Amidines, fluoro

Fluoroethyl fluoroacetate is a compound of considerable toxicity. Its l.c. 50 for rabbits (inhalation) is 0-05 mg./l., i.e. about half as great as for M.F.A. It is therefore placed in class A. Other factors apart from hydrolysis to fluoroethanol and fluoroacetic acid appear to be operative, and it seems that the molecule is toxic per se. The related fluoroacetylimino-2-fluoro-ethyl ether hydrochloride, [CH2F C( NH2) O CH2 CH2F]+CT, is also placed in class A. This is understandable as it is readily hydrolysed by water to 2-fluoroethyl fluoroacetate. Other fluoroacetylimino ether hydrochlorides containing, however, only one fluorine atom fall into class B, as does also fluoroacet-amidine hydrochloride itself. 

When perfluoro-2-methylpent-2-ene reacts with amidine, the products may be vinylamidine, fluoropyrimidine, or hydroxypyrimidine depending on the reactivity of the amidine and on the presence of a catalyst as well as reaction time. In moderately polar media such as diethyl ether, the initial product is vinylamidine, promoting subsequent cyclization and dehydrofluorination the products of these transformations may be isolated and characterized. Meanwhile, other transformations occur with comparable rates. Therefore, the reaction in diethyl ether may not be used for the synthesis of fluoro-pyrimidines. However, hydroxypyrimidine may be obtained under these conditions with a yield of up to 60%. Analogous results were obtained when the reaction was conducted in Freon-113 (97IZY2024). 

An electron-deficient carbon bearing a trifluoromethyl group becomes part of an imidazole ring when Schiff bases (18) made from amidines and hexa-fluoroacetonc are reduced by tin(U) chloride (Scheme 2.2.7). The 5-fluoro-4-trifluoromethylimida2olcs (19) are isolated in 58-65% yields [9-11]. The fluoro substituents in the 5-position are readily displaced by nucleophiles such as alkoxy or cyanide, thereby extending the versatility of these syntheses [9j. 

Alkoxy-3-chloro-3//-diazirines are obtained by the chlorination (aqueous sodium hypo-chlorite/dimethyl sulfoxide) of the corresponding amidines. They serve as precursors for the synthesis of 3-fluoro derivatives via the reaction with anhydrous tetrabutylammonium fluoride (for an improved procedure for the dehydration of commercial tetrabutylammonium fluoride trihydrate, see ref 26). This is a much simpler method than the earlier described preparation of 3-fluoro-3-methoxy-37/-diazirine involving the elemental fluorination reaction and a shatteringly explosive fluoronitrogen intermediate. 

FIGURE 15.32 (a) Replacement of ester ether oxygen by a fluoro-nitrogen (b) Exo-endo amidine in place of a car-... 

We then directed/our attention to the properties of fluoro-methyl cyanide, as it seemed likely, on theoretical grounds, that it would undergo certain addition reactions very readily. Alcohol and dry hydrogen chloride readily converted it into Jluoroacetimino ethyl ether hydrochloride (VI), which was converted into the amidine (VII) by means of alcoholic ammonia. Similar condensation of the cyanide with 2-fluoroethanol and phenol yielded jluoroacetimino 2 jluoroethyl ether hydrochloride (VIII R = CHj CHjF) and the corresponding phenyl imino ether hydrochloride (VIII i2 = Ph) respectively. Analogous experi-... 

Fluorinated synthons have been used to access fluorinated imidazoles. Reduction of Schiff bases derived from amidines and hexafluoroacetone with SnCl2 gives rise to 5-fluoro-4-trifluoromethylimidazoles 110 (Fig. 3.57). ° ° Because the 5-fluoro substituent is readily displaced by nucleophiles such as alkoxide, cyanide, and others, this procedure provides access to a range of trifluoromefliyl-substituted imidazoles (also see below). 

Analogously, a satisfactory yield of IbP was obtained by treating 2,6-dichloro-5-fluoro-3-aminopyridine with substituted acetamide in the presence of oxalyl chloride to give an amidine followed by reaction with potassium carbonate (94HCA1057). 

Kotsuki and co-workers used amidines to synthesize 2-substituted quinazolines. Reaction of 2-fluoro-5-nitro-benzaldehyde with 4-bromo-benzyl amidine gave the corresponding quinazoline in modest yield. This approach was subsequently used by Kotsuki and co-workers to generate a number of 5-nitro- and 5-cyanoquinazolines in modest yields. 

Frutos prepared 2-fluoromethylimidazoles via the cyclization of the amidines formed by the Cu(I)-piomoted addition of a-amino acetals to fluoroacetonitrile (Scheme 19) [29]. The reactions were performed either stepwise or in a one-pot fashion (depending upon the removal of Cu salts before or after the cycUzation) in which the amidine formation was carried out in the absence of any solvent followed by the cyclization using TFA or HQ-MeOH. Thus, the addition of (methylamino) acetaldehyde dimethyl acetal and (benzylamino)acetaldehyde diethyl acetal with fluoroacetonitrile followed by cyclization afforded the corresponding 2-(fluoro-methyl)imidazoles in 96 % and 53 % yields, respectively. 

Thecyclizationof2-fluoro-3-ketoestersderivativeswithl,3-A C/V-bisnucleophiles is general approach to fluorinated pyrimidines. There are a lot of examples of such transformations in the literature. A representative set of the cyclization is listed in Table 5. Besides usual 1,3-ACA-bisnucleophiles, such as amidine, guanidine and... 

Scheme 4.74 Synthesis imidazo[l,2-a]quinoxaline Af-oxides by interaction of l,3-dinitro-4-fluoro (and chloro)benzenes with cyclic amidines...

---