Mechanistic investigation of organolanthanide-mediated hydroamination of aminoallenes: a comprehensive computational assessment of various routes for allene activation

The present mechanistic study comprehensively explores alternative scenarios for activation of the amine-linked allene C=C linkage toward nucleophilic amido attack in the intramolecular hydroamination of a prototypical 1,3-disubstituted aminoallene by a well-characterised samarocene-amido catalyst. Firstly, the non-insertive mechanism by Scott featuring C-N ring closure with concomitant amino proton delivery onto the allene unit has been explored and its key features have been defined. This scenario has been compared and contrasted with the classical stepwise Ln-N σ-bond insertive mechanism that involves rapid substrate association/dissociation equilibria for the Ln-amido-substrate resting state and also for Ln-azacycle intermediates, facile and reversible exocyclic ring closure through migratory allene insertion into the Ln-N amido σ-bond, linked to turnover-limiting Ln-C azacycle aminolysis. The Ln-N σ-bond insertive mechanism prevails for the studied intramolecular hydroamination of 4,5-heptadien-1-ylamine 1 by [Cp*(2)Sm-CH(TMS)(2)] starting material 2. The following aspects are in support of this mechanism: 1) the derived rate law is consistent with the observed empirical rate law; 2) the assessed effective barrier for turnover-limiting aminolysis does agree reasonably well with empirically determined Eyring parameters; 3) the ring-tether double bond selectivity is consistently elucidated. On the other hand, this study reveals that the non-insertive mechanism, which features a prohibitively large barrier, is unachievable. Spatial demands around the lanthanide centre effect the two mechanisms differently. A sufficiently accessible lanthanide is a crucial requirement of the Ln-N σ-bond insertive mechanism and enhanced encumbrance renders the cyclisation step less accessible kinetically. This contrasts with the non-insertive mechanism, where greater lanthanide protection has a rather modest influence. The present study indicates that the non-insertive mechanism would prevail if the lanthanide centre were to be protected effectively against C=C bond approach, whilst ensuring a high polarity of the Ln-N σ-bond together with a sufficiently acidic amino proton.     

Does a Concerted Non‐Insertive Mechanism Prevail over a σ‐Insertive Mechanism in Catalytic Cyclohydroamination by Magnesium Tris(oxazolinyl)phenylborate Compounds? A Computational Study

The present study comprehensively explores alternative mechanistic pathways for intramolecular hydroamination of 2,2-dimethyl-4-penten-1-amine (1) by [{To(M)}MgMe] (To(M)=tris(4,4-dimethyl-2-oxazolinyl)phenylborate) (2) with the aid of density functional theory (DFT) calculations. A single-step amidoalkene → cycloamine conversion through a concerted proton transfer associated with N-C ring closure has been explored as one possible mechanism; its key features have been described. This non-insertive pathway evolves via a six-centre TS structure featuring activation of the olefin unit towards nucleophilic amido attack outside the immediate vicinity of the metal centre by amino proton delivery and describes a viable mechanistic variant for alkaline-earth metal-mediated aminoalkene hydroamination. However, herein is presented sound evidence for the operation of the Mg-N amido σ-bond insertive mechanism, its turnover-limiting activation barrier is found to be 5.0 kcal mol(-1) lower than for the non-insertive mechanism, for the cyclohydroamination of 2,2-disubstituted 4-aminoalkenes by a [{To(M)}Mg-NHR] catalyst. The operative mechanism involves rapid equilibria of the {To(M)}Mg-amidoalkene resting state 3 with its amine adduct, easily accessible and thermodynamically disfavoured, hence reversible, 1,2-olefin insertion into the Mg-N amido σ-bond with ring closure at 3, linked to turnover-limiting Mg-C azacycle tether aminolysis by an adduct substrate molecule, followed by facile cycloamine liberation to regenerate the active catalyst species 3. The following aspects are in support of this scenario: 1) the derived rate law is consistent with the experimentally obtained empirical rate law; 2) the reasonable agreement between the computationally estimated and the observed value of the primary KIE; 3) the assessed effective activation barrier for turnover-limiting aminolysis matches empirically determined Eyring parameters remarkably well; and 4) the observed resistance of isolated 3 to undergo amidoalkene cycloamine/cycloamido transformation until further quantities of substrate is added is consistently explained. The herein unveiled insights into the structure-reactivity relationships will undoubtedly govern the rational design of alkaline-earth metal-based catalysts and likely facilitate further advances in the area.     

Mechanistic elucidation of the yttrium(III)-catalysed intramolecular aminoalkene hydroamination: DFT favours a stepwise σ-insertive mechanism

A comprehensive computational mechanistic study regarding intramolecular hydroamination (HA) of aminoalkenes mediated by a recently reported class of highly active cyclopentadienyl-bis(oxazolinyl)borate {Cpo}Y(III) alkyl compounds is presented. Two distinct mechanistic pathways of catalytic HA mediated by rare earth and alkaline earth compounds have emerged over the years, describing amidoalkene → cycloamine conversion proceeding through a stepwise σ-insertive mechanism or a concerted non-insertive N-C/C-H bond forming pathway. Notably, both mechanisms account equally for reported distinct process features. Non-competitive kinetic demands revealed for the concerted amino proton transfer associated with N-C ring closure, which commences from a {Cpo(M)}Y(NHR)·(NH(2)R) substrate adduct and evolves through a six-centre TS structure, militates against a proton-triggered non-insertive pathway to promote HA for the rare earth catalyst at hand. A stepwise σ-insertive pathway, featuring rapid and reversible olefin insertion into the Y-N amido σ-bond, linked to a less facile and irreversible intramolecular Y-C azacycle tether aminolysis, is found to prevail energetically. The assessed effective barrier for turnover-limiting aminolysis matches the empirically determined Eyring parameter well and the computationally estimated primary KIE is close to the observed values. A recent computational study revealed a similar scenario for an analogous tris(oxazolinyl)borate {To(M)}Mg system. Valuable insights into the catalytic structure-reactivity relationships have been unveiled by a comparison of {Cpo(M)}Y(NHR)- and {To(M)}Mg(NHR)-catalysed hydroaminations.     

Intramolecular hydroamination/cyclization of conjugated aminodienes catalyzed by organolanthanide complexes. Scope, diastereo- and enantioselectivity, and reaction mechanism

Organolanthanide complexes of the general type Cp'(2)LnCH(TMS)(2) (Cp' = eta(5)-Me(5)C(5); Ln = La, Sm, Y; TMS = SiMe(3)) and CGCSmN(TMS)(2) (CGC = Me(2)Si(eta(5)-Me(4)C(5))((t)()BuN)) serve as effective precatalysts for the rapid, regioselective, and highly diastereoselective intramolecular hydroamination/cyclization of primary and secondary amines tethered to conjugated dienes. The rates of aminodiene cyclizations are significantly more rapid than those of the corresponding aminoalkenes. This dienyl group rate enhancement as well as substituent group (R) effects on turnover frequencies is consistent with proposed transition state electronic demands. Kinetic and mechanistic data parallel monosubstituted aminoalkene hydroamination/cyclization, with turnover-limiting C=C insertion into the Ln-N bond to presumably form an Ln-eta(3) allyl intermediate, followed by rapid protonolysis of the resulting Ln-C linkage. The rate law is first-order in [catalyst] and zero-order in [aminodiene]. However, depending on the particular substrate and catalyst combination, deviations from zero-order kinetic behavior reflect competitive product inhibition or self-inhibition by substrate. Lanthanide ionic radius effects and ancillary ligation effects on turnover frequencies suggest a sterically more demanding Ln-N insertion step than in aminoalkene cyclohydroamination, while a substantially more negative DeltaS( double dagger ) implies a more highly organized transition state. Good to excellent diastereoselectivity is obtained in the synthesis of 2,5-trans-disubstituted pyrrolidines (80% de) and 2,6-cis-disubstituted piperidines (99% de). Formation of 2-(prop-1-enyl)piperidine using the chiral C(1)-symmetric precatalyst (S)-Me(2)Si(OHF)(CpR)SmN(TMS)(2) (OHF = eta(5)-octahydrofluorenyl; Cp = eta(5)-C(5)H(3); R = (-)-menthyl) proceeds with up to 71% ee. The highly stereoselective feature of aminodiene cyclization is demonstrated by concise syntheses of naturally occurring alkaloids, (+/-)-pinidine and (+)-coniine from simple diene precursors.     

Mechanism and exo-regioselectivity of organolanthanide-mediated intramolecular hydroamination/cyclization of 1,3-disubstituted aminoallenes: a computational study

The complete catalytic reaction course for the organolanthanide-assisted intramolecular hydroamination/cyclization (IHC) of 4,5-heptadien-1-ylamine by a prototypical [(eta(5)-Me5C5)2LuCH(SiMe3)2] precatalyst has been critically scrutinized by employing a reliable DFT method. A computationally verified mechanistic scenario for the IHC of 1,3-disubstituted aminoallene substrates has been proposed that is consistent with the empirical rate law determined by experiment and accounts for crucial experimental observations. It involves kinetically rapid substrate association and dissociation equilibria, facile and reversible intramolecular allenic C=C insertion into the Ln-N bond, and turnover-limiting protonation of the azacycle's tether functionality, with the amine-amidoallene-Ln adduct complex representing the catalyst's resting state. This mechanistic scenario bears resemblance to the mechanism that has been recently proposed in a computational exploration of aminodiene IHC. The unique features of the IHC of the two substrate classes are discussed. Furthermore, the thermodynamic and kinetic factors that control the regio- and stereoselectivity of aminoallene IHC have been elucidated. These achievements have provided a deeper insight into the catalytic structure-reactivity relationships in organolanthanide-assisted cyclohydroamination of unsaturated C-C functionalities.     

Computational Mechanistic Elucidation of the Intramolecular Aminoalkene Hydroamination Catalysed by Iminoanilide Alkaline‐Earth Compounds

A comprehensive computational exploration of plausible alternative mechanistic pathways for the intramolecular hydroamination (HA) of aminoalkenes by a recently reported class of kinetically stabilised iminoanilide alkaline‐earth silylamido compounds [{N^N}Ae{N(SiMe₃)₂} ? (thf)_n] ({N^N}=iminoanilide; Ae=Ca, Sr, Ba) is presented. On the one hand, a proton‐assisted concerted N?C/C?H bond‐forming pathway to afford the cycloamine in a single step can be invoked and on the other hand, a stepwise σ‐insertive pathway that involves a fast, reversible migratory olefin 1,2‐insertion step linked to a less rapid, irreversible metal?C azacycle tether σ‐bond aminolysis. Notably, these alternative mechanistic avenues are equally consistent with reported key experimental features. The present study, which employs a thoroughly benchmarked and reliable DFT methodology, supports the prevailing mechanism to be a stepwise σ‐insertive pathway that sees an initial conversion of the {N^N}Ae silylamido into the catalytically competent {N^N}Ae amidoalkene compound and involves thereafter facile and reversible insertive N?C bond‐forming ring closure, linked to irreversible intramolecular Ae?C tether σ‐bond aminolysis at the transient {N^N}Ae alkyl intermediate. Turnover‐limiting protonolysis accounts for the substantial primary kinetic isotope effect observed; its DFT‐derived barrier satisfactorily matches the empirically determined Eyring parameter and predicts the decrease in rate observed across the series Ca>Sr>Ba correctly. Non‐competitive kinetic demands militate against the operation of the concerted proton‐assisted pathway, which describes N?C bond‐forming ring closure triggered by concomitant amino proton delivery at the C?C linkage evolving through a multi‐centre TS structure. Valuable insights into the catalytic structure–activity relationships are unveiled by a detailed comparison of [{N^N}Ae(NHR)] catalysts. Moreover, the intriguingly opposite trends in reactivity observed in intramolecular (Ca>Sr>Ba) and intermolecular (Ca<Sr<Ba) HA catalysis for the studied family of iminoanilide alkaline‐earth amido catalysts are rationalised.     

镧系金属有机配合物研究LX: 含碳、氮稀土金属σ键的稀土金属有机配合物的合成和表征

双(2-甲氧乙基环戊二烯基)氯化镧或氯化镱, 在四氢呋喃中, -20℃下,分别与苯乙炔基钠发生交换反应, 生成双(2-甲氧乙基环戊二烯基)苯乙炔基镧或镱, 产率分别为77%和66%。直接将无水三氯化镱或三氯化钇, 在四氢呋喃中, 冰水冷却下, 与两摩尔的双(三甲基甲硅烷基)氨基锂和2-甲氧乙基环戊二烯基钠进行一锅煮反应, 可得2-甲氧乙基环戊二烯基双(双三甲基甲硅烷基氨基)镱或钇, 产率分别为56%和72%。配合物经元素分析, 红外光谱, 核磁共振氢谱和质谱的鉴定, 它们可能是非溶剂化的, 含分子内配位键的中性单体配合物。     

Organolanthanide-mediated intramolecular hydroamination/cyclization of conjugated aminodienes: a computational exploration of diverse mechanistic pathways for the regioselective generation of functionalized azacycles supported by a lanthanocene-based catalyst complex

The complete catalytic reaction course for the organolanthanide-mediated intramolecular hydroamination/cyclization (IHC) of (4E,6)-heptadien-1-amine by a prototypical achiral Cp*(2)LaCH(TMS)(2) precatalyst is critically scrutinized by employing a gradient-corrected DFT method. The condensed free-energy profile for the overall reaction, comprised of thermodynamic and kinetic aspects of individual elementary steps, is presented. A computationally verified, revised mechanistic scenario has been proposed, which is consistent with the empirical rate law, accounts for crucial experimental observations, and provides a first understanding of the origin of the measured negative DeltaS(++). It involves rapid substrate association/dissociation equilibria and facile intramolecular diene insertion, linked to turnover-limiting protonolysis of the eta(3)-butenyl-Ln functionality, with the amine-amidodiene-Ln adduct complex representing the catalyst's resting state. The thermodynamic and kinetic factors that determine the high regio- and stereoselectivity of the mechanistically diverse IHC of aminodienes have been elucidated. These achievements allow a deeper understanding and a consistent rationalization of the experimental results for aminodiene IHC and furthermore enhance the insights into general mechanistic aspects of the organolanthanide-mediated cycloamination.     

Experimental and Computational Mechanistic Studies of the β-Diketiminatoiron(II)-Catalysed Hydroamination of Primary Aminoalkenes

A comprehensive mechanistic study by means of complementary experimental and computational approaches of the exo-cyclohydroamination of primary aminoalkenes mediated by the recently reported β-diketiminatoiron(II) complex B is presented. Kinetic analysis of the cyclisation of 2,2-diphenylpent-4-en-1-amine ( 1 a ) catalysed by B revealed a first-order dependence of the rate on both aminoalkene and catalyst concentrations and a primary kinetic isotope effect (KIE) (k_H/k_D) of 2.7 (90 °C). Eyring analysis afforded ΔH^≠=22.2 kcal mol⁻¹, ΔS^≠=−13.4 cal mol⁻¹ K⁻¹. Plausible mechanistic pathways for competitive avenues of direct intramolecular hydroamination and oxidative amination have been scrutinised computationally. A kinetically challenging proton-assisted concerted N−C/C−H bond-forming non-insertive pathway is seen not to be accessible in the presence of a distinctly faster σ-insertive pathway. This operative pathway involves 1) rapid and reversible syn-migratory 1,2-insertion of the alkene into the Fe−N_amido σ bond at the monomer {N^N}Fe^II amido compound; 2) turnover-limiting Fe−C σ bond aminolysis at the thus generated transient {N^N}Fe^II alkyl intermediate and 3) regeneration of the catalytically competent {N^N}Fe^II amido complex, which favours its dimer, likely representing the catalyst resting state, through rapid cycloamine displacement by substrate. The collectively derived mechanistic picture is consonant with all empirical data obtained from stoichiometric, catalytic and kinetics experiments.     

Intermolecular Hydroamination of Vinylarenes by Iminoanilide Alkaline‐Earth Catalysts: A Computational Scrutiny of Mechanistic Pathways

A thorough computational exploration of the mechanistic intricacies of the intermolecular hydroamination (HA) of vinylarenes by a recently reported class of kinetically stabilised iminoanilide [{N^N}Ae{N(SiMe₃)₂} ? (THF)_n] alkaline‐earth amido compounds (Ae=Ca, Sr, Ba) is presented. Two distinct mechanistic pathways for catalytic HA mediated by alkaline‐earth and rare‐earth compounds have emerged over the years that account equally well for the specific features of the process. On one hand, a concerted proton‐assisted pathway to deliver the amine product in a single step can be invoked and, on the other, a stepwise σ‐insertive pathway that comprises a rapid, reversible migratory olefin insertion step linked to a less facile, irreversible Ae?C alkyl bond aminolysis. The results of the study presented herein, which employed a heavily benchmarked and reliable DFT methodology, supports a stepwise σ‐insertive pathway that involves fast and reversible migratory C?C bond insertion into the polar Ae?N pyrrolido σ bond. This proceeds with strict 2,1 regioselectivity via a highly polarised four‐centre transition state (TS) structure, linked to irreversible intramolecular Ae?C bond aminolysis of the alkaline‐earth alkyl intermediate as the energetically favourable mechanism. Turnover‐limiting aminolysis is consistent with the significant KIE measured; the DFT‐derived effective barrier matches the Eyring parameter empirically determined for the best‐performing {N^N}Ba(NR₂) catalyst gratifyingly well. It also predicts the observed trend in reactivity (Ca<Sr<Ba) correctly and the computationally estimated primary KIE is close to the observed values. Non‐competitive kinetic demands militate against the operation of the alternative concerted proton‐assisted pathway, which describes N?C bond formation triggered by concomitant amino proton transfer at the C?C linkage via a multi‐centre TS structure. A detailed comparison of {N^N}Ae(NR₂) catalysts revealed that the variation in the Ae?pyrrolido bond strength together with the degree of protection of the alkaline earth by a sterically encumbering iminoanilide ligand scaffold not only profoundly influences the performance in HA catalysis, but also the likelihood of traversing rival mechanistic pathways.     

Origin of diastereoselectivity in the organolanthanide-mediated intramolecular hydroamination/cyclisation of aminodienes: a computational exploration of constrained geometry CGC-Ln catalysts

The regulation of ring-substituent diastereoselectivity in the intramolecular hydroamination/cyclisation (IHC) of alpha-substituted aminodienes by constrained geometry CGC-lanthanide catalysts (CGC=[Me(2)Si(eta(5)-Me(4)C(5))(tBuN)](2-)) has been elucidated by means of a reliable DFT method. The first survey of relevant elementary steps for the 1-methyl-(4E,6)-heptadienylamine substrate (1) and the [{Me(2)Si(eta(5)-Me(4)C(5))(tBuN)}Sm{N(TMS)(2)}] starting material (2) identified the following general mechanistic aspects of Ln-catalysed aminodiene IHC. The substrate-adduct 3-S of the active CGC-Ln-amidodiene compound represents the catalyst's resting state, but the substrate-free form 3' with a chelating amidodiene functionality is the direct precursor for cyclisation. This step proceeds with almost complete regioselectivity through exocyclic ring closure by means of a frontal trajectory, giving rise to the CGC-Ln-azacycle intermediate 4. Subsequent protonolysis of 4 is turnover limiting, whilst the ring-substituent diastereoselectivity is dictated by exocyclic ring closure. Unfavourable close interatomic contacts between the substrate's alpha-substituent and the catalyst backbone have been shown to largely govern the trans/cis selectivity. Substituents of sufficient bulk in the alpha-position of the substrate have been identified as being vital for stereochemical induction. The present study has indicated that the diastereoselectivity of ring closure can be considerably modulated. The variation of the lanthanide's ionic radius and introduction of extra steric pressure at the substrate's alpha-position and/or the CGC N centre have been identified as effective handles for tuning the selectivity. The quantification of these factors reported herein represents the first step toward the rational design of improved CGC-Ln catalyst architectures and will thus aid this process.     

Organolathanide-catalyzed regioselective intermolecular hydroamination of alkenes, alkynes, vinylarenes, di- and trivinylarenes, and methylenecyclopropanes. Scope and mechanistic comparison to intramolecular cyclohydroaminations

Organolanthanide complexes of the type Cp'(2)LnCH(SiMe(3))(2) (Cp' = eta(5)-Me(5)C(5); Ln = La, Nd, Sm, Lu) and Me(2)SiCp' '(2)LnCH(SiMe(3))(2) (Cp' ' = eta(5)-Me(4)C(5); Ln = Nd, Sm, Lu) serve as efficient precatalysts for the regioselective intermolecular hydroamination of alkynes R'Ctbd1;CMe (R' = SiMe(3), C(6)H(5), Me), alkenes RCH=CH(2) (R = SiMe(3), CH(3)CH(2)CH(2)), butadiene, vinylarenes ArCH=CH(2) (Ar = phenyl, 4-methylbenzene, naphthyl, 4-fluorobenzene, 4-(trifluoromethyl)benzene, 4-methoxybenzene, 4-(dimethylamino)benzene, 4-(methylthio)benzene), di- and trivinylarenes, and methylenecyclopropanes with primary amines R' 'NH(2) (R' ' = n-propyl, n-butyl, isobutyl, phenyl, 4-methylphenyl, 4-(dimethylamino)phenyl) to yield the corresponding amines and imines. For R = SiMe(3), R = CH(2)=CH lanthanide-mediated intermolecular hydroamination regioselectively generates the anti-Markovnikov addition products (Me(3)SiCH(2)CH(2)NHR' ', (E)-CH(3)CH=CHCH(2)NHR' '). However, for R = CH(3)CH(2)CH(2), the Markovnikov addition product is observed (CH(3)CH(2)CH(2)CHNHR' 'CH(3)). For internal alkynes, it appears that these regioselective transformations occur under significant stereoelectronic control, and for R' = SiMe(3), rearrangement of the product enamines occurs via tautomerization to imines, followed by a 1,3-trimethylsilyl group shift to stable N-SiMe(3)-bonded CH(2)=CMeN(SiMe(3))R' ' structures. For vinylarenes, intermolecular hydroamination with n-propylamine affords the anti-Markovnikov addition product beta-phenylethylamine. In addition, hydroamination of divinylarenes provides a concise synthesis of tetrahydroisoquinoline structures via coupled intermolecular hydroamination/subsequent intramolecular cyclohydroamination sequences. Intermolecular hydroamination of methylenecyclopropane proceeds via highly regioselective exo-methylene C=C insertion into Ln-N bonds, followed by regioselective cyclopropane ring opening to afford the corresponding imine. For the Me(2)SiCp' '(2)Nd-catalyzed reaction of Me(3)SiCtbd1;CMe and H(2)NCH(2)CH(2)CH(2)CH(3), DeltaH() = 17.2 (1.1) kcal mol(-)(1) and DeltaS() = -25.9 (9.7) eu, while the reaction kinetics are zero-order in [amine] and first-order in both [catalyst] and [alkyne]. For the same substrate pair, catalytic turnover frequencies under identical conditions decrease in the order Me(2)SiCp' '(2)NdCH(SiMe(3))(2) > Me(2)SiCp' '(2)SmCH(SiMe(3))(2) > Me(2)SiCp' '(2)LuCH(SiMe(3))(2) > Cp'(2)SmCH(SiMe(3))(2), in accord with documented steric requirements for the insertion of olefinic functionalities into lanthanide-alkyl and -heteroatom sigma-bonds. Kinetic and mechanistic evidence argues that the turnover-limiting step is intermolecular C=C/Ctbd1;C bond insertion into the Ln-N bond followed by rapid protonolysis of the resulting Ln-C bond.     

Highly stereoselective intramolecular hydroamination/cyclization of conjugated aminodienes catalyzed by organolanthanides

Efficient intramolecular hydroamination/cyclization of primary and secondary conjugated aminodienes can be effected by using organolanthanide precatalysts of the type Cp'2LnCH(TMS)2 (Cp' = eta5-Me5C5; Ln = La, Sm, Y; TMS = SiMe3) and CGCSmN(TMS)2 (CGC = Me2Si(eta5-Me4C5)(tBuN)). The transformation proceeds cleanly (>/= 90% conversion) at 25-60 degrees C with good rates and high regioselectivities, and with electronic effects leading to significant rate enhancements. Some features of the reaction parallel monosubstituted aminoalkene hydroamination/cyclization, including rate law (zero order in [aminodiene]), and rate enhancements observed with larger lanthanide ionic radii and/or more open catalyst ligation structures. Good to excellent diastereoselectivity is obtained in the synthesis of 2,5-trans-disubstituted pyrrolidines (80% de) and 2,6-cis-disubstituted piperidines (99% de) with using the corresponding alpha-methyl aminodiene precursors. Formation of 2-(prop-1-enyl)piperidine with the chiral C1-symmetric precatalyst (S)-Me2Si(OHF)(CpR*)SmN(TMS)2 (OHF = eta5-octahydrofluorenyl; Cp = eta5-C5H3; R* = (-)-menthyl) proceeds with up to 69% ee.     

Intramolecular aminoalkene hydroamination mediated by a tethered bis(ureate)zirconium complex: computational perusal of various pathways for aminoalkene activation

The present study comprehensively explores alternative mechanistic pathways for the intramolecular hydroamination of the prototype 2,2-dimethyl-5-penten-1-amine aminoalkene (1) by bis(ureate)Zr(IV)(NMe(2))(2)(HNMe(2)) (2), which proceeds through a Zr(IV)(NHR)(2) intermediate using density functional theory (DFT) calculations. The classical stepwise σ-insertive mechanism that includes insertion of the C═C double bond into the Zr-N amido σ bond followed by Zr-C alkyl-bond aminolysis has been compared with a single-step pathway for amidoalkene → cycloamine conversion through a concerted amino proton transfer associated with N-C ring closure. Noncompetitive kinetics for reversible σ-insertive cyclization, together with the incompatibility of a turnover-limiting insertion step with observed pronounced primary kinetic isotope effects (KIEs), strongly militates against the operation of a σ-insertive mechanism. A noninsertive pathway evolving through an ordered six-center transition-state structure describing N-C bond formation at an axial Zr-N amido σ bond triggered by concurrent proton transfer from an equatorially bound substrate molecule onto the adjacent olefin-carbon center is found to prevail energetically. The proton-triggered noninsertive cyclization commencing from a catalytically relevant Zr(IV)(NHR)(2)(NH(2)R) substrate adduct is strongly downhill, followed by product expulsion via dissociative amine exchange. The assessed effective barrier compares reasonably well with the previously determined Eyring parameters, and the computationally estimated primary KIEs match the observed values pleasingly well. The present study reveals a comparable strength of substrate and product binding in relevant seven-coordinate intermediates, together with a rapid equilibrium between related primary and secondary amido species, which favors the former, as unique features of the studied catalyst. Thus, in line with experimental observations, competitive product inhibition can be discarded. On the basis of all of these findings, it is suggested that a Zr(NHR)(2)(substrate) intermediate corresponds to the catalyst resting state at high substrate concentrations, while it becomes a Zr(NHR)(2)(cycloamine) species when the product concentration is high or with the addition of excess 2-methylpiperidine, and this ambivalent behavior explains the observed operation of two distinct kinetic regimes, depending upon the extent of the reaction.     

Mechanistic Exploration of Intramolecular Aminodiene Hydroamination/Cyclisation Mediated by Constrained Geometry Organoactinide Complexes: A DFT Study

The present computational mechanistic study explores comprehensively the organoactinide‐mediated intramolecular hydroamination/cyclisation (IHC) of aminodienes by employing a reliable DFT method. All the steps of a plausible catalytic reaction course have been scrutinised for the IHC of (4E,6)‐heptadienylamine 1 t by [(CGC)Th(NMe₂)₂] precatalyst 2 (CGC=[Me₂Si(η⁵‐Me₄C₅)(tBuN)]^2?). For each of the relevant elementary steps the most accessible pathway has been identified from a multitude of mechanistic possibilities. The operative mechanism involves rapid substrate association/dissociation equilibria for the 3 t ‐S resting state and also for azacyclic intermediates 4 a , 4 s , easily accessible and reversible exocyclic ring closure, supposedly facile isomerisation of the azacycle’s butenyl tether prior to turnover‐limiting protonolysis. The following aspects are in support of this scenario: 1) the derived rate law is consistent with the experimentally obtained empirical rate law; 2) the accessed barrier for turnover‐limiting protonolysis does agree remarkably well with observed performance data; 3) the ring‐tether double‐bond selectivity is consistently elucidated, which led to predict the product distribution correctly. This study provides a computationally substantiated rationale for observed activity and selectivity data. Steric demands at the CGC framework appear to be an efficient means for modulating both performance and ring‐tether double‐bond selectivity. The careful comparison of (CGC)4f‐element and (CGC)5f‐element catalysts revealed that aminodiene IHC mediated by organoactinides and organolanthanides proceeds through a similar mechanistic scenario. However, cyclisation and protonolysis steps, in particular, feature a markedly different reactivity pattern for the two catalyst classes, owing to enhanced bond covalency of early actinides when compared to lanthanides.     

C2-symmetric bis(oxazolinato)lanthanide catalysts for enantioselective intramolecular hydroamination/cyclization

C(2)-symmetric bis(oxazolinato)lanthanide complexes of the type [(4R,5S)-Ph(2)Box]La[N(TMS)(2)](2), [(4S,5R)-Ar(2)Box]La[N(TMS)(2)](2), and [(4S)-Ph-5,5-Me(2)Box]La[N(TMS)(2)](2) (Box = 2,2'-bis(2-oxazoline)methylenyl; Ar = 4-tert-butylphenyl, 1-naphthyl; TMS = SiMe(3)) serve as precatalysts for the efficient enantioselective intramolecular hydroamination/cyclization of aminoalkenes and aminodienes. These new catalyst systems are conveniently generated in situ from the known metal precursors Ln[N(TMS)(2)](3) or Ln[CH(TMS)(2)](3) (Ln = La, Nd, Sm, Y, Lu) and 1.2 equiv of commercially available or readily prepared bis(oxazoline) ligands such as (4R,5S)-Ph(2)BoxH, (4S,5R)-Ar(2)BoxH, and (4S)-Ph-5,5-Me(2)BoxH. The X-ray crystal structure of [(4S)-(t)BuBox]Lu[CH(TMS)(2)](2) provides insight into the structure of the in situ generated precatalyst species. Lanthanides having the largest ionic radii exhibit the highest turnover frequencies as well as enantioselectivities. Reaction rates maximize near 1:1 BoxH:Ln ratio (ligand acceleration); however, increasing the ratio to 2:1 BoxH:Ln decreases the reaction rate, while affording enantiomeric excesses similar to the 1:1 BoxH:Ln case. A screening study of bis(oxazoline) ligands reveals that aryl stereodirecting groups at the oxazoline ring 4 position and additional substitution (geminal dimethyl or aryl) at the 5 position are crucial for high turnover frequencies and good enantioselectivities. The optimized precatalyst, in situ generated [(4R,5S)-Ph(2)Box]La[N(TMS)(2)](2), exhibits good rates and enantioselectivities, comparable to or greater than those achieved with chiral C(1)-symmetric organolanthanocene catalysts, even for poorly responsive substrates (up to 67% ee at 23 degrees C). Kinetic studies reveal that hydroamination rates are zero order in [amine substrate] and first order in [catalyst], implicating the same general mechanism for organolanthanide-catalyzed hydroamination/cyclizations (intramolecular turnover-limiting olefin insertion followed by the rapid protonolysis of an Ln-C bond by amine substrate) and implying that the active catalytic species is monomeric.     

σ‐Insertive Mechanism versus Concerted Non‐insertive Mechanism in the Intramolecular Hydroamination of Aminoalkenes Catalyzed by Phenoxyamine Magnesium Complexes: A Synthetic and Computational Study

The phenoxyamine magnesium complexes [{ONN}MgCH₂Ph] ( 4 a : {ONN}=2,4‐tBu₂‐6‐(CH₂NMeCH₂CH₂NMe₂)C₆H₂O^?; 4 b : {ONN}=4‐tBu‐2‐(CH₂NMeCH₂CH₂NMe₂)‐6‐(SiPh₃)C₆H₂O^?) have been prepared and investigated with respect to their catalytic activity in the intramolecular hydroamination of aminoalkenes. The sterically more shielded triphenylsilyl‐substituted complex 4 b exhibits better thermal stability and higher catalytic activity. Kinetic investigations using complex 4 b in the cyclisation of 1‐allylcyclohexyl)methylamine ( 5 b ), respectively, 2,2‐dimethylpent‐4‐en‐1‐amine ( 5 c ), reveal a first‐order rate dependence on substrate and catalyst concentration. A significant primary kinetic isotope effect of 3.9±0.2 in the cyclisation of 5 b suggests significant N?H bond disruption in the rate‐determining transition state. The stoichiometric reaction of 4 b with 5 c revealed that at least two substrate molecules are required per magnesium centre to facilitate cyclisation. The reaction mechanism was further scrutinized computationally by examination of two rivalling mechanistic pathways. One scenario involves a coordinated amine molecule assisting in a concerted non‐insertive N?C ring closure with concurrent amino proton transfer from the amine onto the olefin, effectively combining the insertion and protonolysis step to a single step. The alternative mechanistic scenario involves a reversible olefin insertion step followed by rate‐determining protonolysis. DFT reveals that a proton‐assisted concerted N?C/C?H bond‐forming pathway is energetically prohibitive in comparison to the kinetically less demanding σ‐insertive pathway (ΔΔG^≠=5.6 kcal mol^?1). Thus, the σ‐insertive pathway is likely traversed exclusively. The DFT predicted total barrier of 23.1 kcal mol^?1 (relative to the {ONN}Mg pyrrolide catalyst resting state) for magnesium?alkyl bond aminolysis matches the experimentally determined Eyring parameter (ΔG^≠=24.1(±0.6) kcal mol^?1 (298 K)) gratifyingly well.     

Organolanthanide-mediated intermolecular hydroamination of 1,3-dienes: mechanistic insights from a computational exploration of diverse mechanistic pathways for the stereoselective hydroamination of 1,3-butadiene with a primary amine supported by an ansa-neodymocene-based catalyst

The complete catalytic reaction course for the organolanthanide-mediated intermolecular hydroamination of 1,3-butadiene and n-propylamine by an archetypical [Me2Si(eta5-Me4C5)2NdCH(SiMe3)2] precatalyst was critically scrutinized by employing a reliable gradient-corrected DFT method. A free-energy profile of the overall reaction is presented that is based on the thorough characterization of all crucial elementary steps for a tentative catalytic cycle. A computationally verified, revised mechanistic scenario is proposed which is consistent with the experimentally derived empirical rate law and accounts for crucial experimental observations. It involves kinetically mobile reactant association/dissociation equilibria and facile, reversible intermolecular diene insertion into the Nd-amido bond, linked to turnover-limiting protonolysis of the eta3-butenyl-Nd functionality. The computationally predicted effective kinetics (Delta(tot) = 11.3 kcal mol(-1), Delta(tot) = -35.7 e.u.) are in reasonably good agreement with experimental data for the thoroughly studied hydroamination of alkynes. The thermodynamic and kinetic factors that determine the almost complete regio- and stereoselectivity of the mechanistically diverse intermolecular 1,3-diene hydroamination have been unraveled. The present computational study complements experiments because it allows, first, a more detailed understanding and a consistent rationalization of the experimental results for the hydroamination of 1,3-dienes and primary amines and, second, enhances the insights into general mechanistic aspects of organolanthanide-mediated intermolecular hydroamination.     

Intramolecular hydrophosphination/cyclization of phosphinoalkenes and phosphinoalkynes catalyzed by organolanthanides: scope, selectivity, and mechanism

Organolanthanide complexes of the general type Cp'(2)LnE(TMS)(2) (Cp' = eta(5)-Me(5)C(5); Ln = La, Sm, Y, Lu; E = CH, N; TMS = SiMe(3)) serve as effective precatalysts for the rapid intramolecular hydrophosphination/cyclization of the phosphinoalkenes and phosphinoalkynes RHP(CH(2))(n)()CH=CH(2) (R = Ph, H; n = 3, 4) and H(2)P(CH(2))(n)C triple bond C-Ph (n = 3, 4) to afford the corresponding heterocycles and respectively. Kinetic and mechanistic data for these processes exhibit parallels to, as well as distinct differences from, organolanthanide-mediated intramolecular hydroamination/cyclizations. The turnover-limiting step of the present catalytic cycle is insertion of the carbon-carbon unsaturation into the Ln-P bond, followed by rapid protonolysis of the resulting Ln-C linkage. The rate law is first-order in [catalyst] and zero-order in [substrate] over approximately one half-life, with inhibition by heterocyclic product intruding at higher conversions. The catalyst resting state is likely a lanthanocene phosphine-phosphido complex, and dimeric [Cp'(2)YP(H)Ph](2) was isolated and cystallographically characterized. Lanthanide identity and ancillary ligand structure effects on rate and selectivity vary with substrate unsaturation: larger metal ions and more open ligand systems lead to higher turnover frequencies for phosphinoalkynes, and intermediate-sized metal ions with Cp'(2) ligands lead to maximum turnover frequencies for phosphinoalkenes. Diastereoselectivity patterns also vary with substrate, lanthanide ion, and ancillary ligands. Similarities and differences in hydrophosphination vis-à-vis analogous organolanthanide-mediated hydroamination are enumerated.     

Metal-ligand cooperation in catalytic intramolecular hydroamination: a computational study of iridium-pyrazolato cooperative activation of aminoalkenes

The present study comprehensively explores diverse mechanistic pathways for intramolecular hydroamination of prototype 2,2-dimethyl-4-penten-1-amine by Cp*Ir chloropyrazole (1; Cp*=pentamethylcyclopentadienyl) in the presence of KOtBu base with the aid of density functional theory (DFT) calculations. The most accessible mechanistic pathway for catalytic turnover commences from Cp*Ir pyrazolato (Pz) substrate adduct 2?S, representing the catalytically competent compound and proceeds via initial electrophilic activation of the olefin C=C bond by the metal centre. It entails 1) facile and reversible anti nucleophilic amine attack on the iridium-olefin linkage; 2) Ir-C bond protonolysis via stepwise transfer of the ammonium N-H proton at the zwitterionic [Cp*IrPz-alkyl] intermediate onto the metal that is linked to turnover-limiting, reductive, cycloamine elimination commencing from a high-energy, metastable [Cp*IrPz-hydrido-alkyl] species; and 3) subsequent facile cycloamine liberation to regenerate the active catalyst species. The amine-iridium bound 2?a?S likely corresponds to the catalyst resting state and the catalytic reaction is expected to proceed with a significant primary kinetic isotope. This study unveils the vital role of a supportive hydrogen-bonded network involving suitably aligned β-basic pyrazolato and cycloamido moieties together with an external amine molecule in facilitating metal protonation and reductive elimination. Cooperative hydrogen bonding thus appears pivotal for effective catalysis. The mechanistic scenario is consonant with catalyst performance data and furthermore accounts for the variation in performance for [Cp*IrPz] compounds featuring a β- or γ-basic pyrazolato unit. As far as the route that involves amine N-H bond activation is concerned, a thus far undocumented pathway for concerted amidoalkene → cycloamine conversion through olefin protonation by the pyrazole N-H concurrent with N-C ring closure is disclosed as a favourable scenario. Although not practicable in the present system, this pathway describes a novel mechanistic variant in late transition metal-ligand bifunctional hydroamination catalysis that can perhaps be viable for tailored catalyst designs. The insights revealed herein concerning the operative mechanism and the structure-reactivity relationships will likely govern the rational design of late transition metal-ligand bifunctional catalysts and facilitate further conceptual advances in the area.