Mendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1.42) New fluorinated nucleoside analogues with 2-butenolide rings prepared by nucleophilic vinylic fluorine displacement in 4,4-dialkyl-2,3-difluorobut-2-en-4-olides Old ich Paleta,*a Zden k Dudaa and Antonin Holyb a Department of Organic Chemistry, Institute of Chemical Technology, 16628 Prague, Czech Republic. Fax: +4202 2431 1082; e-mail: paletao@vscht.cz b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610 Prague, Czech Republic 10.1070/MC2001v011n01ABEH001377 Sodium salts of adenine, 2,6-diaminopurine, cytosine, 4-methoxypyrimidin-2-one and aliphatic or alicyclic amines reacted with 4,4-dialkyl-2,3-difluorobut-2-en-4-olides by vinylic substitution of fluorine to give 3-substituted butenolides as nucleoside analogues or enamines, while sodium and lithium salts of aliphatic and aromatic amines reacted as hard nucleophiles to attack the carbonyl group thus causing butenolide ring opening. A number of bioactive natural compounds contain butenolide rings.1 Some of them display HIV-enzyme inhibiting,2 anticancer, 3,4 anti-tumour5 and cytostatic6 properties.On the other hand, fluoro substituents are known as strong modifiers of bioactivity. 7.9 On this basis, it can be assumed that a combination of a fluorinated butenolide ring with a pharmacophore moiety, e.g., a nucleoside base, can create biological activity. Nucleoside analogues possessing a butenolide ring instead of a sugar part in the molecule have not been reported in the literature.As a general strategy for the synthesis of these compounds with potential bioactivity, we decided on a study of the modification of 4,4-dialkyl-2,3-difluorobut-2-en-4-olides 1 and 2 by vinylic displacement of fluorine with nitrogen nucleophiles. The reasons for this methodology have been accessible butenolides 110,11 and 2¢Ó and our recent observations11.14 in the chemistry of fluorinated butenolides.It has been observed11.14 that the reactivity of fluorinated but-2-en-4-olides possessing fluorine atoms attached to the double bond, as in compounds 1, 2, 314 and 413 (Scheme 1), is strongly dependent on their structure and character of a reagent: e.g., 1 and 2 reacted with various oxy anions by vinylic fluorine displacement,11,12 while the same reagents caused ring opening in fluorobutenolide13 3 or only tars formation in the reaction with chlorofluorobutenolide14 4.Different results have also been obtained in reactions of halobutenolides (including 2,3-dichlorobutenolide15) with nitrogen nucleophiles13,14 and hard or soft organometals.11.13 The literature data suggest that the following three types of reactions of nitrogen nucleophiles with butenolides 1 and 2 can be expected: displacement of ¥â-fluorine, nucleophilic addition to the double bond and ring opening by a carbonyl group attack. The N-nucleophiles employed in this study included aliphatic or aromatic amines, alkali salts of the amines and sodium salts of nucleoside bases as delocalised soft N-nucleophiles.Generally, the nucleophiles reacted in two different ways, i.e., with displacement of ¥â-fluorine or with a carbonyl group attack followed by butenolide ring opening.Aliphatic amines¢Ô and sodium salts of nucleoside bases¡× reacted with butenolides 1 and 2 by the displacement of vinylic fluorine (Scheme 2) with the formation of enamine-type products possessing neighbouring vinylic fluorine (5.11).It can be presumed that in the reaction mechanism 1,4-addition intermediates are formed primarily11,12 from which a ¥â-fluorine atom is expelled. The reactions with sodium salts of nucleoside bases were carried out at lower temperatures than those reported for non-fluorinated species16 and were completely regioselective to r e ¢Ó New spirocyclic butenolide 2 [2,3-difluoro-4,4-(pentane-1,5-diyl)but- 2-en-4-olide] was prepared analogously10 to compound 1.Cyclohexanol was added to methyl 2,3,3-trifluoroacrylate under photochemical or radical (dibenzoyl peroxide) initiation; the intermediate adduct [R2C(OH)CF2CHFCOOMe] cyclised spontaneously to butanolide during distillation (50.65% yield). The conversion of the intermediate butanolide to target butenolide 2 was performed by a novel procedure using triethylamine as a dehydrofluorinating agent (acetonitrile, room temperature, 10 h), 65.75% yield, bp 102.103 ¡ÆC (8 mmHg). 13C NMR (100.6MHz, CDCl3) d: 21.9 (s, CH2), 24.6 (s, CH2), 33.4 (s, CH2), 80.5 (s, C), 127.1 (d, CF, 1JCF 288 Hz), 160.0 (d, CF, 1JCF 299 Hz), 162.9 (s, C=O). 19F NMR (75.4 MHz, CDCl3) d: .166.4 (s, 1F), .127.4 (s, 1F).Found (%): C, 57.11; H, 5.55. Calc. for C9H10F2O2 (%): C, 57.45; H, 5.36. Table 1 Reactions of butenolides 1 and 2 with N-nucleophiles. Starting compound Nucleophile Product Yielda (%) aIsolated yields. bShifts d in ppm downfield from CFCl3. cComplete conversion, then reverse reaction to form 2. dCalculated from NMR spectra. 19F NMRb 2 EtNH2 5 80 .182.1 1 Et2NH 6 69 .186.8 2 Piperidine 7 70 .177.7 1 Nu(.)Na(+) Nu = adenin-9-yl 8 32 .145.7 1 Nu(.)Na(+) Nu = 4-methoxypyrimidin-2-on-1-yl 9 60 .142.6 2 Nu(.)Na(+) Nu = 2,6-diaminopurin-9-yl 10 51 .145.3 2 Nu(.)Na(+) Nu = cytosin-1-yl 11 81 .144.85 2 (Pri)2NLi 13 59 .135.1 (s) .144.9 (s) 2 PhEtNNa 14 (100)c .127.8 (s) .143.6 (s) 2 PhNHLi, Me3SiCl 15 43d .114.1 (s) .152.2 (s) O O F F O O F F 1 2 O O F 3 O O F Cl 4 Scheme 1 O O F F R R 1,2 Nu.H or Nu Na (.) (+) O O F Nu R R 5.11 5 Nu.H = EtNH.H 6 Nu.H = Et2N.H N H 7 Nu.H = 8 Nu = adenin-9-yl 9 Nu = 4-methoxypyrimidin-2-on-1-yl 10 Nu = 2,6-diaminopurin-9-yl 11 Nu = cytosin-1-yl Scheme 2 O O F N 7 O O F N N OMe O 9 O O F 10 N N N N NH2 H2NMendeleev Communications Electronic Version, Issue 1, 2001 (pp. 1–42) nucleoside bases. Examples of new enamino compounds and nucleoside analogues (7, 9, 10) are shown in Scheme 2.The 19F NMR spectra of new compounds 5–11 show singlet signals with a characteristic shift for each compound class (enamine or nucleoside analogue, Table 1). Aniline and N-ethylaniline, as well as free nucleoside bases, were completely unreactive even on heating to 80 °C. We observed no difference in the reactivity of butenolides 1 and 2 from the kinetic point of view during preparative reactions.This observation is in a sharp contrast to the reactions of butenolides with thiophenol or soft carbanions where butenolide 2 appeared to be completely unreactive.17 Sodium and lithium salts of aliphatic or aromatic amines reacted with butenolides 1 and 2, contrary to reactions of alkoxides,11,12 at the hard electrophilic centre of the carbonyl group with ring opening (Scheme 3).¶ This observation is also in contrast with the reactions15 of dichloro- or dibromobutenolides where vinylic displacement was observed.Hydroxyamides 13 and 14, obtained by quenching the mixture with trifluoroacetic acid, were unstable, and they were rapidly converted to starting butenolide 2 on distillation or slowly converted on storage (the process could be monitored by 19F NMR spectra); hydroxyamide 13 was more stable.To confirm the formation of intermediate 12, we trapped it as trimethylsilyl derivative 15 by silylation at –70 °C. The 19F NMR spectra of 15 and hydroxyamides 13 and 14 show two singlets (Table 1); the absence of mutual fluorine coupling as in starting butenolide 2 confirms (Z)-configuration for the propenamide structure.The structures of all the compounds synthesised were elucidated on the basis of 1H, 13C and 19F NMR spectra, the formulae of isolated products 5–11 were confirmed by microanalysis for carbon and hydrogen. The reported reactions of N-nucleophiles have extended the use of 2-fluoro-3-halogenobut-2-en-4-olides as new fluorinated synthons with a special interest in the preparation of a new type of nucleoside analogues. This work was supported by the Grant Agency of the Czech Republic (grant no. 203/96/1057) and by the Ministry of Education of the Czech Republic (project no. LB98233). References 1 D. W. Knight, Contemp. Org. Synth., 1994, 1, 287. 2 B. E. Roggo, P. Hug, S. Moss, F. Raschorf and H.H. Peter, J. Antibiot., 1994, 47, 143. 3 X.-P. Fang, J. E. Anderson, C.-J. Chang and J. L.McLaughlin, Tetrahedron, 1991, 47, 9751. 4 H. Mori, N. Yoshimi, S. Sugie, T. Tanaka, Y. Morishita, G. Jinlong, M. Torihara and J. Yamahara, Cancer Lett. (Shannon), 1992, 66, 93. 5 P. L. Triozze, J. Ailabouni, J. J. Rinehart and D. T. Witiak, Int. J. Pharm., 1993, 15, 47. 6 X. P. Fang, J.E. Anderson, D. L. Smith, J. L. McLaughlin and K. V.Wood, J. Nat. Prod., 1992, 55, 1655. 7 Organo-fluorine Compounds in Medicinal Chemistry and Biomedical Applications, eds. R. Filler, Y. Kobayashi and L. M. Yagupolskii, Elsevier, Amsterdam, 1993. 8 Fluorine in Medicine in the 21st Century (Conference Papers), eds. R. E. Banks and K. C. Lowe, UMIST, Manchester, 1994. 9 Cancer Chemotherapeutic Agents, ed.W. O. Foye, ACS, Washington D.C., 1995, pp. 49–55. 10 V. P. Šendrik, O. Paleta and V. D dek, Collect. Czech. Chem. Commun., 1977, 42, 2530. 11 O. Paleta, A. Pelter, J. Kebrle, Z. Duda and J. Hajduch, Tetrahedron, 2000, 56, 3197. 12 O. Paleta, A. Pelter and J. Kebrle, Tetrahedron Lett., 1994, 35, 9259. 13 J. Kví ala, J. Plocar, R. Vlasáková, O. Paleta and A.Pelter, Synlett, 1987, 986. 14 O. Paleta, A. Volkov and J. Hetflejš, J. Fluorine Chem., 2000, 102, 147. 15 V. Zikán, L. Vrba, B. Kaká and M. Semonský, Collect. Czech. Chem. Commun., 1973, 38, 1091. 16 P. Alexander and A. Holý, Collect. Czech. Chem. Commun., 1993, 58, 1151. 17 J. Hajduch and O. Paleta, unpublished results. ‡ Typical procedure for preparation of enamines 5–7.In an inert atmosphere, an amine (2.5 mmol) solution in dry and purified tetrahydrofuran (THF, 4 ml) was cooled at –20 to –30 °C and a solution of butenolide (1.2 mmol) in THF (5 ml) was added dropwise during 10–15 min. The mixture was stirred at –10 °C for 6 h and then allowed to warm to room temperature; next, volatile components were evaporated. The residue was purified by column chromatography (silica gel, dichloromethane); the product was recrystallised (chloroform–light petroleum).§ Typical procedure for preparation of nucleoside analogues 8–11. In an inert atmosphere, a mixture of sodium hydride (60% suspension in mineral oil, 1.9 mmol), dry dimethyl formamide (DMF, 10 ml) and a nucleoside base (1.6 mmol) was intensely stirred at room temperature (or elevated temperatures) for 1 h and then cooled at –20 to –40 °C.A butenolide (1.1 mmol) solution in DMF (5 ml) was added dropwise to the nucleoside base solution for 10–15 min, the solution was stirred at –20 to –40 °C for 1–2 h and then allowed to warm to room temperature. Volatile components of the reaction mixture were evaporated in a vacuum, and the solid residue was purified by column chromatography (silica gel), the product was once or twice recrystallised (methanol–light petroleum).¶ Typical reactions of butenolides with the alkali salts of amides. In an inert atmosphere, an amine (1.25 mmol) solution in dry and purified THF (2 ml) was cooled to ca. –70 °C and a butyllithium (1.3 mmol, 2.47 M solution) was added dropwise with intense stirring for 30 min. A solution of butenolide (1.1 mmol) in THF (2 ml) was added dropwise (10–15 min) to the cooled solution at ca. –60 °C, the mixture was stirred for 1 h and then warmed to room temperature for 2 h. The 19F NMR spectrum was measured (100% conversion of butenolide). Then, trifluoroacetic acid was added (equivalent to butyllithium), the mixture was neutralised with Na2CO3, volatile components were evaporated, and the residue was chromatographed (silica gel, dichloromethane) to obtain a mixture of the product and the starting butenolide. 2 NR1R2 O (–) M(+) F F O 12 M(+)NR1R2 (–) NR1R2 O F F O 13, 14 H CF3COOH D HN O F F O Me3Si 15 2 Me3SiCl M = Na, Li 13 R1 = R2 = Pri 14 R1 = Ph, R2 = H Scheme 3 e c c Received: 25th September 2000; Com. 00/1703