PIFA-mediated synthesis of novel pyrazoloquinolin-4-ones as potential ligands for the estrogen receptor

Article abstract of DOI:10.1016/j.tetlet.2008.09.098

A facile and efficient preparation of pyrazoloquinolin-4-ones, as potential ligands for the estrogen receptor, via a PIFA [phenyliodine(III)bis(trifluoroacetate)] promoted cyclization reaction with overall yields up to 29% over six steps is described. The employed strategy, based on an electrophilic amidation reaction as the key step of the synthesis, allows the generation of a diverse array of derivatives.

Full text of DOI:10.1016/j.tetlet.2008.09.098

Tetrahedron Letters 49 (2008) 7100–7102
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
PIFA-mediated synthesis of novel pyrazoloquinolin-4-ones
as potential ligands for the estrogen receptor
Michael S. Christodoulou a, Konstantinos M. Kasiotis a, Nikolas Fokialakis b,
Imanol Tellitu c, Serkos A. Haroutounian a,
*
a Chemistry Laboratory, Agricultural University of Athens, Iera odos 75, Athens 11855, Greece
b Division of Pharmacognosy and Chemistry of Natural Products, Faculty of Pharmacy, University of Athens, Panepistimiopolis, Zografou 15771, Athens, Greece
c Departamento de Química Orgánica II, Facultad de Ciencia y Tecnología, Universidad del País Vasco, Euskal Herriko Unibertsitatea, PO Box 644, 48080 Bilbao, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2008
Revised 6 September 2008
Accepted 17 September 2008
Available online 20 September 2008
A facile and efficient preparation of pyrazoloquinolin-4-ones, as potential ligands for the estrogen recep-
tor, via a PIFA [phenyliodine(III)bis(trifluoroacetate)] promoted cyclization reaction with overall yields up
to 29% over six steps is described. The employed strategy, based on an electrophilic amidation reaction as
the key step of the synthesis, allows the generation of a diverse array of derivatives.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
PIFA
Quinolin-4-ones
Pyrazole
Estrogen receptor
Estrogens stimulate various biological functions via their
molecular target, the estrogen receptor (ER, ER and ERb sub-
OH
a
types).1,2 The latter acts as a ligand activated-transcriptional regu-
lator that binds with a wide spectrum of steroidal and nonsteroidal
ligands.3 The structure of high ER affinity synthetic estrogens,
especially those of nonsteroidal nature, generally consists of a phe-
nolic functionality that mimics the phenol moiety of natural estra-
diol, and is tolerant to other target structural motifs that can be
encompassed.4–6
N
N
N
OMe
O
OH
HO
Thus, intense research activity has been initiated toward the
development of novel Selective Estrogen Receptor Modulators
(SERMs) that possess high affinity and selectivity for an ER subtype
and a broad variety of diverse ligands, based on various parameters
and limitations,7,8 have been considered. In this context, the incor-
poration of a pyrazole moiety in the structures studied represents
an intriguing case, since the propylpyrazoletriol (PPT) 1 (Fig. 1), a
1,3,5-triaryl-4-alkyl-substituted pyrazole derivative, has been
PPT, 1
2
Figure 1. Propylpyrazoletriol (PPT) 1 and quinolinones of type 2.
their utilization by the pharmaceutical and agrochemical indus-
tries.12 The key step for the synthesis of the target compounds is
a hypervalent iodine-promoted electrophilic amidation.
found to possess particularly high ER
a-selective binding affinity
The use of hypervalent iodine compounds for synthetic pur-
poses has gained significant interest. The low toxicity associated
with these reagents in conjunction with the mild reaction condi-
tions employed has resulted in their application in an increasing
number of diverse transformations.13 In this regard, research has
focused on new applications of PIFA [phenyliodine(III)bis(trifluoro-
acetate)] for the efficient syntheses of various bioactive hetero-
cycles. Thus, the syntheses of heterocycle-fused quinolinones of
type 2 (Fig. 1), such as 1,4-diazepin-2-ones, isoquinolinone, and
isoindolinone, have appeared in the literature.14–16 This research
and potency.9
As a part of our ongoing investigation concerning the develop-
ment of novel SERMs, we were intrigued to explore the incorpora-
tion of fused heterocycle–pyrazole ring systems in this class of
compounds. Our involvement was stimulated by the pronounced
synthetic and biological interest10,11 on pyrazole derivatives and
* Corresponding author. Tel.: +30 210 5294247; fax: +30 210 5294265.
E-mail address: sehar@aua.gr (S. A. Haroutounian).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.098

M. S. Christodoulou et al. / Tetrahedron Letters 49 (2008) 7100–7102
7101
Table 1
has now been extended, aimed at the development of a new ap-
proach for the preparation of novel pyrazoloquinolin-4-one deriv-
atives with potential SERM activity.
Substitution patterns of compounds 5a–e, 6a–e, 7a–e, 8a–e, and 9a–e, and their
respective yields
Product
R1
R2
R3
R4
X
Yield (%)
The overall synthetic route utilized for the preparation of the
target pyrazoloquinolin-4-ones 9 is depicted in Scheme 1. The first
step refers to the condensation of various acetophenones 3 with 4-
methoxyphenylhydrazine hydrochloride to provide efficiently the
hydrazones 4. Since hydrazones 4a–e are highly labile, their forma-
tion was revealed through their crude NMRs. Thus, these deriva-
tives were not isolated but transformed directly, without further
purification, into the corresponding pyrazolocarboxaldehydes 5a–
e (Table 1) by treatment with the iminium salt formed from
2,4,6-trichloro(1,3,5)triazine (TCT, cyanuric chloride) and DMF.17
It should be noted, however, that the use of Vilsmeier–Haack reac-
tion conditions (DMF–POCl3, 80 °C) resulted in the formation of
only pyrazole 5a (R1, R2, R3, and R4 = H), since for all other
substrates thermal decomposition or degradation occurred. A
5a
5b
5c
5d
5e
6a
6b
6c
6d
6e
7a
7b
7c
7d
7e
8a
8b
8ca
8d
8e
9a
9b
9c
9d
9e
H
H
H
H
OCH3
H
H
H
H
OCH3
H
H
H
H
OCH3
H
H
H
H
H
OCH3
H
OCH3
H
H
OCH3
H
OCH3
H
H
OCH3
H
OCH3
H
H
OCH3
H
OCH3
H
H
OH
H
OH
H
H
H
OCH3
OCH3
H
H
H
OCH3
OCH3
H
H
H
OCH3
OCH3
H
H
H
OCH3
OCH3
H
H
H
H
H
OCH3
H
H
H
H
OCH3
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
NHOMe
NHOMe
NHOMe
NHOMe
NHOMe
—
—
—
—
—
—
—
—
—
—
60
55
55
50
50
95
95
95
95
95
95
90
90
85
80
57
55
55
50
50
95
95
95
90
90
OMe
OCH3
H
H
H
H
OCH3
H
H
H
H
H
H
OH
OH
H
R1
R4
O
R2
R3
NH
R1
R4
N
a
b
OH
OH
R2
R3
a
50-60%
The spiro compound 10 was also obtained (8%).
(two steps)
3
4
recent report concerning the formation and stability of these hydra-
zones, and their respective pyrazole derivatives has revealed the
impact of a rise in temperature and/or the crucial role of microwave
irradiation, which seriously affects the reaction yield.17 It is evident
that in this case, the substitution pattern of both the acetophenone
and phenylhydrazine ring plays a pivotal role in the stability of the
derived molecules, since the reaction with TCT was carried out at
room temperature without the use of microwave-assisted method-
ologies. Furthermore, the presence of methoxy substituents on
the aromatic rings, in contrast with electron-withdrawing substitu-
ents, such as a nitro group,18 differentiates the chemical behavior
and stability of the intermediate hydrazones 4.
Next, the aldehydes 5a–e were oxidized with NaOCl2 in the
presence of sulfamic acid as a scavenger, producing, almost quan-
titatively, the corresponding carboxylic acids 6a–e. The latter were
converted into the respective amides, 7a–e, by reaction with meth-
oxylamine hydrochloride in the presence of the uronium coupling
reagent TBTU. To promote the cyclization step, PIFA was selected
as the source of hypervalent iodine to induce the generation of
the expected acylnitrenium intermediates. In this context, when
using trifluoroacetic acid (TFA) as additive and CH2Cl2 as solvent,
the pyrazoloquinolin-4-ones 8a–e were obtained in moderate to
good yields (50–57%).19
Additional experiments using trifluoroethanol as solvent pro-
duced the same reaction products in lower yields (ꢀ35%). It should
be noted that under these conditions, the use of amide 7c as
substrate resulted in the formation of two reaction products
(quinoline 8c and the fused-spiro product 10, Scheme 2). The
co-formation of these compounds can be rationalized considering
that they are being obtained through the same pathway via the
formation of the same intermediate, which may either be hydro-
lyzed during the work-up process or via a 1,2-migration process,
which is transformed into a quinoline.20,21 NOESY experiments
proved the proposed structure for product 8c, over other possible
regioisomers, through correlations of H-6 with the N–OCH3 and
the C7–OCH3 groups.
OMe
R1
R4
N
N
5 (X =H)
R2
R3
c (95%)
6 (X =OH)
d (80-95%)
e
7 (X =NHOMe)
X
O
50-57%
OMe
OH
4'
3'
2
N
1
N
R1
1'
2'
N
R1
N
f
R2
R3
9
R2
3
8
7
90-95%
4
5
N
N
O
R3
O
6
R4 OMe
R4 OH
8
9
3a, 4a, 5a, 6a, 7a, 8a R1=
H, R2= H, R3= H, R4= H
3b, 4b, 5b, 6b, 7b, 8b
R1= H, R2= OCH3, R3= H,
R4= H
9a R1= H, R2= H, R3= H, R4= H
9b R1= H, R2= OH, R3= H, R4= H
9c R1= H, R2= H, R3= OH , R4= H
9d R1= H, R2= OH, R3= OH, R4= H
9e R1= OH, R2= H, R3= H, R4= OH
3c, 4c, 5c, 6c, 7c, 8c
R1= H, R2= H, R3= OCH3
R4= H
,
3d, 4d, 5d, 6d, 7d, 8d
R1= H, R2= OCH3, R3=
OCH3, R4= H
3e, 4e, 5e, 6e, 7e, 8e
R1= OCH3, R2= H, R3= H,
R4= OCH3
Finally, the demethylation of the methoxy-protective groups
with BBr3 at À78 °C in CH2Cl2 provided the desired quinolin-4-ones
9 in almost quantitative yields (90–95%) (Table 1).
Scheme 1. Reagents and conditions: (a) 4-methoxyphenylhydrazine hydrochloride
(1.0 equiv), THF; (b) TCT, DMF; (c) NaClO2, H2NSO3H, acetone/H2O, 0 °C; (d) Et3N,
NH2OMeÁHCl, TBTU, MeCN; (e) PIFA, TFA, CH2Cl2; (f) BBr3, CH2Cl2, À78 °C.

7102
M. S. Christodoulou et al. / Tetrahedron Letters 49 (2008) 7100–7102
6. Compton, D. R.; Carlson, K. E.; Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett.
PMP
O
PMP
2004, 14, 5681–5684.
N
N
N
N
7. Blizzard, T. A.; Gude, C.; Morgan, J. D., II; Chan, W.; Birzin, E. T.; Mojena, M.;
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PIFA, -20 °C
PhI, TFA
+
MeO
N
O
N
MeO
CF3COO
HN
7c
_
OMe
OMe
PMP
O
PMP = p-Methoxyphenyl
N
O
N
OMe
10
PMP
N
N
N
13. (a) Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press:
London, 1997; (b) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584;
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PMP
N
N
+
O
MeO
1,2 migration
OMe
MeO
N
O
_
CF3COO
OMe
8c
Scheme 2. Proposed mechanistic pathway for the formation of spiro compound 10
and quinolinone 8c.
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19. General procedure for the cyclization of amides 7a–e with PIFA: A solution
of PIFA (0.28 g, 0.64 mmol) and TFA (0.10 mL, 1.3 mmol) in CH2Cl2 (9 mL)
was added to a cold (À20 °C) solution of amide 7 (0.42 mmol) in CH2Cl2
(4 mL). The mixture was stirred at the same temperature until total
consumption of the starting material (TLC, 1 h). The reaction mixture was
quenched with 10% aq Na2CO3, and extracted with CH2Cl2 (2 Â 20 mL). The
combined organic layers were washed with a saturated solution of NaCl,
dried over Na2SO4, filtered, and evaporated under vacuum. The residue was
purified by flash column chromatography (hexane/EtOAc, 3/7) to furnish the
desired quinolinone 8.
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A. Synlett 2003, 1352–1354.
Acknowledgments
The financial support of COST D28 Action (Working Group D28/
008/03) for the Short Term Scientific Missions (STSMs) of MSC and
KMK to Universidad del País Vasco is gratefully acknowledged.
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