Inés Alonso

Regiocontrolled CuI-Catalyzed Borylation of Propargylic-Functionalized Internal Alkynes

Good to excellent reactivity and regiocontrol have been achieved in the Cu(I)-catalyzed borylation of dialkyl internal alkynes with bis(pinacolato)diboron. The presence of a propargylic polar group (OH, OR, SAr, SO(2)Ar, or NHTs), in combination with PCy(3) as ligand, allowed maximizing the reactivity and site-selectivity (β to the propargylic function). DFT calculations suggest a subtle orbitalic influence from the propargylic group, matched with ligand and substrate size effects, as key factors involved in the high β-selectivity. The vinylboronates allowed the stereoselective synthesis of trisubstituted olefins, while allylic substitution of the SO(2)Py group without affecting the boronate group provided access to formal hydroboration products of unbiased dialkylalkynes.

Understanding the behavior of N-tosyl and N-2-pyridylsulfonyl imines in CuII-catalyzed aza-Friedel-Crafts reactions.

The different behavior of N-tosyl imines and N-(2-pyridyl)sulfonyl imines in Cu (II)-catalyzed AFCR is described. DFT theoretical calculations on the mode of coordination of the copper atom to both types of substrates allow understanding this different reactivity.

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of α‐Iminonitriles

The 1,3-dipolar cycloaddition of azomethine ylides with alkenes is one of the most powerful and convergent methods for the stereoselective synthesis of pyrrolidines, a heterocyclic moiety widely present in the structure of natural products, pharmaceuticals and chiral ligands. Improving the overall chemical and stereochemical efficiency of this reaction, pioneered by Grigg with stoichiometric metal chiral complexes, a great effort has been devoted in recent years in the development of catalytic asymmetric protocols. In this field a wide variety of outstanding chiral complex catalysts have been reported, mainly Ag, Cu and Cu catalysts, but also Zn, Ni and Ca complexes. In addition, several organocatalytic asymmetric methods have been also developed in the last few years. Concerning the scope of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides, although there is an ample tolerance with regard to the nature of the dipolarophile (i.e., a,b-unsaturated esters, maleimides, a,b-unsaturated nitriles, enones, enals, nitroalkenes, vinyl sulfones and fullerene), the structural variety at the azomethine dipole is much more limited. By far most catalytic asymmetric versions reported to date are based on the use of a-iminocarbonyl substrates, specifically a-iminoesters. The great effectiveness of a-iminoesters as dipole precursors relies on the enhanced acidity of the a-position and the formation of a robust five-membered, N,O-bidentate-metalated, azomethine ylide, which facilitates the asymmetric induction from the chiral ligand. The inherent limitation of this strategy is the restricted structural versatility with regard to the substitution at C2, always providing pyrrolidines with a C2 carboxylate ester substitution. To access other types of substituted pyrrolidines, a-iminonitrile precursors are very appealing, since in the resulting 2-cyanopyrrolidines the cyano group could further act as leaving group allowing its formal substitution by hydrogen or by a carbon nucleophile, and thus leading to a wider variety of substituted pyrrolidines. Two decades ago KaneACHTUNGTRENNUNGmasa, Tsuge et al. reported the non-enantioselective thermal and LDA-promoted (LDA= lithium diisopropylACHTUNGTRENNUNGamide)[10] cycloaddition of alkyl-substituted a-iminonitriles with electron-deficient dipolarophiles, but the catalytic asymmetric version of this process remained to be developed. We describe herein the first catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of a-iminonitriles, as well as some synthetic applications and a DFT theoretical study on the presumed nature of the metalated 1,3-dipole. To evaluate the viability of a-iminonitriles as dipole precursors in catalytic asymmetric 1,3-dipolar cycloadditions, we first studied the reaction of N-benzylidenaminoacetonitrile (1) with methyl acrylate in the presence of ligand Fesulphos (2, 10 mol %). This ligand had proved to be very efficient in the 1,3-dipolar cycloadditions of a-iminoesters with a wide variety of dipolarophiles (acrylates, maleates, fumarates, maleimides, enones, bissulfonylethylenes and fullerene), providing the pyrrolidines usually with high control of the endo/exo selectivity and enantioselectivity. However, a very poor reactivity and stereoselectivity was obtained in the reaction of methyl acrylate with a-iminonitrile 1 a in the presence of a variety of copper and silver salts (11% yield and 22 % ee for the major adduct as the best results, Scheme 1). In an attempt to find a more efficient catalyst system for this reaction we next tested a variety of ligands, albeit with moderate success. A promising enantioselectivity was found with AgOAc/Taniaphos (3) as catalyst system (30 % yield, 68 % ee for endo-4). To improve the efficiency of the process we next applied this catalyst system to a more reactive dipolarophile, such as dimethyl fumarate (Table 1). Interestingly, unlike the previously reported thermal or LDA-mediated reactions, which give rise to C2/C5 cis/trans mixtures of isomers, this catalytic asymmetric reaction provided exclusively the C2/C5 [a] R. Robles-Mach n, Dr. I. Alonso, Dr. J. Adrio, Prof. Dr. J. C. Carretero Departamento de Qu mica Org nica, Facultad de Ciencias Universidad Aut noma de Madrid Cantoblanco 28049 Madrid (Spain) Fax: (+34) 914973966 E-mail : javier.adrio@uam.es juancarlos.carretero@uam.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200903443.

Sulfoxides as stereochemical controllers in intermolecular Heck reactions.

The study of a variety of substituted sulfoxides as chiral auxiliaries in intermolecular Heck reactions of sulfinyldihydrofurans and sulfinylcyclopentenes with different iodoarenes is reported. In the presence of [Pd(OAc)2]/Ag2CO3 and a bidentate phosphine ligand, synthetically useful yields and asymmetric inductions were obtained. By far the best diastereoselectivities were obtained by the use of the palladium-coordinating O-(N,N-dimethylamino)phenylsulfinyl group. By final removal of the chiral auxiliary, these sulfoxide-stereocontrolled asymmetric Heck processes were applied to the enantioselective synthesis of 1-aryl-substituted and 1,3-diaryl-substituted dihydrofurans and cyclopentenes.

Highly diastereoselective diels-alder reaction of optically active 2-p-tolylsulphinyl-2-cycloalkenones with cyclopentadiene

Abstract The Diels-Alder reaction of (S)-2-p-tolylsulphinyl-2-cyclopentenone (and 2-cyclohexenone) with cyclopentadiene, catalized by AlCl3 and AlEtCl2, occurs at room temperature with complete facial diastereoselectivity, but with moderate endo-exo selectivity.

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.

Diels-Alder reaction of (S)-2-p-tolylsulfinyl-2-cyclopentenone with Dane's diene: an efficient approach to the enantioselective preparation of perhydro-cyclopenta[a]phenanthrenes

Abstract The reactions of (S)-2-p-tolylsulfinyl-2-cyclopentenone with Danes diene catalyzed by EtAlCl2 yields adducts easily desulfinylated into optically pure perhydro-cyclopenta[a]phenanthrenes. The endo- (controlled by CO group) and regio- (controlled by the substituent at C-2 of diene) selectivities of the asymmetric Diels-Alder reaction are complete. The π—facial selectivity is also very high and dependent on both the sulfinyl configuration and the amount of EtAlCl2 used.

2‐(p‐Tolylsulfinyl)benzyl Halides as Efficient Precursors of Optically Pure trans‐2,3‐Disubstituted Aziridines

Aziridination of (R)-N-sulfinylaldimines (aryl, heteroaryl and alkenyl derivatives) with 2-(p-tolyl sulfinyl)benzyl iodide in the presence of sodium hexamethyl disilazide takes place with almost complete control of the stereoselectivity (facial and anti/syn) and with very high yields affording optically pure N-sulfinyl trans-2,3-disubstituted aziridines 7. Simultaneous removal of both C- and N-p-tolylsulfinyl groups with tBuLi provides the corresponding trans-NH aziridines 8 without affecting their optical purity. Some experimental results suggest these processes evolve through benzyl halocarbenoids as intermediates, whereas theoretical calculations support the formation of benzyl carbanions. These results have served for revising the mechanistic aspects of the reactions of substituted 2-p-tolylsulfinyl benzylcarbanions with electrophiles.

Stereoselective Ag‐Catalyzed 1,3‐Dipolar Cycloaddition of Activated Trifluoromethyl‐Substituted Azomethine Ylides

A silver-catalyzed 1,3-dipolar cycloaddition of fluorinated azomethine ylides and activated olefins is reported. The reaction offers a straightforward and atom-economical procedure for the preparation of fluorinated pyrrolidines. Broad scope and high levels of diastereoselectivity have been achieved simply by using AgOAc/PPh3 as the catalyst system. The high efficiency of the cycloaddition relies on the presence of a metal-coordinating group on the imine moiety, such as an ester or heteroaryl group. The asymmetric version of the cycloaddition has been developed by using Taniaphos as a chiral ligand.

Chiral monofluorobenzyl carbanions: synthesis of enantiopure β-fluorinated β-phenylethylamines.

The preparation of a stabilized monofluorobenzyl carbanion by means of a remote homochiral sulfinyl group and its completely stereoselective reactions with N-p-tolylsulfinylimines are described. The use of these reactions followed by the simultaneous removal of both chiral auxiliaries with tBuLi, which occurs without epimerization at the benzylic position, provides the quickest entry to enantiomerically pure β-fluorinated β-phenylethylamines.