The synthesis of benzo[h]quinolines as topoisomerase inhibitors

Article abstract of DOI:10.1039/a903402a

A range of benzo[h]quinolines of potential biological interest have been prepared by'way of the 2-chloroand the 4-chlorobenzo[h]quinoline-3-carbaldehyde isomers.

Full text of DOI:10.1039/a903402a

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The synthesis of benzo[h]quinolines as topoisomerase inhibitors
Mark A. Kerry,a Gary W. Boyd,b Simon P. Mackay,*a Otto Meth-Cohna and Louise Platta
a Institute of Pharmacy and Chemistry, School of Sciences, University of Sunderland,
Sunderland, UK SR1 3SD
b ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, UK EH4 2XU
Received (in Cambridge) 28th April 1999, Accepted 23rd June 1999
A range of benzo[h]quinolines of potential biological interest have been prepared by way of the 2-chloro-
and the 4-chlorobenzo[h]quinoline-3-carbaldehyde isomers.
Introduction
(i)
Numerous tri- and tetracyclic planar nitrogen heterocycles,
such as amsacrine, the benzo[c]phenanthridines, the ellipticines,
intoplicine and coralyne are well known as topoisomerase
N
N
H
CHO
inhibitors and have been investigated as potential anticancer
Cl
O
agents.1–5 The benzo[h]quinolines can be viewed as being struc-
2
1
turally related to the antitumour benzo[c]phenanthridines by
deletion of a ring, or as heterocyclic isomers of the above-
mentioned acridine and phenanthridine based antitumour
agents. Consequently, given routes to 2-chlorobenzo[h]quino-
(ii)
(iii)
line-3-carbaldehyde, and to the 4-chloro-isomer, a range of
benzo[h]quinolines of potential biological interest will become
available.
N
O
O
N
The synthetic methodologies that have been used to create
N
O
the benzo[h]quinoline nucleus are generally adaptations of the
commonly used methods of quinoline synthesis (e.g. Skraup,
and Doebner and von Miller),6–9 although other routes involv-
ing Diels–Alder reactions10 and Friedlander condensations11
provide alternative, multistep approaches. We have used the
Vilsmeier reaction previously to provide access to a variety of
2,3-substituted and 2,3-fused quinolines12,13 by reacting N,N-
dimethylformamide (DMF) with an appropriate N-arylacet-
amide in the presence of phosphorus oxychloride (POCl3) to
yield, for example, 2-chloroquinoline-3-carbaldehyde. Acetyl-
ation of α-naphthylamine provided us with an alternative
nucleophilic species 1 for reaction with DMF which under
the same conditions yielded the 2-chlorobenzo[h]quinoline-3-
carbaldehyde 2 (Scheme 1). This appropriately substituted
heterocycle along with the corresponding 3,4-substituted
benzo[h]quinoline 17 was recognised as a potential precur-
sor to analogues of a number of agents with anticancer
activity.14–17
R
NH2
Cl
O
4 R = CH3
7 R = H
3
(iv)
(v)
N
N
R = CH3
CH3SO4–
H3C
N
N
+
N
N
R
CH3
5 R = CH3
8 R = H
6
R = H
(v)
Results and discussion
N
Our first target was annelation of a pyrazole ring to the benzo-
[h]quinoline nucleus. This was envisaged to occur via reaction
of the precursor 3 with methylhydrazine. Initial conversion of
the aldehyde group in 2 to the acetal 3 was required in order to
prevent formation of the hydrazone which does not undergo
cyclisation,18 presumably due to the adoption of the unfavour-
able E-configuration. Consequently, after the acetal was
refluxed with methylhydrazine to yield the hydrazine-acetal 4,
cyclisation to the corresponding 10-methyl-10H-benzo[h]-
pyrazolo[3,4-b]quinoline 5 was achieved in hot alcoholic acidic
conditions. The structure was confirmed by NOE experiments.
Irradiation of the N-CH3 signal (4.33 ppm) failed to enhance
any aromatic signals indicating that the secondary amino
group of the N-methylhydrazine had substituted the 2-chloro-
group of the benzo[h]quinoline nucleus. Methylation to give the
N
+
–
–
CH3SO4
CH3SO4
N
N
+
H
+
N
N
H
CH3
CH3
9
10
Scheme 1 Reagents and conditions: (i) DMF, POCl3, 75 ЊC, 6 h, 69%;
(ii) ethylene glycol, toluene-p-sulfonic acid, toluene, reflux, 5 h, 75%;
(iii) N2 atmosphere, reflux, 3 h; N-methylhydrazine (4), 86%; hydrazine
(7), 86%; (iv) ethanol, 2 M HCl (aq), reflux, 5 min; (5) 96%; (8) 86%;
(v) dimethyl sulfate, xylene–nitrobenzene, 130 ЊC, 15 min; (6) 96%; (9)
36%; (10) 22%.
quaternary benzo[h]pyrazolo[3,4-b]quinolinium salt
achieved by refluxing the pyrazoloquinoline 5 with dimethyl
sulfate in toluene. If hydrazine was utilised in place of
6 was
J. Chem. Soc., Perkin Trans. 1, 1999, 2315–2321
2315

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Table 1 IC50 values for the inhibition of topoisomerase I
N-methylhydrazine, the resulting demethyl 10H-benzo[h]pyr-
azolo[3,4-b]quinoline 8 gave a mixture of both the 9-methyl and
10-methyl salts 9 and 10 on methylation which were separated
by flash chromatography and the positions of the respective
methyl groups were confirmed by NOE experiments. The struc-
ture of 10 was also established by treatment with base, which
confirmed 5 as its free base form. The quinolinium salt 6
possesses an electrophilic iminium group and resembles the
pharmacophoric heterocyclic nucleus of the antitumour benzo-
[c]phenanthridines16,19 and has served as a model synthesis
for other related analogues which are now being assessed for
activity. Annelation of a heterocyclic six-membered ring to the
benzo[h]quinoline system by replacement of methylhydrazine
with either urea or guanidine in the above scheme proved
unsuccessful, yielding only the chloro-acetal starting material.
This result is in agreement with earlier studies performed with
the corresponding quinoline analogues.13
Without prior acetalisation of the 2-chlorobenzo[h]quin-
oline-3-carbaldehyde 2, nucleophilic attack takes place at the
formyl group. Analogues of the antitumour agent N-[2-(di-
methylamino)ethyl]acridine-4-carboxamide (DACA)15,17 were
produced by treatment of the 2-chlorobenzo[h]quinoline-3-
carbaldehyde 2 with the N,N-dimethylaminoalkylamine [ethyl
and propyl homologues] followed by reduction of the resulting
imines 11, 12 with sodium borohydride (Scheme 2) gave the
corresponding amines 13, 14.
6
18
20
21
IC50/µM
13.9
34.8
12.9
5.16
Annelation of a heterocyclic 6-membered ring to the benzo-
[h]quinolines 16 and 17 with either urea or guanidine also
proved unsuccessful. Treatment of the chloro-ester 16 with
guanidine using ethylene glycol as the solvent actually produced
the 2-hydroxyethyl ester 19 in 45% yield, the solvent acting as
the reactant. Conversely, reaction with the N,N-dimethylamino-
alkylamines does not result in reaction with the ester group to
produce the corresponding amides, but in a nucleophilic aro-
matic substitution reaction at the 4-chloro position to produce
the two amines 20 and 21 (both recognised as analogues of
DACA).
Refluxing the quinolone-ester 15 with dimethyl sulfate
and potassium carbonate in acetone produced the 4-methoxy
analogue 22. Confirmation of the position of attachment of the
methyl group was achieved by NOE. Irradiation of the methyl
signal (4.16 ppm) resulted in the enhancement of the H-5
signal at 8.14 ppm. Furthermore, the absence of the quinolone
C᎐O stretch in the IR spectrum supported this assignment. N-
᎐
Methylation to give ethyl 1-methyl-4-oxo-1,4-dihydrobenzo[h]-
quinoline-3-carboxylate 23 was achieved using methyl iodide in
the presence of sodium hydride. NOE enhancement of the pro-
ton signals for H-2 and H-10 (8.46 and 8.42 ppm, respectively)
resulted from irradiation of the N-methyl signal at 4.27 ppm,
confirming the proposed structure.
(i)
2
Reaction of the N-methylquinolone ester 23 with hydrazine
produced the hydrazide 24. Subsequent cyclisation to the
pyrazolone with POCl3 and isolation as the hexafluorophos-
phate salt produced a deep red–orange solid. The intractable
nature of this salt precluded its full characterisation. The reac-
tion of 23 with the softer nucleophile ethyl acetoacetate resulted
in 1,4-Michael addition occurring at the 2-position with
subsequent deacetylation to yield ethyl 1-methyl-4-hydroxy-2-
(ethoxycarbonylmethyl)-1,2-dihydrobenzo[h]quinoline-3-carb-
oxylate 25. The structure was confirmed by the IR spectrum
N
N
(CH2)nN(CH3)2
Cl
11 n = 2
12 n = 3
(ii)
containing two C᎐O stretches at 1733 and 1643 cmϪ1. The lower
H
᎐
N
N
wavenumber C᎐O stretch is assigned to the 3-ester due to
᎐
(CH2)nN(CH3)2
intramolecular hydrogen-bonding between the 3-ester and 4-
Cl
1
1
hydroxy groups. H NMR and H1H COSY allowed assign-
ment of the diastereotopic splitting pattern associated with the
ethoxycarbonyl methyl group attached at the chiral C-2 centre.
A number of the benzo[h]quinolines we have prepared bind
to DNA with high affinity, inhibit topoisomerase I but not
topoisomerase II and show varying cytotoxicity against the
K562 and A2780 tumour cell lines. Inhibitory concentrations
against topoisomerase I for those compounds demonstrating
activity are shown in Table 1 and show comparable activity with
the antitumour benzo[c]phenanthridine topoisomerase I inhibi-
tors (fagaronine and nitidine) which formed the basis for their
design (IC50 = 30 and 55 µM respectively).3,23 A more detailed
analysis of the biological data will be reported elsewhere.
13 n = 2
14 n = 3
Scheme 2 Reagents and conditions: (i) N,N-dimethylaminoalkylamine,
ethanol, reflux, 4 h; (11) 75%; (12) 100%; (ii) sodium borohydride,
ethanol, rt, 48 h, ethereal HCl; (13) 52%; (14) 15%.
Preparation of the 3,4-substituted benzo[h]quinolines was
achieved by modifying the Gould–Jacobs synthesis of quinol-
ines.20 Reaction of α-naphthylamine with diethyl ethoxy-
methylenemalonic ester followed by cyclisation in the high
boiling point solvent Dowtherm ‘A’ yielded ethyl 4-oxo-1,4-
dihydrobenzo[h]quinoline-3-carboxylate 15 and provided a
route to [c]-fusion of the pyrazolo ring with the benzo[h]quin-
oline system (Scheme 3). The structural isomer of 2 was pre-
pared by initially chlorinating the quinolone 15 with POCl3 to
yield ethyl 4-chlorobenzo[h]quinoline-3-carboxylate 16. Reduc-
tion of the ester with DIBAL-H in dichloromethane at Ϫ70 ЊC
produced a mixture of both the alcohol and aldehyde 17, which
could be separated by flash chromatography. However, for
preparative purposes, the resulting mixture was oxidised with
activated manganese dioxide to produce the aldehyde 17
exclusively. The corresponding quaternary 2,3-dimethyl-3H-
benzo[h]pyrazolo[4,3-c]quinolinium salt 18 was prepared via
the route described for compound 6.
Experimental
Melting points were determined on a Reichert Hotstage Micro-
scope melting point apparatus and are uncorrected. All NMR
spectra were recorded on a JEOL GSX 270-FT spectro-
photometer operating at 270 MHz and 25 ЊC with tetramethyl-
silane as the internal reference standard unless otherwise stated.
All coupling constants (J values) are quoted in hertz (Hz) and
chemical shifts quoted in ppm. A UNICAM Research Series 1
FTIR spectrophotometer was used to record IR spectra using
the sample preparation stated in the text. Mass spectra were
recorded on a VG 302000.
2316
J. Chem. Soc., Perkin Trans. 1, 1999, 2315–2321

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(xiii)
(xii)
O
O
OH
N
N
N
H3C
COOEt
H3C
CONHNH2
H3C
COOEt
23
(xi)
24
25
COOEt
(x)
CH3
N
O
OCH3
N
CH3
N
H
15
N
+
N
COOEt
COOEt
18
CH3SO4–
22
(i)
(iv-vii)
H
N
(ii,iii)
Cl
(ix)
Cl
(CH2)nN(CH3)2
N
N
N
16
17
COOEt
COOEt
CHO
20 n = 2
21 n = 3
(viii)
Cl
N
O
OH
19
O
Scheme 3 Reagents and conditions: (i) POCl3, 90 ЊC, 25 min, 85%; (ii) DIBAL-H, dry ether, Ϫ70 ЊC, N2 atmosphere, 2 h; (iii) activated MnO2,
dichloromethane, rt, 30 min, overall yield for (ii) and (iii) 69%; (iv) ethylene glycol, toluene-p-sulfonic acid, toluene, reflux, 5 h, 53%; (v) N-methyl-
hydrazine, N2 atmosphere, reflux, 4 h; (vi) ethanol, 2 M HCl (aq), reflux, 15 min, 75%; (vii) dimethyl sulfate, xylene–nitrobenzene, 130 ЊC, 15 min,
59%; (viii) guanidine carbonate, ethylene glycol, 50 ЊC, 5 h, 45%; (ix) N,N-dimethylaminoalkylamine, rt, 1 h, ethereal HCl; (20) 90%; (21) 79%;
(x) dimethyl sulfate, K2CO3, acetone, reflux, 24 h, 23%; (xi) methyl iodide, NaH, toluene, 50 ЊC, 16 h, 86%; (xii) hydrazine, reflux, 30 min, 93%;
(xiii) ethyl acetoacetate, NaH, toluene, reflux, 20 h, 67%.
Elemental analysis was carried out using a Carlo Erba 1106
Elemental Analyser and a Mettler MT5 Microbalance was used
to weigh samples. Accurate masses were performed on a Kratos
MS80RF spectrometer.
Thin-layer chromatography (TLC) was carried out using
Merck silica 60 F254 plates and visualised under short-wave
UV light. Flash chromatography was performed using Acros
silica (35–70 µm particle size) in the specified solvent mixture.
All chemicals were supplied by either Aldrich, Merck or
Lancaster Chemicals and were used as received, unless other-
wise stated.
sample was recrystallised from ethyl acetate–petroleum ether
60–80 ЊC to give the title compound 2 as yellow needles, mp
210–212 ЊC (Found: C, 70.0; H, 3.1; N, 5.9. C14H8ClNO
requires C, 69.7; H, 3.35; N, 5.8%); νmax (KBr disk) 1685 (CO),
1579, 1365, 1054 cmϪ1; δH (CDCl3) 7.77 (1H, d, J 8, H-6), 7.79
(2H, m, H-8,9), 7.89 (1H, d, J 8, H-5), 7.94 (1H, m, H-7),
8.72 (1H, s, H-4), 9.24 (1H, m, H-10), 10.58 (1H, s, CHO); m/z
242 (Mϩ 100%).
2-Chloro-3-(1,3-dioxolan-2-yl)benzo[h]quinoline 3
A solution of 2-chlorobenzo[h]quinoline-3-carbaldehyde 2 (2.0
g, 8.3 mmol) in toluene (100 cm3) containing ethylene glycol
(1.55 g, 25 mmol) and a trace amount of toluene-p-sulfonic acid
was heated under reflux for 5 h using a Dean–Stark water sep-
arator. The cooled solution was treated with saturated aqueous
sodium carbonate (50 cm3), dried (MgSO4), and evaporated to
leave an orange solid (1.78 g, 75%). Recrystallisation from ethyl
acetate–petroleum ether 60–80 ЊC gave the title compound 3 as
yellow cuboids, mp 134–136 ЊC (Found: C, 67.1; H, 4.2; N, 5.1.
C16H12ClNO2 requires C, 67.3; H, 4.2; N, 4.9%); νmax (KBr disk)
1592, 1478, 1359, 1089, 1051 cmϪ1; δH (CDCl3) 4.11–4.28 (4H,
m, 2 × CH2), 6.30 (1H, s, CH), 7.73 (3H, m, H-6,8,9), 7.83 (1H,
d, J 9, H-5), 7.91 (1H, m, H-7), 8.42 (1H, s, H-4), 9.21 (1H, m,
H-10); m/z 286 (Mϩ 100%).
N-Acetyl-1-naphthylamine 1
A mixture of 1-naphthylamine (43.0 g, 0.3 mol) in acetic
anhydride (76.5 g, 0.75 mol) was heated under reflux for 10 min
after which water (50 cm3) was added and the mixture was
refluxed for a further 5 min. The warm solution was then
poured directly onto crushed ice (~30 g). The resulting white
precipitate (49.8 g, 90%) was filtered, washed with water, and
dried in air, and was pure enough for further use. A sample was
recrystallised from ethanol to give the title compound 1 as white
needles, mp 159–160 ЊC (lit.21 159 ЊC); νmax (KBr disk) 3270
(NH), 1656 (CO), 1548, 1398 cmϪ1; δH (d6-DMSO, 50 ЊC) 2.17
(3H, s, COCH-3), 7.46 (1H, t, J 8, H-3), 7.52 (2H, m, H-6,7),
7.68 (1H, d, J 8, H-2), 7.74 (1H, d, J 8, H-4), 7.91 (1H, m, H-5),
8.07 (1H, m, H-8).
2-(1-Methylhydrazino)-3-(1,3-dioxolan-2-yl)benzo[h]quinoline 4
A solution of 2-chloro-3-(1,3-dioxolan-2-yl)benzo[h]quinoline
3 (2.0 g, 7 mmol) in N-methylhydrazine (15.0 g, excess) was
refluxed under nitrogen while stirring for 3 h. N-Methyl-
hydrazine was removed under reduced pressure to leave an
orange oil which was dissolved in dichloromethane (50 cm3).
The organic phase was washed with water (2 × 20 cm3), dried
(MgSO4), filtered, and evaporated under reduced pressure to
2-Chlorobenzo[h]quinoline-3-carbaldehyde 2
To a solution of N-acetyl-1-naphthylamine 1 (1.0 g, 5.4 mmol)
in dry DMF (0.99 g, 14 mmol) was added POCl3 (9.5 cm3, 102
mmol) and the mixture stirred at 75 ЊC for 6 h. The mixture was
poured onto crushed ice (~50 g) and the resulting solid (0.90 g,
69%) filtered, washed with water and dried in an oven. A
J. Chem. Soc., Perkin Trans. 1, 1999, 2315–2321
2317

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give the title product (1.77 g, 86%). Recrystallisation from ethyl
acetate–petroleum ether 60–80 ЊC gave the pure product 4 as
orange cuboids, mp 133–134 ЊC (Found C, 69.2; H, 5.7; N, 14.1.
C17H17N3O2 requires C, 69.1; H, 5.8; N, 14.2%); νmax (KBr disk)
3328 (NH), 3027 (NH), 2861 (NCH3), 1610 cmϪ1; δH (CDCl3)
3.39 (3H, s, NCH3), 4.14 (4H, m, 2 × CH2), 6.63 (1H, s, CH),
7.65 (2H, m, H-5,6), 7.66 (2H, m, H-8,9), 7.86 (1H, m, H-7),
8.37 (1H, s, H-4), 9.16 (1H, m, H-10).
C14H9N3 requires C, 76.7; H, 4.1; N, 19.2%); νmax (KBr disk)
3178–2800 (NH), 1614 cmϪ1; δH (CDCl3) 7.62 (2H, m, H-2,3),
7.63 (1H, d, J 9, H-6), 7.81 (1H, d, J 9, H-5), 7.86 (1H, m, H-4),
8.26 (1H, s, H-7), 8.73 (1H, s, H-8), 9.20 (1H, m, H-1), 12.94
(1H, br s, NH).
Methylation of 10H-benzo[h]pyrazolo[3,4-b]quinoline 8
A solution of 10H-benzo[h]pyrazolo[3,4-b]quinoline 8 (1.72 g,
7.85 mmol) in nitrobenzene (25 cm3) and xylene (12 cm3) was
heated to 130 ЊC and dimethyl sulfate (10 cm3, excess) added
and heating at 130 ЊC was continued for a further 10 min. The
mixture was cooled to room temperature and then triturated
onto rapidly stirred ether (~100 cm3). The resultant orange pre-
cipitate was filtered, washed well with petroleum ether 60–80 ЊC
and allowed to dry in air. TLC analysis of the solid (eluent:
methanol–ethyl acetate–glacial acetic acid, 2:2:1) showed that
it comprised of two compounds (Rf 0.79 and 0.13). Separation
of the two compounds was achieved via flash chromatography
(eluent: ethanol).
10-Methyl-10H-benzo[h]pyrazolo[3,4-b]quinoline 5
To a solution of 2-(1-N-methylhydrazino)-3-(1,3-dioxolan-2-
yl)benzo[h]quinoline 4 (1.0 g, 3.4 mmol) in ethanol (30 cm3) was
added 2 M HCl (4 cm3) and the mixture was refluxed for 5 min.
The cooled solution was poured onto a stirred solution of 2 M
NaOH (~50 cm3) and the yellow precipitate (0.76 g, 96%) was
filtered and washed well with water. Recrystallisation from
ethanol gave the title compound 5 as orange plates, mp 130–
132 ЊC (Found C, 77.3; H, 4.5; N, 17.7. C15H11N3 requires C,
77.2; H, 4.75; N, 18.0%); νmax (KBr disk) 2935 (NCH3), 1602
cmϪ1; δH (CDCl3) 4.35 (3H, s, NCH3), 7.66 (1H, d, J 9, H-6),
7.72 (2H, m, H-2,3), 7.76 (1H, d, J 9, H-5), 7.89 (1H, m, H-4),
8.24 (1H, s, H-7), 8.55 (1H, s, H-8), 9.44 (1H, m, H-1); NOE
Experiments irradiating the NCH3 proton (4.35 ppm) failed to
enhance any other aromatic proton confirming the placement
of the CH3 group within the molecule; m/z 234 (Mϩ 100%).
9-Methyl-10H-benzo[h]pyrazolo[3,4-b]quinolinium
methyl
sulfate 9. Yield 0.98 g, 36% δH (D2O) 4.09 (3H, s, NϩCH3), 7.27
(2H, m, H-3,4), 7.45 (1H, t, J 7, H-2), 7.59 (2H, m, H-5,6), 8.09
(1H, s, H-7), 8.25 (1H, d, J 8, H-1), 8.34 (1H, s, H-8); irradiation
of NϩCH3 protons (4.09 ppm) leads to the enhancement of the
signal of H-8 (8.34 ppm); m/z (ESMS – positive ion mode) 234
(Mϩ), (ESMS – negative ion mode) 111 (ϪOSO3CH3).
9,10-Dimethyl-10H-benzo[h]pyrazolo[3,4-b]quinolinium methyl
sulfate 6
10-Methyl-10H-benzo[h]pyrazolo[3,4-b]quinolinium methyl
sulfate 10. Yield 0.59 g, 22% δH (d6-DMSO–35 ЊC) 4.36 (3H, s,
NϩCH3), 7.62 (1H, d, J 9, H-5), 7.72 (2H, m, H-2,3), 7.80 (1H,
d, J 9, H-6), 7.92 (1H, m, H-4), 8.75 (1H, s, H-7), 8.88 (1H,
s, H-8), 9.21 (1H, m, H-1); irradiation of NϩCH3 protons
(4.36 ppm) does not lead to the enhancement of any aromatic
protons, confirming the placement of the methyl group on
N-10; m/z (ESMS – positive ion mode) 234 (Mϩ), (ESMS –
negative ion mode) 111 (ϪOSO3CH3).
A solution of 10-methyl-10H-benzo[h]pyrazolo[3,4-b]quinoline
5 (1.50 g, 6.4 mmol) in nitrobenzene (50 cm3) and xylene (25
cm3) was heated to 130 ЊC. To the heated solution was added
dimethyl sulfate (25 cm3, excess) and the solution heated for a
further 15 min. After this period the solution was cooled then
triturated onto ether to give a fine orange precipitate. The pre-
cipitate (2.21 g, 96%) was filtered, washed with ether and dried
in an oven. Recrystallisation from glacial acetic acid–ethyl
acetate afforded the title compound 6 as orange needles, mp
>300 ЊC (Found C, 57.0; H, 4.7; N, 11.6. C17H17N3O4S requires
C, 56.8; H, 4.8; N, 11.7%); νmax (KBr disk) 3102–2923 (NCH3),
1635 cmϪ1; δH (D2O) 3.62 (3H, s, NCH3), 3.95 (3H, s, NϩCH3),
7.03 (1H, d, J 8, H-5), 7.13 (1H, d, J 8, H-6), 7.29 (1H, t, J 6,
H-2), 7.41 (1H, d, J 8, H-4), 7.50 (1H, t, J 6, H-3), 7.82 (1H, s,
H-7), 7.97 (1H, d, J 8, H-1), 8.11 (1H, s, H-8); m/z (ESMS –
positive ion mode) 248 (Mϩ), (ESMS – negative ion mode) 111
(counter ion) (ϪOSO3CH3).
2-Chloro-3-[2-(N,N-dimethylamino)alkyliminomethyl]benzo-
[h]quinolines 11,12
A solution of 2-chlorobenzo[h]quinoline-3-carbaldehyde 2 (3 g,
12 mmol) and the N,N-dimethylaminoalkylamine (13 mmol) in
ethanol was refluxed for 4 h. After cooling and removal of the
solvent under reduced pressure, the products were recrystallised
from ethyl acetate–petroleum ether 60–80 ЊC.
2-Hydrazino-3-(1,3-dioxolan-2-yl)benzo[h]quinoline 7
2-Chloro-3-[2-(N,N-dimethylamino)ethyliminomethyl]benzo-
[h]quinoline 11. Yield 2.81 g, 75%; mp 88.9–90.9 ЊC (Found C,
69.46; H, 5.83; N, 13.22. C18H18N3Cl requires C, 69.3; H, 5.8; N,
A solution of 2-chloro-3-(1,3-dioxolan-2-yl)benzo[h]quinoline
3 (1.0 g, 3.5 mmol) in hydrazine monohydrate (8.0 g, excess) was
refluxed under nitrogen while stirring for 2.5 h. The product
(1.77 g, 86%) was recovered via filtration and washed well with
water. Recrystallisation from ethanol gave the pure product 7 as
yellow needles, mp 154–156 ЊC (Found C, 68.5; H, 5.2; N, 14.8.
C16H15N3O2 requires C, 68.3; H, 5.4; N, 14.9%); νmax (KBr disk)
3290 (NH), 3190 (NH), 1611 cmϪ1; δH (CDCl3) 4.17 (4H, m,
2 × CH2), 4.36 (2H, br s, NH2), 5.89 (1H, s, CH), 6.92 (1H, br s,
NH), 7.60 (2H, s, H-5,6), 7.64 (2H, m, H-8,9), 7.86 (1H, m,
H-7), 8.02 (1H, s, H-4), 9.19 (1H, m, H-10).
13.5%); νmax (KBr) 1637 (C᎐N), 1056 (C–Cl) cmϪ1; δH (CDCl3)
᎐
2.29 (6H, s, CH3 × 2), 2.66 (2H, t, J 7, CH2), 3.81 (2H, t, J 7,
᎐NCH ), 7.64 (1H, d, J 8.91, H-5), 7.67 (2H, m, H-8,9), 7.73
᎐
2
(1H, d, J 8.91, H-6), 7.82 (1H, m, H-7), 8.76 (1H, s, H-4), 8.78
(1H, t, N᎐C-H), 9.11 (1H, m, H-10); m/z 312 (Mϩ 100%).
᎐
2-Chloro-3-[3-(N,N-dimethylamino)propyliminomethyl]-
benzo[h]quinoline 12. Yield 4.0 g, 100%; mp 89.7 ЊC (Found
C, 70.26; H, 6.04; N, 12.86. C19H20N3Cl requires C, 70.0; H,
6.14; N, 12.9%); νmax (KBr) 1637 (C᎐N), 1054 (C–Cl) cmϪ1
;
᎐
δH (CDCl3) 1.88 (2H, m, J 7, 7.3, 7.5, CH2), 2.21 (6H, s,
CH3 × 2), 2.35 (2H, t, J 7.5, 7.6, CH2N), 3.73 (2H, t, J 7,
10H-Benzo[h]pyrazolo[3,4-b]quinoline 8
To a solution of 2-hydrazino-3-(1,3-dioxolan-2-yl)benzo[h]-
quinoline 7 (500 mg, 1.8 mmol) in methanol (15 cm3) was added
2 M HCl (2 cm3) and the mixture refluxed for 10 min. The
cooled solution was poured onto a stirred solution of 2 M
NH4OH (~40 cm3) and the orange precipitate (340 mg, 86%)
filtered and washed well with water. Recrystallisation from ethyl
acetate–petroleum ether 60–80 ЊC gave the title compound 8 as
orange needles, mp 250–252 ЊC (Found C, 76.6; H, 3.9; N, 19.0.
᎐NCH ), 7.66 (1H, d, J 8.37, H-5), 7.67 (2H, m, H-8,9), 7.75
᎐
2
(1H, d, J 8.91, H-6), 7.85 (1H, m, H-7), 8.75 (1H, s, H-4), 8.78
(1H, t, N᎐C-H), 9.1 (1H, m, H-10); m/z 326 (Mϩ 100%).
᎐
2-Chloro-3-[2-(N,N-dimethylamino)alkylaminomethyl]benzo-
[h]quinoline dihydrochlorides 13,14
To a solution of the 2-chloro-3-[2-(N,N-dimethylamino)alkyl-
2318
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iminomethyl]benzo[h]quinoline 11, 12 (3.2 mmol) in dry eth-
anol (20 cm3) was added sodium borohydride (0.26 g, 6.8 mmol)
and the mixture stirred for 48 h. Water was added to dissolve
any excess sodium borohydride and the products extracted into
dichloromethane and the organic layer dried (MgSO4). Addi-
tion of ethereal hydrogen chloride precipitated out the hydro-
chloride salts which were recrystallised from ethanol–ethyl
acetate.
(MgSO4) and the ether was removed under reduced pressure to
give an off white solid (452 mg, 85%). Recrystallisation from
petroleum ether 60–80 ЊC gave the title compound 16 as a white
solid, mp 119–120 ЊC (lit.22 120–121 ЊC); νmax (KBr disk) 1725
(CO), 1241, 1168 cmϪ1; δH (CDCl3) 1.46 (3H, t, J 7, CH3), 4.52
(2H, q, J 7, CH2), 7.80 (2H, m, H-8,9), 7.94 (2H, m, H-6,7), 8.27
(1H, d, J 9, H-5), 9.30 (1H, m, H-10), 9.31 (1H, s, H-2); m/z 286
(Mϩ 100%).
2-Chloro-3-[2-(N,N-dimethylamino)ethylaminomethyl]benzo-
[h]quinoline dihydrochloride 13. Yellow needles (0.66 g, 52%);
mp 204–209 ЊC (Found: C, 53.21; H, 5.73; N, 10.14. C18H20N3-
Clؒ2HClؒH2O requires C, 53.4; H, 5.9; N, 10.4%); νmax (KBr)
Reduction of ethyl 4-chlorobenzo[h]quinoline-3-carboxylate 16
with diisobutyl aluminium hydride (DIBAL-H)
A stirred solution of ethyl 4-chlorobenzo[h]quinoline-3-carb-
oxylate 16 (1.0 g, 3.5 mmol) and dichloromethane (5 cm3) was
cooled to Ϫ70 ЊC in dry glassware while under an inert nitrogen
atmosphere. To the cooled solution was added DIBAL-H
[1.0 M solution in dichloromethane] (3.8 cm3, 3.8 mmol) and
the reaction was left for 2 h. After this time 4 drops of glacial
acetic acid were added to deactivate the DIBAL-H and the
reaction was allowed to warm to room temperature. Saturated
ammonium chloride solution (100 cm3) was added to the reac-
tion which was extracted with dichloromethane (4 × 50 cm3),
the organic aliquots combined, washed well with water, dried
(MgSO4) and the solvent removed under reduced pressure to
give a yellow solid. Analysis of the solid via TLC (solvent:
ethyl acetate–petroleum ether 60–80 ЊC, 1:1) showed that it
was composed of two compounds which were separated by
flash chromatography (eluent: ethyl acetate–petroleum ether
60–80 ЊC, 1:5).
3320 (N–H), 2699 (Nϩ–H), 1592 (Nϩ–H), 1056 (C–Cl) cmϪ1
;
δH (DMSO) 2.9 (6H, s, CH3 × 2), 3.6 (4H, m, NϩCH2 × 2), 4.5
(2H, s, NϩCH2Ar), 7.82 (2H, m, H-8,9), 7.90 (1 H, d, J 8.58,
H-5), 8.09 (1H, d, J 7.26, H-6), 8.12 (1H, m, H-7), 8.87 (1H, s,
H-4), 9.02 (1H, m, H-10), 10.11 (H, br s, N–H), 10.88 (1H, br s,
N–H); m/z 314 (Mϩ 100%).
2-Chloro-3-[3-(N,N-dimethylamino)propylaminomethyl]benzo-
[h]quinoline dihydrochloride 14. Yellow needle-like crystals (0.2
g, 15%); mp 205–207 ЊC (Found C, 54.34; H, 6.33; N, 9.91.
C19H22N3Clؒ2HClؒH2O requires C, 54.5; H, 6.2; N, 10.0%); νmax
(KBr) 3394 (N–H), 3297 (N–H), 2711 (Nϩ–H), 1592 (Nϩ–H),
1056 (C–Cl) cmϪ1; δH (DMSO) 2.2 (2H, m, CH2), 2.75 (6H, s,
CH3 × 2), 3.2 (4H, m, 2 × CH2Nϩ), 4.50 (2H, s, NϩCH2Ar), 7.82
(2H, m, H-8,9), 7.90 (1H, d, J 8.58, H-5), 8.09 (1H, d, J 8.58,
H-6), 8.12 (1H, m, H-7), 8.88 (1H, s, H-4), 9.04 (1H, m, H-10),
9.84 (1H, br s, N–H), 10.61 (1H, br s, N–H); m/z 328 (Mϩ
100%).
4-Chlorobenzo[h]quinoline-3-carbaldehyde 17. Yield 319 mg,
39%, mp 195–196 ЊC (Found C, 69.6; H, 3.0; N, 5.8. C14H8ClNO
requires C, 69.6; H, 3.3; N, 5.8%); νmax (KBr disk) 1685 (CO),
1577, 798 (C–Cl) cmϪ1; δH (CDCl3) 7.82 (2H, m, H-8,9), 7.97
(1H, m, H-7), 8.01 (1H, d, J 11, H-6), 8.23 (1H, d, J 11, H-5),
9.34 (1H, m, H-10), 9.36 (1H, s, H-2), 10.76 (1H, s, CHO); m/z
242 (Mϩ 100%).
Diethyl 1-naphthylaminomethylenemalonate
A stirred mixture of 1-naphthylamine (10.0 g, 70 mmol) in
diethyl ethoxymethylenemalonate (15.0 g, 70 mmol) was heated
to 130 ЊC for a period of 2.75 h after which the solution was
cooled to Ϫ70 ЊC. The solid (20.0 g, 91%) was filtered, washed
well with petroleum ether 60–80 ЊC and left to dry. Recrystal-
lisation from ethanol gave the product as white needles, mp 86–
87 ЊC (lit.20 87.5–88.0 ЊC); νmax (KBr disk) 1683 (CO), 1643
(CO) cmϪ1; δH (CDCl3) 1.35 (3H, t, J 8, CH3), 1.43 (3H, t, J 8,
CH3), 4.28 (2H, q, J 8, CH2), 4.39 (2H, q, J 8, CH2), 7.35 (1H, d,
J 7, H-2), 7.48 (1H, t, J 8, H-3), 7.58 (2H, m, H-6,7), 7.70 (1H, d,
J 8, H-4), 7.88 (1H, dd, J 8 and 3, H-5), 8.04 (1H, d, J 8, H-8),
4-Chloro-3-hydroxymethylbenzo[h]quinoline. White needles
(80 mg, 9%), mp 173–175 ЊC (Found C, 68.8; H, 4.0; N, 5.7.
C14H10ClNO requires C, 69.0; H, 4.1; N, 5.75%); νmax (KBr disk)
3400–3200 (br, OH), 1400, 1085 cmϪ1; δH (CDCl3) 5.07 (2H, s,
CH2), 7.75 (2H, m, H-8,9), 7.93 (2H, m, H-6,7), 8.16 (1H, d, J 8,
H-5), 9.05 (1H, s, H-2), 9.28 (1H, m, H-10); m/z 244 (Mϩ 100%).
8.67 (1H, d, J 14, NCH᎐C), 11.49 (1H, br d, J 14, NH).
4-Chlorobenzo[h]quinoline-3-carbaldehyde 17
᎐
To 4-chloro-3-hydroxymethylbenzo[h]quinoline (1.75 g, 7.2
mmol) in dichloromethane (150 cm3) was added activated
manganese() oxide (10.0 g, excess) and the solution stirred at
room temperature for 30 min. The manganese() oxide was
then removed from the solution via filtration and washed well
with dichloromethane. The dichloromethane was removed
under reduced pressure to give a pale yellow solid (1.23 g, 71%).
Recrystallisation from ethyl acetate–petroleum ether 60–80 ЊC
gave the title compound 17 as pale yellow needles, mp 195–
196 ЊC.
Ethyl 4-oxo-1,4-dihydrobenzo[h]quinoline-3-carboxylate 15
To stirred Dowtherm ‘A’ (50 cm3) at 255 ЊC was added diethyl
1-naphthylaminomethylenemalonate (10.0 g, 32 mmol), and
heating was continued at 255 ЊC for 30 min. The mixture was
allowed to cool to room temperature and stand for 30 min. The
resulting solid (6.64 g, 78%) was filtered, washed with petrol-
eum ether 60–80 ЊC and dried in an oven. Recrystallisation
from glacial acetic acid afforded the title compound 15 as white
needles, mp 258–260 ЊC (lit.20 261–262 ЊC); νmax (KBr disk)
2923, 1708 (ester CO), 1635 (amide CO) cmϪ1; δH (d6-DMSO)
1.42 (3H, t, J 7, CH3), 4.38 (2H, q, J 7, CH2), 7.88 (2H, m,
H-8,9), 7.94 (1H, d, J 9, H-6), 8.16 (1H, m, H-7), 8.29 (1H, d,
J 9, H-5), 8.64 (1H, br s, H-2), 8.78 (1H, br s, H-10).
4-Chloro-3-(1,3-dioxolan-2-yl)benzo[h]quinoline
A solution of 4-chlorobenzo[h]quinoline-3-carboxylate 17 (1.18
g, 4.9 mmol) in toluene (50 cm3) containing ethylene glycol
(0.82 cm3, 14.7 mmol) and a trace amount of toluene-p-sulfonic
acid was heated under reflux for 10 h using a Dean–Stark water
separator. The cooled solution was treated with saturated
aqueous sodium carbonate (50 cm3), washed well with several
aliquots of water, dried (MgSO4), and evaporated to leave an
orange solid. Analysis of the solid via TLC (solvent system
ethyl acetate–petroleum ether 60–80 ЊC, 1:1) showed the solid
to contain one major spot (Rf 0.74) and two minor spots (Rf
0.83 and 0.61). Flash chromatography (eluent ethyl acetate–
Ethyl 4-chlorobenzo[h]quinoline-3-carboxylate 16
A stirred solution of ethyl 4-oxo-1,4-dihydrobenzo[h]quinoline-
3-carboxylate 15 (500 mg, 1.9 mmol) in POCl3 (0.3 cm3, 3.2
mmol) was heated to 90 ЊC for a period of 25 min. After
this time, the mixture was cooled and poured into a 10%
ammonium hydroxide solution (30 cm3) while being kept cool
by the addition of crushed ice to the solution. The aqueous
solution was then extracted with ether (4 × 50 cm3), dried
J. Chem. Soc., Perkin Trans. 1, 1999, 2315–2321
2319

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petroleum ether 60–80 ЊC, 1:5) isolated the title compound as a
white solid (740 mg, 53%). Recrystallisation from ethyl acetate–
petroleum ether 60–80 ЊC gave the title compound as white
needles, mp 110.8–111.8 ЊC (Found C, 67.4; H, 3.9; N, 4.9.
C16H12ClNO2 requires C, 67.3; H, 4.2; N, 4.9%); νmax (KBr disk)
1390, 1110, 927 cmϪ1; δH (CDCl3) 4.15 (4H, m, 2 × CH2), 6.38
(1H, s, CH), 7.68 (2H, m, H-8,9), 7.85 (2H, m, H-6,7), 8.11 (1H,
d, J 11, H-5), 9.05 (1H, s, H-2), 9.23 (1H, m, H-10).
Ethyl 4-[2-(N,N-dimethylamino)alkylamino]benzo[h]quinoline-
3-carboxylate hydrochlorides 20, 21
A mixture of ethyl 4-chlorobenzo[h]quinoline-3-carboxylate 16
(500 mg, 1.75 mmol) and N,N-dimethylaminoalkylamine (5
cm3) was stirred at room temperature for a period of 1 h.
Dichloromethane (30 cm3) was added to the reaction mixture
and the organic layer was washed well with saturated sodium
carbonate solution (5 × 20 cm3). The organic layer was then
dried (MgSO4) and an excess of ethereal hydrogen chloride was
added until the hydrochloride salts of the final products precipi-
tated out of solution. Recrystallisation from methanol–ethyl
acetate gave the title compounds.
3-Methyl-3H-benzo[h]pyrazolo[4,3-c]quinoline
A solution of 4-chloro-3-(1,3-dioxolan-2-yl)benzo[h]quinoline
(0.73 g, 2.6 mmol) in N-methylhydrazine (2 cm3, excess)
was refluxed under nitrogen for 4 h. N-Methylhydrazine was
removed under reduced pressure to leave a brown oil. To this oil
was added ethanol (20 cm3) and 2 M HCl (10 cm3, excess) and
the mixture was refluxed for 15 min. The cooled solution was
poured onto a stirred solution of 2 M NaOH (~50 cm3) and the
white precipitate was filtered, washed well with water and left to
dry in air. The product (449 mg, 75%) was isolated via flash
chromatography using an ethyl acetate–petroleum ether, 60–
80 ЊC, 2:3, eluent system. Recrystallisation from ethyl acetate–
petroleum ether 60–80 ЊC gave the title compound as white
needles, mp 155–156 ЊC (Found C, 77.3; H, 4.5; N, 17.9.
C15H11N3 requires C, 77.2; H, 4.75; N, 18.0%); νmax (KBr disk)
2942 (NCH3), 1583 cmϪ1; δH (CDCl3) 4.59 (3H, s, NCH3), 7.74
(2H, m, H-7,8), 7.97 (1H, dd, J 9 and 1, H-6), 7.99 (1H, d, J 9,
H-5), 8.23 (1H, s, H-1), 8.38 (1H, d, J 9, H-4), 9.33 (1H, s,
H-11), 9.42 (1H, d, J 9, H-9). An NOE experiment irradiating
the NCH3 protons (4.59 ppm) leads to an enhancement of H-6
(8.38 ppm) in the aromatic region, confirming the position of
the N-methyl group in the cyclised product.
Ethyl 4-[2-(N,N-dimethylamino)ethylamino]benzo[h]quinol-
ine-3-carboxylate hydrochloride 20. White needles (587 mg,
90%), mp 125 ЊC (softens) (Found C, 55.9; H, 6.8; N, 9.75.
C20H24ClN3O2ؒ3H2O requires C, 56.1; H, 7.1; N, 9.8%); νmax
(KBr disk) 3415 (NH), 3056 and 2958 (CH), 1687 (CO)
cmϪ1; δH (D2O) 1.35 (3H, t, J 7, CO2CH2CH3), 2.82 (6H, s,
N(CH3)2), 3.53 (2H, t, J 6, CH2), 4.16 (2H, t, J 6, CH2), 4.37
(2H, q, J 7, CO2CH2CH3), 7.65 (2H, m, H-8,9), 7.69 (1H, d, J 8,
H-7), 7.74 (1H, d, J 8, H-6), 7.81 (1H, d, J 7, H-5), 8.10 (1H, d,
J 7, H-10), 8.54 (1H, s, H-2); m/z 338 (Mϩ 100%).
Ethyl 4-[3-(N,N-dimethylamino)propylamino]benzo[h]quinol-
ine-3-carboxylate hydrochloride 21. White needles (539 mg,
79%), mp 195–196 ЊC (Found C, 55.0; H, 7.2; N, 9.1. C21H26-
ClN3O2ؒ4H2O requires C, 54.8; H, 7.5; N, 9.1%); νmax (KBr disk)
3409 (NH), 3050 and 2965 (CH), 1689 (CO) cmϪ1; δH (D2O)
1.39 (3H, t, J 7, CO2CH2CH3), 2.16 (2H, t, J 6, CH2), 2.89 (6H,
s, N(CH3)2), 3.22 (2H, t, J 6, CH2), 3.74 (2H, br t, J 6, CH2),
4.33 (2H, q, J 7, CO2CH2CH3), 7.59 (5H, m, H-5–9), 7.87 (1H,
d, J 8, H-10), 8.17 (1H, s, H-2); m/z 352 (Mϩ 100%).
2,3-Dimethyl-3H-benzo[h]pyrazolo[4,3-c]quinolinium
methyl sulfate 18
Ethyl 4-methoxybenzo[h]quinoline-3-carboxylate 22
A solution of 3-methyl-3H-benzo[h]pyrazolo[4,3-c]quinoline
(508 mg, 2.2 mmol) in nitrobenzene (15 cm3) and xylene (8 cm3)
was heated to 130 ЊC. To the heated solution was added
dimethyl sulfate (8 cm3, excess) and the solution was heated for
a further 15 min. After this period the product (459 mg, 59%)
was filtered, washed with ether and allowed to dry. Recrystal-
lisation from methanol–acetonitrile afforded the title com-
pound 18 as white needles, mp 264–266 ЊC (Found C, 57.0; H,
4.9; N, 11.5. C17H17N3O4S requires C, 56.8; H, 4.8; N, 11.7%);
νmax (KBr disk) 3004 and 2958 (NCH3), 1643, 1253 and 1214
(SO) cmϪ1; δH (CF3CO2D) 4.77 (3H, s, NCH3), 4.91 (3H, s,
NϩCH3), 8.12 (2H, m, H-7,8), 8.31 (1H, m, H-6), 8.59 (1H, d,
J 9, H-5), 8.72 (1H, d, J 9, H-4), 8.94 (1H, m, H-9), 9.85 (1H, s,
H-11), 10.26 (1H, s, H-1).
A stirred solution of ethyl 4-oxo-1,4-dihydrobenzo[h]quinoline-
3-carboxylate 15 (2.0 g, 7.5 mmol), anhydrous potassium carb-
onate (1.5 g, excess) in acetone (10 cm3) and dimethyl sulfate
(700 µl, 7.5 mmol) was heated to reflux for 24 h, cooled to room
temperature, and the acetone removed under reduced pressure.
The remaining solid was filtered, washed well with petroleum
ether 60–80 ЊC, water and dried. Flash chromatography (eluent:
ethyl acetate–petroleum ether 60–80 ЊC, 1:4) revealed starting
material (41 mg, mp 258–261 ЊC) and white needles (486 mg,
23%) which were recrystallised from ethyl acetate–petroleum
ether 60–80 ЊC and identified as ethyl 4-methoxybenzo[h]-
quinoline-3-carboxylate 22, mp 53–54 ЊC (Found C, 72.75; H,
5.3; N, 5.1. C17H15NO3 requires C, 72.6; H, 5.4; N, 5.0%); νmax
(KBr disk) 2973 and 2846 (CH), 1724 (CO), 1579, 1309 cmϪ1
;
δH (CDCl3) 1.48 (3H, t, J 5, CH3), 4.16 (3H, s, OCH3), 4.50 (2H,
q, J 5, CH2), 7.74 (2H, m, H-8,9), 7.86 (1H, d, J 8, H-6), 7.93
(1H, m, H-7), 8.14 (1H, d, J 8, H-5), 9.28 (1H, m, H-10), 9.32
(1H, s, H-2); m/z (EIMS) 281 (Mϩ); an NOE difference experi-
ment confirmed the placement of the methyl on the oxygen due
to irradiation of the methyl protons (4.16 ppm) enhancing the
signal of H-5 at 8.14 ppm.
2-Hydroxyethyl 4-chlorobenzo[h]quinoline-3-carboxylate 19
A mixture of ethyl 4-chlorobenzo[h]quinoline-3-carboxylate 16
(1.0 mg, 3.5 mmol) and guanidine carbonate (648 mg, 3.6
mmol) in ethylene glycol (10 cm3, excess) was heated to 50 ЊC
for 5 h, after which the white precipitate (473 mg, 45%) was
filtered, washed well with water and dried. Recrystallisation
from ethyl acetate–petroleum ether 60–80 ЊC gave white needles
of 2-hydroxyethyl 4-chlorobenzo[h]quinoline-3-carboxylate 19,
mp 151–153 ЊC (Found C, 63.8; H, 3.9; N, 4.6. C16H12ClNO3
requires C, 63.8; H, 4.0; N, 4.65%); νmax (KBr disk) 3471 (OH),
1720 (CO), 1243 cmϪ1; δH (CDCl3) 4.04 (2H, t, J 5, CH2), 4.60
(2H, t, J 5, CH2), 7.78 (2H, m, H-8,9), 7.95 (2H, m, H-6,7), 8.25
(1H, d, J 9, H-5), 9.30 (1H, m, H-10), 9.32 (1H, s, H-2); m/z 301
(Mϩ 57%), 257 (Mϩ Ϫ 44, 60), 240 (Mϩ Ϫ 61, 100), 212 (Mϩ Ϫ
89, 60). The filtrate was washed several times with water, dried
(MgSO4) and the ethylene glycol was removed under reduced
pressure to leave a white solid (432 mg, 43%) which was con-
firmed as starting material via its melting point (114–117 ЊC)
and IR analysis.
Ethyl 1-methyl-4-oxo-1,4-dihydrobenzo[h]quinoline-3-
carboxylate 23
Using dry glassware, ethyl 4-oxo-1,4-dihydrobenzo[h]quinoline-
3-carboxylate 15 (2.0 g, 7.5 mmol) and dry toluene (10 cm3)
were cooled to 0 ЊC in an ice bath and sodium hydride (60%
dispersion with mineral oil, 900 mg, 22.5 mmol) was added
slowly. The reaction was stirred at 0 ЊC for 10 min and then
allowed to warm to room temperature. After 15 min methyl
iodide (3.5 cm3, excess) was added and then heated to 50 ЊC
for 16 h. The reaction was cooled to room temperature and
water was carefully added until no further effervescence was
2320
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observed. The solution was extracted with dichloromethane,
washed with water, dried (MgSO4) and the solvent removed in
vacuo to leave ethyl 1-methyl-4-oxo-1,4-dihydrobenzo[h]quinol-
ine-3-carboxylate 23 (1.81 g, 86%). Recrystallisation from ethyl
acetate–petroleum ether 60–80 ЊC afforded the product as white
needles, mp 143–145 ЊC (Found C, 72.6; H, 5.3; N, 5.0. C17H15-
NO3 requires C, 72.6; H, 5.4; N, 5.0%); νmax (KBr disk) 2923
and 2854 (CH), 1685 (CO), 1619, 1213 cmϪ1; δH (CDCl3) 1.40
(3H, t, J 7, CH2CH3), 4.27 (3H, s, NCH3), 4.37 (2H, q, J 7,
CH2CH3), 7.59 (2H, m, H-8,9), 7.69 (1H, d, J 8, H-7), 7.90 (1H,
dd, J 8 and 2, H-6), 8.39 (1H, d, J 8, H-5), 8.42 (1H, d, J 9,
H-10), 8.46 (1H, s, H-2); δC 14.38, 29.63, 47.68, 60.89, 112.97,
122.83, 123.98, 125.22, 125.63, 126.38, 127.92, 129.23, 136.62,
139.10, 151.02, 165.34 (CO), 173.39 (CO); m/z (EI) 281 (Mϩ
100%). NOE difference experiments confirm the placement of
the methyl on the nitrogen; irradiation of the methyl singlet
(4.27 ppm) enhances the signals of H-10 and H-2 at 8.42 and 8.46
ppm respectively.
acetoacetate (92 mg, 0.71 mmol) in dry ether was cooled to 0 ЊC
with the aid of an ice bath. Sodium hydride (60% dispersion in
mineral oil, 100 mg, excess) was added carefully and allowed to
stir for 10 min, before toluene (10 cm3) was added and the
temperature was raised to 100 ЊC for 20 h. The reaction was
cooled to room temperature and water (50 cm3) was added
cautiously to the reaction until effervescence ceased. The
aqueous layer was extracted with ether, dried (MgSO4) and the
solvent removed in vacuo to leave a bright green oil. The oil
was purified by flash chromatography (eluent: ethyl acetate–
petroleum ether 60–80 ЊC, 2:3) and identified as ethyl 1-methyl-
4-hydroxy-2-(ethoxycarbonylmethyl)-1,2-dihydrobenzo[h]-
quinoline-3-carboxylate 25 (180 mg, 67%). A sample was
prepared for analysis by distillation using Kugelröhr apparatus
(bp 200 ЊC/0.02 mbar). νmax (NaCl disk) 3060–2931 (CH), 1733
(CO), 1643 (CO), 1344 cmϪ1; δH (CDCl3) 1.19 (3H, t, J 8,
CH2CH3), 1.39 (3H, t, J 8, CH2CH3), 2.39 (2H, dd, J 8 and 2,
NCHCH2CO), 2.95 (3H, s, NCH3), 4.14 (2H, q, J 8, CH2CH3),
4.34 (2H, dq, J 8 and 3, CH2CH3), 4.67 (1H, dd, J 9 and 7,
NCHCH2), 7.50 (2H, m, H-8,9), 7.57 (1H, d, J 9, H-7), 7.81
(1H, m, H-5), 7.83 (1H, d, J 9, H-6), 8.11 (1H, m, H-10), 12.25
(1H, br s, OH - D2O exchangeable); m/z 369.1570, C21H23NO5
requires 369.1576; a 2D-COSY NMR experiment confirmed
the structure of the product.
1-Methyl-3-hydrazinocarbonyl-4-oxo-1,4-dihydrobenzo[h]-
quinoline 24
A mixture of ethyl 1-methyl-4-oxo-1,4-dihydrobenzo[h]quinol-
ine-3-carboxylate 23 (2.0 g, 7.1 mmol) and hydrazine mono-
hydrate (10 cm3, excess) were heated to reflux for 30 min,
after which the mixture was cooled and basified with saturated
Na2CO3 solution. The resulting solid (1.76 g, 93%) was filtered,
washed well with water and left to dry. Recrystallisation from
ethanol afforded the product 1-methyl-3-hydrazinocarbonyl-
4-oxo-1,4-dihydrobenzo[h]quinoline 24 as off-white needles,
mp 235–237 ЊC (decomp.) (Found C, 67.2; H, 4.85; N, 15.5.
C15H13N3O2 requires C, 67.4; H, 4.9; N, 15.7%); νmax (KBr disk)
~3300 (br, NH), 2923 and 2854 (CH), 1666 (CO) cmϪ1; δH
(d6-DMSO, 50 ЊC) 4.43 (3H, s, NCH3), 4.59 (2H, br s, NH2,
D2O exchangeable), 7.72 (2H, m, H-8,9), 7.91 (1H, d, J 9, H-7),
8.08 (1H, d, J 9, H-6), 8.29 (1H, d, J 9, H-5), 8.75 (1H, d, J 9,
H-10), 8.80 (1H, s, H-2), 10.76 (1H, br s, NH, D2O exchange-
able); δC (d6-DMSO, 50 ЊC) 48.00 (NCH3), 112.30, 121.39,
125.66, 125.95, 126.13, 126.28, 128.27, 128.79, 136.08, 139.15,
149.49, 163.15 (CO), 173.91 (CO).
References
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1,4-dihydrobenzo[h]quinoline 24
1-Methyl-3-hydrazinocarbonyl-4-oxo-1,4-dihydrobenzo[h]-
quinoline 24 (500 mg, 1.9 mmol) was heated to reflux in POCl3
(4.0 cm3, excess) and after 1 h the mixture was cooled to room
temperature. The cooled mixture was poured onto ice–water
and basified with ~50 cm3 of saturated Na2CO3. Upon addition
of NH4PF6 (305 mg, 1.9 mmol) a deep red solid (419 mg)
precipitated out of solution which was collected by vacuum
filtration and allowed to dry. The TLC of the solid (eluent:
methanol–ethyl actetate–glacial acetic acid, 2:2:1) showed
only a baseline orange spot. The IR spectrum indicated that a
hexafluorophosphate salt may be present (844 cmϪ1), however,
the NMR spectrum in CF3CO2D was far too impure to charac-
terise the compound. Attempted purification via recrystallis-
ation in many different solvents failed to improve the purity of
the compound significantly enough to allow the structure of the
product to be determined.
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Ethyl 1-methyl-4-hydroxy-2-(ethoxycarbonylmethyl)-1,2-
dihydrobenzo[h]quinoline-3-carboxylate 25
A stirred solution of ethyl 1-methyl-4-oxo-1,4-dihydrobenzo[h]-
quinoline-3-carboxylate (23) (200 mg, 0.71 mmol) and ethyl
Paper 9/03402A
J. Chem. Soc., Perkin Trans. 1, 1999, 2315–2321
2321