Nucleic Acids Research Volume 2 number 1 1 November 1 975 Voue2nme 1Nvme 95NcecAisR ac Synthesis of substituted 5-fluoro-5, 6-dtbydropyrimidines
D.Cech, L.Hein, R.Wuttke,
M.v.Janta-Lipinsld, A. Otto and P. Langen
Humboldt-University of Berlin, Department of Chemistry, 104 Berlin, GDR Received 15 October 1975
ABSTRACT The reaction of 5-substituted uracils with fluorine in acetic acid and other solvents and the following treatment with different alcohols yielded the corresponding 5-fluoro5, 6-substituted-5, 6-dibydropyrimidines. Tbymine gave 5-fluoro-5-methyl-6-alkoxy-5, 6-dihydropyrimidines. 5-Halogeno uracils and 5-nitro uracil were converted into 5-fluoro-56-dihbydropyrrimidines and the 5-nitrohalogeno-6-hbydroxy-5, analogue, respectively. The structures of the compounds were confirmed by mass
spectrometry. INTRODUCTION
In the past years were prepared a series of fluorine, chlorine and bromine containing 5,6-dihydro derivatives of pyrimidine bases and their nucleosides 1, 2, 3). Some of these compounds showed interesting biochemical effects 4' 5). Recently, Barton and coworkers 6) reported that the addition of fluoroxytrifluoromethane to thymine opens the possibility for synthesizing of 5-fluoro-5-methyl-6-hydroxy-5, 6-dihydropyrimidine. These results prompted us to investigate whether the reaction of fluorine with 5-substituted uracils gives analogously fluorinated dihydropyrimidine derivatives.
RESULTS AND DISCUSSIOEN The corresponding 5-substituted pyrimidines were treated with fluorine diluted with nitrogen in glacial acetic acid at room temperature. Thefluorination was stopped if there was no more UV-active component in the reaction solution (t.l.c. control). After evaporation of the solvent under diminished pressure the residual foam was crystallized by 2177
NudWe Acidt Reseah treatment with various aloohols. Thus, in the case of thymine, treatment of the reaotion residue with ethanol, methanol, water, n-butanol, tort.-butanol, allyl- and benzylalcoholt respectively, gave the corresponding 5-fluoro-5methyl-6-substituted-5, 6-dihydropyrimidines (Ia-g). Scheme 1
R
CH3 HN 0 N H
F H
OR
I
a) R
ethyl, b) R = methyl, c) R = H, d) R = n-butyl, e)R= tert.-butyl, f) R =allyl, g) R = benzyl
F HN oNt H H OH II
a) R = Cl b) R = Br c) H = 102 d) R = F
Under the above mentioned conditions the corresponding dihydropyrimidine derivatives were obtained from 5-chloro-, 5-bromo-,5-nitro- and 5-fluorouracil. Treatment of the fluorination residue with water afforded the correspondig 5-fluoro-5-halogeno-6-hydro3-5 , 6-dihydropyrimidines (IIa, b, d) and the corresponding 5-nitro derivative (IIe), respectively. Uracil itself was also converted into a dihydro derivative, which however is very unstable, and was changed into 5-fluorouracil even by evaporation of the solvent under diminished pressure. In the fluorination step of thymine in acefic acid we could identifY 5-fluoro-5-met l-6-acetoxy5,6-dihydropyrimidine (IV) as an intermediate. An analogues 5-bromo-6-aoetoxY-5 6-dihydrotbymidine was synthesized recently by Cadet TS* The possible 5,6-difluoro-5,6-dibydro compound (III) partioipated presumably in the reaction course
2178
Nucleic Acids Research Scheme 2 0
~~~33
~
H HN
H3
FN
F
HN
IV
III
Ac
=
COCH3
in a solvolysis, and the fluorine in the C-6 position underwent a smoothly nucleophilic displacement by an acetoxy group giving IV. Pormation of compound IV and its low stability towards the treatment with alcohols is in agreement with similar results reported in the literature 1) It is not advantageous, to use CHOl3 and freones as solvent for the fluorination because of the low solubility of the starting pyrimidine bases. By fluorination in liquid hydrogen fluoride we obtained the corresponding 6-hydroxyderivatives, presumably because moisture could not be excluded. All synthesized compounds were subjected to mass spectrometryJ. Ia, Ib, Ic, Ig and IIa-d gave the molecular ion. The compounds Id, Ie and If showed the molecular ion only in low intensities and the basis peak in these spectra corresponded to the peak of the molecular ion of 5-fluoro-5-methyl6-hydroxy-5,6-dinydropyrimidine (Ic) m/e = 162 (MX). However, all the fluoro compounds Id-f showed the same frag,
mentation pattern for the 5-fluoro-5-methyl-6-bydroxy-5,6dihydropyrimidine. Probably these spectra resulted from cleavage of the 0-substituents and stabilization of the formed ions by a transfer of hydrogen. The
structures
were
also
confirmed
by
NXR
spectra and
elemental analysis.
Melting points were taken on a heated microscope stage
2179
Nuleic Acids Research (Boetius) and are unoorreoted. bhin-layer ohromatography was carried out on ready-for-use KIESLGSEL HP254 ( 1E,CK, Darmstadt) silica gel plates in the solvent ethyl acetate-isopropanol-water (12:1:6, upper phase). The mass spectra were recorded on a NS 902 S spectrophotometer (ABI, Manohester) at 130)-1500C.
5-Methl-5-fluoro-6-alkoxy-5 .6-dihydropyrimidines (Ia-g) -general procedure Under stirring and cooling with water elemental fluorine diluted with nitrogen (22 :N2 1:10) was passed through a mixture of o.63 g (5 mmol) thymine in 150 ml glacial acetic acid. The fluorination was stopped if there was no more UV-activity (t.l.c. control). The mixture was evaporated under diminished pressure and the residue coevaporated with three 50 ml portions of acetic acid. The final residue was dissolved either in water (for preparation of the compound Ic) or in the corresponding alcohols (for preparation of the other compounds). After standing overnight at room temperature the solutions were evaporated under diminished pressure and crystaflized from water to afford the compounds Ia-g. Compound Ia: Yield 92%, m.p.154-55°C. For C7H11J203(190.18) ca:od.: 44.21 C, 5.84 H, 14.73 N, 9.99 F; found : 44.18 C, 5.70 H, 14.54 N, 9.50 F. m/e = 190 (M4). Yield 96%, m.p.205-120C. For C6H9N203(176.15) ;u calcd.: 40.91 C, 5.12 H, 15.90 Nt 10.78 F; found : 40.64 C, 4.9u H, 16.00 N, 10.60 1. m/e = 176 (M4). Compound Ic : Yield 93%, m.p.15o-520C. For C 57^I203(162.12) calcd.: 37.04 C, 4.35 H, 17.28 I, 11.72 I; found: 36.96 C, 4.23 H, 17.25 N, 11.5u F. m/e = 162 (M+). Compound Id : Yield 82%, m.p.157°C. F?or C9H5IN2 3 (218.23) calcd.: 49.53 C, 6.93 H, 12.84 N, 8.71 1; found : 49.37 C, 6.84 E, 13.01 N, 8.40 F. m/e = 218 (M+). Compound Ie :Yield 82%,m.p. 1470C. F?or C9H15FN203 (218.23) calcd.: 49.53 C, 6.93 H, 12.84 N, 8.71 F; found ; 49.00 C, 6.44 H, 12.28 N, 8.50 F. Compound If : Yield 89%, m.p.163°C. For C8 iS1203 (202.19) calod.: 47.52 C, 5.48 H, 13.86 Ns, 9.40 F; found : 47.40 C, 2180
Nucleic Acids Research 5.60 H, 13.70 N, 9.30 I. Compound Ig : Yield 88%,m.p. 1800C. For C1213FN203 (252.25) calcd.: 57.14 C, 5.19 H, 11.11 N, 7.53 F; found : 56.97 C, 5.29 H, 11.40 N, 7.U F. 5-Chloro-5-fluoro-6-hydro-5 . 6-dihydro2rimidine (Ia) Jollowing the general procedure a solution of 0.74 g (5mmol) 5-chlorouracil in 150 ml glacial acetic acid was fluorinated. After evaporation under diminished pressure the resulting residue was crystallized from water to afford 0.85 g (927.). of the compound IIa, m.p. 149-520C. For C4H4ClF203 (182.54) calcd.: 26.32 C, 2.21 H, 15.35 N, 10.41 F; found : 25.9 C, 2.2u H, 15.15 N, 10,4 F. m/e = 182 (M4). 5-Bromo-5-fluoro-6-hydrozy-5, 6-dihydropyrimidine (IIb) The compound lIb was prepared from 5-bromouracil analogou-sly as compound TIa in 89% yield, m.p. 1810C. For C4H4BrJr2O, (227.00) calcd.: 21.17 C, 1.78 H,v 12.34 N, 8.37 F; found 21.o C, 1.90 H, 12.38 N, 8.5 F. m/e = 226 (M+). 5-Nitro-5-fluoro-6-hydrozy-5,6-dihydropyrimidine IIc) The compound lIc was prepared from 5-nitrouracil as described under the preparation of IIa in 92%6 yield, m.p. 179-82°C. For C4H4'M1305 (193.09) calcd.: 24.88 C, 2.09 H, 21.76 N, 9.84 F; found: 25.0 C, 2.10 H, 22.00 N, 9.7 F. m/e =193 Bs
(e). 5.*5-Difluoro-6-hydrozy-5 . 6-dihzydropyrimidine (IId) The compound IId was prepared from 5-fluorouracil analogously as compound hIa in 70% yield, m.p. 1920C. For C4H4F21203 (166.08) calod.s 28.93 C, 2.43 H, 16.87 N, 22.88 F; found 28.36 C, 2.45 H, 16.7 N, 22.51 F. m/e = 166 (M+). + Academy of Sciences of
GDR, Central Institute of Molecular Biology, 1115 Berlin-Buch, GDR
1 Duschinsky,R., Gabriel,T., Tautz,W., Nussbaum,., Hoffer,M,, Grunberg 3.,Burchenal,J.H. and Fox., J.J. (1967) J.Med.
Chem.
10, 47
2 Duschiky,. and
Hoffer,Mt. U.S. 3,5021,675 2181
Nucleic Acids Research 3 a) Tee,O.S. and Banerjee,S. (1974) Canad.J.Chem. 52, 451 b) Banerjee,S. and Tee,O.S. (1974) J.C.S.Chem.Comm. 535 c) Cadet,J. and Teoule,R. (1973) Tetrahedron Letters 43,
4245
4.Heidelberger,C. ,Birnie,G.D., Boohar,J. and Wentland,Db (1963) Biochim.Biophys.Acta 76, 315 5 Heidelberger,C., Boohar,J. and Birnie,G.Do (1964) Biochim.Biopbys.Acta 91, 636 6 Barton,D.HoR., Bubb,W.A., Hesse,R.H. and Pechet, M.1M. (1974) J.Chem. Soc. 2095 7 Teoule,R., Fouque,B. and Cadet,J. (1975) Nucleic Acids Res.
2182
2 ,
487
D.Cech, L.Hein, R.Wuttke,
M.v.Janta-Lipinsld, A. Otto and P. Langen
Humboldt-University of Berlin, Department of Chemistry, 104 Berlin, GDR Received 15 October 1975
ABSTRACT The reaction of 5-substituted uracils with fluorine in acetic acid and other solvents and the following treatment with different alcohols yielded the corresponding 5-fluoro5, 6-substituted-5, 6-dibydropyrimidines. Tbymine gave 5-fluoro-5-methyl-6-alkoxy-5, 6-dihydropyrimidines. 5-Halogeno uracils and 5-nitro uracil were converted into 5-fluoro-56-dihbydropyrrimidines and the 5-nitrohalogeno-6-hbydroxy-5, analogue, respectively. The structures of the compounds were confirmed by mass
spectrometry. INTRODUCTION
In the past years were prepared a series of fluorine, chlorine and bromine containing 5,6-dihydro derivatives of pyrimidine bases and their nucleosides 1, 2, 3). Some of these compounds showed interesting biochemical effects 4' 5). Recently, Barton and coworkers 6) reported that the addition of fluoroxytrifluoromethane to thymine opens the possibility for synthesizing of 5-fluoro-5-methyl-6-hydroxy-5, 6-dihydropyrimidine. These results prompted us to investigate whether the reaction of fluorine with 5-substituted uracils gives analogously fluorinated dihydropyrimidine derivatives.
RESULTS AND DISCUSSIOEN The corresponding 5-substituted pyrimidines were treated with fluorine diluted with nitrogen in glacial acetic acid at room temperature. Thefluorination was stopped if there was no more UV-active component in the reaction solution (t.l.c. control). After evaporation of the solvent under diminished pressure the residual foam was crystallized by 2177
NudWe Acidt Reseah treatment with various aloohols. Thus, in the case of thymine, treatment of the reaotion residue with ethanol, methanol, water, n-butanol, tort.-butanol, allyl- and benzylalcoholt respectively, gave the corresponding 5-fluoro-5methyl-6-substituted-5, 6-dihydropyrimidines (Ia-g). Scheme 1
R
CH3 HN 0 N H
F H
OR
I
a) R
ethyl, b) R = methyl, c) R = H, d) R = n-butyl, e)R= tert.-butyl, f) R =allyl, g) R = benzyl
F HN oNt H H OH II
a) R = Cl b) R = Br c) H = 102 d) R = F
Under the above mentioned conditions the corresponding dihydropyrimidine derivatives were obtained from 5-chloro-, 5-bromo-,5-nitro- and 5-fluorouracil. Treatment of the fluorination residue with water afforded the correspondig 5-fluoro-5-halogeno-6-hydro3-5 , 6-dihydropyrimidines (IIa, b, d) and the corresponding 5-nitro derivative (IIe), respectively. Uracil itself was also converted into a dihydro derivative, which however is very unstable, and was changed into 5-fluorouracil even by evaporation of the solvent under diminished pressure. In the fluorination step of thymine in acefic acid we could identifY 5-fluoro-5-met l-6-acetoxy5,6-dihydropyrimidine (IV) as an intermediate. An analogues 5-bromo-6-aoetoxY-5 6-dihydrotbymidine was synthesized recently by Cadet TS* The possible 5,6-difluoro-5,6-dibydro compound (III) partioipated presumably in the reaction course
2178
Nucleic Acids Research Scheme 2 0
~~~33
~
H HN
H3
FN
F
HN
IV
III
Ac
=
COCH3
in a solvolysis, and the fluorine in the C-6 position underwent a smoothly nucleophilic displacement by an acetoxy group giving IV. Pormation of compound IV and its low stability towards the treatment with alcohols is in agreement with similar results reported in the literature 1) It is not advantageous, to use CHOl3 and freones as solvent for the fluorination because of the low solubility of the starting pyrimidine bases. By fluorination in liquid hydrogen fluoride we obtained the corresponding 6-hydroxyderivatives, presumably because moisture could not be excluded. All synthesized compounds were subjected to mass spectrometryJ. Ia, Ib, Ic, Ig and IIa-d gave the molecular ion. The compounds Id, Ie and If showed the molecular ion only in low intensities and the basis peak in these spectra corresponded to the peak of the molecular ion of 5-fluoro-5-methyl6-hydroxy-5,6-dinydropyrimidine (Ic) m/e = 162 (MX). However, all the fluoro compounds Id-f showed the same frag,
mentation pattern for the 5-fluoro-5-methyl-6-bydroxy-5,6dihydropyrimidine. Probably these spectra resulted from cleavage of the 0-substituents and stabilization of the formed ions by a transfer of hydrogen. The
structures
were
also
confirmed
by
NXR
spectra and
elemental analysis.
Melting points were taken on a heated microscope stage
2179
Nuleic Acids Research (Boetius) and are unoorreoted. bhin-layer ohromatography was carried out on ready-for-use KIESLGSEL HP254 ( 1E,CK, Darmstadt) silica gel plates in the solvent ethyl acetate-isopropanol-water (12:1:6, upper phase). The mass spectra were recorded on a NS 902 S spectrophotometer (ABI, Manohester) at 130)-1500C.
5-Methl-5-fluoro-6-alkoxy-5 .6-dihydropyrimidines (Ia-g) -general procedure Under stirring and cooling with water elemental fluorine diluted with nitrogen (22 :N2 1:10) was passed through a mixture of o.63 g (5 mmol) thymine in 150 ml glacial acetic acid. The fluorination was stopped if there was no more UV-activity (t.l.c. control). The mixture was evaporated under diminished pressure and the residue coevaporated with three 50 ml portions of acetic acid. The final residue was dissolved either in water (for preparation of the compound Ic) or in the corresponding alcohols (for preparation of the other compounds). After standing overnight at room temperature the solutions were evaporated under diminished pressure and crystaflized from water to afford the compounds Ia-g. Compound Ia: Yield 92%, m.p.154-55°C. For C7H11J203(190.18) ca:od.: 44.21 C, 5.84 H, 14.73 N, 9.99 F; found : 44.18 C, 5.70 H, 14.54 N, 9.50 F. m/e = 190 (M4). Yield 96%, m.p.205-120C. For C6H9N203(176.15) ;u calcd.: 40.91 C, 5.12 H, 15.90 Nt 10.78 F; found : 40.64 C, 4.9u H, 16.00 N, 10.60 1. m/e = 176 (M4). Compound Ic : Yield 93%, m.p.15o-520C. For C 57^I203(162.12) calcd.: 37.04 C, 4.35 H, 17.28 I, 11.72 I; found: 36.96 C, 4.23 H, 17.25 N, 11.5u F. m/e = 162 (M+). Compound Id : Yield 82%, m.p.157°C. F?or C9H5IN2 3 (218.23) calcd.: 49.53 C, 6.93 H, 12.84 N, 8.71 1; found : 49.37 C, 6.84 E, 13.01 N, 8.40 F. m/e = 218 (M+). Compound Ie :Yield 82%,m.p. 1470C. F?or C9H15FN203 (218.23) calcd.: 49.53 C, 6.93 H, 12.84 N, 8.71 F; found ; 49.00 C, 6.44 H, 12.28 N, 8.50 F. Compound If : Yield 89%, m.p.163°C. For C8 iS1203 (202.19) calod.: 47.52 C, 5.48 H, 13.86 Ns, 9.40 F; found : 47.40 C, 2180
Nucleic Acids Research 5.60 H, 13.70 N, 9.30 I. Compound Ig : Yield 88%,m.p. 1800C. For C1213FN203 (252.25) calcd.: 57.14 C, 5.19 H, 11.11 N, 7.53 F; found : 56.97 C, 5.29 H, 11.40 N, 7.U F. 5-Chloro-5-fluoro-6-hydro-5 . 6-dihydro2rimidine (Ia) Jollowing the general procedure a solution of 0.74 g (5mmol) 5-chlorouracil in 150 ml glacial acetic acid was fluorinated. After evaporation under diminished pressure the resulting residue was crystallized from water to afford 0.85 g (927.). of the compound IIa, m.p. 149-520C. For C4H4ClF203 (182.54) calcd.: 26.32 C, 2.21 H, 15.35 N, 10.41 F; found : 25.9 C, 2.2u H, 15.15 N, 10,4 F. m/e = 182 (M4). 5-Bromo-5-fluoro-6-hydrozy-5, 6-dihydropyrimidine (IIb) The compound lIb was prepared from 5-bromouracil analogou-sly as compound TIa in 89% yield, m.p. 1810C. For C4H4BrJr2O, (227.00) calcd.: 21.17 C, 1.78 H,v 12.34 N, 8.37 F; found 21.o C, 1.90 H, 12.38 N, 8.5 F. m/e = 226 (M+). 5-Nitro-5-fluoro-6-hydrozy-5,6-dihydropyrimidine IIc) The compound lIc was prepared from 5-nitrouracil as described under the preparation of IIa in 92%6 yield, m.p. 179-82°C. For C4H4'M1305 (193.09) calcd.: 24.88 C, 2.09 H, 21.76 N, 9.84 F; found: 25.0 C, 2.10 H, 22.00 N, 9.7 F. m/e =193 Bs
(e). 5.*5-Difluoro-6-hydrozy-5 . 6-dihzydropyrimidine (IId) The compound IId was prepared from 5-fluorouracil analogously as compound hIa in 70% yield, m.p. 1920C. For C4H4F21203 (166.08) calod.s 28.93 C, 2.43 H, 16.87 N, 22.88 F; found 28.36 C, 2.45 H, 16.7 N, 22.51 F. m/e = 166 (M+). + Academy of Sciences of
GDR, Central Institute of Molecular Biology, 1115 Berlin-Buch, GDR
1 Duschinsky,R., Gabriel,T., Tautz,W., Nussbaum,., Hoffer,M,, Grunberg 3.,Burchenal,J.H. and Fox., J.J. (1967) J.Med.
Chem.
10, 47
2 Duschiky,. and
Hoffer,Mt. U.S. 3,5021,675 2181
Nucleic Acids Research 3 a) Tee,O.S. and Banerjee,S. (1974) Canad.J.Chem. 52, 451 b) Banerjee,S. and Tee,O.S. (1974) J.C.S.Chem.Comm. 535 c) Cadet,J. and Teoule,R. (1973) Tetrahedron Letters 43,
4245
4.Heidelberger,C. ,Birnie,G.D., Boohar,J. and Wentland,Db (1963) Biochim.Biophys.Acta 76, 315 5 Heidelberger,C., Boohar,J. and Birnie,G.Do (1964) Biochim.Biopbys.Acta 91, 636 6 Barton,D.HoR., Bubb,W.A., Hesse,R.H. and Pechet, M.1M. (1974) J.Chem. Soc. 2095 7 Teoule,R., Fouque,B. and Cadet,J. (1975) Nucleic Acids Res.
2182
2 ,
487
