Lactones, reaction with ammonia

Aldonamides are readily prepared by reaction of lactones with liquid ammonia (86,99,100), with ammonium hydroxide (101,102), or by bubbling ammonia gas into alcoholic solutions of the sugar lactones (103-104). Aldonamides of the tetronic adds are stable in aqueous solution (105), but penton- or hexon-amides are hydrolyzed, as shown by the change of the optical rotation of the amide solutions (106). The hydrolysis is catalyzed by acids and bases, and the product was the ammonium salt of the aldonic acid. 

A series of solid-state reactions has been explored by Kaupp et al., in which gaseous amines were reacted with aldehydes to give imines. Analogous reactions with solid anhydrides, imides, lactones or carbonates, and isothiocyanates were used to give, respectively, diamides or amidic carboxylic salts or imides, diamides, carbamic acids, and thioureas [24]. In general the yields were found to be quantitative. Ammonia and other gaseous amines, in particular methyl-amine, have also been shown to aminolyse thermoplastic polycarbonates [25]. 

Solid lactones or cyclic carbonates form linear hydroxy amides upon reaction with gaseous ammonia, methylamine, or ethylamine. For example, the compounds 277a-c and (ketonized) 279a-c are quantitatively formed at 0 °C and room temperature, respectively, without melting [12] (Scheme 39). 

In the following paragraph the nucleophilic substitution of some of the activated lactones under aqueous conditions will be discussed in detail, namely the reactions with aqueous ammonia, thereby yielding polyhydroxylated pyrrolidines (azafuranoses) and piperidines (azapyranoses). 

Reaction with ammonia and primary and secondary amines can also give two types of products, 0-hydroxyamides or amino acids (equation 49). The amide is obtained from the reaction of 0-propiolactone with ammonia in water, while the amino acid is obtained from the reaction in acetonitrile, both in good yield. 0-Lactones react very generally with both aliphatic and aromatic amines, but the type of product does not correlate with polarity of solvent or basicity of amine. Fortunately, conditions can usually be found for the formation of the desired product. 

Esters are prepared by reaction of aldonic acids or lactones with an alcohol in the presence of hydrogen chloride 80 the reaction is slower with 1,4-lactones. Amides are readily formed from lactones by reaction with liquid ammonia followed by evaporation of the solvent.81 D-Gluconamide has also been prepared by treatment of D-glucono-1,5-lactone with concentrated ammonium hydroxide and subsequent precipitation with ethanol.82 A-Substituted aldonamides may be obtained by reaction of the aldono-lactones with ethanolamine, diethanolamine, and related species.83... 

Reaction of C-5 activated pentonolactones 13) and of 2,7-diactivated heptonolactones lib, 13) with ammonia gave in both cases 6-membered imino sugars by similar formation of epoxide intermediates (Scheme 4). The 6-bromo-2,6-dideoxy-D-anz6z> 0-hexono- 1,4-lactone gave by reaction with ammonia the 7-membered lactam 14) (Scheme 4). 

Isatin reacts with ammonium hydroxide or ammonium acetate to furnish a mixture of compounds. Amongst them are isamic acid and its corresponding amide, isamide. Since 1877 there had been a discussion as to their structure, which in 1976 was finally elucidated, by Sir John Comforth on the basis of chemical and spectroscopic data228. Isamic acid can be regarded as a dimer formed by the addition/condensation of one equivalent of ammonia with two equivalents of isatin. This intermediate suffers lactonization and subsequent conversion to isamic acid by an internal nucleophilic attack, where upon the acid is converted to isamide by reaction with a second equivalent of ammonia. 1-Methylisatin reacts similarly, furnishing N-methylisamic acid (Scheme 51). 

The y-lactone ring in cardenolides has also been modified.Digitoxigenin (520) or isodigitoxigenin (521) were directly transformed into a mixture of isomeric lactams (523) by treatment with ammonia or methylamine. The lactol-amide intermediate (522) could be isolated when the reaction was performed at room temperature, and this was transformed to the lactam (523) by dilute acid. Gitoxigenin (524) reacted in an analogous way to afford the related lactams (525). From these experiments, it appears that the reaction with cardenolides gives... 

Pyrones, which are the ring-oxygen equivalents of pyridones, are simply a- and y-hydroxy-pyrylium salts from which an 0-proton has been removed. There is little to recommend that 2- and 4-pyrones be viewed as aromatic they are perhaps best seen as cyclic unsaturated lactones and cyclic p-oxy-a,P-unsaturated-ketones, respectively, for example 2-pyrones are hydrolysed by alkali, just like simpler esters (lactones). It is instructive that, whereas the pyrones are converted into pyridones by reaction with amines or ammonia, the reverse is not the case - pyridones are not transformed into pyrones by water or hydroxide. Some electrophilic C-substitutions are known for pyrones and benzopyrenes, the oxygen guiding the electrophile ortho or para, however there is a tendency for electrophihe addition to the C-C double bond of the heterocyclic ring, again reflecting their non-aromatic nature. Easy Diels-Alder additions to 2-pyrones are further evidence for diene, rather than aromatic, character. 

An exactly analogous strategy was used for the synthesis of strychnovo-line (64) from loganin (1) (Scheme 29) (38). Thus, treatment of the unsaturated lactone 297 with ammonia-saturated methanol followed by gaseous HC1 gave 7-O-acetyl-strychnovoline (298), which on reaction with metha-nolic HC1 gave 64, identical with the natural product. 

An example of a condensation reaction with diastereotopic group selectivity (see appendix) is the lactonization of either of the two racemic, C2-symmetrical 5-hydroxy-2,4,6,8-tetramethylnonanedioic acids. This reaction desymmetrizes a compound with two pairs of equivalent stereocenters (C-5 is achiral ) into a product with five different stereocenters. The trilithium salt is generated by reduction of the 2,4,6,8-tetramethyl-5-oxononanedioic acid with lithium in ammonia and then either acidified to pH 3 followed by rapid extraction of the lactones formed (kinetic control) or equilibrated at pH w 1 to the lactone mixture (thermodynamic control). Depending on the steric interactions in the chair-like transition states and in the half-chair lactone products, either kinetic or thermodynamic control leads with high diastereoselectivity to the lactone with trans-configuration at C-5 and C-6 of the tetra-hydro-2/f-pyran-2-one ring (T. R. Hoye, 1984). 

When /8-propiolactone is heated under pressure with anhydrous ammonia, /3-hydroxypropionamide is obtained. A mole of /3-propiolactone (72 g) is heated under pressure with 5.87 moles (100 g) of ammonia for 16 hr at 100 C to obtain a 50 per cent yield of crude /3-hydrox5rpropionamide, which can be purified by vacuum distillation. By a dehydration reaction, the amination of the lactone of a y-hydroxycarboxylic acid yields a stable cyclic amide or lactam, as is the case when y-butyrolactone is converted to a-pyrrolidone. However, owing to the instability of the four-membered ring, a lactam cannot be formed from ammonia and the lactone of a /8-hydroxycarboxylic acid, such as -propiolactone. When hydroxy-propionamide is dehydrated, no lactam is formed. Only unsaturated acid derivatives can be obtained, as shown in the equation below. 

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