Antitumour polycyclic acridines. Part 9. Synthesis of 7H-pyrido[4,3,2-kl]acridines with basic side chains

Article abstract of DOI:10.1039/b106324n

[3 + 2] Cycloaddition of 3-(dialkylamino)-1-triphenylphosphoranylidenepropan-2-ones and 9-azidoacridine affords 9-[5-(dialkylaminomethyl)-1H-1,2,3-triazol-1-yl]acridines. Graebe-Ullmann thermolysis of the triazoles has been guided by differential scanning calorimetry to predict the optimum temperature for nitrogen extrusion. Boiling diphenyl ether (bp 259°C) is a suitable solvent to convert the triazolylacridines to 2-(dialkylaminomethyl)-7H-pyrido[4,3,2-kl]acridines.

Full text of DOI:10.1039/b106324n

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Antitumour polycyclic acridines. Part 9.1 Synthesis of
7H-pyrido[4,3,2-kl]acridines with basic side chains
Michael J. Ellis and Malcolm F. G. Stevens*
1
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham,
Nottingham, UK NG7 2RD. E-mail: malcolm.stevens@nottingham.ac.uk;
Fax: (115) 951 3412; Tel: (115) 951 3414
Received (in Cambridge, UK) 17th July 2001, Accepted 10th October 2001
First published as an Advance Article on the web 7th November 2001
[3 ϩ 2] Cycloaddition of 3-(dialkylamino)-1-triphenylphosphoranylidenepropan-2-ones and 9-azidoacridine affords
9-[5-(dialkylaminomethyl)-1H-1,2,3-triazol-1-yl]acridines. Graebe–Ullmann thermolysis of the triazoles has been
guided by differential scanning calorimetry to predict the optimum temperature for nitrogen extrusion. Boiling
diphenyl ether (bp 259 ЊC) is a suitable solvent to convert the triazolylacridines to 2-(dialkylaminomethyl)-7H-
pyrido[4,3,2-kl]acridines.
cycloaddition of 9-azidoacridine 4 and alkynes to afford
Introduction
9-(triazol-1-yl)acridines
5 which, on thermolysis, extrude
In previous parts of this series we have reported on synthetic
routes to pyrido- and quino-acridine systems 12–4 and the
biophysical properties of the more biologically interesting
products.5,6 In the course of this work we discovered that the
indolizino[7,6,5-kl]acridinium chloride 2, prepared in a simple
3-step reaction from the readily available 9-chloroacridine,3
formed an intercalative ‘hot spot’ within guanine–cytosine
sequences of DNA.7 This interaction may be responsible for
the activity of 2 as a topoisomerase II inhibitor, although
the indolizinoacridine differs from other agents of this class
(e.g. m-AMSA) in not being a substrate for P-glycoprotein
nitrogen to generate the pyridoacridines 6 (Scheme 1).3 With
mediated drug efflux; also
2 maintains activity against
human lung tumour cells with derived resistance to the
non-intercalating topoisomerase-II inhibitor etoposide.8
Scheme 1
unsymmetrical alkynes this route is inefficient in practice,
since a mixture of regioisomeric triazoles 5 is formed which
have to be separated chromatographically. The least sterically
hindered 4-substituted triazole is usually favoured over the
5-substituted isomer in a ratio of 2 : 1. (The 4-substituted tri-
azole isomers afford 3-substituted pyridoacridines on therm-
olysis whereas the 5-substituted isomers yield 2-substituted
pyridoacridines 6.) In this paper we return to the prob-
lem of synthesising 5-substituted triazoles regioselectively4
which might be processed to pyridoacridines bearing useful
substituents in the 2-position.
Recently we have reported the synthesis of the intriguing
pentacyclic acridinium salt 3 which is a potent inhibitor of the
enzyme telomerase.1,9 This enzyme is activated in tumour cells
(but not in most normal cells)10 and serves to maintain the
ends of chromosomes (telomeres) which fray during successive
rounds of DNA replication. Activation of telomerase is one of
the key genetic events leading to tumour cell immortality11 and
the design of inhibitors of this enzyme is of burgeoning interest
to anticancer drug design teams.12
Results and discussion
Synthesis of 9-[5-(dialkylaminomethyl)-1H-1,2,3-triazol-1-yl]-
acridines
The chloroacetonyltriphenylphosphorane ylide 7 reacts with
9-azidoacridine 4 to yield exclusively 9-(5-chloromethyl-1,2,3-
triazol-1-yl)acridine 8 in 67% yield; incubation of 8 with
dimethylamine at 30–40 ЊC in THF gave the pure dimethyl-
amine 11a (72%) which was only the minor isomer formed
Our original route to tetracyclic systems involved the [3 ϩ 2]
3174
J. Chem. Soc., Perkin Trans. 1, 2001, 3174–3179
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106324n

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(22%) in the azide–alkyne cycloaddition route (Scheme 2).8
Problems arose in adapting this substitution method when less
reactive dialkylamines were employed. Reaction with diethyl-
amine required 120 days at 25 ЊC to produce a reasonable yield
of 11b (51%). With piperidine, a brief reflux (1.5 h) afforded the
piperidinylmethyltriazole 11d (70%); more prolonged reflux
(4 h) led to the 9-piperidinylacridine 12d being the major prod-
uct (71%). Brief treatment of 8 with refluxing morpholine gave
the 9-(morpholin-4-yl)acridine 12e (69%) but reaction of 8 and
morpholine in THF furnished the morpholinyltriazole 11e
(41%) after 28 days at 25 ЊC, together with by-product 12e
(17%). Interaction with 8 with hexamethyleneimine (azepane)
at reflux temperature (4 h) in THF yielded the required product
11h (83%).
It is not possible to be precise about the timing of the nucleo-
philic displacement to afford by-products 12: either of the two
triazole systems 8 or 11 could be substrates for this unwanted
intervention. However, problems associated with competitive
nucleophilic substitutions can be circumvented by effecting the
aminations at the chloroacetonyltriphenylphosphorane ylide
stage.13 Ylides 10b–g were prepared from 7 and the appropriate
dialkylamines in acetonitrile at 25 ЊC and then reacted with
9-azidoacridine 4 in refluxing benzene to afford the triazoles
11b–g in yields of 37–90%.
pyridoacridines, differential scanning calorimetry (DSC) was
used to monitor, qualitatively and quantitatively, their Graebe–
Ullmann thermolyses.14 Data from thermograms of represen-
tative triazoles are presented in Table 1. As an example, the
thermogram of the diethylaminomethyltriazole 11b shows a
melting endotherm at 103.4 ЊC together with a sharp therm-
olysis exotherm at 220.3 ЊC. This indicates that boiling diphenyl
ether (bp 259 ЊC) could be a suitable solvent to effect prepar-
ative scale Graebe–Ullmann cyclisation to the corresponding
pyridoacridine. Similarly a sharp distinction between melting
and thermolytic extrusion of nitrogen was observed for the
triazoles 11c, d (Table 1). In contrast, overlapping melting
and decomposition were evident in the thermogram of the
chloromethyltriazole 8 (data not shown). As predicted from the
DSC analysis, thermolysis of 8 in boiling diphenyl ether did not
afford any 2-(chloromethyl)pyridoacridine 9 which might have
been a useful substrate for nucleophilic substitutions to provide
a range of pyridoacridines with additional basic substituents.
The thermolysis of triazole 11a to pyridoacridine 14a (58%)
in boiling triglyme has been reported by us earlier.8 Brief treat-
ment of new triazoles 11b–g in boiling diphenyl ether generally
gave new 2-substituted pyridoacridines 14 in acceptable
(30–90%) yields. However, the pyrrolidinyl derivative 14c and
the diallyl tetracycle 14g could not be isolated. The mechanism
of this reaction may involve a diradical 13 (or isoelectronic
carbene species),15 either of which could then cyclise to the 7H-
pyrido[4,3,2-kl]acridines 14 (Scheme 3). (For comments on a
tetracyclic structure isomeric with 14, see ref. 16.) The possibil-
ity that the diallylamino moiety might intercept these reactive
intermediates may explain the lack of product 14g from 11g but
the inability of the pyrrolidinyltriazole 11c to furnish pyrido-
acridine 14c cannot be explained readily; possibly a lower boil-
ing, water-miscible thermolysis medium might have been more
suitable in this case.
The chemical shifts of the H-4 proton in the triazole ring of
the 5-alkyltriazoles 11b–g were in the range δ 7.97–8.04. We
have shown previously that the corresponding absorptions at
H-5 in the 4-substituted isomers are >δ 8.5.3
Synthesis of 2-(dialkylaminomethyl)-7H-pyrido[4,3,2-kl]-
acridines by Graebe–Ullmann cyclisation of 9-(triazol-1-yl)-
acridines
With triazoles 11b–g available for conversion to their respective
Scheme 2
J. Chem. Soc., Perkin Trans. 1, 2001, 3174–3179
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Table 1 Differential scanning calorimetry (DSC) of the decomposition of selected triazoles 11
Compound
Mp/ЊCa
Decomposition temp./ЊCb
∆Hdec./kJ molϪ1 c
11ad
11b
11c
187.4
103.4
149.3
167.9
224.3
220.3
221.3
230.3
—
Ϫ171.0
Ϫ126.1
Ϫ160.4
11d
a Maximum point on the melting endotherm (T max). b Minimum point on the decomposition exotherm (T min). c Enthalpy of decomposition.
d D. Hagan, PhD thesis, University of Nottingham, 1996.
Scheme 3
The applicability of this new route to 7H-pyrido[4,3,2-kl]-
acridines with potentially ‘drug-like’ substituents in the
2-position was illustrated by an efficient synthesis of the indol-
inylpyridoacridine 17. The precursor triazole 16 could not be
prepared from the chloromethyltriazole 8 and indoline without
competitive nucleophilic substitution at the acridine 9-position.
However, conversion of the chloroacetonyltriphenylphos-
phorane ylide 7 to the indolinyl analogue 15 proceeded
smoothly (73%); cycloaddition with 9-azidoacridine 4 in benz-
Scheme 4
zene then gave the indolinylmethyltriazole 16 (73%) which was
then thermolytically transformed to the 2-(indolinylmethyl)-
pyridoacridine 17 in boiling diphenyl ether (54%) (Scheme 4).
uncorrected. IR spectra were measured on a Mattson 2020
Galaxy Series FT-IR spectrometer, UV spectra on a Pharmacia
The long wavelength absorption at 425 nm (in EtOH) in the UV
Biotech Ultraspec 2000 UV–visible spectrometer and mass
spectrum of tetracycle free base 17 was shifted to 469 nm on
spectra on a Micromass Platform spectrometer. High resolution
mass data were collected on a VG Autospec instrument. Differ-
addition of HCl, indicating that the cation has structure 18 with
protonation at N-1.
The pyridoacridines 14f and 17 were tested in the National
ential scanning calorimetry was performed with a Perkin-Elmer
Pyris 1 instrument as previously reported.2–4 Merck silica gel 60
Cancer Institute (USA) panel of 60 human tumour cell lines
(0.04–0.63 mm) was used for chromatography.
3-Chloro-1-triphenylphosphoranylidenepropan-2-one 7 was
in vitro.17 Results are expressed as a mean GI50 concentration
(concentration of drug required to inhibit the growth of cells by
50% relative to untreated cells) averaged over the 60 cell lines.
We have described previously the potency of the indolizino-
prepared from triphenylphosphine and 1,3-dichloroacetone
in refluxing THF.13 9-(5-Chloromethyl-1H-1,2,3-triazol-1-yl)-
acridine 8 was prepared from 7 and 9-azidoacridine by the
[7,6,5-kl]acridinium chloride 2 which gave a mean GI50 value of
method of Stanslas et al.8 Dialkylaminoacetonyltriphenyl-
0.09 µM.8 The piperazinylmethylpyridoacridine 14f was 16-fold
phosphorane ylides 10b–f were prepared from 7 and the
less cytotoxic (GI50 1.46 µM) and the indolinyl analogue 17 160-
appropriate dialkylamines and cycloalkylamines in acetonitrile
fold less cytotoxic (GI50 14.8 µM). This confirms our earlier
at 25 ЊC by published methods.18
conclusions that tetracyclic acridine systems are less cytotoxic
than their pentacyclic counterparts.8
Synthesis of 9-[5-(dialkylaminomethyl)-1H-1,2,3-triazol-1-yl]-
acridines
Experimental
9-[5-(N,N-Dimethylaminomethyl)-1H-1,2,3-triazol-1-yl]-
NMR spectra were recorded on a Bruker ARX 250 spectro-
meter at room temperature. Chemical shifts are reported in
δ units and referenced to the solvent as internal standard; coup-
ling constants (J values) are in Hz. Melting points were deter-
mined on a Gallenkamp melting point apparatus and are
acridine 11a. (i) Triazolylacridine 8 (0.84 g, 2.8 mmol) and
excess dimethylamine in THF were reacted at 30 ЊC for 5 days.
The precipitate (dimethylamine hydrochloride) was removed by
filtration and the filtrate was evaporated. The dimethylamino-
triazolylacridine 11a was collected and crystallised from ethyl
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acetate as yellow crystals (0.61 g, 72%), mp 194–195 ЊC (lit.8
192–193 ЊC).
(ii) The same product (22%), together with 9-[4-(N,N-di-
methylaminomethyl)-1H-1,2,3-triazol-1-yl]acridine (58%), was
synthesised from 9-azidoacridine 4 and 1-(N,N-dimethyl-
amino)prop-2-yne in toluene at 60 ЊC.8
69.42; H, 5.57; N, 20.36. C20H19N5O requires C, 69.55; H, 5.54;
N, 20.28%); νmax (KBr)/cmϪ1 2859, 2810, 1451, 1242, 1113, 862,
748, 635; δH (250.13 MHz; CDCl3) 8.32 (2 H, d, J 8.8, H-4,5),
7.95 (1 H, s, triazole H-4), 7.82 (2 H, m, H-3,6), 7.53 (2 H, m,
H-2,7), 7.26 (2 H, d, J 8.8, H-1,8), 3.29 (2 H, s, CH2-
morpholinyl), 2.98 (4 H, br s, morpholine CH2), 1.96 (4 H, br s,
morpholine CH2); δC (62.90 MHz; CDCl3) 149.68 (C), 138.14
(C), 137.79 (C), 134.04 (CH), 131.12 (CH), 130.28 (CH), 128.32
(CH), 123.10 (C), 122.84 (CH), 66.56 (CH2), 53.27 (CH2), 51.32
(CH2); m/z (ES) 346.3 (MHϩ, 100%).
9-[5-(N,N-Diethylaminomethyl)-1H-1,2,3-triazol-1-yl]acridine
11b. (i) General Method A: 9-azidoacridine (0.42 g, 1.88 mmol)
and 3-(N,N-diethylamino)-1-triphenylphosphoranylideneprop-
an-2-one (10b, 0.67 g, 1.88 mmol)18 in benzene (10 cm3) were
refluxed (2 h). The solvent was removed by vacuum evaporation
and the product purified by flash column chromatography.
Elution with ethyl acetate–hexane (1 : 1) gave the triazolylacrid-
ine 11b (0.31 g, 49%), mp 103–104 ЊC (Found: C, 72.80; H, 6.24;
N, 21.38. C20H21N5 requires C, 72.50; H, 6.34; N, 21.15%); νmax
(KBr)/cmϪ1 2961, 1553, 1516, 1451, 1437, 1233, 1080, 768;
δH (250.13 MHz; CDCl3) 8.35 (2 H, d, J 8.8, H-4,5), 7.99 (1 H, s,
triazole H-4), 7.86 (2 H, m, H-3,6), 7.57 (2 H, m, H-2,7), 7.33
(2 H, d, J 8.2, H-1,8), 3.39 (2 H, s, CH2NEt2), 2.18 (4 H, q, J 7.1,
NCH2CH3), 0.37 (6 H, t, J 7.1, NCH2CH3); δC (62.90 MHz;
CDCl3) 149.23 (C), 139.40 (C), 137.37 (C), 133.66 (CH), 130.63
(CH), 129.71 (CH), 127.75 (CH), 122.77 (C), 122.55 (CH),
46.41 (CH2), 45.97 (CH2), 11.07 (CH3); m/z (APCI) 332.2
(MHϩ, 18%).
(ii) The same triazolylacridine 11e was formed (41%) when
the chloromethyltriazole 8 (0.17 g) was reacted with mor-
pholine in THF for 28 days at 25 ЊC; a by-product of this
reaction was 9-(morpholin-4-yl)acridine 12 (17%).20 The same
9-(morpholin-4-yl)acridine 12 (69%) was the main product
when 8 was boiled in refluxing morpholine (2 h).
9-[5-(4-Methylpiperazin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]-
acridine 11f. Prepared according to Method A, from 9-azido-
acridine (0.43 g, 1.95 mmol) and 3-(4-methylpiperazin-1-yl)-
1-triphenylphosphoranylidenepropan-2-one (10f, 0. 69 g, 1.81
mmol),18 the triazolylacridine 11f (0.60 g, 92%) had mp 91–
91 ЊC; νmax (KBr)/cmϪ1 2799, 1516, 1451, 1144, 1101, 1009, 754;
δH (250.13 MHz; CDCl3) 8.36 (2 H, d, J 8.8, H-4,5), 7.97 (1 H, s,
triazole H-4), 7.87 (2 H, m, H-3,6), 7.57 (2 H, m, H-2,7), 7.31
(2 H, d, J 8.2, H-1,8), 3.34 (2 H, s, CH2-piperazine), 2.03 (4 H,
br s, piperazine CH2), 1.99 (3 H, s, CH3), 1.66 (4 H, br s, piper-
azine CH2); δC (62.90 MHz; CDCl3) 149.17 (C), 138.08 (C),
137.44 (C), 133.41 (CH), 130.61 (CH), 129.68 (CH), 127.79
(CH), 122.58 (C), 122.43 (CH), 54.12 (CH2), 52.25 (CH2), 50.40
(CH2), 45.53 (CH3); m/z (ES) 359.2 (MHϩ, 100%) [Found: m/z
(HRMS-FAB) 359.1993. C21H23N6 requires MHϩ 359.1984].
(ii) The same product 11b (51%) was formed from the
chloromethyltriazole 8 and diethylamine in 120 days at 25 ЊC.
9-[5-(Pyrrolidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]acridine
11c. Prepared according to Method A, from 9-azidoacridine
(0.54 g, 2.45 mmol) and 3-(pyrrolidin-1-yl)-1-triphenylphos-
phoranylidenepropan-2-one (10c, 0.86 g, 2.45 mmol),17 the tri-
azolylacridine 11c (0.39 g, 37%) had mp 153–155 ЊC (Found: C,
72.78; H, 5.79; N, 20.93. C20H19N5 requires C, 72.93; H, 5.81; N,
21.26%); νmax (KBr)/cmϪ1 2785, 1514, 1437, 1236, 1142, 754;
δH (250.13 MHz; CDCl3) 8.31 (2 H, d, J 8.8, H-4,5), 8.00 (1 H, s,
triazole H-4), 7.83 (2 H, m, H-3,6), 7.53 (2 H, m, H-2,7), 7.26
(2 H, d, J 8.8, H-1,8), 3.37 (2 H, s, CH2-pyrrolidinyl), 2.17 (4 H,
br s, pyrrolidine CH2), 1.43 (4 H, br s, pyrrolidine CH2);
δC (62.90 MHz; CDCl3) 149.27 (C), 139.32 (C), 136.97 (C),
133.01 (CH), 130.70 (CH), 129.77 (CH), 127.91 (CH), 122.79
(C), 122.37 (CH), 53.80 (CH2), 48.11 (CH2), 23.29 (CH2); m/z
(APCI) 330.2 (MHϩ, 41%).
9-[5-(N,N-Diallylaminomethyl)-1H-1,2,3-triazol-1-yl]acridine
11g. The chloroacetonyltriphenylphosphorane ylide 7 (1.97 g,
6.19 mmol) and diallylamine (1.20 g, 12.38 mmol) in aceto-
nitrile (5 cm3) were stirred at 25 ЊC for 48 h. Solvent was
removed by vacuum evaporation and the residue was triturated
with water (15 cm3) and the products were then extracted into
ethyl acetate (3 × 25 cm3). The combined organic extracts were
concentrated and the residue was purified by flash column
chromatography. The 3-(N,N-diallylamino)-1-triphenylphos-
phoranylidenepropan-2-one 10g (2.38 g, 93%) was isolated as
an oil and used without further purification in the next stage
of the reaction. The triphenylphosphoranylidenepropan-2-one
10g was characterised by mass spectrometry [Found: m/z
(HRMS-FAB) 414.2020. C27H29NOP requires 414.1987].
Interaction of 9-azidoacridine (1.15 g, 5.23 mmol) and 3-
(N,N-diallylamino)-1-triphenylphosphoranylidenepropan-2-one
(10g, 1.98 g, 5.23 mmol), according to Method A, gave the
triazolylacridine 11g (1.05 g, 56%) with mp 88–89 ЊC (Found:
C, 74.40; H, 5.93; N, 19.72. C22H21N5 requires C, 74.34; H, 5.96;
N, 19.70%); νmax (KBr)/cmϪ1 2804, 1449, 1235, 1001, 922, 752;
δH (250.13 MHz; CDCl3) 8.37 (2 H, d, J 8.8, H-4,5), 8.01 (1 H, s,
triazole H-4), 7.87 (2 H, m, H-3,6), 7.56 (2 H, m, H-2,7), 7.30
9-[5-(Piperidin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]acridine
11d. (i) Prepared according to Method A, from 9-azidoacridine
(0.44 g, 1.99 mmol) and 3-(piperidin-1-yl)-1-triphenylphos-
phoranylidenepropan-2-one (10d, 0.73 g, 1.82 mmol),17 the tri-
azolylacridine 11d (0.45 g, 71%) had mp 169–171 ЊC (Found: C,
73.07; H, 6.21; N, 20.28. C21H21N5 requires C, 73.44; H, 6.16; N,
20.39%); νmax (KBr)/cmϪ1 2936, 2760, 1514, 1439, 1240, 1111,
754; δH (250.13 MHz; CDCl3) 8.35 (2 H, d, J 8.8, H-4,5), 7.97
(1 H, s, triazole H-4), 7.86 (2 H, m, H-3,6), 7.57 (2 H, m, H-2,7),
7.32 (2 H, d, J 8.8, H-1,8), 3.27 (2 H, s, CH2-piperidinyl), 1.95
(4 H, br s, piperidine CH2), 1.09 (2 H, br s, piperidine CH2),
0.95 (4 H, br s, piperidine CH2); δC (62.90 MHz; CDCl3) 149.70
(C), 139.23 (C), 138.00 (C), 133.79 (CH), 131.08 (CH), 130.16
(CH), 128.19 (CH), 123.18 (C), 123.04 (CH), 54.48 (CH2), 51.88
(CH2), 25.69 (CH2), 24.00 (CH2); m/z (APCI) 344.2 (MHϩ,
100%).
(2 H, d, J 8.8, H-1,8), 4.74 [6 H, br m, CH N(CH CH᎐CH ) ],
᎐
2
2
2 2
3.28 [2 H, s, CH2 CH CH᎐CH ) ], 2.67 [4 H, d, J 3.5,
᎐
2
2 2
CH N(CH CH᎐CH ) ]; δ (62.90 MHz; CDCl3) 149.13 (C),
᎐
2
2
2
2
C
138.89 (C), 137.20 (C), 133.91 (CH), 133.82 (CH), 130.53 (CH),
129.59 (CH), 127.69 (CH), 122.71 (C), 122.50 (CH), 117.70
(CH2), 56.16 (CH2), 45.19 (CH2); m/z (APCI) 356.3 (MHϩ,
100%).
(ii) The same triazolylacridine 11d was formed (70%) when
the chloromethyltriazole 8 (0.12 g) was boiled in piperidine
(3 cm3) for 1.5 h. If refluxing was continued for 4 h the main
product was 9-(piperidin-1-yl)acridine 12d19 (71%).
9-[5-(Azepan-1-ylmethyl)-1H-1,2,3-triazol-1-yl]acridine 11h.
A mixture of the chloromethyltriazole 8 (0.20 g, 0.68 mmol)
and excess hexamethyleneimine (1.0 cm3) in THF (5 cm3) was
boiled for 4 h and the solution was vacuum evaporated. The
residue was crystallised from ethyl acetate to afford the yellow
triazolylacridine 11h (0.20 g, 83%), mp 178–179 ЊC (Found: C,
73.96; H, 6.63; N, 19.77. C22H23N5 requires C, 73.92; H, 6.49; N,
9-[5-(Morpholin-4-ylmethyl)-1H-1,2,3-triazol-1-yl]acridine
11e. (i) Prepared according to Method A, from 9-azidoacridine
(0.51 g, 2.31 mmol) and 3-(morpholin-4-yl)-1-triphenylphos-
phoranylidenepropan-2-one (10e, 0.86 g, 2.12 mmol),18 the tri-
azolylacridine 11e (0.62 g, 85%) had mp 143–144 ЊC (Found: C,
J. Chem. Soc., Perkin Trans. 1, 2001, 3174–3179
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19.59%); νmax (KBr)/cmϪ1 2922, 1514, 1437, 1238, 1141, 835,
756; δH (250.13 MHz; CDCl3) 8.33 (2 H, d, J 8.0, H-4,5), 7.95
(1 H, s, triazole H-4), 7.84 (2 H, m, H-3,6), 7.55 (2 H, m, H-2,7),
7.32 (2 H, d, J 8.6, H-1,8), 3.44 (2 H, s, CH2N-hexamethyl-
eneimine), 2.16 (4H, m, hexamethyleneimine CH2), 1.10 (8 H,
m, hexamethyleneimine CH2); δC (62.90 MHz; CDCl3) 149.76
(C), 140.09 (C), 137.87 (C), 133.68 (CH), 131.08 (CH), 130.22
(CH), 128.23 (CH), 123.08 (C), 123.07 (CH), 56.01 (CH2),
51.96 (CH2), 28.24 (CH2), 26.61 (CH2); m/z (APCI) 358.5
(MHϩ, 100%).
1154, 768; δH (250.13 MHz; CDCl3) 8.52 (1 H, dd, J 1.5, 8.0,
H-11), 7.75 (1 H, br s, NH), 7.40 (1 H, t, J 7.5, H-5), 7.32 (2 H,
m, H-3,9), 7.04 (2 H, m, H-8,10), 6.92 (1 H, d, J 7.5, H-4), 6.64
(1 H, d, J 7.5, H-6), 3.80 (2 H, s, CH2), 2.70 (4 H, m, piperidine
CH2), 1.72 (4 H, m, piperidine CH2), 1.55 (2 H, m, piperidine
CH2); δC (62.90 MHz; CDCl3) 152.44 (C), 151.24 (C), 139.73
(C), 139.68 (C), 138.57 (C), 131.33 (CH), 130.87 (CH), 124.90
(CH), 121.10 (CH), 120.92 (C), 118.45 (CH), 115.30 (CH),
114.98 (CH), 113.27 (CH), 104 67 (CH), 65.37 (CH2), 54.72
(CH2), 25.84 (CH2), 24.22 (CH2); m/z (FAB) 316 (MHϩ,
65%) [Found: m/z (HRMS-FAB) 316.1813. C21H21N3 requires
316.1814].
9-[5-(Indolin-1-ylmethyl)-1H-1,2,3-triazol-1-yl]acridine 16.
The chloroacetonyltriphenylphosphorane ylide 7 (0.78 g, 2.22
mmol) and indoline (0.57 g, 4.77 mmol) in acetonitrile (5 cm3)
were converted to 3-(indolin-1-yl)-1-triphenylphosphoranyl-
idenepropan-2-one 15 according to the preparation of 10g
(see above). The phosphorane 15 (0.65 g, 73%) was isolated as a
yellow gum. The product was characterised by mass spectro-
metry [Found: m/z (HRMS-FAB) 436.1830. C29H27NOP
requires 436.1830] and used without further purification in the
next stage of the reaction.
Prepared according to Method A, from 9-azidoacridine
(0.32 g, 1.46 mmol) and 3-(indolin-1-yl)-1-triphenylphosphor-
anylidenepropan-2-one (15, 0.58 g, 1.33 mmol), the triazolyl-
acridine 16 (0.36 g, 73%) had mp 213–214 ЊC (Found: C, 76.26; H,
5.09; N, 18.67. C24H19N5 requires C, 76.37; H, 5.07; N, 18.55%);
νmax (KBr)/cmϪ1 1605, 1487, 1256, 1065, 762; δH (250.13 MHz;
CDCl3) 8.35 (2 H, d, J 8.8, H-4,5), 8.04 (1 H, s, triazole H-4),
7.86 (2 H, m, H-3,6), 7.56 (2 H, m, H-2,7), 7.33 (2 H, d, J 8.2,
H-1,8), 6.84 (1 H, d, J 7.0, indoline H-4), 6.78 (1 H, t, J 7.7,
indoline H-6), 6.55 (1 H, t, J 7.4, indoline H-5), 5.81 (1 H, d,
J 7.5, indoline H-7), 4.07 (2 H, s, CH2-indoline), 2.88 (2 H, t,
J 8.3, indoline H-2), 2.47 (2 H, t, J 8.3, indoline H-3); δC (62.90
MHz; CDCl3) 150.11 (C), 149.16 (C), 138.38 (C), 136.69 (C),
133.18 (CH), 130.75 (CH), 129.82 (CH), 129.07 (C), 128.05
(CH), 126.96 (CH), 124.31 (CH), 122.67 (C), 122.10 (CH),
118.45 (CH), 106.12 (CH), 53.37 (CH2), 42.48 (CH2), 27.96
(CH2); m/z (ES) 378.3 (MHϩ, 100%).
2-(Morpholin-4-ylmethyl)-7H-pyrido[4,3,2-kl]acridine 14e.
Prepared from 11e by Method B and eluted with ethyl acetate–
hexane (1 : 2), the pyridoacridine 14e (34%) had mp 205–
207 ЊC; νmax (KBr)/cmϪ1 1636, 1601, 1555, 1460, 1341, 1115,
774; δH (250.13 MHz; [2H6]DMSO) 10.69 (1 H, s, NH), 8.29 (1 H,
dd, J 1.6, 8.1, H-11), 7.43 (1 H, t, J 7.9, H-5), 7.39 (1 H, m,
H-9), 7.18 (1 H, s, H-3), 7.09 (1 H, d, J 9.1, H-8), 7.03 (1 H, t,
J 7.5, H-10), 6.95 (1 H, d, J 7.5, H-4), 6.72 (1 H, dd, J 0.7, 7.7,
H-6), 3.62 (6 H, m, CH2 and morpholine CH2), 2.51 (4 H, m,
morpholine CH2); δC (62.90 MHz; [2H6]DMSO) 152.64 (C),
150.93 (C), 140.54 (C), 140.22 (C), 138.53 (C), 132.17 (CH),
131.66 (CH), 124.58 (CH), 121.00 (CH), 120.27 (C), 118.17 (C),
115.88 (CH), 114.49 (CH), 112.71 (CH), 105.10 (CH), 66.54
(CH2), 64.67 (CH2), 53.71 (CH2); m/z (ES) 318 (MHϩ, 100%)
[Found: m/z (HRMS-FAB) 318.1606. C20H20N3O requires
318.1606].
2-(4-Methylpiperazin-1-ylmethyl)-7H-pyrido[4,3,2-kl]acridine
14f. Prepared from 11f by Method B and eluted with ethyl acet-
ate followed by methanol, the pyridoacridine 14f (27%) had mp
122–124 ЊC; νmax (KBr)/cmϪ1 3472, 1640, 1487, 1341, 947, 752;
δH (250.13 MHz; CDCl3) 10.69 (1 H, s, NH), 8.30 (1 H, d, J 6.5,
H-11), 7.41 (2 H, m, H-5,9), 7.17 (1 H, s, H-3), 7.06 (2 H, m,
H-8,10), 6.95 (1 H, d, J 7.5, H-4), 6.72 (1 H, d, J 7.7, H-6), 3.59
(2 H, s, CH2), 2.51–2.25 (8 H, br m, piperazine CH2), 2.16 (3H,
s, CH3); δC (62.90 MHz; CDCl3) 151.95 (C), 151.42 (C), 139.80
(C), 139.75 (C), 138.52 (C), 131.40 (CH), 130.91 (CH), 124.86
(CH), 121.04 (CH), 120.73 (C), 118.44 (C), 115.32 (CH), 115.04
(CH), 113.07 (CH), 104.78 (CH), 64.48 (CH2), 54.91 (CH2),
53.11 (CH2), 45.85 (CH3); m/z (ES) 331 (MHϩ, 100%) [Found:
m/z (HRMS-FAB) 331.1927. C21H23N4 requires 331.1923].
Synthesis of 2-(dialkylaminomethyl)-7H-pyrido[4,3,2-kl]-
acridines
General Method B: the appropriate 9-[5-(dialkylaminomethyl)-
1H-1,2,3-triazol-1-yl]acridine (0.2 g) in diphenyl ether (5 cm3)
was heated to boiling point for 5–15 min until the evolution of
nitrogen had ceased. The reaction mixture was placed on a
silica column and eluted with hexane to remove diphenyl ether.
The pyridoacridine was then eluted with the stated solvent (see
below).
2-(Indolin-1-ylmethyl)-7H-pyrido[4,3,2-kl]acridine 17. Pre-
pared from 16 by Method B and eluted with ethyl acetate–
hexane (1 : 4), the pyridoacridine 17 (54%) had mp 110–111 ЊC
(from ethyl acetate); λmax (EtOH)/nm 208, 232, 250, 308,
320, 425; νmax (KBr)/cmϪ1 1638, 1603, 1557, 1487, 1339, 746;
δH (250.13 MHz; CDCl3) 8.50 (1 H, d, J 8.1, H-11), 7.45 (1 H, t,
J 7.9, H-5), 7.26 (1 H, m, H-9), 7.21 (1 H, s, H-3), 7.13 (1 H, dd,
J 0.7, 7.2, indoline H-4), 7.07 (2 H, m, H-8,10), 6.97 (2 H, m,
indoline H-5,6), 6.79 (1 H, br d, H-4), 6.70 (1 H, dd, J 1.0, 7.4,
indoline H-7), 6.60 (1 H, d, J 7.9, H-6), 4.53 (2 H, s, CH2), 3.62
(2 H, t, J 8.4, indoline H-2), 3.09 (2 H, t, J 8.4, indoline H-3); δC
(62.90 MHz; CDCl3) 152.96 (C), 151.46 (C), 139.92 (C), 139.06
(C), 132.26 (C), 131.82 (CH), 130.27 (CH), 127.80 (C), 125.56
(CH), 124.84 (CH), 122.04 (CH), 120.83 (C), 118.75 (C), 117.93
(CH), 115.53 (CH), 114.44 (CH), 113.86 (CH), 107.55 (CH),
105.54 (CH), 55.81 (CH2), 54.64 (CH2), 29.20 (CH2); m/z
(ES) 350.1 (MHϩ, 100%) [Found: m/z (HRMS-FAB) 350.1672.
C24H20N3 requires 350.1657].
2-(N,N-Dimethylaminomethyl)-7H-pyrido[4,3,2-kl]acridine
14a. This compound was prepared by Method B from triazole
11a in 58% yield.8
2-(N,N-Diethylaminomethyl)-7H-pyrido[4,3,2-kl]acridine 14b
Prepared from 11b by Method B and eluted with ethyl acetate,
the pyridoacridine 14b (31%) had mp 185–187 ЊC (Found: C,
79.45; H, 6.70; N, 13.62. C20H21N3 requires C, 79.20; H, 6.93; N,
13.86%); δH (250.13 MHz; CDCl3) 8.50 (1 H, dd, J 1.5, 8.0,
H-11), 7.34 (1 H, t, J 7.9, H-5), 7.30 (2 H, m, H-3,9), 7.03 (1 H,
t, J 7.7, H-10), 6.96 (1 H, d, J 7.9, H-8), 6.85 (1 H, d, J 7.7, H-4),
6.55 (1 H, d, J 7.4, H-6), 3.86 (2 H, s, CH2), 2.74 (4 H, q, J 7.1,
CH2CH3), 1.17 (6 H, t, J 7.1, CH2CH3); m/z (APCI) 304.2
(MHϩ, 100%).
Acknowledgements
2-(Piperidin-1-ylmethyl)-7H-pyrido[4,3,2-kl]acridine
14d.
We thank the Cancer Research Campaign, UK for supporting
this project and providing a Studentship (to M.J.E.). We are
grateful to the EPSRC National Mass Spectrometry Service
Centre, University of Wales, Swansea, UK for high resolution
mass spectra.
Prepared from 11d by Method B and eluted with ethyl acetate–
hexane (2 : 1), the pyridoacridine 14d (91%) had mp 179–180 ЊC
(Found: C, 79.85; H, 6.69; N, 13.12. C21H21N3 requires C, 79.97;
H, 6.71; N, 13.32%); νmax (KBr)/cmϪ1 1638, 1601, 1555, 1339,
3178
J. Chem. Soc., Perkin Trans. 1, 2001, 3174–3179

View Article Online
11 W. C. Hahn, C. M. Counter, A. S. Lundberg, R. L. Beijersbergen,
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