Synthesis and purification of 3-N-acylaminopyrazolinones using a sequence of functionalized polymers

Article abstract of DOI:10.1016/S0040-4039(03)00738-X

A parallel synthesis route to 3-acylaminopyrazolinones using a sequence of functionalized polymers has been developed. The polymers were utilized as both stoichiometric reagents and purification agents to allow for the clean formation of the desired target compounds.

Full text of DOI:10.1016/S0040-4039(03)00738-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3843–3845
Synthesis and purification of 3-N-acylaminopyrazolinones using a
sequence of functionalized polymers
Jiasheng Fu and Stephen J. Shuttleworth*
Tularik Inc., Two Corporate Drive, South San Francisco, CA 94080, USA
Received 23 January 2003; revised 11 March 2003; accepted 11 March 2003
Abstract—A parallel synthesis route to 3-acylaminopyrazolinones using a sequence of functionalized polymers has been
developed. The polymers were utilized as both stoichiometric reagents and purification agents to allow for the clean formation of
the desired target compounds. © 2003 Elsevier Science Ltd. All rights reserved.
The chemistry of 3-aminopyrazolinones was studied
extensively over a 20 year period beginning in the
1940s.1 However, aside from a small number reports
disclosing the uses of 1-phenyl-3-aminopyrazolinones as
building blocks in the construction of 6,5-fused hetero-
cyclic systems,2–4 these interesting heterocycles have
attracted scarce literature attention over recent years.
quently conducted a statistically-designed series of
experiments in an attempt to attenuate the reactivity of
the substrate 1 and to cleanly isolate the desired 3-
acylaminopyrazolinone product 3. A range of alterna-
tive solvents was examined, including dichloromethane,
dichloroethane, chloroform, acetonitrile, 1,4-dioxane
and tetrahydrofuran. Additionally, we varied the reac-
tion temperature from −20 to 50°C, and a variety of
substrate/reactant ratios were examined. Further, acti-
vated carboxylic acid esters were studied as alternative
substrates to acid chlorides, and the reaction was con-
ducted in the presence and absence of a range of
organic bases, including N-methylmorpholine, Hu¨nig’s
base, 4-dimethylaminopyridine and their polymer-sup-
ported counterparts.7 In all cases, however, we rou-
tinely observed the mixture of components outlined
above.
Our initial investigations into the chemistry of 3-
aminopyrazolinones focused on developing conditions
for N-acylation.5,6 This simple reaction proved to be
extremely capricious, however, and presented several
synthetic challenges. Our first experiment involved
treating 1-phenyl-3-aminopyrazolinone with 2-thio-
phenecarbonyl chloride in N,N-dimethylformamide in
the presence of polymer-supported Hu¨nig’s base
(Scheme 1). After 10 min at room temperature, LCMS
analysis of the reaction mixture indicated the presence
of starting amine 1 and acid chloride 2, the desired
3-N-acylpyrazolinone 3, and a bis-acylated product 4;
this observation was consistent with established—
though limited—literature precendent.1 We subse-
In light of these results, we chose to develop a synthetic
route to 3-N-acylaminopyrazoliones utilizing
a
sequence of functionalized polymers serving as both
stoichiometric reagents and purification media. Based
Scheme 1.
* Corresponding author. E-mail: sshuttleworth@tularik.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00738-X

3844
J. Fu, S. J. Shuttleworth / Tetrahedron Letters 44 (2003) 3843–3845
Scheme 2.
upon our initial findings, we anticipated that isolated
yields of products might be disappointing, but nonethe-
less aimed to develop an approach that could not only
allow for the clean isolation of the desired 3-
acylaminopyrazolinones but which could also be
applied to the rapid parallel synthesis of targeted com-
pound libraries. The synthetic route we developed is
outlined in Scheme 2.
treating 3-aminopyrazolinone 1 (1 weight) with acid
chloride 5 (1 equiv.) in tetrahydrofuran in the presence
of polymer-supported Hu¨nig’s base (1.5 equiv.). The
reaction mixture was agitated for 12 h at room temper-
ature and was then filtered, and the resin was washed
with tetrahydrofuran. The filtrate, containing a mixture
of amine 1, acid chloride 5, bis-acylated derivative 6
and the desired product 7, was subsequently treated
with polymer-supported sulfonic acid resin (1 equiv.),8
and the suspension was agitated for 4 h at room
temperature before being filtered under reduced pres-
Following extensive method development, we con-
cluded that the optimum procedure involved initially
Table 1.

J. Fu, S. J. Shuttleworth / Tetrahedron Letters 44 (2003) 3843–3845
3845
and circumvent a troublesome bis-acylation reaction
allowing for the desired products to be cleanly isolated.
By using this approach we were able to prepare a
library of 400 diverse analogues; we believe this proce-
dure to be the optimum method disclosed to date for
the rapid preparation of 3-N-acylaminopyrazolinone
derivatives.
Acknowledgements
We would like to thank Juan Jaen, Richard Connors,
Shichang Miao, Wayne Inman, and Malgorzata
Wan˜ska.
References
1. For a review, see: Wiley, R. H.; Wiley, P. Pyrazolones,
Pyrazolidones and Derivatives; Weissberger, A., Ed.;
Interscience: New York, 1964; Chapter VIII., Volume 20
of the Series The Chemistry of Heterocyclic Compounds.
2. Cocco, M. T.; Congiu, C.; Onnis, V. J. Het. Chem. 1994,
31, 925.
Figure 1.
3. Elgemeie, G. E. H.; Elghandour, A. H.; Elzanate, A. M.
J. Chem. Res. Synop. 1997, 7, 256.
4. Vanden Eynde, J. J.; Rutot, D. Tetrahedron 1999, 55,
2687.
5. Barr, C. R.; Salminen, I. F.; Weissberger, A. J. Am.
Chem. Soc. 1951, 73, 4131.
6. Graham, B.; Porter, H. D.; Weissberger, A. J. Am. Chem.
sure. Analysis of the filtrate indicated that the sup-
ported acid had effectively scavenged the excess starting
material 1 from the reaction mixture to furnish the
resin-bound amine 8. Finally, the filtrate was treated
with
N-(2-aminoethyl)aminomethylpolystyrene
(4
equiv.),9 which efficiently reacted with the bis-acylated
derivative 6 to liberate the desired product 7 in high
levels of purity; this supported amine also served to
sequester any remaining acid chloride present in the
reaction mixture. All of the reactions in this exercise
were conducted on a scale of 1.14 mmol of substrate
amine using 6 mL of solvent, and a representative
selection of results obtained for the reactions involving
1-phenyl-3-aminopyrazolinone is summarized in Table
1.
Soc. 1949, 71, 983.
7. Polymer-supported Hu¨nig’s base was purchased from
Polymer Laboratories Ltd., catalogue
c
3413-4679.
Polymer-supported N-methylmorpholine and 4-dimethyl-
aminopyridine were both purchased from Argonaut
Technologies Inc., catalogue c 800282 and c 800288,
respectively.
8. Polymer-supported sulfonic acid is commercially-avail-
able from Polymer Laboratories Ltd., catalogue c 3404-
4679.
9. N-(2-Aminoethyl)aminomethylpolystyrene is commer-
cially available from Novabiochem Inc., catalogue c
01-64-0178.
Whilst the isolated yields of products were variable, we
were able to recycle the starting material 1 for further
use by treating the resin-bound amine 8 with a solution
of 2 M ammonia in methanol.11 Additionally, the prod-
ucts were isolated with high purities in all cases. To
illustrate the effectiveness of the functionalized poly-
mers used in this synthetic process, LCMS traces from
the reaction involving 1-phenyl-3-aminopyrazolinone
with benzoyl chloride (Table 1, entry 2) are depicted in
Figure 1.
10. Purity of products was determined using an Agilent 1100
LC/MSD VL ESI system. Representative analytical data
for Table 1, entry 1, consistent with the enol form of
1-phenyl-3-N-acetylaminopyrazolinone: lH (400 MHz,
DMSO-d6) 10.40 (1H, s), 7.70 (2H, d), 7.50–7.40 (2H, d),
6.20 (1H, t), 5.95 (1H, s), 2.00 (3H, s). lc (400 MHz,
DMSO-d6) 167.69, 152.36, 147.17, 138.79, 129.06, 124.94,
124.19, 120.35, 117.81, 80.68, 23.23. M+1 found 218;
C11H11N3O2 requires 217.23.
In summary, a convenient method for the N-acylation
of 3-aminopyrazolinones has been successfully devel-
oped and applied to parallel synthesis. The method
utilizes a sequence of functionalized polymers to pro-
mote N-acylation, recycle unreacted starting material,
11. As a typical example, for Table 1, entry 2, treatment of 8
with methanolic ammonia enabled 27% of amine 1 to be
recycled, corresponding to a 63% overall account of mass
balance; the loss of material in this experiment is
attributed to sub-optimal resin washing in step 3.