Enantioselective Α-chlorination Research Articles

Catalytic Enantioselective Nucleophilic α-Chlorination of Ketones with NaCl.

Catalytic enantioselective α-chlorination of ketones is a highly desirable process. Different from the conventional approaches that employ corrosive electrophilic chlorination reagents, the process disclosed here employs nucleophilic chloride, aqueous NaCl solution, and even seawater, as green inexpensive chlorine sources. This mechanistically distinct and electronically opposite approach provides facile access to diverse highly enantioenriched acyclic α-chloro ketones that are less straightforward by conventional approaches. With a chiral thiourea catalyst, a range of racemic α-keto sulfonium salts underwent enantioconvergent carbon-chlorine bond formation with high efficiency and excellent enantioselectivity under mild conditions. The sulfonium motif plays a crucial triple role by permitting smooth dynamic kinetic resolution to take place via a chiral anion binding mechanism in a well-designed phase-transfer system. This protocol represents a new general platform for the asymmetric nucleophilic α-functionalization of carbonyl compounds.

触媒的エナンチオ選択的α-ハロゲン化反応に潜むハロゲン結合の影響

Enantioselective carbon-halogen (F, Cl, Br) bond formations are particularly important due to their potential as synthetic intermediates as well as marine natural products and pharmaceuticals. Among the various methods available to build carbon-halogen bonds, the enantioselective electrophilic α-halogenation of carbonyl compounds is one of the most common. Over the past few decades, α-halogenation reactions using 1,3-dicarbonyl compounds, aldehydes, and ketones have been well established. However, few reports are available on catalytic enantioselective α-chlorination for carboxylic acid derivatives with pKa that are relatively high, and hence it has been considered to be challenging to generate enolate species catalytically. Here, chiral π-copper(II) complex-catalyzed enantioselective α-fluorination and π-copper(II)-π complex-catalyzed enantioselective α-chlorination and α-bromination reactions of N-acyl-3,5-dimethylpyrazoles are described. The π-copper(II) complex of Cu(OTf)2 with 3-(2-naphthyl)-L-alanine-derived amides greatly accelerate the α-fluorination in the presence of an external base such as 2,6-lutidine. In sharp contrast, the π-copper(II)-π complexation of Cu(OTf)2 with 3-(2-naphthyl)-L-alanine-derived amides further increases the Lewis acidity, and triggers the in situ generation of enolate species without an external base, which has a suppressing effect for α-chlorination and α-bromination due to undesired halogen bonding. This strategy provides facile access to α-halogenated compounds in high yield with excellent enantioselectivity. X-ray crystallographic and ESR analyses of the catalyst complexes suggest that the release of two counter anions (2TfO−) from the copper(II)center might be crucial for the efficient activation of N-acyl-3,5-dimethylpyrazoles.

Photochemical Wolff Rearrangement Initiated Generation and Subsequent α-Chlorination of C1 Ammonium Enolates.

The enantioselective synthesis of α-chlorinated carboxylic acid esters with er up to 99:1 and yields up to 82% was achieved via a one-pot multistep protocol starting from α-diazoketones. This process proceeds via a photochemical Wolff rearrangement, trapping of the generated ketene with a chiral Lewis base catalyst, subsequent enantioselective α-chlorination, and a final nucleophilic displacement of the bound catalyst. The obtained products were successfully utilized for stereospecific nucleophilic displacement reactions with N- and S-nucleophiles.

A π–Cu(II)−π Complex as an Extremely Active Catalyst for Enantioselective α-Halogenation of N-Acyl-3,5-dimethylpyrazoles

Novel chiral π–copper(II)−π complex catalyzed enantioselective α-chlorination and -bromination of N-acyl-3,5-dimethylpyrazoles are described. The π–copper(II)−π complexation of Cu(OTf)2 with 3-(2-naphthyl)-l-alanine-derived amides greatly increases the Lewis acidity and triggers the in situ generation of enolate species without an external base, which has a suppressing effect for α-chlorination and -bromination due to undesired halogen bonding. This strategy provides facile access to α-halogenated compounds in high yield with excellent enantioselectivity. X-ray crystallographic and ESR analyses of the catalyst complexes suggest that the release of two counteranions (2TfO–) from the copper(II) center might be crucial for the efficient activation of N-acyl-3,5-dimethylpyrazoles.

Enantioselective α-Chlorination Reactions of in Situ Generated C1 Ammonium Enolates under Base-Free Conditions.

The asymmetric α-chlorination of activated aryl acetic acid esters can be carried out with high levels of enantioselectivities utilizing commercially available isothiourea catalysts under base-free conditions. The reaction, which proceeds via the in situ formation of chiral C1 ammonium enolates, is best carried out under cryogenic conditions combined with a direct trapping of the activated α-chlorinated ester derivative to prevent epimerization, thus allowing for enantioselectivities of up to e.r. 99:1.

Enantioselective α-chlorination of β-keto esters and amides catalyzed by chiral imidodiphosphoric acids

Chiral imidodiphosphoric acids were employed as catalysts for the enantioselective α-chlorination of β-keto esters and amides using NCS as the chlorine source, providing a series of optically active products with good to high enantioselectivities (74–95% ee) and excellent yields (92–99%). This represents the first report of the Brønsted acid catalyzed enantioselective α-chlorination of cyclic β-keto derivatives.

Iron(III)–Salan Complex Catalyzed Enantioselective α-Chlorination

Key words iron catalysis - chlorination - keto esters - oxindoles

ChemInform Abstract: Cu(II)‐Catalyzed Enantioselective α‐Hydroxylation and α‐Chlorination of β‐Ketoesters with N,N,O‐Tridentate Chiral Phenanthroline Ligand.

The N,N,O-tridentate chiral phenanthroline ligand was employed for Cu(II)-catalyzed enantioselective α-hydroxylation of β-ketoesters with racemic Davis’ oxaziridine to provide the corresponding product. We also tried to understand the plausible mechanism for asymmetric induction of this reaction, achieved by the effective shielding of prochiral Cu(II) enolate. With this working hypothesis, enantioselective α-chlorination of β-ketoesters to give the corresponding products was achieved with high enantioselectivity.

A general, enantioselective synthesis of N-alkyl terminal aziridines and C2-functionalized azetidines via organocatalysis

A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and N-alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50–73% overall yields and 88–94% ee, and azetidines in 22–32% overall yields and 84–92% ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield, >95% dr).

Enantioselective α-chlorination of β-oxo esters catalyzed by chiral diterpenoid alkaloid derivatives

Easily accessible diterpenoid alkaloid derivatives have been used as organocatalysts in the enantioselective α-chlorination of β-oxo esters. The treatment of β-oxo esters with N-chlorophthalimide (NCP) as a chlorine source under mild reaction conditions afforded the corresponding α-chlorinated β-oxo esters in excellent yields (up to 98%) and with moderate enantioselectivities (up to 68% ee) in 30min.

Chiral 2-Amino Alcohol Derivatives Catalyze the Enantioselective α-Chlorination of β-Ketoesters

E-mail: lixiaoyun06@126.comReceived October 29, 2013, Accepted February 22, 2014The enantioselective α-chlorination of cyclic β-ketoesters catalyzed by chiral 2-aminoalcohol derivatives (2f)has been developed. For the optically active α-chlorinated products, the isolated yields are in the range of 85-94% and the enantiomeric excesses are up to 84% ee.Key Words : Enantioselective α-chlorination, 2-Aminoalcohol derivatives, β-KetoestersIntroductionThe enantioselective construction of C-X stereogenicityhas gained considerable momentum in modern organic syn-thesis, drug, discovery and sciences.

Nickel-Catalyzed Enantioselective α-Chlorination

Chiral alkyl chlorides are useful substrates in synthesis due to their stereospecific reactivity with a range of nucleophiles. One of the most important processes to prepare optically active chlorinated compounds is through enantio­selective α-halogenation reactions (see Review below). Building on previous work in fluorination reactions (Sodeoka and co-workers Angew. Chem. Int. Ed. 2007, 46, 5435), the authors present an asymmetric α-chlorination of oxazoli­dinone derivatives of arylacetic acid using a Ni/BINAP catalyst.

Enantioselective α-Chlorination of Aldehydes with Recyclable Fluorous (S)-Pyrrolidine-Thiourea Bifunctional Organocatalyst.

A novel fluorous (S)-pyrrolidine-thiourea bifunctional organocatalyst is prepared. The catalyst shows good activity and enantioselectivity for direct α-chlorination of aldehydes using N-chlorosuccinimide (NCS) as the chlorine source. It can be recovered from the reaction mixture by fluorous solid-phase extraction with excellent purity for direct reuse.

Highly enantioselective α-chlorination of cyclic β-ketoesters catalyzed by N,N′-Dioxide using NCS as the chlorine source

A simple and highly efficient N,N'-dioxide organocatalyst system was developed for the asymmetric alpha-chlorination of cyclic beta-ketoesters using easily available NCS as the chlorine source to provide a series of optically active alpha-chloro-beta-ketoesters in excellent yields with 90-98% ee.