Solid-phase synthesis of pyrazolines and isoxazolines with sodium benzenesulfinate as a traceless linker

Article abstract of DOI:10.1021/ol0340888

(Matrix presented) The preparation of pyrazoline and isoxazoline derivatives with traceless solid-phase sulfone linker strategy is described. Key steps involved in the solid-phase synthetic procedure include (i) sulfinate S-alkylation, (ii) sulfone anion alkylation, (iii) γ-hydroxy sulfone → γ-ketosulfone oxidation, and (iv) traceless product release via elimination-cyclization. A library of 12 pyrazolines and isoxazolines was synthesized.

Full text of DOI:10.1021/ol0340888

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1067-1069
Solid-Phase Synthesis of Pyrazolines
and Isoxazolines with Sodium
Benzenesulfinate as a Traceless Linker
Yu Chen, Yulin Lam,* and Yee-Hing Lai
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlamyl@nus.edu.sg
Received January 19, 2003
ABSTRACT
The preparation of pyrazoline and isoxazoline derivatives with traceless solid-phase sulfone linker strategy is described. Key steps involved
in the solid-phase synthetic procedure include (i) sulfinate S-alkylation, (ii) sulfone anion alkylation, (iii) γ-hydroxy sulfone f γ-ketosulfone
oxidation, and (iv) traceless product release via elimination−cyclization. A library of 12 pyrazolines and isoxazolines was synthesized.
An important feature of solid-phase organic synthesis (SPOS)
is the linker that attaches the compounds being synthesized
onto the solid support.1 Methods of immobilizing compounds
to the solid phase for combinatorial synthesis initially rely
upon traditional solid-phase peptide linkers, which resulted
in the release of carboxylic acids, esters, or amides from the
ester- or amide-bound substrate.2 The presence of these
appendages is acceptable if the final products embody these
functional groups. However, complications may arise if these
vestigial functionalities are redundant and affect the activities
of the compounds. In this regard, one of our interests is to
develop the sulfone linker via polystyrene/1% divinylbenzene
sodium sulfinate (1) as a traceless linker and explore new
applications for it in SPOS. Earlier reports from other
laboratories3,4 and ours5 have demonstrated the use of 1 as
a solid support for SPOS and shown the resulting sulfone
linker derived from 1 to be a versatile and robust tether that
offers a variety of on-resin functionalization or cleavage with
additional changes.
Compounds containing the pyrazoline or isoxazoline
moieties have diverse activities6 and have been developed
as antiinflammatory agents,7 human leukocyte elastase
inhibitors,8 optical brighteners,9 fluorescent switches,10 and
intermediates of various biologically important compounds.11
Although the solid-phase synthesis of isoxazoline with 1,3-
dipolar cycloaddition has been extensively studied,3b,12
examples of their solid-phase synthesis with R,â-unsaturated
(4) (a) Huang, W.; Cheng, S.; Sun, W. Tetrahedron Lett. 2001, 42, 1973-
1974. (b) Farrall, M. J.; Frechet, J. M. J. Org. Chem. 1976, 41, 3877. (c)
Fyles, T. M.; Leznoff, C. C. Can J. Chem. 1976, 54, 935. (d) Fyles, T. M.;
Leznoff, C. C. Can. J. Chem. 1978, 56, 1031.
(5) (a) Chen, Y.; Lam, Y. L.; Lai, Y. H. Org. Lett. 2002, 4, 3935-3937.
(b) Chen, Y.; Lam, Y. L.; Lee, S. Y. Chem. Lett. 2001, 3, 274-275.
(6) Vita-Finzi, P. The Chemistry of Heterocyclic Compounds; Wiley &
Sons: New York, 1991; Vol 4, Part 1, p 417.
(7) (a) Frigola, J.; Colombo, A.; Pares, J.; Martinez, L.; Sagarra, R.;
Roster, R. Eur. J. Med. Chem. 1989, 24, 435-445. (b) Copp, F. C.; Islip,
P. J.; Tateson, J. E. Biochem. Pharmacol. 1984, 33, 339-340.
(8) Groutas, W. C.; Venkataman, R.; Chong, L. S.; Yoder, J. E.; Epp, J.
B.; Stanga, M. A.; Kim, E. Bioorg. Med. Chem. 1995, 3, 125-128.
(9) Dorlars, A.; Schellhammer, C.; Schroeder, J. Angew. Chem., Int. Ed.
1975, 14, 665-679.
(10) Silva, A. P.; Gunaratne, H. Q. N.; Gunnlaugsson, T.; Nieuwenhuizen,
M. Chem. Commun. 1996, 1967-1968.
(11) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410-416.
(1) Guillier, F.; Orain, D.; Bradley, M. Chem. ReV. 2000, 100, 2091-
2157.
(2) Bunin, B. A. The Combinatorial Index; Academic Press: San Diego,
CA, 1998; pp 9-76.
(3) (a) Cheng, W. C.; Kurth, M. J. J. Org. Chem. 2002, 67, 4387-4391.
(b) Cheng, W. C.; Wong, M.; Olmstead, M. M.; Kurth, M. J. Org. Lett.
2002, 4, 741-744. (c) Cheng, W. C.; Lin, C. C.; Kurth, M. J. Tetrahedron
Lett. 2002, 43, 2967-2970. (d) Cheng, W. C.; Olmstead, M. M.; Kurth,
M. J. J. Org. Chem. 2001, 66, 5528. (e) Cheng, W. C.; Halm, C.; Evarts,
J. B.; Olmstead, M. M.; Kurth, M. J. J. Org. Chem. 1999, 64, 8557. (f)
Halm, C.; Evarts, J.; Kurth, M. J. Tetrahedron Lett. 1997, 38, 7709-7712.
10.1021/ol0340888 CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/08/2003

ketone and hydroxylamine are unknown. In addition, to our
knowledge, there have been no reports on the traceless
synthesis of pyrazolines. Herein, we report the extension of
this sulfone-based chemistry to a convenient, traceless
synthesis of pyrazoline or isoxazoline derivatives using R,â-
unsaturated ketone and hydrazine/hydroxylamine.
Scheme 2. Solution-Phase Study
Key steps in the synthesis of pyrazolines or isoxazolines
from 1 include (i) sulfinate S-alkylation, (ii) sulfone anion
alkylation with an epoxide, (iii) γ-hydroxyl sulfone f
γ-ketosulfone oxidation, and (iv) traceless product release
by a one-pot elimination-cyclization reaction (Scheme 1).
Scheme 1. Sulfinate SPOS to Pyrazoline and Isoxazoline
Attempts to cyclize 9 by refluxing it with phenyl hydrazine
and KOH/CH3OH in air gave mainly 1,3,5-triphenyl-1H-
pyrazole (10, 68%) and only 15% of 1,3,5-triphenyl-4,5-
dihydro-1H-pyrazole (5a). However, when the reaction was
carried out under nitrogen condition, 5a was formed in 82%
Since a variety of reagents can be used in steps i, ii, and iv,
the overall strategy appears to be applicable for library
generation.
Solution-Phase Synthesis of Pyrazoline and Isoxazoline.
Prior to the solid-phase synthesis, preliminary solution-phase
studies were carried out to survey the requisite reaction
conditions and establish the modifications required for SPOS.
To begin our investigation, γ-ketosulfone, 3-benzenesulfonyl-
1,3-diphenylpropan-1-one (9) was prepared by treating
sodium benzenesulfinate (6) with benzyl bromide in the
presence of NBu4I/KI/DMF at room temperature to give
phenylsulfonylmethylbenzene (7) in 95% yield (Scheme 2).
Subsequent alkylation of 7 with styrene oxide according to
a procedure from Kurth and co-workers3c provided 3-ben-
zenesulfonyl-1,3-diphenylpropan-1-ol (8) in good yield
(91%). Oxidation of 8 with Jones reagent13 gave 9 in
quantitative yield (97%).
(12) (a) Faita, G.; Mella, M.; Mortoni, A.; Paio, A.; Quadrelli, P.; Seneci,
P. Eur. J. Org. Chem. 2002, 1175-1183. (b) Zou, N.; Jiang, B. J. Comb.
Chem. 2000, 2, 6-7. (c) Ockey, D. A.; Lane, D. R.; Seeley, J. A.; Schore,
N. E. Tetrahedron 2000, 56, 711-717. (d) Kobayashi, S.; Akiyama, R.
Tetrahedron Lett. 1998, 39, 9211-9214. (e) Shankar, B. B.; Yang, D. Y.;
Girton, S.; Ganguly, A. K. Tetrahedron Lett. 1998, 39, 2447-2448. (f)
Cheng, J.; Mjalli, A. M. M. Tetrahedron Lett. 1998, 39, 939-942. (g)
Studer, A.; Curran, D. P. Tetrahedron 1997, 53, 6681-6696. (h) Chan-
drasekhar, S.; Raza, A.; Reddy, M. V.; Yadav, J. S. J. Comb. Chem. 2002,
4, 652-655.
Figure 1. Library of pyrazoline and isoxazoline.
Org. Lett., Vol. 5, No. 7, 2003
(13) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem.
Soc. 1954, 2548-2560.
1068

yield and 10 was not observed at all. Similarly, reaction of
9 with hydroxylamine hydrochloride in nitrogen atmosphere
gave the desired 3,5-diphenyl-4,5-dihydroisoxazole (5d) in
75% yield.
the overall yields of 5a-d and 5f-k were 25-45% (purities
of >95% by NMR), indicating an average yield of greater
than 70% for each step of the four solid-phase reactions.
The lower yield observed for 5e may be attributed to the
greater steric hindrance in the molecule. 5l was prepared via
a five-step reaction from polymer-supported 2-benzenesul-
fonylmethyl-6-methylimidazo[1,2-a]pyridine.5a
The structures of the pyrazolines and isoxazolines were
confirmed by NOESY experiments performed on representa-
tive compounds 5c, 5f, and 5i. The observed data indicate
that 5c has the trans configuration.
Solid-Phase Synthesis of Pyrazoline and Isoxazoline.
With the solution-phase pathway to pyrazoline and isoxazo-
line established, we proceeded to develop the solid-phase
route to these compounds. Polystyrene/1% divinylbenzene
sodium sulfinate (1, 100-200 mesh) in NBu4I/KI/DMF was
allowed to react with benzyl bromide at room temperature
(Scheme 1). The formation of 2 was amenable to KBr FTIR
monitoring (i.e. appearance of the sulfone stretch at 1316,
1151 cm-1). Alkylation of 2 with epoxides gave resin 3,
which could not be reliably analyzed with FTIR. Hence we
proceeded to oxidize resin 3 with Jones reagent (we have
also examined the oxidation of resin 3a with Dress-Martin
reagent and found that the overall yield was comparable to
that obtained from the Jones reagent; since the Jones reagent
was easier to handle, it was used for our library synthesis).
This transformation was monitored by FTIR for the appear-
ance of a new carbonyl stretch (νmax 1687 cm-1). Subsequent
treatment of resin 4 with substituted hydrazine or hydroxyl-
amine in KOH/CH3OH under nitrogen condition gave 5. To
illustrate the versatility of this chemistry, a library of 12
compounds (5a-5l) was prepared (Figure 1). Except for 5e,
In summary, we have demonstrated a traceless solid-phase
synthesis of pyrazoline and isoxazoline that accommodates
four points of diversification (R1 to R4 in 5). The chemistry
used is suitable for combinatorial library preparation.
Acknowledgment. We thank the National University of
Singapore for financial support of this work.
Supporting Information Available: Detailed experi-
mental procedure, NMR and MS data for all compounds,
1H and 13C NMR spectra for 5a-c, and NOESY data for
5c,f,i. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL0340888
Org. Lett., Vol. 5, No. 7, 2003
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