Electrocatalytic dehydrogenative and defluorinative coupling between aldehyde-derived N,N-dialkylhydrazones and fluoromalonates: synthesis of 2-pyrazolines.

An electrocatalytic synthesis of 2-pyrazolines via dehydrogenative and defluorinative cross-coupling reactions between (hetero)arylaldehyde-derived N,N-dialkylhydrazones and fluoromalonates is disclosed. Salient features of this work include (i) readily available starting materials, (ii) practical reaction conditions, and (ii) a formal oxidative (4 + 1)-cycloaddition via triple C-H bond functionalization. Cyclic voltammetry analyses support the electrocatalytic formation of an α-fluoromalonyl radical.

Tsuji-Trost Based Cascades: From Passerini Adducts of Cinnamaldehyde to Allylated Oxazolones.

The Passerini coupling of cinnamaldehyde derivatives affords allylic esters that may behave as both electrophiles and nucleophiles in Tsuji-Trost reactions. We present herein the interaction of the latter with methylallylcarbonate, leading to the formation of oxazolidine-diones. The efficiency of the process relies on the building up of a CO2 overpressure in the medium. A reaction mechanism highlighting the reversibility of the Tsuji-Trost reaction is proposed for the process.

Passerini-Smiles Reaction of α-Ketophosphonates: Platform for Phospha-Brook/Smiles Embedded Cascades.

The Passerini-Smiles reactions of α-ketophosphonates with nitrophenols has been used as a platform to observe complex cascades involving multiple Smiles transfers coupled with phospha-Brook rearrangement. When using 4-nitrophenols a rare 1,3-Truce-Smiles rearrangement is observed leading to diarylacetamide derivatives. 2-Nitro-derivatives lead to a completely different reactivity pattern that may be explained by a nitro to nitroso conversion followed by a σ-π metathesis. All mechanistic assumptions are confirmed by DFT calculations performed on both families of adducts. The potential of this work has been further demonstrated by the use of N-aryl α-ketoamides as alternative starting materials for these cascades as well as the disclosure of new aza-Nazarov access to hydroxy-indolones.

O-Allylated Pudovik and Passerini Adducts as Versatile Scaffolds for Product Diversification.

The palladium-catalyzed O-allylation of α-hydroxyphosphonates and α-hydroxyamides obtained from Pudovik and Passerini multicomponent reactions has allowed interesting and highly straightforward access to a variety of building blocks for product diversification. These post-functionalizations include a selective base- or ruthenium hydride-mediated isomerization/Claisen rearrangement cascade and a ring-closing metathesis that allows access to a variety of diversely functionalized phosphono-oxaheterocycles.

Straightforward access to complex isoindolinones from the Ugi reaction of o-nitrobenzoic acid derivatives.

The Ugi reaction of 2-nitrobenzoic acid derivatives has been used for a diversity oriented synthesis of complex isoindolinones via a SNAr reaction involving the peptidyl position. When the cyclization is triggered by strong bases such as potassium tert-butylate, the SNAr reaction is followed by a deamidification/oxidation sequence leading to 2-hydroxyisoindolinones. The latter may be further transformed into polycyclic fused isoindolinones via Pictet-Spengler type cyclization or O-alkylation/metathesis sequences.

Raising the Diversity of Ugi Reactions Through Selective Alkylations and Allylations of Ugi Adducts.

We report here selective Tsuji-Trost type allylation of Ugi adducts using a strategy based on the enhanced nucleophilicity of amide dianions. Ugi adducts derived from aromatic aldehydes were easily allylated at their peptidyl position with allyl acetate in the presence of palladium catalysts. These substitutions were compared to more classical transition metal free allylations using allyl bromides.

Palladium triggered diene formation from nitro allylic compounds: a versatile entry into naphthalene derivatives.

Nitro allylic derivatives were converted into dienes through the elimination of the nitro group under basic treatment, in the presence of a palladium catalyst. This reaction probably involves the formation of a palladium π-allyl complex followed by a base-promoted ß-hydride elimination. This reaction, combined with the condensation of ketones with nitromethane and the functionalization of the resulting nitrocycloalkenes, constitutes a very powerful synthetic tool for the formation of dienes. Particular attention has been brought to the application of this methodology to the formation of 1-substituted naphthalenes from 1-tetralone.

Propargylation of Ugi Amide Dianion: An Entry into Pyrrolidinone and Benzoindolizidine Alkaloid Analogues.

Propargylation of Ugi adducts under the addition of excess sodium hydride in DMSO leads to direct formation of pyrrolidinone enamides, which are useful precursors of iminium intermediates and may be trapped by various nucleophiles. This approach has been applied to the formation of benzoindolizidine alkaloids with high diversity via a Ugi/propargylation/Pictet-Spengler cyclization.

Mannich reaction of trifluoroacetaldehyde hydrazones: a useful entry to trifluoromethyl substituted heterocycles.

NH-aryl hydrazones derived from trifluoroacetaldehyde hemiacetal may be involved in efficient Mannich type reactions with formaldehydes and aromatic aldehydes. The resulting hydrazones are useful building blocks for the preparation of trifluoromethyl substituted heterocycles as shown by a straightforward preparation of 1,2-diazine derivatives under heating with ß-ketoesters.

ß-Lactam Synthesis through Diodomethane Addition to Amide Dianions.

We present a novel route for the quick and easy synthesis of a broad range of ß-lactams. The synthesis involves a [3+1] cyclization of amide dianions with diiodomethane. In contrast to the seminal work of Hirai et al. from 1979, the reaction proved to be a general and efficient approach towards azetidinones. The ease of the process was confirmed by DFT calculations and its power demonstrated by a diversity-oriented synthesis of ß-lactams with four points of diversity determined by the choice of Ugi adducts as starting materials.

N-N bond formation in Ugi processes: from nitric acid to libraries of nitramines.

The Ugi reaction has drawn considerable attention over the years leading to numerous libraries of heterocycles and various extensions changing the nature of the components of the coupling. We report here the use of nitric acid as carboxylic acids surrogates, displaying the first aminative Ugi-type reaction leading to nitramines.

Selective Tsuji-Trost type C-allylation of hydrazones: a straightforward entry into 4,5-dihydropyrazoles.

The 4,5-dihydropyrazole motif has drawn considerable attention over the years as it was shown to exhibit a plethora of biological and pharmacological properties, including anticancer, antibacterial, antifungal, antiviral, and anti-inflammatory properties. As such, it has been the target of a number of methods and drug discovery programs. We report here a straightforward and highly selective approach featuring a key palladium-catalysed Tsuji-Trost type C-allylation and subsequent intramolecular 1,4-addition of hydrazones.

Multiple Roles of Isocyanides in Palladium-Catalyzed Imidoylative Couplings: A Mechanistic Study.

Kinetic, spectroscopic and computational studies examining a palladium-catalyzed imidoylative coupling highlight the dual role of isocyanides as both substrates and ligands for this class of transformations. The synthesis of secondary amides from aryl halides and water is presented as a case study. The kinetics of the oxidative addition of ArI with RNC-ligated Pd0 species have been studied and the resulting imidoyl complex [(ArC=NR)Pd(CNR)2 I] (Ar=4-F-C6 H4 , R=tBu) has been isolated and characterized by X-ray diffraction. The unprecedented ability of this RNC-ligated imidoyl-Pd complex to undergo reductive elimination at room temperature to give the amide in the presence of water and an F- /HF buffer is demonstrated. Its behavior in solution has also been characterized, revealing an unexpected strong tendency to give cationic complexes, and notably [(ArC=NR)Pd(CNR)3 ]+ with excess isocyanide and [(ArC=NR)Pd(PP^ )(CNR)]+ with bidentate phosphines (PP^ ). These species may be responsible for catalyst deactivation and side-reactions. Ab initio calculations performed at the DFT level allowed us to rationalize the multiple roles of RNC in the different steps of the catalytic cycle.

Optimized Conditions for Passerini-Smiles Reactions and Applications to Benzoxazinone Syntheses.

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones.

Correction: Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines.

Correction for 'Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines' by Abdelbari Ben Abdessalem et al., Chem. Commun., 2015, 51, 1116-1119.

Passerini/Tsuji-Trost strategies towards achieving lactams and cyclopentane derivatives.

The Passerini reaction of α,ß-unsaturated aldehydes affords suitable substrates for the Tsuji-Trost reaction with various carbon based-nucleophiles. The resulting α,ß-unsaturated amides may be cyclized to lactams or converted into cyclopentane derivatives if bis-nucleophiles are used in the Tsuji-Trost step.

Formal [3+2] cycloaddition of Ugi adducts towards pyrrolines.

Ugi adducts derived from aromatic aldehydes may be converted to pyrrolines via addition of Michael acceptors under microwave irradiation. The reaction may proceed via unusual formation of azomethine ylides followed by a [3+2] cycloaddition using Michael acceptors.

Predicting new Ugi-smiles couplings: a combined experimental and theoretical study.

Following our previous mechanistic studies of multicomponent Ugi-type reactions, theoretical calculations have been performed to predict the efficiency of new substrates in Ugi-Smiles couplings. First, as predicted, 2,4,6-trichlorophenol experimentally gave the corresponding aryl-imidate. Theoretical predictions of nitrosophenols as good acidic partners were then successfully confirmed by experiments. In the latter case, the reaction offers a new access to benzimidazoles.

Pyrrolo[2,3-d]pyrimidine synthesis through activation of N-benzyl groups by distal amides.

A new activation mode of CH2-benzylamino groups has been observed during the preparation of pyrrolopyrimidines from Ugi-Smiles adducts of hydroxypyrimidines. The cyclization proceeds via a formal deprotonation of the N-benzyl group followed by trapping of the resulting anion by the alkyne moiety. The key role of the vicinal amide function during the process was pointed out.