11-membered cyclic amide

The five-membered cyclic amide pyrrolidone has achieved widespread attention in the area of heterocyclic polymers since the first preparation and polymerization reactions of l-vinylpyrrolidin-2-one (1) were reported in the early 1940s. Poly(vinylpyrrolidone) (2) and its copolymers are among the most thoroughly studied heterocyclic addition polymers (B-74MI11100). Monomer (1) is readily polymerized (B-77MI11100) both free radically and ionically (Scheme 1). The former method is by far the most important, and allows the preparation of a wide variety of copolymers. Interestingly, in the homopolymerization of vinylpyrrolidone (1), the molecular weight of the polymer obtained does not appear to be influenced by the initiator concentration or the reaction temperature. 

The structure is unusual in that it has a four-membered cyclic amide ring (/3-lactam). It was the first example to be discovered of a natural product with this ring structure. 

The synthesis is straightforward the ester 45 combines with the ketene dimer 6 with catalysis by base providing the base is not in excess. Cyclisation to give a five-membered cyclic amide occurs with more base to give 43 that actually exists as the enol 43a. 

This oxime rearranges under acidic conditions to a seven-membered cyclic amide (caprolactam), that is the monomer used in making one of the most widely used types of nylon, namely nylon-6. A more specialized polyamide, nylon-12, is made in a similar way from cyclododecane (5.82) this polymer finds applications in coating metals and in making plastic components for motor cars. 

Lactams are cyclic amides and are analogous to lactones, which are cyclic esters. In contrast to their lactone counterparts, P-lactams (i.e., four-member cyclic amides) are relatively stable. The antibiotics (penicillin G and cephalexin) are examples of P-lactams. P-Lactam hydrolysis (in presence of water or a nucleophile) is known for antibiotics [9]. P-Lactams are known to form polymers under the right conditions. (An example is ampicillin, in which the primary amine (acting as a nucleophile) attacks the lactam of another ampicillin molecule to form a dimer. A third molecule of ampicillin may attack the lactam of the dimer to form a trimer, and so on). 

A Beckmann rearrangement of the oxime in hot concentrated sulfuric acid then gives the desired seven-membered cyclic amide, s-caprolactam. The crude product forms a separate oily phase which is separated from the reaction mixture and purified by distillation under reduced pressure (b.p. 136-138°C at 10 mm m.p. 72°C). There are also several alternative routes to produce caprolactam [25]. 

The reaction of a-bromolactams with thioamides leads to condensed 4-aminothiazole derivatives (265). The reaction is applied to six-, seven-, and eight-membered cyclic amides (Equation (42)) <94JHC1545>. 

The natural function of the carboxymethylhydantoinase (E. C. 3.5.2.2) is postulated to be the hydrolysis of 5-carboxymethylhydantoin, which is described to be the product of a non-enzymatic cyclization of N-carbamoyl-i-aspartic acid123, 241 and to occur as a side-product in the metabolism of the pyrimidine nucleotide dihydroorotic acid1251. This enzyme often occurs in combination with a ureidosuccinase (E.C. 3.5.1.7)[2S1, which catalyzes the cleavage of the resulting N-carbamoyl aspartic acid to L-aspartic acid (see Fig. 12.4-5). L-5-Carboxymethylhydantoin was first isolated after incubating orotic acid, a six-membered cyclic amide, with crude cell extracts of the anaerobic bacterium Clostridium oroticum125, 261. 

The intramolecular version of this reaction gives tricyclic oxetanes such as 4 which undergoes acid-catalyzed rearrangement to give the seven-membered cyclic amide 5H4 86. The irradiation of a similar phthalimide derivative 6 gives a different product type, presumably by intramolecular oxetane formation 7 and metathetic cleavage to 888. Another side reaction results from intramolecular hydrogen abstraction, for example, 13 is formed via 12 from the imide 9 in addition to the expected main product spiroazepinedione 1189. 

Forming the six-membered ring requires more control. Protection of the ketone (say as the acetal) before reduction will give the six-membered cyclic amide. Now the amide carbonyl must be reduced with LiAlELi (p. 236 in the textbook) and the ketone deprotected. There are many good alternative answers to this problem. 

Poly(A-vinylamides) are another class of synthetic thermo-responsive polymers. Two of the most common polymers of this class are poly(Al-vinylpyrrolidone) (PVP) and poly(A-vinylcaprolactam) (PVCL) (Figure 1.3). PVCL is a water-soluble nonionic amphiphilic polymer with its basic unit comprising a seven-membered cyclic amide with a polar hydrophilic carboxyl group and an amide group connected directly to a hydrophobic vinyl chain. 

Azetidine-2-ones are four-membered cyclic amide commonly known as p-lactams. It is a well-known structural unit to synthetic and medicinal organic chemists. The pharmaceutical activity of famous antibiotics such as penicillin, cephalosporin, carbapenem, and so on containing p-lactam ring occupies 65% of the world total antibiotics market. Besides application as antibiotics, 3-lactams are also in clinical use as 3-lactamase inhibitor and cholesterol absorption inhibitor [29-31]. In recent years, p-lactams have emerged as powerful building blocks in organic synthesis [32]. Therefore, a lot of attention has been paid to the synthesis and chemistry of p-lactams [33]. 

Nitronate(47a) is not the only oxazete derivative. For example, sterically hindered nitroalkenes (42b-d) can be prepared by nitration and halogenation of readily available allenes (48). Compounds (42b-d) are rather smoothly isomerized into the corresponding four-membered cyclic nitronates (47b-d) by the first-order reaction equation (168). Storage of nitronate (47c) is accompanied by its slow transformation into acid chloride (47e) from which amide (47f) can be easily synthesized. 

The reactions of ammonia or primary amines with five-membered cyclic nitronates containing the EWG -group at the C-5 atom involve deoxygenation of the nitronate fragment, aromatization of the ring, and amidation of the ester... 

Modification of Substituents and Functional Groups of Cyclic Nitronates At an ambient temperature, four-membered cyclic nitronate containing the chloronitromethyl group at the C-3 atom is gradually transformed into the corresponding acid chloride even under solvent-free conditions, and treatment of the latter with aqueous ammonia affords amide (168) (Scheme 3.119, Eq. 1). 

This area has received much less attention in the literature than the reactivity of conjugated systems. As noted in CHEC-II(1996) <1996CHEC-II(8)345>, most of the examples studied contain one or two oxo groups in the six-membered ring and are cyclic amide tautomers of the corresponding hydroxyl compounds. 

We observed that cyclic esters (lactones) may be formed when the carboxyl electrophile and hydroxyl nucleophile are in the same molecule (see Section 7.9.1). Similarly, cyclic amides are produced when carboxyl and amine groups are in the same molecule, and are again most favoured when this results in the generation of strain-free five- or six-membered rings. Cyclic esters are termed lactones, whereas cyclic amides are in turn called lactams. The nomenclature of lactams is similar... 

The pioneering work on enantioselective [2,3]-Wittig rearrangement was carried out by Marshall and Lebreton in the ring-contracting rearrangement of a 13-membered cyclic ether using lithium bis(l-phenylethyl) amide (63) as a chiral base (equation 34). Upon treatment with a (S,S)-63 (3 equivalents) in THF at —70 to —15 °C, ether 64 afforded the enantioenriched [2,3]-product 65 in 82% yield with 69% ee. The reaction was applied in the synthesis of (+)-aristolactone (66). 

The synthesis of cis-1,4 polymers was also tried by e use of monomers with an s-cis conformation. The solid-state photopolymerization of pyridone derivatives, which is a six-membered cyclic diene amide and is a tautomer of 2-hydroxypyridine, was attempted [100]. Pyridones make hydrogen-bonded cocrystals with a carboxylic acid in the crystalline state. Because the cyclic structure fixes its s-cis conformation, if the polymerization proceeds, a cis-2,5 polymer would be obtained. Actually, however, the photopolymerization did not occur, contrary to our expectation, but [4-1-4] photodimerization proceeded when the carbon-to-carbon distance for the dimerization was small (less than 4 A) [101]. A closer stacking distance of the 2-pyridone moieties might be required for the topochemical polymerization of cychc diene monomers. 

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