Palladium-catalyzed annulation reactions of methyl o-halobenzoates with azabicyclic alkenes: A general protocol for the construction of benzo[c]phenanthridine derivatives

Article abstract of DOI:10.1039/c3ra42474j

The annulation reaction of methyl o-halobenzoates with azabicyclic alkenes proceeds efficiently to give the corresponding benzo[c]phenanthridine derivatives in good to excellent yields using a developed base-free methodology based on our preliminary studies. Thirty-seven application examples validate the compatibility of the present strategy with different groups, particularly with the electron-deficient ones, that are difficult to access using other traditional methods. In addition, annulation reactions with non-symmetric azabicyclic alkenes are achieved in high regioselectivity.

Full text of DOI:10.1039/c3ra42474j

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Palladium-catalyzed annulation reactions of methyl
o-halobenzoates with azabicyclic alkenes: a general
protocol for the construction of
Cite this: DOI: 10.1039/c3ra42474j
benzo[c]phenanthridine derivatives3
Cui Guo,{ Kanglun Huang,{ Bo Wang, Longguang Xie and Xiaohua Xu*
The annulation reaction of methyl o-halobenzoates with azabicyclic alkenes proceeds efficiently to give
the corresponding benzo[c]phenanthridine derivatives in good to excellent yields using a developed base-
free methodology based on our preliminary studies. Thirty-seven application examples validate the
compatibility of the present strategy with different groups, particularly with the electron-deficient ones,
that are difficult to access using other traditional methods. In addition, annulation reactions with non-
symmetric azabicyclic alkenes are achieved in high regioselectivity.
Received 19th May 2013,
Accepted 8th July 2013
DOI: 10.1039/c3ra42474j
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synthetic pathways of benzo[c]phenanthridine derivatives and
alkaloids in this family is increasingly becoming the primary
Introduction
Benzo[c]phenanthridines (Fig. 1) are naturally occurring
alkaloids widely distributed in the plants of the
Papaveraceae and Rutaceae families with a long history,1
dating back to their initial discovery in 1839.2 By reviewing a
considerable amount of relevant literature, we learned that the
majority of these alkaloids can mediate various biological
properties.3 Sanguinarine, which belongs to a fully aroma-
tized-type alkaloid, exhibits antibacterial4 and antifungal5
activities, whereas nitidine and fagaronine have been investi-
gated for being potential anti-tumor6 and antimalarial7 agents.
Chelidonine, a B/C-cis-hexahydro-type alkaloid representative
that indicates a wide range of pharmacological activities as
well, has been used successfully in experimental oncology.8
Over the last decades, syntheses of these natural products have
been an area of great interest for synthetic chemists, thereby
spurring the rapid development of efficient construction for a
benzo[c]phenanthridine skeleton.9 However, some of these
previously reported benzo[c]phenanthridine synthetic studies
involved multi-step sequences and lacked of generality needed
for these methods to be applied in the pharmaceutical
industry. In addition, an in-depth analysis on the National
Cancer Institute preliminary studies showed that the develop-
ment of several natural products of this family as pharmaceu-
ticals failed to be pursued because of its toxicity and
instability.10 Thus, the development of new and accessible
focus of heterocyclic chemistry. Such developments aim to
solve the toxicological or instability problems that accompany
some of the naturally occurring alkaloids and to find new
target molecules.11 For example, the synthesis and study of the
biological activities of cytostatically active aminodihydro
benzo[c]phenanthridines and NK109 derivatives have been
achieved by Clement12 and Nakanishi,13 respectively.
Substitutes of the natural benzo[c]phenanthridine nucleus
and their synthesizing analogues are almost electron-donating
groups similar to the alkoxy group, whereas a few electron-
deficient groups such as fluorine exist in this family.14 This
information may explain the low cytotoxic activity of some
analogues and the failure of the anti-tumor preclinical trials of
these natural substances. Consequently,
a general and
convergent route to construct varieties of benzo[c]phenanthri-
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin,
300071, People’s Republic of China. E-mail: xiaohuaxu@nankai.edu.cn;
Fax: +86-22-23501652; Tel: +86-22-23501652
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
c3ra42474j
Fig. 1 Naturally occuring benzo[c]phenanthridine alkaloids.
{ These authors contributed equally to this work.
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dines bearing either electron-donating or electron-withdraw-
ing groups is highly necessary.
The palladium-catalyzed ring opening of meso heterobicyc-
lic alkenes, conceived by Lautens, Martin and others,
constitutes an interesting concept in opening new routes to
complex fused ring systems.15 Driven by these findings, a
facile and general method for constructing the ring system of
benzo[c]phenanthridine alkaloids via palladium-mediated
annulation reactions of azabicyclic alkene with methyl
o-iodobenzoates has been reported by our laboratory and
applied in the total synthesis of four typical benzo[c]phenan-
thridine alkaloids.16 In these annulation reactions, electron-
rich substrates generally produced satisfactory yields.
However, the yields were extraordinarily poor when electron-
deficient coupling substrates were tested. Based on these
initial results, we further studied various electron-deficient
methyl o-iodobenzoates to ascertain the scope of tolerance of
its substituent in this annulation reaction and a base-free
methodology was developed. This paper reports the successful
improvement of our developed protocol for the construction of
benzo[c]phenanthridine nucleus using methyl o-halobenzoates
as coupling substrates with azabicyclic alkenes.
Fig. 2 Structures of the two by-products.
whose structures were fully characterized by H and 13C NMR
and HRMS, significantly decreased the efficacy of the reaction.
Control experiments revealed that no reaction occurred in
the absence of palladium complexes and zinc powder or zinc
chloride. However, without the addition of triethylamine as a
base, the rearrangement was unexpectedly suppressed
(Table 1, entries 1 and 2). Previous studies of this catalytic
reaction show that the polarity of the utilized solvents plays an
important role in the coupling of iodo esters with azabicycle.
Therefore, the solvents were extensively screened and the
results are indicated in Table 1. THF, acetonitrile, and toluene
were all inferior to 1,4-dioxane as a solvent. This coupling
reaction did not proceed in DMF (Table 1, entry 7). In addition,
the impacts of triethylamine to these solvents during the
reaction were also compared. For instance, heating in toluene
at 100 uC for 1 h produced a large amount of rearranged
products, yet a minimal amount of the expected product was
obtained. By contrast, 40% yield of product was isolated when
triethylamine was not involved (Table 1, entry 4). Although the
exact pathway of this annulation reaction is not very clear, this
unexpected finding may be helpful for further investigation on
the reaction mechanism. The desired product was finally
obtained in 1,4-dioxane at 100 uC with a satisfactory yield of
93% in only one hour (Table 1, entry 5).
The scope of various substituted methyl o-iodobenzoates
with azabicyclic alkene 2a was investigated under optimal
reaction conditions and the results are summarized in Table 2.
All annulation reactions efficiently gave excellent yields under
the present reaction conditions. The trifluoromethyl-substi-
tuted dihydrobenzo[c]phenanthridin-6-one 3al was obtained in
90% yield using this catalyst system (Table 2, entry 11). The
amino substituted product 3an and N,N-dimethyl substituted
analogues 3ao were also obtained by this method (Table 2,
entries 13 and 14). All substrates with electron-donating
groups underwent efficient annulation reactions and resulted
in excellent yields (Table 2, entries 6, 7, and 8). Coupling with a
nitro-substituted substrate resulted in the same product as the
amino substitute, perhaps because the nitro group was
reduced by zinc powder in this reaction (Table 2, entry 16,
90% and entry 13, 91%). These data showed that the electron
properties of the methyl o-iodobenzoates did not significantly
influence the efficacy of the annulation reaction. Steric effects
seemed important, as 3-substituted methyl o-iodobenzoates
reacted in reduced yield (Table 2, entry 1, 75%; 4, 71%; and
entry 12, 71%). All reactions were generally completed within 1
1
Results and discussion
As a starting point, we chose methyl 4-fluoro-2-iodobenzoate
1a as the representative electron-deficient substrate to couple
with azabicyclic alkene 2a17 under standard conditions of
PdCl2(PPh3)2-Zn-ZnCl2-Et3N-THF at 60 uC for 24 h15 (Table 1,
entry 1). However, the target product in relative configuration
was obtained only in 14% yield, which was improved to 35%
upon raising the reaction temperature from 60 uC to 65 uC. The
conversion of the starting materials was incomplete, and two
by-products 4aa and 5aa (Fig. 2) were isolated as a result of an
unexpected double-bond migration. These two by-products,
Table 1 Optimization of the reaction conditions of methyl 4-fluoro-2-iodo-
benzoate 1a with azabicycle 2aa
Entry
Solvent
T/uC
Time (h)
Yield (%)b
Yield (%)c
1
2
3
4
5
6
7
THF
THF
CH3CN
Toluene
1,4-dioxane
1,4-dioxane
DMF
60
65
80
100
100
60
24
24
24
1
1
10
1
14
35
56
trace
76
63
NR
20
45
70
40
93
87
NR
100
a
Reaction conditions: Pd(PPh3)2Cl2 (5% mmol), 1a (1.0 mmol), 2a
h
with the exception of methyl 5-bromo-2-iodobenzoate
(1.1 equiv), Zn (10 equiv), Et3N (8 equiv), solvent (10 ml), ZnCl2 (0.5
b
c
equiv). Yield of isolated product. Isolated yield without Et3N NR:
no reaction.
(Table 2, entry 9). Monitored by TLC, the corresponding
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Table 2 Scope of the annulation reactions of methyl o-iodobenzoates 1 with
azabicycle 2aa
Table 2 (Continued)
Entry
13
Methyl o-iodobenzoate
Product (yield %)b
Entry
1
Methyl o-iodobenzoate
Product (yield %)b
14
15
2
3
16
3an (90)
4
a
Unless otherwise stated, all reactions were carried out under the
b
c
5
optimized conditions mentioned above. Isolated yields. Reaction
temperature and time for entry 9 was 60 uC and 10 h, respectively.
product 3aj was ultimately obtained at 60 uC after 10 h with an
isolated yield of 86%.
6
These results prompted us to examine this reaction using
the corresponding substituted methyl o-bromobenzoates
under the optimal conditions, which provided almost the
same result as the methyl o-iodobenzoates (Table 3).
Undoubtedly, this unexpected finding broadened the scope
of the application of this catalytic reaction because most
bromo species are commercially available and stable com-
pared with the iodo counterparts.
7
8
Considering that most of the natural benzo[c]phenanthri-
dines bear the 1,3-benzodioxole moiety, 1,3-benzodioxole-
azabicycle 2b18 was selected as the coupling partner to
ascertain the scope of its group compatibility either with the
iodo species or the bromo species. The results are presented in
Table 4. To examine the regioselectivity of the present catalytic
reaction, the scope and value of this method were further
extended by employing two unsymmetrical azabicyclic alkenes,
namely 2c, which bears a methyl group at a bridgehead atom,
and 2d, which comprises two methyl groups (Table 5). The
presence of the methyl group on the bridgehead atom of 2c
appears to block the addition of an organic group to the
nearby double-bond carbon. In the two substrates, namely, 1a
and 1p, the organic groups all added to the olefin carbon distal
to the methyl group, which gave the corresponding regiose-
lective benzo[c]phenanthridines 3ca and 3cp in 76% and 71%
yield, respectively. These could be readily characterized by the
1H NMR in the presence of a single olefin proton resonance. In
contrast to the results observed for 2c, no reaction occurred
9c
10
11
12
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Table 3 Scope of methyl o-bromobenzoate componenta
Table 4 Scope of 1,3-benzodioxole-azabicycle componenta
Entry
1
Methyl o-bromobenzoate
Product (yield %)b
Entry
1
Methyl o-halobenzoate
Product (yield %)b
3aa (91)
2
3ab (73)
2
3
4
5
3
4
5
6
7
3ac (90)
3ad (91)
3ai (94)
3ap (92)
6
7
8
3ba (92)
3bd (93)
8
9
a
Unless otherwise stated, all reactions were carried out under the
a
b
Unless otherwise stated, all reactions were carried out under the
optimized conditions mentioned above. Isolated yields.
b
optimized conditions mentioned above. Isolated yields.
even with the prolonged reaction time when 2d was employed.
Steric effects of the methyl group on the double-bond carbon
may be responsible for this negative result.
which suggests that the method may be applied in the
functionalized synthesis of both fully aromatized-type and
partially hydrogenated-type alkaloids. Additional studies with
regard to the enantioselectivity of this annulation reaction are
currently under investigation in our lab and will be reported in
due course.
Conclusions
In summary, we have developed an improved and generally
applicable base-free methodology for the annulation reaction
of azabicyclic alkenes with substituted methyl o-halobenzo-
ates. The present strategy provides an efficient construction of
benzo[c]phenanthridine nucleus from readily available start-
ing materials. Besides, high regioselectivity product is
achieved when non-symmetric azabicyclic alkene is tested.
Our process has shown broad functional group compatibility,
Experimental section
General remarks
Unless otherwise stated, all reactions were carried out under
argon atmosphere, and all commercially available reagents
were used without further purification. Tetrahydrofuran,
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Table 5 Investigation of the regioselectivity of this annulation reactiona
recrystallized from water and dried in vacuo to afford methyl
o-iodobenzoic acid.
General procedure for the synthesis of methyl o-halobenzoates
to a stirred solution of methyl o-halobenzoic acid (10 mmol) in
CH2Cl2 (50 mL), oxalyl chloride (5.08 g, 20 mmol) was added,
drops of DMF was added to catalyze the forming of benzoyl
chloride. The mixture was stirred 2 h, then the solvent and
excess oxalyl chloride was removed under reduce pressure and
30 mL of methanol was added to the residue in CH2Cl2 (30
mL). After the solution was stirred 30 min, saturated sodium
bicarbonate (30 mL) was added and extracted, followed by
drying over MgSO4, filtered, and concentrated. The residue
was purified by column chromatographic on silica gel with
petroleum ether/ethyl acetate to afford the methyl o-halo-
benzoates.
Entry
1
Methyl o-iodobenzoate
Azabicycle
Product (yield %)b
1a
2c
2
1p
1p
2c
4-Fluoro-2-iodobenzoate (1a)
2.66 g (95% yield), colorless liquid; IR (KBr): n = 1733 cm21
(CLO); 1H NMR (400 MHz, CDCl3) d 7.87 (m, 1H), 7.78–7.68 (m,
1H), 7.19–7.07 (m, 1H), 3.92 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 165.8, 164.8, 162.2, 132.8, 132.7, 128.8, 128.6, 115.3,
115.1, 94.61, 52.54 (extra peaks due to 13C-19F coupling); HRMS
m/z calcd for C8H6FIO2 [M + H]+ 280.9475, found 280.9472.
3
2d
No reaction
a
All reactions were carried out under the optimal conditions.
Isolated yields.
b
3-Chloro-2-iodobenzoate(1e)
2.63 g (89% yield), colorless liquid; IR (KBr): n = 1731 cm21
(CLO); H NMR (400 MHz, CDCl3) d 7.58 (dd, J = 7.9, 1.5 Hz,
1H), 7.47 (dd, J = 7.7, 1.5 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 3.97
(s, 3H); 13C NMR (100 MHz, CDCl3) d 167.6, 140.8, 140.3, 131.4,
129.1, 127.6, 98.1, 52.9; HRMS m/z calcd for C8H6ClIO2 [M +
H]+ 296.9174, found 296.9177.
1
acetonitrile, DMF, toluene, and 1,4-dioxane were purified by
distillation under N2 from Na/benzophenone immediately
prior to use. IR spectra were recorded as thin films or KBr
discs. NMR spectra were recorded with a spectrometer using
CDCl3. Chemical shifts (d) were reported in parts per million
(ppm) relative to either a tetramethylsilane internal standard
or solvent signals. Multiplicity was indicated as follows: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiple), dd
(doublet of doublet). Coupling constants were reported in
Hertz (Hz). The melting points were determined and uncor-
rected. High-resolution mass spectra were conducted using an
Ionspec 7.0T spectrometer by ESI-FTICR technique. Substrates
1b19, 1c20, 1d21, 1f1b, 1g22, 1h23, 1i24, 1q25, 1y26, 2a16, 2b17 and
2d27 are known compounds in literatures and analytical data
was similar to what has been reported.
5-Trifluoromethoxy-2-iodobenzoate (1k)
3.08 g (89% yield), colorless liquid; IR(KBr): n = 1738 cm21
1
(CLO); H NMR (400 MHz, CDCl3) d 8.05 (d, J = 8.6 Hz, 1H),
7.71 (d, J = 2.6 Hz, 1H), 7.15–7.02 (m, 1H), 3.99 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 164.5, 148.0, 141.8, 135.5, 124.2,
122.63, 120.5, 90.12, 51.83; HRMS m/z calcd for C9H6F3IO3 [M
+ H]+ 346.9386, found 346.9380.
4-Trifluoromethyl-2-iodobenzoate(1l)
3.14 g (95% yield), colorless liquid; IR (KBr): n = 1737 cm21
(CLO); 1H NMR (400 MHz, CDCl3) d 8.15 (s, 1H), 7.80 (d, J = 8.1
Hz, 1H), 7.66–7.49 (m, 1H), 3.90 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 165.1, 137.6, 137.0, 133.2, 132.9, 129.9, 123.9 (q),
122.7, 119.98, 92.68, 51.85 (extra peaks due to 13C–19F
coupling); HRMS m/z calcd for C9H6F3IO2 [M + H]+ 330.9437,
found 330.9437.
General procedure for the synthesis of methyl o-iodobenzoic
acid28
substituted anthranilic acid (10 mmol) is suspended in a
mixture of concentrated HCl (5 ml) and water (15 mL), cooled
to 0 uC and stirred. Sodium nitrite (0.83 g, 12 mmol) dissolved
in water (5 ml) is slowly added taking care to maintain the
reaction temperature below 5 uC. Stirring is continued at 0 uC
for 30 min. Potassium iodide (3.32 g, 20 mmol) is dissolved in
a mixture of concentrated H2SO4 (0.6 ml) and water (5 ml) and
added dropwise to the reaction mixture while keeping the
reaction temperature below 10 uC. The mixture is then heated
to 90 uC and stirred for 1 h, then cooled in an ice bath. The
solid which separated was filtered, dissolved in ether (20 mL),
and washed with 20% aqueous thiosulfate solution (3 6 15
mL). The organic layer was dried (MgSO4) and evaporated to
dryness under reduced pressure. The solid residue was
3-Trifluoromethyl-2-iodobenzoate (1m)
3.0 g (91% yield), colorless liquid; 1H NMR (400 MHz, CDCl3) d
7.66 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 7.6
Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 3.91 (s, 3H); 13C NMR (100
MHz, CDCl3) d 168.4, 142.2, 131.7, 129.1(q), 128.1, 123.9,
121.4, 89.9, 53.0 (extra peaks due to 13C–19F coupling); IR
(KBr): n = 1737 cm21 (CLO); HRMS m/z calcd for C9H6F3IO2 [M
+ H]+ 330.9437, found 330.9436.
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5-Amino-2-iodobenzoate (1n)29
Typical procedure for the annulation reactions of azabicyclic
alkenes with o-halobenzoates
To a stirred solution of 1q (0.6 g, 2 mmol) in EtOH (10 ml),
concentrated HCl (10 ml) was added and then tin(II) chloride
dehydrate (1.8 g, 8 mmol) in EtOH(10 ml) was added dropwise.
The mixture was stirred overnight at room temperature and
white suspension appeared. Pour the mixture into water (50
ml) and adjust the pH to 11 by adding 2N NaOH solution,
extracted with Et2O (3 6 50 ml), washed with saturated brine
(50 ml), dried over MgSO4 and evaporated to give 1n as a
yellow oil (0.65 g, 85%). IR (KBr): n = 3375 cm21 (NH2), 1722
To a solution of methyl o-halobenzoates 1 (1 mmol) in 1,4-
dioxane (10 ml), azabicycle 2 (1.2 mmol), Pd(PPh3)2Cl2(0.05
mmol, 28 mg), zinc powder (10 mmol, 0.75 g), and zinc
chloride (0.5 mmol, 68 mg) were added. The mixture was then
heated at 100 uC (1j at 60 uC) under N2 atmosphere. After iodo
ester disappeared (monitored by TLC), the reaction mixture
was cooled, diluted with methylene chloride (15 mL). Then it
was filtered through a short pad of Celite silica gel and washed
with CH2Cl2 several times. After concentration in vacuo, the
crude product was purified by silica gel column using ethyl
acetate/petroleum ether as the eluent to give the correspond-
ing cis-dihydrobenzo[c]phenanthridin-6-ones.
1
cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.68 (d, J = 8.5 Hz,
1H), 7.15 (d, J = 2.9 Hz, 1H), 6.52 (dd, J = 8.5, 2.9 Hz, 1H), 3.92
(s, 3H); 13C NMR (100 MHz, CDCl3) d 167.1, 146.4, 141.6, 135.6,
119.6, 117.5, 78.7, 52.4; HRMS m/z calcd for C8H8INO2 [M + H]+
277.9672, found 277.9670.
9-Fluoro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3aa)
5-N,N-Dimethyl-2-iodobenzoate (1o)30
246 mg (93% yield), white solid, Mp176–178 uC; IR (KBr): n =
1667 cm21(CLO); 1H NMR (400 MHz, CDCl3) d 8.11 (dd, J = 8.5,
5.9 Hz, 1H), 7.33 (dd, J = 15.2, 7.2 Hz, 3H), 7.19 (d, J = 7.2 Hz,
1H), 7.06 (dd, J = 20.1, 5.5 Hz, 2H), 6.65 (dd, J = 9.5, 2.0 Hz, 1H),
5.94 (s, 1H), 5.86 (dd, J = 9.5, 3.1 Hz, 1H), 4.91 (d, J = 5.6 Hz,
1H), 3.91 (s, 1H); 13C NMR (100 MHz, CDCl3) d 166.81, 164.32,
164.29, 142.59, 142.50, 132.6, 132.0, 130.9, 130.8, 129.3, 128.5,
127.9, 127.5, 127.4, 127.2, 124.5, 115.0, 114.8, 114.1, 113.8,
52.3, 38.6 (extra peaks due to 13C–19F coupling); HRMS m/z
calcdfor C17H12NFO [M + H]+ 266.0976, found 266.0975.
To a solution of 1n (0.55 g, 2 mmol) in N,N-dimethyl
formamide (30 mL) was added K2CO3 (0.56 g, 4 mmol) and
methyl iodide (0.85 g, 6 mmol). The solution was stirred
overnight, poured into water and extracted with ethyl acetate.
The organic phase was dried with anhydrous Na2SO4, filtered
and removed by rotary evaporation to yield a residue. The
residue was purified by column chromatography on silica gel
and afforded 1o as a yellow oil (0.53 g, 87%). IR (KBr): n = 1730
1
cm21(CLO); H NMR (400 MHz, CDCl3) d 7.71 (d, J = 8.8 Hz,
1H), 7.11 (d, J = 3.1 Hz, 1H), 6.52 (dd, J = 8.8, 3.1 Hz, 1H), 3.92
(s, 3H), 2.96 (s, 6H); 13C NMR (100 MHz, CDCl3) d 167.7, 149.9,
141.1, 135.5, 116.8, 114.7, 76.3, 52.4, 40.3; HRMS m/z calcd for
C10H12INO2 [M + H]+ 305.9985, found 305.9989.
By-products 4aa
White solid, Mp 304–306 uC; IR (KBr): n = 1665 cm21 (CLO); 1H
NMR (400 MHz, CDCl3) d 8.33–8.03 (m, 1H), 7.59–6.97 (m, 6H),
6.44 (d, J = 45.6 Hz, 2H), 5.44 (s, 1H), 3.99–3.47 (m, 3H); 13C
NMR (100 MHz, CDCl3) d 166.83, 164.53, 164.32, 140.1, 132.2,
128.8, 128.2, 127.5, 125.6, 124.2, 123.6, 115.7, 115.5, 112.2,
109.9, 50.3, 31.6 (extra peaks due to 13C–19F coupling); HRMS
m/z calcd for C17H12NFO [M + H]+ 266.0976, found 266.0973.
Preparation and data for 2c
Prepared according to the method of Carpino et al. from
o-bromofluorobenzene and N-Boc-pyrrole in the presence of
magnesium31. Magnesium turnings (136 mg, 5.5 mmol) were
added to dry THF (5 mL) under argon and stirred with 1,2-
dibromoethane (30 ml) for 10 min to activate Mg. After
initiation, as evidenced by warming, a solution of N-Boc-2-
methylpyrrole (0.91 g, 5 mmol) in THF (8 mL) was added and
the mixture heated to reflux. Through the addition funnel, ca.
one-fourth of a solution of o-bromofluorobenzene (0.9 g, 5
mmol) in THF (5 mL) was introduced. When initiation
occurred, the rest of the solution was added dropwise. After
the addition was complete the mixture was allowed to reflux
for a further 1 h. It was then allowed to cool, quenched with a
solution of NH4Cl (3.0 g) in water (10 mL) and the organic layer
extracted with diethyl ether (3 6 25 mL), dried and the solvent
removed at reduced pressure. The residue was purified by
column chromatography on silica gel and afforded 2c as a
white solid (0.71 g, 55%). Mp 80–82 uC; IR (KBr): n = 1662
cm21(CLO); 1H NMR (400 MHz, CDCl3) d 8.08–8.00 (m, 1H),
7.98–7.89 (m, 1H), 7.74 (s, 1H), 7.62–7.51 (m, 2H), 7.32 (d, J =
7.6 Hz, 1H), 6.79 (s, 1H), 2.69 (s, 3H), 1.59 (s, 9H); 13C NMR
(100 MHz, CDCl3) d 152.8, 132.0, 130.2, 130.0, 126.2, 125.4,
124.7, 123.9, 120.2, 118.3, 79.4, 27.4, 18.2, HRMS m/z calcd for
C16H19NO2 [M + H]+ 258.1490, found 258.1493.
By-products 5aa
White solid, Mp 239–241 uC, IR (KBr): n = 1660 cm21(CLO); 1H
NMR(400 MHz, CDCl3) d 9.83 (s, 1H), 8.51 (s, 1H), 7.66 (s, 1H),
7.42–7.21 (m, 5H), 2.96 (m, 4H); 13CNMR (100 MHz, CDCl3) d
167.2, 137.3, 133.5, 131.3, 129.3, 128.5, 127.4, 121.3, 115.1 ,
114.8, 110.9, 108.3, 108.1, 29.7, 21.6 (extra peaks due to 13C--19
F
coupling); HRMS m/z calcd for C17H12NFO [M + H]+ 266.0976,
found 266.0971.
10-Fluoro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ab)
199 mg (75% yield), white solid, Mp178–180 uC; IR (KBr): n =
1641 cm21(CLO); H NMR (400 MHz, CDCl3) d 7.96 (d, J = 7.7
1
Hz, 1H), 7.55–7.12 (m, 7H), 6.63 (dd, J = 9.5, 2.8 Hz, 1H), 5.69
(d, J = 9.5 Hz, 1H), 5.42 (s, 1H), 4.85 (d, J = 5.3 Hz, 1H), 4.26 (s,
1H); 13C NMR (100 MHz, CDCl3) d 163.9, 160.6, 158.2, 132.68,
131.0,129.8, 128.7, 128.7, 128.4, 128.3, 127.4, 127.3, 126.6,
126.5, 123.9, 119.7, 119.5, 51.8, 32.9 (extra peaks due to 13C–19F
coupling); HRMS m/z calcd for C17H12NFO [M + H]+ 266.0976,
found 266.0974.
8-Fluoro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ac)
246 mg (93% yield), white solid, Mp 222–225 uC; IR (KBr): n =
1670 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.89–7.73 (m,
1
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1H), 7.46–7.14 (m, 6H), 6.75–6.52 (m, 1H), 5.98–5.56 (m, 2H),
4.88 (d, J = 5.6 Hz, 1H), 3.91 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 164.0, 163.5, 161.0, 135.3, 132.6, 131.7, 129.5, 129.0,
128.5, 128.3, 127.6, 127.5, 127.2, 120.2, 120.0, 114.8, 114.6,
52.4, 38.1 (extra peaks due to 13C–19F coupling); HRMS m/z
calcd for C17H12NFO [M + H]+ 266.0976, found 266.0975.
8-Methoxy-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ai)
263 mg (95% yield), white solid, Mp182–184 uC; IR (KBr): n =
1668 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 7.61 (d, J = 2.7
Hz, 1H), 7.38–7.05 (m, 6H), 6.56 (dd, J = 9.6, 2.5 Hz, 1H), 5.77
(dd, J = 9.5, 2.5 Hz, 1H), 5.62 (s, 1H), 4.84 (d, J = 5.6 Hz, 1H),
3.85 (m, 4H); 13C NMR (100 MHz, CDCl3) d 165.0, 159.2, 132.8,
132.0, 131.6, 129.3, 129.0, 128.4, 128.3, 127.6, 127.1, 127.1,
55.6, 52.5, 38.0; HRMS m/z calcd for C18H15NO2 [M + H]+
278.1176, found 278.1177.
9-Chloro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ad)
261 mg (93% yield), white solid, Mp 202–204 uC; IR (KBr): n =
1666 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.02 (d, J = 8.3
Hz, 1H), 7.47–7.25 (m, 5H), 7.18 (d, J = 7.2 Hz, 1H), 6.64 (dd, J =
9.6, 2.3 Hz, 1H), 6.01 (s, 1H), 5.85 (dd, J = 9.5, 3.1 Hz, 1H), 4.89
(d, J = 5.5 Hz, 1H), 3.88 (m, 1H); 13C NMR (100 MHz, CDCl3) d
164.3, 141.4, 139.0, 132.5, 132.0, 129.6, 129.3, 128.5, 128.0,
128.0, 127.5, 127.4, 127.2, 127.1, 126.6, 52.2, 38.4; HRMS m/z
calcd for C17H12NClO [M + H]+ 282.0680, found 282.0675.
8-Bromo-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3aj)
279 mg (86% yield), white solid, Mp 243–245 uC; IR (KBr): n =
1664 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.16 (d, J = 2.0
Hz, 1H), 7.58 (dd, J = 8.1, 2.1 Hz, 1H), 7.37–7.02 (m, 6H), 6.53
(dd, J = 9.6, 2.5 Hz, 1H), 5.70 (dd, J = 9.5, 2.8 Hz, 1H), 5.46 (s,
1H), 4.79 (d, J = 5.6 Hz, 1H), 3.80 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 162.6, 137.4, 134.9, 131.5,130.6, 129.9, 128.8, 128.5,
127.9, 127.5, 126.8, 126.7, 126.5, 126.3, 120.6, 51.2, 37.2, HRMS
m/z calcd for C17H12BrNO [M + H]+ 326.0175, found 326.0175.
10-Chloro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ae)
211 mg (71% yield), white solid, Mp 182–184 uC; IR (KBr): n =
1666 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.06 (d, J = 7.7
Hz, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.38 (dd, J = 10.1, 5.5 Hz, 2H),
7.35–7.20 (m, 3H), 6.63 (dd, J = 9.5, 2.9 Hz, 1H), 5.65 (d, J = 9.5
Hz, 1H), 5.37 (s, 1H), 4.82 (d, J = 5.1 Hz, 1H), 4.34 (s, 1H); 13C
NMR (100 MHz, CDCl3) d 164.0, 137.0, 133.6, 132.9, 132.8,
130.9, 129.9, 129.9, 128.6, 128.4, 128.4, 127.6, 127.4, 126.9,
126.9, 51.7, 36.7; HRMS m/z calcd for C17H12NClO [M + H]+
282.0680, found 282.0680.
8-trifluoromethoxy-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3ak)
301 mg (91% yield), white solid, Mp 174–176 uC; IR (KBr): n =
1
1676 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.94 (s, 1H),
7.41–7.24 (m, 5H), 7.18 (d, J = 7.3 Hz, 1H), 6.61 (dd, J = 9.6, 2.4
Hz, 1H), 5.95–5.67 (m, 2H), 4.88 (d, J = 5.6 Hz, 1H), 3.92 (m,
1H); 13C NMR (100 MHz, CDCl3) d 163.7, 148.7, 138.2, 132.5,
131.6, 129.9, 129.5, 128.9, 128.6, 127.8, 127.6, 127.3, 125.5,
124.3, 121.7, 120.4, 52.2, 38.2 (extra peaks due to 13C–19F
coupling); HRMS m/z calcd for C18H12F3NO2 [M + H]+
332.0893, found 332.0895.
8-Chloro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3af)
253 mg (90% yield), white solid, Mp 219–221 uC; IR (KBr): n =
1672 cm21(CLO); 1H NMR (400 MHz, CDCl3) d 8.09 (s, 1H),
7.84–7.63 (m, 2H), 7.63–7.47 (m, 3H), 7.20 (d, J = 7.3 Hz, 1H),
6.63 (d, J = 7.8 Hz, 1H), 5.91–5.64 (m, 2H), 4.89 (d, J = 5.3 Hz,
1H), 4.34 (t, J = 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
164.0, 137.9, 133.9, 133.0, 132.6, 131.7, 130.9, 129.5, 128.7,
128.6, 128.1, 127.9, 127.7, 127.5, 127.3, 52.2, 38.2; HRMS m/z
calcd for C17H12NClO [M + H]+ 282.0680, found 282.0684.
9-Trifluoromethyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3al)
283 mg (90% yield), white solid, Mp 211–213 uC; IR (KBr): n =
1668 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.19 (d, J = 8.0
Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 21.9 Hz, 1H), 7.44–
7.21 (m, 3H), 7.18 (d, J = 7.2 Hz, 1H), 6.64 (dd, J = 9.6, 2.4 Hz,
1H), 6.03 (s, 1H), 5.84 (dd, J = 9.5, 3.0 Hz, 1H), 4.91 (d, J = 5.7
Hz, 1H), 3.96 (m, 1H); 13C NMR (100 MHz, CDCl3) d 163.8,
140.5, 134.6, 134.3, 132.5, 131.7, 131.2, 129.5,128.7, 128.1,
128.1, 127.5, 127.3, 125.0, 124.62–124.51(m), 124.19–124.09
(m), 124.2, 122.2, 52.2, 38.5 (extra peaks due to 13C–19F
coupling); HRMS m/z calcd for C18H12F3NO [M + H]+ 316.0944,
found 316.0941.
10-Methyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ag)
222 mg (85% yield), white solid, Mp 201–203 uC; IR (KBr): n =
1660 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.00 (d, J = 7.6
Hz, 1H), 7.48–7.12 (m, 6H), 6.62 (dd, J = 9.5, 3.1 Hz, 1H), 5.59
(d, J = 9.5 Hz, 1H), 5.30 (s, 1H), 4.77 (d, J = 5.2 Hz, 1H), 4.03 (s,
1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3) d 165.3, 137.6,
135.0, 134.7, 132.8, 131.6, 129.7, 128.4, 128.3, 128.0, 127.7,
127.5, 127.3, 127.3, 126.2, 51.9, 35.9, HRMS m/z calcd for
C18H15NO [M + H]+ 262.1226, found 262.1229.
10-Trifluoromethyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3am)
8-Methyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3ah)
245 mg (94% yield), white solid, Mp 196–198 uC; IR (KBr): n =
224 mg (71% yield), white solid, Mp 236–238 uC; IR (KBr): n =
1665 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.35 (d, J = 7.7
Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.47–
7.37 (m, 1H), 7.37–7.19 (m, 3H), 6.61 (dd, J = 9.5, 3.0 Hz, 1H),
5.63 (d, J = 9.6 Hz, 1H), 5.44 (s, 1H), 4.80 (d, J = 4.3 Hz, 1H),
4.25 (s, 1H); 13C NMR (100 MHz, CDCl3) d 163.5, 138.2, 132.6,
132.1, 130.8, 130.4–130.2 (m), 130.0, 129.9, 128.5, 128.3, 128.2,
127.9, 127.8, 127.4, 127.1, 125.4, 52.1, 36.4 (extra peaks due to
13C–19F coupling); HRMS m/z calcd for C18H12F3NO [M + H]+
316.0944, found 316.0942.
1
1669 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.90 (s, 1H),
7.37–7.17 (m, 5H), 6.56 (dd, J = 9.6, 2.6 Hz, 1H), 5.79 (dd, J =
9.5, 2.7 Hz, 1H), 5.67 (s, 1H), 4.84 (d, J = 5.7 Hz, 1H), 3.96–3.72
(m, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) d 165.33,
137.50, 136.61, 133.80, 132.75, 132.09, 129.26, 128.92, 128.37,
128.32, 127.76, 127.59, 127.18, 127.09, 127.06, 52.36, 38.34,
21.08; HRMS m/z calcd for C18H15NO [M + H]+ 262.1226, found
262.1228.
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121.1, 106.9, 106.0, 100.7, 51.3, 37.4; HRMS m/z calcd for
C
8-Amino-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3an)
238 mg (91% yield), white solid, Mp 103–105 uC; IR (KBr): n =
18H13NO3 [M + H]+ 292.0968, found 292.0967.
1
1661 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.39 (s, J = 2.6
8,9-Dimethoxy-13,14-cis-dihydrobenzo[c]phenanthridin-6-one
Hz, 1H), 7.35–7.21 (m, 3H), 7.12 (dd, J = 20.6, 7.7 Hz, 2H), 6.84
(dd, J = 8.1, 2.6 Hz, 1H), 6.54 (dd, J = 9.6, 2.6 Hz, 1H), 5.76 (dd, J
= 9.5, 2.6 Hz, 1H), 5.60 (s, 1H), 4.81 (d, J = 5.7 Hz, 1H), 3.79 (dd,
J = 5.5, 2.7 Hz, 2H), 3.70 (s, 1H); 13C NMR (100 MHz, CDCl3) d
165.4, 146.0, 132.8, 132.2, 129.6, 129.2, 129.2, 128.7, 128.22,
128.1, 127.6, 127.0, 126.9, 119.7, 113.8, 52.5, 38.0; HRMS m/z
calcd for C17H14N2O [M + H]+ 263.1179, found 263.1181.
(3az)
292 mg (95% yield), white solid, Mp 238–241 uC; IR (KBr): n =
1672 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.83 (s, 1H),
1
7.37 (s, 1H), 7.26–7.18 (m, 2H), 7.14 (m, 1H), 7.04 (d, J = 7.4 Hz,
1H), 6.66 (s, 1H), 6.49 (dd, J = 9.6, 2.3 Hz, 1H), 5.70 (dd, J = 9.6,
3.3 Hz, 1H), 4.79 (d, J = 6.3 Hz, 1H), 3.88 (s, 3H), 3.75 (s, 3H);
13C NMR (100 MHz, CDCl3) d 167.3, 153.3, 147.6, 132.8, 131.3,
129.4, 128.5, 127.8, 127.1, 126.7, 126.0, 125.9, 117.1, 109.6,
108.1, 55.2, 51.7, 36.1; HRMS m/z calcd for C19H17NO3 [M + H]+
308.1281, found 308.1285.
8-N,N-Dimethyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-one
(3ao)
264 mg (91% yield), white solid, Mp 241–243 uC; IR (KBr): n =
1
1660 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.78–7.62 (m,
9-Fluoro-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3ba)
1H), 7.58–7.42 (m, 2H), 7.36–7.25 (m, 3H), 7.20–7.05 (m, 2H),
6.90 (dd, J = 8.4, 2.8 Hz, 1H), 6.53 (dd, J = 9.6, 2.6 Hz, 1H), 5.77
(dd, J = 9.5, 2.4 Hz, 1H), 5.49 (s, 1H), 4.81 (d, J = 5.6 Hz, 1H),
3.88–3.75 (m, 1H), 2.99 (s, 6H); 13C NMR (100 MHz, CDCl3) d
165.8, 150.1, 132.9, 132.2, 129.8, 129.2, 128.6, 128.2, 127.9,
127.7, 127.0, 126.9, 126.9, 117.1, 111.3, 52.6, 40.7, 37.9; HRMS
m/z calcd for C19H18N2O [M + H]+ 291.1492, found 291.1496.
290 mg (94% yield), white solid, Mp 230–233 uC; IR (KBr): n =
1665 cm21 (CLO); H NMR (400 MHz, CDCl3) d 8.00 (m, 1H),
1
7.05–6.89 (m, 2H), 6.72 (s, 1H), 6.59 (s, 1H), 6.41 (dd, J = 9.5,
2.3, 1H), 5.90 (d, J = 2.8, 2H), 5.78 (s, 1H), 5.64 (dd, J = 9.5, 3.0,
1H), 4.71 (d, J = 5.6, 1H), 3.83–3.67 (m, 1H); 13C NMR (100
MHz, CDCl3) d 166.0, 163.4, 147.1, 146.4, 141.4, 129.9, 129.8,
126.6, 126.1, 124.7, 114.0, 113.8, 113.0, 112.8, 107.2, 106.8,
100.4, 51.4, 37.6 (extra peaks due to 13C–19F coupling); HRMS
m/z calcd for C18H12FNO3 [M + H]+ 310.0874, found 310.0871.
13,14-cis-Dihydrobenzo[c]phenanthridin-6-one (3ap)
227 mg (92% yield), white solid, Mp173–175 uC; IR (KBr): n =
1
1657 cm21 (CLO); H NMR (400 MHz, CDCl3) d 8.08 (dd, J =
8-Fluoro-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3bc)
7.7, 1.1 Hz, 1H), 7.53 (td, J = 7.5, 1.4 Hz, 1H), 7.39 (td, J = 7.6,
1.0 Hz, 1H), 7.36–7.25 (m, 4H), 7.16 (d, J = 7.2 Hz, 1H), 6.58
(dd, J = 9.6, 2.7 Hz, 1H), 5.80 (dd, J = 9.6, 2.7 Hz, 1H), 5.76 (s,
1H), 4.87 (d, J = 5.7 Hz, 1H), 3.89 (dt, J = 5.4, 2.6 Hz, 1H); 13C
NMR (101 MHz, CDCl3) d 165.1, 139.6, 133.0, 132.7, 132.0,
129.3, 128.6, 128.4, 128.0, 128.0, 127.7, 127.62, 127.29, 127.13,
127.1, 52.2, 38.7; HRMS m/z calcd for C17H13NO [M + H]+
248.1070, found 248.1074.
281 mg (91% yield), white solid, Mp 228–230 uC; IR (KBr): n =
1667 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.82–7.53 (m,
1
2H), 7.37–7.13 (m, 2H), 6.77 (s, 1H), 6.67 (s, 1H), 6.46 (dd, J =
9.5, 2.3 Hz, 1H), 5.98 (m, 2H), 4.75 (d, J = 5.5 Hz, 1H), 3.83 (s,
1H); 13C NMR(100 MHz, CDCl3) d 163.2, 147.4, 135.8, 130.9,
128.9, 127.2, 126.6, 125.9, 120.3, 120.1, 114.9, 114.8, 108.5,
107.8, 101.4, 52.5, 38.2 (extra peaks due to 13C–19F coupling);
HRMS m/z calcd for C18H12FNO3 [M + H]+ 310.0874, found
310.0874.
8-Trifluoromethyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3ax)
290 mg (92% yield), white solid, Mp 175–177 uC; IR (KBr): n =
1
1661 cm21 (CLO); H NMR (400 MHz, CDCl3) d 8.25 (s, 1H),
9-Chloro-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3ba)
7.72 (dd, J = 8.0, 1.4 Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.25 (m,
3H), 7.15–7.05 (m, 1H), 6.91 (s, 1H), 6.57 (dd, J = 9.6, 2.4 Hz,
1H), 5.74 (dd, J = 9.6, 3.3 Hz, 1H), 4.87 (d, J = 5.1 Hz, 1H), 3.97–
3.81 (m, 1H); 13C NMR (100 MHz, CDCl3) d 164.2, 142.5, 131.3,
129.7, 129.6, 129.1, 128.6, 127.9, 127.5, 126.9, 126.8, 126.5,
293 mg (90% yield), white solid, Mp 206–209 uC; IR (KBr): n =
1671 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d = 7.93 (m, 1H),
7.26 (m, 2H), 6.73 (s, 1H), 6.60 (s, 1H), 6.43 (dd, J = 9.5, 2.1,
1H), 5.98 (s, 1H), 5.91 (d, J = 3.1, 2H), 5.66 (dd, J = 9.5, 3.0, 1H),
4.71 (d, J = 5.6, 1H), 3.86–3.69 (m, 1H); 13C NMR (100 MHz,
CDCl3) d 164.5, 148.1, 147.5, 141.5, 139.1, 129.6, 128.1, 128.0,
128.0, 127.7, 127.1, 127.1, 126.4, 125.7, 108.3, 107.8, 101.4,
52.4, 38.3; HRMS m/z calcd for C18H12ClNO3 [M + H]+
326.0578, found 326.0577
126.3, 125.5, 124.4, 51.2, 36.9 (extra peaks due to 13C–19
F
coupling); HRMS m/z calcd for C18H12F3NO [M + H]+ 316.0944,
found 316.0943.
8,9-Methylenedioxy-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3ay)
8-Methoxy-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3bi)
274 mg (94% yield), white solid, Mp 227–230 uC; IR (KBr): n =
1
1655 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.45 (s, 1H),
302 mg (94% yield), white solid, Mp 232–234 uC; IR (KBr): n =
7.30–7.19 (m, 3H), 7.09 (d, J = 7.3 Hz, 1H), 6.67 (s, 1H), 6.51
(dd, J = 9.6, 2.6 Hz, 1H), 5.96 (dd, J = 6.9, 1.3 Hz, 2H), 5.69 (dd, J
= 9.5, 2.5 Hz, 1H), 5.43 (s, 1H), 4.75 (d, J = 5.7 Hz, 1H), 3.81–
3.62 (m, 1H); 13C NMR (100 MHz, CDCl3) d 163.6, 150.3, 146.3,
134.1, 131.7, 130.8, 128.3, 127.3, 127.3, 126.5, 126.3, 126.1,
1
1678 cm21 (CLO); H NMR (400 MHz, CDCl3) d 7.71–7.63 (m,
1H), 7.55–7.46 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 8.3,
2.8 Hz, 1H), 6.77 (s, 1H), 6.66 (s, 1H), 6.43 (dd, J = 9.6, 2.6 Hz,
1H), 5.98 (d, J = 1.2 Hz, 2H), 5.66 (dd, J = 9.5, 2.5 Hz, 1H), 5.54
(s, 1H), 4.74 (d, J = 5.7 Hz, 1H), 3.86 (s, 3H), 3.83–3.72 (m, 1H);
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13C NMR (100 MHz, CDCl3) d 165.1, 159.2, 147.3, 132.2, 132.1,
130.9, 128.8, 128.3, 127.3, 126.8, 120.6, 111.1, 108.4, 107.7,
101.5, 65.2, 52.7, 38.3; HRMS m/z calcd for C19H15NO4 [M + H]+
322.1074, found 322.1076.
References
1 (a) T. Ishikawa and H. Ishii, Heterocycles, 1999, 50, 627; (b)
K. Pelz, Collect. Czech. Chem. Commun., 1968, 33, 1852; (c)
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¨
8-Trifluoromethoxy-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3bk)
Nat. Prod., 1984, 47, 1; (d) V. Simanek, in The alkaloids., ed.
A. Brossi, Academic Press Inc., New York, 1985, vol. 26, p.
185.
341 mg (91% yield), white solid, Mp 192–196 uC; IR (KBr): n =
2 Q. M. Probst, Ann, 1839, 29, 113.
1
1680 cm21 (CLO); H NMR (400 MHz, CDCl3) d = 7.91 (s, 1H),
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7.38 (s, 2H), 6.82 (s, 1H), 6.68 (s, 1H), 6.50 (dd, J = 9.6, 2.3, 1H),
6.35 (s, 1H), 5.99 (d, J = 4.8, 2H), 5.70 (dd, J = 9.5, 2.8, 1H), 5.32
(s, 1H), 4.81 (d, J = 5.7, 1H), 3.96–3.83 (m, 1H); 13C NMR (100
MHz, CDCl3) d 163.3, 147.7, 147.2, 146.5, 137.3, 132.0, 131.6,
131.5, 128.47, 127.9, 127.8, 126.6, 126.1, 124.68, 124.66, 124.1,
120.7, 119.4, 107.4, 106.8, 100.4, 51.5, 36.9 (extra peaks due to
13C–19F coupling); HRMS m/z calcd for C19H12F3NO4 [M + H]+
376.0791, found 376.0791.
8-Trifluoromethyl-13,14-cis-dihydrobenzodioxole
benzo[c]phenanthridin-6-one (3bx)
6 D. J. Li, B. P. Zhao, S. P. Sim, T. K. Li, A. Liu, L. F. Liu and E.
J. LaVoie, Bioorg. Med. Chem., 2003, 11, 521.
7 M. Rivaud, A. Mendoza, M. Sauvain, A. Valentin and
V. Jullian, Bioorg. Med. Chem., 2012, 20, 4856.
334 mg (93% yield), white solid, Mp 238–240 uC; IR (KBr): n =
1
1683 cm21 (CLO); H NMR (400 MHz, CDCl3) d 8.39 (s, 1H),
7.90–7.35 (m, 3H), 6.76 (d, J = 41.9, 1H), 6.52 (s, 1H), 6.01 (s,
1H), 5.71 (s, 2H), 4.82 (s, 1H), 3.93 (s, 1H); 13C NMR (100 MHz,
CDCl3) d 162.6, 147.2, 146.5, 142.5, 131.1, 131.0, 130.9, 128.4,
127.7, 127.5, 127.4, 127.2, 126.8, 126.7, 126.1, 124.5, 124.2,
8 G. Grynkiewicz, E. Chojecka-Koryn, M. Gadzikowska,
´
A. Chodkowska and E. Jagiełło-Wojtowicz, Eur. J. Med.
Chem., 2001, 36, 951.
107.3, 106.9, 100.5, 51.3, 37.6 (extra peaks due to 13C–19
F
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2011, 67, 1320; (h) K. Kohno, S. Azuma, T. Choshi,
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T. Yokotsuka, J. Org. Chem., 1998, 63, 4235.
coupling); HRMS m/z calcd for C19H12F3NO3 [M + H]+
360.0842, found 360.0841.
9-Fluoro-12-methyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-
one (3ca)
212 mg (76% yield), white solid, Mp 213–215 uC; IR (KBr): n =
1660 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 7.99 (d, J = 2.5
Hz, 1H), 7.35–7.26 (m, 2H), 7.20 (d, J = 10.6 Hz, 2H), 7.03–6.88
(m, 2H), 5.93 (s, 1H), 5.54 (s, 1H), 4.77 (d, J = 5.6 Hz, 1H), 3.77
(s, 1H), 2.03 (s, 3H); 13CNMR (100 MHz, CDCl3) d 165.2, 163.0,
162.6, 141.5, 141.4, 132.5, 131.1, 130.5, 129.2, 129.1, 127.6,
127.1, 126.6, 125.7, 122.3, 122.1, 113.2, 113.0, 112.4, 112.2,
50.9, 36.6, 28.0 (extra peaks due to 13C–19F coupling); HRMS m/
z calcd for C18H14FNO [M + H]+ 280.1132, found 280.1134.
12-Methyl-13,14-cis-dihydrobenzo[c]phenanthridin-6-one (3cp)
185 mg (71% yield), white solid, Mp 201–203 uC; IR (KBr): n =
1664 cm21 (CLO); 1H NMR (400 MHz, CDCl3) d 8.02 (d, J = 7.3
Hz, 1H), 7.48–7.44 (m, 1H), 7.32–7.30 (m, 3H), 7.26–7.20 (m,
3H), 5.54–5.52 (m, 2H), 4.76 (d, J = 5.5 Hz, 1H), 3.82–3.76 (m,
1H), 2.06–2.01 (m, 3H); 13C NMR (100 MHz, CDCl3) d 164.2,
139.2, 133.4, 132.0, 131.3, 131.0, 129.9, 128.3, 127.8, 127.1,
127.0, 126.6, 126.2, 124.2, 122.9, 51.6, 37.6, 28.7; HRMS m/z
calcd for C18H15NO [M + H]+ 262.1226, found 262.1229.
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Acknowledgements
This study was undertaken with the financial support of
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