Glutarimide intermediate

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). 

That the methyl group in the less substituted isomer of the enamine (20) is axial was borne out by the work of Johnson et al. (18) in the total synthesis of the glutarimide antibiotic //-dehydrocycloheximide (24). The acylation of the morpholine enamine of 2,4-dimethylcyclohexanone (25) with 3-glutarimidylacetylchloride (26), followed by the hydrolysis of the intermediate product (27) with an acid buffer, led to the desired product in 35 % yield. The formation of the product in a rather low yield could most probably be ascribed to the relatively low enamine-type aetivity exhibited by the tetrasubstituted isomer, which fails to undergo the acylation reaction, and also because in trisubstituted isomer one of the CHj groups is axial. Since the methyl groups in the product are trans to each other, the allylic methyl group in the less substituted isomer of the enamine should then be in the axial orientation. 

Reaction of the nitrile oxide (498) with the enone (499) gave after chromatography the expected isoxazoline (500) plus some of its dehydro derivative (76TL3983). Hydrogenation of (500) using 30% Pd/SrC03 as catalyst yielded an enaminoketone (501) which was further hydrolyzed to the diketone (502 Scheme 110). This compound is a gem-dimethyl isomer of dehydrocycloheximide, a key intermediate in a previously reported synthesis of the glutarimide antibiotic cycloheximide. 

It is interesting to compare the dynamic mechanical loss compliance, /", of a MGIM copolymer of intermediate glutarimide content with that of a CMIM copolymer of similar composition, taking as a reference the PMMA response weighted by the %(mol/mol) of MMA in each considered copolymer. Thus, the temperature dependencies of /"(MGIM21) and 0.79 / (PMMA)... 

Comparing the structure of the monomer with that of the polymer as shown in Table I, we see that the polymerization of the / -carboxy-methyl caprolactam must involve isomerization of the monomer ring system. This isomerization may be described by several possible processes, all of which are characterized by reaction between the amide and acid group of the / -carboxymethyl caprolactam. Based upon the results of our studies on the structure of this polymer (5) we may eliminate confidently those processes according to which the formation of the glutarimide moiety results either by intrachain cyclization or by trans-cyclization of certain intermediate polymer structures. The former would involve a polymer formed by a conventional ring opening polymerization ... 

Dieckmann cyclization of diester 201 gave the 3-piperidone derivatives 202, a seco ergoline derivative <04JMC5620>. A stepwise [3+3] annulation was effected by sodium hydride to give glutarimide 203, which was found to be a valuable intermediate for piperidine syntheses... 

With these approaches, we elected to pursue pathways A and B because it is not trivial to build 430 in an optically enriched manner, and a useful enone version of our pivotal aza-[3+3] cycloaddition had yet to be developed. Thus, the key common intermediate 425 would be prepared by an aza-[3+3] cycloaddition of vinylogous urethane 424, which would be accessed in several steps from cw-l,3-disubstituted lactam 433 with glutarimide 431 and bromide 432 as the essential starting points (Scheme 12.107). 

Partial hydrolysis-cyclization of di[ C]nitriles in contrast produces dilabeled amine heterocycles. [2,6- C2]Glutarimides are the most common products because of their utility as intermediates to pyridines they have been prepared by several different methods in yields of up to... 

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