Catalyst-Controlled Intermolecular Homobenzylic C(sp3)-H Amination for the Synthesis of ß-Arylethylamines.

The combination of a tailored sulfamate with a C4-symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp3)-H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to ß-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh2]-nitrene and the C-H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket.

Gold-Catalyzed Heck Reaction.

Herein, we report a gold-catalyzed Heck reaction facilitated by the ligand-enabled Au(I)/Au(III) redox catalysis. The elementary organometallic steps such as migratory insertion and ß-hydride elimination have been realized in the catalytic fashion for the first time in gold chemistry. The present methodology not only overcomes the limitations of previously known transition metal-catalyzed Heck reactions such as the requirement of specialized substrates and formation of a mixture of regioisomeric products as a result of the undesirable chain-walking process but also offers complementary regioselectivity as compared to other transition metal catalysis.

Mechanism of Alkyne Hydroarylation Catalyzed by (P,C)-Cyclometalated Au(III) Complexes.

Over the last 5-10 years, gold(III) catalysis has developed rapidly. It often shows complementary if not unique features compared to gold(I) catalysis. While recent work has enabled major synthetic progress in terms of scope and efficiency, very little is yet known about the mechanism of Au(III)-catalyzed transformations and the relevant key intermediates have rarely been authenticated. Here, we report a detailed experimental/computational mechanistic study of the recently reported intermolecular hydroarylation of alkynes catalyzed by (P,C)-cyclometalated Au(III) complexes. The cationic (P,C)Au(OAcF)+ complex (OAcF = OCOCF3) was authenticated by mass spectrometry (MS) in the gas phase and multi-nuclear NMR spectroscopy in solution at low temperatures. According to density functional theory (DFT) calculations, the OAcF moiety is κ2-coordinated to gold in the ground state, but the corresponding κ1-forms featuring a vacant coordination site sit only slightly higher in energy. Side-on coordination of the alkyne to Au(III) then promotes nucleophilic addition of the arene. The energy profiles for the reaction between trimethoxybenzene (TMB) and diphenylacetylene (DPA) were computed by DFT. The activation barrier is significantly lower for the outer-sphere pathway than for the alternative inner-sphere mechanism involving C-H activation of the arene followed by migratory insertion. The π-complex of DPA was characterized by MS. An unprecedented σ-arene Au(III) complex with TMB was also authenticated both in the gas phase and in solution. The cationic complexes [(P,C)Au(OAcF)]+ and [(P,C)Au(OAcF)(σ-TMB)]+ stand as active species and off-cycle resting state during catalysis, respectively. This study provides a rational basis for the further development of Au(III) catalysis based on π-activation.

Template Synthesis of NPN' Pincer-type Ligands at Titanium Using an Ambiphilic Phosphide Scaffold.

Ti-imido complex [TiCl(NtBu)(BIPP)] [1; BIPP = bis(iminophosphoranyl)phosphide ligand] reacts with terminal alkynes R-C≡CH (R = phenyl, isopropenyl, cyclopropyl, and 2-pyridyl) via P-P bond cleavage of the BIPP ligand. The resulting complexes [TiCl(NPN')(NPhPPh2)] (2a-d) contain a pincer-type NPN' phosphide ligand that incorporates the terminal alkyne and the imido ligand from complex 1. Complexes 2a-d feature two chiral centers (Ti and P) with interdependent absolute configurations; thus, they are formed stereoselectively. Complex 2a (R = phenyl) undergoes chloride abstraction with [Et3SiHSiEt3][B(C6F5)4], yielding [Ti(NPN')(NPhPPh2)][B(C6F5)4] (3). Complex 3 is a moderately active and stereoselective initiator for the ring-opening polymerization of rac-lactide. Complex 3 activates the C═O bond of 4-iodobenzaldehyde to give complex 4 as a single diastereomer despite the presence of three chiral centers. Complex 3 undergoes transmetallation with SbCl3, yielding [Sb(NPN')][B(C6F5)4] (5) and [TiCl3(NPhPPh2)] (6) selectively. The bonding situation in 3 and 5 was analyzed using Bader's atoms in molecules and the electron localization function, showing that the nitrogen atoms of the NPN' ligand are electronically similar, and that the metal-phosphide interaction is more polar in the case of titanium.

Coordinatively Unsaturated Amidotitanocene Cations with Inverted σ and π Bond Strengths: Controlled Release of Aminyl Radicals and Hydrogenation/Dehydrogenation Catalysis.

Cationic amidotitanocene complexes [Cp2 Ti(NPhAr)][B(C6 F5 )4 ] (Cp=η5 -C5 H5 ; Ar=phenyl (1 a), p-tolyl (1 b), p-anisyl (1 c)) were isolated. The bonding situation was studied by DFT (Density Functional Theory) using EDA-NOCV (Energy Decomposition Analysis with Natural Orbitals for Chemical Valence). The polar Ti-N bond in 1 a-c features an unusual inversion of σ and π bond strengths responsible for the balance between stability and reactivity in these coordinatively unsaturated species. In solution, 1 a-c undergo photolytic Ti-N cleavage to release Ti(III) species and aminyl radicals ⋅NPhAr. Reaction of 1 b with H3 BNHMe2 results in fast homolytic Ti-N cleavage to give [Cp2 Ti(H3 BNHMe2 )][B(C6 F5 )4 ] (3). 1 a-c are highly active precatalysts in olefin hydrogenation and silanes/amines cross-dehydrogenative coupling, whilst 3 efficiently catalyzes amine-borane dehydrogenation. The mechanism of olefin hydrogenation was studied by DFT and the cooperative H2 activation key step was disclosed using the Activation Strain Model (ASM).

Nucleophilic Addition to π-Allyl Gold(III) Complexes: Evidence for Direct and Undirect Paths.

π-Allyl complexes play a prominent role in organometallic chemistry and have attracted considerable attention, in particular the π-allyl Pd(II) complexes which are key intermediates in the Tsuji-Trost allylic substitution reaction. Despite the huge interest in π-complexes of gold, π-allyl Au(III) complexes were only authenticated very recently. Herein, we report the reactivity of (P,C)-cyclometalated Au(III) π-allyl complexes toward ß-diketo enolates. Behind an apparently trivial outcome, i.e. the formation of the corresponding allylation products, meticulous NMR studies combined with DFT calculations revealed a complex and rich mechanistic picture. Nucleophilic attack can occur at the central and terminal positions of the π-allyl as well as the metal itself. All paths are observed and are actually competitive, whereas addition to the terminal positions largely prevails for Pd(II). Auracyclobutanes and π-alkene Au(I) complexes were authenticated spectroscopically and crystallographically, and Au(III) σ-allyl complexes were unambiguously characterized by multinuclear NMR spectroscopy. Nucleophilic additions to the central position of the π-allyl and to gold are reversible. Over time, the auracyclobutanes and the Au(III) σ-allyl complexes evolve into the π-alkene Au(I) complexes and release the C-allylation products. The relevance of auracyclobutanes in gold-mediated cyclopropanation was demonstrated by inducing C-C coupling with iodine. The molecular orbitals of the π-allyl Au(III) complexes were analyzed in-depth, and the reaction profiles for the addition of ß-diketo enolates were thoroughly studied by DFT. Special attention was devoted to the regioselectivity of the nucleophilic attack, but C-C coupling to give the allylation products was also considered to give a complete picture of the reaction progress.

C-H Bond Arylation of Pyrazoles at the ß-Position: General Conditions and Computational Elucidation for a High Regioselectivity.

Direct arylation of most five-membered ring heterocycles are generally easily accessible and strongly favored at the α-position using classical palladium-catalysis. Conversely, regioselective functionalization of such heterocycles at the concurrent ß-position remains currently very challenging. Herein, we report general conditions for regioselective direct arylation at the ß-position of pyrazoles, while C-H α-position is free. By using aryl bromides as the aryl source and a judicious choice of solvent, the arylation reaction of variously N-substituted pyrazoles simply proceeds via ß-C-H bond functionalization. The ß-regioselectivity is promoted by a ligand-free palladium catalyst and a simple base without oxidant or further additive, and tolerates a variety of substituents on the bromoarene. DFT calculations revealed that a protic solvent such as 2-ethoxyethan-1-ol significantly enhances the acidity of the proton at ß-position of the pyrazoles and thus favors this direct ß-C-H bond arylation. This selective pyrazoles ß-C-H bond arylation was successfully applied for the straightforward building of π-extended poly(hetero)aromatic structures via further Pd-catalyzed combined α-C-H intermolecular and intramolecular C-H bond arylation in an overall highly atom-economical process.

Cu-Catalyzed P-C bond formation/cleavage: straightforward synthesis/ring-expansion of strained cyclic phosphoniums.

Upon reaction with copper(i), peri-halo naphthyl phosphines readily form peri-bridged naphthyl phosphonium salts. The reaction works with alkyl, aryl and amino substituents at phosphorus, with iodine, bromine and chlorine as a halogen. It proceeds under mild conditions and is quantitative, despite the strain associated with the resulting 4-membered ring structure and the naphthalene framework. The transformation is amenable to catalysis. Under optimized conditions, the peri-iodo naphthyl phosphine 1-I is converted into the corresponding peri-bridged naphthyl phosphonium salt 2b in only 5 minutes at room temperature using 1 mol% of CuI. Based on DFT calculations, the reaction is proposed to involve a Cu(i)/Cu(iii) cycle made of P-coordination, C-X oxidative addition and P-C reductive elimination. This copper-catalyzed route gives a general and efficient access to peri-bridged naphthyl phosphonium salts for the first time. Reactivity studies could thus be initiated and the possibility to insert gold into the strained P-C bond was demonstrated. It leads to (P,C)-cyclometallated gold(iii) complexes. According to experimental observations and DFT calculations, two mechanistic pathways are operating: (i) direct oxidative addition of the strained P-C bond to gold,(ii) backward-formation of the peri-halo naphthyl phosphine (by C-P oxidative addition to copper followed by C-X reductive elimination), copper to gold exchange and oxidative addition of the C-X bond to gold. Detailed analysis of the reaction profiles computed theoretically gives more insight into the influence of the nature of the solvent and halogen atom, and provides rationale for the very different behaviour of copper and gold in this chemistry.

Gold(I) Complexes Nuclearity in Constrained Ferrocenyl Diphosphines: Dramatic Effect in Gold-Catalyzed Enyne Cycloisomerization.

Di-tert-butylated-bis(phosphino)ferrocene ligands bearing phosphino substituents R (R=phenyl, cyclohexyl, iso-propyl, mesityl, or furyl) allow tuning the selective formation of Au(I) halide complexes. Thus, dinuclear linear two-coordinate, but also rare mononuclear trigonal three-coordinate and tetrahedral four-coordinate complexes were formed upon tuning of the conditions. Both Au(I) chloride and rarer Au(I) iodide complexes were synthesized, and their X-ray diffraction analysis are reported. The significance of the control of structure and nuclearity in Au(I) complexes is further illustrated herein by its strong effect on the efficiency and selectivity of gold-catalysed cycloisomerization. Cationic linear digold(I) bis(dicyclohexylphosphino) ferrocenes outperform other catalysts in the demanding regioselective cycloisomerization of enyne sulphonamides into cyclohexadienes. Conversely, tetrahedral and trigonal cationic monogold(I) complexes were found incompetent for enyne cycloaddition. We used the two-coordinate linear electron-rich Au(I) complex 2 b (R=Cy) to extend the scope of selective intramolecular cycloaddition of different 1,6-enyne sulfonylamines with high activity and excellent selectivity to the endo cyclohexadiene products.

Gold(III) π-Allyl Complexes.

Gold(III) π-complexes have been authenticated recently with alkenes, alkynes, and arenes. The key importance of PdII π-allyl complexes in organometallic chemistry (Tsuji-Trost reaction) prompted us to explore gold(III) π-allyl complexes, which have remained elusive so far. The (P,C)AuIII (allyl) and (methallyl) complexes 3 and 3' were readily prepared and isolated as thermally and air-stable solids. Spectroscopic and crystallographic analyses combined with detailed DFT calculations support tight quasi-symmetric η3 -coordination of the allyl moiety. The π-allyl gold(III) complexes are activated towards nucleophilic additions, as substantiated with ß-diketo enolates.

Versatility and adaptative behaviour of the P

The hemilabile P^N ligand MeDalphos enables access to a wide range of stable gold(i) π-complexes with unbiased alkenes and alkynes, as well as electron-rich alkenes and for the first time electron-poor ones. All complexes have been characterized by multi-nuclear NMR spectroscopy and whenever possible, by X-ray diffraction analyses. They all adopt a rare tricoordinate environment around gold(i), with chelation of the P^N ligand and side-on coordination of the alkene, including the electron-rich one, 3,4-dihydro-2H-pyrane. The strength of the N → Au coordination varies significantly in the series. It is the way the P^N ligand accommodates the electronic demand at gold, depending on the alkene. Comparatively, when the chelating P^P ligand (ortho-carboranyl)(PPh2)2 is used, gold(i) π-complexes are only isolable with unbiased alkenes. The bonding situation within the gold(i) P^N π-complexes has been thoroughly analyzed by DFT calculations supplemented by Charge Decomposition Analyses (CDA), Natural Bond Orbital (NBO) and Atoms-in-Molecules (AIM) analyses. Noticeable variations in the donation/back-donation ratio, C[double bond, length as m-dash]C weakening, alkene to gold charge transfer and magnitude of the N → Au coordination were observed. Detailed examination of the descriptors for the Au/alkene interaction and the N → Au coordination actually revealed intimate correlation between the two, with linear response of the MeDalphos ligand to the alkene electronics. The P^N ligand displays non-innocent and adaptative character. The isolated P^N gold(i) π-complexes are reactive and catalytically relevant, as substantiated by the chemo and regio-selective alkylation of indoles.

Reappraising Schmidpeter's bis(iminophosphoranyl)phosphides: coordination to transition metals and bonding analysis.

The synthesis and characterization of a range of bis(iminophosphoranyl)phosphide (BIPP) group 4 and coinage metals complexes is reported. BIPP ligands bind group 4 metals in a pseudo fac-fashion, and the central phosphorus atom enables the formation of d0-d10 heterobimetallic complexes. Various DFT computational tools (including AIM, ELF and NCI) show that the phosphorus-metal interaction is either electrostatic (Ti) or dative (Au, Cu). A bridged homobimetallic Cu-Cu complex was also prepared and its spectroscopic properties were investigated. The theoretical analysis of the P-P bond in BIPP complexes reveals that (i) BIPP are closely related to ambiphilic triphosphenium (TP) cations; (ii) the P-P bonds are normal covalent (i.e. not dative) in both BIPP and TP.

Catalytic Au(i)/Au(iii) arylation with the hemilabile MeDalphos ligand: unusual selectivity for electron-rich iodoarenes and efficient application to indoles.

The ability of the hemilabile (P,N) MeDalphos ligand to trigger oxidative addition of iodoarenes to gold has been thoroughly studied. Competition experiments and Hammett correlations substantiate a clear preference of gold for electron-enriched substrates both in stoichiometric oxidative addition reactions and in catalytic C-C cross-coupling with 1,3,5-trimethoxybenzene. This feature markedly contrasts with the higher reactivity of electron-deprived substrates typically encountered with palladium. Based on DFT calculations and detailed analysis of the key transition states (using NBO, CDA and ETS-NOCV methods in particular), the different behavior of the two metals is proposed to result from inverse electron flow between the substrate and metal. Indeed, oxidative addition of iodobenzene is associated with a charge transfer from the substrate to the metal at the transition state for gold, but opposite for palladium. The higher electrophilicity of the gold center favors electron-rich substrates while important back-donation from palladium favors electron-poor substrates. Facile oxidative addition of iodoarenes combined with the propensity of gold(iii) complexes to readily react with electron-rich (hetero)arenes prompted us to apply the (MeDalphos)AuCl complex in the catalytic arylation of indoles, a challenging but very important transformation. The gold complex proved to be very efficient, general and robust. It displays complete regioselectivity for C3 arylation, it tolerates a variety of functional groups at both the iodoarene and indole partners (NO2, CO2Me, Br, OTf, Bpin, OMe…) and it proceeds under mild conditions (75 °C, 2 h).

Evidence for genuine hydrogen bonding in gold(I) complexes.

The ability of gold to act as proton acceptor and participate in hydrogen bonding remains an open question. Here, we report the synthesis and characterization of cationic gold(I) complexes featuring ditopic phosphine-ammonium (P,NH+) ligands. In addition to the presence of short Au∙∙∙H contacts in the solid state, the presence of Au∙∙∙H-N hydrogen bonds was inferred by NMR and IR spectroscopies. The bonding situation was extensively analyzed computationally. All features were consistent with the presence of three-center four-electron attractive interactions combining electrostatic and orbital components. The role of relativistic effects was examined, and the analysis is extended to other recently described gold(I) complexes.

Cyclometalated gold(iii) complexes: noticeable differences between (N,C) and (P,C) ligands in migratory insertion.

Gold(iii) complexes are garnering increasing interest for opto-electronic, therapeutic and catalytic applications. But so far, very little is known about the factors controlling their reactivity and the very influence of the ancillary ligand. This article reports the first comprehensive study on this topic. The reactivity of a cationic (N,C) gold(iii) complex, namely 1A, towards ethylene has been thoroughly studied and compared with that of the related (P,C) complex 1C. A cationic gold(iii) complex 5A resulting from double insertion of ethylene was selectively obtained. Complex 5A was found to be remarkably stable. It was trapped with chloride and fully characterized. In marked contrast to that observed with 1C, no ß-H elimination or linear-to-branched rearrangement of the alkyl chain occurred with 1A. The energy profile for the reactions of 1A with ethylene has been comprehensively investigated computationally, and the influence of the ancillary ligand has been precisely delineated. Because nitrogen is a weaker donor than carbon (and phosphorus), the (N,C) ligand is very electronically dissymmetric, much more than the (P,C) ligand. This makes the two reactive sites at gold quite different, which noticeably influences the competition between migratory insertion and ß-H elimination, and actually changes the outcome of the olefin insertion at gold. This study provides valuable insight into the influence of ancillary ligands on gold(iii) reactivity, something critical to further develop Au(iii) and Au(i)/Au(iii) catalysis.

Formation of a peri-Bridged Phosphonio-Naphthalene by Cu-Mediated Phosphine-Aryl Coupling.

The peri-iodo naphthyl phosphine 1 reacts with CuI to give the peri-bridged phosphonio-naphthalene 2, which has been fully characterized (multi-nuclear NMR, MS, XRD). The outcome of the reaction differs markedly from that observed with gold. A two-step pathway involving P-assisted C-I oxidative addition to copper, followed by P-C reductive elimination is shown to be energetically feasible by DFT calculations.

Isolation of a Reactive Tricoordinate α-Oxo Gold Carbene Complex.

The [(P,P)Au=C(Ph)CO2 Et]+ complex 3 [where (P,P) is an o-carboranyl diphosphine ligand] was prepared by diazo decomposition at -40 °C. It is the first α-oxo gold carbene complex to be characterized. Its crystallographic structure was determined and DFT calculations have been performed, unraveling the key influence of the chelating (P,P) ligand. The gold center is tricoordinate and the electrophilicity of the carbene center is decreased. Complex 3 mimics transient α-oxo gold carbenes in a series of catalytic transformations, and provides support for the critical role of electrophilicity in the chemoselectivity of phenol functionalization (O-H vs. C-H insertion).

The effect of the metal fragment on the aromaticity and synchronicity of the gold(i)-catalysed divinylcyclopropane-cycloheptadiene rearrangement.

The gold(i)-catalysed divinylcyclopropane-cycloheptadiene rearrangement has been studied computationally within the Density Functional Theory framework. Regardless of the ligand directly attached to the transition metal (L = phosphine, phosphite and N-heterocyclic carbene), the process is found to occur concertedly via endo-boatlike transition structures. The influence of the transition metal fragment on the transformation is analysed and compared to the corresponding uncatalysed process in terms of the computed activation barriers, synchronicity and aromaticity of the associated transition states.

Factors controlling ß-elimination reactions in group†10 metal complexes.

Trends in reactivity of ß-chloride and ß-hydride elimination reactions involving Group 10 transition-metal complexes have been computationally explored and analyzed in detail by DFT. These reactions do not require the initial formation of a vacant coordination site; they proceed concertedly without a prior ligand-dissociation step. Whereas ß-chloride elimination is associated with relatively moderate activation barriers, the high barriers calculated for analogous ß-hydride eliminations suggest that the latter process is unfeasible for this type of compounds. This differential behavior is analyzed within the activation strain model, which provides quantitative insight into the physical factors controlling these ß-elimination reactions. The effects of the nature of the Group 10 transition metal (Ni, Pd, Pt), as well as the substituents attached to the ß-eliminating fragment (R2 CCR2 X; R, X=H, Cl) on the transformation have also been considered and are rationalized herein.