Intermolecular directed

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

For selected reviews encompassing intra- and intermolecular direct reductive coupling of alkynes to carbonyl partners, see [151-158]... 

Fagnou et al. reported the synthesis of mukonine (11) starting from methyl vanillate (644). This synthesis uses both a palladium(0)-catalyzed intermolecular direct arylation and an intramolecular cyclization reaction. Triflation of methyl vanillate (644) afforded the aryl triflate 645. Using a Buchwald-Flartwig amination protocol, the latter was subjected to direct arylation with 2-chloroaniline (646) to furnish the corresponding diarylamine 647. Finally, intramolecular cyclization of 647 afforded mukonine (11). To date, this is the best synthesis (three steps, 75% overall yield) available for mukonine based on commercially available methyl vanillate (644) (582) (Scheme 5.45). 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Scheme 66 A partial double bond shift in an intermolecular directed PKR...

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

The intermolecular direct arylation of simple benzenes was also evaluated [12]. Under conditions established for the fluorinated substrates, none of the desired cross-coupled product was formed. With the goal of increasing the amount of soluble base in the reaction mixture, varying amounts of different carboxylic acids were added. Both the amount and the type of acid was found to influence significantly the reaction outcome, with larger acids used in substoichiometric amounts providing superior outcomes. For example, as the steric bulk is increased from acetic acid to pivalic acid, an increase in conversion is noted. Under optimal conditions, addition of 30 mol% pivalic acid results in 100% conversion of the aryl bromide and an 82% isolated yield of benzene direct arylation is obtained. To rationalize the reactivity, it was proposed that the potassium pivalate may behave as... 

When electronic effects dominate the reactivity of an aromatic substrate, regiose-lectivities can be accomplished in intermolecular direct arylation reactions. Thus far, this approach proved predominantly applicable to the functionalization of heteroarenes with the aid of either palladium- [21], copper-, or rhodium-catalysts [22-27],... 

Lafrance M, Rowley CN, Woo TK, Fagnou K (2006) Catalytic intermolecular direct arylation of perfluorobenzenes. J Am Chem Soc 128 8754-8756... 

Recent advances in intermolecular direct arylation reactions , Campeau, L.-C., Stuart, D. R. and Fagnou, K., Aldrichimica Acta, 2007, 40, 35. 

Intermolecular direct arylations of heteroarenes with aryl halides were thus far predominantly accomplished with palladium or rhodium complexes [31, 39,75, 76], Hence rhodium catalysts proved applicable to various electron-rich heteroarenes. In contrast, less expensive and more versatile palladium catalysts allowed for direct arylations of both electron-rich and electron-deficient substrates. Generally, the problem of achieving regioselectivities in direct arylation reactions of heteroarenes is less pronounced than it is for simple arenes, since in many cases the heteroatom can be considered as an endocyclic directing group. 

Additionally, a set of tripeptide sequences was extracted from the PDB and analyzed to derive torsion histograms describing the conformational preferences of peptidic portions in ligands. Implicitly, these histograms contain the information about the conformational behavior of molecules in a structured molecular environment with varying intermolecular directional forces and dielectric conditions in the... 

Recent advances in intermolecular direct arylation reactions of heterocycles and arenas 07AA35. 

Barbas and researchers identified that the diamine la TFA salt can catalyse the asymmetric intermolecular direct aldol reactions of a,a-dialkylaldehydes with aromatic aldehydes (Scheme 9.2). The bifunctional catalytic system exhibited excellent reactivity to give products with moderate diastereo- and enantioselectivities. Notably, L-proline is an ineffective catalyst for this class of aldol reactions. The re-face attack of an enamine intermediate on an aryl aldehyde was proposed, causing the observed stereochemistry. 

Probably (5)-proline (1) is the most used organocatalyst, being applied in ample spectra of asynunetric reactions with excellent results in a variety of reaction conditions. Its application in the intermolecular direct aldol reaction marked a breakthrough in the organocatalysis research area. In this section the use of proline in different aldol processes will be divided according to the nature of the nucleophilic and electrophilic partner used. 

In 1985, Ohta and coworkers reported on intermolecular direct arylations, and probed the palladium-catalyzed direct arylations of indole derivatives with electron-... 

Scheme 1.35 Palladiumotalyzed intermolecular direct arylation (Ohta, 1985 and 1989).

A homobimetallic rhodium catalyst derived from a P,N-ligand was found to allow for intermolecular direct arylations of unfunctionalized arenes [24]. Interestingly, aryl iodides, bromides-and even chlorides-could be employed as electrophiles, and a variety of valuable functional groups was tolerated by the catalytic system (Scheme 9.12). The C—H bond functionalization of toluene yielded ortho-, meta- and para-substituted regioisomers in a ratio of 71 19 10. Based on this observation and a Hammett correlation, a mechanism proceeding through radical intermediates was suggested. 

Intermolecular direct arylations of heteroarenes, such as indoles, pyrroles or (benzo)furans, were, thus far, predominantly achieved with palladium catalysts (see Chapter 10). However, rhodium complexes proved also competent for the direct functionaUzations of various valuable heteroarenes with comparable or, in some cases, improved catalytic performance. Thus, rhodium-catalyzed C—H bond functionalizations of various N-heterocycles, were elegantly developed by Bergman, Ellman and coworkers. Here, the use of a catalytic system comprising [RhCl(coe)2]2 and PCys led to direct arylations of unprotected benzimidazoles with aryl iodides... 

Expressing the intermolecular direct Coulomb Hamiltonian in second quantization (as described in Section 2.6), namely,... 

Fagnou and co-workers succeeded to combine Heck cyclization with direct arylation in 2009. This interesting domino palladium-catalyzed Heck-intermolecular direct arylation reaction gave new access to a variety of dihydrobenzofurans, indolines, and oxindoles. A variety of sulfur-containing heterocycles such as thiazoles, thiophenes, and benzothiophene could be employed as the direct arylation coupling partner as well and resulted in yields up to 99% (Scheme 2.35). As the authors demonstrated, in addition to... 

Chelate-assisted C-H bond aminations often require the presence of an oxidant in analogy to the previously discussed C-H oxygenations. Therefore, many protocols use a mixture of amine source and oxidant as reagents in order to achieve C-N bond formation. Intermolecular directed C-H aminations have been realized with this approach by Che and coworkers (Scheme 23.36). Remarkably, this methodology is capable of employing a variety of different directing groups as well as primary amides as amine sources [129]. 

Campeau L-C, Stuart DR, Fagnou K (2007) Recent advances in intermolecular direct arylation reactions. Aldrichmica Acta 40 35-41... 

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