Synthesis of 5-(acylethynyl)uracils and their corresponding 2prime;-deoxyribonucleosides through palladium-catalysed reactions

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1993 Synthesis of 5-(Acylethynyl)uracils and their Corresponding 2'-Deoxyribonucleosides through Palladium-catalysed Reactions' Nitya G. Kundu* and Swapan K. Dasgupta Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Calcutta 700 032, India Good yields of the title uracils were obtained by using the palladium-catalysed reaction between 5-iodo-2,4-dimethoxypyrimidine and substituted propargylic alcohols rather than the corresponding ketones. The same strategy works for coupling with the 5-iodo-2'-deoxyuridines. 5-Substituted uracil derivatives have proved to be of interest Results and Discussion and use in cancer2 and viral ~hernotherapy,~-' as enzyme inhibitors9310and in the synthesis of modified nucleotides.11v12 Our interest was in producing potential anticancer and antiviral compounds bearing conjugated acetylenic ketones of structures I and II.I3 0 0 R I R=H, R'=Ar II R = Zdeoxy-D -erythro pentofuranose,FT = Ar In these compounds after their conversion into the corresponding 2'-deoxyribonucleotides 71, the stereoelectronic characteristics of the C-5 substituents were expected to facilitate the attack of the thiol group of the cysteine moiety of the enzyme thymidylate synthase (TS),I4 a critical enzyme needed for cellular multiplication, at the C-6 position of the uracil ring, leading to tight enzyme inhibitor complexes (A and B)." Thus, R C=CH-C-R S-Em OH CH A B these compounds were expected to act as effective inhibitors of the TS enzyme and to have antitumour properties. These expectations have been fulfilled to some extent.The lead compound, 5-(p-toluoylethynyl)uracil I (R = H, R' = p-tolyl), was found to be highly active against both L1210/0 mouse leukaemia and CCRF-CEM human lymphoblastoid cells in uitro. It also inhibited the TS enzyme.I6 In view of the success of 5-(acylethyny1)uracils (AEUs) as antitumour agents and as inhibitors of TS enzyme, we became interested in the development of the corresponding 2'-deoxyribonucleosides II which, we believe, will have stronger antitumour and TS- enzyme-inhibitory properties. In this paper, we describe an improved method for the synthesis of both the AEUs and the corresponding 2'-deoxyribonucleosides. t Strictly speaking, these should be called 2'-deoxy-~-erythro-pento-furanonucleotides. Previously, we have reported two general methods for the synthesis of AEUs.'5y'6 However, these methods suffer from the disadvantages of involving long reaction sequences, being time consuming, and having poor overall yields (10-25).Also, they could not be adapted to the synthesis of the corresponding 2'- deoxyribonucleosides.Thus, we were prompted to develop an alternative method for the synthesis of the AEUs and the corresponding 2'-deoxyribonucleosides. Palladium-catalysed reactions have been developed by Heck and co-workers for carbon+arbon bond formation,' 'and have been utilised by various investigators for carboannulation and heteroannulation processes.' The application of this useful reaction for the synthesis of 5-substituted uracil nucleosides was first reported by Bergstrorn2' and since then has been used by him and other investigators for the synthesis of a number of uracil nucleosides with vinylic moieties or the corresponding saturated entities at the C-5 position of the uracil ring.21 The attachment of alkynyl substituents to aromatic and heterocyclic rings through palladium-catalysed reaction of acetylenic substrates has been reported by other investigators.22 A number of 5-alkynyluracil nucleosides have also been synthesized by coupling of terminal alkynes with 5-iodouracil nucleosides in the presence of palladium catalysts.23 In our attempt towards the palladium-mediated synthesis of AEUs, we started with 5-iodo-2,4-dimethoxypyrimidine1as the starting material (Scheme 1).5-Iodo-2,4-dimethoxypyrimidine was used instead of 5-iodouracil due to the poor solubility of the latter in most organic solvents, and was obtained either by direct iodination of 2,4-dimethoxypyrimidine with N-iodo- succinimide in trifluoroacetic acid-trifluoroacetic anhydride 24 or from 5-iodouracil by the procedure of PrystaS and S~rm.~' The other components for the coupling reaction, e.g. the acetylenic ketones 3, were obtained by the oxidation26 of the corresponding acetylenic alcohols 2 which were synthesized according to the procedure of Jones and McC~mbie.~' The acetylenic ketones were condensed with 5-iodo-2,4-dimeth- oxypyrimidine in the presence of bis(tripheny1phosphine)-palladium(r1) chloride, copper(1) iodide and sodium hydrogen carbonate in acetonitrile at 50 "C to give 5-(acylethynyl)-2,4- dimethoxypyrimidines4 and 6 in 15-19 yield.The poor yields in the palladium-catalysed reaction could be attributed to the polymerisation of the acetylenic ketones under the reaction conditions. The use of other solvents dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and Et3EJl and bases (Et3N) did not improve the yields. In order to obviate the problems associated with polymerisation of acetylenic ketones, we condensed 5-iodo-2,4-dimethoxypyrimidinewith the acetyl- enic alcohols 2 in the presence of bis(tripheny1phosphine)-palladium(I1) chloride and copper(1) iodide in stirred triethyl- amine at 55OC for 6 h.Although there was some dimeris- J. CHEM. SOC. PERKIN TRANS. 1 1993 ?Me 44 HCECCHpOH HCZCCH(0H)R 2 (R = Ph. C~H~MS~, iii c6H40MWJ) / j*.and II 10 7-9 11-13 4Y7 and 11 Ph 598 and 12 Camp;Me -p 6Y9 and 13 C6H40Me-p Scheme 1 Reagents and conditions: i, (PPh,),PdCl,, Cul, NaHCO, 1in MeCN, 50 OC; ii, (PPh,),PdCl,, Cul, Et,N, 55 OC; iii, MnO,, Ch,Cl,; iv, 6 mol dm-3, HCl; v, NaOH in 95 EtOH ation 28 of the acetylenic alcohols, excellent yields (85-99) of 5-(3-aryl-3-hydroxyalkynyl)-2,4-dimethoxypyrimidines 7-9 were obtained under the reaction conditions. It appears that condensation of the acetylenic alcohols with 5-iodo-2,4-dimethoxypyrimidine was faster under palladium catalysis than was the self-dimerisation of the acetylenic alcohols.When propargyl alcohol (prop-2-yn-1-01) was condensed with compound 1 under palladium catalysis, 5-(3-hydroxyprop-2- ynyl)-2,4-dimethoxypyrimidine10 was obtained in a some-what lower yield (63). Compounds 7-10 were well characterised by their IR absorption at 3260 and 2200 cm-' (weak, CX), UV absorption maxima at 280 nm, and their characteristic 'H NMR spectra. They were identical with those reported earlier." The alcohols 7-9 were found to be susceptible to slow aerial oxidation. Oxidation of the alcohols 7-9 with manganese dioxide in dichloromethane led to the corresponding ketones 4-6, which were identical with those synthesized directly by coupling of 5-iodo-2,4-dimethoxypyri-midine with the acetylenic ketones 3.The synthesis of the ketones 4-6 by an alternative route and their conversion into AEUs 11-13 have also been reported by us.15The palladium- catalysed procedure for the synthesis of AEUs 11-13 was, however, found to be much superior (overall yields 4045 based on 5-iodo-2,4-dimethoxypyrimidine)to the Grignard procedure" for the synthesis of ynones 11-13 (overall yields 1620 based on substrate 1) or to the silicon-mediated synthesisI3 for ynones 11-13 (overall yields 7-9 based on 5-acetyluracil). In our efforts towards the synthesis of 2'-deoxyribo-nucleosides of AEUs 11-13, we successfully silylated compounds 11-13 with hexamethyldisilazane and chlorotrimethylsilane.However, the condensation of the silyl derivatives with 2-deoxy- 3,5-di-O-(p-toluoy1)-a-D-erythro-pentofuranosylchloride under various conditions2' failed. The reason could be the weaker nucleophilicity of the N-1 nitrogen atom, due to the presence of an electron-withdrawing group at C-5 of the uracil moiety. We therefore turned to the palladium-catalysed reaction for the synthesis of the 2'-deoxyribonucleosides and this was accom- plished according to Scheme 2.5-Iodo-N' ,N3-dimethyluracil 14 and N1-benzyl-5-iodouracil 15 were studied as model com- pounds. Their condensation with 1-phenylprop-2-yn- 1-01 2 (R = Ph) in the presence of bis(tripheny1phosphine)palla-dium(I1) chloride, copper(1) iodide and triethylamine in DMF took place readily to yield compounds 16 and 17, respectively, in excellent yield.These compounds were oxidised with pyridi- nium chlorochromate (PCC) 30 to afford the corresponding ketones, uiz. 5-(benzoylethyny1)-N',N3-dimethyluracil 18 and 5-(benzoylethyny1)-N '-benzyluracill9. The condensation of 5-iodo-3',5'-di-O-(p-toluoyl)-2'-deoxy-uridine 20 with the acetylenic ketones 3 (R = Ph, C,H,OMe-p) was accomplished in the presence of catalytic amounts of bis(triphenylphosphine)palladium(u) chloride and copper@) iodide in the presence of sodium hydrogen carbonate as a base in stirred acetonitrile at 50 "C for 8 h. However, the yields of the condensation products 25 and 27 were extremely poor ( -20). However, 5-iodo-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine 20 readily condensed with the acetylenic alcohols 2 in the presence of bis(triphenylphosphine)palladium(II) chloride, copper(1) iodide and triethylamine in DMF.The yields of the condensa- tion products were found to be excellent, uiz. 21 (92), 22 (93),23 (88) and 24 (83). In the IR spectra, the condensa- tion products 21-24 showed absorption at -3440 (hydroxy group), 1720 (conjugated carbonyl) and 1660 (ureido) cm-'. No absorption for the acetylenic triple bond could be seen. In the UV spectra, the compounds exhibited absorption maxima between 285 and 291 nm. In the 'H NMR spectra, these compounds exhibited a multiplet at 6 2.08-2.96 (due to 2'-H,), a multiplet at 6 -4.404.88 (due to 4'- and 5'-H,) and another multiplet at 6 5.44-5.74 (due to 3'-H and side-chain 3-H).The 1 '-hydrogen exhibited a double doublet at 6 6.24-6.48, indicating the P-configuration for the nucleosides. The aromatic protons exhibited signals at appropriate positions (see Experimental section). The acetylenic alcohols 21-24 were readily oxidised with PCC in dichloromethane to the corresponding ketones, 5-(acylethynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridines 25-28. These were obtained as solids after column chromatography on silica gel and were identical with the samples previously obtained by the direct condensation of iodide 20 with the acetylenic ketones 3 under palladium-catalysed conditions. In contrast to the acetylenic alcohols 21-24, the ketones 25-28 exhibited strong absorption at -2200 cm-' due to the 2659J.CHEM. SOC. PERKIN TRANS. 1 1993 0 OH HC EC- $-Ph 0 OH I ii ~ OAN and I R' R' 14 and 15 16 and 17 18 and 19 14,16 and 18 R' = f? = Me 15,17 and 19 R' = CH2Ph,f? = H 0 II OANHNc=c-cR ii *Row ROP ROPOR' OK OR' 20 21 -24 4 25-28 HCECCOR 3 (R = Ph, Camp;i40Me-p) and iii iv R 21, 25 and 29 Ph 0 II22, 26 and 30 C6H4Me-p 23, 27 and 31 CeH40Me-p 24, 28 and 32 CeH4Me-O HNcEc-cR20 -28 R' = COC6H4Me-p OAN OH 29 -32 Scheme 2 Reagents: i, (PPh,),PdCl,, Cul, Et3N, DMF; ii, PCC, CH,CI,; iii, (PPh,),PdCl,, Cul, NaHCO,, MeCN; iv, NaOMe, MeOH conjugated acetylenic group. In the UV spectra, the compounds Experimenta1 showed absorption maxima between 323 and 333 nm.In the 'H M.p.s were determined on a Reichert 285980 (Austria) m.p.- NMR spectra, the ketones 25-28 exhibited a multiplet at 6 bath and are uncorrected. UV spectra were recorded on a 2.08-2.96 (2'-H,), a multiplet at 6 4.40-4.96 (4' and 5'-H,) and a Hitachi 20amp;20 spectrometer for solutions in spectrophoto- double doublet at 6 6.16-6.48 (1'-H). 5-(Acylethynyl)-3',5'-di-metric-grade ethanol (Baker). IR spectra were taken on a O-(p-toluoyl)-2'-deoxyuridines25-28on treatment with sodium Perkin-Elmer 298 instrument for samples on KBr plates. 'H methoxide in methanol were smoothly converted into the target NMR spectra were recorded on a Varian XL-200 spectrometer, compounds, the 5-(acylethynyl)-2'-deoxyuridines 29-32.These a 100 MHz FX-100 spectrometer, or on a 60 MHz EM 360L were characterised by their elemental analyses, IR absorption at spectrometer, for samples in solvents as indicated, with 2200 cmP1 (conjugated acetylenic group), W absorption tetramethylsilane as internal standard, J values being in Hz.maxima at 325-335 nm, and their 'H NMR spectra (see Silica gel TLC was performed on 60F-254 precoated sheet Experimental section). (E. Merck) and column chromatography was done on silica gel In conclusion, we report for the first time the condensation of (60-120 mesh). Elemental analyses were performed on a Perkin-conjugated acetylenic ketones with iodopyrimidines and 5- Elmer elemental analyser 240 C. All solvents and reagents were iodouracil nucleosides under palladium-catalysed conditions, reagent-grade materials and were further purified by conven- which proceeded in only poor yield.However, a two-step tional methods. (+)-5-Iodo-2'-deoxyuridine was obtained from procedure involving reaction of acetylenic alcohols with Aldrich Chemical Co., Milwaukee, Wisconsin USA. iodopyrimidines or 5-iodouracil nucleosides under palladium The 1-arylprop-2-yn- 1-01s 2 were synthesized according to catalysis and subsequent oxidation of the products with the published procedure^.^^ The 1-arylprop-2-yn-1-ones 3were PCC led to the pyrimidine- or uracil-substituted conjugated synthesized by oxidation of the corresponding alcohols with acetylenic ketones in excellent yield. Thus, the process has Jones' reagent.26 yielded 5-(acylethyny1)uracils and their corresponding 2'-deoxyribonucleosides in good yield.5-(Acylethyny1)uracils 11-Synthesisof 5-(3-Aryl-3-hydroxyprop-1 -ynyl)-2,4-dimethoxy- 13 were found to be active against CCRF-CEM human pyrimidines by Palladium-catalysed Reactions.-Typical proce-lymphoblastoid cells and L1210/0 mouse leukaemia cells in dure: 5-(3-hydroxy-3-phenylprop-l-ynyl)-2,4-dimethoxypyrimi-culture. They were also inhibitors of the TS enzyme.16 dine 7. A mixture of 5-iodo-2,4-dimethoxypyrimidine124 (300 Biological and biochemical studies on 5-(acylethynyl)-2'-deoxy mg, 1.12 mmol), bis(tripheny1 phosphine)palladium(rr) chloride uridines 29-32are in progress. (10 mg, 0.014 mmol) and copper(1) iodide (10 mg, 0.05 mmol) in triethylamine (10 an3)was stirred under nitrogen for 30 min.1- Phenylprop-2-yn-1-01 (180 mg, 1.36 mmol) was then added to the mixture and this was further stirred at 55-60 "C for 6 h, when TLC indicated complete disappearance of the starting material. The residue, obtained after removal of triethylamine, was treated with water (75 cm3) and extracted with chloroform (3 x 50 cm3). The combined extracts were washed with water (3 x 50 cm3) and dried (Na2S04). After evaporation of the solvent a brown gum was obtained, which was purified by chromatography on a column of silica gel (60-120 mesh; chloroform eluent) to afford 5-(3-hydroxy-3-phenylprop-1-ynyl)-2,4-dimethoxypyrimidine 7 (260 mg, 85) as gum, identical with an authentic sample from spectroscopic (IR, UV, 'H NMR) comparisons.5-3-Hydroxy-3-(p-tolyl)prop-1-ynyl-2,4-dimethoxypyri-midine 8. This was synthesized according to the above procedure from 5-iodo-2,4-dimethoxypyrimidine1 (1 g, 3.76 mmol), bis(triphenylphosphine)palladium(iI) chloride (30 mg, 0.042 mmol), copper(1) iodide (25 mg, 0.13 mmol) and l-(p- tolyl)prop-2-yn- 1-01 (660 mg, 4.52 mmol) to yield compound 8 after column chromatography (SiO,, 60-120 mesh) as a light brown solid (1 g, 94), which was crystallised from diethyl ether-light petroleum (4040deg;C) to give a solid, m.p. 108 "C (lit.," 110 "C). This was identical with an authentic sample from IR, UV and 'H NMR spectroscopic comparisons. 5-3-Hydroxy-3-(p-methoxyphenyl)prop-1-ynyl-2,4-di-methoxypyrimidine 9.This was synthesized, by following the procedure as for compounds 7 and 8, from 5-iodo-2,4-dimethoxypyrimidine 1 (2 g, 7.52 mmol), bis(tripheny1- phosphine)palladium(n) chloride (60 mg, 0.085 mmol), copper(1) iodide (50 mg, 0.26 mmol) and 1-p-methoxyphenyl)prop-2-yn-1-01 (1.80 g, 11.1 mmol) to yield compound 9 (2.24 g, 99) after chromatography (SO2, 60-120 mesh), and which was crystallised from diethyl ether-light petroleum (60-80 "C) to a solid, m.p. 117 "C (lit.," 116-1 17 "C), identical with an authentic sample ' from spectroscopic comparisons. 5-(3-Hydroxyprop- 1 -ynyl)-2,4-dimethoxypyrimidine10. This was synthesized from 5-iodo-2,4-dimethoxypyrimidine1 (1 g, 3.76 mmol), propargyl alcohol (280 mg, 5 mmol), bis(tripheny1- phosphine)palladium(II) chloride (30 mg, 0.043 mmol) and copper(r) iodide (25 mg, 0.13 mmol).After purification by chromatography (SiO,, 60-120 mesh), compound 10, a solid (460 mg, 63), was obtained, which was crystallised from light petroleum (60-8OoC), m.p. 124 "C (lit.,I5 120-122 "C), identical with an authentic sample from spectroscopic comparisons. Synthesisof 5-(A cylethynyl)-2,4-dimethoxypyrimidines4-6-. Method A: Oxidation of compounds 7-9 to the corresponding ketones 4-6 with manganese dioxide. See ref. 15. Method B: Palladium-catalysed reaction. Synthesis of 5-(benzoylethynyl)-2,4-dimethoxypyrimidine4. A mixture of 5-iodo-2,4-dimethoxypyrimidine1 (260 mg, 0.98 mmol) in acetonitrile (1 0 cm3), bis(triphenylphosphine)palladium(n) chloride (1 0 mg, 0.014 mmol) and copper(1) iodide (1 0 mg, 0.05 mmol) was stirred under nitrogen for 15 min.1-Phenylprop-2- yn-1-one (250 mg, 1.92 mmol) was then added to the mixture, followed by addition of sodium hydrogen carbonate (100 mg, 1.2 mmol) after 15 min. The whole mixture was then stirred at room temperature (30 "C) for 1 h and at 50 " for 8 h. The solvent was then removed under reduced pressure to yield a black residue, which was treated with water (50 cm3) and extracted with chloroform (3 x 50 cm3). The combined extracts were washed successively with disodium EDTA (10; 3 x 50 cm3) and water (3 x 50 cm3) and dried (anhydrous sodium sulfate). After removal of solvent, the residue was purified by chromatography SiO,, 60-120 mesh; eluent 10 ethyl acetate in light petroleum (60-80 "C), followed by chloroform to yield compound 4 as a solid (40 mg, 15), which was crystallised J.CHEM. SOC. PERKIN TRANS. 1 1993 from methanal to give a solid, m.p. 125 "C (lit.," 124-125 "C), identical with an authentic sample from spectroscopic comparisons. 2,4-Dimethoxy-5-(p-methoxybenzoylethynyl)pyrimidine6. This was obtained in 19 yield from 5-iodo-2,4-dimethoxypy- rimidine 1 (240 mg, 0.90 mmol), bis(tripheny1phosphine)-palladium(I1) chloride (10 mg, 0.014 mmol), copper(1) iodide (10 mg, 0.05 mmol), 1 -(p-methoxyphenyl)prop-2-yn-1 -one (300 mg, 1.87 mmol) and sodium hydrogen carbonate (100 mg, 1.20 mmol) by following the procedure for compound 4; m.p. 135 "C (lit.," 136 "C).5-( 3-Hydroxy-3-phenylprop- 1 -yny 1)-N ',N3-dimethyluracil 16.A solution of 5-iodo-N1,N3-dimethyuracil14 24 (270 mg, 1 .O mmol) in DMF (1 0 cm3),bis(triphenylphosphine)palladium(n) chloride (30 mg, 0.043 mmol) and copper(i) iodide (30 mg, 0.16 mmol) was stirred under nitrogen for 15 min. 1-Phenylprop-2- yn-1-01 (260 mg, 1.97 mmol) and triethylamine (200 mg, 1.98 mmol) were then added and the mixture was further stirred at 50 "C for 6 h. After removal of solvent, the residue was treated with water (50 cm3) and extracted with chloroform (3 x 50 cm3). The combined extracts were washed with water (3 x 50 cm3), dried (anhydrous sodium sulfate), and the solvent was removed to yield a brown gum, which was purified by chromatography (SO,, 60-120 mesh; eluent 4 methanol in chloroform) to afford compound 16 as a solid (250 mg, 91), which was crystallised from methanol, m.p.203-204 "C (Found: C, 66.5; H, 5.45; N, 10.6. ClsHl4N2O3 requires C, 66.65; H, 5.2; N, 10.4); v,/cm-' 3400,2230, 1690 br and 1633 br; A,,/nm 295 (E 15 480) and 233 (15 770); 6 (2H6) DMSO + CDCl,; 60 MHz 3.33 (3 H, s, 1-Me), 3.39 (3 H, s, 3-Me), 5.60 (1 H, d, J 6, OH), 5.79 (1 H, d, J6, CHOH), 7.26-7.73 (5 H, m, ArH) and 7.79 (1 H, S, 6 -H). 5-(Benzoylethynyl)-N',N3-dimethyZuracil18. To a solution of 5-(3-hydroxy-3-phenylprop-1 -ynyl)-N ,N 3-dimethyluracil 16 (100 mg, 0.37 mmol) in dichloromethane (25 cm3)was added PCC (640 mg, 2.97 mmol). The mixture was stirred at room temperature (30 "C) for 2 h, filtered, and the residue was washed with dichloromethane (3 x 10 cm3).The combined filtrates, on evaporation of solent, furnished a solid, which was purified by chromatography on a short column of silica gel (25 ethyl acetate in chloroform as eluent) (90 mg, 90)and recrystallised from methanol to give compound 18 as a solid, m.p. 275 "C (Found: C, 66.8; H, 4.5; N, 10.3. C,sH,2N,03 requiresc, 67.15; H, 4.5; N, 10.4); vmaw/cm-' 2200vs, 1705,1660,1640 and 1620; A,,,/nm 332 (E 22 040) and 265 (1 1 610); d (C2H6DMSO; 60 MHz) 3.30 (3 H, s, 1-Me), 3.46 (3 H, s, 3-Me), 7.59-7.89 (3 H, m, ArH,,,) 8.16-8.46 (2 H, m, ArH,) and 8.76 (lH, s, 6-H). N'-Benzyl-5-iodouracil 15. A mixture of the potassium salt of 5-iodouracil made by stirring of 5-iodouracil(6 g, 25.21 mmol) and anhydrous potassium carbonate (3.6 g, 26.08 mmol) in DMF (75 cm3)for 2 days at room temperature and benzyl bromide was stirred at room temperature for 6 days.After removal of solvent under reduced pressure and work-up, a semi-solid mass was obtained. This was chromatographed on a column of silica gel (60-120 mesh) to yield N', N3-dibenzyl-5-iodouracil (eluent chloroform) (4.4 g, 42), m.p. 104-105 "C (lit.,24 102-104 "C) and N1-benzyl-5-iodouracil 15 (eluent 25 ethyl acetate in chloroform) (2.2 g, 26), which was crystallised from methanol, m.p. 216-217deg;C (Found: C, 40.5; H, 3.0. C11H91N202 requires C, 40.3; H, 2.8); vmax/cm-' 1715, 1670 and 1610; A,,,/nm 292 (E 10 075); 6(C2H6DMS0 + CDCl,; 60 MHz) 4.92 (2 H, s, 1-CH,), 7.36 (5 H, s, ArH) and 7.89 (1 H, S, 6-H).5-(Benzoylethynyl)-N1-benzyluraciZ19. A mixture of N'-benzyl-5-iodouracil(330 mg, 1 mmol), bis(tripheny1phosphine)-palladium(ii) chloride (70 mg, 0.1 mmol), copper(1) iodide (40 mg, 0.21 mmol), l-phenylprop-2-yn-l-01(270mg, 2 mmol) and triethylamine (200 mg, 1.98 mmol) in DMF (1 0 an3)was stirred J. CHEM. soc. PERKIN TRANS. 1 1993 at 50 "C under nitrogen for 6 h. After removal of solvent, the residue, on work-up and purification by chromatography (SiO,, 60-1 20 mesh; eluent 4 methanol in chloroform), yielded N1-benzyl-5-(3-hydroxy-3-phenylprop-l-ynyl)uracil 17 as a gum (280 mg, 84). A portion of compound 17 (100 mg, 0.3 mmol) was oxidised with PCC (650 mg, 3.02 mmol) in dichloromethane (10 cm3) stirred at room temperature for 2 h.After work-up and purification by column chromato-graphy, a light yellow solid (70 mg, 70) was obtained, which was crystallised from methanol to give compound 17 as a solid, m.p. 210deg;C (Found: C, 72.6; H, 4.3; N, 8.6. C20H14N203 requires C, 72.8; H, 4.3; N, 8.5); v,,,/cm-' 2210, 1715, 1685, 1640 and 1620; A,,/nm 331 (E 23 290) and 266 (12 720); G(C2HBDMSO; 60 MHz) 5.07 (2 H, s, benzylic H), 7.43 (5 H, m, ArH), 7.56-7.86 (3 H, m, ArHm,p), 8.16-8.43 (2 H, m, ArH,) and 8.86 (1 H, s, 6-H). Synthesis of 5-(3-Aryl-3-hydroxyprop-l-ynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridines.-Typical procedure: Synthesis of 5-(3-hydroxy-3-phenylprop-1-ynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine 21.Bis(triphenylphosphine)palladium(Ir) chloride (40 mg, 0.057 mrnol) and copper(1) iodide (20 mg, 0.10 mmol) were added to a magnetically stirred solution of 5-iodo-3',5'-di- O-(p-toluoyl)-2'-deoxyuridine20 (280 mg, 0.47 mmol) in DMF (10 cm3) under nitrogen. After 15 min, 1 -phenylprop-2-yn- 1-01 (150 mg, 1.13 mmol) was added to the mixture, followed by addition of triethylamine (100 mg, 0.99 mmol). The mixture was then heated at 50deg;C for 5 h. After removal of solvent under reduced pressure, the residue was dissolved in chloroform. The chloroform solution was washed successively with 10 aq. disodium EDTA (3 x 50 cm3) and water (3 x 50 cm3) and was dried (anhydrous Na2S04). After removal of solvent, the residue was purified by column chromatography (SiO,, 60-120 mesh; eluent 4 methanol in chloroform) to yield 5-(3-hydroxy- 3-phenylprop- 1 -ynyl)-3', 5'-di-O-(p-toluoyl)-2'-deoxyuridine 21 (260 mg, 92) which was crystallised from chloroform- methanol to give a solid, m.p.205-206 "C (Found: C, 68.7; H, 5.0; N, 5.0. C~,H~ON~O~requires C, 68.7; H, 5.1; N, 4.7); Ymax/cm-' 3420 br, 1720, 1710, 1660 and 1610; Amax/nm 285 (E 14 790) and 239 (42 660); G(CDC1,; 100 MHz), 2.08-2.92 (2 H, 266 1 3450 br, 1710, 1670 and 1610; A,/nm 284 (E 18 200) and 237 (54 950); G(CDC1,; 100 MHz) 2.08-2.96 (2 H, m, 2'-H,), 2.32 (3 H, s, ArMe), 2.40 (3 H, s, ArMe), 3.76 (3 H, s, ArOMe), 4.40- 4.88 (3 H, m, 4'-H and 5'-H,), 5.36-5.68 (2 H, m, 3'- and CHOH), 6.24-6.48 (1 H, dd, 1'-H), 6.72-8.16 (13 H, m, ArH and 6-H) and 8.60 (1 H, br s, NH).5-3-Hydroxy-3-(0- toly1)prop- 1 -ynyl -3', Y-di-O-(p-toluoyl )-2'-deoxyuridine 24. This was prepared in 83 yield from I-(0- tolyl)prop-2-yn-1-01 (I 50 mg, 1.02 mmol) and the other reagents as for compound 22; after purification by chromatography, a foam was obtained; this was crystallised from chloroform- diethyl ether to give compound 24,m.p. 21 6-21 8 "C (Found: C, 68.7; H, 5.1; N, 4.6. C35H,,N,08 requires C, 69.1; H, 5.30; N, 4.60); v,,,/crr-' 3440 br, 1720, 1710, 1670 and 1610; I,,,/nm 291 (E 12 880) and 239 (38 020); G(CDC1,; 200 MHz) 2.22-2.96 (2 H, m, 2'-H2), 2.40 (3 H, s, ArMe), 2.42 (3 H, s, ArMe), 2.46 (3 H, s, ArMe), 4.58-4.86 (3 H, m, 4'-H and 5'-H,). 5.58-5.74 (2 H, m, 3'- and CHOH), 6.36-6.46 (1 H, dd, 1'-H), 7.18-7.40 (7 H, m, ArH), 7.64-7.74 (1 H, m, ArH,), 7.88-8.04 (5 H, m, ArH and 6-H) and 8.94 (1 H, br s, NH).5-(Acylethynyl)-3', 5'-di-O-(p-toluoyl)-2'-deoxyuridines25-28.-Method A. PCC oxidation of 5-(3-aryl-3-hydroxyprop-l-ynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridines. General pro-cedure. To a magnetically stirred solution of 5-(3-hydroxy-3- phenylprop-l-ynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine 21 (100 mg, 0.17 mmol) in dichloromethane (25 cm3) was added PCC (340 mg, 1.58 mmol). The mixture was stirred at room temperature for 2 h, filtered, and the residue was washed with dichloromethane (3 x 10 an3).The combined filtrates, on evaporation of solvent, furnished a solid, which was purified on a short column of silica gel (60-120 mesh; 10 ethyl acetate in chloroform as eluent) to yield 5-(benzoylethynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine 25 as a solid (90 mg, 90), which was crystallised from methanol, m.p.220 "C (Found: C, 68.7; H, 4.9; N, 4.7. C34H28N208 requires C, 68.9; H, 4.8; N, 4.7); v,,/cm-' 2200 s, 1730, 1715, 1695, 1640, 1620, 1610 and 1595; I,,,/nm 325.6 (E 22 390) and 243 (39 810); G(CDC1,; 100 MHz) 2.08-2.96 (2H,m,2'-H,), 2.24(3 H,s, ArMe),2.40(3 H, s,ArMe),4.40-4.96 (3 H, m, 4'-H and 5'-H,), 5.44-5.76 (1 H, apparent doublet, m,2'-H2),2.32(3H,s,ArMe),2.44(3H,s,ArMe),4.52-4.62(1H,3'-H), 6.16-6.48 (1 H, dd, 1'-H), 7.04-8.48 (14 H, m, ArH and m, 4'-H), 4.62-4.80 (2 H, m, 5'-H,), 5.44-5.68 (2 H, m, 3'- and side-chain 3-H), 6.24-6.44 (1 H, dd, 1'-H), 7.08-7.64 (9 H, m, ArH), 7.80-8.04 (5 H, m, ArH and 6-H) and 8.68 (1 H, br s, NH).5- 3-Hydroxy-3-(p-tolyl)prop-1-ynyl-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine 22. This was synthesized by following the above procedure, from compound 20 (280 mg, 0.47 mmol), bis(triphenylphosphine)palladium(n) chloride (40 mg, 0.056 mmol), copper(1) iodide (20 mg, 0.10 mmol), 1-(p-toly1)prop-2- yn-1-01 (140 mg, 0.95 mmol) and triethylamine (100 mg, 0.99 mmol) in DMF (10 ml). After work-up and purification, a foam (270 mg, 93) was obtained, which was crystallised from chloroform-diethyl ether to give compound 22, m.p. 218-219 "C (Found: C, 69.1; H, 5.7; N, 4.8. C35H32N208 requires C, 69.1; H, 5.30; N, 4.60); v,,,/crn-' 3450 br, 1720, 1710,1665 and 1610w; A,,,/nm 291 (E 15 140) and 239 (44670); G(CDC1,; 270 MHz) 6-H) and 8.96 (1 H, br s, NH).3', 5'-Di-O-(p-toluoyl)-5-(p-toluoylethynyl)-2'-deoxyuridine 26. This compound was obtained in 90 yield, and was crystallised from methanol, m.p. 222 "C (Found: C, 69.6; H, 5.4; N, 4.45. C,,H,,N,O, requires C, 69.3; H, 5.0; N, 4.6); vmax/cm-' 2200 s, 1730, 1720, 1695, 1635 and 1605; I,,,/nm 326 (E 24 000) and 241 (37 150); G(CDC1,; 270 MHz) 2.26 (1 H, m, 2'-H), 2.28 (3 H, s, ArMe), 2.44 (6 H, s, ArMe), 2.84 (1 H, m, 2'-H), 4.60-4.86 (3 H, m, 4'-H and 5'-H,), 5.56 (1 H, m, 3'-H), 6.34(1 H,dd, J5.37and8.42, l'-H),7.17-8.15(12H,m,ArH), 8.20 (1 H, s, 6-H) and 8.37 (1 H, s, NH). 5-(p-Methoxybenzoylethynyl)-3',5'-di-O-(p-toluoyl)-2'-de-oxyuridine 27.This compound was prepared in 90 yield, and was crystallised from methanol, m.p. 212-214 "C (Found: C, 67.3; H, 5.0; N, 4.8. C35H30N209 requires C, 67.5; H, 4.9; N, 2.26(1H,m,2'-H),2.32(6H,s,ArMe),2.43(3H,s,ArMe),2.784.50); v,,,/cm-' 2210, 1730, 1720, 1700, 1635, 1615 and 1600; (1 H, m, 2'-H), 4.55-4.82 (3 H, m, 4'-H and 5'-H and 5'-H,), 5.47 (1 H, s, CHOH), 5.58 (1 H, m, 3'-H), 6.36 (1 H, dd, J5.67 and 8.48, 1'-H), 7.10-7.96 (13 H, m, ArH and 6-H) and 8.14 (1 H, s, NH). 5-3-Hydroxy-3-(p-methoxyphenyl)prop-1 -ynyl-3', 5'-di-0- (p-toluoyl)-2'-deoxyuridine23. This was synthesized according to the procedure for compound 22 by utilising 1-(p-methoxy- phenyl)prop-2-yn- 1-01 (160 mg, 0.98 mmol) in 88 yield, which was crystallised from chloroform-diethyl ether, to give compound 23, m.p.222-224 "C (Found: C, 67.3; H, 5.3; N, 4.7. C35H32N209requires C, 67.30; H, 5.2; N, 4.5); v,,,/cm-' I,,,/nm 332.5 (E 38 900) and 242 (56 230); G(CDC1,; 100 MHz) 2.16-2.96 (2 H, m, 2'-H2), 2.24 (3 H, s, ArMe), 2.40 (3 H, s, ArMe), 3.84 (3 H, s, ArOMe), 4.484.88 (3 H, m, 4'-H and 5'-H,), 5.44-5.76 (1 H, apparent d, 3'-H), 6.16-6.48 (1 H, dd, 1 '-H), 6.88-8.32 (1 3 H, m, ArH and 6-H) and 8.72 (1 H, s, NH). 3',5'-Di-O-(p-toluoyl)-5-(o-toluoylethynyl)-2'-deox~ridine 28. This compound was also obtained in 90 yield, from PCC oxidation of the alcohol 24 and was crystallised from methanol, m.p. 223-224 "C (Found: C, 69.6; H, 4.7; N. 4.7. C35H,oN,08 requires C, 69.3; H, 5.0; N, 4.6; v,,,/cm-' 2200 s, 1730, 17 15, 1695, 1640, 1620 and 1610; I,,Jnm 323 (E 28 180) and 242 J.CHEM. SOC. PERKIN TRANS. I 1993 (47 860); G(CDCl,, 100 MHz) 2.08-2.96 (2 H, m, 2'-H,), 2.24 apparent tr, 2'-H,), 3.68 (2 H, m, 5'-H,), 3.84 (4 H, s, ArOMe (3 H, s, ArMe), 2.40 (3 H, s, ArMe), 2.60 (3 H, s, ArMe), 4.48- and 4'-H), 4.32 (1 H, m, 3'-H), 5.28 (2 H, m, 2 x OH), 6.1 2 (1 H, 4.96 (3 H, m, 4'-H and Y-H,) 5.52-5.76 (1 H, apparent d, 3'-H), t, 1'-H), 7.12 (2 H, d, J 10.0, ArH,), 8.16 (2 H, d, J 10.0, ArH,), 6.24-6.48 (1 H, dd, 1'-H), 7.12-8.40 (1 3 H, m, ArH and 6-H) and 8.72 (1 H, s, 6-H) and 1 1.92 (1 H, s, NH). 8.80 (1 H, br s, NH). 5-(0-Toluoylethynyl)-2'-deoxyuridine 32. This compound was Method B.Palladium-mediated synthesis of 5-(acylethyny1)-synthesized from 3',5'-di-O-(p-toluoyl)-5-(o-toluoylethynyl)-2'-3',5'-di-O-(p-toluoyl)-2'-deoxyuridines.Typical procedure.Syn- deoxyuridine 28 in 82 yield, and had m.p. 167-1 68 "C(Found: thesis of 5-(benzoylethynyl)-3',5',-di-O-(p-toluoyl)-2'-deoxy-C,61.5;H,4.8;N,7.7.ClgHl8N,O6requiresC,61.6;H,4.90;N, uridine 25. To a well stirred solution of 5-iodo-3',5'-di-O- 7.6); v,,,/cm-' 2210, 1710, 1690, 1630 and 1610; A,,,/nm 325 (p-toluoyl)-2'-deoxyuridine 20 (280 mg, 0.47 mmol) in (E 21 380); G(C2H6DMSO; 100 MHz) 2.20 (2 H, t, 2'-HJ, 2.56 acetonitrile (10 cm3) under nitrogen were added bis(tripheny1- (3 H,s, ArMe), 3.60 (2 H, m, 5'-H,), 3.84 (1 H, m, 4'-H), 4.24 phosphine)palladium(II) chloride (40 mg, 0.057 mmol), copper(1) (1 H, m, 3'-H), 5.20(2 H, m, 2 x OH), 6.12(1 H, t, 1'-H), 7.28- iodide (20 mg, 0.10 mmol) and, after 15 min, 1 -phenylprop-2-yn- 7.68 (3 H, m, ArH,,,p), 8.24-8.40 (1 H, m, ArH,), 8.72 (1 H, s, 1-one (130 mg, 1 mmol).The mixture was stirred for 1 h and 6-H) and 11.84 (1 H, s, NH). then sodium hydrogen carbonate (100 mg, 1.2 mmol) was added. This mixture was further heated at 50 "C for 8 h and then the solvent was removed to yield a black residue, which was Acknowledgementspurified by chromatography (SiO,, 60-120 mesh; 10 ethyl Financial assistance from the Department of Science and acetate in chloroform as eluent) to give compound 25 as a solid Technology, Government of India, under a grant to N. G. K.(50 mg, 17.80), which was crystallised from methanol, m.p.(Grant No. SP/S1/G-45/88) is gratefully acknowledged. Thanks 218 "C, identical with the sample synthesized by Method A are due to Dr. D. F. Ewing, University of Hull, for the 270 MHz (from spectroscopic comparisons). NMR spectra. We also thank Dr. C. P. Spears of the University 5-(p-Methoxybenzoylethynyl)-3',5'-di-O-(p-toluoyl)-2'-de-of Southern California, Comprehensive Cancer Center, Losoxyuridine 27. This compound was synthesized from compound Angeles, California, USA, for samples of 5-iodo-2'-deoxyuridine. 20 (280 mg, 0.47 mmol), 1 -(p-methoxyphenyl) prop-2-yn- 1-one (160 mg, 1 mmol) and the other reagents as under compound 25 according to Method B. After purification by column chromatography, solid compound 27(60 mg, 20) was obtained, References which was crystallised from methanol, m.p.212 "C, identical 1 Part 19 of our series on Studies on Uracil Derivatives and Analogues; for Part 18, see: N. G. Kundu, S. K. Dasgupta,with the sample synthesized by Method A from spectroscopic L. N. Chaudhuri, J. S. Mahanty, C. P. Spears and A. H. Shahinian, (IR, UV and 'H NMR) comparisons. Eur. J. Med. Chem., 1993,28,473. 2 C. Heidelberger, Pyrimidine and Pyrimidine Antimetabolites, in 5-(Acylethynyl)-2'-deoxyuridines29-32.-Typical procedure. Cancer Medicine, ed. J. F. Holland and E. Frei, Lea and Febiger, Philadelphia, 1984, pp. 801-824. Synthesisof5-(benzoylethynyl)-2'-deoxyuridine29.A mixture of 3 E. De Clercq and R. T. Walker, Pharmacol. Ther., 1984,26, 1.5-(benzoylethynyl)-3',5'-di-O-(p-toluoyl)-2'-deoxyuridine25 (50 mg, 0.08 mmol) and sodium methoxide made from sodium 4 C. Heidelberger and D. H. King, Antiviral Agents in Pharmacology and Therapeutics, ed. D. Shugar, Pergamon Press, Oxford, England, (4.14 mg, 0.18 mmol) and anhydrous methanol (4 cm3) was 1979, vol. 6. p. 427. stirred at room temperature for 6 h, when TLC indicated 5 E. De Clercq, J. Descamps, P. De Somer, P. J. Barr, A. S. Jones and complete conversion of the starting material. The solution was R. T. Walker, Proc. Natl. Acad. Sci. USA, 1979,76,2947. 6 J. P. Horwitz, J. Chua and M. Noel, J. Org. Chem., 1964, 29, 2076; carefully neutralised by addition of Dowex 50-X8 (H') resin, T.-S. Lin and W. H. Prusoff, J. Med. Chem., 1978,21, 109.filtered, and the resin was washed with methanol. The combined 7 H. Mitsuya, K. J. Weinhold, P. A. Furman, M. H. St. Clair, filtrates, on evaporation, gave a solid, which was triturated with S.N. Lehrman, R. C. Gallo, D. Bolognesi, D. W. Barry and S. Broder,diethyl ether three times to remove the ester formed. The Proc. Natl. Acad. Sci. USA, 1985,82,7096. resultant solid (25 mg, 83) was crystallised from ethanol-light 8 M. A. Fischl, D. D. Richman, M. H. Grieco, M. S. Gottlieb, petroleum (60-80 "C; a few drops) and had m.p. 184-185 "C P. A. Volberding, 0. L. Laskin, J. A. Leedom, J. E. Groopman, (Found: c, 60.5; H, 4.2; N, 8.1. C18H16N206 requires c, 60.7; D. Mildvan, R. T. Schoaley, G. G. Jackson, D. T. Durack and H, 4.5; N, 7.9); v,,,/cm-' 2200, 1730, 1685 and 1610; A,,,/nm D.King, N. Engl, J. Med., 1987,317, 185. 330 (E 20 890); 8('H6DMSO; 100 MHz) 2.18 (2 H, m, 2'-H,), 9 E. De Clercq, J. Balzarini, J. Descamps, C. F. Bigge, C. T.-C. Chang, P. Kalaritis and M. P. Mertes, Biochem. Pharmacol., 1981, 30,495;3.68 (2 H, m, 5'-H,), 3.84 (1 H, br s, 4'-H), 4.24 (1 H, m, 3'-H), E. De Clercq, J. Balzarini, P. F. Torrence, M. P. Mertes, 5.28 (2 H, m, 2 x OH), 6.12 (1 H, t, 1'-H), 7.36-8.00 (3 H, m, C. L. Schmidt, D. Shugar, P. J. Barr, A. S. Jones, G. Verhelst and ArHm,p), 8.08-8.40 (2 H, m, ArH,), 8.80 (1 H, s, 6-H) and 1 1.92 R. T. Walker, Mol. Pharmacol., 1981, 19, 321; H. Griengl, (1 H, br s, NH). M. Bodenteich, W. Hayden, E. Wanek, W. Streicher, P. Stutz, 5-(p-Toluoylethynyl)-2'-deoxyuridine30.This compound was H.Bachmayer, I. Ghazzouli and B. Rossenwirth, J. Med. Chem., 1985,28, 1679; C. K. Chu, R. F. Schinazi, M. K. Ahn, G. V. Ullas obtained from 5-(p-toluoylethynyl)-3',5'-di-O-(p-toluoyl)-2'-and Z. P. Gu, J. Med. Chem., 1989,32,612.deoxyuridine 26 by following the above procedure, in 82 yield; 10 D. V. Santi and P. V. Danenberg in Folates and Pterins, Vol. 1. and was crystallised from ethanol-light petroleum (60-80 "C), Chemistry and Biochemistry of Folates, ed. R. L. Blakley and m.p. 188-190 "C (Found: C, 62.0; H, 4.6; N, 7.5. Cl9H1,N,O, S. J. Benkovic, Wiley, New York, 1984; C. Heidelberger, P. V. requires C, 61.6; H, 4.90; N, 7.6); v,,,/cm-' 2210, 1700, 1680, Danenberg and R. G. Moran, Advances in Enzymology and Related 1640,1615 and 1600; amp;,,,/nm 330 nm (E 25 120); G(C2H,DMSO; Areas in Molecular Biology, ed.A. Meister, Wiley, New York, 1983; L. Maggiora, C. C. T.-C. Chang, P. F. Torrence and M. P. Mertes, 200MHz)2.25(2H,m,2'-H2),2.45(3H,s,ArMe),3.70(2H,m, J. Am. Chem. SOC.,1981,103, 3192; P. V. Danenberg, R. S. Bhatt,5'-H,), 3.90 (1 H, m, 4'-H), 4.30 (1 H, m, 3'-H), 5.32 (2 H, m, N. G. Kundu, K. Danenberg and C. Heidelberger, J. Med. Chem., 2 x OH), 6.12 (1 H, t, 1'-H), 7.46 (2 H, d, J 10.0, ArH,), 8.12 (2 1981,24,1537;P. J. Barr, M. J. RobinsandD. V. Santi, Biochemistry, H, d, J 10, ArH,), 8.20 (1 H, s, 6-H) and 11.92 (1 H, br s, NH). 1983,22, 1696. 11 J. L. Ruth, DNA, 1984,3, 123; Oligonucleotides and Their Analogues, 5-(p-Methoxybenzoylethynyl)-2'-deoxyuridine31. This com-pound was prepared in 80 yield and had m.p.205 "C (Found: ed. F. Eckstein, IRL Press, London, 1991, p. 255; J. A. Brumbaugh, L. R. Middendorf, D. L. Grone and J. L. Ruth, Proc. Natl. Acad. Sci. C, 59.1; H, 5.0; N, 7.0. ClgH18N,0, requires C, 59.1; H, 4.7; N, USA, 1988, 85, 5610; J. M. Prober, G. L. Trainer, R. J. Dam,7.25); v,,,/cm-' 2210, 1700, 1670, 1630, 1615 and 1600; F. W. Hobbs, C. W. Robertson, R. J. Zagursky, A. J. Cocuzza, amp;,,,,/nm 335 (E 33 110); G(2H6DMSO: 100 MHz) 2.24 (2 H, M. A. Jensen and K. Baumeister, Science, 1987, 238, 336. J. CHEM. SOC. PERKIN TRANS. 1 1993 12 R. B. Meyer, Jr., J. C. Tabone, G. D. Hurst, T. M. Smith and H. Gamper, J. Am. Chem. SOC., 1989, 111, 8517; T. J. Povsic and P.B. Dervan, J. Am. Chem. SOC., 1990,112,9428. 13 N. G. Kundu, B. Das, A. Majumder and L. N. Chaudhuri, Tetrahedron Lett., 1987,28,5543. 14 L. W. Hardy, J. S. Finer-Moore, W. R. Montfort, M. 0. Jones, D. V. Santi and R. M. Stroud, Science, 1987, 235, 448; W. R. Montfort, K. 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C. L. Weedon, J. Chem. SOC., 1946, 39; C. Djerassi, R. R. Engle and A. Bowers, J. Org. Chem., 1956,21, 1547. 27 E. R. H. Jones and J. T. McCombie, J. Chem. SOC., 1942, 733; K. N. Campbell, B. K. Campbell and L. T. Eby, J. Am. Chem. SOC., 1938,60,2882. 28 N. G. Kundu, M. Pal and C. Chowdhury, unpublished observations. 29 P. J. Barr, A. S. Jones, G. Verhelst and R. T. Walker, J. Chem. SOC., Perkin Trans. I, 1981, 1665; P. J. Barr, A. S. Jones, P. Serafinowski and R. T. Walker, J. Chem. SOC., Perkin Trans. 1, 1978, 1263. 30 E. J. Corey and J. W. Suggs, Tetrahedron Lett., 1975, 2647; G. Piancatelli, A. Scettri and M. Drsquo;Auria, Synthesis, 1982, 245. Paper 3/01 865B Received 1st April 1993 Accepted 14th July 1993 0Copyright 1993 by the Royal Society of Chemistry