HFIP in Organic Synthesis.

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C-H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive Heteroaromatic Enones.

Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophene-yl, and 2-benzothiophene-yl) have traditionally proven difficult or impossible to cyclize with typical Brønsted and Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with typical UV exposure times of 3.

Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315.

Substituted pyrimidine inhibitors of the Clk and Dyrk kinases have been developed, exploring structure-activity relationships around four different chemotypes. The most potent compounds have low-nanomolar inhibitory activity against Clk1, Clk2, Clk4, Dyrk1A and Dyrk1B. Kinome scans with 442 kinases using agents representing three of the chemotypes show these inhibitors to be highly selective for the Clk and Dyrk families.

1,3-allylic strain as a strategic diversification element for constructing libraries of substituted 2-arylpiperidines.

Minimization of 1,3-allylic strain is a recurring element in the design of a stereochemically- and spatially-diverse collection of 2-arylpiperidines. Here, stereochemically-diverse scaffolding is first constructed using A strain to guide the regioselective addition of nucleophiles, which serve as handles for further substitution. -substitution with alkyl and acyl substituents again leverages A strain to direct each stereoisomer to two different conformer populations, doubling the number of library members.

Novel Substitutions of 1-Alkoxy- and 1-Arylsulfonyloxy-η-Allylmolybdenum Complexes. A Case for η-Alkenyl Carbene Complexes as Intermediates.

A series of acyclic and cyclic 1-alkoxy- and 1-arylsulfonyloxy-substituted TpMo(CO)(2)(η(3)-allyl) complexes was synthesized and characterized, and exchange of the oxygenated substituent was investigated under a variety of reaction conditions. 1-Alkoxy-substituted η(3)-allyl and η(3)-butenyl complexes participated in direct, uncatalyzed exchange of the alkoxy substituent with benzylamine, but required a Lewis acid for exchange with alcohols. The 1-alkoxy-substituted η(3)-cyclohexenyl complex was unreactive towards exchange under all conditions investigated.

Organometallic enantiomeric scaffolding. Sequential semipinacol/1,5-"Michael-like" reactions as a strategic approach to bridgehead-quaternary center aza[3.3.1]bicyclics: application to the total synthesis of (-)-adaline.

A nontraditional approach to the enantiocontrolled construction of quaternary center-bearing heteroatom-bridged bicyclo[3.3.1]nonanes (homotropanes) is reported that is based on organometallic enantiomeric scaffolding.

Practical, scalable, high-throughput approaches to eta3-pyranyl and eta3-pyridinyl organometallic enantiomeric scaffolds using the Achmatowicz reaction.

A unified strategy for the high-throughput synthesis of multigram quantities of the eta(3)-oxopyranyl- and eta(3)-oxopyridinylmolybdenum complexes TpMo(CO)(2)(eta(3)-oxopyranyl) and TpMo(CO)(2)(eta(3)-oxopyridinyl) is described (Tp = hydridotrispyrazolylborato). The strategy uses the oxa- and aza-Achmatowicz reaction for the preparation of these organometallic enantiomeric scaffolds, in both racemic and high enantiopurity versions.