Pazhamalai Anbarasan

From Noble Metal to Nobel Prize: Palladium‐Catalyzed Coupling Reactions as Key Methods in Organic Synthesis

Palladium is known to a broad audience as a beautiful, but expensive jewellery metal. In addition, it is nowadays found in nearly every car as part of the automotive catalysts, where palladium is used to eliminate harmful emissions produced by internal combustion engines. On the other hand, and not known to the general public, is the essential role of palladium catalysts in contemporary organic chemistry, a topic which has now been recognized with the Nobel Prize for Chemistry 2010. Have a look at any recent issue of a chemical journal devoted to organic synthesis and you will discover the broad utility of palladium-based catalysts. Among these different palladium-catalyzed reactions, the so-called cross-coupling reactions have become very powerful methods for the creation of new C C bonds. In general, bond formation takes place here between less-reactive organic electrophiles, typically aryl halides, and different carbon nucleophiles with the help of palladium. Remember the situation 50 years ago, when palladium began to make its way into organic chemistry. At that time C C bond formation in organic synthesis was typically achieved by stoichiometric reactions of reactive nucleophiles with electrophiles or by pericyclic reactions. Ironically, however, oxidation catalysis was the start of today s carbon–carbon bond-forming methods: The oxidation of olefins to carbonyl compounds, specifically the synthesis of acetaldehyde from ethylene (Wacker process) by applying palladium(II) catalysts, was an important inspiration for further applications. Probably also for Richard Heck, who worked in the 1960s as an industrial chemist with Hercules Corporation. There, in the late 1960s, he developed several coupling reactions of arylmercury compounds in the presence of either stoichiometric or catalytic amounts of palladium(II). Some of this work was published in 1968 in a remarkable series of seven consecutive articles, with Heck as the sole author! Based on the reaction of phenylmercuric acetate and lithium tetrachloropalladate under an atmosphere of ethylene, which afforded styrene in 80% yield and 10% trans-stilbene, he described in 1972 a protocol for the coupling of iodobenzene with styrene, which today is known as the “Heck reaction”. A very similar reaction had already been published by Tsutomo Mizoroki in 1971. However, Mizoroki didn t follow up on the reaction and died too young from cancer. The coupling protocol for aryl halides with olefins can be considered as a milestone for the development and application of organometallic catalysis in organic synthesis and set the stage for numerous further applications. Hence, palladium-catalyzed coupling reactions were disclosed continuously during the 1970s (Scheme 1). One of the related reactions is the Sonogashira coupling of aryl halides with alkynes, typically in the presence of catalytic amounts of palladium and copper salts.

Well-Defined Iron Catalyst for Improved Hydrogenation of Carbon Dioxide and Bicarbonate

The most efficient, stable, and easy-to-synthesize non-noble metal catalyst system for the reduction of CO(2) and bicarbonates is presented. In the presence of the iron(II)-fluoro-tris(2-(diphenylphosphino)phenyl)phosphino]tetrafluoroborate complex 3, the hydrogenation of bicarbonates proceeds in good yields with high catalyst productivity and activity (TON > 7500, TOF > 750). High-pressure NMR studies of the hydrogenation of carbon dioxide demonstrate that the corresponding iron-hydridodihydrogen complex 4 is crucial in the catalytic cycle.

Integration of chemical catalysis with extractive fermentation to produce fuels

Nearly one hundred years ago, the fermentative production of acetone by Clostridium acetobutylicum provided a crucial alternative source of this solvent for manufacture of the explosive cordite. Today there is a resurgence of interest in solventogenic Clostridium species to produce n-butanol and ethanol for use as renewable alternative transportation fuels. Acetone, a product of acetone–n-butanol–ethanol (ABE) fermentation, harbours a nucleophilic α-carbon, which is amenable to C–C bond formation with the electrophilic alcohols produced in ABE fermentation. This functionality can be used to form higher-molecular-mass hydrocarbons similar to those found in current jet and diesel fuels. Here we describe the integration of biological and chemocatalytic routes to convert ABE fermentation products efficiently into ketones by a palladium-catalysed alkylation. Tuning of the reaction conditions permits the production of either petrol or jet and diesel precursors. Glyceryl tributyrate was used for the in situ selective extraction of both acetone and alcohols to enable the simple integration of ABE fermentation and chemical catalysis, while reducing the energy demand of the overall process. This process provides a means to selectively produce petrol, jet and diesel blend stocks from lignocellulosic and cane sugars at yields near their theoretical maxima.

Palladium-catalyzed carbonylative C-H activation of heteroarenes.

Transition metal catalyzed C H functionalization reactions of arenes and heteroarenes are finding increasing application in the preparation of organic building blocks and therapeutically important scaffolds. Notably, these methods can avoid the use of stoichiometric amounts of organometallic reagents along with any problems associated with their synthesis, stability, and/or functional group compatibility. Recent prominent examples include: transition metal (Rh, Pd, Ru, Ni, Cu) catalyzed arylation, alkylation, alkynylation, alkenylation, and benzylation of (hetero)arenes. In this context, the related carbonylative coupling reactions of (hetero)arenes using C H functionalization to afford carboxylic acid derivatives have been scarcely studied, and previous systems have been limited to chelation-assisted intramolecular reactions. In particular, the apparently simply synthesis of (hetero)aryl ketones from nonchelating substrates through an intermolecular carbonylative coupling reaction has not yet been reported. Among the various ways for the synthesis of (hetero)aryl ketones that have been developed, the palladium-catalyzed carbonylative coupling reactions of aryl halides with organometallic reagents has gained recent interest in modern organic synthesis (Scheme 1). 6] Typical organometallic

A General and Efficient Catalyst for Palladium-Catalyzed C−O Coupling Reactions of Aryl Halides with Primary Alcohols

An efficient procedure for palladium-catalyzed coupling reactions of (hetero)aryl bromides and chlorides with primary aliphatic alcohols has been developed. Key to the success is the synthesis and exploitation of the novel bulky di-1-adamantyl-substituted bipyrazolylphosphine ligand L6. Reaction of aryl halides including activated, nonactivated, and (hetero)aryl bromides as well as aryl chlorides with primary alcohols gave the corresponding alkyl aryl ethers in high yield. Noteworthy, functionalizations of primary alcohols in the presence of secondary and tertiary alcohols proceed with excellent regioselectivity.

Palladium catalyzed aryl(alkyl)thiolation of unactivated arenes.

A general palladium-catalyzed aryl(alkyl)thiolation of various substituted unactivated arenes is accomplished for the synthesis of diverse unsymmetrical diaryl(alkyl) sulfides in good yield employing electrophilic sulfur reagent 6 derived from succinimide. The developed strategy was coupled with intramolecular arylation of a C-H bond to afford dibenzothiphene derivatives, an important moiety in material science as organic semiconductors.

Rhodium Catalyzed Cyanation of Chelation Assisted C–H Bonds

A rhodium-catalyzed cyanation of chelation assisted C-H bonds is described employing N-cyano-N-phenyl-p-methylbenzenesulfonamide as an efficient cyanating reagent. The present method allowed the synthesis of various benzonitirle derivatives in good to excellent yield. A number of chelating groups are also effective in the present cyanation of C-H bonds. In addition, the developed methodology was applied in the formal synthesis of the isoquinoline alkaloid, menisporphine.

Efficient Synthesis of Aryl Fluorides

Selective functionalization reactions of aromatic and heteroaromatic halides with carbon, oxygen, and nitrogen nucleophiles have attracted much attention in the last decades. In addition to typical metal-catalyzed coupling reactions, direct functionalization of aryl halides through the formation of Grignard reagents offer new ways for the efficient construction of biologically interesting carboand heterocycles. Recent elegant examples include the development of LiClmediated preparation of Grignard reagents by Knochel and co-workers. Inspired by their work and our interest in functionalization reactions of aryl halides, we have been fascinated in the direct synthesis of aryl fluoride compounds from aryl Grignard reagents. Although a large number of known pharmaceutical and agrochemical products contain fluorinated arenes (Scheme 1), which enhance solubility, bioavailability, and metabolic stability compared with non-fluorinated analogues, there is no convenient and general synthetic method available for their synthesis. Commonly known methods for the introduction of a fluorine atom to arenes require relatively harsh reaction conditions. Typical examples include the direct fluorination of arenes, the Balz–Schiemann reaction of aryldiazonium salts with HBF4, and the so-called Halex exchange reaction of activated aryl halides with metal fluorides. In addition, transition-metal-promoted fluorinations have been achieved through the use of electrophilic N!F reagents such as Selectfluor or N-fluoropyridinium salts. Unfortunately, in most of these reactions stoichiometric amounts of the transition metal must be used or specific directing groups on the substrate are required. Most recently, Buchwald and co-workers developed an elegant palladium-catalyzed fluorination of aryl triflates using AgF or CsF. Our initial investigations aimed at the fluorination of 4bromoanisole (1), which is a particularly challenging substrate for nucleophilic fluorination, to give 4-fluoroanisole (2 ; Table 1). In our model reaction we converted 1 into the corresponding aryl Grignard 3 mediated by LiCl, according to the procedure developed by Krasovskiy and Knochel. We Scheme 1. Selected examples of therapeutically important aryl fluoride compounds.

Rhodium Catalyzed Direct Arylation of α-Diazoimines

An efficient rhodium catalyzed direct arylation of α-diazoimines, generated from readily accessible 1,2,3-triazole, has been accomplished for the synthesis of 2,2-diaryl enamides. The reaction involves the chemo- and regioselective insertion of rhodium azavinyl carbene into aromatic C(sp(2))-H bonds. Utility of the developed methodology was demonstrated in the synthesis of indole and tetrahydroisoquinoline frameworks.

A Novel and Convenient Synthesis of Benzonitriles: Electrophilic Cyanation of Aryl and Heteroaryl Bromides

N-Cyano-N-phenyl-p-methylbenzenesulfonamide has been used as a more benign electrophilic cyanation reagent for the synthesis of various benzonitriles from (hetero)aryl bromides via formation of Grignard reagents. Electronically different and sterically demanding aryl bromides including functionalized substrates and heteroaryl bromides are successfully cyanated in good to excellent yields. The efficiency of the present methodology is shown by the expeditious syntheses of interesting pharmaceutical intermediates. Notably, chemoselective monocyanation of dibromoarenes is also achieved.