Synthesis of phenanthridine derivatives by microwave-mediated cyclization of o-furyl(allylamino)arenes

Article abstract of DOI:10.1021/jo3027033

A novel and efficient synthesis of phenanthridines and aza analogues is reported. The key step is a microwave-mediated intramolecular Diels-Alder cyclization of o-furyl(allylamino)arenes. In the presence of a catalytic amount of acid, the DA-adduct reacts further to give the dihydrophenanthridines, which easily can be oxidized to fully aromatic compounds by air in the presence of UV light or by DDQ.

Full text of DOI:10.1021/jo3027033

Note
pubs.acs.org/joc
Synthesis of Phenanthridine Derivatives by Microwave-Mediated
Cyclization of o‑Furyl(allylamino)arenes
Matthew Lovell Read and Lise-Lotte Gundersen*
Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, 0315 Oslo, Norway
S
* Supporting Information
ABSTRACT: A novel and efficient synthesis of phenanthridines and
aza analogues is reported. The key step is a microwave-mediated
intramolecular Diels−Alder cyclization of o-furyl(allylamino)arenes. In
the presence of a catalytic amount of acid, the DA-adduct reacts further
to give the dihydrophenanthridines, which easily can be oxidized to
fully aromatic compounds by air in the presence of UV light or by
DDQ.
he phenanthridine ring system is found in a wide range of
bioactive natural products,1 and synthetic compounds of
Scheme 2. Microwave-Mediated Cyclization of o-
Furyl(allylamino)arenes 2
T
medicinal interest, some examples are phototherapeutic2 and
platinum complex3 anticancer compounds, anti-infectives
including antituberculosis4 and antitrypanosomiasis5 com-
pounds, and PET tracers.6 We have previously shown that
allylamino- or allyloxy-furyl(hetero)arenes can undergo intra-
molecular Diels−Alder reaction on furans (IMDAF) reactions
to give complex fused polycyclic heterocycles (Scheme 1).7 The
Scheme 1. Diels−Alder Cyclization of o-
Furyl(allylamino)arenes or -Allyloxyarenes7
An initial screening of solvents showed that degassed MeCN
was an excellent reaction medium. Degassing of solvents was
found to be of critical importance for high yields to be realized;
if the reaction solvent was not degassed, yields were lower due
to breakdown of reagents during the heating process. When
pure MeCN was employed, the reaction stopped at the Diels−
Alder adduct stage, but in the presence of a catalytic amount of
aq HCl, the initially formed DA-adduct spontaneously
underwent ring opening and subsequent aromatization to
afford the dihydrophenanthridines or aza analogues 2. Some of
the dihydro compounds 2 were partly oxidized to the fully
aromatic compounds 3 during workup and purification, but the
total yields of compounds 2 and 3 were generally high even for
substrates 1a, 1c, 1d, 1h, and 1l, which did not undergo the
IMDAF reaction under conventional heating.7 Electron-with-
drawing substituents, especially R1 = Cl, seem to stabilize the
dihydro(aza)phenanthridines. Only 3a, 3c, 3d, and 3h were
formed in significant amounts by spontaneous oxidation during
purification of the dihydro compounds 2.
reactivity of the substrates was highly dependent on the
detailed substitution pattern; a substituent ortho to the allylic
side chain (R1 ≠ H, Scheme 1) was shown to have very positive
influence on reactivity in the cyclization. Our theoretical studies
revealed that the increased reactivity of ortho-substituted
compounds is mainly due to a steric effect, which destabilizes
the minimum conformation of the reactant compared to the
active conformations.7 In order to improve the reaction with
respect to less reactive starting materials, we have now turned
to microwave chemistry, which to some extent has been applied
in IMDAF reactions before.8 We herein report that not only
was the reactivity in the Diels−Alder reaction greatly improved,
also it is possible to carry out one-pot syntheses of
dihydrophenanthridine and aza analogues, if the reaction is
carried out in the presence of acid.
We searched for a mild and convenient method for oxidation
of the dihydro(aza)phenanthridines 2 to the fully aromatic
compounds 3. First we tried to bubble air thru the reaction
Allylaminofurylarenes or -heteroarenes 1, previously reported
or synthesized by the same protocol as known compounds,7
were heated under microwave conditions (Scheme 2, Table 1).
Received: December 12, 2012
Published: January 10, 2013
© 2013 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. Reaction Times and Yields of Dihydrophenanthridines 2 and Phenanthridines 3
Method A
Method B
Method C
a
a
a
a
entry
X
Y
R1
R2
R3
time (h) temp (°C) yield (%) 2 yield (%) 3 time (h) yield (%) 3 time (h) yield (%) 3
1
C
C
C
C
C
C
N
C
C
C
N
N
CH
CH
CH
CH
CH
CH
CH
N
H
H
H
Cl
H
H
H
H
5
1
4
4
1
1
1
5
1
4
6
4
170
150
160
160
125
100
180
170
150
160
100
170
55, 2a
71, 2b
63, 2c
62, 2d
95, 2e
92, 2f
80, 2g
61, 2h
86, 2i
80, 2j
86, 2k
88, 2l
14, 3a
5, 3b
4
3
63, 3a
87, 3b
83, 3c
91, 3d
86, 3e
45, 3f
92, 3g
73, 3h
75, 3i
81, 3j
68, 3k
61, 3l
0.5
0.5
0.5
0.5
0.25
2
69, 3a
90, 3b
67, 3c
86, 3d
87, 3e
69, 3f
57, 3g
78, 3h
85, 3i
77, 3j
73, 3k
85, 3l
2
Cl
H
H
3
H
20, 3c
29, 3d
3
4
H
Cl
Cl
NO2
H
1
5
Cl
Cl
Cl
H
5
6
72
6
7
3, 3g
29, 3h
9, 3i
4
8
H
H
Cl
H
3
0.5
0.5
0.5
5
9
N
Cl
H
H
6
10
11
12
N
H
3
N
Cl
H
H
48
16
N
Cl
0.5
a
Yield of isolated products.
mixture directly after complete microwave cyclization. We soon
realized that the reaction was sensitive to light and found that
expeditious oxidation could be achieved if the reaction was
performed with exposure to UV light (315−400 nm, Method B,
Scheme 2, Table 1). Compounds 2 could be converted to the
(aza)phenanthridines 3 generally in high yield, although some
substrates required prolonged reaction times. Table 2
starting material in these solvents. However, we tried the
microwave-promoted cyclization of the allyloxy derivative 4
(Scheme 3) both in water and in MeCN in the presence of
Scheme 3. Microwave-Mediated Synthesis of the 6H-
Benzo[c]chromene 5
Table 2. Oxidation of Compound 2i to Compound 3i
reaction conditions
a
entry
atm
light
time (h)
% 3i
b
1
2
3
air
air
Ar
dark
19
4
100
18
c
c
UV light
3.5
3.5
UV light
acid, close to the procedure reported for other allyloxy
derivatives.10 In the literature they claim to have run their
reactions at rather harsh conditions of 150 °C and 300 W.
These conditions were not possible to repeat in our oven, so we
set the temperature to 150 °C. The power was ca. 600 W for a
few min, while the temperature rose to 150 °C. After reaching
the desired temperature, the power was stabile at ca. 15−20 W.
When the reaction was carried out in degassed water, there
were solubility problems and clumps of dark oily residue on the
walls of the reaction flask. All starting material 4 seemed to be
consumed, but the product 5 was isolated in only 16%,
probable due to extensive decomposition. The compound 4
easily cyclized in MeCN, and the chromene 5 was isolated
almost pure in ca. 80% yield after chromatography. An
analytical sample (39%) was prepared by recrystallization.
Finally, we explored the posibility of utilizing the microwave-
promoted cyclization for the formation of the pyrrolo[3,2,1-
de]phenanthridine ring skeleton and aza analogues. This
tetracyclic ring system is found in several alkaloids including
3,4-dehydroanhydrolycorine (Scheme 4).11 Compounds 6 were
cyclized under microwave conditions in the presence of a
catalytic amount of acid. The yield of 7b was lower than that for
7a, which is not unexpected. Compound 6b also reacted with
great difficulties to give Diels−Alder adduct under conventional
heating without acid.7
a
b
Formation as determined by 1H NMR. Reaction was carried out in a
c
dark box. 315−400 nm.
summarizes initial attempts to oxidize compound 2i and
demonstrates the importance of both air and UV light for
efficient oxidation (entry 2). Interestingly, oxidation took place,
although slower, in the presence of UV light but in the absence
of air (entry 3). Photo-induced formation of phenanthridines
by cyclization of N-(o-halobenzyl)arylamines followed by
oxidation of the dihydrophenanthridine is reported before,
but in these cases it is not absolutely clear whether the final
oxidation takes place in the course of the reaction or during
workup/purification.9 However, if the latter is true, the
dihydrophenanthridines described in the literature are sub-
stantially more prone to oxidation under workup conditions
compared to our compounds 2.
As an alternative to the light-induced air oxidation, we have
also shown that all dihydro(aza)phenanthridines 2 can be
oxidized to compounds 3 by treatment with DDQ (Method C,
Scheme 2, Table 1). The isolated yields were generally high and
the reaction times shorter compared to the air oxidation;
however, removal of DDQ was problematic in some cases.
During the course of our study, a related microwave-
mediated cyclization of o-furyl(allyloxy)arenes to afford benzo-
[c]chromenes was published.10 Here the cyclization took place
in water without the addition of any acid to aid in the further
transformation of the Diels−Alder adduct intermediate. Our
initial screening of solvents for the cyclization of compound 2a
included both water and water−MeCN (1:1), but in both cases
no products could be isolated mostly due to insolubility of the
In conclusion, we have developed an efficient protocol for
the microwave-mediated cyclization of o-furyl(allylamino)-
arenes to dihydrophenanthridines. MeCN was found to be an
excellent reaction medium and a catalytic amount of acid was
required for further transformations of the Diels−Alder adduct
intermediate. The products can readily be oxidized to fully
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The Journal of Organic Chemistry
Note
chloro-2-(furan-2-yl)pyridin-3-amine (1.22 g, 6.26 mmol), 15-crown-
5-ether (2.00 g, 12.5 mmol), and NaH (500 mg, ca. 12.5 mmol, ca.
60% in mineral oil) in dry toluene (100 mL) was stirred at 0 °C for 10
min under Ar. Allyl bromide (1.14 g, 9.42 mmol) was added, and the
mixture was stirred at rt for 16 h. Water (50 mL) was added. The
mixture was extracted with DCM (2 × 50 mL), dried (MgSO4), and
concentrated in vacuo. The residue was dissolved in dry toluene (100
mL), heated for 16 h at 90 °C under Ar, evaporated onto SiO2, and
purified by flash chromatography with DCM−EtOAc−hexane
(1:4:20); yield 578 mg (39%), yellow oil. 1H NMR (300 MHz,
CDCl3) δ 7.90 (d, J = 2.0, 1H), 7.53 (dd, J = 1.8, 0.8, 1H), 7.00 (dd, J
= 3.5, 0.8, 1H), 6.91 (d, J = 2.0, 1H), 6.56 (dd, J = 3.5, 1.8, 1H), 6.09−
5.82 (m, 2H), 5.39−5.12 (m, 2H), 3.92−3.60 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 154.2, 142.0, 141.4, 135.9, 133.8, 132.7, 131.0, 117.8,
116.9, 111.9, 109.4, 45.7; MS EI m/z (rel %) 236/234 (33/100, M+),
207 (15), 178 (12); HRMS (EI) calcd for C12H11N2ClO 234.0560,
found 234.0555.
Scheme 4. Microwave-Mediated Synthesis of the Tetracyclic
Compounds 7
aromatic compounds by air in the presence of UV light or by
DDQ.
EXPERIMENTAL SECTION
■
General. 1H NMR spectra were recorded at 600, 500, 400, 300, or
200 MHz. The decoupled 13C NMR spectra were recorded at 150,
125, 100, or 75 MHz. All J values are reported in hertz. HRMS-EI was
performed with a double-focusing magnetic sector instrument and
HRMS-ESI with a TOF quadrupole instrument. Microwave experi-
ments were carried out in sealed vessels in a synthesis reactor
Monowave 300, Anton Paar GmbH, equipped with a Ruby
thermometer and internal IR probe. Flash chromatography was
performed on silica gel (Merck no. 09385). The UV lamp was emitting
at 315−400 nm with peaks at 352 and 368 nm. HPLC grade MeCN
was degassed by freeze−pump−thaw cycling using N2(l) and flushed
with Ar. Physical data for known compounds were in agreement with
those reported before.
General Procedure for Synthesis of Compounds 2, 5, and 7
(Method A). A stirring solution of compound 1 and aq HCl (0.5 M,
0.2 equiv) in degassed CH3CN (15 mL) was flushed with Ar for 15
min in a reactor tube and in the microwave oven (reaction time and
temperature, see Table 1). The solvent was removed in vacuo, and the
product purified by flash chromatography.
5,6-Dihydrophenanthridine (2a). The title compound was
synthesized from 1a7 (200 mg, 1.00 mmol). DCM−EtOAc−hexane
(4:6:15) was used for flash chromatography; yield 100 mg (55%) 2a,
mp 118−121 °C (lit.12 126−127) and 25 mg (14%) 3a.13
4-Chloro-5,6-dihydrophenanthridine (2b). The title compound
was synthesized from 1b7 (115 mg, 0.492 mmol). EtOAc−hexane
(1:3) was used for flash chromatography; yield 75 mg (71%) (2b) and
5 mg (5%) 3b.14 Data for 2b: mp 93−95 °C, crystalline. H NMR
1
N-Allyl-2,4-dichloro-6-(furan-2-yl)aniline (1e). Pd(OAc)2 (141
mg, 0.630 mmol), PPh3 (816 mg, 3.11 mmol), potassium furan-2-
yltrifluoroborate (3.30 g, 19.0 mmol), K2CO3 (2.50 g, 18.7 mmol), and
2-bromo-4,6-dichloroaniline (3.00 g, 12.5 mmol) in absolute EtOH
(200 mL) and water (10 mL) was stirred at reflux under Ar for 3 h.
The solvents were removed in vacuo, and the product was purified by
flash chromatography with EtOAc−DCM−hexane (1:4:45); yield 2,4-
dichloro-6-(furan-2-yl)aniline 2.59 g (92%). Mp 66−68 °C, crystalline.
1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 1.8, 0.8, 1H), 7.36 (d, J =
2.4, 1H), 7.22 (d, J = 2.4, 1H), 6.63 (dd, J = 3.4, 0.8, 1H), 6.53 (dd, J =
3.4, 1.8, 1H), 4.65 (s, 2H, NH2); 13C NMR (100 MHz, CDCl3) δ
151.5, 142.2, 138.6, 128.2, 125.8, 122.3, 120.9, 118.0, 111.7, 108.1;
HRMS (EI) calcd for C10H7Cl2NO 226.9905, found 226.9903. 2,4-
Dichloro-6-(furan-2-yl)aniline (1.04 g, 4.58 mmol), 18-crown-6-ether
(1.80 g, 6.82 mmol) and KH (630 mg, ca. 5.50 mmol, ca. 35% in
mineral oil) in dry toluene (100 mL) was stirred for 10 min under Ar
at rt. Allyl bromide (665 mg, 5.50 mmol) was added, and the mixture
was stirred at 35 °C for 2 h. Water (50 mL) was added, the mixture
was extracted with DCM (3 × 50 mL), the organic extracts were dried
(MgSO4) and evaporated, and the product was isolated by flash
chromatography with EtOAc−DCM−hexane (1:4:45); yield 1.03 g
(84%), oil. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 2.4, 1H), 7.49
(d, J = 1.9, 1H), 7.28 (d, J = 2.4, 1H), 6.86 (d, J = 3.3, 1H), 6.51 (dd, J
= 3.3, 1.8, 1H), 5.97−5.72 (m, 1H), 5.25−5.04 (m, 2H), 4.04 (bs,
1H), 3.51 (dt, J = 6.0, 1.5, 2H); 13C NMR (100 MHz, CDCl3) δ 150.4,
142.3, 141.1, 135.8, 128.3, 127.9, 127.0, 126.7, 125.1, 116.5, 112.0,
109.8, 50.1; MS EI m/z (rel %) 271/269/267 (6/50/63, M+), 252/
250/248 (14/74/100), 226 (35); HRMS (EI) calcd for C13H11Cl2NO
267.0218, found 267.0215.
(400 MHz, CDCl3) δ 7.67 (dd, J = 7.8, 1.0, 1H), 7.59 (dd, J = 7.8, 1.5,
1H), 7.31 (app td, J = 7.8, 1.4, 1H), 7.29−7.20 (m, 1H), 7.18 (dd, J =
7.8, 1.5, 1H), 7.13 (d, J = 7.5, 1H), 6.74 (app t, J = 7.8, 1H), 4.66 (s,
1H), 4.48 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 142.1, 132.4,
131.5, 128.8, 127.9, 127.8, 126.3, 123.3, 122.8, 122.1, 119.6, 118.8,
46.1; MS EI m/z (rel %) 217/215 (18/57, M+), 214 (100), 151 (18);
HRMS (EI) calcd for C13H10ClN 215.0502, found 215.0496.
3-Chloro-5,6-dihydrophenanthridine (2c). The title compound
was synthesized from 1c7 (300 mg, 1.28 mmol). EtOAc−DCM−
hexane (1:4:20) followed by (1:4:5) was used for flash chromatog-
raphy; yield 175 mg (63%) 2c, mp 121−123 °C (lit.15 120−122) and
56 mg (20%) 3c.16
2-Chloro-5,6-dihydrophenanthridine (2d). The title compound
was synthesized from 1d7 (110 mg, 0.471 mmol). EtOAc−DCM−
hexane (1:4:16) was used for flash chromatography; yield 63 mg
(62%) 2d, mp 65−67 °C (lit.12 68−69) and 29 mg (29%) 3d.9
2,4-Dichloro-5,6-dihydrophenanthridine (2e). The title com-
pound was synthesized from 1e (100 mg, 0.373 mmol). EtOAc−
DCM−hexane (1:1:18) was used for flash chromatography; yield 89
mg (95%). Mp 66−68 °C, light-yellow crystalline. 1H NMR (600
MHz, CDCl3) δ 7.62 (dd, J = 7.7, 1.4, 1H), 7.56 (d, J = 2.3, 1H), 7.33
(app td, J = 7.7, 1.4, 1H), 7.29 (dd, J = 7.4, 1.3, 1H), 7.20 (d, J = 2.3,
1H), 7.14 (dd, J = 7.7, 7.4, 1H), 4.62 (s, 1H), 4.48 (s, 2H); 13C NMR
(150 MHz, CDCl3) δ 140.6, 132.3, 130.4, 128.4, 128.0, 128.0, 126.3,
124.0, 123.0, 122.9, 122.1, 119.6, 45.9; MS EI m/z (rel %) 253/251/
249 (5/31/54, M+), 252/250/248 (14/74/100), 213 (9), 177 (19);
HRMS (EI) calcd for C13H9Cl2N 249.0112, found 249.0107.
4-Chloro-2-nitro-5,6-dihydrophenanthridine (2f). The title
compound was synthesized from 1f7 (150 mg, 0.538 mmol).
EtOAc−DCM−hexane (1:4:16) was used for flash chromatography;
N-Allyl-5-chloro-2-(furan-2-yl)pyridin-3-amine (1j). 2-Bromo-
5-chloropyridin-3-amine (2.00 g, 9.71 mmol) was reacted with
potassium furan-2-yltrifluoroborate (2.50 g, 14.4 mmol) for 6 h at
80 °C as described in the first step of 1e synthesis. The product was
purified by flash chromatography with EtOAc−DCM−hexane (1:1:8);
yield 5-chloro-2-(furan-2-yl)pyridin-3-amine 1.62 g (86%). Mp 107−
108 °C, yellow crystalline. 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J =
2.0, 1H), 7.55 (dd, J = 1.8, 0.8, 1H), 7.0−6.99 (m, 2H), 6.57 (dd, J =
3.5, 1.8, 1H), 4.75 (s, 2H); 13C NMR (125 MHz, CDCl3) δ 153.8,
142.3, 140.0, 137.8, 132.5, 130.5, 122.9, 112.0, 109.5; HRMS (EI)
calcd for C9H7N2ClO 194.0247, found 194.0244. A solution of 5-
1
yield 129 mg (92%). Mp 159−162 °C, bright-yellow crystalline. H
NMR (400 MHz, CDCl3) δ 8.49 (d, J = 2.3, 1H), 8.12 (d, J = 2.3, 1H),
7.77 (d, J = 7.6, 1H), 7.37 (d, J = 7.6, 1H), 7.35−7.29 (m, 1H), 7.13
(d, J = 7.4 Hz, 1H), 5.27 (bs, 1H), 4.75 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 146.6, 138.4, 130.3, 129.2, 129.0, 128.5, 126.5, 124.8, 122.9,
120.6, 118.0, 117.9, 45.5; MS EI m/z (rel %) 262/260 (21/70, M+),
261/259 (42/100), 213 (56), 178 (23); HRMS (EI) calcd for
C13H9N2O2Cl 260.0353, found 260.0343.
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The Journal of Organic Chemistry
Note
4-Chloro-5,6-dihydrobenzo[c][1,7]naphthyridine (2g). The
title compound was synthesized from 1g7 (102 mg, 0.435 mmol).
EtOAc−DCM−hexane (1:3:9) was used for flash chromatography;
yield 75 mg (80%) 2g and 3 mg (3%) 3g. Data for 2g: light-yellow
1). The solvent was removed in vacuo, and the product purified by
flash chromatography.
Phenanthridine (3a). The title compound was synthesized from
1a7 (100 mg, 0.502 mmol, Method B) or (105 mg, 0.527 mmol,
Method C). EtOAc−DCM−hexane (4:6:15) was used for flash
chromatography; yield 56 mg (63%) Method B, 65 mg (69%) Method
C. Mp 104−106 °C (lit.13 104−105).
4-Chlorophenanthridine (3b). The title compound was synthe-
sized from 1b7 (100 mg, 0.428 mmol, Method B) or (80 mg, 0.34
mmol, Method C). EtOAc−DCM−hexane (6:9:35) was used for flash
chromatography; yield 80 mg (87%) Method B, 66 mg (90%) Method
C. Mp 115−115.5 °C (lit.14 98−100).
3-Chlorophenanthridine (3c). The title compound was synthe-
sized from 1c7 (100 mg, 0.428 mmol, Method B) or (200 mg, 0.856
mmol, Method C). EtOAc−DCM−hexane (6:9:35) was used for flash
chromatography; yield 76 mg (83%) Method B, 123 mg (67%)
Method C. Mp 112−113 °C (lit.16 107−108).
2-Chlorophenanthridine (3d). The title compound was synthe-
sized from 1d7 (100 mg, 0.428 mmol, Method B) or (140 mg, 0.599
mmol, Method C). EtOAc−DCM−hexane (3:3:14) was used for flash
chromatography; yield 83 mg (91%) Method B, 110 mg (86%)
Method C. Mp 139−140 °C (lit.9 154−157).
2,4-Dichlorophenanthridine (3e). The title compound was
synthesized from 1e (100 mg, 0.373 mmol, Method B) or (110 mg,
0.410 mmol, Method C). EtOAc−DCM−hexane (3:3:14) was used
for flash chromatography; yield 80 mg (86%) Method B, 88 mg (87%)
Method C. Mp 196−197 °C, crystalline. 1H NMR (600 MHz, CDCl3)
δ 9.21 (s, 1H), 8.31 (d, J = 8.4, 1H), 8.22 (d, J = 2.3, 1H), 7.97 (d, J =
8.0, 1H), 7.80 (dd, J = 8.4, 7.0, 1H), 7.70 (dd, J = 8.0, 7.0, 1H), 7.67
(d, J = 2.3, 1H); 13C NMR (150 MHz, CDCl3) δ 154.2, 139.2, 135.3,
132.4, 131.7, 131.1, 129.2, 129.0, 128.8, 126.4, 126.2, 122.1, 120.8; MS
EI m/z (rel %) 251/249/247 (12/71/100, M+), 211 (10), 177 (18);
HRMS (EI) calcd for C13H7Cl2N 246.9956, found 246.9955.
4-Chloro-2-nitrophenanthridine (3f). The title compound was
synthesized from 1f7 (261 mg, 0.937 mmol, Method B) or (250 mg,
0.897 mmol, Method C). EtOAc−DCM−hexane (1:1:18) followed by
(1:2:6) was used for flash chromatography; yield 108 mg (45%)
Method B, 160 mg (69%) Method C. Mp 193−194 °C, crystalline. 1H
NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 9.42 (d, J = 2.4, 1H), 8.70
(d, J = 8.4, 1H), 8.66 (d, J = 2.4, 1H), 8.24−8.15 (m, 1H), 8.03 (ddd, J
= 8.4, 7.1, 1.4, 1H), 7.94−7.85 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 157.6, 145.4, 144.0, 136.3, 133.0, 132.5, 129.8, 129.7, 126.8,
125.5, 123.1, 122.6, 117.6; MS EI m/z (rel %) 260/258 (31/100, M+),
212 (26), 200 (26); HRMS (EI) calcd for C13H7N2O2Cl: 258.0196,
found 258.0190.
1
waxy material. H NMR (300 MHz, CDCl3) δ 7.80 (d, J = 5.0, 1H),
7.70−7.65 (m, 1H), 7.43 (d, J = 5.0, 1H), 7.40−7.31 (m, 2H), 7.17−
7.12 (m, 1H), 4.58 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.4,
137.9, 137.4, 133.0, 129.9, 129.6, 129.2, 128.2, 126.6, 123.5, 116.6,
45.6; MS EI m/z (rel %) 218/216 (21/67, M+), 217/215 (42/100),
179 (82), 152 (33); HRMS (EI) calcd for C12H9N2Cl 216.0454, found
216.0449.
5,6-Dihydrobenzo[c][1,5]naphthyridine (2h). The title com-
pound was synthesized from 1h7 (175 mg, 0.874 mmol). EtOAc−
DCM−hexane (2:3:5) was used for flash chromatography; yield 97 mg
(61%) 2h, mp 95−97 °C (lit.17 89−90) and 46 mg (29%) 3h.18
4-Chloro-5,6-dihydrobenzo[c][1,5]naphthyridine (2i). The
title compound was synthesized from 1i7 (205 mg, 0.874 mmol).
EtOAc−DCM−hexane (2:3:20) was used for flash chromatography;
yield 163 mg (86%) 2i and 17 mg (9%) 3i. Data for 2i: mp 121−122
1
°C, crystalline. H NMR (500 MHz, CDCl3) δ 8.22 (dd, J = 7.5, 1.6,
1H), 7.91 (d, J = 5.1, 1H), 7.37 (app td, J = 7.5, 1.5, 1H), 7.33 (app td,
J = 7.5, 1.6, 1H), 7.11 (dd, J = 7.5, 1.4, 1H,), 7.07 (d, J = 5.1, 1H), 4.63
(s, 2H), 4.51 (s, 1H); 13C NMR (125 MHz, CDCl3) δ 141.3, 138.8,
138.2, 132.8, 131.8, 129.6, 128.2, 126.9, 125.9, 124.2, 123.4, 45.4; MS
EI m/z (rel %) 218/216 (17/53, M+), 217/215 (40/100), 179 (15);
HRMS (EI) calcd for C12H9ClN2 216.0454, found 216.0448.
3-Chloro-5,6-dihydrobenzo[c][1,5]naphthyridine (2j). The
title compound was synthesized from 1j (200 mg, 0.852 mmol).
EtOAc−DCM−hexane (2:3:10) was used for flash chromatography;
1
yield 148 mg (80%). Mp 139−141 °C, bright-yellow crystalline. H
NMR (500 MHz, CDCl3) δ 8.17 (dd, J = 7.6, 1.4, 1H), 7.95 (d, J =
2.1, 1H), 7.36 (app td, J = 7.6, 1.3, 1H), 7.30 (app td, J = 7.6, 1.4, 1H),
7.12−7.00 (m, 1H), 6.83 (d, J = 2.1, 1H), 4.53 (s, 2H), 3.99 (s, 1H);
13C NMR (125 MHz, CDCl3) δ 141.8, 138.7, 138.1, 132.6, 131.7,
131.2, 129.3, 128.2, 125.8, 123.7, 120.1, 45.6; MS EI m/z (rel %) 218/
216 (16/51, M+), 217/215 (38/100), 179 (9), 152 (9); HRMS (EI)
calcd for C12H9N2Cl. 216.0454, found 216.0449.
4-Chloro-5,6-dihydropyrimido[5,4-c]isoquinoline (2k). The
title compound was synthesized from 1k7 (105 mg, 0.446 mmol).
EtOAc−DCM−hexane (1:1:3) was used for flash chromatography;
yield 83 mg (86%). Mp 162−164 °C, yellow crystalline. 1H NMR (400
MHz, CDCl3) δ 8.35 (s, 1H), 8.26−8.23 (m, 1H), 7.41 (ddd, J = 7.0,
4.5, 1.8, 2H), 7.13−7.10 (m, 1H), 4.73 (d, J = 1.7, 2H), 4.41 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 147.5, 146.3, 143.8, 135.5, 133.7,
131.6, 129.7, 128.4, 126.2, 124.9, 45.1; MS EI m/z (rel %) 219/217
(23/68, M+), 218/216 (45/100), 180 (69); HRMS (EI) calcd for
C11H8N3Cl 217.0407, found 217.0400.
4-Chlorobenzo[c][1,7]naphthyridine (3g). The title compound
was synthesized from 1g7 (140 mg, 0.597 mmol, Method B) or (280
mg, 1.19 mmol, Method C). EtOAc−DCM−hexane (2:3:5) was used
for flash chromatography; yield 118 mg (92%) Method B, 145 mg
2-Chloro-5,6-dihydropyrimido[5,4-c]isoquinoline (2l). The
title compound was synthesized from 1l7 (105 mg, 0.446 mmol).
EtOAc−DCM−hexane (2:3:5) was used for flash chromatography;
1
(57%) Method C. Mp 191−193 °C, crystalline. H NMR (400 MHz,
1
CDCl3) δ 9.40 (s, 1H), 8.56 (d, J = 8.2, 1H), 8.51 (d, J = 5.5, 1H),
8.26 (d, J = 5.6, 1H), 8.13 (dd, J = 7.9, 1.3, 1H), 7.96 (ddd, J = 8.2, 7.1,
1.3, 1H), 7.93−7.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 155.5,
153.4, 144.2, 136.6, 132.3, 131.6, 130.6, 130.5, 129.3, 127.8, 122.9,
115.6; MS EI m/z (rel %) 216/214 (40/100, M+), 179 (70), 152 (35);
HRMS (EI) calcd for C12H7N2Cl 214.0298, found 214.0299.
yield 85 mg (88%). Mp 210−212 °C, bright-yellow crystalline. H
NMR (500 MHz, DMSO-d6) δ 8.01−7.95 (m, 2H), 7.45 (app td, J =
7.5, 1.5, 1H), 7.38 (app td, J = 7.5, 1.3, 1H), 7.22 (dd, J = 7.5, 1.3, 1H),
6.54 (s, 1H), 4.55 (s, 2H); 13C NMR (125 MHz, DMSO-d6) δ 147.1,
147.0, 143.8, 138.8, 134.6, 131.7, 128.8, 127.9, 126.5, 123.4, 43.6; MS
EI m/z (rel %) 219/217 (15/52, M+), 218/216 (37/100), 180 (9);
HRMS (EI) calcd for C11H8N3Cl 217.0407, found 217.0404.
Benzo[c][1,5]naphthyridine (3h). The title compound was
synthesized from 1h7 (100 mg, 0.499 mmol, Method B) or (105
mg, 0.524 mmol, Method C). EtOAc−DCM−hexane (2:3:5) was used
for flash chromatography; yield 66 mg (73%) Method B, 74 mg (78%)
Method C. Mp 95−96 °C (lit.18 92−93.5).
4-Chlorobenzo[c][1,5]naphthyridine (3i). The title compound
was synthesized from 1i7 (105 mg, 0.447 mmol, Method B or C).
EtOAc−DCM−hexane (6:9:35) was used for flash chromatography;
yield 72 mg (75%) Method B, 82 mg (85%) Method C. Mp 143−145
°C, crystalline. 1H NMR (500 MHz, CDCl3) δ 9.43 (s, 1H), 9.16 (d, J
= 8.2, 1H), 8.87 (d, J = 4.9, 1H), 8.12 (d, J = 8.0, 1H), 7.97 (ddd, J =
8.2, 7.1, 1.4, 1H), 7.86 (ddd, J = 8.0, 7.1, 1.3, 1H), 7.78 (d, J = 4.9,
1H); 13C NMR (125 MHz, CDCl3) δ 154.9, 149.2, 144.1, 142.7,
136.4, 133.5, 132.1, 129.9, 128.7, 128.3, 124.3, 124.0; MS EI m/z (rel
General Procedure for Synthesis of the (Aza)-
phenanthridines 3 (Method B). Compound 1 was cyclized under
microwave conditions (see Method A). The mixture was transferred to
a quartz tube, and the microwave tube was washed with CH3CN (15
mL) and subsequently transferred to the quartz tube. Air was bubbled
through the mixture while exposed to UV light (315−400 nm) at rt
(reaction times, see Table 1). The solvent was removed in vacuo, and
the product was purified by flash chromatography.
General Procedure for Synthesis of the (Aza)-
phenanthridines 3 (Method C). Compound 1 was cyclized under
microwave conditions (see Method A), and the mixture was
concentrated in vacuo. The residue was dissolved in dry DCM (30
mL) and stirred with DDQ (1.2 equiv) at rt (reaction times, see Table
1314
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The Journal of Organic Chemistry
Note
1
%) 216/214 (34/100, M+), 179 (27), 152 (14); HRMS (EI) calcd for
C12H7ClN2 214.0298, found 214.0293.
needles. H NMR (600 MHz, CDCl3) δ 7.66 (dd, J = 7.7, 1.3, 1H),
7.62 (dd, J = 7.8, 1.6, 1H), 7.38 (d, J = 7.6, 1H), 7.35−7.28 (m, 2H),
7.18−7.13 (m, 1H), 6.98 (app t, J = 7.9, 1H), 5.21 (s, 2H); 13C NMR
(100 MHz, CDCl3) δ 150.6, 131.2, 130.0, 129.6, 128.8, 128.4, 124.9,
124.7, 122.7, 122.5, 122.4, 121.8, 69.1; MS EI m/z (rel %) 218/216
(24/75, M+), 217/215 (42/100), 181 (12), 152 (31); HRMS (EI)
calcd for C13H9ClO 216.0342, found 216.0335. Alternative 2:
Compound 4 (349 mg, 1.49 mmol) in degassed water (15 mL) was
heated in the microwave oven for 5 h at 150 °C. The cooled mixture
was extracted with DCM (3 × 50 mL), the combined organic extracts
were dried (MgSO4) and evaporated, and the product was purified by
flash chromatography with DCM−hexane (1:9); yield 52 mg (16%).
7H-Pyrrolo[3,2,1-de]phenanthridine (7a). The title compound
was synthesized from 6a7 (80 mg, 0.36 mmol) and 0.5 M HCl (0.5
equiv). The mixture was heated at 150 °C for 1.5 h. EtOAc−DCM−
hexane (1:4:45) was used for flash chromatography; yield 55 mg
(75%). Mp 127−129.5 °C, crystalline. 1H NMR (500 MHz, CDCl3) δ
7.93 (dd, J = 7.8, 1.3, 1H), 7.55−7.47 (m, 2H), 7.38−7.31 (m, 1H),
7.27 (td, J = 7.5, 1.3, 1H), 7.18 (dd, J = 7.6, 1.3, 1H), 7.15 (d, J = 3.0,
1H), 7.10 (app t, J = 7.6, 1H), 6.55 (d, J = 3.0, 1H), 5.58 (s, 2H); 13C
NMR (125 MHz, CDCl3) δ 133.6, 130.2, 130.2, 128.0, 127.8, 127.3,
126.19, 126.17, 122.9, 120.8, 120.5, 118.5, 113.7, 102.5, 48.0; MS EI
m/z (rel %) 205 (56, M+), 204 (100), 176 (7); HRMS (EI) calcd for
C15H11N 205.0891, found 205.0885. No data reported for 7a19 before.
7H-Benzo[f]pyrimido[4,5,6-hi]indolizine (7b). The title com-
pound was synthesized from 6b7 (300 mg, 1.33 mmol) and 0.5 M HCl
(0.5 equiv). The mixture was heated at 150 °C for 3 h. MeOH−DCM
(1:19) was used for flash chromatography; yield 113 mg (41%). Mp
3-Chlorobenzo[c][1,5]naphthyridine (3j). The title compound
was synthesized from 1j (100 mg, 0.426 mmol, Method B or C).
EtOAc−DCM−hexane (6:9:35) was used for flash chromatography;
yield 74 mg (81%) Method B, 70 mg (77%) Method C. Mp 141.5−
142 °C, crystalline. 1H NMR (500 MHz, CDCl3) δ 9.30 (s, 1H), 9.06
(dd, J = 8.3, 1.2, 1H), 8.89 (d, J = 2.4, 1H), 8.39 (d, J = 2.4, 1H),
8.09−8.02 (m, 1H), 7.93 (ddd, J = 8.3, 7.0, 1.2, 1H), 7.81 (ddd, J =
8.1, 7.0, 1.2, 1H); 13C NMR (125 MHz, CDCl3) δ 155.6, 148.6, 139.5,
135.9, 133.2, 132.0, 131.2, 129.5, 128.3, 128.1, 123.5; MS EI m/z (rel
%) 216/214 (34/100, M+), 179 (16), 152 (11); HRMS (EI) calcd for
C12H7N2Cl 214.0298, found 214.0300.
4-Chloropyrimido[5,4-c]isoquinoline (3k). The title compound
was synthesized from 1k7 (100 mg, 0.424 mmol, Method B) or (320
mg, 1.36 mmol, Method C). EtOAc−DCM−hexane (1:1:3) was used
for flash chromatography; yield 62 mg (68%) Method B, 214 mg
1
(73%) Method C. Mp 186−187 °C, crystalline. H NMR (400 MHz,
CDCl3) δ 9.49 (s, 1H), 9.22 (s, 1H), 9.21−9.15 (m, 1H), 8.26−8.13
(m, 1H), 8.10−7.96 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.7,
156.1, 154.4, 147.0, 133.7, 132.6, 131.9, 131.8, 130.1, 128.4, 124.4; MS
EI m/z (rel %) 217/215 (34/100, M+), 180 (62), 153 (38); HRMS
(EI) calcd for C11H6N3Cl 215.0250, found 215.0245.
2-Chloropyrimido[5,4-c]isoquinoline (3l). The title compound
was synthesized from 1l7 (93 mg, 0.39 mmol, Method B) or (100 mg,
0.424 mmol, Method C). EtOAc−DCM−hexane (4:6:15) was used
for flash chromatography; yield 51 mg (61%) Method B, 78 mg (85%)
Method C. Mp 185−186 °C, crystalline. 1H NMR (500 MHz, CDCl3)
δ 9.47 (s, 1H), 9.38 (s, 1H), 9.11 (dd, J = 8.1, 1.5, 1H), 8.16 (dd, J =
7.4, 1.8, 1H), 8.04 (ddd, J = 8.1, 7.4, 1.5, 1H), 8.00 (app td, J = 7.4, 1.5,
1H); 13C NMR (125 MHz, CDCl3) δ 162.6, 158.2, 156.1, 148.3,
135.1, 132.6, 132.3, 131.0, 130.2, 128.4, 124.3; MS EI m/z (rel %)
217/215 (34/100, M+), 180 (23), 153 (25); HRMS (EI) calcd for
C11H6N3Cl 215.0250, found 215.0245.
1
164−166 °C, crystalline. H NMR (400 MHz, DMSO-d6) δ 8.81 (s,
1H), 8.30 (dd, J = 7.6, 1.6, 1H), 7.95 (d, J = 3.0, 1H), 7.57 (dd, J = 7.6,
1.6, 1H), 7.55−7.49 (m, 1H), 7.46 (d, J = 7.6, 1H), 6.65 (d, J = 3.0,
1H), 5.72 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 151.9, 146.3,
143.3, 134.9, 133.7, 131.5, 128.2, 128.0, 127.9, 123.4, 101.4, 47.1; MS
EI m/z (rel %) 207 (69, M+), 206 (100), 180 (9); HRMS (EI) calcd
for C13H9N3 207.0796, found 207.0802.
2-(2-(Allyloxy)-3-chlorophenyl)furan (4). (Furan-2-yl)-
tributyltin (4.00 g, 11.2 mmol), (Ph3P)2PdCl2 (340 mg, 0.484
mmol), and 1-bromo-3-chloro-2-fluorobenzene (2.00 g, 9.66 mmol)
in DMF (100 mL) was stirred at 80 °C under Ar for 2 h and
evaporated in vacuo. The residue was dissolved in satd KF in THF
(100 mL), stirred at rt for 16 h, and evaporated in vacuo. The product
was purified by flash chromatography with DCM−hexane (1:9); yield
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of all compounds reported.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
2-(3-chloro-2-fluorophenyl)furan 1.73 g (91%), yellow oil. H NMR
(200 MHz, CDCl3) δ 7.82−7.64 (m, 1H), 7.52 (d, J = 1.8, 1H), 7.35−
AUTHOR INFORMATION
Corresponding Author
*E-mail: l.l.gundersen@kjemi.uio.no.
Notes
7.21 (m, 1H), 7.12 (app t, J = 7.9, 1H), 6.97−6.83 (m, 1H), 6.54 (dd, J
■
= 3.5, 1.8, 1H); 13C NMR (100 MHz, CDCl3) δ 153.9 (d, JCF
252.8), 147.1, 142.4, 128.7, 124.6, 124.3 (d, JCF = 2.9), 121.7 (d, JCF
=
=
17.8), 120.6 (d, JCF = 12.1), 112.1 (d, JCF = 1.7), 111.0 (d, JCF = 12.2);
HRMS (EI) calcd for C10H6ClFO 196.0091, found 196.0087. 2-(3-
Chloro-2-fluorophenyl)furan (530 mg, 2.70 mmol), 15-crown-5-ether
(2.30 g, 10.5 mmol), prop-2-en-1-ol (626 mg, 10.8 mmol), and NaH
(540 mg, ca. 14.65 mmol, ca. 65% in mineral oil) in dry toluene (80
mL) was stirred under Ar at 0 °C for 10 min and at 50 °C for 3 h.
Water (100 mL) was added, the mixture was extracted with DCM (3
× 50 mL), the combined organic extracts were dried (MgSO4) and
evaporated, and the product was isolated by flash chromatography
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Department of Chemistry,
University of Oslo (fellowship to M.L.R.). The Norwegian
Research Council is gratefully acknowledged for partial
financing of the NMR instruments used in this study.
1
with DCM−hexane (1:9); yield 620 mg (98%), oil. H NMR (400
MHz, CDCl3) δ 7.73 (dd, J = 7.9, 1.6, 1H), 7.49 (d, J = 1.9, 1H), 7.29
(dd, J = 8.0, 1.6, 1H), 7.11 (app t, J = 7.9, 1H), 7.03 (d, J = 3.4, 1H),
6.51 (dd, J = 3.4, 1.8, 1H), 6.13 (ddt, J = 17.0, 10.5, 5.7, 1H), 5.45 (dd,
J = 17.0, 1.5, 1H), 5.30 (dd, J = 10.5, 1.4, 1H), 4.47 (d, J = 5.5, 2H);
13C NMR (100 MHz, CDCl3) δ 150.6, 149.4, 142.1, 133.5, 129.12,
129.08, 126.7, 125.2, 125.0, 118.3, 112.2, 110.5, 73.0; MS EI m/z (rel
%) 236/234 (16/51, M+), 195/193 (18/52), 167/165 (33/100);
HRMS (EI) calcd for C13H11ClO2 234.0448, found 234.0451.
4-Chloro-6H-benzo[c]chromene (5). Alternative 1: The title
compound was synthesized from 4 (1.00 g, 4.27 mmol) and 0.5 M
HCl (0.5 equiv). The mixture was heated at 170 °C for 2 h. EtOAc−
DCM−hexane (1:1:18) was used for flash chromatography; yield 739
mg nearly pure compound. An analytical sample (356 mg, 39%) was
prepared by being recrystallized from hot MeOH. Mp 63−64 °C,
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The Journal of Organic Chemistry
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