Carboxamides reaction with electrophiles

All attempts to lithiate 5-bromo-l,2,3-triazine and A, A -diethyl-l,2,3-triazine-4-carboxamide with LTMP at -100°C, followed by reaction with electrophiles, were unsuccessful <1998MI119>. 

Dirhodium(II) compounds are reported to be the most suitable catalysts for insertion. Selectivity is higher and yields are greater with dirhodium(II) carboxylates or carboxamidates than with copper catalysts, whereas Ru catalysts are not known to facilitate C-H insertion. As expected by a process that is basically electrophilic, electron-donating substituents that are adjacent to the site of insertion activate that center for C-H insertion ril4]. In addition to electronic influences, however, conformational effects that are basically steric in origin can also control reaction selectivity [115]. 

Amines derived from p-alkoxybenzyl-type linkers, despite not being acid cleav-able, still have synthetic utility. Anilines anchored to Wang resin, once converted into carboxamides or sulfonamides by reaction with the appropriate electrophile, can be cleaved with TFA (Figure 14.6) [34]. Sulfonamides of aliphatic amines may also be cleaved with TFA [36]. Stronger acids are generally required for acyl derivatives of amines but this can cause cleavage of the linker benzylic ether bond, leading to formation of p-hydroxybenzylated by-products. 

A number of 1,2,4-triazines can be lithiated, such as 5-methoxy-l,2,4-triazines 18, 1,2,4-tri-azine-6-carboxamides or 1,2,4-triazine 4-oxides and the thus formed lithio-l,2,4-triazines reacted with electrophiles. This reaction method has been used to introduce the following substituents into the 6-position iodo, carbaldehyde, hydroxyalkyl groups. The reaction of 5-lithio-l,2,4-triazines with electrophiles results in the formation of dimers and no substitution products are formed.44,2 9... 

This reaction showed high enantioselectivity even when (-)-sparteine was added after hthiation of the carboxamide. Also, the racemic lithium carbanion derived from the racemic tin precursor via metal exchange reaction, gave products with high enantioselectivity [Eq. (41)], whereas when the carbanion prepared from the corresponding chiral tin compound was reacted with an electrophile such as TMSCl without (-)-sparteine it yielded racemic product. These results indicate that the reaction of the lithiated 3-phenylpropionamide proceeds through an asymmetric substitution pathway. Furthermore, a warm-cool procedure and then reaction with a substoichiometric amount of an electrophile confirmed a dynamic thermodynamic resolution pathway for this reaction. 

Two relevant examples for categories A and D are presented (Schemes 26.9 and 26.10). Reaction of A,A-diethyl 2-biphenyl carboxamide 39 with i-BuLi/TMEDA (1.1 equiv) at-78°C followed by the addition of an electrophile affords C3-substituted derivatives 40 (DoM process, CIPE mechanism). In contrast, cyclization to give fluorenone 45 occurs with EDA at 0°C-rt (84%, DreM process) [ 1 34]. When an excess of LDA (4 equiv) and TMSCl (4 equiv) are premixed in THE at -78°C prior to addition of A,A-diethyl 2-biphenyl carboxamide 39 (ISQ conditions), the 3-trimethylsilyl derivative 42 is formed exclusively (65%). 

One of the early auxiliary-based carboxamides to be developed for enolate alkylations was the prolinol-derived amide 103, disclosed independently by Evans [77] and Sonnet [78] (Scheme 3.17). The corresponding enolates are sufficiently nucleophilic to participate in a wide range of alkylation reactions with activated and non-activated electrophiles. It was proposed that the high diastereoselectivity observed in the alkylation reaction arose from the chelated enolate 104. As is generally the case for amide-derived enolates, the Z-enolate is exclusively produced in the course of deprotonation. Some of... 

Activation of a C-H bond requires a metallocarbenoid of suitable reactivity and electrophilicity.105-115 Most of the early literature on metal-catalyzed carbenoid reactions used copper complexes as the catalysts.46,116 Several chiral complexes with Ce-symmetric ligands have been explored for selective C-H insertion in the last decade.117-127 However, only a few isolated cases have been reported of impressive asymmetric induction in copper-catalyzed C-H insertion reactions.118,124 The scope of carbenoid-induced C-H insertion expanded greatly with the introduction of dirhodium complexes as catalysts. Building on initial findings from achiral catalysts, four types of chiral rhodium(n) complexes have been developed for enantioselective catalysis in C-H activation reactions. They are rhodium(n) carboxylates, rhodium(n) carboxamidates, rhodium(n) phosphates, and < // < -metallated arylphosphine rhodium(n) complexes. 

An enantioselective Friedel-Crafts alkylation of pyrroles with /V-acylimincs has been reported <070L4065>. The reactions were run in the presence of chiral phosphoric acids. A novel C-H bond activation procedure was developed for the preparation of heteroarylamides including pyrrole-3-carboxamides <07CL872>. The reactions involved imine-substituted pyrroles, isocyanate electrophiles, and a rhenium catalyst. 

The synthon of the a-acrylate anion is available from a secondary a-keto carboxamide by the Shapiro reaction. The secondary a-ketoamide trisylhydrazones ate ptepar in a one-pot synthesis by reaction of the isocyanides with acid chloride, water and trisylhydrazine in sequence. In DME solvent, the hydra-zone (103) is smoothly metallated with BuLi to give Ae trianion (KH). Allylation of the trianion (104) gives the hydrazone (105). Alternatively, warming (104) up to room temperature yields the dianion (106) which can be intercepted with several electrophiles (Scheme 23). The adduct (107) is readily transformed into the rran -iodo lactone (108) stereospecifically (equation 56). This chemistry also has been applied to a new synthesis of -lactams (Scheme 24). ... 

Proton acidity in oxazole follows the order C-2 > C-5 > C-4. The use of 2-lithiooxazoles in synthesis is problematic, however, because they are in tautomeric equilibrium with their open chain form. When 2-lithiooxazole was reacted with DMF at — 75°C and the mixture was warmed to RT, oxazole-2-carbaldehyde (53) was formed quantitatively. Reaction of this product with a second equivalent of lithiooxazole did not give the expected product, but rather an unsymmetrical bis(oxa-zolyl)methanol (54) <9iJOC449> (Scheme 12). Reaction at the 4 position of lithiooxazole was found to be general for aldehydes. Less reactive electrophiles, such as, DMF, benzophenone, and ethyl formate, gave 2-substituted products, and iodobutane, benzyl bromide and ethyl carbonate did not react at all after an extended age at RT. Acylation of 2-lithio-5-phenyloxazole may be accomplished using A-methyl-7V-(2-pyridinyl)-carboxamides <84S1048>. 

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