Amidation proposed mechanism

PROBLEM 17.37 In Section 17.7b, we saw how dicyclohexyl-carbodiimide (DCC) could be used as a dehydrating agent for the formation of amides from carboxylic acids and amines. Another reagent that can be used to good effect is the phosgene derivative A(A -carbonyldiimidazole (CDI). Carboxylic acids and CDI react under mild conditions to form imidazolides, 1, which then easily react with amines to give amides. Propose mechanisms for the formation of 1 from carboxylic acids and CDI, and for the formation of amides from 1 and amines. 

Scheme 4.26 Reaction of carbon dioxide with divalent Group 14 bis(silyl) amides proposed mechanism (adapted from [145])...

Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its mechanism. " Early mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCI3 followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions vide infra), and is no longer favored. 

The second proposed mechanism involves initial ring opening of the phthalimide. Alkoxide attack on one of the imide carbonyls furnishes amide anion 26. Proton transfer affords enolate 27, which undergoes Diekmann type condensation followed by aromatization to afford the requisite isoquinoline 23. 

Carboxylic acids can also be activated by the formation of mixed anhydrides with various phosphoric acid derivatives. Diphenyl phosphoryl azide, for example, is an effective reagent for conversion of amines to amides.140 The proposed mechanism involves formation of the acyl azide as a reactive intermediate. 

Figure 11 Proposed mechanism of cyclization of dehydrated NisA by NisC. The cyclization reaction shown results in the formation of the B-ring of nisin. The possible stabilization through a /3-turn-like structure via hydrogen bonding between the amide NH of Cys and the carbonyl of Dha/Dhb is shown and may explain the high stereoselectivity observed in nonenzymatic cyclizations involving four amino acids as discussed in the text. Reprinted with permission from B. Li W. A. van der Donk, J. Biol. Chem. 2007, 282, 21169-21175.

A very successful example for the use of dendritic polymeric supports in asymmetric synthesis was recently described by Breinbauer and Jacobsen [76]. PA-MAM-dendrimers with [Co(salen)]complexes were used for the hydrolytic kinetic resolution (HKR) of terminal epoxides. For such asymmetric ring opening reactions catalyzed by [Co(salen)]complexes, the proposed mechanism involves cooperative, bimetallic catalysis. For the study of this hypothesis, PAMAM dendrimers of different generation [G1-G3] were derivatized with a covalent salen Hgand through an amide bond (Fig. 7.22). The separation was achieved by precipitation and SEC. The catalytically active [Co "(salen)]dendrimer was subsequently obtained by quantitative oxidation with elemental iodine (Fig. 7.22). 

When 2,2-dichloro-3-phenylpropanal 203 is subjected to standard reaction conditions with chiral triazolium salt 75c, the desired amide is produced in 80% ee and 62% yield Eq. 20. This experiment suggests that the catalyst is involved in an enantioselec-tive protonation event. With this evidence in hand, the proposed mechanism begins with carbene addition to the a-reducible aldehyde followed by formation of activated car-boxylate XLII (Scheme 32). Acyl transfer occurs with HOAt, presumably due to its higher kinetic nucleophilicity under these conditions, thus regenerating the carbene. In turn, intermediate XLin then undergoes nucleophilic attack by the amine and releases the co-catalyst back into the catalytic cycle. 

A proposed mechanism for this transformation, provided in Scheme 42, is based on the identification of alcohol-carbene complexes by Movassaghi and Schmidt. Mesityl substituted imidazolinylidine carbene acts as a Brpnsted base as transesterification occurs to produce LXVII. Upon O N acyl transfer, the observed product is formed. The evidence provided for this mechanism includes the control experiment in which LXVII is resubjected to the reaction conditions and proceeds with amide formation. A similar mechanism has recently been reported in a theoretical study of transesterification by Hu and co-workers [139], In light of this work, it seems reasonable to suggest a similar that mechanism is operative in the transesterification reactions discussed throughout this section. 

Figure 1.28 NMR spectra obtained after saturation transfer of the P nucieus trans to amide in the [Rh(dipamp)(enamide)] diastereoisomer 103a. Direct exchange of magnetisation is observed between the atoms trans to amide in the diastereomers 103a and 103b. The arrows pointing upwards indicate the most affected resonance. The proposed mechanism of intramolecular equilibration of 103a and 103b is shown.

For the hydrogenation of a related cyclopentenyl amide substrate. Brown was able to characterize all steps of the proposed mechanism including the first alkene dihydrides of the missing type using the iridium DIPAMP catalyst [33]... 

The proposed mechanism of the boron-catalyzed amidation is depicted in the Figure. It has been ascertained by H NMR analysis that monoacyloxyboronic add 1 is produced by heating the 2 1 mixture of 4-phenylbutyric add and [3,5-bis(trifluoromethyl)phenyl]boronic acid in toluene under reflux with removal of water. The corresponding diacyloxyboron derivative is not observed at all. When 1 equiv of benzylamine is added to a solution of 1 in toluene, the amidation proceeds even at room temperature, but the reaction stops before 50% conversion because of hydrolysis of 1. These experimental results suggest that the rate-determining step is the generation of 1. 

An example of the use of DMF as CO source in the Pd-catalyzed aminocarbonylation with microwave irradiation is shown in Scheme 28. Thus, n-bromotoluene was reacted with benzylamine (4 equiv.) in the presence of Pd-dppf catalyst, imidazole, KOBu, and DMF (17equiv.) with microwave irradiation for 20min to give amide 196 in 94% yield (Scheme 28). A proposed mechanism (Scheme 28) has a close similarity to that of the aminocarbonylation of aryl bromide with formamide (see Scheme 22). However, in this process, a large excess (4 equiv.) of benzylamine was used to suppress a possible reaction involving dimethylamine generated in situ from DMF under reaction conditions. 

Fig. 18. Proposed mechanism for the reactions of lithium -butyl amide and n-butylamine with [M(CN)r,NO]2 (M = Fe, Ru, Os).

Recently an oxidative amidation protocol, employing copper (I) as a catalyst, was developed by C.-J. Li [14]. The proposed mechanism, shown in Scheme 14.1, involves nucleophilic addition of the amine free base 8 to aldehyde 7 to afford hemiaminal intermediate 9, which is then oxidized by copper(I)/t-butyl hydrogen-peroxide (Cu(l)/TBHP) to generate the desired amide products 10 [15, 16]. 

For the cine amination one would normally consider a mechanism involving the formation of thiophyne. However, several pieces of evidence lead to the rejection of the thiophyne mechanism among them, the marked dependence of product distribution on amide concentration, and the non-formation of aminated product in the reaction of 2-bromo-5-methylthiophene under the same conditions. A normal addition-elimination mechanism (2-bromo -> 3-bromo -> 3-amino) is also invalid since the conversion of 3-bromothiophene to 3-aminothiophene under the same conditions is 200 times slower than the conversion 6f 2-bromothiophene to the 3-amino compound. There is also no evidence from NMR of any initial adduct formation. Considering all these facts, the proposed mechanism (Scheme 164) for cine amination involves attack by amide ion at the /8-position of a di- or tri-bromothiophene to form an aminobromothiophene and subsequent debromination of this species. In support of this is cited the fact that the individual polybromothiophenes are converted to 3-aminothiophene by KNH2 in ammonia. Also, 4-amino-2-bromothiophene (485) has been isolated in the reaction of 2-bromothiophene with sodamide. 

The cycloaddition of carbon dioxide to A,A-diethylaminophenylacetylene leads to aminopyran-4-ones (72TL1131). Initial cycloaddition to the ynamine probably forms (422) which rearranges to the ketene. A further cycloaddition, this time at the conjugated amide, leads to the pyran-4-one (Scheme 142). Supporting evidence for the proposed mechanism includes the formation of the pyranone from the ketene (423) (72TL1135). 

Solution-state NMR studies suggest that the catalysts containing l- and D-Pro adopt p-turns and p-hairpins in solution,respectively. Reactions exhibit first-order dependence on catalyst 24, consistent with a monomeric catalyst in the ratedetermining step of the reaction. These catalysts exhibit enantiospecific rate acceleration, in comparison to the reaction rate when NMI is employed as catalyst. An isosteric replacement of an alkene for a backbone amide in a tetrapeptide catalyst (catalysts 32 and 33, Fig. 4) has lent credence to a proposed mechanism of rate acceleration [31). While catalyst 32 exhibits a fcrei=28 with substrate 27, alkene-containing catalyst 33 is not selective in this kinetic resolution and also affords a reduced reaction rate. This suggests that the prolyl amide is kinetically significant in the stereochemistry-determining step of the reaction. 

Concerning the l.STyli copolyamides (Fig. 92b), the main difference to the lTyli.y copolyamide results deals with the low temperature behaviour. Indeed, instead of the plateau of nSSA occurring for the latter series, there is an increase from - 100 °C. Such an increase of nSSA corresponds, in the proposed mechanism, to a gradual increase in the softening of the material. Indeed, in the l.STyli copolyamides there is an additional y transition, with a maximum around - 90 °C at 1 Hz, due to COaiiPh 2 amide group mo-... 

Figure 6. Proposed mechanism of the amide-knotane formation.

Tetrakis(pyridin-2-yloxy)silane, Si(OPy)4 (6), is a very mild dehydrating agent that can be employed to form amides from acids and amines at 20 °C in THF (Scheme 2), without the need to use any basic promoter such as tertiary amines or 4-(dimethylamino)pyridine. The proposed mechanism (Scheme 3) implicates an intermediate (A) formed from Si(OPy)4 and the acid (7) which reacts with the amine (8) to give the amide (9), with 2-pyridone and silica, (Si02)n, as by products.5... 

The proposed mechanism for formation of 151 is shown in (Scheme 27). Proton abstraction by the hydride base from the activated 2-position of the W-fluoropyridinum triflate yields a highly reactive carbene which undergoes attack by the acetonitrile solvent. The resulting nitrilium ylide eliminates fluoride and subsequently adds the isonitrile with cyclization. Finally, reduction by the hydride reagent and aromatization provide the imidazopyridine 151. The undesired amide 152 is a product of hydrolysis of the intermediate nitrilium compound. 

Scheme 9.27 Proposed mechanism of the amidation of unactivated esters, according to Movassaghi et al.

In the proposed mechanism of hydrolysis (16), the carboxylate anion of 13-15 or acetyl Phe is recognized by the guanidinium ion, and the Cu(n) center subsequently hydrolyzes the amide group. Both the electrostatic interaction between carboxylate and guanidinium ions and the Cu(n)-catalyzed amide cleavage would be facilitated by the microenvironment provided by polystyrene. 

The importance of the reagent on open dimers was also pointed out in the proposed mechanism of deprotonation by lithium amides and alkylation by organolithiums in carbonyl and imine chemistry (Figure 37). This... 

Problem-Solving Strategy Proposing Reaction Mechanisms 1007 Mechanism 21-8 Transesterification 1008 21-7 Hydrolysis of Carboxylic Acid Derivatives 1009 Mechanism 21-9 Saponification of an Ester 1010 Mechanism 21-10 Basic Hydrolysis of an Amide 1012 Mechanism 21-11 Acidic Hydrolysis of an Amide 1012 Mechanism 21-12 Base-Catalyzed Hydrolysis of a Nitrile 1014 21-8 Reduction of Acid Derivatives 1014... 

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