Metal-catalyzed processes

From a synthetic point of view, direct alkylation of lithium and magnesium organometallic compounds has largely been supplanted by transition-metal-catalyzed processes. We will discuss these reactions in Chapter 8 of Part B. 

Large-Scale Synthesis of Thienobenzazepine Derivatives Using Two Efficient Metal Catalyzed Processes Telescoped Nitro Reduction and Intramolecular Aminocarbonylation... 

Most of the synthetic applications of organomercury compounds are in transition metal-catalyzed processes in which the organic substituent is transferred from mercury to the transition metal in the course of the reaction. Examples of this type of reaction... 

Synthetically important substitutions of aromatic compounds can also be done by nucleophilic reagents. There are several general mechanism for substitution by nucleophiles. Unlike nucleophilic substitution at saturated carbon, aromatic nucleophilic substitution does not occur by a single-step mechanism. The broad mechanistic classes that can be recognized include addition-elimination, elimination-addition, and metal-catalyzed processes. (See Section 9.5 of Part A to review these mechanisms.) We first discuss diazonium ions, which can react by several mechanisms. Depending on the substitution pattern, aryl halides can react by either addition-elimination or elimination-addition. Aryl halides and sulfonates also react with nucleophiles by metal-catalyzed mechanisms and these are discussed in Section 11.3. 

Domino transition metal-catalyzed processes can also start with a cross-coupling reaction most often, Suzuki, Stille and Sonogashira reactions are used in this context They can be combined with another Pd-catalyzed transformation, and a number of examples have also been reported where a pericydic reaction, usually a Diels-Alder reaction, follows. An interesting combination is also a Pd-catalyzed borina-tion followed by a Suzuki reaction. 

The objective of this chapter is to detail considerations that must be addressed in order to successfully marry a catalyst technology with catalyst/product separation technology. The focus of this chapter is hydroformylation, but the general principles should apply to many homogeneous precious-metal catalyzed processes. 

For homogeneous precious metal catalyzed processes, there are four major considerations. They are speed (or rate), selectivity, stability and separation. Of these four, speed is the most important since if you can obtain a high or very high reaction rate, you can use the flexibility that high rate provides by, for example, reducing reaction temperature and thereby slowing some byproduct forming reactions. 

Although numerous advantages are associated with the use of supercritical carbon dioxide (scC02) as an ecologically benign and user friendly reaction medium, systematic applications to metal-catalyzed processes are still rare. A notable exception is a recent report on the use of scC02 for the formation of industrially relevant polymers by ROMP and the eyelization of various dienes or enynes via RCM [7]. Both Schrock s molybdenum alkylidene complex 24 and the ruthe-... 

P,A/-ligand. These hybrid ligands have been found to afford superior results in various metal-catalyzed processes. In addition, their modular architecture enables systematic fine tuning of a generalized structure to suit a specific process. 

No examples of such reactions have been disclosed. Displacement of halogens on the parent heterocycle through metal-catalyzed processes have surprisingly not been reported to our knowledge on the neutral heterocycle. Recently, Suzuki-Miyaura cross-coupling reactions of imidazolium bromide 113 with various boronic acids or esters were reported <2005T6207> to proceed in good yield, without deprotonation at the C-3 position (Scheme 35). 

Enantiomerically pure sulfoxides play an important role in asymmetric synthesis either as chiral building blocks or stereodirecting groups [156]. In the last years, metal- and enzyme-catalyzed asymmetric sulfoxidations have been developed for the preparation of optically active sulfoxides. Among the metal-catalyzed processes, the Kagan sulfoxidation [157] is the most efficient, in which the sulfide is enantioselectively oxidized by Ti(OzPr)4/tBuOOH in the presence of tartrate as chirality source. However, only alkyl aryl sulfides may be oxidized by this system in high enantiomeric excesses, and poor enantioselectivities were observed for dialkyl sulfides. 

By contrast, both Ru (79% yield, 35% ee, 5h) and Ir (40% yield, 25% ee, 5h) were able to provide the corresponding chiral allyUc alcohol. The biocatalytic approach must be preferred in the presence of substrates such as functionalized ketones (i.e. 2-chloroacetophenone and 3-chloropropiophenone), with conversions of up to 95% and ee-values of 88% versus no activity for the metal-catalyzed processes. 

A special area of HP NMR in catalysis involves supercritical fluids, which have drawn substantial attention in both industrial applications and basic research [249, 254, 255]. Reactions in supercritical fluids involve only one phase, thereby circumventing the usual liquid/gas mixing problems that can occur in conventional solvents. Further advantages of these media concern their higher diffusivities and lower viscosities [219]. The most commonly used supercritical phase for metal-catalyzed processes is supercritical CO2 (SCCO2), due to its favorable properties [256-260], i. e., nontoxicity, availability, cost, environmental benefits, low critical temperature and moderate critical pressure, as well as facile separation of reactants, catalysts and products after the reaction. 

Table 1.1. Controlling factors of metal-catalyzed processes...

The starting point of our engagement in the control of metal-catalyzed processes was the idea that transition-metal chemistry is a junction point between the classical fields of chemistry (see Scheme 2.1-1). We therefore focused on the application of the approved rules, models and methods of these areas to metalorganic chemistry. On the other hand, a deeper insight into the controlling factors in metalorganic chemistry will trace back to the origins. 

Late transition metal-catalyzed processes also proved to be very useful tools for formation of the C-O bond of the 1,3-oxazine ring from the corresponding alkynes. In the presence of 1-5 mol% of a cationic gold(l) complex, A -BOC-protected alkynylamines 450 were converted to 6-alkylidene-l,3-oxazin-2-ones 451 under very mild conditions (Equation 49) <2006JOC5023>. 

The key success of these metal-catalyzed processes lies in the replacement of an unachievable carbozincation by an alternative carbometallation involving the transition metal catalyst, or another pathway such as an alkene-alkene (or alkyne) oxidative coupling promoted by a group IV transition metal complex, followed by transmetallation. An organozinc is ultimately produced and the latter can be functionalized by reaction with electrophiles. 

As noted previously, the outstanding success of orbital symmetry rules in organic chemistry (75, 242) has led to many attempts to extend these rules to organometallic chemistry and metal-catalyzed processes. These qualitative analyses based on the principle of conservation of orbital symmetry or second-order Jahn-Teller effects have been reviewed extensively (91, 142, 143, 173, 175, 179, 221, 225) and will not be considered in any detail here. 

Of the steps listed in Table 1. some are encountered more frequently, while others are less common. Transition metal catalyzed processes usually begin with oxidative addition or coordination-addition as an Entry, which is commonly followed by transmetalation or insertion in the Attachment phase. The final Detachment step is either reductive elimination, or p-hydride elimination, depending on the nature of the intermediate. 

In a series of late transition metal catalyzed processes the first step in the catalytic cycle is the coordination of the reagent to the metal atom, which is in a positive oxidation state, followed by its covalent attachment through the concomitant breaking of an unsaturated carbon-carbon bond or a carbon-hydrogen bond. These processes usually require a highly electrophilic metal centre and are frequently carried out in an intramolecular fashion. The carbometalation processes that follow a similar course, but take place only at a later stage in the catalytic cycle, will be discussed later. 

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