W. Zhai et al. / Tetrahedron Letters 53 (2012) 267–270
269
Table 1
Preparation of pyrazole-4-hydroxamic acids13
O
HO
N
H
N
N
R1
R2
Compound
R1
R2
% Yieldb
% Purityb
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
Ethyl
4-Isopropylphenyl
Ethoxycarbonylmethylene
Phenyl
7-Chloroquinolin-4-yl
4-Methylsulfonylphenyl
4-t-Butylphenyl
m-Tolyl
4-Isopropylphenyl
2-Carboxyphenyl
4-Methoxyphenyl
4-Carboxyphenyl
2-Pyridyl
85
75
98
92
4-Trifluoromethylphenyl
n-Butyl
4-Methoxyphenyl
4-Chlorophenyl
4-Chlorophenyl
Isopropyl
Phenyl
4-Chlorophenyl
n-Butyl
83a/82
88
95a/95
93
83
90
75
80
65
85
78
95
95
97
94
92
98
90
4-Methoxyphenyl
Isopropyl
t-Butyl
85a/88
88
99a/99
98
4-Chlorophenyl
4-Isopropylphenyl
Methyl
83a/78
92a/89
a
Prepared by the coupling of 1,3-dioxolane protected b-ketoacids onto the amino-oxy resin, otherwise prepared by direct amidation
of b-keto methyl or ethyl esters onto the resin.
b
Based on HPLC analysis of crude samples.
R2
O
O
O
R1
N
R1
NH
R2
O
R1
O
i. DMF-DMA
N
H
N
O
ð5Þ
ii. R3NHNH2
iii. TFA/DCM
DMAP/NMP
N
R3
R2
85 oC, 2 DAYS
8
9
R1 = H for Rin kresin
R1 = alkyl for FMP aldehyde resin via reductive amination
C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.; Isakson, P. C. J.
Med. Chem. 1997, 40, 1347.
2. Cecchi, L.; Melani, F.; Palazzino, G. Farmaco Edizion Scientifica 1984, 39, 953.
3. Stauffer, S. R.; Huang, Y.; Coletta, C. J.; Tedesco, R.; Katzenellenbogen, J. A.
Bioorg. Med. Chem. 2001, 9, 141.
pared from FMP aldehyde resin, and the application of this reaction
to the synthesis of 1,5-disubstituted pyrazole-4-hydroxamic acids
and pyrazole-4-carboxamides in fair to excellent overall yield.
We have successfully applied these procedures to the synthesis
of a number of combinatorial libraries.
4. Hagmann, W. K.; Lark, M. W.; Becker, J. W. Ann. Rep. Med. Chem. 1996, 32, 231–
240.
5. Pendri, A.; Gerritz, S.W; Dodd, D.; Sun, C.; U.S Pat. Appl. Publ. 2005, CODEN:
USXXCO US 2005080087 A1 20050414.
6. Beckett, R. P.; Davidson, A. H.; Drummond, A. H.; Huxley, P.; Whittaker, M. Drug
Discovery Today 1996, 1, 16.
7. Grosche, P.; Holtzel, A.; Walk, T. B.; Trautwein, A. W.; Jung, G. Synthesis 1999,
1961. and references quoted therein.
8. Yin, Z.; Low, K. S.; Lye, P. L. Synthetic Communifications 2005, 35,
2945.
Acknowledgments
We acknowledge the assistance of Dr. Stella Huang for perform-
ing the NMR-NOE experiments for regiochemistry determination,
and Dr. Peter Tidswell, Marianne Vath, and Scott Lapaglia for HPLC
analysis.
9. Menozzi, G.; Mosti, L.; Schenone, P. J. Heterocyclic Chem. 1987, 24,
1669.
10. Garcia, H.; Iborra, S.; Miranda, M.; Primo, J. Heterocycles 1986, 24,
2511.
Supplementary data
11. Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M. Tetrahedron Lett. 1996, 37,
8045.
12. A similar deprotection proceeded smoothly in solution as shown below.
Supplementary data associated with this article can be found, in
H
H
N
PPTS
Acetone/H2O
N
O
O
O
O
O
F
O
O
F
13. General procedures for the synthesis of 2,5-disubstituted pyrazole-4-hydroxamic
acids: To a suspension of amino-oxo resin(1.13 mM/g, in Microkan, 1.0 equiv)
in NMP was added b-keto esters (3.0 equiv) and DMAP (1.0 equiv). The
resulting mixture was warmed to 88 °C and shaken for 24 h. Drained and
washed with NMP (2ꢀ), DMF (3ꢀ), THF (2ꢀ), DCM (2ꢀ), MeOH (3ꢀ), dried in
References and notes
1. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor, S.;
Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D.
J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt,