Propargylic Fluorides Research Articles

Regioselective fluorination of allenes enabled by I(I)/I(III) catalysis

The prominence and versatility of propargylic fluorides in medicinal chemistry, coupled with the potency of F/H and F/OH bioisosterism, has created a powerful impetus to develop efficient methods to facilitate their construction. Motivated by the well-established conversion of propargylic alcohols to allenes, an operationally simple, organocatalysis-based strategy to process these abundant unsaturated precursors to propargylic fluorides would be highly enabling: this would consolidate the bioisosteric relationship that connects propargylic alcohols and fluorides. Herein, we describe a highly regioselective fluorination of unactivated allenes based on I(I)/I(III) catalysis in the presence of an inexpensive HF source that serves a dual role as both nucleophile and Brønsted acid activator. This strategy enables a variety of secondary and tertiary propargylic fluorides to be prepared: these motifs are prevalent across the bioactive small molecule spectrum. Facile product derivatisation, concise synthesis of multi-vicinal fluorinated products together with preliminary validation of enantioselective catalysis are disclosed. The expansive potential of this platform is also demonstrated through the highly regioselective organocatalytic oxidation, chlorination and arylation of allenes. It is envisaged that the transformation will find application in molecular design and accelerate the exploration of organofluorine chemical space.

Synthesis of Chiral Tertiary Allylic- and Propargylic Fluorides from Nonaflates of Chiral α-Fluorinated β-Keto Dicarbonyl Compounds.

The acetyl group of chiral α-fluorinated dicarbonyl compounds was transformed to nonaflates through a reaction with perfluorobutanesulfonyl fluoride in the presence of DBU in 82-95% yield. These nonaflates were used in Suzuki and Sonogashira coupling reactions to afford chiral tertiary allylic fluorides bearing gem-disubstituted terminal alkenes with excellent optical purities (45-91%, ≥94% ee). In addition, chiral tertiary propargylic fluorides were obtained from the reaction of nonaflates with DBU (73-86%, ≥94% ee).

Photoinduced Copper-Catalyzed Monofluoroalkylation of Terminal Alkynes to Propargylic Fluorides.

A photoinduced copper-catalyzed strategy for the monofluoroalkylation of alkynes with readily available monofluoroalkyl triflates was developed. It provides a new protocol to access valuable propargyl fluoride compounds via C-C bond formation by avoiding the use of highly toxic fluorination reagents. This reaction proceeded under mild conditions to afford propargyl monofluorides in moderate to high yields. Preliminary mechanistic studies reveal that a ligand-matched alkynyl copper complex might be the key photoactive substance.

Syntheses and Synthetic Applications of Functionalized Propargylic and Allylic Fluorides.

This account presents the synthesis and application of propargylic and allylic fluorides containing hydroxy or carbonyl functional groups. In particular, the Barbier-type reaction of difluoropropargyl bromides with aldehydes or chloroformates provides versatile propargylic fluorides, and the organocatalytic fluorination of dienamine intermediates has been demonstrated as an effective method to obtain allylic fluorides stereoselectively. Additionally, mechanistic insights into such reactions are discussed with the aid of density functional theory calculations. The report also describes the preparation of fluorinated 1,7-diyne or 1,7-enyne derivatives of these compounds. These propargylic and allylic fluorides can be used as building blocks for fluorinated heterocycles, such as fluorinated furans, tetrahydrofurans, and lactams. Additionally, fluorinated bi- or tri-heterocyclic compounds can be synthesized via transition-metal-catalyzed reactions with fluorinated 1,7-diyne or 1,7-enyne derivatives.

Catalytic Access to Functionalized Allylic gem‐Difluorides via Fluorinative Meyer–Schuster‐Like Rearrangement

AbstractAn unprecedented approach for efficient synthesis of functionalized allylic gem‐difluorides via catalytic fluorinative Meyer–Schuster‐like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low‐cost B–F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem‐difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem‐difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3‐fluorine migration under the assistance of the B–F reagents to give the desired products.

Catalytic Access to Functionalized Allylic gem-Difluorides via Fluorinative Meyer-Schuster-Like Rearrangement.

An unprecedented approach for efficient synthesis of functionalized allylic gem-difluorides via catalytic fluorinative Meyer-Schuster-like rearrangement is disclosed. This transformation proceeded with readily accessible propargylic fluorides, and low-cost B-F reagents and electrophilic reagents by sulfide catalysis. A series of iodinated, brominated, and trifluoromethylthiolated allylic gem-difluorides that were difficult to access by other methods were facilely produced with a wide range of functional groups. Importantly, the obtained iodinated products could be incorporated into different drugs and natural products, and could be expediently converted into many other valuable gem-difluoroalkyl molecules as well. Mechanistic studies revealed that this reaction went through a regioselective fluorination of alkynes followed by a formal 1,3-fluorine migration under the assistance of the B-F reagents to give the desired products.

Fluorinative Rearrangement Involving Cleavage and Recombination of Carbon-Fluorine Bond: Synthesis of Functionalized Allylic gem-Difluorides from Propargylic Fluorides

Fluorinative Rearrangement Involving Cleavage and Recombination of Carbon-Fluorine Bond: Synthesis of Functionalized Allylic <i>gem</i>-Difluorides from Propargylic Fluorides

β‐Amino Propargylic Fluorides through Stereoselective Electrophilic Fluorodesilylation of 4‐Amino‐1‐allenylsilanes

Herein, we present the stereoselective synthesis of anti‐β‐amino propargylic fluorides through the anti‐SE2′ electrophilic fluorodesilylation reaction of 4‐amino‐1‐allenylsilanes with Selectfluor®. The stereoselectivity of the reaction was explained by a preferred N‐inside conformer.

Hydrogen-Bond-Promoted Friedel–Crafts Reaction of Secondary Propargylic Fluorides: Preparation of 1-Alkyl-1-aryl-2-alkynes

We report that aromatic propargylation is achievable with secondary propargylic fluorides, thus affording 1-alkyl-1-aryl-2-alkynes. In the present case, hydrogen bonding is responsible for the activation of the C–F bond. A large excess of arene nucleophile is shown to be necessary to achieve good yields.

Synthesis of Propargylic Fluorides toward Carbo- and Heterocycles with Mono- and gem-Difluorinated Side Chains

This review reports the synthesis of propargylic derivatives with alkyl chains bearing either one fluorine or a <i>gem</i>-difluoro system. The preparation of the different categories of fluorinated derivatives is analyzed in a systematic manner, based on the nature of substituents close to the fluorine atom(s). In the second part of this review are summarized the synthetic applications of these fluorinated propargylic intermediates, focusing mainly on the preparation of carbo- and heterocyclic derivatives. 1 Introduction 2 Synthesis of Propargylic Fluorides 3 Use of Propargylic Fluorides in the Preparation of Carbo- and Heterocycles with Fluorine-Containing Side Chains 4 Conclusions and Perspectives

Synthesis of Novel Fluorinated Benzofurans and Dihydrobenzofurans

Starting from easily accessible propargylic fluorides an intramolecular oxa-Michael addition affords, in good yields, new gem-difluo­rodihydrobenzofurans bearing an electrophilic double bond in position 2. On these intermediates nucleophilic additions and Diels–Alder reactions have been performed affording functionalized fluorinated dihydrobenzofurans. On the other hand, Pd-catalyzed defluorinations give the corresponding fluorine containing benzofurans.

ChemInform Abstract: Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper‐N‐Heterocyclic Carbene Complex.

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.

Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper-N-Heterocyclic Carbene Complex.

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.

Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper–N‐Heterocyclic Carbene Complex

AbstractA catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.

ChemInform Abstract: A New Synthesis of Indanes with Monofluorinated and gem‐Difluoroalkyl Side Chains.

Abstract The preparation of the new title compounds has been performed using a short and efficient strategy. Starting from appropriately substituted propargylic fluorides, intramolecular enyne metathesis reactions afford in excellent yields 1,3 dienes with the fluorinated side chains in internal position. Then, simple Diels–Alder-aromatisation sequences complete the synthesis of the target molecules.

A new synthesis of indanes with monofluorinated and gem-difluoroalkyl side chains

The preparation of the new title compounds has been performed using a short and efficient strategy. Starting from appropriately substituted propargylic fluorides, intramolecular enyne metathesis reactions afford in excellent yields 1,3 dienes with the fluorinated side chains in internal position. Then, simple Diels–Alder-aromatisation sequences complete the synthesis of the target molecules.

Towards chemical libraries based on heterocyclic scaffolds with monofluorinated and difluoroalkyl side chains

The preparation of focused chemical libraries, based on five- and six-membered heteroaromatic systems with mono- and gemdifluoroalkyl side chains, is described. Four heterocyclic scaffolds with a p-bromophenyl group have been easily prepared from readily available propargylic fluorides. Starting from these scaffolds, palladium-catalyzed reactions have been performed, including by automated procedures, to prepare libraries of molecules designed for biological applications.

Diastereoselective synthesis of propargylic fluorides and its application in preparation of monofluorinated sugar

An effective method to diastereoselectively synthesize enantioenriched propargylic fluorides was developed via S N1 type reaction of DAST participated dehydroxy-fluorination of diastereomeric propargylic alcohol cobalt–carbonyl complexes. A serious of propargylic fluorides can be prepared by this approach in good yields with moderate to high diastereoselectivities. To demonstrate the application of this approach in synthesis, monofluorinated sugar 12, an important and versatile building block, was prepared in an efficient manner.

Direct Approach to Chiral Propargylic and Allylic Fluorides

Direct Approach to Chiral Propargylic and Allylic Fluorides

Flexible Synthesis of Pyrimidines with Chiral Monofluorinated and Difluoromethyl Side Chains

Chiral pyrimidines with a fluorine atom in the benzylic position are easily accessible in high enantiomeric excesses from optically active propargylic intermediates by two complementary routes. Both the use of optically active propargylic fluorides and the fluorination of the chiral pyrimidine in the final stage give excellent results in terms of enantiocontrol. On the other hand, original pyrimidines with a difluoromethyl side chain are also obtained in a few steps from new propargylic ketones bearing a CHF(2) substituent on the triple bond.