Divergent,Stereospecific Mono- and Difluoromethylation of Boronic Esters

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH₂F and CHF₂ groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α-fluoro-boronic esters. These unique intermediates can be readily transformed into the corresponding mono- or difluoromethylated compounds through proto- or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2-migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.     

Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

The coupling of ortho ‐ and para ‐phenols with secondary and tertiary boronic esters has been explored. In the case of para ‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph₃BiF₂ or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho ‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho ‐lithiation and borylation gave the coupled product, again with complete stereospecificity.     

Stereocontrolled Synthesis of 1,5‐Stereogenic Centers through Three‐Carbon Homologation of Boronic Esters

Allylic pinacol boronic esters are stable toward 1,3‐borotropic rearrangement. We developed a Pd^II‐mediated isomerization process that gives di‐ or trisubstituted allylic boronic esters with high E selectivity. The combination of this method with lithiation–borylation enables the synthesis of carbon chains that bear 1,5‐stereogenic centers. The utility of this method has been demonstrated in a formal synthesis of (+)‐jasplakinolide.     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

An unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C?H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.     

Palladium(II)‐Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox‐Neutral,Phosphine‐Free Transformation

A redox‐neutral palladium(II)‐catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)₂ catalyst, in combination with the sulfur dioxide surrogate 1,4‐diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high‐yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C‐ or N‐based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one‐pot, two‐step process.     

Homologation and alkylation of boronic esters and boranes by 1,2‐metallate rearrangement of boron ate complexes

Organoboranes and boronic esters readily undergo nucleophilic addition, and if the nucleophile also bears an α‐leaving group, 1,2‐metallate rearrangement of the ate complex results. Through such a process a carbon chain can be extended, usually with high stereocontrol and this is the focus of this review. A chiral boronic ester (substrate control) can be used for stereocontrolled homologations with (dichloromethyl)lithium in the presence of ZnCl₂. Subsequent alkylation by an organometallic reagent also occurs with high levels of stereocontrol. Chiral lithiated carbanions (reagent control) can also be used for the reaction sequence with achiral boronic esters and boranes. Aryl‐stabilized sulfur ylide derived chiral carbanions can be homologated with a range of boranes including vinyl boranes in good yield and high diastereo‐ and enantioselectivity. Lithiated alkyl chlorides react with boronic esters, again with high stereocontrol, but both sets of reactions are limited in scope. Chiral lithiated carbamates show the greatest substrate scope and react with both boronic esters and boranes with excellent enantioselectivity. Furthermore, iterative homologation with chiral lithiated carbamates allows carbon chains to be “grown” with control over relative and absolute stereochemistry. The factors responsible for stereocontrol are discussed. © 2009 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 9: 24–39; 2009: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.20168     

Palladium(II)‐Catalyzed Synthesis of Sulfinates from Boronic Acids and DABSO: A Redox‐Neutral,Phosphine‐Free Transformation

A redox‐neutral palladium(II)‐catalyzed conversion of aryl, heteroaryl, and alkenyl boronic acids into sulfinate intermediates, and onwards to sulfones and sulfonamides, has been realized. A simple Pd(OAc)₂ catalyst, in combination with the sulfur dioxide surrogate 1,4‐diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO), is sufficient to achieve rapid and high‐yielding conversion of the boronic acids into the corresponding sulfinates. Addition of C‐ or N‐based electrophiles then allows conversion into sulfones and sulfonamides, respectively, in a one‐pot, two‐step process.     

Synthesis of Perfluoroalkyl‐Substituted γ‐Lactones and 4,5‐Dihydropyridazin‐3(2H)‐ones via Donor?Acceptor Cyclopropanes

Rh₂(OAc)₄‐Catalyzed decomposition of diazo esters in the presence of perfluoroalkyl‐ or perfluoroaryl‐substituted silyl enol ethers smoothly provided the corresponding alkyl 2‐siloxycyclopropanecarboxylates in very good yields. The generated donor? acceptor cyclopropanes are equivalents of γ‐oxo esters, which we demonstrated by their one‐pot transformations to yield fluorine‐containing heterocycles. A reductive procedure selectively afforded perfluoroalkyl‐substituted γ‐hydroxy esters or γ‐lactones. The treatment of the donor? acceptor cyclopropanes with hydrazine or phenylhydrazine afforded a series of perfluoroalkyl‐ and perfluoroaryl‐substituted 4,5‐dihydropyridazin‐3(2H)‐ones.     

Enhancement of Host–Guest Interactions Using Rationally Designed Macrocyclic Boronic Esters with a Naphthalene Core

Efficient inclusion of electron‐deficient aromatic guest molecules in an organic solvent utilizing π‐stacking interactions was achieved by using two kinds of macrocyclic boronic esters, 1,4‐naph‐ [2+2] and 1,5‐naph‐ [2+2] , which were easily prepared by self‐assembly of 1,4‐naphthalenediboronic acid ( 3 ) or 1,5‐naphthalenediboronic acid ( 4 ) and racemic tetrol 1 with an indacene framework in a protic solvent. The X‐ray crystallographic analyses revealed that the tilt angles of the two naphthalene rings are different: that of 1,4‐naph‐ [2+2] is about 15° and that of 1,5‐naph‐ [2+2] is about 0°. Owing to the parallel alignment of two aromatic rings, 1,5‐naph ‐[2+2] has a much higher binding ability than 1,4‐naph‐ [2+2] . This knowledge could be useful for the design of the new host molecules in organic solvents.     

Reaction of Hydantoin with Boronic Acids

We have examined the reaction of hydantoin (=imidazolidine‐2,4‐dione) with (formylphenyl)boronic acids, where the addition of a boronic acid group is hoped to increase bioactivities. Addition of (2‐formylphenyl)boronic acid to hydantoin gave an unexpected azaborine compound, which presumably arises by initial formation of the (phenylmethylidene)hydantoin, with subsequent loss of H₂O to give the cyclized product. Reactions of (3‐formylphenyl)‐ and (4‐formylphenyl)boronic acids with hydantoin gave the corresponding [(Z)‐phenylmethylidene]hydantoins in good‐to‐excellent yields. Attempts to use (3‐formylthiophen‐2‐yl)boronic acid gave a product where the boronic acid group has been cleaved.     

Synthesis of Enaminone‐Pd(II) Complexes and Their Application in Catalysing Aqueous Suzuki‐Miyaura Cross Coupling Reaction

A series of Pd(II)‐enaminone complexes, termed Pd(eao)₂, have been synthesized and characterized. The investigation on the catalytic activities of these new Pd(II)‐reagents has proved that the Pd(eao)₂‐ 1 possesses excellent catalytic activity for the Suzuki‐ Miyaura cross coupling reactions of aryl bromides/chlorides with aryl/vinyl boronic acids in the environmentally benign media of aqueous PEG400 at low loading (5 mol‰). The superiority of this Pd(II)‐reagent to those commercial Pd(II) and Pd(0) catalysts in catalyzing the reactions has been confirmed by parallel experiments. What's more, Pd(eao)₂‐ 2 has been found as a practical catalyst for the homo‐coupling reactions of aryl boronic acids.     

Enantiospecific Synthesis of ortho‐Substituted 1,1‐Diarylalkanes by a 1,2‐Metalate Rearrangement/anti‐SN2′ Elimination/Rearomatizing Allylic Suzuki–Miyaura Reaction Sequence

The one‐pot sequential coupling of benzylamines, boronic esters, and aryl iodides has been investigated. In the presence of an N‐activator, the boronate complex formed from an ortho‐lithiated benzylamine and a boronic ester undergoes stereospecific 1,2‐metalate rearrangement/anti‐S_N2′ elimination to form a dearomatized tertiary boronic ester. Treatment with an aryl iodide under palladium catalysis leads to rearomatizing γ‐selective allylic Suzuki–Miyaura cross‐coupling to generate 1,1‐diarylalkanes. When enantioenriched α‐substituted benzylamines are employed, the corresponding 1,1‐diarylalkanes are formed with high stereospecificity.     

Synthesis of 2‐Aryl‐ and 2‐Heteroaryl‐3,5‐dimethoxy‐1,4‐benzoquinones Involving Pd‐Catalyzed Cross‐Coupling of (2,3,4,6‐Tetramethoxyphenyl)boronic Acid

A series of 2‐aryl‐ and 2‐heteroaryl‐substituted 3,5‐dimethoxy‐1,4‐benzoquinones (compounds 27 – 36 ) have been synthesized by cross‐coupling of (2,3,4,6‐tetramethoxyphenyl)boronic acid ( 2 ) with aromatic bromides or iodides in the presence of [Pd⁰(Ph₃)₄] and Na₂CO₃, followed by AgO‐promoted oxidation of the resulting biaryl compounds 17 – 26 .     

Reaction‐Based and Single Fluorescent Emitter Decorated Ratiometric Nanoprobe to Detect Hydrogen Peroxide

A novel reaction‐based cross‐linked polymeric nanoprobe with a self‐calibrating ratiometric fluorescence readout to selectively detect H₂O₂ is reported. The polymeric nanoprobe is fabricated by using hydrophobic H₂O₂‐reactive boronic ester groups, crosslinker units, and environmentally sensitive 3‐hydroxyflavone fluorophores through a miniemulsion polymerization. On treatment with H₂O₂, the boronic esters in the polymer are cleaved to form hydrophilic alcohols and subsequently lead to a hydrophobic–hydrophilic transition. Covalently linked 3‐hydroxyflavones manifest the change in polarity as a ratiometric transition from green to blue, accompanied by a 500‐fold increase in volume. Furthermore, this nanoprobe has been used for ratiometric sensing of glucose by monitoring the H₂O₂ generated during the oxidation of glucose by glucose oxidase, and thus successfully distinguished between normal and pathological levels of glucose.     

Lewis Acid Catalyzed Stereoselective Dearomative Coupling of Indolylboron Ate Complexes with Donor–Acceptor Cyclopropanes and Alkyl Halides

Indolylboron ate complexes readily generated from 2‐lithioindoles and boronic esters underwent multicomponent dearomative coupling with D‐A cyclopropanes and alkyl halides in the presence of Sc(OTf)₃ as a catalyst. The reactions proceeded with complete diastereoselectivity and excellent stereospecificity to provide indolines containing three contiguous stereocenters. The valuable boronic ester moiety remains in the product and allows for subsequent functionalization.     

Two closely related {4‐[(N‐substituted amino)(diethoxyphosphoryl)methyl]phenyl}boronic acids

Organic phosphonic acids and organic phosphonic acid esters have been of much interest due to their applications in the fields of medicine, agriculture and industrial chemistry. Boronic acids can act as synthetic intermediates and building blocks and are used in sensing, protein manipulation, therapeutics, biological labelling and separation. The additional introduction of an aminophosphonic acid group into a boronic acid may give new opportunities for application. To study the structure of such multifunctional compounds, we prepared two new derivatives which can be easily converted to the corresponding phosphonic acids. In the title compounds, {4‐[(butylamino)(diethoxyphosphoryl)methyl]phenyl}boronic acid monohydrate, C₁₅H₂₇BNO₅P·H₂O, (I), and {4‐[(diethoxyphosphoryl)(4‐nitroanilino)methyl]phenyl}boronic acid, C₁₇H₂₂BN₂O₇P, (II), three different substituents are attached to a central C—H group, namely 4‐boronophenyl, diethoxyphosphoryl and amine. Compound (I) crystallizes as a monohydrate and O_B—H…N hydrogen bonds link neighbouring molecules into chains along the [001] direction. The solvent water molecule connects two such chains running in opposite directions. Compound (II) crystallizes as an ansolvate and classical hydrogen bonds result in a layer structure in the (001) plane.     

A Comparative Study of the Relative Stability of Representative Chiral and Achiral Boronic Esters Employing Transesterification

A comparative study of the transesterification of five representative chiral and achiral boronic esters with various structurally modified diols was undertaken to qualitatively understand the factors influencing the relative stability of these boronic esters. Several factors such as chelation, conformation, steric bulk of the substituents, size of the heterocycle, and entropy influence the relative rate of transesterification as well as the stability of the boronic esters. Amongst these boronic esters, pinanediol phenylboronic ester was found to be the most stable boronic ester whereas DIPT boronic ester appeared to be thermodynamically the least stable one. The transesterification with sterically hindered diols was observed to be relatively slow, but afforded thermodynamically more stable boronic esters. Boronic esters derived from cis-cyclopentanediols and the bicyclo[2.2.1]heptane-exo,exo-2,3-diols are relatively more stable. This study not only presents the qualitative picture of relative stability of various boronic esters, but also provides helpful hints regarding the possible recovery of chiral auxiliaries. Many C ₂-symmetric chiral auxiliaries, such as 2,3-butanediol, 2,4-pentanediol, DIPT, and cis-cyclohexane-1,2-diol, can be retrieved by simple transesterification of the corresponding boronic esters with commercial inexpensive diols, such as pinacol, 1,3-propanediol, and neopentyl glycol.     

Chemoselective Boronic Ester Synthesis by Controlled Speciation

Control of boronic acid solution speciation is presented as a new strategy for the chemoselective synthesis of boronic esters. Manipulation of the solution equilibria within a cross‐coupling milieu enables the formal homologation of aryl and alkenyl boronic acid pinacol esters. The generation of a new, reactive boronic ester in the presence of an active palladium catalyst also facilitates streamlined iterative catalytic C? C bond formation and provides a method for the controlled oligomerization of sp²‐hybridized boronic esters.     

Enzyme‐Mediated Preparation of (+)‐ and (−)‐β‐Irone and (+)‐ and (−)‐cis‐γ‐Irone from Irone alpha®

The (−)‐ and (+)‐β‐irones ((−)‐ and (+)‐ 2 , resp.), contaminated with ca. 7 – 9% of the (+)‐ and (−)‐trans‐α‐isomer, respectively, were obtained from racemic α‐irone via the 2,6‐trans‐epoxide (±)‐ 4 (Scheme 2). Relevant steps in the sequence were the LiAlH₄ reduction of the latter, to provide the diastereoisomeric‐4,5‐dihydro‐5‐hydroxy‐trans‐α‐irols (±)‐ 6 and (±)‐ 7 , resolved into the enantiomers by lipase‐PS‐mediated acetylation with vinyl acetate. The enantiomerically pure allylic acetate esters (+)‐ and (−)‐ 8 and (+)‐ and (−)‐ 9 , upon treatment with POCl₃/pyridine, were converted to the β‐irol acetate derivatives (+)‐ and (−)‐ 10 , and (+)‐ and (−)‐ 11 , respectively, eventually providing the desired ketones (+)‐ and (−)‐ 2 by base hydrolysis and MnO₂ oxidation. The 2,6‐cis‐epoxide (±)‐ 5 provided the 4,5‐dihydro‐4‐hydroxy‐cis‐α‐irols (±)‐ 13 and (±)‐ 14 in a 3 : 1 mixture with the isomeric 5‐hydroxy derivatives (±)‐ 15 and (±)‐ 16 on hydride treatment (Scheme 1). The POCl₃/pyridine treatment of the enantiomerically pure allylic acetate esters, obtained by enzymic resolution of (±)‐ 13 and (±)‐ 14 , provided enantiomerically pure cis‐α‐irol acetate esters, from which ketones (+)‐ and (−)‐ 22 were prepared (Scheme 4). The same materials were obtained from the (9S) alcohols (+)‐ 13 and (−)‐ 14 , treated first with MnO₂, then with POCl₃/pyridine (Scheme 4). Conversely, the dehydration with POCl₃/pyridine of the enantiomerically pure 2,6‐cis‐5‐hydroxy derivatives obtained from (±)‐ 15 and (±)‐ 16 gave rise to a mixture in which the γ‐irol acetates 25a and 25b and 26a and 26b prevailed over the α‐ and β‐isomers (Scheme 5). The (+)‐ and (−)‐cis‐γ‐irones ((+)‐ and (−)‐ 3 , resp.) were obtained from the latter mixture by a sequence involving as the key step the photochemical isomerization of the α‐double bond to the γ‐double bond. External panel olfactory evaluation assigned to (+)‐β‐irone ((+)‐ 2 ) and to (−)‐cis‐γ‐irone ((−)‐ 3 ) the strongest character and the possibility to be used as dry‐down note.