Lactams, methylation with diazomethane

The general techniques used were also applied to the synthesis of natural alkaloids in the quebrachamine and Aspidosperma series (233). The oxidative cyclization step in the previous step proceeded in only 30-40% yield. In order to improve this process, a more reactive intermediate was used. Condensation of tryptamine with the highly reactive aldehyde-ester 529 gave the lactam 530 as a mixture of C-3 isomers in 90% yield. Lithium aluminum hydride reduction, catalytic reduction, and mesylation gave the familiar mesylate salt 486. Nucleophilic attack by cyanide ion in dimethyl-formamide produced the nine-membered ring intermediates 531 and 532. Hydrolysis and methylation with diazomethane gave vincadine (185) and... 

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. 

Methylation of Lactams with Diazomethane and IR Spectra of Lactams ... 

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

The effect of solvents on the reactions of lactams with diazomethane can be pronounced saccharin gives only A -methyl derivative in benzene solution, but in ethereal solution up to 24% of 0-methyl saccharin is formed in the still more strongly polar solvent di-... 

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. 

Cyclization to the eight-membered lactams 8 is the key step in the synthesis of other 1,5-diazo-cine derivatives.1 In the first step methylation of amides 6 with diazomethane is nonselective, providing the 0-methylated derivatives 7, which are used for the cyclization, and also the (V-methylated derivatives, which are formed as byproducts. 

Gas chromatographic methods have been successfully used for the determination of penicillin molecules bearing neutral side-chains in milk and tissues (95, 97), but cannot be used for amphoteric -lactams. Gas chromatography of penicillin residues is further complicated by the necessity for derivatization with diazomethane. This derivatization step is particularly important because it not only leads to formation of the volatile penicillin methyl esters but also improves their chromatographic properties (thermal stability and decreased polarity). Using a fused-silica capillary column in connection with a thermionic nitrogen-selective detector, excellent separation and sensitivity figures were obtained. 

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 which can be obtained from the infrared spectrum (v C—O). Unfortunately, relatively little is known of the infrared spectra of amide anions. However, 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 between 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 toward 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-1, O-methylation (2) 1680-1720 cm-1, 0- and iV-methylation, with kinetic dependence and (3) 1730-1800 cm 1, iV-methylation. The factual material in Table I is... 

Reaction of cyclic lactams with diazomethane is supposed to involve deprotonation in the first step. Treatment of (219) with diazomethane leads to the formation of A-methylated products (220) in nearly quantitative yields (Equation (27)) <848771 >. On the other hand, tetrone (221) provides O-alkylated product (222) under the same conditions (Equation (28)) <66AP(299)44i >. C-Alkyl derivative (224) is obtained by treatment of the sodium salt of (223) with methyl iodide (Equation (29)) <78TL543>. 

N-Mesyl-3a-methoxycholestan lactam (5 3)y refluxed 1 hr. with NaOH in dioxane-water under Ng, and the product isolated as the methyl ester prepared with diazomethane in ether methyl cholestan-3-one-5 -carboxylate. Y 97%.— This is a step in a reaction sequence for the introduction of angular substituents... 

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