Basicity amidines

Reactions. Although carbapenems are extremely sensitive to many reaction conditions, a wide variety of chemical modifications have been carried out. Many derivatives of the amino, hydroxy, and carboxy group of thienamycin (2) have been prepared primarily to study stmcture—activity relationships (24). The most interesting class of A/-derivatives are the amidines which are usually obtained in good yield by reaction of thienamycin with an imidate ester at pH 8.3. Introduction of this basic but less nucleophilic moiety maintains or improves the potency of the natural material while greatiy increasing the chemical stabiUty. Thus /V-formimidoyl thienamycin [64221-86-9] (MK 0787) (18), C 2H yN204S, (25) was chosen for clinical evaluation and... 

A -Imidazolines (294 Z = NH) are cyclic amidines and exhibit the characteristic resonance stabilization and high basicity. A -Oxazolines (294 Z = 0) are cyclic imino ethers, and A"-thiazolines (294 Z = S) are imino thioethers both are consequently easily hydrolyzed by dilute acid. 

This reaction is believed to proceed via an amidine (34) and it has been shown that the reactivity of the nitrile group toward nucleophiles is a more important factor than amine basicity in controlling cyclization. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

Furthermore we found that kasugamycin forms a chelate compound with basic cupric carbonate (7), which is stable to acid and unstable to heat and base. This evidence together with the results obtained above strongly supports the amidine structure (13) for kasugamycin. Finally the amidine compound was successfully prepared by the reaction of kasuganobiosamine with the diethyl ester of oxalimidic acid (14) and... 

The zinc complex formed with V,V -diphenylformamidinate is structurally analogous to the basic zinc acetate structure, as [Zn4(/i4-0)L6], and the basic beryllium acetate structure. It is prepared by hydrolysis of zinc bis(diphenylformamidinate).184 Mixed metal zinc lithium species were assembled from dimethyl zinc, t-butyl lithium, V.iV -diphenylbenzamidine and molecular oxygen. The amidinate compounds formed are dependent on the solvent and conditions. Zn2Li2 and... 

The charges of the molecule are important for binding. When the amidine group accepts a proton and becomes an amidinium ion, noformycin and amidinomycin become biscationic and bind strongly to AT sequences. These two molecules have large pKa values at both basic sites and, as such, are biscationic at physiological pH. 

The general topic of the basicity of amidines has been recently covered in a chapter74 in the book The Chemistry of Amidines and Related Compounds. Here, the general scheme rationalizing the dependence of basicity on the nature of the substituents is outlined. 

The basicity of compounds containing the amidino group N=C—N depends on the substituents at the three sites (both nitrogens and the amidino carbon atom) and the protonation site is the imino nitrogen atom75. It has been shown76 that, at any of the three sites, in the series of monosubstituted amidines, their pKa values obey Hammett s equation. 

The derivatization of a basic function is exemplified by the amidine peptidomimetic of structure 8.156 (R = Rr = H), an inhibitor of the platelet membrane glycoprotein GPIIbIIIa [202], The compound is a zwitterion at physiological pH and showed limited oral bioavailability. A double prodrug... 

A,A-Dialkylformamide acetals (7) react with primary amines to give the corresponding amidines (8). Kinetics of the reaction of a range of such acetals with ring-substituted anilines—previously measured in neutral solvents such as methanol or benzene —have been extended to pyridine solution. In pyridine, the reactions are irreversible, with first-order kinetics in each reactant, and mechanistically different from those in non-basic solvents. Two mechanisms are proposed to explain Hammett plots for a range of anilines, in which the p value switches from negative to positive at a cr value of ca 0.5. The pyridine solvent substantially enhances the rate in the case of very weakly basic anilines. 

The enhanced basicities of acetamidine [28] and amidines with conjugated double bonds linking the two nitrogen atoms [29] are... 

The alternative possibility of protonation of amidines on the amino-nitrogen depends on its basicity, after its lone pair of electrons has been localized. This localization energy is not known and neither is the inductive effect of the residue attached to the amino-nitrogen in [36], but an amino-nitrogen attached to an -hybridized carbon... 

The even greater basicity of guanidine (p/iLa = 13-6) as compared with amidines is due to an even greater resonance stabilization of the cation, since three equivalent resonance structures enter into resonance [6]. The base itself resonates between three nonequivalent structures [37], and has according to Pauling (1939,... 

The A-nitration of the furazan-based heterocycle (29) has been reported. The corresponding tetranitramine (30) is an unstable substance, but obtained on treating (29) with either trifluoroacetic anhydride (TFAA) in nitric acid or dinitrogen pentoxide in nitric acid. In this case the furazan rings stabilize the 1,4,5,8-tetraazadecalin structure and further reduce the basicity of the amidine amino groups. A number of other furazan and nitrogen-rich nitramines... 

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