Lactam form

A) Keto or lactam form. (B) Enol or lactim form. 

A wide variety of /3-lactams are available by these routes because of the range of substituents possible in either the ketene or its equivalent substituted acetic acid derivative. Considerable diversity in imine structure is also possible. In addition to simple Schiff bases, imino esters and thioethers, amidines, cyclic imines and conjugated imines such as cinnamy-lidineaniline have found wide application in the synthesis of functionalized /3-lactams. A-Acylhydrazones can be used, but phenylhydrazones and O-alkyloximes do not give /3-lactams. These /3-lactam forming reactions give both cis and /raMS-azetidin-2-ones some control over stereochemistry can, however, be exercised by choice of reactants and conditions. 

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). 

H)quinazolinones, which are derivatives of the lactam form of 4-hydroxyquinazoline, are also readily obtained by boiling a solution of o-acylamidobenzoic acid in an inert solvent with the required... 

In general, electron-releasing groups (e.g. —NH2, —OH) diminish or prevent covalent hydration by decreasing the electron deficiency in the nucleus. This diminution becomes ineffective if a new kind of stabilizing resonance is facilitated by the substituent, e.g. the urea-type resonance and the 4-aminopyridine-type resonance in 2- and 6-hydroxypteridine, respectively. The reluctance of the anions of these substances to form hydrates is attributed to the stable benzenoid system, e.g. 42, in the anhydrous anion compared with the predominantly lactam form of the neutral species, e.g. 43. 

The first total synthesis of 87 was published in 1990 (90TL1523). 5-Hydroxyindole (88) was mesylated and then reduced with sodium cyanoborohydride to give an indoline which was brominated to afford the bromoindoline 89 in good yield (Scheme 33). Cross-coupling with ortho-formyl boronic acid under Suzuki conditions, followed by air oxidation of the resulting cyclized product, followed by reduction of the lactam formed with excess Red-Al gave the target compound 87. 

Indeno[l,2-rf]azepin-4-ol and its 10-bromo derivative appear to be in the lactam form 20. In base solution, however, there is UV and HNMR spectroscopic evidence for the 14k fully conjugated anions, e.g. 21.57... 

Induction of asymmetry into the /J-lactam-forming process was inefficient with acyclic imines having chiral groups on the nitrogen [19] but efficient with rigid, cyclic chiral imines (Table 3). One of these was used as a chiral template to produce highly functionalized quaternary systems (Eq. 5) [34]. 

Hydroxy-l,2,4-thiadiazoles can exist in 3-tautomeric forms (Scheme 1). Chemical evidence suggests that the OH form 4 predominates however, UV data suggest that the lactam form 5 is the major tautomer in ethanol <1996CHEC-II(4)307>. 

Table 7 Synthesis of chlorotriazolodiazines from the corresponding hydroxyl derivatives (or their lactam forms)...

Very few enzymes have been characterized as lactam-forming dehydrases. One exception is carbamoylaspartic dehydrase (EC 3.5.2.3), which catalyzes the cyclization of V-carbamoylaspartic acid to dihydroorotic acid en route to pyrimidines (this enzyme is also known as dihydroorotate amidohydrolase when it catalyzes the reverse reaction). 

Lactam-forming activity in rat liver microsomes has been demonstrated with the cyclization of 2-(carbamoyloxy)benzoates (11.139) and 2-(sulfamoyl-oxy)benzoates (11.141) (R = alkyl or aryl R = H, Cl, Br, Me) [158], Good yields (60 - 80%) of the products 11.140 and 11.142, respectively, were obtained following incubation for 20 h at 20 - 25°. Incubation at 35 - 37° yielded mostly salicylamides 11.143, i.e., the common products of ring hydrolysis. No reaction was seen with heat-inactivated microsomes, seemingly ruling out nonenzymatic cyclization. Again, similarity with Sect. 8.5.7 is clear. 

For convenience the group at C—2 of xanthylic acid is represented here as an hydroxyl group, although it actually exists in the carbonyl or lactam form. This liberty is taken with other structures throughout this chapter. 

Fig. 22 Lactams formed by cyclization of an additional nitrogen into an additional ester...

For MOT (3), four tautomeric forms (30a-30d) are considered generally (Scheme 15) one lactim and three lactam forms. 

On the basis of UV spectroscopic data of derivatives with fixed lactam and fixed lactim structures, it was established that the bands characteristic of the lactam form appear between 385 and 438 nm, while those characteristic of the lactim form are found in the range 312-360 nm, depending on the substituents (in 95% ethanol). Coumpound 9, in which the bands are shifted to the higher wavelengths because of the linearly annellated benzene ring is an exception. Most of these compounds exist predominantly in 95% alcohol as the lactim tautomer. In compound 8a, the ratio of the... 

In the isoquinolinones annellated with a benzene ring at the [/] and [/ ] stites, the lactam tautomer predominates, except for the benzo[g]iso-quinolinone (9), which exists in the lactim form [89JCR(S)340] similar to the 1,4-diphenyl derivatives [72JCS(P1)2722]. Cyclopenta[/]-isoquinoli-none is present exclusively in the lactam form in both water and 95% alcohol (75JMC399). 

FIGURE 8-9 Tautomeric forms of uracil. The lactam form predominates at pH 7.0 the other forms become more prominent as pH decreases. The other free pyrimidines and the free purines also have tautomeric forms, but they are more rarely encountered. 

Compounds containing a potential hydroxy group (Section IV,3,b) are drawn in the lactam form. References to hydroxy derivatives in the text are used for convenience and are not intended to implicate a particular tautomer. 

Lykeberg156 examined the tautomerism of 3-oxo derivative 175 and concluded that it existed in the hydroxy form. The majority of reports on 1- and 2-substituted 3-hydroxypyrazolopyridines,19-32,40,44-48-109-116-128 however, quote IR absorptions in the range 1610-1680cm- which are attributed to vc=0. Some workers have also reported absorptions due to v0 H-32 40 44 48 The presence of a significant contribution of the lactam form is more comparable with 3,4-dimethyl-5-hydroxypyrazoles258 than 3-hy droxypyrazoles.259... 

Early infrared (IR) spectroscopy studies were inconclusive some37 38 were considered to indicate that cytosine exists in the amine-lactim form (1) in the solid state, others39-41 that it exists in the amine-lactam form (2 or 3). More recent studies42-50 (for reviews, see refs. 51, 52) on cytidine, 5-halodeoxycytidines, sodium cytidylate, and polycytidylic acid in neutral H20 or D20 solution advocate, however, the structure 2 for the cytosine residue. 

The C-13 magnetic resonance spectra of the naturally occurring uracils79-81 have been interpreted in terms of the diketo structures of the compounds. Similarly the triketo structure 36 has been found81 to predominate for 1 - (/3-D-ribofuranosyl) barbituric acid by a comparison of C-13 spectra of several model nucleosides. Also in the case of 6-hydroxycytidine the equilibrium lies 81 strongly toward the diketo form 37b in comparison with the lactim-lactam form 37a. Very recent N-14... 

The aim of this section is to discuss the physicochemical properties of uracil and thymines and to give a theoretical interpretation of these properties. Since the experimental evidence indicates that uracil and thymine exist essentially in lactam form 32, our discussion will be principally restricted to this form. 

The X-ray crystallographic studies show that thiouracils and 2-thiocytosine exists in the crystalline state in forms 51 and 52, respectively, and that isocytosine exists as a mixture of two amine-lactam forms, 42 and 43. Several experimental studies on these pyrimidines in solution confirm the conclusions from the crystal. However, studies on the tautomerism of the minor pyrimidine bases are few. In a number of cases the conclusions about the dominant structures are intuitive rather than proved. We present the essential experimental data on the structure of the minor pyrimidine bases. 

IR studies38,40,510 suggested that this molecule exists in the solid state as well as in solution in the amine-lactam form 42 and 43, or as a mixture of the two forms. These studies were not able to distinguish... 

Unlike phenols (Section 26-l), structural analysis of many of the hydroxy-substituted aza-aromatic compounds is complicated by isomerism of the keto-enol type, sometimes called lactim-lactam isomerism. For 2-hydro xypyrimidine, 19, these isomers are 19a and 19b, and the lactam form is more stable, as also is true for cytosine, 15, thymine, 16, and the pyrimidine ring of guanine, 18. 

Imidic acid (40) is the lactim tautomer of an acid amide (39 lactam form). Although no substantiated claim has been put forward for the isolation of free imidic acids, imidates (41) (also... 

The optimum pH values of RNase Ta for the hydrolysis of guanosine cyclic phosphate and xanthosine cyclic phosphate are pH 7.2 and 4.5, respectively. The xanthosine cyclic phosphate may have the lactam form (-NH-CO-) susceptible to the enzyme only in the acidic medium (18). 

Lactams substituted only in the 3 position cannot be prepared by the present procedure, since the lactam formed has the nitrogen of the chlorosulfonyl isocyanate attached to the more highly substituted carbon atom of the olefinic double bond in Markownikoff fashion. 2-Azetidinones substituted in the 3 position only have been prepared by Grignard reagent-catalyzed cyclizations of esters of appropriately substituted /3-amino acids.4,5... 

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