Dinuclear Gold Complexes Supported by Wide Bite Angle Diphosphines for Preorganization-Induced Selective Dual-Gold Catalysis

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Lankelma, M.; Vreeken, V.; Siegler, M.A.; van der Vlugt, J.I. DOI 10.3390/inorganics7030028 Publication date 2019 Document Version Final published version Published in Inorganics License CC BY Link to publication

Citation for published version (APA): Lankelma, M., Vreeken, V., Siegler, M. A., & van der Vlugt, J. I. (2019). Dinuclear Gold Complexes Supported by Wide Bite Angle Diphosphines for Preorganization-Induced Selective Dual-Gold Catalysis. Inorganics, 7(3), [28]. https://doi.org/10.3390/inorganics7030028

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Article Dinuclear Gold Complexes Supported by Wide Bite Angle Diphosphines for Preorganization-Induced Selective Dual-Gold Catalysis

Marianne Lankelma 1, Vincent Vreeken 1, Maxime A. Siegler 2 and Jarl Ivar van der Vlugt 1,* 1 Homogeneous, Supramolecular, and Bio-inspired Catalysis, van ’t Hoff Institute for Molecular Sciences, University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The Netherlands; [email protected] (M.L.); [email protected] (V.V.) 2 Small Molecule X-ray Laboratory, Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA; [email protected] * Correspondence: [email protected]; Tel.: +31-20-5256459

Received: 29 January 2019; Accepted: 20 February 2019; Published: 26 February 2019

Abstract: The synthesis, reactivity, and potential of well-defined dinuclear gold complexes as precursors for dual-gold catalysis is explored. Using the preorganizing abilities of well-known wide bite angle diphosphine ligands, DBFPhos and DPEPhos, dinuclear Au(I)–Au(I) complexes 1 and 2 are used as precursors to form well-defined monocationic species with either a chlorido- or acetylido-ligand bridging the two gold centers. These compounds are active catalysts for the dual-gold heterocycloaddition of a urea-functionalized alkyne, and the preorganization of both Au-centers affords efficient σ,π-activation of the substrate, even at high dilution, significantly outperforming benchmark mononuclear catalysts.

Keywords: dinuclear gold complex; wide bite-angle diphosphine ligand; dual-gold catalysis; bridging acetylide; σ,π-activation

1. Introduction Recently, the catalytic activation of substrates using two gold centers has proven to be a valuable strategy for a wide range of transformations in the broader context of gold-mediated catalysis [1–14]. Commonly, mono-gold catalysis relies on π-activation of a substrate (e.g., an alkene) by a cationic Au(I) center. Dual-gold catalysis, on the other hand, can lead to both σ- and π-activation (either of the same functional group within a substrate or of two separate functional groups) by two Au centers. The proximity of both Au-centers has occasionally been credited to enhance reactivity [15–17]. The prevailing strategy utilizes mononuclear Au(I) complexes to induce this mode of activation (Scheme1)[ 18]. However, this approach offers no handles to induce preorganization of both Au-centers to specifically target well-defined σ,π-activation of, for example, C–C multiple bonds whilst avoiding π- or simultaneous σ- and π-coordination (one mode per Au-center), nor does it provide any control over the selective binding of bifunctional substrates (e.g., for heterocyclizations). We have recently reported the catalytic competence of well-defined dinuclear σ,π-alkynide complexes in dual-gold catalysis, highlighting the importance of two preorganized Au centers with respect to regioselectivity and activity for intramolecular hydroamination [19,20]. This was achieved using the ditopic tridentate ligand PNHPiPr (2,20-bis(diisopropylphosphino)-4,40-ditolylamine) (Figure1). However, under certain (catalytically relevant) conditions, the redox-active nature of this scaffold induced significant structural rearrangement of the ligand backbone, giving rise to a carbazolyl-based derivative. In order to eliminate such ligand-centered chemistry leading to structural reorganization, and to exploit more readily available diphosphine ligands, we investigated wide bite angle diphosphine ligands with

Inorganics 2019, 7, 28; doi:10.3390/inorganics7030028 www.mdpi.com/journal/inorganics Inorganics 2019, 7, 28 2 of 13

Inorganics 2018, 6, x 2 of 13 ether backbonesInorganics [21 2018–,29 6, x]. Basic coordination chemistry of these potentially dinucleating2 of 13 ligands diphosphine ligands with ether backbones [21–29]. Basic coordination chemistry of these potentially towarddinucleating golddiphosphine has alreadyligands ligands beentoward with established ethergold backbones has byalready [21–29]. several Basicbeen groups coordination established [30– chemistry32 ].by Furthermore, several of these potentiallygroups Koshevoy [30–32]. et al. dinucleating ligands toward gold has already been established by several groups [30–32]. investigatedFurthermore, the formation Koshevoy and et al. photochemical investigated the properties formation of and bis-gold photochemical complexes properties with the of related bis-gold ligand Furthermore, Koshevoy et al. investigated the formation and photochemical properties of bis-gold Xantphoscomplexes [33complexes–38 with]. the with related the related ligand ligand Xantphos Xantphos [33–38]. [33–38].

redox-activeredox-active

N reactive H N reactive P H P P P highly selective PreviousP work P P+ P [Au] Au highlydual-gold selective Previous work [Au]+ Au dual-goldcatalysis R catalysis σ, π O R P P σ, π O Current work P P Figure 1. Left:Figure Strategy 1. Left: for Strategy the preorganization for the preorganization of two gold-centersof two gold-centers for σ for–π -coordinationσ–π-coordination ofofhydrocarbon Current work π-systems usinghydrocarbon a diphosphine π-systems using platform. a diphosphine Right: platform. previous Right: and previous current and work current on work bis-gold on bis-gold chemistry with chemistry with specific diphosphine ligands. speciﬁcFigure diphosphine 1. Left: Strategy ligands. for the preorganization of two gold-centers for σ–π-coordination of hydrocarbonWe herein π-systems report using on the a formation diphosphine of μ -chloridoplatform. and Right: σ,π-alkynide previous derivatives and current of workAu2Cl on2(κ2 bis-gold-P;P- Wechemistry hereinDBFPhos) with report and specific Au2 onCl 2diphosphine(κ2 the-P;P-DPEPhos) formation ligands. and catalytic of µ activity-chlorido of these and well-definedσ,π-alkynide dinuclear species derivatives of 2 vs. mononuclear benchmarks in the intramolecular2 hydroamidation of functionalized amido-alkenes. Au2Cl2(κ -P;P-DBFPhos) and Au2Cl2(κ -P;P-DPEPhos) and catalytic activity of these well-deﬁned This study emphasizes the positive effect of preorganization of two gold centers for reactions that We herein report on the formation of μ-chlorido and σ,π-alkynide derivatives of Au2Cl2(κ2-P;P- dinuclear speciesproceed vs. via mononuclear simultaneous σ-benchmarks and π-activation in of the a carbon-based intramolecular π-system hydroamidation in a substrate. This ofeffect functionalized DBFPhos) and Au2Cl2(κ2-P;P-DPEPhos) and catalytic activity of these well-defined dinuclear species amido-alkenes.is illustrated This study via a dilution emphasizes study with the mono- positive and di-nuclear effect ofcatalysts. preorganization of two gold centers for vs. mononuclear benchmarks in the intramolecular hydroamidation of functionalized amido-alkenes. reactions that proceed via simultaneous σ- and π-activation of a carbon-based π-system in a substrate. This study2. Results emphasizes and Discussion the positive effect of preorganization of two gold centers for reactions that This effect is illustrated via a dilution study with mono- and di-nuclear catalysts. proceed via simultaneousThe straightforward σ- and reaction π-activation of L1 (DBFPhos) of a carbon-basedand L2 (DPEPhos) π -systemwith AuCl(SMe in a substrate.2) in a 1:2 ratio This effect is illustratedprovided via awhite dilution solids study 1 (31P NMR:with δmono- 23.3) and and 2 (di-nuclear31P NMR: δ 21.6).catalysts. The respective 1H NMR spectra 2. Results andwere Discussion suggestive of C2 symmetric species (Scheme 1). Single crystals suitable for X-ray structure 2. Resultsdetermination and Discussion of 2 were obtained by slow vapor diffusion of acetone into a solution of 2 in CHCl3 The straightforward(Figure 2), while for reaction 1 only a ofconnectivityL1 (DBFPhos) plot could and be reliablyL2 (DPEPhos) obtained (from with single AuCl(SMe crystals grown2) in a 1:2 ratio 31 31 1 10 providedThe whitefrom straightforward solidsCH2Cl2–pentane;1 ( P reaction NMR: see Section δof23.3) L1 3, materials(DBFPhos) and 2 and( andmethods).P NMR: L2 (DPEPhos) Complexδ 21.6). 2 displays Thewith respectiveAuCl(SMe an aurophilic2) inH d a NMR– 1:2 ratio spectra d10 interaction [39–41] with an intramolecular Au1···Au2 distance of 3.0116(4) Å, while in 1 this wereprovided suggestive white of solidsC2 symmetric 1 (31P NMR: species δ 23.3) (Schemeand 2 (31P1 ).NMR: Single δ 21.6). crystals The respective suitable for1H NMR X-ray spectra structure Au···Au distance was approximately 7.57 Å. It should be noted that these structures complement were suggestive of C2 symmetric species (Scheme 1). Single crystals suitable for X-ray structure determinationknown of 2 oneswere for both obtained compounds, by slow with different vapor (a diffusionmounts and/or of acetonecombinations into of) a lattice solution solvents of 2 in CHCl3 (Figuredetermination2), whilepresent for of[30,31]. 12 onlywere aobtained connectivity by slow plot vapor could diffusion be reliably of acetone obtained into (froma solution single of 2 crystals in CHCl grown3 (Figure 2), while for 1 only a connectivity plot could be reliably obtained (from single crystals grown from CH2Cl2–pentane; see Section3, materials and methods). ComplexX 2 displaysX an aurophilic from CH2Cl2–pentane; see Section 3, materials and methods). Complex 2 displays an aurophilic d10– d10–d10 interaction [39–41] with an intramolecular Au1···Au2 distance of 3.0116(4) Å, while in 1 this d10 interaction [39–41] with an intramolecular Au1···Au2 distanceO of 3.0116(4) Å,O while in 1 this Ph2P PPh2 Ph2P PPh2 Au···Au distance was approximatelyCl Au O 7.57 Å. It should be noted thatMeCCMgBr these structures complement Au···Au distanceO was approximatelyPPh2 7.57PPh 2Å. It should beAu notedAu that these structuresAu Au complement Ph2P PPh2 Au THF known ones for both compounds, withCl different (amountsCl and/or combinations of) lattice solvents known onesL1 for (DBFPhos) both compounds, with differentAgX (amounts and/or combinations-78 oC to r.t. of) lattice solvents 1 3 Me 2 equiv. AuCl(SMe2) (X = SbF6, PF6 or NTf2) presentpresent [30,31 [30,31].]. 5 CH Cl CH Cl 2 2 2 2 X X X O O O Ph P PPh Ph P PPh Ph2P PPh2 2 2 2 2 Au Au Au AuO O L2 (DPEPhos) Ph P PPh Ph P PPh Cl Cl 2 Cl 2 2 2 Cl Au O MeCCMgBr O PPh2 2 PPh2 Au4 Au Au Au Ph2P PPh2 Au THF Cl Cl L1 (DBFPhos) AgX -78 oC to r.t. 1 3 Me 2 equiv. AuCl(SMe2) (X = SbF6, PF6 or NTf2) 5 CH Cl CH Cl 2 2 2 2 X

O O O Ph P PPh Ph P PPh Ph2P PPh2 2 2 2 2 Au Au Au Au L2 (DPEPhos) Cl Cl Cl 2 4

Scheme 1. Synthesis of well-deﬁned Au2-complexes 3–5 from Au(I)–Au(I) precursors 1 and 2, generated by reaction of ligands L1 and L2 with 2 equivalent of AuCl(SMe2). Inorganics 2018, 6, x 3 of 13

InorganicsScheme 2018, 61., x Synthesis of well-defined Au2-complexes 3–5 from Au(I)–Au(I) precursors 1 and 23, of 13

generated by reaction of ligands L1 and L2 with 2 equivalent of AuCl(SMe2). Scheme 1. Synthesis of well-defined Au2-complexes 3–5 from Au(I)–Au(I) precursors 1 and 2, Inorganics 2019, 7, 28 3 of 13 generated by reaction of ligands L1 and L2 with 2 equivalent of AuCl(SMe2).

Figure 2. Displacement ellipsoid plots (50% probability level) of 2. The disordered mixture of lattice

FigureCHCl3 2.andDisplacement acetone molecules ellipsoid inplots the asymmetric (50% probability unit, level)as well of as2. Thethe disorderedhydrogen atoms, mixture have of lattice been omittedFigure 2. for Displacement clarity. Selected ellipsoid bond plots lengths (50% (Å) probability and angles level) (°): Au1–P1 of 2. The 2.2393(17); disordered Au2–P2 mixture 2.2441(18); of lattice CHCl3 and acetone molecules in the asymmetric unit, as well as the hydrogen atoms, have been omitted CHCl3 and acetone molecules in the asymmetric unit, as well as the hydrogen atoms, have been forAu1–Cl11 clarity. Selected2.3122(15); bond Au2–Cl2 lengths 2.3419(15); (Å) and angles Au1···Au2 (◦): Au1–P1 3.0116(4); 2.2393(17); P1–Au1–Cl1 Au2–P2 168.48(6); 2.2441(18); P2–Au2–Cl2 Au1–Cl11 omitted for clarity. Selected bond lengths (Å) and angles (°): Au1–P1 2.2393(17); Au2–P2 2.2441(18); 2.3122(15);173.97(7). Au2–Cl2 2.3419(15); Au1···Au2 3.0116(4); P1–Au1–Cl1 168.48(6); P2–Au2–Cl2 173.97(7). Au1–Cl11 2.3122(15); Au2–Cl2 2.3419(15); Au1···Au2 3.0116(4); P1–Au1–Cl1 168.48(6); P2–Au2–Cl2 When173.97(7). exploiting a gold-halide precursor for gold-mediatedgold-mediated catalysis, a prerequisite is the generation ofof aa vacantvacant coordinationcoordination site site via via halide halide abstraction. abstraction. Addition Addition of of one one equivalent equivalent of AgNTfof AgNTf2 or2 When exploiting a gold-halide precursor for gold-mediated catalysis, a prerequisite is the relatedor related silver silver salts salts such such as AgSbF as AgSbF6 or AgPF6 or 6AgPFto 1 or6 to2 led1 or to 2 new led speciesto new 3speciesand 4, respectively,3 and 4, respectively, according generation of31 a vacant coordination site via halide abstraction. Addition of one equivalent of AgNTf2 toaccording31P NMR to spectroscopy,P NMR spectroscopy, with signals with at signalsδ 15.6 at and δ 15.6 20.1 and ppm, 20.1 respectively. ppm, respectively. The relatively The relatively large or related silver salts such31 as AgSbF6 or AgPF6 to 1 or 2 led to new species 3 and 4, respectively, differencelarge difference in the 31inP the chemical P chemical shifts observed shifts observed for 1 and for3 may 1 and be related 3 may to be significant related to reorientation significant according to 31P NMR spectroscopy, with signals at δ 15.6 and 20.1 ppm, respectively. The relatively ofreorientation the phosphorus of the atoms phosphorus upon formation atoms upon of formation the single halideof the single bridgehead. halide bridgehead. Single crystals Single suitable crystals for large difference in the 31P chemical shifts observed for 1 and 3 may be related to significant X-raysuitable structure for X-ray determination structure determination were obtained were by obtained layer-diffusion by layer-diffusion of pentane into of pentane a CH2Cl into2 solution a CH2Cl of2 reorientation of the phosphorus atoms upon formation of the single halide bridgehead. Single crystals complexsolution of3. complex The resulting 3. The molecular resulting structure molecular (Figure structure3) shows (Figure that 3) bothshows gold that centers both gold were centers bridged were by suitable for X-ray structure determination were obtained by∠ layer-diffusion◦ of pentane into a CH2Cl2 abridged single chloridoby a single ligand, chlorido leading ligand, to an acuteleading∠Au1–Cl1–Au2 to an acute ofAu1–Cl1–Au2 78.79(7) . Relative of 78.79(7)°. to “open” Relative complex to solution of complex 3. The resulting molecular structure (Figure 3) shows that both gold centers were 1“open”, the intramolecular complex 1, the Au intramolecular···Au distance Au···Au in 3 was distance significantly in 3 was decreased significantly (∆d ± 4.58decreased Å) due (Δ tod increased± 4.58 Å) bridged by a single chlorido ligand, leading to an acute ∠Au1–Cl1–Au2 of 78.79(7)°. Relative to directionaldue to increased positioning directional of the positioning phosphorus of the lone phos pairs,phorus despite lone the pairs, large despite natural the bite large angle. natural To bite the “open” complex 1, the intramolecular Au···Au distance in 3 was significantly decreased (Δd ± 4.58 Å)I bestangle. of To our the knowledge, best of our theknowledge, existence the of existenc a singlee chloridoof a single bridgehead chlorido bridgehead between two between AuI centers two Au is due to increased directional positioning of the phosphorus lone pairs, despite the large natural bite relativelycenters is relatively rare [42–48 rare]. Notably,[42–48]. Notably, this is only this theis only second the examplesecond example of an intramolecular of an intramolecular Au–Cl–Au Au– angle. To the best of our knowledge, the existence of a single chlorido bridgehead between two AuI bridgeCl–Au stabilizedbridge stabilized by a single by a dinucleating single dinucleating ligand, theligand, first beingthe first our being work our with work the ligandwith thePN ligandHPiPr. centersH iPr is relatively rare [42–48]. Notably, this is only the second example of an intramolecular Au– AttemptsPN P . Attempts to characterize to characterize complex 4 complexvia X-ray 4 crystallography via X-ray crystallography unfortunately unfortunately failed, but spectroscopic failed, but Cl–Au bridge stabilized by a single dinucleating ligand,2 the first being2 + our work with+ the ligand dataspectroscopic support formulationdata support of formulation this species of as this [Au 2species(µ-Cl)( κas- [AuP,P-DPEPhos)]2(μ-Cl)(κ -P,P. -DPEPhos)] . PNHPiPr. Attempts to characterize complex 4 via X-ray crystallography unfortunately failed, but spectroscopic data support formulation of this species as [Au2(μ-Cl)(κ2-P,P-DPEPhos)]+.

Figure 3. Displacement ellipsoid plot (50% probability level) of one of the two crystallographicallycrystallographically

independent cationic parts ofof 33.. The SbFSbF6 counterioncounterion and and hydrogen hydrogen at atomsoms have been omitted for clarity.Figure Selected3. Displacement bond lengths ellipsoid (Å) andplotangles (50% probability (◦) (only given level) for of the one Au1–Au2 of the two cationic crystallographically part): Au1–P1A

2.236(2);independent Au1–Cl1A cationic 2.353(2); parts Au1of 3.··· TheAu2 SbF 2.9871(5);6 counterion P1A–Au1–Cl1A and hydrogen 172.20(8); atoms P2A–Au2–Cl1A have been omitted 174.13(9); for Au1–Cl1A–Au2 78.79(7). Inorganics 2018, 6, x 4 of 13

clarity. Selected bond lengths (Å) and angles (°) (only given for the Au1–Au2 cationic part): Au1–P1A 2.236(2); Au1–Cl1A 2.353(2); Au1···Au2 2.9871(5); P1A–Au1–Cl1A 172.20(8); P2A–Au2–Cl1A Inorganics 2019, 7, 28 4 of 13 174.13(9); Au1–Cl1A–Au2 78.79(7).

ComplexComplex 33 waswas amenable amenable to toreaction reaction with with 1-propynylmagnesium 1-propynylmagnesium bromide, bromide, forming forming σ,π- coordinatedσ,π-coordinated alkynide-bridging alkynide-bridging complex complex 5, akin5, akin to our to previous our previous report report using using the PN theHPNPiPrH scaffold.PiPr scaffold. The 31TheP NMR31P NMRspectrum spectrum of 5 displayed of 5 displayed a singlet a singletat 23.8 atppm 23.8 and ppm the andelemental the elemental composition composition as [Au2(μ as- 2 2 + + CCMe)([Au2(µ-CCMe)(κ -P,P-DBFPhos)]κ -P,P-DBFPhos)] was corroboratedwas corroborated by high-resolut by high-resolutionion electron electron spray ionization spray ionization mass spectrometrymass spectrometry (ESI-MS). (ESI-MS). X-ray structure X-ray structure determination determination of a minute of aamount minute of amountadventitious of adventitious crystalline materialcrystalline obtained material from obtained cyclopentane-CHCl from cyclopentane-CHCl3 showed direct3 showed evidence direct of evidence the dual of interaction the dual interaction of the – Cof≡CMe the –Cligand≡CMe with ligand both withgold centers both gold (i.e., centersσ-coordination (i.e., σ-coordination of the terminal of C37 the carbon terminal to Au2 C37 and carbon π- coordinationto Au2 and πof-coordination the triple bond of to the Au1; triple Figure bond 4). To to Au1;the best Figure of our4). knowledge, To the best this of is our only knowledge, the second crystallographically-characterizedthis is only the second crystallographically-characterized intramolecular Au2(σ intramolecular,π-acetylide) complex Au2(σ,π -acetylide)supported complex by a diphosphinesupported by ligand, a diphosphine and an illustration ligand, and that anpreorganization illustration that of two preorganization gold centers may of two lead gold to selective centers σmay,π-coordination lead to selective of theσ,π -coordinationalkyne moiety. of theComplex alkyne 4 moiety. is envisioned Complex to4 isinitially envisioned react to with initially 1- propynylmagnesiumreact with 1-propynylmagnesium bromide in a bromidesimilar fashion in a similar to provide fashion putative to provide complex putative 6, postulated complex as6 , 2 2 + + [Aupostulated2(μ-CCMe)( as [Auκ -P2(,Pµ-DPEPhos)]-CCMe)(κ -P. ,PHowever,-DPEPhos)] this. However,species and this analogues species and generated analogues by generatedusing 4- ethynyl-by usingα, 4-ethynyl-α,α-trifluorotolueneα,α,α-triﬂuorotoluene proved to be proved highly to sens be highlyitive to sensitive water, toprecluding water, precluding its spectral its characterization.spectral characterization.

2 + FigureFigure 4. 4. DisplacementDisplacement ellipsoid ellipsoid plot plot (50% (50% probability probability level) for 5, [Au [Au2((μµ-CCMe)(-CCMe)(κ2--PP,,PP-DBFPhos)]-DBFPhos)]+. .

TwoTwo lattice cyclopentane so solventlvent molecules, the SbF 6 counterioncounterion and and hydrogen hydrogen atoms, atoms, except except for for those those ◦ onon C39, have beenbeen omittedomitted for for clarity. clarity. Selected Selected bond bond lengths lengths (Å) (Å) and and angles angles ( ): (°): P1–Au P1–Au 2.243(2); 2.243(2); P2–Au2 P2– Au22.267(2); 2.267(2); Au1–Ct(C37–C38) Au1–Ct(C37–C38) 2.236; 2.236; Au2–C37 Au2–C37 2.055(9); 2.055(9) C37–C38; C37–C38 1.18(1); 1.18(1); C38–C39 C38–C391.45(1); 1.45(1); Au1Au1···Au2···Au2 2.9951(8);2.9951(8); P1–Au1–Ct(C37–C38) P1–Au1–Ct(C37–C38) 175.09; 175.09; P2 P2–Au2–C37–Au2–C37 170.4(2); C37–C38–C39 169.3(10). ≡ HavingHaving established established that that ligands ligands L1 andL1 andL2 canL2 facilitatecan facilitate pre-activation pre-activation of C≡C ofbonds C Cin a bonds σ,π- σ π fashion,in a , we-fashion, wondered we about wondered their activity about in their the heterocyclization activity in the heterocyclization (intramolecular hydroamination) (intramolecular ofhydroamination) urea-functionalized of urea-functionalized alkyne A. Previously, alkyne ParadiesA. Previously, and co-workers Paradies compared and co-workers AuCl(Xantphos), compared AuCl(Xantphos), Au Cl (Xantphos), and AuCl(PPh ) for the intermolecular hydroamidation of Au2Cl2(Xantphos), and2 AuCl(PPh2 3) for the intermolecular3 hydroamidation of cyclohexene (and analogscyclohexene thereof) (and and analogs toluene thereof)sulfonamide and in toluene the presence sulfonamide of stoichiometric in the presence amounts of of stoichiometric silver salts as amounts of silver salts as halide abstracting agents [17]. This study concluded that [Au (Xantphos)]2+ halide abstracting agents [17]. This study concluded that [Au2(Xantphos)]2+ and the corresponding2 and the corresponding species [Au (Xantphos) ]2+, which forms from the former, were both species [Au2(Xantphos)2]2+, which forms2 from the former,2 were both catalytically inactive. catalyticallyWe were inactive. curious whether dinuclear σ,π-activation could result in anti-Markovnikov σ π hydroamidationWe were curiousof substrate whether A (Scheme dinuclear 2). This ,reaction-activation was pr couldeviously result reported in anti-Markovnikov by Medio-Simón andhydroamidation co-workers to of form substrate five-memberedA (Scheme 2indole). This B reaction via σ,π was-activation, previously using reported two equivalents by Medio-Sim of theón and co-workers to form ﬁve-membered indole B via σ,π-activation, using two equivalents of the mononuclear gold complex AuCl(PtBu3) as the best catalyst [49]. Using 2.5 mol % of either dihalide mononuclear gold complex AuCl(PtBu ) as the best catalyst [49]. Using 2.5 mol % of either dihalide precursors 1 or 2 with two equiv. of AgSbF3 6, or species 3 or 4 with one equiv. of AgSbF6, in N,N’-DMF 0 atprecursors 60 °C for1 5or h 2ledwith to full two conver equiv.sion of AgSbF and high6, or speciesregioselectivity3 or 4 with to oneB (95–100%), equiv. of AgSbFas determined6, in N,N by-DMF 1H at 60 ◦C for 5 h led to full conversion and high regioselectivity to B (95–100%), as determined 1 by H NMR spectroscopy, in accordance with a selective σ,π-acetylide mechanism. All four Au2 InorganicsInorganics 20192018,, 76,, 28x 55 of 1313

NMR spectroscopy, in accordance with a selective σ,π-acetylide mechanism. All four Au2 systems t systemsoutperformed outperformed the mononuclear the mononuclear benchmark benchmark AuCl(PtBu AuCl(P3) in the Bupresence3) in the of presenceone equiv. of of one AgSbF equiv.6 (80% of Inorganics 2018, 6, x 5 of 13 AgSbFB). When6 (80% no AgSbFB). When6 was no added, AgSbF significantly6 was added, lower significantly regioselec lowertivity regioselectivity and conversion and was conversion observed was for observedeach NMRsystem, for spectroscopy, each presumably system, in accordance presumably due to withslower due a toselective slowergeneration σ generation,π-acetylide of the ofmechanism. theσ,πσ-acetylide,π-acetylide All four species. species.Au2 systems The The high regioselectivityregioselectivityoutperformed achievedachieved the mononuclear withwith thesethese benchmark dinuclear AuCl(P catalystscatalytBusts3) isin attributedthe presence to of the one ligand-enforced equiv. of AgSbF6 proximity(80% of thetheB ). twotwo When Au(I)Au(I) no AgSbF centers.centers.6 was High added, resoluti resolution significantlyon mass lower spectra regioselec of 1:1 tivity mixtures and conversion of 3 or was 4 (with(with observed oror withoutwithoutfor additionaleach system, AgSbFAgSbF 66)presumably and substrate due A ,to measured measured slower generation ten minutes minutes of after afterthe dissolution dissolutionσ,π-acetylide of species.the the two two solidsThe solids high in in DMF, DMF, suggestedsuggestedregioselectivity formationformation achieved ofof σσ,,ππ-complexes -complexeswith these dinuclear withwith formalformal cataly lossstsloss is of ofattributed HCl.HCl. to the ligand-enforced proximity of the two Au(I) centers. High resolution mass spectra of 1:1 mixtures of 3 or 4 (with or without additional AgSbF6) and substrate A, measured ten minutes after dissolution of the two solids in DMF, suggested formation of σ,π-complexes with formal loss of HCl. σ,π-activation π Ph N O -activation N Ph O σ,π-activation N N π NPh O PhHN N H O H -activation NH Ph B O NA N N CO PhHN H H H Scheme 2.2. HeterocyclizationHeterocyclization ofof 1-(ethynylphenyl)urea1-(ethynylphenyl)urea( A(A)) to to either either anti-Markovnikov anti-Markovnikov product product (B B) oror B A C Markovnikov additionaddition productproduct (CC.). Scheme 2. Heterocyclization of 1-(ethynylphenyl)urea (A) to either anti-Markovnikov product B or We hypothesizedMarkovnikov addition that the product high C local. concentration of gold(I) centers provided by these dinuclear We hypothesized that the high local concentration of gold(I) centers provided by these dinuclear gold complexes should render the regioselectivity of the complexes independent of the catalyst gold complexes should render the regioselectivity of the complexes independent of the catalyst loading [50We,51 hypothesized]. Dilution studiesthat the tohigh investigate local concentration the effect of of gold(I) decreased centers catalyst provided loadings by these ondinuclear the level of loadinggold [50,51]. complexes Dilution should studies render to the investigate regioselectivity the effect of the of decreasedcomplexes catalystindependent loadings of the on catalyst the level of regiocontrol for the conversion of A to B and C clearly validated this hypothesis, as the consistently regiocontrolloading [50,51]. for the Dilution conversion studies of toA investigateto B and C the clearly effect ofvalidated decreased this catalyst hypothesis, loadings as on the the consistentlylevel of high regioselectivity to B with catalyst 4 in the presence of one equivalent of AgSbF6 was not dependent high regiocontrolregioselectivity for the to conversion B with catalystof A to B 4and in C the clearly presence validated of thisone hypothesis, equivalent as ofthe AgSbF consistently6 was not on the concentration of gold centers (ranging from 5 to 0.5 mol %) (Figure5). In contrast, dilution high regioselectivity to B with catalyst 4 in the presence of one equivalent of AgSbF6 was not dependent on the concentration of gold centerst (ranging from 5 to 0.5 mol %) (Figure 5). In contrast, experiments with mononuclear AuCl(P Bu3) in the presence of an equimolar amount of AgSbF6 dilutiondependent experiments on the concentration with mononuclear of gold centers AuCl(P (rangitBu3ng) in from the 5 presenceto 0.5 mol of%) an(Figure equimolar 5). In contrast, amount of resulteddilution in a experiments sharp drop wi inth selectivity, mononuclear particularly AuCl(PtBu3) below in the 1presence mol % of an catalyst equimolar loading, amount to aroundof AgSbF6 resulted in a sharp drop in selectivity, particularly below 1 mol % of catalyst loading, to 40% yieldAgSbF of6 resultedB [52]. Thesein a sharp results drop demonstrate in selectivity, the particularly benefits ofbelow well-defined 1 mol % of pre-organization catalyst loading, to of two around 40% yield of B [52]. These results demonstrate the benefits of well-defined pre-organization goldaround centers 40% to enforce yield ofselective B [52]. Theseσ,π-activation results demonstrate and to mediate the bene regioselectivefits of well-defined dual-gold pre-organization catalysis with of two gold centers to enforce selective σ,π-activation and to mediate regioselective dual-gold functionalizedof two gold alkynes, centers evento enforce at low selective catalyst σ loadings.,π-activation and to mediate regioselective dual-gold catalysiscatalysis with with functionalized functionalized alkynes, alkynes, even even atat low catalystcatalyst loadings. loadings.

100 100 90 90

80 80

70 70 60 60 50 [(DPEPhos)Au2][(SbF6)2][Au2(DPEPhos)](SbF6)2 50 [(DPEPhos)Au2][(SbF6)2][Au2(DPEPhos)](SbF6)2 40

40 product B % 30 [P(tBu)3Au][SbF6][Au(PtBu)3]SbF6 % product B % 30 [P(tBu)3Au][SbF6][Au(PtBu)3]SbF6 20

20 10

10 0 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 0 mol % Au-centers with respect to substrate 0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5

mol % Au-centers with respect to substrate Figure 5. Comparison of regioselectivity to indole B under various dilution conditions, obtained with t dinuclear catalyst 4 in the presence of one equiv. of AgSbF6 vs. mononuclear benchmark AuCl(P Bu3) with one equiv. AgSbF6.

Inorganics 2018, 6, x 6 of 13 Inorganics 2019, 7, 28 6 of 13 Figure 5. Comparison of regioselectivity to indole B under various dilution conditions, obtained with dinuclear catalyst 4 in the presence of one equiv. of AgSbF6 vs. mononuclear benchmark AuCl(PtBu3) Encouragedwith one equiv. by this AgSbF proof-of-concept6. demonstration of ligand-induced preorganization of two gold centers for dual-gold catalysis, we explored the structurally related substrate D featuring Encouraged by this proof-of-concept demonstration of ligand-induced preorganization of two an additional methylene unit between the phenyl ring and the urea fragment (Scheme3, gold centers for dual-gold catalysis, we explored the structurally related substrate D featuring an reaction I). This substrate was quantitatively converted via selective 6–endo-dig cyclization additional methylene unit between the phenyl ring and the urea fragment (Scheme 3, reaction I). This to yieldsubstrate product was quantitativelyE when using converted pre-activated via selective dinuclear 6–endo-dig catalystcyclization3 toor yield4 in product the presenceE when of AgSbFusing6. Substrate pre-activatedF, thedinuclear thiourea-derivative catalyst 3 or 4 in of the substrate presenceA of, didAgSbF not6. Substrate provide F the, the corresponding thiourea- N-phenyl-1derivativeH-indole-1-carbothioamide. of substrate A, did not provide Instead, the corresponding product G Nwas-phenyl-1 selectivelyH-indole-1-carbothioamide. obtained via 6-exo -dig cyclizationInstead, (Scheme product 3G, reactionwas selectively II), which obtained is in via line 6-exo with-dig observationscyclization (Scheme by Shi 3, reaction et al., who II), which speculated is on σ,πin-activation line with observations of a propargylic by Shi et thiourea al., who andspeculated subsequent on σ,πN-activation-attack to of obtain a propargylic the same thiourea type and of cyclic subsequent N-attack to obtain the same type of cyclic 6-membered compound [53]. Finally, unlike the 6-membered compound [53]. Finally, unlike the complex [Au2(BIPHEP)](NTf2)2 [54], which despite its dinuclearcomplex nature [Au cannot2(BIPHEP)](NTf accommodate2)2 [54],σ which,π-coordination despite its becausedinuclear of nature steric constraints,cannot accommodate digold complexes σ,π- coordination because of steric constraints, digold complexes 3 and 4 do not dimerize 2-ethynylaniline 3 and 4 do not dimerize 2-ethynylaniline but rather induced selective cyclization to form indole H but rather induced selective cyclization to form indole H (Scheme 3, reaction III), suggesting that σ,π- σ π (Schemecoordination3, reaction of III),one suggesting molecule of that 2-ethynylani, -coordinationline was ofenergetically one molecule more of favorable 2-ethynylaniline than σ- was energeticallycoordination more of favorabletwo molecules than ofσ 2-ethynylaniline-coordination of with two wide molecules bite angle of diphosphine 2-ethynylaniline frameworks with wide that bite angledo diphosphine allow bridging frameworks ligation of acetylenic that do allow substrates. bridging ligation of acetylenic substrates.

SchemeScheme 3. Other 3. catalyticOther catalytic reactions reactions with complexes with complexes3 and 4 with 3 (thio)urea-containingand 4 with (thio)urea-containing phenylacetylenic substratesphenylacetylenicD, F, and 2-ethynylaniline substrates D, F, and to support 2-ethynylaniline the σ,π-activation to support ofthe acetylenic σ,π-activation substrates. of acetylenic substrates. 3. Materials and Methods 3. Materials and Methods 3.1. General Comments

3.1.t General Comments P( Bu)3AuCl, AgSbF6, AgNTf2, and 1-propynylmagnesium bromide (0.5 M in THF) were purchasedP(t fromBu)3AuCl, commercial AgSbF6, AgNTf suppliers2, and and 1-propynylmagnesium used without further bromide purification. (0.5 M in THF) Compound were A purchased from commercial suppliers and used without further purification. Compound A was was prepared according to a literature procedure [49]. AuCl(SMe2) was either purchased from prepared according to a literature procedure [49]. AuCl(SMe2) was either purchased from Sigma Sigma Aldrich (St. Louis, MO, USA) or synthesized by reacting HAuCl4.3H2O with an excess of dimethylsulfide in ethanol at room temperature for ten minutes. 1-Propynylmagnesium bromide was titrated in triplo with I2/LiCl in THF. Tetrahydrofuran and pentane were distilled from sodium benzophenone ketyl. Dichloromethane was distilled from CaH2. All reactions were carried out in flame-dried or oven-dried glassware under a nitrogen atmosphere, unless otherwise stated. Flash column chromatography was performed with silica gel (Screening Devices, 60Å, particle size Inorganics 2019, 7, 28 7 of 13

0.040–0.063 µm). Eluent mixtures are reported as v/v %. Products were visualized by UV light. NMR spectra (1H, 31P{1H}, 13C{1H}) were measured at room temperature on Bruker DRX 500, AV 400, DRX 300 and AV 300 instruments (Bruker, Billerica, MA, USA) and referenced against SiMe4, external H3PO4 or solvent. NMR chemical shifts are reported in ppm, coupling constants (J) are reported in Hertz. High resolution mass spectra were recorded on a JEOL AccuTOF LC JMS-T100LP mass spectrometer (JEOL, Tokyo, Japan) using electron spray ionization (ESI) or ﬁeld desorption (FD). GC-MS spectra were recorded on an Agilent 5973 Network Mass Selective Detector (Agilent, Santa Clara, CA, USA) equipped with a 6890N Network GC System.

3.2. Syntheses of New Complexes

Complex 1, Au2Cl2(DBFPhos). DBFPhos (1 equiv.) and AuCl(SMe2) (2 equiv.) were dissolved in CH2Cl2 and stirred at room temperature for a couple of hours, depending on the scale. The resultant white suspension was concentrated to ca. 0.5 mL. Pentane (20 mL) was added, leading to formation of a white precipitate. The suspension was stirred vigorously for 5 min, after which the precipitate was allowed to settle. The colorless supernatant was removed and the residue was dried under vacuum, yielding 1 as a white solid in quantitative yield. Single crystals suitable for X-ray diffraction were obtained by layering ca. 1.5 mL of pentane on top of a solution of ca. 4 mg of complex 1 in ca. 0.3 mL of 31 1 1 CH2Cl2 in a 2 mL vial. P{ H} NMR (202 MHz, CD2Cl2, ppm): δ 23.3 (s). H NMR (500 MHz, CD2Cl2, ppm): δ 8.23 (d, J = 7.7 Hz, 2H), 7.56–7.51 (m, 12H), 7.48–7.42 (m, 10H), 7.15 (dd, J = 13.4, 7.6 Hz, 2H). 13 1 C{ H} NMR (126 MHz, CD2Cl2, ppm): δ 156.5 (d, J = 4.2 Hz), 134.3 (d, J = 14.6 Hz), 133.1 (d, J = 7.4 Hz), 132.5 (s), 129.4 (d, J = 12.3 Hz), 127.8 (s), 127.3 (s), 124.8 (br. s), 124.4 (d, J = 5.5 Hz), 124.2 (d, J = 9.5 + Hz). HR-MS (ESI) calcd. for [M − Cl] C36H26Au2ClOP2 m/z: 965.0478, found 965.0463.

Complex 2, Au2Cl2(DPEPhos). DPEPhos (1 equiv.) and AuCl(SMe2) (2 equiv.) were dissolved in CH2Cl2 and stirred at room temperature for several hours. The resultant white suspension was concentrated to ca. 0.5 mL. Pentane (20 mL) was added, leading to formation of a white precipitate. The resultant suspension was stirred vigorously for 5 min, after which the precipitate was allowed to settle. The colorless supernatant was removed and the white residue was dried under vacuum, yielding 2 as a white solid in yields around 75%. Single crystals suitable for X-ray diffraction (transparent needles) were obtained by slow vapor diffusion of acetone into a solution of complex 2 in CHCl3. 31 1 1 P{ H} NMR (162 MHz, CD2Cl2, ppm): δ 21.6 (s). H NMR (400 MHz, CD2Cl2, ppm): δ 7.61–7.27 (m, 18H), 7.24–7.12 (m, 6H), 7.05 (dd, J = 8.3, 5.3 Hz, 2H), 6.83-6.69 (m, 2H). 13C{1H} NMR (101 MHz, CD2Cl2, ppm): δ 134.9 (d, J = 14.4 Hz), 134.1 (d, J = 5.3 Hz), 138.9, 133.4 (d, J = 14.0 Hz), 132.0 (d, J = 2.3 Hz), 131.2 (d, J = 2.7 Hz), 129.6 (d, J = 12.3 Hz), 129.2 (d, J = 12.1 Hz), 124.8 (d, J = 9.1 Hz), 120.0 (d, + J = 4.9 Hz). HR-MS (ESI) calcd. for [M − Cl] C36H28Au2ClOP2 m/z: 967.0635, found 967.0604.

Complex 3, [Au2(µ-Cl)(DBFPhos)](X). Inside a nitrogen-filled glovebox, AgSbF6 or AgNTf2 (1 equiv.) was added to complex 1 (1 mol. equiv.) and the reaction vessel was covered in aluminum foil. In air, the mixture was suspended in CH2Cl2 or THF and the suspension was stirred for several hours. The reaction mixture was filtered over 2–3 cm of Celite on top of a frit filter, and the filtrate was evaporated until dry to yield complex 3 as a white solid. Colorless single crystals suitable for X-ray diffraction of the triflimide derivative were obtained by layering ca. 1.5 mL of pentane on top of 31 1 a solution of ca. 4 mg of complex 3 in ca. 0.5 mL of CH2Cl2 in an NMR-tube. P{ H} NMR (121 MHz, 1 CD2Cl2, ppm): δ 15.6 (s). H NMR (300 MHz, CD2Cl2, ppm): δ 8.36 (d, J = 7.8 Hz, 2H), 7.65–7.30 (m, 13 1 22H), 7.02 (dd, J = 12.5, 7.6 Hz, 2H). C{ H} NMR (75 MHz, CD2Cl2, ppm): δ 157.1 (d, J = 5.8 Hz), 134.2 (d, J = 14.3 Hz), 133.6 (d, J = 2.5 Hz), 131.9 (s), 130.1 (d, J = 12.8 Hz), 126.3 (s), 125.2 (d, J = 8.7 Hz), 124.7 (d, J = 5.4 Hz), 124.3 (s), 122.4 (s), 118.1 (s), 113.9 (s), 112.3 (s), 111.5 (s). HR-MS (ESI) calcd. for + [M] C36H26Au2ClOP2 m/z: 965.0478, found 965.0497.

Complex 4 [Au2(µ-Cl)(DPEPhos)](SbF6). Inside a glovebox, AgSbF6 (or a related Ag-salt; 1 mol. equiv.) was added to complex 2 and the reaction vessel was covered in aluminum foil. In air, the mixture was suspended in CH2Cl2 or THF and the suspension was stirred for a couple of hours. Inorganics 2019, 7, 28 8 of 13

The reaction mixture was filtered over ca. 1 cm of Celite on top of a frit filter and the filtrate was evaporated until dry to yield complex 4 as a white solid (average yield 81%). All attempts to grow 31 1 1 single crystals of complex 4 failed. P{ H} NMR (121 MHz, CD2Cl2, ppm): δ 20.1 (s). H NMR (300 MHz, CD2Cl2, ppm): δ 7.66–7.35 (m, 24H), 7.13 (t, J = 7.6 Hz, 2H), 6.83 (ddd, J = 12.7, 7.8, 1.4 Hz, 13 1 2H). C{ H} NMR (75 MHz, CD2Cl2, ppm): δ 160.1 (d, J = 1.5 Hz), 152.2 (d, J = 6.9 Hz), 136.9, 136.3 (d, J = 2.2 Hz), 136.0, 134.4, 133.0, 132.0 (d, J = 2.8 Hz), 131.5 (d, J = 9.3 Hz), 129.6, 128.8 (d, J = 11.7 Hz), + 128.1, 121.2 (d, J = 2.5 Hz), 120.9 (d, J = 3.8 Hz). HR-MS (ESI) calcd. for [M] C36H28Au2ClOP2 m/z: 967.0635, found 967.0664.

Complex 5, [Au2(µ-propynyl)(DBFPhos)](SbF6). Complex 3SbF6 was dissolved in THF and the Schlenk was covered in aluminum foil. At −78 ◦C, a 0.5 M solution of 1-propynylmagnesium bromide in THF (1 equiv.) was added and the resultant orange solution was stirred for ca. 15 min at −78 ◦C followed by 5 h at room temperature. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and the product was extracted three times into CH2Cl2. The aqueous layer was extracted two times with CH2Cl2. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. Sonication with toluene was then performed for 30 min, followed by ﬁltration over paper, and concentration of the ﬁltrate afforded 5 as a white solid. Single crystals (tiny transparent needles) suitable for X-ray diffraction were obtained by layering ca. 1.5 mL of cyclopentane on top of a solution of ca. 4 mg of complex 5 (in its orange form) in ca. 0.3 mL of 31 1 + CHCl3 in a 2 mL vial. P{ H} NMR (162 MHz, CD2Cl2, ppm): δ 23.8 (s). HR-MS (ESI) calcd. for [M] C39H29Au2OP2 m/z: 969.1025, found 969.1513 for the crude solid.

3.3. General Information on Catalytic Studies Synthesis of Substrate D. A solution of (2-ethynylphenyl)methanamine, prepared following a literature procedure [55], (0.84 g, 6.40 mmol) in CH2Cl2 (16 mL) was added to phenyl isocyanate (695 µL, 6.40 mmol). The resultant red suspension was “stirred” for ca. 1.5 h (formation of a solid soon impeded stirring) before being added to a second batch of phenyl isocyanate (695 µL, 6.40 mmol) and stirred for ca. 16 h. The resultant brown suspension was concentrated, impregnated on silica, and puriﬁed by column chromatography (ca. 30 cm of silica gel, Ø NS 29/32, hexane/ethyl acetate 3:1) 1 to yield D as a beige solid (0.92 g, 57% yield). H NMR (300 MHz, acetone-d6, ppm): δ 8.11 (br s, 1H), 7.54–7.08 (m, 8H), 6.91 (t, J = 7.0 Hz, 1H), 6.25 (br s, 1H), 4.58 (d, J = 5.9 Hz, 2H), 3.94 (s, 1H). HR-MS (ESI) calcd. for [M + H]+ [C16H14N2O + H]+ m/z: 251.1184, found 251.1199.

Synthesis of Substrate F. To CH2Cl2 (2 mL) was added 2-ethynylaniline (142 µL, 1.25 mmol) and phenyl isothiocyanate (150 µL, 1.25 mmol). The mixture was stirred for 30 min at room temperature and then heated to reflux for 4 h. The solution was allowed to cool down to room temperature and all volatiles were removed, yielding a light orange solid that was dried under vacuum. The crude product was impregnated on silica and purified by column chromatography (ca. 28 cm of silica gel, Ø NS 29/32, hexane/ethyl acetate 3:1, Rf 0.38) to yield substrate F (202 mg, 64%). 1H NMR (300 MHz, CDCl3, ppm): δ 8.55 (d, J = 8.3 Hz, 1H), 8.30 (br s, 1H), 7.91 (br s, 1H), 7.57–7.35 (m, 7H), 7.12 (t, J = 7.2 Hz, 1H), 3.09 (s, 1H). HR-MS (FD) calcd. for [M]+ C15H12N2S m/z: 252.0721, found 252.0718. General Procedure for Catalytic Studies with Substrates A, D and F. An oven-dried 4 mL vial was charged with the substrate (50 µmol) and a digold complex (2.5 mol %; 1.25 µmol). The solids were 0 ◦ dissolved in anhydrous N,N -DMF (0.5 mL) and stirred in air at 60 C for 5 h. If AgSbF6 was added, this was done either by addition of the dry solid inside a nitrogen-filled glovebox or by addition of 0 a stock solution of AgSbF6 in N,N -DMF. The reaction mixture was transferred to a round-bottom flask with CH2Cl2 or CHCl3 and all solvent was evaporated under reduced pressure. NMR spectra were recorded in CDCl3 or acetone-d6. General Procedure for Dilution Studies. The general procedure for catalysis was applied in seven experiments, each comprising a different catalyst loading. For the dilution studies on Inorganics 2019, 7, 28 9 of 13

[Au2(DPEPhos)](SbF6)2, 4 and AgSbF6 were each added in 2.5 mol %, 1.25 mol %, 0.835 mol %, t 0.5 mol %, 0.4165 mol %, 0.3125 mol %, or 0.25 mol %. For the dilution studies on [AuP( Bu)3]SbF6, t AuClP( Bu)3 and AgSbF6 were each added in 5 mol %, 2.5 mol %, 1.67 mol %, 1 mol %, 0.833 mol %, 0.625 mol %, and 0.5 mol %. The catalyst concentration was; thus, lowered by adding less catalyst whilst keeping the solvent volume 0.5 mL and the amount of substrate 50 µmol (11.8 mg). Stirring and heating to 60 ◦C; however, was done for 20 h instead of 5 h to obtain sufﬁcient conversion in the experiments with very low catalyst concentrations.

3.4. Single Crystal X-ray Crystallography Complex 5. X-ray intensities were measured on a Bruker D8 Quest Eco diffractometer equipped with a Triumph monochromator (λ = 0.71073 Å) and a CMOS Photon 50 detector at a temperature of 150(2) K. Intensity data were integrated with the Bruker APEX2 software [56]. Absorption correction and scaling was performed with SADABS [57]. The structures were solved using intrinsic phasing with the program SHELXT [56]. Least-squares refinement was performed with SHELXL-2013 [58] against F2 of all reflections. Non-hydrogen atoms were refined with anisotropic displacement parameters. The H atoms were placed at calculated positions using the instructions AFIX 13, AFIX 43, or AFIX 137, with isotropic displacement parameters having values 1.2 or 1.5 times Ueq of the attached C atoms. C39H29OP2Au2SbF6, Fw = 1205.28, colorless block, 0.364 × 0.115 × 0.095 mm, monoclinic, P21/c (No: ◦ 3 14)), a = 13.9459(8), b = 31.1012(19), c = 10.9557(7) Å, β = 105.449(2) , V = 4580.2(5) Å , Z = 4, Dx = 1.951 3 −1 g/cm , µ = 7.107 mm . A total of 25854 reflections were measured up to a resolution of (sin θ/λ)max −1 = 0.84 Å . A total of 8204 reflections were unique (Rint = 0.0557), of which 6409 were observed [I > 2σ(I)]. A total of 526 parameters were refined with 0 restraints. R1/wR2 [I > 2σ(I)]: 0.0439/0.0993. R1/wR2 [all refl.]: 0.0682/0.1135. S = 1.125. Residual electron density between −1.313 and 1.141 e/Å3. Complexes 2 and 3. All reflection intensities were measured at 110(2) K using a SuperNova diffractometer (equipped with Atlas detector) with Cu Kα radiation (λ = 1.54178 Å) under the program CrysAlisPro (Version 1.171.37.35 Agilent Technologies, 2014). The same program was used to refine the cell dimensions and for data reduction. The structure was solved with the program SHELXS-2014/7 (Sheldrick, 2015) and was refined on F2 with SHELXL-2014/7 (Sheldrick, 2015). Analytical numeric absorption correction, using a multifaceted crystal model, was applied using CrysAlisPro. The temperature of the data collection was controlled using the system Cryojet (manufactured by Oxford Instruments). The H atoms were placed at calculated positions using the instructions AFIX 13, AFIX 43, or AFIX 137, with isotropic displacement parameters having values 1.2 or 1.5 times Ueq of the attached C atoms. 2: The structure was partly disordered. The asymmetric unit contained a disordered mixture of lattice solvent molecule (CHCl3 and Acetone) at one site. The occupancy factors for the chloroform and acetone molecules were refined to 0.279(3) and 0.721(3), respectively. The crystal that was mounted on the diffractometer was twinned. The two twin components were related by a twofold axis along the reciprocal vector 0.9040a* − 0.0000b* − 0.4276c*. The BASF scale factor was refined to 0.3272(7). 3: The structure was ordered. The crystal that was mounted on the diffractometer was twinned. The two twin components were related by a twofold axis along the reciprocal vector 0.0001a* + 0.0004b* + 1.0000c*. The BASF scale factor was refined to 0.4368(7). CCDC 1893603 (5), 1894224 (2), and 1894225 (3) contain the supplementary crystallographic data for this paper (see Supplementary Materials). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

4. Conclusions In summary, we demonstrate that the wide bite-angle diphosphine ligands, DBFPhos and DPEPhos, provide good platforms for the formation of catalytically relevant bis-gold complexes, featuring a bridging halide or alkynide ligand upon selective halide abstraction and follow-up Inorganics 2019, 7, 28 10 of 13 manipulation. Preorganization of both gold centers allows for selective σ,π-activation of functionalized alkynes. The well-deﬁned dinuclear AuI complexes are excellent precatalysts for dual-gold catalysis involving selective σ,π-activation, inducing high regioselectivity in, for instance, the gold-catalyzed heterocyclization of urea A. Dilution experiments show that the dinuclear catalysts retain high selectivity at decreased catalyst loadings, unlike mononuclear Au(I) catalysts, which are typically employed for this reaction. These results underline the beneﬁts of preorganization of gold centers to invoke selective substrate activation in dual-gold catalysis.

Supplementary Materials: The following are available online at http://www.mdpi.com/2304-6740/7/3/28/s1, 31 1 1 Figure S1: P{ H} NMR spectrum of complex 1 (CD2Cl2, 298 K, 162 MHz), Figure S2: H NMR spectrum of 13 1 complex 1 (CD2Cl2, 298 K, 500 MHz), Figure S3: C{ H} NMR spectrum of complex 1 (CD2Cl2, 298 K, 126 MHz), 31 1 Figure4: Connectivity plot of complex 1, Figure S5: P{ H} NMR spectrum of complex 2 (CD2Cl2, 298 K, 1 13 1 162 MHz), Figure S6: H NMR spectrum of complex 2 (CD2Cl2, 298 K, 500 MHz), Figure S7: C{ H} NMR 31 1 spectrum of complex 2 (CD2Cl2, 298 K, 126 MHz), Figure S8: P{ H} NMR spectrum of complex 3 (CD2Cl2, 298 K, 1 13 1 162 MHz), Figure S9: H NMR spectrum of complex 3 (CD2Cl2, 298 K, 500 MHz), Figure S10: C{ H} NMR 31 1 spectrum of complex 3 (CD2Cl2, 298 K, 126 MHz), Figure S11: P{ H} NMR spectrum of complex 4 (CD2Cl2, 1 13 1 298 K, 162 MHz), Figure S12: H NMR spectrum of complex 4 (CD2Cl2, 298 K, 500 MHz), Figure S13: C{ H} 31 1 NMR spectrum of complex 4 (CD2Cl2, 298 K, 126 MHz), Figure S14: P{ H} NMR spectrum of complex 5 (CD2Cl2, 1 298 K, 162 MHz), Figure S15: H NMR spectrum of product B (98%) and C (2%) (CDCl3, 298 K, 400 MHz), obtained 1 by using complex 1 and two equivalents AgSbF6, Figure S16: H NMR spectrum of product B (100%) (CDCl3, 298 1 K, 400 MHz), obtained by using complex 2 and two equivalents AgSbF6, Figure S17: H NMR spectrum of product B (97%) and C (3%) (CDCl3, 298 K, 400 MHz), obtained by using complex 3 and one equivalent AgSbF6, Figure 1 S18: H NMR spectrum of product B (95%) and C (5%) (CDCl3, 298 K, 400 MHz), obtained by using complex 4 1 and one equivalent AgSbF6, Figure S19: H NMR spectrum of substrate D (acetone-d6, 298 K, 300 MHz), Figure 1 1 S20: H NMR spectrum of product E (acetone-d6, 298 K, 300 MHz), Figure S21: H NMR spectrum of substrate 1 F (CDCl3, 298 K, 300 MHz), Figure S22: H NMR spectrum of product G (CDCl3, 298 K, 300 MHz); CIF and checkCIF data for complexes 2, 3, and 5. Author Contributions: Conceptualization, J.I.v.d.V.; funding acquisition, J.I.v.d.V.; investigation, M.L., V.V., and M.A.S.; supervision, J.I.v.d.V.; writing—original draft, M.L. and J.I.v.d.V. Funding: This research was funded by the European Research Council (ERC) through Starting Grant 279097 (EuReCat) to J.I.v.d.V. Acknowledgments: The authors thank Joost Reek for his interest in our work and Ed Zuidinga for ESI-MS measurements. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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