Synthesis of aza analogues of the anticancer agent batracylin

Article abstract of DOI:10.1016/j.tetlet.2007.05.025

Three series of pyrido-fused pyrimido[2,1-a]isoindol-7-ones were prepared from readily available (aminopyridinyl)(aryl)methanones by reduction followed by a Mitsunobu reaction with phthalimide and acid-catalysed cyclodehydration. This approach provides a wide variety of aza analogues of the antitumour agent batracylin.

Full text of DOI:10.1016/j.tetlet.2007.05.025

Tetrahedron Letters 48 (2007) 4707–4710
Synthesis of aza analogues of the anticancer agent batracylin
*
´
´
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 22 March 2007; revised 18 April 2007; accepted 2 May 2007
Available online 10 May 2007
Dedicated to the memory of Dr. M. V. Laksmikantham (deceased on January 20th, 2006)
Abstract—Three series of pyrido-fused pyrimido[2,1-a]isoindol-7-ones were prepared from readily available (aminopyridinyl)(aryl)-
methanones by reduction followed by a Mitsunobu reaction with phthalimide and acid-catalysed cyclodehydration. This approach
provides a wide variety of aza analogues of the antitumour agent batracylin.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Batracylin (1),1 a topoisomerase II inhibitor,2 displays
antitumoural activity in vivo against murine colon ade-
nocarcinoma 38 and leukaemia P-388 strains that are
resistant to adriamycin, cisplatin and methotrexate.3,4
However, it also induces unscheduled DNA synthesis
in nonreplicating cells;5 its poor solubility in water pre-
vents its oral administration; and its high toxicity limits
the dose that can be administered in vivo. Accordingly,
numerous studies have sought analogues with more
favourable characteristics. Structural modifications
effected in the hope of retaining ability to inhibit topo-
isomerase II while reducing toxicity and increasing
water solubility include the introduction of diverse
substituents on the isoindoloquinazolinone core (Cl,
Br, NO2, Me, CO2Me, OMe, acids, dipeptides and sugar
moieties);5,6 the inclusion of a nitrogen atom in ring A5
or ring D (2, 3);6c an increase in the size of the polycyclic
system (4);6c and contraction of the ring B from six to a
five-membered to obtain benzimidazole (5)5 or indole
(6)7 analogues (Fig. 1).
We recently reported the synthesis of batracylin and 14
related isoindolo[1,2-b]quinazolin-12(10H)-ones from
easily prepared o-aminobenzyl alcohols and phthalimide
by a cascade Mitsunobu coupling/cyclodehydration
process. This approach is suitable for the preparation
of analogues with a variety of substituents at positions
7, 8, 9 and, of particular interest, 10, a position that is
difficult to functionalize by previous approaches.8 We
now report the extension of this methodology to the syn-
thesis of azabatracylins 7–9, in which aniline ring A has
been replaced by a pyrido ring (Fig. 2). The only batra-
cylin derivative of this kind to have been prepared pre-
viously, compound 2, inhibited topoisomerase II
(thought less potently than batracylin) without modify-
ing DNA in nonproliferating cells.5
Figure 1. Batracylin (1) and various reported analogues.
Keywords: Batracylin; Quinazolines; Pyridines; Mitsunobu reaction; Quinazolinones.
*
Corresponding author. Fax: +34 981595012; e-mail: qomingos@usc.es
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.025

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C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 4707–4710
To obtain the target derivatives, three series of (amino-
pyridinyl)(aryl)methanones were prepared from 2-, 3-
and 4-aminopyridines (10–12) by a method described
´
by Queguiner. The key step, the regioselective metalla-
tion of the corresponding pivalamides, is followed by
reaction with commercially available aromatic alde-
hydes (Scheme 1).9
Pivalamides 13–15 were prepared by acylation of the
corresponding aminopyridines 10–12 with pivaloyl chlo-
Figure 2. Aza analogues of batracylin synthesized in this work.
Scheme 1. Reagents and conditions: (i) Me3CCOCl, Et3N, THF/Et2O, 0 ꢁC; (ii) (1) n-BuLi, TMEDA, Et2O, ꢀ70 ꢁC to ꢀ20 ꢁC; (2) ArCHO (a-l),
THF, ꢀ70 ꢁC to rt; (iii) MnO2, CH2Cl2, rt; (iv) HCl 3 M, 95 ꢁC.
Table 1. (Aminopyridinyl)(aryl)methanones 22–24, prepared in four steps from 2-, 3- and 4-aminopyridines (10–12) and ArCHO (a-l),10 as shown in
Scheme 1
Entry
1
Ar
22 (%)
23 (%)
24 (%)
Entry
7
Ar
22 (%)
23 (%)
24 (%)
MeO
60a
35
54
42
—
56
b
MeO
a
OMe
g
2
3
57
43
45
63
56
23
8
9
44
49
28
29
28
39
MeO
b
h
F3C
OMe
c
i
MeO
O
4
5
6
48
51
42
55
36
41
48
10
11
12
58
50
55
8
33
13
31
49
48
OMe
OMe
d
j
b
—
MeO
e
k
O
O
44
N
Et
f
l
a (i) Me3CCOCl, Et3N, THF/Et2O, 0 ꢁC; (ii) (1) n-BuLi, TMEDA, Et2O, ꢀ70 ꢁC to ꢀ20 ꢁC; (2) PhCN, THF, ꢀ70 ꢁC to rt; (iii) HCl 3 M, 95 ꢁC.
b Not prepared.

C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 4707–4710
4709
ride. Following regioselective metallation with n-BuLi
and TMEDA, reaction with aromatic aldehydes a-l
afforded alcohols 16–18.10 Since these compounds were
unstable under acidic deprotection conditions and were
very insoluble and difficult to purify, they were oxidized
to ketones 19–21 with activated manganese dioxide at
room temperature. Finally, removal of the pivaloyl pro-
tecting group by hydrolysis with aqueous HCl afforded
(aminopyridinyl)(aryl)methanones 22–24, mostly in
overall yields of 40–60% (Table 1). The aryls borne by
these compounds include phenyl, phenyls with elec-
tron-donating substituents (alkoxyl, alkyl), phenyl with
an electron-withdrawing substituent (trifluoromethyl),
heteroaryls (furyl, 9-ethyl-3-carbazolyl) and bicyclic
aryls (2-naphthyl).
Compounds 22–24 were reduced with sodium boro-
hydride to obtain alcohols 25–27. These were condensed
with phthalimide under Mitsunobu conditions to obtain
intermediates 28–30,11 which then underwent cyclode-
hydration (most required acid catalysis and heating)12
(Scheme 2 and Table 2).
The pyrido[20,30:4,5]pyrimido[2,1-a]isoindol-7(5H)-ones
7a-l were obtained with overall yields ranging from
42% to 70%, except in the cases of the toluyl and furyl
Scheme 2. Reagents and conditions: (i) NaBH4, EtOH, reflux; (ii) phthalimide, DEAD or DIAD, PPh3, THF, rt; (iii) PTSA, PhMe, reflux, Dean–
Stark.
Table 2. Overall yields (%) of 5-arylpyrido[x0,y0:4,5]pyrimido[2,1-a]isoindol-7(5H)-ones 7–9, prepared in three steps from (aminopyridin-
yl)(aryl)methanones 22–24 as shown in Scheme 2
Entry
Ar
7 (%)
8 (%)
9 (%)
Entry
Ar
7 (%)
8 (%)
9 (%)
MeO
a
1
70
25
26
7
42
—
12
MeO
a
OMe
g
2
3
49
24
29
34
41
8
9
27
53
26
30
27
MeO
b
h
a
c
—
—
F3C
OMe
c
i
MeO
O
c
4
5
6
57
52
40
10
10
14
23
10
11
12
11
42
46
14b
—
OMe
OMe
d
j
a
d
—
—
21
27
MeO
e
k
O
35b
—
d
O
N
Et
f
l
a Not prepared.
b Cyclodehydration took place under the Mitsunobu conditions.
c Decomposition.
d Inseparable mixture with OPPh3.

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C. M. Martı´nez-Viturro, D. Domı´nguez / Tetrahedron Letters 48 (2007) 4707–4710
4. Atassi, G.; Dumont, P.; Kabbe, H. J.; Yoder, O. Drugs
Exp. Clin. Res. 1988, 14, 571.
derivatives (27% and 11%, respectively). The poorer
yields of the [30,40:4,5] and [40,30:4,5] series (8 and 9)
are attributable mainly to two factors: firstly, the lower
reactivity of alcohols 26 and 27 under the Mitsunobu
conditions, even when prolonged reaction times and
2 equiv of phthalimide, PPh3 and DEAD or DIAD were
employed; and secondly, the difficulty in purifying inter-
mediates 29 and 30 and the final pyridopyrimidoiso-
indolones 8 and 9, which were very hard to separate
from OPPh3. Interestingly, when phthalimide was con-
densed with (3-aminopyridin-4-yl)(benzo[d][1,3]dioxol-
5-yl)methanol (26f) and (3-aminopyridin-4-yl)(furan-2-
yl)methanol (26j), the cyclized products 8f and 8j were
obtained directly, without any need for acid catalysis
or heating. This is attributable to the amino group of
29 being more nucleophilic than those of 28 and 30,
and also to the nature of the aryl groups of 29f and
29j, because the other members of series 29 only cyclised
in trace amounts without catalysis and heat.
5. Meegalla, S. K.; Stevens, G. J.; McQueen, C. A.; Chen, A.
Y.; Yu, C.; Liu, L. F.; Barrows, L. R.; LaVoie, E. J. J.
Med. Chem. 1994, 37, 3434, and references cited therein.
6. (a) Rosevear, J.; Wilshire, J. F. K. Aust. J. Chem. 1990, 43,
339; (b) Dzierzbicka, K.; Trzonkowski, P.; Sewerynek, P.
L.; Mysliwski, A. J. Med. Chem. 2003, 46, 978; (c) Yilin,
R.; Yun Feng, C.; Ting, C.; Chen, A. Y.; Yu, C.; Liu, L.
F.; Cheng, C. C. Pharm. Res. 1993, 10, 918.
´
´
7. Guillaumel, J.; Leonce, S.; Pierre, A.; Renard, P.; Pfeiffer,
B.; Arimondo, P. B.; Monneret, C. Eur. J. Med. Chem.
2006, 41, 379.
´
´
8. Martınez-Viturro, C. M.; Domınguez, D. Tetrahedron
Lett. 2007, 48, 1023.
´
9. Estel, L.; Linard, F.; Marsais, F.; Godard, A.; Queguiner,
G. J. Heterocycl. Chem. 1989, 26, 105.
10. In the case of (2-aminopyridin-3-yl)(phenyl)methanone
´
22a, benzonitrile was chosen as the electrophile: Andres, J.
´
I.; Alonso, J. M.; Fernandez, J.; Iturrino, L.; Martinez, P.;
Meert, T. F.; Sipido, V. K. Bioorg. Med. Chem. Lett. 2002,
12, 3573.
11. Typical procedure for the Mitsunobu reaction: DIAD
(0.260 mL, 1.26 mmol) was added dropwise to a deoxy-
genated solution of alcohol 25a (0.207 g, 1.04 mmol),
phthalimide (0.185 g, 1.23 mmol) and PPh3 (0.330 g,
1.25 mmol) in dry THF (14 mL), and the mixture was
stirred under argon at room temperature for 23 h. The
solvent was evaporated and the residue was purified by
flash chromatography on silica gel (3:7 hexanes/EtOAc),
providing 2-[(2-aminopyridin-3-yl)(phenyl)methyl]isoind-
To sum up, a diverse set of aryl-substituted aza
analogues of batracylin have been synthesised from
easily prepared (aminopyridinyl)(aryl)methanones by
reduction to the corresponding alcohols followed by
condensation with phthalimide under Mitsunobu condi-
tions and final acid catalysed cyclodehydration.
oline-1,3-dione (28a) as
a white amorphous solid
Acknowledgements
1
(0.254 g, 74%). H NMR (CDCl3, 250 MHz): d 8.04 (dd,
J = 4.9 and 1.7 Hz, 1H, ArH), 7.88–7.80 (m, 2H, NPht),
7.77–7.68 (m, 2H, NPht), 7.51 (dd, J = 7.6 and 1.4 Hz,
1H, ArH), 7.41–7.27 (m, 5H, ArH), 6.66 (dd, J = 7.6 and
5.0 Hz, 1H, ArH), 6.62 (s, 1H, CH), 4.81 (br s, 2H, NH2).
13C NMR/DEPT (CDCl3, 62.5 MHz): d 168.1 (2 · CO),
156.4 (2 · C), 147.9 (CH), 139.0 (CH), 135.9 (2 · C),
134.3 (2 · CH), 131.4 (CH), 128.5 (2 · CH), 127.83 (CH),
127.79 (2 · CH), 123.5 (CH), 116.5 (C), 113.9 (CH), 53.0
(CH).
Support of this work by the Spanish Ministry of Educa-
tion and Science (Project CTQ2005-02338, in collabora-
tion with ERDF), by the Xunta de Galicia (Project
PGIDITO6PXIC209067PN) and by Johnson & John-
son Pharmaceutical Research and Development is grate-
fully acknowledged. C.M. also thanks the University of
Santiago for a pre-doctoral grant. We also thank M. F.
´
´
Martınez-Esperon for her collaboration in the analytical
12. Typical procedure for the acid catalysed cyclodehydration
reaction: A suspension of 28a (0.254 g, 0.77 mmol) and
PTSA (0.163 g, 0.84 mmol) in PhMe (10 mL) was refluxed
under argon for 25 h using a Dean–Stark trap. The solvent
was evaporated, a solution of the residue in CH2Cl2 was
washed with 1 N NaOH, dried with Na2SO4 and filtered,
and the solvent was removed under reduced pressure,
characterization of compounds.
Supplementary data
General experimental procedures and characterization
data—mp, 1H NMR and 13C NMR/DEPT, MS (CI
and/or EI), HRMS (CI and/or EI) and IR—of com-
pounds 7–30. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.05.025.
providing
indol-7(5H)-one (7a) as a white solid (0.234 g, 98%), mp:
218–220 ꢁC. IR (KBr): 1729, 1641 cmꢀ1 1H NMR
5-phenylpyrido[20,30:4,5]pyrimido[2,1-a]iso-
.
(CDCl3, 300 MHz): d 8.51 (dd, J = 4.7 and 1.8 Hz, 1H,
ArH), 8.21 (td, J = 7.3 and 1.0 Hz, 1H, ArH), 7.82–7.63
(m, 3H, ArH), 7.42 (dd, J = 7.6 and 1.8 Hz, 1H, ArH),
7.35–7.21 (m, 5H, ArH), 7.09 (dd, J = 7.6 and 4.8 Hz, 1H,
ArH), 6.35 (s, 1H, CH). 13C NMR/DEPT (CDCl3,
75 MHz): d 166.3 (CO), 152.8 (C), 152.3 (C), 149.5
(CH), 141.4 (C), 136.4 (CH), 134.3 (C), 133.5 (CH),
132.8 (CH), 130.0 (C), 128.9 (2 · CH), 128.5 (CH), 127.2
(2 · CH), 123.4 (CH), 123.2 (CH), 122.4 (CH), 121.4 (C),
55.8 (CH). MS (CI), m/z (%): 340 ([M+C2H5]+, 24), 312
([M+H]+, 100), 311 (M+, 5), 234 ([MꢀPh]+, 9). MS (EI),
m/z (%): 311 (M+, 62), 234 ([MꢀPh]+, 100). HR-MS (EI):
calcd. for C20H13N3O: 311.1059; found: 311.1058.
References and notes
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Dykes, D. J.; Kabbe, H. J.; Narayanan, V. L.; Yoder, O.
C. Invest. New Drugs 1988, 6, 147.