Functionalized phenanthridine and dibenzopyranone derivatives through benzyne cyclization - Application to the total syntheses of trisphaeridine and N-methylcrinasiadine

Article abstract of DOI:10.1002/ejoc.200600621

A series of regioselectively functionalized benzo[c]chromen-6-ones, phenanthridinones, and phenanthridine derivatives have been prepared by an anionic cyclization and in situ oxidation sequence starting from 2-bromobenzyl-2-fluorophenyl ethers and amines.

Full text of DOI:10.1002/ejoc.200600621

FULL PAPER
DOI: 10.1002/ejoc.200600621
Functionalized Phenanthridine and Dibenzopyranone Derivatives through
Benzyne Cyclization – Application to the Total Syntheses of Trisphaeridine and
N-Methylcrinasiadine
Roberto Sanz,*[a] Yolanda Fernández,[a] M. Pilar Castroviejo,[a] Antonio Pérez,[a] and
Francisco J. Fañanás[b]
Keywords: Anionic cyclizations / Organolithiums / Nitrogen heterocycles / Oxygen heterocycles / Benzynes / Synthetic
methods
A series of regioselectively functionalized benzo[c]chromen-
quent 6-exo-dig cyclization. By applying this methodology to
6-ones, phenanthridinones, and phenanthridine derivatives
the appropriate starting materials, short and efficient synthe-
have been prepared by an anionic cyclization and in situ oxi- ses of Amaryllidaceae alkaloids trisphaeridine and N-meth-
dation sequence starting from 2-bromobenzyl-2-fluorophenyl
ethers and amines. These processes involve the generation
of a benzyne-tethered aryllithium intermediate and subse-
ylcrinasiadine have been achieved in good overall yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
cess that allows the efficient preparation of dihydrophen-
anthridine, dibenzopyran, and dibenzothiopyran derivatives
2 in good yields (Scheme 1).[12b]
Introduction
Benzynes are highly electrophilic intermediates which
have been widely used as versatile intermediates in organic
synthesis.[1,2] The intramolecular addition of an aryne-teth-
ered nucleophile, a process often called benzyne cycliza-
tion,[3] is a well-developed strategy for the creation of
benzo-fused carbocycles and heterocycles.[4] This strategy
has been successfully applied to the synthesis of a variety
of heterocyclic compounds such as benzoxazole,[5] benzo-
thiazole,[6] indoline,[7] isoindolinone,[8] and chromene[9] de-
rivatives. In the vast majority of the reported examples, the
nucleophile is a stabilized carbanion,[10] or a nitrogen, oxy-
gen, or sulfur anion. However, the formation and cycliza-
tion of benzyne-tethered organolithiums remains a largely
unexplored area and only a few examples with alkyllithiums
have been reported.[11]
Scheme 1.
In this field, we have reported the intramolecular 5-exo
anionic cyclization of benzyne-tethered vinyl and aryllithi-
ums and its application to the synthesis of regioselectively
functionalized indole, carbazole, dibenzofuran, and di-
benzothiophene derivatives.[12] We have also demonstrated
the possibility of carrying out 6-exo cyclizations in a pro-
The phenanthrene-type skeleton is present in many natu-
ral products either in the carbocyclic or heterocyclic form.
The Amaryllidaceae alkaloids are a group of natural prod-
ucts having in most cases a phenanthridine-type struc-
ture.[13] Two examples of this group of alkaloids that have
been isolated from a few plants of Amaryllidaceae are tris-
phaeridine[14] and N-methylcrinasiadine[15] (Scheme 1).
These and other phenanthridine and phenanthridinone al-
kaloids have been previously synthesized by several meth-
ods including palladium-catalyzed couplings and further
cyclizations,[16] radical cyclizations,[17] or benzyne-mediated
condensations,[18] among other synthetic methods.[19] These
processes, however, generally lack the flexibility that would
make them suitable for the regioselective introduction of
[a] Área de Química Orgánica, Departamento de Química, Facul-
tad de Ciencias, Universidad de Burgos,
Pza. Misael Bañuelos s/n, 09001 Burgos, Spain
Fax: +34-947258831
E-mail: rsd@ubu.es
[b] Instituto Universitario de Química Organometálica “Enrique
Moles”, Unidad Asociada al C.S.I.C., Universidad de Oviedo,
C/Julián Clavería, 8, 33006 Oviedo, Spain
Fax: +34-985103450
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
62
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Phenanthridine and Dibenzopyranone Derivatives through Benzyne Cyclization
FULL PAPER
functional groups in the same step in which the cyclization which allows easy separation and purification of desired di-
process takes place. benzopyranones 3. In this way, regioselectively function-
Substituted 6H-dibenzo[b,d]pyran-6-ones are widespread alized dibenzopyranones 3a–e have been synthesized in
in nature and exhibit biological activities.[20] In addition, moderate-to-good yields starting from ethers 1a,b
these compounds have been used as intermediates in the (Scheme 2; Table 1, Entries 1–5). For the synthesis of di-
synthesis of cannabinoids and various pharmaceutically benzopyranone 3d, an additional equivalent of PCC was
interesting compounds with potential application as proges- needed because of the oxidation of the initially introduced
terone receptor agonists.[21] Among the various strategies hydroxy(p-tolyl)methyl group to the corresponding ketone.
developed for the synthesis of 6H-dibenzo[b,d]pyran-6-
ones,[22] most of them rely on intramolecular palladium-cat-
alyzed arylation reactions,[23] copper-catalyzed condensa-
tion of 2-bromobenzoic acids with phenols (Hurtley reac-
tion),[24] dienone-phenol rearrangements,[25] or intramolec-
ular radical cyclizations.[26] However, with the use of these
methodologies it is not possible to introduce functional
groups in the cyclization step and highly functionalized
starting materials, not always easily available, are generally
needed to generate regioselectively substituted heterocycles.
Firmly convinced by the potential of the anionic cycliza-
tion of benzyne-tethered aryllithiums as a useful methodol-
ogy for the synthesis of functionalized heterocycles, we initi-
ated a project directed at the search of a protocol for the in
situ oxidation of dibenzo-fused six-membered heterocycles
Scheme 2. Synthesis of dibenzo[b,d]pyran-6-ones 3, phenanthridi-
nones 4, and phenanthridines 5; reagents and conditions: i) tBuLi
(3.3 equiv. for 1a,b, 3.5 equiv. for 1c,d), THF, –110 to 20 °C; ii) E+
(1.5 equiv.), –78 to 20 °C; iii) for 1d, DIBAL-H (1.5 equiv.),
[NiCl2(dppp)] (4 mol-%), toluene, 20 °C; iv) PCC (3 equiv. for 2a–
c, 1 equiv. for 2d), CH2Cl2, reflux.
2. Thus, in this paper we report that regioselectively func-
tionalized phenanthridine and dibenzopyranone derivatives
could be efficiently accessed by anionic cyclization of
benzyne intermediates and further functionalization and
benzylic oxidation. Also, this strategy has been applied to
the short and efficient syntheses of Amaryllidaceae alka-
loids trisphaeridine and N-methylcrinasiadine.
When we applied this strategy to N-(2-bromobenzyl)-2-
fluoro-N-methylaniline (1c), 5H-phenanthridin-6-ones 4
were isolated after benzylic oxidation with PCC of dihy-
drophenanthridine intermediates 2c (Scheme 2; Table 1, En-
tries 6 and 7). Finally, treatment of N-allyl-N-(2-bromoben-
zyl)-2-fluoroaniline (1d) under the same reaction conditions
Results and Discussion
Our studies started with the model reaction of 2-bro- gave rise to 1-functionalized 5-allyl-5,6-dihydrophenanthri-
mobenzyl-2-halophenyl ethers 1a,b, which under treatment dines. Without isolation, the allyl group was easily removed
with 3.3 equiv. of tBuLi in THF from –110 to 20 °C, and by treatment with DIBAL-H and catalytic [NiCl2(dppp)] in
further reaction with different electrophiles, afforded corre- toluene,[27] and crude dihydrophenanthridines 2d were
sponding dibenzopyrans 2a,b.[12b] Without purification, we treated with PCC. In this case, no oxidation of the benzylic
found that 6H-benzo[c]chromenes 2a,b were efficiently oxi- methylene was observed and 1-functionalized phenanthrid-
dized to corresponding 6H-benzo[c]chromen-6-ones 3 with ines 5 were obtained instead of the N-unsubstituted phen-
the use of PCC as an oxidant in CH2Cl2 heated at re- anthridones (Scheme 2; Table 1, Entries 8 and 9). We attrib-
flux.[26b] Moreover, we have observed that the benzylic uted this unexpected result to the absence of substituents on
methylene in the chromene derivatives was selectively oxid- the nitrogen atom in dihydrophenanthridines 2d, compared
ized over the benzylic methylene in uncyclized byproducts, with 2c, which could favor the observed dehydrogenation
Table 1. Synthesis of dibenzo[b,d]pyran-6-ones 3, phenanthridinones 4, and phenanthridines 5.
Entry
Starting product
X
Halogen
R
E+
Product
E
Yield [%][a]
1
2
3
4
5
6
7
8
9
1a
1a
1a
1b
1b
1c
1c
1d
1d
O
O
O
O
F
F
F
Cl
Cl
F
F
F
H
H
H
OMe
OMe
H
H
H
MeOH
Br(CH2)2Br
ClCO2Et
4-MeC6H4CHO 3d
ClCO2Et
3a
3b
3c
H
Br
63
55
CO2Et
4-MeC6H4CO
CO2Et
SPh
CO2Et
Br
57
73[b]
68
O
NMe
NMe
NCH2CH=CH2
NCH2CH=CH2
3e
4a
4b
5a
5b
Ph2S2
36[c]
70
ClCO2Et
Br(CH2)2Br
ClCO2Et
72
F
H
CHO
65[d]
[a] Isolated yields after chromatography based on starting material 1. [b] 4 equiv. of PCC were used. [c] Lower yield is probably due to
further oxidation of the thioether group. [d] 2 equiv. of PCC were used.
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63

R. Sanz, Y. Fernández, M. P. Castroviejo, A. Pérez, F. J. Fañanás
FULL PAPER
after the initial benzylic oxidation. The synthesis of 1-for-
mylphenanthridine 5b was carried out by treatment of 1d
with tBuLi and ethyl chloroformate as the electrophile. The
deallylation process also reduced the ethoxycarbonyl group
to a hydroxymethyl group, and the final reaction with PCC
led to dehydrogenation and oxidation of the hydroxymethyl
group to a formyl functionality.
It is interesting to remark that in all cases, final regiose-
lectively functionalized heterocycles 3–5 were obtained in
moderate-to-good overall yields relative to easily available
starting compounds 1 without the isolation of any interme-
diate product. For instance, the previously reported synthe-
sis of 1-bromophenathridine 5a has been performed in sev-
eral inefficient steps.[28]
Scheme 3. Synthesis of trisphaeridine 7a; reagents and conditions:
i) tBuLi (3.5 equiv.), THF, –110 to 20 °C; ii) E+ (MeOH, excess or
Br(CH2)2Br, 1.5 equiv.), –78 to 20 °C; iii) DIBAL-H (1.5 equiv.),
[NiCl2(dppp)] (4 mol-%), toluene, 20 °C; iv) PCC (1 equiv.),
CH2Cl2, reflux.
The development of this convenient and efficient syn-
thetic route to phenanthridines[29] led us to consider testing
it in the synthesis of trisphaeridine, a phenanthridine alka-
loid from the Amaryllidaceae plant family.[14] Taking into
account the preparation of phenanthridines 5, we envisaged
that N-allyl-N-(2-bromo-4,5-methylenedioxybenzyl)-2-fluo-
roaniline (6a) could be a suitable precursor for the synthesis
of trisphaeridine (Scheme 3). Alkylation of the lithium
amide of readily available N-allyl-2-fluoroaniline[12b] with 2-
bromo-4,5-methylenedioxybenzyl bromide[30] afforded terti-
ary amine 6a in 78% yield.[31] To our delight, when we sub-
jected amine 6a to the above referred reaction conditions,
trisphaeridine 7a was isolated in good overall yield without
isolation of any intermediate product (Scheme 3). First,
treatment of 6a with tBuLi from –110 °C to room tempera-
ture gives rise to benzyne-tethered aryllithium 8 which un-
dergoes an anionic cyclization leading to organolithium 9.
Quenching of the reaction with methanol and removal of
the allyl group with DIBAL-H then affords dihydrophen-
anthridine derivative 10, which on dehydrogenation with
PCC gives rise to isolated phenanthridine 7a. Their physical
and spectroscopic data were identical with those of natural
and synthetic trisphaeridine in all respects.[32] Interestingly,
by using this methodology it is possible to access to func-
tionalized analogues of this natural product substituted at
C-1 by simple treatment of intermediate anion 9 with other
electrophiles. In this way, potentially useful bromine-substi-
tuted phenanthridine 7b could be regioselectively obtained
(Scheme 3). This result also supports the intermediacy of
proposed organolithium 9.
loid that they named 5,6-dihydrobicolorine and, on the ba-
sis of the NMR spectroscopic data, assigned dihydrophen-
anthridine structure 12a.[33] Four years later, Banwell and
coworkers developed a three-step synthesis of 12a[34] and
showed that their synthetic material was spectroscopically
different from the natural product previously characterized
as 5,6-dihydrobicolorine. A comparison of our spectro-
scopic data[32] for 12a with the data reported by Codina[33]
and Banwell,[34a] respectively, revealed that the first pro-
posed structure of 5,6-dihydrobicolorine is not represented
by compound 12a and so, we corroborated the conclusions
outlined by Banwell in his paper. Again, a regioselectively
functionalized derivative of the dihydrophenanthridine par-
ent, 12b, could be obtained by quenching the reaction with
a selected electrophile (Scheme 4).
To examine the general applicability of this methodology
for the synthesis of phenanthridine alkaloids, we next
attempted the
synthesis of
N-methylcrinasiadine
(Scheme 1).[15] With this goal in mind we synthesized amine
6b[31] and subjected it to the usual anionic cyclization reac-
tion conditions (Scheme 4). After quenching with meth-
anol, dihydrophenanthridine intermediate 12a proved to be
Scheme 4. Synthesis of N-methylcrinasiadine 11 and the putative
structure of 5,6-dihydrobicolorine 12a.
Because of the biological significance of benzo-fused
unstable and, upon heating, underwent air oxidation to give phenanthridine alkaloids,[35] we decided to check if our
N-methylcrinasiadine alkaloid 11 in good overall yield methodology could be applied to the synthesis of benzo[k]-
(Scheme 4).[32] Despite the instability of 12a and because of phenanthridines.[36] With this idea in mind, N-allyl-N-(1-
the controversy existing in the literature about this com- bromo-2-naphthylmethyl)-2-fluoroaniline (6c) was prepared
pound, we also isolated and characterized it. In 1990, dur- by alkylation of N-allyl-2-fluoroaniline with 1-bromo-2-
ing the course of an alkaloidal investigation on Spanish bromomethylnaphthalene.[31] Treatment of 6c with tBuLi
Amaryllidaceae, Codina and coworkers isolated a new alka- (3.5 equiv.) in THF cooled at –110 °C, warming to room
64
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Phenanthridine and Dibenzopyranone Derivatives through Benzyne Cyclization
temperature, and further addition of MeOH gave rise to
FULL PAPER
Conclusions
5-allyl-5,6-dihydrobenzo[k]phenanthridine[37] (18a) (E = H)
through anionic cyclization of benzyne intermediate 15
(Scheme 5). Deallylated dihydrobenzo[k]phenanthridine
13a was easily obtained in good overall yield in an analo-
gous way as described for phenanthridine synthesis
(DIBAL-H in the presence of a catalytic amount of
[NiCl2(dppp)]). Benzo[k]phenanthridine 14a was then ob-
tained almost quantitatively by dehydrogenation with PCC
(Scheme 5). Next, we tried to prepare a functionalized
benzo[k]phenanthridine derivative, and it was carried out
by trapping supposed organolithium 16, generated by the
anionic cyclization on benzyne intermediate 15, with tribu-
tyltin chloride. Surprisingly, after deallylation two different
regioisomers 13b and 13c were obtained in ca. 2:1 ratio.
Major isomer 13b was functionalized at C-1, whereas 13c
was functionalized at C-12. Again, dehydrogenation of
13b,c under treatment with PCC gave rise to tributyltin-
substituted benzo[k]phenanthridines 14b,c in very good
yields (Scheme 5).
In summary, we have demonstrated a simple synthetic
procedure for the preparation of phenanthrene-type hetero-
cycles. This anionic cyclization provides an efficient method
for the synthesis of dibenzopyranones, phenanthridinones,
and phenanthridines. In contrast with other methods, our
procedure allows the regioselective introduction of func-
tional groups at C-1 in the cyclization step. On the basis
of this methodology, concise syntheses of phenanthridine
alkaloids trisphaeridine and N-methylcrinasiadine have
been developed.
Experimental Section
General Remarks: Reactions requiring an inert atmosphere were
carried out under an atmosphere of dry nitrogen in oven-dried
glassware. THF was continuously refluxed and freshly distilled
from sodium/benzophenone ketyl immediately prior to use. Flash
column chromatography was carried out on silica gel 230–
400 mesh. Compounds were visualized on analytical thin layer
chromatograms (TLC) by UV light (254 nm) and stained with a
solution of phosphomolybdic acid. Melting points were measured
with a Büchi-Tottoli apparatus with open capillary tubes and are
1
uncorrected. H NMR and 13C NMR spectra were recorded with
400, 300, or 200 MHz Varian spectrometers with CDCl3 (δ =
7.16 ppm in 1H NMR spectra and δ = 76.95 ppm in 13C NMR
1
spectra) or [D6]DMSO (δ = 2.50 ppm in H NMR spectra and δ =
39.52 ppm in 13C NMR spectra) as internal standards by use of
the DEPT pulse sequence. GC–MS analyses were performed with
an HP 6890N/5973 equipped with an HP-5MS column, with a gra-
dient of 150–300 °C (30 °C/min step), and the low-resolution elec-
tron impact mass spectra (EI-LRMS) were obtained at 70 eV (only
the molecular ions and/or base peaks are given). High-resolution
mass spectrometry was carried out with a Micromass Autospec
spectrometer. Elemental analyses were performed with Perkin–
Elmer and LECO elemental analyzers. Only the most important
IR absorptions are given. All commercially available reagents were
used without further purification and were purchased from Aldrich
Chemical Co. or Acros Organics. tBuLi was used as a 1.5  solu-
tion in pentane. BuLi was used as a 2.5  solution in hexane. Com-
pounds 1 were synthesized in our previous work.[12b]
General Procedure for the Synthesis of 1-Functionalized 6H-Di-
benzo[b,d]pyran-6-ones 3 and 5-Methyl-5H-phenanthridin-6-ones 4:
A solution of starting ether 1a,b or amine 1c (2 mmol) in THF
(15 mL) was treated with tBuLi (4.4 mL, 6.6 mmol for 1a,b or
4.7 mL, 7 mmol for 1c) at –110 °C.[12b] The reaction mixture was
stirred for 15 min at this temperature, and the cooling bath was
removed to allow the reaction to reach room temperature for
30 min. The reaction mixture was re-cooled to –78 °C, and the cor-
responding electrophile (3 mmol) was added. The mixture was al-
lowed to reach room temperature and stirred for 3 h. The mixture
was then quenched with water and extracted with EtOAc
(3ϫ15 mL). The combined organic layers were dried with anhy-
drous Na2SO4, the solvent was evaporated, and the residue was
dissolved in CH2Cl2 (20 mL) and treated with PCC (0.431 g,
2 mmol). The reaction mixture was stirred under reflux for 1 h and
then another portion of PCC (0.862 g, 4 mmol) was added and
the stirring continued under reflux for 24 h. After cooling to room
temperature, the precipitate was filtered through a Celite plug and
washed with CH2Cl2 (4ϫ10 mL). The resulting solution was
washed with brine, dried, and the solvents evaporated to dryness.
Scheme 5. Synthesis of dihydrobenzo[k]phenanthridines 13 and
benzo[k]phenanthridines 14; reagents and conditions: i) tBuLi
(3.5 equiv.), THF, –110 to 20 °C; ii) E+ (1.5 equiv.), –78 to 20 °C;
iii) DIBAL-H (1.5 equiv.), [NiCl2(dppp)] (4 mol-%), toluene, 20 °C;
iv) PCC (1 equiv.), CH2Cl2, reflux.
A proposal that accounts for the formation of two re-
gioisomeric compounds 13 is outlined in Scheme 5. Ex-
pected cyclized organolithium 16 has the lithium atom at
C-1 but it could be translocated[38] from C-1 to C-12 to
afford organolithium 17. We think that the ease of this C-
[1,5] lithium shift[39] can be attributed to the steric situation
in organolithium 16. An equilibrium between both anionic
intermediates 16 and 17 could take place, and so, a mixture
of regioisomers 13b,c is obtained after quenching with the
selected electrophile (Scheme 5).
Eur. J. Org. Chem. 2007, 62–69
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65

R. Sanz, Y. Fernández, M. P. Castroviejo, A. Pérez, F. J. Fañanás
FULL PAPER
Column chromatography with hexane/EtOAc as the eluent afforded
products 3 and 4.
was treated with BuLi (4 mL, 10 mmol) at –50 °C. The reaction
mixture was stirred for 15 min, allowed to reach room temperature,
and stirring was continued for 45 min. The reaction mixture was
cooled to –50 °C and the corresponding dibromo derivative
(10 mmol) was added. After 15 min at this temperature, the reac-
tion was warmed up and stirring was continued for 5 h. The mix-
ture was quenched with water, extracted with EtOAc (3ϫ15 mL),
and the combined organic layers were washed with saturated aque-
ous Na2CO3 and dried with anhydrous Na2SO4. The solvents were
removed under vacuum and the residue was purified by silica gel
column chromatography (hexane/EtOAc) to afford the correspond-
ing tertiary amine.
1-Bromo-6H-benzo[c]chromen-6-one (3b): Treatment of ether 1a
(0.562 g, 2 mmol) with tBuLi (4.4 mL, 6.6 mmol) was followed by
the addition of 1,2-dibromoethane (0.564 g, 3 mmol). Further reac-
tion with PCC (1.293 g, 6 mmol) in CH2Cl2 (20 mL) heated at re-
flux and workup as described above yielded 3b (0.303 g, 55%) as a
white solid. M.p. 173–175 °C. 1H NMR (400 MHz, CDCl3): δ =
9.46 (d, J = 8.4 Hz, 1 H), 8.44 (dd, J = 8.0, 1.6 Hz, 1 H), 7.84 (td,
J = 8.4, 1.6 Hz, 1 H), 7.65–7.58 (m, 2 H), 7.34 (dd, J = 8.0, 1.2 Hz,
1 H), 7.24 (t, J = 8.0 Hz, 1 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 160.3 (C), 152.5 (C), 133.9 (CH), 133.8 (C), 132.2
(CH), 130.6 (CH), 129.9 (CH), 129.2 (CH), 125.7 (CH), 121.9 (C),
119.0 (C), 117.7 (CH), 117.5 (C) ppm. LRMS (70eV, EI): m/z (%)
N-Allyl-N-(2-bromo-4,5-methylenedioxybenzyl)-2-fluoroaniline (6a):
Treatment of N-allyl-2-fluoroaniline[12b] (1.51 g, 10 mmol) with
BuLi (4 mL, 10 mmol) was followed by the addition of 2-bromo-
4,5-methylenedioxybenzyl bromide[30] (2.94 g, 10 mmol). Workup
as above yielded 6a (2.84 g, 78%) as a white solid. M.p. 69–71 °C.
1H NMR (400 MHz, CDCl3): δ = 7.05–6.95 (m, 4 H), 6.90–6.82
(m, 2 H), 5.93 (s, 2 H), 5.94–5.86 (m, 1 H), 5.23–5.15 (m, 2 H),
4.33 (s, 2 H), 3.82 (d, J = 5.6 Hz, 2 H) ppm. 13C NMR (100.6 MHz,
CDCl3): δ = 155.0 (d, J = 242.9 Hz, C), 147.5 (C), 147.1 (C), 138.0
(d, J = 7.6 Hz, C), 134.3 (CH), 131.0 (C), 124.1 (CH), 121.1 (d, J
= 7.8 Hz, CH), 120.1 (CH), 117.5 (d, J = 3.1 Hz, CH2), 116.3 (d,
J = 21.5 Hz, CH), 113.1 (C), 112.5 (CH), 108.9 (CH), 101.5 (CH2),
55.5 (d, J = 3.0 Hz, CH2), 55.4 (d, J = 3.8 Hz, CH2) ppm. LRMS
(70eV, EI): m/z (%) = 365 (2) [M + 2]+, 363 (2) [M]+, 215 (99), 213
(100). C17H15BrFNO2 (364.2): calcd. C 56.06, H 4.15, N 3.85;
found C 56.19, H 4.21, N 3.80.
= 276 (100) [M + 2]+, 274 (100) [M]+. IR (KBr): ν = 3071, 1735,
˜
1600, 1413, 1223, 924, 706 cm–1. C13H7BrO2 (275.1): calcd. C
56.76, H 2.56; found C 56.94, H 2.61.
General Procedure for the Synthesis of 1-Functionalized Phenanthri-
dines 5: A solution of amine 1d (0.640 g, 2 mmol) in THF (15 mL)
was treated with tBuLi (4.7 mL, 7 mmol) at –110 °C. The reaction
mixture was stirred for 15 min at this temperature and the cooling
bath was then removed to allow the mixture to reach room tem-
perature for 30 min. The reaction mixture was re-cooled to –78 °C
and the corresponding electrophile (3 mmol) was added. After
15 min at this temperature, the reaction was allowed to reach room
temperature and stirring was continued for 3 h. The mixture was
quenched with water, extracted with EtOAc (3ϫ15 mL), and the
combined organic layers were washed with saturated aqueous
Na2CO3 and dried with anhydrous Na2SO4. The solvents were re-
moved under reduced pressure. The residue and [NiCl2(dppp)]
(0.043 g, 0.08 mmol) were dissolved in toluene (6 mL). DIBAL-H
(2 mL, 1.5  solution in toluene, 3 mmol for 5a, or 4.7 mL, 7 mmol
for 5b) was added at 0 °C and the temperature was increased to
room temperature. After stirring for 2 h, the mixture was treated
with NaOH (0.5 , 2 mL) and Et2O (9 mL), stirred for 1 h, and
then dried directly over anhydrous MgSO4. After evaporation of
the solvent, the residue was dissolved in CH2Cl2 (20 mL) and
treated with PCC (0.431 g, 2 mmol for 5a, or 0.862 g, 4 mmol for
5b). The reaction mixture was stirred under reflux for 2 h. After
cooling to room temperature, the precipitate was filtered through
a Celite plug and washed with CH2Cl2 (4ϫ10 mL). The resulting
solution was extracted with brine, dried with Na2SO4, and the sol-
vents evaporated to dryness. Column chromatography on silica gel
(hexane/EtOAc) afforded compounds 5.
Synthesis of [1,3]Dioxolo[4,5-j]phenanthridine (Trisphaeridine) (7a)
and 1-Bromo[1,3]dioxolo[4,5-j]phenanthridine (7b): A solution of
amine 6a (0.728 g, 2 mmol) in THF (15 mL) was treated with tBuLi
(4.7 mL, 7 mmol) at –110 °C. The reaction mixture was stirred for
15 min at this temperature and the cooling bath was then removed
to allow the mixture to reach room temperature for 30 min. The
reaction mixture was re-cooled to –78 °C and the corresponding
electrophile (3 mmol for 1,2-dibromoethane or excess for MeOH)
was added. After 15 min at this temperature, the reaction was al-
lowed to reach room temperature and stirring was continued for
3 h. The mixture was quenched with water, extracted with EtOAc
(3ϫ15 mL), and the combined organic layers were washed with
saturated aqueous Na2CO3 and dried with anhydrous Na2SO4. The
solvents were removed under reduced pressure. The residue and
[NiCl2(dppp)] (0.043 g, 0.08 mmol) were dissolved in toluene
(6 mL). DIBAL-H (2 mL, 1.5  solution in toluene, 3 mmol) was
added at 0 °C and the temperature was increased to room tempera-
ture. After stirring for 2 h, the mixture was treated with NaOH
(0.5 , 2 mL) and Et2O (9 mL) for 1 h and it was then dried directly
over anhydrous MgSO4. After evaporation of the solvent, the resi-
due was dissolved in CH2Cl2 (20 mL) and it was treated with PCC
(0.431 g, 2 mmol). The reaction mixture was stirred under reflux
for 2 h. After cooling to room temperature, the precipitate was fil-
tered through a Celite plug and washed with CH2Cl2 (4ϫ10 mL).
The resulting solution was extracted with brine, dried with Na2SO4,
and the solvents evaporated to dryness. Column chromatography
(hexane/EtOAc) afforded compounds 7.
1-Bromophenanthridine (5a): Treatment of amine 1d (0.640 g,
2 mmol) with tBuLi (4.7 mL, 7 mmol) was followed by the addition
of 1,2-dibromoethane (0.564 g, 3 mmol). The residue was treated
with DIBAL-H (2.0 mL, 3 mmol) and [NiCl2(dppp)] (0.04 g,
0.08 mmol). Further reaction with PCC (0.431 g, 2 mmol) in
CH2Cl2 (20 mL) at reflux and workup as described above yielded
5a (0.395 g, 72%) as a white solid. M.p. 101–103 °C (ref.[28b] 97–
99 °C). 1H NMR (400 MHz, CDCl3): δ = 9.93 (d, J = 8.8 Hz, 1
H), 9.16 (s, 1 H), 8.11 (dd, J = 8.0, 1.6 Hz, 1 H), 7.94 (dd, J = 8.0,
1.6 Hz, 1 H), 7.91 (dd, J = 8.0, 1.6 Hz, 1 H), 7.81–7.75 (m, 1 H),
7.65 (td, J = 8.0, 7.4 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H) ppm. 13C
NMR (50.3 MHz, CDCl3): δ = 154.2 (CH), 146.5 (C), 134.6 (CH),
131.7 (C), 130.5 (CH), 130.0 (CH), 128.7 (CH), 128.2 (CH), 127.7
(CH), 127.0 (C), 125.4 (CH), 122.9 (C), 118.5 (C) ppm. LRMS
(70eV, EI): m/z (%) = 259 (100) [M + 2]+, 257 (100) [M]+. IR (KBr):
Trisphaeridine [1,3]Dioxolo[4,5-j]phenanthridine (7a): Treatment of
amine 6a (0.728 g, 2 mmol) with tBuLi (4.7 mL, 7 mmol) was fol-
lowed by the addition of MeOH (excess). The residue was treated
with DIBAL-H (2.0 mL, 3 mmol) and [NiCl2(dppp)] (0.04 g,
0.08 mmol). Workup as above yielded 7a (0.214 g, 48%) as a white
solid. M.p. 138–140 °C (ref.[34b] 144.5–145 °C). 1H NMR
(400 MHz, CDCl3): δ = 9.08 (s, 1 H), 8.37 (dd, J = 8.4, 1.2 Hz, 1
ν = 1584, 1553, 908, 807, 753, 613 cm–1. HRMS: calcd. for
˜
C13H8BrN 256.9840; found 256.9848.
General Procedure for the Synthesis of Amines 6: A solution of the
corresponding N-alkyl-2-fluoroaniline (10 mmol) in THF (15 mL)
66
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Eur. J. Org. Chem. 2007, 62–69

Phenanthridine and Dibenzopyranone Derivatives through Benzyne Cyclization
FULL PAPER
H), 8.13 (dd, J = 7.4, 1.2 Hz, 1 H), 7.91 (s, 1 H), 7.68 (td, J = 7.5,
1.2 Hz, 1 H), 7.62 (td, J = 7.5, 1.5 Hz, 1 H), 7.33 (s, 1 H), 6.17 (s,
2 H) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 151.7 (CH), 151.5
5,6-Dihydrobenzo[k]phenanthridine (13a): Treatment of amine 6c
(0.741 g, 2 mmol) with tBuLi (4.7 mL, 7 mmol) was followed by
the addition of MeOH (excess). The residue was treated with DI-
(C), 148.2 (C), 144.0 (C), 130.3 (C), 130.0 (CH), 128.0 (CH), 126.7 BAL-H (2.0 mL, 3 mmol) and [NiCl2(dppp)] (0.04 g, 0.08 mmol).
(CH), 124.3 (C), 123.0 (C), 122.0 (CH), 105.5 (CH), 101.9 (CH2),
Workup as above yielded 13a (0.301 g, 65%) as a colorless oil. Rf
= 0.32 (hexane/EtOAc, 5:1). 1H NMR (200 MHz, CDCl3): δ =
8.68–8.61 (m, 1 H), 8.04 (dd, J = 8.0, 1.2 Hz, 1 H), 7.95–7.88 (m,
1 H), 7.76 (d, J = 8.2 Hz, 1 H), 7.61–7.46 (m, 2 H), 7.29 (d, J =
8.6 Hz, 1 H), 7.21 (dd, J = 7.5, 1.6 Hz, 1 H), 7.04 (td, J = 7.6,
1.2 Hz, 1 H), 6.87 (dd, J = 7.6, 1.2 Hz, 1 H), 4.34 (s, 2 H), 3.90
(br. s, 1 H) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 148.2 (C),
134.3 (C), 134.1 (C), 129.5 (C), 128.8 (C), 128.62 (CH), 128.60
(CH), 127.9 (CH), 127.4 (CH), 126.2 (CH), 125.6 (CH), 125.1
(CH), 123.9 (CH), 123.4 (C), 119.0 (CH), 115.6 (CH), 47.8 (CH2)
ppm. LRMS (70eV, EI): m/z (%) = 231 (45) [M+], 230 (100). IR
99.9 (CH) ppm. LRMS (70eV, EI): m/z (%) = 223 (100) [M]+. IR
(KBr): ν = 2904, 1615, 1576, 1499, 1456, 1246, 831 cm–1. HRMS:
˜
calcd. for C14H9NO2 223.0633; found 223.0626.
Synthesis of 5-Methyl-[1,3]dioxolo[4,5-j]phenanthridin-6(5H)-one
(N-Methylcrinasiadine) (11) and 5,6-Dihydro-5-methyl[1,3]diox-
olo[4,5-j]phenanthridines (12): A solution of amine 6b (0.676 g,
2 mmol) in THF (15 mL) was treated with tBuLi (4.7 mL, 7 mmol)
at –110 °C. The reaction mixture was stirred for 15 min at this tem-
perature and the cooling bath was then removed to allow the mix-
ture to reach room temperature for 30 min. The reaction mixture
was re-cooled to –78 °C and the corresponding electrophile
(3 mmol for p-tolualdehyde or excess for MeOH) was added. After
15 min at this temperature, the reaction was allowed to reach room
temperature and stirring was continued for 3 h. The mixture was
quenched with water, extracted with EtOAc (3ϫ15 mL), and the
combined organic layers were washed with saturated aqueous
Na2CO3 and dried with anhydrous Na2SO4. The solvents were re-
moved under reduced pressure and the residue was purified by flash
column chromatography (hexane/EtOAc) to afford compounds 12.
To obtain 11, crude 12a was heated in an oven until a temperature
of 250 °C was reached. Upon cooling, the residue was purified by
column chromatography (hexane/EtOAc) to afford compound 11.
(KBr): ν = 3440, 3048, 1584, 1491, 765 cm–1. HRMS: calcd. for
˜
C17H13N 231.1048; found 231.1057.
Preparation of Benzo[k]phenanthridines 14: PCC (0.108 g,
0.5 mmol) was added to a solution of corresponding dihydrophen-
antridine 13 (0.5 mmol) in CH2Cl2 (10 mL). The reaction mixture
was stirred under reflux for 2 h. After cooling to room temperature,
the precipitate was filtered through a Celite plug and washed with
CH2Cl2 (3ϫ10 mL). The resulting solution was washed with brine,
dried, and the solvents evaporated to dryness. Silica gel column
chromatography (hexane/EtOAc) afforded products 14.
Benzo[k]phenanthridine (14a): Dihydrobenzophenanthridine 13a
(0.116 g, 0.5 mmol) was treated with PCC (0.108 g, 0.5 mmol).
Workup as described above yielded 14a (0.109 g, 95%) as a yellow
5-Methyl-[1,3]dioxolo[4,5-j]phenanthridin-6(5H)-one (N-Methylcrin-
asiadine) (11): Treatment of amine 6b (0.676 g, 2 mmol) with tBuLi
(4.7 mL, 7 mmol) was followed by the addition of MeOH (excess).
Workup as above yielded crude 12a which was heated to 250 °C.
Purification by column chromatography afforded 11 (0.329 g, 65%)
as a white crystalline solid. M.p. 246–248 °C (ref.[34b] 247.5–
248.5 °C). 1H NMR (300 MHz, CDCl3): δ = 8.10 (dd, J = 8.2,
1.2 Hz, 1 H), 7.91 (s, 1 H), 7.63 (s, 1 H), 7.53 (ddd, J = 8.2, 7.0,
1.2 Hz, 1 H), 7.41 (dd, J = 8.2, 1.2 Hz, 1 H), 7.31 (ddd, J = 8.2, 7.0,
1.2 Hz, 1 H), 6.13 (s, 2 H), 3.81 (s, 3 H) ppm. 13C NMR (75.4 MHz,
CDCl3): δ = 160.9 (C), 152.1 (C), 148.3 (C), 137.3 (C), 130.3 (C),
128.8 (CH), 122.8 (CH), 122.3 (CH), 121.2 (C), 119.1 (C), 115.0
(CH), 106.9 (CH), 101.9 (CH2), 100.4 (CH), 30.0 (CH3) ppm.
1
solid. M.p. 108–110 °C (ref.[36b] 108–110 °C). H NMR (400 MHz,
CDCl3): δ = 9.34 (br. s, 1 H), 9.16 (d, J = 8.0 Hz, 1 H), 9.07 (d, J
= 8.4 Hz, 1 H), 8.33 (br. s, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.99 (d,
J = 8.4 Hz, 1 H), 7.92 (d, J = 8.4 Hz, 1 H), 7.85–7.70 (m, 4 H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ = 152.4 (C), 146.1 (C),
135.1 (C), 131.3 (C), 130.0 (C), 128.9 (CH), 128.8 (CH), 128.7
(CH), 128.3 (CH), 128.0 (CH), 127.9 (CH), 127.0 (CH), 126.9
(CH), 126.8 (CH), 125.0 (CH), 124.5 (C) ppm. LRMS (70eV, EI):
m/z (%) = 229 (100) [M+]. IR (KBr): ν = 2923, 1579, 1451, 1381,
˜
818, 768 cm–1. HRMS: calcd. for C17H11N 229.0891; found
229.0885.
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic and characterization data for the rest of the
compounds. Copies of the NMR spectra of all products and com-
parison of the analytical data of 12a with the different data re-
ported for 5,6-dihydrobicolorine. Comparison of the spectroscopic
data of synthesized trisphaeridine 7a and N-methylcrinasiadine 11
with those of the reported natural and synthetic products.
LRMS (70eV, EI): m/z (%) = 253 (100) [M]+. IR (KBr): ν = 2919,
˜
1650, 1482, 1460, 1346, 1323, 1026, 932 cm–1. HRMS: calcd. for
C15H11NO3 253.0739; found 253.0745.
Preparation of Dihydrobenzo[k]phenanthridines 13a–c: A solution of
amine 6c (0.741 g, 2 mmol) in THF (15 mL) was treated with tBuLi
(4.7 mL, 7 mmol) at –110 °C. The reaction was stirred for 15 min
at this temperature and the cooling bath was then removed to allow
the reaction to reach room temperature for 30 min. The mixture
was re-cooled to –78 °C, and the corresponding electrophile
(3 mmol) was added. The mixture was allowed to reach room tem-
perature and the reaction was stirred for 3 h. The mixture was
quenched with water, extracted with EtOAc (3ϫ15 mL), and the
combined organic layers were washed with saturated aqueous
Na2CO3 and dried with anhydrous Na2SO4. The solvents were re-
moved under reduced pressure. For the removal of the allyl group,
the residue and [NiCl2(dppp)] (0.043 g, 0.08 mmol) were dissolved
in toluene (6 mL). DIBAL-H (2 mL, 1.5  solution in toluene,
3 mmol) was added at 0 °C and the temperature was increased to
room temperature. After stirring for 2 h, the mixture was treated
with NaOH (0.5 , 2 mL) and Et2O (9 mL) for 1 h and it was then
dried directly over anhydrous Na2SO4. After filtration and evapora-
tion of the solvent, the residue was purified by silica gel column
chromatography (hexane/EtOAc) to afford compounds 13.
Acknowledgments
We gratefully thank Junta de Castilla y León (BU012A06) and
Ministerio de Educación y Ciencia and FEDER (CTQ2004-08077-
C02-02/BQU) for financial support. M. P. C. thanks Ministerio de
Educación y Ciencia for a MEC-FPU predoctoral fellowship.
Many thanks are due to Dr. F. R. (Universidad de Oviedo) for
helpful comments.
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R. Sanz, Y. Fernández, M. P. Castroviejo, A. Pérez, F. J. Fañanás
FULL PAPER
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Prepared from piperonyl alcohol by treatment with Br2
1
(1.5 equiv.) in CHCl3. H NMR (400 MHz, CDCl3): δ = 7.00
(s, 1 H), 6.89 (s, 1 H), 5.98 (s, 2 H), 4.54 (s, 2 H) ppm. 13C
NMR (100.6 MHz, CDCl3): δ = 148.7, 147.6, 129.9, 115.6,
113.1, 110.5, 102.1, 34.1 ppm. LRMS (70eV, EI): m/z (%) =
296 (3) [M + 4]+, 294 (7) [M + 2]+, 292 (3) [M]+, 215 (100),
213 (100).
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See Experimental Section for the synthesis of tertiary amines
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See Supporting Information for comparison of NMR spectro-
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alkaloids, see: a) T. Nakanishi, M. Suzuki, A. Mashiba, K.
Ishikawa, T. Yokotsuka, J. Org. Chem. 1998, 63, 4235–4239; b)
T. Harayama, K. Shibaike, Heterocycles 1998, 49, 191–195; c)
T. Nakanishi, M. Suzuki, Org. Lett. 1999, 1, 985–988; d) T.
Harayama, T. Akiyama, H. Akamatsu, K. Kawano, H. Abe, Y.
Takeuchi, Synthesis 2001, 444–450; e) T. N. Le, S. G. Gang, W.-
J. Cho, J. Org. Chem. 2004, 69, 2768–2772.
[35]
[18]
[19]
[36]
Synthesis of benzo[k]phenanthridines: a) By photocyclization
of 4-phenyl-3-vinylquinolines, see: K. Veeramani, P. Shanmu-
gam, Indian J. Chem. 1987, 26B, 116–121; b) By cyclization of
[20]
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a) D. A. Young, D. Ferreira, D. G. Roux, J. Chem. Soc., Perkin
Trans. 1 1983, 2031–2035; b) S. Ghosal, J. Lal, S. K. Singh, Y.
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 62–69

Phenanthridine and Dibenzopyranone Derivatives through Benzyne Cyclization
FULL PAPER
aryl formamides, see: J. H. Boyer, J. R. Patel, Synthesis 1978,
205.
[38] For the introduction of the anion translocation concept, see:
A. Ahmed, J. Clayden, M. Rowley, Chem. Commun. 1998, 297–
298.
[37] 5-Allyl-5,6-dihydrobenzo[k]phenanthridine (18a): yellow solid.
M.p. 131–133 °C. 1H NMR (80 MHz, CDCl3): δ = 8.64–8.46 [39] Metal 1,n-shifts have been observed for some transition metal
(m, 1 H), 8.06–6.80 (m, 9 H), 6.26–5.70 (m, 1 H), 5.50–5.14
(m, 2 H), 4.14 (s, 2 H), 3.90 (dt, J = 5.8, 1.6 Hz, 2 H) ppm.
complexes. For a recent example, see: A. Singh, P. R. Sharp, J.
Am. Chem. Soc. 2006, 128, 5998–5999.
13C NMR (20.2 MHz, CDCl3): δ = 148.6, 134.8, 134.3, 133.9, [40] D. Crich, J.-T. Hwang, J. Org. Chem. 1998, 63, 2765–2770.
129.0, 128.8, 128.7, 128.2, 127.6, 127.3, 126.2, 125.8, 125.1,
124.8, 123.6, 118.2, 118.1, 113.6, 53.4, 53.3 ppm. LRMS (70eV,
Received: July 18, 2006
Published Online: October 27, 2006
EI): m/z (%) = 271 (42) [M]+, 41 (100). IR (KBr): ν = 3071,
˜
1631, 1600, 1370, 749 cm–1.
Eur. J. Org. Chem. 2007, 62–69
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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