Mannich bases hydrolysis

In Sect. 11.4, we examined hydrolytic attack at sp3 C-atoms rendered more electrophilic by the presence of one or more halogen substituents. In a logical follow-up, the present section presents the hydrolysis of Mannich bases [78], L e., compounds that contain the X-CH2-N moiety, where an sp3 C-atom is made more electrophilic by the presence of two flanking heteroatoms, one of which is an N-atom. 

These moieties are found mainly in compounds that are potential prodrugs and generally undergo rapid nonenzymatic hydrolysis, as exemplified by the following overall reaction of an N-Mannich base ... 

As with the O-Mannich bases discussed above, the rate of nonenzymatic hydrolysis of N-Mannich bases depends on factors such as steric hindrance and electrophilicity of the sp3 C-atom. A rather large number of studies have been published on the value and properties of N-Mannich bases as potential prodrugs for amines, amides, and imides [80] [82] [88] [89], Here, we first review available reactivity data and then discuss selected examples of medicinal relevance. 

Table 11.1. Chemical Hydrolysis of (V-Mannich Bases of Model and Medicinal Amides at pH... 

Oxazolidines are five-membered cyclic ft-Mannich bases, some of which have, indeed, been examined as potential produgs of /l-amino alcohols of medicinal relevance such as ephedrines and /3-blockers. For example, 3,4-dime-thyl-5-phenyloxazolidine (11.106), the oxazolidine of ephedrine (11.107) undergoes hydrolysis to ephedrine and formaldehyde slowly at pH 1 and 12, but very rapidly in the neutral pH range (tm < 1 min at 37°) [135], Interestingly, the equilibrium reached between the reactants and products of hydrolysis was markedly pH- and concentration-dependent. However, despite its poor stability in aqueous solution, the oxazolidine was delivered through human skin significantly faster than ephedrine when applied as 1% aqueous solutions of pH 7 - 11. The lower basicity of the oxazolidine (pKa 5.5) compared to that of ephedrine (pKa 9.6) may explain the efficient skin permeation. 

Oxazolidin-5-ones (11.110) are structurally related to oxazolidines, combining the motifs of a lactone and an O-Mannich base. These derivatives have already been discussed in Sect. 8.7.5. However, they serve here as a transition to [3,1 ]benzoxazepin-4-ones as an example of potential prodrugs. Thus, [3,l]benzoxazepin-4-one derivatives (11.111, R = H or Me, R = H, Me, Et, or Ph) were prepared from diclofenac (11.112) [137]. These prodrugs were stable for at least a few hours in simulated gastric juice, but, when administered to rats elicited an anti-inflammatory response comparable to that of diclofenac. One compound (11.111, R = Me, R = Et) was even more active than diclofenac without producing the gastric mucosal injury (ulcers) caused in all rats by diclofenac itself. Here again, there was no indication of whether the mechanism of hydrolysis is chemical or enzymatic. 

Cyclic. S -Mannich bases are rarely encountered in medicinal chemistry. The (R)-thiazolidine-4-carboxylic acids (11.113, Fig. 11.15), which are used as derivatives and chemical delivery systems for L-cysteine (11.114), provide an excellent example of S-Mannich bases. These compounds underwent activation by two distinct mechanisms, directly by nonenzymatic hydrolysis to cysteine and the original aldehyde (Fig. 11.15, Pathway a), and oxidatively (Pathway b) [138]. The latter route involved first oxidation by mitochondrial enzymes to the (f )-4,5-dihydrothiazole-4-carboxylic acid (11.115), followed by (presumably nonenzymatic) hydrolysis to /V-acylcysleine, and, finally, cytosolic hydrolysis to cysteine (11.114). 

Some cyclic AT-Mannich bases have also been reported, for example, the imidazolidin-4-ones (11.116) that were investigated as potential prodrugs of peptides (11.117) [141], The imidazolidin-4-ones, prepared by allowing the peptide to react with acetone under dehydrating conditions, are bases with pKa values of 3 - 4. For most of the derivatives, hydrolysis is spontaneous the protonated form (i.e., at pH < 2) reacts ca. 10 - 30 times slower than does the neutral form (pH > 6). Very large differences in reactivity were noted,... 

Bundgaard, H. and M. Johansen. 1982. Kinetics of hydrolysis of tpHiaJe (An ureid J-Mannich base with platelet antiaggregant activity) in aqueous solution and in plasfon ]. Pharm. Chem., Sci. Ed. 10 139-145. 

First of all, the steric hindrance may seriou,sly affect yield and/or stability of the product, when bulky substituents arc bound to the amine rcagent. Second, complications may arise, as we have seen before, with polyfunctional amines, mainly ammonia and primary amines, due to the pos.sibilily that the unrcacted hydrogen atoms of the amine may undergo further reaction with formaldehyde, thus producing undesired by-products. Similarly, the use of secondary bifunctional amines, such as piperazine, always leads to a bis-Mannich base, due to reaction of both amino groups. Attempts to limit the reaction to only one amine function, as well as hydrolysis of the Mannich product obtained from aminomethylation of mono-N-acylpiperazines, invariably gives the di.substituted piperazine 23. ... 

Although characterized by a quite complex mechanism, the deamination of acetylenic Mannich bases by lithium-alkyF yields interesting substituted acroleins R—CH=CH—CHO, that is, the isomeric form of the corresponding acetylenic hydroxymethyl derivatives R—C C—CH2OH, as a consequence of alkync metallation followed by hydrolysis. 

As far as the reactivity of the above-described Mannich bases is concerned, studies of prcxlucts 469 indicate a much better resistance to alkaline than to acid hydrolysis the nature of the nucleoside also plays a role, as the cytidine derivatives arc much more stable than the purine derivatives. Similar investigations have been madc into the deaminomethylation of Mannich bases of type 466. 

Hydrolysis and hydration—Hydrolysis of functional groups present in Mannich bases is best carried out under acidic conditions in order to improve the stability of the base. Hydrazine has been used in the hydrolysis of phthaiimidc derivatives to obtain products having a primary amino group (see also Fig. 15, Chap. I). The triple bond of acetylenic Mannich bases has been subjected to the addition of water in the presence of mercury salts with the aim of producing P- abed aminoketoncs (Table 30). 

C-Mannich bases deriving from hydrogen cyanide make it possible to obtain, upon hydrolysis of the cyano group, a-amino acids 516, which are employed largely as complexants the well-known ethylenediaminetetraacetic acid (EDTA) is the main representative of this group of compounds. 

It is noteworthy that under certain conditions the mono-Mannich bases are also capable of generating carbocations. Thus on heating compound 182b with methyl iodide, it is converted into the spiro compound 215. The possible mechanism involves a spontaneous elimination of /V-rncthy I piperidine from the intermediate ammonium salts, e.g. 237, and formation of carbocations 211 and 217 as shown in Scheme 44 (cf. Scheme 39)193. Due to the anhydrous media, the immonium salt 238 can be isolated before its hydrolysis. 

Mannich base prodrugs are regenerated by chemical hydrolysis (Section 2.8) without enzymatic catalysis (30). Various other chemical approaches can be used to achieve increased skin permeability by enhancing both water solubility and lipid solubility (31). 

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