2476 J.C.S. Perkin ISynthesis of I84-Oxathian-2-one, 5- Methyl-I ,4-oxathian-Zone, and I ,4-Oxat hiepan -2-oneBy David 1. Davies," Lyn Hughes, and Yashwant D. Venkar, Department of Chemistry, King's College, Strand,Jack E. Baldwin, Department of Chemistry, Massachussets Institute of Technology, Cambridge, MassachussetsLondon WC2R 2LS021 39, U.S.A.Intramolecular dehydration of 2-(2-hydroxyethylthio)acetic acid and of 2-(2-hydroxy-1 -methylethylthio)aceticacid gives 1.4-oxathian-2-one and 5-methyl-l.4-oxathian-2-one, respectively. The precursor hydroxy-acids areformed by hydrolysis of the products of free radical addition of thioglycolic acid to vinyl acetate and propenyl acetaterespectively. Free radical addition of thioglycolic acid to ally1 chloride affords 2-(3-~hloropropylthio)acetic acid,which is cyclised to 1,4-0xathiepan-2-one on treatment with potassium fluoride in glacial acetic acid.A mixture of1.4-oxathiepan-2-one and 5-methyI-l.4-oxathian-2-one is produced on cyclodehydration of the mixture of 1 : 1adducts formed by free radical addition of thioglycolic acid to ally1 alcohol.THE value of free radical reactions in synthetic organicchemistry is most pronounced for free radical additionsR(1) R = H(2) R=MeOwS 0( 3 1to multiple bond^.^*^ As part of a study of free radic,aladdition reactions, the free radical addition of thiols tohave been reported; 4-9 such compounds are of interestboth for their possible physiological activity and forthe effect of the heteroatoms on the conformation ofthe alicyclic s y ~ t e m .~In the improved procedure for the synthesis of (1)now reported, the acetoxy-acid (5) 63 is obtained byfree radical addition of thioglycolic acid to vinyl acetate.Hydrolysis of (5) by boiling at reflux with aqueouspotassium hydroxide under nitrogen gave the hydroxy-acid (4) (95) as a viscous liquid which, within an hourof preparation, began to turn cloudy and to deposit awhite polymeric solid. However, when a dilute solutionCH,-CH0 / 2 + HSaCH,. C02H -+- HO*CHiCHiS*CHiCO2H - ( 1 1olefinic systems has now been utilised at essential stagesin syntheses of 1,4-0xathian-2-one (1) , 5-methyl-l,4-oxathian-2-one (2), and 1,4-0xathiepan-2-one (3). Ofthese only 1,4-0xathian-2-one had been preparedpreviou~ly.~.~ In the procedure 4 9 5 due to Black,5MeCOz.CH = CH, 4- HS-CHj C02Hdistillation of the product of reaction between thio-glycolic acid and ethylene oxide afforded 1,4-0xathian-2-one (1) in 10 yield.The reaction is likely to haveinvolved the in siiu cyclisation of the intermediatehydroxy-acid (4).The preparations of several other derivatives of (1)D. I. Davies and M. J. Parrott, Chem. an Britain, 1975, 11,364.G. Sosnovsky, ' Free Radical Reactions in PreparativeOrganic Chemistry,' Macmillan, New I'ork, 1964, particularlyC . Walling and E. S. Huyser, Org. Reactions, 1963, 13, 91;K. Jankowski, R. Coulombe, and C. Rerse. Rzrll. Arad.chs. 1-3.F. W. Stacey and J. F. Harris, jun., ibid., p. 150.polon. Sci., Ser. Sci. chim., 1971, 19, 661.of (4) in xylene was heated at reflux, in the presence of acatalytic quantity of toluene-$-sulphonic acid, cyclicdehydration of (4) occ.urred to afford 1,4-0xathian-2-oneThis procedure for obtaining (1) appears to be of(1) (79).MeCOz.CHz.CHz~S~CH,-CO,H(5)general validity for the synthesis of substituted 1,4-oxathian-2-ones when substituted vinyl acetates areused in the first step of free radical addition.Forexample the free radical addition of thioglycolic acidto propenyl acetate a 1 : 1 mixture of cis (6) and trans(7) readily took place at 0 "C to afford the acetoxy-acid(8) (35). Hydrolysis of (8) led to the hydroxy-acid1). K. Black, J . Chem. SOC. (C), 1966, 1708.D. Greenwood and H. A. Stevenson, J . Chern. Snc., 1953,1514.7 M.Schubert, J . Amer. Chern. SOC., 1947, 69, 712.L. Horner and K. Sturm, Annalen, 1955, 597, 1.9 H. P. Kaufmann and R . Schickel, Fetfe# Seifen. Anstrirhm..1963, 65, 8511977 2477(9), which on dehydration afforded 5-1nethyl-l,4- EXPERIMENTALoxathian-2-one (2) (82). 2- (2-lliiTethoxycarbony Ze~~yZ~hzo) acetic Acid (5) .-Freshly1,4-Oxathiepa11-2-one (3) I a hitherto unknown seven- distilled vinyl acetate (5 g, 0.058 mol) and thioglycolic acidmembered ring analogue of (1), may also be prepared by (5 g, 0.054 mol) were mixed at room temperature and stirred.MeC02c=c '' 'H + HS.CH2C02H MeC02.CH2.CHMe.S.CHz:CO2HMeC02c=c'H' (7) 'Mea procedure involving free radical addition. Thiogly-colic acid when heated with an excess of allyl chloride 10911under nitrogen at 70-80 "C afforded the chloro-acid(10) 58o/b.A solution of this acid (10) in glacial aceticacid containing potassium fluoride, when boiled atreflux, afforded l14-oxathiepan-2-one (3) (94).The properties of solutions of potassium fluoride inAfter a few minutes a vigorous exothermic reaction ensuedand external cooling was necessary to keep the temperaturebelow 50 "C. After 18 h the excess of vinyl acetate wasevaporated off, and the crude product distilled to affordthe acid (5) (6.5 g) as an oil, b.p. 119-120" a t 0.02 mmHg,nD20 1.493 0 (Found: C, 40.25; H, 5.6; S, 18.25. C,H,,SO,requires C, 40.5; H, 5.6; S, 17.9), 6 (60 MHz; CCl,)2.05 (s, Ac), 2.85 (t, CH,*CH,*S, J 6 Hz), 3.25 (s, CH,.glacial acetic acid have been investigated by Emsley,12and this method for cyclisation is due to Clark andEmsley.l3 The formation of (3) is suggested to proceedby an intramolecular nucleophilic displacement ofchlorine, as shown.The free radical addition of thioglycolic acid to allylalcohol afforded a 19 : 1 mixture (85) of the hydroxy-acids (11) and (9), which we were unable to separateS*CN,C:O), 4.25 (t, O*CH,*C€ a's, J 6 iz), and 11.40 (CO,H) ,Y,.3 600-3 000 (OH), 1 735 (GO), and 1 710 cm-' (GO).2-( 2-HydroxyethyZthio)acetic Acid (4) .--The acetate (5)(8.9 g, 0.05 mol) dissolved in aqueous 40./, potassiumhydroxide (44.8 g, 0.8 mol) was boiled a t reflux undernitrogen for 5 h. The mixture was then cooled, acidifiedwith concentrated hydrochloric acid, and extracted con-tinuously with diethyl ether for 18 h.The extract waswashed with water, dried (MgSO,), and evaporated.(attempts invariably led to some polymerisation and Residual acetic acid was removed by addition of chloro-cyclisation). Dehydration of the mixture gave a 19 : 1 benzene and evaporation first of the acetic acid and then ofmixture (yo) of 1,4-oxathiepan-2-one (3) and 5- chlorobenzene. The residual acid (4) (6.4 g) was a viscousits spectral data: 8 60 MHz; (CD,),SO 2.25 (t, O-CH,.CH,*S, J 6 Hz), 3.25 (s, S*CH,*CO), 3.75 (t, O-CH,*CH,*S,methyl- 1,4-0xathian-2-one (2), which also was not liquid which polymerised rapidly but was recognisable fromseparated.E. Larsson, Ada. Uniu. Lund., Sect. IT, No. 22, 1965l1 C.R.9. Buess, C. N. Yiannios, and W. T. Fitzgerald, J . O y .(Chem. Abs., 1966, 84, 12635).Chew., 1957, 22, 197.l2 J. Emsley, J . Chem. SOC. ( A ) , 1971, 2511.l3 J . H. Clark and J . Emsley, J.C.S. Dalton, 1975, 21292478 J.C.S. Perkin IJ 6 Hz), and 7.0 (OH, C02H), v,,,. 3 600-3 000 (OH) and1710 cm-l (GO).1,4-Oxathian-2-one (1) .-The hydroxy-acid (4) (1 g)dissolved in diethyl ether (20 ml) was added to p-xylene(300 ml) containing toluene-p-sulphonic acid monohydrate 14(5 mg). The mixture was then boiled at reflux in a Dean-Stark water separator; the first part of the distillate (50 ml)was removed and discarded since it contained the diethylether. After 5 h the mixture was cooled, washed withwater (4 x 150 ml), dried (MgSO,), and evaporated.Distillation of the residue afforded 1,4-0xathian-2-one ( 1)(0.69 g), M+ 118, with properties as in the literature,4.5.156 (60 MHz; CDCl,) 3.00 (t, CH,*CH,.S, J 6 Hz), 3.40 (s,S*CH,*CO), and 4.55 (t, CH,.CH,.S, J 6 Hz), v,,,~.1 740cm-l (GO), m/e 118 (50, M+), 89 (30, CH,SCH,C=H),88 (28, CH,SCH,O), 74 (68, SCH,O or CH,CH,-kCH,), 60 (84, CH,kH,), 59 (76), 48 (68), 47 (76),46 (loo, CH,;), 45 (go), 43 (66, CH,C=H), and 42(SO, CH,C=O) .PropenyZ Acetate (6) + (7) .ls-Propionaldehyde (3 g,0.051 7 mol; freshly redistilled under nitrogen), aceticanhydride (12.65 g, 0.124 mol), and potassium acetate(1.01 g, 0.010 3 mol) were heated together for 2 h undernitrogen in a sealed tube a t 150 "C. The tube was thencooled and opened and the mixture washed successivelywith warm water (5 X 70 ml), aqueous 0.5~-sodiumhydrogen carbonate (4 x 50 ml), and warm water (2 x 70ml) to afford a crude product which on distillation afforded a1 : 1 mixture (0.94 g) l7 of cis- (6) and trans- (7) propenylacetate, b.p.104-106" at 750 mmHg (Found: C, 60.0;H, 8.0. Calc. for C5H802: C, 60.0; H, 8.0), 6 (60 MHz;CDC1,) 1.55-1.75 (m, CH,.CH=), 2.17 and 2.22 (singlets forAc of cis- and trans-isomers), 4.65-4.7 (m, CH,*CH=),and 6.9-7.2 (m, CH,.CO*O*CH=), vnmx+ 1760 (GO) and1 680 cm-l (C=C). A fraction collected at 178-180 "C and750 mmHg corresponded to 1, l-diacetoxypropane (lit.,lS184-185" at 760 mmHg) (Found: C, 52.5; H, 7.5. Calc.for C,HI2O4: C, 52.5; H, 7.5), 6 (60 MHz; CDC1,) 0.95 (t,CH,CH,, J 7 Hz), 1.35-2.25 (m, CH,*CH,CH), 2.05 (s,Ac), and 6.70 (t, CH,*CH, J 5 Hz), vnlax.1 745 cm-l (GO).2-(2-MethoxycarbonyZ- l-methyZethyZthio)acetic Acid ( 8 ) .-Freshly distilled propenyl acetate (6) + (7) (2.4 g, 0.03mol) was stirred at 0 "C and thioglycolic acid (2.2 g, 0.03mol) was slowly added. After 15 min the mixture wasallowed to reach room temperature and left overnight withcontinuous stirring. Work-up as in the preparation of (4)gave the acid (8) (1.6 g) as an oil, b.p. 146-148" at 0.1 mmHg(Found: C, 43.8; H, 6.3; S, 16.75. C7H,,S04 requiresC, 43.75; H, 6.25; S, 16.65), 6 (60 MHz; CDCl,) 1.3 (d,CH,CH, J 7 Hz), 2.06 (s, OAc), 2.9-3.8 (m, CH,CH),3.35 (s, S.CH,.CO), 4.15 (d, O-CH,.CH, J 7 Hz), and 11.3(CO,H), vmax.3 600-3 000 (OH), 1 735 (GO), and 1 710cm-l (GO).2-( 2-Hydroxy- 1-methyZethyZthio)acetic Acid (9) .-By theprocedure for the hydrolysis of (5), the ester ( 8 ) (9.6 g)afforded the hydroxy-acid (9) (7.2 g) as a viscous liquid,which rapidly became cloudy and deposited white polymericmaterial, but was recognisable from its spectral data :+l4 W. S. Johnson, V. J. Bauer, J . L. Margrave, M. A. Frisch,L. H. Dreger, and W. N. Hubbard, J . Amer. Chem. Soc., 1961,83, 606.15 K. Jankowski and R. Coulombe, Tetrahedron Letters, 1971,991.8 160 MHz; (CL),),SOJ 1.25 (d, CH,-CH, J 7 Hz), 2.3-3.75(m, CH,*CH), 3.25 (s, S*CH,*CO), 4.25 (d, O*CH,*CH, J7 Hz), and 7.0 (OH, CO,H), v,. 3 600-3 000 (OH) and1 710 cm-l (GO).5-Methyl- 1,4-oxathian-2-one (2) .-By the procedure forthe cyclodehydration of (4), the hydroxy-ester (9) ( 1 g)afforded 5-methyZ-1,4-oxathian-2-one (2) (0.72 g) as a viscousliquid, b.p.75" at 0.1 mmHg, nD25 1.514 0 (Found: C,45.4; H, 6.5. C5H,S0, requires C, 45.45; H, 6.05),6 (60 MHz; CDCl,) 1.30 (d, CH,*CH, J 7 Hz), 3.0-3.6 (m,CH,*CH), 3.32 (s, S*CH,-CO), and 3.9-4.55 (m, O*CH,*CH,), vnlax. 1 740 cm-l (GO), m/e 132 (49, M+), 88 12,CH,CHSCH,O or CH,CH(CH,)kH,, 85 (34), 74(34, CH,CHkH, or SCH,d=O), 73 (31), 60 (loo),55 (58), 46 (1000,/,, CH,), 43 (46, CH,OH), and 42(49, CH,d=O).2-( 3-ChZoro~ro~yZthio)acetic Acid (10) .-A mixture ofthioglycolic acid (1.8 g, 0.029 mol) and allyl chloride (2.5 g,0.032 mol) was heated a t 70-80 "C under nitrogen in asealed tube for 6 h.After cooling, the tube was opened andthe excess of allyl chloride evaporated off. Distillation ofthe crude product afforded the acid (10) (1.9 g) as an oil,b.p. 130" at 0.45 mmHg (Found: C, 35.4; H, 5.9; C1,20.95; S, 18.9. C5H,C10,S requires C, 35.4; H, 5.9;C1, 20.95; S, 18.8), 6 (60 MHz; CDCl,) 1.8-2.3 (m,CH2-CH,*CH2), 2.83 (t, CH,*CH,*CH,*S, J 7 Hz), 3.27(s, S*CH,*CO), 3.65 (t, ClCH,*CH,.CH,, J 7 Hz), and 11.87(s, CO,H), vnlar 1 710 cm-l ( G O ) .1,4-Oxathiepan-2-one (3).-The acid (10) (1.5 g, 0.008 9mol) was added to a hot solution of anhydrous potassiumfluoride (2.1 g, 0.036 mol) in anhydrous glacial acetic acid(18 g, 0.03 mol). The mixture was boiled a t reflux for 30 h,then cooled, diluted with water (50 ml), and immediatelyextracted with diethyl ether (3 x 50 nil).The combinedextracts were concentrated to 75 ml and then quicklywashed with water ( 5 x 75 ml) and dried (Na,SO,). Eva-poration left 1,4-oxathiepan-2-one (3) ( 1.1 g) as a viscousliquid, b.p. 86" at 0.06 mmHg, nDZ5 1.486 0 (Found: C,45.45; H, 6.3. C5H,S0, requires C, 45.45; H, 6.050/,),6 (60 MHz; CDCl,) 1.7-2.3 (m, CH,*CH,*CH,), 2.75 (t,CH,*CH,*S, J 6 Hz), 3.25 (s, S*CH,*CO), and 4.23 (t, O*CH,*CH,, J 6 Hz), v,,,,~ 1725 cm-l (GO), m/e 132 (16, M+),88 (20, CH,SCH,O), 74 (14, CH,kH,CH, or SCH,0), 73 (58, CH,!kH=CH,), 61 (31), 47 (41, GCH,),46 (30. k H , ) , 43 (100 CH,OH), and 42 (18,CH,C=O).19 : 1 Mixture of 2-( 3-Hydroxypro~yZthio)- (1 1) and 2-(2-Hydroxy- l-methylethylthio) -acetic Acid (9) .-Thioglycolicacid (4.6 g, 0.05 mol) was added dropwise, with stirring, toallyl alcohol (3 g, 0.052 mol).After several minutes anexothermic reaction ensued, and the mixture was cooled sothat the temperature was kept below 50 "C. After 18 hthe mixture was dissolved in ether (100 ml) and extractedwith saturated aqueous sodium hydrogen carbonate (5 x 20ml). The extract was acidified with concentrated hydro-chloric acid and continuously extracted with ether over-night. The ethereal extract was dried (MgSO,), filtered,and evaporated to yield a 19 : 1 mixture (6.6 g) of hydroxy-t.l8 P. 2. Bedoukian, Org. Synth., 1949, 29, 14.l7 H. 0. House and V. Kramar, J . Org. Chem., 1963, 28, 3362.R.Wegscheider and E. Spath, Monatsh., 1910, SO. 8461977 2479acids (11) and (9) as a viscous liquid, rapidly becomingcloudy and depositing polymeric white solid but recognisablefrom its spectral data: 6 60 MHz; (CD,),SOJ 1.25 d,CH,.CH in (9), J 7 Hz, 1.5-2.2 m, O*CH,-CH,.CH2*Sof ( l l ) , 2.75 t, CH2*CH,*CH2*S of ( I l ) , J 7 Hz, 3.25 (s,SCH,*CO), 2.65 t, O-CH2.CH,.CH2*S of ( l l ) , J 6 Hz, and6.35 (OH, CO,H) peaks due to OCH,.CH of (9) and CH,CHof (9) in the regions S 3.6 and 3.2 were masked by otherpeaks, vrnkLx. 3 700-2 600 (OH), 2 950 (CH), and 1 720 cm-I1 9 : 1 Mixture of 1,4-Oxathiepan-2-one (3) and 5-Methyl-1,4-oxathinn-2-une (2) .-By the procedure for cyclodehydr-ation of (4), the 19 : 1 mixture of (11) and (9) (1 g) affordeda 19 : 1 mixture of 1,4-oxathiepan-2-one (3) and 5-methyl-1,4-oxathian-2-one (2) as a viscous liquid (0.75 g), 6 (60(C=O) .MHz; ClX1,) 1.2s Ld, CH3CH ol' (2), J ti HzJ, 1.6-2.15m, CH,-CH,.CH2 of (S), 2.65 t, CH,*CH,CH,*S of (3), Jti Hz, 3.15 s, S*CH,-CO of (2) and (3), and 4.15 Lt, 0-CH,.CH,*CH, of (3), J 6 Hz other peaks of (2) were maskedby those of (3).for both components as 132.G.1.c.-mass spectrometry indicated MWe tlianlc the S.R.C. for a CASE award (to I,. H.) atidfinancial support (to Y. L>. V.). We thank Ilrs. 1'. lioffeyand N. J . A. Gutteridge, Lilly Research Centre, Windlesharn,for their help and interest in the work. Financial supportfrom the Lilly Research Centre is also gratefully acknow-ledged.7/940 Received, 1st Jwne, 1977
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