Synthesis of the new ring system 6,8-dihydro-5H-pyrrolo[3,4-h]quinazoline

Article abstract of DOI:10.1016/j.tetlet.2009.07.045

A convenient synthesis of the pyrrolo[3,4-h]quinazoline ring system is reported. Our synthetic approach consisted of the annelation of a pyrimidine ring to an isoindole moiety using tetrahydroisoindole-4-ones as building blocks. The antiproliferative activity of the new compounds was investigated and one of them showed antitumor activity against all the 59 tested cell lines at micromolar concentrations (1.46-18.4 μM).

Full text of DOI:10.1016/j.tetlet.2009.07.045

Tetrahedron Letters 50 (2009) 5389–5391
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Tetrahedron Letters
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Synthesis of the new ring system 6,8-dihydro-5H-pyrrolo[3,4-h]quinazoline
*
Paola Barraja, Virginia Spanò, Patrizia Diana, Anna Carbone, Girolamo Cirrincione
Dipartimento Farmacochimico, Tossicologico e Biologico Università degli Studi di Palermo, Via Archirafi 32, 90123 Palermo, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of the pyrrolo[3,4-h]quinazoline ring system is reported. Our synthetic approach
consisted of the annelation of a pyrimidine ring to an isoindole moiety using tetrahydroisoindole-4-ones
as building blocks. The antiproliferative activity of the new compounds was investigated and one of them
showed antitumor activity against all the 59 tested cell lines at micromolar concentrations (1.46–
Received 16 June 2009
Revised 7 July 2009
Accepted 8 July 2009
Available online 12 July 2009
18.4 lM).
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolo[3,4-h]quinazolines
Antiproliferative activity
Isoindole building blocks
Pyrimidine annelation
The quinazoline nucleus is the scaffold of many antitumor drugs
mainly acting as inhibitors of tyrosine kinase receptors (RTK).
Overexpression of these receptors is found in a number of cancers
(e.g., breast, ovarian, colon, and prostate). In particular VEGF (vas-
cular endothelial growth factor) has been recognized as a key fac-
tor promoting neovascularization of many tumors.1,2 Leading
examples of quinazoline-based inhibitors are the clinically ap-
proved anticancer agent Iressa (ZD1839) 1 and Tarceva (OSI 774/
CP358,774) 2 which is in Phase III clinical trials for cancer.3,4 Both
compounds inhibit the receptor tyrosine kinase of the epidermal
growth factor (EGFR/HER1). Other compounds containing the qui-
nazoline moiety which target the vascular or endothelial growth
factor receptors have been advanced into clinical trials5,6 and qui-
nazoline RTK inhibitors of the platelet-derived growth factor
receptors (PDGFRs) with potent activity have been also reported.7
Moreover fused tricyclic quinazolines such as pyrrolo- and
pyrazoloquinazolines 3 and 4, respectively, showed IC50 values in
the nanomolar range in the inhibition of VEGFR.8 In addition pyr-
rolo[3,2-f]quinazolines of type 5 are effective for neoplastic dis-
eases as inhibitors of the dihydrofolate reductase (DHFR).9
Cl
We have recently studied the synthesis of isoindole-based ring
systems such as the pyrano[2,3-e]isoindol-2-one10 6 and the pyr-
rolo[3,4-h]quinolin-2-one11 7 as heteroanalogues of Angelicin.
F
O
N
NH
N
HN
N
O
O
O
O
O
O
O
O
N
N
O
NH
N
N
1
2
NR
NR
NR
R1
6
7
8
NHAr
N
NH2
RN
N
Considering our interest in the chemistry of pyrrole and encour-
aged by the potent antitumor activity of the above mentioned qui-
nazoline derivatives we decided to investigate the synthesis of
another pyrrolo-fused heterocycle, the pyrrolo[3,4-h]quinazoline
8. Our synthetic strategy for this new ring system consists of the
annelation of a pyrimidine moiety to an isoindole moiety as
described in Scheme 2. The 1-phenyl derivative 12a was
obtained by a multistep sequence starting from 2-[(dimethyl-
X
N
N
N
NH2
H
3 X=CH
4 X=N
5
* Corresponding author. Tel.: +39 0916161606; fax: +39 0916169999.
E-mail address: gcirrinc@unipa.it (G. Cirrincione).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.045

5390
P. Barraja et al. / Tetrahedron Letters 50 (2009) 5389–5391
Table 1
Ph
HO2C
Substrates, reaction times, melting points, and yields for compounds 8a–o
CH
NH
O
O
Substrate
product
Reaction time (h)
Mp (°C)
Yield (%)
NMe2
i
12a
12b
12c
13d
13e
13f
13g
13h
13i
13j
13k
13l
13m
13n
13o
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
3
5
17
7
241–242
92–94
216–217
Oil
100–101
Oil
60
45
70
62
50
45
70
75
60
80
80
70
90
80
60
O
O
10
ii
9
22
22
7
22
24
24
24
20
24
7
Ac
O
Oil
62–63
150–151
111–112
99–100
170–171
Oil
N Ac
Ph
N H
Ph
iii
11
12a
Scheme 1. Synthesis of intermediate 12a. Reagents and conditions: (i) phenylgly-
cine, AcONaÁ3H2O, ethanol, reflux, 4 h, 95%; (ii) Et3N, Ac2O, 30 min, reflux, 83%; (iii)
80% acetic acid, 37% HCl, 30 min, 60 °C, 94%.
Oil
Oil
5
amino)methylene]cyclohexane-1,3-dione
9 which was reacted
tested cell lines (see Supplementary data) at micromolar concen-
tration (1.46–18.4 M).
The best selectivity was achieved for the leukemia (1.46–
3.99 M), and melanoma (2.49–6.81 M) sub-panels.
In conclusion, we have reported a versatile method for the syn-
thesis of derivatives of the new ring system pyrrolo[3,4-h]quinaz-
oline in good overall yields. The antiproliferative activity shown by
derivative 8o makes this class of compounds interesting for further
studies directed toward the synthesis of more potent antiprolifer-
ative agents.
with phenylglycine to give the enaminoacid 10. Cyclization of this
latter in acetic anhydride and triethylamine gave the expected
dihydroisoindole 11. The tetrahydroisoindole-2-one 12a was ob-
tained upon desacetylation by heating in aqueous acetic acid
(80%) and HCl (37%) (Scheme 1).12 Tetrahydroisoindole-4-ones
12b,c were conveniently prepared as described before.10
Ketones 12a–c were functionalized on the nitrogen atom in THF
or DMF using NaH as the base and an alkylating agent such as MeI,
BnCl, ClBnpMe, or ClBnpOMe to give the corresponding N-substi-
tuted derivatives 13d–o (60–98%).
l
l
l
The annelation of the pyrimidine ring on the isoindole moiety
was achieved by the Bredereck method widely used for the synthe-
sis of pyrimidine and their fused derivatives, such as pyrimidinoc-
arbazoles, starting from ketones.13 Thus, heating under reflux
tetrahydroisoindole-4-ones 12a–c or 13d–o in formamide with
tris-(formylamino)-methane in the presence of catalytic amount
of p-toluenesulfonic acid, derivatives 8a–o were obtained in mod-
erate to good yields (45–90%).14 (Scheme 2, Table 1)
All the new compounds were submitted to the NCI of Bethesda
for antiproliferative studies. Derivatives 8b–e,g,i,l,m,o were se-
lected for the one dose (10À5 M) screening on the full panel of 60
human cancer cell lines derived from nine human cancer cell types,
that have been grouped in disease sub-panels including leukemia,
non-small-cell lung, colon, central nervous system, melanoma,
ovarian, renal, prostate, and breast tumor cell lines.
Acknowledgment
This work was financially supported by Ministero dell’Istruzi-
one dell’Università e della Ricerca.
Supplementary data
Supplementary data (Table 2 containing the GI50 of 8o against
59 tested human tumor cell lines and spectroscopic and analytical
data for 8c–o) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2009.07.045.
References and notes
1. Strawn, L. M.; Shawver, L. K. Exp. Opin. Invest. Drugs 1998, 7, 553–573.
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Strawn, L. M. Drug Discovery Today 1997, 2, 50–63.
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Di Orio, C.; Doti, J.; Morin, M. J.; Moyer, M. P.; Neveu, M.; Pollack, V. A.;
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1997, 57, 4838–4848.
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Woodburn, J. R.; Ashton, S. E.; Curry, B. J.; Scarlett, L.; Henton, L.; Richards, L.
Bioorg. Med. Chem. Lett. 2001, 47, 1911–1914.
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D. J.; Dukes, M.; Wedge, S. R.; Kendrew, J.; Curwen, J. O. J. Med. Chem. 2002, 45,
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S.; Boytos, C. M.; Rudolph, S. K.; Knick, V.; Wilson, H. R.; Caddel, J. M.; Friedman,
H. S.; Comley, J. C. W.; Stables, J. N. J. Med. Chem. 1996, 39, 892–903.
10. Barraja, P.; Spanò, V.; Diana, P.; Carbone, A.; Cirrincione, G.; Vedaldi, D.; Salvador,
A.; Viola, G.; Dall’Acqua, F. Bioorg. Med. Chem. Lett. 2009, 19, 1711–1714.
11. Barraja, P.; Diana, P.; Montalbano, A.; Dattolo, G.; Cirrincione, G.; Viola, G;
Salvador, A.; Vedaldi, D.; Dall’Acqua, F. Abstract of Papers, EORTC
Pharmacology and Molecular Mechanisms Group 29th Winter Meeting,
Palermo January 2008, p 85.
Derivative 8o was further tested at five concentrations at 10-
fold dilution (10À4–10À8 M), showing activity against all the 59
R1
R1
O
N
N
R1
O
i
ii
NR
R2
NR
R2
NH
R2
12a-c
13d-o
8a-o
ii
a R=R1=H, R2=Ph; b R=R1=R2=H; c R=H, R1=Me,
R2=CO2Et; d R=Me, R1=R2=H; e R=Bn, R1=R2=H; f
R=BnpMe, R1=R2=H; g R=BnpOMe, R1=R2=H; h
R=Me, R1=Me, R2=CO2Et; i R=Bn, R1=Me, R2=CO2Et;
j R=BnpMe, R1=Me, R2=CO2Et; k R= BnpOMe,
R1=Me, R2=CO2Et; l R=Me, R1=H, R2=Ph; m R=Bn,
R1=H, R2=Ph;
n
R=BnpMe, R1=H, R2=Ph;
o
R=BnpOMe, R1=H, R2=Ph.
Scheme 2. Synthesis of 6,8-dihydro-5H-pyrrolo[3,4-h]quinazolines 8a–o. Reagents
and conditions: (i) NaH, MeI or BnCl or BnpMeCl or BnpOMeCl, THF or DMF, rt or
reflux, 2–24 h, 60–98%; (ii) CH(NHCHO)3, TsOH, formamide, reflux, 3–24 h, 45–90%.

P. Barraja et al. / Tetrahedron Letters 50 (2009) 5389–5391
5391
12. Gabbutt, C. D.; Hepworth, J. D.; Heron, B. M.; Pugh, S. L. J. Chem. Soc., Perkins
Trans. 1 2002, 24, 2799–2808.
13. Gazengel, J. M.; Lancelot, J. C.; Rault, S.; Robba, M. J. Heterocycl. Chem. 1989, 26,
1135–1139.
2 Â CH2), 7.23–7.56 (6H, m, Ar and H-9), 8.47 (1H, s, H-4), 8.84 (1H, s, H-2),
11.71 (1H, s, NH); 13C NMR (DMSO-d6, 50 MHz): d 19.8 (CH2), 25.6 (CH2),
117.6 (C), 118.4 (CH), 119.9 (C), 125.7 (C), 126.0 (C), 126.3 (2 Â CH), 127.1
(CH), 128.7 (2 Â CH), 132.4 (C), 154.2 (CH), 156.7 (CH), 157.9 (C). Anal.
Calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99. Found: C, 77.37; H, 5.59; N,
17.26.
14. Preparation of the appropriate 6,8-dihydro-5H-pyrrolo[3,4-h]quinazoline
8a–o: To
a solution of 12a–c or 13d–o (3 mmol) in formamide (5 mL),
tris-(formylamino)-methane (0.82 g, 6 mmol) and catalytic amount of
p-toluenesulfonic acid were added. The mixture was heated under reflux for
the designated time, poured onto crushed ice and extracted with ethyl acetate.
The crude material was purified by column chromatography, using
dichloromethane/ethyl acetate (9:1) as eluent.
Data for 6,8-dihydro-5H-pyrrolo[3,4-h]quinazoline 8b: IR (CHBr3): 3184 (NH)
cmÀ1 1H NMR (DMSO-d6, 200 MHz): d 2.71 (2H, t, J = 6.2 Hz, CH2), 2.83 (2H,
;
t, J = 6.2 Hz, CH2), 6.68 (1H, s, H-7), 7.86 (1H, s, H-9), 8.43 (1H, s, H-4), 8.79
(1H, s, H-2), 11.17 (1H, s, NH); 13C NMR (DMSO-d6, 50 MHz): d 19.2 (CH2),
25.7 (CH2), 114.5 (CH), 116.7 (CH), 118.3 (C), 120.8 (C), 126.4 (C), 154.1
(CH), 156.6 (CH), 158.1 (C). Anal. Calcd for C10H9N3: C, 70.16; H, 5.30; N,
24.54. Found: C, 70.29; H, 5.12; N, 24.33.
Data for 7-phenyl-6,8-dihydro-5H-pyrrolo[3,4-h] quinazoline 8a: IR (CHBr3):
; d 2.83–2.99 (4H, m,
3139 (NH) cmÀ1 1H NMR (DMSO-d6, 200 MHz):