Editorial

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4 pages, 197 KiB

Open AccessEditorial

Advances in Cross-Coupling Reactions

by José Pérez Sestelo and Luis A. Sarandeses

Molecules 2020, 25(19), 4500; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25194500 - 01 Oct 2020

Cited by 13 | Viewed by 4394

Abstract

Cross-coupling reactions stand among the most important reactions in chemistry [...] Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

Research

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21 pages, 11490 KiB

Open AccessArticle

Palladium (II)–Salan Complexes as Catalysts for Suzuki–Miyaura C–C Cross-Coupling in Water and Air. Effect of the Various Bridging Units within the Diamine Moieties on the Catalytic Performance

by Szilvia Bunda, Krisztina Voronova, Ágnes Kathó, Antal Udvardy and Ferenc Joó

Molecules 2020, 25(17), 3993; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25173993 - 02 Sep 2020

Cited by 8 | Viewed by 2743

Abstract

Water-soluble salan ligands were synthesized by hydrogenation and subsequent sulfonation of salens (N,N’-bis(slicylidene)ethylenediamine and analogues) with various bridging units (linkers) connecting the nitrogen atoms. Pd (II) complexes were obtained in reactions of sulfosalans and [PdCl₄] [...] Read more.

Water-soluble salan ligands were synthesized by hydrogenation and subsequent sulfonation of salens (N,N’-bis(slicylidene)ethylenediamine and analogues) with various bridging units (linkers) connecting the nitrogen atoms. Pd (II) complexes were obtained in reactions of sulfosalans and [PdCl₄]²⁻. Characterization of the ligands and complexes included extensive X-ray diffraction studies, too. The Pd (II) complexes proved highly active catalysts of the Suzuki–Miyaura reaction of aryl halides and arylboronic acid derivatives at 80 °C in water and air. A comparative study of the Pd (II)–sulfosalan catalysts showed that the catalytic activity largely increased with increasing linker length and with increasing steric congestion around the N donor atoms of the ligands; the highest specific activity was 40,000 (mol substrate) (mol catalyst × h)⁻¹. The substrate scope was explored with the use of the two most active catalysts, containing 1,4-butylene and 1,2-diphenylethylene linkers, respectively. Full article

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7 pages, 6569 KiB

Open AccessCommunication

Efficient Palladium-Catalyzed Synthesis of 2-Aryl Propionic Acids

by Helfried Neumann, Alexey G. Sergeev, Anke Spannenberg and Matthias Beller

Molecules 2020, 25(15), 3421; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153421 - 28 Jul 2020

Cited by 4 | Viewed by 2497

Abstract

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling [...] Read more.

A flexible two-step, one-pot procedure was developed to synthesize 2-aryl propionic acids including the anti-inflammatory drugs naproxen and flurbiprofen. Optimal results were obtained in the presence of the novel ligand neoisopinocampheyldiphenylphosphine (NISPCPP) (9) which enabled the efficient sequential palladium-catalyzed Heck coupling of aryl bromides with ethylene and hydroxycarbonylation of the resulting styrenes to 2-aryl propionic acids. This cascade transformation leads with high regioselectivity to the desired products in good yields and avoids the need for additional purification steps. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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20 pages, 4618 KiB

Open AccessArticle

Synthesis and Characterization of New Organic Dyes Containing the Indigo Core

by Daniele Franchi, Massimo Calamante, Carmen Coppola, Alessandro Mordini, Gianna Reginato, Adalgisa Sinicropi and Lorenzo Zani

Molecules 2020, 25(15), 3377; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153377 - 25 Jul 2020

Cited by 11 | Viewed by 5393

Abstract

A new series of symmetrical organic dyes containing an indigo central core decorated with different electron donor groups have been prepared, starting from Tyrian Purple and using the Pd-catalyzed Stille-Migita coupling process. The effect of substituents on the spectroscopic properties of the dyes [...] Read more.

A new series of symmetrical organic dyes containing an indigo central core decorated with different electron donor groups have been prepared, starting from Tyrian Purple and using the Pd-catalyzed Stille-Migita coupling process. The effect of substituents on the spectroscopic properties of the dyes has been investigated theoretically and experimentally. In general, all dyes presented intense light absorption bands, both in the blue and red regions of the visible spectrum, conferring them a bright green color in solution. Using the same approach, an asymmetrically substituted D–A-π–A green dye, bearing a triarylamine electron donor and the cyanoacrylate acceptor/anchoring group, has been synthesized for the first time and fully characterized, confirming that spectroscopic and electrochemical properties are consistent with a possible application in dye-sensitized solar cells (DSSC). Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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18 pages, 3415 KiB

Open AccessArticle

Facile Synthesis of NH-Free 5-(Hetero)Aryl-Pyrrole-2-Carboxylates by Catalytic C–H Borylation and Suzuki Coupling

by Saba Kanwal, Noor-ul- Ann, Saman Fatima, Abdul-Hamid Emwas, Meshari Alazmi, Xin Gao, Maha Ibrar, Rahman Shah Zaib Saleem and Ghayoor Abbas Chotana

Molecules 2020, 25(9), 2106; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25092106 - 30 Apr 2020

Cited by 5 | Viewed by 4519

Abstract

A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N–H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- [...] Read more.

A convenient two-step preparation of NH-free 5-aryl-pyrrole-2-carboxylates is described. The synthetic route consists of catalytic borylation of commercially available pyrrole-2-carboxylate ester followed by Suzuki coupling without going through pyrrole N–H protection and deprotection steps. The resulting 5-aryl substituted pyrrole-2-carboxylates were synthesized in good- to excellent yields. This synthetic route can tolerate a variety of functional groups including those with acidic protons on the aryl bromide coupling partner. This methodology is also applicable for cross-coupling with heteroaryl bromides to yield pyrrole-thiophene, pyrrole-pyridine, and 2,3’-bi-pyrrole based bi-heteroaryls. Full article

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13 pages, 15225 KiB

Open AccessArticle

One-Pot Iridium Catalyzed C–H Borylation/Sonogashira Cross-Coupling: Access to Borylated Aryl Alkynes

by Ghayoor A. Chotana, Jose R. Montero Bastidas, Susanne L. Miller, Milton R. Smith III and Robert E. Maleczka, Jr.

Molecules 2020, 25(7), 1754; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25071754 - 10 Apr 2020

Cited by 5 | Viewed by 4507

Abstract

Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C–H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible [...] Read more.

Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C–H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible a subsequent Sonogashira cross-coupling to access the desired borylated aryl alkynes. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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22 pages, 1456 KiB

Open AccessEditor’s ChoiceArticle

Oxidative Dearomative Cross-Dehydrogenative Coupling of Indoles with Diverse C-H Nucleophiles: Efficient Approach to 2,2-Disubstituted Indolin-3-ones

by Xue Yan, Ying-De Tang, Cheng-Shi Jiang, Xigong Liu and Hua Zhang

Molecules 2020, 25(2), 419; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020419 - 20 Jan 2020

Cited by 13 | Viewed by 4020

Abstract

The oxidative, dearomative cross-dehydrogenative coupling of indoles with various C-H nucleophiles is developed. This process features a broad substrate scope with respect to both indoles and nucleophiles, affording structurally diverse 2,2-disubstituted indolin-3-ones in high yields (up to 99%). The oxidative dimerization and trimerization [...] Read more.

The oxidative, dearomative cross-dehydrogenative coupling of indoles with various C-H nucleophiles is developed. This process features a broad substrate scope with respect to both indoles and nucleophiles, affording structurally diverse 2,2-disubstituted indolin-3-ones in high yields (up to 99%). The oxidative dimerization and trimerization of indoles has also been demonstrated under the same conditions. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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Review

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22 pages, 5050 KiB

Open AccessReview

Impact of Cross-Coupling Reactions in Drug Discovery and Development

by Melissa J. Buskes and Maria-Jesus Blanco

Molecules 2020, 25(15), 3493; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25153493 - 31 Jul 2020

Cited by 122 | Viewed by 12291

Abstract

Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in [...] Read more.

Cross-coupling reactions have played a critical role enabling the rapid expansion of structure–activity relationships (SAR) during the drug discovery phase to identify a clinical candidate and facilitate subsequent drug development processes. The reliability and flexibility of this methodology have attracted great interest in the pharmaceutical industry, becoming one of the most used approaches from Lead Generation to Lead Optimization. In this mini-review, we present an overview of cross-coupling reaction applications to medicinal chemistry efforts, in particular the Suzuki–Miyaura and Buchwald–Hartwig cross-coupling reactions as a remarkable resource for the generation of carbon–carbon and carbon–heteroatom bonds. To further appreciate the impact of this methodology, the authors discuss some recent examples of clinical candidates that utilize key cross-coupling reactions in their large-scale synthetic process. Looking into future opportunities, the authors highlight the versatility of the cross-coupling reactions towards new chemical modalities like DNA-encoded libraries (DELs), new generation of peptides and cyclopeptides, allosteric modulators, and proteolysis targeting chimera (PROTAC) approaches. Full article

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19 pages, 3821 KiB

Open AccessFeature PaperReview

Pd(II)-Catalyzed C-H Acylation of (Hetero)arenes—Recent Advances

by Carlos Santiago, Nuria Sotomayor and Esther Lete

Molecules 2020, 25(14), 3247; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25143247 - 16 Jul 2020

Cited by 18 | Viewed by 4910

Abstract

Di(hetero)aryl ketones are important motifs present in natural products, pharmaceuticals or agrochemicals. In recent years, Pd(II)-catalyzed acylation of (hetero)arenes in the presence of an oxidant has emerged as a catalytic alternative to classical acylation methods, reducing the production of toxic metal waste. Different [...] Read more.

Di(hetero)aryl ketones are important motifs present in natural products, pharmaceuticals or agrochemicals. In recent years, Pd(II)-catalyzed acylation of (hetero)arenes in the presence of an oxidant has emerged as a catalytic alternative to classical acylation methods, reducing the production of toxic metal waste. Different directing groups and acyl sources are being studied for this purpose, although further development is required to face mainly selectivity problems in order to be applied in the synthesis of more complex molecules. Selected recent developments and applications are covered in this review. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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28 pages, 10458 KiB

Open AccessFeature PaperReview

Synthesis of Medium-Sized Heterocycles by Transition-Metal-Catalyzed Intramolecular Cyclization

by Mickael Choury, Alexandra Basilio Lopes, Gaëlle Blond and Mihaela Gulea

Molecules 2020, 25(14), 3147; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25143147 - 09 Jul 2020

Cited by 47 | Viewed by 5934

Abstract

Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In [...] Read more.

Medium-sized heterocycles (with 8 to 11 atoms) constitute important structural components of several biologically active natural compounds and represent promising scaffolds in medicinal chemistry. However, they are under-represented in the screening of chemical libraries as a consequence of being difficult to access. In particular, methods involving intramolecular bond formation are challenging due to unfavorable enthalpic and entropic factors, such as transannular interactions and conformational constraints. The present review focuses on the synthesis of medium-sized heterocycles by transition-metal-catalyzed intramolecular cyclization, which despite its drawbacks remains a straightforward and attractive synthesis strategy. The obtained heterocycles differ in their nature, number of heteroatoms, and ring size. The methods are classified according to the metal used (palladium, copper, gold, silver), then subdivided according to the type of bond formed, namely carbon–carbon or carbon–heteroatom. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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24 pages, 7286 KiB

Open AccessReview

Recent Strides in the Transition Metal-Free Cross-Coupling of Haloacetylenes with Electron-Rich Heterocycles in Solid Media

by Lyubov’ N. Sobenina and Boris A. Trofimov

Molecules 2020, 25(11), 2490; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25112490 - 27 May 2020

Cited by 22 | Viewed by 2372

Abstract

The publications covering new, transition metal-free cross-coupling reactions of pyrroles with electrophilic haloacetylenes in solid medium of metal oxides and salts to regioselectively afford 2-ethynylpyrroles are discussed. The reactions proceed at room temperature without catalyst and base under solvent-free conditions. These ethynylation reactions [...] Read more.

The publications covering new, transition metal-free cross-coupling reactions of pyrroles with electrophilic haloacetylenes in solid medium of metal oxides and salts to regioselectively afford 2-ethynylpyrroles are discussed. The reactions proceed at room temperature without catalyst and base under solvent-free conditions. These ethynylation reactions seem to be particularly important, since the common Sonogashira coupling does not allow ethynylpyrroles with strong electron-withdrawing substituents at the acetylenic fragments to be synthesized. The results on the behavior of furans, thiophenes, and pyrazoles under the conditions of these reactions are also provided. The reactivity and structural peculiarities of nucleophilic addition to the activated acetylene moiety of the novel C-ethynylpyrroles are considered. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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22 pages, 7797 KiB

Open AccessEditor’s ChoiceReview

Palladium-Catalysed Coupling Reactions En Route to Molecular Machines: Sterically Hindered Indenyl and Ferrocenyl Anthracenes and Triptycenes, and Biindenyls

by Michael J. McGlinchey and Kirill Nikitin

Molecules 2020, 25(8), 1950; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25081950 - 22 Apr 2020

Cited by 11 | Viewed by 3532

Abstract

Pd-catalysed Stille and Suzuki cross-couplings were used to prepare 9-(3-indenyl)-, 6, and 9-(2-indenyl)-anthracene, 7; addition of benzyne led to the 9-Indenyl-triptycenes, 8 and 9. In 6, [4 + 2] addition also occurred to the indenyl substituent. Reaction of 6 through 9 with Cr(CO) [...] Read more.

Pd-catalysed Stille and Suzuki cross-couplings were used to prepare 9-(3-indenyl)-, 6, and 9-(2-indenyl)-anthracene, 7; addition of benzyne led to the 9-Indenyl-triptycenes, 8 and 9. In 6, [4 + 2] addition also occurred to the indenyl substituent. Reaction of 6 through 9 with Cr(CO)₆ or Re₂(CO)₁₀ gave their M(CO)₃ derivatives, where the Cr or Re was complexed to a six- or five-membered ring, respectively. In the 9-(2-indenyl)triptycene complexes, slowed rotation of the paddlewheel on the NMR time-scale was apparent in the η⁵-Re(CO)₃ case and, when the η⁶-Cr(CO)₃ was deprotonated, the resulting haptotropic shift of the metal tripod onto the five-membered ring also blocked paddlewheel rotation, thus functioning as an organometallic molecular brake. Suzuki coupling of ferrocenylboronic acid to mono- or dibromoanthracene yielded the ferrocenyl anthracenes en route to the corresponding triptycenes in which stepwise hindered rotations of the ferrocenyl groups behaved like molecular dials. CuCl₂-mediated coupling of methyl- and phenyl-indenes yielded their rac and meso 2,2′-biindenyls; surprisingly, however, the apparently sterically crowded rac 2,2′-Bis(9-triptycyl)biindenyl functioned as a freely rotating set of molecular gears. The predicted high rotation barrier in 9-phenylanthracene was experimentally validated via the Pd-catalysed syntheses of di(3-fluorophenyl)anthracene and 9-(1-naphthyl)-10-phenylanthracene. Full article

(This article belongs to the Special Issue Advances in Cross-Coupling Reactions)

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