reviewed.14 Solid-phase synthesis of pyrazoles has been
studied mainly via hydrazine reactions15 and also via 1,3-
dipolar cycloadditions.16 Acid-cleavable 2-methoxy-
substituted resin has proven very useful in traceless solid-
phase synthesis, and it has been utilized, e.g., in the
synthesis of five-membered nitrogen heterocycles such as
imidazoles,17 1,2,4-triazoles,18 and 1,2,3-triazoles.19 We
now introduce a traceless solid-phase synthesis of N-
unsubstituted pyrazole carboxylates via polymer-bound
sydnones utilizing 2-methoxy resin. The resin protects the
amino group during the N-nitrosation, and after the
reaction steps the products are cleaved from the resin in
a traceless manner yielding N-unsubstituted pyrazoles.
Several amino acid methyl esters were attached to
formyl-functionalized Ameba resin 1 using a reductive
amination (Scheme 1).17,20 The amination, subsequent
hydrolysis of the esters, and N-nitrosation were performed
in a parallel fashion with the Radleys 12-place carousel
reaction station. One-pot cycloaddition with dimethyl acety-
lenedicarboxylate, ethyl propiolate, or methyl propiolate
under microwave irradiation in the presence of a water-
removing agent gave polymer-bound pyrazoles 5. The
products 6 were cleaved from the resin with trifluoroacetic
acid in a parallel fashion by shaking at room temperature in
sealed syringes.
Scheme 1. Solid-Phase Synthesis of Pyrazoles 6
The purity of the crude pyrazoles was analyzed by LC-
MS and 1H NMR. Most of the crude products were
obtained in high purities. The reactions were monitored
with FT-IR and LC-MS. After the reactions, major changes
in the FT-IR spectra were in the carbonyl area. Disap-
pearance of the aldehyde band (1674 cm-1) indicated
successful attachment of the amino acid methyl ester, and
hydrolyzed methyl esters (1725-1735 cm-1) were detected
as sodium salts of the acids (1580-1600 cm-1). N-
Nitrosation and 1,3-dipolar cycloaddition caused also
changes in the carbonyl area and additionally some minor
changes in FT-IR spectra. After the cleavage, analysis of
´
(14) (a) Feliu, L.; Vera-Luque, P.; Albericio, F.; Alvarez, M. J. Comb.
Chem. 2007, 9, 521–565. (b) Harju, K.; Yli-Kauhaluoma, J. Mol. DiVersity
2005, 9, 187–207.
(15) For recent reports, see: (a) Jorand-Lebrun, C.; Brondyk, B.; Lin,
J.; Magar, S.; Murray, R.; Reddy, A.; Shroff, H.; Wands, G.; Weiser, W.;
Xu, Q.; McKenna, S.; Brugger, N. Bioorg. Med. Chem. Lett. 2007, 17,
2080–2085. (b) Sehon, C.; McClure, K.; Hack, M.; Morton, M.; Gomez,
L.; Li, L.; Barrett, T. D.; Shankley, N.; Breitenbucher, J. G. Bioorg. Med.
Chem. Lett. 2006, 16, 77–80. (c) Dodd, D. S.; Martinez, R. L.; Kamau, M.;
Ruan, Z.; Van Kirk, K.; Cooper, C. B.; Hermsmeier, M. A.; Traeger, S. C.;
Poss, M. A. J. Comb. Chem. 2005, 7, 584–588. (d) Hwang, J. Y.; Choi,
H.-S.; Lee, D.-H.; Yoo, S.-e.; Gong, Y.-D. J. Comb. Chem. 2005, 7, 136–
141. (e) Morelli, C. F.; Saladino, A.; Speranza, G.; Manitto, P. Eur. J. Org.
Chem. 2005, 4621–4627, and references therein.
the residual resins showed only traces of the peaks typical
for these products; instead we detected a trifluoroacetate
band (1780 cm-1). LC-MS analyses gave further informa-
tion about the reactions. The intermediate resins were first
treated with TFA-DCM, and the cleaved compounds were
then analyzed with LC-MS. Resin-bound amino acid ester
and amino acid were cleaved in minor amounts coupled
with the 4-hydroxy-2-methoxybenzyl linker. Cycloaddi-
tions were carried out under microwave irradiation at 150
°C for 30 min. Crude pyrazoles were obtained in small
amounts and low purity at a reduced temperature (130
°C, 30 min). Continuing the reaction for 30 min at 150
°C, we obtained a high yield and crude product purity
(>80%). When N-(3-dimethylaminopropyl)-N′-ethylcar-
bodiimide (EDC) was used as a dehydrating agent, instead
of acetic anhydride, the crude product purity was under
(16) (a) Gao, D.; Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2008,
73, 8057–8068. (b) Harju, K.; Kyla¨nlahti, I.; Paananen, T.; Polamo, M.;
Nielsen, J.; Yli-Kauhaluoma, J. J. Comb. Chem. 2006, 8, 344–349. (c) Fuchi,
N.; Doi, T.; Takahashi, T. Chem. Lett. 2005, 34, 438–439. (d) Donohue,
A. C.; Pallich, S.; McCarthy, T. D. J. Chem. Soc., Perkin Trans. 1 2001,
2817–2822. (e) Washizuka, K.-I.; Nagai, K.; Minakata, S.; Ryu, I.; Komatsu,
M. Tetrahedron Lett. 2000, 41, 691–695.
(17) Bilodeau, M. T.; Cunningham, A. M. J. Org. Chem. 1998, 63, 2800–
2801.
(18) (a) Samanta, S. K.; Yli-Kauhaluoma, J. J. Comb. Chem. 2005, 7,
142–146. (b) Larsen, S. D.; DiPaolo, B. A. Org. Lett. 2001, 3, 3341–3344.
(19) Harju, K.; Vahermo, M.; Mutikainen, I.; Yli-Kauhaluoma, J.
J. Comb. Chem. 2003, 5, 826–833.
(20) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C. A.;
Shah, R. D. J. Org. Chem. 1996, 61, 3849–3862
.
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