Kei Manabe

Palladium‐Catalyzed Reductive Carbonylation of Aryl Halides with N‐Formylsaccharin as a CO Source

Aromatic aldehydes are valuable synthetic intermediates in C C bond-forming reactions. The reduction of carboxylic acids or esters to aldehydes is a commonly used synthetic strategy in spite of its drawbacks, that is, the functional groups that it can be applied to are limited, a relatively low temperature is required, and a two-step procedure involving initial activation of the carboxylic acid prior to the reduction is sometimes necessary. Direct formylation of aryl halides is a single-step alternative transformation which can be employed to form aldehydes. The conventional strategy for this conversion involves halogen–metal exchange by alkyllithium and subsequent addition of formylating agents (e.g., DMF). In this procedure, the reaction requires a stoichiometric amount of the metal reagent, the strong basicity of which limits the scope of functional groups which can be tolerated. An efficient and complementary methodology is the palladium-catalyzed reductive carbonylation of aryl halides, which employs CO gas. Because of the pioneering work by Heck and Schoenberg in 1974, several groups have worked on developing this conversion to enhance its utility as a synthetic tool. However, there are still only a few general protocols for reductive carbonylation, 4] especially in comparison to alkoxyand aminocarbonylations. Recently Beller et al. reported the first industrially applied and efficient palladium-catalyzed reductive carbonylation at 5 bar of synthesis gas (CO/H2 1:1). [5]

Palladium-Catalyzed Carbonylation of Aryl, Alkenyl, and Allyl Halides with Phenyl Formate

Highly efficient palladium-catalyzed carbonylation of aryl, alkenyl, and allyl halides with phenyl formate is reported. This procedure does not use carbon monoxide and affords one-carbon-elongated carboxylic acid phenyl esters in excellent yields. The reaction proceeds smoothly under mild conditions and tolerates a wide range of functional groups including aldehyde, ether, ketone, ester, and cyano groups. Furthermore, a variety of heteroaromatic bromides can be converted to the corresponding phenyl esters in high yields.

Trichlorophenyl formate: highly reactive and easily accessible crystalline CO surrogate for palladium-catalyzed carbonylation of aryl/alkenyl halides and triflates.

The high utility of 2,4,6-trichlorophenyl formate, a highly reactive and easily accessible crystalline CO surrogate, is demonstrated. The decarbonylation with NEt(3) to generate CO proceeded rapidly at rt, thereby allowing external-CO-free Pd-catalyzed carbonylation of aryl/alkenyl halides and triflates. The high reactivity of the CO surrogate enabled carbonylation at rt and significantly reduced the quantities of formate to near-stoichiometric levels. The obtained trichlorophenyl esters can be readily converted to a variety of carboxylic acid derivatives in high yields.

Hydroxyterphenylphoshine−Palladium Catalyst for Benzo[b]furan Synthesis from 2-Chlorophenols. Bifunctional Ligand Strategy for Cross-Coupling of Chloroarenes

A catalyst composed of Pd and hydroxyterphenylphosphine was found to be effective for one-pot benzo[b]furan synthesis from 2-chlorophenols and alkynes.

Palladium-Catalyzed Fluorocarbonylation Using N-Formylsaccharin as CO Source: General Access to Carboxylic Acid Derivatives

N-formylsaccharin, an easily accessible crystalline compound, has been employed as an efficient CO source in Pd-catalyzed fluorocarbonylation of aryl halides to afford the corresponding acyl fluorides in high yields. The reactions use a near-stoichiometric amount of the CO source (1.2 equiv) and tolerate diverse functional groups. The acyl fluorides obtained could be readily transformed into various carboxylic acid derivatives such as carboxylic acid, esters, thioesters, and amides in a one-pot procedure.

DHTP Ligands for the Highly Ortho-Selective, Palladium-Catalyzed Cross-Coupling of Dihaloarenes with Grignard Reagents: A Conformational Approach for Catalyst Improvement†

The site-selective cross-coupling of dihaloarenes is a useful method for synthesizing substituted monohaloarenes, which are an important class of compounds that are commonly employed as drug frameworks and synthetic intermediates. To achieve their efficient site-selective cross-coupling, two main problems must be addressed: First, the difficulty in differentiating two reactive sites, particularly when the desired coupling position is sterically and electronically unfavorable, and second, the difficulty in suppressing undesired doubly cross-coupled products. We recently developed the site-selective, palladiumcatalyzed cross-coupling of dibromobenzenes with Grignard reagents. The cross-coupling occurred site-selectively at the positions ortho to the hydroxy or amino groups on the substrate. In most cases, the reactions occurred at sterically and electronically unfavorable sites. The key to this system was the use of hydroxy-substituted terphenylphosphine ligands (1 or 2 ; Scheme 1). We assume that these phosphines form bimetallic palladium/magnesium species in the presence of palladium and Grignard reagents, and that the OMgX moiety acts as a binding site for the substrate (which also exists as the magnesium salt), and holds the ortho halo group close to the palladium center (Scheme 1). In this mechanism, oxidative addition to the palladium atom occurs preferentially at the positions ortho to the OMg group of the substrate. Whilst the ortho selectivity for substrates that have a strongly electron-donating substituent is unique, and cannot be achieved using other phosphine ligands, the selectivities were often modest and the formation of doubly cross-coupled products was a severe problem in many cases. Therefore, improvement of the catalysts was necessary to expand the applicability of this ortho-selective cross-coupling procedure. Herein, we present dihydroxyterphenylphosphine (DHTP) ligands 3–6 that improved the palladium-catalyzed orthoselective cross-coupling of dihaloarenes remarkably and expanded the scope of the reaction. The design of DHTPs was based on the following ideas. The assumed catalytic species formed from 1 or 2 is conformationally rigid owing to the para-terphenyl framework but retains flexibility in rotation of the C C single bonds. As shown in Scheme 2a, the conformation in which the palladium and the magnesium oxido moieties are located proximal to each other is in equilibrium with that in which they are on opposing sides of the terphenyl group. In the latter conformation, the cooperative effect of the palladium and magnesium oxido groups cannot work (Scheme 1). Conversely, when DHTPs are used, there is always a magnesium oxido group on the same face of the terphenyl structure as the palladium atom, even if C C bond rotation occurs (Scheme 2b). Therefore, cooperation between the palladium and magnesium oxido moieties would be more effective when DHTP ligands are used, thus affording higher selectivities in the ortho-selective cross-coupling reaction. The magnesium oxido moiety of the catalytic species also has conformational flexibility (Scheme 2c). Although it was expected that controlling the spatial arrangement of the magnesium atom should affect the catalytic performance, it was unknown how that would affect the ortho-selective crosscoupling. To control the position of the magnesium atom, we introduced two types of substituents at the position ortho to Scheme 1. Structures of terphenylphosphines (1 and 2 ; top left), dihydroxyterphenylphosphines (3–6; top right), and a mechanism for the ortho-selectivity in the site-selective cross-coupling of dibromophenol with a Grignard reagent.

One-Pot Synthesis of Substituted Benzo[b]furans from Mono- and Dichlorophenols Using Palladium Catalysts Bearing Dihydroxyterphenylphosphine

A dihydroxyterphenylphosphine bearing cyclohexyl groups on the phosphorus atom (Cy-DHTP) was found to be a powerful ligand for the palladium-catalyzed one-pot synthesis of substituted benzo[b]furans from 2-chlorophenols and terminal alkynes. This catalyst system was also applicable to the sequential one-pot synthesis of disubstituted benzo[b]furans from dichlorophenols via the Suzuki-Miyaura cross-coupling of chlorobenzo[b]furan with boronic acids. The use of two ligands, Cy-DHTP and XPhos, is the key to promoting the reactions. Mechanistic studies suggest that the Pd-Cy-DHTP catalyst is the active species in the Sonogashira cross-coupling step, while the Pd-XPhos catalyst accelerates the Suzuki-Miyaura cross-coupling step.

One-pot synthesis of 2,4-disubstituted indoles from N-tosyl-2,3-dichloroaniline using palladium-dihydroxyterphenylphosphine catalyst.

4-Chloroindoles were synthesized from readily available 2,3-dichloroaniline derivatives and terminal alkynes. The catalyst composed of palladium and dicyclohexyl(dihydroxyterphenyl)phosphine (Cy-DHTP) enabled ortho-selective Sonogashira coupling, and subsequent cyclization afforded 4-chloroindoles in high yields. This transformation was successfully applied to the one-pot synthesis of 2,4-disubstituted indoles via Suzuki-Miyaura coupling after indole formation.

Pd-Catalyzed Selective Synthesis of Cyclic Sulfonamides and Sulfinamides Using K2S2O5 as a Sulfur Dioxide Surrogate

A variety of cyclic sulfonamides and sulfinamides could be selectively synthesized under Pd catalysis using haloarenes bearing amino groups and a sulfur dioxide (SO2) surrogate. The amount of base was key in determining the selectivity. Mechanistic studies revealed that sulfinamides were initially formed via an unprecedented formal insertion of sulfur monoxide and were oxidized to sulfonamides in the presence of an iodide ion and DMSO.

One-Pot Synthesis of Substituted Benzo[b]furans and Indoles from Dichlorophenols/Dichloroanilines Using a Palladium–Dihydroxyterphenylphosphine Catalyst

Disubstituted benzo[b]furans were synthesized by ortho-selective Sonogashira coupling of dichlorophenols and terminal alkynes, followed by cyclization and Suzuki-Miyaura coupling in one pot, using a palladium-dihydroxyterphenylphosphine (Cy-DHTP) catalyst. The use of substoichiometric amounts of tetrabutylammonium chloride was effective in accelerating the Suzuki-Miyaura coupling. This protocol was also successfully applied to the one-pot synthesis of disubstituted indoles from dichloroaniline derivatives.