Synthesis of the antitumoural agent batracylin and related isoindolo[1,2-b]quinazolin-12(10H)-ones

Article abstract of DOI:10.1016/j.tetlet.2006.11.168

The synthesis of batracylin and related isoindolo[1,2-b]quinazolin-12-ones from easily accessible o-acylanilines is reported. The preparation of these tetracyclic compounds through a Mitsunobu reaction followed by spontaneous cyclodehydration shows the ability of this methodology to afford good yields of a wide variety of diversely 7, 8, 9, 10-substituted isoindoloquinazolinones in two steps.

Full text of DOI:10.1016/j.tetlet.2006.11.168

Tetrahedron Letters 48 (2007) 1023–1026
Synthesis of the antitumoural agent batracylin and related
isoindolo[1,2-b]quinazolin-12(10H)-ones
*
´
´
Carlos M. Martınez-Viturro and Domingo Domınguez
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Facultad de Quı´mica,
Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Received 8 November 2006; revised 23 November 2006; accepted 29 November 2006
Available online 22 December 2006
Abstract—The synthesis of batracylin and related isoindolo[1,2-b]quinazolin-12-ones from easily accessible o-acylanilines is
reported. The preparation of these tetracyclic compounds through a Mitsunobu reaction followed by spontaneous cyclodehydration
shows the ability of this methodology to afford good yields of a wide variety of diversely 7, 8, 9, 10-substituted isoindoloquinazol-
inones in two steps.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Batracylin1 (8-aminoisoindolo[1,2-b]quinazolin-12(10H)-
one) displays antitumour activity in vivo against murine
leukaemia P-388 and colon adenocarcinoma 38 cell lines
that are resistant to adriamycin, cisplatin and metho-
trexate. It acts as a topoisomerase II inhibitor and
induces unscheduled DNA synthesis. Nevertheless, the
low water solubility of batracylin, which limited its oral
administration, and its high toxicity, which reduced the
maximal dose possible to use in vivo, are the causes that
it has never been approved for further clinical trials in
human beings. Structurally, it is a quinazoline fused
with an isoindolone. Similar structures are present in
many natural products of great pharmacological inter-
est,2 including vasicine and tryptanthrin, which have
anti-inflammatory activity, and luotonin A, which has
antitumoural activity (Scheme 1). This structure is also
present in synthetic products with activity against
asthma and Alzheimer’s disease.3
All current methods for the synthesis of batracylin (1)
involve the establishment of a phthalimidylmethyl group
on a 1,4-dinitrogenated benzene ring,1 followed by an
intramolecular cyclodehydration reaction between what
is now the 2-amino unit and a phthalimide carbonyl
group.4 Kabbe,5 for example, proposed the condensation
of 2,5-diaminobenzylamine with phthalic anhydride
(Scheme 2), which involved heating the substrates
in dioxane for 4 h under mild conditions and gave a
yield of 56%. However, 2,5-diaminobenzylamine is not
commercially available, is difficult to prepare, and is very
unstable. LaVoie’s group6 subjected 5-nitro-2-amino-
benzylamine to the same conditions, reducing the
resulting 8-nitroisoindolo[1,2-b]quinazolin-12-one with
hydrogen in the presence of the catalytic amounts of
Pd in glacial acetic acid. A third approach, initially pro-
posed by Rosevear and Wilshire7 and recently improved
by Dzierzbicka’s group,1a uses the Czerniak–Einhorn
OH
O
N
N
N
N
N
B
D
7
N
N
N
A
C
N
8
H2N
O
10
O
O
1
2
3
4
Scheme 1. Batracylin (1) and related natural products: (À)-vasicine (2), tryptanthrin (3) and luotonin A (4).
Keywords: Batracylin; Quinazolines; Mitsunobu reaction; Quinazolinones.
*
Corresponding author. Fax: +34 981 595012; e-mail: qomingos@usc.es
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.168

1024
C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 1023–1026
NHCO2Et
HO
O
O
N
NH2
NH2
N
+
+
O
N
H2N
H2N
O
NHCO2Et
O
O
1
Scheme 2. The Kabbe and Dzierzbicka approaches to batracylin.
NO
2 O
NO2
OH
NO2
OH
N
(iii)
(i)
(ii)
N
O2N
N
O2N
O2N
H2N
O
O
O
5
6
1
Scheme 3. Reagents and conditions: (i) (1) SOCl2, reflux; (2) NaBH4, H2O, 0 ꢁC, 54%; (ii) Phthalimide, DEAD, PPh3, THF, rt, 78% and (iii)
HCO2NH4, Pd/C, EtOH, reflux, 79%.
O
R7
R8
NH2
OH
R7
R8
NH2
R7
R8
NH2
O
R7
R8
N
(i)
(ii)
(iii)
N
N
R9 R10
R9
R9 R10
R10
O
R9 R10
O
7
10
8
9
Scheme 4. Reagents and conditions: (i) NaBH4, EtOH, reflux; (ii) Phthalimide, DEAD or DIAD, PPh3, THF, rt and (iii) THF, rt.
Table 1. 10-Alkylisoindoloquinazolinones 10a–e, prepared by the
Mitsunobu coupling of phthalimide with 2-aminobenzyl alcohols 8a–e
reaction: in the Dzierzbicka version, the reaction of a 1,4-
phenylenedicarbamate (or N,N-diacetyl-1,4-phenylene-
Yielda (%)
diamine) with N-(hydroxymethyl)phthalimide in the
presence of sulfuric acid (Scheme 2), followed by the
removal of the protecting groups and treatment with
ammonia, affords a 39% yield starting from 1,4-
phenylenediamine.
Entry
Quinazolinone
N
N
1
10a
10b
40b
N
O
The above methods have allowed the synthesis of batra-
cylin analogues with modifications at rings A and D.1,7
However, their use for the introduction of diverse sub-
stituents on the quinazoline core, especially at position
10, is hampered by the unavailability and difficult prep-
aration of the required starting materials.
2
52
N
O
N
MeO
MeO
In view of the above, and as part of a broader search for
new structures with potential pharmacological activity,
we have developed a synthetic approach to batracylin
that seems capable of providing access to a wide range
of analogues with different quinazoline substituents.
The new method is simple, rapid and efficient, and
requires only readily available starting materials. It is
based on the use of a Mitsunobu reaction8 as the key
step in the construction of the 2-phthalimidylmethyl-
aniline required for cyclodehydration.
3
4
10c
10d
58
53
N
O
N
O
O
N
O
N
To obtain batracylin itself, one can start from com-
mercial 2,5-dinitrobenzoic acid (Scheme 3). One-pot
reduction of this substrate by conversion to the acid
5
10e
19
N
O
chloride, followed by
a treatment with sodium
a After chromatographic purification.
b From commercially available 2-aminobenzyl alcohol: (1) Phthal-
imide, DEAD, PPh3, THF, rt; (2) BF3ÆOEt2, THF, reflux.
borohydride in water, gave 54% yield of alcohol 5;
treatment of 5 with phthalimide, DEAD and triphen-
ylphosphine gave the phthalimido derivative 6 in a

C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 1023–1026
1025
Table 2. 10-Arylisoindoloquinazolinones 10f–n, prepared by the
Mitsunobu coupling of phthalimide with 2-aminobenzyl alcohols 8f–n
78% yield; and the reduction of 6 with ammonium
formate and catalytic amounts of Pd/C gave a di-
amine that underwent spontaneous cyclodehydration,
affording batracylin in a 79% yield (33% for the three
steps).
Entry
Quinazolinone
Yielda (%)
N
N
1
10f
10g
10h
86
For batracylin analogues with substituent-modified
quinazoline moieties, it is more convenient for benzyl
alcohol 8 required for the Mitsunobu reaction to be
obtained from readily available 2-acyl aniline 7 (Scheme
4). Of the 10-alkyl analogues listed in Table 1, which
were obtained in this way via alcohols 8, only 10a has
been synthesized previously.6 Compound 10a was also
the only analogue for which the cyclodehydration step
did not occur spontaneously, but required heating of
phthalimido intermediate 9a following the treatment
with BF3ÆOEt2. The low yield of pentacyclic compound
10e, obtained starting from 8-aminotetralone,9 is attrib-
utable to the instability of aminotetralol 8e under the
Mitsunobu conditions.
O
N
N
2
3
H2N
27
O
N
N
AcHN
48b
O
Table 2 lists the results of using the new method to
prepare 10-arylisoindoloquinazolinones (10f–n).10 Yields
ranged from 27% for 10g to 88% for 10m. The low
yield of 10g is attributable mainly to losses during
chromatographic purification; N-acetylation of the
crude product of the Mitsunobu reaction raised the
yield to 48% (entry 3). The halogenated compounds
10i–k were obtained in the yields of 47–64%, while
the yields obtained with electron-rich 10-(methoxy-
phenyl) substituents11 depended heavily on the position
of the methoxy group (p, 37%; m, 88%). Entry 9 shows
that the new method also accommodates 10-heteroaryl
substituents.12
N
N
N
N
N
N
4
5
6
Cl
Cl
Cl
10i
10j
10k
64
47
51
O
O
O
F
To sum up, a representative set of substituted batracylin
analogues have been synthesized from commercially
available or easily prepared aminoacetophenones and
aminobenzophenones by reduction to the corresponding
benzylic alcohol followed by cyclocondensation with
phthalimide under Mitsunobu conditions.
Cl
N
N
7
10l
37
O
Acknowledgements
Support of this work by the Spanish Ministries of
Science and Technology (Project BQU2002-01176)
and Education and Science (Project CTQ2005-02338),
in collaboration with ERDF, and by Johnson&
Johnson Pharmaceutical Research and Development,
is gratefully acknowledged. C.M. also thanks the
University of Santiago for a pre-doctoral grant.
OMe
N
N
8
9
10m
88
44
O
OMe
N
N
Supplementary data
10n
IR, 1H NMR and 13C NMR/DEPT, MS (CI and/or EI)
and HRMS (CI and/or EI) spectra of compounds 1, 5,
6, 8b–n and 10a–n, and the procedures for their prepara-
tion. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/
j.tetlet.2006.11.168.
O
N
a After chromatographic purification.
b After acetylation of the crude cycloaddition product 10g: AcCl,
DMAP, CH2Cl2, rt.

1026
C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 1023–1026
(0.250 mL, 0.55 mmol) was added dropwise and the
References and notes
mixture was stirred under argon at room temperature
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hexanes–EtOAc), providing 10-phenylisoindolo[1,2-b]quin-
azolin-12(10H)-one (10f) as a white solid (0.123 g, 86%),
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0.46 mmol), phthalimide (0.083 g, 0.55 mmol) and PPh3
(0.146 g, 0.55 mmol) in dry THF (15 mL), DEAD
mp 206–208 ꢁC. IR (KBr): 1732, 1648 cmÀ1 1H NMR
.
(CDCl3, 300 MHz): d 8.08 (d, J = 7.6 Hz, 1H, ArH), 7.79
(d, J = 7.4 Hz, 1H, ArH), 7.69 (t, J = 7.4 Hz, 1H, ArH),
7.62 (d, J = 7.5 Hz, 1H, ArH), 7.56 (d, J = 8.0 Hz, 1H,
ArH), 7.37–7.12 (m, 7H, ArH), 7.08 (d, J = 7.6 Hz, 1H,
ArH), 6.32 (s, 1H, CH). 13C NMR/DEPT (CDCl3,
75 MHz): d 166.0 (CO), 148.9 (C), 142.2 (C), 139.8 (C),
134.6 (C), 133.1 (CH), 132.1 (CH), 130.4 (C), 128.81 (CH),
128.77 (2 · CH), 128.1 (CH), 128.0 (CH), 127.9 (2 · CH),
127.3 (2 · CH), 126.0 (C), 123.4 (CH), 122.2 (CH), 55.7
(CH). MS (CI), m/z (%): 339 ([M+C2H5]+, 23), 311
[M+H]+, 100), 310 (M+, 39), 233 ([MÀPh]+, 17). MS (EI),
m/z (%): 310 (M+, 14), 233 ([MÀPh]+, 100). HR-MS (EI):
Calcd for C21H14N2O, 310.1106. Found, 310.1100.
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