Convergent synthesis of 2,3-bisarylpyrazolones through cyclization of bisacylated pyrazolidines and hydrazines

Article abstract of DOI:10.1016/j.tetlet.2006.03.063

Cyclization of various bisacylated hydrazines and pyrazolidines using DBU or sodium hydride leads to the formation of various mono-, bi- and tricyclic pyrazolone scaffolds in 41-98% yield. The convergent nature by which the precyclization intermediates are constructed allows for rapid derivatization about the pyrazolone core.

Full text of DOI:10.1016/j.tetlet.2006.03.063

Tetrahedron Letters 47 (2006) 3195–3198
Convergent synthesis of 2,3-bisarylpyrazolones through
cyclization of bisacylated pyrazolidines and hydrazines
Todd A. Brugel,a,* Tomas Hudlicky,b, Michael P. Clark,a Adam Golebiowski,a
Mark Sabat,a Mary Ann A. Endoma,b Vu Bui,b David Adams,b Matthew J. Laufersweiler,a
Jennifer A. Maier,a Roger G. Booklanda and Biswanath Dea
aProcter and Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road, Mason, OH 45040-8006, USA
bDepartment of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
Received 13 February 2006; revised 7 March 2006; accepted 9 March 2006
Available online 29 March 2006
Abstract—Cyclization of various bisacylated hydrazines and pyrazolidines using DBU or sodium hydride leads to the formation of
various mono-, bi- and tricyclic pyrazolone scaffolds in 41–98% yield. The convergent nature by which the precyclization inter-
mediates are constructed allows for rapid derivatization about the pyrazolone core.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
tetrasubstituted pyrazolones. During our efforts to
develop novel anti-inflammatory agents, we became
interested in the synthesis of fully substituted-2,3-
bisarylpyrazolones for potential treatment of arthritis.
This report describes a new procedure applicable to
the rapid construction of these systems.
Medicinal chemists have used pyrazolones extensively as
scaffolds from which to design novel therapeutic agents.
This heterocyclic ring system is found in a number of
compounds showing analgesic (morazone 1 (Fig. 1)),1
immunosuppressant (BTS-71412)2 and anti-inflamma-
tory (asprin–propyphenazone)3 activity. Numerous
methods for general pyrazolone synthesis have been
reported. These methods include cyclocondensation
reactions,4 diphenylcyclopropenone reactions with
hydrazines,5 Mannich reactions of acylhydrazones with
ketene silyl acetals,6 and cyclization of diacyl-
dimethylhydrazines.7 These procedures have been limi-
ted primarily to the formation of simple di-, tri- and
The role of pro-inflammatory cytokines such as tumor
necrosis factor-a (TNF-a) and interleukin-1b (IL-1b)
in the pathogenesis of numerous inflammatory disorders
such as rheumatoid arthritis (RA), osteoarthritis (OA)
and Crohn’s disease has been well documented.8 Cyto-
kines are synthesized via a signal transduction cascade
involving several members of the mitogen-activated
protein (MAP) kinase family such as p38 and c-Jun
N-terminal kinase (JNK). Regulating cytokine over-
expression with small molecule kinase inhibitors is a
major focus of many pharmaceutical companies.9
O
O
N
N
Our efforts in this area have resulted in the synthesis of a
novel class of bicyclic pyrazolone inhibitors.10 The syn-
thesis of these heterocycles was originally accomplished
via the route shown in Scheme 1. Aldol reaction between
4-fluorophenyl acetate 2 and 2-methylsulfanyl pyrimi-
dine-4-carbaldehyde 3 provided b-hydroxyester 4. This
was followed by oxidation with chromium trioxide to
afford b-ketoester 5. Cyclization of 5 with pyrazolidine
dihydrogen chloride produced the desired 2,3-bisaryl-
pyrazolone 6. Oxidation (Oxoneꢁ, THF/MeOH/H2O)
N
1
Figure 1. Anti-inflammatory agent morazone 1.
*
Corresponding author. Tel.: +1 513 622 4498; fax: +1 513 622
3681; e-mail: todd_brugel@msn.com
Present address: Department of Chemistry, Brock University, St.
Catharines, Ontario, Canada L2S 3A1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.063

3196
T. A. Brugel et al. / Tetrahedron Letters 47 (2006) 3195–3198
F
F
c, d
O
Boc
Cbz
O
F
a
O
O
N
N
a, b
OCH3
N
OCH3
Cl
10
OH
CbzN
N
N
N
N
4
8
9
2
SMe
SMe
F
F
O
F
H
O
O
N
N
e
c
OCH3
N
b
O
N
O
N
N
ONa
N
N
N
5
MeS
S
12
N
SMe
11
F
F
O
O
F
F
N
O
ONa
N
d, e
N
N
N
H2O
N
N
N
N
N
N
N
NH
N
6
N
N
SMe
SMe
OH
N
7
MeS
6
13
Scheme 2. Synthesis of 6 via cyclization of a bis-acylated pyrazolidine.
Reagents and conditions: (a) SOCl2, MeOH, 90%; (b) 4-fluorophenyl-
acetyl chloride, NaOH, H2O/CH2Cl2, 96%; (c) H2, Pd/C, methanol,
83%; (d) acid chloride 10, NaOH, H2O, CH2Cl2, 52%; (e) NaH, DMF,
0 ꢂC, 49%.
Scheme 1. Linear synthesis of bicyclic pyrazolones. Reagents and
conditions: (a) LDA, 2-methylsulfanyl-pyrimidine-4-carbaldehyde 3,
THF, ꢀ78 ꢂC, 76%; (b) CrO3, CH2Cl2, pyridine, 43%; (c) Pyridine,
pyrazolidine dihydrogen chloride, 90 ꢂC, 28%; (d) Oxone, THF/
MeOH/H2O; (e) (S)-Methylbenzylamine, toluene, 120 ꢂC, 50%.
eliminate NaOH, or water upon quenching, to produce
pyrazolone 6.
and amine displacement (S-methylbenzylamine, toluene,
120 ꢂC) of the thiomethyl group furnished bicyclic
pyrazolone analog 7. This linear sequence suffered from
low yielding oxidation (4!5) and cyclization (5!7)
steps as well as an inability to rapidly develop SAR
about the two aryl substituents and the pyrazolidine
ring. We now report the development of a new route
to the 2,3-bisarylpyrazolone scaffold that addresses all
of the above issues.
The modest yield for this reaction can in part be
explained by the fact that significant amounts of de-
acylated material (30–40%) were often isolated from
the reaction mixture presumably due to an in situ amide
hydrolysis. Various combinations of bases (LiHMDS,7
Et3N, tetramethylguanadine (TMG), t-BuOK, DBU,
pyridine, LDA, NaOEt) and solvents (DMF, THF,
CH2Cl2, ethanol, toluene) were investigated in order to
improve the yield of this reaction. Only the combination
of DBU/DMF at 80 ꢂC produced comparable results
(53% yield) to the NaH/DMF/0 ꢂC conditions.
2. Results and discussion
The modified synthesis of bicyclic pyrazolone 7 is
described in Scheme 2. Beginning with the differentially
protected pyrazolidine 8,11 removal of the Boc protect-
ing group was accomplished with SOCl2/MeOH. This
was followed by acylation with 4-fluorophenylacetyl
chloride to give monoacylated pyrazolidine 9. Deprotec-
tion of the Cbz group under hydrogenation conditions
followed by a subsequent second acylation with pyrimi-
dine carbonyl chloride 10 gave the desired bis-acylated
pyrazolidine 11 in excellent yield. When 11 was sub-
jected to the cyclization conditions (2.5 equiv NaH,
DMF, 0 ꢂC), the desired bicyclic pyrazolone 6 was
isolated in 49% yield.12 A possible mechanism for this
condensation/cyclization involves a stepwise process in
which deprotonation of an acidic methylene proton on
11 would lead to intramolecular addition of the subse-
quent sodium enolate to the benzoyl carbonyl to give
alkoxide 12. Intermediate 12 would undergo a proton
exchange to afford hydroxy enolate 13 which would
The modest yield for this reaction is in line with previous
reports in this area in which it is described that the steric
bulk about the two acyl groups hinders both initial eno-
late addition to give intermediate 12 as well as the dehy-
dration step (13!6).13 An attempt at promoting the
cyclization under acidic conditions (pTsOH, toluene,
80 ꢂC) led to only recovered starting material and deacyl-
ated products.
Table 1 lists a series of variably substituted 2,3-bisaryl
pyrazolones synthesized using this methodology. In
these cases, the cyclization reaction was performed at
80 ꢂC in DMF using excess DBU in the place of NaH.
As discussed previously, the yields for these reactions
under the alternative conditions are comparable. These
examples highlight the utility of the methodology to
rapidly investigate SAR about the pyrazolone core.

T. A. Brugel et al. / Tetrahedron Letters 47 (2006) 3195–3198
3197
Table 2. Synthesis of substituted 2,3-bisaryl bi- and tricyclic
Table 1. Synthesis of 2,3-bisaryl bicyclic pyrazolones
pyrazolones
Entry
Bis-acylated hydrazine
Product (yield)a
Entry Bis-acylated hydrazine
Product (yield)a
F
F
O
F
F
O
O
O
N
N
N
O
1
N
N
Br
N
N
1
N
N
O
N
S
O
O
14
Br
15 (56%)
N
N
N
22
S
F
F
23 (57%)
O
O
F
F
F
F
N
N
O
O
2
N
H3C
N
O
N
N
N
N
2
O
O
N
O
16
H3C
F
17 (49%)
N
O
N
N
S
O
F
24
S
O
25 (41%)
O
N
N
N
O
O
3
N
N
N
N
N
O
N
O
3
H3C
N
19 (55%)
CH3
N
18
N
N
O
Ph
O
O
F
F
26
O
O
Ph
27 (28%)
O
N
N
N
F
F
4
N
O
O
O
N
CH3
21 (58%)
N
N
CH3
N
N
4
N
S
N
20
N
N
N
S
O
Ph
O
a Conditions: DBU, DMF, 80 ꢂC, 12 h.
28
O
29 (98%)
Ph
a Conditions: NaH, DMF, 0 ꢂC.
Cyclizations were also attempted with substrates where
the simple pyrazolidine ring was replaced by variably
substituted pyrazolidine and pyridazine ring systems.
Table 2 describes results of these studies. Bisacylated
intermediates 22, 24, 26 and 28 were synthesized using
the route described within Scheme 2 in which the appro-
priately substituted analog of pyrazolidine 8 was used.14
The yields for cyclization of substrates containing oxy-
gen substituents including alkoxy (entry 1) and ketal
(entry 2) were comparable to the simple unsubstituted
case. Conversely, in the case of a pyrazolidine contain-
ing a nitrogen substituent (entry 3), a lower yield of
the pyrazolone product was obtained. Finally, the cycli-
zation of a fused heterocyclic pyridazine system (entry 4)
resulted in a near quantitative yield of the desired tri-
cyclic pyrazolone analog 29.
F
F
O
O
b
a
Cl
N
NH2
O
31
30
NBoc
32
F
F
O
N
O
c
N
N
N
HN
O
NBoc
NBoc
O
N
33
34
S
F
d
N
N
This methodology has also been applied to the synthesis
of differentially substituted monocyclic pyrazolones
(Scheme 3).15 Beginning with phenylacetyl chloride 30,
reaction with methylhydrazine at ꢀ78 ꢂC led to selective
formation of the 1,1-disubstituted hydrazide 31 in 61%
yield. Reductive amination with piperidone 32 resulted
in isolation of 33 in excellent yield. A second acylation
with pyrimidine carbonyl chloride 10 gave the bisacyl-
ated precyclization intermediate 34. This material was
cyclized to the asymmetrically substituted monocyclic
pyrazolone 35 in 73% yield. This represents a synthesis
of a class of asymmetrically substituted pyrazolones that
N
N
S
N
Boc
35
Scheme 3. Synthesis of monocyclic pyrazolone 35. Reagents and
conditions: (a) methylhydrazine, CH2Cl2, ꢀ78 ꢂC to rt, 61%; (b)
piperidone 32, EtOH, reflux, 15 min; then NaBH3CN, MeOH, pH 4,
93%; (c) acid chloride 10, pyridine, 20%; (d) NaH, DMF, 0 ꢂC, 73%.
could not be previously obtained using the route out-
lined in Scheme 1.

3198
T. A. Brugel et al. / Tetrahedron Letters 47 (2006) 3195–3198
9. (a) Cirillo, P. F.; Pargellis, C.; Regan, J. Curr. Top. Med.
Conclusions
Chem. 2002, 2, 1021–1035; (b) Adams, J. L.; Badger, A. M.;
Kumar, S.; Lee, J. C. In Progress in Medicinal Chemistry;
King, F. D., Oxford, A. W., Eds.; Elsevier: Amsterdam,
2001; Vol. 39, pp 1–60.
A methodology for the convergent synthesis of 2,3-bis-
aryl pyrazolones has been developed highlighted by
the cyclization of a bisacylated hydrazine intermediate
using either NaH or DBU as base. The route allows
for the synthesis of both simple and substituted bicyclic
and tricyclic pyrazolone scaffolds as well as differentially
substituted monocyclic pyrazolones in moderate to
excellent yield. This new route allows for more rapid
development of SAR about the pyrazolone ring, as well
as entry into more complex and differentially substituted
systems not available by this previous method. Further
development of this methodology towards the synthesis
of other heterocycles is being investigated.
10. Clark, M. P.; Laughlin, S. K.; Laufersweiler, M. J.;
Bookland, R. G.; Brugel, T. A.; Golebiowski, A.; Sabat,
M.; Townes, J. A.; VanRens, J. C.; Djung, J. F.; Natchus,
M. G.; De, B.; Hsieh, L. C.; Xu, S. C.; Walter, R. L.;
Mekel, M. J.; Heitmeyer, S. A.; Brown, K. K.; Juergens,
K.; Taiwo, Y. O.; Janusz, M. J. J. Med. Chem. 2004, 47,
2724–2727.
11. Dutta, A. S.; Morley, J. S. J. Chem. Soc., Perkin Trans. 1
1975, 1712.
12. Representative procedure for the synthesis of pyrazolone 6
from pyrazolidine 11: A solution of 2-(4-fluoro-phenyl)-1-
[2-(2-methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-
1-yl]-ethanone 11 (78.0 g, 0.217 mol) in DMF (400 mL)
was added over 30 min to a 0 ꢂC slurry of NaH (21.6 g of
60% dispersion in mineral oil, 0.540 mol) in DMF
(150 mL). The mixture was stirred at 0 ꢂC for 30 min,
then quenched slowly with saturated aqueous ammonium
chloride solution (6 L). The mixture was extracted with
EtOAc (2 · 2L) and the combined organic layers dried
over Na2SO4, filtered and concentrated in vacuo to give a
viscous oil. The crude product was purified by flash
chromatography on silica gel (600 g SiO2, EtOAc to 10%
MeOH/EtOAc to 20% MeOH/EtOAc) to give product 6
(36.0 g, 49%) as a yellow foam: 1H NMR (300 MHz,
CDCl3) d 8.42 (dd, J = 5.4, 1.5 Hz, 1H), 7.41 (dd, J = 8.4,
5.4 Hz, 2H), 7.07 (dd, J = 8.4, 8.4 Hz, 2H), 6.83 (dd,
J = 5.4, 1.5 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 4.09 (t,
J = 6.9 Hz, 2H), 2.76 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 2H),
2.60 (s, 3H); ESI/MS: 343 (M+H).
Acknowledgements
We thank John VanRens and Steven K. Laughlin for
helpful discussions. We also thank Mark Webster for
chemistry support.
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