Rodolphe Jazzar

Functionalization of Organic Molecules by Transition‐Metal‐Catalyzed C(sp3)H Activation

Transition-metal-catalyzed C-H activation has recently emerged as a powerful tool for the functionalization of organic molecules. While many efforts have focused on the functionalization of arenes and heteroarenes by this strategy in the past two decades, much less research has been devoted to the activation of non-acidic C-H bonds of alkyl groups. This Minireview highlights recent work in this area, with a particular emphasis on synthetically useful methods.

Palladium-Catalyzed β Arylation of Carboxylic Esters†

The direct functionalization of C H bonds is an atomand step-economical alternative to more traditional synthetic methods based on functional-group transformations, which often require multistep sequences. In particular, transitionmetal catalysis has emerged as a powerful tool for the functionalization of otherwise unreactive C(sp) H and C(sp) H bonds. These advances have enabled the construction of a variety of carbon–carbon and carbon–heteroatom bonds with great efficiency and selectivity, even in structurally complex organic molecules. In this context, we previously investigated the intramolecular arylation of unactivated C(sp) H bonds under palladium(0) catalysis. Intermolecular C(sp) H arylation reactions have also been developed through the use of palladium(II) or palladium(0) catalysis and the assistance of a coordinating group, such as a carbonyl group (Scheme 1a). This group directs arylation in the b position through the formation of a chelated palladium homoenolate. The palladium(0)-catalyzed C H arylation a to an electron-withdrawing functional group (Scheme 1b, path 1) has also been established as a powerful method for the construction of C(sp) C(sp) bonds. An enantioselective reaction is also possible with a chiral catalyst. This reaction takes advantage of the acidity of the C H bond a to the electron-withdrawing group—in general a carbonyl group— to generate a palladium enolate, which is converted into the a-arylated product by reductive elimination. Herein, we describe a diversion from this mechanism and the development of a straightforward and conceptually new b-C H arylation method (Scheme 1b, path 2). Because this new type of b arylation is related mechanistically to a arylation, it is complementary to directing-group-controlled b arylation reactions. In this regard, it presents a few interesting features; for example, simple carboxylic esters can be used as substrates at mild temperatures, and no polyarylation products are formed. We also describe the proof of concept of an enantioselective variant with a chiral catalyst and propose a reaction mechanism on the basis of DFT calculations. Our initial studies focused on the palladium-catalyzed arylation of the lithium enolate of tert-butyl isobutyrate (2 a) with ortho-, meta-, and para-fluorobromobenzene (1a–c ; Table 1; the lithium enolate was formed in situ from 2a and lithium dicyclohexylamide (Cy2NLi)). [8] The palladium catalyst was composed of tris(dibenzylideneacetone)dipalladium(0) ([Pd2(dba)3]) and 2-dicyclohexylphosphanyl-2’(N,N-dimethylamino)biphenyl (davephos). The reaction of the lithium enolate of 2a with paraand meta-fluorobromobenzene in toluene at 28 8C gave an approximately 1:1 mixture of a-arylation (compounds 3a,b) and b-arylation products (compounds 4a,b ; Table 1, entries 1 and 2). In contrast, the reaction with ortho-fluorobromobenzene (1c) gave only the b-arylation product 4 c, which was isolated in 63% yield (Table 1, entry 3). Similarly, the reaction of methyl isobutyrate 2b with 1c gave only the b-arylation product 4d (Table 1, entry 4). A slightly higher temperature (50 8C) was required for complete conversion in the reaction of bromide 1c with ester 2a than for other reactions, and the product 4c Scheme 1. a) Directing-group strategy for the palladium-catalyzed b arylation of carbonyl compounds. b) Palladium-catalyzed a and b arylation of enolates generated in situ.

Cyclic (Alkyl)(amino)carbenes (CAACs): Recent Developments

Discovered in 2005, cyclic (alkyl)(amino)carbenes (CAACs) are among the most nucleophilic (σ donating) and also electrophilic (π-accepting) stable carbenes known to date. These properties allow them to activate a variety of small molecules and enthalpically strong bonds, to stabilize highly reactive main-group and transition-metal diamagnetic and paramagnetic species, and to bind strongly to metal centers, which gives rise to very robust catalysts. The most important results published up to the end of 2013 are briefly summarized, while the majority of this Review focuses on findings reported within the last three years.

Diastereo- and enantioselective intramolecular C(sp3)-H arylation for the synthesis of fused cyclopentanes.

All C-H bonds are not equal: The intramolecular arylation of unactivated C(sp(3))-H bonds in the presence of a chiral Pd/binepine catalyst allows the synthesis of fused cyclopentanes efficiently and in an diastereo- and enantioselective manner (see scheme).

Singlet (Phosphino)phosphinidenes are Electrophilic

A room-temperature stable (phosphino)-phosphinidene reacts with carbon monoxide, stable singlet carbenes, including the poor π-accepting imidazol-2-ylidene, and phosphines giving rise to the corresponding phosphaketene, phosphinidene-carbene and phosphinidene-phosphine adducts, respectively. Whereas the electronic ground-state calculations indicate a PP multiple bond character in which the terminal phosphorus is negatively charged, the observed reactivity clearly indicates that (phosphino)phosphinidenes are electrophilic as expected for an electron-deficient species. This is further demonstrated by competition experiments as well as by the results of Fukui function calculations.

On the Mechanism of the Palladium‐Catalyzed β‐Arylation of Ester Enolates

The palladium-catalyzed β-arylation of ester enolates with aryl bromides was studied both experimentally and computationally. First, the effect of the ligand on the selectivity of the α/β-arylation reactions of ortho- and meta-fluorobromobenzene was described. Selective β-arylation was observed for the reaction of o-fluorobromobenzene with a range of biarylphosphine ligands, whereas α-arylation was predominantly observed with m-fluorobromobenzene for all ligands except DavePhos, which gave an approximate 1:1 mixture of α-/β-arylated products. Next, the effect of the substitution pattern of the aryl bromide reactant was studied with DavePhos as the ligand. We showed that electronic factors played a major role in the α/β-arylation selectivity, with electron-withdrawing substituents favoring β-arylation. Kinetic and deuterium-labeling experiments suggested that the rate-limiting step of β-arylation with DavePhos as the ligand was the palladium-enolate-to-homoenolate isomerization, which occurs by a βH-elimination, olefin-rotation, and olefin-insertion sequence. A dimeric oxidative-addition complex, which was shown to be catalytically competent, was isolated and structurally characterized. A common mechanism for α- and β-arylation was described by DFT calculations. With DavePhos as the ligand, the pathway leading to β-arylation was kinetically favored over the pathway leading to α-arylation, with the palladium-enolate-to-homoenolate isomerization being the rate-limiting step of the β-arylation pathway and the transition state for olefin insertion its highest point. The nature of the rate-limiting step changed with PCy(3) and PtBu(3) ligands, and with the latter, α-arylation became kinetically favored. The trend in selectivity observed experimentally with differently substituted aryl bromides agreed well with that observed from the calculations. The presence of electron-withdrawing groups on these bromides mainly affected the α-arylation pathway by disfavoring C-C reductive elimination. The higher activity of the ligands of the biaryldialkylphosphine ligands compared to their corresponding trialkylphosphines could be attributed to stabilizing interactions between the biaryl backbone of the ligands and the metal center, thereby preventing deactivation of the β-arylation pathway.

Synthesis of Hemilabile Cyclic (Alkyl)(amino)carbenes (CAACs) and Applications in Organometallic Chemistry

A versatile methodology, involving readily available starting materials, allows for the synthesis of stable hemilabile bidentate cyclic (alkyl)(amino)carbenes (CAACs) featuring alkene, ether, amine, imine, and phosphine functionalities. The stability of the free carbenes has been exploited for the synthesis of copper(I) and gold(I) complexes. It is shown that the pendant imine moiety stabilizes the gold(III) oxidation state and enables the C-C bond oxidative addition of biphenylene to the corresponding cationic gold(I) complex. The latter and the corresponding copper(I) complex show high catalytic activity for the hydroarylation of α-methylstyrene with N,N-dimethylaniline, and the copper(I) complex promotes the anti-Markovnikov hydrohydrazination of phenyl acetylene with high selectivity.

Borrowing hydrogen: a catalytic route to C?C bond formation from alcoholsElectronic Supplementary Information (ESI) available: Experimental procedures and characterization data for compounds 1, 11, 12, 13, 15 and 17 along with general experimental procedures. See http://www.rsc.org/suppdata/cc/b3/b312162c/

Ruthenium complexes have been shown to perform efficient transfer hydrogenation reactions between alcohols and alkenes; in combination with an in situ Wittig reaction, indirect formation of C-C bonds has been achieved from alcohols.

Palladium-Catalyzed β-Arylation of Silyl Ketene Acetals and Application to the Synthesis of Benzo-Fused δ-Lactones

Silyl ketene acetals are shown to be competent nucleophiles in Pd-catalyzed migrative C(sp(3))-H arylations. Compared to the parent ester lithium enolates, they possess decreased reactivity but enhanced chemoselectivity. This behavior was exploited through the synthesis of valuable benzo-fused δ-lactones such as 1-isochromanones and dihydrocoumarins.

Synthesis of 1-indanols and 1-indanamines by intramolecular palladium(0)-catalyzed C(sp3)-H arylation: impact of conformational effects.

A range of valuable 1-indanols and 1-indanamines containing a tertiary C1 atom were synthesized by intramolecular palladium(0)-catalyzed C(sp(3))-H arylation, despite unfavorable steric interactions. The efficiency of the reaction was found to correlate with the degree of substitution at C2, as expected from the Thorpe-Ingold effect. Additionally, the nature of the heteroatomic substituent at C1 had a marked influence on the diastereoselectivity at C1 and C2; indeed, 1-indanols and 1-indanamines were obtained with the opposite relative configuration. Analysis of the X-ray and DFT-optimized structures of the corresponding reactive intermediates provided useful insights into the subtle conformational effects induced by these substituents.