Synthesis of diversely 1,3,5-trisubstituted pyrazoles via 5-exo-dig cyclization.

5-Exo-dig cyclocondensation of alk-3-yn-1-ones with hydrazines, in the presence of montmorillonite K-10, provides an effective method with a high atom economy for the synthesis of diversely 1,3,5-trisubstituted pyrazoles. The microwave-accelerated reaction proceeds in the absence of solvent and leads to 5-benzyl substituted pyrazoles with good yields (72-91%). The regiochemistry of the process was confirmed by the X-ray crystallographic structure determination of 1-(2-fluorophenyl)-5-(4-methylbenzyl)-3-phenyl-1H-pyrazole.

Enantioselective Friedel-Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids.

The first direct asymmetric synthetic preparation of trifluoro-1-(indol-3-yl)ethanols (TFIEs) is described by an enantioselective organocatalytic method from indoles and inexpensive trifluoroacetaldehyde methyl hemiacetal. The reaction is catalyzed by hydroquinine to produce TFIEs in an almost quantitative yield and with enantioselectivities up to 75% at room temperature. The enantioselectivity is strongly dependent on the concentration of substrates and catalyst due to the competitive noncatalyzed reaction.

Rational design, synthesis, and potency of N-substituted indoles, pyrroles, and triarylpyrazoles as potential fructose 1,6-bisphosphatase inhibitors.

By using computer modeling and lead structures from our earlier SAR results, a broad variety of pyrrole-, indole-, and pyrazole-based compounds were evaluated as potential fructose 1,6-bisphosphatase (FBPase) inhibitors. The docking studies yielded promising structures, and several were selected for synthesis and FBPase inhibition assays: 1-[4-(trifluoromethyl)benzoyl]-1H-indole-5-carboxamide, 1-(alpha-naphthalen-1-ylsulfonyl)-7-nitro-1H-indole, 5-(4-carboxyphenyl)-3-phenyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole, 1-(4-carboxyphenylsulfonyl)-1H-pyrrole, and 1-(4-carbomethoxyphenylsulfonyl)-1H-pyrrole were synthesized and tested for inhibition of FBPase. The IC(50) values were determined to be 0.991 and 1.34 microM, and 575, 135, and 32 nM, respectively. The tested compounds were significantly more potent than the natural inhibitor AMP (4.0 microM) by an order of magnitude; indeed, the best inhibitor showed an IC(50) value toward FBPase more than two orders of magnitude better than that of AMP. This level of activity is virtually the same as that of the best currently known FBPase inhibitors. This work shows that such indole derivatives are promising candidates for drug development in the treatment of type II diabetes.

Microwave-Assisted Preparation of Trifluoroacetaldehyde (Fluoral): Isolation and Applications.

A novel method for the preparation of trifluoroacetaldehyde (fluoral, TFAc, CF(3)CHO) from commercially available trifluoroacetaldehyde ethylhemiacetal (TFAE) by microwave irradiation is described. The isolation, characterization and reaction of fluoral with various nucleophiles were studied to verify the diverse applicability of this new method.