Ramón Gómez Arrayás

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

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.

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.

Copper-catalyzed ortho-C–H amination of protected anilines with secondary amines

A practical Cu-catalyzed picolinamide-directed o-amination of anilines showing excellent mono-substitution selectivity and high functional group tolerance has been developed.

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.

Substrate‐Controlled Diastereoselectivity Switch in Catalytic Asymmetric Direct Mannich Reaction of Glycine Derivatives with Imines: From anti‐ to syn‐α,β‐Diamino Acids

The construction of multiple stereocenters in flexible acyclic molecules in a single operation with complete diastereoand enantiocontrol constitutes a central challenge within the field of asymmetric catalysis. Driven by their biological significance and synthetic value, the synthesis of optically active a,b-diamino acids via catalytic asymmetric direct Mannich reaction between a prochiral nitrogen pronucleophile and an imine represents a touchstone in meeting this challenge and has recently emerged as an active research area. Two complementary approaches are receiving great attention: the direct Mannich reaction of glycine ester Schiff bases (and related species) with imines and the direct azaHenry reaction either between nitro compounds and aimino esters, or between a-nitro acetates and imines. Despite the development of very efficient organometallicbased and metal-free catalytic procedures, which show high asymmetric induction and synor anti-diastereocontrol, the development of diastereoselective switchable methods providing access to either synor anti-configured a,b-diamino acids remains elusive. Just one catalyst system has been shown to enable tuning of diastereoselectivity, leading to either antior syn-configured a,b-diamino acid esters in good yields and high diastereoand enantioselectivities. In such an example, a dramatic anti/syn diastereoselectivity switch was achieved in the Mannich reaction of glycine derivatives with imines by modifying the electronic properties of the chiral phosphine ligand. As a useful complementary method, herein we describe that the synor anti-diastereoselectivity of the Mannich products can be efficiently switched by tuning the steric and electronic properties of the pronucleophile component (i.e., the glycinate imine) while maintaining the same catalyst system. Recently, we reported a route to anti-a,b-diamino acid derivatives based on the Cu–Fesulphos-catalyzed reaction of glycine ester aldimine pronucleophiles with the readily available N-(8-quinolyl)sulfonyl aldimines (Scheme 1 a). We envisioned that the use of ketimine-derived glycine pronucleophiles, instead of aldimine derivatives, could result in new critical steric interactions in the transition state that could potentially lead to a reversal in the sense of facial selectivity of the imine approach to the ester enolate, thus providing access to products with the opposite syn-configuration (Scheme 1 b).

Formal Regiocontrolled Hydroboration of Unbiased Internal Alkynes via Borylation/Allylic Alkylation of Terminal Alkynes

In accessing trisubstituted vinyl boronates from terminal alkynes, a propargyl directing (2-pyridyl)sulfonyl group allows terminal alkynes to undergo Cu-catalyzed B2(pin)2-borylation and subsequent Cu-catalyzed allylic alkylation with Grignard reagents without affecting the pinacolboronate moiety, thereby formally enabling a highly stereo- and regiocontrolled access to hydroboration products of unbiased dialkyl internal alkynes.