In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERbeta. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERbeta in binding. Curiously, on the basis of molecular modeling, the ERbeta binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERalpha vs ERbeta. In transcription assays this pyrazolopyrimidine was fully effective as an ERbeta antagonist while exhibiting no significant activity on ERalpha. Thus, this ligand functions as a potency- and efficacy-selective ERbeta antagonist that would abrogate estrogen action through ERbeta with minimal effects on its activity through ERalpha; as such, it could be used to study the biological function of ERbeta.

The caption of Figure 7 incorrectly suggests that Sprague-Dawley rats were used in studies of HPA activation. Studies of HPA activation were performed using CD-1 mice (as described everywhere else in the manuscript).

We investigated the hydrolysis of anisole to phenol in high-temperature water with and without water-tolerant Lewis acid catalysis. With no catalyst present, anisole hydrolyzes to phenol in 97% yield after 24 hours at 365 °C, our experimentally determined optimal temperature and time. Experiments with varied water density and analysis of comparable literature data suggest that anisole hydrolysis is almost third order in water, when the S(N)2 mechanism dominates. Of the water-tolerant Lewis acid catalysts studied, In(OTf)(3) offered the best phenol yield. Anisole hydrolysis was first order in catalyst and first order in substrate. Introducing In(OTf)(3) catalysis lowered the activation energy for anisole hydrolysis to 31 ± 1 kcal mol(-1). Anisole hydrolysis in high-temperature water with In(OTf)(3) catalysis is competitive with other techniques in the literature based on rate and yield. In the presence of 5 mol% In(OTf)(3) catalyst, anisole hydrolyzes to phenol in 97% yield after 90 minutes at 300 °C.

We explore various aspects of alkyne hydration in high temperature water catalyzed by water-tolerant Lewis acids through experimentation with the hydration of 1-phenyl-1-propyne. Experiments comparing indium triflate, scandium triflate, ytterbium triflate, sulfuric acid, and hydrochloric acid indicate that indium triflate is the most active catalyst toward this reactive system of those tested. Experiments with quartz and stainless steel reactors in conjunction with quartz and stainless steel additive demonstrate that reactor material of construction has no appreciable effect upon the reaction. The reaction is first order in both catalyst and alkyne. We further determine the kinetic parameter k for four temperatures (150, 175, 200, and 225 °C), and find that the frequency factor is 10 8.8(0.3 L/(mol s) and the activation energy is 21.4 ( 0.6 kcal/mol for this transformation. This is the first example of alkyne hydration in high-temperature water catalyzed by water-tolerant Lewis acids.

The sections in this article are Introduction Background Properties of HTW Process Engineering Considerations Theoretical, Computational, and Experimental Methods Classical Theory Molecular and Computational Modeling Experimental Methods p H Effects Recent Progress in HTW Synthesis Hydrogenation C  C Bond Formation Friedel–Crafts Alkylation Heck Coupling Nazarov Cyclization Condensation Hydrolysis Rearrangements Hydration/Dehydration Elimination Partial Oxidation to Form Carboxylic Acids C  C Bond Cleavage H – D Exchange Amidation Acknowledgments