Subsequent Cross-coupling Research Articles

Generation and Cross-Coupling of Organozinc Reagents in Flow.

A versatile flow synthesis method for in situ formation of organozinc reagents and subsequent cross-coupling with aryl halides and activated carboxylic acids is reported. Formation of organozinc reagents is achieved by pumping organic halides, in the presence of ZnCl2 and LiCl, through an activated Mg-packed column under flow conditions. This method provides efficient in situ formation of aryl, primary, secondary, and tertiary alkyl organozinc reagents, which are subsequently telescoped downstream to a Negishi or decarboxylative Negishi cross-coupling reaction. The described method offers access to a variety of C-C bond formations with organozinc reagents that are otherwise commercially unavailable or difficult to prepare under traditional batch reaction conditions.

Dehydrative Cross-Coupling of 1-Phenylethanol Catalysed by Palladium Nanoparticles Formed in situ Under Acidic Conditions

A dehydrative cross-coupling of 1-phenylethanol catalysed by sugar derived, in situ formed palladium(0) nanoparticles under acidic conditions is realised. The acidic conditions allow for use of alcohols as a feedstock in metal-mediated coupling reactions via their in situ dehydration and subsequent cross-coupling. Extensive analysis of the size and morphology of the palladium nanoparticles formed in situ showed that the zero-valent metal was surrounded by hydrophilic hydroxyl groups. EDX-TEM imaging studies using a prototype silicon drift detector provided insight into the problematic role of molecular oxygen in the system. This increased understanding of the catalyst deactivation allowed for the development of the cross-coupling methodology. A 250-12,000 fold increase in molar efficiency was observed when compared to related two-step protocols that use alternative feedstocks for the palladium-mediated synthesis of stilbenes. This work opens up a new research area in which the active catalyst is formed, stabilised and regenerated by a renewable sugar.

Multicatalytic Stereoselective Synthesis of Highly Substituted Alkenes by Sequential Isomerization/Cross-Coupling Reactions.

Starting from readily available alkenyl methyl ethers, the stereoselective preparation of highly substituted alkenes by two complementary multicatalytic sequential isomerization/cross-coupling sequences is described. Both elementary steps of these sequences are challenging processes when considered independently. A cationic iridium catalyst was identified for the stereoselective isomerization of allyl methyl ethers and was found to be compatible with a nickel catalyst for the subsequent cross-coupling of the in situ generated methyl vinyl ethers with various Grignard reagents. The method is compatible with sensitive functional groups and a multitude of olefinic substitution patterns to deliver products with high control of the newly generated C═C bond. A highly enantioselective variant of this [Ir/Ni] sequence has been established using a chiral iridium precatalyst. A complementary [Pd/Ni] catalytic sequence has been optimized for alkenyl methyl ethers with a remote C═C bond. The final alkenes were isolated with a lower level of stereocontrol. Upon proper choice of the Grignard reagent, we demonstrated that C( sp2)-C( sp2) and C( sp2)-C( sp3) bonds can be constructed with both systems delivering products that would be difficult to access by conventional methods.

Application of Tsunoda reagent to the convenient synthesis of drug-like pyrazoles

The versatility of the under-utilised (cyanomethylene)tributylphosphorane (CMBP, Tsunoda reagent) was demonstrated on two occasions in a drug discovery context. Firstly, the high reactivity of the phosphorane allowed the alkylation of a weakly acidic pyrazole when standard Mitsunobu conditions were unsuccessful. Secondly, the clean reaction profile generally obtained using CMBP allowed the direct use of the crude mixture in a subsequent Suzuki cross coupling. This reagent has utility when isolation of the Mitsunobu reaction product (e.g. containing a boronate) is not desirable.

Microwave-assisted synthesis and antibacterial propensity of N′-s-benzylidene-2-propylquinoline-4-carbohydrazide and N′-((s-1H-pyrrol-2-yl)methylene)-2-propylquinoline-4-carbohydrazide motifs

Microwave-assisted approach was utilized as green approach to access a series of 2-propylquinoline-4-carbohydrazide hydrazone derivatives 10a-j of aromatic and heteroaromatic aldehydes in highly encouraging yields. It involved four steps reaction which was initiated with ring opening reaction of isatin in a basified environment and subsequent cross-coupling with pentan-2-one to produce compound 7. Esterification of 7 in acid medium led to the formation of compound 8 which was reacted with hydrazine hydrate to access 9 which upon microwave-assisted condensed with aromatic and heteroaromatic aldehydes furnished the targeted compounds 10a-j. The structures of 10a-j were confirmed by physico-chemical, elemental analyses and spectroscopic characterization which include UV, FT-IR, 1H and 13C NMR as well as DEPT-135. The targeted compounds 10a-j, alongside with gentamicin clinical standard, were investigated for their antibacterial efficacies using agar diffusion method. 2-Propyl-N′-(pyridine-3-ylmethylene) quinoline-4-carbohydrazide 10j emerged as the best antibacterial hydrazide-hydrazone with lowest MIC value of 0.39 ± 0.02 – 1.56 ± 0.02 µg/mL across all the organisms screened.

Laccase-catalyzed, aerobic oxidative coupling of 4-substituted urazoles with sodium arylsulfinates: Green and mild procedure for the synthesis of arylsulfonyl triazolidinediones

The direct aerobic oxidation of 4-substituted urazoles using the laccase enzyme from Trametes versicolor in a phosphate buffer solution at ambient temperature, and subsequent cross-coupling with sodium benzenesulfinates was investigated to afford arylsulfonyl-1,2,4-triazolidine-3,5-dione derivatives in good to high yields.

Haloamination of an aminoallenylether and subsequent palladium-catalyzed cross coupling reactions to afford dihydrobenzoxazole derivatives containing conjugated substituents

Haloamination of an aminoallenylether, which was prepared from commercially available 2-aminophenol via a three-step sequence, provided a versatile halovinyldihydrobenzoxazole intermediate. Subsequent Heck, Sonogashira, and Suzuki coupling reactions yielded dihydrobenzoxazoles possessing the corresponding conjugated substituents.

From Click Chemistry to Cross-Coupling: Designer Polymers from One Efficient Reaction

Palladium-catalyzed Suzuki–Miyaura cross-coupling was demonstrated to be a versatile reaction platform to install functional groups onto well-defined polymers derived from reversible addition–fragmentation chain-transfer (RAFT) polymerization. Cross-coupled products were achieved utilizing a range of functional boronic acids including, but not limited to, furan, alkyloxyphenyl, methacrylamide, trifluorophenyl, anthracene, and dimethylaminophenyl. High to quantitative degrees of functionalization were obtained by employing convenient reaction conditions at low to moderate temperatures (23–60 °C), within short reaction times (2–16 h), while using air-stable reagents at 1.5–3.0 equiv. of boronic acid. Specifically, a custom monomer, N-[2-(4-bromophenyl)ethyl]acrylamide (BPEA), was synthesized bearing a reactive handle for subsequent cross-coupling, and its chemical structure was verified using nuclear magnetic resonance. RAFT polymerization of BPEA revealed attributes of a successful reversible-deactivation ...

Integrated Pd-catalyzed cross-coupling strategies for furnishing α-carbolines

Efficient synthetic strategies for furnishing α-carbolines have been developed by integrating various Pd-catalyzed reactions. The methods involve 1) regioselective 5- or 6- halogenation of α-carbolines which were synthesized through intramolecular Pd-catalyzed direct C-H arylation, and subsequent Pd-catalyzed cross coupling, 2) 8-triflation of α-carbolines constructed by Pd-catalyzed cyclization, followed by Pd-catalyzed cross-coupling reaction, 3) Pd-catalyzed cyclization to tetrahydro-α-carbolines and subsequent Suzuki reaction via the corresponding α-carboline 5-triflates.

Regioselective Diversification of 2,1-Borazaronaphthalenes: Unlocking Isosteric Space via C-H Activation.

Methods for the regioselective C–H borylation and subsequent cross-coupling of the 2,1-borazaronaphthalene core are reported. Azaborines are dependent on B–N/C=C isosterism when employed in strategies for developing diverse heterocyclic scaffolds. Although 2,1-borazaronaphthalene is closely related to naphthalene in terms of structure, the argument is made that the former has electronic similarities to indole. Based on that premise, iridium-mediated C–H activation has enabled facile installation of a versatile, nucleophilic coupling handle at a previously inaccessible site of 2,1-borazaronaphthalenes. A variety of substituted 2,1-borazaronaphthalene cores can be successfully borylated and further cross-coupled in a facile manner to yield diverse C(8)-substituted 2,1-borazaronaphthalenes.

Preparation of Organozinc Reagents via Catalyst Controlled Three-Component Coupling between Alkyne, Iodoarene, and Bis(iodozincio)methane.

Three-component coupling between an alkyne, iodoarene, and bis(iodozincio)methane yields allylic zinc with a tetrasubstituted alkene moiety in the presence of a nickel catalyst. The reaction proceeds via aryl nickelation of the alkyne and subsequent cross-coupling with bis(iodozincio)methane. Meanwhile, the same combination in the presence of a palladium and cobalt catalyst gives tetrasubstituted alkenylzinc. The reaction proceeds via a palladium-catalyzed cross-coupling of iodoarene with bis(iodozincio)methane followed by a cobalt-catalyzed benzylzincation of alkyne.

Stereoselective Peptide Modifications via β-C(sp3)-H Arylations.

Palladium-catalyzed stereoselective β-arylations of phenylalanine, proline- and pipecolinic acid-containing peptides are a versatile tool for peptide modifications. The reactions proceed without epimerization of stereogenic centers in the peptide chain. If suitable functionalized aryl iodides are introduced, subsequent cross coupling reactions can be used for further modifications. The 8-amino quinoline (AQ) directing group can easily be removed, allowing the prolongation of the peptide chain at the C-terminus.

ChemInform Abstract: Iron(III)‐Catalyzed Radical Cross‐Coupling of Thiols with Sodium Sulfinates: A Facile Access to Thiosulfonates.

A convenient and efficient synthesis of symmetrical and asymmetric thiosulfonates from thiols and sodium sulfinates is reported. The protocol involves iron(III)-catalyzed formation of sulfenyl and sulfonyl radicals in situ under aerobic conditions and their subsequent cross-coupling to afford thiosulfonates in 83–96% yield. The utilization of readily available, nontoxic, and inexpensive iron(III) as a catalyst and atmospheric oxygen as an oxidant is within the confines of green and sustainable chemistry.

Iron(III)-Catalyzed Radical Cross-Coupling of Thiols with Sodium Sulfinates: A Facile Access to Thiosulfonates

A convenient and efficient synthesis of symmetrical and asymmetric thiosulfonates from thiols and sodium sulfinates is reported. The protocol involves iron(III)-catalyzed formation of sulfenyl and sulfonyl radicals in situ under aerobic conditions and their subsequent cross-coupling to afford thiosulfonates in 83–96% yield. The utilization of readily available, nontoxic, and inexpensive iron(III) as a catalyst and atmospheric oxygen as an oxidant is within the confines of green and sustainable chemistry.

Modular synthesis of allyl vinyl ethers for the enantioselective construction of functionalized quaternary stereocenters

A flexible synthesis of allyl vinyl ethers, precursors of functionalized quaternary stereocenters, was developed by employing a regioselective Petasis olefination of haloallyl oxalates and subsequent cross-coupling with alkyl- and aryl boronic acids.

Nickel- and Palladium-Catalyzed Coupling of Aryl Fluorosulfonates with Aryl Boronic Acids Enabled by Sulfuryl Fluoride

Herein are reported examples of the nickel- and palladium-catalyzed cross-coupling of aryl fluorosulfonates and aryl boronic acids. These reactions occur in good to excellent yields under mild conditions with excellent functional group compatibility employing either Pd(OAc)2 and inexpensive PPh3 or the inexpensive and readily available NiCl2(PCy3)2. Importantly, the in situ conversion of phenol derivatives to the corresponding aryl fluorosulfonate by reaction with sulfuryl fluoride and a base and subsequent cross-coupling to form biaryls in a single pot are described. The combination of inexpensive sulfuryl fluoride and efficient catalysts reported in these methodologies will enable economical Suzuki coupling of phenols in pharmaceutical and agrochemical processes.

ChemInform Abstract: Continuous Synthesis of Organozinc Halides Coupled to Negishi Reactions.

The Negishi cross-coupling is a powerful CC bond forming reaction. The method is less commonly used relative to other cross-coupling methods in part due to lack of availability of organozinc species. While organozinc species can be prepared, problems with reproducibility and handling of these sensitive species can complicate these reactions. Herein, we describe the continuous formation, using an activated packed-bed of metallic zinc, and subsequent use of organozinc halides. We demonstrate that a single column of zinc can provide excellent yields of organozinc halides and that they can be used downstream in subsequent Negishi cross-couplings. The preparation of the zinc column and the scope of the reaction are discussed.

Late-Stage Functionalization of 1,2-Dihydro-1,2-azaborines via Regioselective Iridium-Catalyzed C-H Borylation: The Development of a New N,N-Bidentate Ligand Scaffold.

The first general late-stage functionalization of monocyclic 1,2-azaborines at the C(6) position is described. Ir-catalyzed C-H borylation occurs regioselectively at the C(6) position of B-substituted 1,2-azaborines and is compatible with a range of substitution patterns at boron (e.g., hydride, alkoxide, alkyl, and aryl substituents). Subsequent Suzuki cross coupling with aryl- and heteroaryl bromides furnishes 1,2-azaborine-based biaryl compounds including 6-[pyrid-2-yl]-1,2-azaborines that represent novel κ(2)-N,N-bidentate ligands. The 6-[pyrid-2-yl]-B-Me-1,2-azaborine ligand has been demonstrated to form an emissive coordination complex with dimesitylboron that exhibits bathochromically shifted absorption and emission maxima and a higher photoluminescence quantum yield compared to its carbonaceous analogue.

Synthesis of disubstituted dithioethers: tert-butoxide promoted elimination/ring opening of 1,3-dithianes followed by palladium-catalyzed C-S bond formation.

We report the tandem base-promoted elimination/ring-opening of 2-benzyl-1,3-dithianes with subsequent cross coupling of the pendent thiol with a range of aryl bromides. A simple Pd(OAc)2/Xantphos catalyst system affects this new reaction and is compatible with a wide range of functional groups, including heteroaromatic coupling partners. The transformation proceeds in good to excellent yields (69-99%) and exhibits strong stereoselectivity, forming the E-alkene as the major diastereomer. This new methodology provides access to nonsymmetric propylene styryl/aryl dithioethers, a previously undisclosed motif.

ChemInform Abstract: Triorganoindium Reagents in Selective Palladium‐Catalyzed Cross‐Coupling with Iodoimidazoles: Synthesis of Neurodazine.

AbstractThe cross‐coupling sequence is used for preparation of neurodazine (VI) and analogs.