Thiosilanes as Thioketalization Reagents Citation Nesbitt, Stephen Lee (1977) Thiosilanes as Thioketalization Reagents. Master's thesis, California Institute of Technology. doi:10.7907/CDYJ-S314. https://resolver.caltech.edu/CaltechTHESIS:04062010-085409602 Abstract Thiosilanes react efficiently with simple aldehydes and ketones when catalyzed with ZnI_2 to produce thioacetals and thioketals. Steroidal diketones were thioketalized with yields and selectivity superior to other methods when allowed to react with thiosilanes and ZnI_2. The overall thioketalization process proceeds through silyl-hemithioketal intermediates which can be detected and isolated from the reaction mixtures. The isolated silylhemithioketals can be resubmitted to the thioketalization reaction conditions and be converted to thioketals. Item Type: Thesis (Master's thesis) Subject Keywords: (Chemistry) Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Evans, David A. Thesis Committee: Unknown, Unknown Defense Date: 21 October 1976 Record Number: CaltechTHESIS:04062010-085409602 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:04062010-085409602 DOI: 10.7907/CDYJ-S314 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 5692 Collection: CaltechTHESIS Deposited By: Tony Diaz Deposited On: 19 Apr 2010 17:44 Last Modified: 28 Oct 2024 22:30 Thesis Files Preview PDF - Final Version See Usage Policy. 1MB Repository Staff Only: item control page

THIOSILANES AS THIOKETALIZATION REAGENTS Thesis by Stephen L. Nesbitt In Partial Fulfillment of the Requirements for the Degree of Master of Science California Institute of Technology Pasadena, California 1977 (Submitted October 21, 1976) ii Acknowledgements I wish to thank Dave Evans whose knowledge of and interest in chemistry seemed endless. A special thanks is due to the graduate students and postdocs who have made my stay here a stimulating, rewarding and unique experience. The excitment of doing chemistry at Caltech is indescribable. Finally, I would like to acknowledge the financial assistance given by the National Institutes of Health, the National Science Foundation and the other agencies who have funded the research in our group. Aili Abstract Thiosilanes react efficiently with simple aldehydes and ketones when catalyzed with ZnI. to produce thioacetals and thioketals. 2 Steroidal diketones were thioketalized with yields and selectivity superior to other methods when allowed to react with thiosilanes and ani. The overall thioketalization process proceeds through silyl- hemithioketal intermediates which can be detected and isolated from the reaction mixtures. The isolated silylhemithioketals can be resubmitted to the thioketalization reaction conditions and be converted to thioketals. iv List of Abbreviations T™sS . . . . . . trimethylsilyl Et . . ° ° . . ethyl Me . * . e . * methyl Bu. . * . ‘ . butyl Ts ° . . . . p-toluenesulfonic Ac e « e . e r acetate Table of Contents Introduction Results and Discussion Experimental Notes and References 15 38 51 INTRODUCTION Aldehydes and ketones are among the most important functional groups in organic chemistry. Because of the extensive use of aldehydes and ketones in synthetic work, it has occasionally become necessary to temporarily limit the reactivity of the carbonyl group during a segment of a synthetic procedure. For this reason, a wide variety of protecting groups have been developed of which thioacetals and thioketals are important members. Thioacetals have also been used to extend the reactivity of aldehydes by reversing the normal electrophilic nature of the carbonyl carbon atom to that of a nucleophilic center, This umpolung (1) or charge affinity inversion (2) of aldehydes has been studied by Seebach'+) and others (213) , A new, mild and efficient procedure for thioketalization has been developed in which a ketone or an aldehyde is reacted with an excess of a thiosilane and a catalytic amount (95) of ZnIp (eq. 1). RS SR 2(CH3)3SiSR + ZnI> (1) + TMS20 The presence of amines inhibits the formation of thioketals and if the thiosilanes are contaminated with amines, only 0-trimethylsilyl- S~alkylthiohemiketals, the suspected reaction intermediates, are produced (eq. 2). RS TMS TMS-SR Zn12 amine (2) 4 PROTECTION OF ALDEHYDES AND KETONES (6-11) are available on aldehyde and Several excellent reviews ketone protection; only the most commonly used protecting groups will be described in this report. 1,3-Dioxalanes are the most widely used carbonyl protecting groups because they are both easily prepared and stable to a wide variety of reaction conditions, both basic and mildly acidic. Structural and electronic differences between various ketones and aldehydes: create differences in the rates of reaction and allow for selective ketalization, Isler (12) selectively protected 2,2,6-trimethyl-1,4—cyclohexanedione, 2, at the less sterically hindered carbonyl to produce the dioxalane derivative, 3, (eq. 3). 6 (CH20H)2 0 TsOH 1 ae 0 (3) 100% £ 3 fT _ McMurray (13) has protected the Wieland-Miescher ketone, 4, at the more reactive, saturated carbonyl and thus, has illustrated the use of electronic differences to selectively ketalize carbonyl groups (eq. 4), [ \ fe) Oo O st “ s ~~ 0 Pap 87% 4 a ofl A plethora of other alcohols have been used to form both cyclic and acyclic ketals with aldehydes and unhindered ketones. However, hindered ketones can be ketalized only with glycois‘24) , Acyclic acetals and ketals can eliminate a molecule of the corresponding alcohol and form enol ethers at higher temperatures +?) or under the influence of strong acids‘25), ‘the diethyl ketal of 4sobutraldehyde, for example, loses a molecule of ethyl alcohol upon treatment with phosphoric acid (eq. 5) (5), OEt OEt * > OEt Acetals and ketals are prepared from the parent carbonyl compound by reaction with the appropriate alcohol or glycol, which is generally the solvent, and an acid catalyst such as snc, (2) , P-CH{CGH)S03H (17-21) » OF BF, *Et,0 (22,23) » The water generated 6 during ketalization must be constantly removed to insure complete reaction, The dehydration has been accomplished by azeotropic distillation (24,25) | molecular sieves (26) | and N,N‘-dicyclo- hexylearbodiinide(2?), Ketals and acetals are most commonly cleaved by treatment with aqueous acid (19,20,28) but the specific conditions are often system dependent. The AtW5-ethyleneketal of 6» -hydroxytestosterone-6,17- diacetate was hydrolyzed by reaction with magnesium sulfate in wet (29) \ é benzene (eq. 6) A mumber of alternate procedures for ketal. hydrolysis have ‘seen . . Q) os . éeveloped. Dierasai\? ‘ bas employed an exchange techniaue with fis Na = > = i] Fr, nha sow a BCS lone 15 acetone in the hydrolysis of the steroidal ketal, 5 aoe ow i > converted to 1,.-dimethyldioxanane, 7, and the ketal is converted oS ry to progesterol, 2, (ea. 7). nt mae) HO acetone TsOH y HO 12 hours ~ 1 (7) a /-\ 6) fe) x Hebart and Gravel (32) have hydrolyzed the aryl nitro substituted aioxalane of 3~pregen-3 3 -0l~20-one acetate, 8, photolytically (eq. 8). 8 5-Pregen-3 -ol-20-one acetate, 1, was produced in an 83% yield along with the by-product, « ~hydroxy-o-nitroacetophenone, The bromo substituted ethylene ketal of 4-tert-butylcyclo- hexanone, Qs was hydrolyzed when treated with activated zinc metal ir refluxing methanol, The ketone, 4~tert-butylcyclohexane, 10, was formed in an 89% yield along with the by-product, allyl bromide an o 9 fe) i Zn. Aa 2 A, HOCH3 + 7S (9) OH g 10 The hemithioketals represent a related class of protecting grvups which, in general, may be formed under milder conditions than the thioketals, The hemithioketals are also stable to both basic and acidic reaction media. Estrone acetate, Als has been converted to the corresponding 17~ethylenehemithioketal, 18, by reaction with (3h G-mercaptoethanol and. ZnCl, feqe 10) (34) | ! S 5 HSCH2CH20H 2nClo _ dioxane” AcO re Hemithioketals are hydrolyzed by reaction with mineral acids in alcoholic solvents or dioxane (3 5 ), Dithioketals are stable to most basic and acidic reaction con- ditions, The dithioketals are prepared from the parent ketone by - 433 reaction with alkyl thiols and ZnCl, (36537) jo, (38-42) | op Ht ,0 43} 3 ( ( or p-CH,C/H,SO (42) » Fieser (43) has converted cholestane-3-one, 3 3 19s to the 1,2-dithiolane derivative, 20, in a 92% yield (eq. 11). H BF 4 Bt S| (CH2SH 25 pers Cs 92 10 Selective protection is also possible in thioketalization reactions. raz (33) has thioketalized progesterone, 12, to form a mixture of thioketals and shown that a, ~unsaturated ketones are more reactive toward thioketalization than are saturated ketones. The 3-ethylenethioketal of progesterone, 2, was the major product and the bis-3,20-ethylenethioketal of progesterone, 4, was the minor product (eq. 12). Faas Ny HSCH2CH»SH HOAC _ 11 A novel method for the preparation of dithioketals has recently been developed by LaLancette (39,40) | however, only acyclic thioketals can be made by this procedure, An alkyl orthothioborate was allowed to react with a ketone or aldehyde to produce the product thioketal or thioacetal, 2-Butanone was converted to 2,2-diethylthiobutane and boric oxide with triethylorthothioborate by this procedure (eq. 13). The conversion of thioketals and thioacetals to the parent ketones and aldehydes has proven to be a challenging task. Mercuri: i salts and aqueous acid (42447) » although the common reagents for thioketal hydrolysis, have often given quite disappointing results, although some modifications of this procedure have resulted in inm- proved yields (48) | Several new methods of hydrolysis have recently beer. developed which are nilder and more efficient than the mercurit SaL% creatment: however, these new methods are often not very gener Ll. Peracid oxidation of the 3-trimethylenethicketal of 3-keto-17- hydroxy~androstane acetate, al, to the bis sulfoxide, followed by treatment with NaQEt gave 3-keto~-17-hydroxyandrostane acetate, Ley ay in a 51% yield (eq. 14) (49) | 12 OAc NCPRAs, NeOrt . 90% Op 7 OAc (Le) Several other oxidizing agents have been employed in similar hyerx - (50-52) P : ‘ 4-4 ames lysis procedures » Chloromine T in aqueous alecholic solutions have been used to convert spiro [1,3-dithane-2,9'-fluorene} to ; (5355) 9-fluorenone in an 86% yield ‘, Oxidation of dithioketals to the monosulfoxide and subsequent treatment with a catalytic amount. of sulfuric acid produces the parent ketone. The dimethylthioacetel of 2-phenylethanol was converted to the monosulfoxide and treated . . (ho, 50% with sulfuric acid, 2-phenylethanol resulted fea. 15) (4945 s PhCH2CH{(SCH3}2 MCPBA. _sulfuric. PhCH2CHO (15) “ acid ~ 88% Silver oxide in aqueous acetonitrile has aiso been used to hydrolyze 13 thicketals in good yielas (57), Oishi and Kamemoto (58) nave studied the hydrolysis of thioketals by treatment with triethyloxonium tetrafluoroborate and aqueous CuSO) Cyclohexanone ethylenethioketal has been hydrolyzed by this procedure to give cyclohexanone in an 81% yield. Enol ethers and thioenol ethers represent yet another class of carbonyl protecting groups, Because «,g-unsaturated ketones and % ,B-unsaturated aldehydes form enol ethers more readily than saturated ketones, selective protection can occur, Djerassi 659’ has prepared the ethylenol ether of androsteredione, 24, in a 60% yield (eq, 16), to almost all noneacidic reaction eon- oD ty a* pp ce? fea a Enol ethers are qutions but they are readily cleaved by even mild treatment with aclds. om 7 = Vapl pray writin Aawder ° Pon, cimethylsilyicvenchyérin derivatives are easily preparec. fron Ly ketones and aldehydes by their reaction with TMS-CN in the presence (60-62) of KCN*18-crown-6 complex » Cyclopentanone was converted to TMSO CN IA KCN () + TMS-CN 18-C-6. (16) 89% l-trimethylsiloxy-l-cyanocyclopentane in an 89% yield (eq. 11) by this procedure, The silylcyanonydrins are hydrolyzed by treatment with AgF®. This regenerates the parent carbonyl compound and forms TMS-F and AgCN. Numerous other funticnalities have been used as carbonyl pro=- tecting groups. For example, semicarbazone oximes and hydrazones are carbonyl protecting groups but their resistance to hydrolysis greatly restricts their use, The ketals and thicketals are, however, the most often used protecting groups for ketones and aldehydes and the thiosilane procedure for thioketalization is a milder alternative for carbonyl derivatization. RESULTS AND DISCUSSION 16 RESULTS AND DISCUSSION Sunnary Aldehydes and ketones have been converted to thioacetals and thioketals, respectively, in excellent yields when allowed to react with an excess of a thiosilane and a catalytic amount (63) of ani, (Table I). Several steroidal diketones have been selectively protected at the %,fj-unsaturated ketone in yields and with selectivity superior to that previously reported (33) | The mechanism of the thioketalization reaction has been investigated and the intermediates are believed to be Silylthiohemiketals, This thioketalization pro- cedure is among the most gentle known and should prove useful in synthetic applications, Preparation of the Thiosilanes ' . A wide variety of alkyl and aryl thiotrimethylsilanes have been prepared by allowing the corresponding sodium thiolates to react (64,65). with chlorotrimethylsilane The ethylthiotrimethylsilane, 38, used in this report was successfully prepared by this procedure. 17 Table I. Preparation of Thioketals and Thioacetals by Reaction with Thiosilanes®, RS~TMs © carbonyl product yield reaction compound (4) time (hours) R=Me heptanal n-hexyl-CH(SMe) 2 93 . 12 R=Et heptanal n-hexyl-CH(SEt)., 92 24 STMS Ss ( | heptanal n-hexyl—{ 75 24 STMS Ss . QO SMe R =Me CX 93 2h Q Me 0 SMe R=Me CX 92 18 Me 0 SEt 0 Ets SEt Et >; 91 12 VA, Et t ~ i 18 ‘able I (continued). Preparation of Thioketals and Thioacetals by Reaction with Thiosilanes®, RS-TMs > carbonyl product yield reaction compound (%) time (hours) STMS 0 Et s STMS Et s R=Me PRCOCH, Phc (SMe) CH, 78 72 R=Et PhCOCH, Phc (SEt) gH, 93 24 SMe R=Me » CHO an 85 24 : Me SEt R=Et. y CHO lan 92 24 Et s ~ 70 24 S D yao O° BtS set R=Et AA 92 2h H TMS STMS "all reactions were catalyzed with gnI,. La 10% excess of the thiosilane was employed in all reactions, 19 EtSH pet EtSNa’ + Ho TBS TMS-SEt (18) Lithium thiolates, prepared from the thiol and n-butyllithiun, have also been silylated with chlorotrimethylailane. The thiosilanes of 1,2-ethanedithiol, 1,3-propanedithiol and methanethiol were pre- pared by this procedure in moderate yields (eq. 19). SH | SLA STMS + n-BuLi Ether. [ IMsciy, ; (19) se 08 sii 60% STMS Hooten and Allred (66) were the first to report a synthesis of thiosilane, 26, Methylthiomagnesium iodide was prepared by allowing methanethiol to react with methylmagnesium iodide. The magnesium thiolate was then allowed to react with chlorotrimethylsilane to produce the thiosilane, 26, The thiosilane, 26, was also prepared by the LiAlH, reduction of dimethyldisulfide and subsequent reaction of the lithium aluminate, (MeS),AlLi, with chlorotrimethylsilane (eq. 20) (67) | ky 20 Table II. Preparation of Thiosilanes,. Thiol ‘Silylation Thiosilane Yield Refs. conditions (%) EtSH NaH, TMSC1 38 68 68 o~ . SH [ n-BuLi, 4O 60 SH TMSC1 ~~ SH n-BuLi ( “TNSCL. 39 40 H MeSH n-BuLi, TMSCL 26 60 MeSH . MeMgBr, TMSC1 26 33 66 LiAlH),» (MeS)o» 26 32 67 | TMSC1 , SH . TMS SNH, H imidazole 40 32 63 SH TMS.NH , C imidazole 22 85 63 21 Although only thiosilane 26 has been prepared by this procedure, undoubtedly this method is general. Glass (63) has developed another method for preparing thio- Silanes, Hexamethyldisilazane, 28, and the corresponding thiol were reacted in the presence of a catalytic amount of imidazole, 29s N. N Ss —_—— > N HN(TMS)2 + «? <—— q? + NH | ns 28 29 30 tr (21) H No Ny TMS-SR + (? : (,” + RSe i ‘rms 31 all Re aryl, alkyl Experiments suggest that imidazole is silylated by the silylamine, 28, and that this silylated imadazole then accepts a proton from the thiot (7°), the thiolate then attacks the protonated imidazole to form the thiosilane and regenerates the catalyst.In order to establish the intermediacy of 30, Glass has shown that when 39 and a thiol were 22 allowed to react, thiosilanes and imidazole were produced (72), Thiosilane, 26, was prepared by the LiAl1H, reduction of dimethyldisulfide, and by the reaction of chlorotrimethylsilane with the lithium or magnesium salts of methanethiol. However, the methylthiotrimethylsilane prepared via the reaction of methylthio- magnesium iodide with chlorotrimethylsilane, contained an impurity which catalyzed the thioketalization reaction. This impurity remained even after repeated distillations and although it was almost certainly another Lewis acid, the exact nature of this contaminant 4s still unknown. Bis-1,2-trimethylthiosiloxyethane and bis-1,3-trimethylthic~ siloxypropane were best prepared by the Glass procedure (63), This method has the advantagc: of not forming inorganic salts and thus does not require a Schlenk filtration. Unfortunately, these reaction mixtures must be very carefully distilled prior to use in thio- ketalization reactions in order to remove all traces of amine. 28. This amine inhibits the formation of thioketals and only silylhemi- thioketals are produced when thiosilanes are contaminated with amines, The sodium thiolates of 1,2-ethanedithiol and 1,3-propanedithiol could not be formed by reaction with NaH under the usual reaction conditions, To circumvent this problem, the thiolates were formed vith n-butyllithium. This procedure, however, generates solid LiCl which must be removed by filtration before distillation. 23 SYNTHESIS OF THIOKETALS AND SILYLHEMITHIOKETALS Ketones and aldehydes react with thiosilanes and a catalytic i amount (4) of dnl, to form thioketals and thioacetals (Table I). Cyclohexanone was converted to 1,1-dimethylthiocyclohexane, 36, oe by reaction with the thiosilane, 26, in a 92% yield (eq. 22) and other simple carbonyis react as efficiently. Ethylthictrimethylsilane, MeS SMe + TMS-SMe Ether (22% Znis > 86e 36 Fa 38, also reacts with carbonyls to produce thioketals and -acetals with efficienty equal to that ot the thicsilane, 26 (fable I}, Enones, such as cholestenors, fail to form a characterizable set of products whe ey ee Set Ce 2 ee ee oe ee Seem weacted with the thicstlan By oleTin migration account for many of these preducts. 24 Table ITI. Thioketalization with Bifunctional Thiosilanes”, Sarbonyl Product Thiosilane? Yield substrate (%) C8Hy 4 cholestenone 39 81 cholestenone 4O 9¢ progesterone LO 3. androsteredione uO ou a. ; . db Ail reactions were catalyzed with “nL ye The reactions were performed with 1.1 equivalents of the thiosilane. 25 Thiosilane, 38, was allowed to react with 2~methyl-2-hydroxy- pentane-4-one and éni,, in an effort to define the mildness of this thioketalization procedure. 2-Trimethylsiloxy-2-methyl-4,4-diethyl- thiopentane was isolated from the reaction mixture ina 92% yield. Although the rapid silylation of the alcohol probably keeps de-~ hydration to a minimum, the absence of significant amounts of dehydration product denmenstrates the mildness of the reaction conditions. Silylhemithicketals and acetals can be prepared and isolated wher ketones anc aldehydes are reacted with an, and a thiosilane which is contaminated with an amine (Table IV). This functional (241) group has been investigated by Chan and Ong in an effort to gevelop another reversed polarity carbonyl equivalent and although they were unsuccessful in generating the requisite anion, silyl- hemithioketale ray still be used as carbonyl protecting groups in 8-Aza~3S-caxrsophenoxy~bicvelol3.2.1] octa-3-one, 42, has been L 7 $ Ss converted to Geaza-o-carbovhencxy~3-trimethylsiloxy—-3-methylthio-~ * “ at 5 ” 5 a phoyelo! 3.2, octane. 43, bY allow. is : A a = ett ae ge it to react with the thiosilane, wt de ye at > nitrogen deactivates thet the amine, 25, La? 26 Table IV. Formation of Silylhemithioketals with Thiosilane 2629? ad carbonyl product yield reaction substrate (%) time (hours) 0 “MeS OTMS Ll we B8 1.5 0 MeS oOTMS td - OTMS n-hexyl-CHo armor 60 1.5 Me Pno PAO \ ro IN| 85 2k SAN a Be) All reactions were catalyzed with anions The reactions were performed with 2 equivalents of 26, 27 Pho Pho TMS -SMe Zn1 (23) XS , OTMS bite 42 26 43 The thiosilane, 39, has been successfully used as a thioketaliza- tion reagent with unsaturated ketones. When the cholestenone was allowed to react with the thiosilane, 39, the 3-propylenethioketal of cholestenone, 49, was formed in an 81% yield. The thiosilane, LO, was also allowed te react with cholestenone, and the 3-ethylLenethic- ketal, 50, was formed. in a 90% yield. Anérosteredione was selectively thioketalized with the thio- silane, x, to give the 3-ethylenethicketal of ancrosteredione, “4. as the major product and the bis-3,17-ethylenethioketal, 45, ~s a neg 83am Fa eof as the sinor product (eq. 24). 28 — O RSCHoCH2SR _ Oo Zni2 ~ (243 s Cy Ss RAN ; ( J R= TMS . 914 Ra Ht 76% be Progesterone was also selectively thioketalized with the thiosilane, 40, to give the 3-ethylenethioketal of progesterone, 46, as the major product and the bis-3,20-ethylenethicketal, 47, as the minor product (eq. 25), Both the overall yield and the positional selectivity of this thioketalization were superior to the normal thioketalization procedure employing ethanedithiol and P-CHAC(H) SC,H Che, some steric hincrance at the g-position of enones may also ve -necessary for successful thioketalization, When cyclohexanone was allowed to react with the thiosilane, 4, a largely uncharacterized mixtuce of products was formed, The main component had an infrared 29 RSCH2CH2SR __ acid ~ (24) S (is 4g pa Re HY = 35% 2% R = TMS 4% 4% spectrum and a proton magnetic resonance spectrum consistent with bis 1,2(3~oxocyclohexylthionyl) ethane, 48. QO Li aN © 48 ~~! 30 MECHANISTIC CONSIDERATIONS The thioketalization reaction presumably proceeds through an O-trimethylsilylalkylthiohemiketal intermediate as illustrated with cyclohexanone (eq. 26). The first step of this reaction is analogous 0 RS OTMS RS SR I ™ nus-se CN TMS SR + (TMS ) 20 to the insertion reactions of carbonyl compounds with other organo- metaliic reagents (64) | Experiments indicate that the thiosiiane 4nsertion process is Lewis acid assisted because no reaction occured when cyclohexanone anc the thiosilane, 26, were mixed and the inter- mediate, L-methylthio~l-trimethylsiloxyeyelohexane, 235 also did not react with the thiosilane, 26, without added Znly. Anionic catalysts, such as potassium cyanide~18~-crown-6-complex, have been used to form the internediate silylhemithioacetals from aldehydes but anionic catalysts will not convert the intermediate silylhemithicketals and -acetals to thioketals and thioacetals. These anionic catalysts do not effect these reactions with ketones, Employing KCN as the catalyst, thiosilane, 28, was allowed to react with Asobutyraidehyde te form l-ethylthio-l-trimethylsiloxy-2- 31 methylpropane, 34, (eq. 27). Benzaldehyde was allowed to react with thiosilane, 38, to form a~-trimethylsiloxy-o-ethylthiotoluene, 35 (eq. 28). TMS-SEt yo + PHCHO + TMS-SEt OTMS Kens ~X (27) SEt 34 OTMS KON. Ph—{ (28) SEt 35 Both the amine, 2c, ang imidazole inhibit the normal thio- ketalization process and even with added 2niy, only silylhemithio-~ nedais are formed. Yariations tn the Lewis acid, even acids as strong as AiCl, and HCl, cause no change in the product. Heating these reaction mixtures caused only extensive elimination. During the course of the thioketalization of cyclohexanone, gas chromatographic analysis revealed the rapid disappearance of the ketone and formation of a new product at longer retention time, 32 The new product had a retention time identical to that of the proposed intermediate, .1-methylthio-1-trimethylsiloxycyclohexane, 32. At longer reaction times this intermediate disappeared and was replaced by the product thioketal, 26. Furthermore, if the reaction was per- formed in the presence of the amine, 28, a substance known to inhibit the second step, the same intermediate peak appeared and isolation and structure proof verified that this intermediate was the hemi- thioketal, 22. The intermediate was then treated with the thiosilane, 28s and ZnI, and converted to the thioketal, 36 (Scheme I), Thus 2 the proposed intermediate, 225 has been observed during the reaction, dsolated from the reaction mixturc and when resubmitted to the reaction conditions, was converted to the product thioketal, 36. Scheme I 28 No Reaction Np Om tN rs R nm VY wes 4 33 It is known that oxygen stabilized carbonium ions are more stable than sulfur stabilized carbonium ions (29) | From this data, it was predicted that if hemithioketal, 325 was allowed to react with hemiketal » Be and énlo, the reaction would follow path A of Scheme II and only thiosilane, 28s would be formed. If, however, path B was faster than or as fast as path A of Scheme II, then thiosilane 38 and l-methylthio-l-ethylthiocyclohexane, 3?) would be formed as a mixture. Unfortunately, the product thiosilanes inter- convert under the reaction condition and lacking kinetic data, no conclusions can be made, A recent report by Chan and Ong (24) described the formation cf O-trimethylsilylmethylthiohemiketals and ~acetals by the reaction of a thiol, pyridine, chlorotrimethylsilane and a ketone or aldehyde, They noted that if pyridine was omitted from the reaction mixture, only thioketals and -acetals were obtained. The mechanism proposed for the formation of thiohemiketals is shown in Scheme II, In light of the results presented here, it is proposed that trimethyl- alkylsilanes are formed in situ and that these thiosilanes react with ketones and aldehydes to produce thiohemiketals and ~acetals whicn in the absence of pyridine and catalyzed by the HCl produced, react further to form thioketals and -acetais. Although no comparative rate siudies of the thiol addition to carbonyl groups and chlorosilanes are presently known, it is not unreasonable to 34 Scheme II OTMS MeS Path B Path A OTMS 35 Scheme II RSH + © = RS~ + O . o© . + RS” R Re ZN, <—_ 1 Ry Re SR © OTMS ° —> mi Rz + TMS~-C1 —— Ry + SR | BR assume that the thiolates attack the silicon atom (a very electrophilic atom) faster than they attack the carbonyl carbon atom, 36 CONCLUSIONS 37 CONCLUSIONS When thiosilanes are allowed to react with aldehydes or ketones and a trace of Zn1ys thioketals and thiocacetals are formed in excellent yields. These conditions are the mildest and most efficient available, In addition, several steroidal diketones were thio- ketalized with yields and selectivity superior to that previously reported, This thioketalization procedure, however, requires the additional preparation of the thiosilane and the thiosilane must be carefully purified before use. In addition, ketones with amide or amine functionalities cannot be thioketalized by this procedure be- cause only silylhemithioketals are produced. The overall thioketalization process proceeds through Silylhemithioketal intermediates which can be detected and isolated from the reaction mixture. Finally, the silylhemithioketals can be submitted to the thioketalization reaction conditions and be converted to thioketals. 38 EXPERIMENTAL 39 General. Infrared spectra were recorded on a Beckman IR-4210. PMR spectra were recorded on a Varian T-60 or A-60-A spectrometer and the chemical shifts are relative to either tetramethylsilane or methylene chloride (317 Hz). Gas chromatographic analysis were performed on a Varian Aerograph Series 1400 gas chromatograph using a 2 meter, stainless-steel column packed with SE-30 on Chromasorb W. Melting points were taken on a Bilchi model SMP-20 melting point apparatus and are uncorrected. All solvents were dried by the procedures described in Perrin, Armarege and perrin(®8) , General Thioketalization Procedure. To a dry, nitrogen-purged, 25-m’., round~bottom flask was added ca. 0.01 g (0.03 mmol) of anhydrous zinc iodide, 5.0 ml of anhydrous ether, and 10 mmol of ketone or aldehyde. To this solution was added 22 mmol of the appropriate thiosilane, RS-TMS, via syringe over a 2 minute period. After stirring at ambient temperature (25°) for 12-24 hours, the reaction was quenched with water and extracted with ether. The etheral extract was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resuiting thioketal was then purified by chromatography on 50 g of alumina (Activity III) eluting with hexane. a,i-Dimethyithioheptane. The general. thioketalizatior procedure (1.40 mi, 10 mmol, heptanal; 3.20 ml, 22 mmol, 26) gave, after chromatography, 1.78 ¢ (93.0%) of the product; ir (neat) 2960-2865, 1465, 1435, 955 om “3 nmr (CCL, ) &§ 3.60 (t, 1, J=7.0 Hz, SCH), Fa 2,10 (s, 6, SCH,), 1.30 (m, 13, CHy)s 0.95 (t, 3, CH.) ppm. af a) Anal. Caled for C : C, 56.19; H, 10.48, Found: C, 56.11; g#2o%2 H, 10.58. 1,1-Diethylthioheptane. The general thioketalization procedure (1.40 ml, 10 mmol, heptanal; 3.60 ml, 22 mmol, 38) gave, after chromatography and molecular distillation (90°/0.02 mm Hg), 2.03 ¢ (92.0%) of the product; ir (neat) 2960-2860, 1450, 1260 em; nmr (CC1,) § 3.75 (t, 1, J=7.0 Hz,CH), 2.68 (a, 4, J=7.0 Hz, SCH,), 1.40 (n, 13, CHy)» 1.30 (t, 6, J=7.0 Hz, CH,) ppm. Anal, Caled for Cy Hoy So? CG, 59.93; H, 10.97. Found: C, 59.78; H, 10.85. 2-Heptyl-1,3-dithiane. The general thioketalization procedure ( 1.40 ml, 10 mmol, heptanal; 3.01 ml, 11 mmol, 39) gave, after chromatography, 0.31 g (75.0%) of the product; ir (neat) 2960-2862, 1462, 1418, 1274,907 cm”; nmr (CC1,)£ 4.00 (t, 1, methyne), 2.82 (m, 4, SCH,), 2.00 (m, 2, SCH,CH.)s 1.50 (m, 10, CH), 0.95 (t, 3, CH,) ppm. Anal, Caled for C,.Ho9S,1 C, 56.763 Hy 9686. Found: C, 58.85; Hy 9.79. 1,1-Dimethyithiocyclopentane. The general thioxetalization procedure a ( 0,89 mi, 10 mmol, cyclepentanone: 3.2C ml, 22 mmol, 26) gave, after chromatography. 1.52 g (93.0%) of the product; ir(neat) 296C- 2870, 1435, 1418 om”: amr (CC1,) $2.95 (ss 6 SCH), 1490 (m, 8 CH) ppm. Anal. Caicd for CoH So# C, 51.80; H, 8.69. Found: C, 52.03; H, 8.68, AL i1,i-Dimethylthiocyclohexane., The general thioketalization procedure (1.04 ml, 10 mmol, cyclohexanone; 3.20 ml, 22 mmol, 26) gave, after chromatography, 1.62 g (92.0%) of the product; ir (neat) 2978- 2860, 1445, 1010, 755 on™}; nmr (cc1,) § 2.05 (s, 6, SCH), 1.70 (m, 10, CH) ppm. Anal. Caled for CoH, 685! C, 54.49; H, 9.15. Found: C, 54.76; H, 8.98, 1,1~Diethylthiocyclohexane. The general thioketalization procedure (1,04 ml, 10 mmol, cyclohexanone; 3.60 ml, 22 mmol, 38) gave, after chromatography, 2.00 g (98.0%) of the product; ir (neat) 2970- 2860, 1442, 1260,1257, 1005 em™; nmr (CC1,) $2.60 (a, 4, J=7.5 He, SCH), 1.75 (m, 10, CHy), 1.27 (t, 6, J=7.5 Hz, CH) ppm Anal. Caled for C3 otaoSo! C, 58.753 Hy 9.86. Found: C, 58.42; H, 9.57. 3,3-Diethylthiopentane. The general thioketalization procedure (1.05 ml, 10 mmol, 3-pentanone; 3,60 ml, 22 mmol, 38) gave, after 3 chromatography, 1.74 g¢ (91.0%) of the product; ir (neat) 2965-2870, un 1450, 1370, 812 cm; nmr (cc1,,) § 2.60 (q, 4, J=7.5 Hz, SCH)» 1.65 (q, 4, J=8.0 Hz, CH)» 1.25 (t, 6, 327.5 Hz, CH) 1,00 (t, 6, J28,0 Hz, CH.) ppm, Anal. Calcd for CHa So! C, 56.193 H, 10.48, Found: C, 56.413 H, 10.28, 2,2-Diethyl-1.3-dithiane, The general thioketalization procedure (1.05 ml, 10 mmol, 3- pentanone; 3,01 ml, 11 mmol, 39) gave, after chromatography, 0.33 g (95.0%) of the product; ir (neat) 2970-2825, 1450, 1418, 903, 877 om™*: nmr (CC1,) 4 2.75 (my 4, SCHy), 1.95 (my 2, 42 CH)» 1.90 (q, 4, CH)» 0.95 (t, 6, CH, ) ppm3 exact mass (75 eV) m/e calcd 176.069, observed 176.069. a,~-Dimethylthiotoluene, The general thioketalization procedure (1.16 ml, 10 mmol, acetophenone; 3.20 ml, 22 mmol, 26) gave, after chromatography and molecular distillation (80°/0.07 mm Hg), 1.53 g (78.0 %) of the product; ir (neat) 3055, 2975-2820, 1593, 1442, 125), 990, 860, 845, 695 cms nmr (CC1,)$ 7.60 (m, 5, aryl-H), 2.10 (s, 6, SCH, ), 2.05 (s, 3, CH, ) ppm. Anal, Caled for Cy H))55: C, 60.553 H, 7.11, Found: C, 60.645 H, 7.05. ma, ~Diethylthiotoluene, The general thioketalization procedure (1.16 ml, 10 mmol, acetophenone; 3.60 ml, 22 mmol, 38) gave, after chromatography, 2.11 g (93.0 %) of the product; ir (neat) 3055, 2965=2930, 1582, 1440, 695 om™*; nmr (CC1,)§ 7.60 (m, 5, aryl-H), 2.62 (ay 4, J=765 Hzs SCH) s 2.10 (s, 3, CH), 1.30 (t, 6, J=7.5 He, cH) ppm. Anal. Caled for Cy oH Sot Cs 63.373 H, 8.01. Found: C, 63,41; H, 7.80. 1,1-Dimethylthio-2-methylpropane. The general thioketalization procedure (0,91 ml, 10 mmol, isobutyraldehyde; 3,20 ml, 22 mmol, 26) gave, after chromatography and molecular distillation (80°/0,04 mm Hg), 1,28 g (85.0 %) of the product; ir (neat) 2960-2870, 1460, 1435, 767 om; nmr (CC1,,)$ 3.42 (d, 1, J:6.0 Hz, SCH), 2.11 (s, 6, SCH,), 1.97 (m, 1, CH), 1.15 (d, 6, J=6.0 Hz, CH,) ppm. Anal, Calcd for CLH, Soi C, 47.943 H, 9.39. Found: C, 47,88; H, 9,42. 43 1,1-Diethylthio-2-methylpropane. The general thioketalization procedure (0,91 ml, 10 mmol, isobutyraldehyde; 3.60 ml, 22 mmol, 38) gave, after chromatography, 1.65 g (92.0 %) of the product; ir (neat) 2962-2930, 1450, 1260 cm"; nmr (CC1,)5 3.62 (a, 1, J=5.0 Hz, CH), 2.64 (q, 4, 328.0 Hz, SCH)» 2.05 (m, 1, CH), 1.28 (t, 6, J=8.0 Hz, SCH,CH, Anal, Caled for CoH, .S,: C, 53.87; H, 10.17. Found: C, 53.69; ), 1.10 (ad, 6, J=5.0 Hz, CH, ) ppm, H, 9,87. 2-(1-Methyl )-ethyl-1,3-dithiane, The general thioketalization procedure (0,91 ml, 10 mmol, isobutyraldehyde; 3.01 ml, 11 mmol, 39) gave, after chromatography, 0.11 g (70.0 %) of the product; ir (neat) 2960~2820, 1452, 1415, 1272, 905 765 om; nmr (CC1,) ¢ 3.60 (d, l, RSCH), 2.80 (t, 4, SCH), 2.05 (m, 1, CH), 2.05 (p, 2, SCHACH) » 1.15 (d, 6, CH) ppm; exact mass (75 eV) m/e calcd 162.054, observed 162.055. 2,2-Diethylthio—4-methyl-4-trimethylsiloxypentane,. The general thioketalization procedure (1.16 g, 10 mmol, 2-hydroxy-2-methyl- pentan-4-one; 5.40 ml, 33 mmol, 38) gave, after chromatography, 2.72 g (92.0 &) of the product; ir (neat) 2980, 2930, 2870, 1445, 1250, 1170, 1035, 858, 840, 750 om"; nmr (CC1,)§ 2.65 (ay 4, 32765 Hz, SCH)» 2.05 (s, 2, CH), 1.70 (s, 3, CHy)» 1.45 (s, 6, CH), 1.30 (t, 6, J=7.5 Hz, SCHCH,), 9.20 (s, 9, SiCH.) ppm; exact mass (75 eV) m/e calcd 204,101 for C.H..S,, observed 204,101, = 18°2 9 Reaction of cholestenone with thiosilane 39. The general thioketaliza- tion procedure (0.193g, 0.5 mmol, cholestenone; 0.31 ml, 1.1 mmol, 39) gave, after chromatography, 0.19 g (81.0 %) of the product; Iw Ady ir (CHC1,) 2940-2850, 1638, 1460, 1378, 1110, 908 om); nmr (cvC1,) ¢ 5.45 (s, 1,=CH), 2.90 (m, 4, SCH)» 2.20-1.10 (m, 30, alkyl), 1.13 (Sy 3, CHy), 0.95 (sy 3, CH), 0.85 (s, 3, CH3), 0.72 (s, 6, CH) 5 exact mass (75 eV) m/e calcd 474.335 for CyoHsoSas observed 474,338. Reaction of cholestenone with thiosilane 40, The general thioketal- ization procedure (0.385 g, 1.0 mmol, cholestenone; 0,28 ml, 1.1 mmol, 4) gave, after recrystalization from acetone, 0.417 g (90.0 %) of the productjmp 110-112 , lit. value ‘@ 106-107 ; ir (CHC1,) 2970- 2850, 1635, 1460, 1433, 1377, 1370, 1272 on™; nmx (CDC1,) § 5.40 (sy 1, CH), 3.30 (m, 4, SCH.) 2.30-1.00 (m, 28, alkyl), 1.00 (s, 3, CHy), 0.90 (s, 3, CH)» 0.85 (s, 3, CHy), 0.70 (sy 6, CH.) ppm. Reaction of androsteredione with thiosilane 40, The general thioketal- ara ization procedure (0.274 g, 1.0 mmol, androsteredione; 0.28 ml, 1,1 mmol, 40) substituting chloroform for ether, gave 0,408 ¢ of crude product after 24 hours. Chromatography on silica gel (20 g) eluting with petroleum ether-benzene (1:2) gave 45 ina 5% yield (mp 270-174 , lit. value ,mp 173-174.5) "3 ar (CHCL,) 2962-2850, 1635 (w) (CxC), 1433, 1130, 1105 om™*, Further elution with benzene-ethyl acetate (19:1) gave aa in a 91 % yield (mp 170.5- 72.5, Lit. value, mp 173-174,5) 2; ir (neat) 3000-2850, 1735 (s) (C=O), 1635 (w) (G70), 1433, 1370, 1130,1205 em; nar (CDCL,) 5 5.55 (s, 1,2CH), 3.35 (m, 4, SCH5)» 2,.50-1.20 (m, 19, alkyl), 1.08 (s, 39 CH5)s 0.90 (s, 3» CH,) ppm. Reaction of progesterone with thiosilane 40, The general thioketal- ization procedure (0,315 g, 1.0 mmol, progesterone; 0.28 ml, 1.1 45 mmol, 40), substituting chloroform for ether, gave 0.459 g of crude product after 24 hours. Chromatography on silica gel (20 g) eluting with petroleum ether-benzene (1:2) gave 4? in a4 % yield (mp 175- 179° , lit. value, mp 179-181.5°)"; ir (CHC1,) 2970-2860, 1635 (w), 1 Further elution with benzene-ethyl acetate (19:1) 1130, 1105 cm™ gave 46 ina 94 % yield (mp 177-181°, lit. value, mp 183-186°) 2, ir (CHC1,) 3000-2850, 1690 (s), 1130, 1105 om +; nmr (CDC1,) § 5-50 (s, 1,=CH), 3.28 (m, 4, SCH, )» 2.10 (s, 3, COCH3), 2.50-1.00 (m, 20, alkyl), 1.00 (s, 3, CH,), 0.60 (s, 3, CH,) ppm. Preparation of 1-trimethylsiloxy-l-methylthiocyclohexane. To a 25-ml, round~bottom flask with a nitrogen atmosphere was added ca. 0.001 g of anly, 2.10 ml (1.96 g, 0.020 mole) of cyclohexanone and 3.20 ml (2.70 g, 0.022 mole) of the thiosilane, 26, which was contaminated with ca. 1 % of the amine, 28. After 1.5 hour, the reaction was quenched with water. This mixture was extracted with ether and the etheral extracts were washed with saturated NaCl solution and dried over anhydrous sodium sulfate. After filtration and solvent removal, the residue was filtered through alumina (Activity III) with hexane. Solvent removal allowed recovery of an 88 % yield of l-methylthio- 1-trimethylsiloxycyclohexanes; ir (neat) 2950-2855, 1441, 1251, 1244, 1089, 1050, 835, 750 om7?; nmr (CCl, ) $2.10 (s, 3, SCH), 1.70 (m, 10, CH)» 0.25 (s, 9, Sick.) ppm; exact mass (75 eV) m/e calcd 203.092 for C SiSO, observed 203.092, gg Preparation of l-methylthio-l-trimethylsiloxyheptane. To a 25-ml, round=bottom flask with a nitrogen atmosphere was added ca, 0.001 g of ZnI,, 2.80 ml (2.28 g, 0.020 mole) of heptanal and 3.20 ml (2.70 g, 46 0,022 mole ) of the thiosilane, 26, which was contaminated to the extent of 1% with the amine, 28. After 1.5 hours, the reaction mixture was quenched with water. This mixture was extracted with ether and the etheral extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and solvent removal, the residue was filtered through alumina (Activity III) with hexane. Solvent removal allowed the recovery of a 60 % yield of the product; ir (neat) 2960-2860, 1245, B40, 750 om "5 nmr (CCL,) $4.70 (t, 1, CH), 2.05 (8, 3, SCH,), 1.30 (m, 13, CH)» 0.25 (Ss, 95 SiCH,) ppm; exact mass (75 eV) m/e caled 219,124 for C SiSO, observed 219.123. 10423 Preparation of l-methylthio-l-trimethylsiloxycyclopentane, To a nitrogen-purged, 25 ml, round-bottom flask was added ca. 0.001g of ZnI,, 1.78 ml (1.68 g, 0.020 mole) of cyclopentanone and 3.20 ml 2 (2.70 g, 0.022 mole) of the thiosilane, 26, which was contaminated with the amine, 28. After 1.0 hour, the reaction was quenched with with water and this mixture was extracted with ether. The etheral extracts were washed. with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and solvent removal, the residue was filtered through alumina (Activity III) with hexane. Solvent removal allowed recovery of a 72 % yield of the product; ir (neat) 2960-287C, 1245, 840, 753 om™*; nmr (cc1,,) § 2.15 (s, 3, SCH.) 1.90 (m, 8, CH)» 0.25 (s, 9, Sick, ) ppm; exact mass (75 eV) m/e caled 189,077 for CgH,,SiSO, observed 189.076. Preparation of 8~aza-8-carbophenoxy-3-trimethylsiloxy-3-methylthio- bicyclo £3.2.1) octane. To a nitrogen purged, 50 ml, round-bottom W7 flask was added ca. 0.010 g of 2nI,, 2.45 g (0.010 mole) of the ketone and 3.20'ml (2.64 g, 0.022 mole) of the thiosilane, 26. After 24 hours the reaction mixture was quenched with water and this mixture was extracted with ether. The etheral extracts were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After solvent removal, the residue was filtered through alumina (Activity III) with benzene. The benzene was removed in vacuo to give an 85 % yield of the product; ir (CHC1,) 3010-2930, 1705, 1410, 1330, 1250, 1095, 1055, 868. 842 cn? ; nmr (CDC1,) $7.85 (m, 5, aryl-H), 4.55 (s, broad,2,NCH), 2.50-2.10 (m, 8, alkyl), 2.25 (s, 3, SCH), 0.35 (s, 9, SiCH,) ppm. Anal. Caled for Cy gin gNO,S45 : C, 59.143 H, 7.45. Found: C, 59.133 H, 7.33. Reaction of l-methylthio-l-trimethylsiloxycyclohexane with thiosilane 38. To a nitrogen-purged, 10 ml, round-bottom flask was added 0.21% g Ne (0.001 mole) of 32, ca. 0,0001 g of ZnI, and 0.485 ml (0,403 g, 0.903 2 mole) of 38. Gas chromatographic analysis after 8 hours revealed a mixture of 3 major constituents, thioketals 36, 37» ben A high resolution mass spectra confirmed the existance of ts exact mass (75 eV) m/e caled 190,085 for C,H.,S.,, observed 190.085. _ i8°2 9 Feaction of 1,.-dimethylthiocyclohexane with thiosilane 38, To 2 al nitrogen-purged, 10 ml, round-bottom flask was added 0.176 ¢ (0.001 mole) of 36, ca. 0.0001 g of ZnI., and 0,323 ml (0.268 g, 2 0,002 mole) of 28. Gas chromatographic analysis revealed a mixture; the 3 major constituents were found to be thioketals 36, 37, and 44, Nw ANS ~ : 48 Reaction of cyclohexanone with thiosilane, 26, and hexamethyl- ~/ disilazane. To a nitrogen-purged, 5~ml flask was added ca. 0.0001 ¢ of 2nlo» 0.10 ml (0.098 g, 0.001 mole) of cyclohexanone, ly of amine, 28, and 0,32 ml (0.264 g, 0.022 mole) of the thiosilane, 26, Gas chromatographic analysis after 0.75 hour indicated the majority of the product was 32 with only a trace of 36. Reaction of silylhemithioketal, 32, with thiosilane, 26, in the ad Ww absence of ZnI,. To a nitrogen-purged, 5-ml flask was added 0,22g (0.001 mole) of the hemithioketal, 32, and 0.16 ml (0.132 g, 0.0011 mole) of the thiosilane, 26, Gas chromatographic analysis indicated no reaction, Reaction of cyclohexanone with the thiosilane, 26, and imidazole. ~~ To a nitrogen-purged, 5-ml flask was added 0.001 g of Znlo, 0.10 mi (0.098 g, 0,001 mole) of cyclohexanone, ca. 0,001 g of imidazole and 0.32 ml (0.264 g, 0,0022 mole) of the thiosilane, 26. Gas chromato- graphic analysis indicated conversion to the hemithioketal, 32, and a trace of the thioketal, 36. ~ Reaction of the silylhemithioketal, 32, with the thiosilane, 26, NG aa To a nitrogen~purgec, 5-mi flask was added ca. 0,001 g of Znl,,» 0.22 g (0,001 mole) of the hemithioketal, 22s and 0.16 ml (0,132 ¢, 2,9011 mole) of the thiosilane, 26, Gas chromatographic analysis indicated the thioketal, os as the only product, Reaction of cyclohexanone with the thiosilane, 26, in the absence ~~ of Znl ys To a nitrogen-purged, 5-ml flask was added 0.10 ml (0.098 g, 0,001 mole} of cyclohexanone and 0.32m1 (0.264 g, 0.0022 mole) of the thiosilane, 2b. Gas chromatographic analysis indicated no reaction. 49 Preparation of the thiosilane, 38. To a nitrogen-purged, l-liter, fi 3-necked, round-bottom flask, equipped with a reflux condensor, a mechanical stirrer and an addition funnel was added 300 ml of anhydrous ether and 48.0 g (1.00 mole) of NaH (50 % dispersion in oil). Ethanethiol, 62.1 g (1.00 mole), was added dropwise over 6.0 hours, To the resulting slurry was added 125 ml (108.0 g, 1.05 mole) of chlorotrimethylsilane dropwise over a period of 1.5 hours. After stirring at ambient temperature for 12.0 hours,the mixture was filtered under nitrogen and distilled to give a 42 % yield of the thiosilane, 383 bp 128-130, lit. value", bp 127-131. Preparation of the thiosilane, 39. Procedure 1. To a nitrogen-purged, oN 250-ml, 3-necked, round-bottom flask, equipped with a reflux condensor, a mechanical stirrer and an addition funnel was added 100 ml of anhydrous ether, 5.00 ml (5.40 g, 0,050 mole) of propane- dithiol, While the reaction flask was cooled in an ice bath, 50.0 ml of ne-butyllithium (2.0 M in hexane) was added dropwise over a period of 0.5 hour, After allowing the reaction mixture to warm to room temperature, 13.0 mi (10.9 g, 0.10 mole) of chlorotrimethylsilane was added over a period of 0.5 hour with efficient stirring. After the mixture hac reacted at reflux temperature for 24 hours a filtration under nitrogen followed by a distillation (bp 75°/0.02 mm Hg) gave the thiosilane, 39s in a 40 % yield; nmr (CC1,) & 2.60 (t, 4, J=6.0 Hz, SCH.) » 2.92 (m, 2, CH)» 0.38 (s, 9, SiCH,) ppm; exact mass (75 eV) m/e caicd 252.086 for C Si,5,, observed 252.086. £ yrrn2 git Preparation of the thiosilane, 39. Procedure 2. To a nitrogen- ws purged, 250-ml, round-bottom flask equipped with a reflux condensor 50 was added 0.30 g of imidazole, 79.0 ml (61.1 g, 0.38 mole) of hexamethyldisilazane and 10.0 ml (10.8 g, 0.10 mole) of 1,3-propane- dithiol, The mixture was heated at reflux temperature for 24 hours. A careful distillation gave 21.6 g (85 %) of the thiosilane, 39, on Preparation of the thiosilane, 40. Procedure 1. To a nitrogen-purged, 100-m1, round-bottom flask equipped with a mechanical stirrer, a reflux condensor and an addition funnel was added 250 m1 of anhydrous ether and 8.4 ml (9.42 g, 0.10 mole) of 1,2-ethanedithiol, While the reaction flask was cooled in an ice bath, 124 ml (0.20 mole) of n-butyllithium (1.61 M in hexane) was added dropwise over 0.5 hour, The reaction mixture was stirred efficiently during this addition. After the mixture was allowed to stand at room temperature for 3 hours, 26.0 ml (21.8 g, 0.20 mole) of chlorotrimethylsilane was added and the mixture was heated at reflux temperature for 12 hours, A filtration under nitrogen and a distillation (bp 80°/0.3 63 mn Hg, lit. value’, bp 145-150/40 mm Hg) gave the thiosilane, 40, in a 60 % yield; nmr (CC1,)§ 2.60 (s, 4, SCH,)» 0.35 (s, i8, SiCH,, PPM e Preparation of the thiosilane, 40, Procedure 2. To a nitrogen-purged, 50-m1, round-bottem flask equipped with a reflux condensor was added 0,150 g of imidazole, 35.0 ml (27.0 g, 0,168 mole) of amine, 28, and 4,2 ml (4.7 g, 0.050 mole) of 1,2-ethanedithiol. This was allowed to react at reflux temperature for 24 hours and then carefully distilled to give a 32 % yield of the thiosilane, 4O, 51 NOTES AND REFERENCES 1. 2e ib 52 NOTES AND REFERENCES a) D. Seebach, M. Kolb, Chem. Ind., 7, 687 (1974); b) D. Seebach, M. Kolb, B. Grobel, Tetrahedron Lett., 317 (1974). D. A. Evans, G. C. Andrews, Accts, Chem, Res., 7, 147 (1974). a) Jd. E. Richman, J. L. Herrman, R. H. Schlessinger, Tetrahedron Lett., 3267 (1973); b) J. C. Herrman, J, E. Richman, R. H. Schlessinger, Tetrahedron Lett., 3275 (1973); ¢}) G. Schill, P. R. Jones, Synthesis, 117 (1974); d) kK. Ogura, G. Tsuchiheshi, Tetrahedron Lett., 3151 (1971); e) I. Hori, T. Hayashi, H. Midorikawa, Synthesis, 705 (1974); f) J, L. Herrman, J. E, Richman, P. J. Weppio, RK. H. 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