M. Ángeles Fernández-Ibáñez

Palladium-catalyzed N-(2-pyridyl)sulfonyl-directed C(sp3)–H γ-arylation of amino acid derivatives

The direct Pd-catalyzed γ-arylation of amino acid esters bearing a removable N-(2-pyridyl)sulfonyl directing group is described. A variety of N-(2-pyridyl)sulfonamide amino acid derivatives, including α-quaternary amino acid and β-amino acid substrates, react with iodoarenes in the presence of Pd(OAc)2 to provide γ-arylated products in synthetically useful yields. An unprecedented remote C(sp3)–H arylation of dipeptides is presented, illustrating the compatibility of the method with the presence of the peptidic bond. The process occurs without racemization at the Cα center and the auxiliary controlling group can be easily installed and removed in the amino acid backbone. A bimetallic PdII γ-metalated complex has been isolated and characterized showing the key role exerted by the (2-pyridyl)sulfonyl unit.

Palladium-catalyzed coupling of arene C-H bonds with methyl- and arylboron reagents assisted by the removable 2-pyridylsulfinyl group.

The Pd(II)-catalyzed direct coupling of arene C-H bonds with organoboron reagents assisted by the 2-pyridylsulfinyl group is reported. Methylboronic acid and arylboronic acid neopentyl esters proved to be efficient coupling partners, furnishing methylated arenes and biaryl products in moderate to good yields. The 2-pyridylsulfinyl group can be easily removed to provide the free biaryls. The essential role of the 2-pyridyl unit in stabilizing the cyclopalladation complex was demonstrated by X-ray diffraction analysis of the palladacycle intermediate.

Catalytic Enantioselective Reformatsky Reaction with Aldehydes

The classical Reformatsky reaction, introduced for the first time in 1887, consists of the zinc-induced formation of bhydroxyesters by the reaction of a-halogenated esters with aldehydes or ketones. Currently, Reformatsky reactions are defined as transformations that result from metal insertions into carbon–halogen bonds activated by carbonyl groups and subsequent addition of different kinds of electrophiles. The Reformatsky reaction is among the most useful methods for the formation of carbon–carbon bonds and an important alternative to the base-induced aldol reaction. Its excellent functional-group tolerance and mild reaction conditions have contributed to its success. The reaction is typically heterogeneous in nature; however, in recent years homogeneous Reformatsky reactions based on the use of Me2Zn or Et2Zn have been described. The asymmetric version of the Reformatsky reaction has been achieved using chiral auxiliaries or ligands. Recently, a catalytic enantioselective version of this transformation has been reported by Cozzi, employing ketones or imines as electrophiles. High enantioselectivities have been reached using chiral [MnCl(salen)] complexes (20 mol %) in the reaction with ketones and N-methylephedrine (20– 30 mol%) in the imino-Reformatsky reaction. However, both methods provide low levels of enantioselectivity in the reaction with benzaldehyde. Herein, we report the first effective catalytic enantioselective Reformatsky reaction with aldehydes using a catalyst based on binol derivatives as the chiral ligand. Several chiral ligands (10 mol%) were tested in a model reaction with benzaldehyde in the presence of Me2Zn and ethyl iodoacetate in a nitrogen atmosphere (Scheme 1). Chiral ligands (S)-L1, (S)-L2, and (S)-L3 gave the highest enantioselectivities (62–69% ee), but unfortunately the conversion into the desired product 1 was only 10–20%. The remaining starting material was recovered, and no 1,2addition product of Me2Zn to benzaldehyde was detected. Therefore, we initially focussed our efforts on the key issue of conversion and chemoselectivity. To increase the conversion, the more reactive Et2Zn and iPr2Zn were used as the zinc source in the model reaction with (S)-L2 as the chiral ligand. Full conversion was obtained in these cases although the enantioselectivity dropped to 26 and 8% ee, respectively. Addition of catalytic amounts of [NiCl2(PPh3)2] or [RhCl(PPh3)3], which are expected to give faster halogen–zinc exchange compared to the direct insertion of Me2Zn, [3] gave nonreproducible results in the addition of ethyl bromoacetate to benzaldehyde using (S)-L2 as the chiral ligand. Finally, to activate the Me2Zn reagent, we decided to exchange the nitrogen atmosphere with air. It is known that Me2Zn in the presence of oxygen forms the more reactive alkyl peroxides (RZnOOR), which are able to initiate radical reactions. 8, 9] Under these conditions, by using 10 mol% of (S)-L2, complete conversion and a promising level of enantioselectivity (58% ee) were obtained (Table 1, entry 1). It is important to note that the reaction was complete in less than 1 h, in sharp contrast with the reaction under nitrogen. Lower and higher temperatures and different additives and iodoacetates were evaluated, and in all cases lower enantioselectivities were obtained. Scheme 1. Model reaction using chiral binol derivatives. TMS= trimethylsilyl, TBDMS= tert-butyldimethylsilyl, TIPS= triisopropylsilyl.

Catalytic enantioselective reformatsky reaction with ortho-substituted diarylketones

The catalytic enantioselective Reformatsky reaction with ortho-substituted diarylketones with good enantioselectivities and moderate to good yields is reported. A readily available BINOL derivative is used as a chiral catalyst, and the reactions are performed with ethyl iodoacetate as a nucleophile and Me2Zn as the zinc source. The presence of air was found to be crucial to achieve an effective C-C bond formation pointing to a radical mechanism.

Catalytic enantioselective Reformatsky reaction with ketones

Chiral tertiary alcohols were obtained with good yields and enantioselectivities via a catalytic Reformatsky reaction with ketones, including the challenging diaryl ketones, using chiral BINOL derivatives.

Experimental and computational studies on the mechanism of the Pd-catalyzed C(sp3)–H γ-arylation of amino acid derivatives assisted by the 2-pyridylsulfonyl group

The Pd(OAc)2-catalyzed γ-arylation of amino acid esters bearing a removable N-(2-pyridyl)sulfonyl directing group via C(sp3)–H activation provides a direct method to form functionalized amino acids without racemization at the α-C and with a high degree of stereoselectivity. The present mechanistic studies suggest that the reaction proceeds via a catalytically active monomeric species, and that the C–H activation is reversible and is not always the turnover limiting step. Moreover, theoretical calculations explain the observed stereoselectivity and suggest that the reaction proceeds through a Pd(II)/Pd(IV) mechanism.

Remote Stereocontrol Mediated by a Sulfinyl Group: Synthesis of Allylic Alcohols via Chemoselective and Diastereoselective Reduction of γ-Methylene δ-Ketosulfoxides

The efficiency of the sulfinyl group as a remote controller of the chemoselectivity and diastereoselectivity of the reduction of alpha, beta-unsaturated alpha-[2-(p-tolylsulfinyl)phenyl] substituted ketones 1 has been demonstrated in reactions carried out under NaBH4 in the presence of Yb(OTf)3 as the chelating agent. The starting unsaturated ketones have been prepared from the corresponding 2-(p-tolylsulfinyl) benzyl alkyl (and aryl) ketones 2 by insertion of the methylidene group under modified Mannich conditions, exploiting ultrasound irradiation to obtain the aminomethylation adducts and silica gel treatment to produce its complete elimination. Desulfinylation of the reduction products yielded the corresponding vinyl carbinols with high enantiomeric purity.

Catalytic asymmetric conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones

An efficient method is reported for the highly enantioselective copper-catalyzed conjugate addition of dialkylzinc reagents to alpha,beta-unsaturated sulfones using a monodentate phosphoramidite ligand.

Ligands Control Reactivity and Selectivity in Palladium‐Catalyzed Functionalization of Unactivated C sp3H Bonds

Transition metal-catalyzed carbon–hydrogen bond functionalization is a powerful method to construct carbon–heteroatom and carbon–carbon bonds. However, many challenges must be overcome before the C H functionalization strategies can become a routine synthetic tool for chemists. Efforts towards increasing the reactivity of the C H bond and the selectivity of the process are crucial for the rapid progress of this field. In this context, the discovery, development, and application of suitable ligands to promote C H functionalization presents the most promising approach to overcome the current challenges. To date, a selected number of ligands have been used to tune the reactivity and selectivity of the direct functionalization of C H bonds. Mono-Nprotected amino acid (MPAA) derivatives and pyridine-based ligands are currently considered the most promising ligands for Pd-catalyzed C H functionalization reactions and have been applied in a range of reactions. However, the reaction scope of these types of ligands has been applied mainly to the functionalization of C sp H bonds. Only a few examples of ligand-enabled C sp H bond activations have been reported (Scheme 1). 6] MPAA and bipyridine-based ligands have been employed for the activation of benzylic C sp H bonds by the groups of Martin and MuÇiz, respectively. On the other hand, Yu et al. have described the use of an alkoxypyridine ligand for the functionalization of remote secondary C sp H bonds with, unfortunately, poor selectivity control towards the monoarylated product. Therefore, the development of ligands that are able to control the selectivity and promote the reactivity of unactivated C sp H bonds remains a challenge. In this context, the very recent work of Yu et al. demonstrates the pivotal role of ligands in promoting the reactivity of unactivated C sp H bonds and controlling the selectivity of the process. The first of their reports describes the func-

Palladium and Organocatalysis: An Excellent Recipe for Asymmetric Synthesis

The dual activation of simple substrates by the combination of organocatalysis and palladium catalysis has been successfully applied in a variety of different asymmetric transformations. Thus, the asymmetric α-allylation of carbonyl compounds, α-fluorination of acyl derivatives, decarboxylative protonation of β-dicarbonyl compounds, cyclization reactions of alkynyl carbonyl compounds and β-functionalization of aldehydes have been efficiently achieved employing this double-catalytic methodology.