A facile synthesis of antitumoral indeno[1,2-c]pyrazole-4-one by mild oxidation with molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2005.08.147

An efficient, convenient, and general synthetic method for indeno[1,2-c]pyrazole-4-ones through oxidation of indenopyrazoles by treatment with a base and molecular oxygen is described, and a possible mechanism for the oxidation is proposed. The product in

Full text of DOI:10.1016/j.tetlet.2005.08.147

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7615–7618
A facile synthesis of antitumoral indeno[1,2-c]pyrazole-4-one
by mild oxidation with molecular oxygen
Zhi-Fu Tao,* Thomas J. Sowin and Nan-Horng Lin
Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA
Received 11 July 2005; revised 23 August 2005; accepted 23 August 2005
Available online 12 September 2005
Abstract—An efficient, convenient, and general synthetic method for indeno[1,2-c]pyrazole-4-ones through oxidation of indeno-
pyrazoles by treatment with a base and molecular oxygen is described, and a possible mechanism for the oxidation is proposed.
The product indeno[1,2-c]pyrazole-4-ones were elaborated further by Suzuki coupling and Mitsunobu reaction.
Ó 2005 Elsevier Ltd. All rights reserved.
Indeno[1,2-c]pyrazole-4-ones are an important class of
heterocycles and exhibit a wide range of biological activi-
ties such as antidepressive1,2 and antitumor activities.3–6
Indeno[1,2-c]pyrazole-4-ones (1) have recently been
explored as a new class of antitumor cyclin dependent
kinase inhibitors.3–6 These compounds show excellent
activity against numerous tumor cell lines and show
selectivity for proliferating cells versus normal cells.
Their synthesis involves a hydrazine-induced cyclization
of triketone (2) as a key step (Scheme 1).1–7 However,
the triketones are synthetically difficult to access,4,8
and the cyclization of the unsymmetric triketone may
produce two regioisomers, whose separation is usually
very tedious. In recent literature, a number of methods
have been reported for the preparation of triketones.4
The yield of indeno[1,2-c]pyrazole-4-ones (1) is highly
dependent on the substituents at the 3-position, and
the substituents on the phenyl ring dramatically affect
the regioselectivity of the cyclization. Consequently,
long synthetic routes or tedious purifications may be
necessary to obtain the desired regioisomer.
During the course of our studies, we discovered mild
conditions for the benzylic oxidation of indenopyrazole
3, which is easily accessible through numerous organic
synthetic methodologies.9 A mixture of 3 (0.5 mmol)
and Cs2CO3 (2.0 mmol) (or NaH) in DMF was stirred
under molecular oxygen at ambient temperature to pro-
duce 1 in quantitative yield as indicated by LC–MS
(Scheme 1, and Table 1). A simple filtration, aqueous
wash, and evaporation of the solvent provided product
1, which usually required no further purification.10 As
shown in Table 1, the reaction conditions tolerated a
variety of functional groups, including the protecting
group SEM (on both N and O, entries A and B), a ben-
zylic alcohol (entry F), and pyridine or pyrazine moieties
(entries G and H).
H
O
N
N2
O
NH2NH2
R
R
R'
R'
4
O
5
2
O
1
O2
base
DMF
H
O
N
O
N
O
NH2NH2
R
R
R
R'
R'
3
Base-induced benzylic oxidations with molecular oxygen
have been described in a variety of substrates such as flu-
orene and its derivatives,11 oxazolines,12 and thiox-
anthene.13 Analogous to the reported mechanism for
the oxidation of methylene-bridged polyarenes,11b a pos-
sible mechanism for the conversion of 3 to ketone 1 is
depicted in Scheme 2. The methylene carbon at the
Scheme 1.
Keywords: Indenopyrazole; Pyrazoloindenone; Oxidation; Molecular
oxygen; Suzuki coupling; Mitsunobu reaction; Antitumor activity.
*
Corresponding author. Tel.: +1 847 938 6772; e-mail: Zhi-Fu.Tao@
abbott.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.08.147

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Z.-F. Tao et al. / Tetrahedron Letters 46 (2005) 7615–7618
Table 1. Oxidation of indenopyrazole (3) in the presence of Cs2CO3 and O2
Entry
Ad
Substrate (3)
Temperature (°C)a/reaction time (h)
Conversion [%]b (1: isolated yield, %)c
SEM
90/24
100 (89)
N
N
H3CO
HO
3A
OSEM
SEM
N
N
H3CO
Bd
50/12
90/7
100 (99)
100 (96)
SEMO
3B
CN
H
N
N
3C
C
Br
H
N
N
D
E
90/12
90/3
90/3
90/5
90/5
100 (95)
100 (97)
85e (77)
98 (90)
3D
Br
H
N
N
O
O
3E
Br
SEM
N
N
O
Fd
G
H
3F
CN
HO
H
N
N
O
O
N
N
N
3G
H
N
N
O
O
100 (92)
3H
a Not optimized.
b Indicated by LC–MS.
c Purified by flash chromatography or recrystallization.
d SEM group could be on either N of pyrazole.
e Major side product is the de-SEM ketone (10%).
H
H
H
N
H
N
N
N
N
N
N
N
R
O2
+ HO-
R'
R'
R
Base
R
R
R'
R'
O
3
H
O
H
1
O
Scheme 2.

Z.-F. Tao et al. / Tetrahedron Letters 46 (2005) 7615–7618
7617
H
N
H
N
ArB(OH)2, Pd(PPh3)2Cl2,
Na2CO3, DME-EtOH-H2O
N
N
160oC in Microwave
Br
Ar
O
O
1C
NH2
O
Ar =
OH
Yield: 83%
Yield: 85%
Scheme 3.
H
N
SEM
SEM
N
N
O
N
N
N
O
O
O
a
b, c
O
HO
CN
O
CN
O
CN
O
SEM
1B
N
Scheme 4. Reagents and conditions: (a) 0.1 N HCl, EtOH–dioxane (35:1), room temperature, 1.5 h, quantitative yield; (b) 3-dimethylaminoprop-
onal, polymer-supported Ph3P, DBAD, THF, room temperature; (c) 2 N HCl, EtOH–dioxane (1:1), room temperature, 77% yield for two steps.
4-position is deprotonated by base, and the resulting
anion is then trapped by molecular oxygen to provide a
peroxy anion. The peroxy anion abstracts a proton from
the benzylic site of the intermediate in an intermolecular
or intramolecular fashion, leading to loss of hydroxide
ion and formation of a carbonyl group. The remarkable
efficiency of this conversion can be attributed to the rela-
tively high acidity of the doubly activated benzylic
protons.11b
tional groups in the substrates. This methodology
should facilitate the exploration of indeno[1,2-c]pyra-
zole-4-ones as important therapeutically useful agents.
References and notes
1. Flores, M. C.; Love, B. US 2989538.
2. Love, B.; Mosher, W. A. US 2969374.
3. Nugiel, D. A.; Etzkorn, A.-M.; Vidwans, A.; Benfield, P.
A.; Boisclair, M.; Burton, C. R.; Cox, S.; Czerniak, P. M.;
Doleniak, D.; Seitz, S. P. J. Med. Chem. 2001, 44, 1334–
1336.
4. Nugiel, D. A.; Vidwans, A.; Etzkorn, A.-M.; Rossi, K. A.;
Benfield, P. A.; Burton, C. R.; Cox, S.; Doleniak, D.;
Seitz, S. P. J. Med. Chem. 2002, 45, 5224–5232.
5. Yue, E. W.; Higley, C. A.; DiMeo, S. V.; Carini, D. J.;
Nugiel, D. A.; Benware, C.; Benfield, P. A.; Burton, C. R.;
Cox, S.; Grafstrom, R. H.; Sharp, D. M.; Sisk, L. M.;
Boylan, J. F.; Muckelbauer, J. K.; Smallwood, A. M.;
Chen, H.; Chang, C.-H.; Seitz, S. P.; Trainor, G. L.
J. Med. Chem. 2002, 45, 5233–5248.
The ease of derivatization of ketone 1 was demonstrated
by the elaboration of the product ketones 1B and 1C. As
shown in Scheme 3, the Suzuki coupling of 1C with aryl-
boronic acids went very smoothly under microwave
heating conditions. The efficiency of microwave flash
heating in accelerating organic transformations (in par-
ticular in cross-coupling reactions) has been well docu-
mented,14 and therefore the microwave-accelerated
Suzuki coupling could be performed in a combinatorial
fashion to provide a large number of biaryl derivatives
for biological screening in a short time.
6. Yue, E. W.; DiMeo, S. V.; Higley, C. A.; Markwalder, J.
A.; Burton, C. R.; Benfield, P. A.; Grafstrom, R. H.; Cox,
S.; Muckelbauer, J. K.; Smallwood, A. M.; Chen, H.;
Chang, C.-H.; Trainor, G. L.; Seitz, S. P. Bioorg. Med.
Chem. Lett. 2004, 14, 343–346.
7. Braun, R. A.; Mosher, W. A. J. Org. Chem. 1959, 24, 648–
650.
8. Kilgore, L. B.; Ford, J. H.; Wolfe, W. C. Ind. Eng. Chem.
1942, 34(4), 494–497.
9. Tong, Y.; Claiborne, A. K.; Li, G.; Lin, N.-H.; Sham, H.
L.; Sowin, T. J.; Tao, Z.-F. US20040259904.
10. All products were unambiguously characterized by proton
NMR and LC–MS.
Selective deprotection of SEM group of 1B at oxygen
was achieved in quantitative yield by treatment with
HCl (0.1 N) ethanol solution (Scheme 4). The resulting
phenol reacted with 3-dimethylamino propanol under
Mitsunobu condition in good yield, and removal of
SEM group from nitrogen released the critical element
for CDK kinase binding.5 The Mitsunobu reaction
could be performed in a parallel manner, providing a
large number of compounds for biological screening in
a short time.
In conclusion, we developed an efficient, convenient,
and general synthetic method for indeno[1,2-c]pyra-
zole-4-ones through oxidation of indenopyrazoles by
treatment with a base and molecular oxygen. The mild
conditions employed are compatible to a variety of func-
11. (a) Dietrich, B.; Lehn, J. M. Tetrahedron Lett. 1973, 1225–
1228; (b) Harvey, R. G.; Abu-shqara, E.; Yang, C. X.
J. Org. Chem. 1992, 57, 6313–6317; (c) Lala, A. K.; Dixit,
R. R. J. Chem. Soc. Chem. Commun. 1989, 636–638; (d)
Grieser, U.; Hafner, K. Chem. Ber. 1994, 127, 2307–

7618
Z.-F. Tao et al. / Tetrahedron Letters 46 (2005) 7615–7618
2314; (e) ADCHEMCO CORP., JP JP2002212126.; (f) 13. Alneri, E.; Bottaccio, G.; Carletti, V. Tetrahedron Lett.
Walters, M. E.; Kolonko, R. P.; Wehmeyer, R. M.
US5545760.
12. Meyers, A. I.; Slade, J. J. Org. Chem. 1980, 45, 2785–2791.
1977, 2117–2118.
14. Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res.
2002, 35, 717–727.