Development and applications of novel HF-based fluorination reagents : DMPU-HF.

The utility of fluorine in medicinal and manufacturing chemistry is undisputed. Despite its usefulness, the incorporation of fluorine in organic molecules is not without challenges. Regardless of their electrophilic or nucleophilic nature, most, if not all, fluorinating reagents derive from HF. Nucleophilic reagents are less expensive compared with their counterparts, and many are not commercially available. The Hammond laboratory is interested in developing and applying HF-based fluorination reagents that are cost effective and capable of enhancing both classical and metal based transformations. The following chapters describe some of the applications of our HF-based reagent. Chapter 2 discusses the preparation and role of DMPU-HF in the fluorination of alkynes in the presence of a metal catalyst. This reaction employs the imidogold precatalyst, which is activated by DMPU-HF to enhance both mono- and di-fluorination of alkynes. Approaches to induce monofluorination and difluorination of terminal alkynes by an HF-based reagent, unprecedented in the literature, are also discussed. In Chapter 3, we describe further the application of DMPU-HF to the diastereoselective synthesis of fluorinated tetrahydropyrans and the N-tosylpiperidine analogues. We also showed that the acidic behavior of DMPU-HF makes it a better fluorinating reagent when compared to existing HF-based reagents in these types of transformations. Further extension of DMPU-HF to the ring opening of aziridines is discussed in Chapter 4. A wide variety of N-tosyl aziridines undergo efficient ring opening in the presence of DMPU-HF at room temperature. The methodology was also extended to some N-substituted aziridines including unactivated substrates, all of which were efficiently fluorinated under these conditions. Chapter 5 gives an overview of some of the applications of DMPU-HF to other known C-F bond formations. Examples of such transformations include but are not limited to the ring opening of epoxides, fluorobromination of unsaturated compounds and the metal free synthesis of fluoroamines. Finally, Chapter 6 provides spectroscopic data for all the new compounds prepared in chapters 2 to 5

Synthesis and structure activity relationship of fluorinated enaminones: Potential antiepileptic compunds

A series of fluorinated enaminones have been synthesized from the condensation of 5-(trifluoromethyl)-1,3-cyclohexanedione and various amines via the synergistic effect of p-toluenesulfonic acid/acetic acid. The activity of 3-(4-chlorophenylamino)-5-(trifluoromethyl)cyclohex-2-enone (ADD 386002) and 3-(benzylamino)-5-(trifluoromethyl)cyclohex-2-enone (ADD 386001) have been established by our research group as lead compounds with significant anticonvulsant activity in the maximal electroshock (MES) seizure test model. The synthesis of these enaminones will help to advance the chemistry of these compounds as well as provide insight to their structural activity relationships, as potential antiepileptic agents. Using the above procedure, we completed the synthesis of fourteen new fluorinated enaminones containing substituted phenyl and heteroaromatic rings. All 14 compounds were characterized by NMR and GC/MS. The lipophilicity of each compound was calculated in order to determine the membrane permeability. All the compounds showed acceptable logP values. Seven compounds are currently undergoing testing at the Antiepiletic Drug Screening branch of NINDS

Copper Catalyzed sp3 C-H α-Acetylation

α-substituted ketones are important chemical targets as synthetic intermediates as well as functionalities in in natural products and pharmaceuticals. We report the sp3 C-H α-acetylation of sp3 C-H substrates R-H with arylmethyl ketones ArC(O)Me to provide α-alkylated ketones ArC(O)CH2R at RT with tBuOOtBu as oxidant via copper(I) β-diketiminato catalysts. Proceeding via alkyl radicals R•, this method enables α-substitution with bulky substituents without competing elimination that occurs in more traditional alkylation reactions between enolates and alkyl electrophiles. DFT studies suggest the intermediacy of copper(II) enolates [CuII](CH2C(O)Ar) that capture alkyl radicals R• to give R-CH2C(O)Ar under competing dimerization of the copper(II) enolate to give the 1,4-diketone ArC(O)CH2CH2C(O)Ar.</p

Preparation of Fluorinated Tetrahydropyrans and Piperidines using a New Nucleophilic Fluorination Reagent DMPU/HF

DMPU/HF (HF content 65 wt %/wt) is an ideal nucleophilic fluorination reagent for the diastereoselective synthesis of substituted 4-fluorotetrahydropyrans and 4-fluoropiperidines via a fluoro-Prins reaction. When compared to classical nucleophilic fluorination reagents like pyridine/HF, DMPU/HF gives both higher yields and better diastereoselectivity

Designer HF-Based Fluorination Reagent: Highly Regioselective Synthesis of Fluoroalkenes and <i>gem</i>-Difluoromethylene Compounds from Alkynes

Hydrogen fluoride (HF) and selected nonbasic and weakly coordinating (toward cationic metal) hydrogen-bond acceptors (e.g., DMPU) can form stable complexes through hydrogen bonding. The DMPU/HF complex is a new nucleophilic fluorination reagent that has high acidity and is compatible with cationic metal catalysts. The gold-catalyzed mono- and dihydrofluorination of alkynes using the DMPU/HF complex yields synthetically important fluoroalkenes and <i>gem</i>-difluoromethlylene compounds regioselectively

Uncovering a copper(II) Alkynyl Complex in C−C Bond Forming Reactions

Copper(II) alkynyl species are proposed as key intermediates in numerous Cu−catalysed C−C coupling reactions. Supported by a β−diketiminate ligand, the three coordinate copper(II) alkynyl [CuII]−C≡CAr (Ar = 2,6−Cl2C6H3) forms upon reaction of the alkyne H−C≡CAr with the copper(II) tert−butoxide complex [CuII]−OtBu. In solution, this [CuII]−C≡CAr species cleanly transforms the to the Glaser coupling product ArC≡C−C≡CAr and [CuI](solvent). Addition of nucleophiles R′C≡CLi (R′ = aryl, silyl) and Ph–Li to [CuII]−C≡CAr affords the corresponding Csp−Csp and Csp−Csp2coupled products RC≡C−C≡CAr and Ph–C≡CAr with concomitant generation of [CuI](solvent) and {[CuI]−C≡CAr}−. Supported by DFT calculations, redox disproportionation forms [CuIII](C≡CAr)(R) species that reductively eliminate R−C≡CAr products. [CuII]−C≡CAr also captures the trityl radical Ph3C• to give Ph3C−C≡CAr. Radical capture represents the key Csp−Csp3 bond forming step in the copper catalysed C-H functionalization of benzylic substrates R−H with alkynes H−C≡CR′ (R′ = (hetero)aryl, silyl) that provide Csp−Csp3 coupled products R−C≡CR via radical relay with tBuOOtBu as oxidant.</p

Achieving regio- and stereo-control in the fluorination of aziridines under acidic conditions

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)We developed an efficient fluorination protocol that converts easily accessible aziridines into beta-fluoroamines, which are important motifs in biologically active molecules. In contrast with traditional fluorination approaches, DMPU-HF has shown both higher reactivity and regioselectivity and good functional group tolerance; thus, a wide scope of beta-fluoroamines can now be accessed conveniently. The stereochemical behavior of the ring opening depends on the substitution pattern of the aziridine substrate.We developed an efficient fluorination protocol that converts easily accessible aziridines into β-fluoroamines, which are important motifs in biologically active molecules. In contrast with traditional fluorination approaches, DMPU–HF has shown both highe52911335313356National Institutes of Health [R15 GM101604-01]National Science Foundation [CHE-1401700]National Science Foundation of China [NSFC-21472018]Sao Paulo Research Foundation (FAPESP) [2015/08541-6]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins

A simple, user-friendly, metal-free protocol for the regioselective anti-Markovnikov hydrofluorination of olefins using readily available and inexpensive reagents has been developed. This new approach displays a broader scope than previously reported methodologies and has been applied to the late-stage fluorination of a complex molecule, giving rise to a fluorosteroid derivative. The stereochemistry of the process has also been studied in some detail