Directed ortho metalation process

The disclosure of a one-pot directed ortho metalation-boronation and Suzuki-Miyaura cross-coupling of derivatized pyridines 44 to give substituted azabiaryls 45 provided an excellent protocol for the in situ utilization of pyridyl boronic acids whose isolation is known to be difficult <07JOC1588>. The disclosed method relies on the in situ compatibility of LDA and B(Oz-Pr)3 and proceeds in good to excellent yields for the multi-step process. The report details a comprehensive survey of pyridyl boronates and is expected to be of considerable value in the synthesis of bioactive molecules. 

Lithium amides add to benzaldehydes to form a-aminoalkoxides that direct ortho metalation, as shown in Scheme In a related process, the a-aminoalkoxides may be metalated by lithium-halogen ex-change. ... 

This process involves a straightforward directed ortho metallation (chapter 7) of the pyridine amide 206 and capture by the indole aldehyde 208. Without work-up, the product 209 is lithiated again and the ellipticine quinone 210 is formed in good yield.26... 

Applications in Retro-Mannich Reactions. Treatment of unprotected gramine with NIS results in smooth conversion to 3-iodoindole (eq 20). 3,4-Disubstituted indoles are obtained by combination of the retro-Mannich process with the directed ortho metalation reaction (DoM) or the Negishi cross-coupling protocol. ... 

Lithiation ortho to functional groups of arenes followed by trapping with electrophiles is an appealing synthetic methodology. The directed ortho metalation (DoM) is the reaction of an alkyllithium compound with an arene bearing a direct metalation group (DMG) that leads to an ori/jo-lithiated intermediate. The abiHty of DMGs to effect the ortho metalation process... 

The ortho substituent stabilizes the molecule by coordination to the lithium as shown in 2. This process is only possible when the lithium occupies the 2-position and so lithiation occurs exclusively at this site. Substituents that can behave in this way are known as directing metal-lation groups (DMG). The coordinating ability of a substituent varies and hence their effectiveness in directing metallation to the ortho position is variable. The process is known as directed orthometallation and is a significant development in the field of aromatic chemistry. 

So far, the only metal in sight to help us form aromatic compounds has been aluminium. Now we look at a metal that activates aromatics in an entirely different way—lithium. Lithium is introduced ortho to a ring substituent that already exists 50 and the process itself called ortho- or directed lithiation. 

Indenes, like cyclobutenones and furans, are common side-products in the reaction of chromium arylalkoxycarbene complexes with alkynes, especially internal alkynes [9]. The in-dene structure comes about by a process that is very similar to naphthol formation annula-tion to the aryl ring still occurs, but without carbon monoxide insertion, and, instead, bond formation takes place directly between an alkyne carbon and the aryl carbon ortho to the metal carbene substituent [Eq. (18)] [4]. Scheme 5-1 shows two pathways that have been suggested for this transformation beginning from the vinylcarbene intermediate 3, naphthol formation can be diverted to intermediate 8, either by direct cyclization (3 -+ 8) or through the chromacyclohexadiene (3->6- 8). Aromatization and decomplexation yield the indene [7 b, d, 43], More detailed mechanistic analyses consider the roles of the stereochemistry of 3, as an ( )- or (Z)-vinylcarbene, as well as the coordination of external ligands, in the production of indenes, naphthols, furans, cyclobutenones, and other common side-products [8 a, 9, 13, 44],... 

One possible explanation for the observed selectivity might be that the interaction of the substrate PCP with the surface of the metal accelerator occurred predominantly via the n-electron system of the aromatic ring so that all the Cl substituents were accessible to the catalyst. The ortho - para directing character of the hydroxyl substituent did not seem to explain the relatively high level of selectivity that was associated with the observed sequential dechlorination process. As an alternative explanation, the removal of bull chlorine substituents from the ring would provide relief of steric strain. The initial loss of Cl from the C-2 or C-6 position (ortho to the hydroxyl and a chlorine substituent) decreased steric strain and repulsion more than the loss of a... 

The presence of a sulfonyl group in 1-azulenyl p-tolylsulfone directs lithiation, by lithium tetramethylpiperidide, to ortho-positions. " Regioselective lithiation, at the 2- and 6-positions, has also been observed in the reaction of l-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran (THF). The metalation involves a rate-limiting deaggregation process with a dimer-based transition state. In the presence of lithium chloride, monomer-based pathways are favoured. ... 

In parallel with the directed hydroarylation of olefins, a series of papers described the formation of ketones from heteroarenes, carbon monoxide, and an alkene. Moore first reported the reaction of CO and ethylene with pyridine at the position a to nitrogen to form a ketone (Equation 18.28). Related reactions at the less-hindered C-H bond in the 4-position of an A/-benzyl imidazole were also reported (Equation 18.29). - Reaction of CO and ethylene to form a ketone at the ortho C-H bond of a 2-arylpyridine or an N-Bu aromatic aldimine has also been reported (Equations 18.30 and 18.31). Reaction at an sp C-H bond of an N-2-pyridylpiperazine results in both alkylative carbonylation and dehydrogenation of the piperazine to form an a,p-unsaturated ketone (Equation 18.32). The proposed mechanism of the alkylative carbonylation reaction is shown in Scheme 18.6. This process is believed to occur by oxidative addition of the C-H bond, insertion of CO into the metal-heteroaryl linkage, insertion of olefin into the metal-acyl bond, and reductive elimination to form the new C-H bond in the product. 

A series of arylations of olefins by C-H bond cleavage without direction by an ortho functional group has also been reported, and these reactions can be divided into two sets. In one case, the C-H bond of an arene adds across an olefin to form an alkylarene product. This reaction has been called hydroarylation. In a second case, oxidative coupling of an arene with an olefin has been reported. This reaction forms an aryl-substituted olefin as product, and has been called an oxidative arylation of olefins. The first reaction forms the same t)q)es of products that are formed from Friedel-Crafts reactions, but with selectivity controlled by the irietal catalyst. For example, the metal-catalyzed process can form products enriched in the isomer resulting from anti-Markovnikov addition, or it could form the products from Markovnikov addition with control of absolute stereochemistry. Examples of hydroarylation and oxidative arylation of olefins are shown in Equations 18.63 - and 18.64. ... 

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