Amides isomerization, nucleophilic

Examples. Either or both microwave reactors have been useful for processes such as esterification, amidation, transesterification, rearrangement, acetalization, nucleophilic substitution, hydrolysis of esters and amides, isomerization, decarboxylation, oxidation, elimination, etherification, and formation of aminoreductones. Examples of such reactions have been tabulated (2,3). 

The nucleophilic catalysis of amide isomerization, whereby the formation of a tetrahedral intermediate disrupts amide resonance and facilitates rotation about the C—N bond (Scheme 10), has hitherto remained uncharacterized. Now, two types have been demonstrated, each of them 1,8-disubstituted naphthalene derivatives. In the first. 

It has been shown that microwave irradiation speeds up the benzil-benzilic acid rearrangement and increases the yield of product. Spiro ketones of the type (223) have been found to be susceptible to nucleophilic-induced retro-Claisen condensations. These have led to molecular rearrangements that destroy spiro connectivity see Scheme 55. The rearrangements of radical anions derived from aliphatic ketones have been studied using electrochemical techniques. A model system has been unveiled in which nucleophilic catalysis of amide isomerization is characterized for... 

Whereas only one dehydrobenzene, benzyne, has been detected, two pyridynes are possible. Thus, the scheme we can write ab initio for the action of a nucleophile on the isomeric monosubstituted derivatives of pyridine involving 2,3- (26) and/or 3,4-pyridyne (31) is more complicated than that for the analogous reaction of the corresponding benzene derivative. The validity of this scheme can be checked using data available in the hterature on reactions of halogenopyridines with potassium amide and hthium piperidide involving pyridynes. 

Nevertheless, the adjacent position of the amide and acetylenic groups was used in another type of heterocyclization. The nitrogen atom in the amide group is a weak nucleophile. Therefore, the N anion should be generated by potassium ethoxide. There are two possible variants of nucleophilic addition to the triple bond. Only one takes place, i.e., the formation of y-lactam. After 7 h of heating in EtOH in the presence of KOH, amide 72 isomerized into the known isoindoline 73 in 80% yield (Scheme 128). 

Two structurally unrelated immunosuppressant drugs, cyclosporin A and FK506, have been shown to bind to separate proteins, which have in common the ability to catalyse the interconversion (8) of the cis and trans rotamers of peptidyl-proline bonds of peptide substrates. A profound change in the conformation, and hence the shape and binding properties of the protein, may result. The mechanism of this isomerization appears, on the basis of recent work (Rosen et al., 1990 Van Duyne et al., 1993 Albers et al., 1990), to involve simple twisting about the amide bond, rather than such alternatives as conversion to a C-N single bond by addition of a nucleophile to C=0.y The proteins which catalyse the reaction may be... 

In another report of Singh and Han [61], Ir-catalyzed decarboxylative amidations of benzyl allyl imidodicarboxylates derived from enantiomerically enriched branched allylic alcohols are described. This reaction proceeded with complete stereospecificity-that is, with complete conservation of enantiomeric purity and retention of configuration. This result underlines once again (cf. Section 9.2.2) that the isomerization of intermediary (allyl) Ir complexes is a slow process in comparison with nucleophilic substitution. 

Hosokawa, Murahashi, and coworkers demonstrated the ability of Pd" to catalyze the oxidative conjugate addition of amide and carbamate nucleophiles to electron-deficient alkenes (Eq. 42) [177]. Approximately 10 years later, Stahl and coworkers discovered that Pd-catalyzed oxidative amination of styrene proceeds with either Markovnikov or anti-Markovnikov regioselectivity. The preferred isomer is dictated by the presence or absence of a Bronsted base (e.g., triethylamine or acetate), respectively (Scheme 12) [178,179]. Both of these reaction classes employ O2 as the stoichiometric oxidant, but optimal conditions include a copper cocatalyst. More recently, Stahl and coworkers found that the oxidative amination of unactivated alkyl olefins proceeds most effectively in the absence of a copper cocatalyst (Eq. 43) [180]. In the presence of 5mol% CUCI2, significant alkene amination is observed, but the product consists of a complicated isomeric mixture arising from migration of the double bond into thermodynamically more stable internal positions. 

The CM of olefins bearing electron-withdrawing functionalities, such as a,/ -unsaturated aldehydes, ketones, amides, and esters, allows for the direct installment of olefin functionality, which can either be retained or utilized as a synthetic handle for further elaboration. The poor nucleophilicity of electron-deficient olefins makes them challenging substrates for olefin CM. As a result, these substrates must generally be paired with more electron-rich crosspartners to proceed. In one of the initial reports in this area, Crowe and Goldberg found that acrylonitrile could participate in CM reactions with various terminal olefins using catalyst 1 (Equation (2))." Acrylonitrile was found not to be active in secondary metathesis isomerization, and no homodimer formation was observed, making it a type III olefin. In addition, as mentioned in Section 11.06.3.2, this reaction represents one of the few examples of Z-selectivity in CM. Subsequent to this report, ruthenium complexes 6 and 7a were also observed to function as competent catalysts for acrylonitrile... 

Dyong and Bendlin52 pointed out the possibility of functionalization of sorbic acid at C-3, -4, and -5 in the desired way. Introduction of two hydroxyl groups, at CA and C-5, may be accomplished stereospecifi-cally by means of cis-hvdroxylation, or by intermediation of an epoxide. Michael-type addition of a nucleophile to C-3 of the conjugated double-bond provides the possibility of obtaining all four diastereo-isomeric products. In this way, N-acetyl-DL-acosamine (137, 3-acet-amido-2,3,6-trideoxy-DL-arabmo-hexopyranose) was synthesized from 133 (obtained from the epoxide 129 in an aluminum chloride-catalyzed reaction with acetone). The amide 134 wasN-acetylated and... 

By the action of phenyllithium, pyridazine is converted to adduct 100 (Table XVI), resulting from nucleophilic attack at position 3.34 The structural assignment is based upon H- and 13C-NMR, starting with pyridazine and its 4,5-dideutero derivative. The site of attachment of the phenyl group is other than that observed with the amide ion in ammonia (C-4). Analysis of the products obtained after hydrolysis and oxidation indicates the presence of nearly 5-6% of 4-phenyIpyridazine. Although this finding implies the formation of a small amount of the isomeric adduct 101, there is no NMR evidence for it. However, both isomeric adducts can be detected when the reaction is carried out in the presence of TMEDA or tetrahydrofuran at a lower temperature. The chemical shift values of adduct 101 are closely similar to those of the amino analog 29. 

Intramolecular catalysis of amide bond isomerization is believed to play a key role in the folding of several proteins and this process has now been demonstrated experimentally including evidence for an H-bond between the side-chain and the prolyl Na in a cis-proline peptidomimetic.143 The amide (178) and the ester (179) have been used as substrates for these studies. Support for intramolecular nucleophilic attack... 

A variation on the aryne mechanism for nucleophilic aromatic substitution (discussed above, Scheme 2.8) is the SrnI mechanism (see also Chapter 10). Product analysis, with or without radical initiation or radical inhibition, played a crucial role in establishing a radical anion mechanism [21]. The four isomeric bromo- and chloro-trimethylbenzenes (23-X and 25-X, Scheme 2.9) reacted with potassium amide in liquid ammonia, as expected for the benzyne mechanism, giving the same product ratio of 25-NH2/23-NH2 = 1.46. As the benzyne intermediate (24) is unsymmetrical, a 1 1 product ratio is not observed. 

One of the characteristics of reactions involving benzyne intermediates is that the nucleophile can bond to the same carbon to which the leaving group was bonded, or it can bond to the carbon adjacent to the one to which the leaving group was bonded. This often results in the formation of isomeric products when substituted aromatic halides are used. For example, the reaction of yo-bromotoluene with sodium dimethyl-amide in dimethylamine as the solvent gives a 50 50 mixture of the meta and para... 

The recent synthesis of furans via isomerization of terminal epoxyalkynes catalysed by RuCl(Tp)(MeCN)2 in the presence of a base at 80 °C in 1,2-dichloroethane is explained by a related intramolecular nucleophilic addition of the oxygen atom of the epoxide onto the a-carbon atom of a ruthenium vinylidene intermediate (Scheme 8) [33]. This reaction is specific of terminal alkynes and tolerates a variety of functional groups (ether, ester, acetal, tosyl-amide, nitrile). 

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