The hydrolysis of iminium ether intermediates formed by a nitrogen insertion sequence involving azido alcohols 1 or 2 and ketones was investigated. Ketones containing 6-12-membered rings were surveyed and shown to provide lactams and lactones in good to excellent overall yield. Reactions employing acetone or 5-nonanone gave similar results, generating analogous amides and esters. The relative amounts of lactone vs lactam produced in a given reaction were found to depend on the structures of the reactants and the pH of the basic media used to hydrolyze the iminium ethers. A mechanism accounting for the formation of each product is discussed in terms of ring strain and the protonation state of ortho ester aminal intermediates. Scheme 1 4381

Abstract:The Lewis acid-promoted reaction between a ketone and an azido alcohol is an efficient route to imidate salts. The hydrolysis of these salts is shown to generate medium to large-ring lactams and lactones in good to excellent yield. The reaction products differ according to the pH of the medium used for hydrolysis of the imidate salts.Imidate salts (iminium ethers) are ambident electrophiles that can be hydrolytically converted into a variety of useful products. 1 Classically, these compounds have been prepared from the corresponding Nhydroxylalkyl amide through a formal dehydration procedure (Scheme 1). More recently, we have demonstrated that imidate salts can also be generated in situ by the Lewis acid-promoted reactions of hydroxy azides with ketones.2-4 The addition of nucleophiles to these imidate salts affords a range of products that includes amines, enamines and ω-substituted alkyl amides. 3 Globally, this mechanistically complex process can involve kinetic addition to the cationic center and proceed directly to product (path A) or involve displacement at the terminal carbon of the azido alcohol (starred, path B). 1,3 In this paper, we show that lactones are also available from iminium ether hydrolysis and demonstrate that a measure of control can be imposed upon the reaction path (A1 vs. A2/B), resulting in enhanced utility of these heterocyclic intermediates in synthesis. In the special case of an α-bromo substituted ketone, an interesting α-amino ester synthesis is also described. Scheme 1Initial studies using cycloheptanone, 1a or 1b, 5 and BF 3 ·OEt 2 resulted in exclusive amide 2 formation when KOH was employed for imidate salt hydrolysis (Scheme 2). Alternatively, the use of NaHCO 3 resulted in the formation of lactone 3 as the major product, in addition to the expected amide 2. 6 Only amide formation was observed in our previous studies with four-to six-membered ring ketones, using either base in the work-up. [2][3][4] The difference in transannular strain associated with the lactams (standard rings, 5-7 members) vs. lactones (medium rings, 8-11 members) formed in these cases most likely accounts for the absence of lactone production. In contrast, both products from the ring expansion of cycloheptanone contain medium-to-large rings and therefore, ring strain is likely to play a less dominant role in product selection. Scheme 2Experiments with 5-nonanone and 1a (Scheme 3) illustrated similar behavior with respect to each work-up procedure, except that some ester was formed under both protocols. 6 Although previously disclosed studies with acetone and 1b showed solely amide product in 86% yield when NaHCO 3 was used, 2 we have had difficulty in repeating this result. Current work to elucidate the effect of ketone and azide structures on the distribution of acyclic products is underway. Scheme 3We decided to explore the reactivity and regiochemistry of the reaction with α-bromocyclohexanone as substrate (Scheme 4). Amide (6) was produced under KOH or NaOH work-up, along with some alkene (...

Hydrolysis of Iminium Ethers Derived from the Reaction of Ketones with Hydroxy Azides: Synthesis of Macrocyclic Lactams and Lactones.-It is shown that the reaction of azido alcohols (II) or (V) with cyclic ketones containing 7-to 12-membered rings affords lactams or lactones whose relative amounts depend mainly on the structures of the reactants and the pH of the basic media used to hydrolyze the iminium ether intermediates. A mechanism is suggested. The results are similar to those obtained earlier with cyclohexanone. All the reactions rarely give only one single product. Acyclic ketones (VIII) also lead to analogous amide and ester products. -(FORSEE, JENNIFER E.; AUBE, JEFFREY;

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.