Esters unactivated

Addition of nucleophiles to both activated and unactivated alkenes is catalyzed by Pd(II). Addition of alcohols or AcOH to alkenes bearing EWGs is catalyzed by PdCl2(PhCN)2 to give the corresponding ethers and esters. The addition of an alcohol to the cyclic acetal of acrolein 82 to give the ether 83 is also possible with the same catalyst[64]. Amines add to the vinylic ether 84 to give 85, but not to simple alkenes[65]. 

The limitations of this reagent are several. It caimot be used to replace a single unactivated halogen atom with the exception of the chloromethyl ether (eq. 5) to form difluoromethyl fluoromethyl ether [461 -63-2]. It also caimot be used to replace a halogen attached to a carbon—carbon double bond. Fluorination of functional group compounds, eg, esters, sulfides, ketones, acids, and aldehydes, produces decomposition products caused by scission of the carbon chains. 

Reaction with Carbon Nucleophiles. Unactivated a2iddines react with the lithium salts of malonates or p-keto esters in the presence of lithium salts to yield 3-substituted pyttohdinones (56—59), where R = alkyl and aryl, and R = alkoxyl, alkyl, and aryl. 

There are two basic strategies for enzyme-catalyzed peptide synthesis equiUbrium- and kineticaHy controlled synthesis. The former is the direct reversal of proteolysis and involves the condensation of an amino component with unactivated carboxyl component. The latter proceeds by the aminolysis of an activated peptide ester. 

The / -(methylmercapto)phenyl ester has been prepared from an /-protected amino acid and 4-tH3SC6H40H (DCC, CH2CI2, 0°, 1 h 20°, 12 h, 60-70% yield). The p-(methylmercapto)phenyl ester serves as an unactivated ester that is activated on oxidation to the sulfone (H2O2, AcOH, 20°, 12 h, 60-80% yield) which then serves as an activated ester in peptide synthesis. ... 

Entries 8 to 15 are examples of intramolecular reactions. Entry 8 involves two unactivated double bonds and was carried out at a temperature of 280°C. The product was a mixture of epimers at the ester site but the methyl group and cyclohexenyl double bond are cis, which indicates that the reaction occurred entirely through an endo TS. 

Unactivated esters, typically alkyl esters, often show low reactivity toward lipase catalyst for transesterifications. In the case of the lipase-catalyzed polycondensation of dialkyl esters with glycols, the polymer of high molecular weight was not obtained. The molecular weight improved when vacuum conditions were used Mw reached more than 2 x 104 in the combination of diethyl sebacate and 1,4-butanediol catalyzed by lipase MM [30]. 

For the anodic substitution of unactivated CH-bonds, some fairly selective reactions for tertiary CH-bonds in hydrocarbons and y—CH-bonds in esters or ketones are available [85-87]. However, in some cases, a better control of follow-up oxidations remains to be developed. Chemically, a number of selective reactions are available, such as the ozone on silica gel for tertiary CH-bonds [88], the Barton or Hoffmann-LoefHer-Freytag reaction for y-CH-bonds [89], and for remote CH-bonds, Cprop)2NCl/H [90, 91], photochlorination of fatty acids adsorbed on alumina [92] or template-directed oxidations [93]. 

Table 24 Amidation of unactivated esters with alkyl amines...

Movassaghi and Schmidt reported that amidation of unactivated esters also occurs in the presence of carbene 3 when 1,2-amino alcohols are nsed [138], A representative sample of the range of esters 277 and amino alcohols 278 is shown in Table 24. A few snbstrates proved problematic under standard reaction conditions. 

We were not able to obtain any cycloadduct from unactivated 2-azadienes 139 and esters of acetylenedicarboxylic acid. However, we found that 139 did cycloadd to typical electron-poor dienophiles such as esters of azodicarboxylic acid and tetracyanoethylene (Scheme 62). Thus, diethyl and diisopropyl azodicarboxylates underwent a concerted [4 + 2] cycloaddition with 139 to afford in a stereoselective manner triazines 278 in 85-90% yield (86CC1179). The minor reaction-rate variations observed with the solvent polarity excluded zwitterionic intermediates on the other hand, AS was calculated to be 48.1 cal K 1 mol-1 in CC14, a value which is in the range of a concerted [4 + 2] cycloaddition. Azadienes 139 again reacted at room temperature with the cyclic azo derivative 4-phenyl-1,2,4-triazoline-3,5-dione, leading stereoselectively to bicyclic derivatives 279... 

Some 30 benzyl bromides, allyl bromide, and different esters of bro-moacetic acid were found to work well in the /V(4)-alkylation reaction. Benzyl chlorides, a-bromo acetophenones, as well as unactivated alkyl bromides, however, did not give satisfactory results. 

This and other similar cycloadditions, however, when unactivated hydrocarbons without heteroatom substituents participate in Diels-Alder reaction, are rarely efficient, requiring forcing conditions (high temperature, high pressure, prolonged reaction time) and giving the addition product in low yield. Diels-Alder reactions work well if electron-poor dienophiles (a, p-un saturated carbonyl compounds, esters, nitriles, nitro compounds, etc.) react with electron-rich dienes. For example, compared to the reaction in Eq. (6.86), 1,3-butadiene reacts with acrolein at 100°C to give formy 1-3-cyclohexene in 100% yield. 

Entry 9 in Table 3.13 is an example of a safety-catch linker, which requires activation by TFA-mediated cleavage of a tert-butyl ether. The unactivated 2-(tm-butoxyj-phenyl esters are cleaved by amines 700 times more slowly than the corresponding 2-hydroxyphenyl esters [289]. A similar linker has been described [290], in which a benzyl ether is used instead of a ferf-butyl ether. Activation of this linker by debenzy-lation was achieved by treatment with HF or HBr/TFA [290]. 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

The biosynthesis of the cyclopropane ring in natural products can occur through transfer of a methylene group from an ylide derived from S-adenosyl methionine to an unactivated olefin such as an oleic ester [468] via a copper(i) carbcne complex [469]. 

The systems described in this chapter possess properties that define supramolecular reactivity and catalysis substrate recognition, reaction within the supermolecule, rate acceleration, inhibition by competitively bound species, structural and chiral selectivity, and catalytic turnover. Many other types of processes may be imagined. In particular, the transacylation reactions mentioned above operate on activated esters as substrates, but the hydrolysis of unactivated esters and especially of amides under biological conditions, presents a challenge [5.77] that chemistry has met in enzymes but not yet in abiotic supramolecular catalysts. However, metal complexes have been found to activate markedly amide hydrolysis [5.48, 5.58a]. Of great interest is the development of supramolecular catalysts performing synthetic... 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

---