Rhodium(I)‐Catalysed Intramolecular [2+2+2] Cyclotrimerisations of 15‐, 20‐ and 25‐Membered Azamacrocycles: Experimental and Theoretical Mechanistic Studies

Number of members makes a difference : The [2+2+2] intramolecular cyclotrimerisation of a new series of 20‐ and 25‐membered azamacrocycles catalysed by the Wilkinson's catalyst are reported (see scheme). The 20‐ and 25‐membered azamacrocycles show different reactivity. Why? Theoretical calculations give insight into the reactivity differences observed for the 20‐ and 25‐membered macrocycles.

     

A Mechanistic Study of the Utilization of arachno‐Diruthenaborane [(Cp*RuCO)2B2H6] as an Active Alkyne‐Cyclotrimerization Catalyst

The reaction of nido‐[1,2‐(Cp*RuH)₂B₃H₇] ( 1 a , Cp*=η⁵‐C₅Me₅) with [Mo(CO)₃(CH₃CN)₃] under mild conditions yields the new metallaborane arachno‐[(Cp*RuCO)₂B₂H₆] ( 2 ). Compound 2 catalyzes the cyclotrimerization of a variety of internal‐ and terminal alkynes to yield mixtures of 1,3,5‐ and 1,2,4‐substituted benzenes. The reactivities of nido‐ 1 a and arachno‐ 2 with alkynes demonstrates that a change in geometry from nido to arachno drives a change in the reaction from alkyne‐insertion to catalytic cyclotrimerization, respectively. Density functional calculations have been used to evaluate the reaction pathways of the cyclotrimerization of alkynes catalyzed by compound 2 . The reaction involves the formation of a ruthenacyclic intermediate and the subsequent alkyne‐insertion step is initiated by a [2+2] cycloaddition between this intermediate and an alkyne. The experimental and quantum‐chemical results also show that the stability of the metallacyclic intermediate is strongly dependent on the nature of the substituents that are present on the alkyne.     

Mechanistic Study of the Rhodium‐Catalyzed [3+2+2] Carbocyclization of Alkenylidenecyclopropanes with Alkynes

A systematic theoretical study has been performed on the recently reported Rh^I‐catalyzed [3+2+2] carbocyclization reactions between alkenylidenecyclopropanes (ACPs) and alkynes. With the aid of theoretical calculations, two possible mechanisms, that is, alkene‐carbometalation‐first and alkyne‐carbometalation‐first mechanisms, are examined in this study. In the oxidative addition step, the possibility of reaction on either the distal or proximal C? C bond of the cyclopropane group has been evaluated. The calculations indicate that the alkene‐activation‐first mechanism is more favored for the overall catalytic cycle. This mechanism involves four steps, that is, oxidative addition of the distal (rather than the proximal) C? C bond of cyclopropane group, alkene carbometalation, alkyne carbometalation, and reductive elimination. The rate‐determining step in the overall catalytic cycle is the carbometalation of the alkyne (i.e., the alkyne‐insertion step) and this step also determines the regioselectivity. Finally, the origin of the regioselectivity is determined by the steric effect (i.e., the steric crowding between the electron‐withdrawing group on alkyne and other ligands on the rhodium center) in the alkyne‐insertion step.     

Stereoselective Rhodium‐Catalysed [2+2+2] Cycloaddition of Linear Allene–Ene/Yne–Allene Substrates: Reactivity and Theoretical Mechanistic Studies

Allene–ene–allene ( 2 and 5 ) and allene–yne–allene ( 3 and 7 ) N‐tosyl and O‐linked substrates were satisfactorily synthesised. The [2+2+2] cycloaddition reaction catalysed by the Wilkinson catalyst [RhCl(PPh₃)₃] was evaluated. Substrates 2 and 5 , which bear a double bond in the central position, gave a tricyclic structure in a reaction in which four contiguous stereogenic centres were formed as a single diastereomer. The reaction of substrates 3 and 7 , which bear a triple bond in the central position, gave a tricyclic structure with a cyclohexenic ring core, again in a diastereoselective manner. All cycloadducts were formed by a regioselective reaction of the inner allene double bond and, therefore, feature an exocyclic diene motif. A Diels–Alder reaction on N‐tosyl linked cycloadducts 8 and 10 allowed pentacyclic scaffolds to be diastereoselectively constructed. The reactivity of the allenes on [2+2+2] cycloaddition reactions was studied for the first time by density functional theory calculations. This mechanistic study rationalizes the order in which the unsaturations take part in the catalytic cycle, the reactivity of the two double bonds of the allene towards the [2+2+2] cycloaddition reaction, and the diastereoselectivity of the reaction.     

Macrocycles All Aflutter: Substitution at an Allylic Center Reveals the Conformational Dynamics of [13]‐Macrodilactones

The shapes adopted by large‐ring macrocyclic compounds play a role in their reactivity and their ability to be bound by biomolecules. We investigated the synthesis, conformational analysis, and properties of a specific family of [13]‐macrodilactones as models of natural‐product macrocycles. The features of our macrodilactones enabled us to study the relationship between stereogenic centers and planar chirality through the modular synthesis of new members of this family of macrocycles. Here we report on insights gained from a new [13]‐macrodilactone that is substituted at a position adjacent to the alkene in the molecule. Analysis of the compound, in comparison to an α‐substituted regioisomer, by using X‐ray crystallography, NMR coupling constants, and reaction‐product characterization in concert with computational chemistry, revealed that the alkene unit is dynamic. That is, the data support a model in which the alkene in our [13]‐macrodilactones oscillates between two conformations. A difference in reactivity of one conformation compared to the other leads to manifestation of this dynamic behavior. The results underscore the local conformational dynamics observed in some natural‐product macrocycles, which could have implications for biomolecule binding.     

Direct Detection of Key Intermediates in Rhodium(I)‐Catalyzed [2+2+2] Cycloadditions of Alkynes by ESI‐MS

The mechanism of the Rh‐catalysed [2+2+2] cycloaddition reaction of diynes with monoynes has been examined using ESI‐MS and ESI‐CID‐MS analysis. The catalytic system used consisted of the combination of a cationic rhodium(I) complex with bisphosphine ligands, which generates highly active complexes that can be detected by ESI(+) experiments. ESI‐MS on‐line monitoring has allowed the detection for the first time of all of the intermediates in the catalytic cycle, supporting the mechanistic proposal based mainly on theoretical calculations. For all ESI‐MS experiments, the structural assignments of ions are supported by tandem mass spectrometry analyses. Computer model studies based on density functional theory (DFT) support the structural proposal made for the monoyne insertion intermediate. The collective studies provide new insight into the reactivity of cationic rhodacyclopentadienes, which should facilitate the design of related rhodium‐catalysed C? C couplings.     

Intramolecular [2+2+2] cycloaddition reactions of yne-ene-yne and yne-yne-ene enediynes catalysed by Rh(I): experimental and theoretical mechanistic studies

N-tosyl-linked open-chain yne-ene-yne enediynes 1 and 2 and yne-yne-ene enediynes 3 and 4 have been satisfactorily synthesised. The [2+2+2] cycloaddition process catalysed by the Wilkinson catalyst [RhCl(PPh(3))(3)] was tested with the above-mentioned substrates resulting in the production of high yields of the cycloadducts. Enediynes 1 and 2 gave standard [2+2+2] cycloaddition reactions whereas enediynes 3 and 4 suffered β-hydride elimination followed by reductive elimination of the Wilkinson catalyst to give cycloadducts, which are isomers of those that would be obtained by standard [2+2+2] cycloaddition reactions. The different reactivities of these two types of enediyne have been rationalised by density functional theory calculations.     

Evidence for a Rapid Degenerate Hetero‐Cope‐Type Rearrangement in [Cp*W(S)2S‐CH2‐CHCH2]

Treatment of the salt [PPh₄]⁺[Cp*W(S)₃]^? ( 6 ) with allyl bromide gave the neutral complex [Cp*W(S)₂S‐CH₂‐CH?CH₂] ( 7 ). The product 7 was characterized by an X‐ray crystal structure analysis. Complex 7 features dynamic NMR spectra that indicate a rapid allyl automerization process. From the analysis of the temperature‐dependent NMR spectra a Gibbs activation energy of ΔG^≠ (278 K)≈13.7±0.1 kcal mol^?1 was obtained [ΔH^≠≈10.4±0.1 kcal mol^?1; ΔS^≠≈?11.4 cal mol^?1 K^?1]. The DFT calculation identified an energetically unfavorable four‐membered transition state of the “forbidden” reaction and a favorable six‐membered transition state of the “Cope‐type” allyl rearrangement process at this transition‐metal complex core.     

Reaction of an N‐Heterocyclic Carbene‐Stabilized Silicon(II) Monohydride with Alkynes: [2+2+1] Cycloaddition versus Hydrogen Abstraction

An in depth study of the reactivity of an N‐heterocyclic carbene (NHC)‐stabilized silylene monohydride with alkynes is reported. The reaction of silylene monohydride 1 , tBu₃Si(H)Si←NHC, with diphenylacetylene afforded silole 2 , tBu₃Si(H)Si(C₄Ph₄). The density functional theory (DFT) calculations for the reaction mechanism of the [2+2+1] cycloaddition revealed that the NHC played a major part stabilizing zwitterionic transition states and intermediates to assist the cyclization pathway. A significantly different outcome was observed, when silylene monohydride 1 was treated with phenylacetylene, which gave rise to supersilyl substituted 1‐alkenyl‐1‐alkynylsilane 3 , tBu₃Si(H)Si(CH?CHPh)(C?CPh). Mechanistic investigations using an isotope labelling technique and DFT calculations suggest that this reaction occurs through a similar zwitterionic intermediate and subsequent hydrogen abstraction from a second molecule of phenylacetylene.     

New Concepts for Designing d10‐M(L)n Catalysts: d Regime,s Regime and Intrinsic Bite‐Angle Flexibility

Our aim is to understand the electronic and steric factors that determine the activity and selectivity of transition‐metal catalysts for cross‐coupling reactions. To this end, we have used the activation strain model to quantum‐chemically analyze the activity of catalyst complexes d¹⁰‐M(L)_n toward methane C?H oxidative addition. We studied the effect of varying the metal center M along the nine d¹⁰ metal centers of Groups 9, 10, and 11 (M=Co^?, Rh^?, Ir^?, Ni, Pd, Pt, Cu⁺, Ag⁺, Au⁺), and, for completeness, included variation from uncoordinated to mono‐ to bisligated systems (n=0, 1, 2), for the ligands L=NH₃, PH₃, and CO. Three concepts emerge from our activation strain analyses: 1) bite‐angle flexibility, 2) d‐regime catalysts, and 3) s‐regime catalysts. These concepts reveal new ways of tuning a catalyst’s activity. Interestingly, the flexibility of a catalyst complex, that is, its ability to adopt a bent L‐M‐L geometry, is shown to be decisive for its activity, not the bite angle as such. Furthermore, the effect of ligands on the catalyst’s activity is totally different, sometimes even opposite, depending on the electronic regime (d or s) of the d¹⁰‐M(L)_n complex. Our findings therefore constitute new tools for a more rational design of catalysts.     

Stereocontrolled Annulations of Indolo[2,3‐a]quinolizidine‐Derived Lactams with a Silylated Nazarov Reagent: Access to Allo and Epiallo Yohimbine‐Type Derivatives

The facial selectivity of double Michael addition reactions of the silylated Nazarov reagent 4 to unsaturated indolo[2,3‐a]quinolizidine lactams 3 has been studied. Pentacyclic 3‐H/15‐H trans adducts 5 are generated from N_ind‐unsubstituted lactams, but the corresponding cis isomers 6 are formed when the indole nitrogen has a tert‐butyloxycarbonyl (Boc) substituent. This reversal in the facial selectivity of the annulation has been rationalized by means of theoretical calculations, which indicate that the initial nucleophilic attack under stereoelectronic control is hampered by the presence of the bulky Boc group. The synthetic usefulness of the pentacyclic Nazarov‐derived adducts is demonstrated by their conversion into allo and epiallo yohimbine‐type targets.     

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold‐catalyzed synthesis of methylidene 2,3‐cyclobutane‐indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two‐step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond‐forming event turned out to be the rate‐determining step.     

Mechanisms of phosphine‐catalyzed [4 + 3] annulation of allenoates with C,N‐cyclic azomethine imines: A DFT investigation

In this article, mechanisms of phosphine‐catalyzed [4 + 3] annulation of allenoates with C, N‐cyclic azomethine imines have been investigated using density functional theory. The catalytic cycle for the title reaction consists of five steps. Namely, the first step is the nucleophilic addition of phosphine catalyst, the second one is the C C bond formation, the third one is the proton transfer process, and the next one is the ring‐closure process, the last one is dissociation of the catalyst and the product generation. The calculated results indicate that the nucleophilic addition of phosphine catalyst is rate‐determining. With the use of Cat as the chiral catalyst, optically active products were obtained in good yields with excellent enantioselectivities while the C C bond formation is stereoselectivity‐determining. Furthermore, the theoretically predicted the main product is SS configuration, which is in good agreement with the experimental results. The special role of the catalysts and origin of stereoselectivity was also identified by NBO, GRI, and FMO analyses. This work might be helpful for understanding the significant roles of phosphine catalyst and thus provide valuable insights on the rational design of potential catalysts for this kind of reactions.     

Synthesis,Structure, and Properties of Near‐Infrared [b]Phenanthrene‐Fused BF2 Azadipyrromethenes

A new class of phenanthrene‐fused BF₂ azadipyrromethene (azaBODIPY) dyes have been synthesized through a tandem Suzuki reaction and oxidative ring‐fusion reaction, or a palladium‐catalyzed intramolecular C−H activation reaction. These phenanthrene‐fused azaBODIPY dyes are highly photostable and display markedly redshifted absorption (up to λ =771 nm) and emission bands (λ ≈800 nm) in the near‐infrared region. DFT calculations and cyclic voltammetry studies indicate that, upon annulation, more pronounced stabilization of the LUMO is the origin of the bathochromic shift of the absorption and high photostability.