A novel isoxazole-based scaffold for combinatorial chemistry

Article abstract of DOI:10.1016/S0040-4039(00)00951-5

A novel isoxazole-based scaffold has been identified for the generation of combinatorial libraries using solid-phase methods. This scaffold has been utilized to afford high value synthetic intermediates through Baylis-Hillman reaction, Wittig reaction, nitroaldol condensation, and imine and oxime formation. The utility of the scaffold has been demonstrated by synthesizing a small library of 32 isoxazole substituted γ-amino alcohol using four activated alkenes and eight amines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00951-5

Tetrahedron Letters 41 (2000) 5971±5974
A novel isoxazole-based sca€old for combinatorial chemistry1
S. Batra,* S. K. Rastogi, B. Kundu, A. Patra and A. P. Bhaduri
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 13 April 2000; accepted 7 June 2000
Abstract
A novel isoxazole-based sca€old has been identi®ed for the generation of combinatorial libraries using
solid-phase methods. This sca€old has been utilized to a€ord high value synthetic intermediates through
Baylis±Hillman reaction, Wittig reaction, nitroaldol condensation, and imine and oxime formation. The
utility of the sca€old has been demonstrated by synthesizing a small library of 32 isoxazole substituted
g-amino alcohol using four activated alkenes and eight amines. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: combinatorial chemistry; 5-isoxazolecarboxaldehyde; SPOS; Baylis±Hillman reaction; Wittig reaction.
The construction of diverse multifunctional libraries of small organic molecules on solid
supports has been the most important feature of the evolution of combinatorial chemistry in the
recent years.2 This approach has led to the syntheses of various biologically active molecules such
as benzodiazepines, hydantoins, dihydro-pyridines, pyridines, benzopyrazones, ureas, sulfonamides,
carbamates, lactams, xanthines, oxazolones, sugar analogs, etc. both in parallel format or when
using the split and mix method.3 Despite this enormous development, much of the solid-phase
synthesis is indeed a direct translation of known solution-phase chemistry to obtain large
numbers of possible analogs of a bioactive molecule. The isoxazole ring system that can be easily
obtained by [3+2] cycloadditions of nitrile oxides with acetylenes is of particular interest since it is
a component of various pharmaceutical agents and also a precursor to useful synthetic
intermediates such as g-amino alcohols and b-hydroxy ketones. Though the synthesis of iso-
xazoles on 2-chlorotrityl resin has been described earlier using the above-mentioned synthetic
strategy no further work on its chemistry is reported on solid-phase.4 In our e€orts towards
exploring the chemistry of isoxazoles on solid-phase we observed that 3-(4-hydroxy-phenyl)-5-
isoxazolecarboxaldehyde can serve as a good sca€old for obtaining structurally diverse
derivatives of isoxazoles. The details of this study are presented here.
* Corresponding author. Tel: 0522-212411-18, extn: 4368, 4383; fax: 91-0522-223405, 223938; e-mail: root@-
cscdri.ren.nic.in
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00951-5

5972
The solid-phase synthesis of various isoxazole derivatives using 3-(4-hydroxyphenyl)-5-iso-
xazolecarboxaldehyde as a novel sca€old has been outlined in Scheme 1. Cleavage of numerous
5±7 mg samples of the resin bound intermediates with subsequent HPLC, FAB MS and PMR of
the resultant products accompanied each step during optimization.
Scheme 1. a) CH2=CHR1, DABCO, DMSO, rt, 1 h; b) R2NH2 or N-methylpiperazine, DMF, 50oC, 12 h; c)
PPh3CH2R3X, NaOMe, THF/MeOH, 60oC, 6 h; d) R4CH2NO2, EtOH/THF, rt, 3 h; e) NH2OH.HCl, pyridine, rt,
overnight; f) R5NH2, TMOF, 3 h
The 3-(4-hydroxyphenyl)-5-isoxazolecarboxaldehyde used as starting material for the present
study was obtained from debenzylation of the corresponding benzyloxy substituted aldehyde in
the presence of acetic acid:HCl mixture (2:1, v/v). In the ®rst step the 3-(4-hydroxyphenyl)-5-
isoxazolecarboxaldehyde was loaded onto 2-chlorotrityl resin (1.4 mmmol/gm) in the presence of
DIEA and DMAP mixture in DMF at 50ꢀC for 12 h. The loading was determined by HPLC after
cleavage and was found to be 1.3 mmol/gm (loading ꢁ93%). Since it had been observed earlier
that these aldehydes are excellent substrates for fast Baylis±Hillman reaction in solution phase,5
the ®rst synthetic strategy involved an adoption of the same approach on the solid-phase.
Treatment of the resin bound 5-isoxazolecarboxaldehyde with a mixture of DABCO and an
activated alkene in DMSO led to formation of Baylis±Hillman adducts 2 within 1 h in excellent
yield and purity.6 This is in contrast to solid-phase Baylis±Hillman reactions reported in the
literature where alkenes are normally anchored onto the solid support and are then treated with
various aldehydes.7,8 In addition, the reaction rates reported for these reactions are usually slow
and yields are invariably moderate even after double coupling. Our ®ndings thus constitute the

5973
®rst report of anchoring the aldehyde on to the solid support and utilizing structurally diverse
activated alkenes for carrying out the Baylis-Hillman reaction.
Further, to investigate the scope and limitation of the sca€old, nitro aldol condensation with
nitromethane and nitroethane, Wittig reaction with triphenyl phosphonium methylene iodide and
triphenyl phosphonium bromoethyl acetate, imine formation with various amines and oxime
formation with hydroxylamine hydrochloride were carried out to obtain numerous versatile
intermediates 4, 5, 6 and 7, respectively. The compounds 4, 6 and 7 were obtained as mixtures of
geometrical isomers, whereas compounds 5 were obtained as diastereomeric mixtures. The
purities of these compounds ranged from 70±95% based on analytical HPLC.
These intermediates are indeed good substrates for developing the isoxazole-based libraries.
This has been demonstrated by carrying out synthesis of a small library of 32 isoxazole-
substituted g-amino alcohols 3 in parallel format by using four activated alkenes and eight
amines. The chemical steps involved in the synthesis of 3 are the formation of a Baylis±Hillman
adduct followed by a Michael addition of amines to the double bond of the intermediate 2. After
optimizing the reaction conditions in syringes, the library was generated through automation on
an Advanced Chemtech 496ꢀ Multiple Organic Synthesizer. The Michael adducts were obtained
as diastereomeric mixtures in good yields with purities ranging from 65±90% (Table 1).
Table 1
Structures, yields and purity of the representative compounds

5974
In summary, we have identi®ed 3-(4-hydroxyphenyl)-5-isoxazolecarboxaldehyde as a novel
building block for the generation of isoxazole-based libraries. This has been exempli®ed by
successfully synthesizing various useful synthetic intermediates, which can be further diversi®ed
to get an array of isoxazole-based novel compounds. The 32-member library of isoxazole-
substituted 1,3-aminoalcohols reported herein is being evaluated in several in vitro assays for the
generation of new leads. The synthetic potential of this novel sca€old is being explored further to
generate novel heterocyclic compounds.
Acknowledgements
The ®nancial support to S.K.R. from the Director (CDRI), and A.P. from Volkswagen
(Germany), respectively, in the form of a fellowship is gratefully acknowledged.
References
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American Chemical Society: Washington D.C., 1996; pp 58±69. (b) Wang, G. T.; Chen, Y.; Wang, S.; Sciotti, R.;
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6. General procedures. Baylis±Hillman reaction: To the resin loaded with aldehyde (50 mg) in DMSO (250 mL) was
added a 15 min premixed solution of DABCO (2.5 equivalents) and alkene (5 equivalents) in DMSO (250 mL) and
the reaction was shaken at 600 rpm for 1 h. Thereafter the resin was sequentially washed with DMF, MeOH,
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freeze dried to obtain the product 2. [R1=CH2CH3: FAB MS 289(M+); 1H NMR (300 MHz, CDCl3) ꢀ 1.25 (t, 3H,
J=7 Hz, CH3), 3.73 (br s, 1H, OH), 4.20 (q, 2H, J=7 Hz, CH2), 5.73 (s, 1H, CHOH), 6.13, 6.44 (2s, 2H, 1H each
of ˆCH2), 6.46 (s, 1H, ˆCH), 6.89 (d, 2H, J=9 Hz, Ar-H), 7.62 (d, 2H, J=9 Hz, Ar-H), 8.95 (brs, 1H, Ar4-OH)].
Michael addition: To the resin (50 mg) in DMF (500 mL) was added amine (10 equivalents) and the reaction was
stirred at 50ꢀC for 12 h. The resin was sequentially washed, cleaved and lyophilized as mentioned above to obtain
the amino derivatives. [R1= CH2CH3, NHR2=(4-methyl-piperazin-1-yl); FAB MS 389 (M+); 1H NMR (300
MHz, CDCl3+ DMSO-d6) ꢀ 1.22 (t, 6H, J=7 Hz, 2ÂCH3), 2.63 (s, 6H, 2ÂCH3), 2.79 (m, 20H, 10ÂCH2), 3.16 (m,
2H, 2ÂCH), 4.18 (q, 4H, J=7 Hz, 2ÂCH2), 5.18 (m, 1H, CH), 5.23 (m, 1H, CH), 6.51 (s, 2H, 2ÂCH), 6.92 (d, 4H,
J=9 Hz, Ar-H), 7.61, 7.64 (d, 4H, J=9 Hz, Ar-H). Wittig reaction: To the resin loaded with aldehyde (50 mg) in
THF (400 mL) was added triphenyl phosphonium methyl iodide (5 equivalents) and solution of NaOMe (6
equivalents) in MeOH (100 mL) and the reaction was stirred at 60ꢀC for 6 h. Thereafter the resin was sequentially
washed with 50% aq. MeOH (10Â4 mL), MeOH and ether (6Â4 mL). The resin was cleaved and freeze dried as
mentioned above to obtain the product. Nitroaldol condensation reaction: To the resin loaded aldehyde (50 mg) in
THF (200 mL) was added nitromethane (30 equivalents), ethanol (30 equivalents) and triethylamine (15
equivalents) and the reaction was shaken at 800 rpm for 3 h. Thereafter the resin was washed with THF, DMF,
MeOH, DCM and ether (5Â3 mL each). The cleavage of resin and freeze-drying of the residue was performed as
mentioned above.
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