Francis Marsais

Connection between metalation and cross-coupling strategies. A new convergent route to azacarbazoles

Abstract New convergent synthesis of azacarbazoles through metalation, cross-coupling reaction and intramolecular substitution via (2-aminobenzene)boronic acid and ortho-fluoroiodopyridines.

Directed Metalation of Pi-Deficient Azaaromatics: Strategies of Functionalization of Pyridines, Quinolines, and Diazines

Publisher Summary This chapter updates the directed ortho metalation (DoM) reaction of pyridines, quinolines, pyrimidines, pyrazines, and pyridazines. Various directed metalation group (DMGs) (halo, NHCOR and NHC02R, OR and OCONR2, 2-oxazolino, CONHR, CONR2, and masked RCHO and RCOR, SO2NR2) have been described, with major emphasis given to the metalation of halo pyridines, an area in which selectivity and mechanistic aspects have been extensively studied. Reactions of powerful alkyllithiums with halo pyridines, quinolines, and diazines may lead to nucleophilic substitution (by addition-elimination or hetaryne mechanisms), ring opening, halogen-scrambling, and coupling reactions that compete with the desired DoM process. Lithiation chemistry of bare pyridines and pyridine N-oxides is presented, followed by the use of the DoM strategy for the synthesis of natural products and biologically active molecules. The exploration of DoM chemistry in haloheteroaromatics is valuable for two reasons: (a) halo derivatives can be readily prepared from accessible amino, hydroxy, and, at times, unsubstituted systems, and (b) halogens can be subsequently induced to undergo a variety of funcionalizations via addition-elimination, metal-halogen exchange, and cross coupling reactions. Some of these transformations are more facile than in the aromatic series. Thus, DoM tactics may lead to diverse substituted heteroaromatics, which can be difficult to obtain by more classical means.

Palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate: an efficient access to (hetero)aryloxazoles.

A straightforward route toward 2-(hetero)arylated and 2,5-di(hetero)arylated oxazoles through regiocontrolled palladium-catalyzed direct (hetero)arylation of ethyl oxazole-4-carboxylate with iodo-, bromo-, and chloro(hetero)aromatics followed by a two-step hydrolysis/decarboxylation sequence was described. The method was applied here to a neat synthesis of two 2,5-di(hetero)aryloxazole natural products, balsoxin and texaline.

New Syntheses of Substituted Pyridines via Bromine–Magnesium Exchange

Abstract Bromine–magnesium exchange using i PrMgCl in THF at room temperature on 2-, 3- and 4-bromopyridines allowed the synthesis of various functionalized pyridines. The methodology was successfully used for the synthesis of 4-azaxanthone. Moreover, single exchange reactions observed on 2,6-, 3,5-, 2,3- and 2,5-dibromopyridines, with complete regioselectivity in the case of 2,3- and 2,5-dibromopyridines, afforded substituted bromopyridines, which were then involved in a second exchange step to provide difunctionalized pyridines.

Review on the metallation of π -deficient heteroaromatic compounds : Regioselective ortho-lithiation of 3-fluoropyridine: Directing effects and application to synthesis of 2,3- or 3,4-disubstituted pyridines

Abstract Metallation of π-deficient heterocyclic compounds is first reviewed, which shows the important recent developments in this research area. A particular aspect of this reaction is then given with the study of the 3-fluoropyridine metallation regioselectivity. Lithiation of 3-fluorophyridine is chemoselective at low temperatures using butyllithium-polyamine chelates or lithium diisopropylamide. Protophilic attack by these strong bases can be directed either at the 2- or 4-position depending on the lithiation conditions. Various reaction parameters are thus studied such as solvent, temperature, reaction time, lithium-chelating agent as well as metallating agent. The high regioselectivity of 3-fluoropyridine lithiation is theoretically discussed, in particular in terms of kinetic of thermodynamic control of the metallation. Chelation between butyllithium and 3-fluoropyridine is proposed, which completely modifies the heterocycle reactivity toward the lithiating agent. This is confirmed by theoretical quantum calculations performed on different models of 3-fluoropyridine using the CNDO/2. These results allow to select the best 3-fluoropyridine-metallation conditions which lead to 3-fluoro-2-lithiopyridine on the one hand and to 3-fluoro-4-lithiopyridine on the other hand. Each of the lithiated isomers is then reacted with a great variety of electrophiles which gives very conveniently the corresponding 2,3- or 3,4-disubstituted pyridines.

Pyridylmagnesium chlorides from bromo and dibromopyridines by brominemagnesium exchange: A convenient access to functionalized pyridines

Various bromopyridines were converted to the corresponding pyridylmagnesium chlorides at room temperature by treatment with iPrMgCl. The resulting Grignard reagents were quenched by various electrophiles to afford functionalized pyridines. The brominemagnesium exchange of some dibromopyridines was also studied.

Direct C-2 arylation of alkyl 4-thiazolecarboxylates: new insights in synthesis of heterocyclic core of thiopeptide antibiotics.

The Pd(0)-catalyzed regioselective C-2 (hetero)arylation of tert-butyl 4-thiazolecarboxylate with a broad (hetero)aryl halide is reported, including the direct coupling of pyridinyl halides. The process has allowed the preparation of valuable 2-pyridynyl-4-thiazolecarboxylates which are components of the complex heterocyclic core of thiopeptides antibiotics. As a first application, a synthesis of a tert-butyl sulfomycinamate thio-analogue from tert-butyl 4-thiazolecarboxylate is here described through a three-step direct pyridinylation, halogenation, and Stille cross-coupling sequence.

Selective alkylations of 1,4:3,6-dianhydro-d-glucitol (isosorbide)

Abstract Each of the two hydroxyl groups of isosorbide can be alkylated selectively, either by direct alkylation with benzyl chloride or allyl bromide according to the reaction conditions, or by a three-step procedure involving selective monoacetylation, alkylation with four different reagents, and finally deacetylation. Monobutyl and monomethyl derivatives from isosorbide are also described.

Metallation regioselective en serie pyridinique: Synthese originale d'amino-2 aroyl-3 pyridines

Abstract Lithium diisopropylamide reacts with 2-fluoropyridine at low temperature: regioselectivity is excellent and metallation occurs without side reactions such as nucleophilic attack. 2-Fluoro-3-lithiopyridine is formed and with aldehydes it gives the corresponding fluorinated alcohols which are then selectively oxidized. Halogen substitution using amines leads to various 3-oxoalkyl- or 3-aroyl-2-aminopyridines.

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

Summary Catalytic direct (hetero)arylation of (hetero)arenes is an attractive alternative to traditional Kumada, Stille, Negishi and Suzuki–Miyaura cross-coupling reactions, notably as it avoids the prior preparation and isolation of (hetero)arylmetals. Developments of this methodology in the oxazole series are reviewed in this article. Methodologies, selectivity, mechanism and future aspects are presented.