666. Organic fluorine compounds. Part XI. Ethyl fluoro-acetoacetates and fluoropyrimidines

Abstract

By ERNST D . BERGMANN, S. COHEN, and I. SHAHAK. Ethyl bromo(or ch1oro)acetate condenses with ethyl fluoroacetate, and ethyl chlorofluoroacetate with ethyl acetate, in Reformatzky-type reactions to give ethyl yand a-fluoroacetoacetate, respectively. The enol from ethyl fluoroacetate condensed with acetyl chloride, benzoyl chloride, ethyl trifluoroacetate, and ethyl pentafluoropropionate to give the P-keto-esters. Fluoroacetone and acetic anhydride under catalysis by boron trifluoride give a P-diketone, probably 3-fl~oropentane-2~4-dione.By condensation of the available P-diketo-compounds with S-ethylisothiouronium bromide or urea, acetamidine, and guanidine several fluorinecontaining pyrimidines have been prepared. Their ultraviolet and infrared spectra are discussed.THE purpose of the present study was to prepare fluoropyrimidines, which we expected to be antagonists of the corresponding hydrogen compounds. This expectation, which was based on the powerful antimetabolite properties of, e.g., fluorophenylalanines and 5-fluorotryptophan, has meanwhile been borne out to some extent for 5-fluorouracil, 5-fluoro-orotic acid, and 5-fluoroadenine. are known, but their preparation is not always easy. Ethyl y-fluoroacetoacetate, for example, has been prepared by Szinai2 from fluoroacetyl chloride and ethyl dihydropyranyl malonate, and from ethyl t-butyl malonate (Fraser et d 2 ) , but both methods are cumbersome, and the product requires lengthy p~rification.~ It has now been found that ethyl y-fluoroacetoacetate is easily accessible by reaction between ethyl bromoacetate (or better chloroacetate), ethyl fluoroacetate, and activated magnesium, though in +40% yield. The reaction has been extended to the preparation of ethyl a-methyl-and (not quite pure) a-ethyl-y-fluoroacetoacetate from ethyl a-bromo-propionate and -butyrate, respectively. The analogous reaction between ethyl bromofluoroacetate (which has already been used for Reformatzky reactions with aldehydes and ketones 4), zinc, and ethyl acetate to give ethyl a-fluoroacetoacetate was made impracticable by the difficulty of preparing the brominated ester and its in~tability.~ However, the analogous ethyl chlorofluoroacetate, which is accessible both by chlorination of ethyl fluoroacetate and by hydrolysis of the ethanol adduct of chlorotrifluoroethylene,~ gives the same Refomatzky-type reaction as the bromo-analogue.* Thus, ethyl a-fluoroacetoacetate was obtained from ethyl chlorofluoroacetate, an excess of ethyl acetate, and activated magnesium in 20% yield. As a by-product, ethyl y-chloro-ay-difluoroacetoacetate was formed. The latter was the principal product , when ethereal ethyl chlorofluoroacetate was refluxed with activated magnesium. Acceptable yields of ethyl a-fluoroacetoacetate can also be obtained by the reaction between the enol of ethyl fluoroacetate (prepared with sodium

Phenoxydifluoromethyl Substituted Nitrogen Heterocycles. Synthesis and Heterocyclization Reactions of Ethyl 4,4-Difluoro- 4-phenoxyacetoacetate

“…The known methyl phenoxydifluoroacetate [6] was used as a starting material. Its reaction with ethyl acetate in the presence of sodium hydride leads to the target ketoester 1 in 75% yield (Scheme 1) The reactivity of 1 in heterocyclization reactions with nitrogen-containing nucleophiles was found to be similar to that of well studied ethyl 4,4,4-trifluoroacetoacetate [7,8]. For example, the reaction of 1 with benzamidine at room temperature leads to 2-phenyl-4-(phenoxydifluoromethyl)-6-hydroxypyrimidine (2) in 93% yield (Scheme 2).…”

Preparation of pyrimidine derivatives through three-component reactions of dialkyl (2-oxo-3,3,3-trifluoropropyl)phosphonates

“…s, OH) 13. C NMR spectrum, , ppm (J, Hz); 15.7 (d, 3 J C-P = 6.3, CH 3 ); 15.9 (d,3 J C-P = 6.0, CH 3 ); 45.3 (d, J C-P = 145.0, C-5); 52.1 (s, C-6); 60.8 (d, 2 J C-P = 6.7, CH 2 ); 61.1 (d, 2 J C-P = 6.5, CH 2 ); 81.1 (qd, 2 J C-F = 31.5, 2 J C-P = 3.1, C-4); 123.3 (qd, J C-F = 290.0, 3 J C-P = 5.0, CF 3 ); 126.9, 127.3, 127.9 (s, C Ph); 140.7 (d, 3 J C-P = 7.1, ipso-C Ph); 154.5 (s, C=O) 19. F NMR spectrum, , ppm: -82.18 (s, CF 3 ) 31.…”

“…In analogous reactions of -dicarbonyl compounds reported in the literature the construction of a pyrimidine ring occurs in two stages with separation of intermediates of type A [18] or B [19], cyclization of which to pyrimidin-2-ones in the subsequent step demands more rigorous conditions and the use of base.…”

“…13 C NMR spectrum, , ppm (J, Hz): 16.0 (d, 3 J C-P = 6.8, CH 3 ); 16.1 (d, 3 J C-P = 6.8, CH 3 ); 61.3 (d, 2 J C-P = 5.3, CH 2 ); 61.6 (d, 2 J C-P = 5.6, CH 2 ); 82.3 (qd, 2 J C-F = 33.7, 2 J C-P = 11.0, C-4); 93.2 (d, J C-P = 203.2, C-5); 123.0 (q, J C-F = 288.3, CF 3 ); 143.0 (d, 3 J C-P = 15.4, C-6); 149.8 (s, C=O). 19 Dimethyl (4-methoxy-2-oxo-4-trifluoromethyl-1,2,3,4-tetrahydropyrimidin-5-yl)phosphonate (4b) was prepared from phosphonate 1b, urea, and triethyl orthoformate. Yield 68%; mp 148-150ºC (MeCN).…”

“…1 H NMR spectra were recorded on a Varian VXR-300 spectrometer (300 MHz) and 13 C NMR, APT, 1 H-1 H COSY, and 13 C-1 H HETCOR spectra on a Bruker Avance 400 (400 and 100 MHz, respectively) for solutions in DMSO-d 6 with residual solvent signals at 2.50 ppm for 1 H and 39.52 ppm for 13 C used as standard. 19 F and 31 P NMR spectra were recorded on a Varian Gemini-200 instrument (188 and 81 MHz respectively) with C 6 F 6 (-162.9 ppm relative to CFCl 3 ) and H 3 PO 4 (0.00 ppm) as internal standards. Mass spectra were taken on an Agilent 1100 series LC/MSD SL instrument with chemical ionization at atmospheric pressure (APCI) as the ionization method.…”