Juan C. Carretero

Novel dipolarophiles and dipoles in the metal-catalyzed enantioselective 1,3-dipolar cycloaddition of azomethine ylides

The catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides constitutes one of the most powerful and atom economical methods for the enantioselective construction of pyrrolidines. This article highlights the recent developments in this area, with special focus on contributions improving the structural scope at the dipolarophile and azomethine ylide partners.

Palladium(II)‐Catalyzed Regioselective Direct C2 Alkenylation of Indoles and Pyrroles Assisted by the N‐(2‐Pyridyl)sulfonyl Protecting Group

Driven by its synthetic power and environmental friendliness, C C bond-forming reactions through catalytic activation of Csp2 H bonds constitutes a hot area of research. Since the pioneering work by Murai et al. and Fujiwara and coworkers, remarkable progress has been made in this field, with palladium occupying a prevalent position. Most of these procedures rely on the use of a coordinating functionality that aids in the transition metal mediated functionalization of a proximal C H bond. However, from a synthetic viewpoint, the practicality of the directing groups can be compromised when the target molecule does not contain such functionality. Therefore, the discovery of efficient and removable directing groups is in high demand. Owing to the prevalence of the indole unit in pharmaceuticals and bioactive natural products, its regioselective C H functionalization represents an important challenge in this area. In contrast to the much more developed C H arylation reactions, direct alkenylations have received much less attention. A particularly challenging transformation is the intermolecular direct alkenylation at the C2-position, for which only three protocols have been reported. Ricci and co-workers reported the palladium(II)-catalyzed regiocontrolled C2 alkenylation of indole directed by a nonremovable N-2-pyridylmethyl group. Gaunt and co-workers described a practical method for the palladium(II)-catalyzed alkenylation of indoles (without an N-protecting group) in which the regioselectivity can be switched from C3 to C2 by varying the nature of the solvent and additives. However, decreased reaction yield was found in C2 alkenylation. Miura, Satoh et al. disclosed the palladium(II)-catalyzed C H alkenylation/decarboxylation of indole-3-carboxylic acids to afford exclusively 2-alkenyl indoles, where the carboxyl group blocks the C3-position and acts as a removable directing group. Despite these important advances there is room for innovation, both in increasing the efficiency of the reaction and in improving the current limited scope with regard to both the alkene component and directing group. To date, only monosubstituted electrophilic alkenes (mainly acrylates) have been applied in the C2 alkenylation of indoles, except for one isolated example of coupling with styrene. We disclose herein a highly efficient and structurally versatile palladium(II)-catalyzed C2 alkenylation of indoles and pyrroles employing the easily installed and removed N-(2pyridyl)sulfonyl directing group. Given the electrophilic nature of the palladium(II) center, our first challenge was to find an N-protecting group for the C2 functionalization of indole instead of the more nucleophilic C3-position. A set of potential directing groups were examined in the reaction of derivatives 2–7 with methyl acrylate under [Pd(CH3CN)2Cl2] catalysis (10 mol%) using Cu(OAc)2·H2O (1 equiv) as an oxidant in DMA at 110 8C (Table 1). Not unexpectedly, under such conditions the indole 1 cleanly underwent C3 alkenylation with complete regiocontrol (Table 1, entry 1). In contrast, the Bocprotected derivative 2 led to a 68:32 mixture of C2/C3 alkenylation products, in very low conversion (Table 1, entry 2). Both C2 regioselectivity and conversion were enhanced by switching to a Ts group (Table 1, entry 3) or a p-Ns group (Table 1, entry 4), albeit at an unpractical level. NHeteroarylsulfonyl groups strongly influenced the reactivity and regiocontrol. For example, the N-(2-thienyl)sulfonyl group in 5 led to low conversion and no regiocontrol

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.

Bis-sulfonyl ethylene as masked acetylene equivalent in catalytic asymmetric [3 + 2] cycloaddition of azomethine ylides.

Enantioenriched 3-pyrrolines have been synthesized by highly enantioselective Fesulphos-Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with trans-1,2-bisphenylsulfonyl ethylene, followed by reductive sulfonyl elimination. High levels of reactivity, exoselectivity, and enantioselectivity have been accomplished for a variety of substituted azomethine ylides. This cycloaddition-desulfonylation strategy has been applied as a key step in the enantioselective synthesis of a biologically active C-azanucleoside.

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.

PdII-Catalyzed Di-o-olefination of Carbazoles Directed by the Protecting N-(2-Pyridyl)sulfonyl Group

Despite the significance of carbazole in pharmacy and material science, examples of the direct C-H functionalization of this privileged unit are quite rare. The N-(2-pyridyl)sulfonyl group enables the Pd(II)-catalyzed ortho-olefination of carbazoles and related systems, acting as both a directing and readily removable protecting group. This method features ample structural versatility, affording typically the double ortho-olefination products (at C1 and C8) in satisfactory yields and complete regiocontrol. The application of this procedure to related heterocyclic systems, such as indoline, is also described.

Palladium-Catalyzed Cross-Coupling Reaction of Secondary Benzylic Bromides with Grignard Reagents

A mild palladium-catalyzed Kumada-Corriu reaction of secondary benzylic bromides with aryl and alkenyl Grignard reagents has been developed. In the presence of the Xantphos ligand, the undesired beta-elimination pathway is minimized, affording the corresponding cross-coupling products in acceptable to good yields. The reaction proceeds with inversion of the configuration.

Direct Mannich Reaction of Glycinate Schiff Bases with N-(8-Quinolyl)sulfonyl Imines: A Catalytic Asymmetric Approach to anti-α,β-Diamino Esters

An efficient catalytic enantioselective direct Mannich reaction of glycinate Schiff bases with aryl imines leading to anticonfigured orthogonally protected alpha,beta-diaminoesters has been realized. Keys to success in this new catalyst system are the use of Fesulphos/Cu(CH3CN)4PF6 (3-5 mol%) as a Lewis acid catalyst and readily available N-(8-quinolyl)sulfonyl-protected aldimines as substrates, affording excellent levels of diastereo- (typically anti/syn > 90:10) and enantiocontrol (typically > or = 90% ee). A remarkable feature of this catalyst system is that it allows the construction of products with a tetrasubstituted carbon stereocenter at C-alpha in a highly diastereo- and enantiocontrolled manner.

Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with α,β-unsaturated ketones

Alpha,beta-unsaturated ketones are no longer the missing dipolarophiles in catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. In the presence of Cu(I)-Fesulphos complexes as catalysts (5 mol %), these substrates combine high reactivity, wide substitution tolerance, moderate to good endo/exo selectivities, and high enantiocontrol. The endo/exo-diastereoselectivity of the reaction is strongly dependent on the cis or trans nature of the enone moiety.

Catalytic Asymmetric Vinylogous Mannich Reaction of N-(2-Thienyl)sulfonylimines

Both cyclic and acyclic silyl dienol ethers participate efficiently in the asymmetric vinylogous Mannich reaction of N-2-thienylsulfonylimines catalyzed by copper(I) complexes of Fesulphos ligands. This procedure displays wide imine and nucleophile versatility, high enantiocontrol, and complete gamma-regioselectivity in most cases examined. The mild sulfonamide deprotection allows the resulting products to be readily transformed into optically active delta-lactams or 5-hydroxy-2-piperidone derivatives.