Methodology in organic synthesis

POxAP Precatalysts and the Negishi Cross-Coupling Reaction

Synthesis 2020, 52, 1, 51-59

Recently developed for the Fukuyama reaction, post-oxidative addition precatalysts (POxAPs) are also very efficient in catalyzing Negishi cross-coupling reactions between organohalides and organozinc reagents. Using very low catalyst loadings, POxAPs show similar catalytic activities to those of classical precatalysts such as XPhos Pd G4 or PEPPSI-IPr, with turnover numbers of up to 93,000. POxAPs are easily prepared, are stable to air and moisture, tolerate a wide range of functional groups in the Negishi cross-coupling reaction and contribute advantageously to the arsenal of organic chemists in terms of Pd precatalysts.

Bihel et al. DOI: 10.1055/s-0039-1690728

Fukuyama Cross-Coupling Approach to Isoprekinamycin: Discovery of the Highly Active and Bench-Stable Palladium Precatalyst POxAP

Organic Letters 2019

An efficient and user-friendly palladium(II) precatalyst, POxAP (post-oxidative-addition precatalyst), was identified for use in Fukuyama cross-coupling reactions. Suitable for storage under air, the POxAP precatalyst allowed reaction between thioesters and organozinc reagents with turnover numbers of ∼90000. A series of 23 ketones were obtained with yields ranging from 53 to 99%. As proof of efficacy, an alternative approach was developed for the synthesis of a key precursor of the natural product isoprekinamycin.


Dioxygenation of styrenes with molecular oxygen in water

Tetrahedron Letters 201859, 15, 1465-1468

Employing Triton X-100 as a surfactant, the tert-butyl hydroperoxide-mediated dioxygenation of styrene with molecular oxygen and N-hydroxyphthalimide was achieved in water at room temperature, providing the corresponding dioxygenated products in 9–93% yield. This facile method is eco-friendly, feasible on gram scale, and applicable to a wide range of styrene derivatives with a variety of functional groups.

Graphical abstract

Efficient and Mild Ullmann‐Type N‐Arylation of Amides, Carbamates, and Azoles in Water

Chemistry, A European Journal 201723, 55, 13676-13683

A simple, sustainable, efficient, mild, and low‐cost protocol was developed for d‐glucose‐assisted Cu‐catalyzed Ullmann reactions in water for amides, carbamates, and nitrogen‐containing heterocycles. The reaction was compatible with diverse aryl/heteroaryl iodides, giving highly substituted pyridine, indole, or indazole rings. This method offers an attractive alternative to existing protocols, because the reaction proceeds in aqueous media, occurs at or near ambient temperature, and provides the N‐arylated products in good to high yields.

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d‐Glucose: An Efficient Reducing Agent for a Copper(II)‐Mediated Arylation of Primary Amines in Water

ChemSusChem 20169, 3244-3249

A copper‐catalyzed Ullmann‐type amination with primary amines in water with a combination of copper(II) triflate [Cu(OTf)2], dipivaloylmethane, and d‐glucose is reported. The mild conditions and the use of an inexpensive catalyst as well as a renewable feedstock (d‐glucose and the surfactant TPGS‐750‐M, which is derived from vitamin E) make this protocol a safe and convenient strategy for efficient C−N bond formation. This easy‐to‐handle procedure is extremely competitive compared to palladium‐based reactions and may be used to synthesize N‐containing molecules, such as drugs or organic light‐emitting diodes (OLEDs).

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Synthesis of 3-amino-3,4-dihydro-1H-quinolin-2-ones through regioselective palladium-catalyzed intramolecular cyclization

Tetrahedron Letters2016, 57(14), 1547-1550

In this Letter we explored the regioselective cyclization of 2-bromophenylalanine derivatives to access enantiopure dihydroquinolinones via an intramolecular regioselective Buchwald–Hartwig cyclization using Pd2(dba)3/XPhos as a catalytic system in the presence of BTPP as organic base. This procedure represents a promising strategy for the direct synthesis of bridged Phe-Xaa dipeptides.



Abstract Tetrahedron letters

Rapid and scalable synthesis of innovative unnatural alpha, beta or gamma-amino acids functionalized with tertiary amines on their side-chains

Organic & Biomolecular Chemistry, 2015, 13(25), 7020-7026

We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural alpha, beta or gamma-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.


Graphical abstract

 Highlights :En direct des laboratoires de l'institut de Chimie

Access to 4-Alkylaminopyridazine Derivatives via Nitrogen-Assisted Regioselective Pd-Catalyzed Reactions

Journal of Organic Chemistry, 2014, 79 (21), 10311 - 10322

3-Substituted, 6-substituted, and unsymmetrical 3,6-disubstituted 4-alkylaminopyridazines were prepared from a sequence of three chemo- and regioselective reactions combining amination and palladium-catalyzed cross-coupling reactions, such as reductive dehalogenation and Suzuki–Miyaura reactions. Extension of the methodology to Sonogashira reaction yielded a novel class of 3-substituted pyrrolopyridazines.

Graphical abstract: Access to 4-Alkylaminopyridazine Derivatives via Nitrogen-Assisted Regioselective Pd-Catalyzed Reactions

t-BuXPhos: a highly efficient ligand for Buchwald–Hartwig coupling in water

Green Chemistry, 2014,16, 4170-4178

An efficient and versatile ‘green’ catalytic system for the Buchwald–Hartwig cross-coupling reaction in water is reported. In an aqueous micellar medium, the combination of t-BuXPhos with [(cinnamyl)PdCl]2 showed excellent performance for coupling arylbromides or chlorides with a large set of amines, amides, ureas and carbamates. The method is functional-group tolerant, proceeds smoothly (30 to 50 °C) and provides rapid access to the target compounds in good to excellent isolated yields. When applied to the synthesis of a known NaV1.8 modulator, this method led to a significant improvement of the E-factor in comparison with classical organic synthesis.

Graphical abstract: t-BuXPhos: a highly efficient ligand for Buchwald–Hartwig coupling in water

Highlights :
CNRS - Lettre-Innovation
A. Dureuil, Industrie-Pharma, 2015, 85, p58

Buchwald–Hartwig reactions in water using surfactants

Tetrahedron, 2014,70, 21, 3413-3421

Examination of the scope and limitation of the Buchwald–Hartwig cross-coupling reaction in micellar medium is reported. An array of aryl or heteroaryl halides were coupled to diverse nitrogen coupling partners using a combination of [(allyl)PdCl]2 and cBRIDP to afford the corresponding products in moderate to excellent yields. 30 examples are reported, including polar solid and fairly water-soluble organic substrates/reagents.

Graphical abstract: Buchwald-Hartwig reactions in water using surfactants

Fully Regiocontrolled Polyarylation of Pyridine

Journal Of Organic Chemistry, 2014,79(3), 908-918

Starting from commercially available 2-chloro-3-hydroxypyridine, a new route leading to the first protypical pentaarylpyridine bearing five different substituents is reported. This strategy involves a set of five sequential but fully regiocontrolled Suzuki–Miyaura reactions and highlights the 2-OBn pyridine protecting group as a key intermediate. The 2-OBn group played a double role: (i) it allowed additional bromination at position 5 and (ii) it could afford the reactive OTf species for the last C-arylation step at the less hindered 2 position of the tetraarylpyridine. The photophysical properties of the novel compounds are also described. The synthesized pentaarylpyridine derivative exhibit a large Stokes shift, strong solvatochromism, and quantum yield values up to 0.47; thus, they constitute promising building blocks for the design of environment-sensitive probes.

Graphical abstract: Fully Regiocontrolled Polyarylation of Pyridine

Nucleophilic Substitution of Azide Acting as a Pseudo Leaving Group: One-Step Synthesis of Various Aza Heterocycles

Journal Of Organic Chemistry, 2013,78(22), 11335-11341

The reaction of 3-azidopropanoic acid with the carbodiimide-based coupling reagent DIC leads to a six-membered-ring intermediate acting as a versatile precursor to a diverse set of aza heterocycles, including mono-, bi-, and tricyclic compounds.

Graphical abstract: Nucleophilic Substitution of Azide Acting as a Pseudo Leaving Group: One-Step Synthesis of Various Aza Heterocycles