Antitumour polycyclic acridines. Part 1. Synthesis of 7H-pyrido- and 8H-quino-[4,3,2-kl]acridines by Graebe-Ullmann thermolysis of 9-(1,2,3-triazol-1-yl)acridines: Application of differential scanning calorimetry to predict optimum cyclisation conditions

Article abstract of DOI:10.1039/a702299i

The thermal decomposition of a series of acridities substituted in the 9-position with 1,2,3-triazol-1-yl, benzotriazol-1-yl and naphthotriazol-1-yl groups has been studied by differential scanning calorimetry. Whereas the monocyclic triazole 7a shows a discrete melting endotherm followed by a decomposition exotherm corresponding to formation of the 7H-pyrido[4,3,2-kl]acridine 8, in the benzotriazoles 10a-e and naphthotriazole 10f these processes coincide with a single sharp exothermic transition attributed to cyclisation to polycyclic acridities 11a-f, respectively. The optimum conditions for the preparative scale synthesis of polycyclic acridines from triazole precursors utilised boiling diphenyl ether as the decomposition medium. A benzotriazol-1-ylacridine 10e substituted in the peri position with a methyl group behaved anomalously: as well as affording the expected 8H-quino[4,3,2-kl]acridine 11e, cyclisation also led to radical mediated loss of the methyl group to form the unsubstituted 8H-quino[4,3,2-kl]acridine 11a and H-abstraction from the methyl group leading to the benzoazepinoacridine 12. Radical cyclisation of 9-(2-iodoanilino)acridine 16 also gave 8H-quino[4,3,2-kl]acridine 11a. The crystal structure of 11a confirms the 8H tautomer arrangement with intermolecular N8-H...N13 hydrogen bonding and exhibits a polycyclic system that is planar with rms deviation 0.044 A.

Full text of DOI:10.1039/a702299i

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Antitumour polycyclic acridines. Part 1. Synthesis of 7H-pyrido-
and 8H-quino-[4,3,2-kl]acridines by Graebe–Ullmann thermolysis
of 9-(1,2,3-triazol-1-yl)acridines: application of differential
scanning calorimetry to predict optimum cyclisation conditions
Damien J. Hagan,a Elena Giménez-Arnau,a Carl H. Schwalbeb and
Malcolm F. G. Stevens*,a
a
Cancer Research Laboratories, Department of Pharmaceutical Sciences,
University of Nottingham, Nottingham, UK NG7 2RD
b Pharmaceutical Sciences Institute, Aston University, Birmingham, UK B4 7ET
The thermal decomposition of a series of acridines substituted in the 9-position with 1,2,3-triazol-1-yl,
benzotriazol-1-yl and naphthotriazol-1-yl groups has been studied by differential scanning calorimetry.
Whereas the monocyclic triazole 7a shows a discrete melting endotherm followed by a decomposition
exotherm corresponding to formation of the 7H -pyrido[4,3,2-kl]acridine 8, in the benzotriazoles 10a–e
and naphthotriazole 10f these processes coincide with a single sharp exothermic transition attributed to
cyclisation to polycyclic acridines 11a–f, respectively. The optimum conditions for the preparative scale
synthesis of polycyclic acridines from triazole precursors utilised boiling diphenyl ether as the
decomposition medium. A benzotriazol-1-ylacridine 10e substituted in the peri position with a methyl
group behaved anomalously: as well as affording the expected 8H -quino[4,3,2-kl]acridine 11e, cyclisation
also led to radical mediated loss of the methyl group to form the unsubstituted 8H -quino[4,3,2-kl]acridine
11a and H -abstraction from the methyl group leading to the benzoazepinoacridine 12. Radical cyclisation
of 9-(2-iodoanilino)acridine 16 also gave 8H -quino[4,3,2-kl]acridine 11a. The crystal structure of 11a
confirms the 8H tautomer arrangement with intermolecular N 8᎐H ؒ ؒ ؒ N 13 hydrogen bonding and exhibits
a polycyclic system that is planar with rms deviation 0.044 Å.
the photolysis of 10a in acetonitrile.15 In both cases recovered
Introduction
yields were <40%. In this paper we report the synthesis of a
range of 9-(substituted-1,2,3-triazol-1-yl)acridines which have
been subjected to differential scanning calorimetry (DSC) to
measure the thermal parameters underlying their decom-
position and cyclisation: using this information we have opti-
mised conditions for their transformation to polycyclic
acridines.
The acridine ring system is an ideal framework for the medicinal
chemist to embellish with a diversity of functional groups.1
Derivatives and salts of acridines are characteristically highly
crystalline, stable, attractively coloured, often strongly fluores-
cent and, rewardingly, display a range of antimicrobial proper-
ties which have given them a secure position in the history of
chemotherapy.2 Since our first venture into acridine chemistry
in 19723 derivatives of this ring system have attracted attention
in the development of cancer chemotherapeutic agents.4 For
example, m-AMSA 1,5 and other DNA binding agents, are now
known to be targeted to topoisomerase II,6,7 a DNA processing
protein overexpressed in many proliferating tumour cell types,
for example in breast cancer.8
MeO
NHSO2Me
HN
N
Topoisomerase II exists in two distinct isoforms in human
cells; the α- (170 kDa) and β-isoforms (180 kDa)9 which differ
in their patterns of expression and sensitivity to anticancer
drugs.10 New agents which might selectively discriminate
between these isoforms could have a different clinical profile
compared with standard drugs of the general topoisomerase II-
inhibitory class such as amsacrine, doxorubicin and etoposide.11
Intriguingly, a series of DNA-intercalating pyridoacridines
isolated from the purple marine Cystodytes sp. ascidian such as
the tetracycle cystodytin A 2a and cystodytin J 2b, the penta-
cyclic pyridoacridines kuanoniamine D 3 and shermilamine B 4
and the heptacycle eilatin 5 have been shown to inhibit topo-
isomerase II.12 The aforementioned structures (Fig. 1) are repre-
sentative of a large number of pyridoacridine based natural
products.13
1
N
N
O
N
S
N
N
H
(CH2)2NHAc
(CH2)2NHR
2
3
a
R = COCH CMe2
R = Ac
b
N
N
N
H
N
O
N
N
H
S
N
It has been shown previously that a pentacyclic acridine 11a
could be synthesised by a thermal Graebe–Ullmann reaction on
the 9-(benzotriazol-1-yl)acridine 10a.14 Subsequently, Mitchell
and Rees, as part of a comprehensive study of the photolysis
of 1-aryl-1,2,3-triazoles,15,16 obtained the same pentacycle from
(CH2)2NHAc
5
4
Fig. 1 Structures of representative topoisomerase II inhibitors amsa-
crine 1 and marine pyridoacridine alkaloids 2–5
J. Chem. Soc., Perkin Trans. 1, 1997
2739

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Results and discussion
N
N
N
2
1
Synthesis of 9-(1,2,3-triazol-1-yl)acridines
3
N
Acridin-9-one 62 was the starting point for the synthesis of the
required triazolylacridines. 9-(1,2,3-Triazol-1-yl)acridine 7a
11
8
10
9
4
5
i
N
N
H
7
6
O
R
7a
8
N
H
N
R1
R2
H2N
HN
R1
R2
N
N
6
7
N
R3
R3
a
b
c
d
e
R = 1,2,3-triazol-l-yl
R = 1,2,3-triazol-2-yl
R = Cl
i
R = N3
N
R = NH2
N
(HCl salts)
(49%) together with the isomeric 9-(1,2,3-triazolyl-2-yl)acridine
7b (26%) were prepared by interaction of 9-chloroacridine 7c,
obtained from 6 and phosphorus oxychloride,3 with the anion
of 1,2,3-triazole generated using sodium hydride in dry DMF.
Interaction of 9-chloroacridine or 1-methyl-9-chloroacridine
with a range of anilines afforded the anilinoacridines 9a–e, iso-
lated as their hydrochloride salts. In the case of the reaction
with 2-amino-4-methylaniline the major product isolated was
the anilinoacridine 9d but NMR analysis of the reaction mix-
ture indicated the presence of a minor product, presumably the
isomer (9: R1 = R3 = H, R2 = Me) in a 5:1 ratio. The naphthyl-
aminoacridine 9f was similarly formed from 2,3-diamino-
naphthalene. Nitrosation of the series 9a–f in hydrochloric acid
furnished the insoluble benzotriazoles 10a–e and naphthotri-
azole 10f in high yields (Scheme 1). Compound 10a has been
prepared previously from the cycloaddition reaction between
9-azidoacridine 7d and benzyne.15,17 Attempts to synthesise the
amine 10g by reduction of 9-(6-nitrobenzotriazol-1-yl)acridine
10c under a range of conditions were not successful because of
reductive fission of the acridine–benzotriazole bond.
10
9
ii
R2
2
R1
1
3
4
R3
N
12
11
10
5
6
N
H
8
7
9
11
R1
R2
R3
a
b
c
d
e
f
H
Cl
H
Me
H
H
H
NO2
H
H
H
The triazolylacridines were readily hydrolysed to acridin-9-
one 6 in hot aqueous mineral acids and effervesced at their
melting-points indicative of triazole ring fragmentation
(Graebe–Ullmann reaction).
H
H
H
Me
H
CH CH CH CH
NH2
g
H
H
Differential scanning calorimetry (DSC)
Scheme 1 Reagents and conditions: i, Sodium nitrite in 2  HCl,
0 ЊC, then aq. NH3; ii, boiling PhOPh, 2 h. Numbering shown for
compound 11 applies to 11a–e and 11g only.
Temperature changes in solid materials can induce a number of
chemical (e.g. degradation) and physical (e.g. melting, recrystal-
lisation) effects. Characterisation of these changes may be
achieved by thermal analysis.18 In practice, DSC involves
placing a small amount of a sample in a DSC pan and
increasing/decreasing the temperature at a predetermined rate.
The flow of heat into this pan is adjusted to ensure that the
temperature of the sample pan is identical to that of the refer-
ence pan which has no sample present. Thus, in the examin-
ation of melting properties (an endothermic process), as the
sample melts more energy in the form of heat must be provided
to the sample pan to maintain the temperature at an equivalent
value to the reference pan. The thermogram of 9-(1,2,3-triazol-
1-yl)acridine 7a [Fig. 2(a)] shows a melting endotherm at
212.1 ЊC with enthalpy of fusion of 813.3 J gϪ1, a range repre-
senting a molten phase (approx. 215–247 ЊC) and a sharp exo-
thermic transition at 249.8 ЊC (Ϫ2414 J gϪ1) corresponding to
thermolytic cyclisation to the pyridoacridine 8. The sharpness
of the transition indicates that the latter process is relatively
free of competing reactions. In contrast, the thermogram of the
isomeric 9-(1,2,3-triazol-2-yl)acridine 7b reveals no melting (or
decomposition) at <300 ЊC (data not shown).
coincide to give an overall exotherm centred at 245.6 ЊC
(Ϫ714.9 J gϪ1). As in the monocyclic triazole example, the
sharpness and singularity of the exothermic transition confirms
that formation of the pentacyclic acridine 11a occurs over a
very narrow temperature range and does not involve a complex
sequence of reactions with the potential to generate significant
impurities. A sample of pure pentacyclic acridine 11a, prepared
independently (see later), melted at 286.8 ЊC [Fig. 2(b), inset].
When the sample of 10a was mixed with diphenyl ether (1 mol
equiv.) the shape of the exotherm was changed [Fig. 2(c)] and
the temperature of maximum energy release, corresponding to
cyclisation, was lowered to 230.1 ЊC. However, the overall
energy release was comparable (Ϫ692.8 J gϪ1) to that liberated
during cyclisation of the unadulterated sample of 10a, showing
that the diphenyl ether was not perturbing the reaction path-
way. The thermogram monitoring the decomposition of 9-
(benzotriazol-1-yl)-1-methylacridine 10e (data not shown)
shows a much broader exothermic transition than that for 10a
with peak irregularities. These features, together with the pro-
nounced baseline drift, were predictive of the generation of a
mixture of products in the preparative thermolysis of 10e.
In the thermogram of 9-(benzotriazol-1-yl)acridine 10a [Fig.
2(b)] it is apparent that only one enthalpy change occurs on
heating the sample. Melting and thermolytic cyclisation
2740
J. Chem. Soc., Perkin Trans. 1, 1997

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Fig. 2 Thermograms monitoring melting and decomposition of: (a) 9-(1,2,3-triazol-1-yl)acridine 7a; (b) 9-(benzotriazol-1-yl)acridine 10a with
(inset) melting of 8H-quino[4,3,2-kl]acridine 11a; (c) melting and decomposition of 9-(benzotriazol-1-yl)acridine 11a with diphenyl ether (1 mol
equiv.)
Table 1 Thermal analysis of 9-(benzotriazol-1-yl)acridines 10 using
differential scanning calorimetry
Preparative thermolysis of 9-(1,2,3-triazol-1-yl)acridines
Using the DSC, the precise decomposition temperatures of the
series of 9-(benzotriazolyl)acridines 10a–f were determined
(Table 1). Clearly the optimum conditions for cyclisation to
pyridoacridines 11a–f should be solid state thermolysis at those
individual temperatures. However, for reactions on a pre-
parative scale which are exothermic and involve rapid nitrogen
release, it was more convenient (and safer) to conduct the
thermolyses in boiling diphenyl ether (bp 259 ЊC for 1 h). Also
this approach allowed us to exploit the lowering of the cyclis-
ation temperature because of the solvation effect of the
solvent.
Decomposition
Energy release
Compound
temperature (T/ЊC)a
(E/J gϪ1
)
10a
10a b
10b
10c
10d
10e
10f
245.6
230.1
242.3
261.9
242.1
220.2
255.2
Ϫ714.9
Ϫ692.8
Ϫ593.3
Ϫ636.8
Ϫ596.6
Ϫ312.9
Ϫ1808.2
a
Minimum point on the exotherm (Tmin). b Mixed with diphenyl ether
Preparative scale thermolysis of 9-(1,2,3-triazol-1-yl)acridine
7a in boiling diphenyl ether gave the red tetracycle 8 in 75%
isolated yield after chromatographic purification (Scheme 1).
The isomeric (triazol-2-yl)acridine 7b was recovered unchanged
from boiling diphenyl ether as predicted from the DSC analysis.
The unsubstituted benzotriazole 10a afforded the 8H-quino-
[4,3,2-kl]acridine 11a in boiling diphenyl ether in an isolated
yield (84%) superior to that recorded in earlier solid state14 or
photolytic Graebe–Ullmann cyclisations.15 Interestingly, reason-
able yields of γ-carbolines have been reported for Graebe–
Ullmann reactions on 4-(benzotriazol-1-yl)pyridines conducted
in pyrophosphoric acid under microwave irradiation.19 Ana-
logues 10b–f cyclised thermally to the corresponding substi-
tuted quinoacridines 11b–f in moderate yields ranging from 50–
65% after chromatographic purification. In the case of the 1-
methylacridine 10e the major product 11e (60%) was accom-
panied by the demethylated pentacycle 11a (12%) and a trace
(<1%) of a product isomeric with 11e. This compound is
assigned, tentatively, the benzoazepinoacridine structure 12
since its EI mass spectrum showed a base peak at Mϩ Ϫ 14
(CH2) mass units contrasting with Mϩ Ϫ 15 (Me) for the isomer
11e. Lack of sufficient material thwarted full characterisation
of this product. Catalytic hydrogenation of the 2-nitro-
quinoacridine 11c gave the corresponding amine 11g (58%).
The mechanism of the photolytic counterpart of the trans-
formation 10a to 11a has been interpreted by Mitchell and
Rees15 as involving an initial triplet diradical 13 which gives rise
to a singlet carbene which, in its ‘dipolar form’ 14, attacks the
acridine 1- (or 8-) position in an electrophilic process (Scheme
2). In the present thermal variant of this cyclisation it is pro-
posed that rotation of the phenyl–amine bond positions the
aryl radical to initiate homolytic substitution at the acridine 1-
(or 8-) position. The pentacyclic diradical 15 would then
(1 mol equiv.).
NH
(or tautomer)
N
12
aromatise to the 13H-tautomer of the observed 8H-quino-
[4,3,2-kl]acridine 11a. (For a discussion on the tautomeric
structures of 11a, see later.)
Two pieces of evidence support this mechanism. The minor
loss of a methyl group in the thermolysis of acridine 10e, yield-
ing the unsubstituted quinoacridine 11a, can be accounted for
by homolysis of the C᎐Me bond (15; Me for H); also, the benzo-
azepine structure 12 probably formed in the same decom-
position could arise by H-abstraction from the methyl group.
More convincingly, 2-iodoanilinoacridine 16 formed from 9-
chloroacridine and 2-iodoaniline, undergoes radical coupling to
yield 11a (32%, unoptimised) via the aryl radical 17 generated
with tributyltin hydride–AIBN. In contrast, the iodoaniline
was stable in boiling diphenyl ether (3 h) without radical
initiation.
Properties and structure of 8H-quino[4,3,2-kl]acridine
Mitchell and Rees assigned the 8H-tautomeric structure to the
quinoacridine 11a on the basis of NOE difference and 2D spec-
tra but no details were given.15 We have confirmed this assign-
J. Chem. Soc., Perkin Trans. 1, 1997
2741

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11%
H
H
H
N
N
N
12%
24%
13%
H
H
N
H
H
N2
24%
10a
H
N
13%
H
N
H
H
9%
8%
10%
8%
14
13
H
12%
12%
Fig. 3 Selected NOE enhancements in 8H-quino[4,3,2-kl]acridine 11a
N
N
H
withdrawing chloro group 11b in the 3-position is significantly
base-weakening (pKa 5.32) and a 3-methyl group 11d base-
strengthening (pKa 6.85).
The monocation 18 formed from 11a readily dissociates in
water to afford the highly fluorescent free base. Unlike 9-chloro-
and 9-azido-acridine4 and the anilinoacridines and triazolyl-
acridines described herein which readily hydrolyse to acridin-9-
one 6, especially in acids, compound 11a is stable in 5  hydro-
chloric acid or sodium hydroxide. The potential product of
such hydrolysis might have been anticipated to be the 1-aryl-
acridinone 19 (Scheme 3). Also compound 11a failed to afford
15
N
HN
N
N
H
13H-tautomer
8H-tautomer
HN
O
NH2
11a
H
11a
–H
N
H
N
H
H
18
19
Scheme 3
HN
N
HN
Bu3SnH
an ethiodide salt when boiled in excess ethyl iodide (24 h).
Clearly these properties are incompatible with a 13H-tauto-
meric (‘tethered’ 9-anilinoacridine) structure for 11a.
I
The electronic absorption spectrum of m-AMSA 1 in ethanol
is relatively simple and shows three bands at 240, 340 and 433
nm; the long wavelength band is shifted to 461 nm on proton-
ation. In contrast the spectra of the pyridoacridine 8 and the
quinoacridines 11a–g display considerable fine structure (Table
2) and the long wavelength absorptions of the free bases in the
range 443–475 nm undergo significant bathochromic shifts (to
488–500 nm) on protonation.
N
17
16
Scheme 2
ment for 11a in both solution and the solid state. Thus 2D
COSY studies were used to analyse the three- and four-spin
systems in the polycyclic nucleus and NOE enhancements (Fig.
3) to identify the terminal protons. Irradiation of the absorp-
tions for H-7 and H-9 (see Scheme 1 for numbering system)
elicited an 8% enhancement of the NH signal at δ 10.8; irradi-
ation of the NH absorption gave a 10% and 9% enhancement
of the protons at positions 7 and 9, respectively. The NOE
enhancements were reduced by exchange of the amine proton
with water in the DMSO. The most significant NOE enhance-
ment (24%) was obtained when the signals for protons 4 and 5
were irradiated; this is indicative of their close proximity in the
pentacycle. NMR and MS analyses were used to confirm the
structures of other polycyclic acridines described in this paper
since microanalytical data were unreliable due to the propensity
of acridines to undergo solvation.2
The pyridoacridine 8 (pKa 6.08, measured by the UV–visible
spectroscopic method) and the unsubstituted pentacycle 11a
(pKa 6.30) and hexacycle 11f (pKa 6.17) are bases of comparable
strength but slightly weaker bases than the reference 9-
anilinoacridine m-AMSA 1 (pKa 7.19).20 9-Aminoacridine 7e is
approximately 10 000-fold a stronger base (pKa 9.99)2 than the
new heterocycles. In the quinoacridine series 11 the presence of
a 2-nitro group in 11c has a dramatic base-weakening effect
(pKa 4.22) whereas the effect of a 2-amino group in 11g is only
marginal (pKa 6.18). As expected, the presence of an electron-
In order to confirm the structure of 11a and facilitate sub-
sequent interpretation of physicochemical and molecular mod-
elling studies on the intercalative interactions of polycyclic
acridines and DNA, an X-ray structure determination was
completed. The molecular structure of 11a is shown in Fig. 4.
Several pieces of crystallographic evidence unanimously indi-
cate that the 8H-tautomer is present in the crystalline state. A
hydrogen atom site 0.96(4) Å from N8 was located in a differ-
ence electron density map and successfully refined. While both
ring bonds to N8 are relatively long, C7a᎐N8 and N8᎐C8a
being 1.370(5) Å and 1.389(4) Å respectively, the much shorter
N13᎐C13a [1.324(4) Å] shows double bond character which
militates against protonation there. The C᎐N᎐C bond angles of
122.6(3)Њ at N(8) and 117.5(3) at N13 show the expected com-
pression by a lone pair at N13. A hydrogen bond links N8 as
donor to N13 of a molecule in equivalent position x, 0.5 Ϫ y,
Ϫ0.5 ϩ z with H ؒ ؒ ؒ N contact distance 2.08(4) Å, N ؒ ؒ ؒ N
3.036(4) Å, and N᎐H ؒ ؒ ؒ N angle 175(4)Њ. Since, notwith-
standing the above evidence, this hydrogen bond could provide
a low-energy pathway for proton transfer from N8 to N13 in
some molecules, heats of formation were calculated for both
tautomers after optimisation of geometry starting from the
crystal structure. Semi-empirical molecular orbital calculations
2742
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 2 Electronic absorption spectra of 7H-pyrido- and 8H-quino-[4,3,2-kl]acridines
Absorbance maxima (λ/nm)
Compound
Neutral speciesa
Protonated speciesb
1 (m-AMSA)
240, 340, 433
240, 342, 461
8
231, 250, 267,* 307,* 319, 409,* 429, 453
236, 260,* 288, 300, 334, 373, 426, 443
238, 264, 286,* 289, 339, 381, 429, 446
235, 271, 292,* 329,* 342, 423, 449
239, 260,* 286, 289, 300,* 336, 375, 425, 444
262, 295, 326, 352, 370,* 382, 399, 421,* 447, 475
235, 275, 326, 434,* 453
238, 278, 301,* 315, 356, 375, 438,* 463, 490
236, 274, 288, 318, 361, 431,* 460, 488
238, 256, 277, 289, 367, 434,* 460, 489
233, 263, 292,* 325,* 409, 433,* 459, 490
239, 277, 289, 319, 363, 435,* 461, 490
267, 294,* 308, 352, 371, 440,* 468, 500
235, 247, 255, 275, 290, 363, 434,* 460, 490
11a
11b
11c
11d
11f
11g
a
Measured in ethanol. b Measured in ethanol containing 4  hydrochloric acid. * Shoulder.
aluminium pan and covered with an aluminium lid which was
then crimped into position. The pan was placed in the DSC
oven together with a blank, prepared in exactly the same way
but without the sample. The sample and blank were purged
continuously with nitrogen gas at a flow-rate of 25 cm3 minϪ1
(1.4 kg cmϪ2) and the thermograms were recorded over a tem-
perature range of 40–290 ЊC with a programmed heating rate of
10 ЊC minϪ1. Temperature calibration was made with an indium
standard (onset temperature 156.6 ЊC) and temperatures are
quoted as those of peak maximum (Tmax) or minimum (Tmin).
9-(1,2,3-Triazol-1-yl)acridine 7a
To a mixture of 95% sodium hydride (0.14 g, 5.5 mmol) in dry
DMF (15 cm3) was added 1H-1,2,3-triazole (0.38 g, 5.5 mmol)
at 25 ЊC. The mixture was stirred (30 min) and a solution of 9-
chloroacridine2 (1.07 g, 5.0 mmol) in dry DMF (5 cm3) was
added slowly (15 min). After being stirred at 60 ЊC (2 h) the
mixture was poured into ice–water (100 cm3) and products were
collected. Flash chromatographic separation (hexane–ethyl
acetate, 1:1) gave a slow moving fraction comprising the tri-
azole 7a which crystallised from ethyl acetate as greenish
needles (0.6 g, 49%), mp 212 ЊC; νmax(KBr)/cmϪ1 3096, 1560,
1449, 1233, 1071, 1007, 756, 637; λmax(EtOH)/nm 209.5, 248.0,
361.0; δH ([2H6]DMSO) 8.96 (d, 1 H, H-5Ј), 8.33 (m, 3 H,
H-4,4Ј,5), 8.00 (m, 2 H, H-3,6), 7.74 (m, 2 H, H-2,7), 7.36 (d, 2
H, H-1,8); δC([2H6]DMSO) 149.5 (C), 138.4 (C), 134.9 (CH),
132.1 (CH), 130.3 (CH), 130.2 (CH), 129.4 (CH), 123.2 (CH),
122.6 (C) (Found: C, 72.9; H, 4.05; N, 22.8; MHϩ [CI], 247.
C15H10N4 requires C, 73.1; H, 4.1; N, 22.8%; MH, 247).
The fast moving fraction gave 9-(1,2,3-triazol-2-yl)acridine
7b (0.32 g, 26%), mp >300 ЊC; νmax(KBr)/cmϪ1 1553, 1520,
1481, 1406, 922, 818, 750, 637; δH ([2H6]DMSO) 8.50 (s, 2 H,
H-4Ј,5Ј), 8.33 (dd, 2 H, H-4,5), 7.99 (m, 2 H, H-3,6), 7.72 (m, 2
H, H-2,7), 7.52 (d, 2 H, H-1,8); δC([2H6]DMSO) 149.7 (C),
138.1 (CH), 132.0 (CH), 130.2 (CH), 129.2 (CH), 123.6 (CH),
122.3 (C) (Found: C, 73.1; H, 4.0; N, 22.5; MHϩ [CI], 247.
C15H10N4 requires C, 73.1; H, 4.1; N, 22.8%; MH, 247).
Fig. 4 ORTEP 22 drawing of 8H-quino[4,3,2-kl]acridine 11a and the
crystallographic numbering scheme
with AM1 parameters in GAMESS21 yielded ∆Hf values 6.6
kcal molϪ1 lower for the 8H- than for the 13H-tautomer.
The heterocyclic framework of 11a is planar within 0.09 Å
with rms deviation 0.044 Å. The acridine ring is slightly creased
along a line approximately from C7 to C12. Thus the fragment
C9 C10 C11 C12 C12a C8a N8 C7a C7 has rms deviation of
only 0.013 Å and makes a dihedral angle of 3.0(2)Њ to another
planar fragment comprising C5a C5 C6 C7 C7a C14 C13a C12a
C12 with rms deviation 0.011 Å. In turn the phenyl ring C1 C2
C3 C4 C4a C1a, also with rms deviation 0.011 Å, is twisted
from the latter plane by 3.1(2)Њ.
We will report on the intriguing biological properties of these
polycyclic systems, and related structures, in future papers in
this series.
Experimental
Melting points were obtained on a Gallenkamp melting point
apparatus and are uncorrected. IR Spectra were measured in
KBr on a Mattson 2020 Galaxy Series FT-IR spectrometer. UV
Spectra were measured in 95% ethanol on a Cecil 1020S scan-
ning spectrometer. 1H and 13C NMR Spectra were recorded on
a Bruker ARX250 spectrometer operating at 250.13 and 62.9
MHz, respectively. 13C Assignments (C = quaternary carbon)
were based on DEPT135 and DEPT90 experiments. Mass spec-
tra were recorded on an AEI MS-902, a VG Micromass 7070E
or a VG Platform spectrometer. Silica gel C60H (40–60 mm)
was used for flash chromatography. TFA = trifluoroacetic acid.
9-(2-Aminoanilino)acridine hydrochloride 9a
1,2-Diaminobenzene (1.08 g) in boiling dry methanol (50 cm3)
was treated with 9-chloroacridine (2.14 g) over 30 min. The
mixture was refluxed for a further 1 h, cooled and diethyl ether
(20 cm3) was added. The anilinoacridine hydrochloride (2.06 g,
64%) was collected and had mp 319–320 ЊC (lit.,14 320–322 ЊC);
νmax(KBr)/cmϪ1 2799, 1632, 1549, 1501, 1474, 1261, 1157, 751;
λmax(EtOH)/nm 212.3, 248.3, 395.3; δH ([2H6]DMSO) 14.74 (br s,
1 H, NH), 11.26 (br s, 1 H, NH), 8.26 (d, 2 H, H-1,8), 8.16
(d, 2 H, H-4,5), 8.01 (m, 2 H, H-3,6), 7.44 (m, 2 H, H-2,7), 7.29
(t, 1 H, H-4Ј), 7.17 (d, 1 H, H-6Ј), 7.00 (d, 1 H, H-3Ј), 6.74
(t, 1 H, H-5Ј), 5.75 (br s, 2 H, NH2).
Differential scanning calorimetry
The following acridines were prepared similarly.
Differential scanning calorimetry was performed with a Perkin-
Elmer DSC-4 instrument using the Thermal Analysis Data
Station (TADS) for data collection, handling and presentation.
Samples for thermal analysis were weighed (1–4 mg) into an
9-(2-Amino-4-chloroanilino)acridine hydrochloride 9b. From
9-chloroacridine and 3,4-diaminochlorobenzene (88%), mp
298–300 ЊC (from methanol); νmax(KBr)/cmϪ1 2895, 1637, 1583,
1551, 1519, 1265, 1160, 746; λmax(EtOH)/nm 212.7, 249, 394.5;
J. Chem. Soc., Perkin Trans. 1, 1997
2743

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δH ([2H6]DMSO) 14.72 (br s, 1 H, NH), 11.06 (br s, 1 H, NH),
8.29 (d, 2 H, H-1,8), 8.11 (d, 2 H, H-4,5), 7.97 (m, 2 H, H-3,6),
7.44 (m, 2 H, H-2,7), 7.14 (d, 1 H, H-6Ј), 6.96 (d, 1 H, H-3Ј),
6.64 (t, 1 H, H-5Ј), 5.98 (br s, 2 H, NH2).
341. C19H11N5O2ؒ0.5H2O requires C, 65.1; H, 3.4; N, 20.0%;
MH, 341).
9-(5-Methylbenzotriazol-1-yl)acridine 10d. From 9d as cream
flakes (56%), mp 242.1 ЊC (decomp.); νmax(KBr)/cmϪ1 3042,
1555, 1498, 1432, 1232, 1065, 750; λmax(EtOH)/nm 203, 248,
361; δH ([2H]TFA) 8.22 (d, 2 H, H-1,8), 8.05 (t, 2 H, H-2,7), 7.72
(s, 1 H, H-4Ј), 7.60 (t, 2 H, H-3,6), 7.38 (m, 3 H, H-4,5,7Ј), 6.95
(d, 1 H, H-6Ј), 2.51 (s, 3 H, CH3); δC([2H]TFA) 143.4 (C), 140.9
(C), 139.5 (CH), 135.5 (CH), 134.9 (C), 131.4 (CH), 129.9 (C),
123.0 (CH), 120.1 (CH), 115.6 (CH), 110.2 (CH), 20.1 (CH3)
(Found: C, 77.6; H, 4.5; N, 18.2; MHϩ [CI], 311. C20H14N4
requires, C, 77.4; H, 4.55; N, 18.05%; MH, 311).
9-(Benzotriazol-1-yl)-1-methylacridine 10e. From 9e as yellow
crystals (84%), mp 220 ЊC (decomp.); νmax(KBr)/cmϪ1 1579,
1474, 1421, 1258, 1093, 758; λmax(EtOH)/nm 200, 253, 362.5;
δH ([2H]TFA) 7.70 (m, 5 H), 7.41 (m, 4 H), 7.07 (m, 2 H), 2.87 (s,
3 H, CH3); δC([2H]TFA) 163.9 (C), 144.2 (C), 142.9 (C), 139.5
(CH), 138.8 (CH), 135.3 (C), 133.1 (CH), 130.3 (CH), 128.9
(CH), 127.6 (CH), 121.9 (C), 120.2 (CH), 119.2 (C), 117.6 (C),
25.4 (CH3).
9-(Naphtho[2,3-d]triazol-1-yl)acridine 10f. From 9f as amber
needles (59%), mp 255.2 ЊC (decomp.); νmax(KBr)/cmϪ1 3036,
1553, 1460, 1424, 1275, 1044, 883, 750; λmax(EtOH)/nm 215,
247, 320, 361; δC([2H]TFA) 141.0 (C), 139.3 (CH), 135.3 (C),
133.2 (C), 130.7 (CH), 129.3 (CH), 129.0 (CH), 127.6 (CH),
127.3 (CH), 124.2 (CH), 123.1 (C), 119.9 (CH), 117.2 (CH),
106.8 (CH) (Found: C, 79.2; H, 3.9; N, 16.0; MHϩ [CI], 346.
C23H14N4O2 requires C, 79.7; H, 4.1; N, 16.2%; MH, 346).
9-(2-Amino-5-nitroanilino)acridine hydrochloride 9c. From 2-
amino-4-nitroaniline (57%), mp 303–306 ЊC (from acetonitrile);
νmax(KBr)/cmϪ1 3411, 3300, 3186, 1637, 1585, 1517, 1475, 1309;
λmax(EtOH)/nm 220, 251.5, 409; δH ([2H6]DMSO) 14.81 (br s, 1
H, NH), 11.12 (br s, 1 H, NH), 8.28 (d, 2 H, H-1,8), 8.14 (m,
2 H, H-4Ј,6Ј), 8.09 (d, 2 H, H-4,5), 7.99 (m, 2 H, H-3,6), 7.46
(t, 2 H, H-2,7), 7.18 (br s, 2 H, NH2), 6.98 (d, 1 H, H-3Ј).
9-(2-Amino-4-methylanilino)acridine hydrochloride 9d. From
2-amino-4-methylaniline (91%), mp 273–275 ЊC (from aceto-
nitrile–methanol); νmax(KBr)/cmϪ1 2706, 1637, 1583, 1553,
1520, 1475, 1158, 748; λmax(EtOH)/nm 215.4, 247.2, 400;
δH ([2H6]DMSO) 14.50 (br s, 1 H, NH), 11.24 (br s, 1 H, NH),
8.30 (d, 2 H, H-1,8), 8.06 (d, 2 H, H-4,5), 7.94 (m, 2 H, H-3,6),
7.38 (t, 2 H, H-2,7), 6.94 (d, 1 H, H-6Ј), 6.73 (d, 1 H, H-3Ј), 6.46
(dd, 1 H, H-5Ј), 2.29 (s, 3 H, CH3).
9-(2-Aminoanilino)-1-methylacridine hydrochloride 9e. From
9-chloro-1-methylacridine23 and 1,2-diaminobenzene (78%),
mp 255–257 ЊC (from methanol); νmax(KBr)/cmϪ1 1632, 1579,
1551, 1474, 1421, 1384, 758; λmax(EtOH)/nm 216.3, 247.2, 390;
δH ([2H6]DMSO) 13.97 (br s, 1 H, NH), 10.43 (br s, 1 H, NH),
7.84 (m, 5 H, H-3,4,5,6,8), 7.17 (m, 3 H, H-2,4Ј,7), 6.95 (d, 1 H,
H-6Ј), 6.76 (d, 1 H, H-3Ј), 6.58 (t, 1 H, H-5Ј), 5.61 (br s, 2 H,
NH2), 2.74 (s, 3 H, CH3).
9-(3-Amino-2-naphthylamino)acridine hydrochloride 9f. From
9-chloroacridine and 2,3-diaminonaphthalene (68%), mp 267–
269 ЊC; νmax(KBr)/cmϪ1 3418, 1636, 1584, 1553, 1507, 1476,
1383, 745; λmax(EtOH)/nm 221.5, 276, 402; δH ([2H6]DMSO)
14.88 (br s, 1 H, NH), 11.40 (br s, 1 H, NH), 8.29 (d, 2 H,
H-1,8), 8.14 (d, 2 H, H-4,5), 7.95 (m, 2 H, H-3,6), 7.75 (s, 1 H,
H-8Ј), 7.68 (d, 1 H, H-4Ј), 7.61 (d, 1 H, H-7Ј), 7.37 (t, 3
H, H-2,6Ј,7), 7.25 (s, 1 H, H-1Ј), 7.16 (t, 1 H, H-5Ј), 5.92 (br s, 2
H, NH2).
Hydrolysis of 9-(triazol-1-yl)acridines
Hydrolysis of 9-(1,2,3-triazol-1-yl)acridine 7a (0.1 g) in boiling
2  hydrochloric acid (2 h) gave a precipitate of acridone 6 (0.06
g)3 when the cooled mixture was adjusted to pH 5. Similarly,
hydrolysis of 9-(benzotriazol-1-yl)acridine 10a gave a mixture
of acridone and benzotriazole (1:1).
9-(Benzotriazol-1-yl)acridine
10a.
9-(2-Aminoanilino)-
7H-Pyrido[4,3,2-kl]acridine 8
acridine hydrochloride 9a (1.61 g), suspended in 2  hydro-
chloric acid (50 cm3) at 0–5 ЊC was treated (30 min) with a
solution of sodium nitrite (0.7 g, 2 mol equiv.) in water (5 cm3).
The suspension was stirred at 0 ЊC for 1 h, basified with concen-
trated aqueous ammonia–ice and the product collected and
crystallised from aqueous DMF. The benzotriazole was formed
as cream crystals (1.01 g, 69%), mp 245.7 ЊC (decomp.) (lit.,15
250 ЊC, decomp.); νmax(KBr)/cmϪ1 3048, 1554, 1491, 1426, 1058,
752, 748; λmax(EtOH)/nm 200, 249, 362; δH ([2H]TFA) 8.24 (d, 2
H, H-1,8), 8.05 (m, 3 H, H-2,4Ј,7), 7.59 (t, 2 H, H-3,6), 7.44 (m,
4 H, H-4,5,5Ј,7Ј), 7.01 (d, 1 H, H-6Ј); δC([2H]TFA) 141.0 (C),
139.4 (CH), 136.0 (C), 132.3 (CH), 131.0 (CH), 129.1 (CH),
123.9 (CH), 123.1 (C), 119.9 (CH), 118.3 (CH), 110.2 (CH).
The following triazolyl-substituted acridines were prepared
similarly.
9-(5-Chlorobenzotriazol-1-yl)acridine 10b. From 9b as yellow
needles (84%), mp 220 ЊC (decomp.); νmax(KBr)/cmϪ1 3050,
1554, 1487, 1431, 1050, 825, 751; λmax(EtOH)/nm 203.5, 248.5,
361.5; δH ([2H]TFA) 8.25 (d, 2 H, H-1,8), 8.09 (m, 3 H, H-2,4Ј,7),
7.65 (t, 2 H, H-3,6), 7.42 (m, 3 H, H-4,5,7Ј), 6.95 (dd, 1 H,
H-6Ј); δC([2H]TFA) 146.0 (C), 141.0 (C) 139.3 (CH), 134.8 (C),
134.4 (C), 132.6 (CH), 130.9 (CH), 123.9 (CH), 123.0 (C), 119.9
(CH), 118.4 (CH), 110.8 (CH) (Found: C, 68.7; H, 3.2; N, 17.0;
MHϩ [CI], 331, 333. C19H11N4Cl requires C, 69.1; H, 3.4; N,
17.0%; MH, 331, 333).
9-(1,2,3-Triazol-1-yl)acridine 7a (0.24 g) was mixed with
diphenyl ether (10 g) and the mixture was heated at reflux tem-
perature until TLC analysis showed that all the triazole had
been consumed (generally 2 h). The mixture was added to the
top of a silica gel column and the column eluted with hexane to
remove diphenyl ether. The product was then eluted with
EtOH–ethyl acetate (1:1), solvent evaporated and the residue
crystallised from aqueous DMF to give red–brown crystals
(0.16 g, 75%), mp 281–282 ЊC; νmax(KBr)/cmϪ1 3449, 3015,
1638, 1547, 1466, 1433, 1343, 762 cmϪ1; δH ([2H6]DMSO) 10.73
(br s, 1 H, NH), 8.32 (d, 1 H, H-11), 8.12 (d, 1 H, H-2), 7.43
(m, 2 H, H-5,9), 7.14 (m, 2 H, H-3,8), 7.04 (t, 1 H, H-10), 6.98
(d, 1 H, H-4), 6.78 (d, 1 H, H-6); δC([2H6]DMSO) 152.0 (C),
145.0 (CH), 141.0 (C), 140.8 (C), 138.5 (C), 132.7 (CH), 132.3
(CH), 125.1 (CH), 121.0 (CH), 119.9 (C), 117.0 (CH), 116.5
(CH), 113.2 (CH), 106.2 (CH) (Found: C, 82.3; H, 4.7; N,
12.65; Mϩ [EI], 218. C15H10N2 requires C, 82.6; H, 4.6; N,
12.8%; M, 218).
Similarly prepared were the following compounds.
8H-Quino[4,3,2-kl]acridine 11a (with C. K. Wong). From
10a, in 84% yield, mp 285–287 ЊC (from aqueous DMF ) (lit.,15
>280 ЊC); νmax(KBr)/cmϪ1 1628, 1597, 1460, 1384, 1331, 1154,
745; δH ([2H6]DMSO) 10.78 (br s, 1 H, NH), 8.56 (d, 1 H, H-12),
8.39 (d, 1 H, H-4), 7.91 (d, 1 H, H-5), 7.83 (d, 1 H, H-1), 7.67 (t,
1 H, H-6), 7.70 (t, 1 H, H-2), 7.48 (t, 1 H, H-10), 7.41 (t, 1 H,
H-3), 7.22 (d, 1 H, H-9), 7.13 (m, 2 H, H-7,11); δC([2H6]DMSO)
150.4 (C), 145.5 (C), 139.9 (C), 132.1 (CH), 131.7 (CH), 129.2
(CH), 128.6 (CH), 124.8 (CH), 122.9 (CH), 122.8 (C), 121.1
(CH), 119.7 (C), 115.9 (CH), 115.1 (C), 110.4 (CH), 109.7 (CH)
(Found: C, 84.8; H, 4.4; N, 10.2; MHϩ [CI], 269. Calc. for
C19H12N2: C, 85.0; H, 4.5; N, 10.45%; MH, 269).
9-(6-Nitrobenzotriazol-1-yl)acridine 10c. From 9c as yellow
needles (55%), mp 261.8 ЊC (decomp.); νmax(KBr)/cmϪ1 2991,
1552, 1489, 1344, 1234, 1061, 752, 748; λmax(EtOH)/nm 230,
362; δH ([2H]TFA) 8.23 (m, 4 H, H-1,4Ј,5Ј,8), 8.04 (t, 2 H, H-2,7),
7.91 (s, 1 H, H-7Ј), 7.58 (t, 2 H, H-3,6), 7.35 (d, 2 H, H-4,5);
δC([2H]TFA) 149.0 (C), 141.1 (C), 139.5 (CH), 135.6 (C), 131.3
(CH), 123.7 (CH), 123.4 (CH), 121.9 (CH), 121.3 (CH), 120.1
(CH), 107.3 (CH) (Found: C, 64.8; H, 3.0; N, 19.95; MHϩ [CI],
3-Chloro-8H-quino[4,3,2-kl]acridine 11b. From 10b, in 50%
yield, mp 240–241 ЊC (from aqueous DMF ); νmax(KBr)/cmϪ1
2744
J. Chem. Soc., Perkin Trans. 1, 1997

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3396, 1625, 1605, 1543, 1466, 1329, 1155, 743; δH ([2H6]DMSO)
10.90 (br s, 1 H, NH), 8.54 (d, 1 H, H-12), 8.24 (s, 1 H, H-4),
7.92 (d, 1 H, H-5), 7.73 (m, 2 H, H-1,6), 7.46 (m, 2 H, H-2,10),
7.22 (d, 1 H, H-9), 7.13 (m, 2 H, H-7,11); δC([2H6]DMSO) 150.5
(C), 140.9 (C), 140.7 (C), 135.9 (C), 134.5 (C), 132.8 (CH),
132.4 (CH), 131.6 (CH), 129.0 (CH), 125.5 (CH), 123.4 (C),
123.3 (CH), 121.8 (CH), 116.7 (CH), 116.0 (C), 111.2 (CH),
110.2 (C), 109.8 (CH) (Found: C, 75.2; H, 3.4; N, 9.2; Mϩ [EI],
302, 304. C19H11ClN2 requires C, 75.4; H, 3.6; N, 9.25%; M,
302, 304).
1630, 1600, 1470, 1384, 1330, 1112, 773; δH ([2H6]DMSO) 10.87
(br s, 1 H, NH), 8.72 (d, 1 H, H-12), 8.13 (d, 1 H, H-4), 7.67 (d,
1 H, H-5), 7.51 (t, 1 H, H-6), 7.45 (t, 1 H, H-10), 7.20 (d, 1 H,
H-9), 6.97 (m, 4 H, H-1,3,7,11), 5.54 (br s, 2 H, NH2);
δC([2H6]DMSO) 150.0 (C), 147.4 (C), 140.1 (C), 134.9 (C), 131.9
(CH), 131.5 (CH), 124.8 (CH), 123.7 (CH), 120.8 (CH), 116.2
(C), 115.9 (CH), 115.1 (CH), 113.4 (C), 109.7 (CH), 109.1 (CH),
107.0 (CH); Mϩ (EI) 283.
9-(2-Iodoanilino)acridine 16
2-Nitro-8H-quino[4,3,2-kl]acridine 11c. From 10c, in 65%
yield, mp >300 ЊC (from aqueous DMF ); νmax(KBr)/cmϪ1 3368,
1626, 1561, 1463, 1437, 1383, 1343, 742; δH ([2H6]DMSO) 11.82
(br s, 1 H, NH), 8.24 (m, 2 H, H-4,12), 8.14 (d, 1 H, H-1), 7.88
(dd, 1 H, H-3), 7.74 (m, 2 H, H-5,6), 7.57 (t, 1 H, H-10), 7.20
(m, 3 H, H-7,9,11); δC([2H6]DMSO) 151.7 (C), 151.2 (C), 142.8
(C), 139.8 (CH), 137.0 (C), 133.4 (C), 132.2 (C), 130.2 (C),
128.5 (CH), 127.9 (CH), 124.7 (CH), 123.9 (CH), 121.4 (CH),
118.8 (CH), 118.0 (CH), 117.3 (CH), 115.8 (C), 113.4 (C)
(Found: C, 62.4; H, 3.7; N, 11.4; Mϩ [EI], 313. C19H11N3O2ؒ
3H2O requires C, 62.1; H, 4.3; N, 11.5%; M, 313).
3-Methyl-8H-quino[4,3,2-kl]acridine 11d. From 10d in 50%
yield, mp 230–232 ЊC (from aqueous DMF ); νmax(KBr)/cmϪ1
2989, 1627, 1600, 1536, 1466, 1330, 1154, 743; δH ([2H6]DMSO)
10.83 (br s, 1 H, NH), 8.57 (dd, 1 H, H-12), 8.23 (s, 1 H, H-4),
7.78 (d, 1 H, H-5), 7.73 (m, 2 H, H-1,6), 7.47 (m, 2 H, H-2,10),
7.19 (d, 1 H, H-9), 7.14 (m, 2 H, H-7,11), 2.52 (s, 3 H, CH3);
δC([2H6]DMSO) 149.6 (C), 143.8 (C), 140.2 (C), 140.0 (C), 134.3
(C), 133.9 (C), 132.0 (CH), 131.7 (CH), 130.9 (CH), 128.7 (CH),
124.8 (C), 122.7 (C), 122.6 (CH), 121.0 (CH), 120.0 (CH), 116.0
(CH), 115.3 (C), 110.4 (CH), 109.6 (CH), 21.4 (CH3) (Found: C,
84.75; H, 4.9; N, 10.1; Mϩ [EI], 282. C20H14N2 requires C, 85.1;
H, 5.0; N, 9.9%; M, 282).
12-Methyl-8H-quino[4,3,2-kl]acridine 11e. From 10e, in 60%
yield, mp 185–187 ЊC (from aqueous DMF ); νmax(KBr)/cmϪ1
3404, 1621, 1600, 1534, 1460, 1384, 1180, 763; δH ([2H6]DMSO)
10.80 (br s, 1 H, NH), 8.40 (d, 1 H, H-4), 7.89 (d, 1 H, H-5), 7.82
(d, H, H-1), 7.64 (m, 2 H, H-2,6), 7.40 (t, 1 H, H-3), 7.29 (t, 1 H,
H-10), 7.08 (m, 2 H, H-7,9), 6.88 (d, 1 H, H-11), 3.12 (s, 3 H,
CH3); δC([2H6]DMSO) 157.2 (C), 150.0 (C), 146.7 (C), 144.1
(C), 139.0 (C), 136.2 (CH), 135.2 (CH), 133.5 (2 × CH), 129.6
(CH), 129.3 (CH), 127.2 (CH), 126.7 (C), 122.8 (C), 120.2 (C),
118.7 (CH), 114.6 (C), 113.6 (CH), 30.9 (CH3) (Found: C, 82.7;
H, 4.9; N, 9.7; Mϩ [EI], 282. C20H14N2ؒ0.5H2O requires C,
82.5; H, 5.15; N, 9.6%; M, 282). Also isolated by flash chrom-
atography of the crude thermolysis mixture were 8H-quino-
[4,3,2-kl]acridine 11a (12%), identical (mp; IR, UV, 1H and 13C
NMR and mass spectra) and a product (<1%) tentatively iden-
tified as the benzoazepinoacridine 12 with Mϩ (EI) 282 and 268
(Mϩ Ϫ CH2).
4H-Benzo[6,7]quino[4,3,2-kl]acridine 11f. Prepared by
thermolysis of 10f, in 60% yield, mp 313–315 ЊC (from aqueous
DMF ); νmax(KBr)/cmϪ1 3449, 1626, 1597, 1535, 1468, 1385,
1155, 739; δH ([2H6]DMSO) 10.95 (br s, 1 H, NH), 8.93 (s, 1 H),
8.51 (dd, 1 H), 8.23 (s, 1 H), 8.08 (d, 1 H), 7.97 (dd, 1 H), 7.91
(dd, 1 H), 7.68 (t, 1 H), 7.39 (m, 3H), 7.16 (d, 2 H), 7.06 (t, 1 H);
δC([2H6]DMSO) 152.0 (C), 140.7 (C), 140.6 (C), 134.5 (C), 134.1
(C), 133.0 (CH), 132.8 (CH), 131.4 (C), 129.0 (C), 125.5 (CH),
128.2 (CH), 127.0 (CH), 125.9 (CH), 125.7 (CH), 123.6 (C),
122.7 (CH), 122.0 (CH), 117.1 (CH), 114.6 (C), 112.6 (CH)
(Found: C, 83.7; H, 4.3; N, 8.5; Mϩ [EI], 318. C23H14N2ؒ1H2O
requires C, 84.1; H, 4.8; N, 8.5%; M, 318).
To a solution of 2-iodoaniline (1.20 g) in refluxing anhydrous
methanol (35 cm3) was added 9-chloroacridine (1.07 g) over
0.5 h. The mixture was boiled (10 h), cooled and excess
diethyl ether added. The precipitated iodoanilinoacridine
hydrochloride salt (75%) was collected (Found: Mϩ [EI], 396.
C19H13IN2 requires M, 396).
The free base, mp 186–188 ЊC (from methanol), was obtained
from the hydrochloride salt by trituration with aqueous
ammonia; νmax(KBr)/cmϪ1 3372, 1626, 1590, 1528, 1474, 1146,
1009, 752; λmax(EtOH)/nm 223, 244, 410; δH ([2H6]DMSO)
11.25 (br s, 1 H, NH), 8.07 (d, 2 H, H-1,8), 7.70 (t, 2 H, H-3,6),
7.52 (m, 4 H), 6.98 (m, 4 H); δC([2H6]DMSO) 155.6 (C), 151.6
(C), 141.0 (C), 140.0 (CH), 132.5 (CH), 130.4 (CH), 127.9
(C), 123.7 (CH), 122.0 (CH), 118.7 (CH), 117.6 (CH), 91.2
(C).
The free base (0.4 g) was dissolved in dry toluene (5 cm3).
Tributyltin hydride (2.5 cm3) was added, the mixture was heated
to reflux under nitrogen and a solution of 2,2Ј-azoisobutyro-
nitrile (0.012 g) in dry toluene (1 cm3) was added dropwise. The
mixture was boiled (12 h) with light exclusion, cooled, diluted
with diethyl ether (20 cm3). The precipitated mixture was separ-
ated by flash chromatography (hexanes–ethyl acetate, 1:1) into
unreacted iodoanilinoacridine and 8H-quino[4,3,2-kl]acridine
1
11a (0.09 g, 32%), identical (mp; UV, IR, H and 13C NMR
spectra) to a sample prepared by thermolysis of 9-(benzo-
triazol-1-yl)acridine 10a (see above).
X-Ray crystal structure determination
Crystal data: C19H12N2, Mr 268.31, monoclinic, space group
P21/c, a = 7.169(1), b = 14.401(3), c = 12.397(3) Å, β = 93.92(2)Њ,
V = 1276.9(4) Å3, Z = 4, Dx = 1.396 g cmϪ3. On an Enraf-
Nonius CAD4 diffractometer with Mo-Kα radiation (λ =
0.71 073 Å) 4778 reflections were collected, of which 2257 were
independent (Rint = 0.0972) and 896 were considered observed
[I > 2σ(I)]. The structure was solved by direct methods,24 all
hydrogen atoms were located in difference electron density
maps, and positional parameters of all atoms together with
appropriate displacement parameters were refined by the full-
matrix least-squares method.25 The final discrepancy indices
were R = 0.048 for observed reflections and wR(F 2) = 0.102 for
all data. The final difference electron density synthesis showed
no feature greater than ±0.18 e ÅϪ3.†
Acknowledgements
This work was supported by a Programme Grant from the Can-
cer Research Campaign (CRC, UK) to the CRC Experimental
Cancer Chemotherapy Research Group at the University of
Nottingham and a Studentship (to D. J. H.). E. G.-A. was
supported by a European Union Fellowship Programme.
† Atomic coordinates, thermal parameters and bond lengths and angles
have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). See Instructions for Authors, J. Chem. Soc., Perkin Trans. 1,
1997, Issue 1. Any request to the CCDC for this material should quote
the full literature citation and the reference number 207/133.
2-Amino-8H-quino[4,3,2-kl]acridine 11g
A suspension of 2-nitro-8H-quino[4,3,2-kl]acridine 11c in
methanol (100 cm3) was hydrogenated over activated
palladium–carbon (0.05 g) for 3 h at 30 psi and 25 ЊC. Removal
of catalyst through Celite, followed by evaporation of solvent
gave the aminoquinoacridine 11g (58% yield, red crystals, from
aqueous DMF ), mp >300 ЊC (decomp.); νmax(KBr)/cmϪ1 3439,
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Paper 7/02299I
Received 3rd April 1997
Accepted 6th June 1997
2746
J. Chem. Soc., Perkin Trans. 1, 1997