Theoretical Studies on Nickel-Catalyzed Cycloaddition of 3

Article pubs.acs.org/Organometallics

Theoretical Studies on Nickel-Catalyzed Cycloaddition of 3‑Azetidinone with Alkynes Yang Li and Zhenyang Lin* Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, People’s Republic of China S Supporting Information *

ABSTRACT: With the aid of DFT calculations, we have examined the mechanism of the Ni-catalyzed cycloaddition of 3-azetidinone with alkynes. Our DFT results did not support the originally proposed mechanism, which involves a ring expansion through β-carbon elimination. Instead, our calculations supported a mechanism which involves oxidative addition of 1-Boc-3-azetidinone to a Ni(0) center to form an intermediate having both Ni−C(O) and Ni−C(sp3) bonds, then alkyne insertion into either the Ni−C(O) or Ni−C(sp3) bond depending on the alkyne substrates being studied, and finally reductive elimination to give the cycloaddition products. The nature of insertion of alkynes into a Ni−C bond was also discussed. When an alkyne substrate inserts into the Ni−C(O) bond, we found that the alkyne acts as a nucleophile to attack the electron-deficient, metal-bonded CO carbon center. When an alkyne substrate inserts into the Ni−C(sp3) bond, the alkyne acts as an electrophile to interact with the Ni−C(sp3) bond.

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INTRODUCTION Substituted piperidines are versatile and useful reagents in numerous bioactive alkaloid natural products and pharmaceuticals.1 Considerable attention has been paid to the synthesis of these motifs.2 Aza-Achmatowicz oxidative rearrangement3 and ring-closing metathesis4 provide access to substituted piperidines. Catalytic reactions using Pd,5 Zn,6 and Au7 complexes are also attractive strategies. However, all of these reactions are almost always carried out in multistep routes. Finding simple and efficient methods for the preparation of substituted piperidines is still a great challenge for chemists.8 Recently, it was reported that a nickel catalyst system is capable of catalyzing intermolecular insertion of alkynes into cyclobutanones to produce substituted 2-cyclohexenones (eq 1).9 On the basis of this experimental finding, Louie et al.

Scheme 1

alkynes (eq 2).10 In the proposed mechanism, oxidative coupling of an alkyne molecule with the carbonyl moiety of an azetidinone molecule to a nickel(0) complex, which affords the metallacycle intermediate I, was considered as the first step. The regioselectivity was sterically controlled in the oxidative coupling step, which leads to the formation of the metallacycle intermediate I, in which the sterically larger substituent RL tends to be away from the quaternary carbon center. Then, the metallacycle intermediate I undergoes β-carbon elimination to cleave a carbon−carbon single bond in the original azetidinone, giving the seven-membered metallacycle II. Subsequently, reductive elimination in the metallacycle II takes place to regenerate the active species.

carried out reactions of 3-azacyclobutanones with alkynes to produce piperidines in a single-step synthesis (eq 2). They also found that the tert-butylmethyl- and (trimethylsilyl)methylalkynes exhibited different regioselectivities.10 It should be pointed out here that slightly earlier than Louie, Aı̈ssa et al. also reported such reactions with a higher catalyst loading.11 A mechanism (Scheme 1) was proposed to account for the Ni-catalyzed cycloaddition reactions of 3-azetidinones with © 2013 American Chemical Society

Received: March 14, 2013 Published: May 9, 2013 3003

dx.doi.org/10.1021/om400211n | Organometallics 2013, 32, 3003−3011

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Figure 1. Free energy profile calculated for the nickel-catalyzed cycloaddition of 1-Boc-3-azetidinone with dimethylacetylene based on the mechanism proposed in Scheme 1. The relative free energies are given in kcal/mol.

mechanism shown in Scheme 1. As mentioned above, Scheme 1 involves oxidative coupling, β-carbon elimination, and reductive elimination steps. In the calculations, we use [(PMe3)2Ni(MeCCMe)] (A) as the model catalyst. We used [(PMe3)2Ni(MeCCMe)] (A), not [(PMe3)2Ni(1-Boc3-azetidinone)], as the reference point, considering that MeCCMe binds with (PMe3)2Ni more strongly than azetidinone does by 0.8 kcal/mol. The choice of the model catalyst is based on the fact that three-coordinate Ni(0) complexes containing alkene or alkyne ligand(s) are known complexes.21 The potential energy profile is shown in Figure 1 with calculated relative free energies (kcal/mol). The ligand substitution of 1-Boc-3-azetidinone for PMe3 is considered to occur as the first step to give the intermediate B, in which the azetidinone molecule coordinates to the metal center via the carbonyl moiety. The free energy barrier calculated for the ligand substitution is 25.7 kcal/mol. From the intermediate B, oxidative coupling between dimethylacetylene and the coordinated carbonyl moiety leads to the formation of the metallacycle C with a free energy barrier of 30.4 kcal/mol. Recoordination of a phosphine ligand gives the metallacycle D. Then, a β-carbon elimination step to cleave a carbon−carbon single bond in D occurs to give the seven-membered metallacycle E via the transition state TSD‑E. We can see that the barrier calculated for the β-carbon elimination is inaccessibly high (46.5 kcal/mol). We also examined an alternative pathway in which the βcarbon elimination takes place prior to the recoordination of a phosphine ligand (Figure 1). From the metallacycle C, a βcarbon elimination step to cleave a carbon−carbon single bond occurs to give the seven-membered metallacycle G via the transition state TSC‑G. The energy barrier of this β-carbon elimination step was calculated to be 46.7 kcal/mol, which is also inaccessibly high and comparable with that calculated for the β-carbon elimination step starting from the metallacycle D (Figure 1). In order to understand the reason why β-carbon elimination has a very high barrier, we examined the key structures involved

The key feature of the proposed mechanism is related to the ring expansion involving the β-carbon elimination. The driving force of the β-carbon elimination likely originates from release of the ring strain in the four-membered ring of an azetidinone substrate molecule.12 Indeed, β-carbon elimination has been used to account for a series of Pd-catalyzed carbon−carbon bond cleavage reactions.13 Meanwhile, it should be pointed out that oxidative addition of carbon−carbon bonds to low-valent transition metals are also an important approach to carbon− carbon bond cleavage.14 In this work, we will examine the feasibility of the proposed reaction mechanism via DFT calculations and at the same time propose an alternative mechanism accounting for the catalytic reactions.

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COMPUTATIONAL DETAILS

Geometry optimizations have been performed at the Becke3LYP (B3LYP) level of the density functional theory.15 The phosphine ligand was modeled by trimethylphosphine, and the alkyl substituents on the alkyne substrates were modeled by methyl groups. Experimentally, a tert-butoxycarbonyl (Boc) substituent at N(1) of 3-azetidinone gives the best yields in the cycloaddition reactions. Therefore, we employed 1-Boc-3-azetidinone in the calculations. The effective core potentials (ECPs) of Hay and Wadt with a double-ζ valence basis set (LanL2DZ)16 were used to describe Ni, P, Si, and Sn. Polarization functions were added for Ni (ζf = 3.130), P (ζd = 0.387), Si (ζd = 0.284), and Sn (ζd = 0.180).17 The 6-31G(d) basis set was used for all other atoms. Frequency calculations were carried out to confirm the characteristics of all of the optimized structures as minima or transition states. Calculations of intrinsic reaction coordinates (IRC)18 were also performed to confirm that transition states connect two relevant minima. To obtain solvation-corrected relative free energies, we employed a continuum medium to do single-point calculations for all species studied, using UAKS radii on the conductor polarizable continuum model (CPCM).19 Toluene was employed as the solvent (according to the reaction conditions) in the CPCM calculations. All calculations were performed with the Gaussian 03 software package.20

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RESULTS AND DISCUSSION We first calculated the energy profile for the cycloaddition of 1Boc-3-azetidinone with dimethylacetylene on the basis of the 3004


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Figure 2. Selected structural parameters (Å) calculated for the species involved in the β-carbon elimination step shown in Figure 1. Hydrogen atoms have been omitted for the purpose of clarity.

in the β-carbon elimination step shown in Figure 1. Figure 2 gives the optimized structures together with the selected structural parameters for the intermediate D and the transition state TSD‑E. The β-carbon elimination step involves cleavage of the C(2)−C(3) and Ni−O bonds in D and formation of Ni− C(2) and CO (π) bonds. From D to TSD‑E, the distance of the C(2)−C(3) bond changes from 1.58 to 2.26 Å and that of the C(3)−O bond from 1.39 to 1.29 Å. In the transition structure TSD‑E, the C(2)−C(3) bond has almost been broken but the Ni···C(2) bond (with a distance of 2.42 Å) has yet to be formed, giving rise to the significantly high barrier calculated for the β-carbon elimination. Clearly, the rigidity of D, as a result of the two rings (a four-membered ring and a five-membered ring) fused together via a common carbon atom, is the major reason for the scenario described above. An alternative mechanism, which avoids involvement of a βcarbon elimination, to account for the nickel-catalyzed cycloaddition reactions of 3-azetidinones with alkynes (eq 2) is presented in Scheme 2. Scheme 2 includes six major stages. (i) Ligand substitution of 1-Boc-3-azetidinone for PMe3 gives the intermediate B, which is the same as that shown in Figure 1. (ii) Instead of oxidative coupling between dimethylacetylene

and the coordinated carbonyl moiety, oxidative addition of the coordinated 1-Boc-3-azetidinone to the Ni(0) center cleaves a C−C(O) single bond and gives the intermediate F. (iii) Insertion of alkyne into the newly formed Ni−C(sp2) or Ni− C(sp3) bond of F gives respectively the seven-membered-ring metallacycle G or G2. In the seven-membered-ring metallacycle G, the CO moiety is coordinated to the metal center. In the seven-membered ring metallacycle G2, an agostic interaction occurs between a C−H moiety and the metal center. (iv) Rearrangement of the seven-membered-ring conformation in G or G2 together with recoordination of a phosphine ligand gives the metallacycle species E or E2. (v) Reductive elimination in the metallacycle E or E2 gives the complex H, in which the cycloaddition product molecule acts as a ligand. (vi) Finally, a ligand substitution of alkyne for the cycloaddition product molecule regenerates the active catalytic species A. Figure 3 shows the energy profile calculated for the alternative mechanism proposed in Scheme 2. First, the ligand substitution of 1-Boc-3-azetidinone for PMe3 gives the CO coordinated intermediate B, which isomerizes to the C−H agostic intermediate B1. From B1, oxidative addition via the transition state TSB1−F occurs to give the intermediate F. The need to pass through B1, instead of directly through B, is due to the fact that the cleaved C−C(O) bond is closer to the metal center in B1 than in B. Two pathways of alkyne insertion from F are possible. Insertion of alkyne into the Ni−C(O) bond occurs via the transition state TSF‑G to give the intermediate G. From the intermediate G, rearrangement of the sevenmembered-ring conformation gives the intermediate G3. Recoordination of a phosphine ligand gives the sevenmembered ring intermediate E. Reductive elimination in E takes place easily to give the complex H. In the other pathway, insertion of alkyne into the Ni−C(sp3) bond occurs via the transition state TSF‑G2 to give the intermediate G2. From the intermediate G2, rearrangement of the seven-membered-ring conformation gives the intermediate G4. Recoordination of a phosphine ligand gives the metallacycle species E2. Then reductive elimination gives the complex H. Reductive elimination to eventually give the complex H can also occur directly from G3 and G4 without recoordination of a phosphine ligand. From G3, the transition state TSG3‑H for the direct reductive elimination was calculated to be lower by 3.5 kcal/mol than TSE‑H. From G4, the transition state TSG4‑H

Scheme 2

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Figure 3. Free energy profile calculated for the nickel-catalyzed cycloaddition of 1-Boc-3-azetidinone with dimethylacetylene on the basis of the mechanism proposed in Scheme 2. The relative free energies are given in kcal/mol.

Figure 4. Selected structural parameters (Å) calculated for the species involved in the alkyne insertion step shown in Figure 3. Hydrogen atoms have been omitted for the purpose of clarity.

of the metal-bonded CO moiety. In other words, we can consider the coordinated alkyne to act as a nucleophile to attack the electron-deficient, metal-bonded CO carbon center. This result is consistent with what we observed in an earlier study of the insertion of CO2 into a Ni−alkyne bond, in which the alkyne ligand also acts as a nucleophile.22 The transition state TSF‑G2 lies higher in energy than TSF‑G, a result of the different natures of orbital interactions involved in the C−C formation process. Here, it should be pointed out that substituents on the alkyne substrates have a significant impact on the preferred insertion pathway. We shall see later that, when MeCCTMS is considered, insertion into the Ni− C(sp3) bond is actually preferred. Another important issue that needs to be addressed is the regioselectivity observed in the cycloaddition reactions of 3azetidinone with alkynes. Experimentally, when tert-butylmethylacetylene was used as the alkyne substrate, the carbonyl carbon preferred to couple with the methyl-substituted carbon (eq 3). When (trimethylsilyl)methylacetylene was used as the alkyne substrate, the carbonyl carbon preferred to couple with the trimethylsilyl-substituted carbon (eq 4). To understand the origin of the interesting regioselectivity observed, we examined various possible C−C coupling pathways on the reactions of 3-

for the direct reductive elimination was calculated to be higher by 2.7 kcal/mol than TSE2‑H. These results suggest that the reductive elimination from G or G2 to H is a very complex process. Despite the complexity, the process is very facile and the relevant details do not affect the reaction outcome. Finally, the ligand substitution starting from H with a barrier of 16.6 kcal/mol releases the cycloaddition product molecule and regenerates the active species A. The overall catalyzed cycloaddition reaction is exergonic by 41.0 kcal/mol. The oxidative addition transition state is rate-determining with an overall reaction barrier of 26.8 kcal/mol. From the energy profile, we can see that the difference between the two alkyne insertion barriers is 3.0 kcal/mol, in favor of the insertion into a Ni−C(O) bond. To understand this result, we examined the transition state structures calculated for the two insertion modes, shown in Figure 4. In the transition state TSF‑G, CO approaches the coordinated alkyne from a direction out of the Ni−alkyne bonding plane. This structural feature suggests that the π⊥ occupied orbital of the coordinated alkyne plays an important role in the C−C bond formation process. In terms of orbital interaction theory, we would expect an orbital interaction between the π⊥ occupied orbital of the coordinated alkyne and the unoccupied π* orbital 3006


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substitution of 1-Boc-3-azetidinone for PMe3 has been omitted, since it is not important for the regioselectivity issue discussed. The oxidative addition transition states TS(B1−F)Bu and TS(B1−F)Bu′ have comparable stabilities, as do the intermediates FBu and FBu′, indicating that the relative orientation of the coordinated alkyne does not have much effect on the oxidative addition process. However, the transition states TS(F‑G)Bu and TS(F‑G2)Bu for the two insertion pathways from FBu (Figure 5a) are energetically much less favorable than the transition states TS(F‑G)Bu′ and TS(F‑G2)Bu′ for the two insertion pathways from FBu′. This result is clearly related to the steric effect caused by the bulky t-Bu substituent. Form Figure 5, we can clearly see that the most favorable pathway is that shown in Figure 5b from ABu to FBu′ via TS(B1−F)Bu′ and then to GBu′ via TS(F‑G)Bu′. Checking back to Figure 3, we easily conclude that the cycloaddition product derived from the intermediate G Bu′ is that observed experimentally, in which the carbonyl carbon couples with the methyl-substituted carbon. Between the two insertion transition states shown in Figure 5b, TS(F‑G)Bu′ is energetically even more favorable than TS(F‑G2)Bu′. As discussed above, the coordinated alkyne acts as a nucleophile and favorably attacks the electron-deficient, metal-bonded CO carbon center. The transition state TS(F‑G)Bu′ is both electronically and sterically favorable. Sterically, the t-Bu substituent is away from the metal-bonded CO moiety. Electronically, the methylsubstituted carbon is π electron rich in comparison with the t-Bu-substituted carbon because of the strong electron-donating property of t-Bu. We also calculated the four corresponding C−C coupling pathways for the reaction of 1-Boc-3-azetidinone with (PMe3)2Ni(MeCCTMS). The calculated energy profiles are presented in Figure 6. From Figure 6, we again see that the barriers of oxidative addition leading to the two different isomers (FTMS and FTMS′) are comparable, regardless of the orientation of the alkyne ligand (MeCCTMS). Similarly, the two insertion transition states TS(F‑G)TMS and TS(F‑G2)TMS from FTMS (Figure 6a) are energetically unfavorable, a result related to the steric effect caused by the bulky TMS substituent. Comparing the four pathways shown in Figure 6, we can see that the most favorable pathway is that shown in Figure 6b from ATMS to FTMS′ via TS(B1−F)TMS′ and then to G2TMS′ via TS(F‑G2)TMS′. This result is very different from what we have seen for the case when MeCC-t-Bu is the alkyne substrate (Figure 5b). It has been noted that a TMS substituent is a strong π acceptor.23 The π-accepting property of TMS will be further elaborated later. Therefore, the methyl-substituted carbon of MeCCTMS is no longer π electron rich. As a result, we cannot expect that the coupling between the methylsubstituted carbon of MeCCTMS and the carbonyl carbon is favorable in view of the nature of the bonding interaction in the transition state: i.e., the coordinated alkyne attacks nucleophilically the electron-deficient, metal-bonded CO carbon center. Conversely, alkyne insertion into the Ni−C(sp3) bond in FTMS′ becomes the most favorable. It is known that insertion of an alkyne or alkene ligand into a metal−C(sp3) bond mainly involves an orbital interaction of the occupied Ni−C(sp3) σ bonding orbital with an unoccupied π* orbital of the alkyne or alkene ligand, implying a nucleophilic attack of the Ni−C(sp3) bond at one of the alkyne or alkene carbons.24 Here, alkyne acts as an electrophile (not nucleophile) when insertion into Ni− C(sp3) is considered. It is important to note that the nature of alkyne insertion into Ni−C(sp3) and Ni−C(O) bonds is

azetidinone with (PMe3)2Ni(MeCC-t-Bu) and (PMe3)2Ni(MeCCTMS). Considering the relative orientations of a coordinated unsymmetric alkyne, oxidative addition of the coordinated 1Boc-3-azetidinone to a Ni(0) center leads to two different isomers, from each of which there are two insertion pathways. Figure 5 shows the energy profiles calculated for the four possible pathways related to the reaction of 1-Boc-3azetidinone with (PMe3)2Ni(MeCC-t-Bu). In the figure, for the purpose of clarity, the step related to the ligand

Figure 5. Free energy profiles calculated for four possible pathways for the reaction of 1-Boc-3-azetidinone with (PMe3)2Ni(MeCC-t-Bu) on the basis of the mechanism proposed in Scheme 2. The relative free energies are given in kcal/mol. 3007


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energy profiles are presented in Figures 7 and 8 for the reactions of 1-Boc-3-azetidinone with (PMe3)2Ni(PhC CTMT) and (PMe3)2Ni(MeCCTMT), respectively. Figure 7 shows that the most favorable pathway is that leading to the formation of GTMTP, which will eventually lead to

Figure 6. Free energy profiles calculated for four possible pathways for the reaction of 1-Boc-3-azetidinone with (PMe3)2Ni(MeCCTMS) on the basis of the mechanism proposed in Scheme 2. The relative free energies are given in kcal/mol.

completely different. The strong π acceptor TMS substituent makes the methyl-substituted carbon of MeCCTMS π electron poor, facilitating the coupling between the methylsubstituted carbon of MeCCTMS and the metal-bonded sp3hybridized carbon and leading to formation of the intermediate G2TMS′. Reductive elimination from the intermediate G2TMS′ gives the experimentally observed cycloaddition products in which the carbonyl carbon couples with the TMS-substituted carbon. Experimentally, interesting regioselectivity was also observed when (tributylstannyl)phenylacetylene and (tributylstannyl)methylacetylene were used as the alkyne substrates. For the (tributylstannyl)phenylacetylene substrate, the carbonyl carbon prefers to couple with the stannyl-substituted carbon (eq 5). However, for the (tributylstannyl)methylacetylene substrate, the carbonyl carbon prefers to couple with the methylsubstituted carbon (eq 6). To investigate the regioselectivity for these two substrates, we followed what we did for MeCC-t-Bu and MeCCTMS and calculated the four corresponding C−C coupling pathways for each of the reactions of 1-Boc-3-azetidinone with (tributylstannyl)phenylacetylene and (tributylstannyl)methylacetylene. To reduce the computational cost, the nbutyl group was modeled by a methyl group. The calculated

Figure 7. Free energy profiles calculated for four possible pathways for the reaction of 1-Boc-3-azetidinone with (PMe3)2Ni(PhCCTMT) on the basis of the mechanism proposed in Scheme 2. The relative free energies are given in kcal/mol.

a cycloaddition product having preferential coupling of the carbonyl carbon with the stannyl-substituted carbon in PhC CTMT. This result is consistent with the experimental observation (eq 5). The regioselectivity observed here is also the same as that observed for MeCCTMS (eq 4). However, the most favorable alkyne insertion step is different from what we found for MeCCTMS. For MeCCTMS, the preferred alkyne insertion corresponds to the insertion into Ni−C(sp3) 3008


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highest occupied and lowest unoccupied molecular orbitals (HOMOs and LUMOs), for the alkyne substrates MeCC-tBu, MeCCTMS, and MeCCTMT (Figure 9). The HOMOs of MeCC-t-Bu, MeCCTMS, and MeC CTMT each correspond to the highest occupied π bonding molecular orbitals in the π system of the substrate. The LUMOs of MeCC-t-Bu, MeCCTMS, and MeCCTMT each correspond to the lowest π* molecular orbitals of the substrate. In the LUMO of MeCC-t-Bu, the two triply bonded carbons contribute equally to the π* molecular orbital. However, in the LUMO of MeCCTMS or MeCCTMT, it is clear that the methyl-substituted carbon contributes significantly more than the TMS-substituted or TMTsubstituted carbon. These results indicate that both TMS and TMT are π acceptors. MeCCTMT has a lower LUMO than MeCCTMS, suggesting that TMT is a stronger π acceptor than TMS. The π-accepting properties of TMT and TMS are mainly associated with the participation of the Sn−Me and Si− Me σ* antibonding orbitals (Figure 9). Therefore, TMT shows stronger π-accepting ability due to the weaker Sn−Me σ bond.

via TS(F‑G2)TMS′ (Figure 6). For PhCCTMT, the preferred alkyne insertion corresponds to the insertion into Ni−C(O) via TS(F‑G)TMTP (Figure 7). We attribute this difference to the πaccepting ability of TMT being stronger than that of TMS (see below). Figure 8 shows that the most favorable pathway is that leading to the formation of G2TMT′, which will eventually also

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CONCLUSIONS The reaction mechanism of the Ni-catalyzed cycloaddition reactions of 1-Boc-3-azetidinone with alkynes has been investigated with the aid of DFT calculations. The mechanism originally proposed involved the β-carbon elimination step. Our calculations have shown that the originally proposed mechanism, which involves a β-carbon elimination step, is not possible because an inaccessibly high barrier of 46.5 kcal/mol is calculated for the β-carbon elimination step. Through our DFT calculations, we have established an alternative mechanism which involves oxidative addition of 1-Boc-3-azetidinone to the Ni(0) center, cleaving the C−C(O) single bond to form an intermediate having both Ni−C(O) and Ni−C(sp3) bonds, then alkyne insertion into either the Ni−C(O) or Ni−C(sp3) bond depending on the alkyne substrates, and finally reductive elimination to give the cycloaddition products. The regioselectivities observed experimentally in the cycloaddition reactions of 1-Boc-3-azetidinone with MeCC-t-Bu, MeCCTMS, PhCCTMT, and MeCCTMT have also been theoretically investigated. Our theoretical calculation results have shown that the regioselectivity is determined in the step involving alkyne insertion into an intermediate having both Ni−C(O) and Ni−C(sp3) bonds. When an alkyne substrate inserts into the Ni−C(O) bond, we found that the alkyne acts as a nucleophile to attack the electron-deficient, metal-bonded CO carbon center. When an alkyne substrate inserts into the Ni−C(sp3) bond, the alkyne acts as an electrophile to interact with the Ni−C(sp3) bond. Our calculation results indicate that in the insertions of both MeCC-t-Bu and MeCCTMS the sterically bulky substituents t-Bu and TMS prevent the t-Bu- and TMS-substituted carbon from coupling with a Ni-bonded carbon. In both cases, we found that the methyl-substituted carbons couple with one of the Ni-bonded carbons. The methyl-substituted carbon of MeCC-t-Bu is π electron rich, while the methyl-substituted carbon of MeCCTMS is π electron deficient, due to the πaccepting properties of TMS. As a result, the methyl-substituted carbon of MeCC-t-Bu couples with the Ni−C(O) carbon while the methyl-substituted carbon of MeCCTMS couples with the Ni−C(sp3) carbon, giving rise to the completely different regioselectivities observed experimentally.

Figure 8. Free energy profiles calculated for four possible pathways for the reaction of 1-Boc-3-azetidinone with (PMe3)2Ni(MeCCTMT) on the basis of the mechanism proposed in Scheme 2. The relative free energies are given in kcal/mol.

lead to a cycloaddition product having preferential coupling of the carbonyl carbon with the stannyl-substituted carbon. Interestingly, we see that the most preferred alkyne insertion corresponds to the insertion into Ni−C(O) via TS(F‑G)TMT (Figure 8), which is consistent with what we found for PhC CTMT (Figure 7). Unexpectedly, this result is inconsistent with the experimental observation. We do not have an explanation for this inconsistency. The results of our theoretical calculations show that, in the two substrates (PhCCTMT and MeCCTMT), the difference in the electronic properties of Ph and Me does not create a difference in the regioselectivity. We feel that more experimental work is needed in order to better understand the regioselectivity issue related to stannyl-substituted alkynes. In the discussion of the reaction of MeCCTMS, we claimed that TMS is a π acceptor. To elaborate this point further, we examined the frontier molecular orbitals, i.e., the 3009


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Figure 9. HOMOs and LUMOs calculated for MeCC-t-Bu, MeCCTMS, and MeCCTMT. The orbital energies are given in eV. The percentage contributions of pπ atomic orbitals are also given in the figure. (8) (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471. (b) Guérinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.; Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808. (9) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem. Soc. 2005, 127, 6932. (10) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026. (11) Ho, K. Y. T.; Aı̈ssa, C. Chem. Eur. J. 2012, 18, 3486. (12) (a) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407. (b) Youn, S. W.; Kim, B. S.; Jagdale, A. R. J. Am. Chem. Soc. 2012, 134, 11308. (13) (a) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2000, 122, 12049. (b) Matsumura, S.; Maeda, Y.; Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862. (c) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 2645. (d) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010. (e) Nishimura, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. J. Org. Chem. 2004, 69, 5342. (f) Nishimura, T.; Araki, H.; Maeda, Y.; Uemura, S. Org. Lett. 2003, 5, 2997. (g) Nishimura, T.; Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.; Uemura, S. Org. Lett. 2005, 7, 2425. (h) Nishimura, T.; Ohe, K.; Uemura, S. J. Org. Chem. 2001, 66, 1455. (14) (a) Huffman, M. A.; Liebeskind, L. S. J. Am. Chem. Soc. 1993, 115, 4895. (b) Murakami, M.; Itahashi, T.; Ito, Y. J. Am. Chem. Soc. 2002, 124, 13976. (c) Kondo, T.; Kaneko, Y.; Taguchi, Y.; Nakamura, A.; Okada, T.; Shiotsuki, M.; Ura, Y.; Wada, K.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 6824. (d) Gandelman, M.; Milstein, D. Chem. Commun. 2000, 1603. (e) Suginome, M.; Matsuda, T.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 11015. (f) Hoberg, J. O.; Jennings, P. W. Organometallics 1996, 15, 3902. (g) Satoh, T.; Jones, W. D. Organometallics 2001, 20, 2916. (15) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200. (c) Lee, C.; Yang, W.; Parr, G. Phys. Rev. B 1988, 37, 785. (d) Stephens, P. J.; Devlin, F. J.; Chaobalowski, C. F. J. Phys. Chem. 1994, 98, 11623. (16) (a) Wadt, W. R.; Hay, P. J. J. Chem. Phys. 1985, 82, 284. (b) Hays, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299. (17) (a) Ehlers, A. W.; Böhme, M.; Dapprich, S.; Gobbi, A.; Höllwarth, A.; Jonas, V.; Köhler, K. F.; Stegmenn, R.; Frenking, G. Chem. Phys. Lett. 1993, 208, 111. (b) Höllwarth, A.; Böhme, M.; Dapprich, S.; Ehlers, A. W.; Gobbi, A.; Jonas, V.; Köhler, K. F.; Stegmenn, R.; Veldkamp, A.; Frenking, G. Chem. Phys. Lett. 1993, 208, 237. (18) (a) Fukui, K. J. Phys. Chem. 1970, 74, 4161. (b) Fukui, K. Acc. Chem. Res. 1981, 14, 363. (19) (a) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669. (b) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1966, 255, 327. (c) Cossi, M.; Barone, V.; Mennucci,

We also examined the C−C coupling pathways for the reactions of PhCCTMT and MeCCTMT and found that the carbonyl carbon prefers to couple with the stannylsubstituted carbon. The results are in agreement with the experimental observation for stannylphenylalkyne, but not for stannylmethylalkyne. We feel that more experimental work is needed in order to better understand the regioselectivity issues related to stannyl-substituted alkynes.

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ASSOCIATED CONTENT

S Supporting Information *

Text giving the complete ref 20 and tables giving the Cartesian coordinates and electronic energies for all of the calculated structures. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail for Z.L.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the Research Grants Council of Hong Kong (HKUST603711).

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REFERENCES

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Organometallics

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Theoretical Studies on Nickel-Catalyzed Cycloaddition of 3

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