Synthesis of dibenzo[c,h][1,6]naphthyridine, [2]benzopyrano[4,3-c]quinoline and benzo[i]phenanthridine analogues of the quaternary benzo[c]phenanthridines

Article abstract of DOI:10.1055/s-2000-6325

Three concise syntheses of the dibenzo[c,h][1,6]naphthyridines, [2]benzopyrano[4,3-c]quinolines and the benzo[i]phenanthridines are reported. All methods involve Vilsmeier chemistry, either to generate a 12-methyl-6-oxo-6H- [2]benzopyrano[4,3-c]quinolinium salt which after hydrolysis with either ammonia or methanol can ultimately be cyclised to the first two target compounds, whereas the latter can be prepared in one step from 2-(1-pyrrolidino)-3,4-dihydronaphthalene and N- methylformanilide in phosphorus oxychloride. These tetracyclic heteroaromatic ring systems are related to the benzo[c]phenanthridines, and form part of our investigations into determining the mechanism of action of this class of compounds as topoisomerase inhibitors.

Full text of DOI:10.1055/s-2000-6325

PAPER
1121
Synthesis of Dibenzo[c,h][1,6]naphthyridine, [2]Benzopyrano[4,3-c]quinoline
and Benzo[i]phenanthridine Analogues of the Quaternary
Benzo[c]phenanthridines
Susan M. Hutton, Simon Paul Mackay,* Otto Meth-Cohn
Institute of Pharmacy and Chemistry, University of Sunderland, Sunderland, SR1 3SD, UK
Received 8 October 1999; revised 6 March 2000
ported any biological data for these compounds. More re-
Abstract: Three concise syntheses of the dibenzo[c,h][1,6]naph-
cently, we have prepared benzo[h]quinoline analogues
with a quaternary pyrazolo ring annelated at both the b
and c ring junctions, which have shown promising antitu-
thyridines, [2]benzopyrano[4,3-c]quinolines and the ben-
zo[i]phenanthridines are reported. All methods involve Vilsmeier
chemistry, either to generate a 12-methyl-6-oxo-6H-[2]benzopyra-
no[4,3-c]quinolinium salt which after hydrolysis with either ammo- mour activity.4
nia or methanol can ultimately be cyclised to the first two target
We wish to report herein the concise and rapid syntheses
compounds, whereas the latter can be prepared in one step from
2-(1-pyrrolidino)-3,4-dihydronaphthalene and N-methylformanil-
ide in phosphorus oxychloride. These tetracyclic heteroaromatic
ring systems are related to the benzo[c]phenanthridines, and form
part of our investigations into determining the mechanism of action
of this class of compounds as topoisomerase inhibitors.
of the dibenzo[c,h][1,6]naphthyridines, [2]benzopyra-
no[4,3-c]quinolines and the benzo[i]phenanthridines,
three tetracyclic heteroaromatic ring systems related to
the benzo[c]phenanthridines, which form part of our in-
vestigations into determining the antitumour mechanism
of action of this class of compounds. We have shown re-
cently that the activity of the quaternary benzo[c]phenan-
thridines is linked to the presence of an iminium bond,5,6
and have consequently concentrated on the development
of tetracyclic analogues which also have this moiety.
Key words: Vilsmeier reaction, quinolines, heterocycles, cyclisa-
tions, benzophenanthridines
There have been numerous structure-activity relationship
studies performed for the quaternary benzo[c]phenan-
thridines with respect to their antitumour activity and a
wide variety of multi-step synthetic strategies developed
to produce the various oxygenated substituent arrange-
ments around the heteroaromatic nucleus.1 To date, few
studies have investigated whether modification of the
benzo[c]phenanthridine ring system itself significantly af-
fects antitumour activity. Cushman and coworkers2 syn-
thesised an analogue of the alkaloid nitidine (1) with a
partially saturated pentacyclic ring B (2) which was active
against both L1210 and P388 leukaemias and B16 mela-
noma, whilst Bisagni and coworkers3 reported the synthe-
sis of the dibenzo[c,h][1,5]naphthyridines (3) with
various oxygenated substituents, but as yet, have not re-
The reaction between homophthalic acid and N-methyl-
formanilide under Vilsmeier conditions, previously re-
ported by Meth-Cohn,7 yields the 12-methyl-6-oxo-6H-
[2]benzopyrano[4,3-c]quinolinium phosphodichloridate
(4), a tetracyclic analogue of the quaternary ben-
zo[c]phenanthridines, which also contains the required
iminium bond. However, the susceptibility of the lactone
moiety of this quinolinium salt to aqueous hydrolysis7
(yielding the 3-(2-carboxyphenyl)-1-methyl-4-oxo-1,4-
dihydroquinoline) rendered it unsuitable for further devel-
opment as an antitumour agent. Consideration of the rela-
tive stability of lactams to hydrolysis led us to the
synthesis of the corresponding dibenzo[c,h][1,6]naphthy-
ridine. There are a number of synthetic procedures to the
Synthesis 2000, No. 8, 1121–1124 ISSN 0039-7881 © Thieme Stuttgart · New York

1122
S. M. Hutton et al.
PAPER
Reagents and conditions: (i) NH3 (aq), reflux, 1 h; (ii) Cs2CO3, acetone, reflux, 48 h; (iii) MeOH/H+, reflux, 3 days; (iv) LiAlH4/THF, 12 h;
(v) PTSA/toluene, reflux, 1.5 h (counterions are omitted for clarity)
Scheme 1
various dibenzonaphthyridine heterocycles,3,8-15 yet for Considering the isomeric nature of the benzo[i]phenan-
the [c,h][1,6] isomer, there are only a few reported meth- thridine with respect to the benzo[c]phenanthridines, it
ods which tend to be laborious and low yielding.16,17 Our surprised us that there were no literature reports investi-
synthesis of the novel 6-methyl-12-oxodiben- gating the potential of this heterocycle as an antitumour
zo[c,h][1,6]naphthyridine is a new, three step approach agent. Various synthetic routes have been developed, but
(Scheme 1) involving the initial formation of the benzopy- most tend to suffer from lengthy approaches and low
rano[4,3-c]quinolinium phosphodichloridate (4), fol- overall yields.18-23 The exception was the method devel-
lowed by cleavage of the lactone moiety with ammonia oped by Rigby and Balasubramanium,24,25 which involved
solution to yield the amide 5.7 Cyclisation in the presence the cyclocondensation reaction between 1-cyclohexenyl
of caesium carbonate in refluxing acetone afforded the ar- isocyanate and the pyrrolidine enamine of b-tetralone to
omatic dibenzo[c,h][1,6]naphthryridine 6 in high yield give the 7,8,9,10,11,12-hexahydrobenzo[i]phenanthridin-
(92%) which equates to an overall yield of 80% in three 5(6H)-one in 61% yield. We have modified this approach
steps and is a significant improvement on earlier methods (Scheme 2) by employing the Reverse-Vilsmeier synthe-
(21%16, 11%17). The cyclisation step involves 1,2-attack sis of quinolinium salts pioneered by Meth-Cohn and Tay-
by the amide nitrogen on the carbonyl moiety of the qui- lor.26 Reaction between the 2-(1-pyrrolidino)-3,4-
nolone heterocycle, with subsequent dehydration to yield dihydronaphthalene (10) with N-methylformanilide (11)
the aromatic heterocycle, and is more efficient than the in- in the presence of phosphorus oxychloride, followed by
volvement of a benzyne intermediate16 or a Beckman re- precipitation of the product with ammonium hexafluoro-
arrangement.17 The lowfield ring C aromatic proton phosphate afforded the quaternary 11,12-dihydro-6-meth-
singlet at d = 9.99 ppm, along with a lowfield methyl sin- ylbenzo[i]-phenanthridinium hexafluorophosphate (12)in
glet at d = 4.93 ppm can be attributed to the mesomeric na- 51% yield. Whilst the yield we report is lower than the
ture of the aromatic system and the consequent method reported by Rigby and Balasubramanium,24,25 the
deshielding effect of the contributory iminium bond.
higher oxidation state of the 11,12-dihydro-6-methylben-
zo[i]phenanthridinium salt renders the target, fully aro-
matic 6-methylbenzo[i]phenanthridinium salt achievable
in fewer steps. Oxidation to the aromatic quaternary ben-
zo[i]phenanthridine (13) was achieved quantitatively by
refluxing an ethanolic solution of 12 in the presence of io-
dine, and confirmed by the absence of the two methylene
triplets at d = 3.10 and 3.62 ppm, and the appearance of
two further aromatic doublets at d = 8.81 and 9.09 ppm
corresponding to H-12 and H-11, respectively.
An alternative stable heterocycle was achieved via con-
version of the 12-methyl-6-oxo-6H-[2]benzopyrano[4,3-
c]quinolinium salt 4 to the corresponding 6-dihydro ana-
logue 9 via the methyl ester 7, followed by reduction with
lithium aluminium hydride to the alcohol 8 (Scheme 1).
The additional reduction of the quinolone moiety to the
chiral ketone in compound 8 was confirmed by the ABX
coupling pattern of the non-equivalent protons at C-2
(Jgem = 11.87 Hz) with H-3 (Jvic = 5.94 Hz) and the associ-
ated diastereotopism exhibited by the benzylic protons The assignment of 1H NMR signals for compounds 6, 9,
(Jgem = 11.87 Hz). Cyclisation of the alcohol 8 via the 12 and 13 were performed by 2D 1H-1H-COSY and NOE
hemiacetal (which spontaneously dehydrated) afforded decoupling experiments (Figure).
the 6-dihydro-12-methyl-[2]benzopyrano[4,3-c]quinolin-
ium salt 9.
Synthesis 2000, No. 8, 1121–1124 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Dibenzo[c,h][1,6]naphthyridine
1123
Reagents and conditions: (i) POCl3, 80 °C, 3 h, NH4PF6; (ii) I2, EtOH, reflux, 48 h (counterions are omitted for clarity)
Scheme 2
and microanalyses were carried out on a Carlo Erba 1106 Elemental
Analyser.
6-Methyl-12-oxodibenzo[c,h][1,6]naphthyridine (6)
12-Methyl-6-oxo-6H-[2]benzopyrano[4,3-c]quinolinium
phos-
phodichloridate (4) (mp 293 °C, Lit.7 291-293 °C) and 3-(2-ami-
nocarbonylphenyl)-1-methyl-4-oxo-1,4-dihydroquinoline (5) (mp
142-143 °C, Lit.7 141-142 °C) were prepared according to the
method described by Meth-Cohn.7 3-(2-Aminocarbonylphenyl)-1-
methyl-4-oxo-1,4-dihydroquinoline (5) (0.46 g, 1.62 mmol) and
Cs2CO3 (1.76 g, 5.4 mmol) were refluxed in dry acetone for 48 h,
after which time, the solvent was removed under reduced pressure,
the residue suspended in H2O and the solid collected by filtration
and recrystallised from a mixture of MeOH and MeCN (0.39 g,
92%), mp: >300 °C.
IR: nmax = 1584 cm-1 (C=O)
1H NMR (TFA-d): d = 4.93 (s, 3H, NCH3), 8.20 (t, J = 7.91, 3-H),
8.25 (t, J = 7.91, 2-H), 8.30 (t, J = 8.57, 9-H), 8.45 (t, J = 8.58,
8-H), 8.52 (d, J = 8.58, 7-H), 8.79 (d, J = 7.91, 4-H), 8.93 (d,
J = 8.60, 1-H), 9.23 (d, J = 8.60, 10-H), 9.99 (s, 5-H).
HRMS (EI): Calcd for C17H12N2O 260.0950. Found: 260.0952.
Anal. Calcd for C17H12N2O: C, 78.4; H, 4.7; N, 10.8. Found: C,
78.0; H, 4.5; N, 10.6..
3-(2-Methoxycarbonylphenyl)-1-methyl-4-oxo-1,4-dihydro-
quinoline (7)
12-Methyl-6-oxo-6H-[2]benzopyrano[4,3-c]quinolinium
phos-
phodichloridate (4) (2.0 g, 5.0 mmol), MeOH (100 mL) and concd
sulfuric acid (0.5 mL) were refluxed for 3 days. The MeOH was
subsequently removed under reduced pressure, the residue added to
a mixture of ice and K2CO3, the resulting white precipitate collected
by filtration and recrystallised from EtOH and H2O (1.4 g, 94%),
mp: 145-147 °C.
Figure
The syntheses of these heterocyclic analogues of the nat-
ural benzo[c]phenanthridines bearing the appropriately
oxygenated substituents for antitumour activity are cur-
rently being pursued in our laboratory.
IR: nmax = 1716 (C = O, ester), 1627 (C=O, quinolone) cm-1.
1H NMR (DMSO-d6): d = 3.50 (s, 3H, OCH3), 3.90 (s, 3H, NCH3),
7.28 (d, 1H, ArH, J = 6.27), 7.35-7.42 (m, 3H, ArH3), 7.49 (t, 1H,
J = 7.26, ArH), 7.69 (m, 2H, ArH2), 7.90 (d, 1H, J = 7.59, ArH),
8.51 (d, 1H, J = 7.26, ArH).
Mps were conducted on a Reichert Kofler hot stage apparatus. IR
spectra were obtained on a Unicam Research Series 1 FTIR as KBr
discs. 1H NMR spectra were recorded on a Jeol 270 (1H, 270 MHz).
Chemical shifts (d) are reported in ppm units with TMS as an inter-
nal standard and coupling constants (J) are given in Hz. The assign-
ments of signals were corroborated by the 2D 1H-1H correlation and
NOE experiments for compounds 6, 9, 12 and 13. Accurate masses
were obtained by HRMS with a Kratos MS80RF mass spectrometer
HRMS (EI): Calcd for C17H15NO3 293.1052. Found: 293.1059.
Anal. Calcd for C18H15NO3: C, 73.7; H, 5.2; N, 4.8. Found: C, 74.0;
H, 5.2; N, 4.8.
3-(2-Hydroxymethylphenyl)-1-methyl-4-oxo-1,4-dihydroquino-
line (8)
To a suspension of 3-(2-methoxycarbonylphenyl)-1-methyl-4-oxo-
1,4-dihydroquinoline (7) (1.0 g, 3.4 mmol) in dry THF (25 mL) was
Synthesis 2000, No. 8, 1121–1124 ISSN 0039-7881 © Thieme Stuttgart · New York

1124
S. M. Hutton et al.
PAPER
added dropwise LiAlH4 (0.2 g, 5.3 mmol) suspended in dry THF
(25 mL) and the mixture stirred for 12 h at r.t. H2O (50 mL) was
added and the reaction mixture extracted with Et2O (2 × 25 mL), the
organic portions were combined and washed with H2O (2 × 25 mL),
dried (MgSO4) and concentrated to afford a yellow solid which was
recrystallised from MeOH and H2O to give yellow needles (0.5 g,
55%), mp: 131-133 °C.
lected by filtration. Recrystallisation from EtOAc gave bright yel-
low needles of the iodide salt (0.46 g, 96%), mp: >300 °C.
1H NMR (DMSO-d6): d = 4.83 (s, 3H, N+CH3), 7.94 (t, J = 6.60, 2-
H), 8.06 (t, J = 6.60, 3-H), 8.16 (t, J = 7.25, 9-H), 8.25 (t, J = 7.25,
8-H), 8.35 (d, J = 7.26, 1-H), 8.61 (d, J = 8.58, 7-H), 8.81 (d,
J11-12 = 9.24, 12-H), 9.09 (d, J11-12 = 9.24, 11-H), 9.15 (d, J = 8.58,
4-H), 9.28 (d, J = 7.26, 10-H), 10.96 (s, 5-H).
IR: nmax = 1664 (C=O), 3480 (OH) cm-1.
HRMS (EI): Calcd for C18H14N 244.1126. Found: 244.1116.
1H NMR (CDCl3): d = 3.00 (br, 1H, OH, (D2O exchangeable)), 3.05
(s, 3H, NCH3), 3.66 (dd, 1H, J2A-2B = 11.87, J2A-3X = 5.94, 2-HA),
3.79 (dd, 1H, J2A-2B = 11.87, J2B-3X = 10.55, 2-HB), 4.31 (dd, 1H,
J2A-3X = 5.94, J2B-3X = 10.55, 3-HX), 4.50 (dd, 2H, JA’B’= 11.88,
CH2O), 6.77 (d, 1H, J = 5.27, ArH), 6.80 (d, 1H, J = 4.00, ArH),
7.28-7.30 (m, 3H, ArH3), 7.42 (t, 1H, J = 5.94, ArH), 7.48 (t, 1H,
J = 6.60, ArH), 7.94 (d, 1H, J = 7.92, ArH).
Anal. Calcd for C18H14N: C, 58.2; H, 3.8; N, 3.8. Found: C, 58.2; H,
3.6; N, 3.8.
References
(1) Mackay, S. P.; Meth-Cohn, O.; Waigh, R. D. Adv. Heterocycl.
Chem. 1996, 67, 345.
(2) Cushman, M.; Mohan, P.; Smith, E. C. R. J. Med. Chem. 1984,
27, 544.
(3) Bisagni, E.; Landras, C.; Thirot, S.; Huel, C. Tetrahedron
1996, 52, 10427.
HRMS (EI): Calcd for C17H17NO2 267.1259. Found: 267.1247.
Anal. Calcd for C17H17NO2: C, 76.4; H, 6.4; N, 5.2. Found: C, 76.2;
H, 6.7; N, 5.2.
(4) Kerry, M. A.; Boyd, G. W.; Mackay, S. P.; Meth-Cohn, O.;
Platt, L. J. Chem. Soc., Perkin Trans 1 1999 2315.
(5) Kerry, M. A.; Duval, O.; Waigh, R. D.; Mackay, S. P. J.
Pharm. Pharmacol. 1998, 50, 1307.
(6) Mackay, S. P.; Comoe, L.; Desoize, B.; Duval, O.; Jardillier,
J, -C.; Waigh, R. D. Anti-Cancer Drug Des. 1998, 13, 797.
(7) Meth-Cohn, O. Synthesis 1986, 76.
(8) Katritzky, A. R.; Rachwal, B.; Rachwal, S. J. Org. Chem.
1995, 60, 7631.
(9) Vijayalakshmi, S.; Rajendram, S. P. Indian J. Chem., Sect. B.
1994, 33B, 159.
6-Dihydro-12-methyl-[2]benzopyrano[4,3-c]quinolinium p-Tol-
uenesulfonate (9)
3-(2-Hydroxymethylphenyl)-1-methyl-4-oxo-1,4-dihydroquinol-
ine (8) (0.25 g, 1 mmol) and p-toluenesulfonic acid (PTSA) in tolu-
ene (50 mL) were refluxed for 1.5 h, after which time, the reaction
mixture was cooled and the yellow precipitate collected by filtration
(0.30 g, 76%), mp: 249-254 °C.
HRMS (EI): Calcd for C17H14NO 248.1075. Found: 248.1068.
1H NMR (DMSO-d6): d = 2.28 (s, 3H, CH3 (PTSA)), 4.50 (s, 3H,
N+CH3), 5.90 (s, 2H, OCH2), 7.10 (d, 2H, J = 7.92, C6H4), 7.44 (t,
1H, J = 6.93, 8-H), 7.49 (d, 2H, J = 8.24, C6H4), 7.54-7.58 (m, 2H,
7-H, 9-H), 7.97 (t, 1H, J = 7.26, 2-H), 8.09 (d, 1H, J = 6.93, 10-H),
8.22 (t, 1H, J = 6.93, 3-H), 8.38 (d, 1H, J = 8.91, 4-H), 8.47 (d, 1H,
J = 6.93, 1-H,), 9.95 (s, 1H, 11-H).
(10) Fiala, W.; Stadbauer, W. J. Prakt. Chem./Chem.-Ztg. 1993,
335, 128.
(11) Polborn, K.; Lechner, G.; Wagner, H.; Gompper, R.; Schmidt,
C.; Beck, W. Z. Naturforsch. B. Chem. Sci. 1992, 47, 1393.
(12) Papageorgiou, C.; Borer, X. Helv. Chim. Acta 1988, 71, 1079.
(13) Godard, A.; Queguiner. G. J. Heterocycl. Chem. 1982, 19,
1289.
11,12-Dihydro-6-methylbenzo[i]phenanthridinium Hexafluo-
rophosphate (12)
(14) Banerji, A.; Sahu, A. Heterocycles 1983, 20, 617.
(15) Majewicz, T. G.; Caluwe, P. J. Org. Chem. 1979, 44, 531.
(16) Kessar, S. V.; Pahwa, P. S.; Pawanjit; Singh, P.; Gupta, Y. P.
Indian J. Chem., Sect. B 1978, 16B, 92.
(17) Papageorgiou, C.; Borer, X. J. Org. Chem. 1987, 52, 4403.
(18) Badger, G. M.; Seidler, J. H. J. Chem. Soc. 1954, 2329.
(19) Gopinath, K. W.; Govindachen, T. R.; Nagarajan, K.;
Punishothaman, K. K. J. Chem. Soc. 1958, 504.
(20) Loader, C. E.; Timmons, C. J. J. Chem. Soc. C 1968, 330.
(21) Kessar, S. V.; Sobti, A. K.; Joshi, G. S. J. Chem. Soc. Section
C 1971, 259.
(22) Arumugan, N.; Krishnamurthi, S.; Shenbagamurthi, P.;
Sivasubramanian, S.; Raman, M. Indian J. Chem. 1974, 12,
664.
(23) Boyer, J. H.; Patel, J. R. Synthesis 1978, 205.
(24) Rigby, J. H.; Balasubramanium, N. J. Org. Chem. 1984, 49,
4569.
2-(1-Pyrrolidino)-3,4-dihydronaphthalene (10) (mp 73-76 °C,
Lit.27 78-79 °C) was prepared according to the method described
by Harvey et al.27 N-methylformanilide (11) (2.70 g, 20 mmol) and
POCl3 (10 mL, 108 mmol) were heated together for 5 min at 80 °C.
The solution was cooled in an ice bath, and the enamine (10)
(4.38 g, 22 mmol) was added with stirring. The reaction mixture
was heated at 80 °C in an oil bath for 3 h, after which time, the con-
tents of the flask were poured onto ice (100 mL) and EtOAc (25
mL). Ammonium hexafluorophosphate was added to the resulting
solution to precipitate the product, which was filtered, washed with
EtOAc and H2O, and dried. Recrystallisation from MeCN and
EtOAc gave the title compound (2.51 g, 51%), mp: 275-276 °C.
IR: nmax = 836 cm-1 (PF6)
1H NMR (DMSO-d6): d = 3.10 [t, 2H, J = 7.26, CH2 (12)], 3.62 [t,
2H, J = 7.25, CH2 (11)], 4.68 (s, 3H, N+CH3), 7.47 (m, 1-H, 2-H,
3-H,), 8.03 (t, J = 8.57, 9-H), 8.11 (d, J = 7.26, 4-H), 8.23 (t,
J = 7.25, 8-H), 8.49 (d, J7-8 = 8.58, 7-H), 8.69 (d, J9-10 = 8.58, 10-
H,), 9.98 (s, 5-H).
(25) Rigby, J. H.; Balasubramanium, N. J. Org. Chem. 1989, 54,
224.
(26) Meth-Cohn, O.; Taylor, D. L. Tetrahedron 1995, 47, 12869.
(27) Harvey, R. G.; Pataki, J.; Cortez, C.; Di Raddo, P.; Yang,
C. -X. J. Org. Chem. 1991, 56, 1210.
(28) Seraphin, D.; Lynch, M. A.; Duval, O. Tetrahedron Lett.
1995, 36, 5731.
HRMS (EI): Calcd for C18H15N 245.1204. Found: 245.1204.
6-Methylbenzo[i]phenanthridinium Iodide (13)
11,12-Dihydro-6-methylbenzo[i]phenanthridinium
hexafluoro-
phosphate (12) (0.5 g, 1.2 mmol) and I2 (0.35 g, 1.4 mmol) were re-
fluxed in EtOH (50 mL) for 48 h,28 after which time, sat. sodium
thiosulfate (50 mL) was added to the mixture and the product col-
Article Identifier:
1437-210X,E;2000,0,08,1121,1124,ftx,en;P06099SS.pdf
Synthesis 2000, No. 8, 1121–1124 ISSN 0039-7881 © Thieme Stuttgart · New York