Ring-opening of azetidiniums by nucleophiles. Synthesis of polysubstituted linear amines.

This microreview focuses on the nucleophilic ring-opening of azetidiniums presenting various substitution patterns at C2, C3, and C4. In most cases, the nucleophilic ring-opening occurred in a stereoselective and regioselective fashion producing functionalized linear amines. Experimental selectivities associated with Density Functional Theory (DFT) calculations have allowed a better understanding of the parameters governing the regioselectivities.

Synthesis of Optically Active α-Trifluoromethylamines by Rearrangement of ß-Amino-α-trifluoromethyl Alcohols.

The synthesis of various optically active α-trifluoromethylamines has been realized from ß-amino-α-trifluoromethyl alcohols via an aziridinium ion intermediate under kinetic conditions.

Access to Enantio-enriched Substituted α-Trifluoromethyl Azepanes from l-Proline.

4-Substituted α-trifluoromethyl azepanes C were synthesized via the ring expansion of trifluoromethyl pyrrolidines A, which were synthesized from l-proline via a regioselective ring-opening of a bicyclic azetidinium intermediate B by various nucleophiles. The regioselectivity of the ring expansion is induced by the presence of a trifluoromethyl group. The chirality of the starting material was transferred to the azepanes with high enantiomeric excess.

Nickel-Catalyzed System for the Cross-Coupling of Alkenyl Methyl Ethers with Grignard Reagents under Mild Conditions.

A nickel-catalyzed cross-coupling of alkenyl methyl ethers with Grignard reagents, under mild conditions, is described. These conditions allowed access to various stilbenes and heterocyclic stilbenic derivatives as well as to a potential anticancer agent DMU-212.

TFA-promoted direct C-H sulfenylation at the C2 position of non-protected indoles.

A simple, efficient and practical metal-free C-H sulfenylation process at the C2 position of non-protected indoles has been developed. 2-Thioindoles were obtained in moderate to high yields using stable and readily available N-(thio)succinimides at room temperature in the presence of TFA.

Modular, Concise, and Efficient Synthesis of Highly Functionalized 5-Fluoropyridazines by a [2 + 1]/[3 + 2]-Cycloaddition Sequence.

An easy access to 5-fluoropyridazines by a [2 + 1]/[3 + 2]-cycloaddition sequence between terminal alkynes, a difluorocarbene, and a diazo compound is reported. This approach does not necessitate the isolation of any intermediates, and a wide range of novel 5-fluoropyridazines was synthesized from readily available starting materials. Additionally, these compounds were used as a platform to access novel and highly diversified pyridazines.

Ring Contraction of 3-Hydroxy-3-(trifluoromethyl)piperidines: Synthesis of 2-Substituted 2-(Trifluoromethyl)pyrrolidines.

A ring contraction of 3-hydroxy-3-(trifluoromethyl)piperidines was achieved via an aziridinium intermediate. This contraction facilitates the synthesis of a series of 2-substituted 2-(trifluoromethyl)pyrrolidines incorporating a quaternary center at the C2 position.

Synthesis of Aryl Sulfides: Metal-Free C-H Sulfenylation of Electron-Rich Arenes.

A simple, efficient, and practical metal-free C-H sulfenylation of substituted electron-rich arenes has been developed. This method is highly regioselective, and the corresponding aryl sulfides were obtained in moderate to excellent yields from stable and readily accessible N-(alkylthio)- and N-(arylthio)succinimides at room temperature in the presence of TFA.

Stereoselective Rearrangement of (Trifluoromethyl)prolinols to Enantioenriched 3-Substituted 2-(Trifluoromethyl)piperidines.

3-Substituted 2-(trifluoromethyl)piperidines B were synthesized by ring expansion of (trifluoromethyl)prolinols A, which were obtained from L-proline via an aziridinium intermediate C. The ring opening of the (trifluoromethyl)aziridinium intermediate by different nucleophiles is regio- and diastereoselective.

Access to optically active 3-substituted piperidines by ring expansion of prolinols and derivatives.

The ring expansion of prolinols via an aziridinium intermediate gives C3-substituted piperidines in good yields and enantiomeric excess, the substituent at the C3 position being derived from the most reactive nucleophile in the reaction mixture. Depending on the nucleophile, the reaction proceeds under thermodynamic or kinetic control. The regioselectivity of attack of nucleophiles on the aziridinium intermediate depends on the nature of the substituents on the nitrogen atom and the C4 position of the starting prolinols.

Palladium-catalyzed phosphonylation: synthesis of C3-, C4-, and C5-phosphonylated pyrazoles.

A palladium-catalyzed cross-coupling between 3-, 4-, and 5-halo-pyrazoles and H-phosphonates, H-phosphinates, and secondary phosphine oxides has been developed. This coupling reaction constitutes the first general method allowing the introduction of a great diversity of phosphorus substituents on the different carbons of the pyrazole ring in a one-step process.

Iridium-catalyzed hydrogen transfer: synthesis of substituted benzofurans, benzothiophenes, and indoles from benzyl alcohols.

An iridium-catalyzed hydrogen transfer has been developed in the presence of p-benzoquinone, allowing the synthesis of a diversity of substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.

XtalFluor-E, an efficient coupling reagent for amidation of carboxylic acids.

Amides were produced from carboxylic acids and amines by using XtalFluor-E as an activator. Even poorly reactive carboxylic acids can be transformed to amides. In addition, optically active amines and/or carboxylic acids were not epimerized/racemized during the process.

Ring expansion of cyclic ß-amino alcohols induced by diethylaminosulfur trifluoride: synthesis of cyclic amines with a tertiary fluorine at C3.

As the replacement of a hydrogen atom by a fluorine atom in a compound can have an important impact on its biological properties, the development of methods allowing the introduction of a fluorine atom is of great importance. The scope and limitations of the ring expansion of cyclic 2-hydroxymethyl amines induced by diethylaminosulfur trifluoride (DAST) to produce cyclic ß-fluoro amines was studied as well as the enantioselectivity of the process.

Asymmetric synthesis of an antagonist of neurokinin receptors: SSR 241586.

SSR 241586 is a 2,2-disubstituted morpholine, developed by Sanofi-Aventis, which is active in the treatment of schizophrenia and irritable bowel syndrome (IBS). Different strategies have been studied to synthesize this molecule and among the strategies an organo-catalyzed Henry reaction, applied to an α-keto ester, has produced SSR 241586 in excellent enantiomeric excess.

Enantioselective synthesis of ß-fluoroamines from ß-amino alcohols: application to the synthesis of LY503430.

N,N-Dialkyl-ß-amino alcohols were enantiospecifically and regioselectively rearranged by using N,N-diethylaminosulfur trifluoride (DAST) to give optically active ß-fluoroamines in excellent yields and enantiomeric excesses. This rearrangement was applied to the enantioselective synthesis of LY503430, a potential therapeutic agent for Parkinson's disease.

Rearrangement of beta-amino alcohols via aziridiniums: a review.

This tutorial review focuses on the rearrangement of beta-amino alcohols via aziridinium intermediates. It covers the literature from 1947 to January 2009 (55 references). The rearrangement of beta-amino alcohols can be performed by activation of the hydroxy group followed by the addition of nucleophiles (Nu). In most examples, an aziridinium intermediate is involved in the rearrangement. The ratio of amines resulting from the attack of nucleophiles at either the C-1 or C-2 position of the aziridinium intermediate, depends on the nature of the nucleophiles and the R(2) substituent. In some cases, solvent as well as temperature can influence the ratio of amines.

Highly enantioselective synthesis of linear beta-amino alcohols.

Beta-amino alcohols derived from alpha-amino acids have been extensively used as a powerful source of chirality. Transforming the alcohol moiety into a good leaving group has allowed the rearrangement of these beta-amino alcohols and the introduction of a large number of nucleophiles through the anchimeric participation of the nitrogen atom. An overview on the recent progress realized on the rearrangement of these beta-amino alcohols in the presence of (CF(3)CO)(2)O and H(2)SO(4) is reported.

Ring expansion of functionalized octahydroindoles to enantiopure cis-decahydroquinolines.

A new synthetic entry to enantiopure cis-decahydroquinolines is reported. Endo and exo derivatives of cis-1-benzyl-2-(hydroxymethyl)octahydroindol-6-one ethylene acetal undergo ring enlargement upon treatment with TFAA and then Et3N (thermodynamic conditions) to give enantiopure 1-benzyl-3-hydroxydecahydroquinolin-7-one derivatives in 77 and 82% yield, respectively. For 2-(1-hydroxyethyl) analogues, the best synthetic result is obtained from the (2S,1'R) endo isomer, which under kinetic reaction conditions (MsCl, THF, -20 degrees C, then AgOAc at rt ) gives the expanded product in 54% yield.