
mon organic solvents and also in water. Its very low solubility in
DMSO allowed only the reliable measurement of the 1H NMR
spectrum. Formation of the hydrochloride salt 1a was also further
supported by an elemental analysis.
2a via the route described in the Scheme 1, the synthesis was not
practical. It was desirable to find a more suitable protecting group.
An adequately acid labile protecting group able to be cleaved during
transformation of a pseudobase to a quaternary salt under mild
conditions could simplify the synthesis of the target dihydrox-
ybenzo[c]phenanthridines 1a,b and 2a,b. The ethoxymethyl
(EOM)17 group was chosen due to it being commercially more af-
fordable than the analogous MOM protecting group.19
Alkylation of the dihydroxybenzaldehyde 4 with ethoxymethyl
chloride (EOMCl) provided the EOM-protected benzaldehyde 12 in
an almost quantitative yield (Scheme 2). Unfortunately, subsequent
condensation of naphtho[2,3-d][1,3]dioxol-5-amine with the
benzaldehyde 12 proceeded with simultaneous cleavage of one
EOM group to give the EOM-monoprotected aldimine 13 (portrayed
in the Z isomeric form for better clarity with regard to the final
benzo[c]phenanthridine heterocyclic system). If condensation was
performed even in anhydrous toluene, still only the aldimine 13
was observed.
To prove the position of the free alcohol in benzo[c]phenan-
thridine 15 a two-step sequence leading to decarine was designed
(Scheme 4). In the first step, methylation of the phenolic hydroxy
group with methyl iodide gave benzo[c]phenanthridine 16. Com-
petitive alkylation of the phenanthridine nitrogen was not ob-
served. The remaining EOM group was removed using dilute
aqueous hydrochloric acid to provide decarine 17. The melting
point and 1H NMR spectrum of the synthesized decarine were in
accordance with reported experimental data.11f,j
Scheme 2. Protection of hydroxy groups with the EOM group before the condensation
step.
The cleavage of the ortho-positioned EOM-protecting group
with respect to the aldehyde functionality might be promoted by
intramolecular hydrogen bonds (Scheme 3). In the first step, the
aminol I could be stabilized by an intramolecular hydrogen bond, as
well as its conformer II. The aminol tautomer III induces the EOM
Scheme 4. Position determination of the remaining EOM group.
Since one EOM group underwent cleavage during the conden-
sation step (Scheme 2) the reduction of the aldimine functionality
proceeded under milder conditions, contrary to the case when the
adjacent hydroxy group remained protected. To avoid undesirable
cleavage of the protecting group and make the reduction milder the
synthetic strategy was changed. Thus both hydroxy groups were
protected after the aldimine reduction was done (Scheme 5).
Condensation of the dihydroxybenzaldehyde 4 with naphtho
[2,3-d][1,3]dioxol-5-amine provided the aldimine 18, which was
reduced to the amine 19. Both synthetic steps took place smoothly
with short reaction times and high yields. The reduction of the
aldimine functionality was possible to carry out under very mild
reaction conditions with sodium borohydride, in contrast to
a similar reaction with benzyl-diprotected aldimine 6 (Scheme 1).
Alkylation of the dihydroxy derivative 19 with ethoxymethyl
chloride in the presence of sodium hydride afforded the EOM-
Scheme 3. Proposed cleavage mechanism of the adjacent EOM-protecting group.

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4673
To synthesize the desired quaternary salts 2a and 2b it was
necessary to perform a transformation of the benzo[c]phenan-
thridine 21 into the pseudobase 22. After treatment of the benzo[c]
phenanthridine 21 with methyl triflate, isolation of the in situ
generated quaternary salt was not possible, despite the alkylation
being performed under strictly anhydrous conditions and fresh
methyl triflate having been used. Formation of other methylated
derivatives was observed. The pseudobase 22 was only obtained if
the N-methylation was carried out in the presence of sodium hy-
dride with subsequent ethanol addition. These facts indicated that
TFA traces might be a trigger of a competitive reaction (Scheme 7)
leading to methylated quaternary salts. The N-methylation step
proceeded faster at 65 ꢀC, however, the reaction sometimes failed
at this elevated temperature. Room temperature was preferred for
reproducibility of the reaction, even though a longer reaction time
(12 days) was required.
Scheme 5. Synthesis of the key EOM-protected intermediate 21 utilizing later in-
troduction of the EOM-protecting group.
protected amine 20 in moderate yield (Scheme 5). Its subsequent
radical cyclization gave the key EOM-protected benzo[c]phenan-
thridine 21. As expected, both EOM-protected hydroxy groups ne-
cessitated additional oxidation with manganese dioxide of the in
situ generated intermediate after radical cyclization. An attempt to
cyclize non-protected amine 19 to provide directly benzo[c]phe-
nanthridine core 1 led to a complicated mixture.
The EOM-protecting groups of the benzo[c]phenanthridine 21
were cleaved with hydrochloric acid to give the desired hydro-
chloride salt 1a (Scheme 6). LC/MS analysis indicated that only one
EOM group was easily cleaved under mild conditions, while the
second EOM-protecting group required higher temperature to be
removed. The different stability of both EOM-protecting groups is
possible to explain by a conjugation of the pyridine ring with the
ortho-positioned EOM-protected oxygen (Fig. 4).
Scheme 7. Assumed competitive methylation.
Preliminary attempts to convert the pseudobase 22 under mild
conditions to the quaternary salt 2 brought remarkable results.
Diluted acetic acid (20%) regioselectively cleaved one EOM group at
room temperature over 72 h. The product was not isolated, only
detected via LC/MS analysis. A different stability of both protecting
groups was already encountered during the condensation step
(Scheme 2) or deprotection of the benzo[c]phenanthridine 21. As
expected, both EOM-protecting groups were completely removed
with hydrochloric acid at higher temperature to yield the desired
quaternary salt 2a as a deep yellow-orange precipitate with very
poor solubility in water and common organic solvents (acetonitrile,
acetone, THF, DMF, DMSO, ethanol, pyridine). To improve the sol-
ubility of the quaternary salt 2, the pseudobase 22 was treated with
neat TFA to give the quaternary trifluoroacetate salt 2b. The NMR
spectra and elemental analysis supported the anticipated structure
of quaternary salts 2a and 2b.
3. Conclusions
In summary, dihydroxybenzo[c]phenanthridine derivatives
1and 2 were prepared via several modified synthetic routes. The
choice of protecting group was an important factor in the synthesis
of both sets of derivatives. While application of the benzyl group
was not favorable, the EOM-protecting group enabled the synthesis
of the desired dihydroxy derivatives in reasonable yields. A differ-
ent stability of EOM groups to acid cleavage was observed that
might potentially be used for regioselective alkylation of the
dihydroxybenzo[c]phenanthridine derivatives. A problem with the
insolubility of dihydroxy chloride derivatives 1a and 2a was over-
come by the treatment of the pseudobase 22 with TFA to afford,
analogous, more soluble trifluoroacetate salts 1b and 2b. To con-
clude, the reported synthesis has the potential to be utilized for
preparation of both dihydroxy synthetic derivatives 1 and 2.
Moreover, independent syntheses of these derivatives will enable
the clarification of the metabolism of these alkaloids and the study
of their biological activity.
Scheme 6. Synthesis endgame of dihydroxy derivatives 1 and 2.
Fig. 4. Conjugationof theortho-positionedEOM-protectedoxygenwiththepyridine ring.
The isolated dihydroxyhydrochloride salt 1a was identical to the
derivative 1a synthesized via the route described above (Scheme 2).
Due to poor solubility of the hydrochloride salt 1a we focused on
preparation of a trifluoroacetate salt in which we expected higher
solubility. An alternative acid cleavage with neat TFA provided tri-
fluoroacetate salt 1b (Scheme 6) at room temperature. Indeed,
substitution of the chloride for trifluoroacetate anion increased
solubility of the trifluoroacetate salt 1b in DMSO. Consequently, it
was possible to measure its 13C NMR spectrum where the tri-
fluoroacetate anion was detected. Elemental analysis also sup-
ported formation of derivative 1b as a trifluoroacetate salt.
4. Experimental section
4.1. General
All starting materials are commercially available. Commercial
reagents were used without purification. Melting points were

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J. Styskala et al. / Tetrahedron 69 (2013) 4670e4678
4674
determined on a Boetius stage and are uncorrected. The infrared
(IR) spectra were measured via KBr disc method. Flash column
chromatography was performed on silica gel (pore size 60 A,
40e63 mm particle size). The LC/MS analyses were carried out on
UHPLCeMS system consisting of UHPLC chromatograph with
58%), was filtered off, washed with ethanol, and dried. Mp
114e116 ꢀC. Rf (toluene) 0.5. 1H NMR (300 MHz, DMSO-d6):
5.12
d
ꢂ
(s, 2H), 5.27 (s, 2H), 6.12 (s, 2H), 6.84 (d, J¼7.1 Hz, 1H), 7.19e7.48
(m, 11H), 7.48e7.57 (m, 4H), 7.64 (d, J¼8.2 Hz, 1H), 8.64 (s, 1H). 13C
NMR (75 MHz, DMSO-d6): d 70.9, 76.0, 100.3, 101.8, 104.1, 112.3,
photodiode array detector and triple quadrupole mass spectrom-
112.4, 117.7, 125.2, 125.6, 125.9, 128.4, 128.7, 128.8, 128.9, 129.0,
129.1, 129.5, 130.8, 131.3, 137.0, 137.4, 147.9, 148.2, 148.3, 148.8,
152.1, 158.0. IR (cmꢁ1): 3032, 2899, 1628, 1462,l 1361, 1250, 1040.
MS (APCI): m/z¼566.0 and 568.0 [MþH]þ. Anal. Calcd for
C32H24BrNO4 (566.4): C, 67.85; H, 4.27; N, 2.47. Found: C, 67.95; H,
4.34; N, 2.36.
eter, using C18 column at 30 ꢀC and flow rate of 800
mL/min. Mobile
phase was (A) 0.01 M ammonium acetate in water, and (B) aceto-
nitrile, linearly programmed from 10% to 80% B over 2.5 min, kept
for 1.5 min. The column was re-equilibrated with 10% of solution B
for 1 min. The APCI source operated at discharge current of 5 mA,
vaporizer temperature of 400 ꢀC, and capillary temperature of
200 ꢀC. The HRMS analyses were carried out on HRMS-Exactive
(Orbitrap) MS, Thermo, USA. The 1H and 13C NMR spectra were
4.1.4. N-[2,3-Bis(benzyloxy)-6-bromo-benzyl]naphtho[2,3-d][1,3]di-
oxol-5-amine (7). To
a solution of the amine 6 (280.0 mg,
measured in DMSO-d6 or CDCl3 at 20 ꢀC; chemical shifts
d
are re-
0.490 mmol) and dimethylaminoborane complex (26.0 mg,
0.440 mmol) in toluene (4 mL) was added acetic acid (0.330 mL,
5.50 mmol), dropwise, under stirring. After 20 min of stirring at
a room temperature, the reaction was quenched with 1 M HCl
(2.3 mL) and continuously stirred for an additional 30 min. Sub-
sequently, a solution of 5 M NaOH was added to the reaction
mixture to make it strongly alkaline. The free base of the prepared
amine was extracted with toluene (2ꢂ4 mL). Combined organic
extracts were washed with water, brine, and dried over MgSO4.
Toluene was removed under reduced pressure and resulting oily
product was triturated with ethanol (5 mL) to give a pale yellow
compound (250.0 mg, 89% yield) of sufficient purity for a next step.
A sample for analysis was prepared by recrystallization from an
ethanol/chloroform mixture. Mp 165e167 ꢀC. Rf (toluene) 0.6. 1H
ported in parts per million.
4.1.1. 6-Bromo-2,3-dihydroxybenzaldehyde (4).14a 6-Bromo-2-hydr
oxy-3-methoxybenzaldehyde (3) (4.78 g, 20.7 mmol) was dis-
solved in DCM (40 mL) and added dropwise under stirring during
30 min to an ice-cooled solution of BBr3 (8.00 mL, 83.0 mmol) in
DCM (60 mL). The reaction mixture was stirred for 2 h at room
temperature and then water (100 mL) was added dropwise under
ice-cooling and rigorous stirring. DCM was distilled off under re-
duced pressure. The resulting yellow precipitate was filtered off
and washed with water. The crude product was crystallized from
a mixture of water and methanol (3:2, v/v) to obtain yellow
crystals (3.82 g, 85% yield). Mp 143e145 ꢀC. Rf (toluene/acetoni-
trile, 10:1) 0.5. 1H NMR (300 MHz, DMSO-d6):
1H), 7.07 (d, J¼8.4 Hz, 1H), 9.92 (br s, 1H), 10.19 (s, 1H), 11.50 (br s,
d
6.99 (d, J¼8.4 Hz,
NMR (300 MHz, DMSO-d6):
d
4.36 (d, J¼3.7 Hz, 2H), 5.04 (s, 2H),
5.21 (s, 2H), 5.73 (t, J¼3.7 Hz, 1H), 6.05 (s, 2H), 6.56 (d, J¼7.5 Hz, 1H),
7.00 (d, J¼8.1 Hz, 1H), 7.07e7.30 (m, 8H), 7.33e7.46 (m, 4H), 7.51 (d,
1H). 13C NMR (75 MHz, DMSO-d6):
d 113.2, 118.0, 122.3, 123.8,
146.1, 152.0, 196.7. IR (cmꢁ1): 3390, 3085, 1638, 1441, 1382, 1275,
1195, 1013, 892, 717, 568. MS (APCI): m/z¼214.8 and 216.8
[MꢁH]ꢁ. Anal. Calcd for C7H5BrO3 (217.0): C, 38.74; H, 2.32. Found
C, 38.59; H, 2.51.
J¼7.0 Hz, 2H), 7.65 (s,1H). 13C NMR (75 MHz, DMSO-d6):
d 43.7, 70.7,
75.7, 99.5, 101.4, 103.7, 104.5, 115.5, 116.3, 119.6, 125.6, 125.9, 128.3,
128.4, 128.6, 128.7, 128.8, 129.0, 129.4, 131.5, 132.8, 137.3, 137.6,
144.0, 146.8, 147.3, 148.4, 151.7. IR (cmꢁ1): 3034, 1460, 1275, 1240,
1040. MS (APCI): m/z¼568.0 and 570.0 [MþH]þ. Anal. Calcd for
C32H26BrNO4 (568.5): C, 67.61; H, 4.61; N, 2.46. Found: C, 67.66; H,
4.73; N, 2.41.
4.1.2. 2,3-Bis(benzyloxy)-6-bromobenzaldehyde (5). To a solution of
the dihydroxybenzaldehyde 4 (1.09 g, 5.00 mmol) in anhydrous
ethanol (7.5 mL) were added benzyl bromide (2.16 g, 12.6 mmol)
and potassium carbonate (0.870 g, 6.30 mmol) under stirring at the
room temperature under an argon atmosphere. The reaction mix-
ture was refluxed for 12 h under continuous stirring. The ethanol
was then evaporated under reduced pressure. Ethyl acetate (40 mL)
and water (20 mL) were added to the resulting oily residue. The
organic layer was separated and the water phase was additionally
extracted with ethyl acetate (2ꢂ40 mL). The collected organic
layers were washed with water (20 mL) and brine (20 mL), and
dried over MgSO4. Finally, ethyl acetate was evaporated under re-
duced pressure. The crude product was crystallized from ethanol
(96%) to give (0.940 g, 47% yield) crystalline compound. Mp
69e71 ꢀC. Rf (toluene/acetonitrile, 10:1) 0.9. 1H NMR (300 MHz,
4.1.5. 1,2-Bis(benzyloxy)-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]-phenan-
thridine (8). To a solution of the amine 7 (740.0 mg, 1.30 mmol) and
Bu3SnH (757.0 mg, 2.60 mmol) in toluene (30 mL) was added AIBN
(320.0 mg, 1.95 mmol) at 70 ꢀC. The formed solution was heated to
reflux for 3 h. After that, the solution was cooled to 70 ꢀC and an
additional portion of Bu3SnH (757.0 mg, 2.60 mmol) and AIBN
(320.0 mg, 1.95 mmol) were added. Then a reaction mixture was
refluxed for additional 4 h. The solution was cooled to room tem-
perature, MnO2 (1.0 g) was added, and resulting mixture was vig-
orously stirred for 2 h. The termination of oxidation depends on
a quality of MnO2.21 Oxidation process was monitored with TLC
using toluene as a mobile phase. The desired product exhibits
yellow-green florescence at 366 nm. After oxidation was complete,
the reaction mixture was filtered through Celite, and filtrate con-
centrated in vacuo. The resulting residue was extracted with cy-
clohexane (25 mL) to remove most of impurities. The undissolved
solid was filtered off, washed with cyclohexane (3ꢂ3 mL), and dried
to give a pale-yellow product (470.0 mg, 74% yield) in purity above
90% (HPLC analysis). A sample for analysis was prepared by re-
DMSO-d6):
d
5.10 (s, 2H), 5.25 (s, 2H), 7.27e7.56 (m, 12H), 10.14 (s,
70.5, 75.6, 110.7, 119.7, 127.9,
1H). 13C NMR (75 MHz, DMSO-d6):
d
128.1, 128.27, 128.3, 128.5, 128.7, 128.8, 129.5, 136.19, 136.24, 150.4,
151.6, 190.3. IR (cmꢁ1): 3063, 3029, 1703, 1567, 1456, 1367, 1301,
1253, 1231, 1061, 960, 697. MS (APCI): m/z¼396.9 and 398.9
[MþH]þ. Anal. Calcd for C21H17BrO3 (397.26): C, 63.49; H, 4.31.
Found C, 63.57; H, 4.22.
crystallization from
a
chloroform/cyclohexane mixture. Mp
5.36 (s,
4.1.3. N-[2,3-Bis(benzyloxy)-6-bromo-benzylidene]naphtho-[2,3-d]
[1,3]dioxol-5-amine (6). A solution of the benzaldehyde 5 (1.40 g,
3.52 mmol) and naphtho[2,3-d][1,3]dioxol-5-ylamine (0.660 g,
3.52 mmol) in toluene (30 mL) was heated to reflux for 4 h. After
that, toluene was removed and the resulting dark yellow oily
product crystallized from a mixture of toluene and ethanol. After
standing at 2 ꢀC for 18 h, the crystalline yellow compound (1.15 g,
192e195 ꢀC. Rf (toluene) 0.4. 1H NMR (300 MHz, CDCl3):
d
4H), 6.15 (s, 2H), 7.27e7.32 (m, 2H), 7.33e7.49 (m, 6H), 7.54 (m, 3H),
7.67 (d, J¼9.0 Hz, 1H), 7.85 (d, J¼9.0 Hz, 1H), 8.35 (d, J¼9.0 Hz, 2H),
8.71 (s, 1H), 9.79 (s, 1H). 13C NMR (75 MHz, CDCl3):
d 72.3, 76.2, 77.3,
101.4, 102.3, 104.5, 118.3, 118.4, 120.0, 120.9, 121.5, 122.4, 127.1, 127.7,
128.3, 128.4, 128.6, 128.7, 128.8, 129.9, 136.8, 137.1, 144.9, 146.8,
148.4, 148.6, 148.7. IR (cmꢁ1): 3029, 2909, 1540, 1465, 1268, 1241,

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J. Styskala et al. / Tetrahedron 69 (2013) 4670e4678
4675
1040. MS (APCI): m/z¼486.3 [MþH]þ. Anal. Calcd for C32H23NO4
temperature. After that diethyl ether (20 mL) and water (30 mL)
was added and the diethyl ether phase was separated. The water
phase was additionally extracted with diethyl ether (2ꢂ20 mL). The
collected organic phases were washed with brine (20 mL) and dried
over MgSO4. After evaporation of diethyl ether a yellow oil (0.930 g,
96% yield) was obtained. Rf (toluene/acetonitrile, 10:1) 0.6. 1H NMR
(485.5): C, 79.16; H, 4.77; N, 2.88. Found: C, 79.32; H, 4.71; N, 2.67.
4.1.6. 13-Ethoxy-1,2-bis(benzyloxy)-12-methyl-12,13-dihydro-[1,3]
dioxolo[40,50:4,5]benzo[1,2-c]phenanthridine (9). To a solution of the
phenanthridine 8 (170.0 mg, 0.350 mmol) in anhydrous toluene
(3 mL) was added NaH (42.0 mg; 1.75 mmol) followed by methyl
triflate (230.0 mg; 1.40 mmol). The resulting suspension was stirred
in a tightly sealed vial at 85 ꢀC for 4 h. After cooling, ethanol (1 mL)
was carefully added dropwise under cooling to the formed yellow
suspension of the quaternary salt. The resulting colorless solution
was evaporated to dryness after 15 min of stirring. The solid was
suspended in water (3 mL), filtered off, washed with water, and
dried to give a beige colored powder (162.0 mg, 85% yield) of about
90% purity, suitable for a next step. A sample for analysis was
prepared by recrystallization from a chloroform/ethanol mixture.
Mp 145e148 ꢀC. Rf (toluene/MeOH, 200:1) 0.3. 1H NMR (300 MHz,
(300 MHz, DMSO-d6):
d
1.10 (t, J¼7.1 Hz, 3H), 1.13 (t, J¼7.0 Hz, 3H),
3.68 (q, J¼7.0 Hz, 2H), 3.71 (q, J¼7.0 Hz, 2H), 5.18 (s, 2H), 5.31 (s, 2H),
7.35 (d, J¼9.0 Hz, 1H), 7.47 (d, J¼8.8 Hz, 1H), 10.24 (s, 1H). 13C NMR
(75 MHz, DMSO-d6):
d 14.8, 14.9, 64.2, 65.2, 93.4, 97.9, 111.8, 121.6,
129.4, 129.7, 149.2, 149.7, 190.4. IR (cmꢁ1): 2976, 2900, 1704, 1572,
1462, 1381, 1256, 1115, 945. HRMS (HESI): MHþ, found 333.0326
and 335.0305. C13H18BrO5 requires 333.0332 and 335.0312.
4.1.10. 3-Bromo-6-(ethoxymethoxy)-2-((naphtho[2,3-d][1,3]dioxol-
5-ylimino)methyl)phenol (13). A mixture of hot solutions of naph-
tho[2,3-d][1,3]dioxol-5-ylamine (493.0 mg, 2.63 mmol) in ethanol
(22 mL) and benzaldehyde 12 (876.0 mg, 2.63 mmol) in ethanol
(22 mL) was heated to reflux for 40 min. The desired compound
started to precipitate. After cooling to 0 ꢀC for 2 h, the precipitated
solid was filtered off and washed with ethanol (10 mL) to give an
orange crystalline compound (1.08 g, 92% yield) of sufficient purity
for a subsequent synthesis. The sample for analysis was prepared by
recrystallization from an ethanol/toluene mixture. Mp 143e146 ꢀC.
CDCl3):
d
1.10 (t, J¼7.0 Hz, 3H), 2.65 (s, 3H), 3.57e3.69 (m, 1H),
3.87e4.02 (m, 1H), 5.06e5.32 (m, 4H), 5.69 (s, 1H), 6.07 (s, 2H), 7.15
(t, J¼4.0 Hz, 2H), 7.30e7.57 (m, 11H), 7.58e7.70 (m, 2H), 7.80 (d,
J¼8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d 15.3, 40.7, 61.7, 71.2, 75.9,
84.8, 100.8, 101.1, 104.7, 114.9, 119.1, 120.3, 122.7, 123.4, 125.5, 126.4,
126.8, 127.1, 127.6, 128.1, 128.2, 128.5, 128.7, 131.1, 137.1, 138.0, 138.8,
146.1, 147.4, 148.0, 151.4. IR (cmꢁ1): 3031, 2868, 1496, 1467, 1240. MS
(APCI): m/z¼500.3 [MþHꢁEtOH]þ. Anal. Calcd for C35H31NO5
(545.6): C, 77.04; H, 5.73; N, 2.57. Found: C, 77.12; H, 5.86; N, 2.51.
Rf (toluene) 0.4. 1H NMR (300 MHz, CDCl3):
d
1.28 (t, J¼7.0 Hz, 3H),
3.85 (q, J¼7.0 Hz, 2H), 5.37 (s, 2H), 5.95e6.26 (m, 2H), 7.05e7.13 (m,
1H), 7.14e7.24 (m, 3H), 7.39 (t, J¼7.8 Hz, 1H), 7.58 (s, 1H), 7.65 (d,
J¼8.1 Hz, 1H), 9.20 (s, 1H), 15.21 (s, 1H). 13C NMR (75 MHz, CDCl3):
4.1.7. 12,13-Dihydro-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]-phenan-
thridine-1,2-diol (10). The pseudobase 9 (65.5 mg, 0.120 mmol) in
THF (10 mL) was hydrogenated with hydrogen (5 bar) under ca-
talysis with 10%-Pd/C (20.0 mg). After 12 h of stirring, the catalyst
was removed by filtration and the solution was evaporated to
dryness. The residue was triturated with chloroform (5 mL) and the
precipitated solid was filtered off to give white solid (33.9 mg, 88%
d
15.2, 64.7, 94.3, 99.6, 101.4, 104.0, 113.4, 117.5, 117.9, 120.6, 122.5,
124.6, 125.4, 126.8, 131.5, 144.0, 146.2, 148.4, 148.7, 155.0, 163.3. IR
(cmꢁ1): 2968, 1592, 1471, 1244, 1108, 954. MS (APCI): m/z¼444.1
and 446.1 [MþH]þ. Anal. Calcd for C21H18BrNO5 (444.3): C, 56.77; H,
4.08; N, 3.15. Found: C, 56.39; H, 4.05; N, 2.96.
yield). Mp 138e143 ꢀC. 1H NMR (300 MHz, DMSO-d6):
d
2.47 (s, 3H),
4.1.11. 3-Bromo-6-(ethoxymethoxy)-2-((naphtho[2,3-d][1,3]dioxol-
5-ylamino)methyl)phenol (14). To a stirred solution of the aldimine
13 (1.00 g, 2.25 mmol) in DMF (15 mL) was added NaBH4 (85.0 mg,
2.25 mmol). After 20 min, the colorless solution was poured into
a mixture of acetic acid (0.25 mL) in water (20 mL). The resulting
white emulsion was extracted with diethyl ether (3ꢂ15 mL). The
collected diethyl ether phases were washed with water (3ꢂ10 mL),
brine (15 mL), and dried over MgSO4. After evaporation of diethyl
ether a semi-solid compound (906.0 mg, 90% yield) of about 90%
purity was afforded. The sample for analysis was purified by a flash
column chromatography on silica gel and eluted with chloroform.
4.13 (s, 2H), 6.12 (s, 2H), 6.80 (d, J¼8.2 Hz, 1H), 7.19 (d, J¼8.2 Hz, 1H),
7.28 (s, 1H), 7.42e7.58 (m, 2H), 7.70 (d, J¼8.6 Hz, 1H), 8.53 (s, 1H),
9.43 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d 41.7, 48.8, 100.2, 101.6,
104.7,114.5,119.7,120.6, 124.1,124.3,125.2, 125.4, 126.3, 130.6, 142.1,
142.6, 145.8, 147.5, 148.3. IR (cmꢁ1): 3361, 2956, 1499, 1474, 1286,
1250, 1039, 859. MS (APCI): m/z¼322.1 [MþH]þ; 320.0 [MꢁH]-.
Anal. Calcd for C19H15NO4 (321.3): C, 71.02; H, 4.71; N, 4.36. Found:
C, 70.88; H, 4.62; N, 4.31.
4.1.8. 12,13-Dihydro-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]-phenan-
thridine-1,2-diol hydrochloride (11). To a solution of the diol 10
(15.0 mg, 0.047 mmol) in THF (3 mL) was added an aqueous solu-
tion of 37%-HCl (0.5 mL). Under continuous stirring a hydrochloride
salt started to precipitate slowly from the colorless solution. After
90 min the precipitated solid was filtered off, washed with water,
and dried to give a yellow compound (12.2 mg, 73% yield). Mp
Rf (CHCl3/MeOH, 200:1) 0.5. 1H NMR (300 MHz, CDCl3):
d 1.25 (t,
J¼7.0 Hz, 3H), 3.76 (q, J¼7.1 Hz, 2H), 4.69 (s, 2H), 5.24 (s, 2H), 6.03 (s,
2H), 6.90 (d, J¼7.1 Hz, 1H), 6.96e7.02 (m, 1H), 7.05e7.12 (m, 2H),
7.15e7.31 (m, 3H). 13C NMR (75 MHz, CDCl3):
d 15.2, 45.2, 64.9, 94.7,
97.5, 101.1, 104.8, 107.0, 116.3, 117.3, 119.0, 120.9, 123.8, 124.2, 125.0,
131.4, 142.3, 144.6, 147.1, 147.4, 147.5. IR (cmꢁ1): 2971, 2888, 1535,
1467, 1244, 1036. HRMS (HESI): MHþ, found 446.0593 and
448.0570. C21H21BrNO5 requires 446.0598 and 448.0577.
205e211 ꢀC dec. 1H NMR (300 MHz, DMSO-d6):
d 2.76 (s, 3H), 4.10
(br s, 1H) 4.47 (s, 2H), 6.20 (s, 2H), 6.94 (d, J¼8.2 Hz, 1H), 7.35 (d,
J¼8.4 Hz, 1H), 7.43 (s, 1H), 7.74e7.88 (m, 2H), 7.96 (s, 1H), 9.83 (br s).
13C NMR (75 MHz, DMSO-d6): the spectrum was not recorded due
to low solubility. MS (APCI): m/z¼322.1 [MþH]þ; 320.0 [MꢁH]ꢁ.
Anal. Calcd for C19H16ClNO4 (357.8): C, 63.78; H, 4.51; N, 3.91.
Found: C, 63.46; H, 4.65; N, 3.58.
4.1.12. 2-(Ethoxymethoxy)-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]phe-
nanthridin-1-ol (15). To a solution of the phenol 14 (500.0 mg,
1.12 mmol) and Bu3SnH (652.0 mg, 2.24 mmol) in toluene (30 mL),
AIBN (276.0 mg, 1.68 mmol) was added at 70 ꢀC. The reaction
mixture was heated to reflux for 2 h under argon. After that toluene
was evaporated on a rotovap and the residue was purified by a flash
column chromatography on silica gel (CHCl3/methanol, 160:1, v/v).
The collected purified compound was triturated with ethanol
(2 mL) to precipitate a pure compound (219.0 mg, 54% yield). The
sample for analysis was prepared by recrystallization from an
ethanol/toluene mixture. Mp 165e168 ꢀC. Rf (CHCl3/MeOH, 160:1)
4.1.9. 6-Bromo-2,3-bis(ethoxymethoxy)benzaldehyde (12). A solu-
tion of the dihydroxybenzaldehyde 4 (0.630 g, 2.90 mmol) in DMF
(5 mL) was added dropwise under cooling (3e5 ꢀC) and stirring to
a suspension of sodium hydride (0.200 g, 8.30 mmol) in DMF (5 mL)
under argon. Then to the continuously cooled and stirred orange
suspension was added (chloromethoxy)ethane (0.750 g,
7.90 mmol). The reaction mixture was stirred for 13 h at room
0.3. 1H NMR (300 MHz, DMSO-d6):
d
1.17 (t, J¼7.1 Hz, 3H), 3.79 (q,

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J. Styskala et al. / Tetrahedron 69 (2013) 4670e4678
4676
J¼7.1 Hz, 2H), 5.37 (s, 2H), 6.21 (s, 2H), 7.50 (s, 1H), 7.76 (d, J¼9.0 Hz,
1H), 7.96 (d, J¼8.9 Hz, 1H), 8.24 (d, J¼9.0 Hz, 1H), 8.51 (d, J¼9.0 Hz,
1H), 8.55 (s, 1H), 9.69 (s, 1H), 10.04 (s, 1H). 13C NMR (75 MHz,
The resulting emulsion was diluted with brine (15 mL). After 15 min
of stirring, the precipitated solid was filtered off, washed thor-
oughly with water, and dried in vacuo at 50 ꢀC for 2 h to give a white
powder (1.19 g, 99% yield) of a sufficient purity for a subsequent
synthesis. The sample for analysis was prepared by recrystallization
from a toluene/ethanol mixture. Mp 130e132 ꢀC. Rf (CHCl3/MeOH,
DMSO-d6):
d 14.9, 63.8, 94.2, 101.0, 101.4, 104.3, 113.1, 117.6, 118.8,
119.6, 122.3, 126.8, 128.2, 129.4, 139.2, 141.4, 143.8, 146.4, 147.9,
148.0. IR (cmꢁ1): 2977, 2900, 1584, 1461, 1360, 1249, 1031. MS
(APCI): m/z¼364.2 [MþH]þ. Anal. Calcd for C21H17NO5 (363.4): C,
69.41; H, 4.72; N, 3.85. Found: C, 69.47; H, 4.62; N, 3.62.
40:1) 0.6. 1H NMR (300 MHz, DMSO-d6):
d 4.41 (s, 2H), 6.07 (s, 2H),
6.64 (d, J¼7.4 Hz, 1H), 6.69 (d, J¼8.6 Hz, 1H), 6.89 (d, J¼8.2 Hz, 1H),
7.01 (d, J¼8.2 Hz, 1H), 7.11 (t, J¼8.0 Hz, 1H), 7.15 (s, 1H), 7.60 (s, 1H),
4.1.13. 2-(Ethoxymethoxy)-1-methoxy-[1,3]dioxolo-[40,50:4,5]benzo
[1,2-c]phenanthridine (16). To a suspension of NaH (95%, 4.40 mg,
0.183 mmol) in anhydrous DMF (3 mL) was added the benzo[c]
phenanthridine 15 (44.3 mg, 0.122 mmol) and, subsequently,
methyl iodide (52.0 mg, 0.366 mmol). After 18 h of stirring, ethanol
(0.5 mL) was added into a reaction mixture and allowed to react for
5 min. Organic solvents were evaporated and the desired com-
pound precipitated from an oily residue by treating with water
(3 mL). The solid was filtered off, washed with water, dried, and
recrystallized from an ethanol/water mixture to give a pale yellow
compound (29.0 mg, 63% yield). Mp 179e183 ꢀC. Rf (CHCl3) 0.4. 1H
9.11 (br s, 1H), 9.65 (br s, 1H). 13C NMR (75 MHz, DMSO-d6):
d 43.6,
99.2, 101.3, 104.2, 104.5, 114.2, 116.0, 116.5, 119.7, 122.9, 124.9, 125.5,
131.4, 143.7, 145.3, 146.3, 146.8, 147.2. IR (cmꢁ1): 3400, 2904, 1617,
1530, 1466, 1247, 1040. MS (APCI): m/z¼388.2 and 390.2 [MþH]þ.
Anal. Calcd for C18H14BrNO4 (388.2): C, 55.69; H, 3.63; N, 3.61.
Found: C, 55.80; H, 3.51; N, 3.69.
4.1.17. N-(6-Bromo-2,3-bis(ethoxymethoxy)benzyl)naphtho-[2,3-d]
[1,3]dioxol-5-amine (20). A solution of the diol 19 (388.2 mg,
1.00 mmol) in anhydrous DMF was added dropwise to a stirred,
cold (5 ꢀC) suspension of sodium hydride (60.8 mg, 2.50 mmol) in
anhydrous DMF (2 mL) under argon. After 10 min (chloromethoxy)
ethane (189.0 mg, 2.00 mmol) was added to a reaction mixture
under continuous stirring and cooling. The resulting reaction
mixture was stirred for 10 min at 5 ꢀC and then at room tempera-
ture for 2 h. The reaction was quenched with water (18 mL) and
resulting mixture was extracted with diethyl ether (2ꢂ20 mL). The
combined organic layers were washed with water (2ꢂ20 mL), brine
(20 mL) and dried over MgSO4. After evaporation of diethyl ether
under reduced pressure the crude oily product was obtained and
subsequently purified by the flash chromatography (deactivated
silica gel with TEA, eluted with toluene/acetonitrile 100:2, v/v) to
NMR (300 MHz, DMSO-d6):
2H), 4.08 (s, 3H), 5.46 (s, 2H), 6.22 (s, 2H), 7.52 (s, 1H), 7.86 (d,
d
1.17 (t, J¼7.1 Hz, 3H), 3.79 (q, J¼7.0 Hz,
J¼9.2 Hz, 1H), 7.99 (d, J¼9.0 Hz, 1H), 8.53e8.57 (m, 2H), 8.58 (d,
J¼3.0 Hz,1H), 9.63 (s, 1H). 13C NMR (75 MHz, DMSO-d6):
d 14.9, 61.7,
64.1, 93.7, 100.9, 101.5, 104.4, 118.7, 119.5, 121.2, 122.6, 127.1, 128.1,
128.2, 129.5, 139.2, 145.3, 146.0, 146.8, 148.0, 148.1. IR (cmꢁ1): 2980,
2901, 1531, 1462, 1261, 1041. MS (APCI): m/z¼378.2 [MþH]þ. Anal.
Calcd for C22H19NO5 (377.4): C, 70.02; H, 5.07; N, 3.71. Found: C,
70.14; H, 5.06; N, 3.64.
4.1.14. 1-Methoxy-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]phenanthridin-
2-ol (17, Decarine). The benzo[c]phenanthridine 16 (14.4 mg,
0.038 mmol) in a mixture of ethanol (1 mL) and 1 M HCl (0.4 mL)
was heated in a sealed vial with stirring at 80 ꢀC for 3 h. The solid
was precipitated after adding water (1 mL) and filtered off, washed
with water, and dried to give a yellow-orange powder (11.5 mg, 94%
yield). Mp 243e245 ꢀC.11f Rf (CHCl3/MeOH, 160:1) 0.3. 1H NMR
give the bis(ethoxymethoxy) derivative 20 as
(265.3 mg, 53% yield). Rf (toluene/acetonitrile, 30:1) 0.5. 1H NMR
(300 MHz, DMSO-d6):
a yellow oil
d
1.00 (t, J¼7.1 Hz, 3H), 1.15 (t, J¼7.1 Hz, 3H),
3.63e3.74 (m, 4H), 4.41 (d, J¼4.6 Hz, 2H), 5.16 (s, 2H), 5.27 (s, 2H),
5.65 (t, J¼4.6 Hz, 1H), 6.06 (s, 2H), 6.60 (d, J¼7.5 Hz, 1H), 7.00 (d,
J¼7.9 Hz, 1H), 7.08e7.17 (m, 3H), 7.37 (d, J¼8.8 Hz, 1H), 7.65 (s, 1H).
(300 MHz, DMSO-d6):
d
4.10 (s, 3H), 6.24 (s, 2H), 7.51 (s, 1H), 7.58 (d,
13C NMR (75 MHz, DMSO-d6):
d 14.8,14.9, 43.1, 64.0, 64.8, 93.3, 97.5,
J¼8.9 Hz, 1H), 8.01 (d, J¼9.0 Hz, 1H), 8.48 (d, J¼9.0 Hz, 1H), 8.51 (d,
J¼9.0 Hz, 1H), 8.66 (s, 1H), 9.53 (s, 1H), 10.10 (br s, 1H). IR (cmꢁ1):
3097, 2910, 2710, 1568, 1479, 1319, 1267, 1040. MS (APCI): m/
z¼320.2 [MþH]þ.
98.8, 100.8, 102.9, 103.9, 115.8, 116.8, 119.0, 124.9, 127.9, 128.6, 130.9,
132.2, 143.4, 146.2, 146.5, 146.7, 149.2. IR (cmꢁ1): 2980, 2888, 1702,
1535, 1467, 1245, 1113, 1038, 946, 842. HRMS (HESI): MHþ, found
504.1007 and 506.0989. C24H27BrNO6 requires 504.1016 and
506.0996.
4.1.15. 4-Bromo-3-((naphtho[2,3-d][1,3]dioxol-5-ylimino)methyl)
benzene-1,2-diol (18). A mixture of hot solutions of the aldehyde 4
(2.00 g, 9.22 mmol) in ethanol (35 mL) and naphtho[2,3-d][1,3]
dioxol-5-ylamine (1.72 g, 9.20 mmol) in ethanol (100 mL) was
heated to reflux for 20 min. After 2 h cooling at 0 ꢀC, the pre-
cipitated compound was filtered off and washed with cold ethanol
(20 mL) to give an orange crystalline compound (3.14 g, 88% yield)
with sufficient purity for a subsequent synthesis. The sample for
analysis was prepared by recrystallization from acetonitrile. Mp
228e232 ꢀC. Rf (CHCl3/MeOH, 80:1) 0.7. 1H NMR (300 MHz, DMSO-
4.1.18. 1,2-Bis(ethoxymethoxy)-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]
phenanthridine (21). To a solution of the amine 20 (759.0 mg,
1.50 mmol) and Bu3SnH (870.0 mg, 3.00 mmol) in toluene (30 mL),
was added AIBN (377.0 mg, 2.3 mmol) at 70 ꢀC. The formed solution
was heated to reflux for 2 h. Due to a low conversion of the amine
20, an additional portion of Bu3SnH (248.0 mg, 0.850 mmol) and
AIBN (69.0 mg, 0.410 mmol) were added at 70 ꢀC. Heating to reflux
was prolonged for an additional 30 min. The solution was cooled to
room temperature. MnO2 (1.15 g) was added and the resulting
mixture was vigorously stirred for 2 h. After oxidation was com-
plete (monitored via TLC), the reaction mixture was filtered
through Celite and the filtrate concentrated in vacuo. The residue
was extracted with cyclohexane (10 mL) at room temperature to
remove most of impurities. The remaining insoluble solid was
recrystallized from a cyclohexane/toluene mixture to give a light
gray microcrystalline compound (399.0 mg, 63% yield). Mp
135e138 ꢀC. Rf (CHCl3/MeOH, 80:1) 0.3. 1H NMR (300 MHz, CDCl3):
d6):
7.30e7.50 (m, 4H), 7.75 (d, J¼7.9 Hz, 1H), 9.09 (s, 1H), 9.57 (s, 1H).
13C NMR (75 MHz, DMSO-d6):
98.7, 102.2, 104.6, 114.0, 114.3, 117.0,
d
6.18 (s, 2H), 6.91 (d, J¼8.5 Hz, 1H), 7.06 (d, J¼8.5 Hz, 1H),
d
120.3, 123.2, 125.0, 125.3, 127.2, 131.6, 143.7, 146.8, 148.5, 148.9,
153.2, 163.8. IR (cmꢁ1): 3440, 2904, 1620, 1475, 1252, 1042. MS
(APCI): m/z¼386.2 and 388.2 [MþH]þ. Anal. Calcd for C18H12BrNO4
(386.2): C, 55.98; H, 3.13; N, 3.63. Found: C, 56.06; H, 3.14; N, 3.53.
4.1.16. 4-Bromo-3-((naphtho[2,3-d][1,3]dioxol-5-ylamino)methyl)
benzene-1,2-diol (19). To a stirred suspension of the aldimine 18
(1.20 g, 3.10 mmol) in ethanol (25 mL) was added NaBH4 (117.0 mg,
3.10 mmol) under argon. After 15 min, the colorless solution was
added to a cold mixture of acetic acid (0.15 mL) in water (150 mL).
d
1.28 (td, J¼7.0, 1.2 Hz, 6H), 3.85 (q, J¼7.1 Hz, 2H), 3.99 (q, J¼7.1 Hz,
2H), 5.39 (s, 2H), 5.49 (s, 2H), 6.12 (s, 2H), 7.28 (s, 1H), 7.71e7.91 (m,
2H), 8.32 (d, J¼9.0 Hz, 2H), 8.71 (s, 1H), 9.80 (s, 1H). 13C NMR
(75 MHz, CDCl3):
d 15.8, 15.9, 65.4, 66.7, 95.1, 98.7, 102.0, 102.9,
105.0, 118.9, 119.1, 120.5, 122.7, 123.1, 127.7, 129.7, 129.8, 130.5, 140.8,

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J. Styskala et al. / Tetrahedron 69 (2013) 4670e4678
4677
143.6, 147.3, 147.4, 149.0, 149.1. IR (cmꢁ1): 2983, 2904, 1529, 1460,
1258, 1102, 1050. MS (APCI): m/z¼422.2 [MþH]þ. Anal. Calcd for
C24H23NO6 (421.4): C, 68.40; H, 5.50; N, 3.32. Found: C, 68.24; H,
5.55; N, 3.26.
[MꢁH]-. Anal. Calcd for C20H12F3NO6 (419.3): C, 57.29; H, 2.88; N,
3.34. Found: C, 57.39; H, 3.01; N, 3.25.
4.1.22. 1,2-Dihydroxy-12-methyl-[1,3]dioxolo[40,50:4,5]-benzo[1,2-c]
phenanthridin-12-ium chloride (2a). A solution of the pseudobase 22
(25.0 mg, 0.052 mmol) in a mixture of acetone (1.5 mL) and 3 M HCl
(0.5 mL) was heated under stirring at 50 ꢀC for 18 h. The formed pre-
cipitatewas filtered off, washed with water, and dried in vacuo at 60 ꢀC
to give a poorly soluble orange powder (12.5 mg, 68% yield). Mp over
4.1.19. 13-Ethoxy-1,2-bis(ethoxymethoxy)-12-methyl-12,13-dihydro-
[1,3]dioxolo[40,50:4,5]-benzo[1,2-c]phenanthridine (22). To a stirred
solution of the benzo[c]phenanthridine 21 (101.0 mg, 0.240 mmol)
in anhydrous toluene (6 mL) was added sodium hydride (85.0 mg,
3.54 mmol) and then methyl triflate (191.0 mg, 1.17 mmol) with
exclusion of air moisture. After 12 days of stirring, ethanol (1 mL)
was carefully added dropwise to the formed yellow suspension of
a quaternary salt under cooling. After 15 min of stirring, the resulting
colorless solution was evaporated to dryness. The solid was sus-
pended in water (5 mL), filtered off, washed with water, and dried to
give a nearly white powder (98.0 mg, 85% yield) of sufficient purity
for a next step. Mp 117e122 ꢀC. Rf (CHCl3/MeOH, 40:1) 0.4. 1H NMR
300 ꢀC dec. 1H NMR (300 MHz, DMSO-d6):
d 4.90 (s, 3H), 6.33 (s, 2H),
7.74 (s, 1H), 7.90 (d, J¼9.0 Hz, 1H), 8.18e8.28 (m, 2H), 8.34 (d, J¼9.0 Hz,
1H), 8.67 (d, J¼9.0 Hz, 1H), 9.99 (s, 1H), 11.04 (br s, 2H). 13C NMR
(75 MHz, DMSO-d6): due to low solubility it was not possible to obtain
the corresponding spectrum. IR (cmꢁ1): 3041, 1549, 1489, 1324, 1256,
1040, 931. MS (APCI): m/z¼320.1 [M]þ. Anal. Calcd for C19H14ClNO4
(355.8): C, 64.14; H, 3.97; N, 3.94. Found: C, 64.31; H, 4.06; N, 3.85.
(300 MHz, CDCl3):
d
1.09 (t, J¼7.0 Hz, 3H), 1.28 (t, J¼7.0 Hz, 3H), 1.34
4.1.23. 1,2-Dihydroxy-12-methyl-[1,3]dioxolo[40,50:4,5]-benzo[1,2-c]
phenanthridin-12-ium trifluoroacetate (2b). The pseudobase 22
(24.0 mg; 0.05 mmol) was dissolved in TFA (1.1 mL) and allowed to
stand with stirring for 18 h. After that, the excess of TFA was re-
moved in vacuo, the residue suspended in DCM (1.5 mL), filtered
off, washed with DCM, and dried in vacuo at 60 ꢀC to give an orange
powder (20.3 mg, 94% yield). Mp 215e225 ꢀC dec (217.5e220 ꢀC).13b
(t, J¼7.0 Hz, 3H), 2.77 (s, 3H), 3.58e4.14 (m, 6H), 5.18e5.41 (m, 4H),
5.74 (s, 1H), 6.08 (s, 2H), 7.15 (s, 1H), 7.30 (d, J¼8.4 Hz, 1H), 7.49 (d,
J¼8.4 Hz, 1H), 7.63 (d, J¼8.6 Hz, 1H), 7.69 (s, 1H), 7.80 (d, J¼8.4 Hz,
1H). 13C NMR (75 MHz, DMSO-d6):
d 15.8, 15.9, 16.0, 41.2, 62.3, 65.1,
66.2, 77.9, 85.3, 94.6, 98.8, 101.3, 101.7, 105.3, 117.5, 120.0, 120.9,
124.0, 126.7, 126.9, 127.3, 131.8, 139.4, 144.8, 148.0, 148.6, 150.2. IR
(cmꢁ1): 2975, 2899, 1494, 1465, 1241, 1114, 937. MS (APCI): m/
z¼436.3 [MþHꢁEtOH]þ. Anal. Calcd for C27H31NO7 (481.5): C, 67.34;
H, 6.49; N, 2.91. Found: C, 67.39; H, 6.71; N, 2.86.
1H NMR (300 MHz, DMSO-d6):
d 4.90 (s, 3H), 6.32 (s, 2H), 7.71 (s,
1H), 7.89 (d, J¼8.8 Hz, 1H), 8.16e8.29 (m, 2H), 8.36 (d, J¼8.8 Hz, 1H),
8.66 (d, J¼8.8 Hz, 1H), 10.00 (s, 1H), 11.22 (br s, 2H). 13C NMR
(75 MHz, DMSO-d6):
d 52.2, 103.2, 104.7, 106.3, 114.5, 116.3, 119.2,
4.1.20. 1,2-Dihydroxy-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]phenan-
thridin-12-ium chloride (1a). (a) From 15: A mixture of the benzo[c]
phenanthridine 15 (50.0 mg, 0.138 mmol) in ethanol (5 mL) and 2 M
HCl (1.5 mL) was heated to reflux for 3 h. The formed precipitate
was filtered off, washed with water, and dried in vacuo at 60 ꢀC to
give an orange powder (40.2 mg, 86% yield). Mp over 300 ꢀC. 1H
120.8,125.9,127.2,128.8.131.1,131.5,132.4,144.6,145.0,149.0,149.1,
151.1, 158.7 (q, J¼36.6 Hz, CF3COO), CF3 was not detected due to low
concentration. IR (cmꢁ1): 3415, 2907, 1688, 1549, 1487, 1324, 1039,
1197. MS (APCI): m/z¼320.1 [M]þ. Anal. Calcd for C21H14F3NO6
(433.3): C, 58.21; H, 3.26; N, 3.23. Found: C, 57.96; H, 3.36; N, 3.40.
NMR (300 MHz, DMSO-d6):
d 6.24 (s, 2H), 7.56 (s, 1H), 7.63 (d,
Acknowledgements
J¼8.8 Hz, 1H), 8.02 (d, J¼9.0 Hz, 1H), 8.24 (d, J¼9.0 Hz, 1H),
8.49e8.60 (m, 2H), 9.64 (s, 1H), 10.11 (br s, 2H). IR (cmꢁ1): 3169,
2838, 1623, 1479, 1298, 1034. MS (APCI): m/z¼306.2 [MþH]þ; 304.2
[MꢁH]ꢁ. Anal. Calcd for C18H12ClNO4 (341.8): C, 63.26; H, 3.54; N,
4.10. Found: C, 63.03; H, 3.77; N, 3.97.
This work was supported by the Operational Program Research
and Development for Innovations (Project CZ.1.05/2.1.00/01.0030)
and Operational Program Education for Competitiveness (Project
CZ.1.07/2.4.00/31.0130).
(b) From 21: A solution of the benzo[c]phenanthridine 21
(7.0 mg, 0.017 mmol) in ethanol (1.5 mL) and 2 M HCl (0.5 mL) was
heated in a sealed vial at 90 ꢀC for 2 h. The precipitate was filtered
off, washed with water, and dried in vacuo at 60 ꢀC to give an or-
ange powder (4.2 mg, 74% yield) with the identical spectral prop-
erties as the compound prepared above.
Supplementary data
Spectroscopic data (1H and 13C NMR) of synthesized compounds
1ae22 are available in the Supplementary data. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.03.105.
4.1.21. 1,2-Dihydroxy-[1,3]dioxolo[40,50:4,5]benzo[1,2-c]phenan-
thridin-12-ium trifluoroacetate (1b). The benzo[c]phenanthridine
21 (40.0 mg, 0.095 mmol) was dissolved under stirring in TFA
(2.0 mL) at room temperature. After 5 min, an orange solid, pre-
dominantly consisting of the monodeprotected compound, started
to precipitate from a solution. Quantitative deprotection of both
EOM groups was reached after 12 h under continuous stirring. Most
of the TFA was removed in vacuo and the remaining part by co-
distillation with methanol. The solid residue was suspended in
water (2 mL), filtered off, washed with a small amount of water, and
dried in vacuo at 60 ꢀC to give an orange powder (27.0 mg, 68%
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d 6.23
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