inorganics Article Metalation Studies on Titanocene Dithiolates Tilmann G. Kießling and Karlheinz Sünkel * ID Department of Chemistry, Ludwig-Maximilians University Munich, 81377 Munich, Germany; [email protected] * Correspondence: [email protected]; Tel.: +49-89-2180-77773 Received: 18 July 2018; Accepted: 22 August 2018; Published: 24 August 2018 Abstract: Titanocene bis-arylthiolates [(C5H4X)(C5H4Y)Ti(SC6H4R)2] (X,Y = H, Cl; R = H, Me) can be prepared from the corresponding titanocene dichlorides by reacting with the thiols in the presence of DABCO as a base. They react with n-butyl lithium to give unstable Ti(III) radical anions. While the unsubstituted thiolates (X = Y = R = H) react with lithium Di-isopropylamide by decomposing to dimeric fulvalene-bridged and thiolate-bridged Ti(III) compounds, the ring-chlorinated compounds can be deprotonated with LDA and give appropriate electrophiles di-substituted and tri-substituted titanocene dithiolates. Keywords: titanocene thiolates; metalation; chlorocyclopentadienyl ligands 1. Introduction Titanocene compounds, i.e., compounds of the type “Cp2TiXn” where “Cp” stands for a substituted or unsubstituted cyclopentadienyl ligand and “X” for any anionic or neutral ligand and n = 0–2 are arguably the second-most studied metallocenes after ferrocene. Soon after the first synthesis of (C5H5)2TiCl2 in 1954 [1], its potential for acting as a polymerization catalyst when combined with certain aluminum compounds was discovered [2]. Further studies showed that a judicious choice of substituents on the cyclopentadienyl ring had a great influence on the stereochemistry of the produced polymers, which gave rise to an enormous number of publications and also many review articles [3–8]. However, it was also found that the titanium catalysts were rather quickly deactivated and the corresponding zirconium compounds showed much higher stability and catalytic activity. Thus, the mainstream research on metallocene catalysts stopped for titanium-based metallocenes nearly completely until recently when the concepts of “Green Chemistry” and “Sustainable Catalysis” came into play [9–12]. Another area of “applied research” opened up after the discovery that Cp2TiCl2 showed antitumor activity [13–15]. Here again, it turned out that the effectiveness of the titanocenes could be enhanced by introducing substituents on the cyclopentadienyl rings [16,17] as well as by modifying the “X”-ligands [17,18]. Lastly, titanocenes were the subject of purely “academic” studies, e.g. studies devoted to synthesis, isolation, and characterization of the “true” titanocenes “Cp2Ti” [19] or of “chiral at titanium” complexes “CpCp’TiXY” [20]. In addition, in these studies, the importance of cyclopentadienyl ring substituents was well established. All of the titanocenes with substituted cyclopentadienyl rings known so-far have been prepared by a reaction of the substituted cyclopentadiene with TiCln (n = 2–4). This method fails for very electronegative substituents or substituents with ligating properties. Since our group focuses on the synthesis of Cyclopentadienyl complexes with such substituents for a long time, using an approach of performing halogen-metal exchange reactions followed by electrophilic substitutions on already coordinated perhalogenated cyclopentadienyl ligands [21], we wondered if our approach was also suitable for the titanocene system. Since our synthetic protocol always involves the use of lithium organyls or lithium amides, there was also the need for a proper titanocene starting material. It has been known for a long time that titanocene Inorganics 2018, 6, 85; doi:10.3390/inorganics6030085 www.mdpi.com/journal/inorganics Inorganics 2018, 6, 85 2 of 12 chloridesInorganics react 2018, with6, x FOR alkyl PEER lithiumsREVIEW to thermally unstable titanocene alkyls Cp2TiR2, which2 of 12 easily decompose to titanium(III) products [22,23] and with lithium amides to mono-cyclopentadienyl alkyl lithiums to thermally unstable titanocene alkyls Cp2TiR2, which easily decomposet to titanium tris-amides CpTi(NR2)3 [24]. In addition, with the often-used base KO Bu, a mixture of titanium(III) products [22,23] and with lithium amides to mono-cyclopentadienyl titanium products including those of splitting off the cyclopentadienyl ligands was observed [25]. We, therefore, tris-amides CpTi(NR2)3 [24]. In addition, with the often-used base KOtBu, a mixture of products decided to look at the also long-known titanocene thiolates Cp Ti(SR) . These compounds are usually including those of splitting off the cyclopentadienyl ligands2 was observed2 [25]. We, therefore, prepared either by a reaction of Cp TiCl with thiols in the presence of the base, which were sometimes decided to look at the also lo2ng-known2 titanocene thiolates Cp2Ti(SR)2. These compounds are contaminatedusually prepared with theeither mixed by a reaction chloride-thiolates of Cp2TiCl2 with Cp2 thiolsTi(SR)Cl in the [26 presence–28] or of by the oxidative base, which addition were of disulfidessometimes to in-situ contaminated prepared with “Cp the2Ti” mixed [29]. chloride-thiolates Some of these thiolatesCp2Ti(SR)Cl showed [26–28] promising or by oxidative antitumor propertiesaddition [30 of,31 disulfides]. to in-situ prepared “Cp2Ti” [29]. Some of these thiolates showed promising antitumorIn this study, properties we report [30,31]. on the synthesis of several titanocene bis(aryl thiolates) (Cp)(Cp’)Ti(SAr)2 and theirIn reactivitythis study, towards we report lithium on the alkyls synthesis and amidesof several including titanocene functionalization bis(aryl thiolates) of the cyclopentadienyl(Cp)(Cp’)Ti(SAr) rings.2 and It their should reactivity be mentioned towards lithium here that alkyls a related and amides approach including was used functionalization for deriving the so-calledof the “Troticenes” cyclopentadienyl CpTi(Cht) rings. [It32 should]. be mentioned here that a related approach was used for deriving the so-called “Troticenes” CpTi(Cht) [32]. 2. Results 2. Results 2.1. Synthesis of Starting Materials 2.1. Synthesis of Starting Materials Treatment of the known titanocene dichlorides (C5H4X)(C5H4Y)TiCl2 (X = Y = H, 1a; Treatment of the known titanocene dichlorides (C5H4X)(C5H4Y)TiCl2 (X = Y = H, 1a; X = H, Y = X = H, Y = Cl, 1b; X = Y = Cl, 1c)[33,34] with HS–C H R (R = H, p-Me) in the Cl, 1b; X = Y = Cl, 1c) [33,34] with HS–C6H4R (R = H, p-Me) 6in 4the presence of DABCO presence(1,4-diazabicyclo[2.2.2]octane) of DABCO (1,4-diazabicyclo[2.2.2]octane) yields the yieldscorresponding the corresponding titanocene titanocene arylthiolates arylthiolates (C5H(C4X)(C5H4X)(C5H45Y)Ti(S–CH4Y)Ti(S–C6H6H4R)4R)2 2(R (R == H, 2a–c,, Me: Me: 3a–c3a–c), ),respectively, respectively, in ingood good yields yields (64% (64% to 89% to89% except except for 3bfor, 19%) 3b, 19%) (Scheme (Scheme1). 1). SchemeScheme 1. 1.Synthesis Synthesis ofof substitutedsubstituted titanocene titanocene thiolates. thiolates. Compounds 2a and 3a had been reported before [26,27]. All compounds were characterized by 1CompoundsH-NMR and 132aC-NMRand 3a andhad mass been spectroscopy reported beforeincluding [26 ,HRMS.27]. All The compounds NMR spectra were of 3b/c characterized show the by 1 13 H-NMRpresence and of C-NMRHS–C6H4 andCH3 massor [S–C spectroscopy6H4–CH3]2 and including very weak HRMS. signals The (<2%) NMR derived spectra from of 3b/c 1b/cshow and the presence(C5H4 ofX)(C HS–C5H4Y)Ti(S–C6H4CH63Hor4R)Cl. [S–C 6H4–CH3]2 and very weak signals (<2%) derived from 1b/c and (C5H4X)(C5H4Y)Ti(S–C6H4R)Cl. 2.2. Reaction of Dithiolates 2a and 3a with Butyllithium 2.2. ReactionTreatment of Dithiolates of a suspension2a and 3a ofwith 2a or Butyllithium 3a with 1.1 equivalents of n-BuLi in THF at −78 °C results in theTreatment formation of aof suspension yellow solutions. of 2a or Warming3a with to 1.1 ro equivalentsom temperature of n-BuLi leads into THFa color at −change78 ◦C resultsfrom in the formationyellow to ofbrown yellow within solutions. five minutes. Warming The to resulting room temperature solutions appear leads to to be a colorparamagnetic change fromsince yellowit turns out impossible to obtain any good-quality 1H- or 13C-NMR spectra. However, the solutions to brown within five minutes. The resulting solutions appear to be paramagnetic since it turns out resulting from 2a show a 7Li-NMR resonance at δ = 2.64 ppm while the solutions resulting from 3a impossible to obtain any good-quality 1H- or 13C-NMR spectra. However, the solutions resulting exhibit a 7Li-NMR signal at δ = 2.74 ppm (Figures S5 and S6). For comparison, the 7Li-NMR signals of from 2a show a 7Li-NMR resonance at δ = 2.64 ppm while the solutions resulting from 3a exhibit a 7Li-NMR signal at δ = 2.74 ppm (Figures S5 and S6). For comparison, the 7Li-NMR signals of THF Inorganics 2018, 6, 85 3 of 12 solutionsInorganics of 2018 Li(C, 65, xH FOR5), PEER LiSC REVIEW6H5, and LiSC6H4CH3 can be found at δ = −8.37, 1.98, and3 1.90 of 12 ppm, respectively). Cooling these solutions down to −78 ◦C leads to a color change and it turns into a violet color.THF Warming solutions up of to Li(C room5H5), temperature LiSC6H5, and reinstatesLiSC6H4CH the3 can brown be found color at δ and = −8.37, evaporation 1.98, and 1.90 of the ppm, solvent respectively). Cooling these solutions down to −78 °C leads to a color change and it turns into a in vacuum leaves a brown residue, 2a0 or 3a0, respectively. When a frozen solution made up from 3a violet color. Warming up to room temperature reinstates the brown color and evaporation of the and four equivalents of butyl lithium in THF is gradually warmed up within a NMR spectrometer, solvent in vacuum leaves a brown residue, 2a′ or 3a′, respectively. When a frozen solution made up 1 ◦ a H-NMRfrom 3a spectrum and four immediately equivalents of taken butyl at lithium−80 C in shows THF nois gradually signals of warmed the Li–CH up 2withinprotons.