CuH-mediated Hydroamination of Styrene

CuH-mediated Hydroamination of StyreneAbstract A detailed computational exploration of mechanical intricacies of the copper(I) hydride (CuH)-catalysed hydroamination of styrene with a prototype hydoxylaminoalkane ester by a new-fangledly reported (dppbz)CuH gas (dppbz PP 1,2-bis(diphenylphosphino)benzene) is corresponded. A variety of plausible mechanistic avenues have been pursued by means of a sophisticated computational methodology, from which a general understanding of the factors controlling hydroamination catalysis emerged. The catalytically adapted PPCuI hydride, which is predominantly present as its dimer, involves in irreversible hydrocupration proceed with complete 2,1 regioselectivity to form a secondary PPCuI benzyl intermediate. Its interception with benzyl aminoalkane ester produces the prongy tertiary amine product and PPCuI benzoate upon intramolecular SN2 disruption of the amine electrophiles N-O linkage to precede passing rapid, strongly exergonic C-N g ravel-forming reductive settlement. The PPCuI benzoate corresponds to the accelerator pedal resting state and its conversion back into the PPCuI hydride upon trans alloyation with a hydrosilane is turnover limiting. The effect of electronic perturbations at the amine electrophile upon the reaction rate for reproductive hydroamination catalysis and alike non-productive reduction of the hydroxylamine ester has been gauged, which unveiled a more fundamental insight into catalytic structure-performance relationships.IntroductionThe catalytic hydroamination (HA) reaction, the direct addition of an N-H bond crosswise an unsaturated carbon-carbon linkage, offers facile access to an industrially relevant organonitrogen commodity and fine chemicals in a green, waste-free and highly atom-efficient manner.1 By focusing on late d-block metal catalysis, several explicit mechanistic pathways have been revealed over the years for the hydroamination of alkenes, including the following principa l processes 1) N-H bond activation with subsequent alkene insertion into the metal-NR2 linkage,2 nucleophilic attack of an amine at a metal-bound alkene,3 nucleophilic attack of a metal amido species at an activated alkene4 and amine coordination to be followed by proton transfer onto an activated alkene.5 Despite the signifi rout outt pass along achieved over the past years the utilisation of these methodologies is still limited by a number of drawbacks.1 The development of a general approach for regio- and enantioselective hydroamination of a large range of alkene substrate classes, in character referenceicular, remains an important challenge in the context of intermolecular HA.Recently, the groups of Miura6 and Buchwald7a reported independently a mechanistically distinct approach for styrene HA that involves copper(I) hydride (CuH) as the catalyst together with amine electrophiles and a hydrosilane hydride source to furnish amines in excellent yields and enantio-/regioselectiv ities under mild conditions.8 Miura and co-workers give away that styrenes react with benzylamine ester reagents in THF at room temperature to afford exclusively branched benzylic tertiary amines in the presence of a (dppbz)CuH catalyst (dppbz PP 1,2-bis(diphenylphosphino)benzene) and a hydrosilane hydride source (Scheme 1).6 Treatment of the Cu(OAc)2/dppbz starting material with Li(OtBu) and a reducing agent likely gives rise to PPCu(OtBu) 2, which becomes converted into the catalytically fitted PPCuI hydride 3 through and through transmetalation with silane.According to plausible mechanistic pathways outlined in Scheme 2 styrene insertion into the Cu-H linkage at 3 leads to PPCuI alkyl 4 that couples with the benzylamine ester electrophile thereafter to fetch amine product P and PPCuI benzoate 6. Various mechanistic pathways can be envisaged for this transformation,9 but its precise details remain largely elusive gum olibanum far. Transmetalation of 6 with hydrosilane regene rates the catalytically competent PPCuI hydride for another(prenominal) catalyst turnover. The performance of HA catalysis via the productive cycle can be compromised by the well known aptitude of the PPCuI hydride to reduce the amine electrophile. This may proceed through various pathways to involve formation of either N-H ( unitary plausible path via a PPCuIII benzoate amido hydride intermediate 7 is exemplified in Scheme 2) or O-H bonds to afford PPCuI benzoate 6 by consumption of a molar equivalent of the amine electrophile.Precise knowledge of twain the operative mechanism and of catalytic structure-performance relationships ar indispensable for the rational design of improved HA catalysts. In light of the fact that precise details of mechanistic intricacies of CuH-mediated vinylarene HA remain largely elusive thus far,10 a sophisticated computational protocol has been employed as an established and predictive means to strike reaction mechanisms and to guide rational cataly st design. The present study scrutinises rival mechanistic pathways for HA of styrene (1a S) with O-benzoyl-N,N-dimethyl-hydroxylamine (1b A) by a catalytically competent dppbz-ligated CuI hydride abstruse in the presence of prototype trimethylsilane (1c H) as hydride source. No morphological simplification (other than replacing O-benzoyl-N,N-diethyl-hydroxylamine and HSiPh3 used in experiment by 1b and 1c, respectively, solely for the purpose of computational efficiency) of any kind has been imposed for any of the find out species involved.The computational methodology employed (highly accurate DLPNO-CCSD(T) in conjunction with basis sets of def2-TZVP quality and a punishing treatment of bulk solvent effects) simulated authentic reaction conditions adequately and mechanistic analysis is based on Gibbs free- brawniness profiles. This computational protocol can confidently be expected to reliably map the energy landscape and this has allowed mechanistic conclusions with substa ntial predictive value to be drawn.As detailed herein, our comprehensive mechanistic examination provides support that effective HA catalysis involves irreversible hydrocupration with strict 2,1 regioselectivity to be followed by generation of the branched tertiary amine product by interception of the thus formed secondary PPCuI benzyl nucleophile with amine electrophile. The agreeing pathway sees the first intramolecular SN2 displacement of the benzoate leaving group and is followed by highly facile and strongly exergonic C-N bond-generating reductive elimination from a highly reactive, intervening PPCuIII species. It leads to amine product and PPCuI benzoate, the last mentioned of which corresponds to the catalyst resting state. Its conversion back into the catalytically competent PPCuI hydride is turnover limiting.Results and DiscussionThe aim of the present study is twofold. A first part scrutinises thoroughly all the relevant elementary go of Scheme 2, with special attention devoted to the several mechanistic avenues that can be invoked regarding the interaction of PPCuI alkyl nucleophile with the amine electrophile and also the productivity-limiting reduction of the amine transfer agent. A second part explores the effect of electronic perturbations at the amine electrophile upon catalyst performance.PPCuH-mediated HA of styrene with amine electrophile 1b Catalyst initiationEffective HA catalysis entails the initial conversion of PPCu(OtBu) 2 into the catalytically competent PPCuI hydride compound. The ability of hydrosilane 1c ( H) to affect transmetalation at 2, although being rather unlikely turnover limiting, will influence the performance of HA catalysis, since it determines the amount of catalytically competent PPCuI hydride species available for catalyst turnover.Hydroxylamine ester 1b (displaying a slight preference for 1-N over 1-O donor ligation) and THF (T) show a like aptitude to bind at copper in 2. However, the entropic costs linked with reactant link place the respective adducts 2A, 2T higher in free energy relative to the separated fragments. This gap widens regularly for ever weaker donor molecules as clearly seen in discover 1 for silane (2H) adducted species. Furthermore, 2 exhibits no propensity toward dimer formation, as all the efforts to localise a dimeric species failed.After the initial facile, but uphill association of trimethylsilane 1c at 2, transmetalation evolves through a metathesis-type transition-state (TS) structure (see jut out S1 in the Supporting Information), which decays thereafter into the PPCuI hydride complex 3 through facile liberation of Me3SiOtBu. Figure 2 reveals an affordable kinetic hindrance (G = 22.4 kcal mol-1 relative to 2 + 1c) for conversion of 2 into the catalytically competent complex 3, which is dictated by a thermodynamic force of substantial amount.PPCuI hydride compoundReactant (styrene S, hydroxylamine ester A, hydrosilane H), amine product (P) and THF (T) solvent molecules can associate in various ways at copper in the catalytically competent hydride compound (see Figure S2 in the Supporting Information) to give rise to a multitude of adducted species, all of which are expected to participate in mobile association/dissociation equilibria.11 Similar to what is give for 2, the copper nerve center can accommodate only a single molecule13 its moderate binding enthalpy, however, cannot compensate for the associated entropic costs, thereby rending the various adducted species to be higher in free energy than the respective separated fragments. Amines (A, P) and styrene (benefitting from coppers ability for backbonding) are found to associate sort of and hence 3A, 3S display an energy gap (relative to separated fragments) that is somewhat smaller than for 3T and 3H (Figure 3). On the other hand, 3 exhibits a pronounced propensity towards dimer formation with 3dim is favoured by 7.5 kcal mol-1 relative to 3 (Figure 3). Hence, the catalytically c ompetent PPCuI hydride is predominantly present as dimer 3dim with relevant adducts 3S (productive cycle, Scheme 2) and 3A (non-productive cycle, Scheme 2) are well separated and higher in free energy by more than 12 kcal mol-1 (Figure 3).Styrene insertion into the Cu-H linkage Following the plausible catalytic scenario in Scheme 2, the productive cycle entails the first generation of PPCuI alkyl 4. Alternative regioisomeric pathways for migratory C=C bond insertion into the Cu-H -bond commencing from 3S have been examined. The possible participation of another reactant, amine product or solvent molecule has been probed explicitly, but neither encounter, product or TS structures featuring a stable coordination of a spectator molecule could be located.13 Common to both pathways for 1,2 and 2,1 insertion is the evolution of C-H bond formation through a four-centre planar TS structure describing metal-mediated migratory insertion of the styrene C=C linkage into the polar Cu-H bond, whi ch occurs at distances of 1.57-1.65 (see Figure S3 in the Supporting Information) for the emerging C-H bond. Following the reaction path further, TS structures decay into primary PPCuI alkyl 4b (1,2 insertion) and secondary PPCuI benzyl 4a (2,1 insertion), respectively.Effective delocalisation of electron density is known to markedly influence the stability of the polarised TS structure describing the interaction of an electron-rich Cu-H -bond with the styrene C=C linkage and also of 4, much(prenominal) that the regioselectivity of the hydrocupration is largely dictated on electronic grounds.14 The -electron-withdrawing arene functionality at the styrene carbon directly adjacent to the copper centre effects an effective depletion of electron density from the nonsubstituted olefinic CH2 centre in the TS structure and also assist through hyperconjugative interaction with the stability of 4a. Hence it electronically stabilises both the TS structure for 2,1 insertion and 4a when compa red to the species involved in 1,2 insertion that are devoid of such an opportunity. The located TS and product species (see Figure S3 in the Supporting Information) give no indication that the electronic predisposition towards 2,1 insertion is likely to be reversed due to favourable PPCu-arene interactions along the 1,2 pathway. Thus, 2,1 insertion is expected to prevail energetically on both kinetic and thermodynamic grounds.Indeed, Figure 4 reveals that migratory olefin insertion proceeds with complete 2,1 regioselectivity to afford secondary PPCuI benzyl 4a by overcoming a barrier of 21.6 kcal mol-1 (G relative to 3dim), whereas the 1,2 pathway remains in amicable due to higher kinetic demands (G = 4.1 kcal mol-1) and is also disfavoured thermodynamically (G = 4.4 kcal mol-1). It characterises hydrocupration via the energetically prevalent 2,1 pathway to be kinetically viable and irreversible.15Amine product generation upon interception of 4 by amine electrophileThe interception of PPCuI alkyl 4 with amine electrophile 1b gives rise to the generation of amine product P and releases PPCuI benzoate 6 (Scheme 2). Various mechanistic scenarios are reasonable for this transformation,9 but, unfortunately, virtually no precise details of the operative mechanism are available.10 This section intends to fill this gap by thoroughly examining several rival pathways. It includes the sectionalization of the hydroxylamine ester N-O linkage via 1) SN2 displacement of the benzoate leaving group 2) intramolecular SN2 displacement and 3) oxidative addition across the N-O linkage. This affords transient PPCuIII intermediate 5, from which P and 6 are likely formed upon C-N bond-forming reductive elimination. The generation of the branched tertiary amine product Pa in a single step through nucleophilic attack of the Cu-C linkage at the positive N(amine) centre with concomitant N-O bond sectionalisation has been probed as a further plausible mechanistic avenue (dashed point er in Scheme 2). Given that hydrocupration proceeds with strict 2,1 regioselectivity, the discussion will focus exclusively on pathways that commence from 4a. Notably, rival paths starting from 4b are found energetically non-competitive in every case studied. The full account of all the studied pathways can be found in the Supporting Information.We start with examining N-O bond cleavage of 1b by nucleophilic PPCuI benzyl 4a. Figure 5 collates the free-energy profile of the most accessible pathway for the various mechanistic scenarios examined, whilst structural aspects of key species involved can be found in Figures S4-S9 (see the Supporting Information). The electrophile 1b binds quite via its N donor centre (1-N) at copper to furnish adducts with the unbound process oxygen pointing either towards (4a1A) or away (4a2A) from the metal, both of which are higher in free energy than the separated fragments. The located TS4a2A5a structure describes N-O bond cleavage that is reminiscen t of a SN2 displacement of the benzoate group, featuring distances of 1.72 and 2.02 for vanishing N-O and emerging Cu-N amido bonds (see Figure S5 in the Supporting Information). Progressing further along the reaction trajectory, the benzoate group binds eventually at copper to fork out transient PPCuIII intermediate 5a. The intramolecular process version commencing from 4a1A evolves through a five-centre TS4a1A-5a that displays similar metrics regarding vanishing N-O and emerging Cu-N amido bonds, but crucially benefits from an already pre-established Cu-O(benzoate) contact (see Figure S7 in the Supporting Information). As it turns out, this contact likely renders 4a1A5a intramolecular SN2 displacement somewhat favourable kinetically over 4a2A5a with both pathways are indistinguishable on thermodynamic grounds. The TSOA4a2A-5a shown in Figure 5 (see also Figure S9 in the Supporting Information) has been located as energetically prevalent three-centre TS structure describing oxida tive addition across the N-O linkage that occurs at distances of 2.43 and 1.89/2.60 for vanishing N-O and newly built Cu-N(amido)/Cu-O bonds, respectively. The condensed free-energy profiles in Figure 5 reveal that for cleavage of the electrophiles N-O linkage by PPCuI benzyl nucleophile the 4a1A5a intramolecular SN2 pathway (G = 19.8 kcal mol-1 relative to 4a+1b) prevails kinetically somewhat over 4a2A5a, with oxidative addition proceeding through TSOA4a2A-5a (G = 31.1 kcal mol-1 relative to 4a+1b) is found substantially more demanding kinetically and hence not accessible. The fine energy balance between the alternative SN2-type pathways is likely be influenced by the diphosphine catalyst backbone.Figure 6 combines the dominant pathway for N-O bond cleavage at amine adduct 4aA with C-N bond-generating reductive elimination at transient PPCuIII 5a taking place thereafter. Given that benzyl and amido functionalities are already preferably arranged in 5a no major structural reorgani sation is required prior to traversing TS5a6Pa, which occurs at a distance of 2.36 of the emerging C-N bond (see Figure S11 in the Supporting Information) and decays thereafter into the branched tertiary amine product that is initially bound to PPCuI benzoate (6Pa), but is readily released thereafter. The reductive elimination is found highly facile (G = 5.2 kcal mol-1 relative to 5a) and driven by a remarkably strong thermodynamic force (Figure 6). Of the two consecutive steps converting PPCuI benzyl 4a into amine product Pa and PPCuI benzoate 6 through interception with electrophile 1b, the first intramolecular SN2 displacement of the benzoate leaving group determines the overall kinetic demands (G = 19.8 kcal mol-1 relative to 4a+1b) with Pa and 6 are then generated from transient, highly reactive PPCuIII intermediate 5 upon rapid and strongly downhill reductive elimination.Nucleophilic attack of the Cu-C linkage at the positive N centre of the amine electrophile with concomitan t N-O cleavage, thereby affording 6a + Pa in a single step, describes an alternative mechanistic scenario. Despite all our efforts, a precise TS structure associated to this pathway could not be located, but examination by means of a state-of-the-art reaction-path-optimisation (chain-of-state see the Computational Methodology) method provided a reasonably approximate TS structure. The multicentre TS4a1A-6Pa describes concerted N-O bond cleavage (2.30 ) together with C-N (2.54 )/Cu-O(2.37 ) bond formation, all occurring in the immediate vicinity of the copper centre (see Figure S12 in the Supporting Information). A substantial barrier of approximately 30.7 kcal mol-1 (G relative to 4a+1b) has to be overcome (Figure 7), which renders the concerted 4a1A6Pa pathway non-accessible kinetically in the presence of the viable trip the light fantastic conversion shown in Figure 6.16PPCuI benzoate compound In light of the strong thermodynamic force associated with generating the C-N bond, the PPCuI benzoate may become, among others, a candidate for the catalyst resting state. Hence, the aptitude of 6 to accommodate additional reactant, amine product and THF solvent molecules has been probed in order to explain its precise identity. In accordance with findings for 2 and 3, a single molecule only can bind at copper at the expense of one of the two Cu-O(carboxylate) linkages, but adduct formation is disfavoured in terms of free energy. Hence the PPCuI benzoate is predominantly present as non-adducted form 6 featuring a 2-O ligated benzoate functionality (Figure 8).Regeneration of PPCuI hydride from PPCuI benzoate Transmetalation of 6 with trimethylsilane 1c regenerates the catalytically competent PPCuI hydride 3 for another catalyst turnover, thereby closing the cycle for productive HA catalysis. Two scenarios have been analysed that are distinguished by which of the carboxylate oxygens at silane adducted 6H participate in Si-O bond formation. The transfer of silyl onto t he oxygen directly bound to Cu evolves through a four-centre metathesis-type TS6H-3OS1 and leads eventually to 3 upon facile liberation of Me3SiOBz. On the other hand, a six-centre TS6H-3OS2 is traversed along an alternative pathway representing silyl transfer onto the unbound carboxylate oxygen (Figure 9 and Figure S13 in the Supporting Information). The enhanced stability of six-centre TS6H-3OS2 versus four-centre TS6H-3OS1 discriminates among the two pathways, which are driven by a thermodynamic force (G = 0.5 kcal mol-1 relative to 6 + 1c) of identical magnitude. The assessed barrier of 26.2 kcal mol-1 (G relative to 6 + 1c) for the most accessible pathway characterises 6 + 1c3 + Me3SiOBz as a kinetically demanding, but viable transformation that is slightly uphill thermodynamically (Figure 9).Reduction of the benzylamine ester by PPCuI hydrideThe well known tendency of the catalytically competent PPCuI hydride to reduce the amine electrophile under N-H bond formation, hence giv ing rise to PPCuI benzoate, or alternatively via O-H bond formation to afford a PPCuI amido can severely compromise the catalyst performance. To this end, several imaginable pathways (some of which are sketched in Scheme 2) have been studied. Whilst focusing on thermodynamic aspects amine reduction with N-H bond formation via 3 + 1b6 + HNMe2 (G = -71.9 kcal mol-1) appears to be strongly favoured over O-H bond generating 3 + 1bPPCuI(NMe2) + benzoic acid (G = -51.3 kcal mol-1). The cleavage of the N-O linkage of 1b at amine adduct 3A does preferably proceed through SN2 displacement of the benzoate leaving group with the intramolecular pathway proved to be somewhat favourable energetically (see Figure S14 in the Supporting Information), whilst oxidative addition of electrophile 1b across the N-O linkage is found substantially more demanding kinetically. All these aspects closely parallel the findings regarding the preferable avenue that leads to generate PPCuIII 5a (see above). Likewi se, N-H bond-forming reductive elimination at PPCuIII amido hydride intermediate 7 is highly facile kinetically and strongly downhill as 5a6a + Pa is. Unfortunately, all the efforts to localise the associated TS structure have not been successful, but the examination of the reaction path thoroughly by means of a chain-of-state method unwaveringly indicates that reductive amine elimination at 7 has an only marginal barrier, if at all, to overcome, hence it proceeds almost instantaneously. Overall, a smooth, kinetically affordable pathway for undesired 3 + 1b6 + HNMe2 conversion has been located that comprises a first intramolecular SN2 cleavage of the N-O bond (G = 26.3 kcal mol-1 relative to 3dim, Figure 10), to be followed by highly rapid reductive amine elimination from an intervening and highly reactive PPCuIII intermediate 7, thus reflecting the well-documented aptitude of 3 to engage in performance-limiting reduction of the electrophilic amination reagent.6, 7Further attempts d evoted upon locating a proper TS structure for the concerted attack of the nucleophilic Cu-H linkage at the N centre of the amine electrophile to be accompanied with N-O bond disruption has not been successful. However, a reasonably approximate TS (see Figure S15 in the Supporting Information) is seen to be above TS31A-7 by another 19.8 kcal mol-1, such that the concerted pathway can confidently be discarded as energetically viable alternative to the operative two-step process.Proposed catalytic cycleThe mechanistic picture based upon the above thoroughly conducted examination of relevant elementary steps is presented in Scheme 3. An energetically smooth and downhill sequence of steps transforms the starting material into the catalytically competent PPCuI hydride 3, which is in a mobile equilibrium11b with its thermodynamically prevalent dimer 3dim. Migratory insertion of the styrene C=C linkage into the Cu-H bond is kinetically facile (G = 21.6 kcal mol-1 relative to 3dim+1a), ther modynamically downhill and proceeds with strict 2,1 regioselectivity. Hence irreversible hydrocupration is regioselectivity determining and occurs prior to the turnover-limiting step. The interception of the thus generated secondary PPCuI benzyl 4a with amine electrophile 1b produces the branched tertiary (Markovnikov) amine product Pa and PPCuI benzoate 6. This transformation favours a two-step process comprising the first intramolecular SN2 displacement of the benzoate leaving group (G = 19.8 kcal mol-1 relative to 3dim+1a+1b) to furnish transient, highly reactive PPCuIII intermediate 5 from which Pa and 6 are generated upon highly rapid and strongly downhill reductive elimination. It renders 6 to be the most stable species of the cycle for productive HA catalysis and it thus corresponds to the catalyst resting state. The regeneration of catalytically competent 3 from 6 through transmetalation with hydrosilane 1c is found most demanding, but affordable, kinetically (G = 26.2 kcal mol-1 relative to 6+1c) and hence is turnover limiting its assessed barrier is compatible with reported catalyst performance data.6 It is worth mentioning that a similar picture regarding hydrocupration and transmetalation steps has emerged from a recent experimental study by the Buchwald group on a DTBM-SEGPHOS-based CuI catalyst.7dA stepwise pathway closely related to 4aA6 + Pa is preferably traversed for the non-productive reduction of amine electrophile by 3. An intramolecular SN2 N-O bond disruption (G = 26.3 kcal mol-1 relative to 3dim+1b) precedes highly facile and strongly downhill reductive amine elimination from intervening, highly reactive PPCuIII intermediate 5a. The assessed small kinetic gap (G = 0.1 kcal mol-1) between discriminative TS structures for productive and non-productive reaction branches reflects adequately the observed close competition between the two processes, which can lead to compromised catalyst performance for improper chosen amine electrophiles. Furthermore, it provides further confidence into the substantial predictive ability of the herein employed high-level computational methodology.17Effect of the amine electrophile upon catalyst performance A second part of this study explores the effect of the amine electrophile upon catalyst performance. To this end, the energy profile for two