cyclization

Tetrahedron Letters 56 (2015) 5587–5590

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Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet

Orbital phase in organolanthanide-catalyzed reactions: hydroamination/cyclization Satoshi Inagaki a,b,⇑, Hirotaka Ikeda c a

Institute of Science and Technology Research, Chubu University, 1200 Matsumoto, Kasugai, Aichi 487-8501, Japan Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan c Computational Science Department, Science and Technology Systems Division, Ryoka Systems Inc., Tokyo Skytree East Tower, 1-1-2, Oshiage, Sumida-ku, Tokyo 131-0045, Japan b

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 25 June 2015 Revised 14 August 2015 Accepted 19 August 2015 Available online 28 August 2015

The frontier orbital theory is applied to investigate an organolanthanide-catalyzed reaction at the electronic level, using hydroamination/cyclization reactions of primary aminoalkynes. The insertion of the alkyne functionality into the Ln–N bond in Cp2LnNH(CH2)3C„CH involved in the turnover-limiting cyclization step is found to be favored by the phases of HOMO of HC„C(CH2)3NH and LUMO of closed-shell Cp2Ln+ (Ln = La, Lu) or the LUMO+2 of excessive spins of open-shell Cp2Sm+. The LUMO and LUMO+1 of Cp2Sm+ are 4f orbitals contracted too much to effectively overlap with HOMO of the counterpart. The HOMO–LUMO/LUMO+2 overlaps are visually shown and numerically confirmed to increase in the order of Ln = La < Sm < Lu in agreement with the observed turnover frequency. Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: Orbital phase Frontier orbital theory Hydroamination Catalysis Organolanthanide

Introduction The chemistry of lanthanide catalysis has made much progress.1 Computational studies have contributed to our understanding of the general mechanisms and complemented experimental developments.2 Marks and co-workers3–5 pioneered the use of lanthanides (Ln) for hydroamination and employed computational investigation in parallel with synthetic developments. A catalytic cycle for organolanthanide-catalyzed hydroamination/cyclization of aminoalkynes (Scheme 1) was experimentally proposed for Ln = Sm and Cp⁄ (pentamethylcyclopentadienyl) and computationally supported for Ln = Sm and Cp (cyclopentadienyl) in place of Cp⁄.5 The activated catalyst is generated from the reaction of the aminoalkyne with the precatalyst Cp⁄2SmCH (TMS)2. The alkyne functionality is inserted into the Ln–N(amido) bond in the rate-limiting step. The subsequent Ln–C protonolysis yields the enamine product and regenerates the activated catalyst to close the catalytic cycle. The computed hydroamination/cyclization energetic barriers were found in agreement with the observed catalytic activities low for La, modest for Sm, and high for Lu,3 which was understood in terms of Ln ion size.5 In this Letter, we disclose some essential aspects of the mechanisms of the hydroamination/cyclization reactions of ⇑ Corresponding author. Tel./fax: +81 3 5841 4733. E-mail addresses: (S. Inagaki).

[email protected],

http://dx.doi.org/10.1016/j.tetlet.2015.08.056 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

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aminoalkynes, including the origin of the effect of lanthanide ion on the reaction rate. Very recently, we successfully applied the frontier orbital theory6 well established in organic reactions to transition metal mediated reactions to gain new insight to the Suzuki–Miyaura cross-coupling reactions7 and the olefin metathesis reaction.8 The success encourages us to apply the theory to the organolanthanide-mediated reactions, that is, hydroamination. Results and discussion Lanthanides (Ln) tend to be Ln3+ in the complexes.9 The electron configuration [Xe] 6s25d04f6 of the samarium atom in the ground state formally changes into [Xe]4f5 of the Sm3+ ion. In the Cp2SmX complexes the Sm atom donates one electron to each of two cyclopentadienyl (Cp) and the ligand (X). According to the Hund rule,10 five 4f-orbitals are occupied by excessive five a-spins with the remaining two f-orbitals unoccupied. In the ground state, Sm3+ has an open-shell electronic structure. The spin-multiplicity is sextet with all spin density (5.0) on the Sm atom. All open-shell calculations here use separate orbitals for the a and b spins. The first step of the catalytic cycle is the C–N bond formation or the insertion of the C„C bond of the alkyne into Ln–N bond (Scheme 1). The HC„C(CH2)3NH and Cp2Sm+ parts are supposed to interact with each other at the transition state. The frontier orbital of HC„C(CH2)3NH is the HOMO because all the molecular orbitals lie high enough in energy due to the negative charge for

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Scheme 1. Catalytic cycle.

this part to be the electron donor. In the sextet state of Cp2Sm+, two vacant 4f-orbitals are found to be the LUMO and LUMO+1 (Fig. 1). The 4f-orbitals are contracted too much13 (on the left-hand side of Fig. 1) relative to 5d and 6s orbitals to effectively overlap with the HOMO. It follows that the most important orbital is the next lowest LUMO+2 for the a-spin (abbreviated here as a-LUMO+2), which is a 5d, 6s, or hybrid orbital. For the b-spins, the vacant 4f orbitals of Cp2Sm+ corresponding to a-LUMO and a-LUMO+1 are found to be LUMO+1 and LUMO+2. The b-LUMO is very similar in shape to a-LUMO+2. However, the b-LUMO energy ( 0.050 au) is higher than a-LUMO+2 energy ( 0.060 au). The HOMO–LUMO interaction for b-spins is less important than the HOMO–LUMO+2 interaction for a-spins. In Figure 1, we depict11 the overlap between a-HOMO of the closed-shell HC„C(CH2)3NH and a-LUMO+2 of the open-shell Cp2Sm+ in the sextet state at the transition structure.12 The a-HOMO of HC„C(CH2)3NH has large amplitudes on the nitrogen atom and the terminal carbon atom (on the right-hand side in

Fig. 1). The a-LUMO+2 of Cp2Sm+ is a 5d orbital of Sm a little hybridized with 6s orbital (on the left-hand side in Fig. 1). The a-HOMO and a-LUMO+2 interact with each other in a cyclic manner (in the middle of Fig. 1). The a-LUMO+2 overlaps in phase with the a-HOMO at the nitrogen atom and the terminal carbon atom. The in-phase overlappings at both sites mutually strengthen the orbital interaction to stabilize the transition state of the cyclization of the HC„C(CH2)3NH . The organolanthanidemediated hydroamination has a feature of the cyclic orbital interaction favored by the orbital phase common with the well-known pericyclic reactions and with the transition-metal mediated Suzuki–Miyaura cross-coupling reactions7 and olefin metathesis reactions.8 The cyclization is taken as an intramolecular nucleophilic addition to an alkyne supported on the Sm atom in the complex. The HOMO of HC„C(CH2)3NH looks like the HOMO of an in-plane homo-1-azaallyl anion composed of a lone pair of the anionic nitrogen and the p bond between the carbon atoms. In fact, there

Figure 1. The in-phase overlappings between LUMO+2 of Cp2Sm+ and HOMO of HC„C(CH2)3NH at the transition state of hydroamination/cyclization process and the orbitals close in energy to the frontier orbitals. The occupied orbitals and the unoccupied orbitals are displayed in the transparent and mesh modes, respectively.

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are such low-lying occupied orbital (HOMO 3) and a high-lying unoccupied orbital (LUMO) as required for the homoazaallyl anion (on the right-hand side in Fig. 1). Direct mechanistic insight into the nucleophilic attack of the anionic nitrogen on the alkyne moiety is gained by the HOMO–LUMO overlapping between the Sm–N and the alkyne moieties. However, any formal application of the present method unfortunately gives the SOMO–SOMO overlapping between the carbon atoms bonded before the division into the two moieties, which indicates the recombination of the radical carbon centers. The HOMO–LUMO overlapping is then depicted between Cp2SmNHCH3 and HC„CC2H5 (Fig. 2), where the geometries of the methyl group on N and the ethyl group on the alkyne carbon are partially optimized (see the Supplementary data). The HOMO of Cp2SmNHCH3 and the LUMO of HC„CC2H5 overlap with each other to a good extent (Fig. 2a). This is the frontier orbital overlapping for the C–N bond formation in the nucleophilic addition. The HOMO–LUMO overlapping for the reverse electron delocalization (Fig. 2b) also occurs to a similar extent, forming the Sm–C bond. La- and Lu-based catalysts are investigated in order to see the effect of the Ln metal. No 4f orbitals are occupied by electrons in La3+ whereas all 4f orbitals are fully occupied by electrons in Lu3+. The Cp2La+, Cp2Lu+, Cp2LaX, and Cp2LuX have closed-shell electronic structures. The spin-multiplicity is singlet. The same orbitals are used for the a and b spins in the calculations. We visualize the overlaps of the HOMO of HC„C(CH2)3NH with the LUMOs of Cp2La+ and Cp2Lu+ and with the a-LUMO+2 of

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Cp2Sm+ at the transition structure of this turnover-limiting insertion step (Fig. 3). The overlap is smaller with the Cp2La+ and larger with the Cp2Lu+, compared with the Cp2Sm+. This trend is confirmed by the calculated overlap integrals and in agreement with the experimental rates:3 the La-based catalyst is less effective than the Sm-based one whereas the Lu-based one is more effective. The second step of the catalytic cycle is the Ln–C protonolysis of the cyclization product by the second substrate amine, accompanied by the dissociation of the cyclic enamine and the regeneration of the active catalyst (Scheme 1). The new amine is modeled with the simpler methylamine in the calculation. The spin-multiplicity of the most stable transition state is found to be sextet. The frontier orbital overlaps between the methylamine part and the counterpart in the transition structure are depicted in Figure 4. The LUMO of the amine part is almost the antibonding orbital (r⁄NH) of the breaking N–H r-bond. The HOMO of the counterpart is the bonding orbital of the Sm–C bond. The HOMO–LUMO overlap (Fig. 4a) is suitable for the breaking of the C–Sm and N–H bonds accompanied by the proton transfer from the amine to HC„C (CH2)3NH . The HOMO–LUMO overlap for the delocalization in the opposite direction is shown in Figure 4b. The HOMO contains the nonbonding orbital on the nitrogen atom of the amine as the main component. The LUMO is almost a d-orbital of Sm. The overlap is suitable to form the Sm–Namido bond, regenerating the active catalyst.

Figure 2. The overlappings (a) between the HOMO of Cp2SmNHCH3 and the LUMO of HC„CC2H5 and (b) between the LUMO+2 of Cp2SmNHCH3 and the HOMO of HC„CC2H5 at the partially optimized transition state of hydroamination/cyclization process. The occupied orbitals and the unoccupied orbitals are displayed in the transparent and mesh modes, respectively.

Figure 3. Overlap integrals between (a) HOMO of HC„C(CH2)3NH and LUMO of Cp2La+, (b) HOMO of HC„C(CH2)3NH and a-LUMO+2 of Cp2Sm+, and (c) HOMO of HC„C (CH2)3NH and LUMO of Cp2Lu+.

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Figure 4. The frontier orbital overlappings between the model methylamine and the counterpart containing Cp2Sm+/the cyclized product at the transition state of the protonolysis: (a) HOMO (rSm–C)–LUMO (r⁄N–H) overlap for the Sm–C bond scission; (b) HOMO (nN)–a-LUMO+2 (dSm) overlap for the Sm–N bond formation.

Conclusion

Supplementary data

We have analyzed the electronic structures of the transition states of the turnover-limiting cyclization and the subsequent protonolysis in the catalytic cycle of organolanthanide-catalyzed hydroamination/cyclization of aminoalkynes (Scheme 1). A cyclic interaction of the HOMO of HC„C(CH2)3NH with LUMO (Ln = La, Lu) or a-LUMO+2 (Ln = Sm) disclosed at the transition state of the cyclization step (Figs. 1 and 3) is strengthened by the in-phase overlapping at the two interacting sites. The LUMO, LUMO+1, and unpaired electron orbitals of Cp2Sm+ containing 4f orbitals as predominant components make no significant contribution to the reactivity because of the insufficient overlap with HOMO of the counterpart. This cyclization is an intramolecular nucleophilic addition to the unsaturated bond supported by the orbital phase involved in the cyclic interaction of HOMO of HC„C(CH2)3NH with a vacant 5d orbital of lanthanides. The protonolysis of the Ln–C bond of the cyclized product (Scheme 1) has been understood in terms of frontier orbitals as usual (Fig. 4). The Ln–C bond is broken by the HOMO (rLnC)–LUMO (r⁄NH of the amine) interaction. The concurrent coordination of the amine to Sm occurs due to HOMO (nN)–LUMO (dSm) interaction (see Fig. 4). The analysis of the overlap and phase relation of the HOMO, LUMO, and some orbitals close in energy at the transition states has been shown to be helpful for understanding the organolanthanide-mediated reactions as well as the transition metalmediated reactions.7,8 Such understanding at the level of orbital of electrons beyond the energies and geometries of reactants, transition states, intermediates, and products is indispensable for the advancement in organic chemistry, as history demonstrates. Hopefully, the present approach can be powerful for not only understanding but also designing organolanthanide-catalyzed reactions.

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.08. 056.

Acknowledgements One of the authors (S.I.) thanks Professor Emeritus of the University of Chicago and Professor of Chubu University, Hisashi Yamamoto, for his suggestion of interesting organolanthanide chemistry and Professor Tomohiko Ohwada of the University of Tokyo for his support.

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