[reaction: see text] Room-temperature reduction of aromatic nitro groups to amines can be accomplished in high yield, with wide functional group tolerance and short reaction times (30 min) using a combination of palladium(II) acetate, aqueous potassium fluoride, and polymethylhydrosiloxane (PMHS). Replacing PMHS/KF with triethylsilane allows aliphatic nitro groups to be reduced to their hydroxylamines.

The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ≤ 50 nM versus CK1δ. The two lead compounds have ≤ 100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.

Catalytic Pd(OAc) 2 and polymethylhydrosiloxane (PMHS), in conjunction with aqueous KF, and a catalytic amount of an aromatic chloride, effects the chemo, regio, and stereoselective deoxygenation of benzylic oxygenated substrates at room temperature in THF. Preliminary mechanistic experiments suggest the process to involve palladium-nanoparticle catalyzed hydrosilylation followed by C-O reduction. The chloroarene additive appears to facilitate the hydrogenolysis process through the slow controlled release of HCl.In the early 1990's, Tour1 and Crabtree2 independently reported on how dispersing palladium throughout a siloxane polymer matrix raises the catalytic activity of the metal. Originally termed Pd-colloids, in 2004 Chauhan 3 unequivocally showed that by mixing Pd(OAc) 2 with polymethylhydrosiloxane (PMHS) formed polysiloxane-encapsulated Pd-nanoclusters.We had previously reported that Pd(OAc) 2 /PMHS in the presence of aqueous KF rapidly hydrodehalogenated chloroarenes.4 Despite PMHS' ability to reduce ketones to alcohols, 5 this system chemoselectively dechlorinated 4-(4-chlorophenyl)-2-butanone (eq 1). In contrast, when 4'-chloroacetophenone was placed under the same conditions, it was fully reduced to ethylbenzene (eq 2).(1) (2) Since transfer hydrogenolysis of activated C-O bonds by PMHS are known, 6 we were not entirely surprised by this result, until we examined the reactivity of acetophenone. After being exposed to the Pd(OAc) 2 /PMHS/KF (aq) conditions for 24 hours, the acetophenone afforded no visible amounts of ethyl benzene, stopping instead at 1-phenylethanol ( Empirically, the presence of a chloro group was influencing the reactivity of the benzylic ketone/alcohol. Yet, GC monitoring of the 4'-chloroacetophenone reduction indicated the intermediacy of acetophenone. Thus the chloro group of 4-chloroacetophenone was not directly enhancing its reactivity. An investigation was undertaken to uncover why in situ generated acetophenone undergoes full deoxygenation, while subjecting acetophenone starting material to the "same" reduction conditions stopped at the alcohol. Through experimentation, we found that by simply starting the reaction in the company of chlorobenzene, acetophenone was quantitatively reduced to ethylbenzene after 1 hour at room temperature. Moreover, 10 mol % chlorobenzene 7 proved equally effective at facilitating the reaction.To the best of our knowledge this is the first example of chlorobenzene serving as a productive additive in Pd-mediated reductions.8 , 9 ,10 To explore this curious finding further, we surveyed a variety of chlorides and related additives against the reaction of acetophenone with Pd (OAc) 2 /PMHS/KF (aq) .Where chlorobenzene efficiently facilitated deoxygenation, among bromobenzene, iodobenzene, and phenyl nonaflate (entries 2-4, 8) only PhBr showed any effectiveness as an additive with its reaction affording ethylbenzene in 22% yield. With PhI and PhONf, the reductions stopped at 1-phenylethanol. It was also noted that relative to chlorobenzene, P...

SUMMARY Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of central nervous system progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/CCdh1) ubiquitin ligase, and conditional deletion of the APC/CCdh1 activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/CCdh1 also downregulates CK1δ during cell cycle exit. Therefore, we conclude that APC/CCdh1 controls CK1δ levels to balance proliferation and cell cycle exit in the developing central nervous system. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a new therapeutic target.