An expedient synthesis of unusual oxoisoaporphine and annelated quinoline derivatives

Article abstract of DOI:10.1055/s-2003-41422

Several 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-ones and 7H-dibenzo[de,h]quinolin-7-ones were catalytically hydrogenated over PtO ₂ in acetic acid to afford 7-hydroxyquinoline and quinolone derivatives with reduced benzene rings.

Full text of DOI:10.1055/s-2003-41422

LETTER
1647
An Expedient Synthesis of Unusual Oxoisoaporphine and Annelated
Quinoline Derivatives
Synthesis of
U
n
d
usual
O
xoiso
u
aporphine
a
a
r
d
Q
uino
d
line
D
erivati
o
ves Sobarzo-Sánchez,*a Bruce K. Cassels,a Luis Castedob
a
Department of Chemistry, Faculty of Sciences, and Millennium Institute for Advanced Studies in Cell Biology and Biotechnology,
University of Chile, Casilla 653, Santiago, Chile
E-mail: esobarzo@usc.es
b
Department of Organic Chemistry and C.S.I.C. Associated Unit, Faculty of Chemistry, University of Santiago, 15782 Santiago de
Compostela, Spain
Received 6 January 2003
drooxoisoaporphines over Adams’ catalyst. This method
is useful for the preparation of new and unusual oxo-
isoaporphine and quinoline derivatives, due to its simp-
licity and efficiency.
Abstract: Several 2,3-dihydro-7H-dibenzo[de,h]quinolin-7-ones
and 7H-dibenzo[de,h]quinolin-7-ones were catalytically hydro-
genated over PtO2 in acetic acid to afford 7-hydroxyquinoline and
quinolone derivatives with reduced benzene rings.
Key words: 7H-dibenzo[de,h]quinolin-7-ones, oxoisoaporphines, The dihydro- and oxoisoaporphines used in this work and
catalytic hydrogenation, reductions, chemoselectivity
the generated products are summarized in Table 1. In all
cases, hydrogenation was carried out for 24 hours at room
temperature at pressures between 60–70 psi.8 Under these
conditions, complete or partial reduction of aromatic ring
D and of the C-N imine bond of the dihydrooxoisoapor-
phines resulted (Scheme 1). However, in the case of the
oxoisoaporphines, aromatic rings B and D were reduced
(Scheme 2). Thus, the chemoreduction shown by these
compounds would seem to depend mainly on the substitu-
tion at C-6 and on the degree of unsaturation of the iso-
quinoline skeleton. When Pd/C was used as catalyst, the
unchanged starting material was recovered.
A limited number of compounds with the 7H-diben-
zo[de,h]quinoline skeleton, known as 1-azabenzan-
thrones, were synthesized three decades ago as
intermediates for the formation of dyes,1 and due to their
possible photo- and electrochemical properties.2 About
the same time, the synthesis of 7H-dibenzo[de,h]quinolin-
7-one derivatives via N-phenethylphthalimides was re-
ported in connection with their possible antiviral activity,3
and the synthesis of some 2,3-dihydro derivatives by cy-
clization of 3-(b-dialkoxyarylethylamino)phthalides was
also reported.4 In the case of the 5-methoxy-2,3-dihydro
analogue (2), this compound was obtained in large enough
quantities to subject it to some preliminary reduction stud-
ies, affording a basic carbinol whose structure, however,
was not adequately confirmed. Since the 1980’s, a small
group of alkaloids possessing the 7H-dibenzo[de,h]quin-
oline skeleton and bearing different substitution patterns
have been isolated from Menispermum dauricum DC.
(Menispermaceae) and designated as oxoisoaporphines.5
Some of them have exhibited cytotoxic activities against
a small panel of cancer cell lines.6 In the structurally sim-
ilar oxoaporphines (7H-dibenzo[de,g]quinolin-7-ones),
which might also be called 6-azabenzanthrones, the re-
duction of the carbonyl group had been carried out under
mild conditions, affording aporphines,7 but no similar re-
sults have been recorded for the oxoisoaporphines. In this
connection it is interesting that, unlike the oxoaporphines,
the oxoisoaporphines are not accompanied in plants by
their reduced (or unoxidized) congeners.
As can be seen in Scheme 1, the 2,3-dihydrooxoisoapor-
phines 1 and 2, lacking a hydroxyl group at C-6, are par-
tially reduced in ring D without affecting the C=N bond,
affording 4 and 5 respectively. Hydrogenation of com-
pound 3, with an OH group at C-6, under identical condi-
tions, led to complete reduction of ring D and the C=N
bond to give 6.
Table 1 Formation of Partially Hydrogenated Oxoisoaporphines 4–
6, 6-Oxoisoaporphine 13 and 7-Hydroxyquinolines 8, 10 and 11 by
Catalytic Hydrogenationa
Substrate
R5
R6
H
Product
Yield [%]
1
2
3
7
9
H
4
5
6
8
53
77
90
81
OMe
OMe
H
H
OH
H
Due to the lack of information on the reactivity of these
compounds under reductive conditions, we have now
studied the catalytic hydrogenation of several 2,3-dihy-
OMe
H
10
11
58
41
12
OMe
OH
13
32
a Conditions: Hydrogenation over PtO2 in AcOH with stirring for 24
hours at room temperature (20–22 °C).
Synlett 2003, No. 11, Print: 02 09 2003. Web: 25 08 2003.
Art Id.1437-2096,E;2003,0,11,1647,1650,ftx,en;S00103ST.pdf.
DOI: 10.1055/s-2003-41422
© Georg Thieme Verlag Stuttgart · New York

1648
E. Sobarzo-Sánchez et al.
LETTER
4
3
4
3
R5
R6
R5
R6
5
MeO
5
2
1
2
1
B
A
B
A
N
NH
H2/PtO2
N
6
HO
6
7 C
7 C
11
10
11
10
AcOH, r.t., 60–70 psi
O
O
O
D
D
8
8
9
9
6
4. R5 = H; R6 = H
5. R5 = OMe; R6 = H
1. R5 = H; R6 = H
2. R5 = OMe; R6 = H
3. R5 = OMe; R6 = OH
Scheme 1 Synthesis of oxoisoaporphine derivatives 4–6 by catalytic hydrogenation over Adams’ catalyst
This unusual reactivity shown by the 2,3-dihydrooxo- ucts. Our present efforts are directed to the synthesis and
isoaporphines is drastically altered when the isoquinoline the exploration of the reactivity of oxoisoaporphines with
A/B rings are fully aromatic. Thus, in 7 benzene ring B is different reduction agents in order to improve our under-
reduced with concomitant enolization of the carbonyl standing of their biogenesis.
group to give 8 as the final product. However, 9 afforded
10 and 11, with reduction of both rings B and D and partial
hydrogenolysis of the methoxyl group (Scheme 2). The
Acknowledgment
E.S.-S. thanks Fundación Andes for a scholarship. This work was
supported in part by FONDECYT Grant No 2010056.
structures of all these reduction products were established
unambiguously using HMQC and HMBC experiments.9
As the reactivity of these completely aromatized oxo-
isoaporphines appeared to be sensitive to substitution on
ring B, the hydrogenation of 12 was also checked. Sur-
prisingly, 12 afforded 13 as the only isolated product,
which could be rationalized as a consequence of reduction
of the carbonyl group at C-7 with subsequent elimination
of water to afford the enone tautomer of the C-6 phenol
function. An analogous mechanism has been proposed for
the reduction of the natural product menisporphine (14) to
bianfugecine (15) under similar conditions (Scheme 3).10
References
(1) For further information on the photo- and electrochemical
properties of azabenzanthrones, see: (a) Pieri, G.; Maria
Carlini, F.; Paffoni, C.; Boffa, G. US Patent 4031096, 1977.
(b) Boffa, G.; Crotti, A.; Pieri, G.; Mangini, A.; Tundo, A.
US Patent 3678053, 1972. (c) Ribaldone, G.; Borsotti, G.;
Gonzati, F. US Patent 3960866, 1976. (d) Ribaldone, G. US
Patent 3943136, 1976. (e) King, J.; Ramage, G. R. J. Chem.
Soc. 1954, 936. (f) Wick, A. K. Helv. Chim. Acta 1966, 49,
1748. (g) Wick, A. K. Helv. Chim. Acta 1966, 49, 1755.
(2) Iwashima, S.; Ueda, T.; Honda, H.; Tsujioka, T.; Ohno, M.;
Auki, J.; Kan, T. J. Chem. Soc., Perkin Trans. 1 1984, 2177.
(3) Fabre, J.-L.; Farge, D.; James, C. US Patent 4128650, 1978.
In conclusion, we report a short, practical method to af-
ford new reduced oxoisoaporphines and other annelated
quinolines which have not been reported as natural prod-
4
3
4
3
2
5
6
5
6
2
A
B
A
B
H2/PtO2
N
N
1
1
7 C
C
7
AcOH, r.t., 60–70 psi
11
11
10
HO
O
D
D
8
10
8
9
9
8
7
MeO
MeO
H2/PtO2
N
N
N
+
AcOH, r.t., 60–70 psi
HO
HO
O
11
10
9
Scheme 2 Synthesis of quinoline derivatives 8, 10 and 11 by catalytic hydrogenation over Adams’ catalyst
Synlett 2003, No. 11, 1647–1650 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Synthesis of Unusual Oxoisoaporphine and Annelated Quinoline Derivatives
1649
MeO
MeO
H2/PtO2
N
N
O
HO
AcOH, r.t., 60–70 psi
O
13
12
4
3
5
MeO
MeO
MeO
2
H2/PtO2
1
N
N
6
7
8
AcOH, r.t.
11
10
O
O
9
OMe
OMe
15
14
MeO
H
MeO
MeO
N
N
N
2(H)
H+
O
O
HO
+
-H3O+
H2O
H
O
13
12
Scheme 3 Conversion of menisporphine (14) to bianfugecine (15) and possible mechanism for the conversion of 12 to 13 under acidic
conditions.
(4) Walker, G. N.; Kempton, R. J. J. Org. Chem. 1971, 36, 1413.
(5) (a) Kunitomo, J.-I.; Satoh, M. Chem. Pharm. Bull. 1982, 30,
2659. (b) Kunitomo, J.-I.; Satoh, M.; Shingu, T.
24.93, 48.85, 124.7, 125.0, 129.1, 131.3, 132.1, 135.2,
139.0, 146.7, 158.5, 185.8. IR (KBr): 2929, 2876, 2855,
1639, 1593, 1296 cm–1. Mp 149–150 ºC. Anal. Calcd. for
C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 80.90; H,
6.47; N, 5.91.
Tetrahedron 1983, 39, 3261. (c) Takani, M.; Takasu, Y.;
Takahashi, K. Chem. Pharm. Bull. 1983, 31, 3091.
(d) Kunitomo, J.-I.; Kaede, S.; Satoh, M. Chem. Pharm.
Bull. 1985, 33, 2778. (e) Hu, S.-M.; Xu, S.-X.; Yao, X.-S.;
Cui, C.-B.; Tezuka, Y.; Kikuchi, T. Chem. Pharm. Bull.
1993, 41, 1866.
Spectroscopic data of 5: 1H NMR (CDCl3, 300 MHz): d 1.75
(m, 4 H), 2.56 (broad s, 2 H), 2.73 (broad s, 2 H), 2.82 (t, 2
H, J = 7.7 Hz), 3.89 (s, 3 H), 4.08 (t, 2 H, J = 7.7 Hz), 6.89
(d, 1 H, J = 2.2 Hz), 7.40 (d, 1 H, J = 2.6 Hz). 13C NMR
(CDCl3, 75 MHz): d 21.65, 21.72, 23.26, 24.26, 25.00,
48.44, 55.65, 107.0, 118.69, 118.71, 130.6, 137.2, 138.5,
146.3, 157.8, 161.5, 185.4. IR (KBr): 2933, 2862, 2840,
1640, 1623, 1601 cm–1. Mp 157–158 ºC. Anal. Calcd. for
C17H17NO2: C, 76.38; H, 6.41; N, 5.24. Found: C, 76.03; H,
6.42; N, 5.26.
(6) Yu, B.-W.; Meng, L.-H.; Chen, J.-Y.; Zhou, T.-X.; Cheng,
K.-F.; Ding, J.; Qin, G.-W. J. Nat. Prod. 2001, 64, 968.
(7) (a) Kupchan, S. M.; Suffness, M. I.; Gordon, E. M. J. Org.
Chem. 1970, 35, 1682. (b) Yang, T.-H. J. Pharm. Soc. Jap.
1962, 82, 804. (c) Kupchan, S. M.; O’Brien, F. J. Chem.
Soc., Chem. Commun. 1973, 915.
(8) Representative Experimental Procedure: A yellow
solution of 2, mp 164–165 ºC, prepared as described,4 (0.5 g,
1.90 mmol) in 50 mL of AcOH was hydrogenated at 68 psi
over PtO2 (0.3 g) for 24 h at r.t. The colorless solution was
diluted with 100 mL water, neutralized with NH3 and
extracted with CHCl3 (200 mL). The CHCl3 extract was
dried over Na2SO4 and concentrated to dryness, and the
residue subjected to flash column chromatography on silica
gel, eluting with 90:10 EtOAc–hexane (v/v) to give 5 (0.390
g, 77% yield), which crystallized in MeOH as yellowish
needles.
Spectroscopic data of 6: 1H NMR (CDCl3, 300 MHz): d 1.00
(m, 1 H), 1.25 (m, 2 H), 1.40 (m, 1 H), 1.60 (m, 1 H), 1.70
(m, 2 H), 2.37 (m, 1 H), 2.61 (m, 2 H), 2.81 (s, 1 H), 2.91 (m,
1 H), 3.11 (dd, 1 H, J = 12.2 Hz, J¢ = 4.6 Hz), 3.44 (m, 1 H),
3.87 (s, 3 H), 4.11 (s, 1 H), 6.78 (s, 1 H), 12.93 (s, 1 H). 13
C
NMR (CDCl3, 75 MHz): d 24.07, 24.15, 26.49, 27.38, 29.36,
44.07, 45.18, 49.74, 57.65, 58.61, 116.1, 119.9, 125.3,
131.0, 148.6, 153.0, 207.6. IR (KBr): 3424, 2929, 2792,
2651, 1640, 1468, 1442, 1302, 1257, 1161, 1092, 1021 cm–
1. Mp 213 ºC (decomp.). Anal. Calcd. for C17H21NO3. HCl.
1.4 H2O: C, 58.44; H, 6.87; N, 4.01. Found: C, 58.58; H,
6.58; N, 3.97.
Spectroscopic data of 4: 1H NMR (CDCl3, 300 MHz): d 1.75
(m, 4 H), 2.57 (broad s, 2 H), 2.74 (broad s, 2 H), 2.85 (t, 2
H, J = 7.8 Hz), 4.11 (t, 2 H, J = 7.8 Hz), 7.37 (d, 1 H, J = 7.8
Hz), 7.47 (dd, 1 H, J = J¢ = 7.7 Hz), 7.94 (d, 1 H, J = 7.8 Hz).
13C NMR (CDCl3, 75 MHz): d 22.01, 22.09, 23.58, 24.72,
Spectroscopic data of 8: 1H NMR (DMSO-d6, 300 MHz): d
2.00 (m, 2 H), 3.05 (m, 4 H), 7.33 (d, 1 H, J = 4.4 Hz), 7.70
(m, 2 H), 8.33 (dd, 1 H, J = 8.2 Hz, J¢ = 1.3 Hz), 8.66 (d, 1
H, J = 4.5 Hz), 9.14 (dd, 1 H, J = 9.1 Hz, J¢ = 1.4 Hz), 9.36
Synlett 2003, No. 11, 1647–1650 ISSN 1234-567-89 © Thieme Stuttgart · New York

1650
E. Sobarzo-Sánchez et al.
LETTER
(d, 1 H, J = 4.3 Hz), 8.62 (s, 1 H). 13C NMR (CDCl3, 75
MHz): d 22.13, 22.70, 22.78, 24.11, 24.84, 25.21, 29.90,
114.3, 118.8, 124.4, 130.2, 133.1, 142.1, 144.3, 145.9,
149.1. IR (KBr): 3432, 2932, 2868, 1636, 1601, 1434, 1361,
1309, 1270, 1192, 1173, 1154, 1090, 1047 cm–1. Mp 160–
161 ºC. Anal. Calcd. for C16H17NO: C, 80.30; H, 7.16; N,
5.85. Found: C, 80.05; H, 7.02; N, 5.81.
(s, 1 H). 13C NMR (DMSO-d6, 75 MHz): d 21.73, 24.28,
29.84, 112.9, 121.2, 122.3, 124.4, 125.0, 126.4, 128.1,
128.2, 131.0, 141.9, 144.3, 145.8, 145.9. IR (KBr): 3426,
2930, 2875, 2820, 1604, 1575, 1434, 1415, 1272, 1253,
1199, 1186, 1098 cm–1. Mp 200 ºC (decomp.). Anal. Calcd.
for C16H13NO: C, 81.68; H, 5.57; N, 5.95. Found: C, 81.55;
H, 5.34; N, 5.93.
Spectroscopic data of 10: 1H NMR (CDCl3, 300 MHz): d
1.85 (broad s, 4 H), 2.71 (m, 2 H), 3.05 (m, 2 H), 3.25 (m, 4
H), 3.45 (s, 3 H), 3.91 (m, 1 H), 7.09 (d, 1 H, J = 4.3 Hz),
8.64 (d, 1 H, J = 4.4 Hz). 13C NMR (CDCl3, 75 MHz): d
22.31, 22.36, 23.95, 25.02, 28.77, 35.02, 56.16, 74.13,
110.7, 119.5, 124.1, 128.4, 134.2, 141.9, 142.1, 146.4,
148.7. IR (KBr): 3433, 3074, 2939, 2859, 1620, 1597, 1524,
1490, 1452, 1407, 1382, 1333, 1277, 1206, 1170, 1043, 1014
cm–1. Mp 181–182 ºC. Anal. Calcd. for C17H19NO2: C,
75.81; H, 7.11; N, 5.20. Found: C, 75.78; H, 7.06; N, 5.05.
Spectroscopic data of 11: 1H NMR (DMSO-d6, 300 MHz): d
1.77 (broad s, 4 H), 1.90 (m, 2 H), 2.73 (broad s, 2 H), 2.91
(m, 4 H), 3.14 (broad s, 2 H), 7.08 (d, 1 H, J = 4.3 Hz), 8.49
Spectroscopic data of 13: 1H NMR (CDCl3, 300 MHz): d
3.27 (s, 3 H), 6.81 (s, 1 H), 7.51 (d, 1 H, J = 4.6 Hz), 7.79
(dd, 1 H, J = J¢ = 6.9 Hz), 7.91 (dd, 1 H, J = J¢ = 7.0 Hz), 8.15
(d, 1 H, J = 7.7 Hz), 9.01 (d, 1 H, J = 4.6 Hz), 9.03 (s, 1 H),
9.31 (d, 1 H, J = 8.4 Hz). 13C NMR (CDCl3, 75 MHz): d
55.95, 110.5, 117.9, 120.5, 124.8, 126.6, 128.9, 130.8,
131.0, 132.5, 134.3, 134.4, 135.5, 144.8, 149.7, 156.0,
179.3. IR (KBr): 2932, 2857, 1653, 1614 cm–1. Mp 203 ºC
(decomp.). Anal. Calcd. for C17H11NO2: C, 78.15; H, 4.24;
N, 5.36. Found: C, 77.88; H, 4.16; N, 5.33.
(9) Sobarzo-Sánchez, E.; Cassels, B. K.; Jullian, C.; Castedo, L.
Magn. Reson. Chem. 2003, 41, 545.
(10) Kunitomo, J.-I.; Miyata, Y. Heterocycles 1986, 24, 437.
Synlett 2003, No. 11, 1647–1650 ISSN 1234-567-89 © Thieme Stuttgart · New York