Intramolecular transamidation

Scheme 6.272 Preparation of bicyclic fused azepinones by intramolecular transamidation.

Acrylamide polymers in aqueous solution undergo thermal hydrolysis and cyclic imide formation. Acrylate, acrylamide and cyclic imide functional groups were detected when a poly(acrylamide) is heated at 150°C in water. The formation of intramolecular imide has been reported in literature. Moradi-Araghi, Hsieh and Westerman reported the formation of cyclic imide in acid, neutral and slightly basic media at 90° C.7 In acidic media, imide formation is favored. In neutral and basic media, both hydrolysis to acrylate and imide formation do occur, but hydrolysis is the dominant reaction. We speculate the high conversion of amine to amide is the result of transamidation, amidation and the nucleophilic addition of the amine to the glutarimide intermediate (Reaction 1). 

Intramolecular transamidation in (3-lactam enediynes can induce concomitant Bergman type cycloaromatization. For instance, Scheme 67, amine 239, which can be stored as its hydrochloride salt in the freezer, reacts in THF at reflux in the presence of cyclohexadiene as a hydrogen donor to produce only trace amounts of the expanded lactam 240 along with aromatic compound 241 as the major compound [173]. 

Scheme 67 Intramolecular transamidation on P-lactams as a trigger of Bergman type cyclo-aromatization...

The thermally induced intramolecular transamidation of aminoethyl-substituted /3-lactams, readily obtained by the Staudinger reaction of ketenes with imines, offers a useful approach to libraries of monocyclic and fused bicyclic l,4-diazepin-5-ones (Scheme 82) <20040L3361, 1998TL9539, 2003EJ01319, 2005T1531>. The transamidation... 

Step 3 Reductive amination of the aldehyde formed in Step 2 followed by intramolecular transamidation. 

Three independent syntheses of alkaloids of the celacinnine group have been published. In the synthesis of celacinnine (117) by Wasserman et al. (104), the central reaction used is the transamidation or Zip-reaction (69,105,106). In the first part, the preparation of the nine-membered intermediate 122 was achieved by two different routes. Heating of 4-phenylazeti-dinone (123) with 2-methoxypyrroline (124) led to the bicyclic 4-oxotetra-hydropyrimidine (125). The reaction seems to proceed via the tricyclic intermediate 126 and involves an intramolecular ring opening of a /J-lactam... 

Compounds of the type 224 (R = CH3) have been prepared by catalytic hydrogenation of nitroacetoacetanilides.274a The 4-mem-bered 226a were converted by intramolecular transamidation to the corresponding diazepines.274b... 

Direct and selective conversion of esters into ketones, a fundamental reaction but difficult to achieve, has been accomplished by Ahn and co-workers [59] by use of organoaluminum-diamine complexes. The reaction of methyl benzoate with MesAl (3.1 equiv.) and A V -dimethylethylenediamine (DMEDA) (1.1 equiv.) in toluene under reflux followed by an aqueous work-up produced only acetophenone in almost quantitative yield (98 %). Notably, ketones and even aldehydes survive under the reaction conditions. A mechanistic investigation established that the conversion proceeds through transamidation and subsequent intramolecular nucleophilic attack mediated by organoaluminum complexes this provides an explanation of the need for 3 equiv. MesAl for the fast reaction (Sch. 35). 

The terminal nitrogen of the 2-hydrazinocarbonyl in 2-(hydrazinocarbonyl)-7V-phenylpyridine-3-carboxamide undergoes intramolecular transamidation by acylation at 200 °C by the 3-carboxamide group to give l.33... 

Martinez et al. have carried out several studies into the Leuckart-Wallach reaction on l-substituted-2-norbomanones.15,16 The expected products result from 2-norbonanone and (li )-Ar-(3,3-dimethyl-2-oxo-l-norbornyl)acetamine, but the reaction of (lR)-N-(7,7-dimethyl-2-oxo-l-norbornyl)acetamine gives rise to an unexpected intramolecular transamidation via a Wagner-Meerwein shift.15... 

A) may compete with the proposed intramolecular degradation process. The water and polymer concentration dependence is also partially caused by hydrolysis of phthalic anhydride, making it less likely to recombine in Step 3, and by transamidation reactions involving trace amounts of secondary amines released by dimethylacetamide (1,7). 

Aminobutyl derivative (39 R = Ph, R = H, X = NH2), derived from aminolysis of the corresponding chloride in liquid ammonia, undergoes base-mediated intramolecular transamidation, affording macrocyclic lactam (42 R = H) in 21% yield (Equation (2)) acylation of this product with cinnamoyl chloride affords (+)-dihydroperiphylline (42 R = PhCHCHCO) <86TL5I5I>. 

Treatment of A-(4-chlorobutyl) )5-lactams with ammonia results in spontaneous intramolecular transamidation of the initially formed amine, affording diazocinones (38 R = Ph, CsH, CvHij, CH2CH(C5H )OSiMe2Bu, R = H) in excellent yield (Scheme 13) <86TL5147>. 

The intramolecular transamidation of nine-membered rings has been exploited in the synthesis of macrocycles. Lactam (124), when treated with acid catalyst in refluxing xylene, gave the 13-membered ring (125) (Equation (6)) <92T3775> (see also <80TL3493 . 

An unexpected intramolecular transamidation via a Wagner-Meerwein shift after the Leuckart-Wallach reaction... 

Muxfeldt reported one of the first apphcations of the reaction in the course of a total synthesis of the alkaloid crinine (Scheme 7.24) [48]. In its key step, cydohex-enol 62 was heated with dimethylacetamide dimethyl acetal (4) to yield amide 63 in 45% yield together with substantial amounts of an elimination product (not shown). Intramolecular transamidation under forcing conditions yielded lactam 64, which was subsequentiy converted into the natural product... 

Finally, the Eschenmoser-Claisen rearrangement has found appUcations in drug synthesis. Mulzer s synthesis of the antidepressant (J )-rolipram serves as an example (Scheme 7.36) [84]. Rearrangement of chiral cinnamyl alcohol 104 gave unsaturated amide 105 with Uttle erosion of optical purity. Ozonolysis and reduction afforded alcohol 106 and set the stage for a subsequent Mitsunobu reaction with hydrazoic acid. Reduction of the azide function followed by intramolecular transamidation gave y-lactam 107, which was converted into (R)-rolipram in two straightforward steps. 

A-Formylamines can be prepared by the Leuckart reaction, a reductive amination of carbonyl compounds by reaction with formamide and formic acid. Evidence for an unprecedented intramolecular transamidation in the mechanism of enantioselective Leuckart reaction of 2-norbornanone with a (l-norbornyl)acetamide is presented. ... 

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