Vol 35 NO S March 1970 USE OF LITHIUM REAGENrs IN KETONE SYNTHESIS 777

The Application of Lithium Reagents from (l-lUethylthio)alkylphosphonate Esters to the Synthesis of Ketones

Eo J COREY AND JOEL I SHULMAN

Department of Chemi8try Harvard Univer8ity Cambridge Massachusett8 02138

Received July 15 1969

Diethyl methylthiomethylphosphonate can be alkylated by suc(essive treatment with n-butyllithium and an n-alkyl iodide to give the corresponding (l-methylthio)alkylphosphonate esters (4) The lithio derivatives of the latter (5) react with earbonyl compounds to form t-alkoxy phosphonate adducts which decompose upon heatillg to 50deg (in tetrahydrofulItII) to form substituted vinyl methyl sulfides (7) Ketones are obtained in good yield by mercury(II )-promoted hydrolysis of the vinyl sulfides 7

Phoiphonate esters containing an electron-withshydrawilg substituent (la-d) form stabilized carbanions which can effect the synthesis of certain olefins from aldehydes and ketoncs 1bull2 Very recently3 the scope of thi reaction has beell extended to include the synshythesis of a-unsaturated sulfones via the phosphonate ester Ie It has also been shown4 that the unstabilized narbanions from If and 19 can be formed as lithio

o OR 0 I II

XCHP(OR)2 (C6H5C-HP(OR2 o I X

la X = COR e X = S02Et 2a X-H o h X-CR3

h X =CR f X-H c X-CN g X= CH3

d X = Ar h X=SCHJ

derivatives and that these aniuns react with carbonyl compounds to produce i3-hydroxy phosphonates eg the adducts 2a and 2b from benzophenone However evell in cases most favorable for olefin formation such as 2a and 2b Wittig elimination does not occur satisshyfactorily either from the iJ-hydroxy phospho nates or their conjugate bases It was concluded4 that the facile Wittig elimination of the 3-alkoxy phosphonates requires the presence of an electron-withdrawing substituent on the carbon a to the phosphorus funcshytion

The ability of bivalent sulfur to stabilize an adjacent carbanion5 suggets the use of the thioalkyl moiety as all activating group X ill the phosphonate olefin ~ynthcsis the product of such a reaction would be a vinyl sulfide a convenifnt precursor to aldehydes or ketoJle through hydrolysiss Indeed Green7 has achicnd limited success with a vinyl Allfide synthesis

(I) (a) W S Wndorth Jrbull and W D Emmons J Amer Chern Soc 83 173gt (1961) (bJ 1 Hurner II Hoffmann and H G Wippel Chern BPI 91 61 (1958)

(2) For a recent review see A V DombrovBkii and V A Dombrovskii us Cltem 1In 35 ii3 (1966)

3) 1 C Popof J L Dever and G R Leader J Oro Chern U 1128 (1969)

(4)middot b J Core) and GT Kwiatkowski J A mer Chern Soc 88 5654 (Wuo)

(5) G Cilento Chern Rev 60 147 (1960) (6) Ca) B S hupin and A Petrov Zh Oro Khimbull I 975 (1967)

(b) J II S Weilund and J F Arens Rec Trav Chim PaY8middotBas 79 1293 i1~GO) (c) T M kaiyama S Fukuyama and T Kumamoto Tetrahedron Lett 3787 (1968)

using Ih as substrate but his reaction conditions severely limit the value of this reaction as a synthetic method 7 We report herein the ready adaptation of the phosphonate olefin synthesis to the preparation of vinyl sulfides and the subsequent hydrolysis of these compounds to unsymmetrical ketones

We found that diethyl methylthiomethylphosphoshynate (3)1 was metalated readily by 1 equiv of ushybutyllithium in tetrahydrofuran at -70deg The alkylashytion of the lithio derivative was a facile reaction afshyfording good yields of diethyl (l-methr lthio) ethylshyphosphonatc (4a) or dietilyl (l-methylthio)nonylshyphosphonate (4b) Sequential treatment of the phosphonates 4 with n-butyllithium and an aldehyde or ketone gave adducts 6 which upon heating at 500

eliminated diethyl phosphate monoanion to give vinyl sulfides 7 The lithio derivatives S could be formed either at -700 in tetmhydrofuran or at 0deg iII cycloshyhexane The intermediacy of the hydroxyphosphonate anion 6 was demonstrated by the aqueous quel1ching of the rraction mixture from Sa and benzaldehyde whereshyupon protonated 6a was obtained in 88 yield

o o II

CH3SCH2P(OEt)2

3

-shy CH3SCHP(OEtl

I R

4a It-CH

nmiddotBuLi-b R CHiCH2)

Li 0 Li I

0 II RRC-O

CF I

P I(OEt)

CHasr-P(OEt)2 RIR2C-CI R R SCH

Sa R-CH3 6a R - CH Rl = CJIs b R - CHaCCH2)

+ It(EtO)2POO-Li + RRzC=CSCH3

7a R - CHa Rl - CJIs Rz - H b R-CH Rl = CH(CH2) R2 - H

The scope ~f the ~ynthesis of vinyl sulfides via the Emmons-HoTrier pliosphonate reaction can be seen from the data in Table I In the two instances which afforded low yields of vinyl sulfides (ie cyclopentanone and acetophenone) substantial amounts of baseshycatalyzed condensation products were obtained inshydicating that for these ketones enolate formation by

j

bull j 1

I

778 COREY AND 8HULMAN

TABLE I

CONVEHSION l HCcf) -- ItdhC=middotClt(8ClIa) USING DIETHYI (l-ll~THYLTIIO )LKYLPHUiIHON ATlS

Yield uf vinyl

R Carhonyl eompd Solventa sulfideb

C fI3 Benzaldehyde T 80C CH Benzuphcnollc T 84 CH Rexanal T 67d

CH IIexanl1 C 67shycn Cyclohexanone T 82 ClII(CRl h Cyciohexnnone T 72 Gl3 Acetophenone T Trace cn Acetupheuone C Trace CIl Cyclopelltanone T 7-10 II Cyclopen tanone C 7-10

a Solvents T tetmhydrofurall C cyclohexnne b After purifieatiop hy preparative tIc Major iHomer E SYc minor isnmer Z 171i dIajor i~omer E 60 mill i~()lIler Z MYo Isumer ratio nut determiled A mixture of IIcetopheshyIHle and its bae-cataly~ed condell~ali(Jn product (a-methyl--i3shybenzoylstyrcne) was recovered in ca 60 yield 2-Cycloshypentylidene cyclupentallone was abo isolahd in 3)1( yield

Such behavior is especially characteristic of cycloshypentnnone in Wittig-lype r~action8

In those intances where the formation of isomeric vinyl sulfiJe was poible (7a alld 7b) the isomer ratios as given in Table I were determined by vpc Stereochemistry was assigned from mnl data in partim lar the chemical lthifL of the vinylic protons were diagnostic Use of the tables of Pascual Ieier and Simon9 which correlate chemical shifts of olefinic protons with their chemical environments indicates that the vinylic proton in 7a-EIO will appear at ) 610 while the spectrum of 7a-ZIO wir have this proton at )

C6HsC=CSCHl CGH CH3C=cH CH3 II SCll

7a-Z 7a-E

CH(CH2kc=cSCHJ CH3(CH2) CH

H elI HC=CCI3

7b-Z 7bmiddotE

03l In fact the nmr of 7a revlaled broad singlets a ) 012 and 640 with the former predollJinating ( 1 ratio) The major isomer is thu asigneJ the E stereochemistry Likewie the chemical shifts of the vinyl protons of 7b-E and 7b-Z are predicted to be ) i H) and 542 respectively In fact these protons appeared as hroad Lriplets at ) 517 and 545 in a 32 ratio The major isomrr is therefore again assigned the E stereochemistry

The hydrolysis of villyl sulfides to ketones (or aldeshyhydes) has usually been effected under rather drastic acidic conditions6 Srcking a mildcr hydrolysis proshycedure wc investigated the use of mercuric chloride

(8) D R CUllIson [Tetrahedron Dell bull 3123 (Hl64) 1 found only 2-cycloshypentylidrme cyclopentanone (O yield) upon reAe1ion of cyclopentan)oe

with (CIIhP=C(CH)OC II G Wittig W Roll and K_-H KrUck [Chern fJer 911 2514 (19flI] could iKolute the deired vinyl ether from the reacti(Jll of cyciopentnnonc dth (Cdh)P=--CHOCII in only 14() yield a large amount of aldol condenlstion product was alsu formed

(9) C PnBcual J Meier and W Iimon lIelv Chim I n 1M (lY6G) om 8le J E BlackyoHI C L G1uri) K L Loening A E Petrarca

and J E Rll~h J Amer Chern 8()c 90 tOO (1)68) for the use of the Entgpl[en-ZU8amrnen priority llOmmwlatllrt) to IIIpecify (onfifCtlrlltion ahout a uouhle twnd

The Journal of Organic Chemistry

in aqueous acetonitrile II and found that this medium afforded high yields of the pure ketones Table ~I shows the results of these hydrolyses To ubtam optimum yields the reaction mixtures were worked up soon after the disappearance of the vinyl sulHd(~s (a8 determined by tic) This avoided aldol condensation of the ketones catalyzed by the acid formed along with the insoluble mercury mercaptide

TABLE II IlYDHOLYSIS OF VINYL ~ULFIDES 10 K~TONER

HRC=CH(SCH) ~ HHCIICOH Temp Yield of

R HI R degC (hr)a ketoneb

ClI3 CIls H 50 (~) 1) 84 CIl3 CII C-lLI S2 (41 j 86 CII (CII)o 25 (2()) 78 CII CII (If) H 25 (6) 14 CII(CI-Lh (ClI) 40 (26) 92 a Aqueous acetonit rile 2 eqlliv of nlPrcllric hloridc b After

purification by short-path distillatioll Purified by colum ll

chrumatography

The success of the yinyl sulfide formation and subshysequent hydrolysis provides a cOIlvcJient efficient syntheis of lptonc of the type neOH where L originates from tn alkylating agent and H embodies the carbon skeleton of a ketone or aldehyde The utility of the ynthesis is best secll in the cae of ecloshyhexyl n-octyl ketone derived from II-octyl iodide and cyclohexanolie This ketone has been preparel by (a) the glycidic ester synthesis l2 (overall yield Cfl li) and (b) the hydrobomtion of l-octene wit h dicycloshyhexylborane and suhsequent carbonyltt iun and oxidtshytion13 (overall yield 71 but contaminated with 1J dicyclohexyl ketone) In compari~on the prccnt synthesi affords eyclohexyl n-octyl lciolle of high purity in good overall yield (tj(j two steps purified intermediate)

Experimental Section

Melting points were taken ill glass capillary tubes with 3

Bllchi apparatus allli n t correeted boiling points are LIn

purredId lnfrurcli spectra WIfl recorded for IIlt dliqllid sample with a Perkin-Elmer llode 137 ~pe((roph(jtI1middotr lIillf( the 624-~ band of pulystyrene Lt ~tallliard HefrHt ivc indic(s were obtained using It Blllisch and Lomb AbbeL refractometer Nudear magnetic resonance data were determined for soluI ions in CnCIa (unless otherwise specified) at 60 11cpraquo using Vifilln Associates Model A-60 or T-60 instruments and are cxprpsseJ ill parts per millinn (ppm) duwnfield from internal tetramethylshysilane Tetrahydrofuran (THF) was dried before use by di(illashytion from lithium fLhlmilllllll hydride Analytienl g middothroshymatogruphy was perforllled Oil the following columns 6 ft X 012 in i Carbowax 20M Oil (as-Chrulll Q F amp 1 lodd ~iO or 1i7iO instrument with flame ionization detection laquo(ollln A) 10 ft X 025 in 5(0 SE-aO silicon rubber on Ointoport H F amp 1 lIodel 300 instrument with thermal eOll(lite( ivity dn1Pf ion (column B) to f1 X 02- in fi QF-l fhlOrosili(J)lIlll lgtiatojlurt S F amp lI Model aoo (column C) Flow rates were for cplllllll

A an mlmin for colulllns B ami C (1) mlmin Elemclltal analyses were carried out by Scandinavian 1 iCloanahmiddotti11 Laboratory Herlev I )cnmark and by Elek Iicrolnalytica LaiJOratory Torrance Calif

(11) See Eo J Corey and D CrrHle J Ory Chern 33 298 (1gt68) for tlJe U8e of this system for the hydrulysis of dithjanc~

(12) II II Morris und 11 L Lllsth J Amer (hem Soc 761217 (W4) These authors also prepafPlti -lome of the kltonC fur comtari~oll by an alkylmiddot cadmium-type (iri~lUrd rellllion Nu yhmiddotld Ilil Ih(gtn

Ol) II C Brown I1ltIM W Ilthk Id 89 4r2l (11107gt II C Brown G W Kabalka and M W Hathke ibid 89 45lO (11167)

778 COREY AND 8HULMAN

TABLE I

CONVEHSION l HCcf) -- ItdhC=middotClt(8ClIa) USING DIETHYI (l-ll~THYLTIIO )LKYLPHUiIHON ATlS

Yield uf vinyl

R Carhonyl eompd Solventa sulfideb

C fI3 Benzaldehyde T 80C CH Benzuphcnollc T 84 CH Rexanal T 67d

CH IIexanl1 C 67shycn Cyclohexanone T 82 ClII(CRl h Cyciohexnnone T 72 Gl3 Acetophenone T Trace cn Acetupheuone C Trace CIl Cyclopelltanone T 7-10 II Cyclopen tanone C 7-10

a Solvents T tetmhydrofurall C cyclohexnne b After purifieatiop hy preparative tIc Major iHomer E SYc minor isnmer Z 171i dIajor i~omer E 60 mill i~()lIler Z MYo Isumer ratio nut determiled A mixture of IIcetopheshyIHle and its bae-cataly~ed condell~ali(Jn product (a-methyl--i3shybenzoylstyrcne) was recovered in ca 60 yield 2-Cycloshypentylidene cyclupentallone was abo isolahd in 3)1( yield

Such behavior is especially characteristic of cycloshypentnnone in Wittig-lype r~action8

In those intances where the formation of isomeric vinyl sulfiJe was poible (7a alld 7b) the isomer ratios as given in Table I were determined by vpc Stereochemistry was assigned from mnl data in partim lar the chemical lthifL of the vinylic protons were diagnostic Use of the tables of Pascual Ieier and Simon9 which correlate chemical shifts of olefinic protons with their chemical environments indicates that the vinylic proton in 7a-EIO will appear at ) 610 while the spectrum of 7a-ZIO wir have this proton at )

C6HsC=CSCHl CGH CH3C=cH CH3 II SCll

7a-Z 7a-E

CH(CH2kc=cSCHJ CH3(CH2) CH

H elI HC=CCI3

7b-Z 7bmiddotE

03l In fact the nmr of 7a revlaled broad singlets a ) 012 and 640 with the former predollJinating ( 1 ratio) The major isomer is thu asigneJ the E stereochemistry Likewie the chemical shifts of the vinyl protons of 7b-E and 7b-Z are predicted to be ) i H) and 542 respectively In fact these protons appeared as hroad Lriplets at ) 517 and 545 in a 32 ratio The major isomrr is therefore again assigned the E stereochemistry

The hydrolysis of villyl sulfides to ketones (or aldeshyhydes) has usually been effected under rather drastic acidic conditions6 Srcking a mildcr hydrolysis proshycedure wc investigated the use of mercuric chloride

(8) D R CUllIson [Tetrahedron Dell bull 3123 (Hl64) 1 found only 2-cycloshypentylidrme cyclopentanone (O yield) upon reAe1ion of cyclopentan)oe

with (CIIhP=C(CH)OC II G Wittig W Roll and K_-H KrUck [Chern fJer 911 2514 (19flI] could iKolute the deired vinyl ether from the reacti(Jll of cyciopentnnonc dth (Cdh)P=--CHOCII in only 14() yield a large amount of aldol condenlstion product was alsu formed

(9) C PnBcual J Meier and W Iimon lIelv Chim I n 1M (lY6G) om 8le J E BlackyoHI C L G1uri) K L Loening A E Petrarca

and J E Rll~h J Amer Chern 8()c 90 tOO (1)68) for the use of the Entgpl[en-ZU8amrnen priority llOmmwlatllrt) to IIIpecify (onfifCtlrlltion ahout a uouhle twnd

The Journal of Organic Chemistry

in aqueous acetonitrile II and found that this medium afforded high yields of the pure ketones Table ~I shows the results of these hydrolyses To ubtam optimum yields the reaction mixtures were worked up soon after the disappearance of the vinyl sulHd(~s (a8 determined by tic) This avoided aldol condensation of the ketones catalyzed by the acid formed along with the insoluble mercury mercaptide

TABLE II IlYDHOLYSIS OF VINYL ~ULFIDES 10 K~TONER

HRC=CH(SCH) ~ HHCIICOH Temp Yield of

R HI R degC (hr)a ketoneb

ClI3 CIls H 50 (~) 1) 84 CIl3 CII C-lLI S2 (41 j 86 CII (CII)o 25 (2()) 78 CII CII (If) H 25 (6) 14 CII(CI-Lh (ClI) 40 (26) 92 a Aqueous acetonit rile 2 eqlliv of nlPrcllric hloridc b After

purification by short-path distillatioll Purified by colum ll

chrumatography

The success of the yinyl sulfide formation and subshysequent hydrolysis provides a cOIlvcJient efficient syntheis of lptonc of the type neOH where L originates from tn alkylating agent and H embodies the carbon skeleton of a ketone or aldehyde The utility of the ynthesis is best secll in the cae of ecloshyhexyl n-octyl ketone derived from II-octyl iodide and cyclohexanolie This ketone has been preparel by (a) the glycidic ester synthesis l2 (overall yield Cfl li) and (b) the hydrobomtion of l-octene wit h dicycloshyhexylborane and suhsequent carbonyltt iun and oxidtshytion13 (overall yield 71 but contaminated with 1J dicyclohexyl ketone) In compari~on the prccnt synthesi affords eyclohexyl n-octyl lciolle of high purity in good overall yield (tj(j two steps purified intermediate)

Experimental Section

Melting points were taken ill glass capillary tubes with 3

Bllchi apparatus allli n t correeted boiling points are LIn

purredId lnfrurcli spectra WIfl recorded for IIlt dliqllid sample with a Perkin-Elmer llode 137 ~pe((roph(jtI1middotr lIillf( the 624-~ band of pulystyrene Lt ~tallliard HefrHt ivc indic(s were obtained using It Blllisch and Lomb AbbeL refractometer Nudear magnetic resonance data were determined for soluI ions in CnCIa (unless otherwise specified) at 60 11cpraquo using Vifilln Associates Model A-60 or T-60 instruments and are cxprpsseJ ill parts per millinn (ppm) duwnfield from internal tetramethylshysilane Tetrahydrofuran (THF) was dried before use by di(illashytion from lithium fLhlmilllllll hydride Analytienl g middothroshymatogruphy was perforllled Oil the following columns 6 ft X 012 in i Carbowax 20M Oil (as-Chrulll Q F amp 1 lodd ~iO or 1i7iO instrument with flame ionization detection laquo(ollln A) 10 ft X 025 in 5(0 SE-aO silicon rubber on Ointoport H F amp 1 lIodel 300 instrument with thermal eOll(lite( ivity dn1Pf ion (column B) to f1 X 02- in fi QF-l fhlOrosili(J)lIlll lgtiatojlurt S F amp lI Model aoo (column C) Flow rates were for cplllllll

A an mlmin for colulllns B ami C (1) mlmin Elemclltal analyses were carried out by Scandinavian 1 iCloanahmiddotti11 Laboratory Herlev I )cnmark and by Elek Iicrolnalytica LaiJOratory Torrance Calif

(11) See Eo J Corey and D CrrHle J Ory Chern 33 298 (1gt68) for tlJe U8e of this system for the hydrulysis of dithjanc~

(12) II II Morris und 11 L Lllsth J Amer (hem Soc 761217 (W4) These authors also prepafPlti -lome of the kltonC fur comtari~oll by an alkylmiddot cadmium-type (iri~lUrd rellllion Nu yhmiddotld Ilil Ih(gtn

Ol) II C Brown I1ltIM W Ilthk Id 89 4r2l (11107gt II C Brown G W Kabalka and M W Hathke ibid 89 45lO (11167)

Fol 86 No3 March 1970

Diethyl (lmiddotmiddotMethylthio )ethylphosphonate (4a)-A solution of 11S- g (GO mmol) of diethyl methyithiomethylphosphonate7

ill WO Illi of ury Tilllt under argon anu (laquooled to _70deg was trcated with iii ml (62 mmol) of 122 III n-butylIithiuIll in pentane tti ITing of the yellow solutioll was continucd for) hr III -70deg after which time 44 ml (lO1) g 70 mIllol) of methyl iodide was added After an additional )() min at -70deg the solushytion Wl~ allowed t( warm to room tenperature The bulk of the solvents were removed Oil a rotary evaporator and the rernailling yellow oil WiS treated with 7 1111 of water and exshytracted with two 7ii-ml portioll of etiIer The eombinrd extracts Wln~ wahul wilh brine dried over anhydrous magnpsiulll blIifate and (list illed Thrre fnwtions were collected total 97ii g (777ltJ at llmpemtures of ii-middot70deg (02() mm) all were shown by nmr 10 [C sutlieiently pure for further use ~[ost of the product hoiled at 6--70deg (00 mm) purity gtJii( by vpc (column A at 150deg retention time 27 min) n23[) J Afl2() nmr () 13ii (triplet 6 II JJlI = 7 (j)~ methyl groups un the ethyl e~ter) 14 (doublet of doubl 3 H Jllll = 7 cps JllI = 16 (Jl~ methyl adjacent to phtl~phoru) 22) (singlet l H methyithio) 270 (~Yll1-

metrical muliplel 1 II mcthine) nnd 420 symrnetrieal multiplet4 JI methylene on ethyl ester) The infrarcd Jlcctrum was eharaderizcd by a stroll 1=0 stretching ahsorptiqn at 800 po ami a CIIOP strelclling vibration at iii1 p

Anal Caled for C7J[ 17Pii03 C )60 If SOS f-I 14GO FuulId C l~IA4 II lUll f 1middot16imiddot

Diethyl Il-lIethylthio Il(Jnylphosphonate 14b)--T a -ltJlllion of IIS g (11 lllIllol) of diIl1 1l11t1middotlthi(llllthylph1IhHllte7

ill 20() IlII uf CIY TllF under aq(lll ami at _iflo was addd ii ml ((j7llllltll) of 122 J[ n-lJulyllilllilllll in pelllllJP Aiter 4 hI uf stirring the solutioll wa treatcd with IS(I g 17- l1l111) of nshyuetyl iodid eulting ill thp iormatil of II jlicclpi(l The III ixt Ilre Vh ~t iI( d [l t - 70 0 for 4 mill t IHII It room Iell perL IIrc fur ]j Ill Hemoval of the bllik of the s()ivCllh jh roa~y eVajHJrltor and work-lip as ahov( afToJ(Ied after di-tillatioll G4t g bp 12-1)2deg (I)l2 mIll) alld (iA2 g bp ll~_Ilo (012 mill) That thee fractions w(e identical wa shown bv nmr The tolal yilld was l2S() g U)) n) 14620 lln li (lS9 ICllJlapsCd triplet-I II tCrmilillsof alkl (hain) 11-20illeudillg j )4 (t riplet bull1 111 = 7 cps) alld a brnad envelope peakillg at 12S (20 II methyl groups on ethyl estels and methylene protons on llkyl chain) ~l- (singlet 3 H methylthio) 260 (broad mulshytiplet 1 II lIIcthinel and 420 (symmrtrical multiplet 4 II lll(thylene~ on ethyl esters) The infrared spectrum contained a tll1llg 1=0 stretching band at 100 p and a CIIOP slIetching vibmtil)1 at R60 po

Anal Caled for CH 31 PS03 C )417 H 1007 H 1033 Found C5441 111000 S102S

Preparation of Diethyl (l-Methyl-l-methylthio-2-hydroxy-2shyphenyltethylpllOsphonate (Protonated 6a) from Diethyl (1shyMethylthio )ethylphosphonate and Benzaldehyde -10 a solution 0 212 fIlg (10 mmol) of diethy (l-methylthio)ethylphosphonute ill I ) illl of dry TIlt under argon and at -70deg was added OSi ml 111 mmol) uf 13 J n-butylliihium in pentane After 17ii hI tIll ~()Iution wa~ treated with 10 ml (lOii g JOO Illlllol) of bcmtldehyde Follnwill~ stilTing at -70 alld (]O for 1 min each Ihe actiolllllixtllle was poured into 10 ml of water and extmcted with j() ml of ethel The extrad waR washed with ~ueces~ive )()-llli portions of saturated iHIUhU lInmonium chloride sudium bi(arhonate and sodium chloride Evacuation at 1 Idll for 17 hI Inrt 2-0 mg (ii) of the hydroxyphosphonate The nml pc(tnlIll showed peaks at [ 120 ((omplex envelope J II Illethyl grollps Oil ethyl csters alJ(1 adjCl((t to phosphorus) J90 and 220 (~illglets 3]f methylthio in Ihreo and erylhro isomers) 420 (multiplet 4 If methylene protons on dhyl esters) 4)6 (singlet I II hydroxyl) iUJ and iIS (pair of duublets 1 H J Ill = II awi G cps methine threo and erythro) and 741 (multiplet II aromatic)

General Pro~edure for the Formation of Vinyl Sulfides-To 11 () mg (2 A mTllol) of diethyl (1-methylthio )e( hylphosphltJJlate or 744 IIlg (21 mlllol) of diethyl (l-methylthio)nonylphosphonate ill 12 ml of dry IHF at -70deg or cyclohexane at 0deg and under argoll was ~lldetl 16 ml (20 mmol) of J 2) M Ii-butyllil hium in ]lelltane The resulting solutio] was stirred at low tcmperature ( --7t) ur 0deg dl~pending ujJon the solvell t) for 4 -(i Ill The carshy()]yl cOlnpound (1 1 mrnol) WlS added neat or in 4 ml of THIlt I eydohxane and st irriag was continued at low temperature for j()(i(J min The clear sulution was next hellted at 50deg under IJll for 15-2) hI to effect elimination of the diethyl phosphute alllon

USE OF LITHIUM HEAmNTS IN KETONE SYNTHESIS 779

The result ing mixture now yellow (varit)u intensities (If brown for reartions that gave poor yield of vinyl sllifides) was treated with 10 ml of water and 10 ml of aturated aqueous ammonium chloride and th extracted with 10 ml of ether The ether extract WitS slHcessively washed with IO-ml portiOIS of sl1turated aqueous sodium bicarbonate and brine all I1queous phases were backmiddotwashed with 10 ml of ether The combined ether extracts were dried over anhydrous mltgnesinm sulfate and conceil trated on a rotary evaporator Isolation of the pure vinyl sulfide was readily accomplished by preparative tl on silica gel PF using 1 1 methylene chloridemiddotcyeJohexane a eluent The vinyl sulfides were all active in the lV with HI values uf ca 07

Methyl a-methylstyryl sulfide (7a) was ubtaiJwd in 80 yield by the addition of neat benzald(middotvde to the anion Sa formed in TIIF Vpe (column A 100deg) showed the liquid pruduct to be h()mogelleou~ The two possible isomers (7a-E retention time iil min 7a-Z retention time 6l min) were prescIt i a fil ratio IImr [ 20() and 21J (dollblets J II J = 1ii cps E and Z vinyJic methyl groups respectively) 220 ami 226 (singlets 3 II Z alld E methylthio groups respeetively) 612 and G40 (hroad singlets 1 IT E and Z vinylic protolls resp(ct ively) and 720 (hroad sillllet ii II aromatic) The infrared spettmm COBshy

tained bands at 620 and (liS po owing to a double bond conshyjugated with an aromatic ring Both infrared and Ilmr spectr were virtually idenUt1 with th)se rfported 6n for the vili- gtltIshyfide The Hussian workers rile not report Ilw iconwl ltin of their vinyl ldfide (folilwd h thc nlItilili of (TiCo( lf wit CIlSlllt gtIll tl miio f th lfillir 111 in ) II [f (fir prodlHt ~etIl(ld tu he lltUq 1hc -~lllli dS i ilf iJ1P~ttii (~

The prodllct ltd n 24 lJ 1li)middotj (iii 1lt I IGi2- Me yl I-methYI-l-heptenyl sulfide (ilJ) Wl PllVUfrl iCi nSi

yip1d hy tht~ hlilijd of LCHIlLi (IH~[ji in SldlltlOll i i ihe hiiioll)J

51 fOllllPd i eithpr TIIF or (yd in V)l( (middotltIllllL A 100deg) sh()middot~d the oil 1() ( hrn~lllCI)h Ild II mij II ot E and h i~()jner~ (rcttIJiioll t-inle~ 21 (llld IS tlill fCo]w(tJvelyi_ The 11m] speetrUlll (oltnilled peak It ) Ol (follllp~ed tnpi( l II methyl at termillu of alkyl chllin) J)O (multiplet (j 1[

methylenes) 1-17 lind IB) (doublet II J = ca Iii VS vinylie methyls 011 E ami Z isonlPls respectivlt-iy) 2J-2j (multiplet2 II IllJylic prutolls) 220 (siuglet a II methylthiu) and 517 and 54) Ihll1ad triplets 1 H vinyl PlOtollH of E and Z isomers respectively) fpe infraled spectrum showed a C=c=C st retehing frequency at 614 p

Anal Calet for CIfS C GS2k II 1146 S 202( Found C GiO H 114) S2022

Methyl a-methyl-3-phenylstyryl sulfide was prepared in gt14gt( yield by the Itddition of a THF soiLltlUn of benwphenone to the anion Sa in THF The product a vaguely yellow wlid mp 3flmiddot-SO was homogeneous hy vpe (column Bat H)Odeg re(pntion time iiS min) nIllr ) 210 (ingletj II) 2IG (singlet l H) and 7~O (multiplet 10 Il) The infrared tpectrum diplayed C=~~C stretehing vibrations I1t 62R and 6)) J

Anal Caled fur C6H6S C 7J04 H 671 S 134 Found C7lJ4 II6Gl SI)2

Methyl (l-cyclohexylidene )ethyl sulfide was obtained ill S2 yield by the addition of a Iutioll of fleshly disi illrd 14 cyeoshyhexluone in TIlllt to the anion Sa formed in TIfF The oily prociu(t was shown to be homogeneous by vp( (culumn C at 100deg retention lime 66 min) nIll [ 14ii (multiplet 6 If alieyclie) lU- (Hinglet) 219 (single) Illai 20-2 ) (multiplet 10 1I villylk llllthyl methylthio and allylic protons respecshytively) The infrared ~pe(truTll cuntaincd a weak C~cC strNchshyillg absorption at 616 IJ

Anal Calcd for CuH18S C 6916 IT J()ci2 S 2052 Found C6S()4 II1024 S2fl()6

Methyl (l-cyclohexylidene )nonyl sulfide was prepared in 72 yield by the addition of a solution of freshly distilled eycloshyhpxanone in Tilllt to the anion Sb abo in TIlF Vpc (e lllln II at IJOdeg retllltiull time 62 min) proved the homoglClJeity uf the oil nmr 0 OSJ (poorly resolved triplet If terminal methyl on the alkyl chain) 130 (broad band 12 II aliphatic methylelles) 153 (broad singlet 6 II alicyclic methylcnes) 213 (sharp singlet a II methylthio) and 20-27 (multiplet 6 H allylic) The infrared spectrum (ontained a weak C=C 51 ret ching freshyqllen(y at 61- po

(1-1) It was obHefvcd that the use of cyclohexauone which had Leon distilled and stured under nitro~en in a 8fgtrUm-Htoppercd flu~k for 5 days gave drastically reduced yields of vinyl sulfide

i 780 COFtEY AND SHULMAN

Anal Calcd for ClsHaoS C 7t H 1U8 ~ 1260 li(mnd C 7577 Hl186 S 1244

Reaction of the Anion Sa with Cyc1opentanone-When the general procedure for the formation of vinyl sulfides was carried out adding a solution of freshly distilled cyclopentanone in THF or cyclohexane to the anion a ill the same solvent only 7-10 of the desired methyl (l-cyclopentylidene)ethyl sulfide could be jjlated H0111ugeneity of the product was proven by vpc (column B at 100deg retention time 4 ) min) nmr Il 169 (multiplet 4 II alicyclic) 196 (tripletlO 3 H J = 15 cps allylic methyl) 22 (singlet) and 21-26 (multiplet 7 II methylthio anll fillylic methylenes) The infrared spectrum contained Il weak C=C stretching ahsorption at 610 p

Anal Calcd for CH14S C 6753 H 992 S 22 )4 Found C 0759 H9S S2190

In addition a 35 yield of 2-cye1opentyli(ilt-ne cyclopentanone was isolated by preparative tIc (U 040 silica gel 1 1 methylene chloride-cyclohexane) The nmr spectrum contained only II

complex envelope of peaks at Ii 13-30 The infrared spectrum contained strong bfinds at 5R2 and 6UJ p16

Reaction of the Anion Sa with Acetophenone--The general vinyl sulfide procedure was carried out with Sa and aeetophenone in either THF or cyclohexane only 3 mg (1cC) of material with the correct R value fot a vinyl sulfide (075) could be isdated this materi~l was not further chanccterized In addition a 60 yield of a mixture of acetophenone and it~ aldol condensation product WllS recovered The condensatiun product had an nmr spectrum containing a villylic methyl at amp 217 and an olefinic proton at Ii 6IIl in addithjll hl aromatic protons

Phenylacetone--To a solutiOlI of 90 mg (0i)5 mmol) f methyl a-methylstyryl sufide in 4 ml of 3 1 acetonitrile--water was added a solution of 30() mg (11 mmol) uf mercuric chloride in 4 ml of the same solvent Rystem The cloudy mixture was stirred at 0deg for 21 hr and then filtered through Hyflo Super Cel with thorough ether washing The filtrate was washed with aqueous sodium Ll(llrbonllte and then with brine and dried over anhyshydrous magnesium sulfate Concentration on the robry evaporashytor and short-path distillation afforded 62 mg (H4(~) of the ketone as a colorless oil which gave a single spot on tlC 17 n24D 15155 (lit]S n20D 15168) nmr amp 213 (singlet 3 H methyl) 369 (singlet 2 H methylene) and 728 (singlet 5 H aromatic) The inframd spectrum contained a C=O stretching frequency at 581 p

ll-Diphenylacetone-To a solution of HO mg (0040 mmol) of methyl a-methyl-tl-phenylstyrylsulfide in 4 ml of 3 1 acetonitrileshywater was added 217 mg (ORO mmol) of mercuric chloride in 4 ml of the same solvent mixture The homogeneous solulion was refluxed (w H2deg) for 41 hr during which time the colorless mercury m~rcaptide precipitated Work-up as above and shortshypath distiliation afforded 72 mg (86) of a colorlesl liquid which solidified upon cooling mp 4a5-450deg (litll mp 4middot-46deg)

(15) Such homoallrlic coupling to cis-oriented protons has precedent for example Ii A lieville and I G Nipllm [Tetrahedron LeU bull 837 (1969) I have noted hat the methyl group t C of compound i is a triplet J - 10 cps due to (Dupling to tht- C~ protonA

aCOOCH1

(16) See Ie Nakanishi Prsc1ifRl Inrared A rption Spectroscopy lL-liCu-DlY I iJ~ San Fraucisco -JiL Hl62 P 165

(17 Siri 1 l nwhylen l ddurid~-middotcy(luhe) OH elucnt (1) () ~tllil ArI -jmiddotel 332 HS (HHHL

Tile Journal of Organic Chemistry

The product gave a single spot on tlc17 nmr amp223 (singlet 3 H methyl) 515 (singlet 1 H methine) and 7n (singlet 10 H aromatic) The infrared spectrum contained a C=O band at 5R2 p

2-0ctanone-To 111 mg (070 mmol) of methyl I-methyl-Imiddot heptenyl sulfide in 4 ml of 3 1 acetonitrile-water was added 180 mg (140 mmol) of mercuric chloride in a ml of the same solvent system A colorless precipitate appeared immediately on mixing After (l hr of stirring at room temperature the milky mixllre WM

ftltered through Hyflo Super Cel with thorough ether washing The filtrate was washed with nqu(olls sodium- biearbmlte and then with brine dried over anhydrous magnesiulll sulfate and concentrated on the rotary evaporator The resulting oil was passed through a short silica gel column (methylene chloride eluent) to remove mercuric salts affording after rcmoval of solvent 67 mg (74) of liquid whosc infrared and nmr spectra were identical with those of authentic 2-octanone nD 14145 (lito noo 104161) The ketone gave l single spot on tlcY

Cyc10hexyl Methyl Ketone -To 19ii mg (125 mmol) of methyl (l-cyclohexylidene)ethyl sulfide ill S ml of a 1 acetonitrile-water was added a solution of 671l mg (25 mmol) of mercuric chloride in 5 ml of the same sohellt system After 20 hr of stirring at room temperature the mixture (a colorless precipitate with a pink 8upernatent Jiquid) Wlci filtered through Hyflo Super Cel with generous ether washing The filtrate was washed with aqueouS sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate Concentration by rotary evaporator and short-path distillation afforded 123 mg (7K) of the clear colorshy less liquid ketone n 25D 14i13 (lit z1 n20n 14))0) The product gave a single spot on tlC 17 nmr (Cel) Il 1 (broad multiplet 10 H alicyclic) 203 (singlet 31I methyl) and 2tH (multiplet 1 II methine) The infrared spectrum contained a (gt=0 band at 583 p

Cyclohexyl n-Octyl Ketone-A nonhomogeneous mixture of 1()2 mg (040 mmol) of methyl (l-cyclohcxylidenc)nonyl sulfide lil o ml of 5 1 acetonitrile-water was treated with 21 i mg (OSO mmol) of mercuric chloride in 3 ml of the same solvent system The eloudy reactioll lIlixtnre was heated at 0deg for 26 hr giving II colorless precipitate and a pink supernatent liquid Work-up as above and short-path distillation gave 83 mg (92) of the ketone as a colorless liquid n251l 1475 (lit n20D 145R52 146(013 ) A single spot was observed on tlc 17 nmr Il 08-20 including fl

poorly resolved triplet at 09J and a broad band at 127 125 II) and 237 (multiplet 3 H protons a to carbonyl) The infrared speetrum contained a C= -0 balld at 582 p

Registry Nomiddot--4a 22966-40-1 4h 22966-41-2 protonatcd 6a 22966-42-3 7a-E 22951-1S-4 7h-E 22951-19-5 7a-Z 22966-52-5 7h-Z 22966-53-6 methyl a-methYl-B-phenylstyryl sulfide 220G()-middotplusmn~-middoti methyl (l-cyclohexylidelle)ethyI sulfide 22966-44-j methyl (l-cyclohexylidene)nonyl sulfide 22HiG-4i-G methyl (1-cyclopenty lidene) ethyI sulfide 22929-24-4

Acknowledgments-This work vm supported by the National Institutes of Health Weare grateful to Mr B W Erickson for his asistance in the early stage~ of this work

(19) R S Yost anl C R lIaller J Amer Chmbull Sor bull 69 2325 (117) This ketone is reported to cr stallize in two lorIng mp -16 and 61deg 8C

R 3toermer Chern Ber J~ 2288 (11106) (20) N A Lange 1Indb()Jk of Chemitry lOlh ed lIcGrawmiddotHill

Houk Co Inc New York N YI Hl67 P 132 (21) N ll Zelinsky sud L ~I Tar~~wwa inn Chfm 1508 115 (tI3middotl