Basicity amidine derivatives

The exceptional basicity of phosphazenes (iminophosphoranes) has been discovered by Schwesinger [83]. The phosphazene derivatives have been proved to be chemically very stable, kinetically active and highly versatile, and the large number of these bases has been synthesized. The gas phase and solution equilibrium basicity measurements for a large number of phosphazenes are conducted by Kaljurand et al. [84], and their PA and pAia values are published in various papers. These measurements show that phosphazenes surpass in their basicity the derivatives of acychc or bicyclic guanidines, amidines and vinamidines (Table 2.11). Extraordinary basicity of phosphazenes was theoretically rationalized by Maksic et al. [85], in terms of effective resonance stabilization of protonated molecules [86]. 

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... 

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Amidines and sulfonamides have also been used as linkers for primary or secondary aliphatic amines (Entries 4, 5, and 7, Table 3.23). These derivatives are stable under basic and acidic reaction conditions and can only be cleaved by strong nucleophiles. Phenylalanine amides can be hydrolyzed by treatment with certain enzymes (Entry 8, Table 3.23), and can therefore be used for linking amines to supports compatible with enzyme-mediated reactions (CPG, some polyacrylamides, macroporous polystyrene, etc.). 

The acyclic amidines 191 and 192 gave only the corresponding kinetic products, i,e., formamides 193 and 194 respectively. The basic hydrolysis of the 7-membered amidine 195 gave only the thermodynamic product 196. However, on partial hydrolysis, 195 gave a mixture of the thermodynamic product 196 and-the kinetic product 197. The six-membered amidines 198 and 199 yielded only the thermodynamic products 200 and 201. Attempts to observe the kinetic products 202 and 203 during partial hydrolysis failed. It was further observed that the basic hydrolysis of the trifluoroacetamide derivatives 204 and 205, two precursors of the kinetic products 202 and 203, yielded directly the thermodynamic products 200 and 201. 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

Except for the abnormally low yield with lactim ethers derived from 3-carbethoxylactams with amidines depends on the stability of the reagents.120 Lactim ethers, just as aliphatic imino ethers, are labile to acidic and alkaline media, hence the yields depend on the rate of cyclization. With basic or enolizable amidines, the... 

That such a delicate balance exists between tautomers is not an obvious prediction based solely on ApK s. The 10 pK unit difference in 9 benzoate favors the amidine-carboxylic acid form by 0.6 eV. However, a simple electrostatic calculation [123] for a positive and negative charge at a salt bridge distance of 3.8 A translates into a stabilization energy of-0.50 eV in the solvent THF, which nearly offsets the stabilization of the amidine-carboxylic acid tautomer derived from the ApfQ. Electron-rich carboxylates such as benzoate are sufficiently basic that the amidine-carboxylic acid hydrogen bond interaction prevails while the interface retains its ionic nature for more acidic carboxylic acids and various sulfonic acids. 

Since the discovery of the synthesis of 1,3,5-triazine-2,4-diamines from biguanide and its derivatives,328-329 a large variety of carboxylic acid derivatives, e.g. acid chlorides,332 342,346 lactones,333 amides,334,335 imides,336,337 ortho esters,338 amidines,338 esters334, 339- 343 and acid anhydrides,332,344,345 have been used as starting materials in the preparation of these triazines (Table 8).330,331 The preferred procedure is the reaction of biguanides 1 with esters 2 in alcoholic solution, sometimes in the presence of a basic catalyst. The reaction mechanism is thought to be as indicated.341... 

With /V-acylthioamides the reaction proceeds very slowly and the products are difficult to purify. Therefore, the Af-acylthioamides 32 are first converted into the S -alkyl derivatives 33 by the reaction with alkyl halides under strongly basic conditions. The resulting A -acylthioimi-dates 33 react with amidines and guanidines in alcoholic solution in the presence of sodium alkoxide to form 2,4,6-trisubstituted 1,3,5-triazines 34 in moderate to good yields.438,439 This procedure is an extension of the synthesis of trisubstituted 1,3,5-triazines from A -acylimidates 17 and amidines (vide supra).325... 

On the other hand, more base-labile amino protecting groups were developed, thereby limiting the exposure of the 2 -0-TBDMS group to extended basic treatment. Aside from the amidine chemicals described in Section II.A.2, the main chemical used in RNA synthesis is phenoxyacetyl (PAC) [13,14,147], mainly used for the ribopurine phosphoramidites because the iV4-acetyl protection of cytidine is quite optimal. Phenoxyacetyl protecting groups and tert-hutyl or isopropyl-phenoxyacetyl derivatives [15] are considerably more labile under basic conditions. Typically, they can be quantitatively cleaved from the exocyclic amino functions after 15 min to 1 h incubation at 65°C using ammonium hydroxide-ethanol (3 1). Alternately, 2 to 4 h at room temperature also allows complete deprotection. 

The basicity of these amine derivatives is due to the construction of highly effective conjugation system after protonation under reversible conditions primitively, it is a reflection of the number of canonical forms, especially isoelectronic forms, in the resonance system (Figure 1.2). This is one of the reasons why guanidines are stronger bases than amidines [5]. 

The influence of the aryl substitution for derivatives bearing the aryl group at the functional carbon depends on the electronic nature of the aryl substituent. Smaller basicity is measured than for acetamidines. Bicychc amidines show larger basicity, compared to the most of simple alkyl derivatives, with the gas phase basicities in the following order DBU > DBD > PMDBD > DBN > 74. DBU has the largest gas phase basicity value of 243.4kcalmol . Five-membered ring amidines display smaller basicity than six- and seven-membered cyclic amidines. 

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