Mechanism of Asymmetric Homologation of Alkenylboronic Acids with CF-Diazomethane via Borotropic Rearrangement.

Density functional theory calculations have been performed to investigate the mechanism for the BINOL-catalyzed asymmetric homologation of alkenylboronic acids with CF-diazomethane. The reaction proceeds via a chiral BINOL ester of the alkenylboronic acid substrate. The calculations reveal a complex scenario for the formation of the chiral BINOL-alkenylboronate species, which is the key intermediate in the catalytic process.

Three-Component Approach to Densely Functionalized Trifluoromethyl Allenols by Asymmetric Organocatalysis.

We have developed a new three-component catalytic coupling reaction of alkynyl boronates, diazomethanes, and aliphatic/aromatic ketones in the presence of BINOL derivatives. The reaction proceeds with a remarkably high enantio- and diastereoselectivity (up to three contiguous stereocenters) affording tertiary CF-allenols in a single operational step. The reaction proceeds under mild, neutral, metal-free conditions, which leads to a high level of functional group tolerance.

Catalytic Homologation-Allylboration Sequence for Diastereo- and Enantioselective Synthesis of Densely Functionalized β-Fluorohydrins with Tertiary Fluoride Stereocenters.

Homologation of trisubstituted fluoroalkenes followed by allylboration of aldehyde, ketone and imine substrates is suitable for synthesis of β-fluorohydrin and amine products. In the presence of (R)-iodo-BINOL catalyst enantioselectivities up to 99 % can be achieved by formation of a single stereoisomer with adjacent stereocenters, of which one is a tertiary C-F center.

Sulfenofunctionalization of Chiral α-Trifluoromethyl Allylboronic Acids: Asymmetric Synthesis of SCF , SCF R, SCN and SAr Compounds.

We report herein a new method for the synthesis of densely functionalized chiral allyl SCF , SCF R, SCN and SAr species with a separate CF functionality. The synthetic approach is based on selenium-catalyzed sulfenofunctionalization of chiral α-CF allylboronic acids. The reactions proceeded with remarkably high stereo-, diastereo- and site-selectivity, based on the formation of a stable thiiranium ion followed by rapid deborylative ring opening.

Asymmetric Organocatalytic Homologation: Access to Diverse Chiral Trifluoromethyl Organoboron Species.

A broad range of aliphatic, aromatic, and heterocyclic boronic acids were successfully homologated using trifluorodiazoethane in the presence of BINOL derivatives to provide the corresponding chiral trifluoromethyl containing boronic acid derivatives in high yields and excellent enantioselectivity. The in situ conversion of the chiral transient boronic acids to the corresponding alcohols or β-CF3 carboxylates are also demonstrated.

Electrophilic Fluorination of Alkenes via Bora-Wagner-Meerwein Rearrangement. Access to β-Difluoroalkyl Boronates.

The electrophilic fluorination of geminal alkyl substituted vinyl-Bmida derivatives proceeds via bora-Wagner-Meerwein rearrangement. According to DFT modelling studies this rearrangement occurs with a low activation barrier via a bora-cyclopropane shaped TS. The Bmida group has a larger migration aptitude than the alkyl moiety in the Wagner-Meerwein rearrangement of the presented electrophilic fluorination reactions.

Base-catalysed F-labelling of trifluoromethyl ketones. Application to the synthesis of F-labelled neutrophil elastase inhibitors.

A new method for the fluorine-18 labelling of trifluoromethyl ketones has been developed. This method is based on the conversion of a-COCF functional group to a difluoro enol silyl ether followed by halogenation and fluorine-18 labelling. The utility of this new method was demonstrated by the synthesis of fluorine-18 labelled neutrophil elastase inhibitors, which are potentially useful for detection of inflammatory disorders.

Organocatalytic Synthesis of α-Trifluoromethyl Allylboronic Acids by Enantioselective 1,2-Borotropic Migration.

Chiral α-substituted allylboronic acids were synthesized by asymmetric homologation of alkenylboronic acids using CF/TMS-diazomethanes in the presence of BINOL catalyst and ethanol. The chiral α-substituted allylboronic acids were reacted with aldehydes or oxidized to alcohols in situ with a high degree of chirality transfer. The oxygen-sensitive allylboronic acids can be purified via their isolated diaminonaphthalene (DanH)-protected derivatives.

Mechanisms of Formation and Rearrangement of Benziodoxole-Based CF and SCF Transfer Reagents.

Togni's benziodoxole-based reagents are widely used in trifluoromethylation reactions. It has been established that the kinetically stable hypervalent iodine form (I-CF) of the reagents is thermodynamically less stable than its acyclic ether isomer (O-CF). On the other hand, the trifluoromethylthio analogue exists in the thermodynamically stable thioperoxide form (O-SCF), and the hypervalent form (I-SCF) has been elusive.

Enantioselective Construction of Tertiary Fluoride Stereocenters by Organocatalytic Fluorocyclization.

1,1-Disubstituted styrenes with internal oxygen and nitrogen nucleophiles undergo oxidative fluorocyclization reactions with generated chiral iodine(III)-catalysts. The resulting fluorinated tetrahydrofurans and pyrrolidines contain a tertiary carbon-fluorine stereocenter. Application of a new 1-naphthyllactic acid-based iodine(III)-catalyst allows the control of tertiary carbon-fluorine stereocenters with up to 96% ee.

Trifluoromethylthiolation, Trifluoromethylation, and Arylation Reactions of Difluoro Enol Silyl Ethers.

This study reports a new application area of difluoro enol silyl ethers, which can be easily obtained from trifluoromethyl ketones. The main focus has been directed to the electrophilic fluoroalkylation and arylation methods. The trifluoromethylthiolation of difluoro enol silyl ethers can be used for the construction of a novel trifluoromethylthio-α,α-difluoroketone (-COCFSCF) functionality.

Rhodium-mediated F-oxyfluorination of diazoketones using a fluorine-18-containing hypervalent iodine reagent.

Geminal F-oxyfluorination of diazoketones was performed in the presence of rhodium mediators. The reactions were performed using a hypervalent iodine-based [F]fluoro-benziodoxole reagent. By this methodology various α-[F]fluoro ethers were obtained in high radiochemical yield (up to 98%) and molar activity (216 GBq μmol).

Trifluoromethylthiolation-arylation of diazocarbonyl compounds by modified Hooz multicomponent coupling.

A new Zn-mediated trifluoromethylthiolation-based bifunctionalization reaction is developed. In this process, simultaneous C-SCF and C-C bond formation takes place in a multicomponent reaction, in which an aryl and a SCF group arise from different reagents. Our studies show that the reaction mechanism is similar to the Hooz multicomponent coupling.

Catalytic asymmetric propargyl- and allylboration of hydrazonoesters: a metal-free approach to sterically encumbered chiral α-amino acid derivatives.

A new asymmetric catalytic propargyl- and allylboration of hydrazonoesters is reported. The reactions utilize allenyl- and allylboronic acids in the presence of the inexpensive parent BINOL catalyst. The reactions can be performed under mild conditions (0 °C) without any metal catalyst or other additives affording sterically encumbered chiral α-amino acids.

Mechanisms of Rh-Catalyzed Oxyaminofluorination and Oxyaminotrifluoromethylthiolation of Diazocarbonyl Compounds with Electrophilic Reagents.

Density functional theory calculations were performed to study the detailed reaction mechanisms of rhodium-catalyzed oxyaminofluorination and oxyaminotrifluoromethylthiolation of diazocarbonyl compounds with electrophilic N-F and N-SCF-based reagents. The calculations show that the operating mechanisms for the two reactions are identical. The catalytic cycle starts with N dissociation to provide a rhodium-carbene intermediate, followed by nucleophilic attack of tetrahydrofuran on the carbene and a rhodium coordination change generating a rhodium-enolate intermediate.

Synthesis of Densely Substituted Conjugated Dienes by Transition-Metal-Free Reductive Coupling of Allenylboronic Acids and Tosylhydrazones.

Tosylhydrazones and allenylboronic acids underwent a transition-metal-free reductive coupling reaction. This process is suitable for synthesis of tetra- and pentasubstituted conjugated dienes. The corresponding allenyl-Bpin substrate showed a very poor reactivity.

Copper-catalyzed synthesis of allenylboronic acids. Access to sterically encumbered homopropargylic alcohols and amines by propargylboration.

Tri- and tetrasubstituted allenylboronic acids were prepared a new versatile copper-catalyzed methodology. The densely functionalized allenylboronic acids readily undergo propargylboration reactions with ketones and imines without any additives. Catalytic asymmetric propargylborylation of ketones is demonstrated with high stereoselectivity allowing for the synthesis of highly enantioenriched tertiary homopropargyl alcohols.

[F]fluoro-benziodoxole: a no-carrier-added electrophilic fluorinating reagent. Rapid, simple radiosynthesis, purification and application for fluorine-18 labelling.

Operationally simple radiosynthesis and purification of [18F]fluoro-benziodoxole was developed starting from a cyclotron produced [18F]F- precursor, [18F]TBAF, and tosyl-benziodoxole. The synthetic utility of [18F]fluoro-benziodoxole was demonstrated by electrophilic fluorocyclization of o-styrilamides proceeding with high RCC (typically 50-90%) and high molar activity (up to 396 GBq μmol-1).

Palladium-Catalyzed Oxidative Borylation of Allylic C-H Bonds in Alkenes.

This communication describes an efficient palladium pincer complex-catalyzed allylic C-H borylation of alkenes. The transformation exhibits high regio- and stereoselectivity with a variety of linear alkenes. A synthetically useful feature of this allylic C-H borylation method is that all allyl-Bpin products can be isolated in usually high yields.

Synthesis of Vinyl-, Allyl-, and 2-Boryl Allylboronates via a Highly Selective Copper-Catalyzed Borylation of Propargylic Alcohols.

An efficient methodology for the synthesis of vinyl-, allyl-, and (E)-2-boryl allylboronates from propargylic alcohols via Cu-catalyzed borylation under mild conditions is reported. In the presence of commercially available Cu(OAc) or Cu(acac) and Xantphos, the reaction affords the desired products in up to 92% yield with a broad substrate scope (43 examples). Isolation of an allenyl boronate as the reaction intermediate suggests that an insertion-elimination-type reaction, followed by borylcupration, is involved in the borylation of propargylic alcohols.

Mechanism and Stereoselectivity of the BINOL-Catalyzed Allylboration of Skatoles.

Density functional theory calculations have been performed to investigate the binaphthol-catalyzed allylboration of skatoles. The high stereoselectivity observed for the reaction is reproduced well by the calculations and was found to be mainly a result of steric repulsions in the corresponding Zimmerman-Traxler transition states. The role of the additive MeOH in enhancing the stereoselectivity was also investigated and is suggested to promote the formation of less reactive allylboronic ester intermediates, thereby suppressing the formation of allylboroxine species, which undergo the facile racemic background reaction.

Trifluoromethylthiolation-Based Bifunctionalization of Diazocarbonyl Compounds by Rhodium Catalysis.

A new Rh-catalyzed, three-component reaction for the oxytrifluoromethylthiolation of α-diazoketones was developed. The SCF functionality was introduced using a stable dibenzenesulfonimide reagent under mild conditions. Alcohols, acetals, and ethers were used as the alkoxy sources.

Fluorinative ring-opening of cyclopropanes by hypervalent iodine reagents. An efficient method for 1,3-oxyfluorination and 1,3-difluorination.

A new method is presented for 1,3-difluorination and 1,3-oxyfluorination reactions. The process is based on iodonium mediated opening of 1,1-disubstituted cyclopropanes. The reaction proceeds with high chemo- and regioselectivity under mild reaction conditions typically at room temperature in a couple of hours.

Copper-Catalyzed, Stereoselective Cross-Coupling of Cyclic Allyl Boronic Acids with α-Diazoketones.

In this study, we present the synthesis of new, stereodefined allylboronic acids employed to investigate the stereochemistry of the Cu-catalyzed cross-coupling of allylboronic acids with α-diazoketones. According to our results, this reaction proceeds with retention of the relative configuration of the allylboronic acid substrate. We suggest that the stereoinduction step involves a syn S2'-type transmetalation of the allylboronic acid substrate with a Cu-carbene species.

Synthesis of Benzyl-, Allyl-, and Allenyl-boronates via Copper-Catalyzed Borylation of Alcohols.

Alcohols are among the most abundant and readily available organic feedstocks in industrial processes. The direct catalytic functionalization of sp C-O bonds of alcohols remains the main challenge in this field. Here, we report a copper-catalyzed synthesis of benzyl-, allyl-, and allenyl-boronates from benzylic, allylic, and propargylic alcohols, respectively.