Electron-deficient substrates

In the presence of strong bases, carbonyl compounds form enolate ions, which may be employed as nucleophilic reagents to attack alkyl halides or other suitably electron-deficient substrates giving carbon-carbon bonds. (The aldol and Claisen condensations... 

Transition metal complexes that are easy to handle and store are usually used for the reaction. The catalytically active species such as Pd(0) and Ni(0) can be generated in situ to enter the reaction cycle. The oxidative addition of aryl-alkenyl halides can occur to these species to generate Pd(II) or Ni(II) complexes. The relative reactivity for aryl-alkenyl halides is RI > ROTf > RBr > RC1 (R = aryl-alkenyl group). Electron-deficient substrates undergo oxidative addition more readily than those electron-rich ones because this step involves the oxidation of the metal and reduction of the organic aryl-alkenyl halides. Usually... 

An interesting question is whether the peroxo ligand in our [Fe (Porph)(02 )] complex is coordinated in a side-on or end-on fashion. Taking into consideration the DMSO coordination and the electrophilic potassium cation in the crown ether lying above the peroxo ligand, [Fe (Porph)(02 )] may in a way represent a model for the proposed (59) nucleophilic attack of the end-on peroxo form, with an axially coordinated solvent molecule, to an electron-deficient substrate (Scheme 14). 

Efforts with electron-deficient substrates and early marginal successes are well reviewed elsewhere. 

The eclipsed tetra-BINAP porphyrin 171 was conveniently synthesized by condensation of the meso-tetrakis(2,6-dihydroxyphenyl)porphyrin 173 with the (S)-BINAP derivative 174 in the presence of K2C03. After removal of the staggered isomer iron was inserted by addition of Fe(CO)5/I2, and the resulting Fe(III)-complex 171 was used as a catalyst (0.2%) to epoxidize a series of six styrene derivatives in the presence of an excess of PhIO. In every case the corresponding (R)-epoxides were preferentially formed in yields up to 72%. The best ee-values were obtained for the electron deficient substrates 2-nitrostyrene (80% ee) and pentafluorostyrene (74% ee), [114],... 

Electron-deficient acetylenes, silylformylation, 11, 483 Electron-deficient substrates, Pauson—Khand reaction, 11,353 Electron-deficient unsaturated bonds boron conjugate additions, 9, 214 cycloadditions to, 9, 314... 

When the reactions are carried out in the presence of electron-rich alkenes (Scheme 14.6), selective introduction of perfluoro-functionalized alkyl groups onto the heteroaromatic bases and quinones take place. This is possible because perfluoroalkyl radicals add more rapidly to alkenes than to the strongly electron-deficient substrates. These radical adducts show a reversed polar character compared to the perfluoroalkyl radicals and thus they react much more rapidly with the electron-deficient substrates, affording products with high selectivity. 

The method is remarkably versatile, and can be used for both electron-rich, and electron-deficient substrates. Unfortunately, because of the need to use peroxymonosulfate, the method is industrially limited due to the high salt loading. 

Arnone et al. studied the epoxidation of various olefins 220 with perfluorinated oxaziridine 80 (Equation 10) <1996JOC8805>. Alkyl-substituted olefins are epoxidized with this oxaziridine under particularly mild conditions. Electron-deficient substrates can also be epoxidized, and the more electron deficient the double bond is, the more severe the reaction conditions become. The reaction is chemoselective and stereoselective, with air-alkenes affording air-epoxides. Various complex and polyfunctionalized substrates of natural origin (monoterpenes, sesquiterpenes, and steroids) have been epoxidized effectively with this reagent (Table 18). 

Scheme 24 displays an example designed by Giese et al.84 The glycosyl-cobalt complex dissociates and the glycosyl radical adds to styrene. This adduct couples to the cobalt(II) species. The coupling product is not isolated and forms mainly the alkene by a formal dehydrocobaltation . The alkane probably stems from a heterolytic cleavage to a radical anion and a cobalt(III) complex, followed by protonation or a direct protonation of the coupling product because this pathway dominates for electron deficient substrates. 

Cycloaddition between electron rich 6-[(dimethylamino)methylene]amino-l,3-dimethyl uracil and various electron deficient substrates gave pyrido[2,3-i pyrimidine derivatives in a high regiospecific manner. The pyrido[2,3-i pyrimidinones 17 and their N-oxides 18, 5-deaza-5,8-dihydropterins 19 and pyrido[2,3-i (]pyrimidinone 20 were synthesized from 6-aminouracils, 6-hydroxyaminouracils, 2,6-diaminopyrimidin-4-one and 6-amino-l,3-dimethyl-5-formyluracil, respectively " . ... 

Methylation of amines in nucleotides and proteins plays important roles in biological function. Methyl transferases accept a wide range of nucleophiles such as halides, amines, hydroxyls, and enolates [reactions (a) and (b), Scheme 8.6] [42-44], For example, in the biosynthesis of novobiocin, methylation takes place at only one phenolic carbon and not the remaining three hydroxyl groups [45, 46]. On the other hand, methyl transfer to electron-deficient substrates often occurs under radical mechanisms requiring methylcobalamin as the cofactor, as shown in the biosynthesis of fosfomycin, where only one of the two enantiotopic hydrogen was replaced by the methyl group [reaction (c), Scheme 8.6] [47]. 

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. 

The contrasting behavior in the DNBF-C6H5NH2 system, where tertiary amine catalysis is not required, reflects the greater stability of a complexes formed by this highly electron deficient substrate. These results and Scheme IV indicate that the more reactive DNBF electrophile can differenti-... 

Cycloaddition between electron-rich 6-[(dimethylamino)methylene]amino-1,3-dimethyl uracil 242 and various electron-deficient substrates such as quinones 243 and coumarins 244 was considered to take place by elimination of dimethyla-mine from the respective cycloadducts, followed by oxidative aromatization in a highly regiospecific manner to give pyrido[2,3-solvent-free conditions, the times were reduced to 6-7 min and the yields were increased from 70-80% to 85-94% (04SL1179). 

The formation of several 2-aminobenzothiazoles via palladium-catalyzed, direct intramolecular oxidative C-H functionalization was recently demonstrated by Batey at the University of Toronto. The substrates used were A -aryl thioureas which in the presence of an interesting co-catalytic Pd(PPh3)4/Mn02 system under oxygen atmosphere, yielded the desired products. In terms of the mechanism, this transformation proceeded presumably through electrophilic palladation, suggested by the higher reactivity of the more electron-deficient substrates. 

The Sn reactions are often accompanied by the formation of radical species due to a single electron transfer (SET) between an electron-rich nucleophile and electron-deficient substrate. 

In 2007 Sun and coworkers reported the use of the proline derived triamine 17 in the presence of weak acids as a highly stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroalkenes (Scheme 11.16). All selected aromatic nitroalkenes gave excellent yields and selectivities, with the exception of electron-deficient substrates (Ar = 4-CN-Ph, 4-N02-Ph), which also require much longer reaction times. 

The radical alkylation of protonated heteroaromatic compounds-the so-called Minisci reaction-has been intensively investigated [2e, g, 111]. Protonated hetero-arenes are electron-deficient substrates, which react with nucleophilic radicals with high regioselectivity to yield the corresponding homolytic aromahc substitution products. For para-substituted pyridine derivatives the reaction occurs with complete regioselectivity at the 2-position, whereas for nonprotonated pyridines, arylations occur with low regioselectivity and in low yields. 

Furthermore, we reported a novel class of chiral proUnol derivatives to promote the hydrosilylation of a-imino and p-imino esters [40]. In nearly all cases, catalyst 9 was the most effective in the reduction of a range of electron-rich and electron-deficient substrates (Scheme 15.13). 

After identifying pivalanilide as the suitable amide moiety, they explored the scope of the reaction showing that the mefa-aiylation tolerated a wide range of substituents at the ortho, meta and para positions to the amide group. Different substituents in the aryl counterpart were tolerated as well, although electron-deficient substrates suffered from poorer activity. ... 

A comparison of Rh and Ru catalysts in the hydroformylation of linear butenes [4] or the strong electron-deficient substrate 3,3,3-trifluoropropene led to the conclusion that the latter are less active [5]. Moreover, in the hydroformylation of propene in comparison with Co and Rh catalysts, an inferior selectivity was noted [6]. In a competition experiment with the iridium-catalyzed hydroformylation of several a-olefins at 13 bar syngas pressure and 100 C, a related PPhj-modified Ru complex revealed no activity [7]. On the other hand, unmodified ruthenium based catalysts were shown to be more active than osmium complexes [8], thus the following rough order of reactivity results ... 

In the reaction of the strong electron-deficient substrate 3,3,3-trifluoropropene, the addition ofPPhj to Ru3(CO)i2 diminished the activity of the catalyst [5]. Noteworthy, the hydrogenation activity was lowered simultaneously. 

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