Kinetic isotope amides

An enantioselective imino-ene reaction was developed by Lectka to provide ct-amino acid derivatives.27 Aryl alkenes (cr-methyl styrene, tetralene), aliphatic alkenes (methylene cyclohexane), and heteroatom-containing enes, all gave high yields and high ee s of the homoallylic amides (Equation (17)). The mechanism of this reaction has been proposed to proceed through a concerted pathway. This mechanism is evidenced by a large kinetic isotope effect observed in the transfer of H(D). 

These observations, along with kinetic isotope effect studies and Hammett correlation studies, support a concerted elimination by a-bond metathesis involving a four-membered transition state (Eq. 2) [23]. A large kinetic isotope effect is observed for the loss of methane from methyl amide complexes lb and lh (Eqs. 3 and 4), comparable to those observed by Buchwald and coworkers for formation of zirconium rj2-thioaldehyde complexes [25] and by Bercaw and coworkers for formation of tantalum rf- imine complexes [5a] through similar transition states. 

The diastereomers of EBTHI zirconaaziridines are formed in comparable amounts via C-H activation, but equilibrate quickly (within an hour) to yield a thermodynamic mixture of diastereomers. Grossman observed little difference in the loss of MeH vs MeD from deuterium-labeled (EBTHI)zirconium methyl amide complexes 161 (Scheme 2). Loss of MeH and of MeD lead to different diastereomers, although their relative rate will also reflect the primary kinetic isotope effect for C-H activation. Neither kxlk2 nor k3lk4 is large, and both are largely the result of isotope effects rather than diastereoselectivity [42]. 

The reactivity of a large number of amides (of widely differing structure) in acid-catalysed nitrosation has been determined (Mirvish, 1975). There appears to be no correlation between the rate constants and the basicity of the amides. In this case (Scheme 7 X = H O) it is not known what the effective rate-limiting step is. Further studies in this area would be helpful, particularly using the solvent kinetic isotope effect. 

Krantz BA, Moran LB, Kentsis A, Sosnick TR (2000) D/H amide kinetic isotope effects reveal when hydrogen bonds form during protein folding. Nat Struct Biol 7 62-71... 

Several explanations have been offered for the preference of amination in the 2-position, If aromatization of the intermediate is the rate-determining step, this behavior may be due to the fact that u-adduct 108 loses a hydride ion more readily than 109 (Scheme 43). This argument is weakened by the lack of a kinetic isotope effect in the Chichibabin amination (65CJC725). Alternatively, the amide ion may be attracted to the 2-position by an ion-dipole interaction with the 3-substituent in the addition step. For a substrate like 3-dimethylami-nopyridine (110), this is a very significant interaction (113), leading exclusively to the 2-amino product (Scheme 44) (73CHE1119). 

Amide hydrolysis in aqueous solution is also catalyzed by acid. Marlier and co-workers reported a detailed kinetic isotope effect study of the acid-catalyzed hydrolysis of formamide (Figure 7.31). The large deuterium... 

Reactions with aikynes may aiso result in the formation of cyclized products. Thus a ruthenium-catalysed reaction with aromatic amides has been used to give isoquinoline derivatives. On the basis of values of the kinetic isotope effect, A h/ d> proposed that the rate-determining step is a concerted acetate-assisted metalation-deprotonation process to yield the intermediate (30), followed by aikyne insertion and ring closure. The reaction of arylketones with alkynes may yield indenols when catalysed by rhodium cyclopentadienyl in the presence of silver and copper salts. The reaction proceeds regioselectively, so that reaction of acetophenone with 1-phenyl-1-propene... 

In agreement with this mechanism, a stopped-flow IR spectroscopic study on the metalation of iV,iV-dialkylbenzamides with s-BuLi/TMEDA [57] suggested the presence of amide-Li complex intamediates before the formation of the lithiated product. Theoretical (MNDO) evidence was also found for the formation of weakly chelated complexes suggesting that a coordination event leads to a deprotonation process [58,59]. Inter- and intramolecular kinetic isotope effect (KIE) studies also support a CIPE mechanism [60, 61]. 

In the palladium-catalysed reaction of phthalimides with mono-, di-, and tri-substituted arenes lacking a DG, it has been shown that steric effects were dominant with ort/io-aminated products being disfavoured.The reaction of arenes with N-tosyloxytrichloroethyl carbamates is catalysed by copper with a neocuproine ligand and yields amidated derivatives. Reaction is faster with electron-rich arenes and the kinetic isotope effect, value of 0.9. The suggested mechanism involves... 

Intramolecular Cyclizations.—Base-induced 1,3-bonding occurs in the conversion of (24) into (25) even though the reaction is a 1,7-elimination. A spiro-product is also obtained in the dehydration of (26) with dicyclohexyl-carbodi-imide (DCQ. The mechanism of the 1,3-elimination from 3-phenyl-propyltrimethylammonium iodide with potassium amide in liquid ammonia has been investigated. The reaction is concurrent with 1,2-elimmation and shows a nitrogen kinetic isotope effect = 1.022 + 0.001). This and deuterium-... 

This variation from the ester hydrolysis mechanism also reflects the poorer leaving ability of amide ions as compared to alkoxide ions. The evidence for the involvement of the dianion comes from kinetic studies and from solvent isotope effects, which suggest that a rate-limiting proton transfer is involved. The reaction is also higher than first-order in hydroxide ion under these circumstances, which is consistent with the dianion mechanism. 

A comparison of the kinetics of hydrolysis and isotopic exchange of amides A and B was carried out. Some of the data are given below. An interesting observation is that there is more C=0 exchange for A than for B. From this observation, and other data given, develop a stepwise mechanism for the hydrolysis of each amide and a qualitative comparison of the substituent effects on the various steps. 

Allylic amide isomerization, 117 Allylic amine isomerization ab initio calculations, 110 catalytic cycle, 104 cobalt-catalyzed, 98 double-bond migration, 104 isotope-labeling experiments, 103 kinetics, 103 mechanism, 103 model system, 110 NMR study, 104 rhodium-catalyzed, 9, 98 Allylnickel halides, 170 Allylpalladium intermediates, 193 Allylsilane protodesilylation, 305 Aluminum, chiral catalysts, 216, 234, 310 Amide dimers, NMR spectra, 282, 284 Amines ... 

Ahlberg and coworkers noted that in some cases the enantioselectivity was increased when running the deprotonations with equimolar amounts of the novel bulk bases and the chiral lithium amide113. This finding initiated a detailed mechanistic investigation using isotopically labeled compounds and multinuclear NMR spectroscopy and kinetics, to elucidate the nature of the reagents and transition states in the deprotonations. They discovered that mixed dimers 23 and 24 are formed in solution from monomers of chiral lithium amide 20 and bulk base 21 and 22, respectively (Scheme 73). 

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