Chemistry of novel compounds with multifunctional carbon structure. Part 3. Synthesis of alpha;-azido-alpha;-fluoro-alpha;-(phenylthio and ethylthio)acetates

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 1149 Chemistry of Novel Compounds with Multifunctional Carbon Structure. Part 3.' Synthesis of a-Azido-a-fluoro-a-(phenylthio and ethy1thio)acetates Yoshio Takeuchi," Masahiro Asahina, Kozo Hori, and Toru Koizumi Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani 2630, Toyama930-01,Japan The synthesis of tri- and tetra-functional carbon compounds which possess three or four different functional groups on the same carbon atom is described. Reactions of ethyl bromofluoro- or chlorofluoro-acetate (4b) or (5) with several heteroatomic nucleophiles give the corresponding a-functionalised a-fluoroacetates (6a-g) in good yields. The trifunctional carbon compounds which have phenylthio and ethylthio functionalities (6a, b) are brominated with NBS to afford the tetrafunctional carbon compounds, ethyl bromofluoro(pheny1thio and ethy1thio)acetates (8a, b).The bromo derivatives (8a, b) can be converted into another type of tetrafunctional carbon compound, ethyl azidofluoro(pheny1thio and ethy1thio)acetates (9a, b) by reaction with sodium azide under phase-transfer conditions. Ethyl azidobromofluoroacetate (12) is prepared from the dibromo derivative (4c) in a similar manner. The noticeable reactivities which are caused by the novel multifunctionalised carbon structures are also reported. 2-Functionalised carbonyl derivatives, e.g. a-amino acids 'or F X-hydroxyaldehyde~,~are extremely useful compounds in ! organic synthesis. In addition to the versatility of the carbonyl Cl-C-COR FXoTMsgroup in functional group interconversions, those difunctional I compounds have the added potential of serving as chiral F F R auxiliaries and as useful starting materials for the synthesis of optically active natural products.Compounds containing a carbon atom bearing more than two different heteroatom- a; R = CH,Phcontaining labile groups, therefore, should be much more a;R = CH2Ph b; R = Phsignificant in theoretical and synthetic chemistry although they b; R = Ph have received little attention. We have recently succeeded in C; R = OCH2Ph C; R = OCH,Ph the first synthesis of such novel structures4 and the term I'multifunctional carbon compounds' was proposed for them.' I Herein we detail a full account of the synthetic approaches to I I1 and structural determination of various azido- and bromine- I containing tetrafunctional carbon compounds.We also report $. the noticeable reactivities observed in the course of this work Fwhich are caused by these novel structures. I Z-C-CORIResults and Discussion Y F Electrophilic Functiona lisation of a-Fluoro Esters.-A1 though fluorine is the best contributor among the halogens to the (4) (3)stabilisation of compounds with such unique structures, it is ~;x=Y=H difficult to achieve selective fluorination of a carbon atom with b; X = H, Y = Br Z = NO,, NRi,SPh plural labile functionalities. Therefore, our initial investigation was based on the strategy of stepwise introduction of function- c; X =Y = Br ality onto the available fluorine-bearing molecules.We first Scheme. 1. Reagents: i, Zn, TMSCl; ii, Z'. TMS = SiMe, attempted functionalisation of a-fluoro esters through the corresponding enol silyl ethers (Scheme 1). Treatment of the reactions associated with the presence of plural labile groups on 2-fluoro ketones or esters (la+) with Zn and trimethylsilyl the same carbon atom or the poor reactivity of the a-fluoro chloride (TMSCl) gave a-fluoro enol silyl ethers (2a-c) in good enolate towards heteroatomic electrophiles. ' yields. Electrophilic nitration of compounds (2a-c) with PrON0,-Bu,NF,6 NH,0N0,-(CF3C0),0,7 and 0,NBF4- Nucleophilic or Radical Functionalisation of a-Fluoro Esters.- HF-pyridine,' amination using R' ,NORZ*' or sulphenylation We next attempted the nucleophilic or radical introduction of with PhSCl or PhSSPh, did not produce any tri- or tetra-heteroatom-centred functional groups.Reactions of bromo-, functional carbon compounds (3), mainly affording instead fluoro-, or chlorofluoro-acetates (4b) and (5) with various undesired complicated products. Direct electrophilic function- nucleophiles such as RS-, RO-, Pht=N-,i and N3-, in the alisation of x-fluoro enolates was also attempted. Reaction of presence of appropriate bases and polar solvents, smoothly a-halogeno esters (4a-c) with NaOEt," NaH," BuLi, or produced the geminally functionalised fluoro esters (6a-g) in LiNPr',, l2 followed by the addition of various electrophiles mentioned above, mostly resulted in the recovery of starting materials.These facts were attributed to the concomitant side- t Pht=N is phthalimido. 1150 J. CHEM. SOC. PERKIN TRANS. I 1988 Y I H-C-C0,EtI Y (7)F F b; Y = SEt II I H-C -CO,Et Et-H-C-CO, \d; V = OEt I I X V (6) F F(4b) X = Br a;Y = SPh e;Y = OCOPh I (5) x = CI b; Y = SEt f; V = Br-C -CO,Et C; Y = OPh 9; V = I Y Yd; Y = OEt h: Y = (8) (9) a;Y = SPh a;Y = SPh b; Y = SEt b; Y = SEt C; V = OPh h; V = S(0)zPh Scheme 2. Reagents: i, NaY or KY; ii, NBS or Br,; iii, NaN,. NPht = phthalimido 68-98% yield (Scheme 2). Although there are a few reports of sulphur- or oxygen-functionalised a-fluoro esters,' nitrogen-ously functionalised a-fluoro acetates, such as imidyl, or azido- fluoroacetates, are unknown.The a-functionalised a-fluoro esters (6b,d) were thermally unstable, thereby providing disproportionated glyoxylate acetal analogues (7b,d) on distillation. With the trifunctional carbon compounds (6a-g) now in hand, we then attempted to convert them into the tetrafunctional carbon compounds. Since the electrophilic introduction of another labile group on the chiral centre of compounds (6a*) seemed infeasible as already shown in Scheme 1, bromination was attempted. After close investigation of the reaction conditions, we succeeded in isolating unstable brominated products. Thus, treatment of compounds (6a,b) with N-bromosuccinimide (NBS) in the presence of 2,2'-azoisobutyronitrile (AIBN) or benzoyl peroxide (BPO), under the controlled conditions described in the Experimental section, produced the bromides (8a,b) in 66 and 32% yield, respectively.a-Fluoro-a-(phenylsulphony1)acetate (6h) obtained by m-chloroperbenzoic acid (MCPBA) oxidation of sulphide (6a) could be also converted into the bromide (8b) in a similar manner. Bromination of compound (6c)was achieved by the use of bromine to produce the bromide (&) in 45% yield. Isolation of the bromides (8d-g) was not possible probably because of decomposition during attempted purification on silica gel. Transformation of the bromides (8a4,h) into another structural type of tetrafunctional carbon compounds was also attempted using various nitrogenous nucleophiles such as R,N-, Pht=N-, NO,-, and N3-.Although most of the reactions resulted in the production of decomposition compounds,* only azido derivatives (%,b) were obtained from (8a,b) in 32 and 40% yield, respectively, by reaction with NaN, under phase-transfer conditions (Scheme 2). The multifunctional carbon compounds are rather volatile and much less polar than expectedI5 in spite of the presence of plural groups with comparatively large dipole moments. An alternative approach to these novel tetrafunctionalised carbon structures was successive nucleophilic displacement of functionality from polyhalogenated acetate derivatives. How- ever, the presence of plural halogens made it difficult to control * Reaction of (8a) with proline ethyl ester gave the reduced product (6a).(7b) iti ti\ 1 /BrI F-C -CO,E tI Br (4c) H-C -CO, Et Et NCOC02Et F-C-C0,EtI I OCH,Ph N3 Scheme 3. Reagents: i, NaSPh; ii, NaSEt; iii, NaOEt; iv, NaOCH,Ph; v, HNEt,; vi, NaN, the reaction, resulting in the formation of several products derived from multiple and unexpected side-reactions. For example, reaction of dibromofluoroacetate (4c) with NaSPh, NaSEt, NaOEt, and NaOCH,Ph yielded, as the only isolable compound, reduced products (6a), (7b), (6d), and (lo),respectively. Reaction of dibromide (4c) with HNEt, afforded the amide (11). The formation of these unexpected products can be explained in terms of either nucleophilic attack on the heteroatoms rather than on the central carbon atom or hydrolysis during work-up (Scheme 3).In contrast, reaction of dibromide (4c) with NaN, under phase-transfer conditions produced the tetrafunctional azido derivative (12) in 47% yield. The unsatisfactory yields of the bromo and azido derivatives can be ascribed to their instability and volatility. All the tetrafunctional carbon compounds obtained here are new, despite their structural simplicity. A survey of the literature revealed no example of structures with a carbon atom J. CHEM. SOC. PERKIN TRANS. I 1988 surrounded by such labile functionalities, even as a part of a larger molecule. From the results above and from many unsuccessful experiments, we can in general terms say that multifunctionality increases reactivity and volatility although it decreases polarity.We have found little consistency between reactivities and functional groups. Spectral analyses of this class of compounds are notable. In the ' n.m.r. spectra, multifunctionality generally lowers the central carbon shifts and raises the carbonyl carbon shifts. In their mass spectra, the first fragmentation peaks are usually derived from (M+ -Br), (M' -F), or (M+ -N,) ions. However, these compounds give secondary fragmentation peaks, which at this time we are at a loss to explain by the conventional mechanisms for fragmentation. All the spectral analyses based on electronic properties of each heteroatom are now under investigation for some other multiply functionalised carbon compounds including nitro derivatives.16 Experimental 1.r.spectra were recorded on a JASCO A-102 spectrophoto-meter. 'H N.m.r. spectra were measured in CDCl, with SiMe, as internal standard and recorded on JEOL PMX-60 (60 MHz) and Varian XL-200 (200 MHz) spectrometers, while "F n.m.r. spectra were measured in CDCl, with CFCl, as internal standard and taken with a JEOL GX-270 (254 MHz) spectro- meter. Upfield shifts are quoted as negative. 13C N.m.r. spectra were measured in CDCl, with SiMe, as internal standard and recorded on Varian XL-200 (50 MHz) spectrometer. EI Mass spectra were taken with a JEOL JMS-D300 spectrometer. Column chromatography and preparative t.1.c. (p.1.c.) were performed using Kieselgel 60 (Merck, Art. 9385 and Art. 7748, respectively). Ethyl Fluoro(phenylthio)acetate (6a).-To a stirred solution of ethyl bromofluoroacetate (4b) (2.22 g, 12 mmol) in tetrahydrofuran (THF) (25 ml) were added successively triethylamine (2.5 ml, 18 mmol) and thiophenol (1.24 ml, 12 mmol) and the mixture was heated at reflux for 1 h.The precipitate was removed by filtration and the filtrate was concentrated using a rotary-evaporator below 35 "C. The residue was purified by silica gel column chromatography with hexane-ether (10:1) as eluant to afford the title compound (6a) as an oil (2.56 g, 95.6%). Distillation under reduced pressure gave an analytical sample; b.p. 125 "C/14 mmHg (Found: C, 55.9; H, 5.3. C,,H,,FO,S requires C, 56.06; H, 5.17%); v,,,,(neat) 1 760 (CO), 1 585 (Ph), and 1045 cm-' (C-F); 6, 1.17 (3 H, t, J 7 Hz, Me), 4.17 (2 H, q, J 7 Hz, CH,), 6.10 (1 H, d, JHAF52 Hz, CFH), and 7.2-7.7 (5 H, m, Ph); 6, -158.7 (d, JF-H53 Hz); 6, 94.2 (dd, Jc-F 235, Jc-H 110 Hz, CHF) and 165.3 (d, JC-F-26 Hz, CO);m/z 214 (M+,44%) and 141 (Mf -CO,Et, 100).Ethyl Ethylthiofluoroacetate (6b).-To a suspension of sodium hydride (60% in mineral oil; 1.20 g, 30 mmol) in THF (10ml) at 0 "C was slowly added ethanethiol(4.43 ml, 60 mmol) during 10 min. After foaming had ceased, a solution of compound (4b) (5.55 g, 30 mmol) in THF (19 ml) was added into the solution via a syringe and the mixture was stirred at 0 "Cfor 1 h. Evaporation of the solvent gave an oil, which was dissolved in ether (40 ml); the solution was washed with water (10 ml) and dried over MgSO,.Evaporation of the solvent gave a crude product, which was purified by silica gel column chromatography with hexane-ether (1 :1) as eluant to give the title compound (6b) as a pale yellow oil (4.61 g, 92.5%);v,,,.(neat) 1 755 (CO) and 1 035 cm-' (C-F); 6,1.33 (3 H, t, J7 Hz, SCH,Me), 1.33 (3 H, t, J7 Hz, OCH,Me), 2.57-3.07 (2 H, 1151 m, SCH,), 4.33 (2 H, q, J 7 Hz, OCH,), and 5.93 (1 H, d, JH-F 52 Hz, CHF); 6, -162.8 (d, JF-H51 Hz); 6c92.3 (dd, Jc-F229, Jc-H 110 Hz, CHF) and 166.3 (d, Jc-F 32 Hz, CO) [Found: M+, 166.0472.C6H1 ,FO,S requires M, 166.0464;m/z 147.0469. C,H,,O,S (M+ -F) requires m/z 147.04791. Attempted distillation for an analytical sample gave ethyl glyoxylate diethyl thioacetal(7b) via decomposition; b.p.99 "C/38 mmHg; 6, 1.23 (6 H, t, J 7 Hz, SCH,Me x 2), 1.30 (3 H, t, J 7 Hz, OCH,Me), 2.87 (4 H, q, J 7 Hz, SCH, x 2), 4.37 (2 H, q, J 7 Hz, OCH,), and 4.47 (1 H, s, CH); m/z 208 (M', 17%), 147 (M' -SEt, 36), and 135 (M' -CO,Et, 100). Ethyl FluoroOlhenoxy)acetate (6c).-To a suspension of sodium hydride (60%in mineral oil; 400 mg, 10 mmol) in THF (10 ml) was added a solution of phenol (940 mg, 10 mmol) in THF (2 ml) and the mixture was stirred at 0 "C for 20 min. A solution of compound (4b) (1.85 g, 10 mmol) in THF (2 ml) was added slowly to the mixture, which was then stirred at room temperature for 30 min. The resultant solution was poured into a mixture of water (5 ml) and ether (20 ml) and the organic layer was dried over MgSO,.Evaporation of the soIvent gave the title compoumd (6c)as an oil (1.94 g, 97.8%);v,,,,(neat) 1 760 (CO), 1 595 (Ph), and 1025 cm-' (C-F); 6, 1.21 (3 H, t, J 7 Hz, Me), 4.21 (2 H, q, J7 Hz, CH,), 5.85 (1 H, d, JH-F60 Hz, CFH), and 6.95-7.30 (5 H, m, Ph); 6, -129.8 (d, JF-H59 Hz); 102.6 (dd, JcWF232, Jc-H 99 Hz, CHF) and 164.0 (d, Jc-F 30 Hz, CO) [Found: M', 198.0688. CIoHIlFO, requires M, 198.0691;m/z 125.0409.C,H6F0 (M+ -C0,Et) requires m/z 125.04031.Attempted distillation of compound (6c) resulted in decomposition. Ethyl EthoxyJIuoroacetate (6d).-To a mixture of sodium hydride (60%in mineral oil; 40 mg, 1 mmol) in THF (1 ml) was added ethanol (46 mg, 1 mmol) under argon. After foaming had ceased completely, a solution of compound (4b) (185 mg, 1 mmol) in THF (0.5 ml) was added to the mixture, which was then stirred at room temperature for 20 min.Water (10 ml) and ether (10 ml) were added and the organic layer was dried over MgSO,. Evaporation of the solvent gave the title compound (6d) as an oil (138 mg, 89.8%);v,,,.(neat) 1760 (CO), 1 115 (C-0), and 1030 cm-' (C-F); 6, 1.33 (3 H, t, J 7 Hz, CHFOCH,Me), 1.37 (3 H, t, J 7 Hz, CO,CH,Me), 3.74.1 (2 H, m, CHFOCH,), 4.37 (2 H, q, J7 Hz, CO,CH,), and 5.53 (1 H, d, JH-F62 Hz, CH) [Found: M+, 150.0657. C6Hl1Fo3 requires M, 150.0691; m/z 131.0718. C6HllO3 (M' -F) requires m/z 131.07071. Attempted distillation to give an analytical sample produced ethyl glyoxylate diethyl acetal (7d) uia decomposition; b.p.78 "(757 mmHg; 6, 1.27 [6 H, t, J 7 Hz, C(OCH,Me) x 2],1.33 (3 H, t, J7 Hz, CO,CH,Me), 3.70 [4 H, q, J 7 Hz, C(OCH,Me) x 2],4.27 (2 H, q, J 7 Hz, CO,CH,), and 4.90 (1 H, s, CH). Ethyl BenzoyloxyJIuoroacetate (6e).-A mixture of compound (4b) (185 mg, 1 mmol) and potassium benzoate (800 mg, 1 mmol) in dimethylformamide (DMF) (2 ml) was stirred at room temperature under argon for 2 h. Water (10 ml) and ether (5 ml) were added and the organic layer was dried over MgSO,. Evaporation of the solvent gave a crude product, which was purified by column chromatography with hexane-ether (1 :1) as eluant to give the title compound (6e) as a pale yellow oil (203 mg, 90.0%); v,,,,(neat) 1755 (CO,Et), 1720 (OCOPh), and 1 015 em-' (C-F); 6, 1.37 (3 H, t, J7 Hz, Me), 4.37 (2 H, q, J7 Hz, 3H,), 6.67 (1 H, d, JH-F52 Hz, CH), and 7.4-8.0 (5 H, m, Ph); 6, -140.4 (d, JF-H55 Hz); 6, 95.3 (dd, JCpF 233, Jc-H 111 Hz, CHF) and 164.2 (d, Jc-F 30 Hz, CO) [Found: M', 226.0639. C, ,H, FO, requires M, 226.0640 m/z 18 1.0373.C,H6F0, (M' -OEt) requires m/z 181.03001. Attempted distillation of compound (6e) resulted in decomposition. 1152 J. CHEM. SOC. PERKIN TRANS. I 1988 Ethyl Fluoro(phthu1imido)acetate (6f).-A mixture of com- pound (5) (16.86 g, 120 mmol) and potassium phthalimide (22.20 g, 120 mmol) in DMF (50 ml) was heated at 100 "C under argon for 5 h. To the mixture was added ether (100 ml) and the precipitate was removed by filtration. The filtrate was washed with water and dried over MgSO,.Evaporation of the solvent gave a crude product, which was chromatographed on silica gel with benzene-ether (19:l) as eluant to afford the title compound (6f) as a solid (26.83 g, 89.1%). Recrystallisation from ethyl acetate gave an analytical sample; m.p. 104-105 "C (lit.,' 103-104 "C) (Found: C, 57.2; H, 4.0; N, 5.9. Calc. for Cl,Hl,FNO,: C, 57.37; H, 4.01; N, 5.58%); v,,,.(KBr) 1 765 (CO,), 1 725 (CON), and 1 065 cm-' (C-F); 6,1.40 (3 H, t, J 7 Hz, Me), 4.43 (2 H, q, J 7 Hz, CH,), 6.37 (1 H, d, JH-F48 Hz, CHF), and 7.8-8.3 (4 H, m, ArH); 6, -155.6 (d, JFWH48 Hz); 6, 81.1 (dd, Jc-F 214, Jc-H94 Hz, CHF) and 164.3 (d, Jc-F 34 Hz, CO); m/z 252 (M' + 1,279 and 178 (M' -CO,Et, 20). Ethyl Azidojuoroacetate (6g).-A solution of compound (4b) (0.52 g, 2.8 mmol) in ether (5 ml) and a solution of sodium azide (2.58 g, 49 mmol) in water (5 ml) were combined.To the two- layered solution was added intermittently ethanol (total 7 ml) during a period of 10 h as the reaction was monitored by n.m.r. spectroscopy of the organic layer. Insoluble materials were removed by filtration. To the filtrate were added water (5 ml) and ether (5 ml), and the organic layer was dried over MgSO,. Evaporation of the solvent gave the title compound (6g) as an almost pure (n.m.r.) oil (0.28 g, 68.0%);v,,,.(neat) 2 120 (N3), 1 755 (CO), and 1 020 cm-' (C-F); 6,1.40 (3 H, t, J 7 Hz, Me), 4.33 (2 H, q, J 7 Hz, CH,), and 5.44 (1 H, br d, JH-F52 Hz, CHF); 6, -147.8 (d, JF-H 5 1 Hz); 6, 93.7 (dd, Jc-F 233, JCpH 95 Hz, CHF) and 164.0 (d, Jc-F 34 Hz, CO).The mass spectrum did not show any rational fragmentation, probably because of ready decomposition. Cautionary note. Attempted distillation (b.p. 83-84 "C/18 mmHg) resulted in explosion. Ethyl Fluoro(phenylsuIphonyl)acetate (6h).-To a solution of the sulphide (6a) (107 mg, 0.5 mmol) in CH,CI, (1 ml) was added dropwise a solution of MCPBA (80%; 216 mg, 1.0 mmol) in CH,CI, (3 ml) and the mixture was stirred for 20 min. The resulting solution was diluted with CH,Cl, (6 ml) and washed successively with saturated aq. NaHCO,, saturated aq. NaCl, then dried over MgSO,. Evaporation of the solvent gave a crude product, which was purified by p.1.c. to afford the title compound (6h) as an oil (41.5 mg, 33.7%);6, 1.33 (3 H, t, J 7 Hz, Me), 4.37 (2 H, q, J 7 Hz, CH,), 5.63 (1 H, d, JH-F49 Hz, CHF), and 7.5-8.2 (5 H, m, Ph) (Found: M', 246.0351.C,,H,,FO,S requires M, 246.0361). Ethyl Bromojuoro(pheny1thio)acetate (8a).-A solution of compound (6a) (214 mg, 1 mmol) and benzoyl peroxide (10 mg) in CCI, (2 ml) was heated at reflux and irradiated with a 250 W sun-lamp for 10 h. During this period, NBS (total 89 mg) and CCl, (total 62 ml) were added in several portions. To the resulting mixture were added hexane (10 ml) and ether (5 ml), and the precipitate was removed by filtration. Evaporation of the solvent gave a crude product, which was purified by column chromatography with hexane-ther (9 : 1) as eluant to give the title compound (8a) as a pale yellow oil (194 mg, 66.2%); v,,,.(neat) 1 755 (CO), 1 575 (Ph), and 1060 cm-' (C-F); 6, 1.20(3H,t,J7Hz,Me),4.20(2H,q,J7Hz,CH2),and7.1-7.7 (5 H, m, Ph); 6, -83.8 (s); 6, 98.1 (d, Jc-F 302 Hz, CF) and 163.7 (d, Jc-F29 Hz, CO); m/z 292,294 (M', 873,219,221 (M' -CO,Et, 12), and 213 (M' -Br, 100) (Found: M', 291.9603.C,,H,,BrFO,S requires M, 291.9570). Attempted distillation of compound (8a) resulted in decomposition. Ethyl Bromo(eth~vlthio)Juoroacetate (8b).-A mixture of compound (6b) (391 mg, 2.36 mmol), NBS (420 mg, 2.36 mmol), and AIBN 5 mg) in CCl, (10 ml) was heated at reflux in an oil-bath for 8 h. More AIBN (20 mg) was added and the mixture was heated at reflux with a 250 W sun-lamp for 6 h. After the mixture had been cooled to room temperature, insoluble materials were removed by filtration.Concentration of the filtrate gave a crude product, which was purified by column chromatography with hexane-ether (9: 1) as eluant to afford the title compound (8b) as a pale yellow oil (184 mg, 31.9%); v,,,.(neat) 1 755 (CO) and 1085 cm-' (C-F); 6, 1.33 (3 H, t, J 7 Hz, SCH,Me), 1.40 (3 H, t, J 7 Hz, OCH,Me), 3.05 (2 H, q, J 7 Hz, SCH,), and 4.43 (2 H, 9, J 7 Hz, OCH,); 6, -81.4 (s); 6, 99.6 (d, Jc-F 302 Hz, CF) and 163.8 (d, Jc-F 24 Hz, CO) (Found: M+, 243.955 73. C,H,,BrFO,S requires M, 243.9570). Attempted distillation of compound (8b) resulted in decomposition. Ethyl BromoJuoro(phenoxy)acetate (8c).-A solution of compound (6c) (99 mg, 0.5 mmol) and bromine (80 mg, 0.5 mmol) in CCl, (1.8 ml) was heated at reflux with a 250 W sun-lamp under argon for 4 h.Concentration of the mixture gave a crude product, which was purified by p.1.c. to give the title compound (8c) as an oil (63 mg, 45.4%);v,,,,.(neat) 1 770 (CO), 1 590 (Ph), 1 200 (C-0), and 1 075 cm-' (C-F); 6,1.43 (3 H, t, J 7 Hz, Me),4.46(2 H,q,J7 Hz,CH,),and 7.37(5 H,m,Ph);6, -58.0 (s); 6, 106.4 (d, Jc-F 302 Hz, CF) and 161.3 (d, JCpF30 Hz, CO); m/z 276, 278 (M', 14%), and 197 (M' -Br, 38) (Found: M', 275.9769. C,oH,,BrFO, requires M, 275.9796). Attempted distillation of compound (&) resulted in decomposi- tion. Ethyl Bromojuoro@henylsulphonyl)acetate (8h).-A mixture of compound (6h) (27 mg, 0.11 mmol), NBS (20 mg, 0.11 mmol), and AIBN (2 mg) in CCl, (1 ml) was heated at reflux in an oil- bath under argon for 44 h.Insoluble materials were removed, and concentration of the filtrate gave a crude product, which was purified by p.1.c. to give the title compound (8h) as an oil (12 mg, 33.6%);6, 1.40 (3 H, g, J 7 Hz, Me), 4.43 (2 H, 9, J 7 Hz, CH,), and 7.2-8.2 (5 H, m, Ph); m/z 324, 326 (M+, 15%), 279, 281 (M+ -OEt, 3), and 141 (SO,Ph, 100). Attempted distillation of compound (8h) resulted in decomposition. Ethyl AzidoJuoro(phenylthio)acetate (9a).-To a solution of compound (8a) (293 mg, 1 mmol) in ethyl acetate (2 ml) were successively added water (1 ml), ethanol (0.5 ml), and sodium azide (650 mg, 10 mmol), and the flask was filled with argon and sealed. The reaction mixture was stirred at 20 "C for 28 h.Water (10 ml) and ether (10 ml) were added to the mixture and the ethereal layer was dried over MgSO,. Evaporation of the solvent gave a crude product, which was purified by p.1.c. to afford the title compound (9a) as a yellow oil (81 mg, 31.8%); v,,,,(neat) 2 135 (N,), 1 755 (CO), and 1045 cm-' (C-F); 6, 1.27 (3 H, t, J7 Hz, Me), 4.28 (2 H, q, J7 Hz, CH,), and 7.2-7.8 (5 H, m, Ph) [Found: M', 255.0709. Cl,Hl,FN,02S requires M, 255.0478; m/z 213.0382. C,,Hl,F02S (M+ -N3) requires m/z 2 13.03843. Attempted distillation of compound (9a) resulted in decomposition. Ethyl Azido(ethy1thio)JEuoroacetute (9b).-To a solution of compound (8b) (130 mg, 0.53 mmol) in ethyl acetate (3 ml) were successively added water (2 ml), ethanol (1 ml), and sodium azide (650 mg, 10 mmol), and the flask was filled with argon and sealed.The reaction mixture was stirred at 20 "C for 16 h. After the same work-up as above, the title compound (9b) was obtained as a yellow oil (44 mg, 40.1%);v,,,.(neat) 2 130 (N,), 1750 (CO), and 1030 cm-' (C-F); 6, 1.33 (3 H, t, J 7 Hz, SCH,Me), 1.37 (3 H, t, J7 Hz, OCH,Me), 2.87 (2 H, q, J7 Hz, SCH,), and 4.34 (2 H, q, J 7 Hz, OCH,) [Found: M', 207.0490. J. CHEM. soc. PERKIN TRANS. I 1988 C6HloFN30,S requires M, 207.0501;m/z 165.0371. C,H,,FOS (M+ -N3)requires m/z 165.03841. Attempted distillation of compound (9b) resulted in decomposition. Ethyl Azidubromojluoroacetate (12).-A mixture of com-pound (4c) (520 mg, 1.97 mmol), sodium azide (1.292 g, 19.8 mmol), and tetrabutylammonium bromide (297 mg, 0.92 mmol) in CH2Cl, (1 ml) and water (1 ml) was stirred in a sealed flask at 20 "C for 140h.The mixture was diluted with water (10 ml) and extracted with CH,Cl, (3 ml x 3). The combined organic layer was dried over MgSO,. Evaporation of the solvent gave a crude product, which was purified by column chromatography with hexane+ther (2 :1) as eluant to give the title compound (12) as an oil (209 mg, 46.9%); v,,,.(neat) 2 230 (N,), 1 760 (CO), and 1 030 cm-' (C-F); 6, 1.37 (3 H, t, J7 Hz, Me) and 4.37 (2 H, q, J 7 Hz, CH,); rn/z 183, 185 (M' -N,, 18%). Cautionary note. Attempted distillation of compound (12) resulted in explosion. Acknowledgements This investigation was partially supported by Grant-in-Aid from the Research Foundation for Pharmaceutical Sciences.References 1 Part 2, Y. Takeuchi, M. Asahina, K. Nagata, and T. Koizumi, J. Chem. Soc., Perkin Trans. I, 1987, 2203. 2 J. Martens, Top. Curr. Chem., 1984, 125, 165; H. C. J. Ottenheijm, Chirnia, 1985,39, 89; L. R. Smith and H. J. Williams, J. Chem. Educ., 1979, 56, 696; R. B. Silverman and M. W. Holladay, J. Am. Chem. Soc., 1981, 103, 7357; D. Seebach, M. Boes, R. Naef, and W. B. Schweizer, ihid., 1983, 105, 5390 P. J. Maurer, C. G. Knudsen, A. D. 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