A Negishi cross-coupling of alkyl pyridinium salts and alkylzinc halides has been developed. This is the first example of alkyl-alkyl bond formation via cross-coupling of an alkyl amine derivative with an unactivated alkyl group, and allows both primary and secondary alkyl pyridinium salts to react with primary alkylzinc halides with high functional group tolerance. When combined with formation of the pyridinium salts from primary amines, this method enables the non-canonical transformation of NH 2 groups into a wide range of alkyl substituents with broad functional group tolerance.
Cerebrovascular dysfunction has an important role in the pathogenesis of multiple brain disorders. Measurement of hemodynamic responses in vivo can be challenging, particularly as techniques are often not described in sufficient detail and vary between laboratories. We present a set of standardized in vivo protocols that describe high-resolution two-photon microscopy and intrinsic optical signal (IOS) imaging to evaluate capillary and arteriolar responses to a stimulus, regional hemodynamic responses, and oxygen delivery to the brain. The protocol also describes how to measure intrinsic NADH fluorescence to understand how blood O supply meets the metabolic demands of activated brain tissue, and to perform resting-state absolute oxygen partial pressure (pO) measurements of brain tissue. These methods can detect cerebrovascular changes at far higher resolution than MRI techniques, although the optical nature of these techniques limits their achievable imaging depths. Each individual procedure requires 1-2 h to complete, with two to three procedures typically performed per animal at a time. These protocols are broadly applicable in studies of cerebrovascular function in healthy and diseased brain in any of the existing mouse models of neurological and vascular disorders. All these procedures can be accomplished by a competent graduate student or experienced technician, except the two-photon measurement of absolute pO level, which is better suited to a more experienced, postdoctoral-level researcher.
Herein, an improved methodology for aryl-cubane cross-coupling is reported. The peculiarities of the cubane core and its behavior during cross-coupling conditions were analyzed, while the versatility of this adapted Baran cross-coupling methodology was demonstrated by the synthesis of various aryl-cubane systems, including coupling products of cubanes and porphyrins. Furthermore, arm extension of alkynyl-cubanes by Sonogashira reactions is demonstrated, showcasing the first proof of the stability of the cubane core in the presence of palladium catalysts.
A series of chemically distinct, highly strained, activated cubane scaffolds was synthesized through optimization of the metal-halogen exchange reactions of iodinated cubane derivatives. This included the first reported successful attachment of both boron and phosphorous; key elements in potential transition metal-catalyzed cross coupling reactions; on the cubane scaffold. Additionally, Zn, Sn, Si, S and various C-based systems were also attached in a high-yielding, one-pot reaction from readily available precursors. A comprehensive program investigating the reactivity of these tertiary cubane nucleophiles towards Suzuki-Miyaura, Negishi and Stille cross-coupling methods, never previously reported with the cubane scaffold; is also described, but proved unsuccessful.
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