Cross-coupling Sequence Research Articles

Exploring nickel-catalyzed organochalcogen synthesis via cross-coupling of benzonitrile and alkyl chalcogenols with computational tools.

The preparation of organochalcogens has increased in recent times due to their promising biological activity properties. This work studies the reaction mechanism of a nickel(0)-catalyzed cross-coupling between benzonitrile and propanethiol to produce new C-S bonds by computational means. The proposed mechanism follows the classical oxidative addition/transmetalation/reductive elimination cross-coupling sequence, involving an unusual oxidative addition of a Ph-CN bond onto the active species. The computed catalytic cycle for thioether synthesis has been examined to determine whether the same protocol could be employed to build the analogous C-Se and C-Te bonds. The proposed mechanism for C-S coupling is validated by microkinetic modeling and shows a very good agreement with available experimental data. The extension of the proposed mechanism to C-Se and C-Te couplings indicates that these new reactions should be operative, although their reaction rates appear to be significantly slower.

Weak Base-Promoted Direct Cross-Coupling of Naphthalene-1,8-diaminato-substituted Arylboron Compounds.

The indispensability of a base in Suzuki-Miyaura coupling (SMC) employing organoboronic acids/esters is well recognized, which occasionally induces competitive protodeborylation in organoboron reagents. This phenomenon is particularly pronounced in fluorine-substituted aryl and heteroaryl boron compounds. Here, we show that direct SMC of naphthalene-1,8-diaminato (dan)-substituted aryl boron compounds, Ar-B(dan), characterized by its remarkable stability toward protodeborylation due to their diminished boron-Lewis acidity, occurs utilizing a weak base in conjunction with a palladium/copper cooperative catalyst system. The approach delineated in this study enables the efficient incorporation of various perfluoroaryl- and heteroaryl-B(dan) reagents, while maintaining high functional group tolerance. Furthermore, the inherent inertness of the B(dan) moiety allowed sequential cross-coupling, where other metallic moieties chemoselectively undergo the reaction, thus leading to the concise, protection-free synthesis of oligoarenes. Our results provide a potent approach to a delicate dilemma between a protodeborylation-resistant property and SMC activity intimately linked to boron-Lewis acidity.

Asymmetric Total Synthesis of Cytotrienin A: Late-stage Installation of C11 Side Chain onto the Macrolactam Scaffold.

Cytotrienin A, an ansamycin-class antibiotic, exhibits potent apoptosis-inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late-stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxyl group via the traceless Staudinger reaction. This study also demonstrated that the boron-Wittig/iterative Suzuki-Miyaura cross-coupling sequence was effective for the concise and selective construction of the (E,E,E)-conjugated triene moiety. The developed route opens new opportunities for the structure-activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies.

Modular and Selective Access to Functionalized Alkynes and Allenes via the Intermediacy of Propargylic Acetates

We report an efficient one-pot, two-step procedure for the modular synthesis of α-difunctionalized alkynes and trisubstituted allenes by sequential cross-coupling of benzal gem-diacetates with organozinc or -copper reagents in the absence of external transition metals. The intermediacy of propargylic acetates enables the divergent and selective synthesis of these valuable products. This method features its readily accessible substrates, relatively mild conditions, wide scope, and scalability in practical synthesis.

A biaryl-cyclohexenone photoelectrocyclization/dearomatization sequence to substituted terpenes

Described here is the development of sequential cross-coupling, photoelectrocyclizations, and reductive dearomatizations of biaryl cyclohexenones as a means of synthesizing terpene skeletons. This methodology promises to provide insight that will enable us and others to use this approach to generate a variety of biologically active small molecules, including members of the abietane and morphinan skeletons.

Dual-Boronic Acid Reagents That Combine Dynamic and Covalent Bioconjugation.

Boronic acids and boronate esters find appreciable use in chemical biology. Molecules containing orthogonal boronic acid pairs can be utilized for sequential metal-catalyzed cross-couplings for facile preparation of complex bioconjugates including protein-protein conjugates. In this paper, we expand bis-boronic acid reagents for tandem covalent and dynamic bioconjugation. Sequential cross-coupling of 2-nitroarylboronic acid with cysteine residues and condensation of phenylboronic acid with salicylhydroxamic acids (SHA) readily afforded bioconjugates under physiological conditions with dual covalent and dynamic linkages. Both small molecule- and macromolecule-protein conjugates were amenable with this approach and reversible upon addition of excess unfunctionalized SHA or reactive oxygen species. These investigations provide new insights into the kinetic stability of SHA adducts.

Stereoselective Synthesis of (E)- and (Z)-Isocyanoalkenes.

(E)- and (Z)-isocyanoalkenes were selectively synthesized via the sequential cross coupling of vinyl iodides with formamide, followed by dehydration. The optimal catalyst, generated in situ from CuII and trans-N,N'-dimethyl-1,2-cyclohexanediamine, rapidly coupled (E)- or (Z)-vinyl iodides with formamide, which minimized the isomerization of the resultant vinyl formamide. The method efficiently provided a range of acyclic, carbocyclic, and heterocyclic isocyanoalkenes; the versatility is illustrated with the selective, stereodivergent syntheses of the diastereomeric isocyanoalkene antibiotics, B371 and E-B371.

Copper-Catalyzed Ultrasonic-Promoted Coupling of Acetylene Analogs, Dialkyl azo dicarboxylate, and Benzazoles to Assemble Tricyclic Fused- Ring [1,2,3]triazolo[3,4-b][1,3]benzazole Analogs

: An unprecedented copper-catalyzed reaction of acetylene analogs with dialkyl azo dicarboxylate and benzazole analogs via a cross-coupling sequence was reported. A library of triazolobenzazole fused ring systems including [1,2,3] triazolo [3,4-b] [1,3] benzothiazole, [1,2,3] triazolo [3,4-b] [1,3] benzoxazole and [1,2,3] triazolo[3,4-b][1,3]benzimidazole structures were obtained in moderate to excellent yields under very mild reaction conditions. Structural confirmation of the final products became possible using different methods like spectroscopy and elemental analysis. The control experiments indicated C-H activation of acetylene by copper salts, followed by cycloaddition between a 2-(phenylethynyl)benzo[d]azol-3(2H)-yl anion and azo dicarboxylate as the key mechanistic feature. The broad substrate scope with simple and easily affordable starting materials, as well as mild reaction conditions are the noticeable attributes of this methodology, which provides facile access to the desired products.

Regio- and Stereoselective Synthesis of Enol Carboxylate, Phosphate, and Sulfonate Esters via Iodo(III)functionalization of Alkynes.

β-Iodo(III)enol carboxylates, phosphates, and tosylates can be efficiently synthesized through regio- and stereoselective iodo(III)functionalization of alkynes. The combination of chlorobenziodoxole and silver salt has proven to generate a versatile cationic iodine(III) electrophile to activate alkynes and engage various carboxylic acids, triethyl phosphate, and p-toluenesulfonic acid as nucleophiles. The β-iodo(III)enol esters serve as starting materials for the synthesis of multisubstituted alkenes through sequential cross-coupling of the C-I(III) and C-O bonds.

Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents.

A variety of functionalized triarylmethane and 1,1‐diarylalkane derivatives were prepared via a transition‐metal‐free, one‐pot and two‐step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross‐coupling is enabled by changing the solvent from THF to toluene, and a two‐step SN1‐type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti‐tuberculosis agent, an anti‐breast cancer agent, a precursor of a sphingosine‐1‐phosphate (S1P) receptor modulator, and a FLAP inhibitor.

Domino Heck/Hiyama cross-coupling: trapping of the σ-alkylpalladium intermediate with arylsilanes.

A palladium-catalyzed domino Heck cyclization/Hiyama coupling reaction by the trapping of the σ-alkylpalladium intermediate with arylsilanes is described. A wide range of aryl-tethered alkenes and arylsilanes are all compatible with the reaction conditions. This approach shows good yields and excellent functional group tolerance, presenting a more practical and sustainable alternative to the conventional domino Heck cyclization/Suzuki coupling reaction.

Facile Synthesis of Tetraarylpyrazines by Sequential Cross-coupling Approach

Abstract A facile synthetic method for unsymmetric tetraarylpyrazines by sequential cross-couplings is disclosed. This 5-step synthesis was achieved from 2-amino-3,5-dibromo-6-chloropyrazine through four-fold cross-coupling and diazotization. Dibenzo-fused quinoxaline synthesis was also accomplished by further intramolecular coupling.

Protein-Protein Cross-Coupling via Palladium-Protein Oxidative Addition Complexes from Cysteine Residues.

Few chemical methods exist for the covalent conjugation of two proteins. We report the preparation of site-specific protein-protein conjugates that arise from the sequential cross-coupling of cysteine residues on two different proteins. The method involves the synthesis of stable palladium-protein oxidative addition complexes (Pd-protein OACs), a process that converts nucleophilic cysteine residues into an electrophilic S-aryl-Pd-X unit by taking advantage of an intramolecular oxidative addition strategy. This process is demonstrated on proteins up to 83 kDa in size and can be conveniently carried out in water and open to air. The resulting Pd-protein OACs can cross-couple with other thiol-containing proteins to arrive at homogeneous protein-protein bioconjugates.

A One-Pot Iodo-Cyclization/Transition Metal-Catalyzed Cross-Coupling Sequence: Synthesis of Substituted Oxazolidin-2-ones from N-Boc-allylamines.

A one-pot iodo-cyclization/transition metal-catalyzed cross-coupling sequence is reported to access various C5-functionalized oxazolidin-2-ones from unsaturated N-Boc-allylamines. Depending on the Grignard reagents used for the cross-coupling, e.g., aryl- or cyclopropylmagnesium bromide, a cobalt or copper catalyst has to be used to obtain the functionalized oxazolidin-2-ones in good yields.

Palladium-Catalyzed Double Reductive Cyclization of 2,3-Dinitro-1,4-dialkenylbenzenes. Synthesis of 1H,8H-Pyrrolo[3,2-g]indoles.

A flexible route to both symmetrical and unsymmetrical 1H,8H-pyrrolo[3,2-g]indole has been developed. The key and ultimate step is a double palladium-catalyzed, carbon monoxide mediated reductive cyclization of 1,4-dialkenyl-2,3-dinitrobenzenes. The cyclization precursors were prepared by a double Kosugi-Migita-Stille cross coupling of 1,4-dibromo-2,3-dinitrobenzene with an alkenyltin reagent to give symmetrical products. Unsymetrical cyclization precursors were prepared by two sequential cross couplings using 4-iodo-2,3-dinitrophenyl trifluoromethanesulfonate as the starting material.

Suzuki-Miyaura Coupling of (Hetero)Aryl Sulfones: Complementary Reactivity Enables Iterative Polyaryl Synthesis.

Ideal organic syntheses involve the rapid construction of C-C bonds, with minimal use of functional group interconversions. The Suzuki-Miyaura cross-coupling (SMC) is a powerful way to form biaryl linkages, but the relatively similar reactivity of electrophilic partners makes iterative syntheses involving more than two sequential coupling events difficult to achieve without additional manipulations. Here we introduce (hetero)aryl sulfones as electrophilic coupling partners for the SMC reaction, which display an intermediate reactivity between those of typical aryl (pseudo)halides and nitroarenes. The new complementary reactivity allows for rapid sequential cross-coupling of arenes bearing chloride, sulfone and nitro leaving groups, affording non-symmetric ter- and quateraryls in only 2 or 3 steps, respectively. The SMC reactivity of (hetero)aryl sulfones is demonstrated in over 30 examples. Mechanistic experiments and DFT calculations are consistent with oxidative addition into the sulfone C-S bond as the turnover-limiting step. The further development of electrophilic cross-coupling partners with complementary reactivity may open new possibilities for divergent iterative synthesis starting from small pools of polyfunctionalized arenes.

Iridium(I)-Catalyzed C-H Borylation in Air by Using Mechanochemistry.

Mechanochemistry has been applied for the first time to an iridium(I)-catalyzed C-H borylation reaction. By using either none or just a catalytic amount of a liquid, the mechanochemical C-H borylation of a series of heteroaromatic compounds proceeded in air to afford the corresponding arylboronates in good-to-excellent yields. A one-pot mechanochemical C-H borylation/Suzuki-Miyaura cross-coupling sequence for the direct synthesis of 2-aryl indole derivatives is also described. The present study constitutes an important milestone towards the development of industrially attractive solvent-free C-H bond functionalization processes in air.

Decarbonylative Borylation of Amides by Palladium Catalysis.

The development of transition-metal-catalyzed borylation reactions is of significant importance for the fields of organic synthesis and medicinal chemistry because of the versatility of organoboron functional groups. Herein, we report the direct decarbonylative borylation of amides by highly selective carbon–nitrogen bond cleavage by palladium catalysis. The approach capitalizes on the ground-state destabilization of the amide bond in N-acyl glutarimides to achieve Pd-catalyzed insertion into the amide N–C bond and decarbonylation (deamidation). Mechanistic studies and the utility of this methodology in orthogonal sequential cross-couplings of robust, bench-stable amides are reported.

An Interrupted Pummerer/Nickel-Catalysed Cross-Coupling Sequence.

An interrupted Pummerer/nickel-catalysed cross-coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one-pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp-, sp2 -, and sp3 -hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo- and heterocyclic alkenyl sulfonium salts for cross-coupling.

An Interrupted Pummerer/Nickel‐Catalysed Cross‐Coupling Sequence

AbstractAn interrupted Pummerer/nickel‐catalysed cross‐coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one‐pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp‐, sp2‐, and sp3‐hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo‐ and heterocyclic alkenyl sulfonium salts for cross‐coupling.