A lactams

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

In anionic polymerization the reaction is initiated by a strong base, eg, a metal hydride, alkah metal alkoxide, organometaHic compounds, or hydroxides, to form a lactamate ... 

Compounds of type (6), (7), (8) and (9), although not strictly derivatives of a saturated heterocyclic system, will be discussed in this chapter. Our discussion of (7) begins and ends here, since oxiranethiones or a-thiolactones are apparently unknown (80AG(E)276). Little is known of (8) and its derivatives, oxiranimines or a-iminolactams. They have been postulated as intermediates in the thermal decomposition of aziridinones (a-lactams) (Scheme 1) but there is no well-established case of the isolation of an oxiranimine (80AG(E)276). 

Where the material is denoted by a single number, viz nylon 6 and nylon 11, preparation from either an co-amino acid or a lactam is indicated. The polymer nylon 66/6.10 (60 40) indicates a copolymer using 60 parts of nylon 6.6 salt with 40 parts of nylon 6.10 salt. 

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

The benzyloxy group on a lactam nitrogen was cleaved by hydrogenolysis (H2, Pd-C) or by TiCl3 [MeOH, H2O, (NH4)2C03, Na2C03]. 

The TJV spectra were measured for practically all the numerous derivatives. Beside the analytical application of these to demonstrate the position of the substituent no detailed interpretation was attempted, however. On the whole, they are similar to the spectra of analogous purine derivatives and also display a similar dependence on Despite the fact that the question of structure with regard to the lactim-lactam (or thiolactim-thiolactam) tautomerism has not been studied in detail, it can be assumed that oxygen and sulfur derivatives, at variance with the conventional way of writing the formulas, possess a lactam or thiolactam structure. This is in agreement with the views on the analogous purine derivatives. 

In the view of the present authors the involvement of an a-lactam intermediate (126) in a process reminiscent of the Pavorskii... 

Thus, the acidity oi a lactam is evidently not a reliable quantity for predicting the course of the methylation. The acidity gives information only as to the reaction velocity. In this connection the reaction course of isomethylreductone (6) is illuminating, " With diazomethane in ether containing 1 mole of water, the enolraethyl ether (7) is formed. However, if water is present only in traces, then the alcoholic hydroxyl group is selectively attacked to give 8. 

A criterion for the position of the extent of the mesomerism of type 9 is given by the bond order of the CO bond, a first approximation to W hich can be obtained from the infrared spectrum (v C=0). Unfortunately, relatively little is known of the infrared spectra of amide anions. How-ever, it can be assumed that the mesomeric relationships in the anions 9 can also be deduced from the infrared spectra of the free amides (4), although, of course, the absolute participation of the canonical forms a and b in structures 4 and 9 is different. If Table I is considered from this point of view, the intimate relationship betw-een the position of the amide band 1 (v C=0) and the orientation (0 or N) of methylation of lactams by diazomethane is unmistakeable. Thus the behavior of a lactam tow ard diazomethane can be deduced from the acidity (velocity of reaction) and the C=0 stretching frequency (orientation of methylation). Three major regions can be differentiated (1) 1620-1680 cm h 0-methylation (2) 1680-1720 cm i, O- and A -methylation, w ith kinetic dependence and (3) 1730-1800 em , A -methylation, The factual material in Table I is... 

The methylation of 4-hydroxyquinol-2-one (71) is interesting. This compound is both an enol and a lactam it forms 80 of 4-methoxyquinol-2-one (70) and 20% of 2,4-dimethoxyquinoline (73). The dimethoxy compound must be formed from 2-methoxyquinol-4-one (72) because 4-methoxyquinol-2-one (70) does not react with diazomethane. 4-Hydroxy l-methylquinol-2-one (75) yields a mixture of the 4-methoxy analog (74) and 2-methoxy-l-methylquinol-4-one (76) the proportions of the products show kinetic dependence on the concentration of the diazomethane. 

Whereas there are numerous examples of the application of the products from diastereoselective 1,3-dipolar cycloaddition reaction in synthesis [7, 8], there are only very few examples on the application of the products from metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction in the synthesis of potential target molecules. The reason for this may be due to the fact that most metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction have been carried out on model systems that have not been optimized for further derivatization. One exception of this is the synthesis of a / -lactam by Kobayashi and Kawamura [84]. The isoxazoli-dine endo-21h, which was obtained in 96% ee from the Yb(OTf)3-BINOL-catalyzed... 

Various bioisosteric replacements for a phenolic hydroxyl have been explored. One such, a lactam NH, is incorporated into the design of the 3-adrenergic blocker, carteolol O)- The fundamental synthon is carbostyril derivative K This is reacted in the usual manner with epichlorohydrin to give which is in turn reacted with t-butylamine to complete the synthesis of carteolol (3 ), a drug that appears to have relatively reduced nonspecific myocardial depressant action. Carrying this de-... 

Polyamides are produced by the reaction between a dicarboxylic acid and a diamine (e.g., nylon 66), ring openings of a lactam, (e.g., nylon 6) or by the polymerization of w-amino acids (e.g., nylon 11). The production of some important nylons is discussed in the following sections. 

Treatment of 5-aminopentanoic acid with DCC (dicyclohexylcarbodiimide) yields a lactam. Show the structure of the product and the mechanism of the reaction. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

Also the novel antifungal antibiotic (-)-PF1163B (211), isolated from Strep-tomyces sp., which features a 13-membered macrocycle incorporating both a lactone and a lactam unit, was synthesized by an RCM route (Scheme 42) [101]. While only poor results were obtained by treatment of diene 210 (containing 8% of an unidentified epimer) with catalyst A, the use of NHC catalyst C led, under the conditions outlined in the scheme, to the corresponding cyclization product in 60% yield along with 10% of a diastereomer resulting from epimer-ization in a previous step. 

Internal N-alkylation has been used to prepare the highly strained compounds a-lactams. ... 

---