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Strategies towards carbon-carbon bond formation via tandem hydrothiolation/Kumada cross-coupling Sabarre, Anthony 2008

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STRATEGIES TOWARDSCARBON-CARBONBOND FORMATIONVIATANDEM HYDROTHIOLATION/KUMADACROSS-COUPLINGbyAnthony SabarreB.Sc., University of British Columbia,2005A THESIS SUBMITTED INPARTIAL FULFILMENTOFTHE REQUIREMENTSFOR THE DEGREEOFMASTER OF SCIENCEinTHE FACULTY OF GRADUATESTUDIES(Chemistry)THE UNIVERSITY OF BRITISHCOLUMBIA(Vancouver)August 2008© Anthony Sabarre, 2008AbstractUsing recently developed methodology from our group, a variety of aryl and aliphaticterminal alkynes were reacted with n-propanethiol to undergo catalytic alkynehydrothiolation in the presenceTp*Rh(PPh3)2.The alkynes examined afforded thebranched isomer with high regioselectivity and moderate-to-high yield. Unsubstitutedaryl alkynes, or those containing an electron-donating substituent at the para position,gave the branched vinyl sulfide in good isolated yield. In contrast, vinyl sulfides derivedfrom aryl alkynes containing an electron-withdrawing substituent at the para positionshowed a decrease in reactivity and yield. The aliphatic alkynes that were investigatedgave the desired branched vinyl sulfide in good yield. The isolated vinyl sulfides werethen subjected to Kumada cross-coupling in the presence of NiC12(PPh3)with variousaryl and aliphatic Grignard reagents, affording the corresponding 1,1 -disubstitutedolefins. While benzyl-, phenyl- and trimethylsilylmagnesium halides were shown to besuitable cross-coupling partners, phenylethynyl-, vinyl- and n-butylmagnesium halideswere not. Once the viability for the Kumada cross-coupling of vinyl sulfides wasestablished, a one-pot protocol was investigated. It was shown that the one-pot procedureafforded the desired 1,1 -disubstituted olefin from readily available terminal alkynes insimilar, and in some cases superior, yields than the two-step process.11Table of ContentsAbstract.iitable of ContentsiiiList of Tablesv[4ist of FiguresviList of Schen.iesviiList of ChartsviiiList of Symbols and AbbreviationsixAco1edgementsxiChapter 1 — Introduction11.1 Background11.2 Hydrothiolation41.2.1 Transition-Metal Catalyzed AlkyneHydrothiolation41.2.1-1 Formation of the BranchedHydrothiolation Product51.2.1-2 Branched Product Isomerization81.3 Metal-Catalyzed Cross-couplingof C-S Bonds for C-C BondFormation91.3.1 Kumada Cross-Coupling ofC-S Bonds121.3.1-1 Cross-Coupling of Sulfides withGrignard Reagents121.3.1-2 Cross-Coupling ofSulfones and Sulfonates withGrignard Reagents... 181.3.1-3 Cross-Coupling of SulfonylChlorides with GrignardReagents 211.3.2 Negishi Cross-Coupling InvolvingC-S Bond Cleavage231.3.3 Stille Cross-Coupling InvolvingC-S Bond Cleavage251.4 Conclusions27Chapter 2 — Catalytic Alkyne HydrothiolationusingTp*Rh(PPh3)2292.1 Introduction292.2 Results and Discussion322.2.1 Procedure and Optimization ofHydrothiolation Reactions321112.2.2 Substrate Scope of Hydrothiolationwith n-Propanethiol332.3 Conclusions372.4 Experimental Procedures382.4.1 General Methods382.4.2 Reagents and Solvents382.4.3 Physical and Spectroscopic Measurements38Chapter 3 — Kumada Cross-Couplingof Vinyl Sulfides463.1 Introduction463.2 Results and Discussion473.2.1 Procedure and Optimization of Cross-CouplingReactions473.2.2 Substrate Scope of Kumada Cross-CouplingReactions483.2.3 One-Pot Hydrothiolation and KumadaCross-Coupling Reactions543.3 Conclusions553.4 Experimental Procedures563.4.1 General Methods563.4.2 Reagents and Solvents563.4.3 Physical and Spectroscopic Measurements57Chapter 4— Summary, Conclusions and FutureWork704.1 Summary704.2 Future Work7173Appendices80Appendix I: ‘H and ‘3C NMR Spectra for HydrothiolationProducts80Appendix II: ‘H and ‘3C NMR Spectra for KumadaCross-Coupling Products87ivList of TablesTable 1.1. N1C12(PPh3)-catalyzed cross-couplingof 1 ,2-disubstituted vinylsulfides13Table 1.2.NiC12(PPh3)-catalyzed cross-couplingof sulfides, sulfoxides andsulfones14Table 1.3. Nickel-catalyzed cross-coupling of 6-alkyland 6-aryl purine derivatives16Table 1.4. Fe(acac)3-catalyzed cross-coupling of phenylvinyl sulfide17Table 1.5. Ni(acac)2-catalyzed cross-coupling of vinylt-butyl sulfones19Table 2.1. Substrate scope alkyne hydrothiolationof n-propanethiol35Table 3.1. Summary ofNiC12(PPh3)-catalyzed cross-couplingof aryi vinyl sulfides.... 50Table 3.2. Summary ofNiC1(PPh-catalyzedcross-coupling of aliphatic vinylsulfides51Table 3.3. Summary of Results for One-PotProtocol55VList of FiguresFigure 1.1. Natural products containing 1,1-disubstituted olefins.2Figure 1.2.Tp*Rh(PPh3)2complex8Figure 1.3. Heterobenzylic sulfonium salts26Figure 2.1. Rhodium pyrazolylborate complexes31viList of SchemesScheme 1.1. Proposed strategy for 1,1-disubstituted olefinsynthesis4Scheme 1.2. Proposed catalytic cyclefor Pd(OAc)2-catalyzedhydrothiolation6Scheme 1.3. Addition of thiophenolto conjugated enynes7Scheme 1.4. Proposed catalytic cycleofPdC12(PhCN)-catalyzed hydrothiolation9Scheme 1.5. Catalytic cycle for Kumada-catalyzedcross-coupling10Scheme 1.6. Formation of ,B-chalcogenoalkenylboranes11Scheme 1.7. Proposed catalytic cycleof Fe-catalyzed cross-couplingof sulfonyl chlorides22Scheme 2.1. Possible productsof alkyne hydrothiolation29Scheme 2.2. Proposed catalytic cycleforTp*Rh(PPh3)2catalyzedhydrothiolation 30viiList of ChartsChart 2.1. Alkyne substrates forhydrothiolation34Chart 3.1. Vinyl sulfidesubstrates for Ni-catalyzedcross-coupling48Chart 3.2. Grignard reagentsfor Ni-catalyzedcross-coupling49viiiList of Symbols andAbbreviationsA angstroms (1W’ometers)mu, microAc acetateacac acetylacetonatea alphaBn benzyl/1 betadppe 1 ,2-bis(diphenylphosphino)ethanedppp 1,3 -bis(diphenylphosphino)propanebr broadBu butylcalcd calculatedcat. catalystCNS central nervoussystemJ coupling constantodegrees°C degrees CelciusD deuteriumdba dibenzylideneacetoneDCE 1 ,2-dichloroethaneDCM dichloromethaneDMAC dimethylacetylenedicarboxylatedppf diphenylphosphinoferrocened doubletdd doublet of doubletsEl electron impactE entgegeneq equationequiv. equivalentEt ethylgammag gramHz hertzHMTA 1 ,3-hexamethylenetetramineHRMS high resolutionmass spectroscopyh hourTp*hydrotris(3 ,5 -dimethylpyrazolylborate)L litreixMHz mega hertzMe methylmg milligrammL millilitremmol millimolmm minuteM molar (mol L’)m multipletNMP N-methylpyrrolidonen normalNMR nuclear magnetic resonanceppm parts per millionPh phenylpip piperidineq quartetquin quintetft room temperaturesxt sextets singlett tertiaryt-Bu tertiary butylTHF tetrahydrofuranTMEDA tetramethylethylenediaminetol tolueneTFP tri(2-furyl)phosphmneTMS trimethylsilylt triplettd triplet of doubletsPPh3 triphenyiphosphineZ zusammenxAcknowledgementsI would first like to thank my supervisor Dr. Jennifer Love for all her support andencouragement in the past three years. Her kindness, patience, and advice in times ofpersonal and research related struggles, has been a huge contribution to my success as agraduate student. I would also like to thank my fellow group members in the Love Lab;Paul Bichier, Heather Buckley, Alex Dauth, Lauren Fraser, Shiva Shoai, Alex Sun, Saravan Rooy, Tongen Wang and Jun Yang for all their help and support throughout thesepast few years.Thanks to my friends and family for being there for me in time of need and forhelping me stay on track. I want to give a special thanks to my parents, Zacarias andAlicia Sabarre, for all their love and support in every respect. Without such wonderfulparents I would not be the person I am today. Thanks to my brother and sister-in-law,Andrew and Cheryl Sabarre for their advice and guidance throughout my educationalcareer, as well as every other aspect of my life. Thank you to Jessica Ubial for your love,encouragement and support.“The LORD is my rock, myfortress and my deliverer;my God is my rock, in whom I take refuge.He is my shield and the horn ofmy salvation, my stronghold.”xiChapter 1 — Introduction1.1 BackgroundSubstituted olefins are present in many biologically activemolecules andsynthetic intermediates.13 Consequently, strategies for theirsynthesis andfunctionalization has been an area of continued interest and development.In particular,the 1,1 -disubstituted double bond motif is present in several naturalproducts such asdysidiolide4(antitumor agent), kainic acid5 (CNS stimulant), laulimalide6(microtubulestabilizer) and pinnatoxin A7 (potent neurotoxin) (Figure 1.1).Methods for theconstruction of 1,1 -disubstituted olefins have been developed to a muchlesser degreethan those for 1 ,2-disubstituted olefins. Even so, a number of methods have emerged,butall have significant limitations.1HOCOOHc)COOHLaulimalide (-)-a-Kainic acidFigure 1.1. Natural products containing 1,1-disubstitutedolefinsTransition-metal catalysis is widely used in organicsynthesis, and can be used inthe synthesis of 1,1 -disubstituted olefins. One example isthe cross-coupling of an arylhalide with an organometallic reagent, which can be obtainedfrom the correspondingvinyl halide.8 The disadvantage of starting with vinyl halideslies in the often harshconditions needed in their synthesis. These conditions typically requirethe use of astrong Lewis or Bronsted-Lowry acid, such as BBr3 or HBr, andtherefore, presentfunctional group incompatibility. An alternative to the use of vinyl halidesin cross-coupling is the use of vinyl triflates; however, their synthesis alsopresents somefunctional group incompatibility.8’9 Another widely used transition-metalcatalyzedreaction in the formation of 1,1 -disubstituted olefins is the cationic Heck reaction.10Thistypically involves the reaction of an aryl halide with a mono-substituted olefin.OnePinnatoxin ADysidiolide2disadvantage to this reaction is thatit is mainly limited to theuse of aryl halides,activated alkyl halides or alkyl halideslacking ,6-hydrogens.”It can be seen thatbyexploring different potential cross-couplingpartners, milder methods forthe synthesis of1,1 -disubstituted olefins can be realized.One of the uses of vinyl sulfides is theirability to act as substratesin metal-catalyzed reactions, allowing for the stereospecificfunctionalization of olefins.Sulfur-containing substrates have had use as electrophiliccross-coupling partnersin reactionswith organotin reagents (Stille-type), areneand heteroarene boronicacids (SuzukiMiyaura type), organozinc chloride (Negishi-type),and Grignard reagents(Kumada-type)in the presence of nickel or palladiumto give the corresponding unsaturatedor saturatedcarbon-carbon bond (eql.l).12R_X + R1McataIyst.R_R+ MX (1.1)M = B : Suzuki-MiyauraM = Sn : StilleM = Zn : NegishiM = Mg KumadaWe proposed that transition-metal catalyzedcross-coupling involvingvinylsulfides could be a useful route for the synthesisof 1,1 -disubstitutedolefins (Scheme1.1). Furthermore, we anticipated that a one-pot procedurefor 1,1-disubstitutedolefinsynthesis may be possible by combining thevinyl sulfide synthesis andcross-couplingreactions. While recent progress has been made inthe area of catalytic C-Sbondformation, a general and dependable synthetic methodfor the formation of1,1 -disubstituted vinyl sulfides from alkynes hasbeen comparatively evasive.The use of3carbon-sulfur bonds in cross-couplingreactions can be an effectiveroute to the synthesisof 1,1 -disubstituted olefms; however,this method requires thatthe corresponding 1,1 -disubstituted vinyl sulfide startingmaterial be available.Consequently, aversatileprocedure for the formation ofbranched vinyl sulfides fromalkynes is needed.As ourproposed strategy involves the formationof 1,1-disubstitutedolefins from terminalalkynes, the metal-catalyzed formationof branched vinyl sulfideswill first be outlined.This will be followed by a review ofthe use of C-S bondcleavage in cross-couplingchemistry.R—SHSRcat.I cat.+__R1R1R1Scheme 1.1. Proposed strategy for1,1 -disubstituted olefinsynthesis1.2 Hydrothiolation1.2.1 Transition-Metal Catalyzed AlkyneHydrothiolationDue to the widespread belief thatthiols and sulfides actas catalyst “poisons,”their reactivity in metal-catalyzed reactions havebeen studied to a muchlesser extentthan other heteroatom-containing nucleophiles,such as amines, alcoholsand phosphines.Nonetheless, metal-catalyzed hydrothiolationof both aryl and alkyithiolsas substrateshas been successful. The formation of carbon-sulfurbonds has been achievedthroughseveral ways, which include radical,’3 nucleophilic’4andcatalyzed4alkyne hydrothiolation. The products of thesereactions can then be used asbuildingblocks in total synthesis and are precursors to more complexmolecular structures.16In 1976, Newton and co-workers showed thatMo02[SC(l-pip)jcan catalyze theaddition of thiophenol to dimethyl acetylenedicarboxylate(DMAC), affording theaddition product as a mixture of E and Z-isomers (19:1)in 25 %yield.l5aSince then,several other metal catalysts have been found to successfullyadd an S-H bond acrossterminal and internal alkynes. There are three possibleproducts resulting from theaddition of the S-H bond across a terminal alkyne:the branched product (A), andthelinear isomers (E and Z, B and C respectively) (eq 1.2).The formation of the branchedisomer will be covered in the following section as it is directly relatedto this thesis.R — + R’SHcataIyst+ RSR+(1.2)1.2.1-1 Formation of the Branched Hydrothiolation ProductIn 1992, Ogawa and co-workers showed that various palladium,platinum, nickeland rhodium complexes could catalyze the reaction of thiophenoland 1 -octyne to affordthe corresponding vinyl su1fides.’5’ From the metal complexes that were examined,theyfound that Pd(OAc)2gave the branched product (A) with high regioselectivityfor avariety of terminal alkynes with aryl thiols. The alkynes usedincluded hydroxyl,trimethylsilyl aryl alkynes, as well as amino substituted aliphaticalkynes. In order togain a better understanding of the mechanism of this reaction, the stoichiometricreaction5of Pd(OAc)2and thiophenol was carried out. From thereaction between Pd(OAc)2andthiophenol, it was observed that a palladium sulfidespecies([Pd(SPh21)and AcOH wasproduced. Furthermore, this palladium-sulfide specieswas capable of catalyzingthehydrothiolation of alkynes with thiophenol.Based on these observations,a catalyticpathway for Pd(OAc)2-catalyzed hydrothiolation wasproposed (Scheme l.2).’’Pd(OAc)22PhSHPd(SPh)2L2AcOHSPhRPhSHRpd(sph)LSPhScheme 1.2. Proposed catalytic cycle for Pd(OAc)2-catalyzedhydrothiolationIn 1994, Bäckvall and co-workers showed that thiophenol canadd to terminalenynes in the presence of Pd(OAc)2to afford the corresponding 2-Qhenylthio)-1,3-dienes(Scheme13)15bThe resulting vinyl sulfides, dependingon the oxidizing agent andreaction conditions, were then selectively converted to sulfoxidesand/or sulfones. For6the thiophenol addition to conjugated enynes, the optimal conditions[enyne (1.00 mmol),PhSH (1.00 mmol), Pd(OAc)2(0.02 mmol) in THF(0.5 mL) at 50 °C] gave 41—75%yield of the branched product across the alkyne, leavingthe alkene untouched.SOPhcat. Pd(OAc)2SPhPhSH[O]SO2PhRScheme1.3.151)Addition of thiophenol to conjugatedenynesIn 2005, our group showed thatTp*Rh(PPh3)2 [Tp*= hydrotris(3,5-dimethylpyrazolylborate)] (Figure 1.2) canregioselectively catalyzealkynehydrothiolation to give the branched additionproduct.15mAlthough alkyl thiols havebeen reportedly ineffective in metal-catalyzed alkynehydrothioiation,l5we rationalizedthat a highly active metal catalyst would permit the useof alkyl thiols. The ability ofTp*Rh(PPh3)2to activate C-H,’7Sn-H, Si-H’8andSHh8bonds prompted us to select thiscomplex for the initial study. The exploratory reactionof phenylacetylene andbenzylthiol in the presence ofTp*Rh(PPh3)2gave exclusively the branched isomerin90% isolated yield after just 20 mm. A variety of aliphatic thiols werethen reacted withboth aryl and aliphatic alkynes, affording the desired branched vinylsulfides in excellentregioselectivities and good-to-excellent yields (eq 1.3). For the differentsubstrate pairsthat were explored, it was found that while the reaction involving aryl thiolswith arylalkynes gave excellent isolated yields (83-90%), a diminished branched:linearproductratio was observed (6:1 to 1.4:1).7Figure 1.2.Tp*Rh(PPh3)2catalystRSH+ R1 — R2mol%Tp*Rh(PPh3)2R1(1.3)DCE:PhCH3(1:1)R: alkylR1: alkyl, aryl63 - 93 %R2: H, alkyl, aryl1.2.1-2 Branched Product IsomerizationIn 1999,Ogawal5and co-workers reportedthe use of PdC12(PhCN)as catalystin the formation of internal vinyl alkynes.This occurred via initialformation of thebranched hydrothiolation productof terminal aliphatic alkynes, followedby sequentialdouble-bond isomerization. In order togain some understanding about themechanism ofthis reaction, Ogawa and co-workerscarried out the stoichiometricreaction ofPdC12(PhCN) with 2 equiv of PhSHto afford palladium complex,[PdCI(SPh)(PhSH)](where n = 1 or 2). The palladium complexwas found to catalyze thereaction ofthiophenol and 1 -octyne to afford the correspondingaddition/isomerisation product.Furthermore, if the branched productwas treated with a catalytic amountof the palladiumcomplex, the double-bond isomerizationproduct could be afforded in almostquantitativeyield. From these results, a catalyticcycle for the hydrothiolationlisomerizationwithPdC12(PhCN) was proposed (Scheme 1.4).8PdCI2(PhCN)PhSHR(CH3HCIPhSR\____Pd(SPh)CI L —R(Pd(SPh)L R’”PdCILPhS+ HCISPhbPhSHRrPd(SPh)Ln.Cr‘PhS Pd(SPh)CILScheme1415gProposed catalytic cycle ofPdC12(PhCN)-catalyzed hydrothiolation1.3 Metal-Catalyzed Cross-Coupling ofC-S Bonds for C-C BondFormationTransition-metal catalyzed cross-couplingreactions for carbon-carbonbondformation began with Kumada’9 and Corriu2°and their co-workers in1972.Independently of one another, these two groupsfound that Grignard reagentscan becoupled with vinyl or aryl halides in a stereospecificmanner in the presence of a nickelcatalyst. Shortly after this initial discovery, Murahashi21et al. introduced the use ofpalladium instead of nickel in the cross-coupling reaction.The catalytic cycle forKumada cross-coupling (Scheme 1.5) involves the reductionof the Ni(II) precatalyst bythe Grignard reagent. The resulting Ni(O) species then oxidativelyadds to the9organohalide, affording a halo(organo)nickel complex. Transmetallationthen takes placeto afford a diorganonickel complex which undergoes reductive elimination, affordingthedesired cross-coupling product and regenerating the active catalyst.53 A radical processfor the cross-coupling is also a possible pathway. Although the coupling ofanorganometallic reagent with organohalides had been recognized as oneof the mostvaluable methods for carbon-carbon bond formation, the attention hadbeen mostlylimited to organohalides. It was not until 1979 that organosulfur compounds were usedas electrophilic partners in nickel-catalyzed cross-coupling reactions.LNiCI2R1MgXLNi°ArNiR1L2ArNi”XL..2MgX2 R1MgXScheme Catalytic cycle for Kumada-catalyzed cross-couplingTakei22 and Wenkert’6’1and their coworkers found that 1,2-disubstituted vinylsulfides could be reacted with various Grignard reagents in the presence of a nickelcatalyst to afford the corresponding 1 ,2-disubstituted olefins. Wenkert also found that the10carbon-sulfur bond of sulfoxides and sulfonesare capable of being replacedby carbon-carbon bonds using this type of chemistry.16” Sincethis initial discovery,a variety ofsulfur containing substrates have been usedas coupling partners in the formationof morehighly functionalized molecules.One example is the synthesis of tn23- andtetrasubstituted24 olefins. In 2001,Hevesi and coworkers reported the rearrangementof 1 -alkynyltrialkyl borates,triggeredby chalcogen (5, Se, Te) electrophiles in high stereoselectivity(Scheme 1.6). These,6-chalcogeno vinylboranes then undergo sequentialprotodeborylation followedby Kumadacross-coupling to afford the corresponding trisubstitutedvinyl sulfides, -selenidesor —tellurides.24 Later, the same group showedthat carbodeborylation of the/3-chalcogenovinyl borane is possible to affordthe corresponding tetrasubstitutedvinylsulfide. These tetrasubstituted vinyl sulfideswere then subjectedto nickel-catalyzedcross-coupling to afford a variety of tetrasubstitutedolefins.24aThe use of the carbon-sulfur bond in metal-catalyzed cross-coupling will bediscussed in the followingsection.___1) n-BuLl, THF -20°C, lhrLieR3YXR1 R2R1 — H R1 —B(R2)32) B(R2)3,r.t., 1 hr-78°C to r.t.R3Y B(R2)Y = S, Se, TeX = CI, Br, IScheme 1.6. Formation of/3-chalcogenoalkenylboranes111.3.1 Kumada Cross-Coupling ofC-S Bonds1.3.1-1 Cross-Coupling of Sulfides withGrignard ReagentsTakei and co-workers22 reportedthe reaction of phenylmagnesiumbromide withphenyl styryl sulfide in the presenceof NiC12(PPh3)affordingstilbene as the cross-coupling product, and biphenyl (homo-coupledproduct) (eq 1.4). Usingphenyl styrylsulfide and PbMgBr as a model reactionin order to optimize thecross-couplingconditions, they found that 3 mol%catalyst loading affordedthe desired substitutedolefin in the highest yields. Increasingthe catalyst loading did notimprove the yield ofthe reaction, but instead led to larger amounts ofthe by-product resulting fromthe homocoupling of the Grignard reagent. NiCl2(PPh3)was also reportedly necessaryfor thereaction to take place, and that organolithiumreagents were not suitablepartners in thecross-coupling reaction. The optimizedconditions were determinedto involve 2.1 equiv.of Grignard reagent in the presence of 3mol% NiC12(PPh3)and refluxingfor 6-20 hoursin THF or Et20. A variety of vinyl sulfides weresuccessfully reacted witharyl andalkylmagnesium bromides in moderate to highyield under these reactionconditions(Table 1.1).PhMgBrITHF reflux(1.4)KSR3 mol% NCI2(PPh3)s,R=Ph,Et96-97%12Table 1 .1.16dNiC12(PPh3)-catalyzed cross-couplingof 1 ,2-disubstitutedvinyl sulfidesRSR+ PhMgBrmoi%NICI2(PPh3)Rphreflux, 6-20 hSulfideGrignard Product Yield (%)SPh PhMgBr‘Ph 60PhSCH3PhMgBr Phh 85PhPhMgBrPh 97SPh PhPhMgBr 81SPhPhThe use of 2.0 equiv. of Grignardreagent was required whenvinyl arylsulfideswere used as coupling partners, whilevinyl alkylsulfides requiredonly 1.0 equiv.Dialkyl thioethers were not suitablesubstrates for this reaction. In general,the use of anexcess amount of Grignard reagent producedthe cross-coupled productsin higher yields.The reaction was found to be highly stereospecificand only proceeded whenvinyl or arylsulfide substrates were coupled with Grignardreagents.Although their initial studies showed thatthe cleavage of the C,3-S bondof analkyl sulfide did not occur, Takei and co-workerslater reported the use ofallylic sulfidesas suitable cross-coupling partners with Grignardreagents in the presence of eitherNiC12(PPh3)or NiC12(dppp).25 Both nickelcomplexes were successful in catalyzingthecoupling reaction; however, NiC12(dppp) wasless reactive than NiC12(PPh3)whensterically hindered allylic sulfides were used. The reactionconditions for allylic sulfideswith Grignard reagents were carried out in the presence of3 mol% NiC12(PPh3)and 1.5-2.4 equiv. of Grignard reagent, refluxing in Et20 for 8-10hours. In general, the cross-13coupling of allylic sulfides was faster than for vinylor aryl sulfides when a 1:1ratio ofGrignard to sulfide was used.In 1979, Wenkert and co-workers’6’showed thatmethylmagnesium and arylmagnesium bromides could be successfully cross-coupledwith vinyl and aryl thiols,sulfides, sulfoxides and sulfones in the presence ofNiC12(PPh3)(Table 1.2). Thecross-coupling reactions of the sulfides were carried out inrefluxing benzene for 1-30hourswith 2-5 equiv. of Grignard reagent and 10 mol%ofNiC12(PPh3).Table1.2.161NiC12(PPh3)-catalyzed cross coupling ofsulfides, sulfoxides and sulfones._SR1+ R2—M Brmol% NICI2(PPh3)CHRSulfide Grignard ProductYield %C6H13..SCHR13C6H13...RRCH3 64R=p-CHC6H4 50-SCH3R=CH3 97iLJR=p-CHC6H4iji 749R = CH3R[jJ [jjR = p-CHC6H4 57SRCH3R70IRp-CHC6H4 I 53R=CH3 97R=p-CHC6H4iLJ4514The results also showed that the sulfur displacementprocess was faster forvinylsulfides than for aryl sulfides, while alkylsulfides could not undergocross-coupling atall. In agreement with what was found by Takeiand co-workers, Wenkertfound that thenickel complex was necessary in order forthe reaction to take place. Furthermore,although NiC12(PPh3)gave high yields invarious different reactions involvingmethyland aryl Grignard reagents, no reaction tookplace when EtMgBr was usedas cross-coupling partner. In this case, NiC12(dppp) wasshown to have betterreactivity,presumably due to the ability of the bidentateligand to better facilitatethe reductiveelimination step, leading to the cross-coupledproduct.26 Wenkert and Takeiboth showedthat alkyl and aryl magnesium halides couldbe used in nickel-catalyzed cross-couplingreactions with aryl, vinyl and allylic sulfides withretention of configuration.Since thesefirst reports by Wenkert and Takei, the useof low-valent nickel in the cross-couplingofsulfides with Grignard reagents has beenextended to a variety of differentsulfurcontaining substrates.In 1985, Takei and co-workers extended this strategyfor the synthesis ofsubstituted 6-alkyl and 6-aryl purine derivatives.27 Startingfrom 6-(methylthio)purine1and various alkyl and aryl Grignard reagents, thecross-coupled product couldbeobtained in good yields in the presence ofNiC12(dppp)(Table 1.3).15Table1.3.27Nickel-catalyzed cross-couplingof 6-alkyl and 6-aryl purinederivatives.SCH3R+NiC(dppp) N”LNGrignard Yield %Grignard Yield%MgX68n-C4H9MgX74nC5H11MgX 62MgX[jJ72n-C6H13MgX 62n-C7H15MgX67J_.MgX 71n-C8H17MgX 68In 2005, Itami and co-workers28 reportedan iron-catalyzed cross-couplingreaction of vinyl sulfides with various Grignardreagents. It was foundthat the cross-coupling between styryl 2-pyrimidyl sulfide(2) and PhMgBr could be catalyzedbyFe(acac)3at room temperature toafford trans-stilbene (45%) (eq1.5). To determinewhether or not the 2-pyrimidal group was necessaryfor the cross-couplingto take place,phenyl vinyl sulfide was reacted with variousGrignard reagents in the presenceofFe(acac)3(Table 1.4).NPh8+ PhMgBrm%Fe(acac)3PhPh (1.5)2(45%)16Table1.4.28Fe(acac)3-catalyzed cross-coupling of phenylvinyl sulfide5 mol% Fe(acac)3+ RMgBrTHEentry Grignard ProductYield (%)IH3CQ—(-—MgBr H3CO—€J--12 -_MgBr 40H3CO H3CO3 (J—MgBr IIOCH3 OCH34H3C_—€J----—_—MgBr - 05N’4MgBr65When p-MeOC6FL1MgBr was used in the cross-coupling reaction,the desiredsubstituted olefin, resulting from the vinyl-S bond cleavage, wasobtained in 74 % yield.The product obtained from the cross-coupling at the aryl-S bond wasproduced in only 2% yield. These results have shown that the reactivity at the vinyl-S positionfar exceedsthat of the aryl-S position. This observation was supportedby the reaction of diphenylsulfide withp-MeOC6H4MgBr, affording the cross-coupled product in lessthan 2 % yield(eq 1.6).28Other iron complexes were also investigated for the cross-coupling,and whileFeC13,FeC12 and Fe(OAc)2were all capable of catalyzing the reactionof phenyl vinylsulfide andp-MeOC6H4MgBr, Fe(acac)3gave the highest yields.17+MgBr5 mol% Fe(acac)3(1.6)H3CO1.3.1-2 Cross-Coupling of Sulfonesand Sulfonates withGrignard ReagentsIn 1982, Julia and co-workersreported the cross-couplingof vinyl t-butylsulfones29 with Grignard reagentsin the presence of Ni(acac)2or Fe(acac)3catalysts(eq1.7). While both Ni(acac)2 and Fe(acac)3were successful in thecross-coupling involvinga variety of vinyl sulfones withPhMgBr, only Ni(acac)2was shown to bereactive whenmethyl Grignard wasused as a coupling partner(Table 1.5). Juliaand co-workers laterreported the use of aryl t-butylsulfones as suitable couplingsubstrates undersimilarconditions.30’3 Arylmagnesiumhalides afforded the desiredcross-coupling productforboth vinyl and aryl t-butyl sulfoneswhile isopropylmagnesiumchloride affordedthereduced product in high yield.I mol% Ni(acac)2ort-BuSO2 CH3Ph CH3/,mo eacac,3/+ PhMgBr (1.7)H CH3H CH3Ni: 68 %Fe: 60 %(<2 %)18Table 1.5. Ni(acac)2-catalyzed cross-couplingof vinyl t-butyl sulfonest-BuSO2 R2H C R2,—KNi(acac)2—+ CH3MgX —R R1R R1R R1 R2X Yield (%)CH3 H CI71CH3 H Br 80CH3 H I80n-C6H13 HCH3 Cl55n-C6H13 H CH3 Br 68n-C6H13 H CH3I 51In 2003, Park and co-workers showed thatthe cross-coupling of alkylarenesulfonates with aryl Grignard reagentsin the presence ofNiC12(dppf) isan excellentmethod for the synthesis of unsymmetrical biaryls.32Although NiC12(dppf)was notcapable of catalyzing the reaction when alkylmagnesiumhalides were used as couplingpartners, the reaction took place in high yields whenNiC12(dppe) was used instead.33Awide variety of alkyl and aryl arenesulfonateswere synthesized and used in thereaction;however, for the purposes of developinga reactivity profile, sulfonates 1 and2 werereacted with various aryl and vinyl Grignard reagents(eq 1.8).+ R1MgBr(dppf)NiCl2Rt(1.8)R = Ph (1), (43 - 95%)H (2)19Due to the loss of SO2 from the neopentyloxysulfonylleaving group, thereactionswere usually accompanied by the productionof the corresponding neopentylalcohol inthe same amount as the desired cross-coupledproduct. In these reactions, itwas foundthat para-substituted alkyl phenylmagnesiumbromides could afford thedesired biarylproduct in high yields, while stericallyhindered vinyl orortho-substituted alkylphenylmagnesium bromides gave the desired couplingproduct in lower yields.Due tocompetitive insertion at the C-O bondof the product, p-methoxyphenylmagnesiumbromide gave lower yields of the desiredbiaryl product, and Grignard reagentswithelectron withdrawing substituents, suchas CF3,were found to be unreactive.33In 2004, Park and co-workers applied verysimilar reaction conditionsas thosedescribed for the cross-coupling of alkyl arenesulfonateswith Grignard reagents, inorderto synthesize unsymmetrical terphenyls.34 The lowreactivity of alkyloxysulfonylgroupsto typical palladium catalysts allowed forthe chemoselective reactionof neopentylbromobenzene sulfonates with arylboronic acids(eq 1.9). This was followedbysequential cross-coupling reaction with arylmagnesiumbromides, to give unsymmetricalterphenyls in high yields (eq 1.10).(HO)2B—--—Y9çBr \=/(1.9)\=/ Pd(PPh3)4/ Na2CO3,110°CPhMgBr (1.10))/—J ii— (dppf)NiCI2>66°C(66 - 84%)(67 - 72%)201.3.1-3 Cross-Coupling of Sulfonyl Chlorides withGrignard ReagentsAlthough the use of palladium in carbon-carboncross-coupling of sulfonylchlorides has been reported, when applied to Kumada-Corriutype cross-couplinginvolving Grignard reagents, palladium or nickelbased catalyst were shownto beunsuccessful.35 In 2006, Vogel and co-workersattempted the use of a palladiumbasedcatalyst in order to carry out the cross-couplingof sulfonyl chlorides withGrignardreagents; however, the desired Kumada-Corriu cross-couplingreaction failed, and onlythe homo-coupled product from the Grignard reagentwas obtained. This led totheinvestigation of other metals to carry outthe reaction. While the reaction of vinylt-butylsulfones29 and aryl t-butyl sulfones30’3are known toundergo nickel and iron-catalyzedcross coupling with Grignard reagents, the firstuse of sulfonyl chlorides in theseiron-catalyzed Kumada-type reactions was reported by Vogeland co-workers in2008.36The carbon-carbon cross-coupling of various aryl,vinyl and alkyl magnesiumhalides were successfully reacted with alkane- andalkenesulfonyl chlorides in thepresence of Fe(acac)3without the use of any additional ligands.The model reactioninvolved n-octanesulfonyl chloride with PhMgBr inthe presence of 5 mol% Fe(acac)3.When the cross-coupling reaction was carried out inTHF at 80 °C, the desired noctylbenzene was afforded in only 28 % yield,accompanied by the correspondingsulfone product in 5 % yield. The reaction carriedout in refluxing Et20 or 1,2-dimethoxyethane also gave poor yields dueto Grignard homo-coupling, while thereaction carried out at room temperature afforded large amountsof sulfone. Although theaddition of TMEDA and HMTA did increase the yield slightly,the optimal conditions forthe reaction were carried out in THF and N-methylpyrrolidone(NMP) at 80 °C in the215 mol%0\\ ,,0Fe(acac)3R—MgX+THF/NMPPh- + SO2 + MgXCI (1.11)R= n-C8H17,n-C613 80°C 61-68%R’S02—Fe(MgX)R’—Fe(MgX)2+ 5021ClCl+co-productsScheme1.7.36Proposed catalytic cycle of Fe-catalyzedcross-couplingof sulfonyl chloridespresence of Fe(acac)3withno additional ligands.36Once these conditionswere obtained,the reaction of various sulfonylchloride and Grignardreagent combinationswere carriedout. In the case of alkenesulfonylchlorides, the cross-couplingproceeded in moderateyields with retention ofconfiguration (eq 1.11).A proposed mechanismfor thedesulfinylative Kumada cross-couplingis shown below (Scheme1.7), and followsFtirstner’s37 suggestion thatlow-valent iron species reactmuch like Pd° catalysts.+ Fe(acac)3RMgXR-R’LFe(MgX)2LR’SO2CIRR’—Fe(MgX)2RMgXR’—Fe(MgX)221.3.2 Negishi Cross-Coupling InvolvingC-S Bond CleavageIn 1997, Liebeskind38 andco-workers showed thataryl, heteroaryl, vinylandbenzylsulfonium salts could undergoNegishi, Mizoroki-Heck,Suzuki-Miyaura,andStille-type cross-coupling reactionsin the presence of Ni orPd catalysts for carbon-carbon bond formation (eq 1.12).From the numerous reactionsthat were performed,itwas found that when benzylic andheterobenzylic sulfoniumsalts were used as couplingpartners, the organostannane reactionworked slightly betterthan the organoboroncounterpart for the metal-catalyzed reaction.This observed trendwas reversed when aryland heteroarylsulfonium salts wereused.R1_SJ+ R2-Mor Ni cat.R1-R2(1.12)PFR1 = aryl, heteroaryl,M = B(OH)2benzylSnBu3R2 = vinylZnXIn 1999, Liebeskind39 and co-workersreported that S-(substituted)thioglycolicacids could undergo Ni-catalyzedcross-coupling with organozincreagents in good-to-excellent yield. In order for the reactionto take place at a reasonablerate, a zinc cofactorwas necessary. They proposed that the zincion could be intramolecularlybound in orderthat the proposed nickel-thiolate intermediatecould be activated,thus facilitatingtransmetallation (eq 1.13). To determinewhich zinc reagent (the “internally”bound oran “external” zinc reagent) was responsiblefor the transmetallationprocess, thefollowing experiments were carriedout. An equimolar amount of thioglycolicacid wasreacted with ZnMe2 in the presenceof NiCl2(PPh3)at room temperature,and no cross-23coupling took place after 50 h; however, vigorous gasevolution was observed. Whenasecond equiv. of ZnMe2 was added to this reactionmixture, the R-Me cross-coupledproduct was afforded in good yield. Furthermore,when ZnEt2 was addedto thepreformed MeZn-thioglycolate species, the R-Etcross-coupled product wasobtained asthe major product. From these experiments, it wasconcluded that an “external” zincreagent is mainly responsible for the transmetallationto nickel, and not the alkylzincthatis internally bound.391 1NiCI2(PPhMe)R—S°2+ R ZnXorR ZnRR—R1 (1.13)HOTHF,50°C,12h149-100%R = aryl, heteroaryl,R = benzyl, alkyl,Rbenzyl, vinylaryl, enolate—Ni—S1 SO2/Zn-OxIn 2006, Vogel and Dubbaka developed a palladium-catalyzedcross-couplingreaction of sulfonyl and organozinc chlorides (eq 1.14). Their initialattempts to cross-couple sulfonyl chlorides with Grignard reagents in the presenceof 1-20 mol% Pd[PQBu)3]2 only gave the homo-coupled Grignard reagent witha small amount of sulfone.The investigation of the cross-coupling reaction under Negishicross-coupling conditionswas also carried out. The reaction of 1 -naphthalenesulfonyl chloridesand 2-methylphenylzinc chloride in the presence of 3-5 mol% Pd[P(t-Bu)3]2as catalyst inboiling THF were found to give the highest yields. The reaction of variousother sulfonylchloride and Grignard reagent combinations were carried out using theoptimized24reaction conditions. It was shown that, in general,arylsulfonyl chlorides gavebetteryields than for allyl and alkylsulfonyl chlorides.35R1-MgCIZnCI23-5 mol% Pd[P(t-Bu)3]2R—SO2CI + R1-ZnCI R—R1 +R1-R(1.14)THF reflux 15-24 hmajor minor1.3.3 Stille Cross-Coupling Involving C-S BondCleavageLiebeskind and co-workers showed that a varietyof tetramethylene, benzylic,heterobenzylic and alkenylsulfonium saltscan undergo Stille cross-coupling withnBu3Sn in the presence of Pd or Ni catalyst.38Very low catalyst loading(0.01-0.5%Pd2dba3)was required in order for the benzylicand heterobenzylic sulfoniumsalt toundergo cross-coupling with n-Bu3SnR. Furthermore,the addition of Ph2P(O)07n-Bu4Nto act as a “n-Bu3Sn” scavenger greatly increasedthe efficiency of the reaction. In1999, Liebeskind and co-workers reported that unlikethe corresponding heterobenzylichalides, sulfonium salts are suitable cross-couplingsubstrates in Stille cross-coupling inthe presence of palladium.4°The exploratory reactions revealedthat for the substrates ofinterest (Figure 1.3), the typical reaction conditions that had previouslybeen obtained,38were not very effective in the general cross-couplingreaction of heterobenzylicsulfonium salts with organometallic reagents.25c/P c/PcIJDFigure 1.3. Heterobenzylicsulfonium saltsThe catalytic system that needed to bedeveloped was one whichcould catalyzethe cross-coupling reaction at low enoughtemperature to minimizethe possibilityofcompetitive decomposition ofthe heterobenzylic couplingpartner and catalystdeactivation. It was concluded that in orderto attain the desired catalyticsystem, asupport ligand was needed thatcould bind the metal wellenough to prevent catalystdecomposition, but weak enoughnot to interfere with thetransmetallation step.4°Furthermore, the support ligand shouldnot be alkylated by the heterobenzylichalide orsulfonium salt. Various support ligandswere surveyed, and it wasfound that the use ofeither P(PPh3)or P(OPh)3 gave excellentyields of the cross-coupledproduct. Furtherinvestigation of solvent, organostannanescavenger and additivesrevealed that theoptimum conditions for the cross-couplingreaction requiredNMP solvent,Pd2(dba)3CHC1/(PhO)P/CuI as the catalystsystem, andPh2P(O)OBnMe3Nas a nBu3Sn scavenger (eq 1.15)•40In the case where an unhinderedvinyistannane was used,Cu! was omitted from the reaction due tothe Cu(I)-induced homocouplingthat occurred.Liebeskind and co-workers also appliedthe use of P(OPh)3 as a supportligand withPd(PhCN)2C1 to cross-couple heterobenyzlicsulfonium salts under Suzukiand Negishicross-coupling conditions.4°26RSnBu34%Pd2(dba).CHCI20% P(OPh)3,40% GuI(L,R (1.15)XPF01.2 equivPhP(O)OBnMeN X6NMP,rt,12hX = 0, N-Boc49 - 97%In 2003, Vogel and Dubbaka showed for the firsttime, thatphenylmethanesulfonyl chloride can undergo Stille cross-coupling withorganostannanesin the presence of palladium and copper.4’ When Pd(PPh3)4was used ascatalyst, theself-coupling of the organostannanes and diarylsulfides were the major productsformed,with only moderate-to-poor yields of the desired cross-coupling product(eq 1.16). Whenthe Pd source was changed to Pd2dba3(1.5 mol%) with TFP(5 mol%) and CuBr•Me2S(10 mol%), the reaction worked successfully with a variety of sulfonylchloride andorganostannane combinations (eq 1.l7).’Pd(PPh3)4R—SQ2CI + R1—SnBu3 R—R1(1.16)10 mol % CuBr Me2STHF, reflux, 2-4 h1941/01.5 mol% Pd2dba3,5 mol% TFPR—SO2CI + R1—SnBu3 R—R1 (1.17)10 mol % CuBr Me2STHF, reflux, 2-4 h25-93%1.4 ConclusionsThe development of strategies for olefin functionalization is an active area ofsynthetic chemistry as substituted double bonds are present in many biologically activemolecules and synthetic intermediates. In this chapter, catalytic alkyne hydrothiolationaffording the branched product was discussed, as well as the use of C-S bond cleavage in27transition-metal catalyzedcross-coupling reactions.We have previouslydisclosed aconvenient methodfor the regioselectiveformation of branchedvinyl sulfides fromalkynes via catalytic alkynehydrothiolation usingTp*Rh(pph3)2.lSmWe anticipatedthatthese vinyl sulfides couldact as pseudo vinyihalidesto undergo subsequentcrosscoupling to afford 1,1-disubstituted olefinsin two steps fromreadily availablealkyrieprecursors. In thefollowing chapters,the synthesisof a series ofbranched npropylthiovinyl sulfideswill be discussed, followedby their subsequentuse in Kumadacross-coupling to afford1,1-disubstituted olefins.Furthermore, we envisioneda one-potprocedure for the catalyticalkyne hydrothiolationand cross-couplingsteps to improvethe efficiency of the reaction.28Chapter 2— Catalytic AlkyneHydrothiolation UsingTp*Rh(PPh3)22.1 IntroductionAlkyne hydrothiolation is the additionof an S-H bond across an alkyne.In thecase of terminal alkynes, three addition productsare possible (Scheme 2.1).Theformation of C-S bonds have been achievedthrough several wayswhich includeradical’3,nucleophilic’4and transition-metal’5catalyzed hydrothiolation; however,untilrecently, the use of alkyl thiols in alkyne hydrothiolationhas been quite limited.RSR1R+ RSHcataIystR_J+ R-SR’+ SR1branched E-linearZ-tinearSR1RLisomerScheme 2.1. Possible products of alkynehydrothiolationPrevious work done by our group hasshown thatTp*Rh(PPh3)2 [Tp*hydrotris(3 ,5-dimethylpyrazolylborate)] catalyzes alkynehydrothiolation of a wide rangeof aliphatic, aromatic and internal alkynes with a variety ofthiols. The structure ofTp*Rh(PPh3)2is shown in Figure 1.2. WhenTp*Rh(PPh3)2was used as catalyst, thebranched isomer (Markovnikov product) was affordedin high yields andselectivity.5m29Based on preliminary mechanistic investigations,a catalytic cycle for theTp*Rh(PPh3)2catalyzed reaction has been proposed (Scheme 2.2);however, further mechanisticstudiesare currently underway.54 We have also recentlyreported that Wilkinson’scatalyst, inthe appropriate solvent, affords the hydrothiolationproduct in high yield and selectivity,with the E-linear isomer as the major product.’5°PPh3HSRPPh3H’NLNTSRPPh3H — R’where:Tp*=HBNScheme 2.2. Proposed catalytic cycle forTp*Rh(PPh3)2catalyzedhydrothioltionH SRH R’NPPh3N PPh3K3H — R’PPh330Recently, the investigation of the reactivityof bis- and trisQyrazolyl)boratecomplexes (Figure 2.1) towards catalytichydrothiolation was carriedout, andtris(pyrazolyl)borate complexes were shownto be superior than the correspondingbis(pyrazolyl)boratecomplexes.lSI’In addition, complexesthat contained substitutiononthe pyrazolyl rings gave higher yieldand selectivity thanthose that containedunsubstituted rings, affording the branchedisomer as the major product.HH—..BS__...PPh3[Bp*Rh(PPh3)2]/NNHBPPh3PPh3[TPPhMeRh(PPh3)2]Figure 2.1. Rhodium pyrazolylboratecomplexesAs previously discussed, one of the syntheticuses of vinyl sulfides is their abilityto act as precursors to a variety of functionalizedmolecules. For example, vinylsulfidescan undergo cross-coupling with an appropriatenucleophile to generate substitutedolefins. We envisioned that we could use our recentlydeveloped methodology in thesynthesis of 1,1 -disubstituted vinyl sulfidesas a synthetic route to 1,1 -disubstitutedPPh3rfp*Rh(pph)]Ph—.<’7 H/‘NPhi N,, PPh3<Ph[TpIThRh(PPh3)2][TpRh(PPh3)2]31olefins from terminal alkynes. In order for efficientcross-coupling to takeplace, thevinyl sulfide cross-coupling partner shouldbe easily obtained, and have a leavinggroupof low molecular weight to minimize waste. Wethought that n-propanethiolwould be asuitable candidate for the reaction with variousalkynes to afford the correspondingvinylsulfides. Propanethiolate would act as the leaving groupin the subsequent cross-couplingreaction. The molecular weight of this leaving groupis similar to that ofbromide, acommonly used leaving group in cross-couplingreactions. Furthermore,we hadestablished in our original communicationon catalytic hydrothiolationusingTp*Rh(PPh3)2,that n-propanethiol reacts withhigh yield and selectivityinhydrothiolation; however, only one exampleusing n-propanethiol was reported.Therefore, our first goal was to establish thathydrothiolation could proceedwith abroader range of alkynes in selectivity and with acceptableyields. This chapter describesthe reaction of n-propanethiol with functionalized aryland aliphatic alkynes.2.2 Results and Discussion2.2.1 Procedure and Optimization of Hydrothiolation ReactionsHydrothiolation reactions were carried outin a nitrogen-filled VacuumAtmospheres glovebox(02 <2 ppm) unless otherwise specified.Tp*Rh(PPh3)2(0.03equiv.) was weighed out in the glove box using a spatula into a20 mL vial equipped witha magnetic stir bar. A 1:1 mixture of DCE:toluene was then addedby syringe, followedby sequential addition of n-propanethiol (1.1 equiv.) andalkyne (1 equiv.) viamicropipette. The vial was then sealed using a screw cap witha foil liner, removed from32glove box and wrapped in foil. The solution was stirredfor the desired reactiontime (2-16 h), and then concentrated. The residue wassubjected to flash chromatographytoafford the desired product. In general, the resultinghydrothiolation products werequitevolatile, making their isolation somewhat difficult.The optimization of the catalytic hydrothiolationreaction involvingTp*Rh(PPh3)2was carried out previously by our group, and revealedthatTp*Rh(PPh3)2gave thehighest yields in a 1:1 mixture of 1 ,2-dichloroethaneand toluene assolvent.lsmIt wasalso found that if left for prolonged periods of time(>2 d) in THF,Tp*Rh(PPh3)2decomposes, forming an inactive complex for hydrothiolation.The use of a 1:1 mixtureof DCE and toluene circumvented this potential problem.Using previously establishedoptimized reaction conditions, n-propanethiol was reactedwith various alkynes in orderto broaden the substrate scope of its use in alkyne hydrothiolation.2.2.2 Substrate Scope of Hydrothiolation with n-PropanethiolIt has been previously reported by our group thatTp*Rh(PPh3)2is an excellentcatalyst for the hydrothiolation of aliphatic and arylthiolswith a variety of aliphatic, aryland internal alkynes, giving good-to-excellent yields. The hydrothiolationresults of npropanethiol with various aryl and aliphatic alkynes(Chart 2.1) are summarized in Table2.1.33Chart 2.1. Alkyne substrates for hydrothiolationAryl AlkynesAliphatic Alkynes70C6H137 8PhO%970H3CO BrN%5434Table 2.1. Substrate scope alkyne hydrothiolationof n-propanethiol__3 mol%Tp*Rh(PPh3)2+ R1 —DCE:PhCH(1:1), rt1 equiv.Entry Alkyne Product Time Yieldas—,.-----1 2h 74%1 102H3COH3CO2h 72%2113Br’16 h69%3 12F3CF3C16 h 15%13I(16 h 0%5 146 2 h83%6 15s—----7 16h86%C5H13C6H13716s—------8 Nc_%.Nc___c 16h65%8 17s—-----9PhO% PhO-L16 h0%9 18aIsolated yield.35The reaction of n-propanethiolwith phenylacetylene(1) in the presence of3mol%Tp*Rh(PPh3)2was carried out first. Thereaction was completeafter 2 h; theformation of product was indicatedby the appearance ofthe two singlet resonancesforthe olefinic protons of the branchedproduct (10) at 6 5.47and 6 5.19. Theemergence ofthe olefinic protons of the branchedproduct was used as adiagnostic tool to indicatetheformation of all the hydrothiolationproducts investigated.Vinyl sulfide 10 wasisolatedvia flash chromatography; however,while removing solvent,a portion of the productwasalso lost due to the volatility ofthe product. Furthermore,if left neat at roomtemperature, the product startsto decompose within hoursand a change froma clear,colorless oil, to a clear yellow oilis observed. Therefore,to minimize the decomposition,vinyl sulfide 10 was storedin the freezer as a solution inpetroleum ether, andto avoidthe loss of product during isolation, vacuumrotary evaporation wascarried out at roomtemperature. A visual change in allof the isolated hydrothiolationproducts of alkynes(1-4, 6-8) with n-propanethiol is observedif left neat at room temperature,indicatingproduct decomposition.The reaction of n-propanethiol with4-ethynyl anisole (2) wasalso complete after2 h, with the singlet resonances forthe olefmic protons of the branchedproduct appearingat 6 5.39 and 6 5.11. For the reaction of aryl alkynes3 and 4, a decrease in reactivitywasobserved, requiring 16 h to reach completion.The reaction involving2-ethynylpyridine(5) did not undergo the hycirothiolation reaction.A possible reason forthis reactioncould be caused by competitive C-H activationof the alkyne. For the aliphaticalkynesthat were investigated, 1 -ethynylcyclohexene(6) showed the highest reactivity,reachingcompletion after 2 h and afforded the branchedproduct in high selectivity andisolated36yield. The hydrothiolation reactionsof 1 -octyne (7) and5-cyanohexyne(8) werecomplete after 16 h; affordingthe branched product inmoderate-to-high isolatedyields.Vinyl sulfides 16 and 17 were proneto isomerisation; however,the avoidance of theuseof chloroform as solvent in eitherchromatography or NMRspectroscopy couldcircumvent this problem. Phenyipropargylether (9) showed noreaction after 16 hatroom temperature to form the correspondingvinyl sulfide.2.3 ConclusionsThe hydrothiolation of n-propanethiol withvarious aryl and aliphaticalkynes inthe presence ofTp*Rh(PPh3)2has been carriedout. The alkynes that underwentthehydrothiolation reaction afforded thebranched vinyl sulfide in highselectivity. Forthearyl alkynes that were investigated wefound that vinyl sulfides derivedfrom eitherunsubstituted or electron-rich aryl alkynes(1 and 2 respectively) wereisolated in highyields. Vinyl sulfides derived from arylalkynes containing electronwithdrawingsubstituents (3 and 4) led toa significant decrease in reactivity.Aliphatic alkynes (6-8)also reacted with n-propanethiol with highselectivity and good isolatedyields (entries6,7 and 8). While product decompostion wasobserved, dilution in petroleumether andstorage at -2 °C minimized decomposition.The use of the isolatedbranched vinylsulfides in Kumada cross-coupling to generate1,1 -disubstituted olefins will bediscussedin the following chapter.372.4 Experimental Procedures2.4.1 General MethodsThe synthesis and manipulation of air and moisturesensitive organometalliccompounds was carried out in a nitrogen-filled VacuumAtmospheres glovebox(02<2ppm). Reactions were carried out at room temperatureand stirred with a Teflon-coatedmagnetic stir bar. Reaction mixtures were concentratedusing rotary evaporationmethodscombined with a high vacuum pump line. Glasswarewas cleaned in thefollowingmanner: submersion in a base bath (500g KOH, 2 L deionized water, 8 L isopropanol)for 16 h, rinsing with copious amounts of deionizedwater, followed by rinsingwithacetone. Flash chromatography was used to separateproducts (Silicycle,60-200i.tm, 70-230 mesh), and the solvent was eluted using air pressure.2.4.2 Reagents and SolventsTp*Rh(PPh3)2[Tp*= hydrotris(3 ,5-dimethylpyrazolylborate)]was prepared by apublishedprocedure.15mHexanes, 1,2-dichloroethane (DCE), THFand toluene weredried by passage through solvent purification columns.All other commercial reagentsand solvents were used without further purification. Deuteratedchloroform was driedusing activated molecular sieves (4A) andd8-toluene was used from1 g ampules.2.4.3 Physical and Spectropscopic MeasurementsNMR spectra were recorded on Bruker Avance 300or Bruker Avance 400spectrometers. ‘H and ‘3C NIVIR spectra are reported in parts permillion and referenced38to residual solvent. Coupling constant values wereextracted assuming first-ordercoupling. The multiplicities are abbreviatedas follows: s = singlet, ci = doublet,t triplet,q = quartet, quin = quintet, sxt = sextet, m = multiplet, dd =doublet of doublets, td =triplet of doublets. All spectra were obtainedat 25 °C. Mass spectra were recordedon aKratos MS-SO mass spectrometer. Higher yields andelemental anlyses of thecompoundswere impeded by product volatility.Reaction of n-Propanethiol and Phenylacetylene(1)SH +qSTp*Rh(PPh3)2(82 mg, 0.089 mmol) was weighed out in the glovebox using a spatulainto a 20 mL vial equipped with a magnetic stir bar. A1:1 mixture of DCE:toluene (5mL) was then added by syringe, followed sequentiallyby n-propanethiol (296 1.iL, 3.26mmol) and phenylacetylene (325 j.tL, 2.96 mmol) viamicropipette. The vial was thensealed using a screw cap with a foil liner, removed from glovebox and wrapped in foil.After stirring for 2 h at room temperature, the solution was concentratedand the residuewas subjected to flash chromatography using petroleum ether as eluentto afford theproduct as a clear, colorless oil with yellow tint (390 mg, 2.19mmol, 74% yield). ‘HNMR (300 MHz, CDCI3)6 7.62 — 7.50 (m, 2 H), 7.42 —7.29 (m,3 H), 5.47 (s, 1 H), 5.19(s, 1 H), 2.69 (t, J7.3 Hz, 2 H), 1.69 (sxt, J=7.3 Hz, 2 H), 1.03(t, J=7.3 Hz, 3 H).39‘3c{’H} NMR (CDC13,75 MHz): 145.2, 139.8, 128.3, 128.3, 127.1, 110.4, 34.1, 21.9,13.5. HRMS (El) mlz calcd forC11H,4S: 178.0816; found: 178.0815.Reaction of n-Propanethiol and 4-ethynylanisole (2)SH +3 mol%Tp*Rh(PPh3)2H3CODCE:PhCH,rt, 2 h272% 11Tp*Rh(PPh3)2(75 mg, 0.08 1 mmol) was weighed out in the glove box using a spatulainto a 20 mL vial equipped with a magnetic stir bar. A 1:1 mixture of DCE:toluene (5mL) was then added by syringe, followed sequentially by n-propanethiol (269 .tL, 2.97mmol) and 4-ethynylanisole (350iiL,2.7 mmol) via micropipette. The vial was thensealed using a screw cap with a foil liner, removed from glove box and wrapped in foil.After stirring for 2 h at room temperature, the solution was concentrated and the residuewas subjected to flash chromatography, using a 4:1 petroleum ether:DCM mixture aseluent, to afford the product as a clear, colorless oil with yellow tint (405 mg, 1.94 mmol,72% yield). ‘H NMR (300 MHz, CDC13)ö 7.50 (d, J=9.1 Hz, 2 H), 6.88 (d, J=9.1 Hz, 2H), 5.39 (s, 1 H), 5.11 (s, 1 H), 3.83 (s, 3 H), 2.72 - 2.62 (t, J7.3 Hz, 2 H), 1.67 (sxt,J=7.3 Hz, 2 H), 1.02 (t, J7.3 Hz, 3 H). ‘3C{’H} NMR (CDC13,75 MHz): ö 159.7,144.6, 132.3, 128.3, 113.6, 109.1, 55.3, 34.1, 21.9, 13.5. HRMS (El) mlz calcd forC12H160S: 208.0922; found: 208.0926.40Reaction of n-Propanethiol and 4-Ethynyl-1-Bromobenzene(3)s—---3 mol%Tp*Rh(PPh3)2+IDCE:PhCH,Br 16h,rtBr369%12Tp*Rh(PPh3)2(84 mg, 0.09 mmol) was weighedout in the glove box usinga spatula intoa 20 mL vial equipped with a magnetic stirbar. A 1:1 mixture of DCE:toluenewas thenadded (3 mL), followed sequentiallyby n-propanethiol (302 jL, 3.33mmol) and 4-ethynyl-l-bromobenzene (549 mg,3.03 mmol), which was weighedout in a 5 mL vialand transferred to the reaction mixture using3 mL of a 1:1 mixture of DCE:toluene.Thevial was then sealed using a screwcap with foil liner, removedfrom glove box andwrapped in foil. After stirring for16 hours at room temperature,the solution wasconcentrated and the residue was subjectedto flash chromatographyusing petroleumether as eluent to afford the product asa white solid (538 mg, 2.09 mmol,69% yield). ‘HNMR (300 MHz, CDC13)ö 7.15 - 7.45 (m, 2H), 7.45 - 7.39 (m, 2 H), 5.45(s, 1 H), 5.19(s, 1 H), 2.67 (t, J7.1 Hz, 2 H), 1.66 (sxt, J7.3,2 H), 1.02 (t, J7.5 Hz,3 H). ‘3C{’H}NMR (CDC13,75 MHz): ö 144.1,138.8, 131.4, 128.7, 122.3, 111.0,34.1, 21.9, 13.5.HRMS (El) m/z calcd forC11H13SBr: 255.9921;found: 255.9924.41Reaction of n-Propanethiol and4-Ethynyl-a,a,a-Trifluorotoluene(41s-.-----+3 mol%Tp*Rh(PPh3)2F3CDCE:PhCH,rtF3C416h,rt1315%Tp*Rh(PPh3)2(50 mg, 0.054 mmol) was weighedout in the glove box using a spatulainto a 20 mL vial equipped with a magnetic stir bar.A 1:1 mixture of DCE:toluenewasthen added (4 mL), followed sequentially byn-propanethiol (181 pL, 1.98 mmol)and 4-ethynyl-a,a,a-trifluorotoluene (293 .tL, 1.8 mmol)via micropipette. The vialwas thensealed using a screw cap with foil liner, removed from glovebox and wrapped in foil.After stirring for 24 hours at room temperature, thesolution was concentratedand theresidue was subjected to flash chromatography usingpetroleum ether as eluent toaffordthe product as a clear, colorless oil (71 mg, 0.288mmol, 16% yield). ‘H NMR(300MHz, CDC13)ö 7.71 - 7.54 (m, 4 H), 5.52 (s, 1 H),5.27 (s, 1 H), 2.69 (t, J=7.3 Hz,2 H),1.77 - 1.59 (m, 2 H), 1.03 (t, J7.3 Hz, 3 H).‘3C{’H} NMR (CDC13,100 MHz):ö 144.1,143,4, 130.2, 127.5, 125.3 (q, J=3.4 Hz), 122.7, 112.2,34.2, 21.9, 13.5. HRMS (El) m/zcaled forC12H,3SF:246.0690; found: 246.0689.42Reaction of n-Propanethiol and 1-Ethynylcyclohexene(6)SH+3 mol%Tp*Rh(pph3)2DCE:PhCH3,rt, 2 h L.J6 83%15Tp*Rh(PPh3)2(75 mg, 0.081 mmol) was weighed outin the glove box using aspatulainto a 20 mL vial equipped with a magnetic stir bar.A 1:1 mixture of DCE:toluene(5mL) was then added by syringe, followed sequentiallyby n-propanethiol (269 jtL,2.97rnmol) and 1-ethynylcyclohexene (317 iL, 2.7mmol) via micropipette.The vial wasthen sealed using a screw cap with a foil liner, removedfrom glove box and wrappedinfoil. After stirring for 2 h at room temperature, thesolution was concentratedand theresidue was subjected to flash chromatography usingpetroleum ether as eluent toaffordthe product as a clear, colorless oil (409 mg, 2.24 mmol,83% yield). ‘H NMR(300MHz, CDC13)6 6.22 (t, J’4.l Hz, 1 H), 5.26 (s, 1 H),4.89 (s, 1 H), 2.66 (t, J7.3Hz, 2H), 2.23 (td, J4.1, 1.94 Hz, 2 H), 2.14 (dt, J3.9, 2.26 Hz,2 H), 1.73 - 1.51 (m, 6 H),1.01 (t, J7.4 Hz, 3 H). ‘3C{1H} NMR (CDC13,75 MHz):8 145.6, 135.4, 127.1, 106.6,33.8, 26.9, 25.7, 22.8, 22.1, 21.9, 13.7. HRIVIS (El) m/zcalcd for C11H18S: 182.1129;found: 182.1133.43Reaction of n-Propanethiol and1-Octyne (713 mol%Tp*Rh(PPh3)2DCE:PhCHjt,16hTp*Rh(PPh3)2(30 mg, 0.033 mmol) was weighed outin the glove box usinga spatulainto a 20 mL vial equipped with a magneticstir bar. A 1:1 mixture of DCE:toluene(4mL) was then added by syringe, followed sequentiallyby n-propanethiol (108 j.tL, 1.19mmol) and 1-octyne (159 tL, 1.08 mmol) via micropipette.The vial was then sealedusing a screw cap with foil liner, removed from glovebox and wrapped in foil.Afterstirring for 16 h at room temperature, the solution wasconcentrated and the residue wassubjected to flash chromatography with petroleum etheras eluent to afford the productasa clear, colorless oil (173 mg, 0.93 mmol, 86% yield).‘H NMR (300 MHz, CDC13)85.01 (s, 1 H), 4.68 (s, I H), 2.68 (t, J7.3 Hz, 2H), 2.22 (t, J=7.5 Hz, 2 H), 1.68(sxt,J=7.3 Hz, 2 H), 1.60 - 1.45 (m, 2 H), 1.30 (m, 6 H), 1.03(t, J7.54 Hz, 3 H), 0.95 - 0.82(m, 3 H). ‘3C{’H} NMR(d9-toluene, 100 MHz): 6 146.7,104.7, 38.12, 33.3, 32.1,29.3,29.1, 23.0, 22.0, 14.3, 13.7. HRMS (El) mlzcalcd for C11H22S: 186.1442; found:186. 1447.44Reaction of n-propanethiol with 5-hexynenitrile(83 mol%Tp*Rh(PPh3)2+ DCE:PhCH3 Nc__ç1 6h,rt17Tp*Rh(PPh3)2(100 mg, 0.108 mmol) was weighed out in theglovebox using a spatulainto a 60 mL schlenck flask equipped with a magneticstir bar and greased glass stopcock.A 1:1 DCE:toluene mixture was then added (4 mL)was then added by syringe.The flaskwas then sealed with a rubber septum, taken out ofthe glovebox and wrapped in foil.nPropanethiol (360 .tL, 3.97 mmol) was then addedfollowed by 5-hexynenitrile(377 tL,3.6 mmol) via micropipette. After stirring for 16 hoursat room temperature, the solutionwas concentrated and the residue was subjected to flash chromatographywith petroleumether as eluent to afford the product as a clear, colorless oil (396mg, 2.34 mmol, 65%yield). ‘H NMR (300 M}{z, CDC13)6 5.08 (s, 1 H), 4.76(s, 1 H), 2.67 (t, J=7.31 Hz, 2H), 2.43 - 2.29 (m, 4 H), 1.89 (quin, J6.97 Hz, 2 H), 1.66 (sxt,J7.31 Hz, 2 H), 1.01 (t,3 H). ‘3C{’H} NMR (CDC13,75 MHz): 6 143.1, 119.3, 107.1,36.0, 33.1, 24.1, 21.5,15.8, 13.5. HRMS (El) mlz calcd forC9H,5NS: 169.0925; found: 169.0924.45Chapter 3— Kumada Cross-Couplingof Vinyl Sulfides3.1 IntroductionThe development of strategies for the constructionand substitution of olefins isanarea of continued interest due to their presence inbiologically active moleculesandadvanced synthetic intermediates. Traditional transition-metalcatalyzed cross-couplingreactions for the synthesis of substituted olefinstypically involve the use of vinylhalideor vinyl triflate starting material. The harshconditions often required for thesynthesis ofthese starting materials present functional groupincompatibility, and haveled to theinvestigation of alternate coupling partnersubstrates.In 1987, Naso and co-workers reported thesynthesis of 1,1-disubstitutedolefinsinvolving the use of 1 -chioro- 1 -phenylthioethene;42however, the substratescope that wasdeveloped for this reaction was limited to onlytwo examples. Thechemoselectiveintroduction of different alkyl groups ontothe double bond was possibledue to thereactivity differences between the carbon-chloride andthe carbon-sulfur bonds towardscross-coupling. When one equiv. of Grignardreagent was reacted withl-chloro-lphenylthioethene in the presence ofNiC12(dppp), reactionoccurred at the carbon-chloridebond first, affording the corresponding vinyl sulfide. Ifanother equiv. of Grignardreagent was added, the cross-coupling at the carbon-sulfurbond occurred, affording thecorresponding disubstituted olefin (eq 3.1). Whilea one-pot protocol was possible,higher yields were obtained when the vinyl sulfideresulting from carbon-chloridecleavage was actually isolated first before a second equiv.of Grignard reagent was addedfor cross-coupling at the carbon sulfur bond.46R1Mg)(INiCI2(dppp)R2MgXINiCI(dppp)(3.1)CI Et20, r.t. R1Et20, r.t. R1A convenient method for the regioselectivesynthesis of 1,1 -disubstitutedvinylsulfides was developed by our group15mand we have shown thatn-propanethiol canundergo alkyne hydrothiolation with variousalkynes in moderateto high isolated yields(Table 2.1). Due to the low molecular weightof n-propanethiol, wepostulate that thecorresponding vinyl sulfide would be a suitablecross-coupling partner forthe synthesisof a variety of 1,1 -disubstituted olefins.In this chapter, the reaction ofvinyl sulfidesderived from the hydrothiolation of variousalkynes with n-propanethiolwith Grignardreagents in the presence ofNiCI2(PPh3)willbe discussed (eq 3.2). Furthermore,we willshow that a one-pot procedure for the synthesisof the 1,1-disubstituted olefinsis possiblefrom readily available alkynes.R+ RMgxNi cat.R(3.2)3.2 Results and Discussion3.2.1 Procedure and Optimization of Cross-Coupling ReactionsThe test reaction was carried in Et20, usingvinyl sulfide 10 (Chart 3.1) andbenzylmagnesium chloride (Chart 3.2,19) in the presence of 5 mol% NiC12(PPh3).Thereaction was allowed to reflux for 16 h; however, itdid not go to completion. Aftervarying the catalyst loading and changing solvents fromEt20 to THF, the optimal47conditions were found to require 10 mol% catalystloading and refluxingin TI-IF (75 °C)for 16 h. Although Et20 was also a suitable solvent,THF was chosen due to itshigherboiling point. When Et20 was used, at the end of therequired reaction time of 16h, thereaction mixture became a thick black paste, and gaveoverall lower yields thanin THF.For each of the reaction combinations, the vinylsulfides (10-13, 15-17)were firstcombined with the NiCI2(PPh3)in TI-IF. When theGrignard reagent was addedin oneportion, an increased amount of the homo-coupled productof the Grignard reagentwasobserved. It was found that the best results were obtainedwhen the Grignard reagentisadded dropwise over a longer period of time (over a periodof 1 h). The reaction mixturewas passed through a plug of Celite, and the organic layerwas extracted with Et20,driedover Mg2SO4 and concentrated. The residuewas then subjected to columnchromatography, and it was found that the cross-coupledproducts tended to be lessvolatile than their corresponding vinyl sulfide startingmaterial.3.2.2 Substrate Scope of Kumada Cross-CouplingReactionsChart 3.1. Vinyl sulfide substrates for Ni-catalyzedcross-couplingF3CC6H1Nc48Chart 3.2. Grignard reagents forNi-catalyzed cross-couplingiMgCIMgBr-MgCIMgBr22 2324The results for the cross-coupling reactionsof various aryl vinylsulfides (10-13)with a variety of Grignard reagents (19-24)are summarized in Table 3.1and the resultsfor the cross-coupling involving aliphaticvinyl sulfides (15-17) aresummarized in Table3.2. One problem encountered was that thecross-coupling reactions involvingvinylsulfide 10 could not be separated from thehomo-coupled Grignard reagentby columnchromatography. As a consequence, theyield was calculated by‘H NMR spectroscopicanalysis using 1,3,5-trimethoxybenzene as an internalstandard. Based on‘H NMRspectroscopic analysis, the cross-couplingof 10 with 19, afforded thedesired 1,1 -disubstitued olefin in 51% yield.The disappearance of the vinylproton singletresonances (6 5.47 and 5.19) of 10indicated that the reaction hadgone to completion,and the appearance of new singlet resonances(6 5.53 and 5.05) indicated that anew 1,1-disubstituted olefin was formed.49Table 3.1. Summary ofNiCI2(PPh3)-catalyzedcross-coupling of arylvinyl sulfidess—--R+ l.MXNiCI2(PPh3)THF, 75°C16 hR1REntry Vinyl SulfideGrignardProduct YieldPhCH2MgCI (19) 51%a(25)23456789BrF3CPhCH2MgCI (19)PhMgBr (20)TMS-CH2MgCI (21)n-BuMgCI (22)CH2CHMgBr (23)PhCCMgBr (24)PhCH2MgCI (19)PhCH2MgCI (19)BrF3C61% (26)43% (27)60%b(28)0%0%0%0%traceaYield determined by111NMR spectroscopic analysis inCDCI3.bR’ = CH3.11•150Table 3.2. Summary ofNiCJ2(PPh3)-catalyzed cross-couplingof aliphatic vinyl sulfidesR1+ l.MXNiCI2(PPh32R THF, 75°C R16 hEntry Vinyl Sulfide GrignardProduct Yield10 PhCH2MgCI (19)55% (29)11 PhMgBr(20)R1 41% (30)12 TMS-CH2MgCI (21)81% (31)13 n-BuMgCI (22)0%0%1415CH2CHMgBr(23)15 PhCCMgBr(24)0%s—----16C6H13PhCH2MgCI(19)c6H1351% (32)16s—”--.---17PhCH2MgCI(19)Nc0%N17Reaction of vinyl sulfide 11 with Grignard reagents19-21 gave the desiredcross-coupling products. We found that vinyl sulfides derivedfrom aryl alkynes containinganelectron-donating substituent at the para position gavehigher yields in the cross-couplingreaction with Grignard reagents than vinyl sulfides derivedfrom unsubstituted arylalkynes. Vinyl sulfides derived from aryl alkynes containingan electron-withdrawingsubstituent at the para position (12-13), gave no cross-couplingproduct or only traceamounts. This reactivity trend is consistent with what was previouslyreported byWenkert arid co-workers when aryl vinyl sulfides anethole,methylisoeugenol andisosafrole were synthesized.43 It can be seen that with increasingelectron donation fromthe aryl ring of the vinyl sulfide, the yield of the cross-couplingproduct also increases.51For the reaction with trimethylsilylmethylmagnesiumchloride (21) with vinylsulfide 11,only the desilated cross-coupled productwas obtained.The cross-coupling reaction involvingvinyl sulfide 12 wasnot successful ingiving the desired substituted olefm,presumably dueto the competitive cross-couplingreaction or metal-halogen exchangeoccurring at the carbon-bromidebond. While thereaction was not expected to besuccessful due to variouspossible side reactions,thereaction was carried out in orderto test the limits of the couplingreaction. The productthat was formed was not isolated;however, it has beenshown that differentleavinggroups show different reactivities towardsthe cross-coupling reaction.One exampleofchemoselective Kumada cross-couplingis the reaction ofGrignard reagentswithchlorophenyl alkyl sulfides in thepresence ofNiC12(PPh3).The reaction occurs firstatthe carbon-chloride bond. Ifa second equiv. of Grignardreagent is added, subsequentreaction occurs at the carbon-sulfurbond, and the disubstitutedbenzene can be obtained.Another example is the previouslymentioned work of Nasoand co-workers42 inthesynthesis of 1,1-disubstituted olefinsfrom 1-chloro-l-phenylthioethene.Anotherreaction that was used in order to testthe limit of the cross-couplingreaction was thereaction involving vinyl sulfide 17, wherethe possible side reactionscould have been theattack of the Grignard reagenton the cyano group or deprotonationof the proton a tothecyano group. The desired cross-couplingproduct was not obtained.The reaction of vinyl sulfide 13 with benzylmagnesiumchloride only gave traceamounts of the cross-coupled product,which was indicated by theappearance of newsinglet resonances (6 5.56 and 5.16)in the olefmic region ofthe ‘H NMR spectrum.Vinyl sulfide 15 reactedwith Grignard reagents 19-21 affordingthe desired cross-52coupling product; however, in contrast to the reaction with vinyl sulfide 11, the silylatedproduct was obtained in high isolated yield when TMS-CH2MgC1 (21) was used asGrignard reagent. Although it was previously mentioned that primary and secondaryGrignard reagents act as reducing agents in the cross-coupling reaction in the presence ofNiC12(PPh3),the absence of/3-hydrogens in TMS-CH2MgC1 allows it to act as a suitablenucleophile in the formation of the desired 1,1 -disubstituted olefin. We should note thatallyl silanes have been used in allylation reactions or as nucleophiles in other cross-coupling reactions.45 Furthermore, all of the products of the cross-coupling reaction of15 have potential to act as Diels-Alder substrates.46Reaction using phenylethynylmagnesium- or n-butylmagnesium bromide ascross-coupling partners did not give the desired substituted olefin when reacted withvinyl sulfides 11 and 15, but instead gave unidentified by-products. It is known thatprimary and secondary Grignard reagents can serve as reducing agents in the reductivecleavage of carbon-sulfur bonds in the presence ofNiCI2(PPh3).26’47 Wenkert and coworkers found that the reduction can be suppressed by changing catalysts fromNiCl2(PPh3)to NiC12(dppp) or NiC12(dppe). It was thought that the role of the ligandwas crucial in determining the reactivityof the catalyst. By replacing thetriphenylphosphine ligands with a bidentate dpppor dppe ligand, the reductiveelimination step leading tocross-coupling could be accelerated, thus decreasing thechance for reductive cleavage to occur.47The use of other nickel-complexes containingbidentate ligands in the cross-coupling reaction is anarea of future exploration in ourgroup.533.2.3 One-Pot Hydrothiolation and KumadaCross-CouplingOnce the feasibility of vinyl sulfides toact as substrates in cross-couplingfor thesynthesis of 1,1 -disubstituted olefins wasestablished, we addressedthe possibility of aone-pot procedure, combining the hydrothiolationand Kumada cross-couplingreactions.Although the hydrothiolation reaction wastypically carried outin a 1:1 DCE:toluenemixture, while the cross-coupling was carriedout in THF, THF was chosenin order tocarry out the one-pot protocol. We previouslymentioned thatTp*Rh(PPh3)2decomposesin TI-IF if left for extended periods(>2 d); however, since thehydrothiolation step iscomplete within 16 h, we did not expectthe use of THF to be problematic.The desired1,1-disubstituted olefms obtained from theone-pot protocol (Table3.3) gave comparable,and in some cases, superior isolated yieldsto those obtained from the two-stepprocedure.To determine what may be the cause of thesuperior yields, the hydrothiolationreactionwas carried out using the NiC12(PPh3)as catalyst and the cross-couplingreaction wascarried out usingTp*Rh(PPh3)2as catalyst. When the hydrothiolationwas carried outusing NiC12(PPh3)as catalyst, only unreacted startingmaterial is observed. WhenTp*Rh(PPh3)2was used as the catalyst for the cross-couplingreaction, a smallamount ofthe cross-coupling product is formed, indicatedby the emergence of new singletresonances in ‘H NMR corresponding tothe vinyl protons of the desiredproduct. Thesuperior yields that is sometimes observed in theone-pot protocol may the resultof boththe NiCl2(PPh3)andTp*Rh(PPh3)2complexes catalyzing the cross-couplingreaction.Alternatively, loss of the vinyl sulfidesubstrates from the hydrothiolationreaction in theisolation step may occur, thus lowering the overallyield of the two-step process.54Table 3.3. Summaryof Results for One-PotProtocol3.3 Conclusionsn-PrS_________________R1-MgX3 mol%Tp*Rh(PPh3)2R10 mol% NiCI2(PPh3)THE, 75°CProductWe have found that vinyl sulfides derivedfrom aryl and aliphaticalkynes and npropanethiol, can undergo nickel-catalyzedKumada-type cross-couplingwith Grignardreagents to afford 1,1 -disubstituted olefins.Furthermore, the vinylsulfides derived fromaryl alkynes that have an electron donatingsubstituent at the paraposition gave higheryields than the unsubstituted variant,which in turn gave betteryields than alkyl vinylsulfides with an electron withdrawingsubstituent at the para position.While aryl andaliphatic Grignard reagents werefound to be suitable cross-couplingpartners, vinylR+n-PrSHR1RTime YieldEntry AlkyneGrignardPhPhPhCH2MgCI(19)Ph16 h 30%a(25)I2 PhCH2MgCI(19)R116 h 65%(26)3jJPhMgBr(20)16 h37% (27)4MeO TMS-CH2MgCI (21)Ar16 h63%b(28)25 PhCH2MgCI(19)R16 h 66%(29)6PhMgBr(20)16 h 30%(30)7 TMS-CH2MgCI(21)16 h60% (31)68C6H1PhCH2MgCI(19)C6H13L16 h78% (32)aYield determined by ‘H NMR spectroscopicanalysis in CDCI3.bR’ = CH3.55Grignard reagents and those containing16-hydrogensdid not afford the desired1,1 -disubstituted olefin. A one-pot protocolhas also been established andprovidescomparable or better isolated yields than the two-stepprocedure, while improvingefficiency in requiring only one workup step. In additionto improving the efficiencyofthe reaction, the avoidance of one purificationstep reduces the use purificationsolventsas well as reaction solvent.3.4 Experimental Procedure3.4.1 General MethodsThe synthesis and manipulation of air and moisturesensitive organometalliccompounds was carried out under N2 atmosphere. Reactionswere refluxed at 75°C for16 h and stirred with a Teflon-coated magnetic stirbar. Reaction mixtureswereconcentrated using rotary evaporation methods combinedwith a high vacuum pumpline.Internal standard yields were obtained via ‘H NMRspectroscopic analysis using 1,3,5-trimethoxybenzene as internal standard. A potassiumhydroxide, isopropanol and waterbase bath was used to clean glassware, followed by subsequentrinsing with deionizedwater and acetone. Flash chromatography was usedto separate products (Silicycle,60-200iim,70-230 mesh), and the solvent was eluted using air.3.4.2 Reagents and SolventsNiCI2(PPh3)was prepared by a published procedure.48Hexanes, 1,2-dichioroethane (DCE), THF and toluene were driedby passage through solvent56purification columns. All other commercial reagentsand solvents were used withoutfurther purification. Deuterated chloroform was driedusing activated molecular sieves(4A).3.4.3 Physical and Spectropscopic MeasurementsNIvIR spectra were recorded on BrukerAvance 300 or Bruker Avance400spectrometers. ‘H and ‘3C NMR spectra are reportedin parts per million andreferencedto residual solvent. Coupling constant values wereextracted assuming first-ordercoupling. The multiplicities are abbreviated as follows:s = singlet, d = doublet, t = triplet,q = quartet, quin = quintet, sxt = sextet, m = multiplet, dd = doublet ofdoublets, td =triplet of doublets. All spectra were obtained at 25 C.Mass spectra were recorded onaKratos MS-50 mass spectrometer. Higher yieldsand elemental analyses of thecompounds were impeded by homo-coupling ofthe Grignard reagent and productvolatility.Reaction of (10) with Benzylmagnesium Chloride (19)s—---L10+1. 10 mol% N1CI2(PPh3)I ,3,5-trimethoxybenzeneTHF, 75°C, 16h2. IM HCI(MCI1951%2557The yield for the above reaction wasdetermined by ‘H NMR spectroscopicanalysisusing 1,3,5-trimethoxybenzene as an internal standard.NiC12(PPh3)(36 mg, 0.056mmol) was weighed out using a spatula ontoweighing paper and addedto a flame-dried25 mL 2-neck round-bottom flask containing vinylsulfide 10 (100 mg, 0.56mmol),l,3,5-trimethoxybenzene (31.3 mg, 0.186mmol) and a magnetic stirbar. The round-bottom flask was sealed using two rubbersepta and flushed with N2 gas. THF(6.8 mL)was then added and the mixture was stirred vigorouslywhile a 1.0 M solutionofbenzylmagnesium chloride (2.2 mL) inEt20 was added dropwise viasyringe over aperiod of 1 h. The reaction flask wasthen equipped with a flame driedreflux condenserand glass stopper, and the resulting brown/blacksolution was heated to 75C for 16 h.The solution was then allowed to cool to room temperatureand a 1 M HC1 solution wasadded (4 mL) followed by Et20 (4 mL). The solutionwas stirred for 5 mm thenfilteredthrough a plug of Celite. The organic layer wasextracted with Et20 (3 x5 mL), driedover Mg2SO4and concentrated under reduced pressure.The residue was dissolved inCDCI3.‘H NMR (300 MHz) spectroscopic analysisindicated the formationof the crosscoupled product49 in 51 % yield. The spectrum shownin Appendix 2 containsresidualtoluene, bibenzyl and tetrahydrofuran.58Reaction of (11) withBenzylmanesium Chloride (19H3CO11. 10 mol% NiCI2(PPh3)+ THF, 75°C, 16h2.IMHCIJjJMgCI61% H3CO2619NiC12(PPh3)(16 mg, 0.026 mmol)was weighed out using a spatulaonto weighing paperand added to a flame-dried 15 mL 2-neckround-bottom flaskcontaining vinyl sulfide11(55 mg, 0.26 mmol) and a magnetic stir bar. Theround-bottom flask wassealed usingtwo rubber septa and flushed withN2 gas. THF (3.7 mL) was thenadded and the mixturewas stirred vigorously while a 1.0 M solutionof benzylmagnesiumchloride (1.1 mL) inEt20 was added dropwise via syringeover a period 1 h. The reactionflask was thenequipped with a flame dried reflux condenserand stopper, and the resultingbrown/blacksolution was heated to 75 C for 16 h.The solution was then allowedto cool to roomtemperature and a 1 M HCI solution wasadded (2 mL) followed by Et20(2 mL). Thesolution was stirred for 5 mm then filtered througha plug of Celite. The organiclayerwas extracted with Et20 (3 x 4 mL), dried over Mg2SO4and concentrated underreducedpressure. The residue was then subjectedto flash chromatography toafford the productas a clear colorless oil (36 mg, 0.16 mmol, 61 %). 1H NMR(300 MHz, CDC13)6 7.39(d,J=8.9 Hz, 2 H), 7.30 — 7.20 (m, 5 H), 6.83 (d, J=8.9Hz, 2 H), 5.44 (s, 1 H), 4.96 (s,1 H),3.83 (s, 2 H), 3.80 (s, 3H). ‘3C{’H} NMR (CDC13,75 MHz): 6 159.0, 146.1, 139.7,59133.2, 128.8, 128.3, 127.2, 126.0, 113.6, 113.0,55.2, 41.7. HRMS (El)mlz calcd forC16H0: 224.1201; found: 224.1202.Reaction of (11) with PhenylmagnesiumBromide (20)s—’---1. 10 mol% NICI2(PPh3)H3COTHF,75°C 16h+2.IMHCII43% H3CO272ONiC12(PPh3)(30 mg, 0.048 mmol) was weighed outusing a spatula onto weighingpaperand added to a flame-dried 25 mE 2-neck round-bottomflask containing vinyl sulfide11(100 mg, 0.48 mmol) and a magnetic stir bar. Theround-bottom flask was sealedusingtwo rubber septa and flushed with N2 gas. THF (6.0 mL) wasthen added and the mixturewas stirred vigorously while a 1.0 M solution of phenylmagnesiumbromide (2 mL) inTHF was added dropwise via syringe over a period of1 h. The reaction flask wasthenequipped with a flame dried reflux condenser and glassstopper, and the resultingbrownlblack solution was heated to 75 C for 16 h. The solutionwas then allowed tocool to room temperature and a 1 M HC1 solution was added (4mL) followed by Et20 (4mL). The solution was stirred for 5 mm then filtered througha plug of Celite. Theorganic layer was extracted with Et20 (3 x 8 mL), dried over Mg2SO4and concentratedunder reduced pressure. The residue was subjected to flash chromatographyto afford theproduct as a white solid (44 mg, 0.21 mmol, 43 %). Characterizationmatches previously60reported data.5° 1H NMR (400 MHz, CDC13)6 7.35- 7.22 (m, 7 H), 6.85 (d, J=9.2 Hz,2H), 5.38 (s, 1 H), 5.34 (s, 1 H), 3.81 (s, 3 H).‘3C{’H} NMR (CDC13,100MHz): 6 159.3,149.5, 141.8, 134.0, 129.4, 128.3, 128.1, 127.6, 113.5, 112.9, 55.3.FIRMS (El) mlzcalcd forC15H140: 210.1045; found: 210.1050.Reaction of (11) with Trimethylsi1ylmethy1manesiumChloride (21)s—--—CH3H3CO’111. 10 mol% NiCI2(PPh3)THF, 75°C, 16h I+HCO2.1MHCII.___60%28Si MgCI21NiC12(PPh3)(30 mg, 0.048 mmol) was weighed out using aspatula onto weighing paperand added to a flame-dried 25 mL 2-neck round-bottom flask containing vinylsulfide 11(100 mg, 0.48 mmol) and a magnetic stir bar. The round-bottom flaskwas sealed usingtwo rubber septa and flushed with N2 gas. THF (6.0 mL) was then addedand the mixturewas stirred vigorously while trimethylsilylmethylmagnesium chloride (2 mL ofa 1.0 Msolution in Et20) was added dropwise via syringe over a period of1 h. The reaction flaskwas then equipped with a flame dried reflux condenser and glass stopper,and theresulting brown/black solution was heated to 75 °C for 16 h. The solutionwas thenallowed to cool to room temperature and a 1 M HCI solution wasadded (4 mL) followedby Et20 (4 mE). The solution was stirred for 5 mm then filtered through a plug of Celite.61The organic layer was extracted withEt20 (3 x 8 mL), driedover Mg2SO4 andconcentrated under reduced pressure. Theresidue was subjectedto flash chromatographyto afford the product as a colorless oil (43 mg, 0.29mmol, 60 %). Upto 10 % of thereduced product is produced as observedby ‘H NMR. Characterizationmatchespreviously reported data.5’ ‘H NMR (300MHz, CDC13)6 7.44 (d,J=8.7 Hz, 2 H), 6.88(d, J=8.7 Hz, 211), 5.30 (s, 1 H), 5.01, (s, 1H), 3.83 (s, 3 H), 2.15 (s,3 H). ‘3C{’H}NMR (CDC13,100 MHz): 6 159,0, 142.5,133.7, 126.6, 113.5, 110.6, 55.3,21.9. HRMS(El) mlz calcd forC10H120: 148.0888; found:148.0885.Reaction of(15) with Benzy1manesium Chloride (19)1.iPPh3)2+ 2.1MHCINiC12(PPh3)(34 mg, 0.055 mmol) was weighedout using a spatula onto weighingpaperand added to a flame-dried 25 mL 2-neck round-bottomflask containing vinyl sulfide15(100 mg, 0.55 mmol) and a magnetic stir bar. Theround-bottom flask was sealedusingtwo rubber septa and flushed with N2 gas. THF (7.7 mL) wasthen added and the mixturewas stirred vigorously while benzylmagnesium chloride(2.2 mL of a 1.0 M solutioninEt20) was added dropwise via syringe over a period of 1 h.The reaction flask was then62equipped with a flame dried reflux condenser and glass stopper,and the resultingbrown/black solution was heated to 75 C for 16h. The solution was then allowedtocool to room temperature and a 1 M HC1 solution was added(5 mL) followed by Et20 (5mL). The solution was stirred for 5 mm then filteredthrough a plug of Celite. Theorganic layer was extracted with Et20 (3 x 8 mL),dried over Mg2SO4and concentratedunder reduced pressure. The residue was subjected to flashchromatography to afford theproduct as a clear, colorless oil (60 mg, 0.30 mmol, 43%). ‘H NMR (300 MHz, CDC13)6.7.32 - 7.24 (m, 2 H), 7.23 - 7.14 (m, 3 H), 5.93 (t, J4.1 Hz,1 H), 5.16 (s, 1 H), 4.74(s,1 H), 3.60 (s, 2 H), 2.26 - 2.18 (m, 2 H), 2.14 - 2.04 (m, 2 H), 1.73- 1.62 (m, 2 H), 1.61 -1.49 (m, 2 H). ‘3C{’H} NMR (CDC13,75 M1-Iz): 6 147.0,140.6, 135.5, 128.7, 128.2,125.7, 125.5, 111.4, 40.1, 26.0, 25.9, 22.9, 22.1. FIRMS(El) m/z calcd for C,5H,8:198.1409; found: 198.1409.Reaction of (151 with PhenyImanesinm Bromide(2011. 10 mol% NICI2(PPh3)15THF, 75°C, 16hI+ 2.IMHCI47%1MgBr302ONiC12(PPh3)(33 mg, 0.052 mmol) was weighed out using a spatula onto weighingpaperand added to a flame-dried 25 mL 2-neck round-bottom flask containing vinylsulfide 1563(95 mg, 0.52 mmol) and a magnetic stir bar. The round-bottom flask was sealed usingtwo rubber septa and flushed with N2 gas. THF (7.5 mL) was then added and the mixturewas stirred vigorously while phenylmagnesium bromide (2.2 mL of a 1.0 M solution inTHF) was added dropwise via syringe over a period of 1 h. The reaction flask was thenequipped with a flame dried reflux condenser and glass stopper, and the resultingbrown/black solution was heated to 75 °C for 16 h. The solution was then allowed tocool to room temperature and a 1 M HC1 solution was added (5 mE) followed by Et20 (5mE). The solution was stirred for 5 mm then filtered through a plug of Celite. Theorganic layer was extracted with Et20 (3 x 8 mL), dried over Mg2SO4and concentratedunder reduced pressure. The residue was subjected to flash chromatography to afford theproduct as a clear, colorless oil (45 mg, 0.24 mmol, 47 %). Characterization matchespreviously reported data.52 ‘H NMR (400 MHz, CDC13)6 7.37 - 7.21 (m, 5 H), 5.63 (t,J4.1 Hz, 1 H), 5.20 (s, 1 H), 4.98 (s, 1 H), 2.32 - 2.19 (m, 2 H), 2.17 - 2.04 (m, 2 H),1.80 - 1.67 (m, 2 H), 1.67 - 1.56 (m, 2 H). ‘3C{’H} NMR (CDC13,100 MHz): 6 151.7,142.1, 137.1, 129.0, 128.7, 127.8, 126.9, 110.9, 26.4, 25.9, 22.9, 22.2. FIRMS (El) mlzcalcd forC14H16:184.1252; found: 184.1251.64Reaction of (15 with Trimethylsily1methylmanesium Chloride (2flNiC12(PPh3)(26 mg, 0.04 1 mmol) was weighed out using a spatula onto weighing paperand added to a flame-dried 25 mL 2-neck round-bottom flask containing vinyl sulfide 15(75 mg, 0.41 mmol) and a magnetic stir bar. The round-bottom flask was sealed usingtwo rubber septa and flushed with N2 gas. THF (5.0 mL) was then added and the mixturewas stirred vigorously while trimethylsilylmethylmagnesium chloride (1.7 mL of a 1.0 Msolution in Et20) was added dropwise via syringe over a period of 1 h. The reaction flaskwas then equipped with a flame dried reflux condenser and glass stopper, and theresulting brown/black solution was heated to 75 °C for 16 h. The solution was thenallowed to cool to room temperature and a 1 M HC1 solution was added (5 mL) followedby Et20 (5 mL). The solution is stirred for 5 mm then filtered through a plug of Celite.The organic layer was extracted with Et20 (3 x 8 mL), dried over Mg2SO4 andconcentrated under reduced pressure. The residue was subjected to flash chromatographyto afford the product as a clear colorless oil (64 mg, 0.33 mmol, 81 %). ‘H NMR (300MHz, CDC13) 5.82 (t, J4.0 Hz., 1 H), 4.86 (s, 1 H), 4.62 (s, 1 H), 2.27 - 2.06 (m, 4 H),1.77 (s, 2 H), 1.73 - 1.52 (m, 4 H), 0.00 (s, 9 H). ‘3C{’H} NMR (CDC13,75 MHz):QZ1. 10 mol% NiCI2(PPh3)THF, 75°C, 16hMgCI2. 1M HCI81%213165ö 146.4, 136.6, 125.1, 106.7, 26.1, 25.9, 23.9, 23.1, 22.2, 1.2. HRMS (El) mlz calcd forC12H22Si: 194.1491; found: 194.1493.Reaction of (16) with Benzvlmanesium Chloride(19)161. 10 mol% N1CI2(PPh3)[ j+ THE, 75°C, 16h86%32MgCI19NiC12(PPh3)(31 mg, 0.062 mmol) was weighed out using a spatula onto weighingpaperand added to a flame-dried 25 mL 2-neck round-bottom flask containing vinyl sulfide 16(115 mg, 0.62 mmol) and a magnetic stir bar. The round-bottom flask was sealed usingtwo rubber septa and flushed with N2 gas. THF (7.0 mL) was then added and the solutionwas stirred vigorously while benzyhnagnesium chloride (2.5mL of a 1.0 M solution inEt20) was added dropwise via syringe over a period of 1 h. The reaction flask was thenequipped with a flame dried reflux condenser and glass stopper, and the resultingbrownlblack solution was heated to 75 C for 16 h. The solution was then allowed tocool to room temperature and a 1 M HC1 solution was added (5 mL) followed by Et20 (5mE). The solution is stirred for 5 mm then filtered through a plug of Celite. The organiclayer was extracted with Et20 (3 x 8 mL), dried over Mg2SO4and concentrated underreduced pressure. The residue was subjected to flash chromatography to afford theproduct as a clear colorless oil (56 mg, 0.32 mmol, 51 %). 1H NMR (300 MHz, CDC13)666 7.37 - 7.13 (m, 5 H), 4.83 (s, 1 H), 4.74(s, 1 H), 3.35 (s, 2 H), 1.98 (t,J=7.5 Hz, 2 H),1.53 - 1.38 (m, 2 H), 1.38 - 1.20(m, 6 H), 0.89 (t, J6.9 Hz,3 H). ‘3C{’H} NMR(CDCI3,175MHz): 6 149.3, 139.9, 129.0,128.2, 126.0, 110.9, 43.0,35.4, 31.7, 29.0,27.6, 22.6, 14.1. HRMS (El) mlz calcdforC15H22:202.1722;found: 202.1716.One-pot hydrothiolation/Kumada cross-couplingGeneral procedureTp*Rh(PPh3)2(25 mg, 0.027 mmol) was weighed out inthe glove box usinga spatulainto a 25 mL two-neck round bottom flaskequipped with a magnetic stirbar. THF (2.5mL) was then added by syringe, followedsequentially by n-propanethiol(90itL, 0.99mmol) and alkyne (0.9 mmol) via micropipette. Thereaction flask was then sealedwithrubber septa, removed from glove box andwrapped with foil. The solutionwas stirred atroom temperature for 2 h unless otherwisespecified. After 2 h the foil wasremoved anda solution ofNiC12(PPh3)(45 mg, 0.072 mmolin 10 mL of THF) wasadded by syringe.While the solution was vigorously stirred,a 1.0 M solution of Grignard reagent(3.6 mL,3.6 mmol) was added dropwise via syringe over1 h. The reaction flask wasthenequipped with a flame dried reflux condenser andglass stopper, and heatedto 75 °C for16 h. The solution was then allowed to cool toroom temperature and a 1 M HC1solution(4 mL) was added, followed by Et20 (4 mL). Afterstirring for 5 mm, the mixturewasfiltered through a plug of Celite. The organic layerwas extracted with Et20 (3 x5 mL).The combined organic extracts were dried over Mg2SO4for10 mm, filetered and thenconcentrated under reduced pressure. The residue wassubjected to flash chromatographyto afford the product. Yields given are isolated yields, unless otherwisespecified.673 mol%Tp*Rh(PPh3)2- sMgCI1 ,3,5-trimethoxybenzene+THF, rt, 2 h 8 mol% NiCI2(PPh3)THF, 75 °C, 16 h- 31%(overtwo steps)Tp*Rh(PPh3)2(27 mg, 0.029 mmol), n-propanetbiol (95jL, 1.05 mmol), alkyne (0.97mmol), NiC12(PPh3)(45 mg, 0.072 mmolin 10 mE of THF), Grignardreagent (3.9 mL,3.6 mmol), 1,3 ,5-trimethoxybenzene (53.2. mg, 0.316mmol). The yield for the abovereaction was determined by ‘H NMR spectroscopicanalysis using 1,3,5-trimethoxybenzene as an internal standard.-H3CO+HSTHF,rt,2hPhMgCI8 mol% NiCI2(PPh3)THF,75°C, 16h65% (over two steps)-MgBrH3CO3 mol%Tp*Rh(PPh)2______________________+THF, rt, 2 hHS8 mol% NICI2(PPh3)THF, 75°C, 16 h37%(over two steps)H3COHS’CH3iMgCIH3COr8 mol% NiCI2(PPh3)THF,75°C, 16h63% (over to steps)68a-__3 mol%Tp*Rh(PPh3)2—+THF, rt, 2 hHS-a______rs__-__Bra3 mol%Tp*Rh(pph3)2La-JTHF, 75 °C, 16 h+ THF,rt,2h8 mol% N1CI2(PPh3)HS30% (over o steps)8 mol% N1CI2(PPh3)THF75°C, 16h66% (over two steps)sidIMgCI3moI%Tp*Rh(pph3)2[a-jTHF,75°C, 16hTHF,rt,2h8 mol% NiCI2(PPh3)HS60% (over two steps)3 mol%+ Tp*Rh(PPh)2THF, rt, 16 hfMCI8 mol% N1CI2(PPh3)THF,75°C, 16h78% (over two steps)69Chapter 4— Summary, Conclusions and FutureWork4.1 SummaryIn this theses, we have shown a useful method for the synthesis of 1,1-disubstituted olefins from readily available terminal alkynes via hydrothiolation followedby nickel-catalyzed Kumada-type cross-coupling with various Grignard reagents. Whileour group previously reported the successful catalytic alkyne hydrothiolationof a varietyof alkynes (aryl and aliphatic) with a series of thiols (aryl and aliphatic) in the presence ofTp*Rh(PPh3)2,the use of n-propanethiol was limited to only one example. Theexpansion of previously established methodology was carried out using n-propanethiol ashydrothiolation substrate with a variety of alkynes to afford the corresponding vinylsulfides in moderate-to-high isolated yields.Vinyl sulfides derived from unsubstituted aryl alkynes or aryl alkynes containingan electron-donating substituent at the para position gave high isolated yields, whilevinyl sulfides derived from aryl alkynes containing an electron-withdrawing substituentat the para position showed a significant decrease in reactivity and yield. Aliphaticalkynes 6, 7 and 8 gave high isolated yields while alkyne 9 showed no reactivity to thehydrothiolation reaction. It should be noted that the vinyl sulfide products are relativelyunstable should be used immediately or stored in the freezer as a solution in petroleumether.The Kumada coupling of the isolated vinyl sulfides from the reaction of aryl andaliphatic alkynes, with various Grignard reagents were then investigated to explore the70feasibility of their use as substrates for 1,1 -disubstituted olefin synthesis. The cross-coupling of vinyl sulfides 10-17 with various Grignard reagents (19-24) was carried out,and it was found that 1,1 -disubstitued olefins can be afforded by the reaction of aryl oraliphatic Grignard reagents with alkyl or aryl vinyl sulfides. We also found that vinylsulfides derived from aryl alkynes containing an electron-donating substituent at the paraposition increased reactivity towards cross-coupling relative to the vinyl sulfide derivedfrom the unsubstituted aryl alkyne. In contrast, vinyl sulfides derived from aryl alkynescontaining an electron-withdrawing substituent at the para position had a significantdecrease in reactivity towards cross-coupling. Alkynylmagnesium halides, vinylmagnesium halides, or Grignard reagents that contain fi-hydrogens were found to beunproductive in the cross-coupling reaction in the presence of NiC12(PPh3).A one-potprotocol was also developed for the formation of 1,1-disubstituted olefins starting fromreadily available alkynes.4.2 Future WorkIn this thesis, the synthesis of a variety of 1,1 -disubstituted olefins was discussedinvolving catalytic alkyne hydrothiolation and subsequent nickel-catalyzed Kumadacross-coupling. The vinyl sulfides obtained from the hydrothiolation involving npropanethiol readily decompose at room temperature. Isolation and characterization ofthese decomposition products may be useful in further optimizing the hydrothiolationprocedure. 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A. unpublished results.79t tC.aC Ct tO. a-I C nCl) atft at t 3V3‘-0—a UI N CD _i0ac-fl- 00— 0 c-fl 000 C0—‘zo*00- -0000-__________________0 000 00--p 0•03—1 N C CM00 k)t30— 0 0-•03-nCi)C)0 0 N C) C)t t 3 ‘00- ‘3N 0GoP 00 0-- 0 a’ 0 0—P 0 0 c’) 0 0 0p 0N C) C-)5V V 300CT’— 0 0-- 0 CT’ 0 0--I—0- 030 -4 0 0) 0 CO 0 0 0 0 0 03C CCsC C N OC’)000- 0 CO--0 0--3-zC)O•J0C’,0 0 0-9.0ppm (fi)Appendix II: ‘H and ‘3C NMR Spectra for KumadaCross-Coupling Products8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0The spectrum above was taken from the crude product and contains the desired cross-coupling product as well as bibenzyl, toluene and tetrahydrofuran. The yield wasdetermined by ‘H NMR spectroscopic analysis using l,3,5-trimethoxybenzene as aninternal standard.25(300 MHz, CDC13,rt)iI87tV-VV33 _&iD__- N-n0-n- a 0-4 0 a-0o0Co CC0 p 0cm 0a 00“3 a,w 0 0 N C C‘43 a,0 00 —so9) 0 -4 0 9) 0 Co 0 0 C) 0 I’) 0 0 0 0t3C C NC C N00—4(0- 0 8 (0- 0 0-t V-3-t12N C)Ce C)aa0IV V330 ‘01%) CoU’ 0t t3—a N C C C1%) CDt 3D 0U’ 0 0a 0 0- 0 0’--0 0—0) 0 0 0 0 0p 0330 0 0 0 C;, 0 0t’JC;, 0 0 030 0 N n C)at3‘9 “3-


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