Subsequent Suzuki-Miyaura Coupling Research Articles

1,2-Carboboration of Arylallenes by In Situ Generated Alkenylboranes for the Synthesis of 1,4-Dienes.

We herein report a novel method for the coupling of unactivated alkynes and arylallenes, which relies on an unprecedented and regioselective 1,2‐carboboration of the allene by an alkenylborane. The alkenylborane is conveniently prepared in situ by hydroboration of an alkyne with Piers’ borane, i. e., HB(C6F5)2. The boryl‐substituted 1,4‐dienes that are formed by this carboboration are well‐suited for a subsequent Suzuki‐Miyaura coupling with aryl iodides. This allowed us to develop a three‐step, one‐pot protocol for the synthesis of aryl‐substituted 1,4‐dienes. The generality of the reaction was demonstrated by the synthesis of twenty dienes with modular variations of all three reaction partners. The mechanism of the new 1,2‐carboboration was investigated using dispersion corrected double‐hybrid DFT computations that allowed us to rationalize the chemo‐ and regioselectivity of this key step.

Palladium-Catalyzed Aromatic C-H Functionalizations Utilizing Electrochemical Oxidations.

Transition-metal-catalyzed electrochemical C-H functionalizations have been extensively studied as atom- and step-economical clean methods in organic synthesis. In this account, we described our efforts on the palladium-catalyzed electrochemical C-H functionalizations, including C-H halogenations of arylpyridines and benzamide derivatives using HCl/HBr and I2 as a halogen source, a one-pot process giving teraryls via the palladium-catalyzed electrochemical C-H iodination and subsequent Suzuki-Miyaura coupling, and an iodine-mediated oxidative homo-coupling reaction of arylpyridines.

Copper-catalyzed borylative cyclization of 1,n-enynyl phosphates leading to five- to eight-membered cyclic 1,4-dienyl boronates

We report here a room temperature, efficient, and broadly applicable copper-catalyzed borylative cyclization of 1,n-enynyl (n=6–9) phosphates for the concise synthesis of structurally diverse 5–8 membered cyclic 1,4-dienyl boronates, which represents the first Cu-catalyzed formal intramolecular alkyne allylboration. Subsequent Suzuki-Miyaura coupling provides a facile access to cyclized 1,4-dienes. A mechanism consisting of alkyne borylcupration, intramolecular alkene addition, and β-elimination has been proposed to explain the experimental results.

ChemInform Abstract: Sequential Alcohol Oxidation/putative Homo Claisen—Tishchenko‐Type Reaction to Give Esters: A Key Process in Accessing Novel Biologically Active Lactone Macrocycles.

We report an efficient methodology for the direct oxidative esterification of primary alcohols to diether-esters using pyridinium chlorochromate (PCC). Numerous studies were carried out to probe the reaction mechanism and at the same time optimize the reaction conditions. The reaction could be conducted with 1 equivalent of PCC and 1 equivalent of BF3·OEt2. Indications based on literature precedent were that the reaction may proceed via a sequential alcohol oxidation to the aldehyde followed by a putative Cr or boron catalyzed Claisen–Tishchenko-type reaction. Using this efficient methodology, we synthesized a family of novel diether-esters in very good yields; some of these molecules were subsequently tested against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). In addition, we also disclose a new synthetic strategy for the synthesis of lactam macrocycles with potential biological activity. This methodology included the regioselective borylation of the ester substrate and a subsequent Suzuki–Miyaura coupling to obtain the desired lactam macrocycle.

Synthesis of Optically Pure 3,3'-Disubstituted-1,1'-Bi-6-Methoxy-2-Phenol (BIPhOL) Derivatives via Diastereomeric Resolution.

A new protocol for the enantioselective synthesis of 3,3'-disubstituted-1,1'-bi-6-methoxy-2-phenol (BIPhOL) derivatives is described. Diastereomeric resolution of racemic BIPhOL boronic acid using a boronic acid moiety as a resolving group generated two diastereomers and subsequent Suzuki-Miyaura coupling reaction of the resulting diastereomers with aryl halides provided BIPhOL derivatives without any loss of enantioselectivity. In addition, the absolute stereochemistry of chiral BIPhOL was determined by comparison of the optical rotation with the reported value.

Synthesis, Properties, and Theoretical Study of Extended Diynes and Their Analogs Bearing Two Amino Moieties

Recently, π-conjugated compounds have received attention because they are known to be key building blocks for pharmaceuticals and potential candidates for electrochemical and optical materials. From this perspective, we have investigated the use of electrochemically assisted coupling reactions for the construction of π-conjugated compounds, and recently reported sequential coupling reactions including the Pd/Cu-catalyzed electro-oxidative homo-coupling of p-bromophenylacetylene (1) to give 1,4-bis(p-bromophenyl)-1,3-diyne (2) and subsequent Suzuki–Miyaura coupling with arylboronic acids leading to 1,4-bis(diaryl)-1,3-butadiynes 3 (Scheme 1).1 Two reaction sites of p-bromophenylacetylene, the terminal alkyne and Br group, could be almost completely discriminated by the on/off application of electricity, and we called the strategy as “Electrochemical Reaction Site Switching (e-RSS)”. Several arylboronic acids can be used in these reactions, which proceed selectively to give 1,4-bis(diaryl)-1,3-butadiynes in good to excellent yields. During the course of our investigation, we found that 1,4-bis(diaryl)-1,3-butadiynes bearing two amino groups at the p-position of the terminal benzene rings exhibited solvatochromic fluorescence. There have been many reports on amines that exhibit solvatochromic fluorescence. Most of the known amines that exhibit solvatochromic fluorescence have a strong acceptor moiety. There have been a few reports on the solvatochromic fluorescence of diamines, which have a small dipole moment. This unexpected result encouraged us to gain deeper insight into this unusual phenomenon. This time, we synthesized their analog 4 which contains an alkyne, and 5 which does not contain a triple bond (Figure 1), and compared their properties with those of 1,4-bis(diaryl)-1,3-butadiynes bearing two amino moieties. To estimate the solvent effect, we also carried out DFT and TD-DFT calculations of their compound. The results of TD-DFT calculations in different solvents indicated that the excitations and the emissions were mainly due to the HOMO–LUMO transitions of these compounds. (1) Mitsudo, K.; Kamimoto, N.; Murakami, H.; Mandai, H.; Wakamiya, A.; Murata, Y.; Suga, S. Org Biomol Chem 2012, 10, 9562-9569. Figure 1

Silver-Catalyzed Regio- and Stereoselective Addition of Carboxylic Acids to Ynol Ethers

A silver-catalyzed trans addition of carboxylic acids to ynol ethers is described. The reaction has a broad scope with respect to carboxylic acids and ynol ethers, delivering (Z)-α-alkoxy enol esters in good yields with excellent regio- and stereoselectivity. Meaningfully, the Ni-catalyzed selective coupling of alkenyl C-OPiv bonds of (Z)-α-alkoxy enol esters with boronic acids enables a convenient route to the access of (E)-enol ethers. As such, the two-step procedure, consisted of a hydrocarboxylation and a subsequent Suzuki-Miyaura coupling, offers a formal trans hydroarylation of ynol ethers, thus providing a good complementary method to our previous report.

Site-Selective Sequential Coupling Reactions Controlled By “Electrochemical Reaction Site Switching”: A Straightforward Approach to 1,4-Bis(diaryl)Buta-1,3-Diynes

Recently, π-conjugated compounds have received considerable attention because they are known to be key building blocks for pharmaceuticals and candidates for electrochemical and optical materials. One of the most straightforward and powerful ways to construct π-skeletons is through transition-metal catalysed cross-coupling reactions using aryl halides or triflates and organometallic species such as in Suzuki–Miyaura coupling. Alternatively, transition metal-catalysed oxidative homo-coupling reactions of aryl metal species (e.g., arylboronic acids and esters) or terminal alkynes have also been shown to be convenient methods for building symmetrical π-structures. In these oxidative homo-coupling reactions, a stoichiometric amount of an oxidant is usually required. One way to overcome this drawback is to use electro-oxidation instead of a stoichiometric oxidant. The electrochemical method is advantageous, not only because it does not require excess oxidant, but also because the system can be switched between oxidative and neutral conditions by the on/off application of electricity. We considered that this feature could make it possible to realize a site selective coupling reaction controlled by the on/off application of electricity, and we call this strategy “Electrochemical Reaction Site Switching (e-RSS)”. This idea prompted us to design a novel integrated sequential reaction that consisted of an oxidative homo-coupling reaction and a typical coupling reaction. As the first example of the construction of π-conjugated compounds by a sequential coupling reaction controlled by e-RSS, we chose π-conjugated compounds that include a diyne moiety as a target; they are of interest due to their unique optical and electrochemical characteristics. The sequential reactions consist of two coupling reactions (Scheme 1). The first step is a Pd/Cu-catalysed electrochemical homo-coupling of p-bromophenylacetylene to give bis(p-bromophenyl)butadiyne (1st step: electricity ON), and the second step is a sequential Suzuki–Miyaura coupling reaction to build up 1,4-bis(diaryl)butadiynes (2nd step: electricity OFF). First, we optimized the reaction conditions of Pd/Cu-catalyzed electro-oxidative homo-coupling of p-bromophenylacetylene (1) (1st step) and we obtained diyne 2 in good yield. With the optimized conditions for the first step in hand, we next carried out the sequential reactions, including the electrooxidative homo-coupling of 1 and subsequent Suzuki–Miyaura coupling with several arylboronic acids on the basis of the e-RSS strategy. After the electro-oxidative homo-coupling of p-bromophenylacetylene, the electricity was turned off and to the resulting mixture were added p-tolylboronic acid, P(t-Bu)3·HBF4, Cs2CO3, and DME, then refluxed to give 1,4-bis(p-tolylphenyl)butadiyne 3a in 95% yield. In a similar manner, i-Pr- or t-Bu-substituted 1,4-bis(diaryl)butadiyne 3b and 3c were obtained in 79 and 86% yields, respectively. Anisole and aniline skeletons can also be introduced (3d and 3e). Arylboronic acids bearing electronwithdrawing functional groups could also be used in the reactions. 1,4-Bis-(diaryl)butadiynes with fluoro (3f), acetyl (3g), and cyano (3h) groups at the p-position can be synthesized by the sequential coupling reactions in respective yields of 68%, 65%, and 47%. The synthesis of aryl-substituted diynes with much greater π-conjugation was achieved by the use of 2-naphthylboronic acid or 2-phenylethenylboronic acid to afford 3i and 3j in 72% and 70% yields, respectively. We will discuss the details of the reactions and further transformations of 1,4-bis(diaryl)buta-1,3-diynes.

Synthesis of 1,4-Bis(diaryl)-1,3-Butadiynes Bearing Two Amino Moieties by Electrochemical Reaction Site Switching and Their Solvatochromic Fluorescence

Recently, π-conjugated compounds have been on focus because they are known to be as key building blocks for pharmaceuticals and potent candidates for electrochemical and optical materials. While the optical and electrochemical properties of π-conjugated compounds highly depends on the structure, it has not been easy to predict these properties. It is the reason why facile and diversity-oriented methodologies to construct π-conjugated structure have been strongly required. From such a point of view, we have investigated electrochemically assisted coupling reactions for constructing π-conjugated compounds, and recently reported sequential coupling reactions which include Pd/Cu-catalyzed electro-oxidative homo-coupling of p-bromophenylacetylene to give 1,4-bis(p-bromophenyl)-1,3-diyne and subsequent Suzuki–Miyaura coupling with arylboronic acids leading to 1,4-bis(diaryl)-1,3-butadiynes.1 Two reaction sites of p-boromophenylacetylene, terminal alkyne and Br group, could be discriminated in a virtually complete manner by on/off application of electricity, and we called the strategy as “Electrochemical Reaction Site Switching (e-RSS)”. Several arylboronic acids could be applied to the reactions, and the reactions proceeded selectively to give 1,4-bis(diaryl)-1,3-butadiynes in good to excellent yields.During the course of the investigation, we unexpectedly found that 1,4-bis(diaryl)-1,3-butadiyne bearing two dimethylamino groups at p-position exhibited solvatochromic fluorescence. To the best of our knowledge, while there have been many reports on the amines which exhibit solvatochromic fluorescence, there have been few reports on the solvatochromic fluorescence of diamines which have small dipole moment. Most of the amines exhibiting solvatochromic fluorescence so far have a strong acceptor moiety. This unexpected result prompted us to get deeper insight into this unusual phenomenon; however the poor solubility of diaminodiynes prevented us from further investigation. We therefore designed novel 1,4-bis(diaryl)-1,3-butadiynes bearing two dialkylamino or diphenylamino groups at p-position of the terminal benzene rings. The butadiynes could be easily synthesized by e-RSS with the corresponding p-aminoarylboronic acids. As expected, thus obtained diynes could be solved into several solvents and they exhibited solvatochromic fluorescence. We will discuss the detail of the synthesis of 1,4-bis(diaryl)-1,3-butadiynes bearing two dialkylamino or diphenylamino groups at p-position, and their unique optical properties. (1) Mitsudo, K.; Kamimoto, N.; Murakami, H.; Mandai, H.; Wakamiya, A.; Murata, Y.; Suga, S. Org Biomol Chem 2012, 10, 9562-9569.

ChemInform Abstract: Synthesis of 3‐(Diarylmethylene)oxindoles via a Palladium‐Catalyzed One‐Pot Reaction: Sonogashira—Heck—Suzuki—Miyaura Combined Reaction.

AbstractA Pd‐catalyzed cascade reaction consisting of an intramolecular Heck‐type cyclization and subsequent Suzuki—Miyaura coupling is achieved under typical Sonogashira reaction conditions to yield diarylmethylene indolones (IV).

Synthesis of 3-aryl-1H-indazoles via iridium-catalysed C–H borylation and Suzuki–Miyaura coupling

The regioselective iridium-catalysed C3-borylation of 1H-indazoles has been achieved. Subsequent Suzuki–Miyaura coupling of the boronate esters with aryl chlorides, bromides and iodides affords 3-aryl-1H-indazoles in good yields.

A General Method for Suzuki–Miyaura Coupling Reactions Using Lithium Triisopropyl Borates

Conditions for the Suzuki-Miyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation, and subsequent Suzuki-Miyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.

Synthesis of substituted asymmetrical biphenyl amino esters as alpha helix mimetics

As part of our ongoing project to develop new molecular probes for estrogen receptor-alpha, we are exploring the utility of internally-substituted asymmetric biphenyls as a proteomimetic scaffold. In this study, we describe synthetic methods for preparing the requisite substituted-bromophenol precursors, their further elaboration, and the subsequent Suzuki–Miyaura coupling of these sterically-hindered and electronically-rich aromatic systems. The results provide an efficient route with which to generate further libraries of novel asymmetric biphenyl compounds as potential proteomimetics.

ChemInform Abstract: Systematic Synthesis and Characterization of a Series of Tetra(5‐aryl‐2‐thienyl)thiophenes.

AbstractAryl‐functionalized tetrathienylthiophenes (IV) are synthesized via selective lithiation/bromination and subsequent Suzuki—Miyaura coupling of key intermediate (II) with arylboronic acids (III).

Site-selective sequential coupling reactions controlled by “Electrochemical Reaction Site Switching”: a straightforward approach to 1,4-bis(diaryl)buta-1,3-diynes

Site-selective sequential coupling reactions directed toward bis(diaryl)butadiynes are described. The reaction site could be controlled completely by the on/off application of electricity. The electro-oxidative homo-coupling of terminal alkynes (electricity ON) and the subsequent Suzuki-Miyaura coupling (electricity OFF) afforded bis(diaryl)butadiynes in high yields. The obtained 1,4-bis(diaryl)butadiynes could be converted to a 2,5-bis(diaryl)thiophene derivative, which exhibited blue fluorescence.

ChemInform Abstract: Synthesis of 8‐Arylquinolines via One‐Pot Pd‐Catalyzed Borylation of Quinoline‐8‐yl Halides and Subsequent Suzuki—Miyaura Coupling.

AbstractThe method provides a general and efficient approach to biologically important 8‐arylquinolines.

Aromatic Ionomers with Highly Acidic Sulfonate Groups: Acidity, Hydration, and Proton Conductivity

A novel sulfonation method that involves iridium-catalyzed aromatic C–H activation/borylation and subsequent Suzuki–Miyaura coupling with sulfonated phenyl bromides was developed for the preparation of aromatic ionomers. Superacidic fluoroalkyl sulfonic acid and less acidic aryl and alkyl sulfonic acids were efficiently incorporated into the aromatic ring of model polystyrene, and the resulting sulfonated ionomers were characterized for their properties as proton-conducting membranes. The membrane properties of ionomers containing sulfonic acid groups with different acidity strengths were compared to study the effect of acidity on the water properties, proton conductivity, and morphology. The superacidic fluoroalkyl sulfonated ionomer (sPS-S1) exhibited a significantly higher proton conductivity than that of the less acidic aryl and alkyl sulfonated ionomers (sPS-S2 and sPS-S3, respectively) at low relative humidity, despite a lower ion exchange capacity and lower water uptake. Hydration behaviors of the ...

Synthesis of 8-Arylquinolines via One-Pot Pd-Catalyzed Borylation of Quinoline-8-yl Halides and Subsequent Suzuki–Miyaura Coupling

A one-pot process has been developed for the synthesis of 8-arylquinolines via Pd-catalyzed borylation of quinoline-8-yl halides and subsequent Suzuki-Miyaura coupling with aryl halides using n-BuPAd(2) as ligand. Yields of up to 98% were obtained.

Iridium‐Catalyzed CH Activation versus Directed ortho Metalation: Complementary Borylation of Aromatics and Heteroaromatics

Systematic studies are presented demonstrating the complementarity of directed ortho metalation (DoM) and Ir-catalyzed strategies for the provision of borylated aromatics and their subsequent Suzuki-Miyaura coupling reactions. A new concept, the use of the TMS group, readily introduced by DoM, as a latent regiodirective moiety to overcome the otherwise problematic production of isomeric borylated product mixtures is presented. Additional electrophile-induced ipso-deborylation and DoM reactions of the Bpin products are described.

ChemInform Abstract: Regioselective Halogenations and Subsequent Suzuki—Miyaura Coupling onto Bicyclic 2‐Pyridones.

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